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The untold story of how Mortal Kombat, NBA Jam, and other arcade classics were created by a ragtag crew in the back of a Chicago factory. Generating billions of dollars, they rode the wave of the booming 90s arcade scene ... until a new enemy appears.

Otopetrins (Otop1–Otop3) comprise one of two known eukaryotic proton-selective channel families. Otop1 is required for otoconia formation and a candidate mammalian sour taste receptor. Here we report cryo-EM structures of zebrafish Otop1 and chicken Otop3 in lipid nanodiscs. The structures reveal a dimeric architecture, with each subunit forming 12 transmembrane helices divided into structurally similar amino (N) and carboxy (C) domains. Cholesterol-like molecules occupy various sites in Otop1 and Otop3 and occlude a central tunnel. In molecular dynamics simulations, hydrophilic vestibules formed by the N and C domains and in the intrasubunit interface between N and C domains form conduits for water entry into the membrane core, suggesting three potential proton conduction pathways. By mutagenesis, we tested the roles of charged residues in each putative permeation pathway. Our results provide a structural basis for understanding selective proton permeation and gating of this conserved family of proton channels.Otopetrins are proton channels and candidate sour taste receptors. Cryo-EM structures of zebrafish Otop1 and chicken Otop3 reveal potential proton conduction pathways.

Most bacteria lack membrane-enclosed organelles and rely on macromolecular scaffolds at different subcellular locations to recruit proteins for specific functions. Here, we demonstrate that the optogenetic CRY2-CIB1 system from Arabidopsis thaliana can be used to rapidly direct proteins to different subcellular locations with varying efficiencies in live Escherichia coli cells, including the nucleoid, the cell pole, the membrane, and the midcell division plane. Such light-induced re-localization can be used to rapidly inhibit cytokinesis in actively dividing E. coli cells. We further show that CRY2-CIBN binding kinetics can be modulated by green light, adding a new dimension of control to the system. Finally, we test this optogenetic system in three additional bacterial species, Bacillus subtilis , Caulobacter crescentus , and Streptococcus pneumoniae , providing important considerations for this system’s applicability in bacterial cell biology. Bacterial proteins are often recruited to specific subcellular locations to carry out their functions. Here, the authors use the optogenetic CRY2-CIB1 system to re-direct proteins to different subcellular locations, and thus manipulate the proteins’ functions, in live bacterial cells.

Zika virus (ZIKV) has emerged as a significant public health concern due to its association with severe neurological outcomes in infants, including microcephaly and congenital Zika syndrome (CZS). However, while the majority of ZIKV infections during pregnancy do not result in CZS, the potential long-term neurological effects of mild or inapparent maternal infections remain poorly understood. In this study, we adapted a model of maternal ZIKV infection in human STAT2 knock-in ( hSTAT2 ) mice to investigate the effects of ZIKV infection during mid-gestation, aiming to mirror typical asymptomatic infections as they occur in humans. We found that maternal ZIKV infection at mid-gestation leads to vertical transmission without causing overt developmental deficits or clinical signs in dams or offspring. Despite the absence of immediate clinical signs, transcriptomic analyses revealed significant changes in the developing fetal brain, particularly in genes related to synaptic function and neuronal development. These molecular alterations were associated with increased synaptic density in the hippocampus and heightened susceptibility to chemically induced seizures in offspring, suggesting subtle yet significant long-term neurological consequences. Using motion sequencing (MoSeq), an unsupervised machine learning approach that profiles naturalistic motor behavior, we also identified persistent, sex-biased alterations in the content and structure of spontaneous behavior in offspring exposed to maternal ZIKV infection. Our findings highlight that even mild maternal ZIKV infections can disrupt fetal neurodevelopment, underscoring the need for enhanced monitoring and public health measures for children exposed to ZIKV in utero but who do not experience severe developmental alterations at birth. Additionally, our study provides a valuable animal model and comprehensive, cell type-specific transcriptomic datasets that will facilitate new lines of investigation into the impact of inapparent maternal ZIKV infections on fetal and childhood brain development.

This study evaluates the association between antivirals (Molnupiravir and Nirmatrelvir-Ritonavir) and all-cause and respiratory mortality and organ dysfunction among high-risk COVID-19 patients during an Omicron outbreak. Two cohorts, Nirmatrelvir-Ritonavir versus control and Molnupiravir versus control, were constructed with inverse probability treatment weighting to balance baseline characteristics. Cox proportional hazards models evaluated the association of their use with all-cause mortality, respiratory mortality, and all-cause sepsis (a composite of circulatory shock, respiratory failure, acute liver injury, coagulopathy, and acute liver impairment). Patients recruited were hospitalized and diagnosed with the COVID-19 Omicron variant between February 22, 2022 and April 15, 2022, and followed up until May 15, 2022. The study included 17,704 patients. There were 4.67 and 22.7 total mortalities per 1000 person-days in the Nirmatrelvir-Ritonavir and control groups respectively before adjustment (weighted incidence rate ratio, − 18.1 [95% CI − 23.0 to − 13.2]; hazard ratio, 0.18 [95% CI, 0.11–0.29]). There were 6.64 and 25.9 total mortalities per 1000 person-days in the Molnupiravir and control groups respectively before adjustment (weighted incidence rate ratio per 1000 person-days, − 19.3 [95% CI − 22.6 to − 15.9]; hazard ratio, 0.23 [95% CI 0.18–0.30]). In all-cause sepsis, there were 13.7 and 35.4 organ dysfunction events per 1000 person-days in the Nirmatrelvir-Ritonavir and control groups respectively before adjustment (weighted incidence rate ratio per 1000 person-days, − 21.7 [95% CI − 26.3 to − 17.1]; hazard ratio, 0.44 [95% CI 0.38–0.52]). There were 23.7 and 40.8 organ dysfunction events in the Molnupiravir and control groups respectively before adjustment (weighted incidence ratio per 1000 person-days, − 17.1 [95% CI, − 20.6 to − 13.6]; hazard ratio, 0.63 [95% CI 0.58–0.69]). Among COVID-19 hospitalized patients, use of either Nirmatrelvir-Ritonavir or Molnupiravir compared with no antiviral use was associated with a significantly lower incidence of 28-days all-cause and respiratory mortality and sepsis.

Introduction: In this study we sought to to assess the extent to which emergency physicians adhered to an institutional protocol for rapid chest pain assessment that incorporates a high sensitivity troponin I (hs-TnI) assay. We also sought to characterize clinical outcomes stratified by protocol adherence. Methods: We conducted a retrospective cohort study that included all adult patients presenting to five major metropolitan hospital emergency departments (ED) with suspected cardiac chest pain who had at least one troponin measured. The study period was November 9, 2020–June 20, 2022. The primary outcome was protocol adherence for indeterminate-risk and high-risk patients, as defined by the protocol in use at the time of each patient’s presentation to hospital. Adjusted odds ratios (aOR) are reported with associated 95% confidence intervals. Results: A total of 14,027 patients were included in the study, among whom 8,962 (63.9%) were classified as low risk, 4,064 (29.0%) as indeterminate risk, and 1,001 (7.1%) who were in the high-risk/rule-in group. Overall, 35.9% of patients had care that adhered to the chest pain pathway protocol—22.1% of indeterminate-risk patients and 91.6% of high-risk/rule-in patients. Protocol adherence among indeterminate-risk patients was 6.6% when the initial troponin was in the range of 4-19 nanograms per liter (ng/L) and 75.4% for initial troponin levels 20-99 ng/L. Male sex was most strongly associated with protocol adherence; among those receiving adherent care, 65.8% were male compared to 34.2% female (aOR 1.67; 95% CI, 1.46-1.91). Patients in the non-adherent group with an initial troponin 4-19 ng/L experienced a significantly higher incidence of major adverse cardiac events (4.5% vs 1.7%, P < .001), compared to those in the low-risk group. Conclusion: Adherence to proposed assessment protocols for patients presenting to the ED with chest pain was low. This lack of adherence appears to disproportionally affect females and is associated with poor outcomes. Improving adherence to evidence-based guidelines in this setting is urgently needed.

ObjectiveThe functional role of interleukin-22 (IL22) in chronic inflammation is controversial, and mechanistic insights into how it regulates target tissue are lacking. In this study, we evaluated the functional role of IL22 in chronic colitis and probed mechanisms of IL22-mediated regulation of colonic epithelial cells.DesignTo investigate the functional role of IL22 in chronic colitis and how it regulates colonic epithelial cells, we employed a three-dimentional mini-gut epithelial organoid system, in vivo disease models and transcriptomic datasets in human IBD.ResultsAs well as inducing transcriptional modules implicated in antimicrobial responses, IL22 also coordinated an endoplasmic reticulum (ER) stress response transcriptional programme in colonic epithelial cells. In the colon of patients with active colonic Crohn’s disease (CD), there was enrichment of IL22-responsive transcriptional modules and ER stress response modules. Strikingly, in an IL22-dependent model of chronic colitis, targeting IL22 alleviated colonic epithelial ER stress and attenuated colitis. Pharmacological modulation of the ER stress response similarly impacted the severity of colitis. In patients with colonic CD, antibody blockade of IL12p40, which simultaneously blocks IL12 and IL23, the key upstream regulator of IL22 production, alleviated the colonic epithelial ER stress response.ConclusionsOur data challenge perceptions of IL22 as a predominantly beneficial cytokine in IBD and provide novel insights into the molecular mechanisms of IL22-mediated pathogenicity in chronic colitis. Targeting IL22-regulated pathways and alleviating colonic epithelial ER stress may represent promising therapeutic strategies in patients with colitis.Trial registration number NCT02749630.

Background. Community-associated (CA) methicillin-resistant Staphylococcus aureus (MRSA) infection has become common worldwide. Some researchers have argued that empirical therapy for MRSA should be given only to patients with suspected CA S. aureus infections who have risk factors for acquisition of MRSA. However, there are no prospective data examining this approach. Methods. We prospectively enrolled consecutive patients who were hospitalized with S. aureus infection, administered a detailed questionnaire, and collected clinical and microbiological information. Results. Of the 280 consenting patients, 180 were adults with CA S. aureus infection. Among these subjects, 108 (60%) had MRSA infection, and 78 (40%) had methicillin-susceptible S. aureus (MSSA) infection. MRSA infection was associated with younger age (P < .0001); skin/soft-tissue infection (P = .015); snorting/smoking illegal drugs (P = .01); recent incarceration (P = .03); lower comorbidity index (P = .01); more frequent visits to bars, raves, and/or clubs (P = .03); and higher frequency of laundering clothes in hot water (P = .05). However, the sensitivity, specificity, and predictive values for these factors for discriminating CA-MRSA infection from CA-MSSA infection were relatively poor. Post-hoc modeling revealed that, even in a 10% (i.e., low) MRSA prevalence population, patients lacking the 3 strongest MRSA risk factors would still have a 7% posttest probability of MRSA. Most MRSA strains belonged to the ST-8/USA300 genotype, contained SCCmec type IV, and shared virulence factors commonly found in the ST1:USA400 clone. MSSA strains were genotypically heterogeneous. Conclusions. We found that clinical and epidemiological risk factors in persons hospitalized for CA S. aureus infection cannot reliably distinguish between MRSA and MSSA. Our findings have important implications for the choice of empirical antibiotic therapy for suspected S. aureus infections and for infection control.

As part of the Reproducibility Project: Cancer Biology , we published Registered Reports that described how we intended to replicate selected experiments from 29 high-impact preclinical cancer biology papers published between 2010 and 2012. Replication experiments were completed and Replication Studies reporting the results were submitted for 18 papers, of which 17 were accepted and published by eLife with the rejected paper posted as a preprint. Here, we report the status and outcomes obtained for the remaining 11 papers. Four papers initiated experimental work but were stopped without any experimental outcomes. Two papers resulted in incomplete outcomes due to unanticipated challenges when conducting the experiments. For the remaining five papers only some of the experiments were completed with the other experiments incomplete due to mundane technical or unanticipated methodological challenges. The experiments from these papers, along with the other experiments attempted as part of the Reproducibility Project: Cancer Biology, provides evidence about the challenges of repeating preclinical cancer biology experiments and the replicability of the completed experiments.

With increasing globalization and hypercompetitive markets, most employers have resorted to headcount management to gain flexibility, remain competitive, and ensure survival. A new employment relationship has emerged. The bond between employer and employee no longer is a long-term relationship involving loyalty and commitment, but a contract-like economic exchange. The authors take a closer look at this new employee relationship in the context of the more traditional employer-employee relationship still found in many organizations. The economic value of the new employee relationship may be less attractive than previously perceived. [PUBLICATION ABSTRACT]