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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>De novo-designed minibinders expand the synthetic biology sensing repertoire</strong> -
<div>
Synthetic and chimeric receptors capable of recognizing and responding to user-defined antigens have enabled "smart" therapeutics based on engineered cells. These cell engineering tools depend on antigen sensors which are most often derived from antibodies. Advances in the de novo design of proteins have enabled the design of protein binders with the potential to target epitopes with unique properties and faster production timelines compared to antibodies. Building upon our previous work combining a de novo-designed minibinder of the Spike protein of SARS-CoV-2 with the synthetic receptor synNotch (SARSNotch), we investigated whether minibinders can be readily adapted to a diversity of cell engineering tools. We show that the Spike minibinder LCB1 easily generalizes to a next-generation proteolytic receptor SNIPR that performs similarly to our previously reported SARSNotch. LCB1-SNIPR successfully enables the detection of live SARS-CoV-2, an improvement over SARSNotch which can only detect cell-expressed Spike. To test the generalizability of minibinders to diverse applications, we tested LCB1 as an antigen sensor for a chimeric antigen receptor (CAR). LCB1-CAR enabled CD8+ T cells to cytotoxically target Spike-expressing cells. Our findings suggest that minibinders represent a novel class of antigen sensors that have the potential to dramatically expand the sensing repertoire of cell engineering tools.
</div>
<div class="article-link article-html-link">
🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2024.01.12.575267v1" target="_blank">De novo-designed minibinders expand the synthetic biology sensing repertoire</a>
</div></li>
<li><strong>mRNA-LNP COVID-19 vaccine lipids induce low level complement activation and production of proinflammatory cytokines: Mechanisms, effects of complement inhibitors, and relevance to adverse reactions</strong> -
<div>
Messenger RNA-containing lipid nanoparticles (mRNA-LNPs) enabled widespread COVID-19 vaccination with a small fraction of vaccine recipients displaying acute or sub-acute inflammatory symptoms. The molecular mechanism of these adverse events (AEs) remains undetermined. Here we report that the mRNA-LNP vaccine, Comirnaty, triggers low-level complement (C) activation and production of inflammatory cytokines, which may be key underlying processes of inflammatory AEs. In serum, Comirnaty and the control PEGylated liposome (Doxebo) caused different rises of C split products, C5a, sC5b-9, Bb and C4d, indicating stimulation of the classical pathway of C activation mainly by the liposomes, while a stronger stimulation of the alternative pathway was equal with the vaccine and the liposomes. Spikevax had similar C activation as Comirnaty, but viral or synthetic mRNAs had no such effect. In autologous serum-supplemented peripheral blood mononuclear cell (PBMC) cultures, Comirnaty caused increases in the levels of sC5b-9 and proinflammatory cytokines in the following order: IL-1 &lt; IFN-{gamma} &lt; IL-1{beta} &lt; TNF- &lt; IL-6 &lt; IL-8, whereas heat-inactivation of serum prevented the rises of IL-1, IL-1{beta}, and TNF-. Clinical C inhibitors, Soliris and Berinert, suppressed vaccine-induced C activation in serum but did not affect cytokine production when applied individually. These findings suggest that the PEGylated lipid coating of mRNA-LNP nanoparticles can trigger C activation mainly via the alternative pathway, which may be causally related to the induction of some, but not all inflammatory cytokines. While innate immune stimulation is essential for the vaccine's efficacy, concurrent production of C- and PBMC-derived inflammatory mediators may contribute to some of the AEs. Pharmacological attenuation of harmful cytokine production using C inhibitors likely requires blocking the C cascade at multiple points.
</div>
<div class="article-link article-html-link">
🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2024.01.12.575122v1" target="_blank">mRNA-LNP COVID-19 vaccine lipids induce low level complement activation and production of proinflammatory cytokines: Mechanisms, effects of complement inhibitors, and relevance to adverse reactions</a>
</div></li>
<li><strong>Primate-specific BTN3A2 protects against SARS-CoV-2 infection by interacting with and reducing ACE2</strong> -
<div>
Coronavirus disease 2019 (COVID-19) is an immune-related disorder caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 invades cells via the entry receptor angiotensin-converting enzyme 2 (ACE2). While several attachment factors and co-receptors for SARS-CoV-2 have been identified, the complete pathogenesis of the virus remains to be determined. Unraveling the molecular mechanisms governing SARS-CoV-2 interactions with host cells is crucial for the formulation of effective prophylactic measures and the advancement of COVID-19 therapeutics. Here, we identified butyrophilin subfamily 3 member A2 (BTN3A2) as a potent inhibitor of SARS-CoV-2 infection. The mRNA level of BTN3A2 was correlated with COVID-19 severity. Upon re-analysis of a human lung single-cell RNA sequencing dataset, BTN3A2 expression was predominantly identified in epithelial cells. Moreover, this expression was elevated in pathological epithelial cells from COVID-19 patients and co-occurred with ACE2 expression in the same cellular subtypes in the lung. Additionally, BTN3A2 primarily targeted the early stage of the viral life cycle by inhibiting SARS-CoV-2 attachment through direct interactions with the receptor-binding domain (RBD) of the Spike protein and ACE2. Furthermore, BTN3A2 inhibited ACE2-mediated SARS-CoV-2 infection by reducing ACE2 in vitro and in a BTN3A2 transgenic mouse model. These results reveal a key role of BTN3A2 in the fight against COVID-19 and broaden our understanding of the pathobiology of SARS-CoV-2 infection. Identifying potential monoclonal antibodies that target BTN3A2 may facilitate disruption of SARS-CoV-2 infection, providing a therapeutic avenue for COVID-19.
</div>
<div class="article-link article-html-link">
🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2024.01.13.575537v1" target="_blank">Primate-specific BTN3A2 protects against SARS-CoV-2 infection by interacting with and reducing ACE2</a>
</div></li>
<li><strong>Intestinal helminth infection impairs vaccine-induced T cell responses and protection against SARS-CoV-2</strong> -
<div>
Although vaccines have reduced COVID-19 disease burden, their efficacy in helminth infection endemic areas is not well characterized. We evaluated the impact of infection by Heligmosomoides polygyrus bakeri (Hpb), a murine intestinal hookworm, on the efficacy of an mRNA vaccine targeting the Wuhan-1 spike protein of SARS-CoV-2. Although immunization generated similar B cell responses in Hpb-infected and uninfected mice, polyfunctional CD4+ and CD8+ T cell responses were markedly reduced in Hpb-infected mice. Hpb-infected and mRNA vaccinated mice were protected against the ancestral SARS-CoV-2 strain WA1/2020, but control of lung infection was diminished against an Omicron variant compared to animals immunized without Hpb infection. Helminth mediated suppression of spike-specific CD8+ T cell responses occurred independently of STAT6 signaling, whereas blockade of IL-10 rescued vaccine-induced CD8+ T cell responses. In mice, intestinal helminth infection impairs vaccine induced T cell responses via an IL-10 pathway and compromises protection against antigenically shifted SARS-CoV-2 variants.
</div>
<div class="article-link article-html-link">
🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2024.01.14.575588v1" target="_blank">Intestinal helminth infection impairs vaccine-induced T cell responses and protection against SARS-CoV-2</a>
</div></li>
<li><strong>Different vaccine platforms result in distinct antibody responses to the same antigen in haemodialysis patients</strong> -
<div>
Generalised immune dysfunction in chronic kidney disease, especially in patients requiring haemodialysis (HD), significantly enhances the risk of severe infections. Moreover, vaccine-induced immunity is typically reduced in HD populations, but the full mechanisms behind this remain unclear. The SARS-CoV-2 pandemic provided an opportunity to examine the magnitude and functionality of antibody responses in HD patients to a previously unencountered antigen, Spike (S)-glycoprotein, after vaccination with different vaccine platforms (viral vector (VV); mRNA (mRV)). Here, we compared total and functional anti-S antibody responses (cross-variant neutralisation and complement binding) in 187 HD patients and 43 healthy controls 21-28 days after serial immunisation. After 2 doses of the same vaccine, HD patients had anti-S antibody levels and complement binding capacity comparable to controls. However, 2 doses of mRV induced greater polyfunctional antibody responses than VV, yet previous SARS-CoV-2 infection or an mRV boost after 2 doses of VV significantly enhanced antibody functionality in HD patients. Therefore, HD patients can generate near-normal, functional antigen-specific antibody responses following serial vaccination to a novel antigen, suggesting largely intact B cell memory. Encouragingly, exploiting immunological memory by using mRNA vaccines and boosting may improve the success of vaccination strategies in this vulnerable patient population.
</div>
<div class="article-link article-html-link">
🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2024.01.14.575569v1" target="_blank">Different vaccine platforms result in distinct antibody responses to the same antigen in haemodialysis patients</a>
</div></li>
<li><strong>Lipid nanoparticle composition for adjuvant formulation modulates disease after influenza virus infection in QIV vaccinated mice.</strong> -
<div>
Adjuvants can enhance vaccine effectiveness of currently licensed influenza vaccines. We tested influenza vaccination in a mouse model with two adjuvants: Sendai virus derived defective interfering (SDI) RNA, a RIG-I agonist, and an amphiphilic imidazoquinoline (IMDQ-PEG-Chol), TLR7/8 adjuvant. The negatively charged SDI RNA was formulated into lipid nanoparticles (LNPs) facilitating the direct delivery of a RIG-I agonist to the cytosol. We have previously tested SDI and IMDQ-PEG-Chol as standalone and combination adjuvants for influenza and SARS-CoV-2 vaccines. Here we tested two different ionizable lipids, K-Ac7-Dsa and S-Ac7-Dog, for LNP formulations. The adjuvanticity of IMDQ-PEG-Chol with and without empty or SDI-loaded LNPs was validated in a licensed vaccine setting (quadrivalent influenza vaccine or QIV) against H1N1 influenza virus, showing robust induction of antibody titres and T cell responses. Depending on the adjuvant combination and LNP lipid composition (K-Ac7-Dsa or S-Ac7-Dog lipids), humoral and cellular vaccine responses could be tailored towards type 1 or type 2 host responses with specific cytokine profiles that correlated with protection during viral infection. The extent of protection conferred by different vaccine/LNP/adjuvant combinations was examined against challenge with the vaccine-matching strain of H1N1 influenza A virus. Groups that received either LNP formulated with SDI, IMDQ-PEG-Chol or both showed very low levels of viral replication in their lungs at five days post virus infection. LNP ionizable lipid composition as well as loading (empty versus SDI) also skewed host responses to infection, as reflected in the cytokine and chemokine levels in lungs of vaccinated animals upon infection. These studies show the potential of LNPs as adjuvant delivery vehicles for licensed vaccines and illustrate the importance of LNP composition for subsequent host responses to infection, an important point of consideration for vaccine safety.
</div>
<div class="article-link article-html-link">
🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2024.01.14.575599v1" target="_blank">Lipid nanoparticle composition for adjuvant formulation modulates disease after influenza virus infection in QIV vaccinated mice.</a>
</div></li>
<li><strong>Eliminating the missing cone challenge through innovative approaches</strong> -
<div>
Microcrystal electron diffraction (MicroED) has emerged as a powerful technique for unraveling molecular structures from microcrystals too small for X-ray diffraction. However, a significant hurdle arises with plate-like crystals that consistently orient themselves flat on the electron microscopy grid. If, as is typically the case, the normal of the plate correlates with the axes of the crystal lattice, the crystal orientations accessible for measurement are restricted because the grid cannot be arbitrarily rotated. This limits the information that can be acquired, resulting in a missing cone of information. We recently introduced a novel crystallization strategy called suspended drop crystallization and proposed that this method could effectively address the challenge of preferred crystal orientation. Here we demonstrate the success of the suspended drop crystallization approach in eliminating the missing cone in two samples that crystallize as thin plates: bovine liver catalase and the COVID-19 main protease (Mpro). This innovative solution proves indispensable for crystals exhibiting preferred orientations, unlocking new possibilities for structure determination by MicroED.
</div>
<div class="article-link article-html-link">
🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2024.01.11.575283v1" target="_blank">Eliminating the missing cone challenge through innovative approaches</a>
</div></li>
<li><strong>Human mobility patterns to inform sampling sites for early pathogen detection and routes of spread: a network modeling and validation study</strong> -
<div>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
Background: Detecting and foreseeing pathogen dispersion is crucial in preventing widespread disease transmission. Human mobility is a critical issue in human transmission of infectious agents. Through a mobility data-driven approach, we determined municipalities in Brazil that could make up an advanced sentinel network, allowing for early detection of circulating pathogens and their associated transmission routes. Methods: We compiled a comprehensive dataset on intercity mobility spanning air, road, and waterway transport, and constructed a graph-based representation of Brazil9s mobility network. The Ford-Fulkerson algorithm, coupled with centrality measures, were employed to rank cities according to their suitability as sentinel hubs. Findings: Our results disentangle the complex transportation network of Brazil, with flights alone transporting 79.9 million (CI 58.3 to 10.1 million) passengers annually during 2017-22, seasonal peaks occurring in late spring and summer, and roadways with a maximum capacity of 78.3 million passengers weekly. We ranked the 5,570 Brazilian cities to offer flexibility in prioritizing locations for early pathogen detection through clinical sample collection. Our findings are validated by epidemiological and genetic data independently collected during the SARS-CoV-2 pandemic period. The mobility-based spread model defined here was able to recapitulate the actual dissemination patterns observed during the pandemic. By providing essential clues for effective pathogen surveillance, our results have the potential to inform public health policy and improve future pandemic response efforts. Interpretation: Our results unlock the potential of designing country-wide clinical sample collection networks using data-informed approaches, an innovative practice that can improve current surveillance systems.
</p>
</div>
<div class="article-link article-html-link">
🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2024.01.12.24301207v1" target="_blank">Human mobility patterns to inform sampling sites for early pathogen detection and routes of spread: a network modeling and validation study</a>
</div></li>
<li><strong>Critically-ill COVID-19 susceptibility gene CCR3 shows natural selection in sub-Saharan Africans</strong> -
<div>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
The prevalence of COVID-19 critical illness varies across ethnicities, with recent studies suggesting that genetic factors may contribute to this variation. The aim of this study was to investigate natural selection signals of genes associated with critically-ill COVID-19 in sub-Saharan Africans. Severe COVID-19 SNPs were obtained from the HGI website. Selection signals were assessed in 661 sub-Sahara Africans from 1000 Genomes Project using integrated haplotype score (iHS), cross-population extended haplotype homozygosity (xpEHH), and fixation index (Fst). Allele frequency trajectory analysis of ancient DNA samples were used to validate the existing of selection in sub-Sahara Africans. We also used Mendelian randomization to decipher the correlation between natural selection and critically-ill COVID-19. We identified that CCR3 exhibited significant natural selection signals in sub-Sahara Africans. Within the CCR3 gene, rs17217831-A showed both high iHS (Standardized iHS = 2) and high XP-EHH (Standardized XP-EHH = 2.5) in sub-Sahara Africans. Allele frequency trajectory of CCR3 rs17217831-A revealed natural selection occurring in the recent 1,500 years. Natural selection resulted in increased CCR3 expression in sub-Sahara Africans. Mendelian Randomization provided evidence that increased blood CCR3 expression and eosinophil counts lowered the risk of critically ill COVID-19. Our findings suggest that sub-Saharan Africans are less vulnerable to critically ill COVID-19 due to natural selection and identify CCR3 as a potential novel therapeutic target.
</p>
</div>
<div class="article-link article-html-link">
🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2024.01.12.24301202v1" target="_blank">Critically-ill COVID-19 susceptibility gene CCR3 shows natural selection in sub-Saharan Africans</a>
</div></li>
<li><strong>Risk factors for experiencing Long-COVID symptoms: Insights from two nationally representative surveys</strong> -
<div>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
Background: Long COVID (LC) is a complex and multisystemic condition marked by a diverse range of symptoms, yet its associated risk factors remain poorly defined. Methods: Leveraging data from the 2022 Behavioral Risk Factor Surveillance System (BRFSS) and National Health Interview Survey (NHIS), both representative of the United States population, this study aimed to identify demographic characteristics associated with LC. The sample was restricted to individuals aged 18 years and older who reported a positive COVID-19 test or doctor9s diagnosis. We performed a descriptive analysis comparing characteristics between participants with and without LC. Furthermore, we developed multivariate logistic regression models on demographic covariates that would have been valid at the time of the COVID-19 infection. Results: Among the 124,313 individuals in BRFSS and 10,131 in the NHIS reporting either a positive test or doctor9s diagnosis for COVID-19 (Table), 26,783 (21.5%) in BRFSS and 1,797 (17.1%) in NHIS reported LC. In the multivariate logistic regression model, we found middle age, female gender, Hispanic ethnicity, lack of a college degree, and residence in non-metropolitan areas associated with higher risk of LC. Notably, the initial severity of acute COVID-19 was strongly associated with LC risk. In contrast, significantly lower ORs were reported for Non-Hispanic Asian and Black Americans compared to Non-Hispanic White. Conclusions: In the United States, there is marked variation in the risk of LC by demographic factors and initial infection severity. Further research is needed to understand the underlying cause of these observations.
</p>
</div>
<div class="article-link article-html-link">
🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2024.01.12.24301170v1" target="_blank">Risk factors for experiencing Long-COVID symptoms: Insights from two nationally representative surveys</a>
</div></li>
<li><strong>Estimated number of lives directly saved by COVID-19 vaccination programs in the WHO European Region, December 2020 to March 2023</strong> -
<div>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
Background: By March 2023, 54 countries, areas and territories (thereafter “CAT”) reported over 2.2 million coronavirus disease 2019 (COVID-19) deaths to the World Health Organization (WHO) Regional Office for Europe (1). Here, we estimate how many lives were directly saved by vaccinating adults in the Region, from December 2020 through March 2023. Methods: We estimated the number of lives directly saved by age-group, vaccine dose and circulating Variant of Concern (VOC) period, both regionally and nationally, using weekly data on COVID-19 mortality and COVID-19 vaccine uptake reported by 34 CAT, and vaccine effectiveness (VE) data from the literature. We calculated the percentage reduction in the number of expected and reported deaths. Findings: We found that vaccines reduced deaths by 57% overall (CAT range: 15% to 75%), representing ~1.4 million lives saved in those aged ≥25 years (range: 0.7 million to 2.6 million): 96% of lives saved were aged ≥60 years and 52% were aged ≥80 years; first boosters saved 51%, and 67% were saved during the Omicron period. Interpretation: Over nearly 2.5 years, most lives saved by COVID-19 vaccination were in older adults by first booster dose and during the Omicron period, reinforcing the importance of up-to-date vaccination among these most at-risk individuals. Further modelling work should evaluate indirect effects of vaccination and public health and social measures.
</p>
</div>
<div class="article-link article-html-link">
🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2024.01.12.24301206v1" target="_blank">Estimated number of lives directly saved by COVID-19 vaccination programs in the WHO European Region, December 2020 to March 2023</a>
</div></li>
<li><strong>The relationship between gut and nasopharyngeal microbiome composition can predict the severity of COVID-19</strong> -
<div>
Background: Coronavirus disease 2019 (COVID-19) is a respiratory illness caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that displays great variability in clinical phenotype. Many factors have been described to be correlated with its severity but no specific determinants of infection outcome have been identified yet, maybe due the complex pathogenic mechanisms. The microbiota could play a key role in the infection and in the progression and outcome of the disease. Hence, SARS-CoV-2 infection has been associated with nasopharyngeal and gut dysbiosis and higher abundance of opportunistic pathogens. Methods: To identify new prognostic markers for the disease, a multicenter prospective observational cohort study was carried out in COVID-19 patients that were divided in three cohorts according to their symptomatology: mild (n=24), moderate (n=51) and severe/critical (n=31). Faecal and nasopharyngeal samples were taken and the microbiota was analysed. Results: Microbiota composition could be associated with the severity of the symptoms and the linear discriminant analysis identified the genera Mycoplasma and Prevotella as severity biomarkers in nasopharyngeal samples, and Allistipes, Enterococcus and Escherichia in faecal samples. Moreover, M. salivarium was defined as a unique microorganism in COVID-19 patients' nasopharyngeal microbiota while P. bivia and P. timonensis were defined in faecal microbiota. A connection between faecal and nasopharyngeal microbiota in COVID-19 patients was also identified as a strong positive correlation between P. timonensis (faeces) towards P. dentalis and M. salivarium(nasopharyngeal) was found in critically ill patients. Conclusions: This ratio could be used as a novel prognostic biomarker for severe COVID-19 patients.
</div>
<div class="article-link article-html-link">
🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2024.01.11.575201v1" target="_blank">The relationship between gut and nasopharyngeal microbiome composition can predict the severity of COVID-19</a>
</div></li>
<li><strong>Drug Discovery in Low Data Regimes: Leveraging a Computational Pipeline for the Discovery of Novel SARS-CoV-2 Nsp14-MTase Inhibitors</strong> -
<div>
The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has led to significant global morbidity and mortality. A crucial viral protein, the non-structural protein 14 (nsp14), catalyzes the methylation of viral RNA and plays a critical role in viral genome replication and transcription. Due to the low mutation rate in the nsp region among various SARS-CoV-2 variants, nsp14 has emerged as a promising therapeutic target. However, discovering potential inhibitors remains a challenge. In this work, we introduce a computational pipeline for the rapid and efficient identification of potential nsp14 inhibitors by leveraging virtual screening and the NCI open compound collection, which contains 250,000 freely available molecules for researchers worldwide. The introduced pipeline provides a cost-effective and efficient approach for early-stage drug discovery by allowing researchers to evaluate promising molecules without incurring synthesis expenses. Our pipeline successfully identified seven promising candidates after experimentally validating only 40 compounds. Notably, we discovered NSC620333, a compound that exhibits a strong binding affinity to nsp14 with a dissociation constant of 427 {+/-} 84 nM. In addition, we gained new insights into the structure and function of this protein through molecular dynamics simulations. We identified new conformational states of the protein and determined that residues Phe367, Tyr368, and Gln354 within the binding pocket serve as stabilizing residues for novel ligand interactions. We also found that metal coordination complexes are crucial for the overall function of the binding pocket. Lastly, we present the solved crystal structure of the nsp14-MTase complexed with SS148 (PDB:8BWU), a potent inhibitor of methyltransferase activity at the nanomolar level (IC50 value of 70 {+/-} 6 nM). Our computational pipeline accurately predicted the binding pose of SS148, demonstrating its effectiveness and potential in accelerating drug discovery efforts against SARS-CoV-2 and other emerging viruses.
</div>
<div class="article-link article-html-link">
🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2023.10.03.560722v3" target="_blank">Drug Discovery in Low Data Regimes: Leveraging a Computational Pipeline for the Discovery of Novel SARS-CoV-2 Nsp14-MTase Inhibitors</a>
</div></li>
<li><strong>Intestinal microbiota programming of alveolar macrophages influences severity of respiratory viral infection</strong> -
<div>
Susceptibility to respiratory virus infections (RVIs) varies widely across individuals. Because the gut microbiome impacts immune function, we investigated the influence of intestinal microbiota composition on RVI and determined that segmented filamentous bacteria (SFB), naturally acquired or exogenously administered, protected mice against influenza virus (IAV) infection. Such protection, which also applied to respiratory syncytial virus and SARS-CoV-2, was independent of interferon and adaptive immunity but required basally resident alveolar macrophages (AM). In SFB-negative mice, AM were quickly depleted as RVI progressed. In contrast, AM from SFB-colonized mice were intrinsically altered to resist IAV-induced depletion and inflammatory signaling. Yet, AM from SFB-colonized mice were not quiescent. Rather, they directly disabled IAV via enhanced complement production and phagocytosis. Accordingly, transfer of SFB-transformed AM into SFB-free hosts recapitulated SFB-mediated protection against IAV. These findings uncover complex interactions that mechanistically link the intestinal microbiota with AM functionality and RVI severity.
</div>
<div class="article-link article-html-link">
🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2023.09.21.558814v2" target="_blank">Intestinal microbiota programming of alveolar macrophages influences severity of respiratory viral infection</a>
</div></li>
<li><strong>Neural Network-Assisted Humanization of COVID-19 Hamster scRNAseq Data Reveals Matching Severity States in Human Disease</strong> -
<div>
Translating findings from animal models to human disease is essential for dissecting disease mechanisms, developing and testing precise therapeutic strategies. The coronavirus disease 2019 (COVID-19) pandemic has highlighted this need, particularly for models showing disease severity-dependent immune responses. Single-cell transcriptomics (scRNAseq) is well poised to reveal similarities and differences between species at the molecular and cellular level with unprecedented resolution. However, computational methods enabling detailed matching are still scarce. Here, we provide a structured scRNAseq-based approach that we applied to scRNAseq from blood leukocytes originating from humans and hamsters affected with moderate or severe COVID-19. Integration of COVID-19 patient data with two hamster models that develop moderate (Syrian hamster, Mesocricetus auratus) or severe (Roborovski hamster, Phodopus roborovskii) disease revealed that most cellular states are shared across species. A neural network-based analysis using variational autoencoders quantified the overall transcriptomic similarity across species and severity levels, showing highest similarity between neutrophils of Roborovski hamsters and severe COVID-19 patients, while Syrian hamsters better matched patients with moderate disease, particularly in classical monocytes. We further used transcriptome-wide differential expression analysis to identify which disease stages and cell types display strongest transcriptional changes. Consistently, hamster's response to COVID-19 was most similar to humans in monocytes and neutrophils. Disease-linked pathways found in all species specifically related to interferon response or inhibition of viral replication. Analysis of candidate genes and signatures supported the results. Our structured neural network-supported workflow could be applied to other diseases, allowing better identification of suitable animal models with similar pathomechanisms across species.
</div>
<div class="article-link article-html-link">
🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2024.01.11.574849v1" target="_blank">Neural Network-Assisted Humanization of COVID-19 Hamster scRNAseq Data Reveals Matching Severity States in Human Disease</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>Sodium Citrate in Smell Retraining for People With Post-COVID-19 Olfactory Dysfunction</strong> - <b>Conditions</b>: Long Haul COVID-19; Post-Acute COVID-19 Syndrome; Anosmia; Olfaction Disorders <br/><b>Interventions</b>: Drug: Sodium Citrate; Drug: Normal Saline; Other: Olfactory Training Kit - “The Olfactory Kit, by AdvancedRx” <br/><b>Sponsors</b>: University of North Carolina, Chapel Hill <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>Phase II, Double Blind, Randomized Trial of CX-4945 in Viral Community Acquired Pneumonia</strong> - <b>Conditions</b>: Community-acquired Pneumonia; SARS-CoV-2 -Associated Pneumonia; Influenza With Pneumonia <br/><b>Interventions</b>: Drug: CX-4945 (SARS-CoV-2 domain); Drug: Placebo (SARS-CoV-2 domain); Drug: CX-4945 (Influenza virus domain); Drug: Placebo (Influenza virus domain) <br/><b>Sponsors</b>: Senhwa Biosciences, Inc. <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>Edge AI-deployed DIGItal Twins for PREDICTing Disease Progression and Need for Early Intervention in Infectious and Cardiovascular Diseases Beyond COVID-19 - Investigation of Biomarkers in Dermal Interstitial Fluid</strong> - <b>Conditions</b>: Heart Failure <br/><b>Interventions</b>: Device: Use of the PELSA System for dISF extraction <br/><b>Sponsors</b>: Charite University, Berlin, Germany <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>Phase III Clinical Study Evaluating the Efficacy and Safety of WPV01 in Patients With Mild/Moderate COVID-19</strong> - <b>Conditions</b>: Mild to Moderate COVID-19 <br/><b>Interventions</b>: Drug: WPV01; Drug: Placebo <br/><b>Sponsors</b>: Westlake Pharmaceuticals (Hangzhou) Co., Ltd. <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>Integrated Mindfulness-based Health Qigong Intervention for COVID-19 Survivors and Caregivers</strong> - <b>Conditions</b>: COVID-19 Infection <br/><b>Interventions</b>: Other: Mindfulness-based Health Qigong Intervention <br/><b>Sponsors</b>: The Hong Kong Polytechnic University <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>Effect of Aerobic Exercises Versus Incentive Spirometer Device on Post-covid Pulmonary Fibrosis Patients</strong> - <b>Conditions</b>: Lung Fibrosis Interstitial; Post-COVID-19 Syndrome <br/><b>Interventions</b>: Other: Aerobic Exercises; Device: Incentive Spirometer Device; Other: Traditional Chest Physiotherapy <br/><b>Sponsors</b>: McCarious Nahad Aziz Abdelshaheed Stephens; Cairo University <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>SARS-CoV-2 and Influenza A/B in Point-of-Care and Non-Laboratory Settings</strong> - <b>Conditions</b>: SARS-CoV-2 Infection; Influenza A; Influenza B <br/><b>Interventions</b>: Diagnostic Test: Aptitude Medical Systems Metrix COVID/Flu Test <br/><b>Sponsors</b>: Aptitude Medical Systems; Biomedical Advanced Research and Development Authority <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>Can Doctors Reduce COVID-19 Misinformation and Increase Vaccine Uptake in Ghana? A Cluster-randomised Controlled Trial</strong> - <b>Conditions</b>: COVID-19 <br/><b>Interventions</b>: Behavioral: Motivational Interviewing, AIMS; Behavioral: Facility engagement <br/><b>Sponsors</b>: London School of Economics and Political Science; Innovations for Poverty Action; Ghana Health Services <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>Long COVID Ultrasound Trial</strong> - <b>Conditions</b>: Long Covid <br/><b>Interventions</b>: Device: Splenic Ultrasound <br/><b>Sponsors</b>: SecondWave Systems Inc.; University of Minnesota; MCDC (United States Department of Defense) <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>Immunogenicity After COVID-19 Vaccines in Adapted Schedules</strong> - <b>Conditions</b>: Coronavirus Disease 2019; COVID-19 <br/><b>Interventions</b>: Drug: BNT162b2 30µg; Drug: BNT162b2 20µg; Drug: BNT162b2 6µg; Drug: mRNA-1273 100µg; Drug: mRNA-1273 50µg; Drug: ChAdOx1-S [Recombinant] <br/><b>Sponsors</b>: Universiteit Antwerpen <br/><b>Completed</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>Update on monkeypox virus infection: Focusing current treatment and prevention approaches</strong> - CONCLUSION: This review highlights the pathogenesis of the virus, disease manifestations, drugs, and vaccines that are being used and those under pipeline for the treatment and prevention of Mpox.</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 infection and dysregulation of nuclear factor erythroid-2-related factor 2 (Nrf2) pathway</strong> - Coronavirus disease 2019 (COVID-19) is a recent pandemic caused by a novel severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) leading to pulmonary and extra-pulmonary manifestations due to the development of oxidative stress (OS) and hyperinflammation. The underlying cause for OS and hyperinflammation in COVID-19 may be related to the inhibition of nuclear factor erythroid 2-related factor 2 (Nrf2), a master regulator of antioxidative responses and cellular homeostasis. The Nrf2…</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>Alarming Rise in Global Rabies Cases Calls for Urgent Attention: Current Vaccination Status and Suggested Key Countermeasures</strong> - In the wake of rising rabies cases worldwide, especially after the COVID-19 pandemic, it is time to understand the scenario better and suggest technically sound and plausible countermeasures. This article is an attempt at this perspective. Although a critical zoonotic viral disease, rabies is preventable. Medico-legally, the ailment is classified as furious rabies and paralytic rabies. The four world bodies, namely, the World Health Organisation (WHO), the Food and Agriculture Organisation…</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>Identification and evaluation of antiviral activity of novel compounds targeting SARS-CoV-2 virus by enzymatic and antiviral assays, and computational analysis</strong> - The viral genome of the SARS-CoV-2 coronavirus, the aetiologic agent of COVID-19, encodes structural, non-structural, and accessory proteins. Most of these components undergo rapid genetic variations, though to a lesser extent the essential viral proteases. Consequently, the protease and/or deubiquitinase activities of the cysteine proteases M^(pro) and PL^(pro) became attractive targets for the design of antiviral agents. Here, we develop and evaluate new bis(benzylidene)cyclohexanones (BBC)…</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>In silico network pharmacology study on Glycyrrhiza glabra: Analyzing the immune-boosting phytochemical properties of Siddha medicinal plant against COVID-19</strong> - Immunosenescence is a pertinent factor in the mortality rate caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). The changes in the immune system are strongly associated with age and provoke the deterioration of the individual’s health. Traditional medical practices in ancient India effectively deal with COVID-19 by boosting natural immunity through medicinal plants. The anti-inflammatory and antiviral properties of Glycyrrhiza glabra are potent in fighting against COVID-19…</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>Discovery of furopyridine-based compounds as novel inhibitors of Janus kinase 2: In silico and in vitro studies</strong> - Janus kinase 2 (JAK2), one of the JAK isoforms participating in a JAK/STAT signaling cascade, has been considered a potential clinical target owing to its critical role in physiological processes involved in cell growth, survival, development, and differentiation of various cell types, especially immune and hematopoietic cells. Substantial studies have proven that the inhibition of this target could disrupt the JAK/STAT pathway and provide therapeutic outcomes for cancer, immune disorders,…</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>Massively parallel profiling of RNA-targeting CRISPR-Cas13d</strong> - CRISPR-Cas13d cleaves RNA and is used in vivo and for diagnostics. However, a systematic understanding of its RNA binding and cleavage specificity is lacking. Here, we describe an RNA Chip-Hybridized Association-Mapping Platform (RNA-CHAMP) for measuring the binding affinity for &gt; 10,000 RNAs containing structural perturbations and other alterations relative to the CRISPR RNA (crRNA). Deep profiling of Cas13d reveals that it does not require a protospacer flanking sequence but is exquisitely…</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>Human conjunctiva organoids to study ocular surface homeostasis and disease</strong> - The conjunctival epithelium covering the eye contains two main cell types: mucus-producing goblet cells and water-secreting keratinocytes, which present mucins on their apical surface. Here, we describe long-term expanding organoids and air-liquid interface representing mouse and human conjunctiva. A single-cell RNA expression atlas of primary and cultured human conjunctiva reveals that keratinocytes express multiple antimicrobial peptides and identifies conjunctival tuft cells. IL-4/-13…</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>Inactivation mechanism of cold plasma combined with 222 nm ultraviolet for spike protein and its application in disinfecting of SARS-CoV-2</strong> - Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly transmissible virus that has precipitated a worldwide pandemic of coronavirus disease since 2019. Developing an effective disinfection strategy is crucial to prevent the risk of surface cross-contamination by SARS-CoV-2. This study employed pseudovirus and the receptor-binding domain (RBD) protein of SARS-CoV-2 as models to investigate the spike protein inactivation process and its underlying mechanisms using a novel…</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>Role of TNF<em>-α</em> in the Pathogenesis of Migraine</strong> - CONCLUSION: To this end, TNF-α plays a critical role in chronification, and inhibiting its signaling would likely be a crucial strategy for migraine therapy.</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>TXM peptides inhibit SARS-CoV-2 infection, syncytia formation, and lower inflammatory consequences</strong> - After three years of the SARS-CoV-2 pandemic, the search and availability of relatively low-cost benchtop therapeutics for people not at high risk for a severe disease are still ongoing. Although vaccines and new SARS-CoV-2 variants reduce the death toll, the long COVID-19 along with neurologic symptoms can develop and persist even after a mild initial infection. Reinfections, which further increase the risk of sequelae in multiple organ systems as well as the risk of death, continue to require…</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>Natural flavonoid pectolinarin computationally targeted as a promising drug candidate against SARS-CoV-2</strong> - Coronavirus disease-2019 (COVID-19) has become a global pandemic, necessitating the development of new medicines. In this investigation, we identified potential natural flavonoids and compared their inhibitory activity against spike glycoprotein, which is a target of SARS-CoV-2 and SARS-CoV. The target site for the interaction of new inhibitors for the treatment of SARS-CoV-2 has 82% sequence identity and the remaining 18% dissimilarities in RBD S1-subunit, S2-subunit, and 2.5% others. Molecular…</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>Structure-based Virtual Screening from Natural Products as Inhibitors of SARS-CoV-2 Spike Protein and ACE2-h Receptor Binding and their Biological Evaluation In vitro</strong> - CONCLUSION: Compound B-8 can be used as a scaffold to develop new and more efficient antiviral drugs.</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>Lipid Metabolism Modulation during SARS-CoV-2 Infection: A Spotlight on Extracellular Vesicles and Therapeutic Prospects</strong> - Extracellular vesicles (EVs) have a significant impact on the pathophysiological processes associated with various diseases such as tumors, inflammation, and infection. They exhibit molecular, biochemical, and entry control characteristics similar to viral infections. Viruses, on the other hand, depend on host metabolic machineries to fulfill their biosynthetic requirements. Due to potential advantages such as biocompatibility, biodegradation, and efficient immune activation, EVs have emerged as…</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>FHL2</em> Inhibits SARS-CoV-2 Replication by Enhancing <em>IFN-β</em> Expression through Regulating <em>IRF-3</em></strong> - SARS-CoV-2 triggered the global COVID-19 pandemic, posing a severe threat to public health worldwide. The innate immune response in cells infected by SARS-CoV-2 is primarily orchestrated by type I interferon (IFN), with IFN-β exhibiting a notable inhibitory impact on SARS-CoV-2 replication. FHL2, acting as a docking site, facilitates the assembly of multiprotein complexes and regulates the transcription of diverse genes. However, the association between SARS-CoV-2 and FHL2 remains unclear. In…</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>The Elusive Promise of a Real 2024 Republican Race Against Donald Trump</strong> - On the Nikki Haley scenario and the eternal optimism of a New Year. - <a href="https://www.newyorker.com/news/letter-from-bidens-washington/the-elusive-promise-of-a-real-2024-republican-race-against-donald-trump">link</a></p></li>
<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>How the Biden Administration Defends Its Israel Policy</strong> - Isaac Chotiner interviews John Kirby, the strategic-communications coördinator for the National Security Council, about the Biden Administration’s policy on Israel. - <a href="https://www.newyorker.com/news/q-and-a/how-the-biden-administration-defends-its-israel-policy">link</a></p></li>
<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Did Nikki Haley Lose Her Nerve?</strong> - The former U.N. Ambassador has been gaining ground on Donald Trump. But, at the fifth Republican debate, she remained stuck in a race for second place. - <a href="https://www.newyorker.com/news/our-columnists/did-nikki-haley-lose-her-nerve">link</a></p></li>
<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Donald Trump Coasts to Victory in the Iowa Republican Caucuses</strong> - About half of the state’s caucus-goers went for the former President, leaving his closest challengers—Nikki Haley and Ron DeSantis—in a desperate race for a distant second place. - <a href="https://www.newyorker.com/news/our-columnists/donald-trump-coasts-to-victory-in-the-iowa-republican-caucuses">link</a></p></li>
<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Trump Receives a Warm Embrace in Frigid Iowa</strong> - Before the caucuses, snow had kept the former President away from his enthusiastic crowds. On Saturday, he finally arrived in Des Moines. - <a href="https://www.newyorker.com/news/dispatch/trump-receives-a-warm-embrace-in-frigid-iowa">link</a></p></li>
</ul>
<h1 data-aos="fade-right" id="from-vox">From Vox</h1>
<ul>
<li><strong>How 50 Cent became the most versatile man in entertainment</strong> -
<figure>
<img alt="" src="https://cdn.vox-cdn.com/thumbor/EGL3rn3ox8ejD69laciMlGS1BVs=/0x0:3556x2667/1310x983/cdn.vox-cdn.com/uploads/chorus_image/image/73058371/GettyImages_1750824605__1_.0.jpg"/>
<figcaption>
50 Cent at a performance on October 22, 2023, in Milan, Italy. The rap star-turned-mogul spent the past year celebrating the 20th anniversary of his landmark album, <em>Get Rich or Die Tryin’</em>. | Sergione Infuso/Corbis via Getty Images
</figcaption>
</figure>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
From rap to the silver screen, it’s (still) 50 Cent’s world.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="0k1Ag8">
There are a few constants in the 50 Cent origin story: He’s the guy who raps <a href="https://www.youtube.com/watch?v=5qm8PH4xAss">one of the most recognizable opening hooks ever</a>. He got <a href="https://www.complex.com/music/a/markelibert/tony-yayo-recalls-50-cent-not-wanting-him-to-visit-hospital">shot nine times</a> and lived to tell about it. For a time, he had every adolescent boy in America doing <a href="https://www.youtube.com/watch?v=KfT49HSvRMI">the G-Unit call-out</a>, and he made <a href="https://news.yahoo.com/50-cent-made-estimated-100m-230731066.html?guccounter=1&amp;guce_referrer=aHR0cHM6Ly93d3cuZ29vZ2xlLmNvbS8&amp;guce_referrer_sig=AQAAAChU_5boaF_6OWkjpKJF3yli2TkjWh-NWeCBAEIPB5R6PoED2z5m1FRlZqpg-uE9xl7HfNysCt1pfxAd9-Em4GRD_jbQUBAlBErUMb7DHK4eHeEwYaxa3bCXzphdNVWXWdRagVOwpStw3QlvnvNYhA0kTjNzFRL-VZ0QwDXsUyFw">a ton of money by investing in Vitaminwater</a> (only to declare <a href="https://www.wsj.com/articles/BL-BANKB-21174">bankruptcy</a> by 2015).
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="RmF7Qz">
It’s a wildly incomplete account of the rapper’s life and career. 50 Cent, also known as Curtis Jackson, was everywhere in the last year, if you knew where to look. On <a href="https://www.vox.com/tv">television</a>, season three of<em> </em><a href="https://www.starz.com/us/en/series/power-book-ii-ghost/58002"><em>Power Book II: Ghost</em></a> — one of three spinoffs of <em>Power</em>, <a href="https://ew.com/tv/welcome-to-the-power-universe/">a series</a> that has established the rapper as a <a href="https://www.vulture.com/article/50-cent-curtis-jackson-in-conversation.html">sought-after television producer</a> with a <a href="https://deadline.com/2023/01/50-cent-eminem-8-mile-tv-show-adaptation-1235214082/">small empire</a> of shows either in production or <a href="https://deadline.com/2023/04/nicki-minaj-animated-series-lady-danger-freevee-curtis-50-cent-jackson-carlton-jordan-crystle-roberson-1235323720/">development</a> — <a href="https://www.hollywoodreporter.com/tv/tv-news/power-book-ii-ghost-ratings-record-starz-1235359200/">broke viewership records for Starz’s streaming platform</a>. His <a href="https://www.instagram.com/thefinallaptour/?hl=en">Final Lap Tour</a>, a celebration of the 20th anniversary of his megahit debut album <a href="https://www.rs500albums.com/300-251/280"><em>Get Rich or Die Tryin’</em></a><em>,</em> took him to 28 <a href="https://www.50cent.com/">countries</a> and sold <a href="https://www.fox5ny.com/news/exclusive-50-cent-on-his-tour-50th-anniversary-of-hip-hop">more than a million tickets</a>. He performed a guest verse on a single from <a href="https://www.youtube.com/watch?v=cz5LXcIsfJk">Nas’s new record</a> <a href="https://www.youtube.com/watch?v=h4sacYq0_lo">and did another verse for Nicki Minaj on</a><em> </em><a href="https://www.rollingstone.com/music/music-news/nicki-minaj-50-cent-beep-beep-new-version-1234924887/"><em>Pink Friday 2 (Gag City Deluxe)</em></a>,<em> </em>which dropped at the end of the year.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="obSKQ9">
If there’s one true constant in the story of 50 Cent, it’s his hustle. “The guy’s a machine; he always been like that, from the block to now,” <a href="https://www.billboard.com/music/features/50-cent-cover-story-interview-tv-new-music-1235250619/">fellow G-Unit member Tony Yayo told Billboard</a> last year.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="NvO80b">
In the beginning, 50 Cent’s brand was rooted in his image as a former boxer and drug dealer who improbably survived being shot multiple times. The rapper was an early expert in self-mythology, building a darkly seductive narrative around his rise from street hustler to rap superstar. He cultivated an image of hip-hop supervillain, ready to go to war with anyone who crossed him, <a href="https://www.insider.com/50-cent-feuds-beef-ja-rule-the-game-camron-2023-9">from Ja Rule to Jay-Z to Kanye West to Rick Ross and former fellow G-Unit member The Game</a>. He’s been called a misogynist for his public <a href="https://www.thedailybeast.com/why-is-50-cent-one-of-the-most-misogynistic-trolls-in-hip-hop">comments and lyrics about women</a>, faced <a href="https://www.complex.com/music/a/backwoodsaltar/50-cent-young-buck-benzino-homophobic-post">backlash for anti-gay social media posts,</a> and criticism for making supportive comments about <a href="https://www.billboard.com/music/rb-hip-hop/50-cent-reverses-donald-trump-endorsement-9472990/">Donald Trump</a> and <a href="https://www.mtv.com/news/d3fm1b/for-the-record-quick-news-on-50-cent-kanye-west-irv-gotti-beyonce-zack-de-la-rocha-alice-in-chains-more">George W. Bush</a>, when many Democrats detested the latter for the Iraq War and his socially conservative policies.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="tJhGxZ">
The rapper still never misses a chance to antagonize his perceived enemies: When singer Cassie recently came forward with sexual assault and abuse <a href="https://www.vox.com/culture/24006759/puffy-diddy-sean-combs-cassie-rape-lawsuit">allegations against Sean “Diddy” Combs</a>, 50 Cent <a href="https://www.blackenterprise.com/50-cent-trolls-diddy/">spent days trolling the Bad Boy Records founder on social media</a>, seeming to <a href="https://pagesix.com/2023/11/18/celebrity-news/50-cent-takes-another-jab-at-sean-diddy-combs-following-abuse-rape-lawsuit-settlement-with-cassie/">relish</a> in a rival’s downfall.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="T50sRq">
Still, for someone with so many enemies, the rapper has shown a surprising ability to keep reinventing himself and thriving, even now, 20 years after he took over the rap game. Why is 50 Cent still here?
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="1vswrG">
The answer is a case study in ambition and adaptability, a kind of narrative that, if it weren’t real, 50 might have made for TV.
</p>
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<strong>Because 50 Cent is primarily known</strong> as one of the dominant musical artists of the early 2000s, the era of George W. Bush and the Iraq War, it can be tempting to lump him in with the general bleakness of that era of American history. To overgeneralize just a <em>little </em>bit: The <a href="https://www.vox.com/culture/22350286/2000s-pop-culture-misogyny-britney-spears-janet-jackson-whitney-houston-monica-lewinsky">culture</a> <a href="https://www.cbc.ca/arts/y2k-didn-t-destroy-everything-but-it-did-usher-in-an-unbelievably-messy-era-of-pop-culture-1.5420788">was bad</a>. The <a href="https://www.refinery29.com/en-us/noughties-fashion">fashion</a> <a href="https://www.harpersbazaar.com/celebrity/red-carpet-dresses/g12025412/early-2000s-fashion/">was worse</a>. The <a href="https://apnews.com/article/iraq-war-wmds-us-intelligence-f9e21ac59d3a0470d9bfcc83544d706e">politics were</a> <a href="https://www.washington.edu/news/2013/10/15/study-nearly-500000-perished-in-iraq-war/">catastrophic</a>. And yeah, “In Da Club” was so ubiquitous that it was impossible to escape it. The song was No. 1 on the Billboard Hot 100 for <a href="https://rockthebells.com/articles/rtb-rewind-50-cent-the-story-of-in-da-club/">nine</a> long weeks. Poet and cultural critic Hanif Abdurraqib posted that he <a href="https://twitter.com/NifMuhammad/status/1702039154161250431">remembers its radio-saturation era</a> as “maybe one of the handful of times I’ve ever felt entirely, completely suffocated by a rap song.”
</p>
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“It really does feel like there was before 50 Cent and after 50 Cent,” says Julianne Escobedo Shepherd, a contributing writer at Pitchfork. “He was the perfect pop star for the Bush era. He was a rampant capitalist. There was a certain level of nihilism to his work, but he was also escapist, despite having a lot of very kind of dark, street narratives in his music. It just took over.”
</p>
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The video for “In Da Club” came out on January 27, 2003, shortly before the release of 50 Cent’s first album, <em>Get Rich or Die Tryin’</em>. In the early scenes, Dr. Dre and Eminem, then already two of the biggest names in hip hop, are white-coated scientists in a high-security lab, working on the launch of a new secret weapon. 50 drops into the frame upside down from a ceiling bar where he’s been doing sit-ups. It wasn’t a coincidence that the rapper’s muscular body took center-screen. As he later told <a href="https://www.menshealth.com/health/a44666641/50-cent-hip-hop-50-interview/"><em>Men’s Health</em></a>, 50 Cent had seen the way women reacted to R&amp;B legend D’Angelo’s <a href="https://www.youtube.com/watch?v=SxVNOnPyvIU">“Untitled (How Does It Feel)” video</a>, and realized that sex appeal was an important way to draw in female fans who were a crucial constituency in hip hop <a href="https://www.vox.com/internet-culture">fandom</a>.
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With “In Da Club” all over the radio and MTV, the album was primed to do numbers. According to SoundScan, which started tracking record sales in 1991, <em>Get Rich or Die Tryin’</em> <a href="https://www.nytimes.com/2003/02/17/business/rapper-50-cent-has-top-selling-first-album.html">sold 872,000 copies in its first four days</a>, making it the best-selling debut album they had ever recorded at the time. After “In Da Club,” another single from the album hit number one on the charts – <a href="https://www.youtube.com/watch?v=cDMhlvbOFaM">“21 Questions</a>” a sing-songy pop song so out of pocket that Dr. Dre <a href="https://www.rollingstone.com/music/music-features/50-cent-interview-twentieth-anniversary-debut-1234676144/">tried to convince him</a> shouldn’t be on the album, according to 50.
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It’s possible now to locate in 50 Cent’s image — in both his personal brand and the narrative of his life — several trends that shaped rap in the years that followed. Though he wasn’t the only rapper to trade on his sexiness (see: <a href="https://www.essence.com/love/eye-candy-ll-cool-j-ladies-choice/#345758">LL Cool J</a>), 50’s crossover appeal helped <a href="https://www.ucpress.edu/blog/64011/at-50-how-hip-hop-went-from-subculture-to-the-mainstream/">accelerate hip-hop’s transformation into a staple of mainstream pop culture</a> with a larger fanbase, and it’s possible to see where that lineage has led us: We now live in an era of hip-hop where rappers aren’t afraid of dealing with <a href="https://www.vox.com/culture/23785854/drake-rap-21-savage-for-all-the-dogs-its-all-a-blur-tour-poetry">the messier realms of emotions and feelings</a>. The contemporary hip-hop scene is also dominated by female artists and their fans, <a href="https://www.nytimes.com/interactive/2023/08/09/magazine/female-rappers.html">many of whom came of age during 50’s era of rap superstardom and made the genre their own</a>, despite the misogyny of the era.
</p>
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Like Minaj, another rapper out of Queens, 50 Cent was a master at telling the story of where he came from and how it prepared him for rap world dominance. “He was such an impressive mythology maker,” Abdurraqib told Vox.
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Orphaned at the age of 8 and raised by his grandmother, 50 Cent’s father wasn’t in his life, but his mother, Sabrina, left an indelible impression on him. There’s little information publicly available about how she died, but in 2003, <a href="https://www.theguardian.com/music/2003/mar/28/artsfeatures">he said</a> that someone had drugged her drink and turned on the gas in her home, killing her. In 2012, he said that <a href="https://www.pride.com/2012/08/15/watch-50-cent-speaks-openly-about-his-mother-being-lesbian">his mother had been a lesbian</a>. He took up boxing at 11 and dealing drugs, like his mother had, at 12; by 19, he was serving a six-month sentence for drugs and gun charges in a boot camp program. A few years later, he started rapping, adopting the nickname “50 Cent” from an <a href="https://en.wikipedia.org/wiki/Kelvin_Martin">infamous stick-up kid</a> <a href="https://www.imdb.com/title/tt0886503/">from the Bronx</a>, and was introduced by a friend to Run DMC’s Jam Master Jay, who taught him to write hooks and count bars.
</p>
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Jackson was preparing to release his debut album with Columbia Records, <em>The Power of the Dollar</em>, when he was shot nine times with a 9 mm handgun in 2000. He survived, but a bullet fragment <a href="https://www.vanityfair.com/hollywood/2013/03/50-cent-bullet-shrapnel-tongue#:~:text=50%20CENT%3A%20I%20have%20a,affected%20the%20way%20I%20talk.">remained lodged in his tongue</a>, changing the way he rapped. Columbia dropped him, but leaked copies of <em>The Power of the Dollar</em> circulated heavily among hip-hop fans, and “How to Rob,” a clever, reference-heavy single that outlined how the rapper planned to steal from some of hip-hop’s biggest stars, established him as a lyrical virtuoso with Napoleonic ambitions. His music made it to Eminem, who persuaded Dr. Dre to sign 50 Cent to Interscope Records.
</p>
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Last year, Dr. Dre reflected on being in the studio with the upstart rapper as a producer for some of the songs on <em>Get Rich or Die Tryin’</em>. “He came in and every track I put up, he had something for it,” Dre <a href="https://www.youtube.com/watch?v=ZzniIHZXFzk">said</a>.
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“He was the real deal. That sort of authenticity was really important at that time,” Escobedo Shepherd says. “You could literally hear it in his music because he rapped differently after he was shot.”
</p>
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Two years later, 50 followed with a second album, <em>The Massacre</em>, which debuted at <a href="https://www.billboard.com/music/music-news/50-cent-massacres-album-chart-competition-63797/">the top of the Billboard charts and sold 1.14 million copies in four days</a>. In between albums, he released music with G-Unit, launched a clothing line, and became a shareholder in the company that then made Vitaminwater. “Few have out-hustled 50 Cent,” the New York Times <a href="https://www.nytimes.com/2004/12/26/arts/music/50-million-for-50-cent.html">noted in a 2004 piece listing the rapper’s many business deals</a>. Sources close to the rapper said he’d “generated income in the $50 million range” in just one year.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="2sYWTh">
50 Cent’s third album, <em>Curtis</em>, came out in 2007, <a href="https://www.grammy.com/news/how-50-cent-vs-kanye-west-beef-2007-was-hard-reset-hip-hop">the marquee event in the rap feud of the year</a>. For months, he and Kanye West traded barbs over whose record would sell more copies; West even moved the release date of his third album, <em>Graduation</em>, up so it would come out on the same day as <em>Curtis</em>.
</p>
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<em>Curtis </em>debuted at No. 2 on the Billboard charts, and both <a href="https://www.billboard.com/music/music-news/kanye-crushes-50-cent-in-huge-album-sales-week-1049182/">the number of albums sold</a> and the <a href="https://www.metacritic.com/music/curtis/50-cent/critic-reviews">critical reception</a> suggested West had the better album. Abdurraqib says that the feud was obviously strategic on 50’s part, as a way to boost album sales. “He was never going to outsell <em>Graduation</em>,” he says. Still, 50 Cent’s era of rap domination seemed over. He’d made enough enemies and employed enough braggadocio that plenty of people seemed <a href="https://www.theverge.com/2015/8/24/9184209/50-cent-bankruptcy-rick-ross-beef">ready to declare his downfall</a>. The rapper’s <a href="https://www.wsj.com/articles/BL-BANKB-21174">highly publicized bankruptcy</a> in 2015 only bolstered that impression.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="91coiu">
But as any <a href="https://edition.cnn.com/2016/06/22/politics/donald-trump-defends-bankruptcy-history/index.html">pugnacious New York entrepreneur will tell you</a>, sometimes <a href="https://www.theguardian.com/music/2020/may/04/50-cent-on-love-cash-and-bankruptcy-when-there-are-setbacks-there-will-be-get-backs">declaring bankruptcy</a> is <a href="https://www.vox.com/the-goods/2019/3/11/18259894/bankruptcy-business-chapter-11-close-stores">a way of protecting your financial future</a>. Plus, 50 Cent had a few other projects up his sleeve.
</p>
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<strong>In 2005, 50 Cent starred</strong> in a semi-autobiographical film about his life, also called <em>Get Rich or Die Tryin’. </em>The film was a critical flop; it received 17 percent on the film review site <a href="https://www.rottentomatoes.com/m/get_rich_or_die_tryin">Rotten Tomatoes</a>. Writer Zadie Smith, in a <a href="https://www.you-books.com/book/Z-Smith/Changing-My-Mind-Occasional-Essays">tongue-in-cheek review</a> for <a href="https://www.telegraph.co.uk/culture/3649575/Shopgirl-is-not-serious.html">the Telegraph</a>, noted the rapper’s love <a href="https://ew.com/article/2009/07/08/gangster-movies-and-hiphop/">for mafia-movie aesthetics</a>, which would define both his music videos and later television work: “I love that you watched <em>Goodfellas</em> and <em>Scarface</em>, like, a million times and decided to ditch all that narrative arc crap and get straight to the point with a minimalist voice-over,” Smith wrote.
</p>
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Undeterred, 50 Cent took tips from producers he met in Hollywood and built his portfolio. In 2009, he founded Cheetah Vision, <a href="https://www.vulture.com/article/randall-emmett-movies.html">a production company that produced action thrillers</a> for foreign markets and video-on-demand services. He also connected with Courtney A. Kemp, a former writer for <em>The Good Wife</em>. With Kemp writing, and 50 Cent offering knowledge gleaned from his formative years in Queens, the two developed <em>Power</em>, a drama starring Omari Hardwick as a drug dealer named James St. Patrick (alias Ghost) trying and failing to break out of a life of crime and make a clean living as a nightclub owner.
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The show built a loyal following over six seasons and became one of Starz’s most watched shows. In marking the final season, the Los Angeles Times <a href="https://www.latimes.com/entertainment-arts/tv/story/2019-08-22/starz-power-final-season-underrated">hailed</a> the show as “a powerhouse of the premium cable landscape,” which helped put the streaming service on the map. <em>Power</em>, the article noted, hadn’t received the same amount of mainstream media attention as its more popular rival, the <a href="https://www.forbes.com/sites/maddieberg/2017/03/20/how-empire-became-the-most-valuable-show-on-broadcast-tv/">Fox drama <em>Empire</em>,</a> but its audience had grown consistently from its first season in 2014 through its end in 2020, leading to multiple spinoff series <a href="https://www.hollywoodreporter.com/tv/tv-news/power-book-ii-ghost-ratings-record-starz-1235359200/">with millions of viewers</a>, along with <a href="https://www.imdb.com/title/tt3281796/awards/">multiple NAACP Image Awards and two People’s Choice Awards</a>. 50 Cent, the series’ executive producer, appeared in the series as Ghost’s foil, Kanan, and later teamed up with Kemp on <a href="https://ew.com/tv/welcome-to-the-power-universe/">spinoffs</a> including <em>Power Book III: Raising Kanan, </em>which is based loosely <a href="https://www.popsugar.co.uk/entertainment/power-book-iii-is-kanan-stark-based-on-50-cent-48426764?utm_medium=redirect&amp;utm_campaign=US:DE&amp;utm_source=www.imdb.com">on the rapper’s early life</a>.
</p>
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It’s impossible not to feel 50 Cent’s influence over the shows, even those that don’t deal explicitly with the details of his life: They are reflected in the aesthetic and the rap-heavy soundtrack, which have carried into his other work as well. The rapper also executive produces the show <em>BMF </em>based on the real-life story of <a href="https://www.newsweek.com/who-was-real-black-mafia-family-bmf-demetrius-terry-flenory-50-cent-1754268">Demetrius “Big Meech” Flenory and the Black Mafia Family</a>.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="pUyn93">
While he was busy building a TV empire, something else interesting happened: The culture started coming back around to his music. Or maybe it’s just that millennials, <a href="https://www.weforum.org/agenda/2021/11/millennials-world-regional-breakdown/">now the largest generation</a> of adults on earth, are getting older and more nostalgic for the songs that defined our youth. In 2020, the video for “In Da Club” became the second rap video of the pre-YouTube era to reach <a href="https://www.prnewswire.com/news-releases/50-cents-in-da-club-reaches-1-billion-views-on-youtube-301174019.html#:~:text=YouTube%20Stats%3A,1.2B%20views%20on%20YouTube.">1 billion views</a> on the streaming platform (behind only Eminem’s “Without Me”) — and it remains a staple of workout classes and dance floors to this day. In 2022, 50 Cent, along with Dr. Dre, Eminem, Snoop Dogg, Kendrick Lamar, and Mary J. Blige, <a href="https://www.youtube.com/watch?v=gdsUKphmB3Y">performed the Super Bowl halftime show</a>, a milestone moment for the genre.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="ftPiFC">
In a way, his chameleon-like ability to reinvent and reintroduce himself for a new era shouldn’t come as a surprise. 50 Cent is a longtime fan of Robert Greene’s <a href="https://www.penguinrandomhouse.com/books/330912/the-48-laws-of-power-special-power-edition-by-robert-greene/"><em>The 48 Laws of Power</em></a>, a Machiavellian self-help book that advises people on how to get what they want. The 48th law is all about the importance of being flexible and learning to change with the times. “Keep yourself adaptable and on the move,” <a href="https://www.google.ch/books/edition/The_48_Laws_Of_Power/P_zMW3EHnTEC?hl=en&amp;gbpv=1&amp;printsec=frontcover">Greene writes in the book</a>. “Accept the fact that nothing is certain and no law is fixed.”
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="sbCS1G">
The rapper obviously saw something in his advice. Never one to let a good opportunity go to waste, the two even teamed up to write a book together. They called it <a href="https://www.theguardian.com/global/2009/sep/05/50-cent-robert-greene-interview"><em>The 50th Law</em></a><em>.</em>
</p></li>
<li><strong>1 winner and 3 losers from the Iowa caucuses</strong> -
<figure>
<img alt="Trump stands in front of a background of American flags." src="https://cdn.vox-cdn.com/thumbor/OpS-dyrYPDuPDH-Mcc9_MaWJ7zY=/447x0:7598x5363/1310x983/cdn.vox-cdn.com/uploads/chorus_image/image/73058092/GettyImages_1928401679.0.jpg"/>
<figcaption>
Former president and Republican presidential hopeful Donald Trump attends a watch party during the 2024 Iowa Republican presidential caucuses in Des Moines, Iowa, on January 15, 2024. | Jim Watson/AFP via Getty Images
</figcaption>
</figure>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
None of the GOP candidates got what they wanted — except for Donald Trump.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="yko8bn">
None of the GOP presidential candidates got what they wanted out of the Iowa caucuses — except for <a href="https://www.vox.com/donald-trump">Donald Trump</a>.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="WzrgTF">
Before the caucuses, I <a href="https://www.vox.com/2024/1/15/24035775/iowa-caucuses-results-2024-trump-haley-desantis">wrote about</a> what each candidate needed to do in Iowa to win the state’s all-important “expectations game” — the strange way this small contest <a href="https://www.vox.com/2024/1/13/24031594/iowa-caucuses-2024-trump-desantis-haley-vivek">can reshape the perceptions</a> of the political world about who can win.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="UHS8dL">
<a href="https://www.vox.com/ron-desantis">Ron DeSantis</a> needed to do really well to show his campaign still had a pulse, but he ended up with a weak, distant second place.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="vQP80Y">
<a href="https://www.vox.com/policy-and-politics/2023/2/14/23599194/nikki-haley-donald-trump-2024-presidential-campaign">Nikki Haley</a> wanted a solid second-place showing but ended up in third place, with some limitations in her support base — her <a href="https://twitter.com/Nate_Cohn/status/1747078440010809647">failure to appeal to</a> non-college-educated Republicans — very apparent.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="Y3Pf7E">
<a href="https://www.vox.com/2024-elections/23720391/vivek-ramaswamy-affirmative-action-woke-capitalism-ideas">Vivek Ramaswamy</a> wanted to show his campaign was for real, but he didn’t, and soon announced he was quitting the race and endorsing Trump.
</p>
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As for Trump? Well, he needed a commanding win about on track with where he was polling — 50 percent — and that’s what he got.
</p>
<h3 id="oZII8X">
Loser: Ron DeSantis
</h3>
<figure class="e-image">
<img alt="Republican presidential candidate Florida Gov. Ron DeSantis speaks at his caucus night event on January 15, 2024 in West Des Moines, Iowa." src="https://cdn.vox-cdn.com/thumbor/P_PehEi_KbvmhxG9-Dy7zb99DDc=/800x0/filters:no_upscale()/cdn.vox-cdn.com/uploads/chorus_asset/file/25228614/GettyImages_1936453086.jpg"/> <cite>Anna Moneymaker/Getty Images</cite>
<figcaption>
Republican presidential candidate Florida Gov. Ron DeSantis speaks at his caucus night event on January 15, 2024, in West Des Moines, Iowa.
</figcaption>
</figure>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="rQTDJQ">
DeSantis had a theory that he could defeat Trump with, effectively, a pincer movement. He’d peel off some voters from the right, assuring them that he’s a more solid and effective conservative than Trump. But he’d also peel off more mainstream voters with concerns over Trump’s electability, arguing his Florida record means he can and would actually win in November.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="mhAQCS">
For many months, these hopes have lain in tatters, with DeSantis having <a href="https://www.realclearpolling.com/polls/president/republican-primary/2024/national">declined in the polls</a>,<a href="https://www.politico.com/news/2023/09/06/desantis-donors-florida-election-00114080"> lost donors</a>, and seen Haley try to supplant him as the second-place candidate.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="HXTjUI">
But Iowa remained his best chance to turn this around. DeSantis <a href="https://www.kcci.com/article/ron-desantis-completes-full-grassley-in-iowa-visits-all-99-counties/46017977">made campaign visits</a> to all 99 of the state’s counties, and won some key endorsements from elites there, like evangelical leader <a href="https://www.politico.com/news/2024/01/10/vander-plaats-desantis-endorsement-trump-00134787">Bob Vander Plaats</a> and Gov. <a href="https://apnews.com/article/desantis-iowa-kim-reynolds-endorsement-president-trump-d37b8809c6869296c37e56d8573d10ca">Kim Reynolds</a> (R).
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="2e8ZKH">
That proved to be enough — for a weak second place. As of Monday night, though counting wasn’t yet finalized, DeSantis had won about 21 percent of the vote, to 19 percent for Haley. Trump was far ahead of both, with 51 percent.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="v2MhP9">
A DeSantis campaign official <a href="https://twitter.com/KitMaherCNN/status/1747107126764306768">told CNN</a> he’d “earned his ticket out of Iowa” and would fight on. But the territory ahead looks forbidding — he’s <a href="https://www.realclearpolitics.com/epolls/2024/president/2024gop.html">polling</a> in the single digits in New Hampshire, and well behind Haley (and of course Trump) in South Carolina. The question of whether he stays in the race likely hinges on whether his last remaining donors abandon him. But he didn’t get the stunning success he needed to show he still has a shot.
</p>
<h3 id="ZuAeS4">
Loser: Nikki Haley
</h3>
<figure class="e-image">
<img alt="Haley speaks with supporters." src="https://cdn.vox-cdn.com/thumbor/xEBe6lyVwvle2Bpx9Shxpg5FJh4=/800x0/filters:no_upscale()/cdn.vox-cdn.com/uploads/chorus_asset/file/25228612/GettyImages_1935517362.jpg"/> <cite>Joe Raedle/Getty Images</cite>
<figcaption>
Republican presidential candidate former UN Ambassador Nikki Haley interacts with people during a campaign stop at the Bread Board on January 15, 2024, in Pella, Iowa.
</figcaption>
</figure>
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The stakes for Haley in Iowa were not as high as they were for DeSantis. She clearly has a significantly better shot to break through in New Hampshire, and even publicly downplayed the caucuses earlier this month, <a href="https://abcnews.go.com/Politics/haley-downplays-iowa-new-hampshire-voters-correct-caucuses/story?id=106100774">saying</a> the Granite State would “correct” their result.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="AAVlsk">
Still, she clearly would have preferred to have done a bit better than she ended up doing. A solid second-place finish in a weak state for her would have been taken by many as a “win,” exceeding expectations and earning her media buzz in the eight days leading up to New Hampshire’s primary. Instead, she’ll end up in third place with around 19 percent of the vote.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="fdFt1D">
The silver lining for Haley is that a mediocre Iowa performance does not, historically, doom a candidate in New Hampshire, where voters often seem to enjoy thumbing their noses at the caucus results.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="Qm2g41">
Yet there was also an ominous sign for her in the results — as the <a href="https://twitter.com/Nate_Cohn/status/1747078440010809647">New York Times’s Nate Cohn pointed out</a>, they showed “an extraordinary educational divide,” with Haley doing well in highly educated areas “but failing to obtain 10 percent in many less educated precincts.” If non-college-educated Republicans overwhelmingly reject Haley, then she can’t win the GOP nomination — it’s that simple.
</p>
<h3 id="VahKAz">
Loser: Vivek Ramaswamy
</h3>
<figure class="e-image">
<img alt="Vivek Ramaswamy speaks into a microphone as he gestures." src="https://cdn.vox-cdn.com/thumbor/VeassR06at4TJfA7eswYymx8wtQ=/800x0/filters:no_upscale()/cdn.vox-cdn.com/uploads/chorus_asset/file/25228611/GettyImages_1935148050.jpg"/> <cite>Kevin Dietsch/Getty Images</cite>
<figcaption>
Republican presidential candidate Vivek Ramaswamy speaks at a campaign event at the Machine Shed restaurant on January 15, 2024, in Urbandale, Iowa.
</figcaption>
</figure>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="dzb5hH">
The former biotech CEO’s <a href="https://www.vox.com/2024-elections/23720391/vivek-ramaswamy-affirmative-action-woke-capitalism-ideas">wild ride of a campaign</a> — going from nowhere in the polls to the high single digits — came to an end Monday night, after Ramaswamy finished in the high single digits in Iowa.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="nOdYN2">
Ramaswamy got a brief burst of attention from the media in mid-2023, but after a certain point, the more voters saw of him, the less they liked him. He hit double digits in several national polls last summer but never managed to do so again once fall began, <a href="https://www.realclearpolling.com/polls/president/republican-primary/2024/national">according to RealClearPolitics</a>. His persona grew more obnoxious as he <a href="https://www.nbcnews.com/politics/2024-election/vivek-ramaswamy-turning-new-talking-points-conspiracy-theories-rcna130187">increasingly pushed</a> far right conspiracy theories.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="JmGZ9C">
As with DeSantis, Iowa was Ramaswamy’s best hope for a turnaround. He didn’t just visit all of Iowa’s 99 counties — he <a href="https://www.nbcnews.com/politics/2024-election/vivek-ramaswamy-completes-double-tour-every-iowa-county-rcna131847">visited them all twice</a>. But as of late Monday night, <a href="https://www.nytimes.com/interactive/2024/01/15/us/elections/results-iowa-caucus.html?smid=nytcore-ios-share&amp;referringSource=articleShare">ongoing tallies</a> had him at about 8 percent of the vote. Having had enough, he <a href="https://www.nytimes.com/2024/01/15/us/politics/vivek-ramaswamy-drops-out.html">quit the race</a>. But we’ll surely hear more of him again.
</p>
<h3 id="6YCrqT">
Winner: Donald Trump
</h3>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="8cZ9A7">
For months, Trump has led every national poll of the <a href="https://www.vox.com/politics/2023/2/23/23611828/2024-republican-presidential-candidates-trump-hurd">GOP primary</a>, and every poll of every key state. But the Iowa caucuses were our first chance to see whether voters would defy the polls. Perhaps, at the last minute, they’d have second thoughts about supporting the guy who tried to steal the last presidential election and who has been indicted in four jurisdictions.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="YjZJl9">
They didn’t. The final <a href="https://www.realclearpolling.com/polls/president/republican-primary/2024/iowa-caucus">RealClearPolitics polling average</a> had Trump at 52.5 percent of the vote. As of Monday night, he was around 51 percent. That number could still move a bit as more votes are counted, but it won’t shift that much — the polls appear to have been basically right.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="spIBOF">
That’s good news for Trump going forward: There wasn’t any sort of massive, unnoticed sea change in the GOP electorate in which voters abandoned him. They are still with him. And we have every reason to believe they’ll be with him in the next primary and caucus contests, too.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="hCQPbG">
Trump <a href="https://www.vox.com/politics/2024/1/15/24039606/iowa-caucus-results-polls-winner-trump-republican-primary">hasn’t locked down the race yet</a>, of course; Iowa is just one state. Haley will get to take her shot in New Hampshire. But the central political fact of the past eight and a half years has been the unshakable loyalty to Trump demonstrated by much of the GOP base. It would take a seismic event to dislodge him as the GOP frontrunner.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="kFmJis">
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="WC7TjQ">
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="Osgjzq">
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="3DsGvw">
</p></li>
<li><strong>Is it over yet? What the Iowa caucus results mean for the GOP presidential race.</strong> -
<figure>
<img alt="Trump stands with his fist raised. An American flag is seen at left. " src="https://cdn.vox-cdn.com/thumbor/leqaDvUQuYwmEF8gGyugP81HHXg=/481x0:4330x2887/1310x983/cdn.vox-cdn.com/uploads/chorus_image/image/73057959/GettyImages_1928397413.0.jpg"/>
<figcaption>
Former US President Donald Trump during the 2024 Iowa Republican caucuses at Horizon Events Center in West Des Moines, Iowa, on January 15, 2024. Trump cruised to victory in the Iowa caucus, according to news outlets, warding off a late challenge from rivals DeSantis and Haley and cementing his status as the clear Republican frontrunner in the race. | Nathan Howard/Bloomberg via Getty Images
</figcaption>
</figure>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
Trump’s rivals missed an opportunity to shake up the race. They’ll get another one in New Hampshire.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="MI22GW">
<a href="https://www.vox.com/donald-trump">Donald Trump</a> won the Iowa caucuses big on Monday. The exact vote tally is still being determined, but he’ll likely end up with around 50 percent of the votes, about 30 percentage points ahead of whoever ends up in second place.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="XN7N2Y">
What happened in these results is the same thing that’s been happening throughout the Republican nomination contest: An opportunity slipped away for Trump’s rivals to shake up the race.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="FQxfLF">
<a href="https://www.vox.com/ron-desantis">Ron DeSantis</a> had bet everything on Iowa as his best shot for a comeback, but he ended up far behind Trump and in a roughly comparable position to <a href="https://www.vox.com/policy-and-politics/2023/2/14/23599194/nikki-haley-donald-trump-2024-presidential-campaign">Nikki Haley</a>, who downplayed the state. (It’s not clear yet which one of them will end up in second place.) Meanwhile, Haley missed an opportunity to finish far ahead of DeSantis and make clear she’s Trump’s only serious rival.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="uQ9W10">
That does not mean Trump’s won just yet. But he’s certainly on track for it, unless something very dramatic happens — very soon — to shake up the contest.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="cY6SkR">
Iowa alone does not settle anything. To win the GOP presidential nomination, a candidate needs a majority of the 2,429 delegates that will be allotted in states’ primary and caucus contests. Iowa is a small state with <a href="https://www.thegreenpapers.com/P24/IA-R">just 40 delegates</a>.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="FN2jWu">
The Iowa caucuses’ importance isn’t about delegates, though. The contest <a href="https://www.vox.com/2024/1/13/24031594/iowa-caucuses-2024-trump-desantis-haley-vivek">matters</a> because a surprising result can reshape the political world’s perceptions about who is most likely to win. Historically, it’s often been a place where something surprising happens.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="mo5rnD">
But sometimes Iowa’s results just affirm the conventional wisdom — and that’s what happened Monday. Trump was the overwhelming favorite, and he remains the overwhelming favorite.
</p>
<h3 id="d3yQ3K">
On to New Hampshire
</h3>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="k6l3N7">
The next opportunity for something surprising to happen to change that state of affairs is New Hampshire’s primary on Tuesday of next week. There, as in Iowa, Trump <a href="https://www.realclearpolitics.com/epolls/2024/president/2024gop.html">leads all polls</a>. But his lead has been significantly smaller, with Nikki Haley aiming for second place (and little polling since Chris Christie dropped out).
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="UNdFbe">
If Trump wins New Hampshire overwhelmingly, it will be a strong signal that Haley too has failed, and that he’ll win the nomination easily. The caveat there is that it too is a small state with a small number of delegates that does not technically lock down the nomination. Some of his rivals may well stay in through the February contests, in hopes that some sort of deus ex machina<em> </em>will remove Trump from contention.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="T4TITX">
But Super Tuesday on March 5 would really be when time runs out. Once that day’s contests are over, <a href="https://www.nbcnews.com/meet-the-press/first-read/gop-will-allocate-clear-majority-delegates-trumps-dc-trial-ends-rcna127344">47 percent of Republican delegates</a> will be allocated. If Trump has won those contests big, it will be functionally impossible to catch up to dethrone him.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="gHLo7y">
Of course, if Haley wins New Hampshire, or if Trump wins it in a squeaker, then the race is on and we’ll have a real contest. Trump would still, of course, be the clear favorite to win that contest. But it would at least be some sort of contestation rather than a total coronation.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="CHO3S9">
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="1rbwi8">
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="UdNHmq">
</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>In Thy Light, River Of Gold, Irish Rockstar, Aralina and Positano please</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>Son Of A Gun and Rasputin show out</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>Jose Mourinho sacked by AS Roma as Serie A club languishes in 9th place after Milan loss</strong> - Mourinho was in his third season at Roma and his contract was due to expire in June.</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>Australian Open | Sumit Nagal stuns World No. 27 to enter 2nd round for first time</strong> - Nagal’s win was the first time in 35 years that an Indian beat a seeded player in a Grand Slam.</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>Steve Smith to take his talents to the top and open Australia’s innings in 1st Test against West Indies</strong> - Smith said the tactics opponents have used against him in the past will now risk blemishing the new ball by landing it halfway down the pitch.</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>4 of family killed in road accident in Chamarajanagar</strong> - The victims were proceeding to Kollegal on a two-wheeler when they hit a paddy harvester vehicle head-on on the Jinakanahalli road</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>One more cheetah dies at Kuno National Park; toll rises to seven</strong> - Kuno National Park which is located in Madhya Pradesh’s Sheopur district is home to several cheetahs translocated from Namibia and South Africa</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>TalentSprint to launch sixth cohort of Women Engineers Programme</strong> - The programme entails 100% scholarship covering the programme fee and an additional cash scholarship of ₹1 lakh</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>Biological E’s Covid vaccine Corbevax gets WHO’s emergency use listing</strong> - Hyderabad firm working on a vaccine to provide protection against currently circulating variants of the virus</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>Republic Day flower show at Lalbagh from January 18-28</strong> - The main attraction at the flower show will be the floral replica of Anubhava Mantapa, Ikya Mantapa, Ishta Linga Prathiroopa and Basavanna’s interactions with the public.</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>Ukraine says it shot down Russian A-50 spy plane</strong> - Army chief Gen Valerii Zaluzhnyi said the air force had “destroyed” an A-50 radar detection aircraft.</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>Two British brothers ‘should be banned from Switzerland’ for museum heist</strong> - Prosecutors say the two British men should be jailed for stealing 14th Century Ming Dynasty artefacts.</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>Cyclone Belal: Mauritius assesses damage after flash flooding</strong> - Authorities say the storm is now moving away from the island nation, but warn that risks still exist.</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>Jose Mourinho: Roma sack former Manchester United, Chelsea and Real Madrid manager</strong> - Jose Mourinho is sacked as Roma manager after less than three years in charge, with the club currently ninth in Serie 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>Italian culture minister probed over stolen painting</strong> - Vittorio Sgarbi is accused of possessing and exhibiting a 17th Century painting.</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>Antifungals are going the way of antibiotics—overused, hitting resistance</strong> - CDC urges clinicians to confirm fungal infections before prescribing antifungal medications. - <a href="https://arstechnica.com/?p=1996151">link</a></p></li>
<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Elon Musk’s recent all-hands meeting at SpaceX was full of interesting news</strong> - Starship exploded during a liquid oxygen vent on its most recent test flight. - <a href="https://arstechnica.com/?p=1995840">link</a></p></li>
<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>AI poisoning could turn open models into destructive “sleeper agents,” says Anthropic</strong> - Trained LLMs that seem normal can generate vulnerable code given different triggers. - <a href="https://arstechnica.com/?p=1995975">link</a></p></li>
<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Scientists identify first known prehistoric person with Turner syndrome</strong> - Studying skeletons could provide further insight into the past’s gender variability. - <a href="https://arstechnica.com/?p=1995066">link</a></p></li>
<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Ants make their own ant-ibiotic for infected wounds</strong> - Ants have a gland that makes an antibiotic, and use it in response to pheromones. - <a href="https://arstechnica.com/?p=1996092">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>53 millionaires walk into a bar to watch the Super Bowl.</strong> - <!-- SC_OFF --></p>
<div class="md">
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
The Bartender says, “Woah! Its the Dallas Cowboys! What can I get you guys?”
</p>
</div>
<!-- SC_ON -->
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"> submitted by <a href="https://www.reddit.com/user/Zombie_Slaya_66"> /u/Zombie_Slaya_66 </a> <br/> <span><a href="https://www.reddit.com/r/Jokes/comments/197o22d/53_millionaires_walk_into_a_bar_to_watch_the/">[link]</a></span> <span><a href="https://www.reddit.com/r/Jokes/comments/197o22d/53_millionaires_walk_into_a_bar_to_watch_the/">[comments]</a></span></p></li>
<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>A man walks in on his wife packing a suitcase</strong> - <!-- SC_OFF --></p>
<div class="md">
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
He says “ honey what are you doing?”
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
Her: “ I read in cosmopolitan that the sex workers in New York City get paid $400 a night to do what I do to you for free!!! so I’m leaving you”
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
One hour later, she walks in and sees him packing his suitcase and says “ where the hell are you going?”
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
Him: “ I’m coming with you, I want to see how somebody is going to afford to live on $800 a year in Manhattan!!!”
</p>
</div>
<!-- SC_ON -->
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"> submitted by <a href="https://www.reddit.com/user/Disastrous-Key4678"> /u/Disastrous-Key4678 </a> <br/> <span><a href="https://www.reddit.com/r/Jokes/comments/197y35m/a_man_walks_in_on_his_wife_packing_a_suitcase/">[link]</a></span> <span><a href="https://www.reddit.com/r/Jokes/comments/197y35m/a_man_walks_in_on_his_wife_packing_a_suitcase/">[comments]</a></span></p></li>
<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>How is Brokeback Mountain like the NFL?</strong> - <!-- SC_OFF --></p>
<div class="md">
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
The Cowboys suck!
</p>
</div>
<!-- SC_ON -->
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"> submitted by <a href="https://www.reddit.com/user/SKA1960"> /u/SKA1960 </a> <br/> <span><a href="https://www.reddit.com/r/Jokes/comments/197s8fg/how_is_brokeback_mountain_like_the_nfl/">[link]</a></span> <span><a href="https://www.reddit.com/r/Jokes/comments/197s8fg/how_is_brokeback_mountain_like_the_nfl/">[comments]</a></span></p></li>
<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Some people are so ungrateful</strong> - <!-- SC_OFF --></p>
<div class="md">
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
If I’ve made you breakfast in bed all I need is a simple “thank you”
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
None of this “how did you get in my house” nonsense
</p>
</div>
<!-- SC_ON -->
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"> submitted by <a href="https://www.reddit.com/user/Phippsy771"> /u/Phippsy771 </a> <br/> <span><a href="https://www.reddit.com/r/Jokes/comments/197uhvx/some_people_are_so_ungrateful/">[link]</a></span> <span><a href="https://www.reddit.com/r/Jokes/comments/197uhvx/some_people_are_so_ungrateful/">[comments]</a></span></p></li>
<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Two stoners on bikes</strong> - <!-- SC_OFF --></p>
<div class="md">
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
Two stoners on bikes were riding through downtown where they saw an old building with ornate decorations that they had to stop to admire. One of the stoners says to the other: this building is so beautiful, man, that I wish it was closer to our house so I can look at it all day. The other stoner agrees and suggests that they try to push the building all the way to their neighborhood. They dismount their bikes and put them on the sidewalk as they make their way to the side of the building and start pushing. While they are doing that, and without noticing, a guy comes and steals their bikes. After a long time of pushing the two stoners decide to take a break. One of them starts to wonder if they were able to push the building at all, when the other says: well, one thing I can tell you, is that we pushed this building so much so that I can’t see our bikes from here.
</p>
</div>
<!-- SC_ON -->
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"> submitted by <a href="https://www.reddit.com/user/kk074"> /u/kk074 </a> <br/> <span><a href="https://www.reddit.com/r/Jokes/comments/197reo9/two_stoners_on_bikes/">[link]</a></span> <span><a href="https://www.reddit.com/r/Jokes/comments/197reo9/two_stoners_on_bikes/">[comments]</a></span></p></li>
</ul>
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