Category Archives: Genome

COLUMBUS, Ohio HIV replication in the human body requires that specific viral RNAs be packaged into progeny virus particles. A new study has found how a small difference in the RNA sequence canallow the viral RNA to be packaged for replication, creating potential targets for future HIV treatments.

The study, published last week in the Proceedings of the National Academy of Sciences, found that HIV chooses its viral RNA genome the source code that it injects into healthy human cells to infect them based on functions attributable to just two nucleotides.

Its just this two-nucleotide difference that makes such a dramatic effect, said Karin Musier-Forsyth, senior author of the study, Ohio Eminent Scholar and a professor of chemistry and biochemistry at The Ohio State University. If we can prevent it from packaging its own genome, we can prevent it from spreading inside the body.

The studys authors, who also include researchers from the National Cancer Institute, hoped to answer a long-standing question in HIV biology research: How does the virus know to package its specific viral RNA to be copied in human cells?

Just like we need a genome encoded by DNA, viruses have their own genomic DNA or RNA in the case of HIV its RNA and they have to package their genomic RNA and thats what this whole study is about, she said. Its an essential step for how we understand the replication of the virus.

RNA is a string of nucleotides, and it is present in some form or another in all living things, including viruses. In HIV, it carries the genetic information that allows the virus to copy itself inside a host the human body. HIV RNA comprises about 9,800 nucleotides.

We have lots of types of RNA in our cells as humans, including messenger RNA (mRNA), which is very abundant and which everyone has heard about now, thanks to COVID-19, Musier-Forsyth said. But the viral genome from HIV is made in small amounts, and it is very selectively packaged as genomic RNA, in addition to serving as mRNA to make viral proteins. How does the virus find this genomic RNA to package and not just package any old RNA in our cells?

Researchers believed if they could find an answer to that question, they might eventually be able to develop drugs that could block the virus from replicating and stop it from infecting healthy human cells.

The researchers examined the structures of two nearly identical HIV RNA strings and found that the virus used a two-nucleotide difference on the very end of the RNA strings to distinguish between genomic RNA and viral mRNA. One, they found, was more efficient at being packaged as a genome than the other due to the conformations, or structures, that it formed.

The findings could have implications for future HIV treatments that target RNA and would be different from current HIV treatments, which primarily target viral proteins. New HIV drugs based on this discovery are likely years away, but Musier-Forsyth said this finding is an important scientific step.

Now that we understand more about the structure of the RNA, we could develop therapeutics, whether they be small molecules or other new nucleic acid therapeutics, that could lock the RNA into a conformation that wouldnt be packaged. If it cant package its genome then it cant replicate, Musier-Forsyth said.

Other Ohio State researchers who contributed to this study include Shuohui Liu and Jonathan P. Kitzrow. This work was supported by the National Institutes of Health.

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CONTACT: Karin Musier-Forsyth, musier-forsyth.1@osu.edu

Written by Laura Arenschield, arenschield.2@osu.edu

Proceedings of the National Academy of Sciences

Selective packaging of HIV-1 RNA genome is guided by the stability of 5 untranslated region polyA stem

14-Dec-2021

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.

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Study shows how HIV copies itself in the body - EurekAlert

Credit: Susanna Hamilton, Broad Communications

Researchers have boosted the efficiency of prime editing, a highly versatile CRISPR-based gene editing technology, and used the improved system to correct disease mutations in cells.

Scientists have developed a suite of molecular tools that increase the efficiency of a gene-editing technique called prime editing for a wide variety of cell types and target genes, expanding the scope of the technologys therapeutic and research applications. In two new studies, the researchers used the improved prime editing systems to correct mutations linked to various neurodegenerative, metabolic, and cardiovascular diseases.

First described in 2019, prime editing is a precise gene-editing method that has the potential to correct the vast majority of known disease-causing genetic variations. Researchers can use prime editing to make DNA substitutions, insertions, and deletions at targeted sites in human cells and animals. Editing efficiency, however, varies depending on the type of cell being edited and the target location in the genome.

To further develop the technology, scientists at the Broad Institute of MIT and Harvard engineered an improvement to a key component of the prime editing system called prime editing guide RNAs, or pegRNAs, which encode the intended edit and direct the prime editing machinery. In a study recently published in Nature Biotechnology, the researchers showed that pegRNAs can degrade in cells, resulting in truncated pegRNAs that interfere with prime editing. They developed new pegRNAs that are protected from degradation in cells, broadly increasing editing efficiency.

In a second study published recently in Cell, Broad researchers, collaborating with scientists at Princeton University and University of California, San Francisco (UCSF), identified cellular pathways that limit prime editing efficiency, and used these insights to develop next-generation prime editing systems.

The researchers on both studies demonstrated that the new systems could more efficiently edit mutations associated with Alzheimers disease, heart disease, sickle cell and prion diseases, type 2 diabetes, and other diseases, while producing fewer unwanted byproducts.

These improved prime editing efficiencies and product purities bring many edits from a regime in which they might be useful as research tools into a regime in which they may have potential as therapeutics, said David Liu, a senior author of both studies, Richard Merkin Professor and director of the Merkin Institute of Transformative Technologies in Healthcare at the Broad Institute, professor at Harvard University, and Howard Hughes Medical Institute investigator.

Credit: Broad Institute

Prime editing allows scientists to correct the vast majority of known disease-causing mutations including substitutions, insertions, or deletions of up to dozens of base pairs at specific sites in the genome. Unlike some other genome editing techniques, prime editing does not involve cutting both strands of DNA, and as a result reduces the chances of unwanted editing outcomes or undesired cellular responses. (See the infographic above for more on how prime editing works.) Hundreds of research groups are now using prime editing to study and correct mutations in a wide range of organisms including rice, wheat, zebrafish, and mice.

After first describing prime editing in 2019, Lius team continued to develop the technique. In the Nature Biotechnology study, they discovered a vulnerability in pegRNAs that decreased efficiency. They found that the long string of RNA at the end of the pegRNA that encodes the edit was susceptible to degradation by cellular enzymes. The degraded pegRNAs cannot mediate prime editing and also poison the prime editing system by blocking target sites from being accessed by intact pegRNAs.

The researchers next looked for protective structures that they could add to pegRNAs. They tested several different RNA sequences, identifying sequences that folded into knot-shaped structures that shield them from RNA-degrading enzymes. When they modified pegRNAs to include the knots and a connecting sequence, they observed a substantial increase in prime editing efficiency, indicating that the new structures preserved the RNA template for editing.

Using engineered pegRNAs, or epegRNAs, in a range of mammalian cell lines, the researchers saw that epegRNAs increased prime editing efficiency three- to four-fold on average, with greater improvements in cell lines in which prime editing had previously been more difficult.

In the Cell study, Lius team and their collaborators engineered the protein component of the prime editing system to further boost efficiency and minimize byproducts produced in a broad range of cell types, including cells from patients.

The researchers aimed to understand more comprehensively the cellular factors that determine prime editing outcomes so that they could design even more efficient systems. The team suspected that certain cellular proteins active during a key part of the prime editing process when the cell repairs DNA molecules created by prime editors could impede or even reverse editing and increase the production of unwanted byproducts. To test this hypothesis, the researchers collaborated with teams led by Britt Adamson, an assistant professor at Princeton University; and Jonathan Weissman, a professor at UCSF when the study began and now a professor at MIT, a member of the Whitehead Institute, and a Howard Hughes Medical Institute investigator. Using CRISPR interference-based screens, the teams systematically studied the effect of turning off each of 476 different DNA repair genes on prime editing.

Based on these results, the researchers focused on a process called mismatch repair, which occurs naturally in cells to correct DNA mismatches generated during DNA replication and repair. They found that mismatch repair interferes with prime editing, decreasing editing efficiency and increasing the fraction of unintended insertions or deletions.

Armed with this insight, the team developed new prime editing systems, which they called PE4 and PE5, that include a protein, MLH1dn, that the researchers engineered to temporarily inhibit one component of mismatch repair. In cells where mismatch repair occurs, the researchers found that PE4 and PE5 substantially increased editing efficiency and produced far fewer byproducts compared to the existing prime editing systems.

Finally, the scientists created PEmax, which optimized the architecture and amino acid sequence of the prime editing machinery. Combining improvements from the PE4 and PE5 systems, PEmax, and epegRNAs resulted in a 10- to 100-fold boost in editing efficiency compared to existing systems.

By combining the expertise of different research groups, we were able to figure out how prime editing works and optimize parts of the system, said Adamson. This study is a beautiful example of how fundamental understanding can drive experimental design.

Liu says that in many cases, the combined improvements of epegRNAs and PE4/5/max make it easier for scientists to create cell models of disease, a critical step toward developing therapeutics.

The team is now using these systems to treat cell and animal models of genetic disease, and will continue to probe the fundamental biology of these systems.

All of these innovations are synergistic, said Liu. With these improvements, weve been able to edit important cell types with an efficiency and cleanliness that may one day help patients who suffer from diseases with a genetic component. These findings also suggest that there are other strategies out there that can further improve prime editing.

References:

Enhanced prime editing systems by manipulating cellular determinants of editing outcomes by Peter J. Chen, Jeffrey A. Hussmann, Jun Yan, Friederike Knipping, Purnima Ravisankar, Pin-Fang Chen, Cidi Chen, James W. Nelson, Gregory A. Newby, Mustafa Sahin, Mark J. Osborn, Jonathan S. Weissman, Britt Adamson and David R. Liu, 14 October 2021, Cell.DOI: 10.1016/j.cell.2021.09.018

Engineered pegRNAs improve prime editing efficiency by James W. Nelson, Peyton B. Randolph, Simon P. Shen, Kelcee A. Everette, Peter J. Chen, Andrew V. Anzalone, Meirui An, Gregory A. Newby, Jonathan C. Chen, Alvin Hsu and David R. Liu, 4 October 2021, Nature Biotechnology.DOI: 10.1038/s41587-021-01039-7

This work was supported by the Merkin Institute of Transformative Technologies in Healthcare, the National Institutes of Health, the Howard Hughes Medical Institute, the Loulou Foundation, and the Bill & Melinda Gates Foundation.

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Next Generation Prime Gene Editing Systems Expands Technologys Therapeutic and Research Applications - SciTechDaily

Introduction

The Global Action Plan on Antimicrobial Resistance drafted by the World Health Organization1 states that there is a need to understand the impact of human activities on the environment, particularly the spread and transfer of antimicrobial resistance genes (ARGs) and strains. The isolation rates of antimicrobial-resistant bacteria (ARB) are lower in Japan than those in other countries, but are steadily increasing.2

In several countries, extended spectrum -lactamase (ESBL)-producing Escherichia coli or carbapenemase-producing organisms have been detected from water environments,3 wastewater treatment plants (WWTP), treated water,4,5 and hospital sewage,4,6 and Japan is no exception.7,8 In particular, hospital wastewater contaminated by ARB and residual antibiotics may generate selective pressure for the development of ARB,9,10 and is considered a hot spot for the growth and propagation of ARB.6

Similar to the general sewage system, hospital sewage is also discharged into a public WWTP and treated by filtering, microbiological treatment, and chlorination, after which the effluent is discharged into a nearby river. Although it is not yet clear whether the hospital wastewater-related ARB disseminate into the waterbodies, ARB is observed to exhibit deleterious effects on human health. In recent years, management strategies for ARB/ARGs and residual antibiotics discharged from hospitals have been studied in several countries.11,12

The aim of this study is to illustrate the contamination of hospital sewage with ARB harboring ARGs using comprehensive metagenomic sequencing.

In addition, this study was conducted in line with the relocation to a new hospital, and the formation of the bacterial flora in the new sewage tank was investigated. We also compared the whole genome sequence of extended spectrum -lactamase (ESBL)-producing organisms (EPOs) isolated from hospital sewage and clinical samples, and analyzed the relationship between clinical and sewage isolates.

The study was conducted at the Ohashi Medical Center in Toho University, located in Jonan area, Tokyo, Japan. The Ohashi Medical Center (35.652573N, 139.685833E), with a capacity of 430 beds, was opened in 1973 with a single East building (BE) and expanded to Central (BC), Administration (BA), and West (BW) buildings to increase patient capacity (Figure 1). Features of each building are as follows: there were intensive care wards in BW; the number of beds was the largest among the old hospital buildings in BC; BE included the highest number of outpatient departments; and many of the rooms in BA were available only for healthcare workers.

Figure 1 Outline of the Ohashi Medical Center, Toho University. Prior to relocation to the new building (BN), the hospital consisted of four buildings: West building (BW), Administration building (BA), Central building (BC), and East building (BE). Each building had respective sewage tanks: BW: STW, BA: STA, BC: STC, BE: STE, BN: STN.

As part of a renovation plan, a new hospital building (BN; 35.652578N, 139.683959E) with 319 beds was constructed approximately 50 m away from the old hospital and was inaugurated on June 20, 2018. Since May 2018, we introduced a policy of restricted hospitalization (Figure S1). We stopped providing services to outpatients from June 16 and transferred the 66 hospitalized patients to the BN on the same day (Figure S1). We started accepting patients on June 20. Both the old and new hospitals have a staff count of 2000. In BN, all outpatient departments and wards were integrated into one building (Figure 1).

In both old and new hospitals, stool and urine are stored in the underground sewage tanks without mixing with other drainage and are pumped to the sewage system several times a day (Figure 1). In the old hospital, each building had respective sewage tanks (sewage tank in BW: STW, in BA: STA, in BC: STC, and in BE: STE as shown in Figure 1); however, the new hospital had two connected storage tanks of 22.5 m3 collecting all the sewage (sewage tank in BN: STN shown in Figure 1). It was impossible to quantify daily inflow and outflow of sewage tanks as there is no system for regular measurement. The sewage discharged from the tanks is sent to the WWTP and treated using filtering, and microbiological and biochemical treatments, after which the effluent is discharged into the nearby river.

In the period between May 8 and June 12, 2018, sewage samples were collected from STW, STA, STC, and STE once a week. In the period from June 6 to July 17, 2018, sewage samples were collected from the STN once a week at 9 a.m. A 20 mL of sewage samples were collected in sterile bottles from manhole of the sewage tanks and processed for analysis within 2 h.

First, 5 mL of sewage was centrifuged at 5000 g for 5 min and the resultant cell pellet was vortexed with remaining 500 L of sewage water. Next, the cell suspension was mixed with 500 L of phenol/chloroform/isoamylalcohol (PCI) in a microcentrifuge tube with 2 mL of ZR BashingBead Lysis tube. Cell breaking was performed using GenoGrinder 2010 by shaking at 1500 rpm for 5 min. The PCI mixture was centrifuged at 8000 rpm for 5 min, followed by DNA purification using a Gel DNA Recovery Kit, Zymoclean-96 (ZYMO RESEARCH, Irvine, CA, USA). A metagenome DNA-seq library was prepared using the QIAseq FX DNA library prep kit (Qiagen, Venlo, Netherlands) and subsequently was performed using NextSeq 500 (Illumina) with the NextSeq 500 mid output kit v2.5 (300 cycles).

To obtain EPOs from hospital sewage, 2 L of sewage sample was mixed with 100 L phosphate-buffered saline (PBS), plated on CHROMagar ESBL (bioMrieux, Marcy-lEtoile, France) for selection of EPOs, and incubated at 36C overnight. Subsequently, first appearance of color formation on each colony suggested that dark pink and metallic blue colonies were in the ratio of 1:4, respectively. Eighty colonies (20 dark pink colonies: potential ESBL-producing E. coli; 60 metallic blue colonies: potential Klebsiella, Enterobacter, Citrobacter) were selected as potential EPOs to identify a unique isolate from the first selection on CHROMagar ESBL plate. Each isolate was used for genomic analysis as described above.

In addition, all bacteria colonies on a single agar plate were harvested and mixed with 1000 L of PBS. The cell suspension was used for metagenomic analysis as described above.

All 20 EPO clinical isolates obtained between May 8 and July 17, 2018, and reported as EPO were subjected to whole genome sequencing and comparative genomics. Among these isolates, 12 isolates were from outpatients and 11 isolates were from urology patients. They included urine, sputum, and central venous catheter samples (75%, 10%, and 10%, respectively). Some specimens were obtained from the same patient through subsequent diagnosis. The Ethics Committee of the Toho University Ohashi Medical Center waived the requirement for consent because the research was conducted without using identifiable biospecimens. Personal data related to clinical information were anonymized, and our procedure does not require a written consent from patients suffering from bacterial infections. Antimicrobial susceptibility was determined through screening (broth microdilution method) and confirmatory tests (the disk diffusion method) according to the Clinical and Laboratory Standards Institute (CLSI) recommendations (CLSI Performance Standards for antimicrobial disk susceptibility tests; Approved standard-13th edition CLSI document M02. Wayne, PA: Clinical and Laboratory Standards Institute; 2018).

The sequencing reads were analyzed using the MePIC2,13 Krona14 and MEGAN v6 software.15 EPO isolates were characterized using Krona,14 multi-locus sequence typing (MLST)16 and ResFinder.17

The sequenced reads were assigned to a taxonomic hierarchy using MEGAN v6 software based on a megaBLAST nucleic acid homology search.

Comparative genomics among obtained E. coli isolates (16 isolates from patients and 21 isolates from hospital sewage) were performed using BWA-MEM18 against the complete chromosome sequence of E. coli STN0717-11, which is the longest genome size among available complete genomes, followed by extraction of single nucleotide variants (SNVs) using VarScan v2.3.4.19 The prophage and repeat regions were predicted using PHASTER20 and MUMmer 3,21 respectively, and the detected SNVs in these regions were excluded. Regions of recombination in the chromosome were predicted using Gubbins v. 2.3.4,22 followed by masking of SNVs in the recombination regions. A maximum likelihood phylogenetic tree was constructed from SNV sites in the core genome region using FastTree2. De novo assembly was performed using SKESA v.2.3.023 with short reads of each strain, followed by analysis of sequence type, putative serotype, and AMR gene prediction using pubMLST (https://pubmlst.org/escherichia/), SeroTypeFinder,24 and Bacterial Antimicrobial Resistance Reference Gene Database (BioProject ID: PRJNA313047), respectively.

Thirty-nine drug components (Table 1) in the sewage samples were analyzed using solid-phase extraction (SPE) and ultra-performance liquid chromatographytandem mass spectrometry (LC-MS/MS) based on a previously described method25 with minor modifications. Briefly, the sample was filtered using a polyethersulfone membrane (0.22 m pore size, Merck) and 100 mL of the filtrate was spiked with 1 g/L ascorbic acid, 1 g/L EDTA, and a surrogate standard mixture, and then concentrated using SPE cartridge (Oasis HLB cartridges, 200 mg/6 cc, Waters, Japan). The analytes concentrated on the cartridge were extracted with 6 mL of methanol, following which they were measured using LC-MS/MS and quantified by the alternative surrogate method.25

Table 1 Concentrations of Chemical Compounds in the Hospital Sewage Tank

Metagenome DNA-seq analysis of sewage samples was conducted to elucidate the differential microbial flora in the hospital sewage tank. The dominant bacteria in the sewage were classified according to the metagenomic data (Supplemental Data Set S1), wherein the proportion of genera varied depending on the building (Figure S2a and S2b).

Similarity and diversity of bacterial population among tanks were analyzed using PCoA based on bacterial genus level (Figure 2). A total of 25 sewage samples from each tank excluding STA were used for PCoA, and the results showed that the STN and STW groups were closely plotted by the presence of Aeromonas, Citrobacter, and Comamonas.

Figure 2 PCoA plot based on NGS read counts detected by metagenome DNA-Seq. PCoA was performed according to Bray Curtis distance (the average linkage). The genera, Acinetobacter, Citrobacter, and Comamonas were frequently detected in STW and STN samples. Most severely ill inpatients were treated in the BW and BN; thus, their excretion may have a major impact on the bacterial content of the sewage tanks.

Metagenome next-generation sequence (NGS) reads corresponding to -lactamase genes were identified in original hospital sewage samples (Figure S3a) and EPOs from each tank selected on CHROMagar ESBL (Figure S3b). In the original hospital sewage samples, the blaIMP gene was detected in STC and STW samples, and the blaCTX-M gene was detected in STW and STN samples (Figure S3a). CHROMagar ESBL selection facilitated the detection of blaIMP and blaCTX-M from all sewage tanks (Figure S3b).

Whole genome sequencing was performed for 80 EPO isolates from STW0522 and STN0717, and 20 EPO clinical isolates (May 8 to July 17, 2018) for comparison of EPOs from sewage tanks and clinical sources. In sewage samples, E. coli, Klebsiella, Enterobacter, Citrobacter, and Achromobacter were detected (Table S1). Clinical isolates included only E. coli and Klebsiella spp.

A pairwise SNV analysis of the core genome was conducted for all E. coli strains (Figure 3). The E. coli STs included ST393, ST38, ST131, ST1011, ST12, ST73, ST9586, and ST224. E. coli ST12, ST73, ST131, and ST1011 were detected exclusively in clinical isolates (Table S2). Clinical isolates (THO-008 and 019 from the same patient) comprised ST393 harbouring blaCTX-M-27 and there was no difference in SNVs between these isolates and those obtained from sewage samples (14 isolates; STN0717-1 to 11, 14, 15, and 19) (Figure 3, Supplemental Data Set S2).

Figure 3 Core genome phylogeny using single-nucleotide variations (SNVs) of ESBL-producing E. coli isolates. Core genome phylogeny was constructed using ESBL-producing E. coli isolates; 20 clinical isolates (THO-number, orange highlighted), one sewage isolate from STW0522 (brown highlighted), and 20 sewage isolates from STN0717 (blue highlighted). The complete genome sequence of STN0717-11 was used as a genome reference and 39.48% of the genome sequence was used as core genome regions among all tested strains. Few clinical isolates were obtained from same patient (, patient No.8; , patient No.9; , patient No.7 in Supplement Data Set S2). Heatmap of pairwise differences of core genome SNVs are shown using a colour gradient with pink and red. The lower half part indicates core genome SNVs among all strains, and the upper half part shows core genome SNVs between indicated two strains. THO-008 and -019 from the same patient showed no SNVs with sewage isolates (14 isolates; STN0717-1 to 11, 14, 15, and 19). There were no identical clones between different patients.

In three ST38 clinical isolates (THO-002, THO-007 and THO-020) harboring blaCTX-M-14, SNV analysis revealed marked 21110 SNVs in the core genome. It was reported that molecular evolution of E. coli genome is possible with less than five SNVs within a 60-day duration.26 By contrast, ST38 sewage isolates harboring blaCTX-M-55 exhibited strict clonality with 3 SNVs, and 123 SNVs were detected in clinical isolates (Figure 3). Five ST131 clinical isolates harboring various CTX-M genes (blaCTX-M-15, CTX-M-27, CTX-M-44) were not identical (Figure 3). Among the 156 CHROMagar ESBL-positive strains from hospital sewage tanks (STW0522 and STN0717; Supplemental Data Set S2), carbapenemase gene (blaIMP-11) was identified only in Pseudomonas monteilii (Table 2).

Table 2 ESBL-Producer in Hospital Sewage and Clinical Isolate

The measurement of the concentrations of chemical contaminants in the tank (Table 1) showed that the most predominant antimicrobial agents were levofloxacin (32,500 ng/L) and clarithromycin (13,500 ng/L), although their concentrations were below minimal inhibitory concentration breakpoints. -Lactam antibiotics were not measured in this study; as they are known to be almost undetectable in environmental samples.27,28

The composition of bacterial flora in hospital sewage has been reported to comprise components of the human gut flora, including Bacteroides, Faecalibacterium, Bifidobacterium, and Blautia, in addition to Klebsiella, Aeromonas, and Enterobacter.6 The bacterial flora in each tank in the old hospital exhibited different bacterial compositions, and that of STC and STE mainly comprised the members of the human gut flora. However, the STW was mainly composed of Citrobacter and Acinetobacter, which are minimally detected in the gut of healthy individuals (Figure S2a and b).29,30 Furthermore, Comamonas and Arcobacter were detected in significant numbers in the STN. Comamonas is generally considered as environmental bacteria with less pathogenicity. Arcobacter spp. are detected in WWTP in several countries.31,32 The hospital sewage is influenced by the patients gut flora,29,33 but it is unclear whether the difference in the bacterial composition of each tank reflects the characteristics of the patients in each building.

Thus, the bacterial composition of STN appears similar to that of STW (Figure 3). BW and BN contain rooms where seriously ill patients are treated (Figure 1). The distribution of bacterial flora in the tanks can be strongly influenced by the severity of illness of the patients in the wards. Furthermore, bacterial flora in the tanks can be instantly affected by excrement because the bacterial composition of STN was comparable to that of STW within 1 month after the relocation. For monitoring department-specific ARB, it may be beneficial to install department-specific sewage tanks.

In Japan, the detection rate of EPO has been reported at 12.2% in healthy adult volunteers.34 Particularly, ST131 is an E. coli strain responsible for a worldwide pandemic and it carries a broad range of pathogenicity and ARGs, including a variety of -lactamase genes on a transferable plasmid.3537 In Japan, it has been reported that 92.9% of EPOs are blaCTX-M gene positive.38 The CTX-M genes (blaCTX-M-14, blaCTX-M-15, blaCTX-M-27 and blaCTX-M-2, listed in descending order of size)39 have been identified in Japan as well, and gene sequences obtained in this study are similar to that (Table 2).

A pairwise SNV analysis showed that the sequences of certain clinical EPO isolates had no difference compared to the SNVs of sewage isolates, suggesting that these sewage isolates may have originated from the patient. Fortunately, there was no strong evidence of a nosocomial outbreak associated with clinical EPOs (Figure 3). Monitoring of ARB/ARGs in hospital sewage may enable detection of latent carriers or nosocomial infections.

The carbapenemase gene (blaIMP-11) in the hospital sewage tanks (STW0522 and STN0717; Supplemental Data Set S2) was identified only in Pseudomonas monteilii (Table 2). P. monteilii was isolated from the environment,40 clinical samples,41 and hospital environment.40,42 P. monteilii is less pathogenic to humans, but may play a role as a metallo--lactamase (MBL) reservoir, and transfer of MBL genes to other species may be a cause of concern, especially in hospital sewage tanks.41,42 Many of these potential EPOs harboring ARGs in the sewage tanks were different from the clinical isolates. It is not clear whether these EPOs were excreted by healthy carriers or were transformed by acquiring the ARGs in the sewage tank.

The concentrations of ciprofloxacin and clarithromycin in hospital wastewater43,44 reported previously were similar to those in the present study. Hospital sewage tanks may promote the development of AMR by high selective pressure on bacteria,9,10,45 even at very low concentrations46 and provide optimal conditions47 for horizontal gene transfer, which is one of the mechanisms associated with the spread of AMR in the environment.48 It is known that the microbial gut flora function as a reservoir for ARGs and horizontal plasmid transfer between bacteria is common.49 This is plausible as sewage tanks consist of an accumulation of excrement and acquisition of resistance may occur frequently. We presume that selective pressure of antibiotics exists in our hospital sewage tanks; however, this will be verified in future studies.

In Japan, KPC-2-producing Klebsiella7 and NDM-5-coproducing E. coli8 were detected in the effluent of WWTP. Effective actions should be taken, including advanced wastewater treatment processes such as ozone and UV treatment11,50 and ultrafiltration51 to accelerate the removal of ARB in WWTP. However, even the above methods do not ensure a complete removal of ARB. Therefore, treatment processes may be introduced prior to the release of hospital sewage into the main sewage to reduce ARB. In Japan, there are a few reports of contamination of hospital sewage tanks with ARB/ARGs.52,53 Nevertheless, this study is the first comprehensive description of AMR in a hospital setting using metagenomic and whole genome analysis.

Our study reveals the presence of ARB/ARGs in the hospital sewage tanks and suggests that every hospital patient/staff/visitor can be a potential source of ARB. Monitoring of ARB/ARGs in hospital sewage is expected to identify the presence of carriers, and control nosocomial outbreaks and dissemination of ARB/ARGs in the environment.

The authors would like to thank Dr Yoshinobu Sumiyama, Chairman, Toho University and Dr Satoshi Iwabuchi, Hospital Director for giving us permission to conduct this research. We are grateful to Mr Umezu Masahiro for helping for sampling of hospital sewage. We gratefully acknowledge the staff members of the Laboratory of Bacterial Genomics, Pathogen Genomics Center, National Institute of Infectious Diseases, Tokyo, Japan.

The authors report no conflicts of interest in this work.

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3. Nascimento T, Cantamessa R, Melo L, et al. International high-risk clones of Klebsiella pneumoniae KPC-2/CC258 and Escherichia coli CTX-M-15/CC10 in urban lake waters. Sci Total Environ. 2017;598:910915. doi:10.1016/j.scitotenv.2017.03.207

4. Proia L, Anzil A, Borrego C, et al. Occurrence and persistence of carbapenemases genes in hospital and wastewater treatment plants and propagation in the receiving river. J Hazard Mater. 2018;358:3343. doi:10.1016/j.jhazmat.2018.06.058

5. Makowska N, Philips A, Dabert M, et al. Metagenomic analysis of beta-lactamase and carbapenemase genes in the wastewater resistome. Water Res. 2020;170:115277. doi:10.1016/j.watres.2019.115277

6. Ng C, Tay M, Tan B, et al. Characterization of Metagenomes in Urban Aquatic Compartments Reveals High Prevalence of Clinically Relevant Antibiotic Resistance Genes in Wastewaters. Front Microbiol. 2017;8:2200. doi:10.3389/fmicb.2017.02200

7. Sekizuka T, Yatsu K, Inamine Y, et al. Complete Genome Sequence of a blaKPC-2-Positive Klebsiella pneumoniae Strain Isolated from the Effluent of an Urban Sewage Treatment Plant in Japan. mSphere. 2018;3(5). doi:10.1128/mSphere.00314-18.

8. Sekizuka T, Inamine Y, Segawa T, Kuroda M. Characterization of NDM-5- and CTX-M-55-coproducing Escherichia coli GSH8M-2 isolated from the effluent of a wastewater treatment plant in Tokyo Bay. Infect Drug Resist. 2019;12:22432249. doi:10.2147/IDR.S215273

9. Lien TQ, Lan PT, Chuc NTK, et al. Antibiotic Resistance and Antibiotic Resistance Genes in Escherichia coli Isolates from Hospital Wastewater in Vietnam. Int J Environ Res Public Health. 2017;14(7):699. doi:10.3390/ijerph14070699

10. Kummerer K, Henninger A. Promoting resistance by the emission of antibiotics from hospitals and households into effluent. Clin Microbiol Infect. 2003;9(12):12031214. doi:10.1111/j.1469-0691.2003.00739.x

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Antimicrobial resistant bacteria in the sewage of a hospital | IDR - Dove Medical Press

It's been a rough year for Cathie Wood's ARK Genomic Revolution ETF (NYSEMKT:ARKG). The exchange-traded fund has fallen more than 30% so far in 2021.In this Motley Fool Live video recorded on Dec. 1, Motley Fool contributors Keith Speights and Brian Orelli discuss whether or not the ETF is a buy after sinking so much.

Keith Speights: Brian, we also had a question on Monday about Cathie Wood's ARK Genomic Revolution ETF falling significantly this year. This ETF is down more than 30% year to date with roughly half of that drop coming over just the last few weeks. Why is this ETF sliding so much and do you think it's a good pick for investors now?

Brian Orelli: Yeah. The top holdings of the ETF are Teladocthat's TDOC, Exact Sciences, EXAS, Pacific Biosciences of Californiawhich is PACB, Fate Therapeutics which is FATE, and Ionis Pharmaceuticals,which is IONIS.

This is an actively managed ETF so it's not easy to track down what was held at the beginning of the year. But of those five only PacBio is up for the year. And it's up big -- 50% -- so perhaps it wasn't even in the top five at the beginning of the year.

Teladoc and Ionis are both down 48% for the year, Exact Sciences is down 27% and then Fate is only down 5%. Then the XBI, which is the SPDR S&P Biotech ETF, which is an index ETF so it doesn't change very often, is down 12% for the year.

It's been a bad year for biotech investors but Cathie Wood's is definitely losing to the broader biotech market for small companies. Should you buy genomics ETF versus investing in individual stocks? I mean, I own three of the top seven, so the sixth and seventh are Vertex Pharmaceuticalsand Twist Biosciences.

I'm kicking myself for not investing in PacBio after Illumina wasn't able to acquire it. That seemed like a good investment, and I didn't make it and definitely PacBio's jumped substantially this year.

I think she's a pretty good stock picker. I guess she is just been unlucky and picked the wrong biotechs this year. Personally, I'd rather know what I own rather than having a moving target owning and actively managed ETFs. But if you're looking for exposure to the biotech sector without needing to do research on a bunch of companies, investing in ARK ETFs seems reasonable, I guess.

Speights: Yeah. I think that's a good answer, Brian and you're right. Cathie Wood is a pretty good stock picker. Her ETFs in general have performed really well. I think several of her ETFs are in the top 10 performers over the last five years.

But the other thing is, don't look at just year-to-date performance. You mentioned quite a few biotechs that are the top holdings. Many, if not all of those, probably have great long-term prospects. This just has been a bad year for biotech, right?

Orelli: Yeah. I mean, of course, Teladoc is down just because there were high expectations of the stock and that's actually the largest holding. I think that's probably dropping the overall ETF return substantially. It's probably due to Teladoc's drop. Although I'm not sure if she's been adding Teladoc to that ETF over the year to get it up to being the top holding.

This article represents the opinion of the writer, who may disagree with the official recommendation position of a Motley Fool premium advisory service. Were motley! Questioning an investing thesis -- even one of our own -- helps us all think critically about investing and make decisions that help us become smarter, happier, and richer.

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Is Cathie Wood's Genomic ETF a Buy After Sinking This Year? - Motley Fool

Vingroup Big Data Institute (VinBigData) announced that it had completed the project on the Database of Genomic Variants for the Vietnamese Population.

With more than 1,000 genomes sequenced and over 40 million variants discovered, the research will lay the foundation for biomedical and precision medicine development, contributing to giving early treatment to each Vietnamese individual in the future.

The database, the first of its kind, also has enough annotations about biological functions and pathological risks.

Prof Ta Thanh Van, chairman of the Council of Hanoi Medical University, said the database would provide an invaluable reference to improve the efficiency of diagnosis and treatment in the country.

Launched in December 2018, the project drew the participation of over 40 scientists from leading universities and units worldwide as well as hundreds of experts and volunteers at home and abroad.

During the three years, they sequenced the genomes of over 1,000 unrelated adults aged 35 to 55 and discovered more than 40 million genetic variants.

Nearly two million of them were representative of the Vietnamese population.

The process was carried out at a lab meeting ISO 15189 standards at Vinmec International General Hospital, using advanced technologies by Google, Illumina and NVIDIA.

Part of the database is now available at genome.vinbigdata.org.

Several hi-speed analysis tools are also offered on trial at the site.

The pioneering project cost over US$4.5mil (RM18.9mil), the largest scale in Vietnam for such a project so far. Vietnam News/ANN

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Database of genomic variants for population completed in Vietnam - The Star Online

The Encyclopedia of DNA Elements(ENCODE) Consortium is an international collaboration of research groups funded by the National Human Genome Research Institute (NHGRI).The goal of ENCODE is to build a comprehensive parts list of functional elements in the human genome, including elements that act at the protein and RNA levels, and regulatory elements that control cells and circumstances in which a gene is active.

ENCODE results from 2007 and later are available from the ENCODE Project Portal,encodeproject.org.This covers data generated during the two production phases 2007-2012and 2013-present. The ENCODE Project Portal also hosts additionalENCODE access tools, and ENCODE project pages including up-to-date information about data releases, publications, and upcoming tutorials.

UCSC coordinated data for the ENCODE Consortium from its inception in 2003 (Pilot phase) to the end of the first 5 year phase of whole-genome data production in 2012. All data produced by ENCODE investigators and the results of ENCODE analysis projects from this period are hosted in the UCSC Genome browser and database.Explore ENCODE data using the image links below or via the left menu bar.All ENCODE data at UCSC are freely available for download and analysis.

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ENCODE at UCSC

Webinar Presenter

Dr. Gwyneth Zai

Dr. Jeffrey Borenstein

New York, Dec. 07, 2021 (GLOBE NEWSWIRE) -- The Brain & Behavior Research Foundation (BBRF) is hosting a free webinar, OCD: Using Genome Data to Predict Risk, Symptoms and Treatment Response on Tuesday, December 14, 2021, from 2pm to 3pm ET. The presenter will be Gwyneth Zai, Assistant Professor at the University of Toronto and recipient of a 2016 Young Investigator Grant.

Dr. Zai will discuss how the human genome holds clues to understanding the heterogeneity and complexity of obsessive-compulsive disorder (OCD). She will explain her team's use of genome data to identify genetic variations that contribute to the risk of developing OCD and which may enable prediction of the response of individual patients to antidepressant medications. Jeffrey Borenstein, M.D., President and CEO of the Brain & Behavior Research Foundation and Host and Executive Producer of the public television series Healthy Minds, will be the moderator. Join by phone or on the web at bbrf.org/decemberwebinar.

This webinar is part of a series of free monthly Meet the Scientist webinars on the latest developments in psychiatry offered by the Brain & Behavior Research Foundation. Please use #BBRFWebinar when sharing or posting about our Meet the Scientist Webinars on social media.

The Brain & Behavior Research Foundation The Brain & Behavior Research Foundation awards research grants to develop improved treatments, cures, and methods of prevention for mental illness. These illnesses include addiction, ADHD, anxiety, autism, bipolar disorder, borderline personality disorder, depression, eating disorders, OCD, PTSD, and schizophrenia, as well as research on suicide prevention. Since 1987, the Foundation has awarded more than $430 million to fund more than 5,100 leading scientists around the world, which has led to over $4 billion in additional funding for these scientists. 100% of every dollar donated for research is invested in research. BBRF operating expenses are covered by separate foundation grants. BBRF is the producer of the Emmy nominated public television series Healthy Minds with Dr. Jeffrey Borenstein, which aims to remove the stigma of mental illness and demonstrate that with help, there is hope.

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OCD: Using Genome Data to Predict Risk, Symptoms and Treatment Response - A Free Webinar from the Brain & Behavior Research Foundation - Yahoo...

What is the current newborn screening?

All babies in the UK are offered the heel prick or blood spot test at around five days old to screen for nine serious health conditions, including cystic fibrosis, sickle cell disease and various metabolic diseases. These conditions, if identified, can be treated or managed. Genetic testing is only offered in certain cases, such as if there is a concern that the baby might be at risk of an inherited disorder.

What is whole-genome sequencing?

Whole-genome sequencing (WGS) reads out the entire DNA code. It is already being used in the NHS to diagnose rare diseases and could be used to screen for mutations that are linked to a wider range of treatable serious diseases that affect babies. Genomics England says that using WGS could allow the current nine conditions screened for to be expanded to more than 200. Genetic data can also be used to predict a persons risk of adulthood diseases, such as Alzheimers and heart disease.

Do other countries offer whole-genome sequencing?

No. There have been pilot studies for whole-genome sequencing for newborn screening, including a trial at Boston Childrens hospital, in which about 7% of families took up the offer. There are also countries that screen for a larger number of childhood diseases using an expanded panel of biochemical and targeted gene tests.

Is this the only approach?

Geneticists are in agreement that the UKs newborn screening should be upgraded. Whole-genome sequencing is one way of achieving this. Another option would be to enhance the existing screening using a panel of genetic tests designed to detect mutations on specific genes. Some argue that these tests would be cheaper, and potentially more accurate for certain conditions.

Are there advantages to WGS?

A key advantage is flexibility: new conditions could be added to the screening list relatively easily since data for the entire genome is already being collected. Such a large dataset of genomic and linked health records would also allow scientists to learn more about genetic predictors of health and disease and potentially help develop new treatments. Some say that genomics will inevitably play an increasingly important role in healthcare and argue that it will be an advantage for participants, and the UK, to be at the forefront of this development.

What are the downsides?

Whole-genome sequencing can be less efficient at predicting some conditions than biochemical tests. This means that WGS would need to be combined with the existing screening process, rather than replacing it. There are also some conditions that are not currently screened for, such as spinal muscular atrophy, which may be detected more readily using a targeted gene test, optimised to pick up certain mutations.

WGS allows scientists to screen for mutations in an almost unlimited number of genes, but screening genes that are less well understood can create a risk of false positives. When genetic mutations of unknown significance are discovered, it can create a diagnostic grey zone. Whole-genome sequencing is also expensive roughly 1,000 per genome once analysis and data storage is accounted for. Based on this estimate, it would cost around 700m to sequence all newborns annually.

There are also significant ethical questions about the consent process for collecting whole-genome data, which can be used to predict health outcomes in adulthood, and questions about who owns this data and how access to it is determined.

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What are pros and cons of whole-genome sequencing for every UK baby? - The Guardian

PUNE With six people tested for the Omicron Covid-19 variant in the Pimpri Chinchwad municipal corporation limits, authorities have shifted their focus to increase the percentage of vaccinations and ensuring Covid appropriate behaviour, which will be monitored on priority.

Around 48% of the population in Pimpri-Chinchwad have completed both doses of the vaccination. Currently, we are not issuing any new orders for Covid regulations, but the focus is on covering more people with both doses of the vaccine, said Rajesh Patil, commissioner, PCMC.

In the last few months, we returned to a normal routine and Covid norms like wearing a mask, and maintaining social distance are not being followed seriously. Now again, it will be monitored strictly. If the situation demands, new orders will be issued in the coming days, added Patil.

In PCMC limits, 138 people have come kin from high-risk countries since Saturday. There have been 86 people subjected to RTPCR tests, of which six were detected with Omicron, while the genome sequencing report of 10 is still awaited.

Five of the six tested for the Omicron variant are asymptomatic, while only one was symptomatic. For those coming from high -risk countries a 14-day quarantine is compulsory, said Patil.

PCMC is currently not considering a sero survey.

The sero survey will be decided on the basis of the booster dose, at this stage we have not thought about it. Discussion about the sero survey is going on, said Patil.

New order on mass gatherings soon

Amid the Omicron threat, PCMC officials are considering a new order on mass gatherings.

We will be coming out with a new order on mass gatherings which will be restricted to reduce the risk of the Omicron variant, said Patil.

Covid vaccination in Pimpri-Chinchwad

48%: Both doses

88%: First dose

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Genome sequencing of 10 cases awaited in PCMC - Hindustan Times

The genome sequencing reports of the five merchant navy crew are expected to arrive by Wednesday or Thursday.

Five people, including two Russian nationals, who arrived in Goa on board a merchant navy ship were isolated after they tested positive for Covid-19 and their samples have been sent for genome sequencing to detect the presence of the Omicron variant, an official said on Monday.

State Epidemiologist Utkarsh Betodkar said the five are being treated as Omicron suspects and the genome sequencing reports are expected to arrive from Pune in neighbouring Maharashtra on Wednesday or Thursday.

"The ship had arrived in Goa on November 18 after leaving Cape Town in South Africa on October 31, and the two Russians had boarded it en route. The testing of crew first revealed one Covid-19 case and then five, he said.

The five have been isolated at the community health centre in Cansaulim as per Central government guidelines for such cases, he added.

Click here for IndiaToday.ins complete coverage of the coronavirus pandemic.

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Omicron: 5 merchant navy ship crew isolated in Goa awaiting genome test report - India Today