+SARS-CoV-2 provokes devastating tissue damage by cytokine release syndrome and leads to multi-organ failure. Modeling the process of immune cell activation and subsequent tissue damage is a significant task. Organoids from human tissues advanced our understanding of SARS-CoV-2 infection mechanisms though, they are missing crucial components: immune cells and endothelial cells. This study aims to generate organoids with these components. We established vascular immune organoids from human pluripotent stem cells and examined the effect of SARS-CoV-2 infection. We demonstrated that infections activated inflammatory macrophages. Notably, the upregulation of interferon signaling supports macrophages role in cytokine release syndrome. We propose vascular immune organoids are a useful platform to model and discover factors that ameliorate SARS-CoV-2-mediated cytokine release syndrome.
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Deep learning of antibody epitopes using molecular permutation vectors -
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+The accurate computational prediction of B cell epitopes can vastly reduce the cost and time required for identifying potential epitope candidates for the design of vaccines and immunodiagnostics. However, current computational tools for B cell epitope prediction perform poorly and are not fit-for-purpose, and there remains enormous room for improvement and the need for superior prediction strategies. Here we propose a novel approach that improves B cell epitope prediction by encoding epitopes as binary molecular permutation vectors that represent the position and structural properties of the amino acids within a protein antigen sequence that interact with an antibody, rather than the traditional approach of defining epitopes as scores per amino acid on a protein sequence that pertain to their probability of partaking in a B cell epitope antibody interaction. In addition to defining epitopes as a binary molecular permutation vectors, the approach also uses the 3D macrostructure features of the unbound 3D protein structures, and in turn uses these features to train another deep learning model on the corresponding antibody-bound protein 3D structures. We demonstrate that the strategy predicts B cell epitopes with improved accuracy compared to the existing tools, and reliably identifies the majority of experimentally verified epitopes on the spike protein of SARS-CoV-2 not seen by the model in training. With the approach described herein, a primary protein sequence with the query molecular permutation vector alone is required to predict B cell epitopes in a reliable manner, potentially advancing the use of computational prediction of B cell epitopes in biomedical research applications.
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Simulation-Driven Design of Stabilized SARS-CoV-2 Spike S2 Immunogens -
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+The full-length prefusion-stabilized SARS-CoV-2 spike (S) is the principal antigen of COVID-19 vaccines. Vaccine efficacy has been impacted by emerging variants of concern that accumulate most of the sequence modifications in the immunodominant S1 subunit. S2, in contrast, is the most evolutionarily conserved region of the spike and can elicit broadly neutralizing and protective antibodies. Yet, S2s usage as an alternative vaccine strategy is hampered by its general instability. Here, we use a simulation-driven approach to design S2-only immunogens stabilized in a closed prefusion conformation. Molecular simulations provide a mechanistic characterization of the S2 trimers opening, informing the design of tryptophan substitutions that impart kinetic and thermodynamic stabilization. Structural characterization via cryo-EM shows the molecular basis of S2 stabilization in the closed prefusion conformation. Informed by molecular simulations and corroborated by experiments, we report an engineered S2 immunogen that exhibits increased protein expression, superior thermostability, and preserved immunogenicity against sarbecoviruses.
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Identifying causal role of COVID-19 in immunopsychiatry models -
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+This preprint is a 1000-word Viewpoint that explores methodological considerations of the COVID-19 pandemic for immunopsychiatry. It has been accepted for publication in Brain, Behavior, and Immunity for a special issue on Immunopsychiatry and COVID-19. Specifically, we discuss the treatment of COVID-19 as a confounding versus mediating variable in immunopsychiatric research. We leverage simulated data varied in sample and effect size to illustrate key considerations. Further, we highlight the statistical implications of each of these scenarios. Recommendations and key considerations for the field are briefly discussed.
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The advent of the COVID-19 epidemic did not affect Americansâ endorsement of moral foundations -
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+Prior work has suggested that existential threats in the form of terror attacks may shift liberalsâ reliance on moral foundations to more resemble those of conservatives. We therefore hypothesized that endorsement of these moral foundations would have increased when the COVID-19 epidemic became a salient threat. To examine this hypothesis we conducted a longitudinal study with 237 American participants across the liberal-conservative spectrum, in which their endorsement of various moral foundations were measured before and after the advent of the pandemic. We did not find evidence of any systematic change in the endorsement of any moral foundation, neither in general nor specifically among liberals or specifically among those who perceived the greatest threat from COVID-19. We conclude that the threat from the pandemic does not seem to have had any substantial effect on the moral foundations that people rely on. This finding is consistent with other longitudinal studies of the effect of the COVID-19 pandemic on measures related to conservatism.
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Development of radiofluorinated MLN-4760 derivatives for PET imaging of the SARS-CoV-2 entry receptor ACE2 -
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+Purpose: The angiotensin converting enzyme 2 (ACE2) plays a regulatory role in the cardiovascular system and serves SARS-CoV-2 as an entry receptor. The aim of this study was to synthesize and evaluate radiofluorinated derivatives of the ACE2 inhibitor MLN-4760. [18F]F-MLN-4760 and [18F]F-Aza-MLN-4760 were demonstrated to be suitable for non-invasive imaging of ACE2, potentially enabling a better understanding of its expression dynamics. Methods: Based on computational molecular modeling, the ACE2-binding modes of F-MLN-4760 and F-Aza-MLN-4760 were similar to that of MLN-4760. Co-crystallization of the hACE2/F-MLN-4760 protein complex was performed for confirmation. Displacement experiments using [3H]MLN-4760 enabled the determination of the binding affinities of the synthesized F-MLN-4760 and F-Aza-MLN-4760 to ACE2 expressed in HEK-ACE2 cells. Aryl trimethylstannane-based and pyridine-based radiofluorination precursors were synthesized and used for the preparation of the respective radiotracers. [18F]F-MLN-4760 and [18F]F-Aza-MLN-4760 were evaluated with regard to the uptake in HEK-ACE2 and HEK-ACE cells and in vitro binding to tissue sections of HEK-ACE2 xenografts and normal organs of mice. Biodistribution and PET/CT imaging studies of [18F]F-MLN-4760 and [18F]F-Aza-MLN-4760 were performed using HEK-ACE2 and HEK-ACE xenografted nude mice. Results: Crystallography data revealed an equal ACE2-binding mode for F-MLN-4760 as previously found for MLN-4760 and indicated that the same would hold true for F-Aza-MLN-4760. The IC50 values were all in the high nM range, but three-fold lower for F-MLN-4760 and seven-fold lower for F-Aza-MLN-4760 than for MLN-4760. [18F]F-MLN-4760 and [18F]F-Aza-MLN-4760 were obtained in 1.4 +/- 0.3 GBq and 0.5 +/- 0.1 GBq activity with >99% radiochemical purity in a 5.3% and 1.2% radiochemical yield, respectively. Uptake in HEK-ACE2 cells was higher for [18F]F-MLN-4760 (67 +/- 9%) than for [18F]F-Aza-MLN-4760 (37 +/- 8%) after 3 h incubation while negligible uptake was seen in HEK-ACE cells (<0.3%). [18F]F-MLN-4760 and [18F]F-Aza-MLN-4760 accumulated specifically in HEK-ACE2 xenografts of mice (13 +/- 2% IA/g and 15 +/- 2% IA/g at 1 h p.i.) with almost no uptake observed in HEK-ACE xenografts (<0.3% IA/g). This was confirmed by PET/CT imaging, which also visualized unspecific accumulation in the gall bladder and intestinal tract. Conclusion: Both radiotracers showed specific and selective binding to ACE2 in vitro and in vivo. [18F]F-MLN-4760 was, however, obtained in higher yields and the ACE2-binding affinity was superior over that of [18F]F-Aza-MLN-4760. [18F]F-MLN-4760 would, thus, be the candidate of choice for further developlment to enable PET imaging of ACE2 in patients.
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Validation of RT-qPCR primers and probes for new and old variants of SARS-CoV-2 in a world scale -
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+Introduction: The demand for molecular diagnosis of pathogens has surged dramatically since the onset of the COVID-19 pandemic. In this context, different diagnostic tests have been developed to identify SARS-CoV-2 in patient samples. The emergence of new variants of SARS-CoV-2 raises questions about whether the molecular tests available for diagnosis continue to be effective in detecting the virus in biological samples. Objective: This study analyzed the viability of molecular targets directed to N, E and RdRp genes available against the new variants of SARS-CoV-2. Methodology: For this, we used bioinformatics tools to analyze SARS-CoV-2 genomic data of different variants deposited in GSAID and NCBI virus genomic databases to assess the accuracy of molecular tests available for the diagnosis of COVID-19. We also developed software for analyzing mutation frequencies in different molecular targets from the mutation database. Results: Mutation frequency analysis revealed a high rate of mutations in the N, E and RdRp genes and targets, although the target regions were more conserved. Only three SNPs were recurrent in the sequences of the variants identified in different continents and all in different targets. On the other hand, the registered mutations are not consistent and do not appear frequently in isolates of the same variant in all regions of the world. Conclusion: Our data suggest that the molecular targets designed for the first SARS-CoV-2 variants remain valid for the identification of new virus variants despite the large number of identified haplotypes. However, false negative test failures can be identified by using more than one molecular target for the same sample. Genomic regions that are under evolutive selective pressure should be avoided in the use of the diagnostic, once the emergence of new variants may affect the efficiency of molecular testing on a global scale.
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Quantitating SARS-CoV-2 Neutralizing Antibodies from Human Dried Blood Spots -
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+Background: In the earliest days of COVID-19 pandemic, the collection of dried blood spots (DBS) enabled public health laboratories to undertake population-scale seroprevalence studies to estimate rates of SARS-CoV-2 exposure. With SARS-CoV-2 seropositivity levels now estimated to exceed 94% in the United States, attention has turned to using DBS to assess functional (neutralizing) antibodies within cohorts of interest. Methods: Contrived DBS eluates from convalescent, fully vaccinated and pre-COVID-19 serum samples were evaluated in SARS-CoV-2 plaque reduction neutralization titer (PRNT) assays, a SARS-CoV-2 specific 8-plex microsphere immunoassay, a cell-based pseudovirus assay, and two different spike-ACE2 inhibition assays. Results: DBS eluates from convalescent individuals were compatible with RBD-ACE2 inhibition assays, an in-house Luminex-based RBD-ACE2 inhibition assay, and commercial real-time PCR-based neutralization assay (NAB-Sure) but not cell-based pseudovirus assays or PRNT. The insensitivity of cell-based pseudovirus assays was overcome with DBS eluates from vaccinated individuals with high SARS-CoV-2 antibody titers. Conclusion: SARS-CoV-2 neutralizing titers can be derived with confidence from DBS eluates, thereby opening the door to the use of these biospecimens for the analysis of vulnerable populations and normally hard to reach communities.
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No Utilitarians in a Pandemic? Shifts in Moral Reasoning during the COVID-19 Global Health Crisis -
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+The COVID-19 pandemic poses many real-world moral dilemmas, which can pit the needs and rights of the many against the needs and rights of the few. We investigated the influence of this contemporary global crisis on moral judgments in older adults, who are at greatest personal risk from the pandemic. We hypothesized that during this pandemic, individuals would give fewer utilitarian responses to hypothetical dilemmas, accompanied by higher levels of confidence and emotion elicitation. Our pre-registered analysis (https://osf.io/g2wtp) involved two waves of data collection, before (2014) and during (2020) the COVID-19 pandemic, regarding three categories of moral dilemmas (personal rights, agent-centered permissions, and special obligations). While utilitarian responses considered across all categories of dilemma did not differ, participants during the 2020 wave gave fewer utilitarian responses to dilemmas involving personal rights; that is, they were less willing to violate the personal rights of others to produce the best overall outcomes.
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Accurately estimating pathway activity in single cells for clustering and differential analysis -
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+Inferring which and how biological pathways and gene sets are changing is a key question in many studies that utilize single-cell RNA sequencing. Typically, these questions are addressed by quantifying the enrichment of known gene sets in lists of genes derived from global analysis. Here we offer SiPSiC, a new method to infer pathway activity in each cell. This allows more sensitive differential analysis and utilizing pathway scores to cluster cells and compute UMAP or other similar projections. We apply our method on datasets of COVID-19, lung adenocarcinoma and glioma, and demonstrate its utility. SiPSiC analysis is consistent with findings reported by previous analyses in many cases, but also reveals the differential activity of novel pathways, enabling us to suggest new mechanisms underlying the pathophysiology of these diseases and demonstrating SiPSiCâs high accuracy and sensitivity in detecting biological function and traits. In addition, we demonstrate how it can be used to better classify cells based on activity of biological pathways instead of single genes and its ability to overcome patient specific artifacts.
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Concepts and methods for predicting viral evolution -
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+The seasonal human influenza virus undergoes rapid evolution, leading to significant changes in circulating viral strains from year to year. These changes are typically driven by adaptive mutations, particularly in the antigenic epitopes, the regions of the viral surface protein haemagglutinin targeted by human antibodies. Here we describe a consistent set of methods for data-driven predictive analysis of viral evolution. Our pipeline integrates four types of data: (1) sequence data of viral isolates collected on a worldwide scale, (2) epidemiological data on incidences, (3) antigenic characterization of circulating viruses, and (4) intrinsic viral phenotypes. From the combined analysis of these data, we obtain estimates of relative fitness for circulating strains and predictions of clade frequencies for periods of up to one year. Furthermore, we obtain comparative estimates of protection against future viral populations for candidate vaccine strains, providing a basis for pre-emptive vaccine strain selection. Continuously updated predictions obtained from the prediction pipeline for influenza and SARS-CoV-2 are available on the website https://previr.app.
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Differences in Vaccine and SARS-CoV-2 Replication Derived mRNA: Implications for Cell Biology and Future Disease -
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+Codon optimization describes the process used to increase protein production by use of alternative but synonymous codon changes. In SARS-CoV-2 mRNA vaccines codon optimizations can result in differential secondary conformations that inevitably affect a proteinâs function with significant consequences to the cell. Importantly, when codon optimization increases the GC content of synthetic mRNAs, there can be an inevitable enrichment of G-quartets which potentially form G-quadruplex structures. The emerging G-quadruplexes are favorable binding sites of RNA binding proteins like helicases that inevitably affect epigenetic reprogramming of the cell by altering transcription, translation and replication. In this study, we performed a RNAfold analysis to investigate alterations in secondary structures of mRNAs in SARS-CoV-2 vaccines due to codon optimization. We show a significant increase in the GC content of mRNAs in vaccines as compared to native SARS-CoV-2 RNA sequences encoding the spike protein. As the GC enrichment leads to more G-quadruplex structure formations, these may contribute to potential pathological processes initiated by SARS-CoV-2 molecular vaccination.
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Lateral Flow Assays Biotesting by Utilizing Plasmonic Nanoparticles Made of Inexpensive Metals - Replacing Colloidal Gold -
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+Nanoparticles (NPs) can be conjugated with diverse biomolecules and employed in biosensing to detect target analytes in biological samples. This proven concept was primarily used during the COVID-19 pandemic with gold NPs-based lateral flow assays (LFAs). Considering the gold price and its worldwide depletion, here we show that novel plasmonic nanoparticles (NPs) based on inexpensive metals, titanium nitride (TiN) and copper covered with a gold shell (Cu@Au), perform comparable or even better than gold nanoparticles. After conjugation, these novel nanoparticles provided high figures of merit for LFA testing, such as high signals and specificity and robust naked-eye signal recognition. To the best of our knowledge, our study represents the 1st application of laser-ablation-fabricated nanoparticles (TiN) in the LFA and dot-blot biotesting. Since the main cost of the Au NPs in commercial testing kits is in the colloidal synthesis, our development with TiN is very exciting, offering potentially very inexpensive plasmonic nanomaterials for various bio-testing applications. Moreover, our machine learning study showed that the bio-detection with TiN is more accurate than that with Au.
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Hidden evolutionary constraints dictate the retention of coronavirus accessory genes -
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+Coronaviruses exhibit many mechanisms of genetic innovation (1-5), including the acquisition of accessory genes that originate by capture of cellular genes or through duplication of existing viral genes (6,7). Accessory genes influence viral host range and cellular tropism, but little is known about how selection acts on these variable regions of virus genomes. We used experimental evolution of mouse hepatitis virus (MHV) encoding a cellular AKAP7 phosphodiesterase and an inactive native phosphodiesterase, NS2 (ref 8) to simulate the capture of a host gene and analyze its evolution. After courses of serial infection, the gene encoding inactive NS2, ORF2, unexpectedly remained intact, suggesting it is under cryptic constraint uncoupled from the function of NS2. In contrast, AKAP7 was retained under strong selection but rapidly lost under relaxed selection. Guided by the retention of ORF2 and similar patterns in related betacoronaviruses, we analyzed ORF8 of SARS-CoV-2, which arose via gene duplication6 and contains premature stop codons in several globally successful lineages. As with MHV ORF2, the coding-defective SARS-CoV-2 ORF8 gene remains largely intact, mirroring patterns observed during MHV experimental evolution, challenging assumptions on the dynamics of gene loss in virus genomes and extending these findings to viruses currently adapting to humans.
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Identification of unique and potent inhibitors of SARS-CoV-2 main protease from DNA-encoded chemical libraries -
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+In vitro screening of large libraries of compounds with automated High-throughput screening is expensive, time consuming and requires dedicated infrastructures. Conversely, the screening of DNA-encoded chemical libraries can be rapidly performed with basic equipment available in most laboratories. In this study we identified novel inhibitors of SARS-CoV-2 main protease (Mpro) through the affinity screening of the commercially available ''DELopen'' library, containing 4.2 billion compounds. The identified inhibitors were peptidomimetics compounds containing a C-terminal electrophilic group able to covalently bind to Mpro reactive Cys145 (confirmed by x-ray crystallography). Compound SLL11 had IC50 = 30nM and was found to be well optimized, proving that the rapid exploration of large chemical spaces, enabled by DECL technology, allows the direct identification of potent inhibitors avoiding several rounds of iterative medicinal chemistry. Compound MP6, a close analogue of SLL11, showed antiviral activity against SARS-CoV-2 in the low micromolar range when tested in Caco-2 and Calu-3 (EC50 = 2.3 M) cell lines. As peptidomimetics compounds can suffer from low cell permeability and metabolic stability, the cyclization of the compounds as well as the substitution of selected residues with D-enantiomers will be explored in the future to improve the antiviral activity of these novel compounds.
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Valacyclovir Plus Celecoxib for Post-Acute Sequelae of SARS-CoV-2 - Conditions: Long COVID; PASC Post Acute Sequelae of COVID 19 Interventions: Drug: Valacyclovir celecoxib dose 1; Drug: Valacyclovir celecoxib dose 2; Drug: Placebo Sponsors: Bateman Horne Center Recruiting
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Supervised Computerized Active Program for People With Post-COVID Syndrome (SuperCAP Study) - Conditions: Post-COVID Condition Interventions: Device: SuperCAP Program Sponsors: FundaciĂłn FLS de Lucha Contra el Sida, las Enfermedades Infecciosas y la PromociĂłn de la Salud y la Ciencia; Institut de Recerca de la SIDA IrsiCaixa; Germans Trias i Pujol Hospital Recruiting
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Utilizing Novel Blood RNA Biomarkers as a Diagnostic Tool in the Identification of Long COVID-19 - Conditions: Long COVID Interventions: Diagnostic Test: RNA Biomarker Blood Test Sponsors: MaxWell Clinic, PLC Recruiting
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Home-Based Circuit Training in Overweight/Obese Older Adult Patients With Knee Osteoarthritis and Type 2 Diabetes - Conditions: Aerobic Exercise; Strength Training; Glycemic Control; Blood Pressure; Oxidative Stress; Metabolic Syndrome Interventions: Behavioral: 12-week home-based circuit training (HBCT); Behavioral: Standard of care (CONT) Sponsors: Princess Nourah Bint Abdulrahman University Completed
SVF for Treating Pulmonary Fibrosis Post COVID-19 - Conditions: Pulmonary Fibrosis Interventions: Biological: Autologous adipose-derived SVF IV administration Sponsors: Michael H Carstens; Ministerio de Salud de Nicaragua; Wake Forest University; National Autonomous University of Nicaragua Completed
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RECOVER-AUTONOMIC: Platform Protocol, Appendix B (Ivabradine) - Conditions: Long COVID; Long Covid19; Long Covid-19 Interventions: Drug: Ivabradine; Drug: Ivabradine Placebo; Behavioral: Coordinated Care; Behavioral: Usual Care Sponsors: Kanecia Obie Zimmerman Enrolling by invitation
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RECOVER-AUTONOMIC: Platform Protocol, Appendix A (IVIG) - Conditions: Long COVID; Long Coronavirus Disease 2019 (Covid19); Long Covid-19 Interventions: Drug: IVIG (intravenous immunoglobulin); Drug: IVIG Placebo; Behavioral: Coordinated Care; Behavioral: Usual Care Sponsors: Kanecia Obie Zimmerman Enrolling by invitation
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Understanding Adaptive Immune Response After COVID-19 Vaccination Boosters to Improve Vaccination Strategies in Vulnerable Groups. - Conditions: COVID-19 Interventions: Other: Analisys of cellular response and humoral response to SARS-CoV-2 vaccine booster doses Sponsors: IRCCS Sacro Cuore Don Calabria di Negrar Recruiting
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From PubMed
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N-Arylsulfonamide-based adenosine analogues to target RNA cap N7-methyltransferase nsp14 of SARS-CoV-2 - RNA cap methylations have been shown to be crucial for the life cycle, replication, and infection of ssRNA viruses, as well as for evading the hostâs innate immune system. Viral methyltransferases (MTases) therefore represent an attractive target for the development of compounds as tools and inhibitors. In coronaviruses, N7-methyltransferase function is localized in nsp14, which has become an increasingly important therapeutic target with the COVID-19 pandemic. In recent years, we have beenâŠ
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Unusual NiNi interaction in Ni(ii) complexes as potential inhibitors for the development of new anti-SARS-CoV-2 Omicron drugs - Two nickel(ii) coordination complexes Ni(L)(1) and Ni(L)(2) of a tetradentate Schiff base ligand (H(2)L) derived from 2-hydroxy-1-naphthaldehyde with ethylenediamine were synthesized, designed, and characterized via spectroscopic and single crystal XRD analyses. Both nickel(ii) complexes exhibited unusual NiâŻNi interactions and were fully characterized via single-crystal X-ray crystallography. Nickel(ii) complexes Ni(L)(1) and Ni(L)(2) crystallize in monoclinic and triclinicâŠ
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Integrating virtual screening, pharmacoinformatics profiling, and molecular dynamics: identification of promising inhibitors targeting 3CLpro of SARS-CoV-2 - Introduction: The pursuit of effective therapeutic solutions for SARS-CoV-2 infections and COVID-19 necessitates the repurposing of existing compounds. This study focuses on the detailed examination of the central protease, 3-chymotrypsin-like protease (3CLpro), a pivotal player in virus replication. The combined approach of molecular dynamics simulations and virtual screening is employed to identify potential inhibitors targeting 3CLpro. Methods: A comprehensive virtual screening of 7120âŠ
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TRIM6 facilitates SARS-CoV-2 proliferation by catalyzing the K29-typed ubiquitination of NP to enhance the ability to bind viral genomes - The Nucleocapsid Protein (NP) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is not only the core structural protein required for viral packaging, but also participates in the regulation of viral replication, and its post-translational modifications such as phosphorylation have been shown to be an important strategy for regulating virus proliferation. Our previous work identified NP could be ubiquitinated, as confirmed by two independent studies. But the function of NPâŠ
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Identification of FasL as a crucial host factor driving COVID-19 pathology and lethality - The dysregulated immune response and inflammation resulting in severe COVID-19 are still incompletely understood. Having recently determined that aberrant death-ligand-induced cell death can cause lethal inflammation, we hypothesized that this process might also cause or contribute to inflammatory disease and lung failure following SARS-CoV-2 infection. To test this hypothesis, we developed a novel mouse-adapted SARS-CoV-2 model (MA20) that recapitulates key pathological features of COVID-19âŠ.
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No immunological interference or concerns about safety when seasonal quadrivalent influenza vaccine is co-administered with a COVID-19 mRNA-1273 booster vaccine in adults: A randomized trial - The objective of the study was to assess the safety and immunogenicity of mRNA-1273 COVID-19 booster vaccination when co-administered with an egg-based standard dose seasonal quadrivalent influenza vaccine (QIV). This was a phase 3, randomized, open-label study. Eligible adults aged â„ 18 years were randomly assigned (1:1) to receive mRNA-1273 (50 ”g) booster vaccination and QIV 2 weeks apart (Seq group) or concomitantly (Coad group). Primary objectives were non-inferiority of haemagglutininâŠ
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Targeted degradation of zDHHC-PATs decreases substrate S-palmitoylation - Reversible S-palmitoylation of protein cysteines, catalysed by a family of integral membrane zDHHC-motif containing palmitoyl acyl transferases (zDHHC-PATs), controls the localisation, activity, and interactions of numerous integral and peripheral membrane proteins. There are compelling reasons to want to inhibit the activity of individual zDHHC-PATs in both the laboratory and the clinic, but the specificity of existing tools is poor. Given the extensive conservation of the zDHHC-PAT activeâŠ
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Inhibitory effects of senkyuchachosan on SARS-CoV-2 papain-like protease activity in vitro - Papain-like protease (PLpro) enzyme plays a vital role in viral replication as it breaks down polyproteins and disrupts the hostâs immune response. There are few reports on Kampo formulas that focus on PLpro activity. In this study, we evaluated the inhibitory effects of senkyuchachosan, a traditional Japanese medicine, on PLpro of SARS-CoV-2, the virus responsible for causing COVID-19. We purified the PLpro enzyme and conducted in vitro enzymatic assays using specific substrates. Among the nineâŠ
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Identification of inositol monophosphatase as a broad-spectrum antiviral target of ivermectin - Ivermectin has broad-spectrum antiviral activities. Despite the failure in clinical application of COVID-19, it can serve as a lead compound for the development of more effective broad-spectrum antivirals, for which a better understanding of its antiviral mechanisms is essential. We thus searched for potential novel targets of ivermectin in host cells by label-free thermal proteomic profiling using Huh-7 cells. Inositol monophosphatase (IMPase) was found among the proteins with shifted thermalâŠ
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Optimized Recombinant Expression and Purification of the SARS-CoV-2 Polymerase Complex - An optimized protocol has been developed to express and purify the core RNA-dependent RNA polymerase (RdRP) complex from the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). The expression and purification of active core SARS-CoV-2 RdRp complex is challenging due to the complex multidomain fold of nsp12, and the assembly of the multimeric complex involving nsp7, nsp8, and nsp12. Our approach adapts a previously published method to express the core SARS-CoV-2 RdRP complex inâŠ
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Supporting underrepresented students in health sciences: a fuzzy cognitive mapping approach to program evaluation - CONCLUSIONS: The findings from a multipronged analysis of mapping data demonstrate the value of this innovative approach to the field, especially when looking to incorporate student voices.
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An ascidian Polycarpa aurata-derived pan-inhibitor against coronaviruses targeting Mpro - Coronaviruses (CoVs) are responsible for a wide range of illnesses in both animals and human. The main protease (M^(pro)) of CoVs is an attractive drug target, owing its critical and highly conserved role in viral replication. Here, we developed and refined an enzymatic technique to identify putative M^(pro) inhibitors from 189 marine chemicals and 46 terrestrial natural products. The IC(50) values of Polycarpine (1a), a marine natural substance we studied and synthesized, are 30.0 ± 2.5 nM forâŠ
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SARS-CoV-2 Orf6 is positioned in the nuclear pore complex by Rae1 to control nucleo-cytoplasmic transport - The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) accessory protein Orf6 works as an interferon antagonist, in part, by inhibiting the nuclear import activated p-STAT1, an activator of interferon-stimulated genes, and the export of the poly(A) RNA. Insight into the transport regulatory function of Orf6 has come from the observation that Orf6 binds to the nuclear pore complex (NPC) components Rae1 and Nup98. To gain further insight into the mechanism of Orf6-mediated transportâŠ
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A retrospective cohort study on early antibiotic use in vaccinated and unvaccinated COVID-19 patients - The bacteriophage behavior of SARS-CoV-2 during the acute and post-COVID-19 phases appears to be an important factor in the development of the disease. The early use of antibiotics seems to be crucial to inhibit disease progression-to prevent viral replication in the gut microbiome, and control toxicological production from the human microbiome. To study the impact of specific antibiotics on recovery from COVID-19 and long COVID (LC) taking into account: vaccination status, comorbidities,âŠ
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Yemazhui () ameliorates lipopolysaccharide-induced acute lung injury modulation of the toll-like receptor 4/nuclear factor kappa-B/nod-like receptor family pyrin domain-containing 3 protein signaling pathway and intestinal flora in rats - CONCLUSIONS: In summary, our findings revealed that HEL has a protective effect on LPS-induced ALI in rats, and its mechanism may be related to inhibiting TLR4/ NF-ÎșB/NLRP3 signaling pathway and improving intestinal flora disturbance.
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From Patent Search
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+Daily-Dose
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How Quinta Brunson Hacked the Sitcom with âAbbott Elementaryâ - With âAbbott Elementary,â the comedian and writer found fresh humor and mass appeal in a world she knew well. - link
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The Crime Rings Stealing Everything from Purses to Power Tools - In Los Angeles, a task force of detectives is battling organized retail theft, in which boosted goods often end up for sale onlineâor commingled on store shelves with legitimate items. - link
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How Julienâs Auctions Leads the Booming Market in Celebrity Memorabilia - As the art market cools, Julienâs Auctions earns millions selling celebrity ephemeraâand used its connections to help Kim Kardashian borrow Marilyn Monroeâs J.F.K.-birthday dress. - link
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Has Putinâs Invasion of Ukraine Improved His Standing in Russia? - As Russians go to the polls, the economy is booming and the public feels hopeful about the future. But the politics of Putinism still depend on the absence of any means to challenge it. - link
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Why Robert Hur Called Biden an âElderly Man with a Poor Memoryâ - In his first interview after the release of his controversial report, the former special counsel insists that it was not his job to write for the public. - link
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From Vox
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Why March Madness is all about Caitlin Clark -
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+Caitlin Clark and Iowa won the Big 10 Womenâs Basketball Tournament earlier this month. | Photo by Adam Bettcher/Getty Images
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+The most exciting player in college basketball, explained.
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+For the uninitiated, college basketball may seem like a complicated sport. Nearly every second is packed with plays, screens, cuts, and defenses that can be hard to follow. Commentators spray you with names and phrases that youâre supposed to already know. (Izzo? Geno? The 1-3-1? Pac-12?) And letâs not even get started on advanced metrics, unless you can explain usage rate.
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+But if youâve ever wanted to see basketball beautifully simplified â as clean as putting a ball through the hoop â all you need to do is watch Caitlin Clark, the 22-year-old superstar making headlines with the Iowa Hawkeyes.
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+In both the menâs and womenâs college game, there has never been a more prolific scorer than Clark, no shooter as flashy. Sheâs the record-breaking scoring leader among all Division I college basketball players in NCAA history, smashing âPistol Peteâ Maravichâs more than 50-year-old record this season. Clarkâs gaudy numbers and the manner in which she scores â pulling up from anywhere in the gym, no matter how distant from the basket â have brought mainstream attention to womenâs college basketball, a sport historically eclipsed by its menâs counterpart.
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+ Photo by Matthew Holst/Getty Images
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+The spot where Caitlin Clark broke the NCAA womenâs scoring record at Carver-Hawkeye Arena
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+Her impact is being called the Caitlin Clark Effect. The Hawkeyes sold out their season tickets for their entire home schedule for the first time in school history, and Iowaâs road games have set attendance bests for opposing schools. Tickets for Iowaâs first two March Madness games, which begin on Saturday, sold out in 30 minutes. Earlier this month, her game against Ohio State â in which she broke Maravichâs aforementioned record â was watched by nearly 4 million TV viewers, the highest for a regular-season womenâs basketball game (i.e., no championships involved) since 1999.
+
+
+Clark is the exception among her exceptional peers, and it isnât just because of her incredible long-range shot. Itâs that she knows what makes basketball exciting. She sees the spotlight and the pressure, the wins and the heartbreaks as a privilege, and she has embraced being both a hero and a villain. Thatâs what allows her to be the most thrilling player in college basketball.
+
+
+How Caitlin Clark changed womenâs basketball
+
+
+Over the past four years, Caitlin Clark has scored 3,771 points â the most for a player of any gender in Division I college basketball. That list includes male Hall of Famers like Maravich and Larry Bird as well as Brittney Griner, Maya Moore, Elena Delle Donne, and Chamique Holdsclaw, some of the best womenâs players of all time.
+
+
+Beginning her freshman season in 2020, Clark averaged 26.6 points per game and has upped that number each year to reach her current 31.9 as a senior. That stunning stat goes along with 8.9 assists per game and 7.3 rebounds. Sheâs currently shooting nearly 50 percent from the field, 38 percent from three, and 86 percent from the free throw line.
+
+
+Those numbers are stellar, but basketball is a team sport, and Clarkâs play elevates the Hawkeyes as a whole.
+
+
+Clark is a scoring point guard. That means she touches the ball virtually every single time Iowa comes down the court on offense. Whether itâs shooting or setting up her teammates, getting points on the board is her responsibility. Opposing teams know this and go into each contest with the goal of shutting her down, playing Clark with lots of physicality and throwing double and even triple teams at her.
+
+
+Yet all season, sheâs been scoring at a high clip and doing so with efficiency. Her gravitational pull has also freed up her teammates: When opponents double-team Clark, it leaves at least one of her fellow Hawkeyes open, allowing them more space for cuts to the basket.
+
+Clarkâs offense has changed the Iowa program, bringing the team close to an NCAA championship.
+
+
+Three years ago, during her freshman season, Clark and the Hawkeyes overachieved to make the NCAA Sweet 16 as a No. 5 seed, upsetting Kentucky before losing to UConn. Two years ago, Clark helped Iowa win the Big 10 tournament and clinch a No. 2 seed in the NCAA tournament.
+
+
+Last year, she made program history and brought Iowa to the national championship game, beating the overall favorite South Carolina before losing in the final game to LSU. After a remarkable 2023â2024 season and another Big 10 tournament win, Iowaâs womenâs team got a No. 1 seed for March Madness â just the third time in program history â and is ranked second overall.
+
+
+Taking the Hawkeyes to the national championship last year and getting them poised for another deep tourney run is an especially remarkable achievement when you consider the composition of the Iowa squad.
+
+â The Playersâ Tribune (@PlayersTribune) April 1, 2023
+
+
+
+Clarkâs teammates werenât highly ranked All-Americans in high school, the primary evaluation of how good an incoming college player is compared to her cohort. While ESPN ranked Clark herself fourth in the 2020 class, her next-best teammate, Hannah Stuelke, was ranked 45 coming out of high school and averaged 6.5 points per game in the 2022â2023 season. Clark is the only five-star recruit on Iowaâs roster.
+
+
+By comparison, South Carolina, the top-ranked team heading into the tournament, is littered with highly rated players. Sophomore Raven Johnson was ranked second and named the Womenâs Basketball Coachâs Association high school player of the year going into college. Thereâs also senior Kamilla Cardoso, who was ranked fifth on recruiting lists and was later named Freshman of the Year in her conference. There are many other stars, including Te-Hina Paopao, Bree Hall, and Milaysia Fulwiley.
+
+
+To be clear, Clark isnât a perfect player. Her defense is improving, but she and Iowa would much prefer to outscore their opponents than lock them down defensively. Iowa gives up around 72 points per game to its opponents, while teams like South Carolina, UConn, and Texas donât let their rivals hit 60. Plus, coach Lisa Bluderâs failure to find Clark a blue-chip teammate or two throughout her college career is probably the reason why Iowa didnât win the championship last year and still isnât the favorite to win this year.
+
+
+But Clark is special because her massive offensive talent makes her team better and allows Iowa to compete with more talented rosters. As Iowa has shown us this year and last, anything can happen with her on the floor.
+
+
+Caitlin Clark isnât afraid to be a star (or a villain)
+
+
+Clark makes you feel like youâre watching magic. Thatâs why so many people, even some womenâs basketball naysayers, are so interested.
+
+
+Womenâs basketball is often negatively compared to the menâs game. With the rim at the same height regardless of gender, men can make more athletic plays (dunks, putbacks, alley-oops) closer to the basket due to theirheight and strength. In the paint and on fast breaks, womenâs basketball isnât going to look as glitzy as the menâs. But physical advantages donât have a bearing on shooting and court vision, and thatâs where Clark excels.
+
+
+Clark regularly pulls up from beyond the 3-point line, sometimes even a step or two over half court (the vaunted âlogoâ three), and sinks them. The farther she shoots from, the more spectacular the basket. Her shooting range has inspired the next generation of womenâs basketball players, and helped her ink lucrative NIL (name, image, and likeness) deals with brands like Nike, Gatorade, and State Farm. Clark and Iowa, as the Wall Street Journal discussed, have been part of the most-watched womenâs basketball games on six different networks.
+
+
+Her countless fans also include Steph Curry, arguably the best menâs shooter of all time. âWhen you watch them play, she just adds the element of surprise that you canât really game-plan for,â Curry told ESPN last March.
+
+
+
+
+Caitlin Clark is ridiculous. Logo shot and another monster game.
+In a sport where women are told they canât do the things men do, Clark defies expectations. Not that many menâs college basketball stars shoot from where Clark does and with her confidence.
+
+
+That belief in herself adds to the spectacle of her games. Like other greats before her, Clark is unafraid to be both the hometown hero and the visiting villain. Sheâs extremely fun to cheer on, especially if youâre an Iowa fan; sheâs also extremely fun to root against and beat if youâre not.
+
+
+Last year during the NCAA tournament, Clark employed John Cenaâs âYou canât see meâ gesture in a win over Louisville. Clark tallied a triple double â 41 points, 12 assists, 10 rebounds â and sank eight 3-pointers, suggesting that Louisville, in fact, did not see her. In her Final Four win against South Carolina, Clark waved off an opposing player, daring them to shoot. Said player didnât shoot.
+
+
+That clip went viral, with some fans calling the play disrespectful (positive and funny) and others calling it disrespectful (negative and unfunny). In the championship game, LSU returned the favor by sinking 64 percent of its 3s. Angel Reese, the LSU star who goes by the nickname âBayou Barbie,â gave Clark some of her own medicine and taunted her as the game came to a close. Clark had nothing but compliments for Reese and LSU after the game.
+
+
+ Photo by Steven Branscombe/Getty Images
+
+When Caitlin Clark walks into the building, sheâs in range.
+
+
+
+Clark and Iowaâs NCAA tournament bracket isnât easy this year, as Kansas State â a team that beat them in the regular season â looms as a potential Sweet 16 matchup. Defending champion LSU and a resurgent UCLA team are also in Clarkâs region.
+
+
+Whether Clark finishes the season with a loss or a national championship, itâll be her last one as a college player. She announced that sheâll move onto the WNBA despite having one year of eligibility left for college ball. Experts have already weighed in on how valuable sheâll be as a pro. If she continues on her current trajectory, barring injury, sheâll likely challenge for a WNBA championship and Olympic gold. Her professional career hasnât even begun, and thereâs still so much to be written.
+
+
+Caitlin Clarkâs next game: Iowa vs. Holy Cross at 3:00 pm on March 23, 2024
+
+
+
Baseball superstar Shohei Ohtani has been caught up in a gambling controversy. He wonât be the last. -
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+
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+Getty Images
+
+
+
+From baseball to March Madness, how gambling is ruining sports.
+
+Eight members of the Chicago White Sox were accused of taking money from gamblers to purposefully lose the World Series. Though some maintained their innocence, all eight were eventually banned from baseball for life.
+
+
+If that punishment was harsh, it was largely justified. No sport can be expected to thrive if fans have reasonable suspicions that the games arenât on the level.
+
+
+In the decades that followed, sports did all they could to distance themselves from gambling. To this day, every sports commissionerâs worst nightmare is waking up to hear that one of their top players has been involved in a gambling scandal.
+
+
+Which is basically what happened to Major League Baseball (MLB) this week.
+
+
+Oh no, Ohtani
+
+
+Shortly after the Los Angeles Dodgers and the San Diego Padres opened up the 2024 regular season with MLBâs first-ever game in South Korea this week, news broke that Japanese Dodgers superstar Shohei Ohtaniâs interpreter Ippei Mizuhara had been fired after Ohtaniâs representatives accused him of stealing millions of dollars to place illegal bets.
+
+
+At this point, no one is accusing Ohtani of engaging in gambling on baseball, which is strictly forbidden by the sport.
+
+
+But still, thereâs some weirdness here, not least that Mizuhara reportedly gave an interview to ESPN claiming that Ohtani has transferred millions of dollars from his account to Mizuhara to cover the interpreterâs gambling debts, only for Ohtaniâs representatives to later say that no, he had actually been the victim of theft.
+
+But thatâs the thing about gambling and sports. You donât have to be sure that players are placing bets to wonder if everything is on the up and up. Just suspicion is enough to erode the integrity of the game.
+
+
+Which, of course, is why sports put so much effort into putting walls between the games and the athletes and the bookies. At least, until recently.
+
+
+The big game of sports gaming
+
+
+As I write this, March Madness has just tipped off, which means, as we explained Monday, that weâre in the midst of the biggest mainstream betting event of the year. US bettors will put more than $2.72 billion on the menâs and womenâs college basketball tournaments using legalized sportsbooks.
+
+
+Putting aside the fact that $2.72 billion is roughly $2.72 billion more than the amateur men and women participating in these tournaments are directly paid for their work, itâs more than twice what the NCAA brought in from March Madness in 2021. Which just goes to prove that gambling has gone from a shadow sideshow in pro and college sports to, increasingly, the main attraction.
+
+
+In 2023, as my former Vox colleague Emily Stewart has reported, Americans spent $120 billion on sports gambling, a 28 percent increase from the year before. The staggering growth in sports gambling has been enabled by the growing legalization of legal sports betting throughout the US, which really kicked off with a 2018 Supreme Court decision striking down a 1992 federal law that effectively banned the practice in most states.
+
+
+Once the decision on whether or not to allow sports gambling was left up to individual states, most of those states said âYes, please, give us more.â As a result, sports betting is legal in some form in three dozen states, and online sports betting is legal in two dozen states.
+
+
+That second part is important. Sports gambling hasnât just migrated away from the quasi-legal black market; itâs migrated to the object we keep closer on hand than anything else: our phones.
+
+
+From DraftKings to FanDuel, the last few years have seen the rise of sports betting apps that take one known compulsive activity â gambling itself â and marry it with the best (or worst) in gamifying, addiction-generating social media.
+
+
+Unsurprisingly, Americans spent a record 67.1 million minutes on sports gambling sites in October 2023, a 66 percent increase from the year before. (Disclosure: The sports network SB Nation, which is owned by Voxâs parent company, Vox Media, has a partnership with DraftKings.)
+
+
+In response to these changes, sports could have kept the walls up.
+
+
+They did not â you can now make bets on site at many stadiums and arenas, analysis of odds are a major part of pregame shows, and this week, the NBA even started allowing fans to place bets directly on its official League Pass app.
+
+
+Sports is now gambling in the US, and gambling is sports.
+
+
+A losing bet
+
+
+There are a lot of drawbacks to the expansion of sports betting, not least that it means more people end up gambling.
+
+
+While as many as 5 percent of American adults will experience some problem gambling in their lifetime, much of the existing research was done before the great legalization wave. The Connecticut Council on Problem Gambling, for instance, saw a 91 percent increase in calls to its addiction helpline in 2022 â the year that mobile gambling became legal in the state.
+
+
+Whatâs even harder to see â though increasingly palpable â is the impact that the ubiquity of gambling is having on sports itself. You donât have to go full Field of Dreams to lament the way that gambling essentially financializes sports and the athletes who play it, transforming what should be human drama into over-unders, prop bets, and teasers.
+
+
+If you donât believe me, listen to the players and the coaches. Indiana Pacers star Tyrese Haliburton recently complained that âto half the world, Iâm just helping them make money on DraftKings ⊠Iâm just a prop.â Cleveland Cavaliers coach J.B. Bickerstaff has said that he received threats from gamblers last year. (The Cavaliers, it should be noted, have a sportsbook inside their arena.)
+
+
+At this point, many experts believe that itâs a matter of when, not if, a major gambling scandal devastates a top US sport.
+
+
+As March Madness demonstrates with its stirring upsets every year, one of the most powerful forces in sports is belief. But that belief can be shattered by something even more powerful: greed.
+
+Itâs not hard to understand why. The ongoing war in Ukraine has seen drones transform from a bespoke counterterrorism tool â one largely controlled by the US and its allies â into a ubiquitous feature of the modern battlefield.
+
+
+Russian drones have rained down death on cities and destroyed energy infrastructure across Ukraine, inflicting serious pain on the civilian population. Ukrainian drones have made much of the Black Sea a no-go zone for Russiaâs navy â despite the fact that Ukraine has virtually no navy of its own â and in recent days, drones have been able to reach deep into Russian territory.
+
+
+On the front lines, surveillance drones are used as spotters for artillery, making such weapons far more effective and likely contributing to a stalemate, one where neither side is able to maneuver or take advantage of the element of surprise.
+
+Not surprisingly, the Pentagon is looking to learn lessons from these battlefields, particularly as it eyes a potential future conflict with China. But while technological advances from the longbow to the atom bomb have changed the nature of warfare â just as war has driven technological innovation â what distinguishes the new age of drone warfare from previous military innovations is how it will play out. With drones, the military with the advantage isnât necessarily the one with the most advanced or most powerful weapons, but the one that has these new weapons en masse and can quickly build and replace them.
+
+These drones arenât anywhere near as accurate or powerful as manned aircraft or high-end military drones like the USâs Reaper, which costs about $32 million â but they donât need to be. If one is lost, itâs just not that big a deal. The result is that drones can be a kind of leveler for materially disadvantaged forces, whether they be the Houthi rebels disrupting the global trading system or Ukraineâs beleaguered defenders coping with shortfalls in artillery supplies.
+
+
+All of that is bad news for the US military, which has long relied on sheer technological superiority. In response, the Pentagon is taking an âif you canât beat them, join themâ approach, launching an ambitious plan called Replicator to build thousands of cheap, replaceable â or âattritable,â in the Pentagonâs lexicon â drones, all in anticipation of a potential superpower conflict with China.
+
+
+Advocates see the initiative not just as a new weapon but as a fundamental transformation of how Americaâs military equips itself for the wars of the future. Yet even the staunchest Replicator boosters concede that doing so will require a wholesale change in mindset for one of the US governmentâs most entrenched bureaucracies, one complicated by the fact that itâs all supposed to happen very, very fast.
+
+
+The rise of Replicator
+
+
+Last August, Deputy Secretary of Defense Kathleen Hicks announced the launch of Replicator with the goal of fielding âattritable autonomous systems at scale of multiple thousands, in multiple domains, within the next 18-to-24 months.â Hicks was very clear on these weaponsâ intended target: the worldâs largest military by manpower.
+
+
+âReplicator is meant to help us overcome the PRCâs biggest advantage, which is mass,â she said, referring to the Peopleâs Republic of China. âMore ships. More missiles. More people.â We donât know exactly how these drones will operate, but itâs likely they could form coordinated swarms to counter Chinaâs advantages in mass and proximity to a future battlefield.
+
+
+The stakes could hardly be higher. âThe purpose of Replicator is to deter a conflict with the PRC, and if forced to fight, to have the capabilities we need to do so,â Aditi Kumar, a deputy director at the Pentagonâs Silicon Valley-based Defense Innovation Unit (DIU), told Vox.
+
+
+We are now nearly seven months into Hicksâs timeline and the public still doesnât have a good idea of what these systems will look like or who will be building them. According to the Department of Defense, there are around half a billion dollars for Replicator in its fiscal year 2024 budget â though Congress being Congress, that budget has still not been passed, and the department has been funded through a series of stopgap funding bills â and another half billion in its just-released fiscal year 2025 budget.
+
+
+Thatâs pretty modest within the Pentagonâs $850 billion budget request. Kumar told Vox that an initial list of systems has been approved and that the department has contracts âready to executeâ as soon as it receives procurement funding from Congress.
+
+
+The name âReplicatorâ refers to the fact that the department hopes the procedures used to fast-track the program can be âreplicatedâ across the department. But as a number of the initial articles greeting Hicksâs announcement pointed out, itâs also sure to remind any Star Trek: The Next Generation fan of the devices used by the Enterprise crew to conjure anything up to âtea, Earl Grey, hotâ out of thin air.
+
+
+This Replicator wonât be quite that fast, but Kumar said a lesson the DIU has gained from conversations with Ukrainian operators is that modern drone warfare not only requires large numbers of systems, but that those systems have to be adaptable to a rapidly changing environment. In Ukraine, for instance, the drone war often comes down to a race to adapt the machines to the other sideâs electronic countermeasures and jamming systems.
+
+
+âBasically every 90 days, the environment completely changes,â Kumar said, referring to lessons learned from the Ukrainian operators. âWhatever capabilities they are fielding, countermeasures developed for those and so they have to keep staying ahead of the curve.â
+
+
+ Diego Herrera Carcedo/Anadolu via Getty Images
+
+A Ukrainian soldier operates a drone during a training session in Kharkiv, Ukraine, on March 11, 2024.
+
+
+
+The robots are coming
+
+
+Fielding fleets of drones at this scale is also likely to speed up the militaryâs adoption of artificial intelligence. âThe only way that thousands of drones work is if you have some measure of autonomy in the drones,â said Paul Scharre, a former Defense Department official now with the Center for a New American Security (CNAS). âBecause they have thousands of systems of control, then you would need thousands of people operating them, and thatâs a big personnel cost for the military.â
+
+Scharre is among the scholars raising concerns about the risks that an autonomous weapon could inadvertently trigger an international crisis by taking some risky action that a human in the loop might have decided against. (Another worry is that the speed of future conflicts and the pace of AI innovation may create pressure to take humans out of the loop.) He told Vox that autonomous weapons systems are more difficult to test than other applications of AI, such as self-driving cars, because of the difficulty of simulating the conditions under which they will be used. âYou wonât get feedback on how something works until the war happened,â he said.
+
+Regardless, the age of AI aircraft is likely coming fast. The Air Force is also pursuing a separate program to develop so-called collaborative combat aircraft, or ârobot wingmanâ drones: highly autonomous drones that will fly alongside crewed aircraft. Pentagon officials have described that program as âcomplementaryâ to Replicator.
+
+
+Made in America
+
+
+Building these drones on Hicksâs timeline sounds ambitious enough, but thatâs just the beginning.
+
+
+âReplicator is about fielding multiple thousands of autonomous systems by 2025, and thatâs the metric we will be measured by in terms of success or failure,â said a senior Pentagon official authorized to speak with Vox on condition of anonymity. âBut more important is the departmentâs culture change, in getting us to use our authority in a more creative way to accelerate delivery to the warfighter.â
+
+
+Replicator takes aim at an outmoded Pentagon acquisitions and development process that has caused the average time for the development of US weapons systems, from research and development to deployment, to roughly quadruple since the 1970s.
+
+
+And while the US has slowed down, potential adversaries have sped up. In 2018, Michael Griffin, then undersecretary of defense for research and engineering, estimated that it takes the US roughly 16 years to deliver a new idea to operational capacity, versus fewer than seven for China.
+
+
+William Greenwalt, a former deputy undersecretary of defense for industrial policy now at the American Enterprise Institute, blames these delays on a culture of âsystems analysis run amokâ â the insistence on exhaustive testing and analysis for new systems. Itâs âthe greatest jobs program the Pentagon has ever developed,â he told Vox. âAnd as long as you donât have a near peer competitor, you can have a jobs program.â
+
+
+Thatâs no longer the case, given Chinaâs rapidly rising capabilities and the countryâs own investments in drones and autonomous systems. The senior Pentagon official acknowledged that the department had to find ways to get new systems from idea to operation, and that this would mean building âa culture where itâs okay to take acceptable risks, not irresponsible risks, but acceptable risks.â
+
+
+Greenwalt predicted that the biggest technical challenge to Replicator will not be aerodynamics, range, or software, but manufacturing. Consider that itâs projected to take until 2025 for the US to ramp up production of 155-millimeter artillery ammunition â a system that hasnât been altered that much since the early 20th century â to meet Ukraineâs battlefield needs. Replicator, a far more complex and completely new system, one that hasnât even gone into production yet, is supposedly going to be built on a much faster timeline.
+
+
+Adding to the headaches is the fact that the US commercial drone sector lags behind Chinaâs, where Chinese companies like DJI dominate the market for the types of technologies that could be adapted for dual use. Ukraineâs forces have been celebrated for adapting these off-the-shelf systems for military purposes, and Kyiv now buys about 60 percent of the worldâs supply of DJIâs popular Mavic quadcopter. But thatâs obviously not an option for the US when China itself is the anticipated adversary.
+
+
+Still, Greenwalt is cautiously excited about the level of ambition involved. âCan we basically adopt a manufacturing capability from scratch with new technology? That, I think, is the real revolutionary potential of Replicator.â
+
+
+What Ukraine canât teach us
+
+
+As futuristic as Replicator may sound, thereâs still a risk that the US is simply fighting the last war. Stacie Pettyjohn, director of the defense program at CNAS and author of a recent study of drone innovation in the war in Ukraine, questions the degree to which the lessons of that war â one where small, less capable, but easily replaceable drones have played a major role â would be applicable to combat in the Pacific with China.
+
+
+âThe geography and the distances involved in the Pacific theater are so much greater than in Ukraine, and the type of drones that the United States would employ need to have more range and endurance because theyâre likely to be based at least several hundred miles away at the closest and probably much farther than that,â Pettyjohn told Vox. âSo unless the United States is going to be pre-positioning drones on Taiwan, itâs going to need a different class of system.â
+
+
+Pettyjohn worries that given the strict timelines established for Replicator, âthe type of drones that it is going to end up producing are not going to be a lot of the ones that would be helpful.â
+
+
+Pentagon officials declined to comment on the specific operational needs for Replicator but Kumar acknowledged that, âWe are dealing with a very different environment, an amphibious environment. And that presents a different set of concepts of operations and targets [than Ukraine].â
+
+
+Automatic weapons
+
+
+The main advantage of drones, of course, is that they decrease the risks to human troops. âIt does allow us to have fewer people in the line of fire by replicating what our soldiers, sailors, airmen, marines, and guardians do very well,â the Pentagon senior official said.
+
+
+The shift to a great emphasis on autonomous systems comes at a time when the military is scaling back on its human manpower. In February, the Army announced it was cutting the size of its force by 24,000 â around 5 percent â mainly by not filling already empty posts. The move is part of a deliberate restructuring as the Army shifts away from its post-9/11 focus on counterterrorism, with deep cuts to special operations forces and more staff for drones, air defense, and cyber capabilities. It also comes as the Army has been consistently missing its recruiting goals.
+
+
+A potential war with China is likely to involve greater numbers of troops in combat, and greater casualties, than the US has seen in decades. Itâs possible that in the future, robots may be able to make up, to some extent, for human manpower in wars like these. We can only hope we wonât have to find out.
+
+
+
From The Hindu: Sports
+
+
Indian Premier League 2024 | Shreyas Iyerâs comeback in spotlight in Starc vs Cummins showdown - On paper, KKR with a star-studded batting and spin-heavy attack to complement Starcâs pace, will be overwhelming favourites.
+
Indian Premier League 2024 | Comeback-man Pant the highlight as Delhi Capitals take on Punjab Kings - Punjab Kings have rarely come together as a unit to go the distance, making Delhi Capitals the favourites for the day game
Motor racing | Verstappen wants more focus on car, not Red Bull drama - Verstappen, who has won the last three world championships with Red Bull, said the internal strife had no impact on his performance or comfort within the team.
+
Badminton | Treesa-Gayatri win, Tanisha-Ashwini lose in Swiss Open - World no. 26 Treesa and Gayatri will face Australiaâs Setyana Mapasa
+
+
From The Hindu: National News
+
+
ASAP Kerala invites applications for cybersecurity course - With no prior experience necessary to apply, the programme is accessible to beginners
+
Aviation regulator DGCA slaps âč80 lakh fine on Air India for violations of norms related to flight duty time limitations - The DGCA said there were instances of exceeding duty periods, wrongly marked training records and overlapping duties.
+
Tiruchi Corporation expedites repairs at Periyar Nagar Collector Well - Of the 2,40,000 households in the city, 1,20,000 dependen on the Corporationâs water supply; the civic body recently introduced alternate day water supply
+
After withdrawing from Lok Sabha poll race, Congress national spokesperson Rohan Gupta now quits party - Rohan Gupta, who had been given a Lok Sabha ticket from the Ahmedabad East seat by the Congress, withdrew from the race last Monday citing his fatherâs ill health
+
Water storage in Indiaâs key reservoirs is at 38% ahead of summer season - Reservoirs in the South have reported lower storage levels compared to last year, data shows
+
+
From BBC: Europe
+
+
Blackouts hit Ukraine after wave of Russia strikes - Ukraine says Russia trying to cause failure of countryâs energy system after widespread attack.
+
Fleeing Ukraineâs embattled border villages - Ukrainians are leaving villages occupied by Russia amid a rise in cross-border attacks by both sides.
+
Bosnia and Herzegovina to begin talks to join EU - The bloc has given the green light to start membership talks with the country, eight years after it first applied.
+
Big missile attack targets Ukrainian capital - At least 17 people were injured as debris from more than 30 intercepted missiles fell on Kyiv, officials say.
+
Ukraine, Iceland, Georgia & Greece in finals - Ukraine will play Iceland in Wroclaw, Georgia will host Greece, and Poland will visit Wales in Tuesdayâs three Euro 2024 play-off finals.
+
+
From Ars Technica
+
+
Never-before-seen data wiper may have been used by Russia against Ukraine - AcidRain, discovered in 2022, is tied to AcidPour. Both are attributed to Russia. - link
+
More than half of chickenpox diagnoses are wrong, study finds - Vaccination has dramatically reduced cases, making clinical diagnoses tricky. - link
+
SpaceXâs workhorse launch pad now has the accoutrements for astronauts - âThis system will help us scale to bigger towers and spaceships.â - link
+
Worldâs first global AI resolution unanimously adopted by United Nations - Nonbinding agreement seeks to protect personal data and safeguard human rights. - link
+
Appleâs green message bubbles draw wrath of US attorney general - RCS and green bubbles in iPhone-to-Android texts play role in Apple/DOJ battle. - link
+
+
From Jokes Subreddit
+
+
Playful CEO -
+
+
+A CEO of a multinational corporation was flying across the Pacific and decided he had to go to the bathroom. So he got up and started walking down the aisle, but just as he passed the plane door it malfunctioned, opened and he was sucked out.
+
+
+Miraculously he survived landing in the water and saw a tropical island nearby. He swam to it, certain that he would soon be rescued. However, fifteen years passed and no one came to his rescue. Fortunately there was a spring on the island and he survived on coconuts and fish.
+
+
+Finally one day, as he was drawing sand pictures at the beach, he sees a woman in a trim-fitting scuba outfit emerge from the ocean.
+
+
+She is beautiful!
+
+
+She says, âAre you Fred Jacobson?â He says, âWhy yes I am.â
+
+
+âCongratulations, I am from Rescue Inc., and we have been attempting to find you since you were lost. Now tell me, how long has it been since youâve had a smoke?â
+
+
+âWell, of course itâs been about 15 years.â
+
+
+So she reaches down the front of her wet-suit on the left side and pulls out a package of Players cigarettes. âHow in the world did you know that my favorite brand was Players?â
+
+
+âWe have researched all of your preferences very carefully Fred, we want to do a good job.â
+
+
+So as Fred is taking a deep, satisfying drag on his cigarette, the rescuer says, âAnd how long has it been since youâve had a drink?â
+
+
+âWell, thatâs fifteen years too.â And so she reaches down inside the wetsuit on the other side and pulls out a bottle of Jack Daniels.
+
+
+âHow did you know that Jack Daniels was my favorite drink?â
+
+
+âWell, Fred, as I said we have looked into all of those things too, do you mind if I have a drink too?â
+
+
+âNo, of course not.â And they both put a couple away.
+
+
+Then, as she starts to peel off the wet suit she says, âAnd tell me Fred, how long has it been since youâve played around?â
+
+
+âDonât tell me youâve got a set of golf clubs in there!â
+
Three men were talking about their teenage daughters: The first says âI was cleaning my daughterâs room the other day and found a packet of cigarettes. I didnât even know she smokedâ. -
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+The second says âThatâs nothing. I was cleaning my daughterâs room the other day when I came across a full bottle of Vodka. I was really shocked as I didnât even know she drankâ. Then the third speaks up. âBoth of you have got nothing to worry about. I was cleaning my daughterâs room the other day and I found a packet of condoms. I was really shocked. I didnât even know she had a penisâ.
+
A boy comes home for dinner looking exhausted and disheveled⊠-
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+His mother sees his state and asks him, âWhat on earth have you been up to all day?â The boy turns to his mother and proudly says, âWell Mom, Iâve been out fucking and fighting all day.â His mother is shocked by his words and angrily responds, âHow dare you speak like that? You go to your room, this minute and no supper for you! Just wait till your father gets home and I tell him what you said!â The boy just skulks up to his room, head bowed in shame.
+
+
+A little while later, the father comes home and calls out, âHi honey Iâm home!â Immediately, the mother approaches him and tells him, âDo you know what your son said to me? When I asked him how his day was, he told me he was out fucking and fighting all day.â Taken aback, the father replies, âHe said what?â Again, the mother repeats, âHe told me he was fucking and fighting all day, in those wordsâ.
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+Furiously, the man throws down his bag and jacket and storms into the kitchen. He rifles through the cupboards, pulling out a large iron skillet. The wife looks at him frightened and asks, âPlease dear, what do you plan on doing with that?â
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+The father turns to her and, with a smile says, âIâm going to fry him up a steak. The poor boy canât be out fucking and fighting all day on an empty stomach now can he?â
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Photo by Matthew Holst/Getty Images
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Photo by Steven Branscombe/Getty Images
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Diego Herrera Carcedo/Anadolu via Getty Images
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