Identification of key residues in MERS-CoV and SARS-CoV-2 main proteases for resistance against clinically applied inhibitors nirmatrelvir and ensitrelvir -
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+The Middle East Respiratory Syndrome Coronavirus (MERS-CoV) is an epidemic, zoonotically emerging pathogen initially reported in Saudi Arabia in 2012. MERS-CoV has the potential to mutate or recombine with other coronaviruses, thus acquiring the ability to efficiently spread among humans and become pandemic. Its high mortality rate of up to 35 % and the absence of effective targeted therapies call for the development of antiviral drugs for this pathogen. Since the beginning of the SARS-CoV-2 pandemic, extensive research has focused on identifying protease inhibitors for the treatment of SARS-CoV-2. Our intention was therefore to assess whether these protease inhibitors are viable options for combating MERS-CoV. To that end, we used previously established protease assays to quantify inhibition of the SARS-CoV-2 and MERS-CoV main proteases. Furthermore, we selected MERS-CoV-Mpro mutants resistant against nirmatrelvir, the most effective inhibitor of this protease, with a safe, surrogate virus-based system, and suggest putative resistance mechanisms. Notably, nirmatrelvir demonstrated effectiveness against various viral proteases, illustrating its potential as a broad-spectrum coronavirus inhibitor. To adress the inherent resistance of MERS-CoV-Mpro to ensitrelvir, we applied directed mutagenesis to a key ensitrelvir-interacting residue and provided structural models.
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Sex-Specific Systemic Inflammatory Responses in Mice Infected with a SARS-CoV-2-like Virus and Femur Fracture -
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+This study investigates the systemic inflammatory response in mice infected with a murine coronavirus (MHV), which shares a common genus with SARS-CoV-2, and sustaining a fracture. The study reveals that the combined inflammatory incidents of MHV infection and fracture disrupt the systemic immune response in both female and male mice, likely leading to immune dysregulation, altered cell recruitment, and disruption of the typical inflammatory cascade. Notably, the study uncovers sex-specific responses that modulate circulating immune factors. Females exhibit elevated levels of inflammatory factors, whereas males demonstrate a diminished response. This divergence is mirrored in cell populations, suggesting that the quantity of immune factors released may contribute to these discrepancies. The findings suggest that an overproduction of proinflammatory cytokines may induce a dysregulated immune response, contributing to the observed poorer prognosis in comorbid cases. These insights could pave the way for therapeutic advancements and treatment strategies aimed at reducing mortality rates in COVID-19 patients with fractures.
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In field use of water samples for genomic surveillance of ISKNV infecting tilapia fish in Lake Volta, Ghana -
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+Viral outbreaks are a constant threat to aquaculture, limiting production for better global food security. A lack of diagnostic testing and monitoring in resource-limited areas hinders the capacity to respond rapidly to disease outbreaks and to prevent viral pathogens becoming endemic in fisheries productive waters. Recent developments in diagnostic testing for emerging viruses, however, offers a solution for rapid in situ monitoring of viral outbreaks. Genomic epidemiology has furthermore proven highly effective in detecting viral mutations involved in pathogenesis and assisting in resolving chains of transmission. Here, we demonstrate the application of an in-field epidemiological tool kit to track viral outbreaks in aquaculture on farms with reduced access to diagnostic labs, and with non-destructive sampling. Inspired by the "lab in a suitcase" approach used for genomic surveillance of human viral pathogens and wastewater monitoring of COVID19, we evaluated the feasibility of real-time genome sequencing surveillance of the fish pathogen, Infectious spleen and kidney necrosis virus (ISKNV) in Lake Volta. Viral fractions from water samples collected from cages holding Nile tilapia (Oreochromis niloticus) with suspected ongoing ISKNV infections were concentrated and used as a template for whole genome sequencing, using a previously developed tiled PCR method for ISKNV. Mutations in ISKNV in samples collected from the water surrounding the cages matched those collected from infected caged fish, illustrating that water samples can be used for detecting predominant ISKNV variants in an ongoing outbreak. This approach allows for the detection of ISKNV and tracking of the dynamics of variant frequencies, and may thus assist in guiding control measures for the rapid isolation and quarantine of infected farms and facilities.
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+The outbreak of COVID-19 exposed the inadequacy of our technical tools for home health surveillance, and recent studies have shown the potential of smartphones as a universal optical microscopic imaging platform for such applications. However, most of them use laboratory-grade optomechanical components and transmitted illuminations to ensure focus tuning capability and imaging quality, which keeps the cost of the equipment high. Here we propose an ultra-low-cost solution for smartphone microscopy. To realize focus tunability, we designed a seesaw-like structure capable of converting large displacements on one side into small displacements on the other (reduced to [~]9.1%), which leverages the intrinsic flexibility of 3D printing materials. We achieved a focus-tuning accuracy of [~] 5 m, which is 40 times higher than the machining accuracy of the 3D-printed lens holder itself. For microscopic imaging, we use an off-the-shelf smartphone camera lens as the objective and the built-in flashlight as the illumination. To compensate for the resulting image quality degradation, we developed a learning-based image enhancement method. We use the CycleGAN architecture to establish the mapping from smartphone microscope images to benchtop microscope images without pairing. We verified the imaging performance on different biomedical samples. Except for the smartphone, we kept the full costs of the device under 4 USD. We think these efforts to lower the costs of smartphone microscopes will benefit their applications in various scenarios, such as point-of-care testing, on-site diagnosis, and home health surveillance.
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Social isolation, mental health, and use of digital interventions in youth during the COVID-19 pandemic: a nationally representative survey -
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+Summary Background: Public health measures to curb SARS-CoV-2 transmission rates may have negative psychosocial consequences in youth. Digital interventions may help to mitigate these effects. We investigated the associations between social isolation, cognitive preoccupation, worries, and anxiety, objective social risk indicators, psychological distress as well as use of, and attitude towards, mobile health (mHealth) interventions in youth during the COVID-19 pandemic. Methods: Data were collected as part of the ‘Mental Health And Innovation During COVID-19 Survey’ —a cross-sectional panel study including a representative sample of individuals aged 16 to 25 years (N=666; Mage 21·3) (assessment period: 07.05.-16.05.2020). Outcomes: Overall, 38% of youth met criteria for moderate psychological distress and 30% felt ‘often’ or ‘very often’ socially isolated, even after most restrictive infection control measures had been lifted. Social isolation, COVID-19-related worries and anxiety, and objective risk indicators were associated with psychological distress, with evidence of dose-response relationships for some of these associations. For instance, psychological distress was progressively more likely to occur as levels of social isolation increased (reporting ‘never’ as reference group: ‘occasionally’: adjusted odds ratio [aOR] 9·1, 95% confidence interval [CI] 4·3 – 19·1, p<0·001; ‘often’: aOR 22·2, CI 9·8 – 50·2, p<0·001;’very often’: aOR 42·3, CI 14·1 – 126·8, p<0·001). There was evidence that psychological distress, worries, and anxiety were associated with a positive attitude towards using digital interventions, whereas high levels of psychological distress, worries, and anxiety were associated with actual use. Interpretation: Public health measures during pandemics may be associated with poor mental health in youth. Digital interventions may help mitigate the negative psychosocial impact given there is an objective need and subjective demand.
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Failure to protect: COVID infection control policy privileges poor-quality evidence -
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+The failure to immediately recognize the urgent need to control airborne spread of COVID-19, including use of adequate personal protective equipment for an airborne pathogen, represents a major medical error that cost “an enormous number of lives”. Made in the face of significant scientific evidence and a clear requirement to adhere to a precautionary approach, it has still not been fully remedied. To understand the substantial, ongoing gap between science and policy, we carried out an in-depth investigation of an illustrative publication authored by prominent authorities in the fields of Public Health and Infection Prevention and Control, describing a trial of medical masks and N95 respirators for the prevention of COVID-19. Although it was portrayed as among the highest quality evidence available within the Evidence-Based Medicine decision-making paradigm, we found this work to be deeply flawed to the extent that it does not meet basic standards of scientific rigour. Extensive prior work in the respiratory protection field – sufficiently well-established to be incorporated into both national standards and specific recommendations made to address infection control failures in SARS – was ignored. Randomization was compromised, with a statistically significant correlation between female sex and allocation to the higher-risk arm of the trial. Significant conflicts of interest in favour of the reported finding that medical masks are noninferior to N95 respirators in preventing COVID-19 transmission were not disclosed. Prespecified analyses were omitted, and the finding of noninferiority is entirely a product of inappropriate alterations to the trial that were not prospectively registered. Despite numerous flaws biasing the outcome towards a finding of noninferiority, re-analysis using the prespecified approach and noninferiority criterion unambiguously reverses the reported outcome of the trial.
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The Last Confirmed Case is Not the Last Infection and Catastrophic Outbreaks do Not Require Transmission -
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+Efforts to prevent transmission of the infectious agent that causes an infectious disease in its capacity as a pathogen are praised and victory is declared after the last case of the expected outcomes of the event in which this disease occurs is confirmed. After all, it is assumed that such expected outcomes of the event in which the pathogen causes the infectious disease are manifestations of this disease and therefore that the last confirmed case in which such outcomes are observed is the last case of infection. But the results obtained while forging the path to immunological concepts which have eluded us since the birth of the repeatedly proven germ theory with the method by which Einstein approximated astronomical reality conceptually while developing General Relativity reveal that outcomes of the event in which the pathogen causes the infectious disease are not manifestations of this disease but rather consequences of the comanifestation of different diseases in the spectrum of the infectious disease. These results enable us to account for the differences between such outcomes which, for instance, in patients with COVID-19 that the current theory of infectious disease pathogenesis expects to produce outcomes that affect the upper respiratory disease, include unexpected conditions such as the chronic ones seen in Long COVID patients and in patients with mpox, which this theory logically deduced to be a skin-affecting disease, include deadly conditions like encephalitis with the consequence that outcomes with such deadly conditions are attributed to underlying conditions even after Spain’s health ministry reported deaths from such outcomes in healthy individuals. And the consequence of the same results is that the last cases of expected outcomes such as those that affect the skin of individuals who are infected with the mpox virus are not the last cases of infection but rather the last cases in which such outcomes appear as the sterile causes of the non-infectious diseases that co-manifest with the infectious disease for the emergence of such outcomes disappear from the population in which undetected spread of the infectious agent occurred long before the widespread appearance of such expected outcomes that called attention to this pathogen or an earlier form of the pathogen, such as the smallpox virus, which is assumed to have been eradicated. It follows in the reality which was visualized to obtain these results that even as the disappearance of such outcomes is being celebrated, the sterile causes of non-infectious diseases which co-manifest with the infectious disease for the emergence of unexpected deadly outcomes, such as those with encephalitis and toxic shock, may be appearing in the population which is already harboring the pathogen silently. And without exciting cause or warning, such deadly outcomes will become widespread in our populations and will decimate them if the only treatments available at the time are still those that reduce viral replication which are unable to bring about the remission of such outcomes. Instead of celebrating the disappearance of cases when the sterile causes of the non-infectious diseases that co-manifest with mpox for the emergence of those expected skin-affecting outcomes disappear, we ought to quickly elucidate the conditions that permit the immunological mechanisms of infection and vaccination to bring about uneventful exposure to such sterile causes even after deadly outcomes of such events have already appeared as achieved, in some cases, by the vaccines of William Coley and Julius Wagner-Jauregg even at a time when nothing was known about the nature of such immunological mechanisms and the remission that followed therapeutic infection in such cases was attributed to fever.
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Genome-wide Bioinformatics Analysis of Human Protease Capacity for Proteolytic Cleavage of the SARS-CoV-2 Spike Glycoprotein -
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+The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) primarily enters the cell by binding the virus’s spike (S) glycoprotein to the angiotensin-converting enzyme 2 (ACE2) receptor on the cell surface, followed by proteolytic cleavage by host proteases. Studies have identified furin and TMPRSS2 proteases in priming and triggering cleavages of the S glycoprotein, converting it into a fusion-competent form and initiating membrane fusion, respectively. Alternatively, SARS-CoV-2 can enter the cell through the endocytic pathway, where activation is triggered by lysosomal cathepsin L. However, other proteases are also suspected to be involved in both entry routes. In this study, we conducted a genome-wide bioinformatics analysis to explore the capacity of human proteases in hydrolyzing peptide bonds of the S glycoprotein. Predictive models of sequence specificity for 169 human proteases were constructed and applied to the S glycoprotein together with the method for predicting structural susceptibility to proteolysis of protein regions. After validating our approach on extensively studied S2’ and S1/S2 cleavage sites, we applied our method to each peptide bond of the S glycoprotein across all 169 proteases. Our results indicate that various members of the PCSK, TTSP, and kallikrein families, as well as specific coagulation factors, are capable of cleaving S2’ or S1/S2 sites. We have also identified a potential cleavage site of cathepsin L at the K790 position within the S2’ loop. Structural analysis suggests that cleavage of this site induces conformational changes similar to the cleavage at the R815 (S2’) position, leading to the exposure of the fusion peptide and subsequent fusion with the membrane. Other potential cleavage sites and the influence of mutations in common SARS-CoV-2 variants on proteolytic efficiency are discussed.
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Murine Alveolar Macrophages Rapidly Accumulate Intranasally Administered SARS-CoV-2 Spike Protein leading to Neutrophil Recruitment and Damage -
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+The trimeric SARS-CoV-2 Spike protein mediates viral attachment facilitating cell entry. Most COVID-19 vaccines direct mammalian cells to express the Spike protein or deliver it directly via inoculation to engender a protective immune response. The trafficking and cellular tropism of the Spike protein in vivo and its impact on immune cells remains incompletely elucidated. In this study we inoculated mice intranasally, intravenously, and subcutaneously with fluorescently labeled recombinant SARS-CoV-2 Spike protein. Using flow cytometry and imaging techniques we analyzed its localization, immune cell tropism, and acute functional impact. Intranasal administration led to rapid lung alveolar macrophage uptake, pulmonary vascular leakage, and neutrophil recruitment and damage. When injected near the inguinal lymph node medullary, but not subcapsular macrophages, captured the protein, while scrotal injection recruited and fragmented neutrophils. Wide-spread endothelial and liver Kupffer cell uptake followed intravenous administration. Human peripheral blood cells B cells, neutrophils, monocytes, and myeloid dendritic cells all efficiently bound Spike protein. Exposure to the Spike protein enhanced neutrophil NETosis and augmented human macrophage TNF- and IL-6 production. Human and murine immune cells employed C-type lectin receptors and Siglecs to help capture the Spike protein. This study highlights the potential toxicity of the SARS-CoV-2 Spike protein for mammalian cells and illustrates the central role for alveolar macrophage in pathogenic protein uptake.
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Gut microbiome remains stable following COVID-19 vaccination in healthy and immuno-compromised individuals -
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+The bidirectional interaction between the immune system and the gut microbiota is a key contributor to various host physiological functions. Immune-associated diseases such as cancer and autoimmunity, as well as the efficacy of immunomodulatory therapies, have been linked to microbiome variation. While COVID-19 infection has been shown to cause microbial dysbiosis, it remains understudied whether the inflammatory response associated with vaccination also impacts the microbiota. Here, we investigate the temporal impact of COVID-19 vaccination on the gut microbiome in healthy and immuno-compromised individuals; the latter included patients with primary immunodeficiency and cancer patients on immunomodulating therapies. We find that the gut microbiome remained remarkably stable post-vaccination irrespective of diverse immune status, vaccine response, and microbial composition spanned by the cohort. The stability is evident at all evaluated levels including diversity, phylum, species, and functional capacity. Our results indicate the resilience of the gut microbiome to host immune changes triggered by COVID-19 vaccination and suggest minimal, if any, impact on microbiome-mediated processes. These findings encourage vaccine acceptance, particularly when contrasted with the significant microbiome shifts observed during COVID-19 infection.
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Don’t Say It’s Over: The Perceived Epidemic Stage and Covid Preventive Behaviour -
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+The risks for people during the epidemic are evolving. For COVID-19 pandemic one important feature was its multiwave pattern, where, within each wave, the pandemic dynamic could be described as the curve. This study aimed to explore how people’s perceptions of such a pandemic process associates with the risk perceptions and the preventive behaviour. A sample of 1,343 university students in the beginning of COVID-19 pandemic have assessed the pandemic stage, perceived risks, mental health and trust to different bodies in regard to pandemic. They also reported their involvement in the COVID topic and a wide range of implemented behaviour. The study participants differed in their perception of the pandemic stage despite being in the same environment. The belief that the curve pick is left behind was associated with the less perceived risk and decrease in preventive behaviour implementation, while there was no difference in the perception of risks or behaviour between belief in living the period in the epidemic peak or the beginning of the wave. The lack of COVID involvement, distrust to authorities and official COVID information were associated with the less perceived risk and preventive behaviour. Mental health characteristics were significantly associated with the social preventive behaviours - the higher depression level was the predictor of the decreasing of communication with other people while the anxiety was the predictor of more risky behaviour due to increase in face-to-face communication. Overall the perception that the epidemic wave is on its final stage could be an independent predictor of more risky behaviour. Communication of the epidemic dynamic should be provided with extreme caution.
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Memory B cells dominate the early antibody-secreting cell response to SARS-CoV-2 mRNA vaccination in naive individuals independently of their antibody affinity -
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+Memory B cells (MBCs) formed over the individual's lifetime constitute nearly half of the adult peripheral blood B cell repertoire in humans. To assess their response to novel antigens, we tracked the origin and followed the differentiation paths of MBCs in the early anti-S response to mRNA vaccination in SARS-CoV-2-naïve individuals on single-cell and monoclonal antibody level. Newly generated and pre-existing MBCs differed in their differentiation paths despite similar levels of SARS-CoV-2 and common corona virus S-reactivity. Pre-existing highly mutated MBCs showed no signs of germinal center re-entry and rapidly developed into mature antibody secreting cells (ASCs). In contrast, newly generated MBCs derived from naïve precursors showed strong signs of antibody affinity maturation before differentiating into ASCs. Thus, although pre-existing human MBCs have an intrinsic propensity to differentiate into ASCs, the quality of the anti-S antibody and MBC response improved through the clonal selection and affinity maturation of naïve precursors.
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Design of SARS-CoV-2 papain-like protease inhibitor with antiviral efficacy in a mouse model -
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+The emergence of SARS-CoV-2 variants and drug-resistant mutants calls for additional oral antivirals. The SARS-CoV-2 papain-like protease (PLpro) is a promising but challenging drug target. In this study, we designed and synthesized 85 noncovalent PLpro inhibitors that bind to the newly discovered Val70Ub site and the known BL2 groove pocket. Potent compounds inhibited PLpro with inhibitory constant Ki values from 13.2 to 88.2 nM. The co-crystal structures of PLpro with eight leads revealed their interaction modes. The in vivo lead Jun12682 inhibited SARS-CoV-2 and its variants, including nirmatrelvir-resistant strains with EC50 from 0.44 to 2.02 microM. Oral treatment with Jun12682 significantly improved survival and reduced lung viral loads and lesions in a SARS-CoV-2 infection mouse model, suggesting PLpro inhibitors are promising oral SARS-CoV-2 antiviral candidates.
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Substrate recognition and selectivity in SARS-CoV-2 main protease: Unveiling the role of subsite interactions through dynamical nonequilibrium molecular dynamics simulations -
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+The main protease (Mpro) of the SARS-CoV-2 coronavirus employs a cysteine-histidine dyad in its active site to catalyse hydrolysis of the viral polyproteins. It is well established that binding of the substrate P1-Gln in the S1 subsite of Mpro active site is crucial for catalysis and this interaction has been employed to inform inhibitor design; however, how Mpro dynamically recognises and responds to substrate binding remains difficult to probe by experimental methods. We thus employed the dynamical nonequilibrium molecular dynamics (D-NEMD) approach to probe the response of Mpro to systematic substrate variations. The results emphasise the importance of P1-Gln for initiating a productive enzymatic reaction. Specifically, substituting P1-Gln with alanine disrupts the conformations of the Cys145 and His41 dyad, causing Cys145 to transition from the productive gauche conformation to the non-productive trans conformation. Importantly, our findings indicate that Mpro exhibits dynamic responses to substrate binding and likely to substrate-mimicking inhibitors within each of the S4-S2' subsites. The results inform on the substrate selectivity requirements and shed light on the observed variations in hydrolytic efficiencies of Mpro towards different substrates. Some interactions between substrate residues and enzyme subsites involve more induced fit than others, implying that differences in functional group flexibility may optimise the binding of a substrate or inhibitor in a particular subsite.
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High-throughput ML-guided design of diverse single-domain antibodies against SARS-CoV-2 -
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+Treating rapidly evolving pathogenic diseases such as COVID-19 requires a therapeutic approach that accommodates the emergence of viral variants over time. Our machine learning (ML)-guided sequence design platform combines high-throughput experiments with ML to generate highly diverse single-domain antibodies (VHHs) that bind and neutralize SARS-CoV-1 and SARS-CoV-2. Crucially, the model, trained using binding data against early SARS-CoV variants, accurately captures the relationship between VHH sequence and binding activity across a broad swathe of sequence space. We discover ML-designed VHHs that exhibit considerable cross-reactivity and successfully neutralize targets not seen during training, including the Delta and Omicron BA.1 variants of SARS-CoV-2. Our ML-designed VHHs include thousands of variants 4-15 mutations from the parent sequence with significantly improved activity, demonstrating that ML-guided sequence design can successfully navigate vast regions of sequence space to unlock and future-proof potential therapeutics against rapidly evolving pathogens.
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Effect of Metformin in Reducing Fatigue in Long COVID in Adolescents - Conditions: Long COVID Interventions: Drug: Metformin; Other: Placebo Sponsors: Trust for Vaccines and Immunization, Pakistan Not yet recruiting
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A Randomized Trial Evaluating a mRNA VLP Vaccine’s Immunogenicity and Safety for COVID-19 - Conditions: COVID-19; SARS-CoV-2 Infection Interventions: Biological: AZD9838; Biological: Licensed mRNA vaccine Sponsors: AstraZeneca Not yet recruiting
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“The Effect of Aerobic Exercise and Strength Training on Physical Activity Level, Quality of Life and Anxiety-Stress Disorder in Young Adults With and Without Covid-19” - Conditions: COVID-19 Interventions: Behavioral: Aerobic Exercise and Strength Training Sponsors: Pamukkale University Active, not recruiting
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Safety Study of SLV213 for the Treatment of COVID-19. - Conditions: COVID-19 Interventions: Other: Placebo for SLV213; Drug: SLV213 Sponsors: National Institute of Allergy and Infectious Diseases (NIAID) Not yet recruiting
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Vale+Tú Salud: Corner-Based Randomized Trial to Test a Latino Day Laborer Program Adapted to Prevent COVID-19 - Conditions: COVID-19 Interventions: Behavioral: COVID-19 Group Problem Solving; Behavioral: Standard of Care; Behavioral: Booster session Sponsors: The University of Texas Health Science Center, Houston; National Institute on Minority Health and Health Disparities (NIMHD) Recruiting
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Collection of Additional Biological Samples From Potentially COVID-19 Patients for Monitoring of Biological Parameters Carried Out as Part of the Routine - Conditions: SARS CoV 2 Infection Interventions: Diagnostic Test: RIPH2 Sponsors: CerbaXpert Not yet recruiting
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Promoting Engagement and COVID-19 Testing for Health - Conditions: COVID-19 Interventions: Behavioral: COVID-19 Test Reporting; Behavioral: Personalized Nudges via Text Messaging; Behavioral: Non-personalized Nudges via Text Messaging Sponsors: Emory University; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); Morehouse School of Medicine; Georgia Institute of Technology Not yet recruiting
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Mitigating Mental and Social Health Outcomes of COVID-19: A Counseling Approach - Conditions: Social Determinants of Health; Mental Health Issue; COVID-19 Interventions: Behavioral: Individual counseling; Behavioral: Group counseling; Other: Resources Sponsors: Idaho State University Not yet recruiting
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Development and Qualification of Methods for Analyzing the Mucosal Immune Response to COVID-19 - Conditions: Certain Disorders Involving the Immune Mechanism Interventions: Biological: Sampling; Biological: PCR (polymerase chain reaction) SARS-CoV-2 Sponsors: University Hospital, Tours Not yet recruiting
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Water-based Activity to Enhance Recovery in Long COVID - Conditions: Long COVID Interventions: Behavioral: WATER+CT; Behavioral: Usual Care Sponsors: VA Office of Research and Development Not yet recruiting
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Performance Evaluation of the Lucira COVID-19 & Flu Test - Conditions: COVID-19; Influenza Interventions: Device: Lucira COVID-19 & Flu Test Sponsors: Lucira Health Inc Completed
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Efficacy of Two Therapeutic Exercise Modalities for Patients With Persistent COVID - Conditions: Persistent COVID-19 Interventions: Other: exercise programe Sponsors: Facultat de ciencies de la Salut Universitat Ramon Llull Recruiting
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From PubMed
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Molecular mechanisms of dexamethasone actions in COVID-19: Ion channels and airway surface liquid dynamics - The COVID-19 pandemic has been a global health crisis of unprecedented magnitude. In the battle against the SARS-CoV-2 coronavirus, dexamethasone, a widely used corticosteroid with potent anti-inflammatory properties, has emerged as a promising therapy in the fight against severe COVID-19. Dexamethasone is a synthetic glucocorticoid that exerts its therapeutic effects by suppressing the immune system and reducing inflammation. In the context of COVID-19, the severe form of the disease is often…
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Pilot Study of High-Dose Pemetrexed in Patients with Progressive Chordoma - CONCLUSIONS: High-dose pemetrexed appears tolerable and shows objective antitumor activity in patients with chordoma. Phase II studies of high-dose pemetrexed are warranted.
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Antiviral Effects of Pyrroloquinoline Quinone through Redox Catalysis To Prevent Coronavirus Infection - The global spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) coronavirus disease (COVID-19) is ongoing. Therefore, effective prevention of virus infection is required. Pyrroloquinoline quinone (PQQ), a natural compound found in various foods and human breast milk, plays a role in various physiological processes and is associated with health benefits. In this study, we aimed to determine the effects of PQQ on preventing coronavirus infections using a proxy Feline Infectious…
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Dobrava hantavirus and coinciding SARS-CoV-2 infection mimicking thrombotic microangiopathy and responding to a single dose of eculizumab - The current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has refocused scientific interest on gaining insight into the pathophysiology of systemic viral diseases. Complement activation has been characterized as a driver of endothelial injury and microvascular thrombosis in acute respiratory distress syndrome as well as hantavirus hemorrhagic fever with renal syndrome. On this occasion, we wish to report a case of severe hantavirus disease with coinciding SARS-CoV-2…
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Cardiovascular safety pharmacology of ivermectin assessed using the isoflurane-anesthetized beagle dogs: ICH S7B follow-up study - Antiparasitic ivermectin has been reported to induce cardiovascular adverse events, including orthostatic hypotension, tachycardia and cardiopulmonary arrest, of which the underlying pathophysiology remains unknown. Since its drug repurposing as an antiviral agent is underway at higher doses than those for antiparasitic, we evaluated the cardiovascular safety pharmacology of ivermectin using isoflurane-anesthetized beagle dogs (n=4). Ivermectin in doses of 0.1 followed by 1 mg/kg was…
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Ligand concentration determines antiviral efficacy of silica multivalent nanoparticles - We have learned from the recent COVID-19 pandemic that the emergence of a new virus can quickly become a global health burden and kill millions of lives. Antiviral drugs are essential in our fight against viral diseases, but most of them are virus-specific and are prone to viral mutations. We have developed broad-spectrum antivirals based on multivalent nanoparticles grafted with ligands that mimic the target of viral attachment ligands (VALs). We have shown that when the ligand has a…
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Broad-spectrum antiviral activity of two structurally analogous CYP3A inhibitors against pathogenic human coronaviruses in vitro - Coronaviruses pose a permanent risk of outbreaks, with three highly pathogenic species and strains (SARS-CoV, MERS-CoV, SARS-CoV-2) having emerged in the last twenty years. Limited antiviral therapies are currently available and their efficacy in randomized clinical trials enrolling SARS-CoV-2 patients has not been consistent, highlighting the need for more potent treatments. We previously showed that cobicistat, a clinically approved inhibitor of Cytochrome P450-3A (CYP3A), has direct antiviral…
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Protection effects of mice liver and lung injury induced by coronavirus infection of Qingfei Paidu decoction involve inhibition of the NLRP3 signaling pathway - CONCLUSIONS: To sum up, our current study demonstrated that QFPD treatment has the capacity to alleviate infection-related symptoms, mitigate tissue damage in infected organs, and suppress viral replication in coronavirus-infected mice. The protective attributes of QFPD in coronavirus-infected mice are plausibly associated with its modulation of the NLRP3 signaling pathway. We further infer that QFPD holds substantial promise in the context of coronavirus infection therapy.
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A broadly reactive antibody targeting the N-terminal domain of SARS-CoV-2 spike confers Fc-mediated protection - Most neutralizing anti-SARS-CoV-2 monoclonal antibodies (mAbs) target the receptor binding domain (RBD) of the spike (S) protein. Here, we characterize a panel of mAbs targeting the N-terminal domain (NTD) or other non-RBD epitopes of S. A subset of NTD mAbs inhibits SARS-CoV-2 entry at a post-attachment step and avidly binds the surface of infected cells. One neutralizing NTD mAb, SARS2-57, protects K18-hACE2 mice against SARS-CoV-2 infection in an Fc-dependent manner. Structural analysis…
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Chemical Composition of Thyme (Thymus vulgaris) Extracts, Potential Inhibition of SARS-CoV-2 Spike Protein-ACE2 Binding and ACE2 Activity, and Radical Scavenging Capacity - Water and ethanol extracts of dried thyme (Thymus vulgaris) were analyzed for chemical composition, inhibition of the SARS-CoV-2 spike protein-ACE2 interaction, inhibition of ACE2 activity, and free radical scavenging capacity. Thirty-two compounds were identified in water extract (WE) and 27 were identified in ethanol extract (EE) of thyme through HPLC-MS. The WE (33.3 mg/mL) and EE (3.3 mg/mL) of thyme inhibited the spike protein-ACE2 interaction by 82.6 and 86.4%, respectively. The thyme WE…
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Pre-pandemic Executive Function Protects Against Pandemic Anxiety in Children with and Without Autism Spectrum Disorder - The COVID-19 pandemic may have exacerbated depression, anxiety, and executive function (EF) difficulties in children with autism spectrum disorder (ASD). EF skills have been positively associated with mental health outcomes. Here, we probed the psychosocial impacts of pandemic responses in children with and without ASD by relating pre-pandemic EF assessments with anxiety and depression symptoms several months into the pandemic. We found that pre-pandemic inhibition and shifting difficulties,…
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Implementing PCR testing in general practice-a qualitative study using normalization process theory - CONCLUSION: In its current form, the added diagnostic value of using POC PCR testing in general practice was not sufficient for the professionals to justify the increased work connected to the usage of the diagnostic procedure in daily practice.
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Inhibition of bradykinin in SARS-CoV-2 infection: a randomised, double-blind trial of icatibant compared with placebo (ICASARS) - SARS-CoV-2 binds to ACE2 receptors and enters cells. The symptoms are cough, breathlessness, loss of taste/smell and X-ray evidence of infiltrates on chest imaging initially caused by oedema, and subsequently by a lymphocytic pneumonitis. Coagulopathy, thrombosis and hypotension occur. Worse disease occurs with age, obesity, ischaemic heart disease, hypertension and diabetes.These features may be due to abnormal activation of the contact system. This triggers coagulation and the kallikrein-kinin…
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Antiviral peptides inhibiting the main protease of SARS-CoV-2 investigated by computational screening and in vitro protease assay - The main protease (Mpro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) plays an important role in viral replication and transcription and received great attention as a vital target for drug/peptide development. Therapeutic agents such as small-molecule drugs or peptides that interact with the Cys-His present in the catalytic site of Mpro are an efficient way to inhibit the protease. Although several emergency-approved vaccines showed good efficacy and drastically dropped the…
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Plant-Derived Natural Compounds as an Emerging Antiviral in Combating COVID-19 - Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a human virus that burst at Wuhan in China and spread quickly over the world, leading to millions of deaths globally. The journey of this deadly virus to different mutant strains is still ongoing. The plethora of drugs and vaccines have been tested to cope up this pandemic. The herbal plants and different spices have received great attention during pandemic, because of their anti-inflammatory, and immunomodulatory properties in…
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From Patent Search
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The Difference That Sandra Day O’Connor Made - The late Supreme Court Justice had a keen feeling for the real-world impact of the Court’s decisions. - link
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Columbia Suspended Pro-Palestine Student Groups. The Faculty Revolted - Like other universities, the school has cracked down on activism among students, citing fears of antisemitism. Some professors think it’s gone too far. - link
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Why Washington Couldn’t Quit Kissinger - Despite his controversial record, the former Secretary of State never fell out of the good graces of the D.C. establishment. - link
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Donald Trump’s Latino Campaign Begins - Democrats fear that Univision has turned to the right, but the network may be the least of their problems. - link
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Dolly Parton “Busted a Gut” Reaching for the High Notes on “Rockstar” - The country legend finds freedom in her first venture into rock. Plus, Jill Lepore, Jelani Cobb, and Evan Osnos on how American democracy got so precarious. - link
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From Vox
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Russia’s absurd claim that the LGBTQ community is extremist, explained -
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+Participants hold a rainbow flag during a gay pride demonstration in St. Petersburg in 2017. | Igor Russak/SOPA Images/LightRocket via Getty Images
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+It’s part of Putin’s strategy to paint himself as Russia’s protector against Western immorality.
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+Life in Russia became even more restricted for queer people last week, after a decade of increasing repression against the LGBTQ community there.
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+On November 30, Russia’s Supreme Court labeled the international LGBTQ movement an “extremist organization,” claiming that it incites “social and religious hatred.”
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+The new ruling is alarming in its own right, in that it could subject LGBTQ people and activist groups in Russia to legal penalties for openly supporting queer and trans rights. But it is also connected to Russian President Vladimir Putin’s greater ideological project. As part of that project, Putin has worked during his presidency, and over the last decade in particular, to create a narrative of “traditionalist” Russian history and culture that has led to the ongoing war in Ukraine and the exclusion of minorities like LGBTQ people, among other things.
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+The Russian Ministry of Justice brought the case to the Supreme Court on November 17, according to the New York Times, where it was ruled on in a secret, four-hour session. No opposing arguments were permitted in the case, Russian media reported.
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+The new designation means, according to the SOVA Center for Information and Analysis, a Russian civil rights organization, that organizers and members of LGBTQ organizations could face prison sentences of up to 10 or six years, respectively, and that displaying symbols of the movement, like a rainbow flag, in public could result in a sentence of up to four years. Even “approving statements” about the LGBTQ movement could potentially result in punishment.
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+Anti-LGBTQ extremism in the Russian government is nothing new, and over the past decade-plus, repression against LGBTQ people and organizations has gotten increasingly more extreme. “This is a continuation of a long-established effort that’s been going on for a decade, at least, and that actually already builds upon a whole anti-LGBTQ+ institution in Russia,” said Alexander Kondakov, a Russian sociologist at University College Dublin who studies how the legal and security systems affect LGBTQ life. “It’s not just an instance of state homophobia, but it’s a wholesale institution.”
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+Though the new designation is absurd and shocking, it’s years in the making — and it’s part of Putin’s broader strategy to justify his place as Russia’s protector against “Western values,” particularly as Russia’s invasion of Ukraine reaches the two-year mark and he tries to secure yet another presidential term.
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+Putin’s regime erodes civil society and human rights to protect “traditional values”
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+Thursday’s legal decision represents the intersection of three different but intertwined social and legal trends under Putin: the illegalization of “extremism,” the oppression of LGBTQ Russians dating back a decade, and Putin’s efforts to create an alternative Russian cultural and historical narrative to justify his repressive rule and imperialist aspirations.
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+“[Anti-LGBTQ] Russian legislation specifically highlights patriotism, strong family, and religiosity (Orthodoxy in particular) as important ‘traditional values’ helping to protect and strengthen the nation,” Radzhana Buyantueva, a researcher studying LGBTQ communities in Russia and their intersection with the political sphere, explained to Vox over email. “In the 1990s-2000s, Russia experienced a range of issues such as economic and demographic crises and the loss of its impactful role on the international stage, causing the perceived ‘emasculation’ of the population. The Kremlin has utilized these insecurities in its anti-gender queerphobic propaganda,” cracking down on LGBTQ groups and other perceived opponents while also militarizing society and “culminating in the escalating military aggression toward neighboring states (Georgia in 2008 and Ukraine since 2014).”
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+The roots of this trend date back early into Putin’s tenure: In 2002, the Russian government adopted the Federal Law on Combating Extremist Activity in the wake of Russia’s wars in Chechnya and the global “war on terror.” Part of its definition of extremism is the “kindling of social, racial, ethnic, or religious discord,” as the court now claims the international LGBTQ movement does. It was initially used against Muslim groups in the North Caucasus that represented a threat to the Kremlin and its control over Russia, as well as “skinhead organizations, different kinds of neo-Nazis, Russian nationalists — different violent organizations that had discrimination of various ethnic or racial communities at the core of their ideology,” Kondakov said. “But then it shifted toward us against any enemies of the current government.”
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+The law allows for the persecution of “non-traditional” religious groups, like the Jehovah’s Witnesses, as well as media outlets and, increasingly, civil society organizations that the Russian state deems extremist, as analyst Maria Kravchenko wrote in a 2018 report for the US Commission on International Religious Freedom.
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+Following those protests — the largest in Russia since the 1990s — and Putin’s return to power in 2012, the government in 2013 passed a law banning LGBTQ “propaganda,” unrelated to the extremism law. It was, essentially, an apolitical distraction and a nod to the socially conservative sectors that had helped elect him.
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+Similar to the American right, the Russian political class had begun looking for wedge issues to consolidate their base, Sam Greene, director for democratic resilience at the Center for European Policy Analysis, told Vox in an interview.
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+“They kind of just [started] throwing stuff at the wall to see what sticks,” he said. And while Russia’s laws surrounding LGBTQ rights were quite liberal and had been since the 1990s, the policy came before the widespread cultural understanding of LGBTQ life and queer identity — so, Greene said, “religion sticks, LGBT sticks.” It also was in line with Putin’s hypermasculine, misogynistic posturing and the lack of visibility and public conversation about sexuality.
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+And that political posture had real consequences for queer people. The 2013 legislation placed heavy fines on sharing information with minors about “non-traditional sexual relations.” At the time, Reuters reported in 2013, several municipalities in Russia already had similar laws, and anti-LGBTQ violence was becoming an increasing concern for queer Russians.
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+Since then, Putin’s government has increasingly used legislation as a weapon against LGBTQ people and organizations. In 2022, the Russian government passed a law banning any depiction in the media of queer life and just this summer passed a law criminalizing gender transition.
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+“Promotion of conservatism and assertiveness toward Western liberalism have accompanied Russia’s increasing authoritarianism and efforts to ‘manage’ civil society,” Buyantueva said. “Prior to [last week’s ruling], the most harmful in this regard has been the legislation on ‘foreign agents’ and ‘unwelcome organizations’ that explicitly targets links between Russian NGOs and Western donors,” demonizing those organizations and making it more difficult for them to operate in Russia.
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+Life is already terrifying for LGBTQ Russians
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+Since Thursday’s ruling, Russian authorities have already raided a number of queer venues including two bars and a bathhouse in Moscow, according to the Associated Press.
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+“Of course [the ruling] affects people in absolutely terrible ways — it’s part of a violent crackdown that is unleashed by the state and is performed by the state, but also by non-state actors and agents and wider society,” Kondakov told Vox in an interview. “It has an absolutely devastating effect on so many different levels — on a psychological level, but also real violence.”
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+That violence is perpetrated not only by the state — the FSB, or Russian Federal Security Service, and the police — but also by criminal groups that attack LGBTQ people and organizations with the tacit acceptance of the state, Greene said.
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+“One of the things that happens is when the state starts identifying a community as extremist, and thus, by definition, beyond the pale of legality, not deserving of the protection of the law, that gives carte blanche to vigilantes to go off and do what they do,” he told Vox. “So even from the very beginning in 2012, 2013, when the state starts pushing against the LGBT community, you see a significant uptick in violence against members of that community that’s mostly not done by the state. It’s mostly skinheads, Christian nationalists, that kind of thing.”
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+And since there’s no way to visibly identify queer people, and “no such organization as ‘international LGBT public movement,’” Buyantueva said, general police repression and public homophobia will likely increase under the new law. “Basically, anyone suspected/accused to be a part of the ‘movement’ might be harassed, prosecuted, and/or face violence,” she said.
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+Given that, many LGBTQ Russians may choose to leave, especially as Putin’s homophobic and anti-Western rhetoric increases during his campaign for the 2024 presidency; he’s campaigning on saving Russian traditional values through the war on Ukraine.
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+As Kondakov told Vox, the government’s oppressive anti-gay policy “doesn’t work as well as it used to, and probably they need the injection of homophobia more and more frequently nowadays” to distract people from the Kremlin’s “crisis of legitimacy” over the unsuccessful and unpopular war and increasing isolation from the rest of the world.
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An oil executive is leading the UN climate summit. It’s going as well as you’d expect. -
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+UAE Industry and Advanced Technology Minister and President of COP28, Sultan bin Ahmed Al Jaber, has faced backlash for recent comments. | Nuran Erkul Kaya/Anadolu/Getty Images
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+The head of COP28 is facing widespread backlash for his comments on fossil fuels.
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+As the United Nations’ annual climate summit COP28 continues, controversial comments by Sultan Ahmed al-Jaber, the head of the conference, are roiling the event and raising questions about how substantive any new fossil fuel agreement emerging from the gathering will be.
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+In a meeting one week before the conference, Jaber — who is the United Arab Emirates minister of industry and advanced technology as well as the chairman of the Abu Dhabi National Oil Company — told a panel he believed there was no science to suggest eliminating fossil fuels would help keep global temperature increases below the key threshold of 1.5 degrees Celsius.
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+“There is no science out there, or no scenario out there, that says that the phase-out of fossil fuel is what’s going to achieve 1.5C,” Jaber said during a late November climate panel hosted by the climate nonprofit She Changes Climate as first reported by the Guardian. Additionally, he seemed to push back against a fossil fuel phase-out entirely: “Please help me, show me the roadmap for a phase-out of fossil fuel that will allow for sustainable socioeconomic development, unless you want to take the world back into caves.” (He did later call a phase-out “inevitable” and “essential.”)
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+As Vox’s Umair Irfan has explained, a vast majority of countries previously agreed to try to limit the average global temperature to 1.5°C more than what the average Earth temperature was prior to the Industrial Revolution. The idea is that limiting the increase to 1.5°C is the most realistic strategy for minimizing extreme weather events and other climate catastrophes. Because of the number’s international importance, Jaber’s critics took his statement as undermining research regarding the causes of climate change, and as a threat to COP’s goals.
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+Climate scientists have emphasized that Jaber’s statements are inaccurate, with some noting that they’re reminiscent of arguments the fossil fuel industry is known for making. According to the 2023 report from the Intergovernmental Panel on Climate Change, greenhouse gas emissions — which are heavily caused by the usage of fossil fuels — would need to be slashed to almost half by 2030 to keep the temperature increase below 1.5°C. Scientists have also worried that it’s too late to even limit the temperature increase to that level and that the goal is no longer tenable. As Irfan noted, for example, 2023 might be the first year the world’s average temperatures rise above the 1.5°C mark.
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+“Al Jaber’s comments are absurd and troubling, betraying both an ignorance about the science and a dismissiveness about the need for rapid decarbonization, which is at the very center of the proceedings over which he is in principle presiding as COP28 president,” University of Pennsylvania climate scientist Michael Mann told Vox.
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+Jaber’s comments also directly conflict with statements made by many world leaders, including UN Secretary-General Antonio Guterres, who said on Friday: “The science is clear: The 1.5C limit is only possible if we ultimately stop burning all fossil fuels. Not reduce, not abate. Phase out, with a clear timeframe.”
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+Jaber has since responded to the blowback, claiming that he is focused on ensuring that “everything we do is centered around the science” and that there has been a “misrepresentation” of his statements. In remarks on Monday, Jaber reiterated that he believes “the phase-out and phase-down of fossil fuel is inevitable,” comments he previously made during the She Changes panel as well.
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+His remarks during the panel have served only to deepen existing scrutiny of Jaber’s leadership of COP given his role as the head of a national oil and gas company and reports that he was capitalizing on this position to advance the UAE’s business interests. (He has denied these allegations.)
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+His statements also come as participants at the annual climate talks address a heated debate about the future of fossil fuels and weigh an agreement that could significantly curb or eliminate their usage down the line. As CNBC reports, many climate experts believe that this year’s COP won’t be considered a success unless attendees reach a deal about phasing out the usage of fossil fuels, a decision some countries have balked at. Attendees pushing for a weaker option are urging a “phase-down,” which would reduce rather than eliminate fossil fuel usage.
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+Jaber’s previous remarks fuel uncertainty around how aggressive countries will be in any COP agreements pushing to wind down fossil fuel usage.
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+Jaber’s fossil fuel comments come amid a big debate
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+As multiple climate experts have emphasized, the scientific evidence directly conflicts with Jaber’s remarks. As NPR’s Rebecca Hersher writes, scientific studies have found that there need to be drastic cuts in fossil fuel usage and carbon emissions to limit global temperature increases. Hersher explains: “In order to limit global warming to 1.5 degrees Celsius, carbon dioxide emissions would need to decrease 80% by 2040 and 99% by 2050, compared to levels in 2019, according to the most comprehensive global scientific consensus report on climate change.”
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+Fossil fuel production would need to be slashed drastically — if not eliminated — starting immediately to meet those targets; 2040 is just over 16 years away. That’s why climate experts and activists want to see global leaders emerge from this year’s COP with an aggressive but workable plan to quickly phase out fossil fuels. As summit members discuss next steps for reducing fossil fuel usage, there are key disagreements over the approach that could be used, which could have a measurable impact on any efforts to stay within 1.5°C.
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+The debate over a “phase-out” or a “phase-down” is one key point of contention. Climate scientists have advocated heavily for the former as a means of rapidly curbing emissions from oil and gas, while Jaber and members of the fossil fuel industry have kept the door open to the latter. A phase-down would reduce fossil fuel usage over time and be more gradual.
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+“The outcome of COP28 must be that all the oil, gas, and coal nations of the world see that now we are truly at the beginning of the end of the fossil fuel era for the world economy. And that we are now starting to bend the curve, properly,” Johan Rockstrom, director of the Potsdam Institute for Climate Impact Research, told CNBC.
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+Jaber’s remarks raise questions about how strong the fossil fuels agreement coming out of the summit will be and where exactly he stands on the issue given his remarks at the She Changes Climate event, which seemed critical of a phase-out. “I have said over and over that the phase-down and the phase-out of fossil fuel is inevitable. In fact, it is essential … it needs to be orderly, fair, just, and responsible,” Jaber said at his Monday press conference.
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What Timothée Chalamet’s Wonka has in common with Paddington Bear -
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+A kinder, gentler Wonka (Timothée Chalet, center). | Warner Bros.
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+A director, a worldview, a vibe, and a love of cute hats.
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+At this point, the Paddingtonmovies are a universally beloved internet phenomenon, adored by children and adults alike. (Well, I don’t know tons of kids who are as obsessed with Paddington as some adults I know, but let’s just go with it.) Back when the first Paddington was gearing up for release, however, that fate didn’t seem predetermined.
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+One of the first looks at the film turned into a meme that deemed the sweet bear “creepy” and the release date was pushed into January, signaling that the distributor didn’t have the highest hopes for its success. (In another sign of how times have changed: The initial Paddington was distributed in the US by a subsidiary of The Weinstein Company.) But we should have never feared. Paddington was a delight, and Paddington 2 was a masterpiece.
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+Which brings me to Wonka, the new movie that shares director Paul King with the bear-centric tales. The early buzz on Wonka has ranged from confused to derisive. Why, exactly, do we need a prequel story about Roald Dahl’s somewhat menacing chocolatier from Charlie and the Chocolate Factory? Is Timothée Chalamet the true heir to Gene Wilder’s legacy? Is this nothing more than “Twonka,” a.k.a. Twink Wonka?
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+But, like Paddington, Wonka defies expectations. The movie, which is out in theaters December 15, is absolutely charming and, dare I say, extremely Paddington-core. King has infused that same sort of warm, intelligent energy into his tale of an ambitious, kooky sweets purveyor who arrives in a vaguely European town with the hope of opening up a shop, only to have his dreams stifled by a pair of scheming launderers and an evil chocolate cartel. Timothée Chalamet may not be a furry little bear, but his Wonka is akin to Paddington. He’s an oddball optimist who inspires those around him — all except for the naysayers who see his good mood as an imposition.
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+It’s a worthy bit of holiday entertainment, the kind of movie that hits just right in these winter months. It’s sweet but not too treacly, not quite as perfect as Paddington 2 (what is?) but it does the trick.
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+What is Wonka about?
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+The biggest ding against Wonka sight unseen was the problem that no one was clamoring for a Willy Wonka origin story. Wonka’s progenitor, Roald Dahl, is a tricky figure, whose legacy of children’s stories is partially undone by his legacy of virulent antisemitism. At the same time, Wonka as originally written was never a warm and cuddly figure. He’s a mysterious man with a mysterious factory and a penchant for torturing children he believes are badly behaved. In 1971’s Willy Wonka & the Chocolate Factory, Gene Wilder mashed up mischief and menace, playing Wonka like a kind of trickster god, who was, quite, frankly, a little scary.
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+While Chalamet’s Willy shares a similar fashion sense with Wilder — and there are homages to the 1971 film, including a rendition of the song “Pure Imagination” in Wonka — it’s helpful to look at this version of the character with completely fresh eyes. King and co-writer Simon Farnaby, who also wrote Paddington 2 with the director, have made Willy fresh-faced and naive.
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+ Warner Bros.
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+Wonka (Chalamet) and that troublesome Oompa Loompa, Lofty (Hugh Grant).
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+He’s a young sailor who has finally bid farewell to life at sea with “12 silver sovereigns” in his pocket as he seeks to start life anew. By the end of his first song, he has no silver sovereigns but is offered a place to stay at a boarding house/laundry by proprietor Mrs. Scrubbit (Olivia Colman) and her menacing partner Bleacher (Tom Davis), who, with their ruddy faces and brash cockney accents, have a hint of the Thenardiers from Les Misérables to them.
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+All Willy supposedly has to do to get a room is pay a single sovereign the next day and sign a lengthy contract. He does the latter despite the warning from a girl named Noodle (Calah Lane). (Turns out Willy learned to make chocolate from his beloved mother, played by Paddington veteran Sally Hawkins, but not how to read — literally.)
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+Willy’s decision not to analyze the fine print means he owes a lot more to Scrubbit and Bleacher, who imprison those indebted to them in their laundry. These are a lowly group — portrayed by Jim Carter of Downton Abbey fame and Natasha Rothwell of Insecure and The White Lotus — who sing a sad but funny song about their lives as they “scrub scrub.” Willy refuses to be confined and breaks out to sell his goodies with help from Noodle. There are other obstacles out there, including a consortium of chocolatiers who do not want him ruining their business. Their chocolate empire operates out of a cathedral guarded by a chocoholic priest (Rowan Atkinson, naturally). Meanwhile, a pesky Oompa Loompa named Lofty (Hugh Grant, naturally), keeps stealing Willy’s supplies.
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+All the while, this is a full-blown musical, with charming if not always memorable original songs by Neil Hannon, and big production numbers. Just like Willy’s new friends, you’re swept up by his optimism, as well as the delicate touches King brings to every scenario. He creates the world so completely that you’re invested in a detail as minute as the love lives of minor characters. Still, Chalamet’s sweet-faced Willy takes center stage.
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+How is it Paddington-core?
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+Well, there’s the obvious: King directed it and his style is unmistakable. He even echoes some of his own set pieces, including a church bit from Paddington 2 and a nighttime rooftop sequence from Paddington. He employs some of the same cast members as well, including Hawkins, once again playing a kindly mother figure, and Davis, once again playing a baritone criminal. And then there’s Hugh Grant, whose turn as a dastardly actor in Paddington 2 was the highlight of his latter-day career, now sporting an orange face and green hair as a particularly sassy Oompa Loompa.
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+But most of all Paddington-core is in Paddington’s spirit, which Willy himself embodies here. As played by Chalamet, who is at his most earnest, Willy is just lightly kooky. He’s mostly sprightly and irrepressibly joyful, a glass-half-full kind of guy who makes treats from giraffe milk and a fly from Mumbai. Like Paddington, this Wonka is an innocent. Sure, with his desire to make a fortune, he’s a bit more of a capitalist than the bear, but even though he’s supposedly seen the world, he seems shocked when anyone’s intentions aren’t pure.
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+If you’re looking for a film that grapples with the spiky edges of Dahl’s work and his legacy, this is not it. (Watch Wes Anderson’s Netflix shorts for that.) It’s not that there isn’t peril — Willy, after all, is forced into indentured servitude — but whimsy trumps that. It’s like how, in Paddington 2, Paddington is sent to prison only to end up teaching his fellow inmates how to make marmalade. Anything can be softened with the right kind of sweets.
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+In Willy Wonka & the Chocolate Factory with Gene Wilder, eating one of Willy’s confections has the potential for peril because Willy himself is maniacal. Here, Willy’s goodies are sources of wonderment. Nothing has yet soured his worldview. He hasn’t developed a scheme to suss out good children from bad or gotten himself an army of Oompa Loompa slaves. For now, we can just think of this not as Dahl’s version of Wonka but as Paul King’s. And it’s a sweet treat.
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From The Hindu: Sports
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Champions Way, Fondness Of You, Immortal Beauty, Priceless Prince and Bold Act excel -
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Running Star pleases -
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Bangor On Dee should win the Pronto Pronto Plate -
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New Zealand eye comeback final Test win in Bangladesh - The Kiwis, who started their long season with a tour to Pakistan in April, have also played series in Britain, Bangladesh and the United Arab Emirates, before playing in the World Cup in India
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Bavuma, Rabada rested for white-ball series against India - Both India and South Africa are gearing up for the new World Test Championships cycle, starting with the Boxing Day Test in Centurion on December 26
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From The Hindu: National News
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Jayalalithaa’s death anniversary observed in Chennai -
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Doubts raised over events that led to death of elephant Arjuna - A mahout who was part of the operation has said that Arjuna suffered a bullet injury during the operation, because of which he could not fight.
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Michaung cyclone crosses A.P. coast with 90-100 kmph winds -
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Farewell to Arjuna: Hundreds of people bid adieu to Karnataka’s beloved tusker - The popular gentle giant was laid to rest at a Forest Department plantation in Sakaleshpur. Arjuna’s mahout, Vinod, was inconsolable and could be seen trying to wake the tusker up, unwilling to believe that he was no more.
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Cyclone Michaung | Aamir Khan rescued from flood; pics with Vishnu Vishal and Jwala Gutta go viral - Aamir Khan had reportedly shifted residence to Chennai in October to be with his ailing mother, Zeenat Hussain, who is undergoing treatment in a private medical facility in the city
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From BBC: Europe
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Spread of gang violence wrecks Sweden’s peaceful image - Several passers-by are among those killed in gangland shootings and bombings beyond the big cities.
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Villejuif: Small plane makes emergency landing in Paris suburb - An engine failure forces the pilot to make an emergency landing, crashing into an apartment building.
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Firefighters rescue injured owl from crows - An injured owl in the Russian city of Smolensk has the good fortune to end up outside a fire station.
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Panini: First ever World Cup Sticker album up for sale - The first ever Panini World Cup sticker album is going up for auction and could sell for thousands of pounds!
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Paris attack near Eiffel Tower leaves one dead and two injured - The suspect tells police he was upset by “so many Muslims dying in Afghanistan and in Palestine”.
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From Ars Technica
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Grand Theft Auto VI trailer arrives early with a crime-crazy Florida - First female protagonist and sun-soaked, satire-drenched tone on display. - link
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Don’t count on NASA to return humans to the Moon in 2025 or 2026, GAO says - No surprise: SpaceX’s lunar lander and Axiom’s spacesuits pace the Artemis III schedule. - link
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Texas sues Pfizer with COVID anti-vax argument that is pure stupid - Texas Attorney General Ken Paxton struggles with relative vs. absolute risk. - link
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Hackers stole ancestry data of 6.9 million users, 23andMe finally confirmed - Majority of impacted users are now being notified, 23andMe confirmed. - link
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After a chaotic three years, GPU sales are starting to look normal-ish again - Supply and demand are syncing back up after years of GPU market turmoil. - link
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From Jokes Subreddit
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A large university class is taking the final exam… -
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+…about 300 students are writing away in their blue books and the professor warns two minutes til pencils down. Then one minute. Then he calls out that the exam is over, please stop writing.
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+As the body of students slowly lines up to turn in their exams, one student keeps writing. The professor sternly says if you do not stop writing now, I will not accept you exam. The student keeps writing. The en professor says again the exam is over. The student keeps writing, but the professor has give up at this point.
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+Finally, at the back of the line, the student comes to turn in his blue book. The professor says, I’m sorry, I gave you multiple warnings, you wrote for several minutes past the end, I’m not going to accept your exam.
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+The student says, indignant, “Do you have any idea who I am?”
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+The, now shocked, professor says, “No, I don’t.”
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+And with that, the student lifts up half of the exams, shoves his into the middle of the pile, and walks out.
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A college professor had just finished explaining an important research project to the class -
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+He emphasized that this paper was an absolute requirement for passing the class, and that there would be only two acceptable excuses for being late. Those were a medically certifiable illness or a death in the student’s immediate family. A prankster student in the back of the classroom waved his hand and spoke up, “But what about extreme sexual exhaustion, professor?” As you would expect the class exploded in laughter. When the students had finally settled down, the professor froze the young man with a glaring look. “Well,” he responded, “I guess you’ll have to learn how to write with your other hand then…”
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+A man and woman who had never met before, but were both married to other people, found themselves assigned to the same sleeping compartment on a transcontinental train. Though initially embarrassed and uneasy over sharing a room, they were both very tired and fell asleep quickly, the man in the upper berth and the woman in the lower one.
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+At 1:00 am, the man leaned down and gently woke the woman saying “Ma’am, I’m sorry to bother you, but would you be willing to reach into the closet and get me a blanket? I’m awfully cold.”
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+“I have a better idea,” she replied, “Just for tonight, let’s pretend that we’re married.”
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+“Wow, that’s a great idea!” he exclaimed.
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+“Good,” she replied. “Get your own fucking blanket.”
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GOD said, Adam, I want you to do something for me. Gladly, Lord, replied Adam. What do you want me to do? Go down into the valley. Whats a valley? asked Adam. -
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+God explained to him, then said, Cross the river. Whats a river? God explained it to him, and then continued, Go over the hill. Whats a hill? God explained to Adam what a hill was, then said, On the other side of the hill, you will find a cave. Whats a cave? After God explained, he said, In the cave you will find a woman. Adam asked, Whats a woman? So God explained that to him too. He continued, I want you to reproduce. How do I do that? Jeez, God muttered under his breath. He then sighed and explained the birds and the bees to Adam. He liked that concept very much, so he went down into the valley, across the river, over the hill and into the cave where he found a woman. A little while later, Adam returned and asked God, Whats a headache?
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+/cdn.vox-cdn.com/uploads/chorus_asset/file/25131792/wonka_hugh_grant_071123_c5d00819793b491f980131ab9a9da854.jpg)
Warner Bros.
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