Within the paradigm of the two-signal model of lymphocyte activation, the interest in costimulation has witnessed a remarkable emergence in the past few years with the discovery of a large array of molecules that can serve this role, including some with an inhibitory function. Interest has been further enhanced by the realization of these molecules' potential as targets to modulate clinical immune responses. Although the therapeutic translation of mechanistic knowledge in costimulatory molecules has been relatively straightforward, the capacity to target their inhibitory counterparts has remained limited. This limited capacity is particularly apparent in the case of the cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), a major negative regulator of T cell responses. Because there have been several previous comprehensive reviews on the function of this molecule, we focus here on the physiological implications of its structural features. Such an exercise may ultimately help us to design immunotherapeutic agents that target CTLA-4.

The alternative sigma factor RpoS controls the expression of many stationary-phase genes in Escherichia coli and other bacteria. Though the RpoS regulon is a large, conserved system that is critical for adaptation to nutrient deprivation and other stresses, it remains incompletely characterized. In this study, we have used oligonucleotide arrays to delineate the transcriptome that is controlled by RpoS during entry into stationary phase of cultures growing in rich medium. The expression of known RpoS-dependent genes was confirmed to be regulated by RpoS, thus validating the use of microarrays for expression analysis. The total number of positively regulated stationary-phase genes was found to be greater than 100. More than 45 new genes were identified as positively controlled by RpoS. Surprisingly, a similar number of genes were found to be negatively regulated by RpoS, and these included almost all genes required for flagellum biosynthesis, genes encoding enzymes of the TCA cycle, and a physically contiguous group of genes located in the Rac prophage region. Negative regulation by RpoS is thus much more extensive than has previously been recognized, and is likely to be an important contributing factor to the competitive growth advantage of rpoS mutants reported in previous studies.

Stomatin-like protein 2 (SLP-2) is a widely expressed mitochondrial inner membrane protein of unknown function. Here we show that human SLP-2 interacts with prohibitin-1 and -2 and binds to the mitochondrial membrane phospholipid cardiolipin. Upregulation of SLP-2 expression increases cardiolipin content and the formation of metabolically active mitochondrial membranes and induces mitochondrial biogenesis. In human T lymphocytes, these events correlate with increased complex I and II activities, increased intracellular ATP stores, and increased resistance to apoptosis through the intrinsic pathway, ultimately enhancing cellular responses. We propose that the function of SLP-2 is to recruit prohibitins to cardiolipin to form cardiolipinenriched microdomains in which electron transport complexes are optimally assembled. Likely through the prohibitin functional interactome, SLP-2 then regulates mitochondrial biogenesis and function.

RpoS is a major regulator of genes required for adaptation to stationary phase in E. coli. However, the exponential phase expression of some genes is affected by rpoS mutation, suggesting RpoS may also have an important physiological role in growing cells. To test this hypothesis, we examined the regulatory role of RpoS in exponential phase using both genomic and biochemical approaches. Microarray expression data revealed that, in the rpoS mutant, the expression of 268 genes was attenuated while the expression of 24 genes was enhanced. Genes responsible for carbon source transport (the mal operon for maltose), protein folding (dnaK and mopAB), and iron acquisition (fepBD, entCBA, fecI, and exbBD) were positively controlled by RpoS. The importance of RpoS-mediated control of iron acquisition was confirmed by cellular metal analysis which revealed that the intracellular iron content of wild type cells was two-fold higher than in rpoS mutant cells. Surprisingly, many previously identified RpoS stationary-phase dependent genes were not controlled by RpoS in exponential phase and several genes were RpoS-regulated only in exponential phase, suggesting the involvement of other regulators. The expression of RpoS-dependent genes osmY, tnaA and malK was controlled by Crl, a transcriptional regulator that modulates RpoS activity. In summary, the identification of a group of exponential phase genes controlled by RpoS reveals a novel aspect of RpoS function.

Background: Hidradenitis suppurativa (HS) is associated with comorbidities that contribute to poor health, impaired life quality, and mortality risk.Objective: To provide evidence-based screening recommendations for comorbidities linked to HS.Methods: Systematic reviews were performed to summarize evidence on the prevalence and incidence of 30 comorbidities in patients with HS relative to the general population. The screening recommendation for each comorbidity was informed by the consistency and quality of existing studies, disease prevalence, and

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RpoS is a conserved alternative sigma factor that regulates the expression of many stress response genes in Escherichia coli. The RpoS regulon is large but has not yet been completely characterized. In this study, we report the identification of over 100 RpoS-dependent fusions in a genetic screen based on the differential expression of an operon-lacZ fusion bank in rpoS mutant and wild-type backgrounds. Forty-eight independent gene fusions were identified, including several in well-characterized RpoS-regulated genes, such as osmY, katE, and otsA. Many of the other fusions mapped to genes of unknown function or to genes that were not previously known to be under RpoS control. Based on the homology to other known bacterial genes, some of the RpoS-regulated genes of unknown functions are likely important in nutrient scavenging.RpoS, an alternative sigma factor, controls a large regulon that is specifically expressed when the cell is nutrient deprived or is subjected to external stress, such as osmotic shock (32). Genes that are dependent on RpoS have been identified in different contexts from many studies of regulation in various gram-negative bacteria (38). From these studies it is clear that the regulon encodes many proteins that help bacteria adapt to adverse conditions, including those that are involved in nutrient scavenging, DNA repair, protein turnover, and protection from external environmental insult (31).Characterization of the RpoS regulon has relied on several experimental approaches, including two-dimensional gel electrophoresis (50), identification of genes that are induced by RpoS-related stimuli such as carbon starvation (85), and by identifying gene fusions that depend on RpoS for expression (66). Use of bacterial cDNA microarrays or macroarrays, while potentially useful in identifying additional members of the RpoS regulon, have been employed in only a few studies of Escherichia coli and have not yet been used to directly assess RpoS dependence of genes in isogenic wild-type and rpoS mutant strains. In a previous study (66), our lab introduced an RpoS-null allele into a bank of random operon-lacZ fusions to facilitate the identification of RpoS-dependent genes based solely on RpoS requirement. This resulted in the identification of several new highly RpoS-dependent genes in E. coli (66), and similar approaches have been employed with Salmonella spp. where other RpoS-dependent genes have been identified (37). Lac gene fusions are useful measures of gene expression, because the product, ␤-galactosidase, is stable and easily assayed (16). This makes lacZ fusions particularly suitable for the study of genes that are expressed in stationary phase, where the stability of the RNA and protein products of the affected gene is not known.In this study, we report the completion of the identification of reporter fusions identified in a previous genetic screen of lacZ-expressing fusion mutants. In addition, we examined the expression of the RpoS-dependent operon fusions in rich and minimal media and classified ...

Immune-mediated diseases and immunotherapeutics can negatively affect normal immune functioning and, consequently, vaccine safety and response. The COVID-19 pandemic has incited research aimed at developing a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine. As SARS-CoV-2 vaccines are developed and made available, the assessment of anticipated safety and efficacy in patients with immune-mediated dermatologic diseases and requiring immunosuppressive and/or immunomodulatory therapy is particularly important. A review of the literature was conducted by a multidisciplinary committee to provide guidance on the safety and efficacy of SARS-CoV-2 vaccination for dermatologists and other clinicians when prescribing immunotherapeutics. The vaccine platforms being used to develop SARS-CoV-2 vaccines are expected to be safe and potentially effective for dermatology patients on immunotherapeutics. Current guidelines for the vaccination of an immunocompromised host remain appropriate when considering future administration of SARS-CoV-2 vaccines.