To identify starting points for therapeutics targeting SARS-CoV-2, the Paul Scherrer Institute and Idorsia decided to collaboratively perform an X-ray crystallographic fragment screen against its main protease. Fragment-based screening was carried out using crystals with a pronounced open conformation of the substrate-binding pocket. Of 631 soaked fragments, a total of 29 hits bound either in the active site (24 hits), a remote binding pocket (three hits) or at crystal-packing interfaces (two hits). Notably, two fragments with a pose that was sterically incompatible with a more occluded crystal form were identified. Two isatin-based electrophilic fragments bound covalently to the catalytic cysteine residue. The structures also revealed a surprisingly strong influence of the crystal form on the binding pose of three published fragments used as positive controls, with implications for fragment screening by crystallography.

To better understand the evolution, transmission patterns, and disease progression of SARS-CoV-2 — the virus that causes COVID-19 — genome sequence data should be integrated with patient clinical data and epidemiological data, says a new report from the National Academies of Sciences, Engineering, and Medicine.

In a statement, the presidents of the National Academies urge that investigations of the origins of SARS-CoV-2 and COVID-19 be guided by scientific principles.

PepsiCo’s Pepsi, Purchase N.Y, and Little Caesars, Detroit. Mich. announced the return of the fan-favorite Pepsi Pineapple, available exclusively at Little Caesars for a limited time only.

A data driven report on the spread of COVID 19 in Middlesex County, Massachusetts

Considering the major societal disruptions brought on by government mandates responding to the COVID19 pandemic, all communities owe their residents an objective review of the mandates imposed.

Since the start of the COVID-19 pandemic, the virus that causes the illness - SARS-CoV-2 - has had a practically infinite number of opportunities to mutate

Since the start of the COVID-19 pandemic, the virus that causes the illness - SARS-CoV-2 - has had a practically infinite number of opportunities to mutate

Diving into the proteomic atlas of SARS-CoV-2 infected cells  Nature.com

Hamid Sarshar will lead the 50-year-old company into the next strategic phase of growth and innovation within the UFT platform.

The shortest phishing scam e-mail ever!

Another lame attempt at defrauding honest tax-paying South Africans. These phishing scammers could have at least used a better logo in their e-mail.

The main protease (3CL Mpro) from SARS–CoV-2, the etiological agent of COVID-19, is an essential enzyme for viral replication. 3CL Mpro possesses an unusual catalytic dyad composed of Cys145 and His41 residues. A critical question in the field has been what the protonation states of the ionizable residues in the substrate-binding active-site cavity are; resolving this point would help understand the catalytic details of the enzyme and inform rational drug development against this pernicious virus. Here, we present the room-temperature neutron structure of 3CL Mpro, which allowed direct determination of hydrogen atom positions and, hence, protonation states in the protease. We observe that the catalytic site natively adopts a zwitterionic reactive form in which Cys145 is in the negatively charged thiolate state and His41 is doubly protonated and positively charged, instead of the neutral unreactive state usually envisaged. The neutron structure also identified the protonation states, and thus electrical charges, of all other amino acid residues and revealed intricate hydrogen-bonding networks in the active-site cavity and at the dimer interface. The fine atomic details present in this structure were made possible by the unique scattering properties of the neutron, which is an ideal probe for locating hydrogen positions and experimentally determining protonation states at near-physiological temperature. Our observations provide critical information for structure-assisted and computational drug design, allowing precise tailoring of inhibitors to the enzyme's electrostatic environment.

The novel severe acute respiratory syndrome coronavirus (SARS-CoV-2) has emerged to a pandemic and caused global public health crisis. Human angiotensin-converting enzyme 2(ACE2) was identified as the entry receptor for SARS-CoV-2. As a carboxypeptidase, ACE2 cleaves many biological substrates besides angiotensin II to control vasodilatation and vascular permeability. Given the nanomolar high affinity between ACE2 and SARS-CoV-2 spike protein, we investigated how this interaction would affect the enzymatic activity of ACE2. Surprisingly, SARS-CoV-2 trimeric spike protein increased ACE2 proteolytic activity ∼3-10 fold against model peptide substrates, such as caspase-1 substrate and Bradykinin-analog. The enhancement in ACE2 enzymatic function was mediated by the binding of SARS-CoV-2 spike RBD domain. These results highlighted the potential for SARS-CoV-2 infection to enhance ACE2 activity, which may be relevant to the cardiovascular symptoms associated with COVID-19.

As the COVID-19 pandemic continues to spread, thousands of scientists around the globe have changed research direction to understand better how the virus works and to find out how it may be tackled. The number of manuscripts on preprint servers is soaring and peer-reviewed publications using MS-based proteomics are beginning to emerge. To facilitate proteomic research on SARS-CoV-2, the virus that causes COVID-19, this report presents deep-scale proteomes (10,000 proteins; >130,000 peptides) of common cell line models, notably Vero E6, Calu-3, Caco-2, and ACE2-A549 that characterize their protein expression profiles including viral entry factors such as ACE2 or TMPRSS2. Using the 9 kDa protein SRP9 and the breast cancer oncogene BRCA1 as examples, we show how the proteome expression data can be used to refine the annotation of protein-coding regions of the African green monkey and the Vero cell line genomes. Monitoring changes of the proteome on viral infection revealed widespread expression changes including transcriptional regulators, protease inhibitors, and proteins involved in innate immunity. Based on a library of 98 stable-isotope labeled synthetic peptides representing 11 SARS-CoV-2 proteins, we developed PRM (parallel reaction monitoring) assays for nano-flow and micro-flow LC–MS/MS. We assessed the merits of these PRM assays using supernatants of virus-infected Vero E6 cells and challenged the assays by analyzing two diagnostic cohorts of 24 (+30) SARS-CoV-2 positive and 28 (+9) negative cases. In light of the results obtained and including recent publications or manuscripts on preprint servers, we critically discuss the merits of MS-based proteomics for SARS-CoV-2 research and testing.

The glycoprotein spike (S) on the surface of SARS-CoV-2 is a determinant for viral invasion and host immune response. Herein, we characterized the site-specific N-glycosylation of S protein at the level of intact glycopeptides. All 22 potential N-glycosites were identified in the S-protein protomer and were found to be preserved among the 753 SARS-CoV-2 genome sequences. The glycosites exhibited glycoform heterogeneity as expected for a human cell-expressed protein subunit. We identified masses that correspond to 157 N-glycans, primarily of the complex type. In contrast, the insect cell-expressed S protein contained 38 N-glycans, completely of the high-mannose type. Our results revealed that the glycan types were highly determined by the differential processing of N-glycans among human and insect cells, regardless of the glycosites’ location. Moreover, the N-glycan compositions were conserved among different sizes of subunits. Our study indicate that the S protein N-glycosylation occurs regularly at each site, albeit the occupied N-glycans were diverse and heterogenous. This N-glycosylation landscape and the differential N-glycan patterns among distinct host cells are expected to shed light on the infection mechanism and present a positive view for the development of vaccines and targeted drugs.

SA's tax ombud has had "informal discussions" with its counterpart in Australia over combating refund scams as it investigates the hijacking of eFiling profiles.

SARS continues to deny amaBhungane and the Financial Mail's requests for access to former president Jacob Zuma's tax records despite the seminal judgment of the Constitutional Court handed down in May 2023.

Half of the participants in the Taxing Times survey still find compliance with tax obligations difficult

The COVID-19 pandemic has highlighted the critical role of genomic surveillance for guiding policy and control. Timeliness is key, but sequence alignment and phylogeny slow most surveillance techniques. Millions of SARS-CoV-2 genomes have been assembled. Phylogenetic methods are ill equipped to handle this sheer scale. We introduce a pangenomic measure that examines the information diversity of a k-mer library drawn from a country's complete set of clinical, pooled, or wastewater sequence. Quantifying diversity is central to ecology. Hill numbers, or the effective number of species in a sample, provide a simple metric for comparing species diversity across environments. The more diverse the sample, the higher the Hill number. We adopt this ecological approach and consider each k-mer an individual and each genome a transect in the pangenome of the species. Structured in this way, Hill numbers summarize the temporal trajectory of pandemic variants, collapsing each day's assemblies into genome equivalents. For pooled or wastewater sequence, we instead compare days using survey sequence divorced from individual infections. Across data from the UK, USA, and South Africa, we trace the ascendance of new variants of concern as they emerge in local populations well before these variants are named and added to phylogenetic databases. Using data from San Diego wastewater, we monitor these same population changes from raw, unassembled sequence. This history of emerging variants senses all available data as it is sequenced, intimating variant sweeps to dominance or declines to extinction at the leading edge of the COVID-19 pandemic.

The SARS-CoV-2 frameshifting element (FSE) has been intensely studied and explored as a therapeutic target for coronavirus diseases, including COVID-19. Besides the intriguing virology, this small RNA is known to adopt many length-dependent conformations, as verified by multiple experimental and computational approaches. However, the role these alternative conformations play in the frameshifting mechanism and how to quantify this structural abundance has been an ongoing challenge. Here, we show by DMS and dual-luciferase functional assays that previously predicted FSE mutants (using the RAG graph theory approach) suppress structural transitions and abolish frameshifting. Furthermore, correlated mutation analysis of DMS data by three programs (DREEM, DRACO, and DANCE-MaP) reveals important differences in their estimation of specific RNA conformations, suggesting caution in the interpretation of such complex conformational landscapes. Overall, the abolished frameshifting in three different mutants confirms that all alternative conformations play a role in the pathways of ribosomal transition.

Caesars Mr. Chow Announcement

In the Arab American-majority city of Dearborn, Michigan, Donald Trump beat Kamala Harris by over six percentage points, with third-party candidate Jill Stein capturing nearly one-fifth of the vote. During the primary elections, a majority of Democratic voters in Dearborn selected “uncommitted” over then-presumptive nominee Joe Biden, citing disapproval of the president’s handling of Israel’s aggression in the Middle East. “Uncommitted” voters continued to press the Harris campaign to shift its Israel policy as the election went on, but were routinely ignored. Democrats “made a calculation that they did not need Arab American, Muslim American and Palestinian American voters,” says Palestinian American organizer Linda Sarsour, who was in Dearborn on election night. We speak to Sarsour about the Harris campaign’s failure to secure the support of a previously key part of the Democratic base. “We are going to be in big trouble, and I blame that solely on the Democratic Party and one of the worst campaigns I have seen in my 23 years in organizing.”

Highlights: Interest in re-purposing neutralizing antibodies for therapeutic use against related viruses has been w

The study describes the compound’s remarkable ability to disrupt the entry of enveloped viruses into the host’s cell and prevent infection

National Bureau of Economic Research

On December 2019, Wuhan Municipal Health Commission reported a cluster of cases of pneumonia which was later identified as the novel coronavirus. In May, the advent of COVID-19 is in the sixth month, which has caused 276, 690 deaths globally and

In another release, the ministry said the Institute of Genomics and Integrative Biology (CSIR-IGIB) and Tata Sons have signed a licensing agreement for a paper strip-based test called Feluda for Covid 19's rapid diagnosis.

The study said that the increase in frequency of this strain is happening at an alarming rate, which indicates that this strain has an advantage over the original strain from Wuhan in terms of fitness.

Four new tutorials are available that provide illustrated examples for the use of the functionalities of the Query tool , the AOP workflow for Skin Sensitization, the information form the ECHA CHEM database and the capability to analyse tautomeric structures. The examples cover both human health (skin sensitisation) and environmental (acute aquatic toxicity to fish) endpoints.

The coronavirus disease (COVID-19)is an infectious disease caused by coronaviruses, a family of viruses that also causes severe acute respiratory syndrome (SARS). Both COVID-19 and SARS are caused by a strain of coronaviruses that caused SARS, known as SARS-CoV in 2003

On December 2019, Wuhan Municipal Health Commission reported a cluster of cases of pneumonia which was later identified as the novel coronavirus. In May, the advent of COVID-19 is in the sixth month, which has caused 276, 690 deaths globally and

They landed at Kozhikode and Kochi airports

Researchers use cryo-EM to show how the drug stops RNA replication