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<title>19 February, 2024</title>
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<title>Covid-19 Sentry</title><meta content="width=device-width, initial-scale=1.0" name="viewport"/><link href="styles/simple.css" rel="stylesheet"/><link href="../styles/simple.css" rel="stylesheet"/><link href="https://unpkg.com/aos@2.3.1/dist/aos.css" rel="stylesheet"/><script src="https://unpkg.com/aos@2.3.1/dist/aos.js"></script></head>
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<h1 data-aos="fade-down" id="covid-19-sentry">Covid-19 Sentry</h1>
<h1 data-aos="fade-right" data-aos-anchor-placement="top-bottom" id="contents">Contents</h1>
<ul>
<li><a href="#from-preprints">From Preprints</a></li>
<li><a href="#from-clinical-trials">From Clinical Trials</a></li>
<li><a href="#from-pubmed">From PubMed</a></li>
<li><a href="#from-patent-search">From Patent Search</a></li>
</ul>
<h1 data-aos="fade-right" id="from-preprints">From Preprints</h1>
<ul>
<li><strong>A critical reexamination of recovered SARS-CoV-2 sequencing data</strong> -
<div>
SARS-CoV-2 genomes collected at the onset of the Covid-19 pandemic are valuable because they could help understand how the virus entered the human population. In 2021, Jesse Bloom reported on the recovery of a sequencing dataset that had been removed from the NCBI SRA database at the request of the data generators, a scientific team at Wuhan University. Bloom suggested that the data may have been removed in order to obfuscate the origin of SARS-CoV-2, questioning the generating authors' statements that the samples had been collected on and after January 30, 2020. Here, we show that sample collection dates were published in 2020 together with the sequencing data, and match the dates given by the authors in 2021. We examine mutations in these sequences and confirm that they are entirely consistent with the previously known genetic diversity of SARS-CoV-2 of late January 2020. Finally, we explain how an apparent phylogenetic rooting paradox described by Bloom was resolved by subsequent analysis. Our reanalysis demonstrates that allegations of cover-up or metadata manipulation were unwarranted.
</div>
<div class="article-link article-html-link">
🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2024.02.15.580500v1" target="_blank">A critical reexamination of recovered SARS-CoV-2 sequencing data</a>
</div></li>
<li><strong>Robust Neutralization of SARS-CoV-2 Variants Including JN.1 and BA.2.87.1 by Trivalent XBB Vaccine-Induced Antibodies</strong> -
<div>
Newly emerged SARS-CoV-2 variants like JN.1, and more recently, the hypermutated BA.2.87.1, have raised global concern. We recruited two groups of participants who had BA.5/BF.7 breakthrough infection post three doses of inactivated vaccines: one group experienced subsequent XBB reinfection, while the other received the XBB-containing trivalent WSK-V102C vaccine. Our comparative analysis of their serum neutralization activities revealed that the WSK-V102C vaccine induced stronger antibody responses against a wide range of variants, notably including JN.1 and the highly escaped BA.2.87.1. Furthermore, our investigation into specific mutations revealed that fragment deletions in NTD significantly contribute to the immune evasion of the BA.2.87.1 variant. Our findings emphasize the necessity for ongoing vaccine development and adaptation to address the dynamic nature of SARS-CoV-2 variants.
</div>
<div class="article-link article-html-link">
🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2024.02.16.580615v1" target="_blank">Robust Neutralization of SARS-CoV-2 Variants Including JN.1 and BA.2.87.1 by Trivalent XBB Vaccine-Induced Antibodies</a>
</div></li>
<li><strong>MobileLAMP: A portable, low-cost, open-source device for isothermal nucleic acid amplification</strong> -
<div>
Isothermal amplification-based methods for pathogen DNA or RNA detection offer high sensitivity, rapid detection, and the potential for deployment in remote fields and home testing. Consequently, they are emerging as alternatives to PCR and saw a surge in research activity and deployment for the rapid detection of SARS-CoV-2 during the Covid-19 pandemic. The most common isothermal DNA detection methods rely on minimal reagents for DNA amplification and simple hardware that can maintain isothermal conditions and read-out a fluorescent or colorimetric signal. Many researchers globally are working on improving these components based on diverse end-user needs. In this work, we have recognized the need for an open-source hardware device for isothermal amplification, composed of off-the-shelf components that are easily accessible in any part of the world, is easily manufacturable in a distributed and scalable way using 3D printing, and that can be powered using a wide diversity of batteries and power sources. We demonstrate the easy assembly of our device design and demonstrate its efficacy using colorimetric LAMP for both RNA and DNA targets.
</div>
<div class="article-link article-html-link">
🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2024.02.13.580127v1" target="_blank">MobileLAMP: A portable, low-cost, open-source device for isothermal nucleic acid amplification</a>
</div></li>
<li><strong>Disaster, Facial Recognition Technology, and the Problem of the Corpse</strong> -
<div>
The overlapping disasters of the Australian 2019-2020 bushfire season and the COVID-19 pandemic, figured alongside the imaginary of projected future disasters, have provided a space of legitimation to experiment with controversial facial recognition technologies (FRTs). Drawing upon interviews conducted with senior Australian government administrators and researchers, I argue that FRTs are being used to respond to the trauma of disaster through its novel mediation and refiguration, tied to discourses of resilience which have been used to justify the expansion of FRT as a means for relief and the provision of aid. This legitimation however is challenged by the difficulty FRT encounters in capturing the face in its vital and its mortal malleability. What I term ‘the problem of the corpse’ serves to bring to light the ‘paranoid’ gaze of the biometric apparatus, disrupting the aim of using biometric infrastructure to produce a ‘new normal’ in the ongoing aftermath of disaster.
</div>
<div class="article-link article-html-link">
🖺 Full Text HTML: <a href="https://osf.io/preprints/socarxiv/j4wdh/" target="_blank">Disaster, Facial Recognition Technology, and the Problem of the Corpse</a>
</div></li>
<li><strong>Viral Automation: The Case of COVID-19</strong> -
<div>
Manuscript of editor’s introduction to forthcoming special issue for New Media &amp; Society on legacies of the COVID-19 pandemic for automated decision-making.
</div>
<div class="article-link article-html-link">
🖺 Full Text HTML: <a href="https://osf.io/preprints/socarxiv/u6fht/" target="_blank">Viral Automation: The Case of COVID-19</a>
</div></li>
<li><strong>UBA1-CDK16: A Sex-Specific Chimeric RNA and Its Role in Immune Sexual Dimorphism</strong> -
<div>
RNA processing mechanisms, such as alternative splicing and RNA editing, have been recognized as critical means to expand the transcriptome. Chimeric RNAs formed by intergenic splicing provide another potential layer of RNA diversification. By analyzing a large set of RNA-Seq data and validating results in over 1,200 blood samples, we identified UBA1-CDK16, a female-specific chimeric transcript. Intriguingly, both parental genes, are expressed in males and females. Mechanistically, UBA1-CDK16 is produced by cis-splicing between the two adjacent X-linked genes, originating from the inactive X chromosome. A female-specific chromatin loop, formed between the junction sites, facilitates the alternative splicing of its readthrough precursor. This unique chimeric transcript exhibits evolutionary conservation, evolving to be female-specific from non-human primates to humans. Furthermore, our investigation reveals that UBA1-CDK16 is enriched in the myeloid lineage and plays a regulatory role in myeloid differentiation. Notably, female COVID-19 patients who tested negative for this chimeric transcript displayed higher counts of neutrophils, highlighting its potential role in disease pathogenesis. These findings support the notion that chimeric RNAs represent a new repertoire of transcripts that can be regulated independently from the parental genes, and a new class of RNA variance with potential implications in sexual dimorphism and immune responses.
</div>
<div class="article-link article-html-link">
🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2024.02.13.580120v1" target="_blank">UBA1-CDK16: A Sex-Specific Chimeric RNA and Its Role in Immune Sexual Dimorphism</a>
</div></li>
<li><strong>SARS-CoV-2 serosurvey of healthy, privately owned cats presenting to a New York City animal hospital in the early phase of the COVID-19 pandemic (2020-2021)</strong> -
<div>
Both domestic and non-domestic cats are now established to be susceptible to infection by SARS-CoV-2, the cause of the ongoing COVID-19 pandemic. While serious disease in cats may occur in some instances, the majority of infections appear to be subclinical. Differing prevalence data for SARS-CoV-2 infection of cats have been reported, and are highly context-dependent. Here, we report a retrospective serological survey of cats presented to an animal practice in New York City, located in close proximity to a large medical center that treated the first wave of COVID-19 patients in the US in the Spring of 2020. We sampled 79, mostly indoor, cats between June 2020 to May 2021, the early part of which time the community was under a strict public health lock-down. Using a highly sensitive and specific fluorescent bead-based multiplex assay, we found an overall prevalence of 13/79 (16%) serologically-positive animals for the study period; however, cats sampled in the Fall of 2020 had a confirmed positive prevalence of 44%. For SARS-CoV-2 seropositive cats, we performed viral neutralization test with live SARS-CoV-2 to additionally confirm presence of SARS-CoV-2 specific antibodies. Of the thirteen seropositive cats, 7/13 (54%) were also positive by virus neutralization, and 2 of seropositive cats had previously documented respiratory signs, with high neutralization titers of 1:1024 and 1:4096; overall however, there was no statistically significant association of SARS-CoV-2 seropositivity with respiratory signs, or with breed, sex or age of the animals. Follow up sampling of cats, while limited in scope, showed that positive serological titers were maintained over time. In comparison, we found an overall confirmed positive prevalence of 51% for feline coronavirus (FCoV), an endemic virus of cats, with 30% confirmed negative for FCoV. We demonstrate the impact of SARS-CoV in a defined feline population during the first wave of SARS-CoV-2 infection of humans, and suggest that human-cat transmission was substantial in our study group. Our data provide a new context for SARS-CoV-2 transmission events across species.
</div>
<div class="article-link article-html-link">
🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2024.02.13.580068v1" target="_blank">SARS-CoV-2 serosurvey of healthy, privately owned cats presenting to a New York City animal hospital in the early phase of the COVID-19 pandemic (2020-2021)</a>
</div></li>
<li><strong>A single-dose MCMV-based vaccine elicits long-lasting immune protection in mice against distinct SARS-CoV-2 variants</strong> -
<div>
Current vaccines against COVID-19 elicit immune responses that are overall strong but wane rapidly. As a consequence, the necessary booster shots have led to vaccine fatigue. Hence, vaccines that would provide lasting protection against COVID-19 are needed, but are still unavailable. Cytomegaloviruses (CMV) elicit lasting and uniquely strong immune responses. Used as vaccine vectors, they may be attractive tools that obviate the need for boosters. Therefore, we tested the murine CMV (MCMV) as a vaccine vector against COVID-19 in relevant preclinical models of immunization and challenge. We have previously developed a recombinant murine CMV (MCMV) vaccine vector expressing the spike protein of the ancestral SARS-CoV-2 (MCMVS). In this study, we show that the MCMVS elicits a robust and lasting protection in young and aged mice. Notably, S-specific humoral and cellular immunity was not only maintained but even increased over a period of at least 6 months. During that time, antibody avidity continuously increased and expanded in breadth, resulting in neutralization of genetically distant variants, like Omicron BA.1. A single dose of MCMVS conferred rapid virus clearance upon challenge. Moreover, MCMVS vaccination controlled two immune-evading variants of concern (VoCs), the Beta (B.1.135) and the Omicron (BA.1) variants. Thus, CMV vectors provide unique advantages over other vaccine technologies, eliciting broadly reactive and long-lasting immune responses against COVID-19.
</div>
<div class="article-link article-html-link">
🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2022.11.25.517953v2" target="_blank">A single-dose MCMV-based vaccine elicits long-lasting immune protection in mice against distinct SARS-CoV-2 variants</a>
</div></li>
<li><strong>Infer metabolic directions and magnitudes from moment differences of mass-weighted intensity distributions</strong> -
<div>
Metabolic pathways are fundamental maps in biochemistry that detail how molecules are transformed through various reactions. Metabolomics refers to the large-scale study of small molecules. High-throughput, untargeted, mass spectrometry-based metabolomics experiments typically depend on libraries for structural annotation, which is necessary for pathway analysis. However, only a small fraction of spectra can be matched to known structures in these libraries and only a portion of annotated metabolites can be associated with specific pathways, considering that numerous pathways are yet to be discovered. The complexity of metabolic pathways, where a single compound can play a part in multiple pathways, poses an additional challenge. This study introduces a different concept: mass spectra distribution, which is the empirical distribution of the intensities times their associated m/z values. Analysis of COVID-19 and mouse brain datasets shows that by estimating the differences of the point estimations of these distributions, it becomes possible to infer the metabolic directions and magnitudes without requiring knowledge of the exact chemical structures of these compounds and their related pathways. The overall metabolic momentum map, named as momentome, has the potential to bypass the current bottleneck and provide fresh insights into metabolomics studies. This brief report thus provides a mathematical framing for a classic biological concept.
</div>
<div class="article-link article-html-link">
🖺 Full Text HTML: <a href="https://osf.io/jmgea/" target="_blank">Infer metabolic directions and magnitudes from moment differences of mass-weighted intensity distributions</a>
</div></li>
<li><strong>“Some distance between us:” a mixed methods study exploring experiences of remote care for eating disorders during COIVD-19</strong> -
<div>
Introduction: COVID-19 necessitated a rapid move from face-to-face services to remote care for eating disorders/eating distress (EDs). This study explores the advantages and challenges of remote care, identifying future implications for service provision. Methods: Using a mixed methods approach, data were collected from 211 people with lived experience (PWLE); 27 participating in semi-structured interviews/workshops and 184 via an online survey. Participants reported on their ED status; the impact of the pandemic on symptoms; benefits and challenges of remote care (and type of support accessed); any reasons for not accessing support; and future recommendations. Participation was open to PWLE with and without formal diagnosis. Results: ED symptoms were reported as worsening during the pandemic with contributing factors including isolation, lack of routine, negative emotions, and feeling like the external situation was outside of one’s control. Exercise was reported as a coping mechanism (although it is noted that responses did not allow for clarifications of respondents’ understanding of what constitutes healthy or unhealthy exercise). Remote care was positively attributed to increased flexibility and facilitation of social connection. However, identified barriers to access included a lack of awareness about support availability, digital access and/or literacy, and competing commitments (e.g., childcare). Further challenges included approaches being perceived as too clinical; uncertainty around remote care quality, and concerns that remote platforms may facilitate masking of symptoms. Participants also reflected heavily upon distress caused by default self-view during video calls. Participants expressed a need for more holistic approaches including “real stories” of recovery, and hybrid (online and offline) options for greater flexibility and widening of access choices; complimented by appropriate training to mitigate digital literacy barriers. Discussion: Future recommendations emphasise user-centered holistic, hybrid approaches to ED remote support, supported by training to address digital literacy barriers and facilitate user control of platform functionalities (e.g., self-view). The study underscores the need for continued remote care with a focus on inclusivity and user empowerment.
</div>
<div class="article-link article-html-link">
🖺 Full Text HTML: <a href="https://osf.io/5rpg3/" target="_blank">“Some distance between us:” a mixed methods study exploring experiences of remote care for eating disorders during COIVD-19</a>
</div></li>
<li><strong>A Broad-Spectrum Multi-Antigen mRNA/LNP-Based Pan-Coronavirus Vaccine Induced Potent Cross-Protective Immunity Against Infection and Disease Caused by Highly Pathogenic and Heavily Spike-Mutated SARS-CoV-2 Variants of Concern in the Syrian Hamster Model</strong> -
<div>
The first-generation Spike-alone-based COVID-19 vaccines have successfully contributed to reducing the risk of hospitalization, serious illness, and death caused by SARS-CoV-2 infections. However, waning immunity induced by these vaccines failed to prevent immune escape by many variants of concern (VOCs) that emerged from 2020 to 2024, resulting in a prolonged COVID-19 pandemic. We hypothesize that a next-generation Coronavirus (CoV) vaccine incorporating highly conserved non-Spike SARS-CoV-2 antigens would confer stronger and broader cross-protective immunity against multiple VOCs. In the present study, we identified ten non-Spike antigens that are highly conserved in 8.7 million SARS-CoV-2 strains, twenty-one VOCs, SARS-CoV, MERS-CoV, Common Cold CoVs, and animal CoVs. Seven of the 10 antigens were preferentially recognized by CD8+ and CD4+ T-cells from unvaccinated asymptomatic COVID-19 patients, irrespective of VOC infection. Three out of the seven conserved non-Spike T cell antigens belong to the early expressed Replication and Transcription Complex (RTC) region, when administered to the golden Syrian hamsters, in combination with Spike, as nucleoside-modified mRNA encapsulated in lipid nanoparticles (LNP) (i.e., combined mRNA/LNP-based pan-CoV vaccine): (i) Induced high frequencies of lung-resident antigen-specific CXCR5+CD4+ T follicular helper (TFH) cells, GzmB+CD4+ and GzmB+CD8+ cytotoxic T cells (TCYT), and CD69+IFN-g+TNF-a+CD4+ and CD69+IFN-g+TNFa+CD8+ effector T cells (TEFF); and (ii) Reduced viral load and COVID-19-like symptoms caused by various VOCs, including the highly pathogenic B.1.617.2 Delta variant and the highly transmittable heavily Spike-mutated XBB1.5 Omicron sub-variant. The combined mRNA/LNP-based pan-CoV vaccine could be rapidly adapted for clinical use to confer broader cross-protective immunity against emerging highly mutated and pathogenic VOCs.
</div>
<div class="article-link article-html-link">
🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2024.02.14.580225v1" target="_blank">A Broad-Spectrum Multi-Antigen mRNA/LNP-Based Pan-Coronavirus Vaccine Induced Potent Cross-Protective Immunity Against Infection and Disease Caused by Highly Pathogenic and Heavily Spike-Mutated SARS-CoV-2 Variants of Concern in the Syrian Hamster Model</a>
</div></li>
<li><strong>Probability Discounting and Adherence to Preventive Behaviors During the COVID-19 Pandemic</strong> -
<div>
This brief communication reports preliminary findings of a study conducted to investigate the relationship between probability discounting and people’s adherence to preventive behaviors recommended during the COVID-19 pandemic. A sample of 112 adults living in Brazil completed an online survey composed of a Probability Discounting Questionnaire (PDQ) and a 10-item assessment of how often they complied with the health authorities’ recommendations (e.g., wash the hands frequently, practice social distancing, stay at home as much as possible, wear a mask when in public). Data analysis included the participants who showed higher (n = 40) and lower (n = 40) adherence to preventive behaviors. Results revealed that probability discounting measures are related to people’s preventive actions. Participants in the higher adherence group present significantly larger risk aversion indices (i.e., larger h values) than participants in the lower adherence group. Also, participants who showed lower adherence to preventive behaviors were more likely to perform risky choices in the PDQ than participants who demonstrated higher compliance with health authorities’ recommendations. These preliminary results suggest that probability discounting can play an essential role in people’s self-protective decisions during a global health emergency, such as the COVID-19 pandemic.
</div>
<div class="article-link article-html-link">
🖺 Full Text HTML: <a href="https://osf.io/preprints/psyarxiv/p4a76/" target="_blank">Probability Discounting and Adherence to Preventive Behaviors During the COVID-19 Pandemic</a>
</div></li>
<li><strong>Pooled PPIseq: screening the SARS-CoV-2 and human interface with a scalable multiplexed protein-protein interaction assay platform</strong> -
<div>
Protein-Protein Interactions (PPIs) are a key interface between virus and host, and these interactions are important to both viral reprogramming of the host and to host restriction of viral infection. In particular, viral-host PPI networks can be used to further our understanding of the molecular mechanisms of tissue specificity, host range, and virulence. At higher scales, viral-host PPI screening could also be used to screen for small-molecule antivirals that interfere with essential viral-host interactions, or to explore how the PPI networks between interacting viral and host genomes co-evolve. Current high-throughput PPI assays have screened entire viral-host PPI networks. However, these studies are time consuming, often require specialized equipment, and are difficult to further scale. Here, we develop methods that make larger-scale viral-host PPI screening more accessible. This approach combines the mDHFR split-tag reporter with the iSeq2 interaction-barcoding system to permit massively-multiplexed PPI quantification by simple pooled engineering of barcoded constructs, integration of these constructs into budding yeast, and fitness measurements by pooled cell competitions and barcode-sequencing. We applied this method to screen for PPIs between SARS-CoV-2 proteins and human proteins, screening in triplicate &gt;180,000 ORF-ORF combinations represented by &gt;1,000,000 barcoded lineages. Our results complement previous screens by identifying 74 putative PPIs, including interactions between ORF7A with the taste receptors TAS2R41 and TAS2R7, and between NSP4 with the transmembrane KDELR2 and KDELR3. We show that this PPI screening method is highly scalable, enabling larger studies aimed at generating a broad understanding of how viral effector proteins converge on cellular targets to effect replication.
</div>
<div class="article-link article-html-link">
🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2024.02.13.580123v1" target="_blank">Pooled PPIseq: screening the SARS-CoV-2 and human interface with a scalable multiplexed protein-protein interaction assay platform</a>
</div></li>
<li><strong>Single-cell Masked Autoencoder: An Accurate and Interpretable Automated Immunophenotyper</strong> -
<div>
High-throughput single-cell cytometry data are crucial for understanding immune system's involvement in diseases and responses to treatment. Traditional methods for annotating cytometry data, specifically manual gating and clustering, face challenges in scalability, robustness, and accuracy. In this study, we propose a single-cell masked autoencoder (scMAE), which offers an automated solution for immunophenotyping tasks including cell type annotation. The scMAE model is designed to uphold user-defined cell type definitions, thereby facilitating easier interpretation and cross-study comparisons. The scMAE model operates on a pre-train and fine-tune approach. In the pre-training phase, scMAE employs Masked Single-cell Modelling (MScM) to learn relationships between protein markers in immune cells solely based on protein expression, without relying on prior information such as cell identity and cell type-specific marker proteins. Subsequently, the pre-trained scMAE is fine-tuned on multiple specialized tasks via task-specific supervised learning. The pre-trained scMAE addresses the shortcomings of manual gating and clustering methods by providing accurate and interpretable predictions. Through validation across multiple cohorts, we demonstrate that scMAE effectively identifies co-occurrence patterns of bound labeled antibodies, delivers accurate and interpretable cellular immunophenotyping, and improves the prediction of subject metadata status. Specifically, we evaluated scMAE for cell type annotation and imputation at the cellular-level and SARS-CoV-2 infection prediction, secondary immune response prediction against COVID-19, and prediction the infection stage in the COVID-19 progression at the subject-level. The introduction of scMAE marks a significant step forward in immunology research, particularly in large-scale and high-throughput human immune profiling. It offers new possibilities for predicting and interpretating cellular-level and subject-level phenotypes in both health and disease.
</div>
<div class="article-link article-html-link">
🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2024.02.13.580114v1" target="_blank">Single-cell Masked Autoencoder: An Accurate and Interpretable Automated Immunophenotyper</a>
</div></li>
<li><strong>A spring-loaded and leakage-tolerant synthetic gene switch for in-vitro detection of DNA and RNA</strong> -
<div>
Nucleic acid tests (NATs) are essential for biomedical diagnostics. Traditional NATs, often complex and expensive, have prompted the exploration of Toehold-Mediated Strand Displacement (TMSD) circuits as an economical alternative. However, the wide application of TMSD-based reactions is limited by leakage-the spurious activation of the reaction leading to high background signals and false positives. Here we introduce a new TMSD cascade that recognizes a custom nucleic acid input and generates an amplified output. The system is based on a pair of thermodynamically spring-loaded DNA modules. The binding of a predefined nucleic acid target triggers an intermolecular reaction that activates a T7 promoter, leading to the perpetual transcription of a fluorescent aptamer that can be detected by a smartphone camera. The system is designed to permit the selective depletion of leakage byproducts to achieve high sensitivity and zero-background signal in the absence of the correct trigger. Using Zika virus (ZIKV)- and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-derived nucleic acid sequences, we show that the assay generates a reliable target-specific readout. Native RNA can be directly detected under isothermal conditions, without requiring reverse transcription, with a sensitivity as low as 200 attomole. The modularity of the assay allows easy re-programming for the detection of other targets by exchanging a single sequence domain. This work provides a low-complexity and high-fidelity synthetic biology tool for point-of-care diagnostics and for the construction of more complex biomolecular computations.
</div>
<div class="article-link article-html-link">
🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2024.02.12.579921v1" target="_blank">A spring-loaded and leakage-tolerant synthetic gene switch for in-vitro detection of DNA and RNA</a>
</div></li>
</ul>
<h1 data-aos="fade-right" id="from-clinical-trials">From Clinical Trials</h1>
<ul>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Correlation of Antibody Response to COVID-19 Vaccination in Pregnant Woman and Transplacental Passage Into Cord Blood.</strong> - <b>Conditions</b>: Covid-19 <br/><b>Interventions</b>: Diagnostic Test: COVID-19 Spike Protein IgG Quantitative Antibody (CMIA) <br/><b>Sponsors</b>: Vachira Phuket Hospital <br/><b>Recruiting</b></p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>UNAIR Inactivated COVID-19 Vaccine as Homologue Booster (Immunobridging Study)</strong> - <b>Conditions</b>: COVID-19 Pandemic; COVID-19 Vaccines; COVID-19 Virus Disease <br/><b>Interventions</b>: Biological: INAVAC (Vaksin Merah Putih - UA- SARS CoV-2 (Vero Cell Inactivated) 5 μg <br/><b>Sponsors</b>: Dr. Soetomo General Hospital; Universitas Airlangga; Biotis Pharmaceuticals, Indonesia; Indonesia-MoH <br/><b>Recruiting</b></p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Safety and Immunogenicity of a Sub-unit Protein CD40.RBDv Bivalent COVID-19 Vaccine, Adjuvanted or Not, as a Booster in Volunteers.</strong> - <b>Conditions</b>: COVID-19 <br/><b>Interventions</b>: Drug: CD40.RBDv vaccin (SARS-Cov2 Vaccin) <br/><b>Sponsors</b>: ANRS, Emerging Infectious Diseases; LinKinVax; Vaccine Research Institute (VRI), France <br/><b>Not yet recruiting</b></p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>High-definition Transcranial Direct Current Ctimulation and Chlorella Pyrenoidosa to Reduce Cardiovascular Risk</strong> - <b>Conditions</b>: Cardiovascular Diseases; Long Covid19 <br/><b>Interventions</b>: Other: High Definition-transcranial Direct Current Stimulation; Dietary Supplement: Chlorella Pyrenoidosa <br/><b>Sponsors</b>: Federal University of Paraíba; City University of New York <br/><b>Recruiting</b></p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>SGB for COVID-induced Parosmia</strong> - <b>Conditions</b>: COVID-19-Induced Parosmia <br/><b>Interventions</b>: Drug: Stellate Ganglion Block; Drug: Placebo Sham Injection <br/><b>Sponsors</b>: Washington University School of Medicine <br/><b>Recruiting</b></p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Effects of Physiotherapy Via Video Calls in Patients With COVID-19</strong> - <b>Conditions</b>: COVID-19; Long COVID-19; Cardiopulmonary Function; Physical Function <br/><b>Interventions</b>: Behavioral: Exercise training <br/><b>Sponsors</b>: Chulabhorn Hospital <br/><b>Active, not recruiting</b></p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Investigating the Effectiveness of Vimida</strong> - <b>Conditions</b>: Long COVID; Post COVID-19 Condition <br/><b>Interventions</b>: Behavioral: vimida <br/><b>Sponsors</b>: Gaia AG; Medical School Hamburg; Institut Long-Covid Rostock <br/><b>Not yet recruiting</b></p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Acute Cardiovascular Responses to a Single Exercise Session in Patients With Post-COVID-19 Syndrome</strong> - <b>Conditions</b>: Post-Acute COVID-19 Syndrome <br/><b>Interventions</b>: Behavioral: Exercise session; Behavioral: Control session <br/><b>Sponsors</b>: University of Nove de Julho <br/><b>Not yet recruiting</b></p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Reducing Respiratory Virus Transmission in Bangladeshi Classrooms</strong> - <b>Conditions</b>: SARS-CoV2 Infection; Influenza Viral Infections; Respiratory Viral Infection <br/><b>Interventions</b>: Device: Box Fan; Device: UV Germicidal Irradiation Lamp Unit; Device: Combined: Box Fan and UV Germicidal Irradiation Lamp Units <br/><b>Sponsors</b>: Stanford University; Centers for Disease Control and Prevention; International Centre for Diarrhoeal Disease Research, Bangladesh <br/><b>Not yet recruiting</b></p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>SMILE: Clinical Trial to Evaluate Mindfulness as Intervention for Racial and Ethnic Populations During COVID-19</strong> - <b>Conditions</b>: Anxiety; COVID-19 Pandemic <br/><b>Interventions</b>: Behavioral: Mindfulness <br/><b>Sponsors</b>: University of North Carolina, Chapel Hill; National Institute on Minority Health and Health Disparities (NIMHD); RTI International <br/><b>Not yet recruiting</b></p></li>
</ul>
<h1 data-aos="fade-right" id="from-pubmed">From PubMed</h1>
<ul>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Development of a quantitative ELISA for SARS-CoV-2 vaccine candidate, NDV-HXP-S, with CpG 1018® adjuvant</strong> - NDV-HXP-S is a Newcastle disease virus (NDV) vectored vaccine candidate which expresses the S-antigen of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This vaccine candidate is under evaluation in human clinical studies with and without cytosine phosphate guanine (CpG) 1018® adjuvant. Existing potency methods for NDV-HXP-S do not allow for quantification of the S-antigen when the adjuvant is present. To support evaluation of NDV-HXP-S with CpG 1018® adjuvant, an inhibition…</p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong><em>Syringa reticulata</em> potently inhibits the activity of SARS-CoV-2 3CL protease</strong> - The ongoing coronavirus infectious disease (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) still urgently requires effective treatments. The 3C-like (3CL) protease of SARS-CoV-2 is a highly conserved cysteine protease that plays an important role in the viral life cycle and host inflammation, providing an ideal target for developing broad-spectrum antiviral drugs. Herein, we describe the discovery of a large number of herbs mainly produced in…</p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>A Case Report of Drug Interactions Between Nirmatrelvir/Ritonavir and Tacrolimus in a Patient With Systemic Lupus Erythematosus</strong> - Nirmatrelvir/ritonavir is a treatment for COVID-19 consisting of nirmatrelvir, which has anti-SARS-CoV-2 activity, and ritonavir, a booster to maintain blood levels. Ritonavir is known to be a potent inhibitor of cytochrome P450 3A (CYP3A), and interactions with CYP3A-metabolized drugs, such as the immunosuppressant tacrolimus, can be problematic. Ritonavir’s inhibition of CYP3A is irreversible due to covalent binding, and its inhibitory effects are expected to persist until replaced by new…</p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Second Boost of Omicron SARS-CoV-2 S1 Subunit Vaccine Induced Broad Humoral Immune Responses in Elderly Mice</strong> - Currently approved COVID-19 vaccines prevent symptomatic infection, hospitalization, and death from the disease. However, repeated homologous boosters, while considered a solution for severe forms of the disease caused by new SARS-CoV-2 variants in elderly individuals and immunocompromised patients, cannot provide complete protection against breakthrough infections. This highlights the need for alternative platforms for booster vaccines. In our previous study, we assessed the boost effect of the…</p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Preparation and characterization of a fluorogenic ddRFP-M biosensor as a specific SARS-CoV-2 main protease substrate</strong> - The conventional peptide substrates of SARS-CoV-2 main protease (Mpro) are frequently associated with high cost, unstable kinetics, and multistep synthesis. Hence, there is an urgent need to design affordable and stable Mpro substrates for pharmacological research. Herein, we designed a functional Mpro substrate based on a dimerization-dependent red fluorescent protein (ddRFP) for the evaluation of Mpro inhibitors in vitro. The codon-optimized DNA fragment encoding RFP-A(1) domain, a polypeptide…</p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Neutralizing antibodies to block viral entry and for identification of entry inhibitors</strong> - Neutralizing antibodies (NAbs) are naturally produced by our immune system to combat viral infections. Clinically, neutralizing antibodies with potent efficacy and high specificity have been extensively used to prevent and treat a wide variety of viral infections, including Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), Human Immunodeficiency Virus (HIV), Dengue Virus (DENV) and Hepatitis B Virus (HBV). An overwhelmingly large subset of clinically effective NAbs operates by…</p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Interferon-stimulated gene PVRL4 broadly suppresses viral entry by inhibiting viral-cellular membrane fusion</strong> - CONCLUSION: Overall, our studies not only identify PVRL4 as an intrinsic broad-spectrum antiviral ISG, but also provide a candidate host-directed target for antiviral therapy against various viruses including SARS-CoV-2 and its variants in the future.</p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>FEOpti-ACVP: identification of novel anti-coronavirus peptide sequences based on feature engineering and optimization</strong> - Anti-coronavirus peptides (ACVPs) represent a relatively novel approach of inhibiting the adsorption and fusion of the virus with human cells. Several peptide-based inhibitors showed promise as potential therapeutic drug candidates. However, identifying such peptides in laboratory experiments is both costly and time consuming. Therefore, there is growing interest in using computational methods to predict ACVPs. Here, we describe a model for the prediction of ACVPs that is based on the…</p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Taming the cytokine storm: small molecule inhibitors targeting IL-6/IL-6α receptor</strong> - Given the increasing effectiveness of immune-based therapies, management of their associated toxicities is of utmost importance. Cytokine release syndrome (CRS), characterized by elevated levels of cytokine, poses a significant challenge following the administration of antibodies and CAR-T cell therapies. CRS also contributes to multiple organ dysfunction in severe viral infections, notably in COVID-19. Given the pivotal role of IL-6 cytokine in initiating CRS, it has been considered a most…</p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>How can we promote vaccination of the mass population?-Lessons from the COVID-19 vaccination defaults</strong> - While vaccines are pivotal in combating COVID-19, concerns about side effects and complex procedures have hindered complete vaccination. Prior studies suggest that individuals defaulted to opt-out exhibit higher COVID-19 vaccination rates compared to those in opt-in systems. However, these studies were conducted in countries with a tolerant attitude towards vaccination and default changes, targeting specific age groups, and did not address potential deterrents like the increase in cancellation…</p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Nanobody engineering for SARS-CoV-2 neutralization and detection</strong> - In response to the ongoing COVID-19 pandemic, the quest for coronavirus inhibitors has inspired research on a variety of small proteins beyond conventional antibodies, including robust single-domain antibody fragments, i.e., “nanobodies.” Here, we explore the potential of nanobody engineering in the development of antivirals and diagnostic tools. Through fusion of nanobody domains that target distinct binding sites, we engineered multimodular nanobody constructs that neutralize wild-type…</p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Effect of rifampicin administration on CYP induction in a dermatomyositis patient with vasospastic angina attributable to nilmatrelvir/ritonavir-induced blood tacrolimus elevation: A case report</strong> - Ritonavir (RTV), which is used in combination with nilmatrelvir (NMV) to treat coronavirus disease 2019 (COVID-19), inhibits cytochrome P450 (CYP) 3A, thereby increasing blood tacrolimus (TAC) levels through a drug-drug interaction (DDI). We experienced a case in which a DDI between the two drugs led to markedly increased blood TAC levels, resulting in vasospastic angina (VSA) and acute kidney injury (AKI). Rifampicin (RFP) was administered to induce CYP3A and promote TAC metabolism. A…</p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>SARS-CoV-2 spike protein receptor binding domain promotes IL-6 and IL-8 release via ATP/P2Y<sub>2</sub> and ERK1/2 signaling pathways in human bronchial epithelia</strong> - The spike protein of SARS-CoV-2 as well as its receptor binding domain (RBD) has been demonstrated to be capable of activating the release of pro-inflammatory mediators in endothelial cells and immune cells such as monocytes. However, the effects of spike protein or its RBD on airway epithelial cells and mechanisms underlying these effects have not been adequately characterized. Here, we show that the RBD of spike protein alone can induce bronchial epithelial inflammation in a manner of…</p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Targeting mevalonate pathway by zoledronate ameliorated pulmonary fibrosis in a rat model: Promising therapy against post-COVID-19 pulmonary fibrosis</strong> - CONCLUSION: ZA in a dose-dependent manner prevented the pathological effect of CCl4 in the lung by targeting mevalonate pathway. It could be promising therapy against PCPF.</p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Methotrexate Inhibits the Binding of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Receptor Binding Domain to the Host-Cell Angiotensin-Converting Enzyme-2 (ACE-2) Receptor</strong> - As the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus mutates, finding effective drugs becomes more challenging. In this study, we use ultrasensitive frequency locked microtoroid optical resonators in combination with in silico screening to search for COVID-19 drugs that can stop the virus from attaching to the human angiotensin-converting enzyme 2 (hACE2) receptor in the lungs. We found 29 promising candidates that could block the binding site and selected four of them that…</p></li>
</ul>
<h1 data-aos="fade-right" id="from-patent-search">From Patent Search</h1>
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<h1 data-aos="fade-down" id="daily-dose">Daily-Dose</h1>
<h1 data-aos="fade-right" data-aos-anchor-placement="top-bottom" id="contents">Contents</h1>
<ul>
<li><a href="#from-new-yorker">From New Yorker</a></li>
<li><a href="#from-vox">From Vox</a></li>
<li><a href="#from-the-hindu-sports">From The Hindu: Sports</a></li>
<li><a href="#from-the-hindu-national-news">From The Hindu: National News</a></li>
<li><a href="#from-bbc-europe">From BBC: Europe</a></li>
<li><a href="#from-ars-technica">From Ars Technica</a></li>
<li><a href="#from-jokes-subreddit">From Jokes Subreddit</a></li>
</ul>
<h1 data-aos="fade-right" id="from-new-yorker">From New Yorker</h1>
<ul>
<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Legal Weed in New York Was Going to Be a Revolution. What Happened?</strong> - Lawsuits. Unlicensed dispensaries. Corporations pushing to get in. The messy rollout of a law that has tried to deliver social justice with marijuana. - <a href="https://www.newyorker.com/magazine/2024/02/26/legal-weed-in-new-york-was-going-to-be-just-and-fair-what-happened">link</a></p></li>
<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>The Snake with the Emoji-Patterned Skin</strong> - In the wild, ball pythons are usually brown and tan. In America, breeding them to produce eye-catching offspring has become a lucrative, frenetic, and—for some—troubling enterprise. - <a href="https://www.newyorker.com/magazine/2024/02/26/inside-the-world-of-designer-ball-pythons">link</a></p></li>
<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Matt Gaetz’s Chaos Agenda</strong> - The Florida Republican is among the most brazen and controversial figures in Donald Trump’s G.O.P. He’s also among the most influential. - <a href="https://www.newyorker.com/magazine/2024/02/26/matt-gaetz-profile">link</a></p></li>
<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>The Trials of Alejandro Mayorkas</strong> - The Secretary of Homeland Security has been forced to respond to an unprecedented flow of migrants to the U.S.-Mexico border. Why are Republicans in Congress impeaching him for it? - <a href="https://www.newyorker.com/magazine/2024/02/26/the-trials-of-alejandro-mayorkas">link</a></p></li>
<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Is the Media Prepared for an Extinction-Level Event?</strong> - Ads are scarce, search and social traffic is dying, and readers are burned out. The future will require fundamentally rethinking the press’s relationship to its audience. - <a href="https://www.newyorker.com/news/the-weekend-essay/is-the-media-prepared-for-an-extinction-level-event">link</a></p></li>
</ul>
<h1 data-aos="fade-right" id="from-vox">From Vox</h1>
<ul>
<li><strong>Jon Stewart is as funny as ever. But the world has changed around him.</strong> -
<figure>
<img alt="Jon Stewart sits at a desk wearing a black suit jacket and light blue tie, smiling. " src="https://cdn.vox-cdn.com/thumbor/aQb88bvtq5s4G7qTy6SYxppqcw8=/405x0:4181x2832/1310x983/cdn.vox-cdn.com/uploads/chorus_image/image/73149365/GettyImages_483217408.0.jpg"/>
<figcaption>
Jon Stewart hosting <em>The Daily Show</em> last time around, on August 6, 2015. | Brad Barket/Getty Images for Comedy Central
</figcaption>
</figure>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
The host’s return to The Daily Show is a coda to a golden age.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="PpKcEu">
<a href="https://www.vox.com/culture/22715358/problem-with-jon-stewart-review-apple-tv-plus">Jon Stewart</a>’s return to <em>The</em> <em>Daily Show</em> has been, on the metrics, a success. According to Comedy Central, his first episode back on February 12 was watched by 1.85 million total viewers across premiere simulcasts and encores, up 110 percent from Trevor Noah’s final episode in 2022. It’s also a major improvement on Stewart’s last show. <em>The Problem with Jon Stewart</em>, which ran on Apple TV+ from 2021 to 2023, was routinely <a href="https://screenrant.com/problem-with-jon-stewart-show-ratings-decline/">drawing in audiences as low as 40,000 people</a>.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="y9FjO7">
“Jon Stewart” and “<em>The Daily Show”</em> on their own are flawed brands. “Jon Stewart on <em>The Daily Show</em>,” on the other hand? That’s a combination of such heady nostalgia that the viewers pour in.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="8BEmU2">
Still, Stewart’s first episode proved that his appeal is not just pure nostalgia. There is some kind of alchemy that occurs when Jon Stewart gets behind that old <em>Daily Show</em> desk. He knows the format of the show so well; he plays it like a virtuoso.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="tDWABf">
He eases into his monologue with no rush, breaking out the same Borscht Belt voices and self-deprecating barbs he used to play with in 2015, talking in the same relaxed patter that builds to the same crescendo of righteousness. He is so delighted by the chance to play a gotcha reel (in this case, members of the Trump family repeating “I can’t recall” during depositions after a discussion of <a href="https://www.vox.com/politics/2024/2/8/24066529/biden-special-counsel-report-memory">Biden’s allegedly failing memory</a>) that he almost manages to make the old trick feel new again. He almost manages to make you think, “Wow, Jon Stewart could have done something with the Trump era.” Almost.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="gHJm6a">
Jon Stewart’s great satirical gift is his ability to puncture hypocrisy, which is why he became one of the most <a href="https://www.nytimes.com/2008/08/17/arts/television/17kaku.html">trusted sources of news</a> in America during the 2000s. George W. Bush was Stewart’s perfect foil: a president who talked of compassionate conservatism and grand existential battles of good versus evil while <a href="https://www.vox.com/2016/7/9/12123022/george-w-bush-lies-iraq-war">lying to the public</a> and embroiling America in dirty, vicious <a href="https://www.vox.com/22639548/911-anniversary-war-on-terror-liberal-interventionism">wars that dragged on for decades</a>. No one could puncture Bush’s pieties as well as Jon Stewart. Nothing was more satisfying to watch than Stewart’s mugging face, eyes wide with faux shock, next to a video montage that promised to expose, once and for all, that Bush administration doublespeak.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="5pgH7a">
Stewart’s version of <em>The Daily Show</em> lost some of its urgency during the Obama administration, as the brand of liberal centrism he championed ascended to cultural primacy and he lost his ability to position himself as the scrappy outsider unmasking a lying president. Still, most presidents have their hypocrisies, and Stewart found plenty to puncture during the Obama years: his initially tepid <a href="https://www.theguardian.com/media/2010/oct/03/jon-stewart-barack-obama">support of gay marriage</a>, the <a href="https://www.theatlantic.com/culture/archive/2014/02/jon-stewart-dissects-obamas-love-affair-drones/358305/">drone warfare</a>, the IRS targeting of <a href="https://theweek.com/articles/464289/watch-jon-stewart-finds-two-people-who-cant-criticize-obama">Tea Party groups</a>. He left <em>The Daily Show</em> in 2015, just before Trump became the Republican candidate and the liberal consensus worldview of <em>Daily Show</em> viewers shattered.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="bPShKy">
Stewart, by and large, sat out the Trump years, so we don’t know for sure what his comedy would have looked like in that troubled era. We did, however, watch all the comedians who came up on <em>The Daily Show</em> try and fail to grapple with Trump, a president who never bothered to veil his indiscretions, who was so straightforwardly villainous that he had no hypocrisy there to be exposed. Stephen Colbert, Samantha Bee, John Oliver, Trevor Noah — the more they talked about Trump, the more they seemed to become less funny and more earnest. They could not make his actions more absurd by hyperbole. <a href="https://www.nytimes.com/2020/10/07/magazine/trump-liberal-comedy-tv.html">Sarcasm was no longer attractive to audiences</a>, who craved clear demarcations between the comedians who were on their side and those on Trump’s side. Robbed of their most effective weapons, liberal comics ended up spending the Trump years like much of the left did: alternating between rage and tears.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="ih7hPk">
“For the last 20 years we [the left] have owned the cultural terrain of comedy and irony, arguably to good effect,” <a href="https://www.vox.com/the-highlight/23440579/comedy-wars-greg-gutfeld-jon-stewart-stephen-colbert-liberal-conservative">Nick Marx, a media scholar</a> who studies political humor, told me in 2022. “The Trump era made liberals forget that. It made our comedians want to act like paternal figures who would pat us on the head.”
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="gO1EP9">
As liberal comedy faltered, right-wing comedy rushed to fill the power vacuum. <a href="https://www.vox.com/the-highlight/23440579/comedy-wars-greg-gutfeld-jon-stewart-stephen-colbert-liberal-conservative">Conservative comedians</a> now position themselves as the truly edgy and transgressive ones, the people speaking truth to the power of liberal elitists, the heirs apparent to the tradition begun by Jon Stewart.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="bLqHGw">
“There’s a rebelliousness in the way people think of this right-wing comedy, right?” Matt Sienkiewicz said in 2022. Sienkiewicz co-authored <a href="https://bookshop.org/p/books/that-s-not-funny-how-the-right-makes-comedy-work-for-them-nick-marx/17429690?ean=9780520382138"><em>That’s Not Funny: How the Right Makes Comedy Work for Them</em></a> alongside Marx. “Even if it really is regressive and pointing back to old dominant ideas. But it can be branded as being the opposite of Stephen Colbert crying about January 6 during his monologue, which is very much not cool to the teens.”
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="8KLm5n">
Stewart’s return comes not during the Trump era but during the Biden presidency, just as the country begins to stare down the possibility of a second Trump term. Biden is the sort of traditional president Stewart excels at handling; it’s not surprising that the sharpest moment of his first episode came when he criticized Biden’s administration for trying to shame the press out of covering criticism of Biden’s age. But Stewart has yet to prove his ability to cover a man like <a href="https://www.vox.com/donald-trump">Donald Trump</a>, especially in a moment when the right has successfully positioned itself as the home of transgressive comedy.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="VnnaFF">
As good as Jon Stewart’s ratings were on his first night, <em>The Daily Show</em> wasn’t the most-watched show on late-night. Over on <a href="https://www.vox.com/media">Fox News</a>, <a href="https://radaronline.com/p/fox-news-gutfeld-jon-stewart-daily-show-return-ratings-2m-total-viewers/"><em>Gutfeld!</em> got 2.2 million views</a>. No matter how skillful Stewart’s performance has been, it’s hard to avoid the sense that he’s delivering a coda to a golden age that ended long ago.
</p></li>
<li><strong>The Supreme Court will decide whether to let civilians own automatic weapons</strong> -
<figure>
<img alt="A man wearing a brown jacket and jeans holds a bump stock on the left while fitting it onto an AK-47 semi-automatic rifle on the right. Behind him are shelves of ammunition." src="https://cdn.vox-cdn.com/thumbor/dXMQHK7LyjoZXOi0EIaBVFLgCf0=/94x0:4315x3166/1310x983/cdn.vox-cdn.com/uploads/chorus_image/image/73149335/857945106.0.jpg"/>
<figcaption>
A bump stock device, at left, which fits on a semi-automatic rifle to allow it to fire much like a fully automatic rifle, is installed on an AK-47 at a Utah gun store in 2017. | George Frey/Getty Images
</figcaption>
</figure>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
Garland v. Cargill asks whether gun makers can evade the ban on machine guns with a device called a bump stock.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="PSKKFq">
On February 28, the <a href="https://www.vox.com/scotus">Supreme Court</a> will hear a case that could effectively make it legal for civilians to own automatic weapons <a href="https://www.vox.com/scotus/2023/11/3/23943399/supreme-court-automatic-weapons-bump-stocks-gun-policy">capable of firing as many as nine bullets every second</a>.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="m7ncGT">
The case, known as <a href="https://www.scotusblog.com/case-files/cases/garland-v-cargill/"><em>Garland v. Cargill</em></a>, involves bump stocks, devices that use a gun’s recoil to repeatedly fire the weapon. Bump stocks cause a semiautomatic firearm’s trigger to buck against the shooter’s finger, as the gun’s recoil causes it to jerk back and forth — repeatedly “bumping” the trigger and causing the gun to fire as if it were fully automatic.
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<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="t3Te4k">
A “semiautomatic” weapon refers to a gun that loads a bullet into the chamber or otherwise prepares itself to fire again after discharging a bullet, but that will not fire a second bullet until the shooter pulls the trigger a second time. An “automatic” weapon, by contrast, will fire a continuous stream of bullets — though the shooter often must hold down the trigger to do so.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="Aib9xP">
The <a href="https://www.vox.com/trump-administration">Trump administration</a> issued a regulation banning bump stocks in 2018, after a gunman <a href="https://www.vox.com/scotus/2023/11/3/23943399/supreme-court-automatic-weapons-bump-stocks-gun-policy">used one to kill 60 people and wound hundreds more</a> during a country music festival in Las Vegas. A 1986 law<a href="https://www.law.cornell.edu/uscode/text/18/922"> makes it a crime to own a “machinegun,”</a> and the Trump administration determined that this law extends to bump stocks.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="31HcPA">
But federal courts have divided on whether federal law<a href="https://www.law.cornell.edu/uscode/text/26/5845"> defines the term “machinegun”</a> broadly enough to include bump stocks, and the law does appear to be genuinely ambiguous on this point.
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<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="XuAp1j">
If this case, which was brought by an individual gun owner who wants to own bump stocks, had arisen just a few years ago, it would have been a slam dunk victory for the government. The Supreme Court’s decision in <a href="https://www.law.cornell.edu/supremecourt/text/467/837"><em>Chevron v. Natural Resources Defense Council</em></a><em> </em>(1984) generally calls for judges to defer to a federal agency’s reading of an ambiguous federal law, so <em>Chevron</em> calls for the courts to defer to the government’s interpretation of what constitutes a “machinegun.”
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<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="2dAV42">
But the Court is <a href="https://www.vox.com/scotus/2024/1/10/24025127/supreme-court-chevron-deference-loper-bright-relentless-raimondo">likely to overrule <em>Chevron</em></a> in a pair of cases it heard in January, shifting final authority over a simply enormous array of policy questions away from the executive branch of government and to the Court itself. And that means that the fate of the current ban on bump stocks most likely rests entirely upon whether five justices want such a ban to exist.
</p>
<h3 id="Aj22XH">
The federal ban on automatic weapons is genuinely ambiguous
</h3>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="1isVcA">
Federal law defines a “machinegun” to include “any weapon which shoots, is designed to shoot, or can be readily restored to shoot, automatically more than one shot, without manual reloading, by a single function of the trigger.” The plaintiff in <em>Cargill</em> makes two separate arguments that this definition doesn’t extend to bump stocks.
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<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="zttBOJ">
One of these arguments is fairly plausible, while the other is not.
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<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="oFghrE">
Starting with the plaintiff’s weaker argument, his lawyers claim that a gun equipped with a bump stock does not fire “automatically.” The US Court of Appeals for the Fifth Circuit, a far-right court that <a href="https://www.vox.com/policy-and-politics/2022/12/27/23496264/supreme-court-fifth-circuit-trump-court-immigration-housing-sexual-harrassment">routinely issues dubiously reasoned decisions</a> implementing conservative policy goals, <a href="https://casetext.com/case/cargill-v-garland-3">agreed with this argument</a>, concluding that the bump stocks at issue in this case do not allow automatic fire because they only function if the shooter maintains “manual, forward pressure on the barrel and manual, backward pressure on the trigger ledge.”
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The problem with this argument is that it proves far too much. If a gun cannot be an automatic weapon if it requires the shooter to maintain continuous pressure on some part of the gun, then virtually all automatic weapons do not qualify as “machineguns.”
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<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="ObjCN0">
As the Justice Department explains in its brief to the justices, most traditional machine guns “<a href="https://www.supremecourt.gov/DocketPDF/22/22-976/293668/20231218165513713_22-976tsUnitedStates.pdf">fire only by maintaining constant rearward pressure on the trigger</a>” — that is, the shooter must hold down the trigger or the gun stops firing. As the DOJ argues, there is “no meaningful difference” between a weapon that requires continuous pressure on the trigger and one that requires continuous pressure on some other part of the gun. Both types of guns should be considered automatic weapons because both kinds of guns continue firing until the shooter stops making the gun fire.
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<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="WRgy3e">
The <em>Cargill</em> plaintiff’s stronger argument, meanwhile, turns on the federal law’s statement that a machine gun must engage in automatic fire “by a single function of the trigger.” Federal judges are quite divided on how to read this provision, which does appear to be genuinely ambiguous.
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<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="7fxp3j">
Some courts, like the left-leaning DC Circuit, concluded that this reference to “a single function of the trigger” should be read to mean “a single pull of the trigger from the perspective of the shooter.” Thus, as that court said in <a href="https://law.justia.com/cases/federal/appellate-courts/cadc/19-5042/19-5042-2019-04-01.html"><em>Guedes v. ATF</em></a> (2019), a semiautomatic weapon equipped with a bump stock counts as a machine gun because “the shooter engages in a single pull of the trigger with her trigger finger, and that action, via the operation of the bump stock, yields a continuous stream of fire as long she keeps her finger stationary and does not release it.”
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<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="f1eCCz">
Alternatively, much of the Fifth Circuit concluded that a bump stock-equipped gun does not count as a machine gun because the trigger itself moves back and forth while such a gun is being fired. Although these judges conceded that bump stocks allow semiautomatic weapons to be rapidly fired, they claimed that “the fact remains that only <a href="https://affordablecareactlitigation.files.wordpress.com/2023/01/20-51016-cv2.pdf">one bullet is fired each time the shooter pulls the trigger</a>.”
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<h3 id="mS6Ire">
So how should the Supreme Court resolve this ambiguity?
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<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="HbQzEe">
Both sides of this case can point to competing rules guiding how statutes should be interpreted to support their preferred outcome.
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<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="KiOKlf">
Many judges who’ve ruled against the bump stock ban point to something called the “<a href="https://www.opn.ca6.uscourts.gov/opinions.pdf/23a0086p-06.pdf">rule of lenity</a>” to justify that decision. Generally speaking, this rule establishes that, when a criminal law is ambiguous, it should be construed in favor of defendants. As the Supreme Court said in <a href="https://supreme.justia.com/cases/federal/us/401/808/"><em>Rewis v. United States</em></a> (1971), “ambiguity concerning the ambit of criminal statutes should be resolved in favor of lenity.”
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="3MERMW">
But the rule of lenity is also a very weak peg to hang any legal decision upon. That’s because, in <a href="https://scholar.google.com/scholar_case?case=15392382174933080428&amp;hl=en&amp;as_sdt=6,47&amp;as_vis=1"><em>Barber v. Thomas</em></a> (2010), the Supreme Court concluded that “the rule of lenity only applies if, after considering text, structure, history, and purpose, there remains a ‘grievous ambiguity or uncertainty in the statute,’ such that the Court must simply ‘guess as to what Congress intended.’”
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<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="Le59aZ">
The Justice Department, meanwhile, points to a rule known as the “<a href="https://www.supremecourt.gov/DocketPDF/22/22-976/293668/20231218165513713_22-976tsUnitedStates.pdf">presumption against ineffectiveness</a>” to justify leaving the bump stock ban in place. This rule holds that statutes generally should not be construed in ways that aid in “evasion of the law.”
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<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="8xDadz">
It is also a very old rule. The DOJ’s brief cites a 200-year-old Supreme Court decision, known as <a href="https://supreme.justia.com/cases/federal/us/22/381/"><em>The Emily and the Caroline</em></a> (1824), which warns against reading laws in ways that would render “the law in a great measure nugatory and enable offenders to elude its provisions in the most easy manner.” (“Nugatory” means that the law is inoperative or unable to function.)
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“In construing a statute, penal as well as others,” the Court explained in <em>The Emily</em>, “we must look to the object in view, and never adopt an interpretation that will defeat its own purpose if it will admit of any other reasonable construction.” Thus, if a law can fairly be read in more than one way, a court should avoid reading it in a way that renders the law ineffective.
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<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="svcL0Z">
There is some recent evidence, moreover, that a majority of the justices may be sympathetic to the DOJ’s argument that laws should not be read to make them ineffective — even though this very conservative Supreme Court <a href="https://www.vox.com/2022/6/23/23180205/supreme-court-new-york-rifle-pistol-clarence-thomas-second-amendment-guns">tends to be sympathetic to arguments made by gun rights plaintiffs</a>.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="kjgEji">
Last August, the Supreme Court temporarily <a href="https://www.vox.com/scotus/2023/8/8/23824635/supreme-court-ghost-guns-garland-vanderstok-amy-coney-barrett-shadow-docket">blocked a lower court’s decision permitting the sale of “ghost guns,”</a> firearms that are sold in a dismantled state in order to evade certain federal gun laws.
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Federal law typically requires gun purchasers to submit to a background check, and it also requires guns to be marked with a serial number to help track the weapon if it is used in a crime. These requirements apply to “any weapon … which will or is designed to or <a href="https://www.law.cornell.edu/uscode/text/18/921">may readily be converted to expel a projectile by the action of an explosive</a>.” To prevent gun sellers from evading this law by selling dismantled guns as individual parts, the same federal law also applies to “the frame or receiver of any such weapon,” the skeletal part of a firearm that houses other components, such as the barrel or trigger mechanism.
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<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="qlCS93">
Ghost guns seek to evade these requirements because they are sold dismantled, and the frame or receiver is sold incomplete — although often they can be completed with minimal work, <a href="https://www.vox.com/scotus/2023/8/8/23824635/supreme-court-ghost-guns-garland-vanderstok-amy-coney-barrett-shadow-docket">such as drilling a single hole in the frame</a>.
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<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="9C4TF9">
In any event, a majority of the justices decided, in <a href="https://www.supremecourt.gov/orders/courtorders/080823zr_dc8f.pdf"><em>Garland v. VanDerStok</em></a>, to block a lower court decision that would have allowed these ghost guns to be sold without background checks or serial numbers. <em>VanDerStok</em> was a 5-4 decision, with Chief Justice John Roberts and <a href="https://www.vox.com/2020/9/26/21457704/trump-amy-coney-barrett-supreme-court-nominee">Justice Amy Coney Barrett</a> crossing over to vote with the Court’s three Democratic appointees.
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<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="x3N7D8">
So that’s, at least, some evidence that this Court will apply a presumption against ineffectiveness to gun laws like the one at issue in <em>Cargill</em>.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="aX3cnr">
Regardless, the bump stocks case does turn on a genuinely ambiguous provision of federal law. That means that, in a world without <em>Chevron</em>, the question of whether gun manufacturers can sell devices that evade the ban on machine guns will turn on which outcome a majority of the justices prefer.
</p>
<ul>
<li><strong>An attempt to reckon with True Detective: Night Country’s bonkers season finale</strong> -
<figure>
<img alt="A woman holds a flashlight while kneeling, the light showing ice-covered water." src="https://cdn.vox-cdn.com/thumbor/vFTPVU8ZgsMtZe0XSEmdyp9pEho=/133x0:1844x1283/1310x983/cdn.vox-cdn.com/uploads/chorus_image/image/73148985/td_kali_reis_1.0.jpg"/>
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Kali Reis explores the ice in <em>True Detective: Night Country.</em> | Michele K. Short/HBO
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<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
What True Detective’s fourth season gets wrong about True Detective.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="m7tIA5">
To be a <em>True Detective</em> fan is to wrestle with uncomfortable contradictions. The first season is both a masterpiece of cosmic horror noir and a piece of art that feels like it was created not just by, but for men. It was a gritty treatise against toxic masculinity that still dehumanized women and ultimately reified the very thing it attempted to deconstruct.
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<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="vmmsRH">
For all its critical acclaim and influence on prestige drama in the years that followed, <em>True Detective</em> also generated a deeply toxic fanbase. These fans were men who missed the point but who saw themselves as a vital part of the show’s metatextuality, the real “true detectives” all along. Ever since, that first season has primarily been remembered, not for its incredible acting, its brilliant aesthetic touches, that legendary six-minute <a href="https://www.youtube.com/watch?v=vnRTITzYnXs">tracking shot</a>, nor even the now-ubiquitous line, “Time is a flat circle,” but for the misogyny. Its two subsequent seasons have mostly been forgotten altogether.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="GOWL3r">
All of these uneasy truths loom large over season four, <em>True Detective: Night Country</em>, 10 years after its progenitor. Every succeeding season of this anthology series has occupied a lose-lose position simply by not being season one. But season four, by virtue of being centered around two women — a local chief of police (Jodie Foster) and a state trooper (Kali Reis) trying to solve a mysterious set of murders in the unforgiving Alaskan north — has simultaneously raised the stakes for the series and revived all of <em>True Detective</em>’s messy paradoxes.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="rAJXZP">
<em>Night Country</em>’s new showrunner and writer/director Issa López needed to accomplish two risky, ambitious goals: The season had to justify itself as a creative follow-up to a work that’s very difficult to follow up, and rectify the notorious sexism of season one in a way that would hopefully allow the series to forge a new path. Its sixth episode, which aired Sunday on <a href="https://www.vox.com/hbo">HBO</a>, had to reconcile both goals in a satisfying finale.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="ljb0Vc">
To many among <em>True Detective</em>’s original fanbase, outrage at the second goal has precluded an objective view of how well it’s succeeding at the first. By the same token, many longtime fans are so eager to see the second project succeed that they’re quick to dismiss all critiques of season four’s creative aims as pure misogyny.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="0TlJiC">
These seem like unbridgeable positions. But there’s unfortunately a third view: that <em>Night Country</em>’s creative flaws ultimately torpedo its efforts at feminist reclamation, shifting the season finale away from a compelling cosmic mystery and toward a hamfisted Me Too revenge plot that leaves a comic number of plot points unresolved and arguably weakens the whole series.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="dvl9wa">
(Note: Spoilers for Sunday’s season four finale abound.)
</p>
<h3 id="KdLY8F">
Season Four’s clunky writing and direction never got what made <em>True Detective</em> work
</h3>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="fwVetw">
To be fair to López, this isn’t the first season of <em>True Detective</em> to miss the mark by a mile. Season two, a hasty, shoddy 2015 follow-up from series creator and season one writer Nic Pizzolatto, featured all the worst parts of season one on speed — the tortured masculinity, the presentation of women as little more than sexy window-dressing, and a poor imitation of all of Matthew McConaughey’s famous existential monologues as Rust Cohle shoehorned into vapid machismo nonsense from Colin Farrell’s dysfunctional detective. Perhaps to shift himself and HBO away from <a href="https://www.dailydot.com/upstream/true-detective-weird-fiction-is-not-plagiarism/">misplaced</a> allegations of <a href="https://slate.com/culture/2014/08/true-detective-plagiarized-no-nic-pizzolatto-did-not-plagiarize-thomas-ligotti.html?pay=1708113002847&amp;support_journalism=please">plagiarism</a>, Pizzolatto cut out most of season one’s mesmerizing <a href="https://www.vox.com/culture/21363945/hp-lovecraft-racism-examples-explained-what-is-lovecraftian-weird-fiction">Weird fiction</a> elements: murky occult figures, arcane Lovecraftian rituals, and worship of the “Yellow King.”
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="iapbi8">
If season two had too little of the supernatural, 2019’s third season was a true return to form, with Pizzolatto returning to the deep South and to a cold case tinged with occult horror, floating on a sense of nonlinear time, and backed by a soul-filled T Bone Burnett soundtrack. But by then, the world was a much different place, and <em>True Detective</em> had to compete with a field of its own descendants — shows as disparate as 2017’s <a href="https://www.vox.com/culture/2017/10/14/16474370/mindhunter-review-netflix-fincher"><em>Mindhunter</em></a> and 2018’s <a href="https://www.vox.com/culture/2018/3/26/17163368/the-terror-review-amc-dan-simmons-jared-harris"><em>The Terror</em></a>, each successful at cordoning off a sliver of <em>True Detective</em>’s genius for themselves.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="UCHAUU">
Still, anchored by Mahershala Ali’s pitch-perfect turn as an aging detective who spends decades trying to solve a cold case, season three really clarified the <em>True Detective </em>formula: A labyrinthine mystery driven by deep characterization, replete with hints of a dark otherworldly version of reality, filmed with an attention to aesthetics, and written with a certain literary flourish. Perhaps most of all, <em>True Detective</em> has to have a philosophy — a commitment to engaging with those eldritch horrors, if only to nod to them and be on your way.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="mJVCT4">
On paper, <em>Night Country</em> ticks a lot of those boxes. Inspired by the recently solved Dyatlov Pass incident (<a href="https://www.vice.com/en/article/m7vwg8/the-dyatlov-pass-mystery-may-have-just-been-solved-by-new-video-evidence">an avalanche did it</a>), the season follows a quest to solve the gruesome deaths of a team of scientists. The group was found naked, frozen, and apparently terrified to death in the tundra near the small town of Ennis, Alaska. Populated mainly by Iñupiat residents whose water has turned black due to pollution from an evil mining plant, Ennis has plunged into its annual winter stretch of sunless <a href="https://www.newyorker.com/culture/photo-booth/life-in-alaska-during-the-round-the-clock-darkness-of-polar-night">polar night</a>, and tensions are high as the local police begin their investigation. Sheriff Danvers (Foster) and Trooper Navarro (Reis) work to solve the murders while navigating their own rocky history. The brutal, still-unsolved murder of an Iñupiaq activist has unexpected connections to the current crime; the women quickly realize they have to bury their differences and work together to solve all the murders at once.
</p>
<figure class="e-image">
<img alt="Two women in police uniforms and winter gear look out over a snowy landscape, a police SUV with its lights on illuminating the scene." src="https://cdn.vox-cdn.com/thumbor/Y1bJFreAR1rDeSd3YYIAArIfMwY=/800x0/filters:no_upscale()/cdn.vox-cdn.com/uploads/chorus_asset/file/25289871/td_jodie_foster_kali_reis.jpg"/> <cite>Michele K. Short/HBO</cite>
<figcaption>
Jodie Foster and Kali Reis explore the terror of the Arctic.
</figcaption>
</figure>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="Ho9AvN">
Like season one, the finale brings us to a literal labyrinth, this time deep in the ice caves beneath Ennis. López has exchanged the Yellow King for an unnamed divine feminine spirit, perhaps <a href="https://guidetogreenland.com/travel-blogs/Christina-gamborg-holm/storytelling-up-north-the-inuit-legend-of-sedna/">Sedna</a> or Mother Nature. (There’s also a tongue-in-cheek reference to the “Blue King” crab company throughout.) The locals all seem to be aware of “her,” and as our story progresses it becomes clear that some of them view the spirit of the murdered activist as synonymous with this ancient entity. In the final episode, we finally meet her — or at least we come as close to “her” as we can get.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="aSQoOM">
But the similarities to that first season are all surface. López <a href="https://www.polygon.com/24033358/true-detective-night-country-issa-lopez-interview-spoiler-free">didn’t originally plan</a> to create <em>Night Country</em> as a part of the <em>True Detective</em> universe, and her efforts to incorporate callbacks to previous <em>True Detective</em> seasons make that painfully clear. Throughout season four, references to season one recur, but they usually lack context and aren’t justified by anything happening around them. We learn a season four character had a relationship with Rust Cohle’s father; but so what? We learn our evil mining corporation has ties to evil corporate overlords from previous seasons … and? There are spirals everywhere, but we gain no enhanced understanding of what this familiar motif means.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="RWMNdG">
López picks up on the well-known line, “You’re asking the wrong question.” She has characters repeat variants of this statement over and over again throughout season four until it becomes preposterous, an annoying substitute for meaningful writing. Each reference, from “flat circle” to Funyuns, is purely fan service, a distracting blip on the map that contributes nothing to our understanding of the <em>True Detective</em> universe.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="pwfUFA">
The same goes for <em>Night Country</em>’s over-the-top horror elements, which range from pointless jump scares to spectral phenomena that appear for no reason. Where season two was completely devoid of the supernatural, <em>Night Country</em> is so full of ghosts that they lose all significance.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="2KhLVW">
Other aesthetic choices are so baffling as to be unintentionally hilarious. <em>Night Country</em> utilizes a bizarrely off-kilter soundtrack of somber minor-key covers of famous pop songs that are absolutely incongruous with the mood of the show, from Eagle-Eye Cherry’s 1997 bop “Save Tonight” to eerie Christmas music. In the finale, we get a dark emo needle drop of “Twist and Shout,” and the gravely intoned “Shake it up, baby” lands with such unbelievable dissonance that I burst into laughter.
</p>
<h3 id="pDAYrc">
Night Country’s finale goes belly-up in the most frustrating way possible
</h3>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="W1kSya">
To be clear, both Foster and Reis are fantastic. Foster’s Sheriff Danvers keeps up a gruff loner hostility, pushing away her family, her partner, and her community, even as she works tirelessly to protect them all. When her exterior finally cracks open, it’s to reveal an unforgettable tapestry of grief and resilience. By contrast, Reis’s Navarro bleeds raw vulnerability throughout, running hot and then hotter as she gets closer to the truth in her long quest to find a killer, and perhaps an even more ancient quest to pursue the unknown spirit of the north.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="EWs9Zg">
As individual characters, they fully fit into the tradition of <em>True Detective</em>’s spiritually clashing sleuths who galvanize each other through a charged mix of loathing and shared desperation. Yet Danvers’ cynicism and Navarro’s spirituality never satisfyingly cohere — a fundamental flaw that <em>Night Country</em> doesn’t fully overcome. For all that Reis is excellent, when she and Foster are onscreen together she seems stifled, limited to churlishness and sarcasm. In episode six, Foster delivers an acting master class as her character finally reveals a little of her personal heartbreak, only to be met with a disconnected non-response from Navarro. It’s as if López didn’t know how to follow her own mic drop, so didn’t bother trying. It’s a hesitance that encapsulates a season full of baffling choices and inconsistent characterizations.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="y0WXjH">
Perhaps the most baffling choice of all comes in the finale, when we finally learn that the murders of the scientists were facilitated by the women of Ennis, as payback for the murder of the activist — who, it turns out, the scientists themselves murdered and covered up, years ago. The show fully glosses over the improbable way the women learn about this cover-up to barrel toward what’s meant to be a righteous showstopper: They break into the science lab, armed to the teeth, and enact their vengeance, forcing the scientists to undress and fend for themselves in the brutal Arctic night.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="cRfISP">
This climax comes off as a ludicrous, unearned payoff, with undeveloped cardboard villagers standing in as mouthpieces for larger political stances, as they have throughout the season for environmental activism and <a href="https://www.vox.com/culture/23559583/roe-abortion-dobbs-reproductive-rights">post-<em>Roe</em> medical care</a>. Here, though, it’s as if López was determined to reverse-engineer a feminist morality play, even if it meant superseding all attempts at coherent storytelling. To add insult to injury, the biggest unresolved “mystery” of the show — the one we’re left to assume was the work of the mysterious Arctic god — involves a human tongue being dropped on the floor. That’s right. We’re meant to believe “she” made her presence known by … spectrally drop-kicking a tongue under a lab table.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="k8UvSf">
(The season’s second-biggest mystery, Navarro’s fate at the end, gets left deliberately ambiguous in the finale’s closing shot. Did she walk into the tundra for good, following the siren song of the ice goddess a la <a href="https://www.vox.com/culture/2019/11/19/20966783/frozen-2-soundtrack-best-songs-into-the-unknown"><em>Frozen 2</em></a>, or did she come back alive? We can’t be certain, but the idea that she’s now a ghost herself would feel more satisfying if Navarro’s struggle and escalating mental breakdown had felt less like a casual aside every now and then.)
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="PVSw7n">
This absurd plot resolution comes well after Pizzolatto himself reportedly shaded this season, <a href="https://www.ign.com/articles/true-detective-night-country-showrunner-responds-original-creators-criticisms">calling the writing “stupid,”</a> much to the delight of fanboys who couldn’t wait to bash the show purely on the basis of its female representation. Who do we root for? Of course we want to root for <em>Night Country</em> under these conditions, and the show has won a high score of “<a href="https://www.metacritic.com/tv/true-detective/season-4/">universal acclaim</a>” on Metacritic. And yet I’ve got a dirty tongue backed by the world’s worst Lana Del Rey album that begs to differ.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="28suep">
What’s most frustrating about all of this is that this mess needn’t have happened. There are plenty of examples of better written, better directed female crime-solving duos in communities of sisters doing it for themselves. Last year’s criminally underrated Australian dramedy <a href="https://slate.com/culture/2023/07/deadloch-amazon-prime-video-crime-drama-murder-mystery-finale.html"><em>Deadloch</em></a>, for example, mined this formula for comedy gold <em>and</em> plenty of suspense alongside well-earned feminist proselytizing. But it did so by relying on whip-smart writing, a story that bears out the moral, and phenomenal acting and chemistry between its two leads — arguably the truest detectives of all in this farce.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="VopdxL">
The downgrade from Pizzolatto’s season one craft to the clunky sophomoric writing of season four was probably avoidable. If <em>Night Country</em> had just been allowed to be its own thing, without any pressure to either live up to season one or abide by its Weird parameters, it probably would have been a much better show. We can’t fault HBO for wanting to revive one of its best franchises. But <em>Night Country</em> may ultimately go down as a reminder that sometimes it’s best to let sleeping eldritch creations lie.
</p></li>
</ul>
<h1 data-aos="fade-right" id="from-the-hindu-sports">From The Hindu: Sports</h1>
<ul>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Dash, Thalassa and The Panther impress</strong> -</p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Irish Rockstar, Macron, Positano and Armory impress</strong> -</p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Daily Quiz | On history of the World Championships</strong> - With the 75th edition of Formula 1 World Championship going to commence from February 29 in Bahrain, here’s a quiz on the history of the World Championships held so far</p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Bumrah likely to be rested, fit-again Rahul set to be back for Ranchi Test</strong> - The decision to rest Bumrah doesn’t come as a surprise considering he bowled 80.5 overs in the first three Tests</p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>India’s show of bench strength eases transition concerns</strong> - With Shreyas Iyer struggling to meet the demands of test cricket and K.L. Rahul battling fitness issues, India have been left wondering how to plug the gaping hole in the middle order</p></li>
</ul>
<h1 data-aos="fade-right" id="from-the-hindu-national-news">From The Hindu: National News</h1>
<ul>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>SC examines divorced Muslim women’s right to maintenance under Section 125 of the CrPC | Explained</strong> - The Supreme Court has decided to examine if a divorced Muslim woman can avail of maintenance under Section 125 CrPC despite existing personal laws — what is the case and what do judcial precedents stipulate?</p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Newborn kidnapped in Karimnagar rescued within 24 hours, two including a woman arrested</strong> - The baby was born to a couple from Bihar</p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Telangana | TSPSC cancels Group-I notification; new notification likely today or tomorrow</strong> -</p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Here are the big stories from Karnataka today</strong> - 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.</p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Probe underway into potential mid-air collision between two IndiGo aircrafts in November 2023, one bound for Hyderabad</strong> -</p></li>
</ul>
<h1 data-aos="fade-right" id="from-bbc-europe">From BBC: Europe</h1>
<ul>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Alexei Navalny’s widow vows to continue his work in fight for ‘free Russia’</strong> - Yulia Navalnya releases a video calling on supporters to stand with her, as she meets European ministers in Brussels.</p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Navalny’s ‘principled and fearless’ widow</strong> - Yulia Navalnaya kept a low profile in the past, but her husband’s death could see her take a more public role.</p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>‘Lose-lose’ anxiety marks global security talks in Munich</strong> - The conflicts in Gaza and Ukraine underline deepening geopolitical tensions and economic uncertainties.</p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Determination and despair in Ukraine front-line town</strong> - In Lyman, eastern Ukraine, some want peace on any terms, while others still hope for victory.</p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>US and UK ambassadors to Russia lay Navalny tributes</strong> - Diplomats in Moscow pay their respects to the Russian opposition leader who died in prison on Friday.</p></li>
</ul>
<h1 data-aos="fade-right" id="from-ars-technica">From Ars Technica</h1>
<ul>
<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>That time the Morgan Motor Company designed a modern coupe, the Aeromax</strong> - Morgan is still best known for making throwback roadsters and for still using wood. - <a href="https://arstechnica.com/?p=1995617">link</a></p></li>
<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>SpaceX wants to take over a Florida launch pad from rival ULA</strong> - SpaceX now plans at least four Starship launch pads, two in Texas and two in Florida. - <a href="https://arstechnica.com/?p=2004247">link</a></p></li>
<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Flowers grown floating on polluted waterways can help clean up nutrient runoff</strong> - Cut-flower farms could be a sustainable option for mitigating water pollution. - <a href="https://arstechnica.com/?p=2004198">link</a></p></li>
<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>New FDA-approved drug makes severe food allergies less life-threatening</strong> - Injections over several months allowed people to tolerate larger doses of trigger foods. - <a href="https://arstechnica.com/?p=2004231">link</a></p></li>
<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Elon Musk’s X allows China-based propaganda banned on other platforms</strong> - X accused of overlooking propaganda flagged by Meta and criminal prosecutors. - <a href="https://arstechnica.com/?p=2004185">link</a></p></li>
</ul>
<h1 data-aos="fade-right" id="from-jokes-subreddit">From Jokes Subreddit</h1>
<ul>
<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>The phone rings at 1 a.m.</strong> - <!-- SC_OFF --></p>
<div class="md">
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
The husband picks it up and yells “how the hell do I know? I’m not a weatherman” and slams down the phone.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
“Who was that?” the wife says.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
The husband replies “some jerk who wants to know if the coast is clear.”
</p>
</div>
<!-- SC_ON -->
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"> submitted by <a href="https://www.reddit.com/user/AssociationSubject85"> /u/AssociationSubject85 </a> <br/> <span><a href="https://www.reddit.com/r/Jokes/comments/1auadkp/the_phone_rings_at_1_am/">[link]</a></span> <span><a href="https://www.reddit.com/r/Jokes/comments/1auadkp/the_phone_rings_at_1_am/">[comments]</a></span></p></li>
<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>The bartender says “We don’t serve time travellers here”</strong> - <!-- SC_OFF --></p>
<div class="md">
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
A time traveller walks in a bar.
</p>
</div>
<!-- SC_ON -->
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"> submitted by <a href="https://www.reddit.com/user/Raggedy-Man"> /u/Raggedy-Man </a> <br/> <span><a href="https://www.reddit.com/r/Jokes/comments/1auk4wn/the_bartender_says_we_dont_serve_time_travellers/">[link]</a></span> <span><a href="https://www.reddit.com/r/Jokes/comments/1auk4wn/the_bartender_says_we_dont_serve_time_travellers/">[comments]</a></span></p></li>
<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>A man is preparing to board a train…..</strong> - <!-- SC_OFF --></p>
<div class="md">
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
when he hears that the Pope is also going to be using that mode of transportation because he apparently wanted to try something different.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
“This is exciting,” the man thinks. “I’ve always been a big fan of the Pope. Perhaps I’ll be able to see him in person.”
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
Imagine his surprise when the Pope sits down in the seat next to him. But the gentleman was too shy to speak to the Pontiff.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
Shortly after taking his seat, the Pope began a crossword puzzle.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
“This is fantastic,” the man thinks. “I’m really good at crosswords. Perhaps, if the Pope gets stuck, he’ll ask me for assistance.”
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
Almost immediately, the Pope turns to the gentleman and says, “Excuse me, but do you know a four letter word referring to intercourse that ends in ‘k’?”
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
Only one word leaps to mind. The man feels uncomfortable. “My goodness,” he thinks, “I can’t tell the Pope that. There must be another word.” He thinks for a while, then it hits him and he says, “I think the word you’re looking for is ‘talk’.”
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
“Of course,” replies the Pope. “Do you have an eraser?”
</p>
</div>
<!-- SC_ON -->
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"> submitted by <a href="https://www.reddit.com/user/vect77"> /u/vect77 </a> <br/> <span><a href="https://www.reddit.com/r/Jokes/comments/1au0ru8/a_man_is_preparing_to_board_a_train/">[link]</a></span> <span><a href="https://www.reddit.com/r/Jokes/comments/1au0ru8/a_man_is_preparing_to_board_a_train/">[comments]</a></span></p></li>
<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Few people remember Canada had two Prime-Ministers with the same surname.</strong> - <!-- SC_OFF --></p>
<div class="md">
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
It’s Trudeau
</p>
</div>
<!-- SC_ON -->
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"> submitted by <a href="https://www.reddit.com/user/trubol"> /u/trubol </a> <br/> <span><a href="https://www.reddit.com/r/Jokes/comments/1aubcud/few_people_remember_canada_had_two_primeministers/">[link]</a></span> <span><a href="https://www.reddit.com/r/Jokes/comments/1aubcud/few_people_remember_canada_had_two_primeministers/">[comments]</a></span></p></li>
<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>An ego and a superego walk into a bar.</strong> - <!-- SC_OFF --></p>
<div class="md">
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
The bartender says “I’m going to need to see some id”.
</p>
</div>
<!-- SC_ON -->
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"> submitted by <a href="https://www.reddit.com/user/Gil-Gandel"> /u/Gil-Gandel </a> <br/> <span><a href="https://www.reddit.com/r/Jokes/comments/1aukxdi/an_ego_and_a_superego_walk_into_a_bar/">[link]</a></span> <span><a href="https://www.reddit.com/r/Jokes/comments/1aukxdi/an_ego_and_a_superego_walk_into_a_bar/">[comments]</a></span></p></li>
</ul>
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