All the latest Covid-19 news from around the world.

Five new Covid-19 cases have been recorded among prison inmates and three Department of Correctional Services officials have recovered.

Eleven members of the Secret Service have tested positive for COVID-19, according a new report. Yahoo News reported Friday it has seen Department of Homeland Security documents which show that 11 individuals currently have the virus and that 23 members of the Secret Service have recovered from the disease. Another 60 employees of the agency…

The post Report: Secret Service Discovers Nearly a Dozen Coronavirus Cases in Its Own Ranks appeared first on The Western Journal.

Data Governance sounds like a candidate for the most boring topic in technology: something dreamed up by middle-managers to add friction to data scientists’ lives. The funny thing about governance, though, is that it’s closely related to data discovery. And data discovery is neither dull nor additional friction; it’s an exciting process that enables great […]

Nicholas Love's Penguin Classics cover generator lets you upload an image and set type in humorous imitation of the label. It can also do the similar but inverted Oxford World Classics look. But sadly not the classic classics look.

Many excellent designs in this twitter thread; embedded here is my contribution. Read the rest

Dr. Deena Hinshaw, who reported 81 new cases of the disease in her daily update, says there are 4,020 recovered and 1,963 active cases.

Grey Bruce provincial police say the OPP canine unit found human remains in Meaford, and one person is under arrest.

The following article, BREAKING: 43-Yr-Old Father Of 9, Dollar Store Sec Guard, Shot DEAD While Allegedly Trying To Enforce MI Gov Whitmer’s Face Covering Exec Order, was first published on 100PercentFedUp.com.

Will the mainstream media report about the senseless death of a 43-year-old father of nine, who would have been alive today if it were not for VP wannabe, Gretchen Whitmer's executive order that forced him to respond to a customer not wearing a face mask? 

Continue reading: BREAKING: 43-Yr-Old Father Of 9, Dollar Store Sec Guard, Shot DEAD While Allegedly Trying To Enforce MI Gov Whitmer’s Face Covering Exec Order ...

After being pulled over for what started as a traffic violation, two Windsor men were arrested and face multiple drug, property, and weapon related charges.

The rapid emergence and dissemination of methicillin-resistant Staphylococcus aureus (MRSA) strains poses a major threat to public health. MRSA possesses an arsenal of secreted host-damaging virulence factors that mediate pathogenicity and blunt immune defenses. Panton–Valentine leukocidin (PVL) and α-toxin are exotoxins that create lytic pores in the host cell membrane. They are recognized as being important for the development of invasive MRSA infections and are thus potential targets for antivirulence therapies. Here, we report the high-resolution X-ray crystal structures of both PVL and α-toxin in their soluble, monomeric, and oligomeric membrane-inserted pore states in complex with n-tetradecylphosphocholine (C14PC). The structures revealed two evolutionarily conserved phosphatidylcholine-binding mechanisms and their roles in modulating host cell attachment, oligomer assembly, and membrane perforation. Moreover, we demonstrate that the soluble C14PC compound protects primary human immune cells in vitro against cytolysis by PVL and α-toxin and hence may serve as the basis for the development of an antivirulence agent for managing MRSA infections.

Corporate Members Event Nominees Breakfast Briefing Partners and Major Corporates

Event participants

Robert Yates, Head, Centre on Global Health Security, Chatham House
Chair: Professor David R Harper, Senior Consulting Fellow, Centre on Global Health Security, Chatham House; Managing Director, Harper Public Health Consulting Limited
 

17 February 2020

Corporate Members Event Webinar

Francesca Viliani, Consultant Researcher, Global Health Programme, Chatham House; Director, Public Health, International SOS

Sven Smit, Co-Chair, McKinsey Global Institute and Senior Partner, McKinsey & Company, Amsterdam

Chair: Creon Butler, Research Director, Trade, Investment & New Governance Models: Director, Global Economy and Finance Programme, Chatham House

The redox-based modifications of cysteine residues in proteins regulate their function in many biological processes. The gas molecule H₂S has been shown to persulfidate redox sensitive cysteine residues resulting in an H₂S-modified proteome known as the sulfhydrome. Tandem Mass Tags (TMT) multiplexing strategies for large-scale proteomic analyses have become increasingly prevalent in detecting cysteine modifications. Here we developed a TMT-based proteomics approach for selectively trapping and tagging cysteine persulfides in the cellular proteomes. We revealed the natural protein sulfhydrome of two human cell lines, and identified insulin as a novel substrate in pancreatic beta cells. Moreover, we showed that under oxidative stress conditions, increased H₂S can target enzymes involved in energy metabolism by switching specific cysteine modifications to persulfides. Specifically, we discovered a Redox Thiol Switch, from protein S-glutathioinylation to S-persulfidation (RTS^GS). We propose that the RTS^GS from S-glutathioinylation to S-persulfidation is a potential mechanism to fine tune cellular energy metabolism in response to different levels of oxidative stress.

The rapid emergence and dissemination of methicillin-resistant Staphylococcus aureus (MRSA) strains poses a major threat to public health. MRSA possesses an arsenal of secreted host-damaging virulence factors that mediate pathogenicity and blunt immune defenses. Panton–Valentine leukocidin (PVL) and α-toxin are exotoxins that create lytic pores in the host cell membrane. They are recognized as being important for the development of invasive MRSA infections and are thus potential targets for antivirulence therapies. Here, we report the high-resolution X-ray crystal structures of both PVL and α-toxin in their soluble, monomeric, and oligomeric membrane-inserted pore states in complex with n-tetradecylphosphocholine (C14PC). The structures revealed two evolutionarily conserved phosphatidylcholine-binding mechanisms and their roles in modulating host cell attachment, oligomer assembly, and membrane perforation. Moreover, we demonstrate that the soluble C14PC compound protects primary human immune cells in vitro against cytolysis by PVL and α-toxin and hence may serve as the basis for the development of an antivirulence agent for managing MRSA infections.

Invitation Only Research Event

Event participants

Dr Tedros Adhanom Ghebreyesus, Director-General, World Health Organization 

Acne is one of the most common dermatological conditions, but the details of its pathology are unclear, and current management regimens often have adverse effects. Cutibacterium acnes is known as a major acne-associated bacterium that derives energy from lipase-mediated sebum lipid degradation. C. acnes is commensal, but lipase activity has been observed to differ among C. acnes types. For example, higher populations of the type IA strains are present in acne lesions with higher lipase activity. In the present study, we examined a conserved lipase in types IB and II that was truncated in type IA C. acnes strains. Closed, blocked, and open structures of C. acnes ATCC11828 lipases were elucidated by X-ray crystallography at 1.6–2.4 Å. The closed crystal structure, which is the most common form in aqueous solution, revealed that a hydrophobic lid domain shields the active site. By comparing closed, blocked, and open structures, we found that the lid domain-opening mechanisms of C. acnes lipases (_CAlipases) involve the lid-opening residues, Phe-179 and Phe-211. To the best of our knowledge, this is the first structure-function study of _CAlipases, which may help to shed light on the mechanisms involved in acne development and may aid in future drug design.

Archimedes was one of the most brilliant people ever, on a par with Einstein and Newton. Yet very little of what he wrote still exists because of the passage of time, and because many copies of his works were erased and the cleaned pages were used again. One of those written-over works (called a palimpsest) has resurfaced, and advanced digital imaging techniques using statistics and linear algebra have revealed his previously unknown discoveries in combinatorics and calculus. This leads to a question that would stump even Archimedes: How much further would mathematics and science have progressed had these discoveries not been erased? One of the most dramatic revelations of Archimedes. work was done using X-ray fluorescence. A painting, forged in the 1940s by one of the book.s former owners, obscured the original text, but X-rays penetrated the painting and highlighted the iron in the ancient ink, revealing a page of Archimedes. treatise The Method of Mechanical Theorems. The entire process of uncovering this and his other ideas is made possible by modern mathematics and physics, which are built on his discoveries and techniques. This completion of a circle of progress is entirely appropriate since one of Archimedes. accomplishments that wasn.t lost is his approximation of pi. For More Information: The Archimedes Codex, Reviel Netz and William Noel, 2007.

Archimedes was one of the most brilliant people ever, on a par with Einstein and Newton. Yet very little of what he wrote still exists because of the passage of time, and because many copies of his works were erased and the cleaned pages were used again. One of those written-over works (called a palimpsest) has resurfaced, and advanced digital imaging techniques using statistics and linear algebra have revealed his previously unknown discoveries in combinatorics and calculus. This leads to a question that would stump even Archimedes: How much further would mathematics and science have progressed had these discoveries not been erased? One of the most dramatic revelations of Archimedes. work was done using X-ray fluorescence. A painting, forged in the 1940s by one of the book.s former owners, obscured the original text, but X-rays penetrated the painting and highlighted the iron in the ancient ink, revealing a page of Archimedes. treatise The Method of Mechanical Theorems. The entire process of uncovering this and his other ideas is made possible by modern mathematics and physics, which are built on his discoveries and techniques. This completion of a circle of progress is entirely appropriate since one of Archimedes. accomplishments that wasn.t lost is his approximation of pi. For More Information: The Archimedes Codex, Reviel Netz and William Noel, 2007.

The rapid emergence and dissemination of methicillin-resistant Staphylococcus aureus (MRSA) strains poses a major threat to public health. MRSA possesses an arsenal of secreted host-damaging virulence factors that mediate pathogenicity and blunt immune defenses. Panton–Valentine leukocidin (PVL) and α-toxin are exotoxins that create lytic pores in the host cell membrane. They are recognized as being important for the development of invasive MRSA infections and are thus potential targets for antivirulence therapies. Here, we report the high-resolution X-ray crystal structures of both PVL and α-toxin in their soluble, monomeric, and oligomeric membrane-inserted pore states in complex with n-tetradecylphosphocholine (C14PC). The structures revealed two evolutionarily conserved phosphatidylcholine-binding mechanisms and their roles in modulating host cell attachment, oligomer assembly, and membrane perforation. Moreover, we demonstrate that the soluble C14PC compound protects primary human immune cells in vitro against cytolysis by PVL and α-toxin and hence may serve as the basis for the development of an antivirulence agent for managing MRSA infections.

(Flinders University) New physiotherapy guidelines are targeting COVID-19 patient recovery for respiratory management, exercise and mobilisation in acute hospital wards and Intensive Care Units. The new guidelines published in Australian Journal of Physiotherapy aim to prevent complications of the respiratory system and muscle deconditioning, speed up recovery from mechanical ventilation, and improve long-term physical function and recovery.

Vladimir Dragović and Irina Goryuchkina
Bull. Amer. Math. Soc. 57 (2020), 293-299.
Abstract, references and article information

(US Department of Agriculture - Agricultural Research Service) A new freeze-resistant Trichinella species has been discovered in wolverines by Agricultural Research Service scientists and their colleagues. Trichinella are parasites that cause the disease trichinosis (formally referred to as trichinellosis), which people can get by eating raw or undercooked meat from infected animals.

Researchers have engineered bacteria to produce new versions of a potential antibiotic molecule, some with potent antimalarial properties.

Last month, Prime Minister Andrew Holness announced the establishment of an Economic Recovery Task Force, chaired by Finance Minister Dr Nigel Clarke. The multisectoral task force, which is mandated to oversee Jamaica's economic recovery from...

Eelke P. Béguin
Apr 24, 2020; 0:RA120.001964v1-mcp.RA120.001964
Research

Xing-Huang Gao
May 1, 2020; 19:852-870
Research

Dorte B. Bekker-Jensen
Apr 1, 2020; 19:716-729
Technological Innovation and Resources

3 October 2019

The Chatham House Africa Programme designed the Sudan Stakeholder Dialogues series to help identify the factors that have led to the current economic crisis, the immediate steps that need to be taken to avert collapse and stabilize the economy, and the longer-term structural reforms required to set Sudan on the path to recovery. The project is funded by Humanity United.

Invitation Only Research Event

Event participants

Professor Nick Binedell, Founding Director and Sasol Chair of Strategic Management, Gordon Institute of Business Science (GIBS), University of Pretoria

Mycobacterial Ser/Thr protein kinases (STPKs) play a critical role in signal transduction pathways that ultimately determine mycobacterial growth and metabolic adaptation. Identification of key physiological substrates of these protein kinases is, therefore, crucial to better understand how Ser/Thr phosphorylation contributes to mycobacterial environmental adaptation, including response to stress, cell division, and host-pathogen interactions. Various substrate detection methods have been employed with limited success, with direct targets of STPKs remaining elusive. Recently developed mass spectrometry (MS)-based phosphoproteomic approaches have expanded the list of potential STPK substrate identifications, yet further investigation is required to define the most functionally significant phosphosites and their physiological importance. Prior to the application of MS workflows, for instance, GarA was the only known and validated physiological substrate for protein kinase G (PknG) from pathogenic mycobacteria. A subsequent list of at least 28 candidate PknG substrates has since been reported with the use of MS-based analyses. Herein, we integrate and critically review MS-generated datasets available on novel STPK substrates and report new functional and subcellular localization enrichment analyses on novel candidate protein kinase A (PknA), protein kinase B (PknB) and PknG substrates to deduce the possible physiological roles of these kinases. In addition, we assess substrate specificity patterns across different mycobacterial STPKs by analyzing reported sets of phosphopeptides, in order to determine whether novel motifs or consensus regions exist for mycobacterial Ser/Thr phosphorylation sites. This review focuses on MS-based techniques employed for STPK substrate identification in mycobacteria, while highlighting the advantages and challenges of the various applications.

The use of protein biomarkers as surrogates for clinical endpoints requires extensive multilevel validation including development of robust and sensitive assays for precise measurement of protein concentration. Multiple reaction monitoring (MRM) is a well-established mass-spectrometric method that can be used for reproducible protein-concentration measurements in biological specimens collected via microsampling. The dried blood spot (DBS) microsampling technique can be performed non-invasively without the expertise of a phlebotomist, and can enhance analyte stability which facilitate the application of this technique in retrospective studies while providing lower storage and shipping costs, because cold-chain logistics can be eliminated. Thus, precise, sensitive, and multiplexed methods for measuring protein concentrations in DBSs can be used for de novo biomarker discovery and for biomarker quantification or verification experiments. To achieve this goal, MRM assays were developed for multiplexed concentration measurement of proteins in DBSs.

The lower limit of quantification (LLOQ) was found to have a median total coefficient of variation (CV) of 18% for 245 proteins, whereas the median LLOQ was 5 fmol of peptide injected on column, and the median inter-day CV over 4 days for measuring endogenous protein concentration was 8%. The majority (88%) of the assays displayed parallelism, whereas the peptide standards remained stable throughout the assay workflow and after exposure to multiple freeze-thaw cycles. For 190 proteins, the measured protein concentrations remained stable in DBS stored at ambient laboratory temperature for up to 2 months. Finally, the developed assays were used to measure the concentration ranges for 200 proteins in twenty same sex, same race and age matched individuals.

Mass spectrometry (MS) and proteomics offer comprehensive characterization and identification of microorganisms and discovery of protein biomarkers that are applicable for diagnostics of infectious diseases. The use of biomarkers for diagnostics is widely applied in the clinic and the use of peptide biomarkers is increasingly being investigated for applications in the clinical laboratory. Respiratory-tract infections are a predominant cause for medical treatment, although, clinical assessments and standard clinical laboratory protocols are time-consuming and often inadequate for reliable diagnoses. Novel methods, preferably applied directly to clinical samples, excluding cultivation steps, are needed to improve diagnostics of infectious diseases, provide adequate treatment and reduce the use of antibiotics and associated development of antibiotic resistance. This study applied nano-liquid chromatography (LC) coupled with tandem MS, with a bioinformatics pipeline and an in-house database of curated high-quality reference genome sequences to identify species-unique peptides as potential biomarkers for four bacterial pathogens commonly found in respiratory tract infections (RTIs): Staphylococcus aureus; Moraxella catarrhalis; Haemophilus influenzae and Streptococcus pneumoniae. The species-unique peptides were initially identified in pure cultures of bacterial reference strains, reflecting the genomic variation in the four species and, furthermore, in clinical respiratory tract samples, without prior cultivation, elucidating proteins expressed in clinical conditions of infection. For each of the four bacterial pathogens, the peptide biomarker candidates most predominantly found in clinical samples, are presented. Data are available via ProteomeXchange with identifier PXD014522. As proof-of-principle, the most promising species-unique peptides were applied in targeted tandem MS-analyses of clinical samples and their relevance for identifications of the pathogens, i.e. proteotyping, was validated, thus demonstrating their potential as peptide biomarker candidates for diagnostics of infectious diseases.

State-of-the-art proteomics-grade mass spectrometers can measure peptide precursors and their fragments with ppm mass accuracy at sequencing speeds of tens of peptides per second with attomolar sensitivity. Here we describe a compact and robust quadrupole-orbitrap mass spectrometer equipped with a front-end High Field Asymmetric Waveform Ion Mobility Spectrometry (FAIMS) Interface. The performance of the Orbitrap Exploris 480 mass spectrometer is evaluated in data-dependent acquisition (DDA) and data-independent acquisition (DIA) modes in combination with FAIMS. We demonstrate that different compensation voltages (CVs) for FAIMS are optimal for DDA and DIA, respectively. Combining DIA with FAIMS using single CVs, the instrument surpasses 2500 peptides identified per minute. This enables quantification of >5000 proteins with short online LC gradients delivered by the Evosep One LC system allowing acquisition of 60 samples per day. The raw sensitivity of the instrument is evaluated by analyzing 5 ng of a HeLa digest from which >1000 proteins were reproducibly identified with 5 min LC gradients using DIA-FAIMS. To demonstrate the versatility of the instrument, we recorded an organ-wide map of proteome expression across 12 rat tissues quantified by tandem mass tags and label-free quantification using DIA with FAIMS to a depth of >10,000 proteins.

The redox-based modifications of cysteine residues in proteins regulate their function in many biological processes. The gas molecule H₂S has been shown to persulfidate redox sensitive cysteine residues resulting in an H₂S-modified proteome known as the sulfhydrome. Tandem Mass Tags (TMT) multiplexing strategies for large-scale proteomic analyses have become increasingly prevalent in detecting cysteine modifications. Here we developed a TMT-based proteomics approach for selectively trapping and tagging cysteine persulfides in the cellular proteomes. We revealed the natural protein sulfhydrome of two human cell lines, and identified insulin as a novel substrate in pancreatic beta cells. Moreover, we showed that under oxidative stress conditions, increased H₂S can target enzymes involved in energy metabolism by switching specific cysteine modifications to persulfides. Specifically, we discovered a Redox Thiol Switch, from protein S-glutathioinylation to S-persulfidation (RTS^GS). We propose that the RTS^GS from S-glutathioinylation to S-persulfidation is a potential mechanism to fine tune cellular energy metabolism in response to different levels of oxidative stress.

17 February 2020

Corporate Members Event Webinar

Francesca Viliani, Consultant Researcher, Global Health Programme, Chatham House; Director, Public Health, International SOS

Sven Smit, Co-Chair, McKinsey Global Institute and Senior Partner, McKinsey & Company, Amsterdam

Chair: Creon Butler, Research Director, Trade, Investment & New Governance Models: Director, Global Economy and Finance Programme, Chatham House

Hyo Jung Kim
May 1, 2020; 61:722-733
Research Articles

The vessel wall is continuously exposed to hemodynamic forces generated by blood flow. Endothelial mechanosensors perceive and translate mechanical signals via cellular signaling pathways into biological processes that control endothelial development, phenotype and function. To assess the hemodynamic effects on the endothelium on a system-wide level, we applied a quantitative mass spectrometry approach combined with cell surface chemical footprinting. SILAC-labeled endothelial cells were subjected to flow-induced shear stress for 0, 24 or 48 hours, followed by chemical labeling of surface proteins using a non-membrane permeable biotin label, and analysis of the whole proteome and the cell surface proteome by LC-MS/MS analysis. These studies revealed that of the >5000 quantified proteins 104 were altered, which were highly enriched for extracellular matrix proteins and proteins involved in cell-matrix adhesion. Cell surface proteomics indicated that LAMA4 was proteolytically processed upon flow-exposure, which corresponded to the decreased LAMA4 mass observed on immunoblot. Immunofluorescence microscopy studies highlighted that the endothelial basement membrane was drastically remodeled upon flow exposure. We observed a network-like pattern of LAMA4 and LAMA5, which corresponded to the localization of laminin-adhesion molecules ITGA6 and ITGB4. Furthermore, the adaptation to flow-exposure did not affect the inflammatory response to tumor necrosis factor α, indicating that inflammation and flow trigger fundamentally distinct endothelial signaling pathways with limited reciprocity and synergy. Taken together, this study uncovers the blood flow-induced remodeling of the basement membrane and stresses the importance of the subendothelial basement membrane in vascular homeostasis.

Acne is one of the most common dermatological conditions, but the details of its pathology are unclear, and current management regimens often have adverse effects. Cutibacterium acnes is known as a major acne-associated bacterium that derives energy from lipase-mediated sebum lipid degradation. C. acnes is commensal, but lipase activity has been observed to differ among C. acnes types. For example, higher populations of the type IA strains are present in acne lesions with higher lipase activity. In the present study, we examined a conserved lipase in types IB and II that was truncated in type IA C. acnes strains. Closed, blocked, and open structures of C. acnes ATCC11828 lipases were elucidated by X-ray crystallography at 1.6–2.4 Å. The closed crystal structure, which is the most common form in aqueous solution, revealed that a hydrophobic lid domain shields the active site. By comparing closed, blocked, and open structures, we found that the lid domain-opening mechanisms of C. acnes lipases (_CAlipases) involve the lid-opening residues, Phe-179 and Phe-211. To the best of our knowledge, this is the first structure-function study of _CAlipases, which may help to shed light on the mechanisms involved in acne development and may aid in future drug design.

Steven Duggar and Ryder Jones continue to take steps forward in their rehab, as they were both cleared to take batting practice on the field Friday for the first time since their September surgeries.