Yeast-based production platform for potent and stable heavy chain-only antibodies -
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+Monoclonal antibodies are the leading drug of the biopharmaceutical market because of their high specificity and tolerability, but the current CHO-based manufacturing platform remains expensive and time-consuming leading to limited accessibility, especially in the case of diseases with high incidence and pandemics. Therefore, there is an urgent need for an alternative production system. In this study, we present a rapid and cost-effective microbial platform for heavy chain-only antibodies (VHH-Fc) in the methylotrophic yeast Komagataella phaffii (aka Pichia pastoris). We demonstrate the potential of this platform using a simplified single-gene VHH-Fc fusion construct instead of the conventional monoclonal antibody format, as this is more easily expressed in Pichia pastoris. We demonstrate that the Pichia-produced VHH-Fc fusion construct is stable and that a Pichia-produced VHH-Fc directed against the SARS-CoV-2 spike has potent SARS-CoV-2 neutralizing activity in vitro and in vivo. We expect that this platform will pave the way towards faster and cheaper development and production of broadly neutralizing single-chain antibodies in yeast.
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Filopodial Mechanotransduction is regulated by Angiotensin-Converting Enzyme 2 (ACE2) and by SARS-CoV-2 spike protein -
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+Filopodia are dynamic, actin-rich cellular protrusions, increasingly linked to cellular mechanotransduction. However, how dynamic filopodia translate external mechanical cues remains poorly understood. Recent studies show that the SARS-CoV-2 spike (S) protein binds the ACE2 receptor on airway multicilia and that cilia are required for viral infection(1) and sufficient to induce filopodial extension and viral binding. To test if spike protein is sufficient to induce filopodial expansion, we employed live-cell single-particle tracking with quantum dots targeting ACE2, to reveal a robust filopodia extension and virus binding mechanism requiring the enzymatic activity of ACE2. Using time-lapse imaging, we reveal that spike protein binding to filopodia is associated with intracellular actin remodeling, alterations in bulk cell stiffness, and an elevation in intracellular calcium levels linked to actin-rearrangement, filopodia initiation, and persistence. We propose the activation of ACE2 creates an active signaling and mechanosensory environment within adherent cells and airway epithelial cells that allows the remodeling of actin in filopodia to trap virus and potentially organize viral exit from cells.
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Why is the Omicron main protease of SARS-CoV-2 less stable than its wild-type counterpart? A crystallographic, biophysical, and theoretical study of the free enzyme and its complex with inhibitor 13b-K -
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+During the continuing evolution of SARS-CoV-2, the Omicron variant of concern emerged in the second half of 2021 and has been dominant since November that year. Along with its sublineages, it has maintained a prominent role ever since. The Nsp5 main protease (Mpro) of the Omicron virus is characterized by a single dominant mutation, P132H. Here we determined the X-ray crystal structures of the P132H mutant (or O-Mpro) as free enzyme and in complex with the Mpro inhibitor, the alpha-ketoamide 13b-K, and we conducted enzymology, biophysical as well as theoretical studies to characterize the O-Mpro. We found that O-Mpro has a similar overall structure and binding with 13b-K; however, it displays lower enzymatic activity and lower thermal stability compared to the WT-Mpro (with "WT" referring to the original Wuhan-1 strain). Intriguingly, the imidazole ring of His132 and the carboxylate plane of Glu240 are in a stacked configuration in the X-ray structures determined here. The empirical folding free energy calculations suggest that the O-Mpro dimer is destabilized relative to the WT-Mpro due to the less favorable van der Waals interactions and backbone conformation in the individual protomers. The all-atom continuous constant pH molecular dynamics (MD) simulations reveal that His132 and Glu240 display coupled titration. At pH 7, His132 is predominantly neutral and in a stacked configuration with respect to Glu240 which is charged. In order to examine whether the Omicron mutation eases the emergence of further Mpro mutations, we also determined crystal structures of the relatively frequent P132H+T169S double mutant but found little evidence for a correlation between the two sites.
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A 10-valent composite mRNA vaccine against both influenza and COVID-19 -
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+The COVID-19 pandemic caused by SARS-CoV-2 viruses has had a persistent and significant impact on global public health for four years. Recently, there has been a resurgence of seasonal influenza transmission worldwide. The co-circulation of SARS-CoV-2 and seasonal influenza viruses results in a dual burden on communities. Additionally, the pandemic potential of zoonotic influenza viruses, such as avian Influenza A/H5N1 and A/H7N9, remains a concern. Therefore, a combined vaccine against all these respiratory diseases is in urgent need. mRNA vaccines, with their superior efficacy, speed in development, flexibility, and cost-effectiveness, offer a promising solution for such infectious diseases and potential future pandemics. In this study, we present FLUCOV-10, a novel 10-valent mRNA vaccine created from our proven platform. This vaccine encodes hemagglutinin (HA) proteins from four seasonal influenza viruses and two avian influenza viruses with pandemic potential, as well as spike proteins from four SARS-CoV-2 variants. A two-dose immunization with the FLUCOV-10 elicited robust immune responses in mice, producing IgG antibodies, neutralizing antibodies, and antigen-specific cellular immune responses against all the vaccine-matched viruses of influenza and SARS-CoV-2. Remarkably, the FLUCOV-10 immunization provided complete protection in mouse models against both homologous and heterologous strains of influenza and SARS-CoV-2. These results highlight the potential of FLUCOV-10 as an effective vaccine candidate for the prevention of influenza and COVID-19.
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SARS-CoV-2 modulates NK cell responses via induction of HLA-E and triggers expansion of adaptive NK cells during acute infection -
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+HLA-E expression plays a central role for modulation of NK cell function by interaction with inhibitory NKG2A and stimulatory NKG2C receptors on canonical and adaptive NK cells, respectively. Here, we demonstrate that infection of human primary lung tissue with SARS-CoV-2 leads to increased HLA-E expression and show that processing of the peptide YLQPRTFLL from the spike protein is primarily responsible for the strong, dose-dependent increase of HLA-E. Targeting the peptide site within the spike protein revealed that a single point mutation was sufficient to abrogate the increase in HLA-E expression. Spike-mediated induction of HLA-E differentially affected NK cell function: whereas degranulation, IFN-gamma production, and target cell cytotoxicity were enhanced in NKG2C+ adaptive NK cells, effector functions were inhibited in NKG2A+ canonical NK cells. Analysis of a cohort of COVID-19 patients in the acute phase of infection revealed that adaptive NK cells were induced irrespective of the HCMV status, challenging the paradigm that adaptive NK cells are only generated during HCMV infection. During the first week of hospitalization, patients exhibited a selective increase of early NKG2C+CD57- adaptive NK cells whereas mature NKG2C+CD57+ cells remained unchanged. Further analysis of recovered patients suggested that the adaptive NK cell response is primarily driven by a wave of early adaptive NK cells during acute infection that wanes once the infection is cleared. Together, this study suggests that NK cell responses to SARS-CoV-2 infection are majorly influenced by the balance between canonical and adaptive NK cells via the HLA-E/NKG2A/C axis.
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Biological modifications of the immune response to COVID-19 vaccine in patients treated with anti-CD20 agents and immune-checkpoint inhibitors -
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+Investigating the impact of immune-modulating therapies on mRNA vaccine efficacy remains vital, transcending the immediate context of the COVID-19 pandemic. This study focuses on the differential immune responses to COVID-19 mRNA booster vaccines among healthy subjects, cancer patients undergoing treatment with immune-checkpoint inhibitors (ICIs), and those treated with B-cell depleting agents such as rituximab. Utilizing RNA sequencing, serology, and interferon gamma release assays, we charted the temporal dynamics of the immune response. Our findings indicate that ICIs maintain an immune profile similar to that of healthy individuals, whereas treatments like rituximab lead to a significant reduction in immune competence, affecting both humoral and cellular immunity. This research may not only help tailoring of vaccination strategies for those under immune-modulating treatments, but also deepens our understanding of the sophisticated interplay within the immune system in health and disease states, potentially informing therapeutic strategies across a spectrum of immunological conditions.
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Iterative In Silico Screening for Optimizing Stable Conformation of Anti-SARS-CoV-2 Nanobodies -
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+Nanobodies (Nbs or VHHs) are single-domain antibodies (sdAbs) derived from camelid heavy-chain antibodies. The variable region of these nanobodies has special and unique characteristics, such as small size, good tissue penetration, and cost-effective production, making nanobodies a good candidate for the diagnosis and treatment of viruses. Identifying effective nanobodies against the COVID-19 would help us defeat this dangerous virus or other unknown variants in future. Herein, we introduce an in silico screening strategy for optimizing stable conformation of anti-SARS-CoV-2 nanobodies. Firstly, various complexes containing nanobodies were downloaded from the RCSB database, which were identified from immunized llamas. The primary docking between nanobodies and the SARS-CoV-2 spike protein receptor-binding domain was performed through ClusPro program, with the manually screening that leaving the reasonable conformation to the next step. Then, the binding distances of atoms between the antigen-antibody interfaces were measured through the NeighborSearch algorithm. Finally, filtered nanobodies were acquired according to HADDOCK scores through HADDOCK docking the COVID spike protein with nanobodies under restrictions of calculated molecular distance between active residues and antigenic epitopes less than 4.5 A. In this way, those nanobodies which with more reasonable conformation and with stronger neutralizing efficacy were acquired. To validate the efficacy ranking of the nanobodies we obtained, we calculated the binding affinities and dissociation constants (Kd) of all screened nanobodies using the PRODIGY web tool, and predicted the stability changes induced by all possible point mutations in nanobodies using the MAESTROWeb server. Furthermore, we examined the performance of the relationship between nanobodies’ ranking and their number of mutation-sensitive sites (Spearman correlation > 0.68), the results revealed a robust correlation, indicating that the superior nanobodies identified through our screening process exhibited fewer mutation hotspots and higher stability. This correlation analysis demonstrates the validity of our screening criteria, underscoring the suitability of these nanobodies for future development and practical implementation. In conclusion, this three-step screening strategy iteratively in silico greatly improved the accuracy of screening desired nanobodies compared to using only ClusPro docking or default HADDOCK docking settings. It provides new ideas for the screening of novel antibodies and computer-aided screening methods.
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Prioritizing Lifestyle Factors for Effective Emotion Regulation: A Daily Study on First-Year College Students’ Well-Being During COVID-19 -
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+The COVID-19 pandemic disrupted emerging adult first-year college students’ daily lives and well-being. Adaptive emotion regulation skills are crucial for this population that is in a transitioning phase of development during challenging times. This study assessed 1,796 ecological momentary assessments from 76 first-year college students’ daily usage of adaptive Dialectical Behavior Therapy (DBT) emotion regulation (ER) skills and momentary experiences of well-being during COVID-19 in the Spring of 2020. Participants were emerging adults aged 18 to 20 years, 71% female, and 46% white. Results from multilevel models revealed that specific ER skills consistently predict momentary well-being even when controlling for dispositional well-being. Moreover, on days of sufficient sleep reported, students reported higher well-being levels; on days with more interaction with others, students were more likely to engage in ER behaviors; and on weekends, students were less likely to engage in ER behaviors (but not avoid substances like alcohol).
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Re-annotation of SARS-CoV-2 proteins using an HHpred-based approach opens new opportunities for a better understanding of this virus -
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+Since the publication of the genome of SARS-CoV-2 - the causative agent of COVID-19 - in January 2020, many bioinformatic tools have been applied to annotate its proteins. Although efficient methods have been used, such as the identification of protein domains stored in Pfam, most of the proteins of this virus have no detectable homologous protein domains outside the viral taxa. As it is now well established that some viral proteins share similarities with proteins of their hosts, we decided to explore the hypothesis that this lack of homologies could be, at least in part, the result of the documented loss of sensitivity of Pfam Hidden Markov Models (HMMs) when searching for domains in “divergent organisms”. To improve the annotation of SARS-CoV-2 proteins, we used here the HHpred protein annotation tool and an available custom HH-suite database of HMMs specific to Homo sapiens proteins. To avoid “false positive predictions” as much as possible, we designed a robustness procedure to evaluate the HHpred results. In total, 6 robust similarities involving 6 distinct SARS-CoV-2 proteins were detected. Of these 6 similarities, 3 are already known and well documented, and one is in agreement with recent crystallographic results. We then examined carefully the two similarities that have not yet been reported in the literature. We first show that the C-terminal part of Spike S (the protein that binds the virion to the cell membrane by interacting with the host receptor, triggering infection) has similarities with the human prominin-1/CD133; after reviewing what is known about prominin-1/CD133, we suggest that the C-terminal part of Spike S could both improve the docking of Spike S to ACE2 (the main cell entry receptor for SARS-CoV-2) and be involved in the delivery of virions to regions where ACE2 is located in cells. Secondly, we show that the SARS-CoV-2 ORF3a protein shares similarities with human G protein-coupled receptors (GPCRs) belonging mainly to the “Rhodopsin family”. We conclude that the approach described here (or similar approaches) opens up new avenues of research to better understand SARS-CoV-2 and could be used to complement virus annotations, particularly for less-studied viruses.
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Engineering customized viral receptors for various coronaviruses -
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+Coronaviruses display versatile receptor usage, yet in-depth characterization of coronaviruses lacking known receptor identities has been impeded by the absence of feasible infection models. Here, we developed an innovative strategy to engineer functional customized viral receptors (CVRs). The modular design relies on building receptor frameworks comprising various function modules and generating specific epitope-targeting viral binding domains. We showed the key factors for CVRs to efficiently facilitate spike cleavage, membrane fusion, pseudovirus entry, and authentic virus amplification for various coronaviruses, resembling their native receptors. Applying this strategy, we delineated the accessible receptor binding epitopes for functional SARS-CoV-2 CVR design and elucidated the mechanism of entry supported by an amino-terminus domain (NTD) targeting S2L20-CVR. Furthermore, we created CVR-expressing cells for assessing antibodies and inhibitors against 12 representative coronaviruses from six subgenera, most of which lacking known receptors. Notably, a pan-sarbecovirus CVR supported entry of various sarbecoviruses, as well as amplification of a replicable HKU3 pseudovirus and the authentic strain RsHuB2019A. Through combining an HKU5-specific CVR with reverse genetics, we successfully rescued and cultured wild-type and fluorescence protein-incorporated HKU5, a receptor-unidentified merbecovirus. Our study demonstrated the great potential of CVR strategy in establishing native receptor-independent infection models, paving the way for studying various viruses that are challenging to culture due to the lack of susceptible cells.
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Heterogeneous hybrid immunity against Omicron variant JN.1 at 11 months following breakthrough infection -
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+A highly transmissible SARS-CoV-2 variant JN.1 is rapidly spreading throughout the nation, becoming the predominant strain in China and worldwide. However, the current immunity against the circulating JN.1 at population level has yet to be fully evaluated. We recruited representative cohorts with stratified age groups and diverse combinations of vaccination and/or infection in recent months, and promptly assessed humoral immunity for these subjects predominantly exhibiting hybrid immunity. We report that at 11 months following BA.5-wave breakthrough infection (BTI), these vaccinated individuals generally showed above-the-threshold yet low level of neutralizing activity against JN.1, with slightly greater potency observed in children and adolescents compared to adults and seniors. Meanwhile, XBB/EG.5-wave reinfection post-BTI significantly boosted the neutralizing antibodies against Omicron variants, including JN.1 in both adults (13.4- fold increase) and seniors (24.9-fold increase). To better understand respiratory mucosal protection against JN.1 over an extended period of months post-BTI, we profiled the humoral immunity in bronchoalveolar lavage samples obtained from vaccinated subjects with or without BTI, and revealed increased potency of neutralizing activity against the BA.5 and JN.1 variants in the respiratory mucosa through natural infection. Notably, at 11 months post-BTI, memory B cell responses against prototype and JN.1 were detectable in both blood and respiratory mucosa, displaying distinct memory features in the circulation and airway compartments. XBB/EG.5-wave reinfection drove the expansion of JN.1-specific B cells, along with the back-boosting of B cells responding to the ancestral viral strain, suggesting the involvement of immune imprinting. Together, this study indicates heterogeneous hybrid immunity over 11 months post-BTI, and underscores the vulnerability of individuals, particularly high-risk seniors, to JN.1 breakthrough infection. An additional booster with XBB-containing vaccine may greatly alleviate the onward transmission of immune-evasive SARS-CoV-2 variants.
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B cell maturation restored ancestral germlines to control Omicron BA.2.86 -
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+The unceasing interplay between SARS-CoV-2 and the human immune system has led to a continuous maturation of the virus and B cell response providing an opportunity to track their evolution in real time. We longitudinally analyzed the functional activity of almost 1,000 neutralizing human monoclonal antibodies (nAbs) isolated from vaccinated people, and from individuals with hybrid and super hybrid immunity (SH), developed after three mRNA vaccine doses and two breakthrough infections. The most potent neutralization and Fc functions against highly mutated variants, including BA.2.86, were found in the SH cohort. Despite different priming, epitope mapping revealed a convergent maturation of the functional antibody response. Neutralization was mainly driven by Class 1/2 nAbs while Fc functions were induced by Class 3/4 antibodies. Remarkably, broad neutralization was mediated by restored IGHV3-53/3-66 B cell germlines which, after heterogenous exposure to SARS-CoV-2 S proteins, increased their level of somatic hypermutations. Our study shows the resilience of the human immune system which restored previously expanded germlines and activated naive B cells to broaden the antibody repertoire of antibodies to control future SARS-CoV-2 variants.
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Newcastle Disease Virus Vector-Based SARS-CoV-2 Vaccine Candidate AVX/COVID-12 Activates T Cells and Is Recognized by Antibodies from COVID-19 Patients and Vaccinated -
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+Several effective vaccines for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been developed and implemented in the population. However, the current production capacity falls short of meeting global demand. Therefore, it is crucial to further develop novel vaccine platforms that can bridge the distribution gap. AVX/COVID-12 is a vector-based vaccine that utilizes the Newcastle Disease virus (NDV) to present the SARS-CoV-2 spike protein to the immune system. This study analyses the antigenicity of the vaccine candidate by examining antibody binding and T-cell activation in individuals infected with SARS-CoV-2 or variants of concern (VOCs), as well as in healthy volunteers who received coronavirus disease 2019 (COVID-19) vaccinations. Our findings indicate that the vaccine effectively binds antibodies and activates T-cells in individuals who received 2 or 3 doses of BNT162b2 or AZ/ChAdOx-1-S vaccines. Furthermore, the stimulation of T-cells from patients and vaccine recipients with AVX/COVID-12 resulted in their proliferation and secretion of interferon-gamma (IFN-{gamma}) in both CD4+ and CD8+ T-cells. In conclusion, the AVX/COVID-12 vectored vaccine candidate demonstrates the ability to stimulate robust cellular responses and is recognized by antibodies primed by the spike protein present in SARS-CoV-2 viruses that infected patients, as well as in the mRNA BNT162b2 and AZ/ChAdOx-1-S vaccines. These results support the inclusion of the AVX/COVID-12 vaccine as a booster in vaccination programs aimed at addressing COVID-19 caused by SARS-CoV-2 and its VOCs.
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Identification of the host reservoir of SARS-CoV-2 and determining when it spilled over into humans -
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+Since the emergence of SARS-CoV-2 in Wuhan in 2019 its host reservoir has not been established. Phylogenetic analysis was performed on whole genome sequences (WGS) of 71 coronaviruses and a Breda virus. A subset comprising two SARS-CoV-2 Wuhan viruses and 8 of the most closely related coronavirus sequences were used for host reservoir analysis using Bayesian Evolutionary Analysis Sampling Trees (BEAST). Within these genomes, 20 core genome fragments were combined into 2 groups each with similar clock rates (5.9x10 -3 and 1.1x10 -3 subs/site/year). Pooling the results from these fragment groups yielded a most recent common ancestor (MRCA) shared between SARS-COV-2 and the bat isolate RaTG13 around 2007 (95% HPD: 2003, 2011). Further, the host of the MRCA was most likely a bat (probability 0.64 - 0.87). Hence, the spillover into humans must have occurred at some point between 2007 and 2019 and bats may have been the most likely host reservoir.
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The Effect of Analytical Thinking on Irrational Behaviors in Times of COVID-19: the Mediating Role of Misinformation Beliefs -
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+The present study was to investigate the influence of analytical thinking on irrational behaviors evoked by COVID-19 (including excessive epidemic prevention and hoarding behavior) and the mediating role of misinformation beliefs related to COVID-19 (including social and pseudoscientific beliefs) in a public health crisis. 1968 Chinese participants completed the Analytical Thinking Test, Misinformation Beliefs Questionnaire and Irrational Behavior Questionnaire online. The results showed that (1) Analytical thinking had a negative prediction on both excessive epidemic prevention and hoarding behavior; (2) misinformation beliefs, even social misinformation beliefs, partly mediated the relationship between the analytical thinking and irrational behaviors. These findings provide some useful references for effectively reducing people’s irrational behaviors during a public health crisis.
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Phase 3 Study of the Safety and Immunogenicity of COVID-19 and Influenza Combination Vaccine - Conditions: COVID-19 Interventions: Biological: CIC Vaccine Co-formulated tNIV2 , SARSCoV-2 rS and Matrix-M Adjuvant; Biological: Novavax COVID-19 Vaccine; Biological: Comparator Influenza Vaccine - Fluarix; Biological: Comparator Influenza Vaccine -Fluarix High Dose; Biological: Placebo 0.9% sodium chloride for injection Sponsors: Novavax Not yet recruiting
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Evaluation of KGR Prescriptions in Suppressing COVID-19 Infection. - Conditions: Coronavirus Disease 2019; Severe Acute Respiratory Syndrome Coronavirus 2 Infection Interventions: Combination Product: Kang Guan Recipe (Treat); Combination Product: Kang Guan Recipe (Placebo) Sponsors: Sheng-Teng Huang Completed
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SHEN211 Tablets for the Treatment of Mild and Moderate Novel Corona Virus Infections (COVID-19) - Conditions: COVID-19 Interventions: Drug: SHEN211 Tablets; Procedure: Placebo for SHEN211 Tablets Sponsors: JKT Biopharma Co., Ltd. Not yet recruiting
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INAVAC Vaccine Phase III (Immunobridging Study) in Healthy Population Aged 12 to 17 Years Old - Conditions: COVID-19 Pandemic; COVID-19 Vaccines Interventions: Biological: INAVAC (Vaksin Merah Putih - UA-SARS CoV-2 (Vero Cell Inactivated) 5 µg Sponsors: Dr. Soetomo General Hospital; Indonesia-MoH; Universitas Airlangga; PT Biotis Pharmaceuticals, Indonesia Recruiting
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Study to Evaluate the Safety & Immunogenicity of IMNN-101 Administered in Healthy Adults Previously Vaccinated Against SARS-CoV-2 - Conditions: SARS CoV 2 Infection Interventions: Biological: IMNN-101 Sponsors: Imunon Not yet recruiting
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Immunogenicity and Safety Study of Self-amplifying mRNA COVID-19 Vaccine Administered With Influenza Vaccines in Adults - Conditions: COVID-19 Interventions: Biological: ARCT-2303; Biological: Influenza vaccine; Biological: Influenza vaccine, adjuvanted; Other: Placebo Sponsors: Arcturus Therapeutics, Inc.; Seqirus; Novotech (Australia) Pty Limited Not yet recruiting
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Effectiveness of a Nasal Spray on Viral Respiratory Infections - Conditions: Acute Respiratory Tract Infection; Flu, Human; COVID-19; Common Cold Interventions: Device: Nasal Spray HSV Treatment Sponsors: CEN Biotech; Urgo Research, Innovation & Development Recruiting
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GS-441524 for COVID-19 SAD, FE, and MAD Study in Healthy Subjects - Conditions: COVID-19 Interventions: Drug: GS-441524; Drug: Placebo Sponsors: National Center for Advancing Translational Sciences (NCATS); Leidos Biomedical Research, Inc.; ICON Government and Public Health Solutions, Inc Not yet recruiting
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UNAIR Inactivated COVID-19 Vaccine INAVAC as Heterologue Booster (Immunobridging Study) in Adolescent Subjects - Conditions: COVID-19 Pandemic; COVID-19 Vaccines Interventions: Biological: INAVAC (Vaksin Merah Putih - UA- SARS CoV-2 (Vero Cell Inactivated) 5 μg Sponsors: Dr. Soetomo General Hospital; Indonesia-MoH; Universitas Airlangga; PT Biotis Pharmaceuticals, Indonesia Active, not recruiting
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The Aerobic Exercise Capacity and Muscle Strenght in Individuals With COVID-19 - Conditions: COVID-19 Pneumonia; COVID-19 Interventions: Device: Kardiopulmonary exercise test (Quark KPET C12x/T12x device connected to the Omnia version 1.6.8 COSMED system); Device: Peripheral muscle strength measurement (microFET3 (Hoggan Health Industries, Fabrication Enterprises, lnc) and JAMAR hydraulic hand dynamometer (Sammons Preston, Rolyon, Bolingbrook).; Device: Standard exercise tolerance test (a bicycle ergometer and recorded through the ergoline rehabilitation system 2 Version 1.08 SPI.); Device: Aerobic exercise training (a bicycle ergometer and recorded through the ergoline rehabilitation system 2 Version 1.08 SPI.) Sponsors: Selda Sarıkaya; Zonguldak Bulent Ecevit University Completed
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From PubMed
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Immunomodulatory and anticytokine therapeutic potential of three Indian spices constituents and its hyaluronic acid conjugates for prevention and post COVID-19 complications: a computational modeling approach - Targeted drug delivery to SARS-CoV-2 host target proteins for preventing or blocking COVID-19 infection is making serious concern during COVID-19 pandemic and its consequent waves around the globe. People seek reliable, effective folkloric preventive medication for immediate and precautionary relief from COVID-19. These folkloric medicines were effective and saved many patients during the past COVID-19 pandemic. The current research study aims to deliver antiviral Indian spices phytocompounds…
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Altered DNA methylation underlies monocyte dysregulation and immune exhaustion memory in sepsis - Monocytes can develop an exhausted memory state characterized by reduced differentiation, pathogenic inflammation, and immune suppression that drives immune dysregulation during sepsis. Chromatin alterations, notably via histone modifications, underlie innate immune memory, but the contribution of DNA methylation remains poorly understood. Using an ex vivo sepsis model, we show altered DNA methylation throughout the genome of exhausted monocytes, including genes implicated in immune…
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Targeting SIRT1 by Scopoletin to Inhibit XBB.1.5 COVID-19 Life Cycle - Natural products have historically driven pharmaceutical discovery, but their reliance has diminished with synthetic drugs. Approximately 35% of medicines originate from natural products. Scopoletin, a natural coumarin compound found in herbs, exhibits antioxidant, hepatoprotective, antiviral, and antimicrobial properties through diverse intracellular signaling mechanisms. Furthermore, it also enhances the activity of antioxidants. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)…
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What kind of a problem is loneliness? Representations of connectedness and participation from a study of telepresence technologies in the UK - Loneliness is represented in UK policy as a public health problem with consequences in terms of individual suffering, population burden and service use. However, loneliness is historically and culturally produced; manifestations of loneliness and social isolation also require social and cultural analysis. We explored meanings of loneliness and social isolation in the UK 2020-2022 and considered what the solutions of telepresence technologies reveal about the problems they are used to address….
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Integrated Metabolomic and transcriptomic analyses reveal deoxycholic acid promotes transmissible gastroenteritis virus infection by inhibiting phosphorylation of NF-kappaB and STAT3 - CONCLUSIONS: We identified a significant metabolite, DCA, related to TGEV replication. It added TGEV replication in host cells by inhibiting phosphorylation of NF-κB and STAT3. This study provided novel insights into the metabolomic and transcriptomic alterations related to TGEV infection and revealed potential molecular and metabolic targets for the regulation of TGEV infection.
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Therapeutic role of miR-19a/b protection from influenza virus infection in patients with coronary heart disease - Patients with pre-existing medical conditions are at a heightened risk of contracting severe acute respiratory syndrome (SARS), SARS-CoV-2, and influenza viruses, which can result in more severe disease progression and increased mortality rates. Nevertheless, the molecular mechanism behind this phenomenon remained largely unidentified. Here, we found that microRNA-19a/b (miR-19a/b), which is a constituent of the miR-17-92 cluster, exhibits reduced expression levels in patients with coronary…
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Simple virus-free mouse models of COVID-19 pathologies and oral therapeutic intervention - The paucity of preclinical models that recapitulate COVID-19 pathology without requiring SARS-COV-2 adaptation and humanized/transgenic mice limits research into new therapeutics against the frequently emerging variants-of-concern. We developed virus-free models by C57BL/6 mice receiving oropharyngeal instillations of a SARS-COV-2 ribo-oligonucleotide common in all variants or specific to Delta/Omicron variants, concurrently with low-dose bleomycin. Mice developed COVID-19-like lung pathologies…
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Comparative Immunogenicity and Neutralization Potency of Four Approved COVID-19 Vaccines in BALB/c Mice - CONCLUSION: Our results indicate significant immunogenicity and neutralization efficacy induced by PastoCovac Plus and Sinopharm, but not by Noora and SpikoGen. This suggests the need for additional comparative assessment of the potency and efficacy of these four vaccines in vaccinated subjects.
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Potential Therapeutic Strategies and Drugs That Target Vascular Permeability in Severe Infectious Diseases - Severe infection pathogenicity is induced by processes such as pathogen exposure, immune cell activation, inflammatory cytokine production, and vascular hyperpermeability. Highly effective drugs, such as antipathogenic agents, steroids, and antibodies that suppress cytokine function, have been developed to treat the first three processes. However, these drugs cannot completely suppress severe infectious diseases, such as coronavirus disease 2019 (COVID-19). Therefore, developing novel drugs that…
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Preliminary report on therapeutic potential of coal-derived carbon quantum dots against SARS-CoV-2 virus - Due to the pandemic of COVID-19 and subsequent emerging of new mutant strains, there has been a worldwide hunt for therapeutic and protective agents for its inhibition. In this short communication, for the first time, we report the coal-derived carbon quantum dot (CQD) for the possible therapeutic application against SARS-CoV-2. The synthesized C1-CQD is observed to be safe towards the normal cell line at highest dose, while effectively inhibiting growth of SARS-CoV2 (>95%) with IC(50) value of…
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SARS-CoV-2 Membrane protein regulates the function of Spike by inhibiting its plasma membrane localization and enzymatic activity of Furin - The presence of a multibasic cleavage site in the Spike protein of SARS-CoV-2 makes it prone to be cleaved by Furin at the S1/S2 junction (aa. 685-686), which enhances the usage of TMPRSS2 to promote cell-cell fusion to form syncytia. Syncytia may contribute to pathology by facilitating viral dissemination, cytopathicity, immune evasion, and inflammation. However, the role of other SARS-CoV-2 encoding viral proteins in syncytia formation remains largely unknown. Here, we report that SARS-CoV-2 M…
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Role of telerehabilitation in the rehabilitation of children with cerebral palsy during COVID-19: A review - Individuals with cerebral palsy (CP) have limited mobility and are unable to actively participate in tasks that are part of their daily living. Thus, continuous therapeutic sessions are required to keep such individuals active and engaged in the environment. Due to the coronavirus disease of 2019 (COVID-19) lockdowns, rehabilitation for children with CP was inhibited which consequently put them at risk of losing their functional gains which were obtained through previous in-person therapies. In…
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Prophylactic effect of ensitrelvir in mice infected with SARS-CoV-2 - Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiological cause of coronavirus disease 2019 (COVID-19) and continues to be a major health concern worldwide. Strategies to protect individuals at high risk of COVID-19 are critical but are currently a largely unmet need. We evaluated the oral antiviral drug ensitrelvir, which specifically targets the SARS-CoV-2 3CL protease, for its efficacy as a pre-exposure prophylactic treatment. Aged BALB/c mice were subcutaneously treated…
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Priming congruence and COVID-19 vaccination intention: a mediation analysis - CONCLUSIONS: Implications of these results are discussed in light of the socially situated cognition perspective and the congruence of (a) a societal context of communication toward the vaccine and the unvaccinated, (b) the participant’s degree of adherence to that communication, (c) the theme of priming, whether or not related to feeling connected to others. Implications of materialism priming are discussed, and the effect of commitment on intention to get vaccinated.
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A subunit-based influenza/SARS-CoV-2 Omicron combined vaccine induced potent protective immunity in BALB/c mice - Infection with influenza A virus (IAV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a significant risk to human life, health, and the global economy. Vaccination is one of the most effective strategies in the fight against infectious viruses. In this study, we, for the first time, have evaluated the immunogenicity and protective effect of an influenza/SARS-CoV-2 Omicron subunit combined vaccine adjuvanted with MF59 and administered to BALB/c mice. Results showed that…
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From Patent Search
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What Biden Should Say About the Economy During the State of the Union - With the President’s economic approval rating standing at just forty per cent, it’s imperative for him to highlight some of his substantive achievements and talk about the future. - link
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Forty-three Mexican Students Went Missing. What Really Happened to Them? - One night in 2014, a group of young men from a rural teachers’ college vanished. Since then, their families have fought for answers. - link
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Lucy Prebble’s Dramas of High Anxiety - In plays such as “The Effect” and TV shows such as “I Hate Suzie” and “Succession,” the writer has become an expert at getting deep inside worried characters’ heads. - link
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Joe Biden’s Last Campaign - Trailing Trump in polls and facing doubts about his age, the President voices defiant confidence in his prospects for reëlection. - link
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The Legacy of RuPaul’s “Drag Race” - The drag star brought the form mainstream, and made an empire out of queer expression. Now he fears “the absolute worst.” - link
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From Vox
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Democrats’ latest problem: 1 in 5 Latino voters are considering switching parties -
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+A Trump 2024 flag waves at a “Freedom Rally” in support of Cubans demonstrating against their government in Miami on July 17, 2021. | Eva Marie Uzcategui/AFP via Getty Images
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+Both Democrats and Republicans are considering making a change, but it’s Biden’s party that has more to lose.
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+Since 2020, one of the major questions hanging over the 2024 election is whether Latino voters will continue to ditch Democrats in favor of the GOP. Now, a new national poll of Latino voters offers some warning signs for Republicans as well as Democrats as the general election crystallizes: A sizable chunk of Latino voters appear to be willing to rethink their party loyalties.
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+Some 19.4 percent, or about one in five Latino voters, say they have considered changing their political affiliation either by switching parties or becoming independents, according to a national survey released by Florida International University (FIU) and the marketing firm Adsmovil. A majority of those wavering voters (61.1 percent) say they’d be open to leaving the Democratic Party and a plurality of those Democratic waverers (38.1 percent) would become Republicans.
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+Though that’s a small share of all Latino voters, that’s still a significant number for a demographic group whose loyalty to Democrats has been eroding since Donald Trump’s presidency.
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+“We used to say in political science that party [identification] was one of the most stable things that we could use to study,” Eduardo Gamarra, the co-director of FIU’s Latino Public Opinion Forum and the author of this study, told me. “It was generational. You could go back three or four generations of voters and [party ID] would remain stable. Now, all of that is changing, and especially so among Hispanics.”
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+To be sure, a majority of Latino respondents say they are still pretty firm in their political identity and affiliation. Democrats — including President Joe Biden — still win the support of an outright majority of Latino voters.
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+Some caveats are also in order when looking at polls: This result is just one data point — a snapshot in time at the end of 2023. And the election is still eight months away, so dynamics could definitely change.
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+But it’s a large, high-quality piece of data — a nationally representative sample of 1,221 Latino voters instead of an extrapolation from a tiny crosstab sample of a few hundred. Since 2020, other surveys and election results have also shown that Democrats are struggling to retain the support of Latino voters and reverse Republican gains. This FIU report suggests that trend is continuing.
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+It also suggests that 2024 is shaping up to be a tumultuous year for American voters, particularly those younger and more diverse constituencies that make up a core part of the Democratic coalition, including Latino and Hispanic voters. These voters are feeling pressure from many directions, and Republicans have an opportunity to expand the inroads they have made and held since the 2020 election.
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+The Democratic coalition is changing. The open question is just how drastic that change will be.
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+Latinos’ partisanship has been fairly stable
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+Gamarra is right when he says that partisanship has tended to be a pretty static factor in American politics; the same is roughly true for Latino voters. Looking at survey data from 1994 to 2017, the Pew Research Center reports that partisan affiliation among all registered voters has generally not changed in those two decades. The same has been true for Hispanic and Latino voters in the years for which Pew has data available: The share of Latino voters identifying as Democrats or leaning to that party has stayed roughly the same from 2004 to 2017 with about a 60-30 split in affiliation.
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+But more recently, those allegiances have shifted a bit — and to Democrats’ detriment. Trump made electoral gains with Latinos in 2020 that Republican candidates were generally able to keep during the 2022 midterms. And the Democratic advantage in Latino partisan affiliation began to shrink during and after Trump’s presidency. In 2017, for example, Democrats enjoyed a 35-point advantage over Republicans with whom Latino voters identified; two years later, that advantage was 28 points, according to Pew’s numbers. That smaller gap stuck around in 2022.
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+Those are small shifts, but they point to there being fertile ground for additional changes in partisan loyalty during the 2024 cycle.
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+And this is where the FIU/Adsmovil study adds new insights: Those 19 percent of Hispanic and Latino voters who say they’d be open to switching parties are mostly voters who’d be open to leaving the Democratic coalition — about 60 percent of those voters.
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+More specifically, 38.1 percent of these wavering voters would flip affiliation from Democratic to Republican. An additional 23 percent would switch from Democratic to independent.
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+The survey also showed Latino Republicans rethinking their chosen party. But those Democratic losses are greater than whatever gains they would make from Republicans changing their loyalty. Of these waverers, 11.1 percent would flip from Republican to Democrat and 6.2 percent would leave the Republicans to become independent.
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+There’s a silver lining for Democrats among self-described independent Latino voters who are considering a change. There, 9 percent would become Democrats, as opposed to the 5.3 percent who would become Republicans.
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+These numbers confirm a finding from Pew after the 2022 midterms that, though partisan affiliation has been relatively stable for most of the last 20 years, the future of these patterns “remains uncertain.” A good deal of Latino voters are the kind of partisans “with soft ties to the political parties.” According to Pew, there are about one in 10 Latino voters who call themselves Democrat or Republican but hold political and ideological views that are much closer to the opposite political party.
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+These are the kind of cross-pressured, persuadable voters that could be won over through smart campaigning, tailored messaging, and exploiting the preexisting sense of dissatisfaction many voters have with both parties.
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+An opportunity doesn’t guarantee an outcome
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+These figures all suggest that Republicans have a big opportunity in 2024 to reorder demographic and political coalitions. But it won’t be easy.
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+When asked which political party would better handle specific issues, Democrats still receive the support of a majority of Latino voters on traditionally Democratic topics, like education or health care, in this FIU/Adsmovil study. But they only get a plurality of support on the economy, immigration, and foreign policy — areas that make sense for Republicans to center as campaign issues this cycle.
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+At the presidential level, the FIU poll also shows that Trump and Republicans can hold onto their 2020 gains. A third of Latino voters say they’d back Trump now, while a slight majority of 53 percent would back Biden. A separate 13 percent aren’t sure about their pick, and it’s this wavering group of voters that Republicans have a chance to attract and that may have a wavering loyalty to Biden specifically.
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+Still, about 60 percent of Latino voters in this poll think the Democrats are the political party that best represents them, compared to the 24 percent who say that about Republicans. That 60 percent is higher than both the share of voters who would call themselves Democrats (56 percent), and who would back Biden now (53 percent), which suggests room for Democratic growth and a challenge for Republicans who will have to do a lot of persuasion in the next few months.
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+And there will be more to complicate the path for Republicans: Latino voters have a lower propensity to vote, to be tuned into the political cycle at this point, and to hear from political candidates, meaning they’ll have to invest heavily in outreach and specific messaging to these communities. Democrats have a slight leg up on this, given how much they have relied on Latino voters before.
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+But all the signs are pointing toward an electorate in churn. It may still shift a lot in the coming months, and it may surprise a lot of people come November.
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Republicans just passed up the chance to win a historic landslide -
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+Nikki Haley waves to supporters in Texas. | Mark Felix/Bloomberg via Getty Images
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+If Republicans ever figure out how to nominate a normal human, Democrats could be in trouble.
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+Donald Trump and Joe Biden are among the mostunpopular politicians in their respective parties. And yet, both routed their competition in Super Tuesday’s primary elections. Unless either man dies or abruptly retires, they will both be on the presidential ballot this November.
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+Although both parties are uniting behind weak standard-bearers, the Democrats’ apparent strategic failure has attracted greater scrutiny. Which is understandable. After all, it is Biden — not Trump — who is on pace to lose, if current polls are any guide. Given the president’s advanced age and extraordinarily low approval rating, it’s hard to believe that he is Blue America’s best hope.
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+And yet, when pollsters ask voters for their preference in a hypothetical race between Trump and various other prominent Democrats, no Biden alternative consistently outperforms the president. An Emerson College poll released last month showed Trump leading Biden by 1 point, besting Kamala Harris by 3 points, and routing California Gov. Gavin Newsom and Michigan Gov. Gretchen Whitmer by 10 and 12 points respectively.
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+These results likely reflect Whitmer’s and Newsom’s low national name recognition more than anything else (in Michigan, where Whitmer is widely known, she does much better than Biden against Trump). Nevertheless, it remains the case that there is no stack of polling data showing any given Democrat trouncing Trump. And there has also been no challenger in the Democratic primary field capable of winning a non-negligible share of the vote.
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+Things are different in Red America. Former South Carolina Gov. Nikki Haley never posed a serious threat to Trump’s renomination.
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+If she had beaten him, however, polls suggest that Republicans could all but guarantee their coalition’s triumph in November. Instead, they’ve settled on a candidate that a majority of voters disdain.
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+In national polls of a hypothetical 2024 race, Haley leads Biden by an average of 5 points, while Trump edges the president by just 2. And the gap between the two Republicans’ respective showings is more pronounced in some of America’s most highly regarded surveys. The latest New York Times/Siena College poll, for example, puts Trump’s lead over Biden at 5 points and Haley’s at 10. More remarkably, Haley’s double-digit advantage in the poll comes despite the fact that a quarter of Trump’s supporters wouldn’t commit to backing her. Were Haley to consolidate the support of voters who prefer Trump over Biden, her lead over the president would swell to 24 points.
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+Haley has also secured landslide margins in some battleground-state polls. Last month, a Marquette Law School survey showed Trump statistically tied with Biden in Wisconsin, even as Haley bested the president in the pivotal swing state by 15 points.
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+All this should make both parties uncomfortable.
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+By all appearances, Republicans have just forfeited the opportunity to secure a Reagan-esque national landslide. Beyond likely ensuring Biden’s defeat, a Haley nomination would have given the GOP an excellent chance of amassing large congressional majorities to boot. In today’s America, all politics is national. Voters tend to back the same party up and down the ballot. A Haley landslide would therefore have translated into massive Republican success in House, Senate, and state elections.
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+This in turn would have made many of the conservative movement’s longtime goals more legislatively feasible. Republicans came one vote shy of partially repealing the Affordable Care Act in 2017. At that time, they held only 51 Senate seats. With larger majorities, the GOP would likely be able to slash federal health care spending and top tax rates. More consequentially, a large Republican Senate majority would plausibly have the votes to abolish the legislative filibuster, and then enact nationwide restrictions on abortion, sharp cuts in legal immigration, and myriad other conservative aspirations.
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+A relatively narrow Trump victory, by contrast, could leave much of the right’s agenda unfulfilled. A close Republican win at the presidential level would even be compatible with Democrats winning a House majority, an outcome that would tightly constrain conservatives’ policy gains.
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+In other words, the conservative movement had a golden opportunity in 2024 to secure an electoral landslide with transformational policy implications. Republicans won’t get to run against an 81-year-old man with a 56 percent disapproval rating every election cycle. Widespread discontent with post-Covid inflation and distrust of Biden’s mental fitness has created an opening for the GOP to win big without making significant ideological compromises (Haley is a very conservative Republican, by any reasonable metric). Instead, Republicans decided to throw Biden a lifeline by mobilizing behind a serially indicted demagogue whom a majority of Americans dislike.
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+Thus, Democrats dodged a bullet. But that brush with electoral devastation should inspire more concern than relief. Trump won’t be around forever. A post-MAGA Republican Party is coming. And for the moment, the Democratic brand looks to be in dire shape.
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+Last fall, voters told Gallup that they believed Republicans would do a better job than Democrats on “keeping the country prosperous” by a margin of 53 to 39 percent. In the past three decades of Gallup’s polling, Republicans have never had a larger edge on economic management.
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+According to the same survey, the GOP also boasts a 22-point advantage on national security and an 8-point one on “the problem you think is most important” (whatever that may be).
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+Gallup’s findings are consistent with those of other recent surveys. An NBC News poll from late last year found voters trusting Republicans over Democrats on the economy by a 21-point margin and on immigration by an 18-point one. Other recent polling indicates that these are the most politically salient issues to Americans at the moment. Perhaps most alarmingly, however, NBC found Republicans nearly erasing the Democrats’ perennial lead on “looking out for the middle class.” Since the New Deal era, the perception that Democrats are uniquely concerned with the plight of ordinary Americans has been one of the party’s core strengths.
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+Democratic leaders are not fully to blame for their party’s damaged reputation. Virtually every country suffered a spike in inflation when their economies reopened following the Covid crisis. And virtually every party that happened to be in power when prices surged has seen its approval numbers collapse. Biden’s polling is terrible by historical standards but not by international ones. While Biden’s approval rating sits at a measly 38 percent, Canadian Prime Minister Justin Trudeau’s is at 32 percent, and British Prime Minister Rishi Sunak’s has fallen to 21 percent.
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+Nevertheless, the costs of presiding over widely resented economic conditions can be long-lasting. As the political scientists Larry Bartels and Christopher Achen have shown, parties that found themselves in power when the Great Depression struck tended to struggle electorally for a generation, regardless of their ideological orientation. America has scarcely suffered an economic cataclysm on Biden’s watch, but the Democrats’ association with a period of anomalously fast price growth threatens to reinforce damaging stereotypes about liberals’ fiscal irresponsibility.
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+Democrats must therefore hope that Trump’s unique toxicity combined with the US economy’s objective strength allow Biden to overcome both the globe-spanning backlash to incumbents and his own personal liabilities. In the longer run, however, the party must somehow regain the American public’s trust on economic management before Republicans figure out how to nominate a normal presidential candidate.
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No one wants an Oscar as badly as Bradley Cooper -
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+This is Bradley Cooper’s face. | Axelle/Bauer-Griffin/FilmMagic
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+Maestro’s Oscar campaign has shown us the real Bradley Cooper: He’s a try-hard.
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+Where were you when you realized that you knew too much about Bradley Cooper? Was it when he revealed he spent six years studying conducting to perform as Leonard Bernstein in his auteurist Netflix original film Maestro? Or perhaps it was the time he cried in front of Bernstein’s surviving family. Maybe it was when he said his dad walked around naked his whole childhood? Or when you learned that he reportedly “hates” chairs, and banned them on his set because they suck the energy out of the people who sit in them?
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+The reason many of us know a lot about Cooper at this moment is that he’s in the home stretch of an Oscar campaign for Maestro, which he directed, co-wrote, and starred in. The film is up for seven Oscars, including Best Picture and Best Actor for Cooper.And an Oscar campaign means a lot of talking about the movie in the hope that what you say will sway voters to give said film awards. Cooper currently has zero Oscars, despite 12 total nominations, and the interviews he’s been giving indicate that he would very much like to change that goose egg.
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+What’s perhaps strange to some is that Bradley Cooper is a man who became famous for being cool and hot, and for starring in movies — Wet Hot American Summer,Wedding Crashers, The Hangover, Guardians of the Galaxy — that aren’t Oscar stuff.
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+When did the guy who voices a machine gun-toting space raccoon start caring about the interior life of Leonard Bernstein? When exactly did the bro in Wedding Crashers become a method actor? Why is a guy who is so good at being likable in some movies so unbelievably bad at being likable in real life?
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+The thing is: It’s the other way around. This extremely serious, try-hard man who hates chairs and loves Leonard Bernstein is who Bradley Cooper has always been — whether we like him or not.
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+What if Bradley Cooper has always been a try-hard?
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+Cooper has been in the conversation for acting Oscars since 2012’s Silver Linings Playbook. Cooper wasn’t going to beat Daniel Day-Lewis’s turn as Abraham Lincoln at that year’s ceremony, but he was largely seen as a talented underdog who showed more versatility than his previous roles. Looking back, Cooper probably should have received more awards for his 2018 directorial debut, A Star is Born. He could have taken home the Best Actor award that year — Rami Malek’s win for Bohemian Rhapsody seems more clownish by the day — and even if the film was not Best Picture, it’s clear no film should have lost to Green Book.
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+ Wiktor Szymanowicz/Future Publishing via Getty Images
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+Honestly, Bradley Cooper probably shouldn’t have lost to Green Book. No one should have lost to Green Book.
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+But it was during that latter Oscar run that something shifted.
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+In September 2018, during the Oscar campaign for A Star is Born, the New York Times published a story on Cooper entitled “Bradley Cooper Is Not Really Into This Profile.” Journalist Taffy Brodesser-Akner detailed at length how reluctant Cooper was to give her personal details about the extremely powerful film he created, to the point where Cooper seemed disenchanted, even annoyed at her. He basically told her that she and anyone else who isn’t an artist like Cooper would never fully understand the way he creates art.
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+The Hollywood Reporter’s Scott Feinberg explained at the time that the New York Timesprofile soured Cooper’s image, that he was no longer seen as the talented, lovable hunk but an actor-director who had suddenly become insufferably self-serious.
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+But the thing is, and what Brodesser-Akner highlights so well in that profile, is that Cooper was never a stud who accidentally became a serious actor. It’s the other way around. Cooper has always been a serious theater kid, one who got his MFA at the Actors Studio, who just happened to get famous for playing hot idiot bros.
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+There is no better evidence of who Bradley Cooper is than footage from his time as a student at the Actors Studio, where successful thespians often dropped by — on camera! — to share their wisdom. Cooper has said that he learned firsthand from Ellen Burstyn, and he famously asked Robert De Niro an extremely nerdy question about his mannerisms and the nuance behind his gestures. There’s also a clip of Cooper geeking out and asking Sean Penn about David Mamet’s Hurlyburly and what it was like to revisit a theater role for a movie adaptation.
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+When Cooper returned to the Actors Studio in 2011, this time as a pro, he spoke about The Hangover at length. In that film, Cooper’s character is attacked by a tiger during a Vegas bachelor party, so presumably the actor tried to bring nuance to getting lacerated by a big cat, saying that he was invigorated to “play the truth” of that moment and the movie’s other hijinks.
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+I am not an expert actor nor a victim of a big cat attack, but I can confidently say that Bradley Cooper is extremely serious about acting. Directing, starring in, and writing movies like A Star is Born and Maestro are actually what he’s always wanted, even though he’s so good at playing dudes who are the exact opposite. And what’s made it so strange is that people, including some of his biggest critics, prefer the latter.
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+In retrospect, Cooper snobbily withholding personal details during A Star is Born couldn’t be more different from Cooper bombarding us with TMI about Maestro. Going from telling Brodesser-Akner nothing to telling anyone everything is a stark contrast. But as dissimilar as Cooper’s behavior has been across the two campaigns, they both indicate that this man seriously wants an Oscar.
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+Cooper’s desire just seems much more blazingly obvious with Maestro, a movie that checks so many Oscar-bait boxes — prosthetics, a famous male subject, Mid-Atlantic accents, closeted gayness, Hollywood and Broadway as settings, and a lot of people calling each other “darling,” sometimes in very hostile ways — but has not been the favorite this season.
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+The Maestro press tour has been as endless as it has been winless
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+Campaigning for Maestro has given us the clearest glimpse into Bradley Cooper’s most serious form. Since its release in September, the movie has been accompanied — if not eclipsed — by Cooper talking about how hard the film was to make, how committed he was in making the biopic, and how the experience changed him on an empirical level.
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+For starters: his vendetta against chairs. Talking to fellow director Spike Lee for Variety, Cooper said that chairs are like vampires. Seats, you see, suck the power from people on them. It might seem like a rest for achy knees or a respite for your barking dogs, but to Cooper that’s all a trap. “I’ve always hated chairs on sets; your energy dips the minute you sit down in a chair,” he told Lee.
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+ Gotham/GC Images
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+Bradley Cooper on the set of Maestro with Steven Spielberg and not a chair to be seen!
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+In addition to running his movies with the same spirit as a Zara floor manager, Cooper also told Lee that he was so deep into the role of Leonard Bernstein that he would give out orders in Leonard Bernstein’s voice. “Yes, I was playing Lenny throughout his life,” he said. “It was hilarious, because on days when I was young Lenny, the energy of the set was faster and we got more done. And then when I was old Lenny, it had a slower gear. If you ask the crew or cast, Lenny directed the movie.”
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+Yet, despite six years studying how conductors’ arms move (up, down, side to side), not sitting, and developing an emotional attachment to Bernstein so powerful that his spirit moves the director to cry, Cooper has lost every major acting award that he’s been up for this past year. That wouldn’t be an issue if Cooper didn’t seem to care so much.
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+If Cooper is finding out in real time that Hollywood doesn’t care how hard you work, he is also learning, in real time, another cold truth: There are few things people love to dislike more than an actor who talks endlessly about how hard they work.
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+The awards show circuit has galvanized the chortling and “get a load of this guy” quips during the Maestro press tour into mildly malicious glee at watching Cooper lose prize after prize. Screencaps of Cooper’s reaction after losing to Cillian Murphy at the Golden Globes and the SAGs have gone viral. Of course, no one but Cooper knows what’s going on in Cooper’s brain after these losses. But given the rounds he’s done in the media and spontaneous crying, his haters have created their own popular narrative about how much this must hurt a man who wants all the awards so bad.
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+Adding possible insult to injury, Murphy, who will probably beat Cooper at the Oscars this week, said it took him only six months to prepare for Oppenheimer. Six months is nothing compared to six years. (Although, if it helps, Murphy might not have been allowed to sit on set.)
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+Bradley Cooper just can’t win — and that’s the part we hate most
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+The backlash against Cooper isn’t unlike the kind of conversations that surround fellow thespians Jared Leto and Jeremy Strong. People find their deep, serious commitment to the craft — which usually manifests in some sort of anecdote about method acting — annoying if not insufferable. It just seems so difficult for certain actors, whose professions are all about being perceived in very specific ways, to not be annoying. If their job is about faking it, why can’t they just fake this one thinga little bit? And if you’re lucky enough to be in the middle of an Oscars campaign, isn’t that part of the job?
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+Perhaps it’s because they’ve never really had to worry about it too much.
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+Actresses have found it more difficult than their male counterparts when it comes to likability. After winning Oscars in 2013, Anne Hathaway and Jennifer Lawrence were each dragged for trying so hard to be good at their jobs and acceptably charming in interviews. Every movie they’re in now seems to come with an implicit acknowledgment of how sexist and horrible we were to them back then.
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+ AaronP/Bauer-Griffin/GC Images
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+For someone so anti-chair, Bradley Cooper seems extremely comfortable sitting in one.
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+For men, being annoying is usually forgiven if the final product is worth it. The quality of their movies has always been more important than whether or not they seem like fun to be around. That measure of quality is perhaps why certain actors (Daniel Day-Lewis) get a pass with being pretentious, and why an actor’s placing on the insufferable index isn’t permanent (Christian Bale seems to float in and out of it).
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+For actors-turned-directors, the pipeline is even more forgiving, provided the work turns out. Kevin Costner and Mel Gibson were both mocked for their first projects — Dances with Wolves was derided as “Kevin’s Gate,” a nod to the notoriously time-consuming Terrence Malick film “Heaven’s Gate,” and Braveheart’s notoriously inaccurate history was a point of fun — but those jokes seemingly disappeared when the films became award winners. Similarly, Clint Eastwood’s career highs as a director have made it exponentially easier to forget some of the egregious stinkers he’s created or his outspoken politics.
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+Perhaps the prime model for actor-directors who tend to be a little embarrassing is Ben Affleck. Affleck seems to always be on the brink of anguish or on the verge of a cultural renaissance. His career is peppered with redemptive directorial highs like Gone Baby Gone, The Town, and Best Picture winner Argo; but also sad Batman, sad phoenix tattoo Affleck, and the saga of Bennifer 2.0. Instead of trying to fight the scrutiny, the mockery, and public perception, Affleck now simply states: I am who I am.
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+For Cooper, he’s always had the privilege of being more concerned with people liking the stuff he creates than people personally liking him. That’s what the New York Timesprofile got at: a guy who was so obsessed with the movie he made that he couldn’t help but sound like an absolute jerk about it.
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+Directing and acting in a movie is Cooper in his most honest form.
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+The problem is that this time around, Maestro isn’t stellar enough to warrant everything Bradley Cooper has been saying about the making of Maestro. This, of course, shouldn’t deter Cooper from directing, but if he focused on acting, just for a moment, it might make us believe that he doesn’t care quite as much as he clearly, painfully does.
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From The Hindu: Sports
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West Brook, Jersey King, African Gold, Emeraldo and Carat Love excelled -
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Come September shines -
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Spanish prosecutors accuse Real Madrid coach Carlo Ancelotti of alleged tax fraud - They accused the Italian coach of having defrauded 1 million euros in 2014 and 2015.
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Shabnim Ismail bowls fastest delivery in women’s cricket, breaches 130kph - Playing for Mumbai Indians in their Women’s Premier League match against Delhi Capitals at the Arun Jaitley Stadium, Ismail shattered the record by clocking 132.1km/h
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Champions League | Kane double sends Bayern past Lazio into quarterfinal; Mbappe brace sees PSG through - Bayern Munich have now made it to at least the final eight in 12 of the last 13 Champions League campaigns.
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From The Hindu: National News
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Social security law for State’s gig workers in final stage, says Sivankutty - Labour Minister announces Thozhilali Sreshta awards in nineteen categories
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Here are the big stories from Karnataka today - Welcome to the Karnataka Today newsletter, your guide from The Hindu on the major news stories to follow today. Curated and written by Nalme Nachiyar.
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Bengaluru Rameshwaram Cafe blast | NIA announces ₹10 lakh reward for information on prime suspect - At least 10 people were injured in the blast at Rameshwaram Cafe in Brookfield in East Bengaluru on March 1
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Watch | Explained: What led to the violence in Sandeshkhali? - Women of this region in West Bengal have alleged sexual assault and land grab by local Trinamool Congress leaders, and at the centre of the storm is Sheikh Shahjahan
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PM Modi will visit Arunachal Pradesh on March 9 to inaugurate strategic Sela Tunnel - PM Modi will also lay the foundation stone for around 20 development projects, before proceeding to neighbouring Assam
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From BBC: Europe
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Row over ‘woke’ map as Paris gears up for Olympics - Conservatives in France are taking aim at a missing cross and the absence of the French tricolour.
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German ambassador to UK not sorry for leaked call - Miguel Berger told the BBC one of the participants had likely dialled in over a mobile phone or hotel internet.
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ICC issues arrest warrants for Russian commanders - The International Criminal Court has issued the arrest warrants over alleged war crimes in Ukraine.
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Ukraine says seven killed in attack on Russian ship - Kyiv says the Sergei Kotov patrol ship sunk in the Black Sea after a sea drone attack.
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Suspected bird poisonings threaten much-loved Serbian owls - The death of hundreds of birds could harm the wider ecosystem, including a population of long-eared owls.
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From Ars Technica
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Max confirms 2024 password crackdown, explores adding transactional ads - WBD looking for ways to grow newfound streaming business profitability. - link
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SpaceX just showed us what every day could be like in spaceflight - SpaceX wants to make these kinds of days the norm, not the exception. - link
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We drive Mini’s first electric crossover, the 2025 Countryman SE ALL4 - The Countryman SE goes on sale later in 2024, starting at $45,200. - link
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After collecting $22 million, AlphV ransomware group stages FBI takedown - Affiliate claims payment came from AlphV victim, and AlphV took the money and ran. - link
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Microsoft argues Supreme Court’s VCR ruling should doom NYT’s OpenAI lawsuit - Microsoft: Copyright law “no more an obstacle to the LLM than it was to the VCR.” - link
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From Jokes Subreddit
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What’s the difference between a prostitute, a girlfriend and a wife? -
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+A prostitute says “Faster, faster!” A girlfriend says “More, more!” A wife says “Beige… I think I’ll paint the ceiling beige.”
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One day Jimmy John went to into a brothel on the west coast of Canada. -
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+He was greeted by a stunning hostess that politely asked how they can be of service.
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+Jimmy, with his Newfoundland accent says: “ I would like to see Peggy Sue.”
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+The hostess replies: “ok, she is just finishing up and will be with you momentarily.”
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+Peggy Sue comes out and leads Jim John into the back where she immediately gets right to business. Peg says “$100 for a bj and $200 for the full meal deal.” Jimmy hands her 200 and she rocks his world.
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+The next day, Jim comes back, at the same time and asks the same hostess to see Peggy Sue. This time, Peg was on standby and ready. Peggy, remembering Jimmy, asked him if he wanted to do the same as the day before. Jim nods, hands peg 2 c-notes and away they go.
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+The third day, Jim is back. The hostess says: “let me guess, you’re here to see Peggy Sue.” Jimmy replied “yes bye!” The hostess directed him down the hall to the back room where she was.
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+Peggy, now warming up to Jimmy starts to get into a little small talk with him. She asks Jimmy John: “where are you from? Jim proudly says: “St. John’s, Newfoundland!” Peggy’s expression shows even more curiosity as she says: “so am I! What neighborhood do you live in? !” Jim replies: “East Meadows.” Startled, Peggy Sue says “my parents live in East Meadows!” Jimmy John says: “I know. They’re next door to me and asked me to bring you $600.”
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Wiktor Szymanowicz/Future Publishing via Getty Images
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Gotham/GC Images
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AaronP/Bauer-Griffin/GC Images
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