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Bionano Genomics Announces Peer-Reviewed Publication from Johns Hopkins University Outlining a Stepwise Approach to the Adoption of Optical Genome…

Posted: November 23, 2021 at 3:57 pm

SAN DIEGO, Nov. 22, 2021 (GLOBE NEWSWIRE) -- Bionano Genomics, Inc. (BNGO), provider of optical genome mapping (OGM) solutions on the Saphyr system and the leading software for genomic data visualization, interpretation and reporting, today announced the publication of a study by Johns Hopkins University in the Journal of Clinical & Anatomic Pathology outlining a stepwise approach to adoption of OGM for cancer analysis in the cytogenetics lab.

This publication is by an outstanding team at Johns Hopkins University and we believe it represents the type of foundational work needed to establish where OGM fits in the cancer analysis lab and the types of subjects and samples that should be analyzed with OGM, commented Dr. Alka Chaubey, chief medical officer of Bionano Genomics. Knowing how different samples perform with OGM and the variants it detects can allow us to build a paradigm for working with OGM alongside other powerful tools in molecular pathology and cytogenomics as we push forward in our mission to transform the way the world sees the genome.

Conducted as a blinded comparison to a comprehensive collection of tools, this study compared results from OGM to those from whole-genome chromosomal microarrays (CMA) from Illumina, fluorescence in-situ hybridization (FISH) probes from Abbott, a targeted panel by next-generation sequencing (NGS) from Illumina, a gene fusion panel by gene expression on the nCounter from NanoString and traditional g-banding by karyotyping. The cohort comprised five different cancer subjects and multiple sample types: four leukemia/lymphoma subjects and one solid tumor subject across three bone marrow samples, one peripheral blood sample and one solid tumor sample (kidney tissue from a Wilms tumor subject).

The findings by OGM were concordant with those obtained by CMA and NGS for copy number variants (CNVs) and FISH and karyotyping for balanced structural variations (SVs) such as inversions and translocations. Sensitivity compared to CMA was 96% (22/23 CNVs detected) excluding copy neutral loss of heterozygosity calls. Sensitivity compared to karyotyping and FISH was 100% (98/98 loci detected). OGM also revealed substantially more SVs than the traditional methods, including an additional 51 CNVs and 20 SVs. Of the variants revealed by OGM that were not detected by the standard methods, 52% involved genes and 7.7% of them involved known cancer genes. The other 48% were classified as variants of unknown significance (VOUSs). The authors point out that these VOUSs have the potential to play a role in further refining patient diagnosis and identifying novel proteins that could be therapeutic targets.

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OGM was also used in the study to provide high resolution analysis of subjects with complex karyotypes exhibiting chromothripsis. Chromothripsis, or chromosome shattering, results in highly complex chromosomal structures that are typically very challenging to unravel by CMA, FISH and karyotyping. OGM provides a more comprehensive view across the genome that targeted methods like FISH cannot give and it has been shown to have a higher resolution than traditional methods as well. Compared to karyotyping, which has a resolution of 5 Mbp, OGMs resolution is 10,000 times higher and compared to CMA, OGMs resolution is 20-100 times higher, depending on the probe density used on the array. The authors used OGM to reveal and characterize chromothripsis (complex genome structures) in leukemia subjects with unprecedented scope and resolution, which they said can be extremely helpful in determining if there are druggable variants present, markers consistent with aggressive disease or disease thats treatment refractory.

The principal conclusions of this publication is that OGM provides an alternative workflow that provides valuable genomic information often with higher resolution than traditional methods without sacrificing sensitivity. OGM is complementary to methods like NGS, which reveal sequence variants, and provides an opportunity to simplify and consolidate workflows for SV analysis by using OGM as an alternative to CMA, FISH and karyotyping.

This publication is available at http://www.clinpathology.com/wp-content/uploads/2021/05/JCAP-6-117.pdf.

About Bionano Genomics

Bionano is a provider of genome analysis solutions that can enable researchers and clinicians to reveal answers to challenging questions in biology and medicine. The Companys mission is to transform the way the world sees the genome through OGM solutions, diagnostic services and software. The Company offers OGM solutions for applications across basic, translational and clinical research. Through its Lineagen business, the Company also provides diagnostic testing for patients with clinical presentations consistent with autism spectrum disorder and other neurodevelopmental disabilities. Through its BioDiscovery business, the Company also offers an industry-leading, platform-agnostic software solution, which integrates next-generation sequencing and microarray data designed to provide analysis, visualization, interpretation and reporting of copy number variants, single-nucleotide variants and absence of heterozygosity across the genome in one consolidated view. For more information, visit http://www.bionanogenomics.com, http://www.lineagen.com or http://www.biodiscovery.com.

Forward-Looking Statements of Bionano Genomics

This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Words such as may, will, expect, plan, anticipate, estimate, intend and similar expressions (as well as other words or expressions referencing future events, conditions or circumstances) convey uncertainty of future events or outcomes and are intended to identify these forward-looking statements. Forward-looking statements include statements regarding our intentions, beliefs, projections, outlook, analyses or current expectations concerning, among other things: our ability to build a paradigm for working with OGM alongside other tools in molecular pathology and cytogenomics; the potential role of VOUSs, including those detected by OGM, in refining patient diagnosis and identifying possible therapeutic targets; and OGMs ability to simplify workflows for SV analysis as compared to CMA, FISH and karyoptyping and be complementary to NGS. Each of these forward-looking statements involves risks and uncertainties. Actual results or developments may differ materially from those projected or implied in these forward-looking statements. Factors that may cause such a difference include the risks and uncertainties associated with: the impact of the COVID-19 pandemic on our business and the global economy; general market conditions; changes in the competitive landscape and the introduction of competitive products or improvements on existing methods, such as CMA, FISH, karyotyping and NGS; failure of future study results to support those demonstrated in the study referenced in this press release; changes in our strategic and commercial plans; inability to obtain sufficient financing to fund our strategic plans and commercialization efforts; the ability of medical and research institutions to obtain funding to support adoption or continued use of our technologies; the loss of key members of management and our commercial team; and the risks and uncertainties associated with our business and financial condition in general, including the risks and uncertainties described in our filings with the Securities and Exchange Commission, including, without limitation, our Annual Report on Form 10-K for the year ended December 31, 2020 and in other filings subsequently made by us with the Securities and Exchange Commission. All forward-looking statements contained in this press release speak only as of the date on which they were made and are based on managements assumptions and estimates as of such date. We do not undertake any obligation to publicly update any forward-looking statements, whether as a result of the receipt of new information, the occurrence of future events or otherwise.

CONTACTSCompany Contact:Erik Holmlin, CEOBionano Genomics, Inc.+1 (858) 888-7610eholmlin@bionanogenomics.com

Investor Relations:Amy ConradJuniper Point+1 (858) 366-3243amy@juniper-point.com

Media Relations:Michael SullivanSeismic+1 (503) 799-7520michael@teamseismic.com

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Bionano Genomics Announces Peer-Reviewed Publication from Johns Hopkins University Outlining a Stepwise Approach to the Adoption of Optical Genome...

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Opinion: Toward inclusive global governance of human genome editing – pnas.org

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In recent years, many have considered how best to govern increasingly powerful genome editing technologies. Since 2015, more than 60 statements, declarations, and other codes of practice have been published by international organizations and scientific institutions (1). In particular, the 2018 birth of two twins, Lulu and Nanawhose HIV-receptors CCR5 were altered by biophysics researcher He Jiankuitriggered widespread condemnation from the scientific community, the public, and even legal institutions. Eminent organizations that have opined on the matter include the World Health Organizations Expert Advisory Committee on Developing Global Standards for Governance and Oversight of Human Genome Editing (WHO committee) and the International Commission on the Clinical Use of Human Germline Genome Editing (the international commission).

To date, reports have expressed common concerns over various issues in the governance of human genome editingfor example, whether to impose moratoriums on basic research and clinical activities in human heritable genome editing. They have also agreed on some general actions, such as encouraging public input and implementing regulations on preclinical and clinical research in human heritable genome editingin particular as it pertains to the transparent disclosure of experiments underway and the documenting of protocols and patient consent responsibly.

When it comes to genome editing technologies, we need to acknowledge and account for very different points of view from researchers and regions around the world. Image credit: Shutterstock/vchal.

The ethical implications of genome editing seemingly exacerbate the divergent views among stakeholders, especially those with different cultural backgrounds, ideologies, religious views, and commercial interests.

But although most of the opinions, guidelines, and issues discussed in these reports are noteworthy and defensible, we argue that their effectiveness in guiding global governance is limited. Genome editing technology has grown too quickly, and stakeholders in the debate are too diverse, for current approaches to establish a robust, credible, and lasting regulatory regime. We need to acknowledge and account for very different points of view from researchers and regions around the world.

Existing governance mechanisms share features with the Asilomar statement in 1975, which is generally seen as providing effective regulation on recombinant DNA technologies (2). Features of that approach include 1) a governance body led by a commission of leading experts from one or a few countries and supported by several influential international and professional organizations; 2) proposed governance tools that are nonbinding; 3) guidelines implemented either through direct regulation and restraining the behaviors of the global research community, or having the guidelines absorbed into government regulations and funding agency policies.

Such a governance model has its merits. Indeed, a small group of leading experts can reach consensus quickly and effectively. And if academic journals and funding agencies adopt and adhere to such guidelines, scientists will follow. In such cases, the strong network of leading experts frequently allows guidelines they produce to influence government regulations (3). For instance, the final statement of Asilomar conference later served as a template for the future recommendation of the NIH Recombinant DNA Advisory Committee (4).

However, we are far from achieving a consensus on critical governing issues related to human genome editing at the global level, as illustrated by the divergence of existing guidelines (1). In the case of moratorium on heritable genome editing, for example, some guidelines (e.g., the one developed by European Group on Ethics in Science and New Technologies) suggested broad prohibition on gene editing of human embryos or gametes which would result in the modification of the human genome (5), whereas others (e.g., the one developed by the United States National Academies of Sciences, Engineering, and Medicine Committee) tentatively supported germline editing under certain specified conditions (6). Debate and critiques have continued, especially after the gene editing fiasco spearheaded by researcher He Jiankui (7).

Notably, diverse opinions emerged among the scientific community regarding the moratorium on heritable human genome editing. For instance, some leading scientists, such as Eric Lander (8), called for a global moratorium on clinical use of human heritable genome editing for a defined period of time to enable the development of international guidelines. In contrast, some prestigious researchers expressed objections to such a proposal, arguing that it would be open-ended in duration and could impede scientific research and delay the deployment of life-saving technologies for patients who cannot wait (9).

The global scientific community did engage in fierce debates on how to regulate recombinant DNA technology when the Asilomar statement was developed. However, the current landscape of human genome editing is very different. It renders a global governance model led by a small group of scientists and scientific organizations outdated and counter to an inclusive framework that encompasses views and opinions of a diverse set of stakeholders reaching both inside and outside of academia.

When the Asilomar statement was put forward in 1975, there were around 30 authors who had related scientific publications, far fewer than the 140 participants who attended the Asilomar meeting. Moreover, although the total number of authors grew to around 900 in 1978, more than 70% of their affiliated institutions are based in the United States. In other words, the recombinant DNA research community was much smaller and far less diverse, making it relatively easy for the Asilomar conference to reach a consensus and then convince others in the community to agree.

Today, the scientific community is very diverse geographically and culturally. Between 2012 and 2018, there were more than 8,000 publications on genome editing, carrying the names of more than 36,000 authors. Around 4,000 institutions across 94 countries/regions in all major continents are involved in the field of genome editing (see Table 1). The ethical implications of genome editing seemingly exacerbate the divergent views among stakeholders, especially those with different cultural backgrounds, ideologies, religious views, and commercial interests.

The global distribution of publications, countries/regions, institutions, and authors for recombinant DNA (19721978) and genome editing (20122018)

To investigate further, we conducted a global online survey with the corresponding authors of human genome editing-related publications. We sent out questionnaires to 3,326 authors and received 201 validated responses. We do note limitations for our survey, including the potentially biased opinions of corresponding authors and a relatively low response rate (6%). Nevertheless, we gleaned some insights into researchers attitudes toward current guidelines and their opinions regarding basic and clinical research of human somatic and germline editing and enhancement research. We also asked for their preference for global governance models in this field.

Specifically, we selected five representative governance guidelines developed by the most authoritative institutions and asked the scientists about their familiarity with these guidelines. Around 40% of the respondents said they had never heard of them, and less than 20% said they had read the guidelines in detail. More importantly, we find very different attitudes toward some crucial issues. For instance, around 30% of respondents wanted to see a moratorium on even basic research in the field. Some 56% disagreed with this idea, and 14% were neutral. There were important regional differences. For instance, scientists from North America and Europe were the least conservative and tended to disagree with imposing moratoriums. Those from Asia were more likely to take a neutral stand, whereas those from other regions (e.g., Africa and South America) were more conservative, tending to agree with the need for a moratorium.

For our part, we believe that a global moratorium is not warranted, but that it is necessary to impose certain restrictions on the research and on clinical trials directed at human genome editing. However, the question of when and how the restrictions should be implemented requires discussions on a global scale and consensus among a broad range of stakeholders from different regions.

That group of stakeholders includes many based in or working with the private sector, which makes the context for global governance quite different from that of the Asilomar period. In the 1970s, most of the scientists engaged in recombinant DNA research were working in public institutions; today, many scientists working in genome editing have conflicts of interest over intellectual property or act as advisors for commercial companies (10). These conflicts are not systematically declared in the guidelines they produce.

Public engagement is also extremely important, as some existing efforts appreciate. For example, the international commission recommends that extensive social dialogue should be undertaken before a country makes a decision on whether to permit clinical use of heritable human genome editing and recognize the efforts by civil society on the global level to promote international cooperation on approaches to responsible development (11). We agree with the commissions suggestion that organizations like WHO and the United Nations Educational, Scientific and Cultural Organization (UNESCO) take the responsibility to evaluate and make recommendations. In particular, we appreciate the new framework developed by the WHO committee (12), which highlights the role of various tools, institutions, and processes for the governance of human genome editing.

Key to achieving these goals is more inclusive engagement of the global scientific community. First, effective public engagement and discussion require basic information on this subject, such as the differences between human genome editing in somatic cells and the germ line. This condition is particularly hard to fulfill in the less-developed regions where access to education and information are more limited. If experts in these regions have more opportunities to engage in global dialogues, they could bring back up-to-date information and various arguments to inform public debates in these countries.

Second, most guidelines and frameworks being suggested by international bodies have no legal authority or jurisdiction. The effectiveness of such approaches therefore depends on national regulators willingness to voluntarily follow these global rules, creating an enforcement challenge that fails to account for nonadopters. If researchers and representatives of professional institutions from more countries could be involved in global policymaking, they could serve as policy entrepreneurs to inform the national policymakers and provide policy suggestions based on their first-hand experience in the global arena, for a more authoritative local framework. Third, the establishment of stringent global rules requires a high degree of consensus around the worldwide stakeholders. Therefore, inclusive dialogue and the effort to achieve global consensus within the global scientific community are indispensable.

For all these reasons, it is time we go beyond the traditional governance model in the field of biotechnology and draw lessons from broader global governance practices. This can be done in several ways.

First, leading academic journals as well as professional conferences with international influence should serve as more open and inclusive platforms for dialogue on contentious governance issues related to human genome editing. More scientists and experts from less developed countries should be invited to express their views in these journals and speak at international conferences; their opinions need to be seriously considered. Notably, the conference known as CRISPRcon has provided such an inclusive venue for diverse opinions to be shared. There is a silent majority of researchers and stakeholders who have not had the chance to provide meaningful input.

Previous experiences in global governance reveal that ensuring voices are heard is a critical first step towards global governance improvement. One example is the policy-making process of the UN Sustainable Development Goals (SDGs). To generate a consensus on the new set of global sustainable development goals for the period of 2015 to 2030, the UN developed various open platforms for institutions and individuals around the world to provide their opinions. For instance, the UN Sustainable Development Solution Network (UNSDSN) was established to bring together global experts from all regions and all sectors to promote practical solutions for sustainable development (13). They also initiated the UN My World survey to invite voices from around the world into policymaking at the global level (14).

Second, the international professional organizations developing standards and rules for human genome editing should expand their networks to include more historically neglected countries and regions. For example, the international commission is poised to play an important role in the field, but there are only 10 countries academies of sciences and medicines involved thus far. Efforts should be made to bring in more leading experts from less developed countries; right now, leaders in influential international professional organizations, such as the International Society for Stem Cell Research, are mostly from developed countries. A good model is the World Medical Association, which represents the national associations of physicians of more than 110 countries. Over the years, the association has developed many successful and inclusive standards and rules, including the influential Declaration of Helsinki on research ethics.

Third, public and private funding agencies of science and medicine around the world should work together to initiate collective actions to govern human genome editing. If influential funders could jointly recognize basic principles and standards that strengthen ethical review, accountability, and transparency, large numbers of researchers around the world who have received or wish to receive funding could be incentivized to heed these principles and standards. The Human Genome Project illustrates the impact of funding agencies in forging a community spirit (15). In 1996, the Wellcome Trust sponsored a leadership gathering of the largest labs in the publicly funded genome project coordinated by the NIH. The outcome of this meeting is the famous Bermuda Agreement, in which scientists pledged to release human sequence data as soon as possible and submit their data to a public database. Because of the substantial power of these funders, this rule successfully reshaped practice nearly instantly in the field, even without any legal authority (16).

Science is evolving at a feverish pace. Technological development is no longer the purview of a few leading academic institutes and a handful of entrepreneurial forerunners, as illustrated with the rise of CRISPR-based technologies driving the democratization of genome editing. Accordingly, governance by the few for all is no longer appropriate nor acceptable. Each approach suggested above has seen some historical success and has potential to improve governance of human genome editing. We must combine these tools into an integrated network. Standards and agreements independently launched by academic journals, funding agencies, and international professional organizations could mutually reinforce each other. Key individuals and organizations could play the critical role as the bridges connecting different approaches. The global governance of human genome editing urgently needs the wisdom of the entire global scientific community as well as those in related fields and interested members of the general public.

The work was supported by the National Natural Science Foundation of China (Grant 72004169).

Competing interest statement: R.B. is a cofounder of Intellia Therapeutics, Locus Biosciences, TreeCo, Ancilia Biosciences, and CRISPR Biotechnologies, and is a shareholder of Caribou Biosciences and Inari Ag.

Any opinions, findings, conclusions, or recommendations expressed in this work are those of the authors and have not been endorsed by the National Academy of Sciences.

This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.2118540118/-/DCSupplemental.

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Genomic and Proteomic Tools Market: Rise in the number of cancer patients across the world to drive the market – BioSpace

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Genomic and Proteomic Tools Market: Introduction

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Key Drivers and Opportunities of Global Genomic and Proteomic Tools Market

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North America to Capture Major Share of Global Genomic and Proteomic Tools Market

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Genomic and Proteomic Tools Market: Rise in the number of cancer patients across the world to drive the market - BioSpace

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Harnessing the Power of CRISPR to Reduce Poverty and Malnutrition – Newswise

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Newswise A five-year partnership being launched by the InnovativeGenomicsInstitute (IGI) a non-profit founded by Nobel Laureate Jennifer Doudna andCGIAR, the worlds largest publicly-funded agricultural research partnership, will harness the power of science to help millions of people overcome poverty, hunger, and malnutrition.

One in four people globally, and rising, are unable to afford a healthydiet.COVID-19 has exacerbated this trend by disrupting food production and distribution, driving upby 20 percentthe number of people threatened by hunger in 2020. The pandemic is unfolding amidst an environmental and climate crisis which is undermining food production andour ability to nourish the world.

According to Barbara Wells, Global Director for Genetic Innovation at CGIAR: World-class science is vital for facilitating farmer adaptation and mitigating our food systems contribution to climate change. Plant-breeding innovations can help ramp up food production while making farms more climate resilient, profitable, and environmentally friendly.

Technologies such asgene editing,which enable scientists tomaketargeted changes to a cropsDNA, can accelerate the development ofmore disease-resistant,water-efficientvarieties that can improve food production and nutrition in areas that are especially vulnerable to climate change,Dr.Wellsexplained.

CGIAR has produced and promoted innovations that are boosting thesustainableproduction of nutritious foodin Africa, Asia and Latin America.Over the past five decades, CGIAR scientists and national partners have developed and disseminatedrobust and highly productive crop varieties and livestock breedstailored to theneedsoflocalmen and women. Those innovationshavehelped hundreds of millions of peopleacross the Global Southovercome hunger and poverty.

TheIGIis a collaboration ofthe University of California, Berkeley andtheUniversity of California, San Francisco with amissiontodeveloprevolutionarygenome-editing tools that enableaffordable and accessible solutions in human health, climate, and agriculture.The IGIs Climate & Sustainable Agriculture program focuses ondeveloping crops that are resistant to pestsanddiseases,resilient toa changing climate, and less dependent onfarmer inputs.Whereas the IGIis a pioneer inappliedgenomic research, CGIAR focuses ontranslatingdiscoveries intoimproved crop varieties and cropping systems.This partnership provides an accelerated pipeline from upstream innovation to real-world impact.

The IGI is testing technologies with great potential to benefit people in the countries where CGIAR is active, such as a way of removing the cyanide found in cassavaa staple upon which nearly a billion people depend and fighting diseases in economically important crops like wheat, rice, and bananas, said Dr. Brian Staskawicz, the IGI Director of Sustainable Agriculture.

The IGI is also pioneering new ways to reduce methane emissions from rice farming, which accounts for 2.5 percent of humanitys contribution to global warming, by using genomic approaches to reduce methane production by soilmicrobes, he added.

By partnering with CGIAR, the IGI can ensure that the products of its research will benefit farmers and consumers in some of the worlds poorest countries, where CGIAR has been working for 50 years and has extensive partner networks, said Dr. Melinda Kliegman, Director of Public Impact at the IGI. Together we can accelerate the development and delivery of more climate-resilient, productive and nutritious crops for resource-poor farmers and consumers.

Over the next five years, the IGI andCGIARwillusethe latest breakthroughs in genomic sciencetoenhancethe resilience and productivity of farmers inlow- and middle-incomecountries andimprove thewellbeing andlivelihoods ofwomen and men insome of the worlds poorestcommunities.

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Harnessing the Power of CRISPR to Reduce Poverty and Malnutrition - Newswise

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Studies Reveal Designs of Nucleus and DNA – Discovery Institute

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Image credit: Miroslaw Miras, via Pixabay.

You may have heard that all the DNA in your body, if stretched out, could reach to the Sun and back more than 70 times. What is even more amazing is that all this DNA occupies only a tiny fraction of the space within your body it is packed away inside the tiny nucleus of each cell. Furthermore, the DNA is not merely packed away and sitting idly; rather, it is a dynamic molecule taking part in several active processes including gene expression and cell division. Three new scientific papers have been published in recent weeks that reveal exquisite patterns of design in the DNA and nucleus in which it is housed.

The human genome is organized in 23 pairs of chromosomes. Most of the pairs are of similar length, but in the final 23rd pair, the first chromosome designated X is much longer than the second chromosome designated Y. That is not the only unique characteristic of the 23rd pair. These so-called sex chromosomes differ between the genders. While males have both an X and Y chromosome, females have two X chromosomes. As if to avoid a double dose of X chromosome genes, females inactivate one of their two X chromosomes during embryonic development. As for which of the two X chromosomes is inactivated, this appears to be done randomly in each cell. This means that females, unlike males, have two different functional genomes operating in their bodies, making for a fascinating twist to female genetics. That is, in some cells of the female, the first X chromosome is active whereas in the remainder of the cells the other X chromosome is active. A classic example is the colorful calico cat whose two X chromosomes code for two different colors.

Exactly how the developing female embryo inactivates one of the X chromosomes has not been well understood. What has been clear is that the story involves a region on the X chromosome itself, and information in that region that codes for a long RNA molecule, known as Xist. The name Xist stands forX-inactive specific transcript, a direct reference to its function of inactivating the X chromosome. But a genetic region that, ultimately, causes the inactivation of the entire chromosome must be handled very carefully. It is present on all X chromosomes but causes inactivation not of the single male X chromosome, and not of one of the two female X chromosomes. Importantly it causes inactivation only of the other female X chromosome.

In addition to the fact that Xist must be very carefully controlled, new research1is shedding light on how this single molecule can produce such a significant result. While it seemed that a very large number of Xist molecules must be required to inactivate the much larger X chromosome, the researchers studied mouse embryonic stem cells and found that only about one hundred Xists are required. The Xists, operating in pairs, recruit a large number of proteins. The result is about 50 complexes, each consisting of two Xists and an army of proteins, spaced along the X chromosome. Some of the proteins twist and condense the overall chromosome, compressing it so that most of the genes are close to one of the 50 complexes. Other proteins act to silence those nearby genes, thus essentially inactivating the entire X chromosome. Obviously, there are many important, coordinated, steps in this inactivation process, allowing for a small number of Xists to manage this big job. As the papers lead author remarked, It was kind of shocking to us that from just 50 sites, Xist manages to silence a thousand genes.2

X chromosome inactivation is not the only function that RNA molecules perform in the nucleus. They also, for example, help to maintain the overall three-dimensional structure of the various macromolecules in the nucleus, including the DNA. This is important because otherwise in the crowded nucleus, molecules can inadvertently chemically bond, or link, to one another. DNA crosslinking, for example, can result from environmental toxins and radiation. Such crosslinking, whether between DNA or other molecules, can cause cell death and is the goal in some chemotherapies. But crosslinking also is proving to be a valuable research tool. As another new paper reports,3crosslinking is now being used, along with several other complicated steps, to map out the three-dimensional structure of the DNA, various RNAs, and many proteins, within the nucleus. Simply put, the general idea is to link together molecules that are in close proximity. The cell is then broken down into clusters of linked molecules which can be identified and mapped out to reconstruct the structures within the nucleus.

The researchers found the certain RNA molecules serve to recruit and organize other RNA and protein molecules. Those recruited RNA and protein molecules, which otherwise would randomly move about, then serve important regulatory roles in accessing and processing the DNAs genetic information. The researchers also found that several high-concentration territories are formed within the nucleus, where these molecules cluster and function. As the paper explains, the organizing RNA molecules recruit diffusible RNA and protein regulators into precise 3D structures. What we are seeing is a much more detailed, elegant, and exacting picture of the nucleus than textbooks have ever envisioned.

The problem of organizing and maintaining the molecular structures within the nucleus becomes even more intriguing when one considers cellular division. When a cell divides, producing two daughter cells, the precise 3D nucleus structure discussed above must somehow be reestablished in the new cells. Certain proteins have been known to be important in this process, and another new study4has now identified a single protein that is particularly important in this cell division process. The protein, called lamin C, is, according to the paper, uniquely required for large-scale chromosome organization, and global 3D genome organization in the daughter cells.

During the process lamin C is phosphorylated, meaning a phosphoryl group is attached by special proteins. The phosphoryl group is removed when lamin C is done with its job, which is just one part of a larger, more complex process. As the lead researcher explained, There is this exquisite choreography of the different lamin proteins and DNA to get things just as they should be.5

Beyond this exquisite choreography, the crucial role of lamin C highlights another hallmark of design; namely, the teleology implicit when a part is required for its own production. Because lamin C, a protein, is produced by cellular protein synthesis. That is a process that begins with the genome in the nucleus, which is maintained by lamin C. In other words, lamin C is required for the production of lamin C.

These three studies of the structures within the cells nucleus continue to reveal a natural world that gives evidence design in many different ways.

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Identification of downstream effectors of retinoic acid specifying the zebrafish pancreas by integrative genomics | Scientific Reports – Nature.com

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Retinoic acid affects the transcriptome of zebrafish endodermal cells

To identify genes regulated by RA in zebrafish endodermal cells, we used the transgenic Tg(sox17:GFP) line which drives GFP expression in endodermal cells and allows their selection by fluorescence activated cell sorting (FACS). Tg(sox17:GFP) embryos were treated either with RA, BMS493 (pan-RAR inverse-agonist) or DMSO (control) from 1.25 to 11hpf, a time window that covers the whole blastula and gastrula periods. Endodermal GFP+ cells were next selected by FACS from embryos at 3-somites (3-S) and 8-somites (8-S) stages (11 hpf and 13 hpf, respectively). Non-endodermal (GFP) cells were also selected from the DMSO-treated control embryos in order to compare with GFP+ endodermal cells and identify genes displaying endodermal enriched expression. RNA-seq was performed on all these FACS-isolated cells prepared in triplicate (24 samples in total) and transcriptomes were analysed using the bioinformatic pipeline as described in Materials and methods. Principal component analysis of all RNA-seq data (Fig.1A) shows (i) a tight clustering of all triplicate samples confirming a high reproducibility in the experiment, (ii) a strong difference between the transcriptome of endodermal and non-endodermal (NE) cells (discriminated along the first axis of the PCA plot), (iii) relatively similar transcriptomes of cells isolated at 3-S and 8-S stages, and (iv) a clustering of BMS493 samples near DMSO samples indicating a much weaker effect of BMS493 treatments compared to the RA treatments. These conclusions were further confirmed by the differential gene expression analyses between the different conditions. Indeed, more differentially expressed genes were identified between endodermal and non-endodermal cells (1370 and 1410 differentially expressed genes at 3-S and 8-S stages, respectively with a FDR<0.01) than between endodermal cells treated with RA versus DMSO (756 and 514 RA-regulated genes at 3-S and 8-S stages, respectively with FDR<0.01) or with BMS493 versus DMSO (32 and 71 BMS493-regulated genes at 3-S and 8-S stages, respectively). We found a large overlap among the sets of genes having an endodermal-enriched expression at 3-S and at 8-S stages (Fig. S1A; list of genes given in Table S1) and these sets include all known endodermal markers including sox17, gata5/6 and foxa1/2/3, validating the accurate sorting of endodermal cells. RA-regulated genes consist of a large set of up- and down-regulated genes (Table S2), many of them being regulated at both 3-S and 8-S stages (Fig. S1B). These RA-regulated genes include known RAR-direct targets such as cyp26b1/a1, dhrs3a, nr2f2 and several hox genes, validating our protocol and the of RA treatments. Interestingly, BMS493 treatment led mostly to down-regulation of gene expression. Indeed at 3-S stage, the 32 BMS493-regulated genes were all repressed, and, at 8-S stage, 68 genes were repressed while only 3 genes were up-regulated by BMS493 treatment (Tables S3). A large overlap was also observed between the genes down-regulated by BMS493 at 3-S and at 8-S stage (Fig. S1C). As expected, a large proportion of genes down-regulated by BMS493 were up-regulated by RA treatment, this observation being evident mostly at 3-S stage where 72% of genes repressed by the RAR inverse-agonist were induced by RA, while this proportion decreased to 40% at 8-S stage (Fig.1B,C). Tables 1 and 2 show the genes significantly up-regulated by RA and down-regulated by BMS493 as well as those enriched in the endoderm at 3- and 8-somites stage, respectively (shown in bold). gata6, insm1a and ascl1b are the only known pancreatic regulatory genes which were regulated by both RA and BMS493 (Table 1). Other pancreatic transcription factors, like mnx1, insm1b, hnf1ba, nr5a2 or neuroD1, were induced by the RA-treatment but not significantly repressed by BMS493. Inversely, other pancreatic regulators were inhibited by BMS493 but not significantly induced by RA like pdx1, rfx6 and myt1b (Tables S3 and S6). We can assume that the induction of pancreatic fate by RA (and the absence of pancreas upon BMS439 treatment) is mediated, at least in part, by the direct or indirect regulation of these pancreatic regulatory factors. In conclusion, these RNA-seq data highlight all the genes with an enriched expression in zebrafish endodermal cells and which are regulated by RA signalling. This gene set notably includes regulators involved in the AP patterning of the endoderm, such as hox genes, and known factors involved in the specification of pancreatic progenitors.

Effect of RA and BMS493 on the transcriptome of endodermal cells. (A) Principle component analysis (PCA) of the 24 RNA-seq data obtained on cells isolated at 3-somites stage (circle) and 8-somites stage (triangle). The colors indicate the data for non-endodermal cells (NE) (grey), and endodermal cells treated with RA (purple), BMS493 (red) and DMSO as control (green). The plot shows high reproducibility between triplicates. The strongest transcriptomic differences occur between endodermal and non-endodermal cell (along PC1), then between endodermal cells treated with RA and DMSO (along PC2), while BMS493 treatment has minimal influences. Consistent with the inverse-agonist action of BMS493 and with the agonist action of RA, these samples are located far from each other, the DMSO-samples being located between them. (B,C) Venn diagram displaying the number of genes up-regulated by RA (purple), down-regulated by BMS493 (red) and endodermal enriched (green) at 3-somites (B) and 8-somites stage (C).

To further identify the genes directly regulated by RAR and determine if some pancreatic regulatory genes are direct targets of RA signalling, we performed ChIP-seq experiments at the end of gastrulation. In absence of validated commercialized ChIP-grade antibody recognizing zebrafish RAR, we chose to express a tagged RARaa in zebrafish gastrulae by injecting zebrafish fertilized eggs with the mRNA coding for the zebrafish RARaa protein fused to a Myc-tag at its C-terminal end. RARaa was chosen as the RNA-seq data indicated that it is the most highly expressed RA receptor in zebrafish endodermal cells. We injected very small amount of this mRNA (about 30pg) in order to avoid high non-physiological levels of RARa protein within embryos; the development of embryos were not affected by these injections. Chromatin was prepared at 11.5 hpf (3 somites stage) from about 2000 injected zebrafish embryos and immunoprecipitation was performed with a ChIP-grade Myc antibody. Comparison of reads obtained with the Myc-RAR ChIP and the input negative control led to the identification of 4858 RAR peaks. In order to identify bona fide RAR binding sites showing strong affinity, we selected all peaks with a height score above 50 (Table S4). By choosing such criteria, 2848 robust RAR binding sites were identified in the zebrafish genome. As shown in Fig.2A, a majority of these sites are located near or within genes: 8% were found in promoters (i.e. 1kb upstream of the gene TSS, Transcription Start Site), 30% in upstream sequences (from 1 to 10kb), 22% in introns, 4% in exons, and only 33% in intergenic regions. Sequence analysis of all RAR peaks revealed that the highest represented motif corresponds to the Direct Repeat of the RGKTCA motif separated by 5 bases (reported as DR5) and being the RAR/RXR consensus binding sequence (present in 39% of identified RAR peaks) (Fig.2B)1. The next most abundant motifs are also repetitions of the RGKTCA motif with different spacings (TR4 being a Direct Repeat separated by 1 and 2 bases : DR1/DR2) and orientations (Rxra being an Inverted Repeat with no base separation : IR0). Furthermore, many RAR peaks were found near genes reported to be RAR-direct target genes in other species, such as cyp26a1, dhrs3, nr2f2 or the hoxb1a-hoxb4a genomic region (Fig.2C and data not shown). All these observations confirm the accuracy of the ChIP-seq data. Interestingly, many identified zebrafish RAR sites are located in evolutionary conserved genomic sequences as shown by the fish PhastCons track (Fig.2C and see below).

Identification of RAR binding sites in the zebrafish endoderm. (A) Distribution of ChIP-seq peaks to the different regions of the zebrafish genome. (B) Top 3 motifs overrepresented in all ChIP-seq peak sequences with the percentage of sites containing the motifs and the p-value of enrichment. The three motifs consist to a repetition of the A/GGGTCA sequence; the first corresponds to the classical DR5 recognized by the RARA:RXR complex, the second (TR4) is a superposition of DR1 and DR2, and the third is a IR0. (C) Visualization of RARaa binding sites around the dhrs3a gene (upper panel), cyp26a1 (middle panel) and hoxb1a-hoxb4a genomic region (below panel). Tracks in gold correspond to RARaa ChIP-seq reads and identified RARaa peaks. The track in blue shows the location of conserved genomic sequences (from the UCSC Genome Browser obtained from comparison of 5 fish species).

The RAR ChIP-seq peaks located within 250kb from the TSS of a gene were assigned to this gene and when several genes were lying in the vicinity of a RAR site, the closest gene was considered as the putative RAR-regulated gene. Using this strategy, amongst the 2848 RAR sites, 2144 were linked to a gene. Correlation analysis between RA gene expression regulated by RA and the number of RAR sites near the gene showed that RAR acts mainly as a transcriptional activator (Fig.3A), supporting the classical model where RAR/RXR heterodimers mainly recruit co-activators upon RA ligand binding1. However, this correlation is not very high and genes down-regulated by RA can harbour nearby RAR sites. Indeed, from the gene set having RAR sites, 61 were down-regulated and 94 genes were up-regulated by RA at 3-S stage (Fig.3B, Tables S5). Among the genes up-regulated by RA and harbouring a RAR site, we identified the pancreatic regulatory genes hnf1ba/b, gata6, insm1b, jag2b and mnx1 indicating that these genes are direct targets of RA. As for the genes down-regulated by BMS493, we found that a large number of them (i.e. 18 genes out of 32) contain RAR sites and amongst them 13 are also upregulated by RA (Fig.3B, see legends for gene names). In conclusion, the ChIP-seq data allowed us to define the zebrafish RAR cistrome at the end of gastrulation and identify putative RAR direct target genes.

Integrated analysis of the ChIP-seq and RNA-seq data. (A) Correlation of RA gene regulation (log2 fold change of expression RA versus DMSO) according to the number of neighbouring RARaa ChIP-seq peaks. Only RA-regulated genes were included in the plot. (B) Venn diagram showing the overlap of genes harbouring nearby RARa binding sites (yellow) and those up-regulated by RA (purple), or down-regulated by RA (blue). The below panel also shows the overlap with the genes down-regulated by BMS493 (red). The 13 genes showing up-regulation by RA, down-regulation by BMS493 and harbouring a RAR site are tshz1, nr6a1b, foxg1b, nr2f5, gata6, dhrs3a, hoxb1b, slc22a3, ppm1h, nrip1a, col7a1l, hoxc1a and hoxb5b.

Functionally important regulatory regions are expected to be conserved during evolution. To determine which RAR binding sites are conserved in vertebrates, we compared our zebrafish ChIP-seq data with those of Chatagon and colleagues19 who identified RAR binding sites in the murine genome using the F9 embryonal carcinoma cells whose differentiation into primitive endodermal cell is induced by RA treatment. This comparison revealed that, among the 2144 zebrafish genes harbouring a RAR site, 722 have also a RAR site near the murine orthologous genes. This list of conserved RAR-bound genes comprises notably cyp26a1/b1, dhrs3a, nr2f2, many hox genes, raraa/b as well as pancreatic genes gata6, hnf1ba, insm1 and mnx1. We next determined which of these RAR binding sites are located in conserved regulatory sequences. To that end, we retrieved the list of conserved non-coding elements (CNEs) identified in zebrafish by comparing multiple fish and tetrapod genomes34. Amongst the 722 conserved RAR-bound genes, 116 RAR binding sites were located in CNEs, supporting a regulatory function (Table S6). Amongst them, 24 CNEs were even conserved from fish to mouse and are called here HCNE for highly conserved non-coding elements. They are found for example near the meis1/2, srsf6, qki, nrip1 and ncoa3 genes (Table S6). As already reported, several RAR sites controlling the expression of hox genes are located in these HCNEs17. Interestingly, we identified here a novel RAR site in a HCNE located 25kb downstream of the zebrafish hoxb cluster in the fourth intron of the skap1 gene. This intron contains 4 strong RAR sites in the zebrafish and murine sequences (green boxes in Fig.4A,B) and the sequence of the second RAR site has been maintained throughout vertebrate evolution and shows a motif similar to a DR5 RARE (Fig.4C). The transcriptional regulatory function of this HCNE was tested by transgenesis by inserting one copy of this element upstream of a minimal cfos promoter driving GFP. As shown in Fig.5A, this reporter transgene is expressed in the gut and in the neural tube. Highest GFP levels were detected in the posterior hindbrain, in a pattern highly reminiscent of hoxb1b gene expression (shown on Fig.5D). Furthermore, when transgenic embryos were treated with exogenous RA, GFP expression was drastically increased and detected in the whole morphologically affected embryos in a similar manner to hoxb1b (Fig.5B,E). Conversely, treatments with the RA inverse-agonist BMS493 turned off the expression of this DR5-RAR-skap1:GFP transgene (Fig.5C) as well as of hoxb1b, except in the tailbud region (Fig.5F). This confirms the RARE function of this element and indicates a role in hoxbb cluster regulation.

Examples of RARa binding sites conserved among vertebrates. (A,B) Genome browser views around HoxB-Skap1 locus in mouse (A) and zebrafish (B) showing the RAR binding sites detected by ChIP-seq (in gold) in both species. All RAR sites are located in CNEs but only the RAR sites located in skap1 gene 4th intron (green box) display sequence conservation from zebrafish to human. Other RAR sites located at similar places in the murine and zebrafish loci (red boxes) are probable orthologous RAR sites but their sequences cannot be aligned between zebrafish and mice. Conserved regions from the UCSC genome browser is shown below the murine RAR ChIP-seq peaks in panel (A). (C) Alignment of 9 vertebrate sequences corresponding to the second RAR sites located in skap1 gene 4th intron, showing the conservation of a DR5-like motif (blue boxes; inverse orientation) recognized by the RARRXR complex. Sequences highlighted in green are identical in all 9 species.

The conserved RAR site from skap1 gene 4th intron is a functional RARE. Pictures of the DR5-RAR-skap1:GFP transgenic embryos treated with DMSO (control, panel A), with RA (panel B) or with BMS493 (panel C). Upper panels display GFP fluorescent expression and lower panels (A, B and C) display embryo morphology. GFP Expression in the posterior endoderm gut is indicated by yellow arrows.

We also verified the regulatory role of some other RAR sites identified near zebrafish pancreatic regulatory genes. For example, we tested the activity of a RAR site located near a CNE downstream of the zebrafish mnx1 gene. A RAR binding site is also found at a similar location downstream of the murine Mnx1 gene (Fig. S2A). This RAR element was able to target GFP expression to the posterior endoderm at low level and in the dorsal pancreatic bud at higher levels (Fig. S2BD). When the RAR-mnx1:GFP transgenic embryos were treated with RA, GFP expression was slightly increased in whole endoderm; conversely, treatment with BMS493 abolished GFP expression (Fig. S2DF).

In conclusion, these analyses show that a large fraction of RAR sites has been conserved during evolution and transgenic assays confirm that some elements are sufficient to drive expression in endoderm and confer a RA-response.

RARRXR complexes control gene expression through the recruitment of corepressors (e.g. NCoR/Smart) and coactivators (NCoA) which control chromatin compaction via HDACs and HATs, respectively2, 3. Thus, one possible strategy to identify functional RAREs is to perform a genome-wide analysis of chromatin accessibility modifications following RA or RA inverse-agonist treatments by ATAC-seq assays33 allowing the identification of open chromatin and nucleosome-free regions induced or repressed by RA signaling. As most nucleosome-free regions correspond to regulatory sequences, ATAC-seq can also highlight the enhancers or promoters whose accessibility is modified by RA signalling indirectly, i.e. through the binding of transcription factors whose expression is induced by RA. Thus, sequence analysis of all RA-induced ATAC-seq peaks can give clues on the identity of transcription factors acting in the subsequent steps of the RA-induced regulatory cascade.

As for the RNA-seq assays, zebrafish embryos were treated with RA, BMS493 and DMSO during blastula and gastrulation and about 10,000 endodermal cells were selected by FACS at 3-somites stage (11 hpf). Non-endodermal cells from control DMSO-treated embryos were also analysed in parallel. Cell preparations and ATAC-seq experiments were done in triplicate for each condition and analysed as described in Materials and methods. We first verified the accuracy of the data by several quality control analyses. First, for all samples, the analysis of the ATAC-seq fragment size distribution revealed the expected pattern with abundant short (<150bp) fragments corresponding to nucleosome-free regions and larger fragments of about 200 and 400bp corresponding to mono- and bi-nucleosome regions, respectively (Fig. S3A). Secondly, as reported previously33, 35, genome mapping of the nucleosome-free fragments showed a clear enrichment in promoter regions immediately upstream of transcriptional start sites (TSSs), while mono-nucleosomes were depleted from TSSs and rather mapped just downstream of the TSSs in a periodic manner (Fig. S3B). Thirdly, we verified that the ATAC-seq fragments correspond to many zebrafish regulatory regions by comparing them with regions harbouring the histone modifications H3K4me3 and H3K27ac marks identified in zebrafish embryos at 10hpf36. Heatmap plots of ATAC-seq reads from all samples showed an obvious enrichment at loci harbouring these two histone modifications (Fig.6A and Fig. S4). As regulatory regions often display sequence conservation, we also compared our ATAC-seq reads to the collection of zebrafish evolutionary-conserved non-coding elements (zCNEs)34. Heat-maps of ATAC-seq reads from each sample also showed a strong correlation with zCNEs (Fig.6A and Fig. S4). These observations confirm that regions identified by ATAC-seq exhibited hallmarks of active regulatory elements. The reproducibility of ATAC-seq data was also analysed by PCA (Fig.6B). This PCA showed that (i) triplicate samples are tightly clustered, and (ii) endodermal and non-endodermal (NE) cell clusters are separated along the PC2 axis, while the RA-treated cluster is separated from the DMSO- and BMS-cell cluster along the PC3 axis. Thus, as observed for the RNA-seq data (Fig.1A), stronger differences are observed between GFP+ and GFP cells compared to the differences between RA-treated and DMSO-treated endodermal cells. The samples corresponding to the BMS493-treated cells and DMSO-treated cells were not clearly segregated and did not reveal significant effects of BMS493 on the chromatin accessibility.

Identification of nucleosome-free regions in zebrafish endodermal cells and following RA treatments by ATAC-seq assays. (A) Heat maps showing enrichment of ATAC-seq reads at the middle of chromatin regions harbouring H3K4me3 and H3K27Ac epigenetic marks and at genomic areas corresponding to zCNE. The maps display intervals flanking 10kb up and downstream of the features. The heat map plots shown on this figure corresponds to the ATAC-seq data obtained with control endodermal cells (DMSO-treated). Similar results were obtained for the other samples (see Suppl. Fig.4). (B) PCA plots obtained for the ATAC-seq libraries. ATAC-seq data from endodermal and non-endodermal cells are separated along the PC2 axis, while those from RA-treated versus control and BMS493 are separated along the PC3 axis. The plot shows clustering of triplicates and no obvious separation of the DMSO- and BMS493- treated cells. (C,D) Top 3 enriched motifs found in nucleosome-free regions detected specifically in endoderm (C) and detected following RA-treatments (D). (E) Plot showing the correlation of RA-induced gene expression (log2 fold change) and the number of RA-induced nucleosome-free elements located nearby the genes. Only genes showing significant RA gene induction were included.

From all 12 ATAC-seq samples, a total of 156,604 nucleosome-free regions were identified within the zebrafish genome. Differential peak intensity analyses revealed that 9722 and 12,974 regions are more accessible in endodermal and non-endodermal cells, respectively (with FDR<0.05, Tables S7). Interestingly, sequence analysis of all endodermal-specific ATAC-seq regions highlight a significant enrichment of the binding site motifs for the Gata, Fox and Sox protein families (Fig.6C), in accordance with the well-known function of Gata4/5/6, Foxa1/2/3 and Sox32/17 in endodermal cell differentiation6. Also, these endoderm-enriched ATAC-seq peaks are often identified near endodermal and pancreatic regulatory genes, such as in the foxa2, nkx6.1, hnf4g, sox17 or mnx1 loci (Fig. S5 and data not shown), suggesting the presence of endoderm-specific enhancers at these locations.

As expected, the RA treatments had less influence on ATAC-seq peaks compared to the cell type identity (i.e. endoderm versus non-endoderm). Still, 1240 genomic regions were found to be more accessible and 749 regions were less accessible in the RA-treated endoderm compared to the DMSO-treated controls (with FDR<0.05). If the RA-treated samples were directly compared with the BMS493-treated samples, more peaks were detected as treatment-dependent: 3277 regions were more accessible in RA-treated while 1762 were more accessible in the BMS493-treated cells (Tables S8). Annotation of the RA-induced ATAC-seq peaks to the closest gene revealed that they were often located near RA-upregulated genes identified above by RNA-seq. Moreover, we found a significant correlation between the level of RA-induced gene expression and the number of RA-induced ATAC-seq elements (Fig.6E). Interestingly, 11% of RA-induced ATAC-seq peaks corresponded to RAR binding sites identified by ChIP-seq and possess the DR5 motif recognized by the RAR/RXR complex (Fig.6D). This was the case for RA-induced peaks in the dhrs3a, cyp26a1/b1 and insm1b genes (see black boxes in Fig. S6 and data not shown). However, many identified RAR sites did not display a significant increase in accessibility, such as those located in the hoxba locus (see green boxes in Fig. S6). Furthermore, the majority of RA-induced ATAC-seq peaks did not harbour RAR binding sites although they were usually found near RA-upregulated genes; instead, such peaks often harbour Gata or Hnf1b binding motifs (38% and 13% of all RA-induced elements, respectively; Fig.6D). Thus, it can reasonably be assumed that these genes are indirectly stimulated by RA signalling. For example, the pancreatic regulatory genes pdx1, insm1a, rfx6 or neurod1, all upregulated by RA-treatment but devoid of RAR binding sites, had RA-induced ATAC-seq peaks located in their genomic neighbourhood and contained either Hnf1b or Gata binding motifs in such peaks (Fig. S7 and data not shown). To identify the GATA and Hnf1b family members involved in these indirect RA-regulations, we searched in the list of RA-stimulated genes (Table S2) for these 2 types of transcription factors and we also determined if RAR sites are detected in their genomic loci (Tables S4 and S5). hnf1ba and hnf1bb were both induced by RA but the level of expression of hnf1ba was about 200-fold higher than hnf1bb in endodermal cells. Furthermore, hnf1ba contains three RAR binding sites located in evolutionary-conserved and nucleosome-free regions (Fig.7A), while hnf1bb has only one weak RAR site (data not shown). Out of the 10 members of the GATA family, only gata4 and gata6 were significantly induced by RA but gata6 was expressed in the endoderm at about 40-fold higher level compared to gata4. Furthermore, gata6 has a high affinity RAR binding site in a nucleosome-free region located about 30kb upstream from its TSS (Fig.7B) while no such RAR site was present around the gata4 gene locus (data not shown). Thus, all these analyses strongly suggest that, upon RA induction, RARRXR complexes directly activate expression of Gata6 and Hnf1ba, which in turn will open regulatory chromatin regions of many genes, including those coding for several pancreatic regulatory factors.

Location of RARa binding sites and of nucleosome-free regions in the hnf1ba (panel A) and gata6 (panel B)gene loci. Visualization of ATAC-seq reads from the merged 3 replicates obtained from endoderm treated with BMS493, DMSO or RA and from non-endodermal cells (NE), in addition to tracks showing RARaa binding sites, H3K27Ac and H3K3me3 marks determined by ChIP-seq. Regions showing conservation of genomic sequences among 5 fish species are also shown by blue boxes below the tracks. The RAR binding sites are highlighted by gold boxes.

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Digital World Acquisition Confirms the Internet Belongs to the Right – Investorplace.com

Posted: at 3:55 pm

Before we dive into a discussion on Digital World Acquisition Corp (NASDAQ:DWAC) stock, the controversial special purpose acquisition company that will take Trump Media and Technology Group (TMTG) public, its helpful to separate the noise from the narrative.

Source: NESPIX / Shutterstock.com

In other words, your personal feelings about former President Trump should not dictate your ultimate decision on DWAC stock.

Instead, its more productive to acknowledge the reality of the underlying situation. For instance, Trump is incredibly popular. I cant think of any former president that had as much sway post-election than The Donald.

That alone is enough to warrant a look at DWAC stock. After all, were in a market environment where collective sentiment plays a greater role than usual.

But what is the source of Trumps charisma? According to an opinion piece by Salon, America loves a bully. Bluntly, contributor Amanda Marcotte wrote in September 2015 that Trump is the affluent bully who revels in his privilege and enjoys stomping on those with less unearned social power than he has. And the Republican base is eating it up.

Granted, Salon leans left politically and the right will find Marcottes description of the former president ungenerous. Nevertheless, the author may be onto something, noting that conservative-leaning audiences lap up shock jocks like the late Rush Limbaugh and Ann Coulter.

I can tell you one thing. The country that brought the world Hollywood loves simple, digestible narratives: North versus south. Left versus right. Cowboys and Indigenous Americans.

Naturally, DWAC stock by virtue of underlining TMTGs Truth Social platform caters to the binarism that dominates most social and political discourse in the U.S.

Further, when grievances both real and perceived undergird said binarism, you have an incredibly powerful, perhaps unprecedented catalyst.

You want evidence of this catalyst? Then-candidate Donald Trump was able to corral the hurt and suffering whether real or perceived, it doesnt matter of his core voting base and it propelled him to the White House.

He didnt win on the issues. Remember, when Ron Paul was vying for the Republican nomination, the conservative audience booed him for promoting an anti-interventionist stance regarding sanctions on Iran. Just a few years later, then-President Trump attempted a peace negotiation with North Korea.

From the Axis of Evil to shaking hands with Kim Jong Un, Trumps charisma combined with Americas love for binary narratives resulted in astounding events in U.S. history. But somehow, DWAC stock is going to be a failure? It could be, dont get me wrong but the SPAC has less of a credibility challenge to climb.

More importantly, data from the Pew Research Center shows that the underlying business of DWAC stock features a massive addressable market. To no ones surprise, young people regularly consume news through social media platforms.

Significantly, though, two demographics whites and the modestly educated consume a large portion of their news through social media.

Granted, overall, Democrats dominate social media usage relative to Republicans. However, platforms like Truth Social have an opportunity to reach many under-the-radar conservatives, particularly those who feel they have been shamed and denigrated by mainstream institutions.

Again, Trump spoke to millions of Americans who felt this way and it led to powerful results. Why wouldnt the same apply for DWAC stock?

Business Insider provided an interesting take that Generation Z is more conservative than many realize. Considering that conservative social media content creators think alt-right channels before they got de-platformed were outrageously successful, DWACs prospective investors should be licking their lips.

To be clear, no guarantee exists that DWAC stock will be successful. Certainly, anti-Trump advocates on the left are doing everything they can to stymie its progress. However, in my opinion, conservative, even right-wing ideologies taking over social media and the internet is an inevitability.

Why? Liberal and progressive ideologies have become the social norm. Today, we are more socially aware across a library of issues than we ever have been. At some point, being even more liberal and more progressive yields a lower rate of return. Its the sociological version of the law of large numbers.

But you know what will gain quicker and more robust success? Being anti-establishment, deliberately stoking politically incorrect talking points. Its based (as the kids like to say) and its so entertaining because it tickles the reptilian part of our brain.

And tickling, if you think about it, is why the internet exists. Ultimately, binary audiences are easier to manipulate and thereby monetize. Its how one old man got eviscerated for wanting to be friends with Iran but how another old man was celebrated for befriending North Korea.

Binarism. Theres no drug like it. And thats exactly what a share of DWAC stock gets you.

On the date of publication, Josh Enomoto did not have (either directly or indirectly) any positions in the securities mentioned in this article.The opinions expressed in this article are those of the writer, subject to the InvestorPlace.comPublishing Guidelines.

A former senior business analyst for Sony Electronics, Josh Enomoto has helped broker major contracts with Fortune Global 500 companies. Over the past several years, he has delivered unique, critical insights for the investment markets, as well as various other industries including legal, construction management, and healthcare.

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At least 6 Senate candidates have refused a COVID vaccine and they’re all Republican – The American Independent

Posted: at 3:55 pm

The American Independent Foundation asked every major candidate running for U.S. Senate in 2022 about their COVID-19 vaccination status.

At least six candidates running for U.S. Senate in 2022 remain unvaccinated against the coronavirus, an American Independent Foundation analysis shows.

All of the unvaccinated candidates are Republicans, conforming with trends showing a wide partisan gap in the United States' vaccination rate. Every Democratic candidate for Senate has received at least one COVID-19 shot.

There are 91 major Senate candidates running for office in 2022. That number includes incumbents seeking re-election, challengers seeking to replace those candidates, and individuals running in states with open seats.

Of those candidates identified, 50 had spoken publicly to their status as vaccinated against COVID-19 or were reported to be fully or partially vaccinated by other news organizations. Five had previously stated publicly that they were not vaccinated or were reported to be so. And the remainder had not commented on whether they had received the shots.

All U.S. senators seeking re-election are vaccinated except for two: Sens. Ron Johnson (R-WI) andRand Paul (R-KY). Johnson has yet to formally announce his re-election bid but is expected to seek another term. "I'm not going to get the vaccine," Johnson said in a recent interview with C-SPAN. He added that if members of Congress were required to get vaccinated, "I would just stop coming here."

Paul, like Johnson, has previously contracted the virus, and the two argue that grants them a so-called "natural immunity" such that they do not require vaccination. Though studies have shown that previous infection does provide some level of protection, the CDC still recommends that everyone eligible gets vaccinated against COVID-19. Moreover, a recent CDC study showed that unvaccinated Americans who previously contracted the virus were over five times more likely to get COVID again than those who were fully vaccinated.

Former Missouri Gov. Eric Greitens, who running to replace Sen. Roy Blunt (R-MO), told a local radio show in August that he was not vaccinated. He has also come under fire for not having a plan to get more people vaccinated. Greitens' campaign did not respond to multiple inquiries about his vaccination status.

Fellow Missouri Senate candidate Mark McCloskey has similarly refused to get vaccinated, according to the Missouri Independent. McCloskey rose to prominence after he and his wife brandished guns at protestors demonstrating in response to the murder of George Floyd. McCloskey recently suggested that people who refuse the vaccine would get "their name on a list" and would eventually "get eliminated." His campaign did not respond to multiple inquiries.

Mark Pukita, an Ohio IT executive seeking to replace Sen. Rob Portman (R-OH), bragged in a GOP candidate forum earlier this month that he was the "only one up here" who was not vaccinated, though fellow GOP candidate Josh Mandell has refused to disclose his vaccination status and did not respond to multiple inquiries. Pukita may remain unvaccinated, but he holds up to $50,000 in Johnson & Johnson stock and up to $15,000 in Pfizer stock, two companies that manufacture COVID-19 vaccines.

Jason Beebe, who serves as mayor of Prineville, Oregon, and recently announced a long-shot bid to oust incumbent Sen. Ron Wyden (D-OR), confirmed to the American Independent Foundation in an email that he was unvaccinated. "I have talked with my doctor and am waiting for more testing and results," Beebe said.

Beyond those who have stated publicly or confirmed privately that they were unvaccinated, several leading candidates have refused to disclose their status altogether.

Herschel Walker, a retired football player running to unseat Sen. Raphael Warnock (D-GA), has refused to say if he is vaccinated. In October, Walker's campaign canceled a fundraiser with a conservative film producer whose Twitter profile picture showed a swastika made of needles. Walker's campaigndid not respond to multiple inquiries about his vaccination status.

Senate candidate Marc Brnovich, who currently serves as Arizona's attorney general, has also refused to say whether he has been vaccinated. A reporter asked Brnovich about his vaccination status on Monday, to which he responded, "Have you had an STD?" Brnovich's campaign did not respond to multiple inquiries from the American Independent Foundation.

Public health officials are increasingly worried about a resurgence of COVID-19 cases heading into the winter months. Still, research has found that hesitant people may be persuaded to get vaccinated with the encouragement of local officials they know and trust, including their political representatives. Public opinion research has shown that as more conservative leaders come to support vaccines, so do their followers.

"If you can get Republican [leaders] to stand up for science, to stand up for public health, to stand up for vaccines, you're going to have an easier time convincing Republicans in public to do the same," Matt Motta, assistant professor of political science at Oklahoma State University, told the American Independent Foundation in August.

Published with permission of The American Independent Foundation.

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At least 6 Senate candidates have refused a COVID vaccine and they're all Republican - The American Independent

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Women Resign From Law School FedSoc Board After Realizing What FedSoc Is All About – Above the Law

Posted: at 3:55 pm

OH! So thats why everyone was talking about hacked voting machines.

The only women on the board of NYUs Federalist Society chapter resigned in protest after the chapter decided to invite a male anti-abortion speaker who doesnt even bother with fig leaf legal justifications for his opposition to Roe and instead just thinks the courts should embrace theocracy. This prompted the resigning board members to draft a letter outlining their frustrations with the whole process and their systematic marginalization.

Not to belittle the honest concerns of these women, but this letter reads like we joined the Zombie Cannibalism Club for the camaraderie and were shocked and dismayed by all the zombie cannibalism going on around here.

In a discussion following the second vote, the President admitted that the motivation for this event was to have a pro-life vs. pro-choice debate and express a view of what the law should be, admitting his initial reasoning for the event (a discussion of the legal arguments in Dobbs) was pretextual. This runs in direct opposition to one of the primary tenets of the Federalist Society rule of law, which is for the judiciary to say what the law is and not what it should be.

Oh. No. Thats not the primary tenet of this organization at all. If there is a primary tenet to the Federalist Society it might actually be the word pretextual. Its just a debate society to the extent it dupes the occasional moderate lawyer into showing up and lending the organization their credibility. But the core mission is always to cultivate a right-wing legal subculture.

Instead, certain board members have suggested the most polarising Ben Shapiro-esque activist lawyer types to come talk. .

Yeah thats the Federalist Society. Chapters of this organization invited anti-gay bigots to rail against Windsor and Obergefell while they were coming up and cultivated a borderline obsession with Chick-fil-A that carries on to this day. Chapters run counter Pride Days! The authors decry their chapters antics as if this is some sort of new turn, but this is what the Federalist Society has always been.

Except they used to serve pizza.

Speakers who will alienate female members of the board, will draw a lot of anger from the NYU Law community, and make it clear that NYU Law FedSoc does not stand for the principles it claims it stands for of being a nonpartisan organisation interested in rule of law and individual rights, and instead is an activist conservative Republican organisation disinterested in legitimate legal inquiry.

On the subject of giving out free pizza, theres always one or two FedSoc members who just stumbled into a classroom looking for a cheap meal and who really dont care about the clubs ideological mission. But one would hope that by the time a student makes it onto the BOARD theyd figured out what was up. The organizations leadership was actively moonlighting for the Trump White House. The whole point of the Federalist Society is to identify and nurture right-wing law students so they can become right-wing jurists when they get older. Or maybe they dont even need to get older first. Its a purely ideological mission.

Please accept our sincerest apologies for failing to prevent NYU Laws chapter of the Federalist Society from following the national trend of becoming Turning Point USA, Law School Edition.

Ill just let the astronauts answer this one.

Giving these women the benefit of the doubt, maybe theyd hoped to make the NYU chapter into a more old-school Ron Paul libertarian sort of thing. But thats not how these things work. The motivation for most people joining this club will always be to shore up connections with right-wing legal figures and, for better or worse, that favors the most aggressive trolling. There may have been a kernel of a civil, measured Federalist Society at one point, but a civil, measured Federalist Society doesnt get people plugged in with the power players in the conservative legal movement and those power players are folks like these activist anti-abortion attorneys. The group will always gravitate to the more radical corners of the movement because the people they need to impress to get their clerkships and Jones Day offers and House internships are all firmly ensconced in the more radical corners of the movement.

And so it goes.

Joe Patriceis a senior editor at Above the Law and co-host of Thinking Like A Lawyer. Feel free toemail any tips, questions, or comments. Follow him onTwitterif youre interested in law, politics, and a healthy dose of college sports news. Joe also serves as a Managing Director at RPN Executive Search.

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Women Resign From Law School FedSoc Board After Realizing What FedSoc Is All About - Above the Law

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From Bush to Obama, and Trump to Biden, U.S. Militarism Is the Great Unifier – The Intercept

Posted: at 3:55 pm

Many Democrats, liberals, traditional conservatives, and even some leftists continue to tell themselves that the election of Joe Biden was the first step toward restoring U.S. standing in the world after the damage caused by Donald Trump. And in a variety of ways many stylistic and some substantive that perspective has merit. But when it comes to national security policy, the U.S. has been on a steady, hypermilitarized arc for decades. Taken broadly, U.S. policy has been largely consistent on national security and counterterrorism matters from 9/11 to the present.

The ascent of the charlatan businessman Trump to the presidency in 2016 was a logical if somewhat on-the-nose plot twist in the U.S. imperial saga that managed to distill many truths about this nation into a four-year televised and live-tweeted debacle.

The continued media drumbeat that Trump remains the gravest enduring threat to U.S. democracy is fueled by legitimate concerns over Trumps frantic efforts to use the office of the presidency to overturn the election results, which came to a head with the violent demonstrations at the U.S. Capitol on January 6, 2021. These dangerous actions, taken in concert with ongoing Republican efforts at voter disenfranchisement and the peddling of false conspiracy theories, merit serious concern. The Trumpist movement, especially its members in Congress, poses a clear threat to the democratic process. But even in the face of this threat, the bipartisan imperial consensus was so strong that the Democrats continued to increase Trumps national security powers throughout his presidency.

The bipartisan imperial consensus was so strong that the Democrats continued to increase Trumps national security powers throughout his presidency.

This reflexive bipartisan militarism stands in stark opposition to the Democratic Partys sweeping and fallacious rhetoric that the bad face of the U.S. emerges only when Republicans seize executive power and that the sole remedy is electing Democrats. Civilian victims of Barack Obamas drone strikes might have another view. Before Trump, according to Democratic doctrine, the evils of U.S. policy originated with George W. Bush and his co-president Dick Cheney. Yet under both Trump and Bush, the rhetoric from many Democrats was pathologically disconnected from their support for ever-expanding militarist and surveillance policies.

The Democratic party, in its self-tailored version of history, has always been a steadfast force of resistance against GOP excesses and abuses. The Democrats appear to see no contradiction between fighting Republican attacks on voting rights and their own enthusiastic embrace of empire in foreign policy. Without support from the leadership of the Democratic Party and votes from rank-and-file congressional Democrats many of the worst national security policies of the past two decades would have been impossible to implement or would have required enormous political battles or an even greater, and abusive, use of executive power to accomplish.

If the Democratic Party offered a true resistance to the GOP, the history of the post-9/11 world would be very different. Instead of California Democrat Rep.Barbara Lee standing as the lone vote in the entire Congress against the Authorization for the Use of Military Force the blank check for global war days after September 11, 2001, we would have seen the majority of Democrats join her in a chorus of opposition and restraint. Sen.Russ Feingold, Democrat from Wisconsin, would not have been the only senator to vote against the Patriot Act. The legislative authorities for the Iraq War would have been thwarted without the support of a majority of Democratic senators: 29 voted in its favor, including the current president. Without that backing, the Bush-Cheney administration would have had to openly and publicly own its maniacal belief that when it comes to national security policy, the executive branch can and should function as a de facto dictatorship.

While a vocal minority of Democrats spent much of the two terms of the Bush administration fighting against the Iraq War and the grave human rights abuses being committed by the CIA and military, the leadership of the party consistently abetted the Bush-Cheney agenda. When it mattered most, the party failed to offer more than meager protests.After the Democrats gained a House majority in the 2006 midterm elections, incoming House Speaker Nancy Pelosi made clear there would be no accountability at the highest levels of power. I have said it before and I will say it again: Impeachment is off the table, Pelosi asserted. We pledge partnerships with Congress and the Republicans in Congress, and the president not partisanship.

There is an understandable tendency to view the past20 years of U.S. militarism as a defining era unto itself. And, in some crucial ways, the full spectrum of U.S. responses to the September 11 attacks did alter the world and, with it, the U.S. way of war. But at their core, the most consequential actions emanating from Washington, D.C., after 9/11 were already in motion. The Bush administration came to power with an eye toward regime change in Iraq. But it did so emboldened by the bipartisan vote during Bill Clintons tenure that made regime change official U.S. policy, backed up by constant bombings of Iraq throughout Clintons two terms. Even Bernie Sanders, then a House representative,supported that bill, which was largely the work of the neoconservative Project for a New American Century. Under Clinton, the U.S. was already moving toward a system of remote lethal strikes and small wars, though it was much more reliant on legacy systems like cruise missiles rather than the now ubiquitous armed drones. The precursor of the Patriot Act was passed with significant support from both parties, with Biden serving as one of its lead architects, a fact he regularly and proudly cited. The U.S. was already operating a well-oiled economic warfare machine with its use of crippling sanctions in an effort to overthrow governments or punish populations into submission.

The most significant milestones of the past two decades liein the synergy that exists among the various political factions between U.S. elections.

In its malignant genius, the Bush-Cheney administration stacked with career hawks who knew how to work the levers of power saw opportunity in the rubble of the World Trade Center and the Pentagon. They saw the value of tapping into the rage, shock, and, most importantly, fear that gripped the nation in the aftermath of the terror attacks to accelerate the implementation of their agenda. The Democratic Party willingly folded itself into the Bush administrations aspirations and bestowed upon it sweeping war and surveillance powers. The most significant milestones of the past two decades lie not with the victories of extroverted villainous Republicans like Bush or Trump, but in the synergy that exists among the various political factions between U.S. elections.

Yemeni children look at graffiti protesting U.S. drone strikes on Sept. 19, 2018, in Sanaa, Yemen.

Photo: Mohammed Hamoud/Getty Images

When Barack Obama won the presidency in 2008, the party had an opportunity to showcase what an antidote to Bush-Cheney policymaking would look like. This prospect was a major part of the success of the Obama campaigns against both Hillary Clinton, an Iraq War supporter, and John McCain, a notorious militarist. Instead, Obama expanded some of the most dangerous aspects of the Bush-Cheney war apparatus while shielding the CIA, military leaders, and the entire Bush administration from any accountability. Obama surged troops in Afghanistan and empowered both the CIA and Joint Special Operations Command to engage in expanded global targeted killing operations. He embraced the widespread use of covert operations, ratcheted up drone strikes in both Afghanistan and Pakistan, initiated air wars in Somalia and Yemen that endure to this day, and waged a disastrous regime change war in Libya.

Obama used his credibility among the base of the Democratic Party in an effort to normalize assassination as an acceptable, if not preferable, tool of U.S. policy. Obama relied so heavily on drone strikes that they became a policy unto themselves, and he publicly asserted the right of the U.S. president to assassinate American citizens by means of targeted killing, based on the vague notion that they might someday threaten national security or even U.S. interests. While the U.S. government has long engaged in covert assassinations, Obama transformed and legitimizedsuch operationswith his intricate attempts to rebrand the practice and to publicly argue in favor of its legality and morality.

Obamas Justice Department defended former Defense Secretary Donald Rumsfeld and others against charges of war crimes in civil litigation and refused to hold the CIA accountable for its widespread use of torture and extraordinary rendition. Obama simultaneously prosecuted whistleblowers with a vengeance using a warped interpretation of the 1917 Espionage Act. His CIA director, John Brennan,lied about the agency spying on U.S. Senate torture investigators, and his director of national intelligence, James Clapper, lied under oath when testifying about mass surveillance and the bulk collection of communications among U.S. citizens.

By the time Obama prepared to leave office, his administration had built up what amounted to a secret parallel judicial system to enforce the long-standing U.S. global killing regime. During Obamas second term, his administration cobbled together a ramshackle set of guidelines for targeted killings that he said he hoped would bring legal structure, oversight, and transparency to his signature military tactic. But these guidelines had no teeth that the next commander in chief could not easily knock out. In selling his targeted killing policy, Obama repeatedly banked on the notion that he could be personally trusted to make these decisions in secret. That mentality led to a total absence of meaningful checks, by the time the 2016 election was decided, against a dangerous and now institutionalized claim of sweeping and lethal presidential powers.

President Donald Trump speaks to the troops during a surprise Thanksgiving Day visit at Bagram Airfield in Afghanistan on Nov. 28, 2019.

Photo: Olivier Douliery/AFP via Getty Images

Donald Trumps defeat of Hillary Clinton sent shockwaves through the national security state and the Washington, D.C., political establishment. On war policy, Trump was difficult to assess before assuming office because his messaging and pronouncements were often contradicted by other statements or moves he made. As a candidate, and as president, Trump would stake out Ron Paul-esque libertarian opposition to U.S. wars and militarism, and in the next speech and sometimes next breath he would engage in a grotesque soliloquy about taking a nations oil, murdering families of terror suspects, or wiping countries off the map. Rhetoric can itself be dangerous when it is emanating from the mouth of a man who controls nuclear weapons and vast military forces, so it was always reasonable to be deeply concerned over thetemperamentalravings of the 45th president. Yet in the end, most of his rants fizzled into bluster. This was in part a byproduct of the competing factions within the administration pushing contradictory agendas, including on war policy and the response to the 2020 election results.

In matters of war, the truth is that there were not many substantive national security anomalies brought about by Trumps control of the White House. Trump was far more belligerent than Jimmy Carter, but he was not even in the same league as Bush and Cheney when it came to global mass killing. While steering clear of the sustained large-scale ground operations that marked both Bush presidencies in Iraq, Trump and Obama showed great willingness to use U.S. military and CIA force, particularly in undeclared war zones, and ran operations that consistently killed large numbers of civilians. Obama initiated new military action in more countries than Trump.

The truth is that there were not many substantive national security anomalies brought about by Trumps control of the White House.

Stylistically, of course, there were many differences between Trump and former U.S. presidents, and his rhetoric was often terrifying and appalling. But in national security policy, Trump generally operated within the norms of the modern U.S. presidency and received mainstream praise for it. How could anyone forget the moments early in his tenure when establishment media pundits declared that Trump became president after he unleashed missiles on Syria or after he spoke during the State of the Union of a U.S. soldier killed in a deadly and unnecessary ground operation that he had authorized in Yemen?

Trump swiftly undid many of the modest rules implemented during Obamas second term aimed at reducing civilian deaths in U.S. drone and other airstrikes and gave greater latitude to field commanders and mid-level officials to authorize such strikes. Trump dispensed with Obamas superfluous policies for acknowledging deaths caused by CIA actions and lowered the threshold for killing unknown people, particularly military aged males.

Trump easily did away with virtually all the policy constraints and scholarly debates. His rules glance at law, and lay bare how easily a president thinks it may be set aside in service of vague national security interests. Its hard not to see these rules as a license to kill, argued Hina Shamsi, head of the American Civil Liberties Unions national security project. The Trump rules served as open-ended authorization for the United States to kill virtually anyone it designates as a terrorist threat, anywhere in the world, without reference to the laws prohibiting extrajudicial killing under human rights law. The Trump rules may seem more extreme but in core ways they merely continue an unlawful U.S. extrajudicial killing program.

While using the military to continue pummeling Afghanistan, Iraq, and Syria, Trump expanded the U.S. drone war ratcheted up by Obama in Somalia. By the end of Trumps presidency, the civilian death toll from U.S. drone strikes, mostly during Obama and Trump years, was astonishing. A report from U.K.-based watchdog group Airwars found that at least 22,679, and potentially as many as 48,308 civilians, have been likely killed by US strikes since 9/11.

Yemen policy under Trump was in step with decades of U.S. support for the brutal dictatorship of Saudi Arabia, and he did his absolute best to top the Bush family in cozying up to the royals. Once Trump took power, a narrative emerged that pretended it was Trump, not Obama, who started the U.S.-fueled horror show in Yemen. While he certainly escalated U.S. support for Saudi Arabias murderous campaign, it was the Obama administration that began a secret and sustained U.S. bombing campaign in Yemen in 2009 and gave the Saudis the official green light for aerial bombardment of Yemen in 2015 with the aid of U.S. weapons. In September 2016, at the end of his presidency, Obama approved a $115 billion arms sale to the Saudis, which at the time was the most of any U.S. administration in the 71-year U.S.-Saudi alliance. Under pressure from human rights activists and some members of Congress, Obama excluded the sale of certain precision-guided munitions, citing the worsening situation in Yemen. Trump reversed Obamas exclusion and included the weapons as part of his own tremendous arms deal with the Saudis announced in May 2017. Absent the brutal murder of journalist Jamal Khashoggi by Saudi agents in Turkey in 2018, it is not certain that the effort to confront U.S. support for Saudi Arabias genocidal war in Yemen would have gained its unprecedented momentum. Trumps grotesque embrace of the Saudi dictatorship, particularly his defense of Crown Prince Mohammed bin Salman after the murder, was also a decisive factor in gaining some Republican support for cutting off weapons shipments. Trump vetoed the legislation.

Trumps appointment of neoconservatives to his war cabinet, chief among them John Bolton and Mike Pompeo, at times resulted in a strange mixture of Cheney-style policymaking that undermined Trumps more dominant rhetorical projection of a right-wing libertarian foreign policy outlook. Among Trumps most dangerous military acts as president was the assassination of Iranian Maj. Gen. Qassim Suleimani in Baghdad. That strike risked starting a full-blown war with Iran. While many Democrats expressed strong opposition to the strike, there is and has long been a powerful chorus of voices within the party that actually believes more military confrontation of Iran is warranted, so it is hardly a given that Democrats would have stopped Trump from moving forward. Some top Democrats, while criticizing Trump for keeping the operation secret from congressional leaders and offering other procedural objections, celebrated the assassination. Then-Senate Minority Leader Chuck Schumer, D-N.Y.,said Suleimani was a notorious terrorist and that no one should shed a tear over his death.

For four years, the most prominent figures in the Democratic Party, along with most of its congressional foot soldiers, told us that Trump was a Russian stooge and the most dangerous president in history all while simultaneously lavishing his administration with sweeping surveillance powers and record-shattering military budgets. In 2019, months before the Suleimani strike, Rep.Ro Khanna, a Democrat from California, offered an amendment to the National Defense Authorization Act that would have prohibited such actions, but it was removed from the final bill. Any member who voted for the NDAA a blank check cant now express dismay that Trump may have launched another war in the Middle East, Khanna wrote on Twitter after Suleimanis assassination. My Amendment, which was stripped, would have cut off $$ for any offensive attack against Iran including against officials like Soleimani.

The NDAA passed with overwhelming Democratic support. We saw the same pattern when Democrats sided with their Republican colleagues in extending the Foreign Intelligence Surveillance Act, one of the key state organs of domestic spy operations. In 2020, at the peak of Trumps insanity, 10 Democrats blocked an effort by Sen.Ron Wyden, D-Ore., to stop the FBIs warrantless surveillance of web browser history. Some leading Democrats joined with neoconservative Republicans in the waning days of Trumps presidency in an effort to impede him from ending the war in Afghanistan.

It would be a mistake to view these congressional actions as hypocrisy. They should be seen, rather, as key indicators of the core agenda of the Democratic Party leadership on matters of militarism and national security. Even with a president in power whom its members constantly portrayed as an unstable authoritarian, the Democratic Party refused to close the spigot on the commander in chiefs vast powers.

President Joe Biden addresses the 76th Session of the U.N. General Assembly at the U.N. headquarters in New York City on Sept. 21, 2021.

Photo: Eduardo Munoz/Getty Images

On war policy, Joe Biden was never the grandfatherly career politician who would heal the nation after Trump and move us to a new era of peace. For the national security establishment in D.C., Biden represented the only viable candidate to stop Bernie Sanders in the primary and to bring decorum back to imperialism by unseating Trump. Unlike Trump, Biden is a lifelong creature of Washington and one of the most consequential politicians in the shaping of modern U.S. foreign and national security policy. Biden was an essential player in the premiere foreign policy debacle of modern U.S. history: the invasion of Iraq. He was a strong supporter of the invasion of Afghanistan, claimed credit for authoring large parts of the Patriot Act, and was one of the most passionate defenders of Israeli aggression and war crimes in Congress. As Obamas vice president, he helped shape the U.S. military posture as a global, high-tech octopus whose tentacles can strike anywhere at any time in the name of national security.

In September, Biden delivered his first address as president before the United Nations General Assembly. I stand here today, for the first time in 20 years, with the United States not at war, Biden said. Weve turned the page. It was an astonishing, brazen statement. While Biden did withdraw from Afghanistan, he has made clear that the U.S. will continue to use drone strikes and other methods to wage war in the country. By the time he appeared on the dais at U.N. headquarters, Biden had already authorized bombings in Syria and Iraq and drone strikes in Somalia and Afghanistan. Embedded within Bidens false turned the page claim was a recurring theme of American Exceptionalism: the U.S. governments characterizations of its own actions need not be based in reality or supported by facts.

Biden deserves credit for moving forward, in the face of some powerful opposition, with the withdrawal from Afghanistan. But the plan he implemented was primarily developed by the Trump administration. Biden has indicated that he would have approached the withdrawal differently, but ultimately justified proceeding under the terms of the Doha agreement with the Taliban by stating that the U.S. needed to respect its international agreements. It is perhaps not what I would have negotiated myself, but it was an agreement made by the United States government, and that means something, Biden said in April when he announced the withdrawal.

Biden was in a tough spot. If he did not move forward at that moment, the U.S. presence would likely have dragged on indefinitely, despite his pledges. Instead, he knowingly subjected himself to cheap shots, mostly from Republican political figures and the conservative media who seized on the chaos to blame him for implementing Trumps policy. More significantly, Biden forcefully rejected pressure from military brass, two prominent former secretaries of state, and some lawmakers within his own party. There are legitimate questions that demand answers about the bloodshed that accompanied the withdrawal, and the Biden administration must answer for these. But the deadly attack on the Kabul airport at the onset of the withdrawal and the heartbreaking scenes of Afghans desperately trying to escape against the backdrop of the Taliban waltzing back to power will be far more seriously scrutinized in the months ahead on Capitol Hill than the much-needed reckoning with the 20-year catastrophe of U.S. policy in Afghanistan.

It is not difficult to imagine a plausible alternative scenario in which Biden kept small teams of CIA and JSOC operators inside Afghanistan for years to come, as he proposed in 2009 when he was vice president and argued against the surge. The option to keep a few thousand troops was being pushed by military officials as well as some influential Democratic senators. That could have laid the groundwork for episodic surges of conventional forces, as happened after Obama withdrew from Iraq. Biden clearly did not want to face the prospect of taking ownership of an utterly failed 20-year-old war that was always going to end with the Taliban in power. While he deserves credit for staying the course on withdrawal, it was Trump who put that policy into motion.

Despite the withdrawal, the Biden administration has already shown that it will continue to use drones and covert strike teams to hit targets in nations where the U.S. lacks ground capabilities. These assassinations are now being officially rebranded as over-the-horizon operations, the chosen messaging for a long-standing policy of conducting drone strikes in countries with which the U.S. is not officially at war.

Relatives and neighbors of the Ahmadi family gathered around the incinerated husk of their car, which was targeted and hit by an American drone strike in Kabul, Afghanistan, on Aug. 30, 2021.

Photo: Marcus Yam/Los Angeles Times via Getty Images

When Biden was sworn into office, his administration said it was undertaking a comprehensive review of the targeted killing process and reviewing the changes made by Trump to determine its own policy. Biden did not authorize any known drone strikes during his first six months in office. In March, the New York Times reported that the administration had quietly imposed some limits on drone strikes, rolling back Trumps delegation of authority to strike. The order was issued bynational security adviserJake Sullivan on the day of Bidens inauguration. The military and the C.I.A. must now obtain White House permission to attack terrorism suspects in poorly governed places where there are scant American ground troops, like Somalia and Yemen, said the Times. Bidens no-drone-strike streak was broken in late July when the military conducted a strike in Somalia, claiming it was a defensive measure. That was followed by two more strikes. Biden has also authorized drone strikes in Syria.

But it was an August 29 drone strike during the withdrawal from Afghanistan that provided the most harrowing flashback to the Obama era. The Pentagon claimed the target was a car driven by Islamic State members transporting explosives to be used in another attack on the Kabul airport. Two days after the strike, Biden held up the operation as proof of the concept that the U.S. would continue to hammer the nails of terrorism remotely. We have whats called over-the-horizon capabilities, which means we can strike terrorists and targets without American boots on the ground, Biden said. With flashes of Bush-like bravado, Biden boasted: Weve shown that capacity just in the last week. We struck ISIS-K remotely, days after they murdered 13 of our servicemembers and dozens of innocent Afghans. And to ISIS-K: We are not done with you yet.

But the victims were not ISIS members. They were civilians.

The strike had actually wiped out a family, seven of them children. The driver of the car, Zemari Ahmadi, was a longtime employee of a U.S. aid organization. Almost everything senior defense officials asserted in the hours, and then days, and then weeks after the Aug.29 drone strike turned out to be false, reportedthe New York Times, whose investigation exposed the stream of lies and misinformation offered by U.S. officials. Despite the fact that at least one child could clearly be seen in footage filmed as part of the eight-hour surveillance operation before the strike, a Pentagon internal inquiry cleared all U.S. personnel of any wrongdoing. The general in charge of the review said the operatives who carried out the strike had a genuine belief that there was an imminent threat to U.S. forces.

The bipartisan self-exoneration machine for U.S. crimes abroad has long been a centerpiece of the imperial stance and complements the broad consensus in Washington, D.C., on a range of national security issues. Biden pledged early on in his administration that he was ending all American support for offensive operations in the war in Yemen. In reality, the U.S. has continued to support the Saudi scorched earth campaign by pretending it is defensive when it is clearly not and continues to allow U.S. naval operations in support of the catastrophic Saudi blockade. Saudi Arabias aim is to starve Yemen into a state of subjugation. While the supposed target is the pro-Iranian Houthi movement that seized power in Sanaa in 2015, the lethal suffering is being meted out against ordinary Yemenis of various political and tribal affiliations. In August, UNICEFassessed that the situation is worsening on all levels, especially for children, with five million Yemenis one step away from succumbing to famine and the diseases that go with it, and 10 million more are right behind them.

Far from treating Crown Prince Mohammed bin Salman and the Saudi regime as pariahs, as Biden promised on the campaign trail, his administration has continued to support the kingdoms genocidal war in Yemen and to maintain an intimate military and diplomatic relationship with Riyadh. This is not to say that there are no differences between Biden and Trump on the U.S. approach to Saudi Arabia. Trump broke with U.S. tradition and chose Riyadh as his first foreign destination as president. During the trip, Trump announced a significant expansion of U.S. support for the Saudis in the form of what he claimed was a 10-year, $350 billion arms deal and participated in a bizarre gathering with King Salman and other despots laying hands on a glowing orb. By contrast, Biden has refused to meet with the crown prince, the de facto Saudi ruler, and, as The Intercept recently reported, the Saudis have retaliated against what they consider to be Bidens degradation of their status by intentionally driving up oil prices.

Rather than cutting off the Saudis, the Biden policy is to evaluate, on a case-by-case basis, proposed weapons sales and transfers based on two criteria: our interests and our values.

Despite U.S. intelligence concluding that the crown prince ordered Khashoggis execution in Turkey, Biden has refused to impose sanctions or deliver any meaningful U.S. response to the murder. We have talked about this, in terms of our partnership with Saudi Arabia, as a recalibration. Its not a rupture, said State Department spokesperson Ned Price when asked about Bidens retreat from his make them in fact the pariah that they are campaign pledge. I would contextualize that by making the point that it is undeniable that Saudi Arabia is a hugely influential country in the Arab world and beyond. Price made clear we stand with Saudi Arabia in its efforts to defend itself, including with U.S. weaponry and intelligence. Rather than cutting off the Saudis, Price said, the Biden policy is to evaluate, on a case-by-case basis, proposed weapons sales and transfers based on two criteria: our interests and our values. In September, the Biden administration approved a $500 million allocation to support a range of Saudi attack helicopters and in early November sent Congress notification of its first proposed weapons sale to the kingdom: some $650 million in missile systems. The State Department claims that the weapon deals will support U.S. foreign policy and national security of the United States by helping to improve the security of a friendly country that continues to be an important force for political and economic progress in the Middle East. Bidens tough talk, it seems, was substantively a stream of opportunistic election-year hot air.

We should never be selling human rights abusers weapons, but we certainly should not be doing so in the midst of a humanitarian crisis they are responsible for,said Rep. Ilhan Omar, a Democrat from Minnesota.Omar has been steadfast in opposing the arms sales to Saudi Arabia, and on November 12 she introduced a joint resolution to block it.Congress has the authority to stop these sales, and we must exercise that power. Republican Sen. Rand Paul of Kentucky, a tenacious opponent of U.S. support for Saudi Arabia, is spearheading a related effortwith Bernie Sandersin the Senate to ban the sales.

Less than a year into its tenure, the Biden administration has approveda range ofweapons sales to nearly two dozen countries, including a host of nations with atrocious human rights records. Despite Bidens campaign pledge that there would be no more blank checks for the Egyptian dictator Abdel Fattah el-Sisi, a man Trump lovingly referred to as his favorite dictator, the administration has already approved more than $1 billion in security assistance to Egypt, withholding only a symbolic portion of the aid in response to widespread human rights abuses. Biden has moved forward with Trumps $23 billion weapons deal for the United Arab Emirates, including armed drones and F-35 attack planes. The highly touted Abraham Accords that supposedly broke a decades-long bottleneck in Arab-Israeli peacemaking have turned into an arms bonanza, observedMohamad Bazzi,director of the Hagop Kevorkian Center for Near Eastern Studies at New York University. Biden, he charged, is turning the normalization agreements between Israel and Arab countries into an arms race that could fuel new conflicts in the Middle East. In June, the White House notified Congress of its intent to sell some $2.5 billion in fighter jets, missiles, and other weapons to the Philippines, which is ruled by the despotic leader Rodrigo Duterte who has boasted, I dont care about human rights.

While it has almost entirely disappeared from the discourse, the U.S. still has some 2,500 publicly acknowledged troops on the ground in Iraq under the auspices of containing ISIS and supporting Iraqi forces. Biden has stated that by the end of 2021 these troops will no longer be part of a combat mission. Instead, they are being reclassified as advisers to Iraqi troops and serve as quick response forces to take action against remaining ISIS fighters. Most of those soldiers are projected to remain in Iraq indefinitely, as will the 900 U.S. troops on the ground in northeast Syria. Lingering over these ongoing troop deployments is the unresolved question of Bidens approach to Iran, which is geographically situated near a series of U.S. military disasters, including Afghanistan, Iraq, Yemen, and Syria. Tehran is also facing yet another Israeli administration that wants to escalate the conflict between the two countries and is publicly lobbying Biden to act more aggressively.

Throughout the 2020 campaign, Biden touted his role, as vice president, in securing the Iran nuclear deal and vowed to reverse Trumps abandonment of it. Two of Bidens top national security officials, Jake Sullivan and Secretary of State Anthony Blinken, spearheaded the Obama administrations Iran negotiations. But nearly a year into the new presidency, there has been little momentum. After four years of Trumps open hostilities, threats, expanded sanctions, and the assassination of Suleimani, Iran has erected even greater barriers to negotiations with the U.S. While the Iranian people continue to suffer from U.S. sanctions, Tehran has steadily engaged in a realignment, and the so-called hard-liners who opposed a deal with the West have been emboldened by the failures of the short-lived agreement with the Obama administration. For his part, Biden has not made resuming talks a major priority or shown a willingness to make concessions.

President Joe Biden meets with Israeli Prime Minister Naftali Bennett in the Oval Office at the White House in Washington, D.C., on Aug. 27, 2021.

Photo: Sarahbeth Maney/Getty Images

Sitting alongside newly elected Israeli Prime Minister Naftali Bennett at the White House in late August, Biden said, If diplomacy fails with Iran, were ready to turn to other options. As an indication of how the U.S. embrace of drone warfare has spread globally, the Biden administration has accused Iran of sponsoring a series of drone strikes against a U.S. outpost in Syria in October. With regards to the issue of how were going to respond to their actions against interest of the U.S., whether they are drone strikes or anything else, is were going to respond, Biden said at a press conference at the end of the G20 summit in Rome. We will continue to respond.On November 10, the U.S. Navys Fifth Fleet began a series of jointmilitary exercises with Israel, the UAE, and Bahrain in the Red Sea. The exercises were the first-ever confirmed among these nations and grew out ofthe Trump administrations so-called Abraham Accords. It is exciting to see US forces training with regional partners to enhance our collective maritime security capabilities, said the commander of U.S. Naval Forces Central Command.

Alongside this rhetoric, the White House also appears to be intensifying its behind-the-scenes efforts to target Iran economically. The Biden administration, according to a report from Reuters, has begun encouraging China to cut off Iranian oil imports, a move that could indicate the White House is contemplating a greater expansion of sanctions and other methods of economic warfare. During his first speech to the U.N. General Assembly in September, Irans newly elected leader Ebrahim Raisi struck a pessimistic note about prospects for a substantive shift in policy from Trump to Biden. The world doesnt care about America First or America is Back, he said. Economic sanctions are the U.S.s new way of war with the nations of the world, he said. Sanctions, especially sanctions on medicine at the time of the Covid-19 pandemic, are crimes against humanity. He added, We dont trust the promises made by the U.S. government.

Those sentiments seem to be underscored by a significant number of Iranians, according to an October poll by the University of Maryland. The poll found that a large majority of respondents did not believe the U.S. would abide by the nuclear deal if the U.S. reentered and that Iranians had only a marginally more favorable view of Biden than Trump. With regular skirmishesbetween U.S. and Iranian ships in international waters and U.S. accusations that Iran is facilitating drone strikes and other attacks on U.S. forces in Syria, there will be consistent pressure on Biden to escalate the situation. This scenario could also benefit hard-line factions in Iran who oppose reengagement with the U.S. and its allies. In early November, Irans foreign ministry laid out its conditions for returning to the nuclear deal. Among its demands was the lifting of all economic sanctions imposed after Trump abandoned the agreement, that the U.S. admit its responsibility for destroying it, and that Biden pledge that the U.S. will not renege on its commitments again.

The Israeli Iron Dome missile defense system intercepts Hamas rockets in the sky above the Gaza Strip on May 16, 2021.

Photo: Anas Baba/AFP via Getty Images

While there is much media focus these days on the intensely polarized dynamic on Capitol Hill between Democrats and Republicans, as well as domestic legislative battles among Democrats, none of this has stopped the work of the empire from moving forward.Legislation aimed at increasing funding for social programs, education, and other public goods is consistently held hostage by politicians harping over the costs. This has been the case with Bidens Build Back Better legislation, which has seen some conservative Democrats join their Republican colleagues in gutting social spending in the name of fiscal responsibility. The original BBB 10-year projection was $3.5 trillion and has been steadily chiseled down to half that size to appease critics.Juxtapose this with the bipartisan defense spending spree that has theU.S. on course to produce a Pentagon budget of more than $7 trillion over the next decade, and the priorities of this governments political class come into sharp focus.

The Biden administrations staunch defense of Israels war of annihilation against the Palestinians and its collective punishment of the citizens of Gaza through a sustained bombing campaign last spring is now a footnote. Bidens unwavering support for his great, great friend Benjamin Netanyahu during the Ramadan siege of Gaza, as well as his embrace of Trumps shambolic Abraham Accords, indicates how little substantive distance there is between the previous administration and Biden on some core international priorities. From Trump to Biden, U.S. policy has been consistent, with large bipartisan majorities in Congress continuing the upward trajectory of U.S. military aid and weapons sales to Israel.

In September, after Biden asked for the increased funding to replenish the rockets used by Israel during its siege of Gaza earlier in the year, the House authorized a whopping $1 billion for Israels Iron Dome system in a blowout 420-9 vote. Thank you to the members of the U.S. House of Representatives, Democrats and Republicans alike, for the sweeping support for Israel and commitment to its security, saidBennett, the Israeli prime minister, taking a swipe at the tiny group of eight Democrats and one Republican who voted against it. Those who try to challenge this support received a timeless answer. That money is in addition to the $500 million the U.S. gives to Israel for missile defense every year as part of a nearly $4 billion annual package. The funding being appropriated today simply continues and strengthens this support, said Pelosi. Passage of this bill reflects the great unity, in Congress on a bipartisan and bicameral basis, for Israel. Security assistance to Israel is vital, because Israel security is an imperative for Americas security.

The same month, a large bipartisan majority in the House of Representatives passed a massive $768 billion defense spending bill, allocating some $25 billion more than the Biden administration requested. Efforts by some progressive Democrats to thwart the unrequested increase were defeated when more than a dozen Democrats joined the Republicans to block their amendments. We have produced a product that everybody in this House can be proud of, said Democratic Rep.Adam Smith, chair of the Armed Services Committee. The ranking Republican on that committee, Republican Mike Rogers, told Politico that the bill is laser-focused on preparing our military to prevail in a conflict with China.

Soldiers hold machine guns and grenade launchers in position as part of a military exercise simulating the defense against the intrusion of Chinese military, amid rising tensions between Taipei and Beijing, in Tainan, Taiwan, on Nov. 11, 2021.

Photo: Ceng Shou Yi/NurPhoto via Getty Images

Perhaps the most enduring foreign policy moves to come in the Biden administration will center around the U.S. posture toward Beijing. Successive U.S. administrations have gradually shifted toward a more adversarial China stance. At the same time, China has steadily spread its sphere of soft power influence globally and, along with Russia, has reasserted itself as an alternative to the U.S. as a prime business and diplomatic partner. On Capitol Hill, a sort of bloodlust has been brewing over China, with Democratic and Republican lawmakers pushing for more aggressive U.S. policy, particularly to confront Chinas actions in self-governed Taiwan. Under the Trump administration, the U.S. was moving toward a strategy that would enable Taiwan to develop an effective asymmetric defense strategy and capabilities that will help ensure its security, freedom from coercion, resilience and ability to engage China on its own terms, according to a declassified strategy document that also called for an enhanced combat-credible U.S. military presence and posture in the Indo-Pacific region to uphold U.S. interests and security commitments. The objective is to defeat Chinese actions across the spectrum of conflict.

At a CNN town hall on October 22, Biden was asked whether the U.S. could keep up with China militarily and whether it would defend Taiwan. Yes and yes, Biden replied. Militarily, China, Russia, and the rest of the world knows we have the most powerful military in the history of the world. Dont worry about whether were going to theyre going to be more powerful. What you do have to worry about is whether or not theyre going to engage in activities that will put them in a position where there they may make a serious mistake. Asked directly if the U.S. would come to Taiwans aid if China attacked it, Biden said, Yes, we have a commitment to do that. At least one Democratic lawmaker has floated the idea of preemptively giving Biden war powers against China in the form of a very narrow and specific contingent authorization for the use of military force to prevent China from invading Taiwan, or deter them. Rep. Elaine Luria, the vice chair of the House Armed Services Committee and a retired Navy officer, told Politico the aim would be to remove strategic ambiguity and the need to wait for congressional debate.

Secretary of State Anthony Blinken has staked out a hard-line position on Taiwan, calling for a return to Taiwans independent participation at the U.N., which has not happened since 1971. Beijings Foreign Ministry spokesperson strongly rebuked this move, sayingBlinkens statement seriously violates the one-China principle and the stipulations of the three China-US joint communiqus, violates the promise it has made, violates the basic norms governing international relations, and has sent a seriously wrong signals to the Taiwan independence forces.

Under Bush, Obama, and Trump, the U.S. has increased arms sales to Taiwan, and the islands president recently confirmed in an interview with CNN the presence there of U.S. soldiers. It was the first official confirmation of the U.S. military deployment by a Taiwanese president in decades. It has been an open secret for some time that U.S. special operations forces are operating in Taiwan, and the Pentagon actually posted a since-deleted video in 2020 showing its special forces engaged in a joint training exercise,called Balance Tamper, with Taiwanese troops. In August, the Biden administration proposed its first $750 million arms sale to Taiwan following Trumps approval of more than $20 billion dollars in sales of a range of tanks, MQ-9 Reaper drones, and other sophisticated attack aircraft, as well as cruise missiles. The Obama administration approved roughly $14 billion worth of sales. Beijing, which has intensified its military maneuvers around Taiwan, has expressed outrage at the acceleration of the weapons sales. Chinese President Xi Jinping recently warned that the Asia-Pacific region cannot and should not relapse into the confrontation and division of the cold war era.

Duringa virtual summit between Biden and Xi on November 15, bothleaders acknowledged the potential for grave dangers posed by an acrimonious relationship, and the White House sought to portray the meeting as Bidens effort to mold a competition-without-conflict doctrine on China. Still, Xi warned Biden that the U.S. was playing with fire with its stance on Taiwan and cautioned againstbuildingdivisions and alliances that wouldinevitably bring disaster to the world.

The fact remains that the U.S. is the largest arms dealer in the world.

While U.S. rhetoric about China has grownincrementally belligerent over the past decade, it is important to note that the U.S. spends more on defense than China, Russia, India, the U.K., Germany, France, Japan, South Korea, and Australia combined. U.S. politicians go to great lengths to emphasize the menacing nature of Russia and China on the international stage, but the fact remains that the U.S. is the largest arms dealer in the world. A recent report from the Stockholm International Peace Research Institute, which has documented international weapons sales and trafficking since 1950, found that since 2011, the U.S. has significantly increased its share of global arms sales, as have NATO members Germany and France. During the same period, Russian and Chinese weapons exports have decreased.

China is a robust military power within its sphere of influence and geographic control, but its ability to impose its will globally by force is anemic compared to the U.S., particularly when combined with the broader capabilities and spending power of the NATO alliance. [T]he view that China is the United States chief competitor and even adversary has become widespread and ingrained, and the similarities in the two administrations approaches far outweigh any differences, noted Richard Haass, president of the Council on Foreign Relations. U.S. policy toward China has hardly changed since Biden became president.

President Joe Biden and NATO Secretary General Jens Stoltenberg, right, talk at a 9/11 memorial after a summit at NATO headquarters in Brussels on June 14, 2021.

Photo: Brendan Smialowski/AFP via Getty Images

On Bidens first trip to Europe as president, to attend the June G7 summit and then meetings with NATO, he was welcomed as a hero. Trump had consistently ridiculed NATO and many European countries and repeatedly violated diplomatic norms, threatening to pull the U.S. out of the alliance and characterizing it as an unnecessary and irrelevant waste of U.S. resources. Such talk, contrasted with Trumps warm rhetoric about Russian leader Vladimir Putin, was a cause of constant concern among NATO nations. Trumps threats to withdraw had sent officials scrambling to prevent the annual gathering of NATO leaders in Brussels last July from turning into a disaster, reported the New York Times in 2019. The Times added that a NATO summit in Washington, D.C., to mark the alliances 70th anniversary was downgraded to a foreign ministers gathering, as some diplomats feared that Mr.Trump could use a Washington summit meeting to renew his attacks on the alliance. Foreign Policy described Bidens reception at the NATO gathering last June: A long-lost friend returned to the global stage, just as he promised his country would do. And who could ignore the expressions of relief even joy on the faces of global leaders. It was the return of the prodigal superpower.

At the NATO meetings, Biden and other leaders emphasized expanding the scope of what they consider to be the alliances role in protecting Western interests with a focus on the growing influence not only of Russia, but also of China, a nation far from the north Atlantic. NATO is critically important for U.S. interests in and of itself. If there werent one, wed have to invent one, Biden said. It allows America to conduct its business around the world in a way that never would have occurred were it not for NATO. Jens Stoltenberg, NATOs secretary general, celebrated the return of Biden and spoke of the need to confront Beijing. China is rapidly expanding its nuclear arsenal with more warheads and a larger number of sophisticated delivery systems, he said. It is opaque in implementing its military modernization. It is cooperating militarily with Russia, including through exercises in the Euro-Atlantic area.

Biden welcomed the launch of the NATO 2030 agenda, which lays the groundwork for an increasingly confrontational disposition toward both Russia and China. The last time NATO put together a strategic plan was back in 2010, when Russia was considered a partner and China wasnt even mentioned, Biden observed. That era, he noted, was over. We talked about the long-term systemic challenges that Chinas activities pose to our collective security today. A NATO fact sheet on the 2030 agenda states: The rules-based international order, which underpins the security, freedom and prosperity of Allies, is under pressure from authoritarian countries, like Russia and China, that do not share our values. This has implications for our security, values, and democratic way of life.

U.S. policy has, for years, steadily pushed China and Russia into even tighter partnership. The escalation of rhetoric from NATO, particularly about China, is likely to further embolden leaders in both Beijing and Moscow. This dynamic in turn strengthens the position of neo-Cold Warriors in Congress and the U.S. national security bureaucracy who have agitated for a more hostile U.S. and NATO posture.

Biden has long been a staunch supporter of NATO expansion and was instrumental in several NATO military actions in the 1990s, including the 1999 bombing of Serbia and Montenegro. In that case, Biden was a chief architect of President Bill Clintons 78-day bombing campaign, which was waged in defiance of congressional opposition. But after the 9/11 attacks, Biden praised the Bush administration for its overtures to Putin. In remarks delivered at a Foreign Relations Committee hearing in 2002, Biden emphasized the centrality of NATO expansion to U.S. interests and expressed optimism that the U.S. could work with Putin. Im pleased that President Bush is carrying on an important work begun by the last administration of bringing new members into NATO and reaching out to Russia. 9/11 has created historic opportunities to continue to process a reconciliation with Russia, Biden said, describing Putin as a Western-friendly Russian leader of a type not seen since Peter the Great.

Bidens rosy assessment of Putin would soon fade away as the mirage of post-9/11 camaraderie disappeared, and Biden and Putin found themselves at sharp odds over NATO expansion. NATOs aggressive push eastward since the fall of the Berlin Wall and the collapse of the Soviet Union has been a constant point of concern and anger in Russia, and Putin in particular has made challenging that expansion a priority. Biden claims that as vice president in 2011 he told Putin directly, Im looking into your eyes, and I dont think you have a soul. Putin, he said, looked back at me, and he smiled, and he said, We understand one another.

The elite foreign policy consensus on Putin often reduces Moscows actions to cartoonish villainy.

The elite foreign policy consensus on Putin often reduces Moscows actions to cartoonish villainy. This perspective, which was also shared by a powerful faction of Russia hawks within the Trump administration, encourages a view that the U.S. with its foreign military bases and multiple simultaneous wars has the moral standing and credibility to judge and police Russias actions. Russia is, without question, a violent actor that has repeatedly shown little hesitation to use force both internally and externally. But refusing to consider the security and sovereignty concerns that fuel some of Moscows actions bolsters an ahistorical narrative.

During the Obama presidency, the deteriorating relations culminated in an incendiary situation when a pro-Western government seized power in Ukraine in 2014, following sustained anti-government protests backed by the U.S. and European Union nations. The Russian government accused the U.S. and NATO of fomenting an anti-constitutional armed coup that brought down the pro-Russian President Viktor Yanukovych. A civil war erupted. On one side were supporters of the new government, including not just military and police forces but also neo-Nazi paramilitaries; on the other were pro-Russian militia backed by Moscow. In response, Putin deployed Russian troops to annex the Crimean Peninsula, which the U.S., NATO, and Ukraine all maintain is Ukrainian territory. At the time, Biden was the Obama administrations point man on Ukraine and an aggressive proponent of moving Ukraine toward NATO membership.

In 2015, Noam Chomsky who would go on to win the praise of mainstream liberals for his criticisms of Trump and support for Biden argued that it was a mistake to ignore Russias overarching concerns about the U.S. and NATO roles in Ukraine. Whatever you think about Putin think hes the worst monster since Hitler they still have a case, and its a case that no Russian leader is going to back down from, Chomsky said on Democracy Now! in 2015, noting that the new Ukrainian government passed a resolution to move forward with NATO membership. Russia is surrounded by U.S. offensive weapons sometimes theyre called defense, but theyre all offensive weapons. No Russian leader, no matter who it is, could tolerate Ukraine, right at the geostrategic center of Russian concerns, joining a hostile military alliance.

Since then, Moscow has periodically deployed forces in large numbers to border areas of Ukraine, sparking saber-rattling from the U.S. This dynamic has made the former Soviet republic an increasingly important front line in NATOs fight to push east and Putins campaign to reverse it. The U.S. has steadily ramped up its support, both overt and covert, for anti-Russian forces in Ukraine. The Kremlin has simultaneously supported armed, pro-Russian separatist militias, particularly in the east of the country, where thousands have died in a bloody civil war raging over the past seven years.Since 2015, the U.S. has had troops in western Ukraine on what is officially a training mission, and, under Biden, the U.S. and NATO have increased naval activities in the Black Sea region. Moscow has accused the administration of seeking to provoke Russia through such aggressive U.S. military action. In October, after NATO expelledeight Russian diplomats from Brussels and accused them of beingundeclared intelligence agents,the Kremlinannounced it was ending its diplomatic engagement with NATO andshutting down the alliances diplomatic mission in Moscow.

Ukraine is set to receive nearly half a billion dollars in security assistance, with Biden continuing the Trump administrations transfer of lethal weapons and military training. In November, Ukraines embassy in Washington, D.C., posted a tweet, boasting that it had received the delivery of approx 80,000 kilos of ammunition from the U.S., stating that it was part of the increased security assistance directed by President Biden asa demonstration ofcommitment to the success of a stable, democratic, & free Ukraine. The November 14 tweet contained images of what appeared to be the offloading of munitions at an airstrip. The situation has steadily deterioratedduring the first year of Bidens presidency and, with Moscow and the U.S. and NATO all intensifying their activities around Ukraine, some analysts of the region have warnedthat the developments could once again lead to overt conflict.There are very, very dark clouds on the horizon,Michael Kofman, director of the Russia studies program at the Center for Naval Analyses, toldU.S. military publication Stars and Stripes. Russia, he said, has full control over how they deliver gas supplies to Europe, adding, Winter is perfect time for a military operation.

Biden has maintained the Trump administrations opposition to the Nord Stream 2 pipeline under the Baltic to Germany, which could double Russian gas exports to Europe and cut off a source of income to Ukraine. In mid-November, German energy regulators, citing laws governing the operation of subsidiaries, temporarily suspended certification of the project amid pressure from Washington,some EU states,and Ukraine. Kyiv has accused Russia ofblackmailing Europe by inflating gas pricesand argued that if Moscow is allowed to circumvent Ukraine, it wouldemboldenPutin to consider a full invasion.

As vice president, Biden was a central player in bolstering Ukraines military and intelligence capabilities while simultaneously working to impose and expand sanctions on Russia over its Ukraine policies. (That role came under intense scrutiny as the scandals that led to Trumps first impeachment unfolded.) The United States does not and will never recognize Russias purported annexation of the [Crimean] peninsula, and we will stand with Ukraine against Russias aggressive acts, Biden said a month into his presidency. We will continue to work to hold Russia accountable for its abuses and aggression in Ukraine.

Despite Trumps subservient rhetoric toward Putin, on a policy level there is more continuity than difference between the two administrations. The Trump administration was an aggressive opponent of many of Russias international actions, expelling Russian diplomats and imposing an array of sanctions against government officials and private citizens. Russia hawks within the Trump administration fought to increase funding to the European Defense Initiative by more than 40 percent from Obama-era levels and opened the official flow of lethal aid to Ukraine, a move Obama had publicly resisted. Daniel Vajdich, a senior fellow at the pro-NATO Atlantic Council, argued, When you actually look at the substance of what [the Trump] administration has done, not the rhetoric but the substance, this administration has been much tougher on Russia than any in the post-Cold War era.

Those sentiments were echoed by Richard Haass, the Council on Foreign Relations president. [W]hatever Trumps personal regard for Putin, the Trump administrations posture toward Russia was in fact fairly tough. It introduced new sanctions, closed Russian consulates in the United States, and enhanced and expanded U.S. military support to Ukraine all of which has continued under Biden, Haass wrote in a blunt assessment of the foreign and national security policies of the Biden administration. Haass asserted that there is far more continuity between the foreign policy of the current president and that of the former president than is typically recognized.

President Donald Trump and First Lady Melania Trump watch a Navy Blue Angels and Air Force Thunderbirds fly over at Trumps Salute to America event on the South Lawn of the White House in Washington, D.C., on July 4, 2020.

Photo: Saul Loeb/AFP via Getty Images

The Trump era was, for many people, terrifying. And for understandable reasons. Yet it is important to strip away the veneer of Trumps insanity and audacity, without minimizing the actual dangers he posed, so that we can analyze his administrations policies and set them in a proper historical context. Doing so makes clear that U.S. commitments to militarism and permanent global war are enduring and bipartisan even when large swaths of the electorate and the political class despise a president and view him as corrupt, incompetent, and dangerous.

What does it say about a country that manages to stay the imperial course through such a diverse succession of leaders as George W. Bush (and Dick Cheney), Barack Obama, Donald Trump, and Joe Biden?

A nation that was willing to confront its bipartisan addiction to wars, militarism, and the national security state would have viewed Trump as an extroverted and blunt representation of the worst aspects of the U.S. role in the world. His time in office should have spurred deep reflection and a desire to change course. Instead, mainstream discourse has devolved into a stream of ahistorical drivel that treats Trump as a grand anomaly and pretends that the pre-Trump course was somehow just, moral, or smart.

The Biden presidency is a caretaker government, and its constituency is the War Party.

Biden has spent a half-century in public office in what has effectively been a career-spanning run for the presidency. In the end, his long-sought victory in 2020 was the product of the stubborn inevitability that has marked his political life and that of Americas enduring militarist juggernaut. It is fitting that Bidens rise to the nations highest office follows the historic election of a former reality television star. Bidens ascent embodies the essence of a decaying empire struggling to maintain its dominance by steering the ship of state back to familiar waters. But the Biden presidency is, perhaps more than any in recent history, a caretaker government, and on issues of counterterrorism, militarism, and national security, its constituency is the War Party. The bedrock principles of this bipartisan coalition revolve around a nonnegotiable set of understandings:

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From Bush to Obama, and Trump to Biden, U.S. Militarism Is the Great Unifier - The Intercept

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