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Squamous cell carcinomas (SCCs), arising from the skin, head and neck, lungs, esophagus, and cervix, are collectively among the most common cancers and a frequent cause of cancer morbidity and mortality. Despite distinct stratified epithelial tissues of origin, converging evidence points toward shared biologic pathways across SCCs. With recent breakthroughs in molecular technologies have come novel SCC treatment paradigms, including immunotherapies and targeted therapy. This review compares commonalities and differences across SCCs from different anatomical sites, including risk factors and genetics, as well as cellular and molecular programs driving tumorigenesis. We review landmark discoveries of the "cancer stem cells" (CSCs) that initiate and propagate SCCs and their gene and translational regulation programs. This has led to an appreciation that interactions between CSCs and the immune system play key roles in invasion and therapeutic resistance. Here, we review the unifying principles of SCCs that have emerged from these exciting advances in our understanding of these epithelial cancers.

Chlamydia muridarum (Cm) is a moderately prevalent, gram-negative, intracellular bacterium that affects laboratory mice, causing subclinical to severe disease, depending on the host's immune status. The effectiveness of various antibiotic regimens aimed at eradicating Cm in both immunodeficient and immunocompetent laboratory mice was evaluated. NSG mice were cohoused with Cm-shedding BALB/cJ mice for 14 d to simulate natural exposure. Four groups of 8 infected NSG mice were treated for 7 d with either 0.08% sulfamethoxazole and 0.016% trimethoprim (TMS) in water, 0.0625% doxycycline in feed, 0.124%/0.025% TMS in feed, or 0.12% amoxicillin in feed. A control group was provided standard water and feed. The impact of treatment on gastrointestinal microbiota (GM) was investigated using next-generation shotgun sequencing on the last day of treatment. TMS and amoxicillin had negligible effects on GM, while doxycycline had the largest effect. All antibiotic-treated NSG mice exhibited clinical disease, including dehydration, hunched posture, greater than 20% weight loss, and dyspnea, leading to euthanasia 21 to 40 d posttreatment (32.6 +/- 4.2 d; mean +/- SD). Untreated controls were euthanized 14 to 33 d postexposure (23.75 +/- 5.9 d). All mice were fecal PCR positive for Cm at euthanasia. Histologic evaluation revealed multifocal histiocytic and neutrophilic bronchointerstitial pneumonia and/or bronchiolitis featuring prominent intralesional chlamydial inclusion bodies in all mice. Subsequently, groups of 8 C57BL/6J, BALB/cJ, NOD.SCID, and NSG mice infected with Cm were treated with 0.124%/0.025% TMS in feed for 7 (BALB/cJ and C57BL/6J) or 21 d (NSG and NOD.SCID). All immunocompetent and NOD.SCID mice were negative for Cm by PCR 14 d posttreatment, remained clinically normal, and had no evidence of Cm infection at necropsy, and all NSG mice remained Cm positive and were euthanized. While these findings highlight the difficulties in eradicating Cm from highly immunodeficient mice, eradication of Cm from immunocompetent or moderately immunocompromised mice with antibiotics is feasible.

The Nicobar pigeon (Caloenas nicobarica), the closest living relative of the extinct Dodo (Raphus cucullatus), is endemic to Southeast Asia with a fragmented distribution across numerous small islands. It suffers from habitat loss, hunting, and predation from invasive species, resulting in its classification as Near Threatened by the International Union for the Conservation of Nature. We have generated a haplotype-resolved and chromosome-level genome assembly of the Nicobar pigeon using a combination of PacBio HiFi long-read sequencing and Arima Hi-C chromatin interaction mapping. This assembly includes two haplotypes, each spanning approximately 1.2 Gb. Haplotype 1 has a contig N50 of 25.2 Mb and a scaffold N50 of 79.7 Mb, whereas haplotype 2 has a contig N50 of 24.7 Mb and a scaffold N50 of 107.9 Mb. As the first high-quality genome assembly of any bird in the Columbidae Indo-Pacific clade, this resource provides valuable insights for phylogenetic studies. Furthermore, the phylogenetic proximity of the Nicobar pigeon to the Dodo (R. cucullatus) and the Rodrigues Solitaire (Pezophaps solitaria) offers a unique opportunity to study these extinct species, making this assembly a critical resource for evolutionary studies. It also offers a unique model for studying genetic diversity, adaptation, and speciation in island environments. This genomic resource will not only enhance our understanding of the evolutionary history of the Nicobar pigeon but also serve as a valuable tool for future conservation efforts aimed at preserving this unique species and its fragile island ecosystem.

Cells fine-tune gene expression in response to cellular stress, a process critical for tumorigenesis. However, mechanisms governing stress-responsive transcription remain incompletely understood. This study shows that the MED1 subunit of the Mediator coactivator complex is acetylated in its intrinsically disordered region (IDR). Under stress, SIRT1 associates with the super elongation complex to deacetylate MED1 in promoter-proximal regions. The deacetylated (or acetylation-defective mutant) MED1 amplified stress-activated cytoprotective genes and rescued stress-suppressed growth-supportive genes in estrogen-receptor-positive breast cancer (ER+ BC) cells. Mechanistically, deacetylated MED1 promotes chromatin incorporation of RNA polymerase II (Pol II) through IDR-mediated interactions. Functionally, ER+ BC cells with deacetylated MED1 exhibit faster growth and enhanced stress resistance in culture and in an orthotopic mouse model. These findings advance our understanding of Pol II regulation under cellular stress and potentially suggest therapeutic strategies targeting oncogenic transcription driven by MED1 and Mediator.

The molecular mechanisms that enable memories to persist over long timescales from days to weeks and months are still poorly understood1. Here, to develop insights into this process, we created a behavioural task in which mice formed multiple memories but only consolidated some, while forgetting others, over the span of weeks. We then monitored circuit-specific molecular programs that diverged between consolidated and forgotten memories. We identified multiple distinct waves of transcription, that is, cellular macrostates, in the thalamocortical circuit that defined memory persistence. Of note, a small set of transcriptional regulators orchestrated broad molecular programs that enabled entry into these macrostates. Targeted CRISPR-knockout studies revealed that although these transcriptional regulators had no effects on memory formation, they had prominent, causal and strikingly time-dependent roles in memory stabilization. In particular, the calmodulin-dependent transcription factor CAMTA1 was required for initial memory maintenance over days, whereas the transcription factor TCF4 and the histone methyltransferase ASH1L were required later to maintain memory over weeks. These results identify a critical CAMTA1-TCF4-ASH1L thalamocortical transcriptional cascade that is required for memory stabilization and put forth a model in which the sequential recruitment of circuit-specific transcriptional programs enables memory maintenance over progressively longer timescales.

Sensory compensation occurs when loss of one sense leads to enhanced perception by another sense. We have identified a previously undescribed mechanism of sensory compensation in female Aedes aegypti mosquitoes. Odorant receptor co-receptor (Orco) mutants show enhanced attraction to human skin temperature and increased heat-evoked neuronal activity in foreleg sensory neurons. Ir140, a foreleg-enriched member of the ionotropic receptor (IR) superfamily of sensory receptors, is up-regulated in Orco mutant legs. Ir140, Orco double mutants do not show the enhanced heat seeking seen in Orco single mutants, suggesting that up-regulation of Ir140 in the foreleg is a key mechanism underlying sensory compensation in Orco mutants. Because Orco expression is sparse in legs, this sensory compensation requires an indirect, long-range mechanism. Our findings highlight how female Aedes aegypti mosquitoes, despite suffering olfactory sensory loss, maintain the overall effectiveness of their host-seeking behavior by up-regulating attraction to human skin temperature, further enhancing their status as the most dangerous predator of humans.

Decades of research into human neurodegenerative diseases have revealed important similarities as well as dissimilarities between diseases. While investigations of specific mechanistic aspects of diseases have been aided by cell and animal models, true advances in the understanding of neurodegeneration require that we deal with the daunting complexities of the human brain. In this review, we discuss novel molecular profiling methods that have been applied to human postmortem brain tissue during the last decade and highlight insights into cell type-specific molecular characteristics and disease-associated changes in both vulnerable and resilient cell types in Huntington's disease, Parkinson's disease, and Alzheimer's disease. We also illustrate how these approaches can complement human genetic analyses and studies of animal models to advance our understanding of human neurodegeneration.

Aims This narrative expert review aims to elucidate the role of biomarkers in the diagnosis and treatment of interstitial cystitis/bladder pain syndrome (IC/BPS), highlighting their potential to enhance patient care by enabling more precise and individualized therapeutic strategies.Methods and Results We performed a comprehensive review of literature focused on biomarkers relevant to IC/BPS, including bladder capacity, symptom intensity, bladder wall thickness, as well as serum and urinary inflammatory cytokines and other biomarkers of inflammation, oxidative stress, and urothelial and extracellular matrix remodeling. Evidence indicates that biomarkers such as TNF-alpha, IL-8, and bladder capacity can differentiate between Hunner lesion and non-Hunner lesion IC subtypes, predict treatment responses, and guide effective interventions. Furthermore, advanced statistical methods and machine learning applications show promise in improving diagnostic accuracy and treatment outcome predictions through clustering of the biomarker data.Conclusions Reliable biomarkers are vital for improving diagnostic precision and tailoring therapies for IC/BPS patients. Ongoing research and validation of these biomarkers are essential for advancing understanding, guiding treatment decisions, and enhancing the quality of life for individuals affected by this complex syndrome. The need for integrated biomarker profiles and multipronged research approaches is crucial for the future of IC/BPS management.

Background and Aims:Hepatitis B virus (HBV) and hepatitis C virus (HCV) share transmission routes and often coinfect the liver, leading to accelerated liver disease progression. In the era of direct-acting antivirals (DAAs) for HCV, the clinical impact of coinfection is further complicated by reports of HBV reactivation following HCV cure. While HCV-induced interferon (IFN) responses are known to suppress HBV, the underlying mechanisms remain incompletely understood. This study aimed to investigate how HCV modulates HBV infection in the setting of coinfection and to identify strategies to prevent HBV reactivation post-HCV clearance.Approach and Results:We utilized a multicellular liver culture model composed of human-induced pluripotent stem cell (hiPSC)-derived hepatocytes, hepatic stellate cells, and macrophages, which supports productive HBV and HCV infection and recapitulates clinical coinfection dynamics. We found that IL1 beta derived from HCV-activated macrophage suppresses HBV replication independent of IFN signaling. Mechanistically, IL1 beta downregulated the HBV receptor SLC10A1 in hepatocytes via induction of a truncated C/EBP beta isoform that negatively regulates the full-length variant. Concurrently, IL1 beta induced ISG20 expression through USF1 phosphorylation, further inhibiting HBV replication. A combination treatment of DAAs and an HBV entry inhibitor effectively prevented HBV reactivation in the model.Conclusions:Our findings reveal a macrophage-derived, IFN-independent mechanism by which HCV suppresses HBV infection, mediated through IL1 beta. These insights highlight the complex crosstalk between hepatotropic viruses during coinfection and suggest that targeting IL1 beta-regulated pathways may offer therapeutic potential to prevent HBV reactivation in DAA-treated patients.

Choline is an essential micronutrient critical for cellular and organismal homeostasis. As a core component of phospholipids and sphingolipids, it is indispensable for membrane architecture and function. Additionally, choline is a precursor for acetylcholine, a key neurotransmitter, and betaine, a methyl donor important for epigenetic regulation. Consistent with its pleiotropic role in cellular physiology, choline metabolism contributes to numerous developmental and physiological processes in the brain, liver, kidney, lung and immune system, and both choline deficiency and excess are implicated in human disease. Mutations in the genes encoding choline metabolism proteins lead to inborn errors of metabolism, which manifest in diverse clinical pathologies. While the identities of many enzymes involved in choline metabolism were identified decades ago, only recently has the field begun to understand the diverse mechanisms by which choline availability is regulated and fuelled via metabolite transport/recycling and nutrient acquisition. This review provides a comprehensive overview of choline metabolism, emphasizing emerging concepts and their implications for human health and disease.