CGRP inhibits SARS-CoV-2 infection of bronchial epithelial cells and its pulmonary levels correlate with viral clearance in critical COVID-19 patients -
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+Upon infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), patients with critical coronavirus disease 2019 (COVID-19) present with life-threatening respiratory distress, pulmonary damage and cytokine storm. One unexplored hub in COVID-19 is the neuropeptide calcitonin gene-related peptide (CGRP), which is highly abundant in the airways and could converge in multiple aspects of COVID-19-related pulmonary pathophysiology. Whether CGRP affects SARS-CoV-2 infection directly remains elusive. We show that in critical COVID-19 patients, CGRP is increased in both plasma and lungs. Importantly, CGRP pulmonary levels are elevated in early SARS-CoV-2-positive patients, and restore to baseline upon subsequent viral clearance in SARS-CoV-2-negative patients. We further show that CGRP and its stable analogue SAX directly inhibit infection of bronchial Calu-3 epithelial cells with SARS-CoV-2 Omicron and Alpha variants in a dose-dependent manner. Both pre- and post-infection treatment with GRRP and/or SAX is enough to block SARS-CoV-2 productive infection of Calu3 cells. CGRP-mediated inhibition occurs via activation of the CGRP receptor and involves down-regulation of SARS-CoV-2 entry receptors at the surface of Calu-3 cells. Together, we propose that increased pulmonary CGRP mediates beneficial viral clearance in critical COVID-19 patients, by directly inhibiting SARS-CoV-2 infection. Hence, CGRP-based interventions could be harnessed for management of COVID-19.
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Rapid Emergence and Evolution of SARS-CoV-2 Variants in Advanced HIV Infection -
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+Previous studies have linked the evolution of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) genetic variants to persistent infections in people with immunocompromising conditions, but the evolutionary processes underlying these observations are incompletely understood. Here we used high-throughput, single-genome amplification and sequencing (HT-SGS) to obtain up to ~103 SARS-CoV-2 spike gene sequences in each of 184 respiratory samples from 22 people with HIV (PWH) and 25 people without HIV (PWOH). Twelve of 22 PWH had advanced HIV infection, defined by peripheral blood CD4 T cell counts (i.e., CD4 counts) <200 cells/L. In PWOH and PWH with CD4 counts [ā„]200 cells/L, most single-genome spike sequences in each person matched one haplotype that predominated throughout the infection. By contrast, people with advanced HIV showed elevated intra-host spike diversity with a median of 46 haplotypes per person (IQR 14-114). Higher intra-host spike diversity immediately after COVID-19 symptom onset predicted longer SARS-CoV-2 RNA shedding among PWH, and intra-host spike diversity at this timepoint was significantly higher in people with advanced HIV than in PWOH. Composition of spike sequence populations in people with advanced HIV fluctuated rapidly over time, with founder sequences often replaced by groups of new haplotypes. These population-level changes were associated with a high total burden of intra-host mutations and positive selection at functionally important residues. In several cases, delayed emergence of detectable serum binding to spike was associated with positive selection for presumptive antibody-escape mutations. Taken together, our findings show remarkable intra-host genetic diversity of SARS-CoV-2 in advanced HIV infection and suggest that adaptive intra-host SARS-CoV-2 evolution in this setting may contribute to the emergence of new variants of concern (VOCs).
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Antigen-display exosomes provide adjuvant-free protection against SARS-CoV-2 disease at nanogram levels of spike protein -
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+As the only bionormal nanovesicle, exosomes have high potential as a nanovesicle for delivering vaccines and therapeutics. We show here that the loading of type-1 membrane proteins into the exosome membrane is induced by exosome membrane anchor domains, EMADs, that maximize protein delivery to the plasma membrane, minimize protein sorting to other compartments, and direct proteins into exosome membranes. Using SARS-CoV-2 spike as an example and EMAD13 as our most effective exosome membrane anchor, we show that cells expressing a spike-EMAD13 fusion protein produced exosomes that carry dense arrays of spike trimers on 50% of all exosomes. Moreover, we find that immunization with spike-EMAD13 exosomes induced strong neutralizing antibody responses and protected hamsters against SARS-CoV-2 disease at doses of just 0.5-5 ng of spike protein, without adjuvant, demonstrating that antigen-display exosomes are particularly immunogenic, with important implications for both structural and expression-dependent vaccines.
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Longitudinal transcriptional changes reveal genes from the natural killer cell-mediated cytotoxicity pathway as critical players underlying COVID-19 progression -
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+Patients present a wide range of clinical severities in response SARS-CoV-2 infection, but the underlying molecular and cellular reasons why clinical outcomes vary so greatly within the population remains unknown. Here, we report that negative clinical outcomes in severely ill patients were associated with divergent RNA transcriptome profiles in peripheral immune cells compared with mild cases during the first weeks after disease onset. Protein-protein interaction analysis indicated that early-responding cytotoxic NK cells were associated with an effective clearance of the virus and a less severe outcome. This innate immune response was associated with the activation of select cytokine-cytokine receptor pathways and robust Th1/Th2 cell differentiation profiles. In contrast, severely ill patients exhibited a dysregulation between innate and adaptive responses affiliated with divergent Th1/Th2 profiles and negative outcomes. This knowledge forms the basis of clinical triage that may be used to preemptively detect high-risk patients before life-threatening outcomes ensue.
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Revisit the Inhibitory Effects of Glucocorticoids on Immunocytes -
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+Glucocorticoids (GCs) are efficacious agents for reducing inflammation and suppressing immune responses, exerting various effects on immune cells through the intracellular glucocorticoid receptor (GR), and impacting both innate and adaptive immunity. In the context of COVID-19, glucocorticoids are often used to treat severe cases of patients by reducing inflammation, suppressing immune responses, and ameliorating the severity of COVID-19. However, the precise inhibitory effects on immune cells have yet to be comprehensively delineated. In this study, we extensively examined the inhibitory effects of treating Balb/c mice with dexamethasone (DEX) on lymphoid and myeloid cells. We observed that high doses of DEX treatment resulted in a reduction in the number of immunocytes and an attenuation of their activity. Particularly noteworthy, macrophages, DC cells, and monocytes were diminished by approximately 90% following high doses of DEX, while B cells experienced a reduction of about 70% and CD3 T cells were less affected. Furthermore, our findings demonstrated that DEX induces the inhibition of immune cells by engaging in high-affinity binding to GR. Consequently, we conclude that DEX treatments affect a broad range of immune cells, encompassing both lymphoid and myeloid cells, through depletion or the down-regulation of immune function, potentially acting via the GR signaling pathway. These findings may enhance the clinical applicability of DEX in achieving transient immune deficiency.
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Stably-Inverted Apical-Out Human Upper Airway Organoids for SARS-CoV-2 Infection and Therapeutic Testing -
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+Apical-out organoids produced through eversion triggered by extra-organoid extracellular matrix (ECM) removal or degradation are generally small, structurally variable, and limited for viral infection and therapeutics testing. This work describes ECM-encapsulating, stably-inverted apical-out human upper airway organoids (AORBs) that are large (~500 um diameter), consistently spherical, recapitulate in vivo-like cellular heterogeneity, and maintain their inverted morphology for over 60 days. Treatment of AORBs with IL-13 skews differentiation towards goblet cells and the apical-out geometry allows extra-organoid mucus collection. AORB maturation for 14 days induces strong co-expression of ACE2 and TMPRSS2 to allow high-yield infection with five SARS-CoV-2 variants. Dose-response analysis of three well-studied SARS-CoV-2 antiviral compounds [remdesivir, bemnifosbuvir (AT-511), and nirmatrelvir] shows AORB antiviral assays to be comparable to gold-standard air-liquid interface cultures, but with higher throughput (~10-fold) and fewer cells (~100-fold). While this work focuses on SARS-CoV-2 applications, the consistent AORB shape and size, and one-organoid-per-well modularity broadly impacts in vitro human cell model standardization efforts in line with economic imperatives and recently updated FDA regulation on therapeutic testing.
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A speed limit on serial strain replacement from original antigenic sin -
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+Many pathogens evolve to escape immunity, yet it remains difficult to predict whether immune pressure will lead to diversification, serial replacement of one variant by another, or more complex patterns. Pathogen strain dynamics are mediated by cross-protective immunity, whereby exposure to one strain partially protects against infection by antigenically diverged strains. There is growing evidence that this protection is influenced by early exposures, a phenomenon referred to as original antigenic sin (OAS) or imprinting. In this paper, we derive new constraints on the emergence of the pattern of successive strain replacements demonstrated by influenza, SARS-CoV-2, seasonal coronaviruses, and other pathogens. We find that OAS implies that the limited diversity characteristic of successive strain replacement can only be maintained if R0 is less than a threshold set by the characteristic antigenic distances for cross-protection and for the creation of new immune memory. This bound implies a "speed limit" on the evolution of new strains and a minimum variance of the distribution of infecting strains in antigenic space at any time. To carry out this analysis, we develop a theoretical model of pathogen evolution in antigenic space that implements OAS by decoupling the antigenic distances required for protection from infection and strain-specific memory creation. Our results demonstrate that OAS can play an integral role in the emergence of strain structure from host immune dynamics, preventing highly transmissible pathogens from maintaining serial strain replacement without diversification.
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Lethal Infection of Human ACE2-Transgenic Mice Caused by SARS-CoV-2-related Pangolin Coronavirus GX_P2V(short_3UTR) -
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+SARS-CoV-2-related pangolin coronavirus GX_P2V(short_3UTR) can cause 100% mortality in human ACE2-transgenic mice, potentially attributable to late-stage brain infection. This underscores a spillover risk of GX_P2V into humans and provides a unique model for understanding the pathogenic mechanisms of SARS-CoV-2-related viruses.
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A Murine Model of Post-acute Neurological Sequelae Following SARS-CoV-2 Variant Infection -
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+Viral variant is one known risk factor associated with post-acute sequelae of COVID-19 (PASC), yet the pathogenesis is largely unknown. Here, we studied SARS-CoV-2 Delta variant-induced PASC in K18-hACE2 mice. The virus replicated productively, induced robust inflammatory responses in lung and brain tissues, and caused weight loss and mortality during the acute infection. Longitudinal behavior studies in surviving mice up to 4 months post-acute infection revealed persistent abnormalities in neuropsychiatric state and motor behaviors, while reflex and sensory functions recovered over time. Surviving mice showed no detectable viral RNA in the brain and minimal neuroinflammation post-acute infection. Transcriptome analysis revealed persistent activation of immune pathways, including humoral responses, complement, and phagocytosis, and reduced levels of genes associated with ataxia telangiectasia, impaired cognitive function and memory recall, and neuronal dysfunction and degeneration. Furthermore, surviving mice maintained potent T helper 1 prone cellular immune responses and high neutralizing antibodies against Delta and Omicron variants in the periphery for months post-acute infection. Overall, infection in K18-hACE2 mice recapitulates the persistent clinical symptoms reported in long COVID patients and may be useful for future assessment of the efficacy of vaccines and therapeutics against SARS-CoV-2 variants.
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Prototype mRNA vaccines imprint broadly neutralizing human serum antibodies after Omicron variant-matched boosting -
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+Immune imprinting is a phenomenon in which an individual's prior antigenic experiences influence responses to subsequent infection or vaccination. Here, using antibody depletion and multiplexed spike-binding assays, we characterized the type-specificity and cross-reactivity of serum antibody responses after mRNA vaccination in mice and human clinical trial participants. In mice, a single priming dose of a preclinical version of mRNA-1273 vaccine encoding Wuhan-1 spike minimally imprinted serum responses elicited by Omicron boosters, enabling a robust generation of type-specific antibodies. However, substantial imprinting was observed in mice receiving an Omicron booster after two priming doses of mRNA-1273, an effect that was mitigated by a second booster dose of Omicron mRNA vaccine. In humans who received two BA.5 or XBB.1.5 Omicron-matched boosters after two or more doses of the prototype mRNA-1273 vaccine, spike-binding and neutralizing serum antibodies cross-reacted with circulating Omicron variants as well as more distantly related sarbecoviruses. Because the serum neutralizing response against Omicron strains and other sarbecoviruses was completely abrogated after pre-clearing with the Wuhan-1 spike protein, antibodies induced by XBB.1.5 boosting in humans focus on conserved epitopes shaped and shared by the antecedent mRNA-1273 primary series. Our depletion analysis also identified cross-reactive neutralizing antibodies that recognize distinct epitopes in the receptor binding domain (RBD) and S2 proteins with differential inhibitory effects on members of the sarbecovirus subgenus. Thus, although the serum antibody response to Omicron-based boosters in humans is dominantly imprinted by prior immunizations with prototype mRNA-1273 vaccines, this outcome can be beneficial as it drives expansion of multiple classes of cross-neutralizing antibodies that inhibit infection of emerging SARS-CoV-2 variants and extend activity to distantly related sarbecoviruses.
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Change in Anti-COVID-19 Behavior and Prejudice against Minorities during the COVID-19 Pandemic: Longitudinal Evidence from Five European Countries -
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+In the COVID-19 pandemic, it is vital to identify factors increasing behaviors that limit the transmission of COVID-19 (i.e., anti-COVID-19 behavior) and factors protecting against the negative consequences of the pandemic on societies (i.e., prejudice). A simultaneous investigation of a change in anti-COVID behavior and prejudice during the pandemic is essential because some factors (e.g., fear of COVID-19) could increase both outcomes, whilst other factors (e.g., norms in anti-COVID behavior or intergroup contact in prejudice) could bring desirable changes in one outcome without negatively affecting the other. In a three-wave longitudinal study (NT1 = 4275) in five European countries from April to October 2020, we employed a latent change score model to distinguish between intra- and inter-individual changes in anti-COVID-19 behavior and prejudice. On the intra-individual level, anti-COVID-19 behavior was increased by anti-COVID-19 norms; and prejudice against migrants from the Middle East was influenced by positive and negative direct and mass-media intergroup contact.
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Mutation of highly conserved residues in loop 2 of the coronavirus macrodomain demonstrates that enhanced ADP-ribose binding is detrimental to infection -
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+All coronaviruses (CoVs) encode for a conserved macrodomain (Mac1) located in nonstructural protein 3 (nsp3). Mac1 is an ADP-ribosylhydrolase that binds and hydrolyzes mono-ADP-ribose from target proteins. Previous work has shown that Mac1 is important for virus replication and pathogenesis. Within Mac1, there are several regions that are highly conserved across CoVs, including the GIF (glycine-isoleucine-phenylalanine) motif. To determine how the biochemical activities of these residues impact CoV replication, the isoleucine and the phenylalanine residues were mutated to alanine (I-A/F-A) in both recombinant Mac1 proteins and recombinant CoVs, including murine hepatitis virus (MHV), Middle East respiratory syndrome coronavirus (MERS-CoV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The F-A mutant proteins had ADP-ribose binding and/or hydrolysis defects that led to attenuated replication and pathogenesis in cell culture and mice. In contrast, the I-A mutations had normal enzyme activity and enhanced ADP-ribose binding. Despite increased ADP-ribose binding, I-A mutant MERS-CoV and SARS-CoV-2 were highly attenuated in both cell culture and mice, indicating that this isoleucine residue acts as a gate that controls ADP-ribose binding for efficient virus replication. These results highlight the function of this highly conserved residue and provide unique insight into how macrodomains control ADP-ribose binding and hydrolysis to promote viral replication and pathogenesis.
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BCG activation of trained immunity is associated with induction of cross reactive COVID-19 antibodies in a BCG vaccinated population. -
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+Background: During the current COVID 19 pandemic, the rate of morbidity and mortality was considerably lower in BCG vaccinated countries like Pakistan. BCG has been shown to provide cross protection to both disseminated TB as well as non related viral infections in BCG vaccinated children which is consistent with COVID 19 morbidity in the younger age group. Recently, this cross protection was attributed to trained immunity (TI) associated with BCG recall responses in the innate arm of the immune system. Little is known about the longevity of BCG Trained Immunity (TI) beyond early childhood. Objective: To assess the BCG induced recall responses in healthy individuals by cytokines secreted from the TI network and its potential role in providing cross protection against COVID 19 and other viral infections. Study Design: In this cross sectional study, healthy young adults and adolescents (n=20) were recruited from 16-40 years of age, with no prior history of TB treatment, autoimmune, or chronic inflammatory condition. Methods: BCG induced cytokine responses were assessed using prototypic markers for cells of the TI network macrophages [M1 (TNF alpha, IFN gamma), M2 (IL10)], NK (IL2), Gamma delta (gamma delta]) T (IL17, IL4)} and SARS CoV2 IgG antibodies against RBD using short term (12 hours) cultures assay. Results: Significant differences were observed in the magnitude of recall responses to BCG with macrophage cytokines showing the highest mean levels of TNF alpha (9148 pg/ml) followed by IL10 (488 pg/ml) and IFN gamma(355 pg/ml). The ratio of unstimulated vs BCG stimulated cytokines was 132 fold higher for TNF alpha, 40 fold for IL10, and 27 fold for IFN gamma. Furthermore, SARS-CoV-2 antibodies were also detected in unstimulated plasma which showed cross reactivity with BCG. Conclusion: The presence of cross reactive antibodies to SARS-CoV-2 and the relative ratio of pro and anti inflammatory cytokines secreted by activated TI cellular network may play a pivotal role in protection in the early stages of infection as observed during the COVID 19 pandemic in the younger age groups resulting in lower morbidity and mortality.
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VLP-Based Model for Study of Airborne Viral Pathogens -
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+The recent COVID-19 pandemic has underscored the danger of airborne viral pathogens. The lack of model systems to study airborne pathogens limits the understanding of airborne pathogen distribution, as well as potential surveillance and mitigation strategies. In this work, we develop a novel model system to study airborne pathogens using virus like particles (VLP). Specifically, we demonstrate the ability to aerosolize VLP and detect and quantify aerosolized VLP RNA by Reverse Transcription-Loop-Mediated Isothermal Amplification (RT-LAMP) in real-time fluorescent and colorimetric assays. Importantly, the VLP model presents many advantages for the study of airborne viral pathogens: (i) similarity in size and surface components; (ii) ease of generation and noninfectious nature enabling study of BSL3 and BSL4 viruses; (iii) facile characterization of aerosolization parameters; (iv) ability to adapt the system to other viral envelope proteins including those of newly discovered pathogens and mutant variants; (v) the ability to introduce viral sequences to develop nucleic acid amplification assays.
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Antigen non-specific CD8+ T cells accelerate cognitive decline in aged mice following respiratory coronavirus infection -
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+Primarily a respiratory infection, numerous patients infected with SARS-CoV-2 present with neurologic symptoms, some continuing long after viral clearance as a persistent symptomatic phase termed long COVID. Advanced age increases the risk of severe disease, as well as incidence of long COVID. We hypothesized that perturbations in the aged immune response predispose elderly individuals to severe coronavirus infection and post-infectious sequelae. Using a murine model of respiratory coronavirus, mouse hepatitis virus strain A59 (MHV-A59), we found that aging increased clinical illness and lethality to MHV infection, with aged animals harboring increased virus in the brain during acute infection. This was coupled with an unexpected increase in activated CD8+ T cells within the brains of aged animals but reduced antigen specificity of those CD8+ T cells. Aged animals demonstrated spatial learning impairment following MHV infection, which correlated with increased neuronal cell death and reduced neuronal regeneration in aged hippocampus. Using primary cell culture, we demonstrated that activated CD8+ T cells induce neuronal death, independent of antigen-specificity. Specifically, higher levels of CD8+ T cell-derived IFN-{gamma} correlated with neuronal death. These results support the evidence that CD8+ T cells in the brain directly contribute to cognitive dysfunction following coronavirus infection in aged individuals.
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SARS-CoV-2 and Influenza A/B in Point-of-Care and Non-Laboratory Settings - Conditions: SARS-CoV-2 Infection; Influenza A; Influenza B Interventions: Diagnostic Test: Aptitude Medical Systems Metrix COVID/Flu Test Sponsors: Aptitude Medical Systems; Biomedical Advanced Research and Development Authority Recruiting
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Effect of Aerobic Exercises Versus Incentive Spirometer Device on Post-covid Pulmonary Fibrosis Patients - Conditions: Lung Fibrosis Interstitial; Post-COVID-19 Syndrome Interventions: Other: Aerobic Exercises; Device: Incentive Spirometer Device; Other: Traditional Chest Physiotherapy Sponsors: McCarious Nahad Aziz Abdelshaheed Stephens; Cairo University Active, not recruiting
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Can Doctors Reduce COVID-19 Misinformation and Increase Vaccine Uptake in Ghana? A Cluster-randomised Controlled Trial - Conditions: COVID-19 Interventions: Behavioral: Motivational Interviewing, AIMS; Behavioral: Facility engagement Sponsors: London School of Economics and Political Science; Innovations for Poverty Action; Ghana Health Services Not yet recruiting
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Long COVID Ultrasound Trial - Conditions: Long Covid Interventions: Device: Splenic Ultrasound Sponsors: SecondWave Systems Inc.; University of Minnesota; MCDC (United States Department of Defense) Not yet recruiting
Could Wearing Face Mask Have Affected Demodex Parasite - Conditions: Pandemic, COVID-19; Demodex Infestation Interventions: Diagnostic Test: standard superficial skin biopsy (SSSB) Sponsors: Nurhan Dƶner AktaÅ Completed
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TDCS Stimulation After Covid-19 Infection - Conditions: COVID-19 Interventions: Procedure: Transcranial Direct Stimulation Sponsors: Istanbul Medipol University Hospital; Alanya Alaaddin Keykubat University Recruiting
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Safety and Immunogenicity of a Booster Vaccination With an Adapted Vaccine - Conditions: SARS-CoV2 Infection Interventions: Biological: PHH-1V81; Biological: Comirnaty Omicron XBB1.5 Sponsors: Hipra Scientific, S.L.U Active, not recruiting
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From PubMed
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Studying SARS-CoV-2 interactions using phage-displayed receptor binding domain as a model protein - SARS-CoV-2 receptor binding domain (RBD) mediates viral entry into human cells through its interaction with angiotensin converting enzyme 2 (ACE2). Most neutralizing antibodies elicited by infection or vaccination target this domain. Such a functional relevance, together with large RBD sequence variability arising during viral spreading, point to the need of exploring the complex landscape of interactions between RBD-derived variants, ACE2 and antibodies. The current work was aimed at developingā¦
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Development of an integrated sample amplification control for salivary point-of-care pathogen testing - BACKGROUND: The COVID-19 pandemic has led to a rise in point-of-care (POC) and home-based tests, but concerns over usability, accuracy, and effectiveness have arisen. The incorporation of internal amplification controls (IACs), essential control for translational POC diagnostics, could mitigate false-negative and false-positive results due to sample matrix interference or inhibition. Although emerging POC nucleic acid amplification tests (NAATs) for detecting SARS-CoV-2 show impressiveā¦
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Multifunctional polymeric guanidine and hydantoin halamines with broad biocidal activity - Prolonged and excessive use of biocides during the coronavirus disease era calls for incorporating new antiviral polymers that enhance the surface design and functionality for existing and potential future pandemics. Herein, we investigated previously unexplored polyamines with nucleophilic biguanide, guanidine, and hydantoin groups that all can be halogenated leading to high contents of oxidizing halogen that enables enhancement of the biocidal activity. Primary amino groups can be used toā¦
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Olgotrelvir, a dual inhibitor of SARS-CoV-2 Mpro and cathepsin L, as a standalone antiviral oral intervention candidate for COVID-19 - CONCLUSIONS: Olgotrelvir is an oral inhibitor targeting M^(pro) and CTSL with high antiviral activity and plasma exposure and is a standalone treatment candidate for COVID-19.
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Ligand fishing approach to explore Amaryllidaceae alkaloids as potential antiviral candidates targeting SARS-CoV-2 Nsp4 - Ligand fishing, also described as affinity-based assay, represents a convenient and efficient approach to separate potential ligands from complex matrixes or chemical libraries. This approach contributes to the identification of lead compounds that can bind to a specific target. In the context of COVID-19, the search for novel therapeutic agents is crucial. Small molecule-based antiviral drugs, such as Amaryllidaceae alkaloids, have been described as potential candidates because they can inhibitā¦
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Regulation of innate immune and inflammatory responses by supersulfides - Innate immunity plays an important role in host defense against microbial infections. It also participates in activation of acquired immunity through cytokine production and antigen presentation. Pattern recognition receptors such as Toll-like receptors and nucleotide oligomerization domain-like receptors sense invading pathogens and associated tissue injury, after which inflammatory mediators such as pro-inflammatory cytokines and nitric oxide are induced. Supersulfides are molecular speciesā¦
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Evaluation of the humoral and mucosal immune response of a multiepitope vaccine against COVID-19 in pigs - INTRODUCTION: This study evaluated the immune response to a multiepitope recombinant chimeric protein (CHIVAX) containing B- and T-cell epitopes of the SARS-CoV-2 spikeās receptor binding domain (RBD) in a translational porcine model for pre-clinical studies.
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In Silico Study on Natural Chemical Compounds from Citric Essential Oils as Potential Inhibitors of an Omicron (BA.1) SARS-CoV-2 Mutantsā Spike Glycoprotein - CONCLUSION: The outcomes of this investigation hold significant potential for the utilization of a homology modeling approach for the prediction of RBDās secondary structure based on its sequence when the 3D structure of a mutated protein is not available. This opens the opportunities for further advancing the drug discovery process, offering novel avenues for the development of multifunctional, non-toxic natural medications.
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A Comprehensive Review of the Clinical Pharmacokinetics, Pharmacodynamics, and Drug Interactions of Nirmatrelvir/Ritonavir - Nirmatrelvir is a potent and selective inhibitor of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease that is used as an oral antiviral coronavirus disease 2019 (COVID-19) treatment. To sustain unbound systemic trough concentrations above the antiviral in vitro 90% effective concentration value (EC(90)), nirmatrelvir is coadministered with 100 mg of ritonavir, a pharmacokinetic enhancer. Ritonavir inhibits nirmatrelvirās cytochrome P450 (CYP) 3A4-mediated metabolismā¦
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A stapled lipopeptide platform for preventing and treating highly pathogenic viruses of pandemic potential - The continued emergence of highly pathogenic viruses, which either thwart immune- and small molecule-based therapies or lack interventions entirely, mandates alternative approaches, particularly for prompt and facile pre- and post-exposure prophylaxis. Many highly pathogenic viruses, including coronaviruses, employ the six-helix bundle heptad repeat membrane fusion mechanism to achieve infection. Although heptad-repeat-2 decoys can inhibit viral entry by blocking six-helix bundle assembly, theā¦
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ACE2 Receptor-Targeted Inhaled Nanoemulsions Inhibit SARS-CoV-2 and Attenuate Inflammatory Responses - Three kinds of coronaviruses are highly pathogenic to humans, and two of them mainly infect humans through Angiotensin-converting enzyme 2 ļ¼ACE2ļ¼receptors. Therefore, specifically blocking ACE2 binding at the interface with the receptor-binding domain is promising to achieve both preventive and therapeutic effects of coronaviruses. Alternatively, drug-targeted delivery based on ACE2 receptors can further improve the efficacy and safety of inhalation drugs. Here, these two approaches areā¦
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TRIM28-mediated nucleocapsid protein SUMOylation enhances SARS-CoV-2 virulence - Viruses, as opportunistic intracellular parasites, hijack the cellular machinery of host cells to support their survival and propagation. Numerous viral proteins are subjected to host-mediated post-translational modifications. Here, we demonstrate that the SARS-CoV-2 nucleocapsid protein (SARS2-NP) is SUMOylated on the lysine 65 residue, which efficiently mediates SARS2-NPās ability in homo-oligomerization, RNA association, liquid-liquid phase separation (LLPS). Thereby the innate antiviralā¦
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Plant extracts modulate cellular stress to inhibit replication of mouse Coronavirus MHV-A59 - The Covid-19 infection outbreak led to a global epidemic, and although several vaccines have been developed, the appearance of mutations has allowed the virus to evade the immune response. Added to this is the existing risk of the appearance of new emerging viruses. Therefore, it is necessary to explore novel antiviral therapies. Here, we investigate the potential in vitro of plant extracts to modulate cellular stress and inhibit murine hepatitis virus (MHV)-A59 replication. L929 cells wereā¦
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A randomized double-blind placebo-controlled trial of an inhibitor of plasminogen activator inhibitor-1 (TM5614) in mild to moderate COVID-19 - An inhibitor of plasminogen activator inhibitor (PAI)-1, TM5614, inhibited thrombosis, inflammation, and fibrosis in several experimental mouse models. To evaluate the efficacy and safety of TM5614 in human COVID-19 pneumonia, phase IIa and IIb trials were conducted. In an open-label, single-arm trial, 26 Japanese COVID-19 patients with mild to moderate pneumonia were treated with 120-180 mg of TM5614 daily, and all were discharged without any notable side effects. Then, a randomized,ā¦
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Antiviral effect of palmatine against infectious bronchitis virus through regulation of NF-ĪŗB/IRF7/JAK-STAT signalling pathway and apoptosis - 1. Infectious bronchitis virus (IBV), a gamma-coronavirus, can infect chickens of all ages and leads to an acute contact respiratory infection. This study evaluated the anti-viral activity of palmatine, a natural non-flavonoid alkaloid, against IBV in chicken embryo kidney (CEK) cells.2. The half toxic concentration (CC(50)) of palmatine was 672.92 Ī¼M, the half inhibitory concentration (IC(50)) of palmatine against IBV was 7.76 Ī¼M and the selection index (SI) was 86.74.3. Mode of action assayā¦
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From Patent Search
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Whatās Behind Israelās Crackdown in the West Bank? - The Palestinian political analyst Ibrahim Dalalsha on the politics behind the violence and settlement expansion since October 7th. - link
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The Ghost of January 6th Haunts 2024 - The impending Biden-vs.-Trump rematch already has one dominant theme. - link
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The California Town Owned by a New York Investment Firm - Scotia was created, a century and a half ago, so that lumberjacks could live near the trees they cut down. Its current owners have been trying for more than a decade to bring new residents to town. - link
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How Trump Captured Iowaās Religious Right - The stateās evangelical voters were once skeptical of the former President. Now they are among his strongest supporters. - link
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Why Some Academics Are Reluctant to Call Claudine Gay a Plagiarist - A political-science professor wrestles with his role in the drama surrounding the former Harvard president. - link
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From Vox
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The shoplifting scare might not have been real ā but its effects are -
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+New York City Mayor Eric Adams speaks during a press conference on reducing shoplifting. | Barry Williams/NY Daily News via Getty Images
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+It turns out shoplifting isnāt spiraling out of control, but lawmakers are pushing for tougher penalties for low-level and nonviolent crimes anyway.
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+Over the last couple of years, it seemed that America was experiencing a shoplifting epidemic. Videos of people brazenly stealing merchandise from retailers often went viral; chains closed some of their stores and cited a rise in theft as the primary reason; and drugstores such as CVS and Walgreens started locking up more of their inventory, including everyday items like toothpaste, soaps, and snacks. Lawmakers from both major parties called for, and in some cases even implemented, more punitive law enforcement policies aimed at bucking the apparent trend.
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+But evidence of a spike in shoplifting, it turns out, was mostly anecdotal. In fact, thereās little data to suggest that thereās a nationwide problem in need of an immediate response from city councils or state legislatures. Instead, what America seems to be experiencing is less of a shoplifting wave and more of a moral panic.
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+For some time, retailers had indeed been complaining about a rise in theft. In April, the National Retail Federation, a lobbying group for retailers, published a report to back up that claim. It said that nearly half of all inventory loss in 2021, which amounted to roughly $94 billion, was driven by āorganized retail crimeā ā that is, coordinated shoplifting for the purpose of reselling goods on the black market. As it turned out, organized shoplifting didnāt come close to costing businesses that much: With a few exceptions, major US cities actually saw lower shoplifting rates in 2022 than in 2019, and in December, the National Retail Federation retracted its alarming claim.
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+Thatās not to say that shoplifting ought to be ignored. Particularly concerning are reports of organized rings stealing merchandise to turn a profit, rather than people who steal products they need but canāt afford, like baby formula. One expert told the New York Times that organized retail theft accounts for roughly 5 percent of total inventory loss ā a far more modest estimate than the National Retail Federationās original erroneous claim, but one that still amounts to billions of dollars a year. While thatās a minuscule problem for big retailers, small businesses that are targeted can feel the pinch. Added security measures also mean a more unpleasant experience for consumers, as well as a potentially more expensive one because, as some analysts say, the added costs for retailers are reflected in higher prices.
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+In the years leading up to the Covid-19 pandemic, progressive prosecutors, who pushed for a more lenient and less punitive criminal justice system, had been gaining ground. But their critics have pounced on faulty statistics like the one put out by the National Retail Federation as evidence that America needs to expand policing and once again impose harsher penalties for petty crimes, reversing reforms that have sought to reduce incarceration rates, including looser enforcement of laws around things like drug possession, loitering, or, in some cases, shoplifting low-cost goods.
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+Now, those more forgiving criminal justice policies are at risk, in part because of a perceived trend that appears to have been overblown.
+
+
+What we actually know about shoplifting
+
+
+In the early months of Covid, shoplifting declined because businesses closed and people stayed home. But as life started going back to normal, so did shoplifting, and rates of retail theft started to creep up again.
+
+
+The change since 2020 wasnāt at all drastic. A report by the nonpartisan Council on Criminal Justice, which looked at 24 big cities, found that amid generally lower shoplifting rates in most cities, seven saw increases. Some were modest ā shoplifting incidents in Pittsburgh grew by 8 percent between 2019 and 2023 ā but others were more serious. New York City, for example, saw a 64 percent increase in that period, though even there, the trend seems to be coming to an end: The city saw lower shoplifting rates in the first half of 2023 than in 2022.
+
+
+There had been evidence that fears of a major shoplifting wave were overblown. In 2021, Walgreens closed five stores in San Francisco, citing a rise in organized shoplifting. When the San Francisco Chronicle analyzed police data, the newspaper found that there was little evidence to back up Walgreensās claim. The Chronicle reported that āthe five stores slated to close had fewer than two recorded shoplifting incidents a month on average since 2018.ā
+
+
+In an earnings call with investors last year, a Walgreens executive suggested that the company had indeed overstated concerns about shoplifting. āMaybe we cried too much,ā he said, adding that it may have resulted in the retailer spending more than it should have to bolster security.
+
+
+So where did the National Retail Federation get the number that nearly half of retailersā āshrinkā ā the industry term for inventory loss due to a range of factors, including theft but also damage and tracking mistakes ā was a result of shoplifting? A spokesperson for the group told Reuters that it came from 2021 congressional testimony from the former president of the advocacy group the Coalition of Law Enforcement and Retail, who claimed that retailers lose $45 billion a year because of organized retail theft. But itās unclear where that number came from.
+
+
+Previous reports from the National Retail Federation showed that shoplifting was nowhere near as dire. In a 2020 report, the lobbying group found that retailers lost, on average, roughly $720,000 for every $1 billion in sales due to organized retail theft. Shoplifting, in other words, amounts to less than 0.1 percent of total revenue ā a cost that retailers often accept as part of operating a business.
+
+
+Like any crime, shoplifting is often underreported, and itās hard to figure out the extent to which it is. Thatās in part because there is no national data set to parse, and many law enforcement agencies have not reported their recent crime data to the FBI, according to the Marshall Project. But Adam Gelb, the president and CEO of the Council on Criminal Justice, said there are factors other than the total number of reported incidents to consider when trying to understand the overall picture, including how shoplifting incidents have changed.
+
+
+The Council on Criminal Justice report found that the number of shoplifting incidents that involved another crime, including assault, increased by 9 percent between 2019 and 2021. That could mean shoplifters have a higher tolerance for risk than they used to: an argument that security might be too lax. It could also indicate more organized crime. Still, those incidents accounted for less than 2 percent of overall shoplifting events, and they also started to decline in the first half of 2023.
+
+
+Regardless, part of the reason so many retailers and lawmakers have sounded the alarm on a rise in thefts might be because reports of shoplifting had plummeted when Covid first hit, and then shot back up after stores reopened. That created the impression that the problem was spiraling out of control when in reality, shoplifting rates remained below pre-pandemic levels.
+
+
+āPeople donāt know if something is high or low or medium on some scale, historical or otherwise. But they have a sense of whether itās getting better or getting worse,ā Gelb said. āAnd when things are moving in the wrong direction, people want to see action.ā
+
+
+The great American shoplifting scare has already had consequences
+
+
+Since the number of reported shoplifting incidents rose after the initial collapse in 2020, there have been plenty of media reports and viral videos about the potential crime wave. Republicans used the alleged lawlessness, particularly in big Democratic cities, to paint a grim picture of Joe Bidenās America. It didnāt matter what the reality was; it seemed that the publicās perception of rising crime was enough for politicians from both major parties to feel the need to look tougher ā be they Eric Adams, the Democratic mayor of New York City, or Ron DeSantis, the Republican governor of Florida and candidate for president.
+
+
+As a result, many policies that were championed by progressive criminal justice reform advocates, including the progressive prosecutor movement, have come under scrutiny, criticized as not only insufficient at combating crime but as policies that promote breaking the law.
+
+
+Evidence points to the contrary. In Boston, a former district attorney implemented a policy of declining to prosecute certain low-level offenses that are associated with poverty, such as shoplifting. In one study, researchers found that the new policy had positive impacts ā not only in reducing the number of people who get sucked into the criminal justice system but also in reducing the likelihood of reoffending. Low-level and nonviolent crimes, researchers found, also did not increase as a result of looser enforcement.
+
+
+As shoddy data about shoplifting helps stir up fear of a potential crime wave, voters are becoming less tolerant of those kinds of policies, and progressive prosecutors have faced tough election cycles in recent years as a result. That includes Boston, and other places, too: Chesa Boudin, the former San Francisco district attorney who became nationally prominent for his more lenient approach to addressing low-level crime, was recalled in 2022, for example, after a fearmongering campaign about rising crime, including shoplifting, was launched against him.
+
+
+Legislatures have also started passing stricter laws. Since 2022, at least nine states have imposed harsher penalties for organized retail crime offenses, according to CNBC.
+
+
+But given how unclear the data on shoplifting actually is and how much is still unknown, this could ultimately be a misdirection of resources ā as Walgreens seems to have figured out after beefing up security measures. And given that preliminary data from 2023 shows that the apparent shoplifting trend might actually be moderating, itās worth waiting for more data before drafting up laws that could have lasting consequences.
+
+
+In a presidential election year, that might be too much to ask for. Everything, after all, is politics, and shoplifting ā real or imagined ā is no exception.
+
+
What Houthi attacks in the Red Sea mean for global shipping ā and conflict -
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+
+
+Fareed Kotb/Anadolu via Getty Images
+
+
+
+The Yemen-based, Iran-backed group hasnāt been fazed by a US-led response.
+
+
+Houthi rebels based in Yemen launched another attack on commercial vessels transiting the Red Sea Thursday, sending an explosive, unmanned vessel near a US Navy ship ā within a day of warnings from a US-led coalition, dubbed Operation Prosperity Guardian, meant to protect the area.
+
+
+The attacks, which have been ongoing for weeks, threaten to significantly disrupt the flow of commercial goods through the Red Sea and Suez Canal, an important route for trade between Asia and Western countries. Itās an approach that, for relatively little cost to the Houthis and their Iranian sponsors, has exposed the ineffectiveness of the US coalition response ā and has ratcheted up the tension in the region, which has been increasing on multiple fronts after Hamasā attacks in Israel on October 7.
+
+
+In a statement Wednesday, the US and its 12 coalition partners issued a final warning to the Houthis that they would ābear the responsibility of the consequencesā should they continue attacks on container ships transiting the maritime route. In response to that vague warning, the group detonated an explosive unmanned surface vessel (USV) in the vicinity of several commercial vessels, as well as a US Navy ship, though none of the vessels were damaged. And on Saturday, a US warship shot down a drone launched from Houthi-controlled territory āāāin international waters of the Southern Red Sea in the vicinity of multiple commercial vessels,ā according to a statement from US Central Command.
+
+
+With the Houthis committed to antagonizing commercial vessels, the question of a possible response remains ā and the coalition doesnāt have many clear options that could effectively stop the attacks without risking open conflict with Iran. Meanwhile, with Iranian support, the Houthis have shown that their approach is effective, even against the worldās major naval power.
+
+The Houthis have carried out around two dozen attacks on commercial vessels in the area since November 18, NAVCENT Commander Vice Admiral Brad Cooper told reporters Thursday, including launching ballistic missiles, drones, and now a USV. The US announced Operation Prosperity Guardian on December 18, naming Canada, Spain, the United Kingdom, Bahrain, the Seychelles, France, the Netherlands, Italy, and Norway, as partners in the effort.
+
+
+As Craig Fuller, the CEO of FreightWaves, told Bloombergās Odd Lots podcast this week, āThe United States has the largest navy in the world, itās also one of the only blue water naviesā it can go anywhere, defend any place on the planet,ā and āthe whole purpose of that is to protect freight lanes. One of the primary calls of the US Navy is its role to protect commerce and ensure global trade.ā
+
+
+Cooper told the press that āabout 1,500 merchant ships have safely transited the waters of the Red Sea since the operation began.ā But as Bloomberg reported in late December, shortly after the coalition was announced, shipping traffic was down 40 percent in the Bab al-Mandab Strait at the southern end of the Red Sea. Both that waterway and the Suez Canal are critical to international trade ā not just the oil and energy products that come from the Middle East, but container ships that carry consumer goods, as well as the machinery and parts necessary for manufacturing, affecting supply chains at several different levels.
+
+
+And even if some cargo ships are transiting safely, the increased insurance costs or risks could be too much for some companies to bear. Furthermore, despite US warnings, the attacks havenāt stopped. āItās very clear from the way the conflict has proceeded in the way the Houthi attacks have escalated, even as the US has tried to respond, that what the US is doing is not really having a deterrent effect of any sort,ā Jennifer Kavanagh, senior fellow in the American Statecraft Program at the Carnegie Endowment for International Peace, told Vox.
+
+
+The attacks are pushing shipping companies to change their transit routes, with industry leader Maersk saying it will pull its vessels from the Red Sea route in favor of a longer route around the Cape of Good Hope āfor the foreseeable futureā after Houthi militants attacked one of its ships January 1. Maersk controls about a sixth of global container shipping, according to Reuters, and the alternate route tacks on as much as three weeks to shipping times.
+
+
+Not only does it take longer for products to reach their destinations, but the extra time also leads to extra costs for shipping companies ā for fuel, salaries, and insurance, for example ā as shipping firm Hapag-Lloyd told Reuters Friday. Companies then pass on those increases to consumers.
+
+
+āI think the clear lesson from whatās unfolded in the Red Sea is that it doesnāt take all that much to disrupt shipping,ā Kavanagh said. āAnd these types of gray zone attacks,ā or attacks by non-state actors like the Houthis, āon commercial ships are very difficult for the United States to respond to in a measured way, while also balancing escalation risks.ā
+
+
+The US has few good options
+
+
+The US told the Houthis Wednesday that they should not expect another warning should they continue their attacks in the region; now that that warning has been ignored, the coalitionās plan for a response has to deter attacks without escalating the overall regional conflict. But itās not clear the coalition can actually accomplish that task.
+
+
+The Wall Street Journal reported Wednesday that the US is exploring options to strike Houthi targets, which could include hitting missile and drone launchers, radar locations on the Yemeni coast, and Houthi munitions facilities.
+
+
+There are many complications in using force against the Houthis, not the least of which is that many of their weapons systems are mobile. But, as Kavanagh said, thereās only so far the US can go in retaliating. āThey can shoot down the drones and missiles, which is inefficient and very costlyā for the US. āThey can take a step up from that and strike targets, inside of Yemen, the staging areas where some of these fast boats are, that unmanned sea vessels are leaving from or, as theyāve already done, try to attack ammunition or munitions depots. But then above that, whatās the next step that you take that doesnāt lead to direct attacks on Iran?ā
+
+
+The Houthis, meanwhile, can continue to frustrate the global shipping industry āmainly by increasing [the] volume of attacks,ā Daniel Byman, senior fellow at the Center for Strategic and International Studies told Vox.
+
+
+Critically, the Houthi attacks have not targeted oil tankers or other energy cargo, as Fuller pointed out ā preserving one of the regionās most important commodities so as not to inflame regional actors like Saudi Arabia, the United Arab Emirates, and Qatar, who hope to stop a wider regional escalation.
+
+
+āMost of the countries in the region have opted out [of the US-led coalition], because theyāre worried about Iran, and ā¦ they donāt want to be seen as protecting Israel, because the Houthis have said that Israel is their target.ā Kavanagh said. āSo there has been very big coalition response [that] has been very ineffective at the same time ā the goals of that coalition have also been very unclear. So they have very little participation, very limited capabilities, and no clear goals.ā
+
+
+Even if the coalition is somehow able to decrease the number of Houthi attacks while avoiding direct conflict with Iran, other regional fronts continue to escalate; in Lebanon, for example, a senior Hamas leader was killed Tuesday, apparently by Israel. The war has also brought about renewed attacks on US posts in Iraq and Syria by Iran-backed groups, and the Iraqi government is preparing to remove US coalition forces from the country.
+
+
+āāāPeople think about escalation in the region as like a switch was flipped ā and I think itās important to recognize that the alternative is also possible,ā Kavanagh said. āYou actually see it happening already, which is just sort of a steady increase of violence, and tit-for-tat strikes get gradually more and suddenly, youāre at [an] intolerable level.ā
+
+
+
+
Will Gypsy-Rose Blanchard really benefit from this media circus? -
+
+
+
+Gypsy-Rose Blanchard and Ryan Anderson on January 5 in New York City. | Raymond Hall/GC Images
+
+
+
+Leave Gypsy alone!
+
+
+When a prisoner leaves the carceral system, questions related to their stability and support are paramount: Can they find steady work? Can they secure adequate housing? Can they reintegrate themselves into a positive social environment?
+
+The story of Blanchard-Anderson, her mother Dee Dee, and the disturbing events that ultimately culminated in Dee Deeās murder in 2015, has been told and retold across the media landscape, most notably in a 2016 BuzzFeed article, a 2017 HBO docuseries, and a fictionalized 2019 Hulu drama, The Act. But Gypsy has received perhaps her biggest stage ever in the wake of her December 29 release. She has trended across social media, done high-profileinterviews, and celebrated with her now-famous prison pen pal turned husband, Ryan Anderson. Sheās also been promoting an upcoming Lifetime docuseries filmed while she was in prison. Throughout it all, sheās been upbeat, charming, and even inspiring.
+
+
+However her recent media appearances might frame her, we shouldnāt assume that Blanchard-Anderson will naturally step into the role of public figure.
+
+
+Anderson, now 32, was 24 when she was sentenced to 10 years for her part in the brutal murder of her mother, Dee Dee Blanchard. She ultimately served just eight years. Her light prison time was primarily due to a giant mitigating factor: the lifetime of horrific, bizarre abuse to which Dee Dee had subjected her. From Gypsyās childhood, Dee Dee had insisted her daughter had muscular dystrophy as well as other debilitating ailments that required her to constantly use a wheelchair and a feeding tube, and undergo a series of dangerous, painful, and unnecessary surgeries. (Although Dee Dee Blanchard was never formally diagnosed with MĆ¼nchausen syndrome by proxy, itās widely understood she most likely had the disorder; this was the true crime case that brought the syndrome to the publicās attention.)
+
+
+In order to further the fantasy and swindle supporters and benefit agencies out of funds, Dee Dee infantilized Gypsy, lying about her age and claiming she was developmentally disabled and had the mind of a small child. Gypsy received only a second-grade education and continued to perform the role of a very young girl well past puberty. Though her mother restricted her access to the outside world, Gypsy sought connections online, where she met 23-year-old Nicholas Godejohn, who became her secret boyfriend. Gypsy was then 22, but she spoke and acted like a girl in her early teens. Although she was legally an adult, her mother had gained power of attorney over her; she controlled nearly every aspect of Gypsyās life and rarely allowed her to leave the house.
+
+
+Compounding all of this, Gypsy has also alleged sexual abuse at the hands of her grandfather, who hasnāt explicitly denied it. He also allegedly sexually abused Dee Dee, which paints a picture of the role family dysfunction and generational trauma have played in this tragic case. Itās little wonder, then, that Gypsy looked for a way out. For her, this meant convincing Godejohn that murdering her mother was the only way she could ever truly be free. Godejohn is now serving a life sentence without parole for his role in the crime.
+
+
+In many ways, itās a relief to watch Blanchard-Anderson as she performs this press tour: She looks healthy, and her voice, long that of an eerie childās, more closely matches her real age. She largely seems unscathed from her time in prison, and she certainly seems to have plenty of support.
+
+
+Yet itās also hard to know what to make of the public frenzy and the media circus surrounding her. Sheās been compared to the wrongfully convicted true crime celebrity Amanda Knox, but Knox came from a stable middle-class family ā she was never trying to flee her life. Some have compared her to George Santos, but unlike Santos, Blanchard-Andersonās persona was never hers to control.
+
+Britney was a Disney child star; young Gypsy performed for her supporters, who donated to fundraisers for her fake medical bills. Each of them was manipulated into becoming an entertainer early in life. Both were robbed of their childhoods, left with little to no agency over their own lives and even their own personalities. Subsequently, where most adults would be settling into the middle phases of their lives, Britney and Gypsy have had to begin with the very basics of building their identities for themselves. And both women will now have to navigate that delicate path under the watchful eyes of millions.
+
+
+Thereās an inherent performativity as well to this post-prisoner life for both women: Britney has been tasked with setting the distorted, toxic record of her own life straight, while Gypsy has been tasked with communicating her own successful rehabilitation. At a basic level, this is because thatās what parolees need to do, but the publicās zeal for reclaiming her ā even to the point of forgetting there was an actual murder involved ā takes Gypsyās mea culpa tour to new heights. Her followers have been eagerly awaiting her release since it was first announced in September 2023; anticipation is high for whatever she does next. A certain ominous glee mingles with that excitement, a type of salacious, prurient interest in watching her succeed or fail. Again, itās impossible to not think of Britney and the nonstop public scrutiny that followed her at both the peak of her career and the end of her conservatorship.
+
+
+Itās difficult to contemplate Blanchard-Anderson, the budding media personality, without remembering the traumatized girl who only gained the publicās attention after resorting to an unthinkable act in response to a lifetime of unthinkable abuse. We may be excited for Gypsy-Rose, but we shouldnāt assume we know who she is. Like Britney, who has had her share of ups and downs since her conservatorship finally ended, Gypsy has to fully reinvent herself. Thatās a daunting prospect if she also has to frequently stop and give another interview to People magazine.
+
+
+We shouldnāt assume, either, that her story fits into familiar tropes. As another inadvertent true crime celebrity, Vili Fualaau, recently told the Hollywood Reporter, these stories often arenāt as black and white as the media likes to paint them. Blanchard-Anderson was absolutely a victim, but arguably to some degree so was Godejohn; itās much harder to valorize the person holding the murder weapon than the one who urged them to use it, but both, in the end, are culpable. There are parts of Blanchard-Andersonās story that will never fit neatly into the kind of reality TV survival narrative that the media currently seems anxious to place her within.
+
+
+Itās not clear, either, whether any of this publicity will be helpful to her at all, even if sheās besotted with fame. The answer may not be as simple as āLeave Gypsy alone,ā but turning her into some kind of Chicago-esque celebrity murderess probably isnāt the way forward either.
+
+
+So what if we get a Gypsy-Rose season of Dancing With the Stars? She might have fun ā along with the audience, sure ā but would that ultimately aid her recovery? Thereās a trepidation in watching this redemption arc up close, especially when youāre not sure youāre supposed to be watching at all.
+
+
+
From The Hindu: Sports
+
+
ICC rejects Usman Khawajaās appeal against armband sanction - ICC regulations prevent cricketers from displaying messages of political, religious or racial causes during international matches.
+
Nadal to skip Australian Open due to muscle injury - Rafael Nadal has confirmed that he will miss the Australian Open as he has suffered an injury
+
De Villiers blames T20 cricket for short India-South Africa series - De Villiers said āsomething has to changeā if the best team in the world is to be identified, advocating longer series.
+
Brisbane tennis championship | Confident Rybakina demolishes Sabalenka to claim title - The Russian-born Kazakh won the first eight games in a row over the Australian Open champion in a repeat of the 2023 Melbourne Park final.
+
Morning Digest | Digital tools set to save Kashmiri script from disuse; DGCA directs airlines to inspect emergency exits in Boeing 737-8 Max planes, and more - Here is a select list of stories to start the day
+
+
From The Hindu: National News
+
+
Two killed, seven injured as TSRTC bus hits parked lorry in Nellore district of Andhra Pradesh - The bus was going to Tirupati from Miryalaguda in Nalgonda district of Telangana
+
No difference between old guard and new generation in TMC, says Abhishek Banerjee - TMC national general secretary dismissed allegations that he intended to become inactive within the party, labelling such reports as āwrong and baselessā.
+
Aditya-L1 mission a big moment for PSUs in Kerala - Four State public sector units had contributed to the Indian Space Research Organisation mission meant to study the sun
+
Changes in norms mandatory to encourage new entrepreneurs, say industrialists - The existing three industrial estates in Madurai ā SIDCO industrial estates in K. Pudur and Kappalur and Madurai Hosiery Industries Association (MHIA) at Uranganpatti ā are known for their varied business.
+
Renewable energy to light up 75 tribal houses in Hunsur - The cost of the project is ā¹30 lakh and it will provide access to clean and green energy for tribals in the hamlets
+
+
From BBC: Europe
+
+
Ukraine-Russia war: Putin citizenship decree violates childrenās rights, Ukraine says - Kyiv condemns Putinās decree to give citizenship to Ukrainian children who were taken to Russia.
+
Ukraine war: Some residents leave Belgorod after deadly attacks - Twenty-five people were killed last weekend in Belgorod - the biggest Russian city near Ukraine.
+
Christine Granville: The Polish aristocrat who was Churchillās favourite spy - Christine Granville risked her life in missions across Europe only to be killed by her former lover.
+
Ukraine war: Atesh, the group spying on Russians in occupied Crimea - Atesh, meaning fire in Crimean Tatar, says it collects data on Russian forces in occupied Ukraine.
+
Ukraine war: US says Russia using North Korea ballistic missiles - The US promises to raise what it calls a significant and concerning escalation at the UN Security Council.
+
+
From Ars Technica
+
+
Navajo objection to flying human ashes to the Moon wonāt delay launch - āTheyāre not going to remove the human remains and keep them here on Earth.ā - link
+
East Coast land continues to collapse at a worrying rate - Itās steadily sinking or subsiding, which is destabilizing levees, roads, and airports. - link
+
Big evolutionary change tied to lots of small differences - Lots of genes changed as a species of snail went from laying eggs to live births. - link
+
Hereās a first look at United Launch Allianceās new Vulcan rocket - ULAās first flight-ready Vulcan rocket is finally on the launch pad. - link
+
Experimental antibiotic kills deadly superbug, opens whole new class of drugs - The relatively large molecule clogs a transport system, leading to lethal toxicity. - link
+
+
From Jokes Subreddit
+
+
A string walked into a barā¦ -
+
+
+and the bartender, having put up with his shenanigans in the past immediately speaks upā¦
+
+
+āHey, you, get out! We donāt serve your kind here!ā
+
+
+So the string went outside, where he threw himself down some stairs and into traffic, until he was quite the tangled mess. He then returned to the bar. where the bartender looked up and and saidā¦ āHey, arenāt you that piece of string I threw out earlier?ā
+
+
+He looked up at the man, his loose hair a mop on his tangled body and says āno, Iām a frayed knot.ā
+
+A man reported his wife had gone missing. A few days later, a police officer shows up at his door.
+
+
+The officer, hat in hand, says, āSir I have bad news, good news, and great news.ā
+
+
+Fearing the worst, the man asks for the bad news first.
+
+
+āIt appears your wifeās car went over the cliff on the side of Charleston Rd, we found a broken guardrail that led to finding the car submerged in the ocean. Iām sorry to say she was discovered inside when we found the car.ā
+
+
+For several moments he was gripped in sorrow. Then asked, āOkay, whatās the great news?ā
+
+
+The cop answered, āWhen we pulled her from the water, there were three golden king crabs, two blue king crabs, and three snow crabs clinging to her body. Since it was your wife, you have a claim to a portion of the crabsā monetary value.ā
+
+
+Stunned, he asked, āWhatās the good news?ā
+
This might be the last chance I have to tell this joke for a while; So a man and his dog walk into a bar to watch the Packers/Bears gameā¦ [Long] -
+
+
+A man and his dog walk into a bar to watch the football game between the Green Bay Packers and the Chicago Bears. The man takes a seat at the bar and his dogs hops up onto the empty stool right next to him and they both settle in for what is sure to be an exciting game.
+
+
+Sure enough, itās a battle for the ages. Early in the first quarter, Green Bay kicks a field goal to go up 3-0. The dog jumps off his chair, runs in a tight circle around his bar stool, barks happily, and jumps back up. Later in the first quarter, Chicago scores a touchdown to take the lead, 7-3. The Dog growls at the TV and grabs a stack of coasters in his mouth and shakes them angrily, making a bit of a mess. The bartender looks on with a concerned look but figures, theyāre only coasters, theyāre inexpensive, and the people nearby are enjoying watching to see what the dog will do, so he lets it slide.
+
+
+Green Bay scores a touchdown to end the first quarter and sure enough, the dog jumps out of his seat, runs in a tight circle three times, barks excitedly and jumps back up onto its seat.
+
+
+Back and forth the two teams go, trading the leadā¦ every time Chicago scores, a menacing growl and minor destruction of some bar supplies. Every time The Packers score, a display of excited approval, each more elaborate than the last. By this time the entire bar has taken notice of the dog and everyone is eagerly anticipating the end of the game.
+
+
+Then, at the end of the 4th quarter, with only 4 seconds left on the clock and trailing by 2, Green Bay kicks a 53 yard field goal to beat the Bears, 36-35.
+
+
+In a final display of celebration, the dog jumps up on the bar, runs the length giving everyone else at the bar a lick and a high paw, jumps off the end of the bar, does a backflip and runs out of the bar, barking the whole way as everyone cheers wildly!
+
+
+Finally, the bartender comes over to the man. āHey buddy, I gotta say, thatās one of the most incredible things Iāve ever seen. But I gotta ask, what happens when the Bears beat the Packers? What does your dog do then?ā
+
+
+The guy just shrugsā¦ āI donāt know man, the dogās only 5 years old.ā
+
+I was about to propose to my girlfriend when my roommate Joseph barged into the garden out of nowhere, tripped, and fell over, breaking a glass table with his face. Totally ruined the mood. Now I donāt know Joseph THAT well, donāt even remember where he was from, but letās say I put my plans on hold to help him through his injuries.
+
+
+Joseph had gotten a big glass shard in his eye, making him completely blind in that eye. He was walking around with one of those big cotton pads on his eye for a couple of months. Then suddenly, he disappeared, along with my girlfriend.
+
+
+Apparently theyād bonded during the time after his injuries, and eloped together, leaving me behind without as much as a note. I tried to track them down, but never could.
+
+
+In conclusion, if it hadnāt been for Joe with his cotton eye, Iād have been married a long time ago. Where did you come from, where did you go? Where did you come from, cotton eye Joe?
+
+
+
+