Unfolded Von Willebrand Factor Binds Protein S and Reduces Anticoagulant Activity -
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+Protein S (PS), the critical plasma cofactor for the anticoagulants tissue factor (TF) pathway inhibitor (TFPI) and activated protein C (APC), circulates in two functionally distinct pools: free (anticoagulant) or bound to complement component 4b-binding protein (C4BP) (anti-inflammatory). Acquired free PS deficiency is detected in several viral infections, but its cause is unclear. Here, we identified a shear-dependent interaction between PS and von Willebrand Factor (VWF) by mass spectrometry. Consistently, plasma PS and VWF comigrated in both native and agarose gel electrophoresis. The PS/VWF interaction was blocked by TFPI but not APC, suggesting an interaction with the C-terminal sex hormone binding globulin (SHBG) region of PS. Microfluidic systems, mimicking arterial laminar flow or disrupted turbulent flow, demonstrated that PS stably binds VWF as VWF unfolds under turbulent flow. PS/VWF complexes also localized to platelet thrombi under laminar arterial flow. In thrombin generation-based assays, shearing plasma decreased PS activity, an effect not seen in the absence of VWF. Finally, free PS deficiency in COVID-19 patients, measured using an antibody that binds near the C4BP binding site in SHBG, correlated with changes in VWF, but not C4BP, and with thrombin generation. Our data suggest that PS binds to a shear-exposed site on VWF, thus sequestering free PS and decreasing its anticoagulant activity, which would account for the increased thrombin generation potential. As many viral infections present with free PS deficiency, elevated circulating VWF, and increased vascular shear, we propose that the PS/VWF interaction reported here is a likely contributor to virus-associated thrombotic risk.
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Distinct evolution of SARS-CoV-2 Omicron XBB and BA.2.86/JN.1 lineages combining increased fitness and antibody evasion -
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+The unceasing circulation of SARS-CoV-2 leads to the continuous emergence of novel viral sublineages. Here, we isolated and characterized XBB.1, XBB.1.5, XBB.1.9.1, XBB.1.16.1, EG.5.1.1, EG.5.1.3, XBF, BA.2.86.1 and JN.1 variants, representing >80% of circulating variants in January 2024. The XBB subvariants carry few but recurrent mutations in the spike, whereas BA.2.86.1 and JN.1 harbor >30 additional changes. These variants replicated in IGROV-1 but no longer in Vero E6 and were not markedly fusogenic. They potently infected nasal epithelial cells, with EG.5.1.3 exhibiting the highest fitness. Antivirals remained active. Neutralizing antibody (NAb) responses from vaccinees and BA.1/BA.2-infected individuals were markedly lower compared to BA.1, without major differences between variants. An XBB breakthrough infection enhanced NAb responses against both XBB and BA.2.86 variants. JN.1 displayed lower affinity to ACE2 and higher immune evasion properties compared to BA.2.86.1. Thus, while distinct, the evolutionary trajectory of these variants combines increased fitness and antibody evasion.
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Forecasting dominance of SARS-CoV-2 lineages by anomaly detection using deep AutoEncoders -
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+The coronavirus disease of 2019 (COVID-19) pandemic is characterized by sequential emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants and lineages outcompeting previously circulating ones because of, among other factors, increased transmissibility and immune escape. We devised an unsupervised deep learning AutoEncoder for viral genomes anomaly detection to predict future dominant lineages (FDLs), i.e., lineages or sublineages comprising >= 10% of viral sequences added to the GISAID database on a given week. The algorithm was trained and validated by assembling global and country specific data sets from 16,187,950 Spike protein sequences sampled between December 24th, 2019, and November 8th, 2023. The AutoEncoder flags low frequency FDLs (0.01% - 3%), with median lead times of 4-16 weeks. Over time, positive predictive values oscillate, decreasing linearly with the number of unique sequences per data set, showing average performance up to 30 times better than baseline approaches. The B.1.617.2 vaccine reference strain was flagged as FDL when its frequency was only 0.01%, more than one year earlier of being considered for an updated COVID-19 vaccine. Our AutoEncoder, applicable in principle to any pathogen, also pinpoints specific mutations potentially linked to increased fitness, and may provide significant insights for the optimization of public health pre-emptive intervention strategies.
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The Importance of Cause-of-Death Certification for the COVID-19 Burden Assessment: the Case of Central Europe -
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+Background: In Central Europe, the increase in mortality during the COVID-19 pandemic exceeded the number of deaths registered due to coronavirus disease. Miscertification of COVID-19 has been suggested as one of the possible explanations. Analysis of all mentions from death certificates allows us to identify cases where COVID-19 was reported as a contributing rather than the underlying cause of death (UCoD). Methods: Analysis of 187,000 death certificates with a COVID-19 mention from Austria, Bavaria, Czechia, Lithuania and Poland, 2020–2021. Cause of Death Association Indicators (CDAIs) and Contributing CDAIs were calculated to identify and measure the strength of associations between COVID-19, reported as UCoD or not, and all other medical mentions. Results: Death certificates reporting COVID-19 included on average more medical information than other death certificates. In 171,600 deaths with COVID-19 as the UCoD, ten groups of comorbidities and ten types of complications revealed significant and strong association with COVID-19. Further 15,700 deaths were certified with COVID-19 only as a contributing condition, of which almost 20% were assigned to typical coronavirus complications, such as cerebral infarction, Acute Myocardial Infarction, renal failure. In Austria, Bavaria, Czechia and Lithuania the reported scale of COVID-19 mortality would have been 18-27% higher had COVID-19 been coded as the UCoD in all the cases. Conclusions: Complete death certificate information allows us to assess the scale of COVID-19 miscertification and the burden of COVID-19. Deaths registered with a coronavirus comorbidity were equivalent to the total estimated excess mortality in Austria and Czech Republic, and a large proportion of in Lithuania and Bavaria.
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+Immunization with mosaic-8b [60-mer nanoparticles presenting 8 SARS-like betacoronavirus (sarbecovirus) receptor-binding domains (RBDs)] elicits more broadly cross-reactive antibodies than homotypic SARS-CoV-2 RBD-only nanoparticles and protects against sarbecoviruses. To investigate original antigenic sin (OAS) effects on mosaic-8b efficacy, we evaluated effects of prior COVID-19 vaccinations in non-human primates and mice on sarbecovirus response breadths elicited by mosaic-8b, admix-8b (8 homotypics), and homotypic SARS-CoV-2, finding greatest cross-reactivity for mosaic-8b. As demonstrated by molecular fate-mapping in which antibodies derived from specific cohorts of B cells are differentially detected, B cells primed by WA1 spike mRNA-LNP dominated antibody responses after RBD-nanoparticle boosting. While mosaic-8b and homotypic-nanoparticles boosted cross-reactive antibodies, de novo antibodies were predominantly induced with mosaic-8b boosting, and these were specific for variant RBDs with increased identity to RBDs on mosaic-8b. These results inform OAS mechanisms and support using mosaic-8b to protect COVID-19 vaccinated/infected humans against as-yet-unknown SARS-CoV-2 variants and animal sarbecoviruses with human spillover potential.
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Use of substances to cope predicts PTSD symptom persistence: Investigating patterns of interactions between PTSD symptoms and its maintaining mechanisms -
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+Objective. Post-traumatic stress disorder (PTSD) remains a growing public health challenge across the globe and is associated with negative and persistent long-term consequences. The last decades of research identified different mechanisms associated with the development and persistence of PTSD, including maladaptive coping strategies, cognitive and experiential avoidance, positive, and negative metacognitions. Despite these advances, little is known about how these different processes interact with specific PTSD symptoms, and how they influence each other over time at the within-person level. Method. Leveraging a large (N > 1,800) longitudinal dataset representative of the Norwegian population during the COVID-19 pandemic, this pre-registered study investigated these symptom-process interactions over an eight-month period. Results. Our panel graphical vector autoregressive (GVAR) network model revealed the dominating role of substance use to cope in predicting higher levels of PTSD symptoms over time and increases in PTSD symptomatology within more proximal time-windows (i.e., within six weeks). Threat monitoring was associated with increased suicidal ideation, while threat monitoring itself was increasing upon decreased avoidance behavior, greater presence of negative metacognitions, and higher use of substances to cope. Conclusions. Our findings speak to the importance of attending to different coping strategies, particularly the use of substances as a coping behavior in efforts to prevent PTSD chronicity upon symptom onset. We outline future directions for research efforts to better understand the complex interactions and temporal pathways leading up to the development and maintenance of PTSD symptomatology.
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Dimensionality reduction distills complex evolutionary relationships in seasonal influenza and SARS-CoV-2 -
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+Public health researchers and practitioners commonly infer phylogenies from viral genome sequences to understand transmission dynamics and identify clusters of genetically-related samples. However, viruses that reassort or recombine violate phylogenetic assumptions and require more sophisticated methods. Even when phylogenies are appropriate, they can be unnecessary or difficult to interpret without specialty knowledge. For example, pairwise distances between sequences can be enough to identify clusters of related samples or assign new samples to existing phylogenetic clusters. In this work, we tested whether dimensionality reduction methods could capture known genetic groups within two human pathogenic viruses that cause substantial human morbidity and mortality and frequently reassort or recombine, respectively: seasonal influenza A/H3N2 and SARS-CoV-2. We applied principal component analysis (PCA), multidimensional scaling (MDS), t-distributed stochastic neighbor embedding (t-SNE), and uniform manifold approximation and projection (UMAP) to sequences with well-defined phylogenetic clades and either reassortment (H3N2) or recombination (SARS-CoV-2). For each low-dimensional embedding of sequences, we calculated the correlation between pairwise genetic and Euclidean distances in the embedding and applied a hierarchical clustering method to identify clusters in the embedding. We measured the accuracy of clusters compared to previously defined phylogenetic clades, reassortment clusters, or recombinant lineages. We found that MDS maintained the strongest correlation between pairwise genetic and Euclidean distances between sequences and best captured the intermediate placement of recombinant lineages between parental lineages. Clusters from t-SNE most accurately recapitulated known phylogenetic clades and recombinant lineages. Both MDS and t-SNE accurately identified reassortment groups. We show that simple statistical methods without a biological model can accurately represent known genetic relationships for relevant human pathogenic viruses. Our open source implementation of these methods for analysis of viral genome sequences can be easily applied when phylogenetic methods are either unnecessary or inappropriate.
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Identification of B cell subsets based on antigen receptor sequences using deep learning -
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+B cell receptors (BCRs) denote antigen specificity, while corresponding cell subsets indicate B cell functionality. Since each B cell uniquely encodes this combination, physical isolation and subsequent processing of individual B cells become indispensable to identify both attributes. However, this approach accompanies high costs and inevitable information loss, hindering high-throughput investigation of B cell populations. Here, we present BCR-SORT, a deep learning model that predicts cell subsets from their corresponding BCR sequences by leveraging B cell activation and maturation signatures encoded within BCR sequences. Subsequently, BCR-SORT is demonstrated to improve reconstruction of BCR phylogenetic trees, and reproduce results consistent with those verified using physical isolation-based methods or prior knowledge. Notably, when applied to BCR sequences from COVID-19 vaccine recipients, it revealed inter-individual heterogeneity of evolutionary trajectories towards Omicron-binding memory B cells. Overall, BCR-SORT offers great potential to improve our understanding of B cell responses.
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BootCellNet, a resampling-based procedure, promotes unsupervised identification of cell populations via robust inference of gene regulatory networks. -
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+Recent advances in measurement technologies, particularly single-cell RNA sequencing (scRNA-seq), have revolutionized our ability to acquire large amounts of omics-level data on cellular states. As measurement techniques evolve, there has been an increasing need for data analysis methodologies, especially those focused on cell-type identification and inference of gene regulatory networks (GRNs). We have developed a new method named BootCellNet, which employs smoothing and resampling to infer GRNs. Using the inferred GRNs, BootCellNet further infers the minimum dominating set (MDS), a set of genes that determines the dynamics of the entire network. We have demonstrated that BootCellNet robustly infers GRNs and their MDSs from scRNA-seq data and facilitates unsupervised cell labeling using scRNA-seq datasets of peripheral blood mononuclear cells and hematopoiesis. It has also identified COVID-19 patient-specific cells and their potential regulatory transcription factors. BootCellNet not only identifies cell types in an unsupervised and explainable way but also provides insights into the characteristics of identified cell types through the inference of GRNs and MDS.
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Social Sharing of Emotion During the Collective Crisis of COVID-19 -
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+We collected data from two sources — social media and online questionnaires — to investigate the emotional consequences of social sharing during the COVID-19 pandemic. Study 1 tracked and analysed sentiment of tweets posted over the course of a month in the crisis period and found that users who tweeted more frequently about COVID-19 expressed decreasing negative sentiment and increasing positive sentiment over time. Granger-causality tests confirmed that this association was better interpreted in the forward direction (sharing levels predicting sentiment) than in the reverse direction (sentiment predicting sharing levels). Study 2 focused on immediate emotional consequences of sharing COVID-related events and found that participants reported improved overall affect about an event to after sharing it, especially when that event was a personal experience rather than a news story. Reported positive feelings about both kinds of event were also significantly higher after sharing. Taken together, both studies suggested that social sharing is linked with emotional relief and may therefore help people to deal with their negative experiences during a persistent collective crisis.
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Simulation-Driven Design of Stabilized SARS-CoV-2 Spike S2 Immunogens -
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+The full-length prefusion-stabilized SARS-CoV-2 spike (S) is the principal antigen of COVID-19 vaccines. Vaccine efficacy has been impacted by emerging variants of concern that accumulate most of the sequence modifications in the immunodominant S1 subunit. S2, in contrast, is the most evolutionarily conserved region of the spike and can elicit broadly neutralizing and protective antibodies. Yet, the usage of S2 as an alternative vaccine strategy is hampered by its general instability. Here, we use a simulation-driven approach to design S2-only immunogens stabilized in a closed prefusion conformation. Molecular simulations provide a mechanistic characterization of S2 trimer opening, informing the design of tryptophan substitutions that impart kinetic and thermodynamic stabilization. Structural characterization via cryo-EM shows the molecular basis of S2 stabilization in the closed prefusion conformation. Moreover, a corroborating set of experiments indicate that the engineered S2 immunogen exhibits increased protein expression, superior thermostability, and preserved immunogenicity against sarbecoviruses.
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Trait Intolerance of Uncertainty Is Associated with Decreased Reappraisal Capacity and Increased Suppression Tendency -
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+The COVID-19 pandemic has been a time of great uncertainty for the general population and highlights the need to understand how attitudes towards uncertainty may affect well-being. Intolerance of uncertainty is a trait associated with worry, anxiety, and mood disorders. As adaptive emotion regulation supports well-being and mental health, it is possible that intolerance of uncertainty is also associated with the ability and tendency to regulate emotions. However, the relationships between intolerance of uncertainty and widely studied cognitive emotion regulation strategies — such as reappraisal and suppression — have received little attention. In two studies that recruited participants online from the United States, we tested the hypotheses that higher trait intolerance of uncertainty would be associated with greater worry, decreased capacity and tendency to use reappraisal, and increased tendency to use suppression in daily life. Study 1 provided an initial test of our hypotheses. Study 2 was a confirmatory, preregistered study that replicated findings in a young adult sample, demonstrating that scores on the Intolerance of Uncertainty Scale (IUS) were associated with greater COVID-related worry, decreased capacity to regulate negative emotions on a task that manipulated the use of reappraisal, and greater self-reported use of suppression in daily life. Together, these results indicate that intolerance of uncertainty is associated with the capacity and tendency to use emotion regulation strategies important for well-being.
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Boosting Positive Mood During Stress: A Daily Coping Toolkit Replication in College Undergraduates -
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+College students today face significant challenges. Evidence suggests mental-health burdens are substantial and resources limited. We sought to replicate prior evidence supporting a one-time daily ambulatory intervention to facilitate adaptive regulation of negative emotion and increase generation of positive emotions. The Daily Coping Toolkit (DCT) was developed at the outset of the COVID-19 Pandemic and was effective in boosting mood in front-line medical personnel (Coifman et al., 2021). This investigation aimed to replicate against a valid control condition in college students returning to campus in 2021. N = 125 college students were randomized to one of two experimental conditions (high v. low dose) or the control condition. Data analyses was pre-registered. Results indicated students in experimental groups experienced significant decreases in negative and increases in positive emotion when compared to controls, providing evidence of efficacy. This was notable because a high proportion of participants reported prior mental illness. Although, there was no difference by dose (high v. low) on emotional reports, there was preliminary evidence that low-dose condition was associated with greater adaptive coping (e.g., exercise, social support seeking). Overall, the results suggest the DCT is an efficacious emotion-regulation intervention that can boost mood during high stress.
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copepodTCR: Identification of Antigen-Specific T Cell Receptors with combinatorial peptide pooling -
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+T cell receptor (TCR) repertoire diversity enables the orchestration of antigen-specific immune responses against the vast space of possible pathogens. Identifying TCR/antigen binding pairs from the large TCR repertoire and antigen space is crucial for biomedical research. Here, we introduce copepodTCR, an open-access tool for the design and interpretation of high-throughput experimental assays to determine TCR specificity. copepodTCR implements a combinatorial peptide pooling scheme for efficient experimental testing of T cell responses against large overlapping peptide libraries, useful for “deorphaning” TCRs of unknown specificity. The scheme detects experimental errors and, coupled with a hierarchical Bayesian model for unbiased results interpretation, identifies the response-eliciting peptide for a TCR of interest out of hundreds of peptides tested using a simple experimental set-up. We experimentally validated our approach on a library of 253 overlapping peptides covering the SARS-CoV-2 spike protein. We provide experimental guides for efficient design of larger screens covering thousands of peptides which will be crucial for the identification of antigen-specific T cells and their targets from limited clinical material.
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Can Worries about COVID-19 Enhance Well-Being? Evidence from a Cross-National Study -
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+Can worrying about COVID-19 have positive consequences for well-being? In a preregistered study, we examined the effect of worries about COVID-19 on well-being through divergent associations with social interaction and depression. In August 2020, participants from high and low prevalence regions in the United States and Italy (N = 857) completed assessments of COVID-19 worry, social interaction, depression, and well-being. Worries about COVID-19 predicted both more social interaction and more depression. In mediational analyses, an adaptive pathway of COVID-19 worry through social interaction was associated with higher well-being, whereas a maladaptive pathway through depression was associated with lower well-being. Further, a comparison of high and low COVID-19 prevalence regions replicated the mediational findings for social interaction, providing evidence against reverse causation and common method variance. Findings suggest that normative worries about acute stressors can both benefit and undermine well-being, depending on their impact on social behavior or depression.
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Investigating the Effectiveness of Vimida - Conditions: Long COVID; Post COVID-19 Condition Interventions: Behavioral: vimida Sponsors: Gaia AG; Medical School Hamburg; Institut Long-Covid Rostock Not yet recruiting
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Effects of Physiotherapy Via Video Calls on Cardiopulmonary Functions, Physical Function, Cognitive Function, Activity Daily Livings, and Quality of Life in Patients With COVID-19 - Conditions: COVID-19; Long COVID-19; Cardiopulmonary Function; Physical Function Interventions: Behavioral: Exercise training Sponsors: Chulabhorn Hospital Enrolling by invitation
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Acute Cardiovascular Responses to a Single Exercise Session in Patients With Post-COVID-19 Syndrome - Conditions: Post-Acute COVID-19 Syndrome Interventions: Behavioral: Exercise session; Behavioral: Control session Sponsors: University of Nove de Julho Not yet recruiting
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Reducing Respiratory Virus Transmission in Bangladeshi Classrooms - Conditions: SARS-CoV2 Infection; Influenza Viral Infections; Respiratory Viral Infection Interventions: Device: Box Fan; Device: UV Germicidal Irradiation Lamp Unit; Device: Combined: Box Fan and UV Germicidal Irradiation Lamp Units Sponsors: Stanford University; Centers for Disease Control and Prevention; International Centre for Diarrhoeal Disease Research, Bangladesh Not yet recruiting
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SMILE: Clinical Trial to Evaluate Mindfulness as Intervention for Racial and Ethnic Populations During COVID-19 - Conditions: Anxiety; COVID-19 Pandemic Interventions: Behavioral: Mindfulness Sponsors: University of North Carolina, Chapel Hill; National Institute on Minority Health and Health Disparities (NIMHD); RTI International Not yet recruiting
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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 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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From PubMed
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SARS-CoV-2 Nsp1 cooperates with initiation factors EIF1 and 1A to selectively enhance translation of viral RNA - A better mechanistic understanding of virus-host dependencies can help reveal vulnerabilities and identify opportunities for therapeutic intervention. Of particular interest are essential interactions that enable production of viral proteins, as those could target an early step in the virus lifecycle. Here, we use subcellular proteomics, ribosome profiling analyses and reporter assays to detect changes in protein synthesis dynamics during SARS-CoV-2 (CoV2) infection. We identify specific…
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Application of a Biomimetic Nanoparticle-Based Mock Virus to Determine SARS-CoV-2 Neutralizing Antibody Levels in Blood Samples Using a Lateral Flow Assay - The presence of neutralizing antibodies against SARS-CoV-2 in blood, acquired through previous infection or vaccination, is known to prevent the (re)occurrence of outbreaks unless the virus mutates. Therefore, the measurement of neutralizing antibodies constitutes an indispensable tool in assessing an individual’s and a population’s immunity against SARS-CoV-2. For this reason, we have developed an innovative lateral flow assay (LFA) capable of detecting blood-derived neutralizing antibodies…
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Kidney organoids reveal redundancy in viral entry pathways during ACE2-dependent SARS-CoV-2 infection - With a high incidence of acute kidney injury among hospitalized COVID-19 patients, considerable attention has been focussed on whether SARS-CoV-2 specifically targets kidney cells to directly impact renal function, or whether renal damage is primarily an indirect outcome. To date, several studies have utilized kidney organoids to understand the pathogenesis of COVID-19, revealing the ability for SARS-CoV-2 to predominantly infect cells of the proximal tubule (PT), with reduced infectivity…
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Role of PCSK9 inhibition during the inflammatory stage of SARS-COV-2: an updated review - The potential role of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition in the management of COVID-19 and other medical conditions has emerged as an intriguing area of research. PCSK9 is primarily known for its impact on cholesterol metabolism, but recent studies have unveiled its involvement in various physiological processes, including inflammation, immune regulation, and thrombosis. In this abstract, the authors review the rationale and potential implications of PCSK9…
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Case report: Ensitrelvir for treatment of persistent COVID-19 in lymphoma patients: a report of two cases - Persistent COVID-19 is a well recognized issue of concern in patients with hematological malignancies. Such patients are not only at risk of mortality due to the infection itself, but are also at risk of suboptimal malignancy-related outcomes because of delays and terminations of chemotherapy. We report two lymphoma patients with heavily pretreated persistent COVID-19 in which ensitrelvir brought about radical changes in the clinical course leading to rapid remissions. Patient 1 was on ibrutinib…
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TMPRSS2 inhibitors for the treatment of COVID-19 in adults: a systematic review and meta-analysis of nafamostat and camostat mesylate randomised clinical trials - CONCLUSION: The RCT evidence is inconclusive to determine whether there is a mortality reduction and safety with either nafamostat or camostat for the treatment of adults with COVID-19. There were high risk-of-bias, small sample size, and high heterogeneity between RCTs.
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A rationally designed antimicrobial peptide from structural and functional insights of Clostridioides difficile translation initiation factor 1 - A significant increase of hospital-acquired bacterial infections during the COVID-19 pandemic has become an urgent medical problem. Clostridioides difficile is an urgent antibiotic-resistant bacterial pathogen and a leading causative agent of nosocomial infections. The increasing recurrence of C. difficile infection and antibiotic resistance in C. difficile has led to an unmet need for the discovery of new compounds distinctly different from present antimicrobials, while antimicrobial peptides…
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BRD4354 Is a Potent Covalent Inhibitor against the SARS-CoV-2 Main Protease - Numerous organic molecules are known to inhibit the main protease (M^(Pro)) of SARS-CoV-2, the pathogen of Coronavirus Disease 2019 (COVID-19). Guided by previous research on zinc-ligand inhibitors of M^(Pro) and zinc-dependent histone deacetylases (HDACs), we identified BRD4354 as a potent inhibitor of M^(Pro). The in vitro protease activity assays show that BRD4354 displays time-dependent inhibition against M^(Pro) with an IC(50) (concentration that inhibits activity by 50%) of 0.72 ± 0.04 μM…
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Assessing the mitochondrial safety profile of the molnupiravir active metabolite, β-d-N4-hydroxycytidine (NHC), in the physiologically relevant HepaRG model - CONCLUSIONS: Overall, NHC does not cause direct mitochondrial toxicity in HepaRG cells at clinically relevant concentrations, but may induce minor cellular perturbations. As HepaRG cells have increased physiological relevance, these findings provide additional assurance of the mitochondrial safety profile of NHC.
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Identification of CD8 T-cell dysfunction associated with symptoms in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Long COVID and treatment with a nebulized antioxidant/anti-pathogen agent in a retrospective case series - CONCLUSIONS: Here, in this small study, we present two observations that appear potentially fundamental to the pathogenesis and treatment of Long COVID and ME/CFS. The first is that both disorders appear to be characterized by dysfunctional CD8 T-cells with severe deficiencies in their abilities to produce IFNγ and TNFα. The second is that in a small retrospective Long COVID and ME/CFS case series, this immune dysfunction and patient health improved in parallel with treatment with an…
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Arbidol attenuates liver fibrosis and activation of hepatic stellate cells by blocking TGF-β1 signaling - Chronic liver diseases (CLD) impact over 800 million people globally, causing about 2 million deaths annually. Arbidol (ARB), an indole-derivative used to treat influenza virus infection, was extensively used during COVID-19 pandemic in China. In recent years, studies have shown that ARB, compared to other antiviral drugs, exhibits greater liver-protective efficacy, indicating a potential hepatoprotective effect beyond its antiviral activity. However, the mechanism remains unclear. In this…
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Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) binds with spike protein and inhibits the entry of SARS-CoV-2 into host cells - CONCLUSIONS: Our investigations suggest that this interaction of GAPDH interferes in the viral docking with hACE2 receptors, thereby affecting viral ingress into mammalian cells.
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TREG cells and CXCR3+ circulating TFH cells concordantly shape the neutralizing antibody responses in individuals who have recovered from mild COVID-19 - Regulatory T (TREG) cells are involved in the antiviral immune response in patients with COVID-19; however, whether TREG cells are involved in the neutralizing antibody (nAb) response remains unclear. Here, we found that individuals who recovered from mild but not severe COVID-19 had significantly greater frequencies of TREG cells and lower frequencies of CXCR3+ circulating TFH (cTFH) cells than healthy controls. Furthermore, TREG and CXCR3+ cTFH cells were negatively and positively correlated…
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Influenza vaccine compatibility among hospitalized patients during and after the COVID-19 pandemic - INTRODUCTION: Following the significant decrease in SARS-CoV-2 cases worldwide, Israel, as well as other countries, have again been faced with a rise in seasonal influenza. This study compared circulating influenza A and B in hospitalized patients in Israel with the influenza strains in the vaccine following the 2021-2022 winter season which was dominated by the omicron variant.
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Molecular docking as a tool for the discovery of novel insight about the role of acid sphingomyelinase inhibitors in SARS- CoV-2 infectivity - Recently, COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants, caused > 6 million deaths. Symptoms included respiratory strain and complications, leading to severe pneumonia. SARS-CoV-2 attaches to the ACE-2 receptor of the host cell membrane to enter. Targeting the SARS-CoV-2 entry may effectively inhibit infection. Acid sphingomyelinase (ASMase) is a lysosomal protein that catalyzes the conversion of sphingolipid (sphingomyelin) to ceramide….
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From Patent Search
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Trying to Keep His Family Safe in Rafah - As Israel’s military campaign turns to what has become Gaza’s home for displaced civilians, a Palestinian aid worker describes his long journey to the city, and how he talks to his kids about air strikes. - link
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Is the Media Prepared for an Extinction-Level Event? - Ads are scarce, search and social traffic is dying, and readers are burned out. The future will require fundamentally rethinking the press’s relationship to its audience. - link
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The Friendship Challenge - How envy destroyed the perfect connection between two teen-age girls. - link
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The Art World Before and After Thelma Golden, by Calvin Tomkins - When Golden was a young curator in the nineties, her shows, centering Black artists, were unprecedented. Today, those artists are the stars of the art market. - link
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A Teen’s Fatal Plunge Into the London Underworld - After Zac Brettler mysteriously plummeted into the Thames, his grieving parents were shocked to learn that he’d been posing as an oligarch’s son. Would the police help them solve the puzzle of his death? - link
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From Vox
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Beware: A cheese crisis looms -
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+A chunk of camembert melts off a spatula. | Jonathan Knowles/Getty Images
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+Gird your curds! Say a prayer for Camembert! A collapse in microbe diversity puts these French cheeses at risk.
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+Camembert, I’m sorry to report, is in trouble.
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+The soft cheese, which smells a bit like feet, is on the “verge of extinction,” according to the French National Center for Scientific Research (CNRS). Other cheeses, including brie and various blues, are under threat, too, the group has warned.
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+This looming cheese crisis, this Camembert calamity, stems from a much bigger problem: a collapse in microbial diversity.
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+Each hunk of Camembert or smear of brie is an ecosystem, an assortment of fungi and bacteria that turn milk fats and proteins into hundreds of different compounds. Those compounds produce the flavors, smells, and textures we love.
+
+
+In recent decades, however, the genetic diversity of some of those microbes has caved. And today, some of the most famous French cheeses rely on just a single fragile strain of fungi that is at risk of dying out.
+
+
+This is bad news for France, bad news for bread, and bad news for lovers of fine cheese the world over. And it’s a reminder that biodiversity matters, even when you can’t see it. Life’s finer things, indeed, depend on it.
+
+
+ Benji Jones on assignment for Vox
+
+A wheel of Camembert that this author was forced to buy and taste for this story.
+
+
+
+Why Camembert as we know it could disappear
+
+
+To make cheese, producers typically take fresh milk and mix in bacteria and often fungi, including both yeasts and molds (fungi that tend to be fuzzy). Different microbe melanges produce different varieties of cheese.
+
+
+Historically, Camemberts and bries likely relied on mold strains from a species of fungi called Penicillium biforme, according to Jeanne Ropars, an evolutionary biologist who works at a lab affiliated with CNRS. Each strain was slightly different genetically, and so the resulting cheeses had slightly different colors, flavors, and smells.
+
+
+Roughly a century ago, however, cheesemakers identified a particular strain of P. biforme that was fast-growing and albino; it produced a fluffy white mold that was, apparently, quite appetizing. This strain, known as Penicillium camemberti, was henceforth considered the gold standard for brie and Camembert (which differ from one another mainly in size). It quickly dominated the cheese industry, and the diverse group of other mold strains used to make Camembert and brie, and the colors they produced, vanished from disuse.
+
+
+Today, all Camembert and brie cheeses worldwide are inoculated with this one genetically identical albino strain of fungi, which is not found in the wild, Ropars said. That means that a brie from a grocery store in France and one from a bodega in New York City have identical (or nearly identical) Penicillium microbes.
+
+
+This is a good thing for those who value uniformity; for people who expect their brie to look a certain way, just as they might want their tomatoes to be perfectly round and their apples bright red.
+
+
+But uniformity comes at a cost.
+
+
+ Zoccolan/AFP via Getty Images
+
+A worker of the Farm Cite des Vents shows cheese curds, in Saint-Flour, central France, on February 28, 2023.
+
+
+
+For reasons that are not totally clear, the albino strain can’t reproduce sexually, like most molds can — meaning, it can’t “breed” with another individual to create new genetic diversity. So to create more of this fungi, cheesemakers have to clone it, not unlike how you propagate a plant using a cutting. Yet decades of replicating the same individual can introduce harmful errors into its genome, Ropars said.
+
+
+That’s what’s happened with P. camemberti. In recent decades, the albino fungus picked up mutations that interfere with its ability to produce spores, and that makes it much harder to clone. Put simply: It’s now difficult for cheesemakers to grow the key fungus used to make brie and Camembert.
+
+
+“Camembert is not going to disappear tomorrow,” Ropars said, and it’s not clear how these challenges will impact cheese supply. “But it’s going to be more and more difficult to produce.”
+
+
+Our foods, more broadly, are losing resilience
+
+
+In the world of cheese, this problem is not unique to Camembert and brie. The diversity of fungi used to make blue cheeses, like Gorgonzola and Roquefort, has also shrunk dramatically in recent decades, Ropars said. Farmers have similarly selected certain strains that produce the right look, aroma, and flavor, narrowing the genetic pool. So far, these strains — which are considered “domesticated” microbes — can still reproduce, but some are nearly infertile.
+
+
+This rapid caving of genetic diversity threatens other food industries, too, as the author Dan Saladino writes in his book Eating to Extinction: The World’s Rarest Foods and Why We Need to Save Them. Most bananas we eat, for example, are genetically similar. That means that if a pathogen evolves the right machinery to kill one, it can kill many — which is a very real threat.
+
+
+ Sean Gallup/Getty Images
+
+A cheese stand in Berlin, Germany.
+
+
+
+Uniformity is especially bad in a warming world. Different genetic varieties of plants, such as wheat, have different strengths and weaknesses; some might be more tolerant to, say, long periods of drought. Losing diversity means losing different strengths that may ensure the survival of a particular food.
+
+
+“When you lose diversity within a species, you lose adaptability,” said Tatiana Giraud, a colleague of Ropars who also works at CNRS.
+
+
+This diversity matters among communities of wild organisms, as well, Giraud said, whether or not you can see them. Fungal communities, though poorly studied, are invisible forces in the environment, operating in the background to ensure that ecosystems function properly. They can break down dead leaves and branches, help plants absorb nutrients, and clear toxins from the soil. Protecting the diversity of fungal species, scientists say, safeguards these critical services.
+
+
+Get comfortable with funkier cheeses
+
+
+Ultimately, this doesn’t mean that we must bid farewell to brie, or that Camembert on toast is, let’s say, toast. There is a way to save these cheeses, though it requires some changes in our own taste and tolerance.
+
+
+To make Camembert or brie, cheese producers could simply inoculate cow’s milk with other Penicillium biforme molds, which are naturally present in raw milk (these microbes would need to be manually added if the milk is pasteurized). As a group, Penicillium biforme has a lot of genetic diversity and these molds are able to produce sexually, Ropars said, which is key to maintaining genetic diversity.
+
+
+P. biforme is closely related to the albino strain, though it might give the cheeses a slightly different look and aroma. Perhaps your wheel of brie would be a bit more blue or gray, or slightly funkier. But this is something that consumers should embrace, Ropars said: a diverse mix of flavors, of smells, a resilient collection of bugs.
+
+
Taylor Swift, the NFL, and two routes to cultural dominance -
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+
+
+Super Bowl 2024 is a classic American story and these two are our main characters. | Patrick Smith/Getty Images
+
+
+
+An extra-super Super Bowl is in store.
+
+
+Sometime on Sunday, the white-hot center of the biggest spectator events of the past year will arrive in Las Vegas. Their every move will be tracked by relentless media and even more relentless fans.
+
+
+Also, a football game will be played.
+
+
+There will be no shortage of storylines at Super Bowl LVIII, which — I’ll save you the Google search — kicks off at 6:30 pm ET on February 11. Can Kansas City Chiefs coach Andy Reid and quarterback Patrick Mahomes win their second-straight title? Will Mr. Irrelevant — San Francisco 49ers quarterback Brock Purdy — strike a blow for anyone who was ever picked last in gym class and take home the Lombardi trophy? Will Las Vegas sports books clean up on the $16 billion — more than the total GDP of Madagascar — Americans are projected to bet on the big game? (My predictions: yes, no, and absolutely.)
+
+
+What will make this Super Bowl so important, at least for many of the more than 120 million Americans who will probably tune in to watch the game, will be the expected presence of one Taylor Alison Swift. A brief recap for anyone who until recently took up residence under a rock: This past fall, Swift started dating Chiefs tight end Travis Kelce and began showing up to his games. People — everyone, really, but especially guys like this — went crazy.
+
+
+For all their differences — Swift ruthlessly mines her emotions for her music; emotions can result in a 15-yard penalty in the NFL — what Swift and pro football have in common is sheer cultural weight.
+
+
+
+Swift’s Eras Tour is the highest-grossing concert tour ever, taking in more than the next two biggest 2023 tours combined. She broke the record for most global streams ever on Spotify at more than 26.1 billion in 2023 — or more than three streams for every human on Earth — and had four of the 10 most-consumed albums this year, all without actually releasing an album of new music. When she made history with her fourth Album of the Year Grammy last week, it was just one more jewel in the tiara.
+
+Swift and the NFL are each bigger than big. But what’s really illustrative of American entertainment today is how different their paths to the top have been.
+
+
+No one player is bigger than the NFL
+
+
+If you check out SportsPro’s ranking of the 50 most marketable global athletes, you have to go all the way down to 35 — past NBA stars, F1 drivers, and soccer players — to get to an NFL player: Travis Kelce. And with all due respect to Kelce’s Hall of Fame career, I have a feeling that has more to do with his girlfriend than his 74 career touchdown receptions.
+
+
+In any other sport, the fact that the most successful team, the Chiefs, is based in the league’s 25th-biggest media market would be a problem. When the small-market Denver Nuggets won last year’s NBA finals, ratings notably dipped. But such things don’t matter in the NFL, where the Chiefs set ratings records in last year’s Super Bowl and will likely do so again.
+
+
+Other sports are also dependent on individual players to generate interest: see Messi-mania in Major League Soccer. When Michael Jordan finally retired, NBA viewership plunged for years as the league struggled to find a new star around which to orbit. Contrast that to the NFL, which just spent its first season since 1999 without Tom Brady. Brady — as much as it pains everyone outside the greater Boston area to say, including me — is the NFL’s equivalent to Jordan, with one more ring. Yet when Brady left, ratings just kept going up and up.
+
+
+It wasn’t primarily Brady or Mahomes or Kelce that people were tuning in to see. It’s NFL football itself, and no player is bigger than the National Football League.
+
+
+But no one is bigger than Taylor Swift.
+
+
+A singular superstar
+
+
+If the NFL has made itself into the biggest, most powerful, most watched institution in entertainment, Swift has risen to the pinnacle by disrupting every institution around her. Get into a dispute with your former record label over ownership of your original album masters? Just re-record and release the albums — and watch years-old songs zoom to the top of the charts. Want to make a concert film of your epic Eras Tour? Cut out the middlemen and make a deal directly with the theater chain AMC — and watch that movie become the highest-grossing concert film ever. As Swift told Time magazine, which made her its 2023 Person of the Year: “I bet on myself.”
+
+
+Swift is able to do all this not just because she has talent and moxie, but because she has been able to forge an unusually strong relationship with her fans. That’s how you create so much enthusiasm that your concert fans generate the equivalent of a 2.3-magnitude earthquake at a Seattle show (one twice as powerful as the seismic activity generated during a 2011 NFL playoff game in Seattle).
+
+
+Attending an Eras show is not unlike attending, say, a Green Bay Packers game at Lambeau Field: The emotions are intense, the screaming never stops, and a lot of people are incostume. The difference is that everyone at an Eras show is there to see Taylor and Taylor alone — and she always wins.
+
+
+So when Swift meets the NFL at Super Bowl LVIII, it won’t just be a collision of pop and jocks, women and men, glitter and grime. It’ll be the singular superstar contrasted with what might be America’s last, best collective industry.
+
+
+And should Travis Kelce get down on one knee before Swift after the game — something that, like everything else in the Super Bowl, you can place a bet on — then through one prism, it’ll be a classic American story: the football captain and the homecoming queen living happily ever after.
+
+
+Viewed another way, it’ll still be another kind of classic American story: a corporate mega-merger that ends up with the big getting bigger.
+
Why Ukraine’s new top general is known as the “butcher” -
+
+
+
+Ukrainian President Volodymyr Zelenskyy attends a flag-hoisting ceremony in Izium after the Ukrainian forces took control of the city from the Russian forces in Kharkiv, Ukraine, on September 14, 2022. | Metin AktaÅ/Anadolu Agency via Getty Images
+
+
+
+A major military shake-up comes amid a fight in Congress over US funding for Ukraine.
+
+
+Ukraine’s military underwent a major leadership shake-up this week, a decision that President Volodymyr Zelenskyy framed as a reset for the country’s stalled war effort.
+
+
+On Thursday, Zelenskyy announced that he’d be replacing General Valery Zaluzhny as the military’s leader after the two clashed over whether to back a new conscription push as well as how to frame the war’s lack of progress to the public. In his stead, Zelenskyy has named Colonel-General Oleksandr Syrskyi, the head of the military’s ground forces, as the country’s new commander-in-chief. Syrskyi is known for being a seasoned military leader who’s also been criticized for a willingness to put his troops at risk, so much so that some soldiers colloquially refer to him as the “butcher.”
+
+
+This change comes at a crucial time for Ukraine’s war with Russia, which is nearly in its third year. While Ukraine had a string of early successes, including surprising the world by holding off an onslaught against Kyiv and retaking some territory in the summer of that year, its progress has slowed due to Russia’s entrenchment, dwindling funds, and limited manpower and weaponry. Currently, Ukraine is still waiting on the US Congress to approve another $60 billion in military aid — a critical infusion of funding — and conservatives have balked at doing so.
+
+
+All those issues mean replacing the country’s top general is unlikely to result in significant changes to Ukraine’s existing trajectory, and there may be elements of Syrskyi’s demonstrated style so far that worsen soldiers’ morale.
+
+
+Zelenskyy described the decision to switch commanders-in-chief at this point as fueled, in part, by a need for “effective changes in the basis of our defense,” so Ukraine can be successful moving forward. Beyond Zelenskyy’s strategic disagreements with Zaluzhny, some experts believe the president saw the general, who was quite popular among Ukrainians, as a political threat.
+
+
+“During wartime, you want the president of the country and the top military chief to be working hand in glove and that did not seem to have been the case between the two of them,” Charles Kupchan, a senior fellow at the Council on Foreign Relations, told Vox.
+
+
+The shift to Syrskyi means Ukraine now has a military commander who is much more closely aligned with Zelenskyy, including any goals he has of launching more high-profile assaults this coming year.
+
+
+Who is Syrskyi?
+
+
+Oleksandr Syrskyi is an experienced Ukrainian military leader who has led the country’s ground troops since 2019. In some ways, he’s seen by political experts as the logical Zaluzhny replacement given his extensive military expertise. He oversaw Ukraine’s success in Kyiv as well as a victory the country achieved in a 2022 counteroffensive in Kharkiv.
+
+
+At the same time, his pick has been controversial among soldiers because of how he handled a battle in the Ukrainian city of Bakhmut, which lasted for more than nine months. That battle resulted in thousands of casualties and Russia ultimately taking the city. Syrskyi’s decision to stay in Bakhmut was scrutinized given how many people Ukraine lost and questions over whether the city was strategically important enough to justify those casualties.
+
+
+Syrskyi reportedly argued that the losses were acceptable because Ukraine killed far more Russians in the battle for Bakhmut than it lost. Many of his troops disagreed, however, and his strategy has since led some soldiers to give him some less-than-flattering nicknames.
+
+If Zaluzhny was seen as disagreeing with Zelenskyy on strategic goals, Syrskyi is viewed as someone who is more closely aligned with him, in a way that some soldiers are wary of. As one major in Eastern Ukraine told the Post, Zelenskyy is known for wanting splashier wins, which could come at soldiers’ expense. Given Syrskyi’s record and alignment with Zelenskyy, that major feared he’d be less likely to try to fight the president on these ideas than his predecessor — a worry shared by others in the military.
+
+
+Syrskyi seemed to try to acknowledge soldiers’ morale in his first statements. In a Telegram post after his appointment, he said he is focused on ensuring that forces at the front lines will have a chance at “restoration” and that he is committed to investing in technologies like drones. “New tasks are on the agenda,” he wrote.
+
+
+Why is Zelenskyy shaking things up now?
+
+
+Zaluzhny has been part of Ukraine’s military operation since Russia invaded Ukraine in February 2022. Nicknamed the “Iron General,” he’s widely respected in Ukrainian society.
+
+
+As Ukraine’s progress in the war has stalled, US military leadership has criticized Ukrainian tactics, with some indicating that the Ukrainians were too risk-averse and had failed to utilize complex approaches, according to the Financial Times. Ukrainian officials and other experts have pushed back against that characterization. For example, Michael Kofman, director of the Russia Studies Program at CNA, and Rob Lee, senior fellow in the Foreign Policy Research Institute’s Eurasia Program, argued in a report for War on the Rocks that although insufficient tactical assistance — notably airpower — is part of Ukraine’s problem, an insufficient Western understanding of the battlefield hasn’t helped either.
+
+
+Ukraine had hoped to turn the tide of the war in a much-touted June offensive. Instead, the battlefield returned to a state of attrition, with Ukraine “focused on reconstitution and digging in to defend against continued Russian attacks” amid diminishing Western reserves, according to Kofman, Lee, and Dara Massicot, senior fellow in the Russia and Eurasia Program at the Carnegie Endowment for International Peace.
+
+
+In December, Russia and Ukraine traded drone attacks, with Russia targeting critical and civilian infrastructure as well as Ukraine’s defense industrial facilities in an attempt to degrade Ukraine’s ability to arm itself. Ukraine has tried to expand its defense industrial base amid wavering support from the international community, and especially its main military supporter, the US.
+
+
+Those setbacks have left Ukraine with few options in an existential battle in which Russia is refusing to back down.
+
+
+Mykhailo Podolyak, a Ukrainian politician and adviser to Zelenskyy’s office, wrote on his Telegram channel Thursday that the personnel change was “due to the need to review the tactics of actions” in the June offensive, which “did not fully ensure the proper result.” Podolyak also pointed to “the need to prevent stagnation on the front line, which negatively affects public sentiment, to find new functional and high-tech solutions” on the battlefield.
+
+
+Beyond military issues, political concerns are also part of the shake-up. The rift between Zelenskyy and Zaluzhny is the most significant political conflict yet during the nearly two-year war. Overall, Ukraine’s political class and population have presented a united front in the face of Russia’s attacks, but some cracks are starting to show.
+
+
+For example, 2024 presidential elections have been postponed due to the war; though “an overwhelming majority of Ukrainians understand that it doesn’t make sense to have elections right now,” Andrew D’Anieri, a resident fellow at the Atlantic Council’s Eurasia Center, said, not everyone agrees. There is particular tension about the delay between the president’s office and Ukraine’s mayors, particularly Vitali Klitschko of Kyiv.
+
+
+The disagreement between Zelenskyy and the military leadership “is very frustrating for the government,” Simon Schlegel, senior Ukraine analyst at the International Crisis Group. “The main strength of [the Ukrainian] government has been its strong communication both with international partners, whose support is so important, but also with its own population. And losing a grip on that, I think that was one of the main drivers behind this decision.”
+
+
+Essentially, Zaluzhny’s departure is meant to ensure unity is maintained — not just between politicians and the populace but among the top levels of Zelenskyy’s administration.
+
+Amid the drone proliferation on the battlefield, Zaluzhny publicly called for more investment into advanced technology, as well as for more aggressive legislation around mobilization that would have expanded conscription to offset Ukraine’s battlefield losses and Ukrainian troops’ overextension.
+
+
+Zelenskyy has tried to maintain an optimistic outlook about the war, both for the sake of Ukrainians and to garner support from the international community, the Associated Press reported in late January, while Zaluzhny took a darker view of the conflict. The two also disagreed about mobilization tactics — and that disjunction, according to Schlegel, may not improve under Syrskyi’s leadership.
+
+
+“Zelenskyy has always underlined that he doesn’t want to sacrifice soldiers if he can save them, and I think that was one of the main sources of tension between Zelenskyy and Zaluzhny,” he told Vox. “It’s probably also going to be a source of tension between Zelenskyy and Syrskyi — that army leadership wants more resources and more human resources, and the government has only so much.”
+
+
+In 2024, Ukraine’s tactics will largely be defensive, Schlegel said. On the battlefield, this will consist of building fortified defensive positions — like underground bunkers and tunnels, as Kofman, Lee, and Massicot write — while building up tactical capacity to make the most of remaining Western weaponry, ensuring greater mobilization of troops, and improving and scaling up training programs with the support of Western forces.
+
+
+Significant wins will be difficult to accomplish without sustained Western support. The European Union recently approved a 50 billion euro support package for Ukraine, but that won’t be enough to make up the difference should Republicans in Congress continue to hold up military aid to Ukraine or refuse to supply it altogether.
+
+
+
From The Hindu: Sports
+
+
Field Of Dreams, and Endurance catch the eye -
+
Spinners will play key role in upcoming T20 WC: Maharaj - South Africa’s Keshav Maharaj believes that the T20 format will help in the growth and development of cricket
+
Ind vs Eng Tests | Kohli out for remainder of series; pacer Akash Deep gets maiden call-up - The only new face in the 17-man squad is Bengal speedster Akash Deep, who has been rewarded for his consistent show in first-class cricket and in recent India A vs England Lions Test series.
+
Morning Digest | Bihar BJP MLAs shifted to Bodh Gaya ahead of floor test; five dead in violence after demolition of ‘illegal’ structures in Uttarakhand’s Haldwani, and more - Here is a select list of stories to start the day
+
Wrestling trials for Olympic qualifiers and Asian wrestling championships postponed - The trials for men (freestyle and Greco-Roman) will be held at Sonepat, while Patiala will host the women’s trials
+
+
From The Hindu: National News
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+
Injured leopard dies in Tirupati Zoo -
+
Parliamentary proceedings | Five years of 17th Lok Sabha was of reform, perform, transform: PM Modi - Modi said that during the last five years, game-changing reforms were made in which a strong foundation of a 21st century India can be seen
+
‘Anti-farmer’ Land Reforms Act, 2020, brought in by BJP will be amended, Siddaramaiah assures farmers - “Raitha Sangha leader Nanjundaswamy’s struggle is a political inspiration for me,” the Karnataka Chief Minister says
+
Telangana Govt to order enquiry into construction of Secretariat and Martyrs Memorial -
+
South-bound private buses in Chennai can pick up and drop passengers from in and around Koyambedu CMBT: Madras High Court - The Court however has ordered that these garages could not be listed as official pick-up or drop-off points; she said this interim measure could continue until all issues pertaining to bus companies completely shifting to the new Kilambakkam terminus were ironed out
+
+
From BBC: Europe
+
+
Seven killed after Russia drone hits Kharkiv petrol station - Three children are among the dead after the strike caused a fire that engulfed homes.
+
The Ukrainians ‘disappearing’ in Russia’s prisons - Finding Ukrainian civilians in Russian captivity is hard - and there is no formal way to secure their release.
+
From Poland to Spain, farmers ramp up protests - Europe’s farmers block roads in several countries complaining about EU measures and rising prices.
+
Putin takes charge as Carlson gives free rein to Kremlin - The Russian leader was given the opportunity to expound familiar grievances unchallenged.
+
Spain’s LGBT matador: ‘More will come out because of me’ - Mario Alcalde is said to be Spain’s first openly LGBT matador, after revealing he is pansexual.
+
+
From Ars Technica
+
+
Building durable basketball players from the ground up (way up) - Can new scientific insights help the newest crop of NBA stars stay healthy? - link
+
Fake grass, real injuries? Dissecting the NFL’s artificial turf debate - Artificial turf has its advantages, but the NFLPA wants it banished from the NFL. - link
+
Canada declares Flipper Zero public enemy No. 1 in car-theft crackdown - How do you ban a device built with open source hardware and software anyway? - link
+
A sleuthing enthusiast says he found the US military’s X-37B spaceplane - Officials didn’t disclose details about the X-37B’s orbit after its December launch. - link
+
Big Pharma spends billions more on executives and stockholders than on R&D - Senate report points to greed and “patent thickets” as key reasons for high prices. - link
+
+
From Jokes Subreddit
+
+
What’s the difference between a Nirvana concert and a pirate orgy? -
+
+
+Either you come as you are, or you ARRR as you cum
+
A chicken farmer went to a local bar, sat next to a woman and ordered a glass of champagne. -
+
+
+The woman saw this and said, “How about that? I just ordered a glass of champagne, too!”
+
+
+“What a coincidence!” the farmer said, “This is a special day for me, I am celebrating.”
+
+
+“This is a special day for me too, I am also celebrating,” said the woman.
+
+
+“What a coincidence!” said the farmer.
+
+
+As they clinked glasses, he asked, “What are you celebrating?”
+
+
+“My husband and I have been trying to have a child for years, and today my gynecologist told me that I am pregnant!” she said.
+
+
+“What a coincidence!” said the man. “I’m a chicken farmer and for years all of my hens were infertile, but today they are all laying fertilized eggs.”
+
+
+“That’s great!” said the woman, “How did your hens become fertile?”
+
+
+“I used a different cock!” he replied.
+
+
+The woman smiled, clinked her glass against the farmer’s and said, “what a coincidence!”
+
+/cdn.vox-cdn.com/uploads/chorus_asset/file/25276794/IMG_5769.jpeg)
Benji Jones on assignment for Vox
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Zoccolan/AFP via Getty Images
+/cdn.vox-cdn.com/uploads/chorus_asset/file/25274939/GettyImages_907139116.jpg)
Sean Gallup/Getty Images
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