Development of a cell-based DIFF-rGFP assay system for generalized discovery of viral protease Inhibitors -
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+Viral protease is an attractive target for antiviral therapeutics, but current viral protease inhibitor screening methods still need to be improved. Here, we systematically investigated the sites that may accommodate exogenous short peptides within Enhanced Green Fluorescent Protein (EGFP)and constructed a series of recombinant green fluorescent proteins (rGFPs). Meanwhile, a cell-based, simple and reliable assay system named DIFF-rGFP was developed relying on the co-expression of rGFP and the protease for protease inhibitor screening with the example of 3CLpro, in which the fluorescence intensity increases with the action of the inhibitor. The DIFF-rGFP assay avoided the requirement of a higher biosafety lab and can be performed in a high-throughput manner. For proof of concept, we demonstrated this method to discover novel inhibitors against SARS-CoV-2. We believe the proposed method, in combination with available drug libraries, may accelerate the identification of novel antivirals.
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OpenSAFELY: a platform for analysing electronic health records designed for reproducible research -
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+Electronic health records (EHRs) and other administrative health data are increasingly used in research to generate evidence on the effectiveness, safety, and utilisation of medical products and services, and to inform public health guidance and policy. Reproducibility is a fundamental step for research credibility and promotes trust in evidence generated from EHRs. At present, ensuring research using EHRs is reproducible can be challenging for researchers. Research software platforms can provide technical solutions to enhance the reproducibility of research conducted using EHRs. In response to the COVID-19 pandemic, we developed the secure, transparent, analytic open-source software platform OpenSAFELY designed with reproducible research in mind. OpenSAFELY mitigates common barriers to reproducible research by: standardising key workflows around data preparation; removing barriers to code-sharing in secure analysis environments; enforcing public sharing of programming code and codelists; ensuring the same computational environment is used everywhere; integrating new and existing tools that encourage and enable the use of reproducible working practices; and providing an audit trail for all code that is run against the real data to increase transparency. This paper describes OpenSAFELY’s reproducibility-by-design approach in detail.
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Recapitulating memory B cell responses in a Lymphoid Organ-Chip to evaluate mRNA vaccine boosting strategies -
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+Predicting the immunogenicity of candidate vaccines in humans remains a challenge. To address this issue, we developed a Lymphoid Organ-Chip (LO chip) model based on a microfluidic chip seeded with human PBMC at high density within a 3D collagen matrix. Perfusion of the SARS-CoV-2 Spike protein mimicked a vaccine boost by inducing a massive amplification of Spike-specific memory B cells, plasmablast differentiation, and Spike-specific antibody secretion. Features of lymphoid tissue, including the formation of activated CD4+ T cell/B cell clusters and the emigration of matured plasmablasts, were recapitulated in the LO chip. Importantly, myeloid cells were competent at capturing and expressing mRNA vectored by lipid nanoparticles, enabling the assessment of responses to mRNA vaccines. Comparison of on-chip responses to Wuhan monovalent and Wuhan/Omicron bivalent mRNA vaccine boosts showed equivalent induction of Omicron neutralizing antibodies, pointing at immune imprinting as reported in vivo. The LO chip thus represents a versatile platform suited to the preclinical evaluation of vaccine boosting strategies.
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Stratification of viral shedding patterns in saliva of COVID-19 patients -
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+Living with COVID-19 requires continued vigilance against the spread and emergence of variants of concern (VOCs). Rapid and accurate saliva diagnostic testing, alongside basic public health responses, is a viable option contributing to effective transmission control. Nevertheless, our knowledge regarding the dynamics of SARS-CoV-2 infection in saliva is not as advanced as our understanding of the respiratory tract. Here we analyzed longitudinal viral load data of SARS-CoV-2 in saliva samples from 144 patients with mild COVID-19 (a combination of our collected data and published data). Using a mathematical model, we successfully stratified infection dynamics into three distinct groups with clear patterns of viral shedding: viral shedding durations in the three groups were 11.5 days (95% CI: 10.6 to 12.4), 17.4 days (16.6 to 18.2), and 30.0 days (28.1 to 31.8), respectively. Surprisingly, this stratified grouping remained unexplained despite our analysis of 47 types of clinical data, including basic demographic information, clinical symptoms, results of blood tests, and vital signs. Additionally, we quantified the expression levels of 92 micro-RNAs in a subset of saliva samples, but these also failed to explain the observed stratification, although the mir-1846 level may have been weakly correlated with peak viral load. Our study provides insights into SARS-CoV-2 infection dynamics in saliva, highlighting the challenges in predicting the duration of viral shedding without indicators that directly reflect an individual's immune response, such as antibody induction. Given the significant individual heterogeneity in the kinetics of saliva viral shedding, identifying biomarker(s) for viral shedding patterns will be crucial for improving public health interventions in the era of living with COVID-19.
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Adaptive Regularized Tri-Factor Non-Negative Matrix Factorization for Cell Type Deconvolution -
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+Motivation: Accurate deconvolution of cell types from bulk gene ex- pression is crucial for understanding cellular compositions and uncovering cell-type specific differential expression and physiological states of diseased tissues. Existing deconvolution methods have limitations, such as requiring complete cellular gene expression signatures or neglecting partial biological information. Moreover, these methods often overlook varying cell-type mRNA amounts, leading to biased proportion estimates. Additionally, they do not effectively utilize valuable reference information from external studies, such as means and ranges of population cell-type proportions. Results: To address these challenges, we introduce an Adaptive Regular- ized Tri-factor non-negative matrix factorization approach for deconvolution (ARTdeConv). We rigorously establish the numerical convergence of our algorithm. Through benchmark simulations, we demonstrate the superior per- formance of ARTdeConv compared to state-of-the-art reference-free methods. In a real-world application, our method accurately estimates cell proportions, as evidenced by the nearly perfect Pearson’s correlation between ARTdeConv estimates and flow cytometry measurements in a dataset from a trivalent influenza vaccine study. Moreover, our analysis of ARTdeConv estimates in COVID-19 patients reveals patterns consistent with important immunological phenomena observed in other studies. Availability and implementation: The proposed method, ARTdeConv, is implemented as an R package and can be accessed on GitHub for researchers and practitioners at https://github.com/gr8lawrence/ARTDeConv. Keywords: Cell-type deconvolution, Convergence analysis, Multiplicative update algorithm, Non-negative matrix factorization, RNA sequencing, Single cell data
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The pandemic’s comparative impact on constitutional checks and balances within the EU -
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+COVID-19 has changed public and private live significantly. Some changes remain permanently. Although COVID-19 is no longer an immediate global health crisis, which has brought healthcare systems in particular close to collapse, the impact on social and economic systems is still being felt. Despite government subsidies, many companies have not survived the effects of the crisis. In addition, many people’s working lives and education have changed. Digital tools, such as online meetings and the option to work from home, are now part of everyday life, unlike before the pandemic. During the pandemic, short-term and fast-acting measures were necessary, which had to be issued by the various powers in special procedures. In most countries, the executive branch took on a central role in order to ensure the ability to act. At the same time, the legislative powers were restricted in their mode of operation. Plenary sessions of the parliaments could only be held to a very limited extent. The measures taken must be reviewed in terms of their effectiveness, but also in terms of their impact on constitutional checks and balances, in order to be able to take more effective, proportionate and constitutional measures for future pandemics. This research paper thus analyses and discusses the consequences of pandemic crisis measures on constitutional democracy in a number of European countries—in particular Germany, France, the UK, Italy, Sweden—, by examining the effects of Covid-19 measures on constitutional checks and balances, and the relations between the executives and legislatures. With a glimpse over the Atlantic some actions will be compared to those on US federal as well as state level.
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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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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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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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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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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
Possible pharmacological targets and mechanisms of sivelestat in protecting acute lung injury - Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is a life-threatening syndrome induced by various diseases, including COVID-19. In the progression of ALI/ARDS, activated neutrophils play a central role by releasing various inflammatory mediators, including elastase. Sivelestat is a selective and competitive inhibitor of neutrophil elastase. Although its protective effects on attenuating ALI/ARDS have been confirmed in several models of lung injury, clinical trials have presented…
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Natural products from Streptomyces spp. as potential inhibitors of the major factors (holoRdRp and nsp13) for SARS-CoV-2 replication: an in silico approach - The COVID-19 pandemic caused unprecedented damage to humanity, and while vaccines have been developed, they are not fully effective against the SARS-CoV-2 virus. Limited targeted drugs, such as Remdesivir and Paxlovid, are available against the virus. Hence, there is an urgent need to explore and develop new drugs to combat COVID-19. This study focuses on exploring microbial natural products from soil-isolated bacteria Streptomyces sp. strain 196 and RI.24 as a potential source of new targeted…
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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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An Impressive Jobs Report Shows the U.S. Economy Powering Into an Election Year - Strong employment growth and improving consumer sentiment are good news for any Presidential incumbent seeking reëlection. - 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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Are you catastrophizing? Here’s how to stop assuming the worst. -
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+Nine experts weigh in on curbing and diffusing your overly negative thoughts.
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+If you’re a person who spends even a minuscule amount of time consuming news of any kind, you may find yourself in a doom spiral: ongoing war, the upcoming presidential election, climate change, the withering of the media. It isn’t just news that can inspire despair. Life is full of anxiety-inducing interactions, high-stakes scenarios, and unavoidable conflicts that can lead to overthinking, hopelessness, and catastrophic thinking.
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+Catastrophizing is a common thought pattern where you assume the worst possible scenario. If you fail a test, you might believe you’ll never get a job in the future. When the group chat is silent after you initiate plans, you jump to conclusions and take it to mean everyone hates you. Your boss says she wants to talk and you assume you’re getting fired. Catastrophic thinking escalates the most benign interactions into crises. Very often, though, these predictions do not come to fruition.
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+People catastrophize in order to prepare for these worst-case scenarios. Catastrophic thinking, however, can lead to heightened anxiety, prolonged feelings of physical pain, risk aversion, and less confidence in problem-solving when big issues do arise. “If you find that you are constantly looking for what could go drastically wrong in your life, this could reflect deeper concerns about safety, security, or self-protection,” says Scott Glassman, director of the master of applied positive psychology program at Philadelphia College of Osteopathic Medicine. “This style of thinking can emerge if you’ve experienced an unexpected traumatic event, like a loss or serious injury, or if you grew up in an environment where fears were often amplified and responded to with panic or overprotection.”
+
+
+Climbing out of the spiral that is catastrophic thinking requires both in-the-moment grounding techniques and big-picture reframing. Focusing on the reality of a situation — and not the story you’re telling yourself — can help blunt the anxiety of catastrophizing, experts say. Here are more therapist-approved tactics to help you avoid catastrophic thinking.
+
+
+Responses have been edited and condensed for clarity.
+
+
+Catch yourself in the act
+
+
+“Instead of viewing the [catastrophic] thought as a prediction of the future, you can simply say, ‘This is a catastrophic thought. I’ve had these thoughts before and things have turned out fine.’ Remind yourself of the times that you’ve engaged in catastrophic thinking and survived it. You will survive this one, too.”
+
+“One of my favorite tips for catastrophizing is asking clients, ‘What is the worst thing that could possibly happen?’ and following it up with the powerful question of, ‘Could I survive that?’ Most of the time, we can survive those worst-case scenarios, but our anxiety gets in the way and makes us believe we can’t get through it. When we can slow ourselves down to examine the evidence, I find that we are often in a better place to reason with ourselves and realize that we can get through hard things.”
+
+Follow the negative thoughts to see where they lead
+
+
+“In the midst of catastrophic thinking, there are two options. One is to create a positive thought (change ‘no one likes me’ to ‘some people like me’) and repeat it. The other is to follow the negative thinking train to the end and see where the illogical thinking takes you. For example, thinking that no one likes me leads to ‘I will die alone,’ which leads to ‘I need to buy a dog because it will bark when I stop responding and the barking will annoy the neighbors and they will call 911.’ When one begins to plan for these negative events, the reality is that these worries are possibilities, not probabilities.”
+
+
+—Diane Urban, licensed psychologist and adjunct professor at Manhattan College and Southern New Hampshire University
+
+
+Remind yourself that you are not your thoughts
+
+
+“Clients who struggle with catastrophizing tend to internalize their thought processes. For example, they may say things like, ‘I am a horrible person,’ ‘Nothing will ever work out for me,’ ‘I am a failure.’ By using these ‘I’ statements, we are allowing our anxious thoughts to become our personality and who we are. One subtle yet effective strategy is creating separation from your thoughts. ‘I am a horrible person’ changes to ‘I am having the thought that I am a horrible person,’ ‘I am a failure’ changes to ‘My brain is telling me that I am a failure.’ This helps to externalize our thoughts so that they do not feel as consuming.”
+
+“One approach that has proven particularly beneficial is grounding techniques. These are simple exercises to help bring your focus back to the present moment when your thoughts start spiraling. For instance, you might engage your senses by naming five things you can see, four you can touch, three you can hear, two you can smell, and one you can taste. This technique can interrupt the cycle of negative thinking and bring you back to reality.”
+
+
+—Elvis Rosales, licensed clinical social worker and the clinical director at Align Recovery Centers
+
+
+Pay attention when things go well
+
+
+“We understandably pay more attention to bad things happening in our lives because, let’s face it, they are upsetting. Catastrophizers, however, have a habit of devoting large amounts of time, attention, and energy to thinking about the worst-case what-ifs, in addition to any bad things that might be happening each day. To neutralize or reverse this tendency, we often need to start taking notice of when things turn out okay or go well. Keeping a daily list can be a reminder of the real rates of good versus upsetting events.
+
+
+“At the same time, we want to make notes about when our catastrophic predictions don’t come true. The more we see the errors of our predictions, the more likely we will treat them with doubt when they arise. We’ll start to quickly notice when our mind is crying wolf and be better able to stop the ruminative cycle before it has revved up. A core belief that can drive catastrophic thinking is, ‘I can’t handle this.’ It’s important to explore that underlying belief and challenge it with contradictory evidence. Keeping a record of big problems you’ve been able to solve could help weaken that belief.”
+
+
+—Scott Glassman, director of the master of applied positive psychology program at Philadelphia College of Osteopathic Medicine
+
+
+Accept bad things when they happen
+
+
+“This may sound strange, but I talk with patients about the idea of getting better at suffering. It always elicits a joke: ‘Oh, I’m already great at that.’ But there’s a difference between obsessing about bad things versus accepting them. Catastrophizing seems like an effort [toward] acceptance but it’s actually a strategy for avoidance. The work here is to move toward the very real sadness and stress of uncertainty rather than trying to bargain with it. The world comes with uncertainty, bad things happen, someday we’ll die.”
+
+
+—Matt Lundquist, founder and clinical director of Tribeca Therapy
+
+
+Try to problem-solve instead of searching for problems
+
+
+“If you are engaged in catastrophic thinking, you may have thought about how daunting the situation is and ways you are unable to fix it. Problem-solving may be helpful. Try breaking down the situation into more manageable parts instead of focusing on options that are overwhelming and frustrating.
+
+
+“For example, if you have the belief that you have no friends, you would first identify the problem. The second step would be to check the facts by finding evidence that supports these thoughts to determine if you are indeed assuming the worst without reason. The third step would be to establish your goal. If your goal is to make friends, engage in more social interaction, or find a sense of community or belonging, then you would establish that goal and brainstorm possible solutions to achieve that goal by breaking down your goal into actionable steps. You would then select your solution and, if necessary, it would be helpful to develop a pros and cons list to help put that thought into action. Most of all, have self-compassion and give yourself grace because breaking negative thought patterns can be very challenging.”
+
+“The minute your train of thought starts to get off the rails, force yourself to think that you are not the master. You do not have control over the future. But you do have the power to either fight it or accept it. So think about all the positive ways you will deal with that catastrophic event.”
+
The Supreme Court weighs whether to end affirmative action at West Point -
+
+
+
+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
+
+
+
+The guy behind the Harvard lawsuit attacking affirmative action turns his ire on the service academies.
+
+
+Editor’s note, February 2, 5:30 pm ET: The Supreme Court released an order late afternoon on February 2 ruling in favor of West Point. The order, however, indicates that the justices only did so because they believe that a ruling by the Supreme Court would be premature right now. The unsigned order, with no noted dissents, says that “the record before this Court is underdeveloped, and this order should not be construed as expressing any view on the merits of the constitutional question.”
+
+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.
+
+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.
+
+
+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.”
+
+
+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.
+
+
+“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.
+
+
+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.”
+
+
+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.
+
+
+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.
+
+
A calendar of Trump’s upcoming court dates — and how they could overshadow the GOP primary -
+
+
+
+Former US President Donald Trump sits in the courtroom during his civil fraud trial at the New York Supreme Court on January 11, 2024, in New York City. | Michael M. Santiago/Getty Images
+
+
+
+The 2024 election season may be defined by Trump’s legal troubles.
+
+
+Donald Trump breezed through the first two contests on the 2024 primary calendar. The question, though, is whether he can sustain his momentum through a primary season — and then general election — interrupted by his many upcoming court dates.
+
+
+The former president is fighting a multifront legal war that has consumed millions of his campaign funds. He’s been ordered to pay $83 million in damages in E. Jean Carroll’s defamation case against him, a ruling that his lawyers have vowed to appeal. That would mark a significant blow to his cash reserves, which Bloomberg estimates at around $600 million, and he wouldn’t be able to use campaign funds to cover it.
+
+
+But there’s still much more to come: There’s the Justice Department case concerning his attempt to overthrow the results of the 2020 election on January 6, 2021, in which the trial, originally scheduled to begin March 4, has now been canceled — but may be rescheduled depending on whether the DC Circuit Court rules that Trump has legal immunity for acts committed while he was president.
+
+
+There’s the ongoing New York state court case in which he’s already been found liable for fraud for inflating the value of his businesses. And Colorado and Maine officials have ordered Trump removed from the ballot in 2024, subject to the approval of the US Supreme Court.
+
+“Is it ratcheting a noose around his campaign or not?” said Dave Wilson, a GOP strategist based in South Carolina. “Do you really want somebody who’s going to be potentially on trial or convicted going up against an already weakened Joe Biden?”
+
+
+In the meantime, his court appearances might help him further cement his dominance in the GOP primary, where he is coasting with a lead of more than 57 percentage points on average. Most Republican voters say he should remain the party’s nominee even if he’s convicted of a crime.
+
+
+“It allows him to go to the states and say, ‘If they’re coming after me, they’re going to come after you,’” Wilson said. “Every appearance that Donald Trump makes in court is a visual reminder to his voters that he’s ‘fighting for them.’”
+
+
+Here are the big dates on Trump’s political and legal calendar:
+
+
+Early to mid-February
+
+
+By mid-February, the New York Supreme Court isaiming to issue a written decision in the civil fraud case concerning Trump’s inflation of the value of his businesses. Though the court has already found him liable for fraud and ordered the dissolution of his New York business licenses, what’s still left to be decided is what kind of financial penalties Trump may face; New York Attorney General Letitia James is seeking $370 million. Trump will likely appeal whatever final decision is reached.
+
+Second, oral arguments are scheduled in the US Supreme Court case Trump v. Anderson over Trump’s removal from the ballot in Colorado. The Colorado electors who sought his removal have argued that his incitement of the January 6, 2021, insurrection at the US Capitol constituted a violation of his presidential oath to uphold the US Constitution under the 14th Amendment, disqualifying him from running for office. The case will likely determine the outcome of the ballot challenges Trump is facing in dozens of other states.
+
+
+February 15
+
+
+Trump is expected to attend a hearing in the hush money case concerning Stormy Daniels — in which Trump is accused of 34 felony counts of falsifying business documents — that will determine whether the case will be dismissed and when the trial date will be discussed. It may be delayed to allow the DOJ’s 2020 election case to go first.
+
+
+There will also be a hearing in the Georgia case over Trump’s interference in the 2020 election. The court will consider a motion that seeks to dismiss the indictment against him and disqualify Fulton County District Attorney Fani Willis and her office from prosecuting the case.
+
+
+February 24
+
+
+South Carolina Republican primary
+
+
+February 27
+
+
+Michigan Republican primary
+
+
+March 5
+
+
+Super Tuesday primaries, including the Colorado and Maine primaries. Trump’s appearance on the ballot in those states will depend on what the Supreme Court rules.
+
+
+March 25
+
+
+The trial in the hush money case is currently slated to begin on March 25, but it could be subject to change depending on how the DOJ’s 2020 election case proceeds.
+
+
+May 20
+
+
+The federal trial in the case concerning Trump’s alleged mishandling of classified documents that he kept at his Mar-a-Lago estate in Florida after he left the White House is scheduled to begin on this date. He is charged with 32 counts of violating the Espionage Act, six counts of obstruction, and two counts of making false statements.
+
+
+July 15–18
+
+
+Republican National Convention
+
+
+August 5
+
+
+Willis has proposed the trial in the Georgia 2020 election case begins on this date. Willis has argued that the Trump campaign was at the center of a criminal enterprise and that many of the 19 individuals named in the case helped assist in the organization’s attempt to overturn the Georgia 2020 election results. Establishing that Trump and his allies were part of an enterprise — a person, group, or business engaged in legal or illegal behavior — is key to Willis’s assertion that the defendants violated Georgia’s Racketeer Influenced and Corrupt Organizations (RICO) Act.
+
+
+Correction, January 18, 9:40 am: This story, originally published January 17, has been updated to reflect that the New York Supreme Court, not the state Court of Appeals, will decide the damages in the Trump civil fraud case.
+
+
+Update, February 2, 4:40 pm: This story, originally published January 17, has been updated multiple times, mostly recently to include information on the timeline for a ruling in the New York civil fraud case against Trump and to reflect that the March 4 trial in the DOJ’s 2020 election case was canceled, at least temporarily.
+
+
+
+
+
+
+
From The Hindu: Sports
+
+
El Asesino, Ricardo, Czar, and Corinthian impress -
+
Sea The Sun, and Big Red please -
+
Why do we need turning tracks, we need to play on good wickets: Ganguly - It wasn’t entirely surprising then to see Ganguly airing his views in favour of decks.
+
India vs Pakistan Davis Cup | Ramkumar, Balaji deliver in high-pressure contest, give India 2-0 lead - Aisam-ul-haq Qureshi gave his all in a tight opening singles but a hamstring injury in third set prevented a close finish to a hard-fought contest.
+
Barcelona president Laporta to ‘rethink everything’ if Super League doesn’t start in 1-2 years - Barcelona, along with rivals Real Madrid, are the only clubs still supporting the breakaway Super League project.
+
+
From The Hindu: National News
+
+
Defence Minister Rajnath Singh commissions survey vessel INS Sandhayak into Navy at Eastern Naval base in Visakhapatnam - Addressing the gathering, Mr. Singh said that the ship will further strengthen India’s role as a superpower in the Indo-Pacific region
+
AP government should take initiative to prevent Odisha’s domination in Kotia villages: Lok Satta Party - Bhisetti Babji feared that Andhra Pradesh would not have any right if it failed to protect the villages which were given to AP during bifurcation of the States in the year 1956.
+
65,000 ‘ghost patients’ underwent tests at Mohalla clinics in Delhi last year: Anti-Corruption Bureau - “Two private labs conducted nearly 22 lakh tests during February-December, 2023, out of which 65,000 were found to be fake,” officials said.
+
Support for BJP is waning across the country: IUML national president - K.M. Kader Mohideen said even though the BJP had secured 34% of votes in the last elections, nearly 66% of people had voted against the party
+
West Bengal CM Mamata Banerjee announces transfer of funds to 21 lakh unpaid MGNREGA workers by Feb. 21 - The TMC supremo also said that her party will go all out against the BJP in the Lok Sabha polls.
+
+
From BBC: Europe
+
+
Three wounded in Paris train station knife attack - One suspect is arrested following the attack at Gare de Lyon, which wounded three people.
+
UN top court can rule on Ukraine case against Russia - Ukraine brought the case in 2022, accusing Russia of falsely using genocide law to justify its invasion.
+
Thunberg cleared after unlawful protest arrest - Greta Thunberg was arrested at a protest in October, with the judge ruling the law was unclear.
+
Mafia boss who fled jail using bed sheets captured - Marco Raduano had been on the run for a year before he was tracked down in Corsica, France.
+
Turkey ‘arrests seven for passing Israel information’ - President Erdogan has warned Israel of “serious consequences” if it targets Hamas on Turkish soil.
+
+
From Ars Technica
+
+
Hermit crabs find new homes in plastic waste: Shell shortage or clever choice? - The crustaceans are making the most of what they find on the seafloor. - link
+
The 2024 Rolex 24 at Daytona put on very close racing for a record crowd - The around-the-clock race marked the start of the North American racing calendar. - link
+
Google will no longer back up the Internet: Cached webpages are dead - Google Search will no longer make site backups while crawling the web. - link
+
Our oldest microbial ancestors were way ahead of their time - Specialized internal structures were present over 1.5 billion years ago. - link
+
“Rasti Computer” is a detailed GRiD Compass tribute made from Framework innards - It’s a custom keyboard, an artfully dinged-up case, and a wonderful throwback. - link
+
+
From Jokes Subreddit
+
+
Two jokes with the same punchline -
+
+
+So this guy is sitting with a dog and the other guy asks him “Does your dog bite?”
+
+
+He says no and the other guy pets the dog and it bites him.
+
+
+He says “I thought you said your dog didn’t bite.”
+
+
+He says “Not my dog.”
+
+
+
+
+
+So this lady is at the doctor and he sees she has badly scraped knees. He asks “What happened to your knees.”
+
A guy gets a call from a friend. “I found a lamp, I think it has a genie inside”. -
+
+
+The guy hangs up, and goes to meet with his friend. When he arrives, he sees his friend indeed has a lamp in his one hand, and a very sizeable pig’s foot in the other. He doesn’t look too happy.
+
+
+“What’s the matter, did the genie scam you?” he asks, half joking. “See for yourself”, the friend answers, and he hands him the lamp. He rubs the lamp. And indeed, a genie comes out.
+
+
+“I will grant you one wish”, says the genie. “But only one, so, choose carefully!”. He considers his options for a brief moment, and then tells the genie: “I want a billion dollars.”
+
+
+“So be it”, says the genie. As he disappears back into the lamp, the sky cracks open, and dolls fall out of the sky. An endless stream of dolls, rapidly covering the ground. The two friends decide to make a run for it before they get buried under the mountain of plastic.
+
+
+“This is bullshit, I asked for dollars, not dolls!”, the guy yells at his friend, while they are still running. “Is this genie deaf or what?”
+
+
+“No shit, Sherlock!” answers the friend. “You really think I asked for a big HOCK?”
+
+He says: “My penis has turned blue all of a sudden and it stopped working”
+
+
+The doctor examines the man’s blue penis carefully before delivering his devastating diagnosis: “I’m afraid your penis has atrophied and the only way forward is to have it amputated”
+
+
+The man, shocked and furious says: “I don’t think you know what you’re doing. I would like to get a second opinon” as he storms out of the doctor’s office and on his way to see an older, more seasoned doctor.
+
+
+He walks into the second doctor’s clinic and immediately tells him what the other doctor had said.
+
+
+The doctor proceeds to examine his blue penis. He then looks at the man and says: “Amputation you say?”
+
+
+The man nods.
+
+
+The doctor says: “You were absolutely right, your previous doctor clearly didn’t know what he was doing”.
+
+
+The man is relieved: “See I knew it the minute I saw him. He looked like a rookie at best. So what is your diagnosis, doctor?”
+
+
+The doctor replies matter-of-factedly: “Amputation is absolutely not necessary. Just stand up and wiggle it around for a minute, it will fall off on its own”
+
+and felt really left out, because he was the only one without a horn. Their horns were beautiful and he wanted to make friends, so the next week he booked an appointment with a plastic surgeon to get one too.
+
+
+Next time he went to the bar, now sporting his new horn, he was devastated when many of the unicorns were rolling their eyes at him, looking at him quizzically.
+
+
+He asked the bartender:
+
+
+“Why is everyone looking at me like this? I look just like you now!”
+
+
+The bartender replied:
+
+
+“Nah, sorry mate, you really don’t. That isn’t a horn, just some silly cone.”
+
+My friend parked there and left his Maroon 5 tickets in the passenger seat. And in less than 15 minutes, someone broke into his car and left two more tickets
+
+
+
+