Fully synthetic whole proteins in reach

Solid-phase peptide synthesis of homogeneous peptides longer than about 50 amino acids has been a long-standing challenge because of inefficient coupling and side reactions. Hartrampf et al. used an automated chemistry platform to optimize fast-flow peptide synthesis and were able to produce fully synthetic single-domain proteins (see the Perspective by Proulx). The targets included proinsulin and enzymes such as barnase and a version of HIV-1 protease containing multiple noncanonical amino acids. Refolded peptides were nearly indistinguishable from recombinant proteins, and the synthesized enzymes had activity close to that of their ribosomally synthesized counterparts. This method will enable fast, on-demand synthesis of small proteins with a vastly expanded pool of precursor amino acids.

Science, this issue p. 980; see also p. 941

Ribosomes can produce proteins in minutes and are largely constrained to proteinogenic amino acids. Here, we report highly efficient chemistry matched with an automated fast-flow instrument for the direct manufacturing of peptide chains up to 164 amino acids long over 327 consecutive reactions. The machine is rapid: Peptide chain elongation is complete in hours. We demonstrate the utility of this approach by the chemical synthesis of nine different protein chains that represent enzymes, structural units, and regulatory factors. After purification and folding, the synthetic materials display biophysical and enzymatic properties comparable to the biologically expressed proteins. High-fidelity automated flow chemistry is an alternative for producing single-domain proteins without the ribosome.

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Synthesis of proteins by automated flow chemistry - Science Magazine

Much of our understanding of proteins in general is relative to their function in the human diet. To be sure, one of the major functions of protein in the human body is to provide the structural building blocks so essential for building and maintaining muscles. However, as we begin to build a larger understanding of the many proteins and their functions, it becomes clear that there is much more to proteins than muscles and nutrition.

The Protein Catalog Is Much Larger Than You May Think

To understand the vast diversity of protein function, it is helpful to discuss just how many proteins there really are. Dependent on cell type, there are anywhere between 20,000 and 100,000 different proteins in each human cell. Each has been identified as a unique protein, and each has its own function to perform within the human body.

Some proteins bond together to lend rigidity to the cell and shape neurons, muscles, organs, and more. Other proteins act as catalysts for chemical reactions, or serve as transportation for other molecules. Whatever their function, all proteins exhibit folding, which enables each protein to perform its job within the cell.

What Is Protein Folding?

Protein folding and its opposite, protein unfolding, are exactly what they sound like the very structure of a protein folds in upon itself, forming a unique shape. Once you view proteins on a more molecular level, you can begin to see that protein folding is much more than a random overlapping. Instead, the way in which each protein folds is critical to its structure and function.

Proteins are composed of chains of amino acids, bound together in a certain sequence unique to each protein. Within each protein these amino acids interact with each other, forming secondary structures known as -helices and -sheets, which make up the backbone and side chains. Next, tertiary structures form as a result of the three-dimensional folding of -helixes and -sheets, which produces a variety of interactions on the globular protein. These interactions cause the protein to attain its final, quaternary, structure.

Why Is Protein Folding Important?

The end result on the proteins three dimensional structure holds a great deal of biological importance. The final structure of the protein exposes a number of channels, receptors, and binding sites, and affects how it interacts with other proteins and molecules. Building an understanding of the way in which proteins fold leads to a better analysis of countless molecular processes and structures.

When proteins fold correctly, its function proceeds without a hitch. Folding errors, however, can result from a mutation of one of the primary amino acids in the structure or another random error. Unfortunately, when folding goes wrong, a variety of diseases and syndromes can result from the changes caused.

A reduction in the amount of properly folded protein in the body results in a shortage of the amount of workers available to perform its function. Dependent on the function, protein shortages can cause diseases ranging from cancer to cystic fibrosis. Other improperly folded proteins can be negatively affected by their odd shape, and eventually gather into clumps called aggregates. Researchers believe these random aggregates may contribute to conditions such as Alzheimers disease.

Looking Ahead

As research continues, a better understanding of protein folding and unfolding errors can help lead to treatments and therapies for these diseases and more. During this research, it is important to maintain the proper conditions for proteins under observation; thus, the factors that affect protein folding are doubly important. Technologies that assess and provide protein stability, protein functional changes and protein-related disease prevention and therapies are at the forefront of protein research today.

Sources:

https://www.sciencedirect.com/topics/neuroscience/protein-folding

https://chem.libretexts.org/Bookshelves/Biological_Chemistry/Supplemental_Modules_(Biological_Chemistry)/Proteins/Protein_Structure/Protein_Folding

http://sitn.hms.harvard.edu/flash/2010/issue65/ https://nanotempertech.com/blog/is-the-protein-folding-mystery-close-to-being-solved/

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Why Is Protein Folding Important in Biology?

Japan has a long history of whaling, purportedly dating back to the 12th century. Historically, whale meat was a dietary staple. The nutritious and protein-rich meat-fed families and comprised school lunches throughout the nation for centuries. Nevertheless, the practice is considered barbaric by many members of the larger community. After announcing the end of the 30-year-old moratorium of its whaling program, government officials are facing complaints from numerous global leaders and activist groups. Unshaken,whalers are excitedto revive the practice they consider a part of their cultural heritage.

The History of Whaling In Japan

Japan's history of whaling dates back to the Jomon period (14,000 300 BCE) when stranded whales were harvested for community consumption. Other early accounts of the practice stem from the spirituality and folklore of the Ainu, the native ethnic group of Japan. Yet, the practice did not begin to reflect the modern industry until the use of harpoons in the 12th century.

By the 16th century, whaling was highly organized with open-boat expeditions beginning in the 1570s. As the industry continued to mature throughout the 17th century, fisheries and organized hunting groups developed netting techniques. Hunting groups would spot whales offshore, quickly dispatch, and harvest their catch immediately upon returning to shore. The entire carcass was harvested for meat as well as for making lamp oils, fertilizers, folding fans, and many other products.

The Meiji period of Japan saw the introduction of the expeditious Norwegian-style of whaling. This industrialized technique relied heavily on power-driven vessels, munitions, and other imported expertise.

Whaler Juro Oka benefited greatly during this period. Considered the "father of modern Japanese whaling," he established the first modern Japanese whaling company in 1899. Under his dominance, the industry grew in size.

Although historians and authors had historically lamented the effect of whaling on whale populations, the industry began to face significant blowback during the 20th century. Confrontations erupted with local Japanese communities adversely affected by runoff and other oceanic pollution. Throughout the 1970s and the 1980s, a whaling moratorium was fiercely debated by the international community. Despite political resistance, the government was eventually forced to concede to the ban in 1988 under the threat of United States sanctions.

Whaling Nationalism and Lifting the Moratorium

Like all nations, Japan has a nationalist streak. Writing in the Japan Times,Shaun O'Dwyer suggestedthat a resurging cultural nostalgia has reignited a Japanese interest in its unique whaling culinary culture. Indeed, certain whaling communities and whalers themselves maintain interest in a practice that many considered anachronistic and unethical.

Politicians like Shintaro Maeda, mayor of the whaling city Shimonoseki, have aggressively campaigned for the resurgence. According to the above-mentioned Japan Times article, Maeda suggested at a public forum that an official declaration of whaling history and culture as Japanese Heritage' be made through the Cultural Affairs Agency, a special body of the Ministry of Education, Culture, Sports, Science and Technology that promotes arts and culture. The initiative implies state subsidies be allocated to reinvigorate the industry.

Maeda is not alone. Shigeto Hase, head of the fisheries ministry, has also championed a resurgence of whaling. Hetold the BBC, "the resumption of commercial whaling has been an ardent wish for whalers across the country." He continued, "the culture and way of life will be passed on to the next generation.

It would appear that the LDP and Prime Minister Shinzo Abe were sensitive to such nostalgia. In December 2018, the Japanese government withdrew from the IWC. Previously limited to scientific research, commercial whaling reconvened in the country in 2019.

Domestic and International Outcry

Unsurprisingly, the decision was met with widespread criticism. Conservation groups and numerous governments were forced to denounce reinvigorating the industry. Australialabeled the decision "regrettable,"while others called on the country to realign with international standards. Sam Annesley, executive director at Greenpeace Japan,saidthe move was "out of step with the international community, let alone the protection needed to safeguard the future of our oceans and these majestic creatures." He also called on the Japanese government to conserve marine ecosystems.

Perhaps such criticisms are easy to support. Prior to 1987, whale meat was widely served in Japanese schools for lunch. Since its removal following the moratorium, the consumption of the meat has dropped precipitously as many now consider it an uncommon delicacy popular with a minority of residents. Reports of mercury contamination makes matters worse.

Observations such as these have inspired a burgeoning sense of domestic activism in Japan. Angered by how the industry distorts the image of their country abroad, opponents like Takayo Yamaguchihave launched online campaigns in defense of marine mammals. Members of Greenpeace, on the other hand, have worked aggressively to blow the whistle on whalers operating under the guise of scientific research.

Activists do this because the Japanese public is sensitively poised when it comes to the legality of the traditional marine stock. As mentioned, interest in whale meat has in general declined. Nevertheless, many residents do not want to appear complicit or be seen as folding to unruly international pressure.

Their unease is justifiable. Actors such as Sea Shepherd and Australian anti-whalers have instigated confrontations with whalers, and perhaps unwittingly, undermined their cause in terms of domestic support. Others still cringe when outlets such as theNew York Times suggestthat whales are highly intelligent and implies that their slaughter is tantamount to murder.

Nevertheless, criticism comes easily. Celebrities likely Ricky Gervais and Joanna Lumley havespoken out. In an open letter, the two, among other personalities, attempted to shame Japanese politicians. Others still called for an "international whaling intervention" to be staged at G20 summit meetings.

However, Japanese officials appear unsympathetic. Riding a wave of nationalism, they are likely uninterested in denying cultural and nationalist initiatives. After all, whale meat helped the nation survive post-WWII poverty, and the moratorium was essentially a foreign intervention. Folding to foreign intervention again would not serve nationalist sentiment.

Nevertheless, if Japan continues with commercial whaling, it will be forced to endure calls of "barbarism" and "anti-environmentalism" from the larger community.

Read more stories from grape Japan.

-- Japanese artists striking illustrations show Tokyo overrun by whales and giant flowers

-- Chef YouTuber shows how to prepare giant seafood catches to make mouth-watering Japanese cuisine

-- This Tanuki Raccoon dog has been spoiled by its owner

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Japanese politicians and whalers ignore criticism as whaling industry is revived - Japan Today

Abstract

Existing long -helix mimicking necessitates the retention of most natural amino acid residues to maintain their biological activity. Here, we report the exploration of helical sulfono--AApeptides with entire unnatural backbones for their ability to structurally and functionally mimic glucagon-like peptide 1 (GLP-1). Our findings suggest that efficient construction of novel GLP-1 receptor (GLP-1R) agonists could be achieved with nanomolar potencies. In addition, the resulting sulfono--AApeptides were also proved to display remarkable stability against enzymatic degradation compared to GLP-1, augmenting their biological potential. This alternative strategy of -helix mimicking, as a proof of concept, could provide a new paradigm to prepare GLP-1R agonists.

The glucagon-like peptide 1 receptor (GLP-1R) (14) belongs to the class B family of G proteincoupled receptors, and its incretin helical peptide ligand GLP-1 (57) analogs are a promising drug candidate for treating type 2 diabetes and obesity. However, the half-life of GLP-1 is very short owing to rapid degradation by proteases (812). Stabilizing GLP-1 is critical in the development of drugs to treat diabetes. Side-chain cross-linking strategies have been used for conformational and metabolic stabilization of GLP-1 (1315). However, unintended contacts between the cross-links and GLP-1R may occur, and the extent of proteolytic stabilization may be limited. It is conceivable that helical foldamers may provide an alternative strategy to develop proteolytically stable GLP-1R agonists. Gellman et al. (16, 17) reported beautiful work mimicking endogenous GLP-1 using conformationally constrained amino acid residues to replace some native residues. The properly designed /-peptides displayed potent and prolonged activity in vivo. Goudreau et al. recently reported the use of oligourea moieties in GLP-1 sequence to improve the pharmaceutical properties of GLP-1 (18). Very recently, Levine et al. (19) used the O-GlcNAcylation to GLP-1 to improve the stability and in vivo activity. However, to the best of our knowledge, there is no report on mimicking GLP-1 using entire unnatural backbones. Mimicking a long -helix by unnatural peptidomimetics is highly challenging owing to the difference in helicity between -helix and helical foldamers yet appealing because complete unnatural backbone could be more resistant to proteolysis than peptide hybrids.

Sulfono--AApeptides are recently introduced as a new class of helical mimetics to address some enduring challenges in disrupting -helixmediated protein-protein interactions (2027). As proteolytically stable peptidomimetics, sulfono--AApeptides exhibit unusual folding stability by adopting a series of helical structures with well-defined hydrogen bonding patterns (21). Half of the residues are introduced by sulfonyl chlorides in sulfono--AApeptides (Fig. 1A), providing enormous chemical diversity. Furthermore, the single crystal of the homogeneous sulfono--AA foldamers reveals a precise three-dimensional (3D) arrangement of their side functional groups and the helical pitch (5.1 versus 5.4 of -helix) (21), leading to helical mimetics for targeting various -helixinteracting proteins (Fig. 1, B and C) (23, 24). We were intrigued whether this -helixmimicking strategy could be used to mimic GLP-1, a very long helical peptide. Functionally, it was unclear whether native GLP-1 could be mimicked by sulfono--AApeptide-based helical foldamers to form potent GLP-1R agonists. Could the critical residues in native GLP-1 still play an important role in sulfono--AApeptides? Additional questions could arise from the monolithic helix structure of sulfono--AApeptides instead of peptide hybrids that may pose extra challenges in interacting with GLP-1R. Without mimicking the exact structure of GLP-1, would the sulfono--AApeptide be capable of mimicking residues on multiple faces of GLP-1 helix? If successful, it would provide a general strategy for the development of GLP-1R agonists with chemically diverse functional groups based on sulfono--AApeptides. This mode of -helix mimicking would offer a new paradigm for mimicking a myriad of long and complex helical peptides. Here, as a proof of concept, we report the first example of foldameric peptidomimetics with entire unnatural residues for GLP-1 mimicking.

(A) The chemical structure of sulfono--AApeptides. a and b denote the chiral side chain and the sulfonamido side chain from the building block, respectively. (B) The crystal structure of a sulfono--AApeptide; the cartoon structure was drawn by PyMoL. (C) Top view of (B). (D and E) Schematic representation of distribution of side chains from sulfono--AApeptides. (D) Side view. (E) Top view, helical wheel.

Analysis of GLP-1/GLP-1R interaction reveals the critical residues on GLP-1 that are responsible for tight binding to GLP-1R (4, 28). Briefly, GLP-1 engages both its N-terminal domain and C-terminal domain to interact with GLP-1R (Fig. 2A). Of the N-terminal domain, interaction of the polar residues H7, E9, T11, T13, and S17 with the seven-transmembrane domain of the receptor is the most crucial (Fig. 2B). Truncated N-terminal domain GLP-1 peptide derivatives are agonists of GLP-1R at nanomolar concentrations in a cyclic adenosine monophosphate (cAMP) assay (29). Sometimes, such N-terminal truncation results in GLP-1R antagonists like GLP-1(9-36) and exendin (9-39) (30, 31). In contrast, hydrophobic residues F28 and L32 dominate the interaction of C-terminal -helix of GLP-1 with the extracellular domain of GLP-1R. Cryotransmission electron microscopy studies indicate that the entire GLP-1 peptides form a fairly straight -helix (4) instead of the G22-kinked helix (2), suggesting that the kink at G22 may be due to the artifact of crystal packing, which alleviates the challenge to mimic both N- and C-terminal domains of GLP-1 simultaneously. A close view of the critical residues on GLP-1 (Fig. 2, B and C) reveals that H7 and T11 are on the same face (X) of the helix, whereas F28 and L32 are on face Y; E9, T13, and T11 are on face Z (X, Y, and Z are designated arbitrarily).

(A) GLP-1 binds to GLP-1R (Protein Data Bank: 5VAI). GLP-1 (7-36) is shown in blue and GLP-1R is represented in green cartoon. (B) The helical domain of GLP-1 with critical residues showing as sticks. (C) Design of sulfono--AApeptide 3, with side chains mimicking the important residues in B. (The helix was built on the crystal structure shown in Fig. 1. X, Y, and Z were designated to indicate the face of residues on the helix, respectively.)

The preliminary analysis prompted our design of helical sulfono--AApeptides that potentially mimic GLP-1. As shown in Fig. 1 (D and E), chiral side chains and sulfonyl sides are distributed perfectly on four faces of helical scaffold, which could be used to mimic critical residues of a native GLP-1 helical domain that interact with GLP-1R. An intimate comparison suggests that side chains 1a and 3a could mimic residues on the X face of GLP-1, 11b and 13b could potentially reproduce the functionality of residues on the Y face of GLP-1, whereas 2a, 4a, and 6a were speculated to capture the ability of E9, T13, and S17. This strategy led to the synthesis of series of sulfono--AApeptides (Table 1, 3 to 16). For comparison purposes, the native GLP-1 peptides were also synthesized (Table 1 and Fig. 3, 1 and 2). The agonistic activity of these peptides was obtained by measuring the receptor-mediated cAMP production in the Chinese hamster ovary (Chok1) cells overexpressed with the hGLP-1R (14, 32). The N-terminal capped and uncapped sulfono--AApeptides 3 and 4 contain desired side chains shown in Fig. 2C. The potency of sulfono--AApeptide 3 is only two orders of magnitude lower than that of GLP-1 1 (39.79 nM versus 0.11 nM) and ~10-fold lower than that of the capped GLP-1 2 (39.79 nM versus 3.33 nM, respectively).

Our findings demonstrate that the design of full-length unnatural peptidomimetics of GLP-1 is viable. The acetyl capped sulfono--AApeptides displayed more potent agonistic effects than those with an unmodified N terminus. The opposite effect was observed for the regular GLP-1 peptides 1 and 2 (Table 1) where acetylation of the N terminus reduced the agonistic potency of GLP-1 (16, 17). These observations are consistent with different helical scaffolds in GLP-1 and the sulfono--AApeptides.

The functional group on position 6b is not highly critical, as the change of methyl group (3 and 4) to a bulky anisole group only resulted in a fourfold decrease in binding affinity (Table 1 and Fig. 3, 5 and 6). Consistent with previous findings, the C-terminal domain is less important than the N-terminal domain, as replacement of the benzyl group on position 11b with a methyl group (7 and 8) only resulted in a twofold decrease in activity compared with 5 and 6. It is known that H7 is a critical residue for both receptor binding and activation, and replacement of H7 with other aromatic groups, such as Phe, virtually retains the same biological function of GLP-1, implying that aromaticity is critical at the N-terminal end (5). This is similarly observed in sulfono--AApeptides (3 and 4). Substitution of phenyl group for Lys side chain resulted in complete loss of activity (9 and 10). As expected, the side chain on position 4a is highly critical. Replacement of the 2-hydroxylpropyl group (the side chain to mimic T13) with a benzyl group led to completely inactive sequences 11 and 12 (Table 1). It is intriguing that the first side chain preferred is the aromatic group, as the longer sequences (13 to 16) completely abolished the activity to activate cAMP release. Overall, these studies revealed excellent structure-activity relationship for sulfono--AApeptides to mimic GLP-1.

To obtain further structural information and assess any conformational changes resulting from chemical modifications, we investigated the secondary structure of homogeneous sulfono--AApeptides 3 to 16 and compared it with that of regular GLP-1 peptides 1 and 2. Circular dichroism (CD) spectra were recorded between 190 and 270 nm in phosphate-buffered saline (PBS). As anticipated, the regular GLP-1 peptides 1 and 2 adopted a right-handed helical conformation, whereas sulfono--AApeptides 3 to 16 reveal a strong cotton effect with a positive maximum at around 208 nm, which is a characteristic of a well-defined left-handed 414 helix (Fig. 4) (21) similar to previously reported homogeneous sulfono--AApeptides.

A major problem limiting the use of GLP-1 analogs is their instability due to the rapid degradation by proteases. Having found peptides 3 and 5 as the lead candidates based on their in vitro potency, we next examined their enzymatic stability in comparison to the regular GLP-1 peptides. The assays were performed by incubating 0.1 mg/ml of peptides 3 and 5 and the regular peptides (1 and 2) with pronase (0.1 mg/ml) in 100 mM ammonium bicarbonate buffer (pH 7.8) at 37C for 24 hours. High-performance liquid chromatography (HPLC)mass spectrometry was then used to analyze the stability of the examined peptides. Unlike the regular GLP-1 peptides 1 and 2, which degraded completely with no intact peptide remaining, sulfono--AApeptides 3 and 5 showed no detectable degradation (Fig. 5A). These results display notable enhancement in the stability of the sulfono--AApeptides against enzymatic degradation, augmenting their potential in therapeutic application. In addition, peptides 3 and 5 also showed remarkable stability in the presence of serum for 24 hours (Fig. 5B), whereas peptides 1 and 2 had more than 60% degradation under the same condition.

(A) Analytic HPLC traces of 1, 2, 3, and 5 before and after incubation with Pronase (0.1 mg/ml). (B) The serum stability of 1, 2, 3, and 5 was determined in 25% serum (v/v) at 37C for 24 hours. (C and D) Pharmacodynamics of the GLP-1 mimic peptides in mice. A Single dose of peptides was intraperitoneally administered into mice 1 hour before the oral glucose tolerance test (OGTT) (2 g/kg glucose). (C) Blood glucose concentrations were monitored for up to 120 min after oral glucose challenge. (D) Average area under the curve (AUC) calculated from OGTT data. Results show mean SEM of six mice per treatment group; *P < 0.05 versus vehicle; t test.

Next, we examined the blood glucoselowering effect of the lead sulfono--AApeptide 3 in comparison to native GLP-1 (Fig. 5, C and D). The peptides were administered as single doses intraperitoneally to C57BL/6 mice (overnight fasted; n = 6 per group) 60 min before a glucose challenge. Two doses of sulfono--AApeptide 3 (4 and 40 mg/kg) were tested, and their efficacies were compared with native GLP-1 (1 mg/kg) and vehicle control. At both doses, sulfono--AApeptide 3 markedly decreased blood glucose levels at the time points of 30 and 45 min with the dose of 40 mg/kg showing a more pronounced effect, suggesting good pharmacodynamic effect in vivo (Fig. 5C). A dose-related decrease in glucose clearance was observed for 3 at both 4 and 40 mg/kg doses (Fig. 5D), consistent with the abovementioned results of the cell-based assay.

In conclusion, we have developed a series of helical sulfono--AApeptides that can structurally and functionally mimic residues on the multiple faces of the -helical domain of GLP-1. These unnatural helical peptidomimetics display potent GLP-1R agonistic activity in cell-based assay and oral glucose tolerance test (OGTT). To the best of our knowledge, this work represents the first example of foldameric peptidomimetics based on an entire unnatural backbone for GLP-1 mimicking. The excellent proteolytic stability of these helical sulfono--AApeptides augments their biological potential. This alternative strategy of -helix mimicking based on sulfono--AApeptides provides a new paradigm for the preparation of GLP-1R agonists. Exploration of this new strategy for the development of more potent GLP-1R agonists is currently underway.

The resin was swelled in N,N-dimethylformamide (DMF) for 5 min before use, followed by treatment with 20% piperidine/DMF solution (2 ml) for 15 min (2) to remove an Fmoc (9-fluorenyl methoxycarbonyl) protecting group, and washed with DCM (3) and DMF (3) afterward. A premixed solution of the Fmoc protected regular amino acid/sulfono--AApeptide building block (2 eq), HOBt (4 eq), and dissolved inorganic carbon (4 eq) in 2 ml of DMF was added to the resin and shaken for 4 hours to complete the coupling reaction. After washing with DCM and DMF, the resin was treated with 20% piperidine/DMF solution for 15 min (2). Another Fmoc protected regular amino acid/sulfono--AApeptide building block (2 eq) was attached on the resin following the procedure in the first coupling step, and the Fmoc protecting group was removed after the coupling reaction was done. The reaction cycles were repeated until the desired sulfono--AApeptides were synthesized. For the capped sequence, the N terminus was treated with acetic anhydride (1 ml) in pyridine (2 ml) (15 min 2). The final sequence was cleaved using trifluoroacetic acid (TFA)/DCM (3 ml, 1:1, v/v) for 3 hours. The cleavage solution was collected, and the beads were washed with DCM (3 ml 2). The solution was combined and evaporated under air flow to give the crude product, which was analyzed and purified by the Water Alliance HPLC System, at flow rates of 1 and 16 ml/min for analytic and preparative HPLC, respectively. The gradient elution method of 5 to 100% of solvent B [0.1% TFA in acetonitrile (MeCN)] in A (0.1% TFA in H2O) over 50 min was performed. All the sulfono--AApeptides were obtained with a purity >95% after prep-HPLC purification.

CD spectra were measured on an Aviv 215 CD spectrometer using a 1-mm path length quartz cuvette, and compound solutions in PBS buffer were prepared using dry weight of the lyophilized solid followed by dilution to give the desired concentration (100 M) and solvent combination (23, 24). Ten scans were averaged for each sample, three times of independent experiments were conducted, and the spectra were averaged. The final spectra were normalized by subtracting the average blank spectra. Molar ellipticity [] (degcm2dmol1) was calculated using the equation[]=obs/(nlc10)where obs is the measured ellipticity in millidegrees, while n is the number of side groups, l is path length in centimeters (0.1 cm), and c is the concentration of the sulfono--AA peptide in molar units.

Chok1 cells overexpressed with GLP-1R were incubated with increased concentration of tested compounds for 30 min at 37C. The dose response is plotted as the HTRF ratio (EM665/615 nm). Data points are the mean SEM of 3 independent experiments with duplicate measurements for each experiment. Half maximal effective concentration (EC50) values were calculated for each duplicate and the mean values for cAMP EC50 SEM are reported in the table (15).

Lead compounds (3 and 5) and regular GLP-1 peptides (1 and 2) (0.1 mg/ml) were incubated with protease (0.1 mg/ml) in 100 mM ammonium bicarbonate buffer (pH 7.8) at 37C for 24 hours (23, 24). Then, the reaction mixtures were concentrated in a speed vacuum at medium temperature to remove water and ammonium bicarbonate. The resulting residues were redissolved in H2O/MeCN and analyzed on a Waters Alliance HPLC system with a flow rate of 1 ml/min and 5 to 100% linear gradient of solvent B (0.1% TFA in MeCN) in A (0.1% TFA in H2O) over a duration of 50 min. The ultraviolet detector was set to 215 nm.

The serum stabilities of peptides were determined in 25% (v/v) aqueous pooled serum from human male AB plasma (Sigma-Aldrich, Milan, Italy) (33). Peptides were dissolved in H2O/MeCN (70:30 v/v) and then diluted in serum and incubated at 37C for 24 hours. Fifty microliters of solution was added to 50 l of MeCN on ice for 20 min and then was centrifuged at 4C for 15 min. The supernatant was diluted with H2O (0.1% TFA) at a final concentration of 0.1 mg/ml analyzed by reversed-phase HPLC. The amount of intact peptide was estimated by integrating the area under the corresponding elution peak monitored at 215 nm.

All animal care and experimental procedures were approved by the Institutional Animal Care and Use Committee of California Institute for Biomedical Research (Calibr) and strictly followed the NIH guidelines for humane treatment of animals. Female Charles River C57BL/6 mice were fasted overnight and then intraperitoneally administered with 100 l of each peptide in PBS (pH 8.2) containing 1% dimethyl sulfoxide. After 60 min, mice were orally or intraperitoneally administered with 2 g of glucose solution per kilogram of body weight and their tail blood glucose levels were measured before (0 min) and after glucose challenge for 2 to 3 hours.

This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license, which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.

Acknowledgments: Funding: This work was supported by NSF1351265 and NIH1R01GM112652-01A1. Author contributions: W.S. and J.C. designed research; P.S., Z.Z., Y.S., and Z.A. performed research; P.S., C.L., D.H., T.O., V.T.B.N.-T., W.S., and J.C. analyzed data; and P.S., W.S., and J.C. wrote the paper. Competing interests: The authors declare that they have no competing interests. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. Additional data related to this paper may be requested from the authors.

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The activity of sulfono--AApeptide helical foldamers that mimic GLP-1 - Science Advances

Since the coronavirus pandemic took over, people around the world have been hearing and reading about 'flattening thecurve.' While simply referencing a graph of COVID-19 infections or deaths plotted against time, it is data, and if coronavirus has taught us anything, it is that data is crucialto solving the challenges facing a highly-interconnected world. However, under the current circumstances, there is a dangerthat most of the world's data will continue to be owned by so fewcompanies.

This is not ideal considering how influential data can be in political, economic, and scientific decision-making. Companies who own the data on people's interests, issues and preferences will be able to outdo their rivals when it comes to advertising or investment decisions. Social issues are also business opportunities for companies with the right solutions, even if the dividends are not immediate. For instance, experts predict that companies like Apple and Googleare likely to come out of the crisis more influential than ever before. Coronavirus contact tracing, proximity alerts and mapping apps are technologies built on big data, and this often comes fromlocationinformation collected by tech giants, including Facebook and Google. Two companies whotrack quite a lot ofonline user information already. The widespread use of these newer tools will, in turn, help tech companies collect invaluable data that they can rely on when evolving their own products and services.

Related: How To Use Facebook's New COVID-19 Symptom Tracker Map

This situation could result in an even greater widening of the already deep data inequalityissue. In fact, the expectation of this outcome recently prompted a surprise response from one of the big tech companies. Microsoft has now launched an Open Data Campaign, in collaboration with the Open Data Institute and The Governance Lab, to deal with data inequality among companies, as well as regions. The campaign aims to facilitate open and secure sharing of large-scale data, and especially information that could help in tackling some of the biggest challenges facing society, like healthcare, sustainability, and urban socioeconomic issues.Microsoft has declared that it is going to be part of more thantwenty data projects to helpfight the data divide issue and this number includes some of its own projects, such astheAirband initiative, which looks to improve broadband connectivity in the US.In addition,Microsoft says it will share datasets from the project openly on GitHuband willpublish the resultsof its COVID-19 research project, aimedat decoding the response of the immune system to the virus.

Microsoft researchers have found that less than 100 companies collect more than 50 percent of the data produced today. These companies profit enormously from this, while highlighting the staggering divide in data ownership right now. However, it is not just about the economic inequality that such a situation creates, as data ownership also gives considerable political power to companies, andFacebook isa perfect example. The social media giant's effectivenessat swaying political opinion is down to how much informationit has access to. Facebook's unique platform allows the company to customize content to suitindividual interests, making it a perfectdelivery system for targeted political ads.

However, this need not be the case and big data can be a force for good.For that to happen,data needs to be usable, openly shared, securely stored, and not a threat to the privacy of individuals.Microsoft's campaign is just the latest in the list of recent open data projects intent on helping with that. In fact, the pandemic period has witnessed widespread open publishing of research to enable scientists all over the worldto work on the issue. One of the major initiatives is the Folding@Home's open-science projectwhich intends tosimulate protein folding in viruses, thus helping to design drugs thatmightcure specific issues, like COVID-19 andCancer. Even among tech companies, open publishing of research is catching up, with the likes Google now sharingits work on open repositories, including arXiv.org.

Going forward, data is going to play a significant role in shaping society. From climate action and curing deadly diseases to fighting crime and solving severe socioeconomic issues, data-driven AI tools will be key in finding ways to overcome these global challenges. Until then, if data remains disproportionately concentrated in the hands of a few, the world is unlikely to solve these issues, and the economic disparity will continue to get worse in the post-coronavirus world.

Next: How To Donate Your Cough Online To Help COVID-19 Screening Reasearch

Source: Microsoft

The Son of Juggernaut Is NOT What X-Men Fans Expect

A passionate reader, writer and photographer, Aswin is a journalist based in Kerala, India. He has worked as a feature writer for The Hindu, one of the biggest English newspapers in India, and has authored a travel-tourism book on a wildlife sanctuary in Kerala. As a writer for Screen Rant he focuses on speculative fiction, adaptions of real-life stories, Indian cinema (Not just Bollywood!), technology and science in pop-culture. When not writing, you might find him watching soccer videos, analyzing Ghibli movies, finding joy in Emilia Clarke interviews, fanboying over Greta Gerwig, aspiring to be Alan Moore, worshiping John Oliver, listening to Eric Clapton songs and re-watching old BBC series 'Yes Minister', which he considers to be the greatest TV production of all time. Aswin graduated from University College London with an M.Sc in Science, Technology & Society.

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Why Closing The Data Divide Is Now More Important Than Ever - Screen Rant

Right now the whole world is engulfed in panic because of the COVID-19 pandemic. There are a lot of theories circulating regarding the origins of the virus, and a lot of them have a conspiratorial bent to them. Some believe that a pathogen escaped from a lab in Wuhan, others blame the government (any government) for the spread of the virus and its debilitating effect on everyone's lives. And while people are searching for someone to blame, medical researchers have all hands on deck looking for a vaccine that could stop the infection and rid the world of COVID-19, maybe forever. Some analysts are predicting that it could take at least a year to develop a proper vaccine while Johnson & Johnson recently announced that their test-vaccine is going to be ready by September. However, even if the medical device corporation manages to produce a vaccine that early, it might take a while before it can be used in widespread manner. Most projections have a vaccine rollout penciled in around the beginning of 2021.

Like other industries, the crypto community has united to provide support in the all-important vaccine search. While it may seem that blockchain technology has nothing to do with the medical field, crossover projects have proven that it can be useful if applied correctly. One of the main sectors involved in the research right now is crypto miners who are teaming up to aid in the development process. The largest U.S-based Ethereum miner, CoreWeave, announced their plans to use the power of more than 6,000 computers, which had been earning more than $3,000 per day, to create a decentralized super-computer that will contribute to the development of the vaccine. Independent miners all around the world are joining the initiative and adding to the potential of the development process.

Another important project in this field, Folding@home, which was actually created 20 years ago, has been picking up a lot of traction recently due to the current circumstances. This project allows medical researchers to use the pooled computing powers of project participants to help solve their calculations. Results are processed in order to analyze protein folding and find spaces for other molecules to fit in a way that can interfere with the virus's function.

Though Folding@Home has been working on researching several different diseases over the course of its existence, it has recently made COVID-19 research its main focus. In March, when the public was informed of the beginning of the pandemic, Folding@Home suddenly went from 30,000 volunteers contributing to the project to 700,000. Because of the sudden surge of the number of users involved, databases ran out of the relevant calculations and servers overloaded.

Despite these complications, as a result of the uptick in participation, the project reached its peak performance of 1.5 exaFLOPs, making it more than seven times faster than the world's fastest supercomputer. So the potential of this computing power for research is enormous. If the research efforts are successful, new drugs and treatments can be discovered to help end the disease.

Several crypto communities have gotten involved with the project over the last couple of months. Bitcoin-related Folding@Home teams, and eight other cryptocurrency-related teams, collectively account for 3000 CPUs. The aforementioned Ethereum mining firm, CoreWeave, has dedicated over 7000 GPUs to protein folding. Dogecoin and Tezos communities incentivized their members to participate by offering small rewards for the work that each user contributes to the team. While the rewards are not very significant, many users joined the initiative and others donated to the prize pool.

There are also several cryptocurrency projects allowing users to earn rewards directly at Folding@Home. Gridcoin, Curecoin, and Foldingcoin all offer users small amounts of cryptocurrency based on how much work they contribute to the platform. It is also important to notice that all of these cryptocurrency projects are not only contributing themselves but they are also promoting Folding@Home and urging many others to join. In addition, some exchanges are assisting the project while supporting the coins involved. For example, HitBTC published an exclusive interview with the Curecoin team to inform the public of their mission and how it can be completed successfully. The support that Folding@Home has received from the crypto community has armed it well in its fight against the virus and has inspired hope around the world for a timely solution to the pandemic.

The first decentralized artificial intelligence hackathon, COVIDathon, has been designed to assist the global medical industry in creating solutions to combat COVID-19. It was launched by the Decentralized AI Alliance, or DAIA, that currently has more than 50 members, including SingularityNET, Ocean Protocol, Aragon, Shivom, NEM, InboundJunction, as well as communities of healthcare professionals, biotechnologists and geneticists. The goal is to bring together AI and blockchain projects to create intelligent decentralized tools to combat COVID-19 in the present and reduce risks for future outbreaks.

There is another Bitcoin-related initiative focused on the development of COVID-19 vaccine. Instead of just contributing their computing power to another project, Bitcoiners have united to crowdfund a DIY plasmid DNA vaccine. The people behind the project identified their goal as developing a potential vaccine by designing the necessary protocols and components, and subsequently by manufacturing it themselves. Any DNA sequences and hardware they develop during this project will be made publicly available and accessible under permissive licenses. Due to the nature of this research, and potential liability issues, the team is anonymous. However, the biologist involved has over 10 years of experience in bioproduction, including large-scale manufacturing of DNA vaccines in FDA-compliant laboratories, the project claims.

Overall, the hardship of the current situation has brought out the positive in the crypto community. It showed how quickly and efficiently projects involved in the industry and their vast user bases can unite in the goal of reaching something helpful for humanity. It is the same better future promise of Satoshi's vision for the crypto but now put to a real-life test. Hopefully, results will be seen very soon and well be able to thank all of those in the community that have helped out in this difficult search for the COVID-19 vaccine.

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Unexpected Importance of the Blockchain Technology in Search of the COVID-19 Vaccine - Crypto Daily

We're all now familiar with the spiky look of the coronavirus protein. But what do you think it might sound like?

An engineering professor at the Massachusetts Institute of Technology has shown us. By assigning musical notes to each part of the virus' structure, he has created a whole composition which, as it turns out, is similar to the ambient music pioneered by Brian Eno.

"What you hear is a musical representation of the virus spike protein, which is the protein that affects the human cells," Professor Markus Buehler told the World Vs Virus podcast.

His musical representation of the virus is, he says, more accurate than classical static diagrams that fail to show the virus' constant movement and vibration.

"They don't actually look like they look in a chemistry textbook because atoms and molecules are continuously moving. They kind of look like a vibrating string."

And it is that vibration that fascinates Buehler, who is looking at whether it can be exploited to combat the virus.

"That is something we have been thinking about for this protein and other proteins in the last couple of years, to use the knowledge of the nanoscopic vibrations as a way of actually disintegrating the structure.

"I do a lot of research on fracturing of materials in my work and a lot of times we're trying to prevent fracturing from happening. But in this case, we actually are trying to find a pathway to deliberately destroy a structure. Vibrations are a really important pathway to do that."

A new strain of Coronavirus, COVID 19, is spreading around the world, causing deaths and major disruption to the global economy.

Responding to this crisis requires global cooperation among governments, international organizations and the business community, which is at the centre of the World Economic Forums mission as the International Organization for Public-Private Cooperation.

The Forum has created the COVID Action Platform, a global platform to convene the business community for collective action, protect peoples livelihoods and facilitate business continuity, and mobilize support for the COVID-19 response. The platform is created with the support of the World Health Organization and is open to all businesses and industry groups, as well as other stakeholders, aiming to integrate and inform joint action.

As an organization, the Forum has a track record of supporting efforts to contain epidemics. In 2017, at our Annual Meeting, the Coalition for Epidemic Preparedness Innovations (CEPI) was launched bringing together experts from government, business, health, academia and civil society to accelerate the development of vaccines. CEPI is currently supporting the race to develop a vaccine against this strand of the coronavirus.

And the interlinking harmonies created by musically mapping proteins might also tell us something about our own creative process.

"Counterpoint is something that musicians have played with and explored for a couple of centuries and we actually find that this idea of counterpoint is really prominent in the structure of proteins, in particular in the folding, as well as the folding of our brain," Buehler said.

That means we could look at music, "not only as a display of art or creativity, but actually as a way of learning about the underlying structure that has created this art" - the human brain.

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If a virus could sing ... Could this musical version of COVID-19 help us defeat the disease? - World Economic Forum

Looking at the Open Source COVID-19 Medical Supplies production tally of handcrafted masks and faceshields, were trying to answer that question in our weekly discussions about COVID-19, robots and us. We talked to Rachel McCrafty Saddhas been building systems and automation for COVID mask making, as the founder of Project Mask Making and #distillmyheart projects in the SF Bay Area, an artist and also as Executive Director of Ace Monster Toys makerspace/studio. Rachel has been organizing volunteers and automating workflows to get 1700 cloth masks hand sewn and distributed to people at risk before the end of April. Wheres my f*king robot! was the theme of her short presentation.

If you think that volunteer efforts arent able to make a dent in the problems, heres the most recent (4/20/20) production tally for the group Open Source COVID-19 Medical Supplies, who speak regularly on this web series. One volunteer group has tallied efforts by volunteers across 45 countries who have so far produced 2,315,559 pieces of PPE. And thats not counting the #distillmyheart masks. Heres Rachels recent interview on KTVU. Those masks arent going to make themselves, people!

We also heard from Robin Murphy, Expert in Rescue Robotics & Raytheon Professor at Texas A&M University, who updated her slides on the way in which robots are being used in COVID-19 response. You can find more information on Robotics for Infectious Diseases, an organization formed in response to the Ebola outbreak and chaired by Dr Murphy. There is also a series of interviews answering any questions a roboticist might have about deploying robots with public health, public safety and emergency managers.

Next we heard from Missy Cummings, Expert in Robotics Safety & Professor at Duke University. Ive been doing robotics, certification testing and certification for almost 10 years now. I started out in drones. And then kind of did a segue over into driverless cars and I also work on medical systems. So I work in this field of safety critical systems, where the operation of the robot in terms of the drone or the car or the medical robot, it can actually do damage to people if not designed correctly. Heres a link to a paper that Ive written for AI Magazine thats really looking at the maturity of driverless cars.

I spent a ridiculous amount of time on Capitol Hill trying to to be a middle ground between, yes, these are good technologies. We want to do research and investment and keep keep building a capacity. But no, were not ready to have widespread deployment yet. And I dont care what Elon Musk says youre not getting full self driving anytime soon.

Any reasoning system has to go through four levels of reasoning, you start at the basics, what we call skill based reasoning, then you go up to rule knowledge and expert based reasoning. And so where do we see that in cars? When you learn to drive you had to learn skill based reasoning, which was learning for example, how to track light lines on the road. Once you did that, maybe 20 minutes to learn that then you never actually have a problem with that again.

So once you have the cognitive capacity that youve learned skills, then you have enough spare mental capacity to think about rule based reasoning. And thats when you start to understand, Okay, I see this octagon in front of me, it is a stop sign its read, I know that what it means theres a set of procedures that go along with stopping and Im going to follow those when I see it. Then once you have the rules of the environment that youve learned, then you have the spare capacity to start thinking about knowledge base reasoning, the big jump between rule and knowledge base reasoning is the ability to judge under uncertainty. So this is where you start to see the uncertainty arrow growing. So when you go up to knowledge base reasoning, you are starting to have to make guesses about the world with imperfect information.

So I like to show this picture of a stop sign partially obscured by vegetation. There are many many, many driverless car system computer vision systems right now that cannot figure this out that if they see some level of partially obscured stop sign, they just cannot see because they dont see the way that we see. They dont see the complete picture. And so they dont judge that theres a stop sign there. And you might have seen the recent case of the Tesla being tricked by a partially modified 35 mile per hour sign with a little bit of tape to make it see 85 miles per hour. Its a really good illustration of just how brittle machine learning deep learning is when it comes to perceptual based reasoning. And then we get to the highest level of reasoning where you really have to make judgments under maximum uncertainty.

I love this illustration of this stop sign with these four different arrows. You cannot do this, you cannot turn left, you cannot go right, you cannot go straight and you cannot go back. So Id be curious, Id like to see what any driverless car would do in this situation. Because what do you do in the situation? You have to break one of these rules, you have to make a judgment, you have to figure out what is the best possible way to get yourself out of the system. And it means that youre going to have to break rules inside the system. So the expert base reasoning knowledge base reasoning there is what we call top down reasoning, its you taking experience judgment in the world that youve had. As youve gotten older in life and had more experiences, you bring that to bear to make better guesses about what you should do in the future.

Bottom up reasoning is, is essentially what is happening in machine learning. Youre taking all the bits and bytes of information from the world, and then processing that to then make some kind of action. So right now Computers are really good at skill based reasoning, some rule based reasoning, humans are really the best at knowledge and expert based reasoning. And this is something we call functional allocation. But the problem is theres a big break between rule and knowledge. Driverless cars cannot do this right now, until we can make that jump into knowledge and expert base reasoning. What are we going to do have to do? [Missy Cummings, Robot Safety Expert]

Michael Sayre, CEO Cognicept said Im working with a company called Cognizant as CEO. Were essentially solving a lot of the problems that Missy highlighted, which is that, you know, when we look at autonomy, and moving robots into the real world, there are a lot of complexities about the real world that cause what we call edge case failure in these systems. And so what weve built is essentially a system that allows a confused robot to dial out for human operator.

Human in the loop is not a new idea. This is something that self driving cars have used. What weve built is essentially a system and a service that allows this confused robot to dialogue for help on real time basis. We essentially listen for intervention requests from robots. So that can be an error code, or, you know, some kind of failure of the system timeouts, whatever it is really, we can listen for that event. And then we cause a ticket to be registered in our system, which our operators will then see, that connects them to the robot, they can kind of get a sense of whats happening in the robots environment, they can get sensor information, populated in a 3d canvas, we can see videos and so forth, that allow the operator to make judgments on the robots behalf.

Self driving vehicles is probably not the best example for us. But maybe you would be able to use our system in something like a last mile delivery vehicle, which will face a lot of the same problems. Maybe the robots uncertain about whether it can cross the road. We can have a look at the video feed from that robot, understand what the traffic signals are saying, or what the environment looks like. And then give the robotic command to essentially help it with getting past the scenario that caused that Case failure. So we see this as sort of a way to help get robots into more useful service.

You know, right now, even at 1% failure rate for a lot of these applications can be a deal breaker. You know, we, especially for self driving cars, as everybody mentioned, you know, the cost of failure is really high. But even in other sort of less critical cases, like in building delivery, you see, you know, if something is spinning around in a circle or not performing its job, it causes people to lose confidence in the system stopped using it. And its also you know, during the time that its confused, not performing its function. So we essentially built this system as a way to bring robots into a broader range of applications and improve the sort of uptime of the system so that it doesnt get into these positions where its stuck during its operation.

Similarly, we have robots that get lost in spaces that are widely variable. So you know, a warehouse that has boxes or pallets that move in and out of the space very frequently. Thats going to confuse the robot because its internal map is static in most cases. And when you have a very large change, the robots going to be confused about its location, and then not be able to proceed with its its normal operation. Thats something that we can help with we essentially will be able to look at the robots environment and understand where it is in its space and then update its location. Again, you know, we look at different types of obstacles. You know, a plastic bag is not really an obstacle, we can, you can run through that. But on a LIDAR, it shows up the same way as a pile of bricks.

So by having a human in the loop element, we are able to sort of handle these edge case failures and get robots to perform functions that they wouldnt otherwise be able to perform and be useful in applications that were maybe too challenging for full autonomy. I think a lot of it has to do with sort of how dangerous is the robot in question. So, you know, for a self driving vehicle, very dangerous, right, weve got a half ton of steel, you know, moving at, you know, relatively rapid speeds. This is a dangerous system.

On the other hand, in building delivery robots, were doing some work in quarantine zones, making deliveries in buildings that allow social distancing to be maintained. We can put needed supplies inside of this delivery robot and send it in a building to the delivery room. So worst case scenario, we might bump into somebody. Its just inconvenient and might sort of ruin the either the economics of the usefulness of the robot. That would be a good case for these less critical systems. So things like in-building delivery, material handling and logistics spaces. Maybe like a picking arm like a robot arm pulling things out of a box and putting it into a shipping container, or into another robot for in-building delivery.

While we try to get as fast as we can, youre still talking about 30 seconds, maybe before you can really respond to the problem in a meaningful way. So, you know, 30 seconds is an eternity for a self driving vehicle, whereas for an in-building delivery robot, its not a big deal. So I think you know, the answer to that its pretty application dependent and also system dependent, you know, how dangerous is the system inherently? [Michael Sayre, CEO of Cognicept]

Rex St John, ARM IOT Ecosystem Evangelist presented an unusual COVID-19 response topic. This isnt quite a robotics topic. But a few weeks ago, I began working on a project called Rosetta@home. So if youre not familiar, theres a lot of researchers that are studying protein folding, and other aspects of biological research. And they dont have the funding to pay for supercomputer time. So what they do is they they distribute the research workloads to volunteer networks all around the world through this program called boink. So theres a lot of these programs, theres SETI@home, and Rosetta@home and Fold@home. And theres all these people that volunteer their extra compute cycles by downloading this client. And then researchers upload work, jobs to the cloud, and then those jobs are distributed to these home computers.

So because I work at arm, we realize that Fold@home and Rosetta@home. are two projects which are used specifically to study protein folding. They did not have arm 64 bit clients available, which means you cant run them on a Raspberry Pi four, you cant run them on some of the newer arm hardware. So there are a lot of people in the community that were wanting to help out with Fold@home and Rosetta@home, which are now being used extensively by researchers specifically to study COVID-19. So we put together this community project. And it came together very, very quickly. Because once everybody learned about this opportunity, they jumped on board very quickly. So what happened was these guys from Neocortex, its a startup out of San Jose. They jumped on this and their CTO ported all the key libraries from Rosetta@home to arm 64 and then within a couple weeks a week or two actually, were now up to 793 arm 64 bit devices that are supporting researchers studying COVID-19 so anybody that wants to help out if youve got a Raspberry Pi four or an arm 64 bit device you can install Rosetta@home on your Raspberry Pi four and begin crunching on proteins to help researchers fight back COVID-19. https://www.neocortix.com/coronavirus

You can see this is the spike protein right there of COVID-19. COVID-19 uses the spike protein to sort of latch on to the the receptors of human cells and thats how it kind of invades your body. So theyre doing a lot of work to understand the structure and behavior that spike protein on Rosetta and Fold@home. [Rex St John ARM IoT Evangelist]

Ken Goldberg, Director of CITRIS People and Robots Initiative said I do have one thought that Id like to share that occurred to me this week, which is that I wonder if were shifting from what used to be called the High Tech High Touch concept from John Naisbitt. He wrote Mega Trends about how we were moving as we got toward more high tech, wed also just as much crave that touch. And I wonder if were moving toward a low touch future where we actually will see new value in things that are dont involve touch. Its been so interesting for me to be you know, to be in the house. Ive gotten a whole new appreciation for things like washing machines and even vacuum cleaners. Theyre incredible these mechanisms that help us do things, that rather than us reaching down and touching everything they basically do it for us.

Ive been thinking about you before this pandemic. There are a lot of things out there like robot vending machines that I was a little skeptical about. And I thought, well, I dont really see whats the big advantage, given a choice Id rather have a human making a hamburger or coffee. But now Im starting to really think that equation has changed. And I wonder if thats going to change permanently. In other words, are we actually going to see this a real trend toward things like these robot coffee making baristas and robot burgers like Creator, the company in San Francisco. or Miso robotics is developing fast food making robots. I think its time to really reevaluate those trends because I think there is going to be an actual visceral appeal for this kind of low touch future. [Ken Goldberg CITRIS People and Robots]

Therell be more next week on Tuesday April 28 so sign up for COVID-19, robots and us with guest speakers focusing on regulations, risks and opportunities:

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Where are the robots when you need them! - Robohub

This is one of the high-scoring protein designs that will be turned into an actual protein binder for testing as an coronavirus-blocking agent. (Stomjoh via Foldit / UW Institute for Protein Design)

Who would have thought a video game could identify potential treatments for COVID-19? Researchers at the University of Washingtons Institute for Protein Design certainly thought so, and so far the game has produced 99 chances to win.

The game is a protein-folding puzzler called Foldit, which was created at UWs Center for Game Science more than a decade ago and has attracted nearly more than 750,000 registered players since then.

Foldits fans find ways to twist virtual protein structures into all sorts of contortions. Some of those contortions turn out to have therapeutic value, which can raise a players score in the game. And that can have real-world implications for countering the coronavirus.

On the cellular level, protein structures can switch on biological processes, or act as keys to spring open the locks that protect cells from harm. For example, the coronavirus that causes COVID-19, known as SARS-Cov-2, has a spike-like protein structure thats particularly well-shaped for unlocking a cells defenses and getting inside to do its dirty work.

Once researchers mapped the virus shape, the Institute for Protein Design set up a challenge for Foldits players. They were tasked with folding virtual proteins into shapes that could latch onto the coronavirus skeleton key and gum it up, rendering it useless for a cellular break-in.

Thousands of designs were submitted and scored over the course of three rounds of competition. Now the institutes researchers have selected 99 designs, 33 from each round, that will be turned into real-world proteins known as binders for testing as antiviral agents.

It will be a few more weeks before genes arrive and we can begin experiments on the Foldit designs, Brian Koepnick, a UW biochemist who focuses on Foldit, told players in blog post. In the meantime, well continue to work on designing better binders in Foldit.

In an earlier blog post, Koepnick cautioned players that the synthetic proteins dont always work as well in the real world as they do in Foldits computer-generated chemistry lab.

Protein binder design is a very hard problem one at the forefront of computational biology and there are other physical factors that are difficult to account for, he wrote. Even if our metrics look good on paper or on a computer, only laboratory testing will tell us whether these designer proteins actually fold and bind to the target.

But if the institute can turn one of the 99 designs into a workable drug that can stop coronavirus in its tracks, Foldit players wont be the only winners.

To get in on the game, head on over to the Foldit website, download the software and follow the instructions. After you get a feel for the game by playing the tutorials, check out this 49-minute video for tips on tackling the coronavirus puzzles.

Update for 11:35 p.m. PT April 1: Weve updated some outdated figures for the number of registered Foldit players.

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A protein puzzle game called Foldit turns up 99 promising ways to confound coronavirus - GeekWire

OXFORD, UK April 2, 2020 OXGENE and The Native Antigen Company today announced a collaboration to scale up production of SARS-CoV-2 (COVID-19) reagents by combining OXGENEs proprietary Adenoviral Protein Machine Technology with The Native Antigen Companys antigen development expertise. Together, OXGENE and The Native Antigen Company will aim to scale their antigen manufacturing capabilities to deliver high-purity, recombinant proteins for the development of diagnostics and vaccines.

The Native Antigen Companys Novel Coronavirus antigens.

The Native Antigen Company

OXGENE and The Native Antigen Company are developing an improved, scalable approach to SARS-CoV-2 antigen manufacture. The Native Antigen Company was one of the first recognized suppliers of SARS-CoV-2 antigens in February 2020, demonstrating their ability to rapidly support the diagnostic and vaccine industries with high-quality infectious disease reagents. OXGENEs Protein Machine Technology allows for the scalable production of viral proteins in mammalian cells using their proprietary adenoviral expression vector. Through genetic modification, the adenovirus is tricked into making SARS-CoV-2 proteins rather than its own, thereby harnessing the innate power of highly scalable viral protein production.

Our novel Protein Machine Technology represents a significant development in the rapid and scalable generation of high-quality viral proteins," said Dr. Ryan Cawood, chief executive, OXGENE."Were delighted that by collaborating with The Native Antigen Company, we can take advantage of our technology to support the needs of researchers racing to develop much-needed diagnostics and vaccines against COVID-19.

The Native Antigen Companys recombinant SARS-CoV-2 antigens are produced in mammalian cells to ensure full glycosylation and proper protein folding, both of which are essential for full biological and antigenic activity. The rapid scale up production of SARS-CoV-2 antigens is critical for the development of widely available diagnostic tests.

Unlike the PCR tests that are currently being used, these diagnostics will be able to confirm past infections and determine levels of immunity to SARS-CoV-2. This could be invaluable for disease modeling and public health policy, as true transmission rates and case fatality rates can be determined. These tests could also be instrumental for the diagnosis of health care workers who have been exposed to the virus to ensure that they have developed natural immunity before returning to work, and to help measure patient immune responses for the rapid development of a SARS-CoV-2 vaccine.

This collaboration builds on a long-standing collegiate relationship between the two Oxford-based businesses as they work toward developing more scalable technologies for the diagnosis of disease, and the cost-effective manufacture of high-quality diagnostics and vaccines.

"We are committed to developing the highest-quality reagents in rapid response to emerging epidemic diseases," said Dr. Andy Lane, commercial director, The Native Antigen Company. "Since the start of the crisis, the demand for our COVID-19 antigens has increased significantly, and by scaling up production of these vital reagents in collaboration with OXGENE, we hope to be able to support more researchers in their critical work developing diagnostics and vaccines.

OXGENE and The Native Antigen Company aim to complete the first validation of this new paradigm in protein expression within the next month, which could have a demonstrable impact on the race to develop diagnostic kits and vaccines against this virus.

For further information about The Native Antigen Companys Coronavirus Antigens, please visit: https://thenativeantigencompany.com/coronavirus-dashboard/

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Collaboration to Increase COVID-19 Antigen Production for Diagnostic Kits and Vaccine Development - Lab Manager Magazine

By Monica Obradovic, St. Louis Post-Dispatch

ST. LOUIS For many Balkan women, making the dish is like a reflex. Its technique gets passed down from generation to generation.

For my baba, gibanica is a cheese and phyllo-dough creation she lovingly feeds (overfeeds?) her family. For Loryn Nalic of Balkan Treat Box, the same dish is called sirnica, one of the first Balkan recipes she learned. For me, its the cheese-filled wonder Id always hoped to learn how to make, partly as a way of carrying on my familys heritage, partly because its just so delicious.

Even though my name might seem foreign to some (its O-BRAD-o-vic, and its Serbian), the food that derives from the culture of it might not. St. Louis has quickly become a haven for Balkan cuisine. With the influx of immigrants over the past 20 years, Balkan foods and restaurants such as the acclaimed Balkan Treat Box have become a part of St. Louis food culture.

My dads family came to the U.S. when he was 8. He later married my Italian mother. Unfortunately, not many of my dads Serbian traditions were handed down to my two brothers and me. We dont speak Serbian (except for curse words thanks, Uncle Dennis), we dont go to Serbian church, and we definitely dont roast a whole pig on a spit in our front yard.

But what we do have is gibanica.

Gibanica is to Serbs what pizza is for Americans. Its a simple dish consisting mostly of eggs, cheese and oil sandwiched between layers of phyllo dough. People eat it for breakfast, lunch, dinner, a snack, to fix hangovers.

Every time my family goes to visit my Serbian grandmother, or Baba, we joke how the whole neighborhood smells like Serbian food. No matter how much my father stresses that were just stopping by, Baba will make enough food to feed a small village. Theres never enough gibanica, though.

Its the first food my family eats at gatherings, and its the first food to disappear.

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Everything about it evokes nostalgia in me: the gooey, cheesy texture; the crunch of the outside layers. Besides the calories, you cant go wrong with gibanica.

Theres no one way to make gibanica, the same way there isnt a single way to make a hamburger. Almost every Balkan or Slavic country has a version of the dish or something similar to it. Many countries make Burek, a phyllo dough-based pie stuffed with beef and sometimes cheese. Greeks have their spinach pie, spanakopita.

The word gibanica itself is a combination of two separate languages: the Croatian verb gibati and Serbian verb ??????, meaning to fold, sway, rock. Altogether, it means folded pie.

When I asked Balkan Treat Boxs owner and chef Loryn Nalic about the dish, she knew it as sirnica.

Its one of my kids favorite dishes, Nalic says. It was the first thing I learned to make when Edo and I were together because he loves it so much.

Loryn and her husband, Edo, turned their food truck into a brick-and-mortar restaurant last year to national acclaim. They invited me into their restaurant on a Monday afternoon, when the day was dim but the wood fire in their oven burned bright.

Everyone makes gibanica and its variants differently. Nalic makes hers with fresh dough and cheese she makes herself. I use store-bought phyllo dough and cottage cheese. Loryn lines dollops of cheese and rolls the filling with the dough into one big coil. I sprinkle oil and cheese on layer after layer of dough.

Its a pretty universally loved dish, Nalic says.

Despite that, its not on the menu at Balkan Treat Box yet. Nalic says the restaurant recently got a few new ovens and may start serving it. As a special treat, the restaurant will serve it Wednesday and Thursday.

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Its a very simple dish once you get the technique down. Theres a certain way to handle the dough, whether youre making it yourself or buying it from a store.

Nalic says the first time she watched someone make phyllo dough from scratch, it brought tears to her eyes. It is an art form, she says.

When I saw Nalic and her mother-in-law, Zeta, make and stretch the phyllo dough, I was near tears, too. The way she expertly expanded the dough on a table brought to my mind the countless generations of Balkan women teaching their daughters how to make it and how that knowledge spread to my Baba through a great-grandmother I never met, and now me.

Each time I ask Baba for a written recipe (there have been many times), shell recite the ingredients and say, Just make it. I asked her to teach me how to make it again for this article, with pen and paper in hand.

Now, Im the one making the neighborhood smell like Serbian food.

GIBANICA

Yield: 10 servings

2 pounds phyllo dough, preferably the thickest, country style type

7 eggs

1 1/2 pounds cottage cheese

1 teaspoon salt

1 teaspoon baking powder

1/2 pound farmers cheese or feta, crumbled

3 tablespoons soda water

2/3 cup corn oil, divided

Notes: Use the deepest metal baking pan you have, preferably at least 2 1/2 inches.

Thaw phyllo dough according to package instructions. Grease bottom of an extra-large baking pan, preferably 11-by-16-inches (available at European markets). Preheat oven to 425 degrees.

Whisk eggs in a large bowl, then stir in the cottage cheese, salt, baking powder and farmers cheese. Stir in the soda water.

Cover the bottom of the pan with a single layer of phyllo dough, making sure some of the pieces hang over the sides. Evenly sprinkle 1 tablespoon oil over the dough.

Take a piece of phyllo dough and wrinkle it into the dish with as many bumps as possible so it doesnt lie flat. Depending on the size of your pan, use 2 to 3 pieces of dough for each layer. Evenly sprinkle 1 tablespoon oil on the dough, including the sides and corners. Do not allow the oil to pool.

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Sprinkle 1/2 to 3/4 cup egg-and-cheese mixture on the dough, including the sides, enough to make sure the edges and crevices are covered. Do not allow the mixture to pool.

Repeat laying down 2 to 3 pieces of wrinkled dough and sprinkling them with oil and the egg-and-cheese mixture until you have 1 layer of dough left. Cover the top of the dish with that last remaining layer, folding in any excess on the sides. Cover the top with a final layer of the egg-and-cheese mixture and oil, but do not dump any mixture leftovers on top.

Bake 40 minutes or until the top turns golden brown and the sides separate from the pan.

Per serving: 568 calories; 30 g fat; 9 g saturated fat; 43 mg cholesterol; 21 g protein; 53 g carbohydrate; 4 g sugar; 2 g fiber; 1,139 mg sodium; 260 mg calcium

Source: Monica Obradovic

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Phyllo, cheese, heaven: Balkan women have been making these treats for centuries - The Gazette

The proteins that make up all living things are alive with music. Just ask Markus Buehler: The musician and MIT professor develops artificial intelligence models to design new proteins, sometimes by translating them into sound. His goal is to create new biological materials for sustainable, non-toxic applications. In a project with theMIT-IBM Watson AI Lab, Buehler is searching for a protein to extend the shelf-life of perishable food. In anew studyin Extreme Mechanics Letters, he and his colleagues offer a promising candidate: a silk protein made by honeybees for use in hive building.

Inanother recent study, in APL Bioengineering, he went a step further and used AI discover an entirely new protein. As both studies went to print, the Covid-19 outbreak was surging in the United States, and Buehler turned his attention to the spike protein of SARS-CoV-2, the appendage that makes the novel coronavirus so contagious. He and his colleagues are trying to unpack its vibrational properties through molecular-based sound spectra, which could hold one key to stopping the virus. Buehler recently sat down to discuss the art and science of his work.

Q:Your work focuses on the alpha helix proteins found in skin and hair. Why makes this protein so intriguing?

A: Proteins are the bricks and mortar that make up our cells, organs, and body. Alpha helix proteins are especially important. Their spring-like structure gives them elasticity and resilience, which is why skin, hair, feathers, hooves, and even cell membranes are so durable. But theyre not just tough mechanically, they have built-in antimicrobial properties. With IBM, were trying to harness this biochemical trait to create a protein coating that can slow the spoilage of quick-to-rot foods like strawberries.

Q:How did you enlist AI to produce this silk protein?

A:We trained a deep learning model on the Protein Data Bank, which contains the amino acid sequences and three-dimensional shapes of about 120,000 proteins. We then fed the model a snippet of an amino acid chain for honeybee silk and asked it to predict the proteins shape, atom-by-atom. We validated our work by synthesizing the protein for the first time in a lab a first step toward developing a thin antimicrobial, structurally-durable coating that can be applied to food. My colleague,Benedetto Marelli, specializes in this part of the process. We also used the platform to predict the structure of proteins that dont yet exist in nature. Thats how we designed our entirely new protein in the APL Bioengineering study.

Q: How does your model improve on other protein prediction methods?

A: We use end-to-end prediction. The model builds the proteins structure directly from its sequence, translating amino acid patterns into three-dimensional geometries. Its like translating a set of IKEA instructions into a built bookshelf, minus the frustration. Through this approach, the model effectively learns how to build a protein from the protein itself, via the language of its amino acids. Remarkably, our method can accurately predict protein structure without a template. It outperforms other folding methods and is significantly faster than physics-based modeling. Because the Protein Data Bank is limited to proteins found in nature, we needed a way to visualize new structures to make new proteins from scratch.

Q: How could the model be used to design an actual protein?

A: We can build atom-by-atom models for sequences found in nature that havent yet been studied, as we did in the APL Bioengineering study using a different method. We can visualize the proteins structure and use other computational methods to assess its function by analyzing its stablity and the other proteins it binds to in cells. Our model could be used in drug design or to interfere with protein-mediated biochemical pathways in infectious disease.

Q:Whats the benefit of translating proteins into sound?

A: Our brains are great at processing sound! In one sweep, our ears pick up all of its hierarchical features: pitch, timbre, volume, melody, rhythm, and chords. We would need a high-powered microscope to see the equivalent detail in an image, and we could never see it all at once. Sound is such an elegant way to access the information stored in a protein.

Typically, sound is made from vibrating a material, like a guitar string, and music is made by arranging sounds in hierarchical patterns. With AI we can combine these concepts, and use molecular vibrations and neural networks to construct new musical forms. Weve been working on methods to turn protein structures into audible representations, and translate these representations into new materials.

Q: What can the sonification of SARS-CoV-2's "spike" protein tell us?

A: Its protein spikecontains three protein chains folded into an intriguing pattern. These structures are too small for the eye to see, but they can be heard. We represented the physical protein structure, with its entangled chains, as interwoven melodies that form a multi-layered composition. The spike proteins amino acid sequence, its secondary structure patterns, and its intricate three-dimensional folds are all featured. The resulting piece is a form of counterpoint music, in which notes are played against notes. Like a symphony, the musical patterns reflect the proteins intersecting geometry realized by materializing its DNA code.

Q: What did you learn?

A: The virus has an uncanny ability to deceive and exploit the host for its own multiplication. Its genome hijacks the host cells protein manufacturing machinery, and forces it to replicate the viral genome and produce viral proteins to make new viruses. As you listen, you may be surprised by the pleasant, even relaxing, tone of the music. But it tricks our ear in the same way the virus tricks our cells. Its an invader disguised as a friendly visitor. Through music, we can see the SARS-CoV-2 spike from a new angle, and appreciate the urgent need to learn the language of proteins.

Q: Can any of this address Covid-19, and the virus that causes it?

A:In the longer term, yes. Translating proteins into sound gives scientists another tool to understand and design proteins. Even a small mutation can limit or enhance the pathogenic power of SARS-CoV-2. Through sonification, we can also compare the biochemical processes of its spike protein with previous coronaviruses, like SARS or MERS.

In the music we created, we analyzed the vibrational structure of the spike protein that infects the host. Understanding these vibrational patterns is critical for drug design and much more. Vibrations may change as temperatures warm, for example, and they may also tell us why the SARS-CoV-2 spike gravitates toward human cells more than other viruses. Were exploring these questions in current, ongoing research with my graduate students.

We might also use a compositional approach to design drugs to attack the virus. We could search for a new protein that matches the melody and rhythm of an antibody capable of binding to the spike protein, interfering with its ability to infect.

Q: How can music aid protein design?

A: You can think of music as an algorithmic reflection of structure. Bachs Goldberg Variations, for example, are a brilliant realization of counterpoint, a principle weve also found in proteins. We can now hear this concept as nature composed it, and compare it to ideas in our imagination, or use AI to speak the language of protein design and let it imagine new structures. We believe that the analysis of sound and music can help us understand the material world better. Artistic expression is, after all, just a model of the world within us and around us.

Co-authors of the study in Extreme Mechanics Letters are: Zhao Qin, Hui Sun, Eugene Lim and Benedetto Marelli at MIT; and Lingfei Wu, Siyu Huo, Tengfei Ma and Pin-Yu Chen at IBM Research. Co-author of the study in APL Bioengineering is Chi-Hua Yu. Buehlers sonification work is supported by MITs Center for Art, Science and Technology (CAST) and the Mellon Foundation.

Link:
Q&A: Markus Buehler on setting coronavirus and AI-inspired proteins to music - MIT News

Beef Wellington for Christmas Dinner, Thursday, Dec. 5, 2019. Photo by Hillary Levin, hlevin@post-dispatch.com

Yield: 8 to 10 servings

3 pints (1 pounds) white button mushrooms

2 shallots, peeled and roughly chopped

4 garlic cloves

8 sprigs fresh thyme, leaves only, divided

Salt and pepper

1 (3-pound) center-cut beef tenderloin, trimmed

Olive oil

12 thin slices prosciutto

2 tablespoons Dijon or English mustard

Flour, for rolling out puff pastry

1 pound puff pastry, homemade (see recipe) or store-bought, thawed if frozen.

2 large eggs, lightly beaten

teaspoon coarse sea salt

Note: The duxelles and the homemade puff pastry (if using) can be made a day or two ahead of time.

1. For the duxelles: Add mushrooms, shallots, garlic and the leaves of 2 of the sprigs of thyme to a food processor and pulse until finely chopped. Place a large saut pan over medium heat, add the shallot-and-mushroom mixture, and saut until most of the liquid it releases has evaporated. Season with salt and pepper, and set aside to cool. May be refrigerated for up to 3 days.

2. For the beef: Tie the tenderloin in 4 places so it holds its cylindrical shape while cooking. Drizzle with olive oil, then season with salt and pepper and sear all over, including the ends, in a hot, heavy-bottomed skillet lightly coated with olive oil.

3. Meanwhile, set out your prosciutto on a sheet of plastic wrap at least a foot and a half in length. Shingle the prosciutto so it forms a rectangle that is big enough to encompass the entire filet of beef. Using a rubber spatula, cover prosciutto evenly with a thin layer of duxelles, and season with salt and pepper. Sprinkle with leaves from the remaining 6 sprigs of thyme.

4. When the beef is seared, remove from heat, cut off twine and smear lightly all over with mustard. Allow to cool slightly, then roll up in the duxelles-covered prosciutto, using the plastic wrap to tie it up tightly. Tuck in the ends of the prosciutto as you roll to completely encompass the beef. Twist ends of plastic to seal it completely and hold it in a log shape. Refrigerate 30 minutes to ensure it maintains its shape.

5. Preheat oven to 425 degrees.

6. On a lightly floured surface, roll out the puff pastry to form a rectangle large enough to completely encompass the beef (this is vital if necessary, overlap 2 sheets and press them together). Remove plastic from beef and set meat in middle of the pastry. Fold the longer sides over the meat, brushing the edges with beaten egg to seal. Brush ends with beaten egg to seal, and fold over to completely seal the beef. Trim ends if necessary. Top with coarse sea salt. Place seam-side down on a baking sheet.

7. Brush the top of the pastry with egg, then make a few slits in the top of the pastry, using the tip of a paring knife, to allow steam to escape while cooking. Bake 35 to 45 minutes until pastry is golden brown and beef registers 125 to 130 degrees on a meat thermometer for medium rare, 135 to 140 degrees for medium, 140 to 145 degrees for medium well or 150 to 155 for well done.

8. Allow to rest before cutting into thick slices.

Per serving (based on 8): 762 calories; 41g fat; 11g saturated fat; 194mg cholesterol; 64g protein; 33g carbohydrate; 3g sugar; 2g fiber; 1,779mg sodium; 68mg calcium

Adapted from a recipe by Tyler Florence, via Food Network

ROUGH PUFF PASTRY

Yield: 12 servings

2 cups all-purpose flour, preferably chilled

teaspoon fine sea salt

20 tablespoons (2 sticks) unsalted butter, chilled and diced

cup ice-cold water

Note:This is best prepared in a cool kitchen, on a cool work surface, using light and assertive gestures to prevent overheating the dough. Dont attempt it when the oven is on.

1.In a medium bowl, sift together the flour and salt. Using a pastry blender or two knives, cut the butter into the flour, stopping when the mixture looks crumbly but fairly even, with the average piece of butter about the size of a large pea.

2.Turn out onto a clean and cool work surface and form a well in the center. Pour in the water and work it into the flour and butter mixture with a bench scraper or a wooden spoon. Knead lightly, just enough so that the dough comes together in a ball, and shape into a rough square. There should be little pieces of butter visible in the dough. If you have time, refrigerate 30 minutes.

3.Flour your work surface lightly. Using a lightly floured rolling pin, roll out the dough in one direction into a rectangle about 20 inches long. Add more flour as needed to prevent sticking. Brush to remove excess flour and fold the dough in three, like a letter, so the top and bottom overlap, dusting again after the first fold.

4.Give the dough a quarter of a turn, and repeat the rolling and folding steps. Repeat until youve rolled and folded a total of four times. You should get a neat rectangle or square pad of dough. If you find the dough becomes sticky at any point, refrigerate for 30 minutes to cool again.

5.Put the dough on a plate, cover and refrigerate for at least 1 hour or overnight before using. If the dough seems too stiff when you take it out of the fridge, let it come to room temperature for 15 to 20 minutes before using.

Per serving:246 calories; 19g fat; 12g saturated fat; 51mg cholesterol; 2g protein; 16g carbohydrate; no sugar; 1g fiber; 100mg sodium; 9mg calcium

Adapted from Tasting Paris, by Clotilde Dusoulier

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Our best recipes from 2019 | Food and cooking - STLtoday.com

Its time to relax and do some reading. While youre waiting to tuck into some turkey, put your feet up and settle into some of the best long reads weve published this year.

Here is a selection of our best long form journalism from 2019. Not enough? You can find even more of our in-depth journalism in our long form archive. And well be back in 2020 with more stories about how science and technology are changing our world, for better or worse.

Samples in United Neuroscience's laboratory

Alzheimers robs patients of their memories, as plaque builds in the brain, fibres get tangled and connections are lost between nerve cells. When Mei Mei Hu realised her mother, Chang Yi Wang, had created a completely unique vaccine to prevent the disease, she urged her to set up a new company. At United Neuroscience, the mother and daughter duo have combined their scientific and consulting knowledge to find a potential cure that has long eluded researchers. And Alzheimers isnt the only disease in their sights cancer and HIV are next on the list.

Read the full story

Economist Mariana Mazzucato has demonstrated that the real driver of innovation isn't lone geniuses but state investment. Her work to break down tired myths about innovation is now informing governments around the world. Shes currently working with the UK government, EU and UN to apply her moonshot approach to the world's biggest challenges.

Read the full story

In 2010, SoftBank Group CEO Masayoshi Son unveiled his 300-year vision for the future. The company's $100 billion investment arm, the Vision Fund is the biggest tech fund in history

Ryan Pfluger / August

SoftBank is taking over tech one company at a time, with Masayoshi Son as its leader. In 2017 he compared the company to the gentry of the Industrial Revolution the powerful, monied few who funded huge technological and societal changes. Softbank owns stakes in Uber, WeWork and Sprint, among others, and while it may not be a household name like Google or Microsoft, Son has been striving for decades to make it the biggest company in the world.

Read the full story

A Jakarta resident wades past a flooded mosque near the waterfront

Christoffer Rudquist

Jakarta, one of the worlds fastest growing megacities, has a problem: its sinking. Taking clean water from the underground reservoirs that prop up the city means it is slowly collapsing into the mud. The number of people in the city and the timescale needed to solve the problem means that authorities are scrambling to save the Indonesian capital. But the desperate efforts could come too late.

Read the full story

16-year-old Greta Thunberg has mobilised millions of young people to demand action on the world's climate crisis

AORTA

Greta Thunberg has become the face of the climate crisis protest movement, travelling across the world to urge those in power to act decisively before its too late. Despite her 3.7 million Twitter followers and nine million Instagram followers, the 16-year-old doesnt see herself as a celebrity. I just hope that this movement will continue and we do something about the climate because that is the only thing that matters.

Read the full story

Angela Saini's new book, Superior, exposes the re-emergence of dangerous race science based on genetics

Sebastian Nevols

In the world of genetics, race has long been a factor that scientists have tried to pin down. Some have tried to say that certain races are less intelligent, or more adept at certain tasks. And when a study is published appearing to corroborate such claims, racists eat it up. We keep looking into race, but find very little. In this edited extract from her book, Superior, Angela Saini examines the dangerous belief that with enough data, science could take race a set of categories invented by the powerful to control the weak and somehow make it real.

Read the full story

Makenna Kelly, 13. Her YouTube channel, Life With MaK, has nearly 1.4 million subscribers

JUCO

Makenna Kelly, a 13-year old YouTube star, gets sent money to eat cookies, drink milk and tap on objects for money. $50 buys a ten minute video, while $30 gets you five minutes. Its all in the name of ASMR the euphoric feeling people get from certain audio stimuli. But videos like these are controversial. Is it right for children as young as five to make videos that give adults brain orgasms?

Read the full story

When the first Fast Radio Bursts, or FRBs were detected by a physics student, it seemed like an incredibly rare phenomenon. Now astronomers agree that one probably happens every second. Thanks to Yuri Milner, a US-based Israeli-Russian billionaire, and his obsession with finding extraterrestrial life, one of the most complex and far-reaching scans has received much-needed funding.

Read the full story

Amos Chapple / Radio Free Europe / Radio Liberty

As global temperatures rise, Siberia is melting. Amongst the thawing tundra, hunters are searching for tusks. China banned the import and sales of elephant ivory in 2017, but finding long-dead mammoths provides a loophole. While it may seem like a safe option, encouraging ivory sales is fraught with risk.

Read the full story

DeepMind co-founder and CEO Demis Hassabis

Jason Madara

DeepMind's algorithms have conquered games. Now they're taking on something much harder: science. In September we profiled the Google-owned artificial intelligence firm as it sets its smarts on protein folding, which biologists consider to be the building blocks of life. As it continues to pursue its stated mission to solve intelligence, we go inside the secretive London firm to explore exactly what its up to.

Read the full story

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The best WIRED long reads of 2019 - Wired.co.uk

Cookies are as much a part of Christmas as candles and caroling. They are the gift that everyone loves, the holiday snack supreme. In many respects, they are the reason for the season.

And it is not just in America, by any means. In other parts of the world, too.

So this year, I decided to make holiday cookies from around the globe. To be honest, most of them come from Europe, because many of the best cookies come from there.

Ill start with New Mexico's state cookie,Biscochitos.They are typically served for big occasions and especially for the holidays. The crispy shortbread cookies are infused with anise and orange, and topped with a sprinkling of cinnamon sugar. In the version included here, I used shortening instead of lard.

Next we have Joulutorttu, Finnish Christmas pinwheels with a dollop of prune jam in the middle of each one. If you don't like the idea of prune jam, use raspberry jam. This recipe uses whipped cream and the dough is folded over on itself like puff pastry.

The French shortbread cookie recipe is the one chef Jacques Pepin makes every Christmas. You could think of them as a version of sabls, the traditional French shortbread cookie from Sabl-sur-Sarthe that are often made with almonds.

Austria's Vienna Tarts are flaky crescents rolled up around a bit of apricot jam, topped with chopped walnuts and powdered sugar.

Vanilla Kipferl also come from Austria. These tasty little treats are deceptive; they are easy to make, but they pack an enormous amount of flavor. In fact, my two taste testers said it was their favorite of all the cookies.

There are two reasons for the cookies being so addictive. One is that most of their bulk comes from toasted, ground almonds. And the other is the vanilla. Not only is there vanilla in the dough, but the cookies, once baked, are rolled in a mixture of superfine sugar and blended whole vanilla bean. They are sophisticated and delightful.

According to the King Arthur Flour Cookie Companion cookbook, Mailanderli are Switzerlands favorite holiday cookie. One taste is all it takes to understand why. These crisp and buttery cookies have a subtle flavor of lemon.

And finally, Chocolate-Glazed Lebkuchen is a cookie bar treat from Germany made with a spiced honey cake. With its cinnamon, cardamom, cloves, nutmeg and ginger, plus its candied fruit, it tastes just like the holidays.

And the chocolate glaze on top? Thats like a special Christmas present to you and your friends.

Yield: About 25 cookies

3 cups all-purpose flour

1 1/2 teaspoons baking powder

1/2 teaspoon salt

1 tablespoon anise seed, crushed

Zest of 1 orange

1 1/4 cups lard or vegetable shortening

3/4 cup plus 1/2 cup granulated sugar, divided

1 large egg

1 teaspoon vanilla extract

1 teaspoon ground cinnamon

1. In a large bowl, sift together flour, baking powder and salt. Whisk in the anise and orange zest.

2. In a separate bowl, combine 3/4 cup of the sugar and the lard or shortening. Using an electric mixer, beat the lard or shortening and sugar until light and fluffy, about 3 minutes. Add the egg and vanilla and beat to combine. Gradually beat in the flour mixture and stop as soon as mixture is combined. Dough should be thick and similar in consistency to pie crust dough. Refrigerate for 30 minutes.

3. Preheat oven to 350 degrees. Line baking sheet with parchment paper. In a small bowl, combine the remaining 1/2 cup sugar and cinnamon for topping.

4. On a lightly floured surface, roll out dough to 1/4-inch thickness. Cut out cookies (a 21/2-inch cookie cutter yields a good size). Place cookies on prepared baking sheet and bake until just barely golden and set, about 10 to 12 minutes. Be careful not to overcook. Let cookies cool for 1 minute, then carefully dunk them into the sugar mixture. Place on cookie rack until completely cooled.

Per cookie: 157 calories; 9 g fat; 3g saturated fat; 15 mg cholesterol; 2 g protein; 18 g carbohydrate; 6 g sugar; 1 g fiber; 50 mg sodium; 24 mg calcium

Recipe by somethewiser.com

Yield: Around 45 cookies

2 sticks plus 2 tablespoons butter

1 1/4 cups granulated sugar

3 large eggs, at room temperature

3/4 teaspoon salt

1 tablespoon finely grated lemon zest, or 1/8 teaspoon lemon oil

4 1/3 cups all-purpose flour

1 egg yolk plus 1 teaspoon milk, for brushing

1. In a large mixing bowl, beat the butter until soft and creamy. Beat in the sugar. Add the eggs, one at a time, beating well after each addition; scrape down the sides of the bowl once or twice while adding the eggs. Beat in the salt and the lemon zest.

2. Sift the flour and add it, half at a time, to the butter mixture. Mix only until the flour is well incorporated. Gather the dough into a bowl, flatten it into a disk, and refrigerate it for 2 to 3 hours, or overnight.

3. Preheat the oven to 350 degrees. Lightly grease (or line with parchment paper) 2 or 3 baking sheets.

4. Remove the dough from the refrigerator. If its very hard, allow it to warm a little before trying to roll it out. Its best to work with small pieces, about 1/4 of the dough at a time; refrigerate the rest until youre ready to roll it out. On a lightly floured work surface, or between two pieces of plastic wrap, roll the dough to a 1/8-inch thickness. Cut out different shapes with cookie cutters dipped in flour. Transfer the dough to the prepared baking sheets. Re-roll the scraps to make more cookies.

5. Mix the egg yolk and milk in a bowl. Brush the cookies with the egg wash. If possible, refrigerate the cookies for 10 to 15 minutes before baking.

6. Bake the cookies in the middle of the oven for 10 minutes or until theyre an even, pale golden brown. Remove the cookies from the oven. Transfer the baking sheets to a rack to cool almost completely, then transfer to a rack.

Per cookie: 112 calories; 5 g fat; 3 g saturated fat; 29 mg cholesterol; 2 g protein; 15 g carbohydrate; 6 g sugar; no fiber; 45 mg sodium; 6 mg calcium

Recipe from The King Arthur Flour Cookie Companion

Yield: Around 40 cookies

1 3/4 sticks (14 tablespoons) unsalted butter

1/2 teaspoon salt

7 tablespoons plus 1/4 cup granulated sugar, divided

1 teaspoon vanilla extract

1 3/4 cups all-purpose flour

Scant 2 1/3 cups almond flour (from ground almonds that have preferably been toasted)

1/2 to 1 vanilla bean

1. In a medium-sized bowl, beat together the butter, salt, 7 tablespoons of the sugar and vanilla extract until smooth. Add the flour and almond flour, stirring to make a cohesive dough. Wrap the dough in plastic wrap and refrigerate it for at least 1 hour, or overnight.

2. Preheat the oven to 350 degrees. Lightly grease (or line with parchment) two baking sheets.

3. Break off walnut-sized pieces of the dough, and roll them into short (about 2-inch) logs. Shape the logs into crescents, then gently press them to flatten them slightly. Place the cookies on the prepared sheets.

4. Bake for 8 to 10 minutes, until theyre a light, golden brown. Remove them from the oven and let cool on the pan for 10 minutes.

5. While the cookies are cooling, process the remaining 1/4 cup sugar and vanilla bean in a food processor or blender until the bean is thoroughly ground and the sugar is almost powdery. While the cookies are still warm, gently roll them in the vanilla sugar. Transfer them to a rack to cool completely.

Per cookie: 106 calories; 5 g fat; 3 g saturated fat; 11 mg cholesterol; 2 g protein; 9 g carbohydrate; 4 g sugar; no fiber; 30 mg sodium; 2 mg calcium

Recipe from The King Arthur Flour Cookie Companion

Yield: Around 30 cookies

3 cups all-purpose flour

1 teaspoon baking powder

1 1/2 cups heavy cream, whipped

1 cup unsalted butter, softened

1/2 cup plus 2 tablespoons prune jam (recipe follows) or raspberry jam

1 egg

1 tablespoon milk

Powdered sugar for sprinkling

1. In the bowl of a stand mixer fitted with a paddle attachment, combine the flour and baking powder. Mix in the whipped heavy cream, followed by the softened butter.

2. On a lightly floured surface, knead the dough until soft and smooth. Shape into a disc, wrap in plastic and refrigerate for at least 1 hour.

3. Preheat oven to 400 degrees. Line 2 baking sheets with parchment paper, or lightly grease.

4. On a lightly floured surface, roll out the dough until 1/4 inch thick. Fold the dough into thirds by folding one-third toward the center, followed by the other third toward the center (fold like a letter). Roll the dough out again, turn, and fold into thirds again along the other side to form the dough into a square. Roll out a third time to make a square about 1/4-inch thick.

5. Cut the sheet of dough into 3-inch squares. To make the traditional shape, use a sharp knife to make cuts from each quarter about halfway toward the center. Place a teaspoon of jam in the center of the square.

6. Lift every other split corner toward the center over the jam filing and pinch together in the middle to form a pinwheel shape. Place on the prepared baking sheets.

7. In a small bowl, beat together the egg and milk. Brush the top of each Joulutorttu with the beaten egg wash. Bake until golden, 7 to 10 minutes.

8. Allow to cool to room temperature and top with powdered sugar. Store in an airtight container if not serving immediately.

Per cookie: 160 calories; 11 g fat; 7 g saturated fat; 36 mg cholesterol; 2 g protein; 14 g carbohydrate; 2 g sugar; no fiber; 7 mg sodium; 30 mg calcium

Recipe from tarasmulticuturaltable.com

Yield: 1 3/4 cups

10 1/2 ounces pitted prunes

1/4 cup granulated sugar

1. Cover the prunes with water and soak for 2 hours. Drain, rinse, and place in a medium saucepan. Add the sugar, top with just enough water to cover, and place over high heat.

2. Once boiling, reduce heat to a simmer and cook, stirring often, until the prunes have softened and are easily mashed, about 20 minutes. If needed, add a little more water to keep the mixture from burning.

3. Mash the jam to desired consistency, or pure. Refrigerate until ready to use.

Per ( 2 tablespoon) serving: 86 calories; no fat; no saturated fat; no cholesterol; no protein; 23 g carbohydrate; 4 g sugar; no fiber; 1 mg sodium; 15 mg calcium

Recipe from tarasmulticulturaltable.com

Yield: 24 cookies

3/4 cup granulated sugar

1 cup plus 1 tablespoon honey

1 tablespoon water

4 tablespoons (1/2 stick) butter, cut into pieces

3/4 cup chopped unblanched almonds

1/3 cup finely chopped candied or dried pineapple (or any other good candied fruit)

1/3 cup lightly beaten egg (more than 1 large egg)

3 tablespoons fresh orange juice

1/2 teaspoon almond extract

1 2/3 cup sifted all-purpose flour

1 teaspoon baking powder

1/2 teaspoon baking soda

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Holiday cookies from around the world | Features - yoursun.com

As the 10 most important product innovations of 2019 showfrom plant-based burgers to alternate reality headsetsthe world still has plenty of room for innovation in meatspace. The brightest products of the past year arent just enticing or convenient for users. These products are often using design to question the ritual of consumption as we know it.

[Photo: Motorola]The original Motorola Razr (2004) changed the world of technology forever, turning clunky phones into sleek, fashion-forward objects of desire. The followup, 15 years later, features a folding OLED display. Its a mechanical marvel, and the first flexible screen device that makes any real sense at all, because it turns our too-large smartphones into pocketable devices. The Razr offers an early taste of the bendable, ergonomic electronics to come. [Link]

[Photo: Logitech]Video game controllers are now so advanced that the military uses them to control tanks and drones. But they require fine motor control that can leave people with disabilities behind. The Xbox Adaptive Controller launched last year, with two giant buttons and lots of extra input options to allow users to connect extra buttons as needed. Then, this year, Logitech decided to actually make those extra buttons. Its $99 kit includes mix-and-match hardware thats built less for profitability than the needs of diverse users. [Link]

[Photo: Air Co.]My dad always said there was no problem too great that you couldnt drink yourself out of it. Okay, that isnt true. But carbon-capturing vodka comes pretty close. A company called Air Co. uses recaptured carbon in the place of yeast to produce vodka. Each bottle scrubs the air as effectively as eight trees breathing for a day. And as an added bonus, Air Co.s production footprint needs just 500 to 1,000 square feet compared with the acres of land required by traditional distilling. Then take a sip while wearing this compelling, carbon-negative raincoat, and you wont have to worry about spilling on yourself. [Link]

[Photo: Motorola]First responders are going into some of the most dangerous places on earth, and in these places, your typical iPhone wont do because it relies on an infrastructure of fallible antennas to work. Instead, first responders still rely on long-range walkie-talkies. Anew walkie-talkie from Motorola Solutions, the APX Next, can be used both hands-free and without an operator on the other end of the line, thanks to a novel voice assistant that helps you access private information without direct internet access. Siri may be an overrated way to find sushi. But the APX Next can literally help save lives; as a firefighter or police officer uses two hands to free someone from a pile of rubble, she can use the APX Next to simultaneously call for help. [Link]

[Photo: Analogue]The Nintendo Switch is the best portable gaming system ever madethanks to a perfect size, a massive library of games, the option to seamlessly dock it to a TV, and controllers that put smartphones to shame. And yet, 2019 brought us two compelling handheld video game consoles (both expected to be released in 2020). Each proves that the independent spirit of hardware design is alive and well.

Analogue Pocket is a $199 Game Boy reboot, which runs vintage console cartridges but in an industrial design that meshes stark minimalism with a cutting-edge display. Oh, its also an instrument for electronic music. What? [Link]

The Playdate is another enticing bit of gaming hardware, but its more experimental. A surprising crank on the side offers a zany way to play games. And its being released with software partners who are designing new, bite-sized titles for the Playdate and the Playdate alone. Playdate teased a model in which you could buy new seasons of games in packs, and in doing so, Playdate is combining a closed hardware/software ecosystem in a way that only giants such as Apple and Nintendo have ever managed to pull off. [Link]

[Photos: Impossible Foods, Burger King]If 2019 was the year of anything, it was the year of fake meat. Beyond Meat and Impossible both made their mainstream mark. The Impossible Whopperwas such a hit, it gave Burger King its best quarter in four years, cementing nearly a decade of investment in the biology, flavor, and mouthfeel behind a fully engineered burger.Even if faux meats dont outright replace real meat, a little savings in the flexitarian market goes a long way: A pound of beef costs 1,800 gallons of water on top of all sorts of other environmental hazards, which is why experts would like to see beef consumption drop by 50% to save the planet. The Impossible Whopper might not be the best burger youve ever had, but then again, neither is anything else you get at Burger King. [Link]

[Photo: Microsoft]If theres a more complicated industrial design story in 2019 than how Microsoft designed the Hololens 2 augmented reality headset, I havent read it. Its an AR headset that goes on as easily as a baseball cap, making it easy and effortless to hop into the digital world. The combination of materials and hard and soft parts in this design is staggering. And its full of tiny decisions of ergonomics, which work in harmony with technology that requires picometer-level precision (if some parts of the headset come out of the tiniest threshold of alignment, it would literally make you want to vomit). [Link]

[Photo: courtesy Korvaa]The headband is made from lactic acid produced by yeast. The ear padding is a bubbling protein produced by fungus. The leather is mycelium, or the core of a mushroom. And the mesh on your ears is biosynthetic spider silk. Dubbed Korvaa, this is the worlds first microbe-grown pair of headphones. And they are beautiful in their own way. As we reckon with our environmental footprint, projects such as Korvaa are a reminder that there really is another way than simply producing more plastic. [Link]

[Photo: Adidas]The Adidas Loop is a shoethat can be ground down at the end of its life and used to help make new Loop shoes. Whether its the textiles made from plastic, or the business modelwhich may require Adidas to incentivize buybacks of old shoes to make new onesLoop teases an increasingly complicated future for consumer goods (and consumption) in which companies and customers alike are forced to deal with the long-term impacts of products. None of this would matter if Loop shoes were terrible, of course. But they are also a tantalizing garment in their own right, with a shimmery woven plastic thats both beautiful and comfortable. [Link]

Read more:

The 10 most compelling product innovations of 2019 - Fast Company

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Latest Study by Grand View Research, Inc. titled Biologics Market Analysis By Source (Microbial, Mammalian), By Products (Monoclonal Antibodies, Vaccines, Recombinant Proteins, Antisense, RNAi), By Disease Category, By Manufacturing, & Segment Forecasts, 2018 - 2025 announce that the global biologics market is anticipated to reach USD 399.5 billion by 2025, according to a new report by Grand View Research, Inc. Introduction of targeted therapies coupled with rising adoption of patient centric personalized medicine anticipated to fuel demand. Ever-increasing understanding of the cell physiology and stress, as well as the factors involved in protein production and heterologous gene expression have empowered the use of different living factories.

Some key findings from the report:

These living factories are the prokaryotic and eukaryotic cells. Enhancement of drug functionality through achieving successful protein folding and post-translational modifications is supportive for projected progress rate.

Moreover, rising adoption of biopharmaceuticals over chemically synthesized molecules is expected to propel revenue generation significantly. In addition to this, presence of several metabolic disorders that can be treated through the use of biologics is attributive to influence demand.

Combination of advanced bioengineering technologies for biopharmaceutical production is expected to boost progress in pharmaceutical industry. With recent advances in automation, the selection process can be done through high throughput screening (HTS) system for selection of viable clones.

Aforementioned method enables robust production of biopharmaceutical products by obtaining high-producing cell line. Advances with respect to upstream and downstream processing would directly translate into the growth in revenue for this market at a larger level.

However, development of biosimilars is expected to restrain the biologics year on year growth to certain extent. Although, the regulatory approval pathway for these products is not framed yet some drug manufacturers are opting to invest in the development of biobetters.

For More Details Please Visit To This Link: https://www.grandviewresearch.com/industry-analysis/biologics-market/

The final report on global biologics market has been segmented on the basis of application and region:

Biologics Source Outlook (Revenue, USD Billion, 2014 - 2025)

Biologics Product Outlook (Revenue, USD Billion, 2014 - 2025)

Biologics Manufacturing Outlook (Revenue, USD Billion, 2014 - 2025)

Biologics Disease Category Outlook (Revenue, USD Billion, 2014 - 2025)

Biologics Regional Outlook (Revenue, USD Billion, 2014 - 2025)

Get Sample of biologics market @ https://www.grandviewresearch.com/industry-analysis/biologics-market/request/rs1/

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Biologics Market Size Expand at a CAGR of 3.9 With $399.5 Billion By 2025 - MENAFN.COM

Parkinsons and multisystem atrophy (MSA) both of them neurodegenerative diseases are associated with the accumulation of alpha-synuclein proteins in the brain. Researchers at the German Center for Neurodegenerative Diseases (DZNE) and the Max Planck Institute for Biophysical Chemistry (MPI-BPC) have investigated the molecular makeup of these protein deposits finding structural diversity. Experts from South Korea, Australia, and Argentina were also involved in the study. The results suggest that Parkinsons might be related to diverse types of protein aggregates.

Alpha-synuclein is a protein that occurs naturally in the body. It is assumed to be involved in signal transmission between neurons. The protein appears both at the cell membrane and solved floating, so to speak - in the cells interior. In addition to these normal variants, there are others that manifest in brain diseases. This applies e. g. to Parkinsons disease and MSA. Both can be associated with various neurological impairments, including movement disorders. In Parkinsons and MSA alpha-synuclein molecules stick together. As a result, elongated aggregates arise that are deposited inside neurons and other brain cells. These deposits successively appear in various areas of the brain. They are a disease hallmark, explains Prof. Markus Zweckstetter, who heads a research group at the DZNE and the MPI-BPC. There is evidence that these aggregates are harmful to neurons and promote disease progression.

A matter of folding

These deposits represent a potential starting point for medicines. The idea is that drugs might prevent alpha-synuclein molecules from sticking together or dissolve existing aggregates. To identify potential docking sites for agents, data on the aggregates fine structure is required. Thus, the question is: What kind of shape (also known as folding) do the molecules adopt within the aggregates? So far, information on this topic had been limited to data from laboratory experiments. Previous studies investigated the molecular structure of aggregates that were synthesized in a test tube. We asked ourselves how well such artificially produced specimens reflect the patients situation. That is why we studied aggregates generated from tissue samples from patients, said Zweckstetter. We collaborated closely with international partners on this project. In fact, the tissue samples originated in Australia and the aggregates were synthesized in South Korea. We then did the structural studies in Gttingen.

Aggregates from brain samples taken from five deceased Parkinsons patients and five deceased MSA patients were examined. For comparison, the researchers artificially produced different variants of alpha-synuclein aggregates. For this, they used standard procedures. To compare the structure of the different aggregates, they applied nuclear magnetic resonance spectroscopy and other methods.

Structural differences

We found that aggregated proteins that came from the lab were structurally different to all aggregates generated from patient material, Dr. Timo Strohker, first author of the study, commented on the findings. In addition, proteins of MSA patients differed from those of Parkinsons patients. If one looks at the data more closely, you notice that the proteins of the MSA patients all had a largely similar shape. The proteins of the patients with Parkinsons were more heterogeneous. When comparing the proteins of individual Parkinsons patients, there is a certain structural diversity.

The alpha-synuclein proteins of all aggregates contain beta sheets, which is in line with previous investigations. Accordingly, the molecular backbone is twisted in a way that the proteins are largely two-dimensional. Within the aggregates, the proteins stick together in layers. However, folding does not encompass the whole protein. Each protein also contains areas that are unstructured. Besides, orientation of the beta sheets bears significance. It is a question of how much of a protein is folded and also how it is folded, Zweckstetter stated.

Various types of aggregates in Parkinsons

In the structure of the alpha-synuclein associated with Parkinsons, there were some significant differences between patients. This might be due to the fact that the course of Parkinsons can vary quite considerably between individuals. The variability of Parkinsons disease could be related to differences in the folding of aggregated alpha-synuclein. This would be in contrast to the one disease-one strain hypothesis, that is to say that Parkinsons disease is associated with one, clearly defined aggregate form. However, in view of our relatively small sample of five patients, this is just a guess, said Zweckstetter. Yet, our results certainly prove that studies with tissue samples from patients are necessary to complement lab experiments in a sensible way.

Reference

Strohker et al. (2019) Structural heterogeneity of -synuclein fibrils amplified from patient brain extracts. Nature Communications. DOI: https://doi.org/10.1038/s41467-019-13564-w

This article has been republished from the following materials. Note: material may have been edited for length and content. For further information, please contact the cited source.

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Exploring the Diversity of Parkinson's Proteins - Technology Networks

Dec 23, 2019 05:03 AM EST

Origami's new role in the field of science and technology has definitely taken a turn for the better in the recent decade. Better known as origami engineering, the practice is used to reduce structures or maximize space and function.

Origami engineering has made great strides in the medical field in particular. The same principles used in origami, when applied to medical devices, allows implants to be folded to minuscule sizes and then unfolded to its actual size. The reverse is also applicable, where like toothpaste tubes, can be fully de-compressed.

Folding techniques could transform flat objects with wrinkles to increase resilience, shock-absorbance, strength, or rigidity. Origami provides a unique insight into how single pieces could sustainably be packaged without cutting, welding, or riveting, allowing for cheaper manufacturing costs and easier assembly.

The utility of origami engineering has captured the attention of people such as Rebecca Taylor, assistant professor at Carnegie Mellon University's Department of Mechanical Engineering. Taylor specializes in microfabrication and biomechanics, a study that has helped her fabricate microscale sensors to reliably assess cardiomyocytes derived from stem cells. A natural inclination to similar practice, Dr. Taylor has developed an origami-based DNA synthetic cardiac contractile protein, which allowed her to observe merging mechanics in multiprotein, acto-myosinc contractile systems.

As a professor, Taylor expands on the utilization of DNA origami in medicine. This technique (also referred to by Dr. Taylor as "bottom-up manufacturing"), allows improvement in nanomanufacturing and nanomechanics of multiprotein systems, paving the way for heart stents that could unfold in a very precise location.

The problem, however, is on how to deploy these structures in a 100% fault-free way. To illustrate this, a common problem that impedes the creation of pop-up tents that could self-assemble at the press of the button is when the folds of the tent get stuck during the folding process on occasion.

Understandably, this raises some concern among those who are keen to use self-folding nanomachines in medicine.

So this is where origami comes in.

According to University of Chicago scientists, the limits of self-folding structures could be intrinsic in that so-called "sticking points" seem to be unavoidable.

Previously thought possible to engineer around, the researchers observed the capacity of foldable structures by creating mathematical models. During the experiment, the team had designed structures capable of self-folding, such as paper origami and nanobots, and creating creases in them beforehand. The result was that when more pre-creases were added to the folds, the more branches in the next folding process could form and the more likely the self-folding mechanism is to get stuck.

Origami engineering is a relatively new innovation. Its application is vast and can be of use to not only technology but to medicine as well. The development of the field itself, then, needs to pick up at a faster pace in order to cater to the intelligent design of foldable structures and materials. But while there are creases in the field that needs to be smoothed out, the greater promise of origami engineering has brought about several research papers in its wake.

RELATED ARTICLE: Swallowed a Battery? Ingestible Origami Robot Made from Pig Gut Can Remove It,Stop Stomach Bleeding

2018 NatureWorldNews.com All rights reserved. Do not reproduce without permission.

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The Art of Origami is Now A Key Tool That Helps Doctors Save Lives - Nature World News

Associate Professor Roger Pocock, from the Monash Biomedicine Discovery Institute (BDI), and colleagues from the University of Cambridge led by Professor David Rubinsztein, found that microRNAs are important in controlling protein aggregates, proteins that have amassed due to a malfunction in the process of folding that determines their shape.

Their findings were published in eLife on December 4, 2019.

MicroRNAs, short strands of genetic material, are tiny but powerful molecules that regulate many different genes simultaneously. The scientists sought to identify particular microRNAs that are important for regulating protein aggregates and homed in on miR-1, which is found in low levels in patients with neurodegenerative diseases such as Parkinsons disease.

The sequence of miR-1 is 100 percent conserved; its the same sequence in the Caenorhabditis elegans worm as in humans even though they are separated by 600 million years of evolution, Associate Professor Pocock said.

We deleted miR-1 in the worm and looked at the effect in a preclinical model of Huntingtons and found that when you dont have this microRNA theres more aggregation, he said. This suggested miR-1 was important to remove Huntingtons aggregates.

The researchers then showed that miR-1 helped protect against toxic protein aggregates by controlling the expression of the TBC-7 protein in worms. This protein regulates the process of autophagy, the bodys way of removing and recycling damaged cells and is crucial for clearing toxic proteins from cells.

When you dont have miR-1, autophagy doesnt work correctly and you have aggregation of these Huntingtons proteins in worms, Associate Professor Pocock said.

Professor Rubinsztein then conducted research which showed that the same microRNA regulates a related pathway to control autophagy in human cells.

Expressing more miR-1 removes Huntingtons aggregates in human cells, Associate Professor Pocock said.

Its a novel pathway that can control these aggregation-prone proteins. As a potential means of alleviating neurodegenerative disease, its up there, he said.

Additional work by Associate Professor Pococks colleagues showed that when human cells are supplied with a molecule called interferon-b the miR-1 pathway is upregulated, revealing a way of manipulating it.

He said the studies demonstrated the fundamental importance of discovery research. We asked a fundamental biological question to dissect a molecular mechanism that now is shown to be really important for potential therapies.

The researchers have provisionally patented their findings and are in discussions with pharmaceutical companies about translating the research. They will further test it in preclinical models for Huntingtons and Parkinsons disease.

Reference: Interferon--induced miR-1 alleviates toxic protein accumulation by controlling autophagy by Camilla Nehammer, Patrick Ejlerskov, Sandeep Gopal, Ava Handley, Leelee Ng, Pedro Moreira, Huikyong Lee, Shohreh Issazadeh-Navikas, David C Rubinsztein and Roger Pocock, 4 Dcember 2019, eLife.DOI: 10.7554/eLife.49930

This research was supported by the Australian NHMRC.

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Ancient Worm Reveals Way to Destroy Toxic Cells Potential New Therapy for Huntingtons and Parkinsons - SciTechDaily