Simultaneous Identification of Changepoints and Model Parameters in Switching Dynamical Systems -
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+Many complex natural systems undergo shifts in dynamics at particular points in time. Examples include phase transitions in gene expression during the cell cycle, introduced species affecting predator-prey interactions, and disease outbreaks responding to intervention measures. Such changepoints partition timeseries into different dynamical regimes characterized by distinct parameter sets, and inference on both the changepoints and regime-specific dynamical parameters is of primary interest. Conventional approaches to analyzing switching dynamical systems first estimate changepoints, and then estimate dynamical parameters assuming the changepoints are fixed and known. Such two-stage approaches are ad-hoc, can introduce biases in the analysis, and do not fully account for uncertainty. Here, we introduce a rigorous, simulation-based inference framework that simultaneously estimates changepoints and model parameters from noisy data while admitting full uncertainty. We use simulation studies of oscillatory predator-prey dynamics and stochastic gene expression to demonstrate that our method yields accurate estimates of changepoints and model parameters together with appropriate uncertainty bounds. We then apply our approach to a real-world case study of COVID-19 intervention effects, and show that our inferred changepoints aligned closely with the actual dates of intervention implementation. Taken together, these results suggest that our framework will have broad utility in diverse scientific domains.
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The Effect of COVID-19 on Home Advantage in High- and Low-Stake Situations: Evidence from the European National Football Competitions -
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+The Covid-19 pandemic has significantly altered the way sporting events are observed. With the absence or limited presence of spectators in stadiums, the traditional advantage enjoyed by home teams has diminished considerably. This underscores the notion that the support of home fans can often be considered a key factor of the home advantage (HA) phenomenon, wherein teams perform better in front of their own supporters. However, the impact of reduced attendance on games with higher stakes, as opposed to low-stakes friendly matches, remains uncertain. In this study, we investigate the recently concluded European football championship (EURO 20), wherein several teams had the advantage of playing at home in high-stakes games with only one-third of the stadium capacity filled. Firstly, we demonstrate that the Covid-19 restrictions, leading to reduced fan attendance, resulted in a nearly 50% decrease in HA compared to the HA exhibited by the same teams during the qualification stage preceding EURO 20, even after accounting for team strength. Secondly, we show that while low-stakes friendly matches generally exhibit a smaller overall HA compared to high-stakes games, the absence of fans led to a similar reduction in HA during the low-stakes matches. Utilizing the recently developed Home Advantage Mediated (HAM) model (Bilalić et al., 2021, Scientific Reports, 21558), we were able to attribute the reduction in both high- and low-stakes games to poorer team performance, with no significant contribution from referee bias.
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Young people’s condom use during the COVID-19 pandemic: Cross-cultural differences and what predict them -
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+According to the Behavioural Immune System (BIS) theory, humans are motivated to avoid exposure to harmful pathogens. However, most sources of infection are impossible to avoid completely, leading to the development of tools to reduce pathogen threat. Condoms are one example of an effective tool that can be used to avoid exposure to sexually transmitted infections (STIs). Within this framework, it would be expected that condom use would increase after the spread of a novel coronavirus (i.e., COVID-19), but the evidence to date is inconsistent. The present study aimed to clarify these inconsistencies by examining changes in condom use cross-culturally. First, Study 1 aimed to uncover whether condom use after the initial outbreak period was consistent with the BIS theory among an Australian sample (N1 = 129). Contrary to the BIS, but inline with other findings in Australia, there was a general decline of condom use. Second, Study 2 aimed to examine whether cross-cultural condom use was consistent with the BIS. Sexually active participants (N2 = 3843) across 17 countries were asked about their condom use. Results revealed a significant decline in Canada, Portugal, Vietnam, Uganda, and Taiwan. Vaccination percentage and lockdown stringency were associated with this decline cross-culturally. In sum, there was no evidence supporting the BIS theory, and these findings continue to add concerns about the spread of STIs among young people during the pandemic.
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Multiple crises in mind, biodiversity out of sight? Insights from a behavioral study in Germany -
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+Biodiversity loss is one of the key challenges of our time. This paper explores how negative information due to other societal challenges influences attention toward biodiversity loss. With the help of an information provision experiment, we remind experimental participants recruited from the general population of Germany of Covid-19 and the war in Ukraine. We find less priority given to biodiversity loss after being reminded of these societal crises. However, this effect is both low in magnitude and not statistically significant at any conventional level. In contrast, personal importance of biodiversity to individuals is a much stronger behavioral predictor.
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A novel microporous biomaterial vaccine platform for long-lasting antibody mediated immunity against viral infection. -
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+Current antigen delivery platforms, such as alum and nanoparticles, are not readily tunable, thus may not generate optimal adaptive immune responses. We created an antigen delivery platform by loading lyophilized Microporous Annealed Particle (MAP) with aqueous solution containing target antigens. Upon administration of antigen loaded MAP (VaxMAP), the biomaterial reconstitution forms an instant antigen-loaded porous scaffold area with a sustained release profile to maximize humoral immunity. VaxMAP induced CD4+ T follicular helper (Tfh) cells and germinal center (GC) B cell responses in the lymph nodes similar to Alum. VaxMAP loaded with SARS-CoV-2 spike protein improved the magnitude and duration of anti-receptor binding domain antibodies compared to Alum and mRNA-vaccinated mice. A single injection of Influenza specific HA1-loaded-VaxMAP enhanced neutralizing antibodies and elicited greater protection against influenza virus challenge than HA1-loaded-Alum. Thus, VaxMAP is a platform that can be used to promote adaptive immune cell responses to generate more robust neutralizing antibodies, and better protection upon pathogen challenge.
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An isothermal calorimetry assay for determining steady state kinetic and enzyme inhibition parameters for SARS-CoV-2 3CL-protease -
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+This manuscript describes the application of Isothermal Titration Calorimetry (ITC) to characterize the kinetics of 3CLpro from the Severe Acute Respiratory Syndrome CoronaVirus-2 (SARS-CoV-2) and its inhibition by Ensitrelvir, a known non-covalent inhibitor. 3CLpro is the main protease that plays a crucial role of producing the whole array of proteins necessary for the viral infection that caused the spread of COVID-19, responsible for millions of deaths worldwide as well as global economic and healthcare crises in recent years. The proposed calorimetric method proved to have several advantages over the two types of enzymatic assays so far applied to this system, namely Forster Resonance Energy Transfer (FRET) and Liquid Chromatography-Mass Spectrometry (LC-MS). The developed ITC-based assay provided a rapid response to 3CLpro activity, which was used to directly derive the kinetic enzymatic constants KM and kcat reliably and reproducibly, as well as their temperature dependence, from which the activation energy of the reaction was obtained for the first time. The assay further revealed the existence of two modes of inhibition of 3CLpro by Ensitrelvir, namely a competitive mode as previously inferred by crystallography as well as an unprecedented uncompetitive mode, further yielding the respective inhibition constants with high precision. The calorimetric method described in this paper is thus proposed to be generally and widely used in the discovery and development of drugs targeting 3CLpro.
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Spike N354 glycosylation augments SARS-CoV-2 fitness for human adaptation through multiple mechanisms -
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+Selective pressures have given rise to a number of SARS-CoV-2 variants during the prolonged course of the COVID-19 pandemic. Recently evolved variants differ from ancestors in additional glycosylation within the spike protein receptor-binding domain (RBD). Details of how the acquisition of glycosylation impacts viral fitness and human adaptation are not clearly understood. Here, we dissected the role of N354-linked glycosylation, acquired by BA.2.86 sub-lineages, as a RBD conformational control element in attenuating viral infectivity. The reduced infectivity could be recovered in the presence of heparin sulfate, which targets the N354 pocket to ease restrictions of conformational transition resulting in a RBD-up state, thereby conferring an adjustable infectivity. Furthermore, N354 glycosylation improved spike cleavage and cell-cell fusion, and in particular escaped one subset of ADCC antibodies. Together with reduced immunogenicity in hybrid immunity background, these indicate a single spike amino acid glycosylation event provides selective advantage in humans through multiple mechanisms.
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A general platform for targeting MHC-II antigens via a single loop -
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+Class-II major histocompatibility complexes (MHC-IIs) are central to the communications between CD4+ T cells and antigen presenting cells (APCs), but intrinsic structural features associated with MHC-II make it difficult to develop a general targeting system with high affinity and antigen specificity. Here, we introduce a protein platform, Targeted Recognition of Antigen-MHC Complex Reporter for MHC-II (TRACeR-II), to enable the rapid development of peptide-specific MHC-II binders. TRACeR-II has a small helical bundle scaffold and uses an unconventional mechanism to recognize antigens via a single loop. This unique antigen-recognition mechanism renders this platform highly versatile and amenable to direct structural modeling of the interactions with the antigen. We demonstrate that TRACeR-II binders can be rapidly evolved across multiple alleles, while computational protein design can produce specific binding sequences for a SARS-CoV-2 peptide of unknown complex structure. TRACeR-II sheds light on a simple and straightforward approach to address the MHC peptide targeting challenge, without relying on combinatorial selection on complementarity determining region (CDR) loops. It presents a promising basis for further exploration in immune response modulation as well as a broad range of theragnostic applications.
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Some mechanistic underpinnings of molecular adaptations of SARS-COV-2 spike protein by integrating candidate adaptive polymorphisms with protein dynamics -
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+We integrate evolutionary predictions based on the neutral theory of molecular evolution with protein dynamics to generate mechanistic insight into the molecular adaptations of the SARS-COV-2 Spike (S) protein. With this approach, we first identified Candidate Adaptive Polymorphisms (CAPs) of the SARS-CoV-2 Spike protein and assessed the impact of these CAPs through dynamics analysis. Not only have we found that CAPs frequently overlap with well-known functional sites, but also, using several different dynamics-based metrics, we reveal the critical allosteric interplay between SARS-CoV-2 CAPs and the S protein binding sites with the human ACE2 (hACE2) protein. CAPs interact far differently with the hACE2 binding site residues in the open conformation of S protein compared to the closed form. In particular, the CAP sites control the dynamics binding residues in the open state, suggesting an allosteric control of hACE2 binding. We also explored the characteristic mutations of different SARS-CoV-2 strains to find dynamic hallmarks and potential effects of future mutations. Our analyses reveal that Delta strain-specific variants have non-additive (i.e., epistatic) interactions with CAP sites, whereas the less pathogenic Omicron strains have mostly compensatory variants. Finally, our dynamics-based analysis suggests that the novel mutations observed in the Omicron strain epistatically interact with the CAP sites to help escape antibody binding.
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Low-coverage whole genome sequencing for a highly selective cohort of severe COVID-19 patients -
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+Despite advances in identifying genetic markers associated to severe COVID-19, the full genetic characterisation of the disease remains elusive. This study explores the use of imputation in low-coverage whole genome sequencing for a severe COVID-19 patient cohort. We generated a dataset of 79 imputed variant call format files using the GLIMPSE1 tool, each containing an average of 9.5 million single nucleotide variants. Validation revealed a high imputation accuracy (squared Pearson correlation {approx}0.97) across sequencing platforms, showing GLIMPSE1's ability to confidently impute variants with minor allele frequencies as low as 2% in Spanish ancestry individuals. We conducted a comprehensive analysis of the patient cohort, examining hospitalisation and intensive care utilisation, sex and age-based differences, and clinical phenotypes using a standardised set of medical terms developed to characterise severe COVID-19 symptoms. The methods and findings presented here may be leveraged in future genomic projects, providing vital insights for health challenges like COVID-19.
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Discovery of orally active SARS-CoV-2 papain-like protease (PLpro) inhibitors -
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+Vaccines and first-generation antiviral therapeutics have provided important protection against coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, there remains a need for additional therapeutic options that provide enhanced efficacy and protection against potential viral resistance. The SARS-CoV-2 papain-like protease (PLpro) is one of two essential cysteine proteases involved in viral replication. While inhibitors of the SARS-CoV-2 main protease (Mpro) have demonstrated clinical efficacy, known PLpro inhibitors have to date lacked the inhibitory potency and requisite pharmacokinetics to demonstrate that targeting PLpro translates to in vivo efficacy in a preclinical setting. Herein, we report the machine learning-driven discovery of potent, selective, and orally available SARS-CoV-2 PLpro inhibitors, with lead compound PF-07957472 (4) providing robust efficacy in a mouse-adapted model of COVID-19 infection.
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Multiple layers of innate immune response antagonism of SARS-CoV-2 -
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+Several SARS-CoV-2 proteins have been shown to counteract the host innate immune response, mostly using in vitro protein expression, which may not fully reflect their role in the context of viral infection. In addition, while each viral protein was characterized in a different experimental system, their relative contribution in immunosuppression remains unclear. Here we used a SARS-CoV-2 bacterial artificial chromosome with en passant mutagenesis to recover a panel of twelve infectious recombinant SARS-CoV-2 viruses, each with mutations in either NSP1, NSP2, NSP3, NSP6, NSP12, NSP13, NSP14, NSP15, NSP16, ORF3a, ORF6 or ORF8. We used the interferon-stimulated response element (ISRE)-driven luciferase assay in 293T-ACE2/TMPRSS2 cells to test the panel, demonstrating that mutations in many proteins, especially in NSP1 and NSP15, increased the type I interferon response relative to the parental wild-type virus. RNA-seq analysis of mutant-virus infected Calu-3 cells showed that the mutations in NSP1 or NSP15 lead to higher expression of multiple genes involved in innate immune response, cytokine-mediated signaling and regulation of lymphocyte proliferation. Furthermore, mutations in either NSP1 or NSP15 resulted in a greater maturation of human monocyte-derived dendritic cells in vitro. Infection of K18 hACE2 transgenic mice with either NSP1 or NSP15 mutated viruses demonstrated attentuated respiratory tract replication. Analysis of lung immune cells from infected mice by single-cell RNA-seq identified 15 populations of major myeloid and lymphoid cells with changes in the pattern of their activation associated with viral infection. The effects of mutations in NSP1 or NSP15 on these responses are consistent with differences in the immunosuppressive mechanisms utilized by the two proteins. Overall, these data demonstrate different and redundant mechanisms of innate immune antagonism by SARS-CoV-2 and suppression of activation of antigen presenting cells and T and B lymphocytes mediated by multiple viral proteins.
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Nanobody repertoire generated against the spike protein of ancestral SARS-CoV-2 remains efficacious against the rapidly evolving virus -
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+To date, all major modes of monoclonal antibody therapy targeting SARS-CoV-2 have lost significant efficacy against the latest circulating variants. As SARS-CoV-2 omicron sublineages account for over 90% of COVID-19 infections, evasion of immune responses generated by vaccination or exposure to previous variants poses a significant challenge. A compelling new therapeutic strategy against SARS-CoV-2 is that of single domain antibodies, termed nanobodies, which address certain limitations of monoclonal antibodies. Here we demonstrate that our high-affinity nanobody repertoire, generated against wild-type SARS-CoV-2 spike protein (Mast, Fridy et al. 2021), remains effective against variants of concern, including omicron BA.4/BA.5; a subset is predicted to counter resistance in emerging XBB and BQ.1.1 sublineages. Furthermore, we reveal the synergistic potential of nanobody cocktails in neutralizing emerging variants. Our study highlights the power of nanobody technology as a versatile therapeutic and diagnostic tool to combat rapidly evolving infectious diseases such as SARS-CoV-2.
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Economic precarity and changing levels of anxiety and stress among Canadians with disabilities and chronic health conditions throughout the COVID-19 pandemic -
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+Early in the COVID-19 pandemic, multiple event stressors converged to exacerbate a growing mental health crisis in Canada with differing effects across status groups. However, less is known about changing mental health situations throughout the pandemic, especially among individuals more likely to experience chronic stress because of their disability and health status. Using data from two waves of a targeted online survey of people with disabilities and chronic health conditions in Canada (N = 563 individuals, June 2020 and July 2021), we find that approximately 25% of respondents experienced additional increases in stress and anxiety levels in 2021. These increases were partly explained by worsening perceived financial insecurity and, in the case of stress, additional negative financial effects tied to the pandemic. This paper understands mental health disparities as a function of social status and social group membership. By linking stress process models and a minority stress framework with a social model of disability, we allude to how structural and contextual barriers make functional limitations disabling and in turn, life stressors.
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Impact of the COVID-19 Pandemic on Undergraduate Research in the Department of Biology at Western University: Effect on project types, learning outcomes, and student perceptions. -
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+Undergraduate research is a high impact practice that offers numerous benefits to students, academic institutions, and the wider scientific community. Unfortunately, undergraduate research has faced restrictions due to the COVID-19 pandemic. This study aimed to assess how the COVID-19 pandemic has impacted: (1) the number and types of undergraduate research projects performed in the Department of Biology at the University of Western Ontario, and (2) the satisfaction-levels and perceived learning outcomes of students performing these projects. This study also aimed to incorporate a One Health framework through an emphasis on stakeholder involvement and the need for future action. A survey of 33 students who completed an undergraduate research project in the Department of Biology in the 2020/2021 academic year, and 68 students who completed an undergraduate research project in the 5 years prior was conducted. In keeping with the One Health approach, key stakeholders were identified, and a stakeholder map was constructed. The number of projects performed did not change dramatically despite COVID-19 restrictions. However, a shift towards dry research was observed with 87.9% of students in the 2020/2021 academic year conducting dry research, compared to 16.4% of students in the 5 years prior. Students who conducted research in the 2020/2021 academic year indicated lower overall levels of satisfaction and enjoyment, though their perceived learning outcomes were consistent with students who completed their projects in the 5 years prior. 53 key stakeholders from academia, government, industry, media, and the public were identified. Students provided invaluable feedback on their undergraduate research experiences that can be used to improve the quality of undergraduate research courses in the Department of Biology in the future. Findings may be of use to other departments and educational institutions that are seeking to improve their own undergraduate research courses amidst the COVID-19 pandemic or looking to incorporate experiential-based learning techniques into existing online courses.
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A Study to Learn About a Combined COVID-19 and Influenza Shot in Healthy Adults - Conditions: Influenza, Human, SARS-CoV-2 Infection, COVID-19 Interventions: Biological: BNT162b2 (Omi XBB.1.5)/RIV; Biological: BNT162b2 (Omi XBB.1.5); Biological: RIV; Other: Normal saline placebo Sponsors: Pfizer Not yet recruiting
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The Effects of Nutritional Intervention on Health Parameters in Participants With Type 2 Diabetes Mellitus - Conditions: Diabetes Mellitus Type 2; Diabetes Mellitus Type 2 in Obese; Diabetes; Diabetes Mellitus Non-insulin-dependent; Hypertension; Type 2 Diabetes Mellitus Interventions: Behavioral: Nutritional Intervention Sponsors: Sao Jose do Rio Preto Medical School; Fundação de Amparo à Pesquisa do Estado de São Paulo Completed
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The Impact of the Covid-19 Pandemic on Orthopedic Trauma Management - Conditions: Trauma; COVID-19 Pandemic Interventions: Other: epidemyolojical Sponsors: Bakirkoy Dr. Sadi Konuk Research and Training Hospital Completed
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Open-label, Multi-centre, Non-Inferiority Study of Safety and Immunogenicity of BIMERVAX for the Prevention of COVID-19 in Adolescents From 12 Years to Less Than 18 Years of Age. - Conditions: SARS CoV 2 Infection Interventions: Biological: BIMERVAX Sponsors: Hipra Scientific, S.L.U; Veristat, Inc.; VHIR; Asphalion Recruiting
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A Study of Amantadine for Cognitive Dysfunction in Patients With Long-Covid - Conditions: Long COVID; Post-Acute COVID-19 Syndrome Interventions: Drug: Amantadine; Other: Physical, Occupational, Speech Therapy; Other: Provider Counseling; Other: Medications for symptoms management Sponsors: University of Texas Southwestern Medical Center Not yet recruiting
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Study on the Effect of Incentive Spirometer-based Respiratory Training on the Long COVID-19 - Conditions: COVID-19 Pandemic; Diabetes; Hypertension; Cardiac Disease; Long COVID Interventions: Behavioral: Incentive Spirometer respiratory training Sponsors: National Taipei University of Nursing and Health Sciences; Tri-Service General Hospital Not yet recruiting
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Balance Acceptance and Commitment Therapy for Long COVID - Conditions: Post-COVID-19 Syndrome; Long COVID Interventions: Behavioral: Balance Acceptance and Commitment Therapy Sponsors: King’s College London Not yet recruiting
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Predict + Protect Study: Exploring the Effectiveness of a Predictive Health Education Intervention on the Adoption of Protective Behaviors Related to ILI - Conditions: Influenza; Influenza A; Influenza B; COVID-19; Respiratory Syncytial Virus (RSV) Interventions: Behavioral: ILI Predictive Alerts, Reactive Content, and Proactive Content; Behavioral: ILI Predictive Alerts, Reactive Content; Behavioral: Proactive Content; Behavioral: No Intervention Sponsors: Evidation Health; Biomedical Advanced Research and Development Authority Not yet recruiting
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Long COVID-19 [11C]CPPC Study - Conditions: COVID Long-Haul Interventions: Drug: [11C]CPPC Injection; Drug: [11C]CPPC Injection Sponsors: Johns Hopkins University; Radiological Society of North America Recruiting
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Thrombohemorrhagic Complications of COVID-19 - Conditions: COVID-19 (Coronavirus Disease 2019) Interventions: Diagnostic Test: Prevention algorithm Sponsors: Volgograd State Medical University Active, not recruiting
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Combined Use of Immunoglobulin and Pulse Steroid Therapies in Severe Covid-19 Patients - Conditions: Pulse Steroid and Immunoglobulins Drugs in Covid 19 Patients Interventions: Drug: pulse steroid and nanogam Sponsors: Konya City Hospital Completed
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Beneficial Effects of Natural Products on Management of Xerostomia - Conditions: Xerostomia; Diabetes Mellitus; Hypertension; Post COVID-19 Condition Interventions: Other: (Manuka honey-green tea- ginger) Sponsors: British University In Egypt Completed
Diet and Fasting for Long COVID - Conditions: Long Covid19; Long COVID Interventions: Other: Low sugar diet and 10-12 hour eating window; Other: Low sugar diet, 8 hour eating window and fasting Sponsors: Pacific Northwest University of Health Sciences Recruiting
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From PubMed
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NSP6 inhibits the production of ACE2-containing exosomes to promote SARS-CoV-2 infectivity - The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has triggered a global pandemic, which severely endangers public health. Our and others’ works have shown that the angiotensin-converting enzyme 2 (ACE2)-containing exosomes (ACE2-exos) have superior antiviral efficacies, especially in response to emerging variants. However, the mechanisms of how the virus counteracts the host and regulates ACE2-exos remain unclear. Here, we identified that SARS-CoV-2 nonstructural…
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Activity and inhibition of the SARS-CoV-2 Omicron nsp13 R392C variant using RNA duplex unwinding assays - SARS-CoV-2 nsp13 helicase is an essential enzyme for viral replication and a promising target for antiviral drug development. This study compares the double-stranded RNA (dsRNA) unwinding activity of nsp13 and the Omicron nsp13^(R392C) variant, which is predominant in currently circulating lineages. Using in vitro gel- and fluorescence-based assays, we found that both nsp13 and nsp13^(R392C) have dsRNA unwinding activity with equivalent kinetics. Furthermore, the R392C mutation had no effect on…
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Phospho-eIF4E stimulation regulates coronavirus entry by selective expression of cell membrane-residential factors - The eukaryotic translation initiation factor eIF4E can regulate cellular translation via phosphorylation on serine 209. In a recent study, by two rounds of TMT relative quantitative proteomics, we found that phosphorylated eIF4E (p-eIF4E) favors the translation of selected mRNAs, and the encoded proteins are mainly involved in ECM-receptor, focal adhesion, and PI3K-Akt signaling. The current paper is focused on the relationship between p-eIF4E and the downstream host cell proteins, and their…
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Comparative immunogenicity and neutralizing antibody responses post heterologous vaccination with CoronaVac (Sinovac) and Vaxzevria (AstraZeneca) in HIV-infected patients with varying CD4+ T lymphocyte counts - The immune response to heterologous coronavirus disease (COVID-19) vaccination in people living with HIV (PLWH) is still unclear. Herein, our prospective cohort study aimed to compare the immune response of heterologous vaccination with CoronaVac (Sinovac) and Vaxzevria (AstraZeneca) between PLWH having CD4 counts ≤ 200 cells/µL (low CD4+) and > 200 cells/µL (high CD4+). Anti-receptor-binding domain (RBD) immunoglobulin G (IgG) levels and the percentage inhibition of neutralizing antibodies…
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Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial - Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual…
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Effects of antineoplastic and immunomodulating agents on postvaccination SARS-CoV-2 breakthrough infections, antibody response, and serological cytokine profile - CONCLUSIONS: Antineoplastic and immunomodulating medications associate with an elevated risk of postimmunization SARS-CoV-2 infection in a drug-specific manner. This comprehensive, unbiased analysis of all WHO ATC classified antineoplastic and immunomodulating medications identifies medications associated with greatest risk. These findings are crucial in guiding and refining vaccination strategies for patients prescribed these treatments, ensuring optimized protection for this susceptible…
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G3BP1-dependent condensation of translationally inactive viral RNAs antagonizes infection - G3BP1 is an RNA binding protein that condenses untranslating messenger RNAs into stress granules (SGs). G3BP1 is inactivated by multiple viruses and is thought to antagonize viral replication by SG-enhanced antiviral signaling. Here, we show that neither G3BP1 nor SGs generally alter the activation of innate immune pathways. Instead, we show that the RNAs encoded by West Nile virus, Zika virus, and severe acute respiratory syndrome coronavirus 2 are prone to G3BP1-dependent RNA condensation,…
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Triple in silico targeting of IMPDH enzyme and RNA-dependent RNA polymerase of both SARS-CoV-2 and Rhizopus oryzae - Aim: Mucormycosis has been associated with SARS-CoV-2 infections during the last year. The aim of this study was to triple-hit viral and fungal RNA-dependent RNA polymerases (RdRps) and human inosine monophosphate dehydrogenase (IMPDH). Materials & methods: Molecular docking and molecular dynamics simulation were used to test nucleotide inhibitors (NIs) against the RdRps of SARS-CoV-2 and Rhizopus oryzae RdRp. These same inhibitors targeted IMPDH. Results: Four NIs revealed a comparable binding…
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High-throughput screening for a SARS-CoV-2 frameshifting inhibitor using a cell-free protein synthesis system - Programmed-1 ribosomal frameshifting (-1 PRF) is a translational mechanism adopted by some viruses, including SARS-CoV-2. To find a compound that can inhibit -1 PRF in SARS-CoV-2, we set up a high-throughput screening system using a HeLa cell extract-derived cell-free protein synthesis (CFPS) system. A total of 32,000 compounds were individually incubated with the CFPS system programmed with a -1 PRF-EGFP template. Several compounds were observed to decrease the -1 PRF-driven fluorescence, and…
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Prevention of lipid droplet accumulation by DGAT1 inhibition ameliorates sepsis-induced liver injury and inflammation - CONCLUSIONS: Our results indicate that sepsis triggers lipid metabolism alterations that culminate in increased liver LD accumulation. Increased LDs are associated with disease severity and liver injury. Moreover, inhibition of LD accumulation decreased the production of inflammatory mediators and lipid peroxidation while improving tissue function, suggesting that LDs contribute to the pathogenesis of liver injury triggered by sepsis.
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Pharmacokinetic analysis of placental transfer of ritonavir as a component of paxlovid using microdialysis in pregnant rats - BACKGROUND: Ritonavir is one of the most potent CYP3A4 inhibitor currently on the market, and is often used together with other antiviral drugs to increase their bioavailability and efficacy. Paxlovid, consisting of nirmatrelvir and ritonavir, was approved for the treatment of COVID-19. As previous studies regarding the use of ritonavir during pregnancy were limited to ex-vivo experiments and systemic safety data, to fully explore the detailed pharmacokinetics of ritonavir in pregnant rats’…
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Efficacy and safety of aniseed powder for treating gastrointestinal symptoms of COVID-19: a randomized, placebo-controlled trial - Background: Gastrointestinal symptoms are prevalent amongst patients with a confirmed diagnosis of COVID-19 and may be associated with an increased risk of disease severity. This trial aimed to evaluate the efficacy and safety of aniseed (Pimpinella anisum L.) powder as an add-on therapy to standard care for treating gastrointestinal symptoms experienced by adults with an acute SARS-CoV-2 infection. Methods: The study was a randomized parallel-group double-blinded placebo-controlled add-on…
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A narrative review on tofacitinib: The properties, function, and usefulness to treat coronavirus disease 2019 - In coronavirus disease 2019 (COVID-19), the formation of cytokine storm may have a role in worsening of the disease. By attaching the cytokines like interleukin-6 to the cytokine receptors on a cell surface, Janus kinase (JAK)-signal transducers and activators of transcription (STAT) pathway will be activated in the cytoplasm lead to hyperinflammatory conditions and acute respiratory distress syndrome. Inhibition of JAK/STAT pathway may be useful to prevent the formation of cytokine storm….
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A critical review of advances on tumor metabolism abnormalities induced by nitrosamine disinfection by-products in drinking water - Intensified sanitation practices amid the recent SARS-CoV-2 outbreak might result in the increased release of chloramine disinfectants into surface water, significantly promoting the formation of nitrosamine disinfection by-products (DBPs) in drinking water. Unfortunately, these nitrosamine DBPs exhibit significant genotoxic, carcinogenic, and mutagenic properties, while chlorinating disinfectants remain in global practice. The current review provides valuable insights into the occurrence,…
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Cleavage of HDAC6 to dampen its antiviral activity by nsp5 is a common strategy of swine enteric coronaviruses - HDAC6, a structurally and functionally unique member of the histone deacetylase (HDAC) family, is an important host factor that restricts viral infection. The broad-spectrum antiviral activity of HDAC6 makes it a potent antiviral agent. Previously, we found that HDAC6 functions to antagonize porcine deltacoronavirus (PDCoV), an emerging enteropathogenic coronavirus with zoonotic potential. However, the final outcome is typically a productive infection that materializes as cells succumb to viral…
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From Patent Search
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The Senate’s False Hope of a Grand Bargain Meets Its Trumpy Demise - Whether folly, hubris, or denial, it was always going to end this way. - link
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The Rural Ski Slope Caught Up in an International Scam - A federal program promised to bring foreign investment to remote parts of the country. It soon became rife with fraud. - link
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Inside the Music Industry’s High-Stakes A.I. Experiments - Lucian Grainge, the chairman of UMG, has helped record labels rake in billions of dollars from streaming. Can he do the same with generative artificial intelligence? - link
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The Perverse Policies That Fuel Wildfires - We thought we could master nature, but we were playing with fire. - link
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Ukraine’s Democracy in Darkness - With elections postponed and no end to the war with Russia in sight, Volodymyr Zelensky and his political allies are becoming like the officials they once promised to root out: entrenched. - link
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From Vox
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The Supreme Court weighs whether to end affirmative action at West Point -
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+West Point cadets cheer at a football game between the Army Black Knights and the Navy Midshipmen on December 9, 2023, at Gillette Stadium in Foxboro, Massachusetts. | Fred Kfoury III/Icon Sportswire via Getty Images
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+The guy behind the Harvard lawsuit attacking affirmative action turns his ire on the service academies.
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+The Court’s decision in Students for Fair Admissions v. Harvard applies to civilian schools, but the Court also said in a footnote that it was not deciding whether academies such as West Point or the Naval Academy may continue to take steps to diversify their student bodies that the decision forbade in other schools. That footnote referred to the “potentially distinct interests that military academies may present,” but didn’t clarify what the six Republican justices who joined the Harvard decision think these “distinct interests” might be.
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+The West Point case is distinct from the Harvard case, however, in that it presents a conflict between two competing values that the Court’s current Republican majority genuinely cares about.
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+On the one hand, the Republican justices are hostile to virtually any policy that takes account of race, regardless of whether that policy exists to advance white supremacy or to eradicate its legacy. The Court’s decision in Harvard compares that school’s former admissions program, which sought to diversify its campus by giving a slight preference to some applicants from underrepresented racial groups, to the Jim Crow school segregation regime struck down in Brown v. Board of Education(1954).
+
+
+At the same time, the Supreme Court has historically shown a great deal of deference to the military. As the Court said in Gilligan v. Morgan (1973), “[I]t is difficult to conceive of an area of governmental activity in which the courts have less competence” than questions involving “the composition, training, equipping, and control of a military force.”
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+Moreover, while the Court’s current majority has raced to overturn many precedents that are out of step with the Republican Party’s policy preferences — Harvard, after all, overruled nearly a half-century of decisions permitting universities to take limited account of race in admissions — several of the Court’s Republican appointees appear to believe that Gilligan should remain good law.
+
+So there’s a real chance that this Court, despite its recent opinion in Harvard, could decide that the judiciary’s long tradition of deferring to the military on personnel and related matters should continue to hold in the West Point case.
+
+
+In her brief to the justices, Solicitor General Elizabeth Prelogar warns that “a lack of diversity in leadership can jeopardize the Army’s ability to win wars.” Indeed, she writes that the lack of non-white officers during the Vietnam War led to widespread violence within the military’s ranks.
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+“Plagued by accusations that white officers were using minority service members as ‘cannon fodder,’” Prelogar tells the justices, “the Army confronted racial violence that ‘extended from fire bases in Vietnam to army posts within the United States to installations in West Germany, Korea, Thailand, and Okinawa.’” To reduce the risk of this happening again, West Point takes some account of race in its admissions to help ensure that non-white enlisted personnel will look at their commanders and see some faces that resemble their own.
+
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+West Point cadets are commissioned as army officers upon their graduation.
+
+
+It’s worth noting that the two sides of the West Point case can’t seem to agree on just how much of a role race plays in West Point’s admissions. The plaintiffs claim that race completely pervades the process, that the military academy sets very precise racial targets for who is admitted, and that “for each of the six years of complete data in the record, West Point never missed its target for blacks or Hispanics by more than 3.6 percentage points.”
+
+
+The Justice Department’s brief, meanwhile, paints a completely different picture. As it describes the admissions process at West Point, the dominant factor determining admissions is which applicants are nominated by a member of Congress or other high-ranking official to become a cadet, and race is merely a small factor that comes into play later in the process.
+
+
+The fact that the two parties aren’t sure what they are arguing about is a good reason for the Supreme Court to give this case a miss — at least for now. As Prelogar notes, this lawsuit is “only four months old,” and lower courts have not yet conducted the rigorous fact-finding process that occurs in later stages of the litigation. So, if the justices were to block West Point’s admissions policy now, they couldn’t even be sure what they are blocking.
+
+
+Prelogar also warns that “West Point is in the middle of an admissions cycle” right now, and some applicants have already been offered seats in the incoming class. So, if the Supreme Court were to intervene now, that could force West Point to “either rescind offers already issued or apply different criteria to candidates based on the happenstance of when their applications were reviewed.”
+
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+So it’s also reasonably likely that a majority of the justices will want to put off deciding this case until they know more about how West Point’s system works, or to some time in the future when a Supreme Court decision won’t disrupt an ongoing admissions cycle.
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+
+Ultimately, however, it is unlikely that the Court will delay forever. And when the justices do weigh in on the question they put off in the Harvard case, we will learn about whether they care more about their racial agenda or ensuring that military decisions are made by people who actually know something about military readiness.
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This camel has a very important job -
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+Aaron Robey for Vox
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+A new solution to save the iconic Joshua tree uses a distant relative of one of the Mojave’s ancient seed distributors: The camel.
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+In the summer of 2020, the Dome Fire leaped across the Mojave National Preserve in southeastern California, killing more than 1.3 million Joshua trees.
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+Three years later in 2023, which would go on to become the hottest year on Earth since record-keeping began, the 93,078-acre York Fire more than doubled the acreage of the Dome Fire, scorching large forests of the eastern species of the wild-armed yuccas. Entering these burn scars is surreal. A majority of the trees stand like tombstones, their trunks bone white.
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+ Miles W. Griffis for Vox
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+A view of the Dome Fire burn scar with a surviving Joshua tree in the foreground.
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+Such deadly fires, combined with the increasing aridity and warming wrought by climate change, have made the fate of both the eastern and western species of the iconic Joshua tree tenuous.
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+While some Joshua tree spouts have formed naturally in the ashes of these fires, their modern distributors, seed-caching rodents, only travel a short distance from their burrows, making it difficult for the yuccas to migrate across the massive burn scars and reestablish themselves. In short, Joshua trees are disappearing faster than the sprouts can take root.
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+In the absence of large megafauna like giant ground sloths that some scientists hypothesize served as seed dispersers for Joshua trees over 12,000 years ago, human volunteers organized by the National Park Service have taken over by planting sprouts of the beloved yuccas across the landscape.
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+In the years that the rehabilitation project has been underway, Park Service volunteers and rangers have planted thousands of Joshua tree sprouts in the scar of the Dome Fire. For some volunteer planting days in 2021 and 2023, they received the help of a distant cousin of a possible ancient seed distributor: the camel.
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+“Chico puts the drama in dromedary,” the camels’ owner, Jennifer Lagusker, said as he grumbled loudly, exposing his slimy tongue as volunteers loaded water jugs onto his frame on a warm day in late 2023. Lagusker wore a wide-brimmed hat, cargo pants, and a green volunteer T-shirt. She told me Chico is a dromedary camel recognizable by his single hump. His comrade, Sully, is a stunningly handsome but aloof Bactrian camel (two humps), while hard-working Herbie is a hybrid of the two species.
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+Chico, Sully, and Herbie helped volunteers by lugging water, heavy Joshua tree sprouts, and other supplies to remote locations in the burn scar.
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+ Aaron Robey for Vox
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+Volunteers load Joshua tree sprouts into canvas saddlebags that a trio of camels shortly thereafter carried.
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+ Aaron Robey for Vox
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+Herbie hangs back as volunteers introduce new Joshua trees to their native landscape.
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+Camels are well adapted to carrying heavy loads and walking long distances because their feet are giant pads that distribute their weight evenly on the ground, making them more efficient and less impactful in desert environments than horses or mules, Lagusker explained.
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+But their presence in the Mojave National Preserve — in all their floppy-lipped goofiness — is significant: It harks back not only to the use of camels as surveyors of historic routes throughout the Mojave Desert in the mid-1800s, but also to their long-distant relatives, Camelops hesternus, or “yesterday’s camel,” that once lived in what is now the Mojave.
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+These modern camels aren’t eating Joshua tree fruits and distributing the hockey-puck-shaped seeds as yesterday’s camel is hypothesized to have done, but using them to carry Joshua tree sprouts and water offers an echo of the past and an intriguing solution for today’s challenge to save a tree that’s especially vulnerable to vanishing in a changing climate: What if we restored big mammals, capable of spreading seeds farther and faster, to the ecosystems that need them?
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+ Aaron Robey for Vox
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+A volunteer leads Herbie, Sully, and Chico before crew members unload Joshua tree sproutlings.
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+Modern camels all share a common ancestor, Paracamelus, which diverged from yesterday’s camel millions of years ago and crossed the land bridge into Eurasia — eventually bringing them to share a common landscape with the Joshua tree. Camelops disappeared during the megafaunal extinction at the end of the Pleistocene alongside the giant ground sloth, marking the demise of what might have been the trees’ megafauna seed distributors. The evidence for this isn’t complete, however, and some scientists say that the spread of Joshua tree seeds has long relied on rodents.
+
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+Lagusker was inspired to help plant trees with her camels after joining a camel trek in 2021 led by her friend, Nance Fite, who once owned the “world’s highest-ranking camel” after it was named a deputy as part of the Los Angeles Sheriff’s Department. Their trek followed a portion of the historic Mojave Road that bisects Mojave National Preserve and was traveled by surveyors riding camels brought in from ports in the Mediterranean during the “sinister” United States Camel Corps experiment in the 1850s.
+
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+“A lot of Route 66 was surveyed off camel,” Fite said, detailing her multi-day camel treks on the historic road originally made and navigated by the ancestors of the Mojave people. Once she heard about the planting efforts in the preserve, Fite suggested she and Lagusker volunteer with the camels to help with the first restoration efforts in the Dome Fire burn scar. “We wanted to do everything we could to help after the fire happened,” Fite said.
+
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+ Aaron Robey for Vox
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+Approximately one-year-old Joshua tree seedlings sit in canvas bags, seen from above as spiky green sprouts in squares of dark soil. Thousands have been planted within the Dome Fire burn scar.
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+In the years ahead, Lagusker hopes to work more closely with the NPS to organize a long train of camels, as many as 12 strong, if they’re invited back for future volunteer efforts. This will make the planting and watering processes more efficient in the future, as some of the sites are many miles from roads and each needs at least 5 gallons of water. Fite said they’re also open to helping private landowners affected by the York Fire. They both believe the use of camels could be a powerful solution to restore Joshua tree forests after wildfires.
+
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+Brendan Cummings, the conservation director of the Center for Biological Diversity, has participated in the planting effort in the Preserve many times, even joining the camels in 2021. He said they hold great potential for being able to scale up restoration efforts in more remote areas, especially since the Mojave is getting hotter and drier, meaning the sprouts will need more water to survive. The NPS said this August that 80 percent of the trees planted between 2021 and 2022 have died. Saving Joshua trees, Cummings said, will take a lot of groundwork and money in these more extreme conditions. Anything that can be used to advance the effort should be implemented.
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+ Miles W. Griffis for Vox
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+Sully enjoys the early-morning blue sky, awaiting the day’s work.
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+ Miles W. Griffis for Vox
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+Sully shows off puffs of hair on his head and neck while posing for the camera with what appears to be a smile.
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+“Even if they are only a small part, camels bring a certain je ne sais quoi to the event that adds a mix of absurdity plus practicality,” Cummings said, “which pretty much sums up what a camel is.”
+
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+At the end of a long day on the preserve late last year, three camels walked in a neat, efficient line, their long-humped shadows stretching across the burn scar. With 24 new Joshua tree sprouts planted and watered on Cima Dome, they trekked back to the planting headquarters with light loads. They put one padded foot in front of the other, passing by torched yuccas and invasive grasses lit gold by the sunset.
+
+
How Nevada botched its key role in the GOP primary -
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+Supporters of former US president and 2024 presidential hopeful Donald Trump watch his speech on a screen outside a Commit to Caucus Rally in Las Vegas, Nevada, on January 27, 2024. | Patrick T. Fallon/AFP via Getty Images
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+Nevada’s dueling primary and caucuses are wreaking avoidable chaos.
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+Nevada is doing things differently this election season, and not necessarily for the better.
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+Former President Donald Trump and his former US ambassador to the United Nations, Nikki Haley, are competing in Nevada as the last two major candidates vying for the Republican presidential nomination. But, confusingly, they’ll do so on two separate days — and in two entirely different types of contests.
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+Haley will appear on the state’s primary ballot on February 6, and Trump will appear on the state’s caucus ballot on February 8. Voters can participate in both contests, but only one really matters: The state Republican Party decided that only the latter will determine who receives the state’s 26 delegates, and any candidate who competes in the primary cannot also compete in the caucuses.
+
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+If this seems to make no sense, it’s because it doesn’t. But it’s the unfortunate product of political infighting and a national shift away from caucuses after 2020, and it already appears to be leading to confusion for voters. Trump would have been dominant in Nevada no matter the format — he has a more than 50 percentage point lead on average in national polls. But now he’s assured of winning all of the state’s delegates simply because his only major opponent opted not to participate in the caucuses. And that makes it difficult to learn anything new about the depth of Trump’s support in Nevada from the results.
+
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+“I don’t want to say the Nevada caucuses and primary are meaningless at this point, but it’s certainly a foregone conclusion,” said Zachary Moyle, a GOP strategist based in Nevada.
+
+
+Nevada wanted to move away from caucuses. What happened?
+
+
+Nevada has historically held caucuses, contests in which voters gather in local meetings run by their state parties to say who they’d prefer to be their presidential nominee. But following bungled Iowa caucuses in 2020 that led to delays in reporting the results, Nevada lawmakers joined a chorus of activists nationwide calling for caucus states to hold primaries instead.
+
+
+Reformist lawmakers argued that primaries were not only smoother to run but also more inclusive: Participating in caucuses can take hours, and they typically only attract the most ardent partisans who can afford to spend an entire evening in a school gym.
+
+
+“We’ve made it easier for people to register to vote here in Nevada in recent years and now we should make it easier for people to vote in the presidential contests,” former US Senate Majority Leader Harry Reid, who during his life wasa Democratic giant in Nevada politics, said in 2020.
+
+
+So the Democrat-controlled Nevada legislature enacted a law mandating that a primary, preceded by 10 days of early voting, be held on the first Tuesday in February. This year, that’s February 6.
+
+
+But the change didn’t come without opposition from Republican leaders in Nevada and other caucus states. “We want to make clear that we stand together in protecting the presidential nominating schedule as it has existed for many years,” a group of pro-caucus GOP lawmakers (from Nevada and three other states) said in a joint statement in 2021 after the Nevada law was signed. They didn’t want to lose out on the kind of resources and attention that caucuses typically bring to state parties, Moyle said. In part because they are such an extended affair — and one that produces made-for-television visuals of crowds of energetic voters gathering in chanting groups — caucuses tend to attract national and international media attention and are a big moneymaker every four years.
+
+
+That was especially true for Nevada, which had some of the most diverse caucuses early in the primary calendar. They were closely watched for clues about the Latino vote, given that Nevada’s population is nearly a third Hispanic.
+
+
+All that meant that while a primary was legally mandated this year, the GOP wasn’t ready to give up its caucuses. Republicans challenged the Nevada primary law in court but dropped the lawsuit when a judge told them they would not be locked into holding a primary. So, while the state government is holding a primary, the state party has charged ahead with caucuses. And only the results of the caucuses will determine who Nevada’s delegates will support as their nominee for president at the GOP national convention this summer. But even Republican Gov. Joe Lombardo isn’t happy about it.
+
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+“I think that’s unacceptable for the voters and the understanding of how things should be done,” he said on the Nevada Newsmakerspodcast in October.
+
+
+Adding to the confusion about the two contests was controversy: There were allegations that the caucus rules were crafted to favor Trump — specifically, a new rule enacted in September, which banned super PAC employees from attending the caucuses.
+
+
+Haley and Florida Gov. Ron DeSantis, who later dropped out of the race, claimed that the rule put them at a severe and unfair disadvantage. DeSantis had depended heavily on two super PACs for support in early-voting states. Haley’s campaign has also relied on super PACs, though to a lesser degree, now that she has the support of the Koch network. That left them without a fighting chance against Trump, who already commanded the kind of grassroots support that is typically rewarded in caucuses.
+
+
+What does all this chaos mean?
+
+
+The only consolation is that all this confusion likely won’t impact who wins the GOP nomination, which Trump has basically locked down after his dominant performance in Iowa and New Hampshire. But it sets a troubling precedent: What if this were a competitive primary that hinged on Nevada?
+
+
+Haley didn’t campaign in Nevada because of all the messiness, as well as her limited campaign resources, which have forced her to be selective about where she spends her time and money. Instead, she turned her focus to her home state of South Carolina, where she previously served as governor, ahead of its February 24 primary as she faces pressure from her party to drop out.
+
+
+However, Moyle said Haley should have opted to participate in the Nevada caucuses instead of the primary, since she likely would have picked up some delegates for coming in second. And if Trump unexpectedly drops out of the race, she would have been able to pick up his Nevada delegates. There might be some strategic benefit to her being able to claim that she won the Nevada primary (even if that contest is only symbolic), but “the reality is, Nikki Haley is going to have zero delegates from the state,” Moyle said. “She’s going to win a meaningless straw poll, which is what the Republican primary is in Nevada.”
+
+
+So Trump had effectively scooped up all of Nevada’s delegates before a single voter had even cast a ballot or entered a caucus site.
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+Still, in insisting on having two contests, Republicans are obscuring just how strong Trump’s candidacy is among voters in the state (especially amid a Latino demographic in which he made gains last cycle) and could be disrupting the democratic process.
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+
+Sadmira Ramic, the voting rights staff attorney at the ACLU of Nevada, said that last weekend, the organization heard from Republicans who showed up to vote for Trump during early voting in the primary, were confused as to why he wasn’t on the ballot, and did not understand that their party would not award delegates based on the outcome of the primary. The Nevada GOP hasn’t been doing enough voter education to guide them through the complicated process this year, she said.
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+“It’s disenfranchising these Republican voters,” she said. “This is harming the voters on their end, that they decided to go this route.”
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+That means Trump’s expected caucus victory in Nevada won’t reveal anything about his actual dominance compared to prior contests in Iowa and New Hampshire. Again, Trump is an unusually strong candidate, meaning even a less-than-stellar showing in Nevada likely wouldn’t have derailed what appears to be his smooth march to the nomination.
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+
+But in a closer contest, signals like margin of victory — and, more importantly, narrow differences in delegate count — take on greater importance. It’s not clear whether the dual primary and caucusing system will survive till the 2028 presidential election, when the GOP field and nomination process is likely to be significantly more competitive. That decision depends on GOP leadership in Nevada, and if Lombardo is reelected in 2026, he’d be in a good position to argue that the process should be consolidated in a single contest, Moyle said.
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+Otherwise, these shenanigans risk diluting the vote in a very important state. Nevada is now the third state on the presidential nominating calendar for Republicans, and early-voting states tend to exert outsize influence on candidates’ trajectories. In some cases, they can make or break a candidate’s presidential aspirations. The fact that it’s playing effectively no role in the nominating process should be concerning.
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From The Hindu: Sports
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Amit, Ishneet, Sachin move to semifinals of Boxam International - Amit put up a brilliant performance as he eked out a stunning 3-2 split decision win to defeat Mexico’s Miguel Angel Martinez.
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Davis Cup: Strong Indian team is firm favourite against Pakistan in historic clash - India have never lost to Pakistan in Davis Cup history, winning all seven ties so far, and the trend is likely to continue.
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Saudi Arabia and the politics of sportswashing - From buying foreign teams to inking multi-billion-dollar athlete contracts, Saudi Arabia is investing heavily in sport in a bid to change the global narrative around the country’s image
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Stokes looks to make good use of Anderson’s experience -
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India has always bounced back well, says Bharat -
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From The Hindu: National News
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Self-reliance in strategic materials vital to secure Atmanirbharta, says former Scientific Advisor to Defence Minister - G. Satheesh Reddy was speaking at the inauguration of the industry connect meet on Strategic Materials and Manufacturing Technologies organised by CSIR-National Institute for Interdisciplinary Science and Technology
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People happy about Ram temple, but it does not mean they will vote for BJP: Raj Thackeray - Mr. Thackeray appeared non-committal on his party contesting the Lok Sabha elections.
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Here are the big stories from Tamil Nadu today - Welcome to the Tamil Nadu Today newsletter, your guide from The Hindu on the major news stories to follow today. Curated and written by Lalitha Ranjani
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PhD admission row: After seven months, Syndicate panel to ask Kerala ex-SFI leader K. Vidya to submit her statement - Syndicate sub-committee of Sree Sankaracharya University of Sanskrit has been probing allegations that norms were violated to admit K. Vidya secure admission into PhD programme in 2020
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Amid political drama, 44 Jharkhand MLAs land in Hyderabad -
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From BBC: Europe
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State of emergency in Catalonia over worst ever drought - Residents face a raft of restrictions on water use as the Spanish region faces its worst drought on record.
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Hostages freed after nine hours at US plant in Turkey - A man apparently protesting over Gaza is detained after the incident at a Proctor & Gamble’s factory.
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German ex-spy chief investigated for extremism - Hans-Georg Maassen has said his party could work with the far right - breaking a taboo in German politics.
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EU leaders unlock €50bn support package for Ukraine - The agreement came earlier than expected, overcoming previous opposition from Hungary’s Viktor Orban.
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Ukraine ‘hits Russian missile boat in Black Sea’ - Military intelligence says the Ivanovets, a small warship, was destroyed in a special operation off Crimea.
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From Ars Technica
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Rocket Report: SpaceX at the service of a rival; Endeavour goes vertical - The US military appears interested in owning and operating its own fleet of Starships. - link
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Convicted console hacker says he paid Nintendo $25 a month from prison - As Gary Bowser rebuilds his life, fellow Team Xecuter indictees have yet to face trial. - link
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Agencies using vulnerable Ivanti products have until Saturday to disconnect them - Things were already bad with two critical zero-days. Then Ivanti disclosed a new one. - link
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Cops arrest 17-year-old suspected of hundreds of swattings nationwide - Police traced swatting calls to teen’s home IP addresses. - link
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FCC to declare AI-generated voices in robocalls illegal under existing law - Robocalls with AI voices to be regulated under Telephone Consumer Protection Act. - link
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From Jokes Subreddit
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A group of military officers are sitting around discussing how much work and fun is involved in having sex. -
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+First the lieutenant says, “Having sex is about 80% fun and 20% work.”
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+Then captain replies, “No, there’s more work involved than that. I would say that it’s 60% fun and 40% work.”
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+The major chimes in, “No, having sex is definitely way more work than that. I would say that it’s 20% fun and 80% work.”
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+As the discussion continued on, a private suddenly walked by the room.
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+The officers call the private over, explain the situation and ask for his opinion.
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+The private quickly replies, “Gentlemen, having sex must be 100% fun.”
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+One of the officers asks, “Well how did you come to that conclusion so easily?”
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+The private says, “Very simple, Sir. If there was any work involved you guys would have me doing it for you.”
+
+… and around 3 a.m. Sherlock nudges his totally-hetero partner awake.
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+“Watson,” he says, “look up.”
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+“I see stars,” murmurs a sleepy Watson.
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+“And do the stars tell you?”
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+Watson considers this. “That we are part of a vast cosmos. That many of those stars could have their own worlds, with their own civilisations, with cultures which we cannot dare to dream. That we are a mere speck in the vastness of creation, and that perhaps we should not be so enamoured with our ravaging of this world.”
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+After a moment of contemplative silence, Watson asks: “Tell me, Sherlock, what do the stars tell you?”
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+“Watson,” says Sherlock with infinite patience, “they tell me that someone has nicked our fucking tent.”
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A girl in college calls her father after having sex for the first time. -
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+She says, “Dad, I have a confession to make. I ain’t a virgin anymore.”
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+Hearing this, the dad gets furious and shouts, “I work my ass off to get you into one of the best universities in the state, and you still say ain’t!?”
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+So Taylor Swift stumbles upon a Time Machine. She accidentally goes back in time and wanders into a university. As she’s looking around an older man walks in talking to someone about how galaxies are moving away from us.
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+The man sees her and asks, “who might you be, young lady?”
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+“I’m Taylor Swift,” she answers, and he is about to introduce himself when she holds up her hand to stop him. “I knew you were Hubble when you walked in. “
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Miles W. Griffis for Vox
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Aaron Robey for Vox
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Aaron Robey for Vox
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Aaron Robey for Vox
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Aaron Robey for Vox
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Miles W. Griffis for Vox
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Miles W. Griffis for Vox
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