Search

Acne vulgaris, rosacea, and hidradenitis suppurativa are enduring inflammatory skin conditions that frequently manifest with akin clinical attributes, posing a considerable challenge for their distinctive diagnosis. While these conditions do exhibit certain resemblances, they also demonstrate distinct underlying pathophysiological mechanisms and treatment modalities. Delving into both the molecular parallels and disparities among these three disorders can yield invaluable insights for refined diagnostics, effective management, and targeted therapeutic interventions. In this report, we present a comparative analysis of transcriptomic data across these three diseases, elucidating differentially expressed genes and enriched pathways specific to each ailment, as well as those shared among them. Specifically, we identified multiple zinc‐binding proteins (SERPINA1, S100A7, S100A8, S100A9 and KRT16) as consistently highly upregulated genes across all three diseases. Our hypothesis suggests that these proteins could bind and sequester zinc, potentially leading to localized zinc deficiency and heightened inflammation. We identified high‐dose dietary zinc as a promising therapeutic approach and confirmed its effectiveness through validation in an acne mouse model. [ABSTRACT FROM AUTHOR]

Innate lymphoid cells (ILCs) are a diverse population of cells that include NK cells and contribute to tissue homeostasis and repair, inflammation, and provide protection from infection. The interplay between human blood ILCs, as well as their responses to HIV‐1 infection, remains poorly understood. This study used transcriptional and chromatin profiling to explore these questions. Transcriptional profiling and flow cytometry analysis support that there are four main ILC subsets found in human blood. Unlike in mice, human NK cells expressed the tissue repair protein amphiregulin (AREG). AREG production was induced by TCF7/WNT, IL‐2, and IL‐15, and inhibited by TGFB1, a cytokine increased in people living with HIV‐1. In HIV‐1 infection, the percentage of AREG+ NK cells correlated positively with the numbers of ILCs and CD4+ T cells but negatively with the concentration of inflammatory cytokine IL‐6. NK‐cell knockout of the TGFB1‐stimulated WNT antagonist RUNX3 increased AREG production. Antiviral gene expression was increased in all ILC subsets from HIV‐1 viremic people, and anti‐inflammatory gene MYDGF was increased in an NK‐cell subset from HIV‐1‐infected people whose viral load was undetectable in the absence of antiretroviral therapy. The percentage of defective NK cells in people living with HIV‐1 correlated inversely with ILC percentage and CD4+ T‐cell counts. CD4+ T cells and their production of IL‐2 prevented the loss of NK‐cell function by activating mTOR. These studies clarify how ILC subsets are interrelated and provide insight into how HIV‐1 infection disrupts NK cells, including an uncharacterized homeostatic function in NK cells. Synopsis: The complex interplay between human blood innate lymphoid cells (ILCs) and natural killer (NK) cells, as well as their responses to HIV‐1 infection, remains poorly understood. In this study, we provide a more comprehensive understanding of the relationship among these cellular subsets, uncover a novel homeostatic function in human NK cells, and illuminate how HIV‐1 infection disrupts these cellular subsets and their functions.Human blood CD56hi NK cells inhabit an intermediary state between ILCs and a cluster comprising CD56dim and CD56− NK cells.In contrast to mice, human NK cells are major producers of the homeostatic cytokine amphiregulin (AREG).The production of AREG by NK cells is WNT/TCF7‐dependent and inhibited by TGFB1 and RUNX3. Furthermore, its production is reduced in people living with HIV‐1.During HIV‐1 infection, nonfunctional, MTOR‐deficient, CD56− NK cells are generated from epigenetically similar CD56dim NK cells, a process influenced by deficits in CD4+ T cells and IL‐2. [ABSTRACT FROM AUTHOR]

Efficient genome editing with Cas9-sgRNA in vivo has required the use of viral delivery systems, which have limitations for clinical applications. Translational efforts to develop other RNA therapeutics have shown that judicious chemical modification of RNAs can improve therapeutic efficacy by reducing susceptibility to nuclease degradation. Guided by the structure of the Cas9-sgRNA complex, we identify regions of sgRNA that can be modified while maintaining or enhancing genome-editing activity, and we develop an optimal set of chemical modifications for in vivo applications. Using lipid nanoparticle formulations of these enhanced sgRNAs (e-sgRNA) and mRNA encoding Cas9, we show that a single intravenous injection into mice induces >80% editing of Pcsk9 in the liver. Serum Pcsk9 is reduced to undetectable levels, and cholesterol levels are significantly lowered about 35% to 40% in animals. This strategy may enable non-viral, Cas9-based genome editing in the liver in clinical settings. [ABSTRACT FROM AUTHOR]

High-purity copper has emerged as a preferred construction material for ultra-low-background HPGe spectrometers and offers excellent bulk radiopurity along with good electrical, thermal, and vacuum properties. Recently, these materials and techniques have been applied to the construction of low-background internal-source gas proportional counters. This work describes the design, construction, and testing of an ultra-low-background internal-source gas proportional counter built primarily of high purity electroformed copper. Energy resolution of ~10% FWHM at 59.5 keV has been achieved, a low-energy threshold of ~3 keV has been reached, and gas gain stability over a 4-week period has been demonstrated. Progress toward low-background operation is described. [ABSTRACT FROM AUTHOR]