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MRL/lpr mice develop systemic lupus erythematosus-like autoimmunity due to defective FAS-mediated apoptosis. We generated Fas ^lpr mice deficient in EAF2, a transcription elongation-associated factor known to promote apoptosis in germinal center (GC) B cells and crucial for preventing autoimmunity. Contrary to expectations, EAF2 deficiency significantly reduced lymphadenopathy and splenomegaly, extended lifespan, and alleviated nephritis by decreasing renal immune complex deposition. Additionally, EAF2 deficiency markedly reduced accumulation of activated B cells, GC B cells, plasma cells, and the abnormal B220⁺CD3⁺ T cells in Fas ^lpr mice. Further analysis revealed that Eaf2 ^-/- Fas ^lpr B cells showed hyperactivation upon various stimulations, followed by increased death. RNA sequencing of the B220⁺CD3⁺ cells revealed a downregulation in survival-promoting genes such as Bcl-2 and Akt and an upregulation of proapoptotic genes. We conclude that the combined deficiency in FAS- and EAF2-mediated apoptotic pathways leads to B cell hyperactivation and subsequent death, thereby ameliorating systemic autoimmunity in this model.

In people with HIV-1 (PWH), Mycobacterium tuberculosis (MTB) infection poses a significant threat. While active tuberculosis (TB) accelerates immunodeficiency, the interaction between MTB and HIV-1 during asymptomatic phases remains unclear. Analysis of peripheral blood mononuclear cells (PBMC) transcriptomic profiles in PWH, with and without controlled viral loads, revealed distinct clustering in MTB-infected individuals. Functional annotation identified alterations in IL-6, TNF, and KRAS pathways. Notably, MTB-related genes displayed an inverse correlation with HIV-1 viremia, at both individual and signature score levels. These findings suggest that MTB infection in PWH induces a shift in immune system activation, inversely related to HIV-1 viral load. These results may explain the observed enhanced antiretroviral control in MTB-infected PWH. This study highlights the complex interplay between MTB and HIV-1, emphasizing the importance of understanding their interaction for managing co-infections in this population.

MOTS-c is a mitochondrial microprotein that improves metabolism. Here, we demonstrate CK2 is a direct and functional target of MOTS-c. MOTS-c directly binds to CK2 and activates it in cell-free systems. MOTS-c administration to mice prevented skeletal muscle atrophy and enhanced muscle glucose uptake, which were blunted by suppressing CK2 activity. Interestingly, the effects of MOTS-c are tissue-specific. Systemically administered MOTS-c binds to CK2 in fat and muscle, yet stimulates CK2 activity in muscle while suppressing it in fat by differentially modifying CK2-interacting proteins. Notably, a naturally occurring MOTS-c variant, K14Q MOTS-c, has reduced binding to CK2 and does not activate it or elicit its effects. Male K14Q MOTS-c carriers exhibited a higher risk of sarcopenia and type 2 diabetes (T2D) in an age- and physical-activity-dependent manner, whereas females had an age-specific reduced risk of T2D. Altogether, these findings provide evidence that CK2 is required for MOTS-c effects.

The cochlea contains two extracellular fluids, perilymph and endolymph. Endolymph exhibits high potential of approximately +80 to +110 mV (depending on species), which sensitizes sensory hair cells. Other properties of this unique fluid remain elusive, owing to its minuscule volume in rodent cochlea. We therefore developed a technique to collect high-purity endolymph from mouse cochleae. Comprehensive proteomic analysis of sampled endolymph using liquid chromatography with mass spectrometry identified 301 proteins, dominated by molecules engaged in immunity and proteostasis. Approximately 30% of these proteins were undetectable in our perilymph. A combination of mass spectrometry and different approaches revealed that, compared to perilymph, endolymph was enriched with α₂-macroglobulin, osteopontin, apolipoprotein D, apolipoprotein E, and apolipoprotein J/clusterin. In other cells or tissues, α₂-macroglobulin, apolipoprotein E, and apolipoprotein J contribute to the clearance of degraded proteins from extracellular fluid. Altogether, with the proteins described here, endolymph may play a protective role in stabilizing cochlear homeostasis.

Viruses transmitted by Aedes mosquitoes (e.g., dengue [DENV], Zika [ZIKV]) have demonstrated high potential to spill over from their ancestral, sylvatic cycles in non-human primates to establish transmission in humans. Epidemiological models require accurate knowledge of the contact structure between hosts and vectors, which is highly sensitive to any impacts of virus infection in mosquitoes or hosts on mosquito feeding behavior. Current evidence for whether these viruses affect vector behavior is mixed. Here we leveraged a study on sylvatic DENV-2 and ZIKV transmission between two species of monkey and Aedes albopictus to determine whether virus infection of either host or vector alters vector feeding behavior. Engorgement rates varied from 0% to 100%, but this was not driven by vector nor host infection, but rather by the individual host, host species, and host body temperature. This study highlights the importance of incorporating individual-level heterogeneity of vector biting in arbovirus transmission models.

The main task of the Intergovernmental Panel on Climate Change (IPCC) is to provide comprehensive assessments of climate science. However, there are accusations of bias toward certain research fields based on limited empirical evidence. By analyzing the evidence base of Working Group 3 (WG3) reports, we show that integrated assessment modeling (IAM) research was influential in all six assessments, and overrepresented in the Summary for Policymakers (SPM). Further, we show that a small number of men working in Western Europe and the USA dominate IAM research. Thus, global climate negotiations and science may have historically prioritized mitigation solutions suggested by an unrepresentative scientific sample and missed solutions from other perspectives like those of females and non-Western cultures. However, we also show that IAM research influence decreased in AR6, implying a leveling playing field between research fields. But more effort is needed to ensure a comprehensive assessment.

We employed a three-step approach to evaluate serum immunoassay-based biomarkers for detecting non-small cell lung cancer (NSCLC). In the first step, we performed a systematic review and meta-analysis and implemented the Laboratory Medicine Best Practices (LMBP) method to identify potential biomarkers. From potential biomarkers, Carcinoembryonic antigen (CEA), cytokeratin 19-fragments (Cyfra 21-1), and human epididymis protein-4 (HE4) were categorized as LMBP "recommend." In the second step, we conducted matched-case-control validation on these recommended biomarkers and SAA, identified as the most accurate in the first step. In the third step, a re-meta-analysis was performed by integrating our experimental results and considering covariates. The final results revealed that HE4 emerged as the most reliable biomarker, offering balanced sensitivity and specificity, with accuracy unaffected by tumor stage, making it suitable for early diagnosis. Our findings support the inclusion of HE4 in clinical guidelines for NSCLC diagnosis, alongside well-established biomarkers such as Cyfra 21-1 and CEA.

Generative design of promoters has enhanced the efficiency of de novo creation of functional sequences. Though several deep generative models have been employed in biological sequence generation, including variational autoencoder (VAE) or Wasserstein generative adversarial network (WGAN), these models might struggle with mode collapse and low sample diversity. In this study, we introduce the multinomial diffusion model (MDM) for promoter sequence design and propose a structured set of criteria for effectively comparing the performance of generative models. In silico experiments demonstrate that MDM outperforms existing generative AI approaches. MDM demonstrates superior performance in various computational evaluations, remains robust during the training process, and exhibits a strong ability in capturing weak signals. In addition, we experimentally validated that the majority of our model designed promoters have expression activities in vivo, indicating the practicality and potential of MDM for bioengineering.