Abstract
The Earth is home to environments characterized by low pH, including the gastrointestinal tract of vertebrates and large areas of acidic soil. Most bacteria are neutralophiles, but can ...survive fluctuations in pH. Herein, we review how Escherichia, Salmonella, Helicobacter, Brucella, and other acid-resistant Gram-negative bacteria adapt to acidic environments. We discuss the constitutive and inducible defense mechanisms that promote survival, including proton-consuming or ammonia-producing processes, cellular remodeling affecting membranes and chaperones, and chemotaxis. We provide insights into how Gram-negative bacteria sense environmental acidity using membrane-integrated and cytosolic pH sensors. Finally, we address in more detail the powerful proton-consuming decarboxylase systems by examining the phylogeny of their regulatory components and their collective functionality in a population.
The authors focus on the manifold adaptive responses of neutralophilic Gram-negative proteobacteria and the molecular mechanisms of sensing acid stress.
We conducted a meta-analysis to identify new susceptibility loci for testicular germ cell tumor (TGCT). In the discovery phase, we analyzed 931 affected individuals and 1,975 controls from 3 ...genome-wide association studies (GWAS). We conducted replication in 6 independent sample sets comprising 3,211 affected individuals and 7,591 controls. In the combined analysis, risk of TGCT was significantly associated with markers at four previously unreported loci: 4q22.2 in HPGDS (per-allele odds ratio (OR) = 1.19, 95% confidence interval (CI) = 1.12-1.26; P = 1.11 × 10(-8)), 7p22.3 in MAD1L1 (OR = 1.21, 95% CI = 1.14-1.29; P = 5.59 × 10(-9)), 16q22.3 in RFWD3 (OR = 1.26, 95% CI = 1.18-1.34; P = 5.15 × 10(-12)) and 17q22 (rs9905704: OR = 1.27, 95% CI = 1.18-1.33; P = 4.32 × 10(-13) and rs7221274: OR = 1.20, 95% CI = 1.12-1.28; P = 4.04 × 10(-9)), a locus that includes TEX14, RAD51C and PPM1E. These new TGCT susceptibility loci contain biologically plausible genes encoding proteins important for male germ cell development, chromosomal segregation and the DNA damage response.
Colorectal cancer is treated with antibodies blocking epidermal growth factor receptor (EGF-R), but therapeutic success is limited. EGF-R is stimulated by soluble ligands, which are derived from ...transmembrane precursors by ADAM17-mediated proteolytic cleavage. In mouse intestinal cancer models in the absence of ADAM17, tumorigenesis was almost completely inhibited, and the few remaining tumors were of low-grade dysplasia. RNA sequencing analysis demonstrated down-regulation of STAT3 and Wnt pathway components. Because EGF-R on myeloid cells, but not on intestinal epithelial cells, is required for intestinal cancer and because IL-6 is induced via EGF-R stimulation, we analyzed the role of IL-6 signaling. Tumor formation was equally impaired in IL-6
mice and sgp130Fc transgenic mice, in which only trans-signaling via soluble IL-6R is abrogated. ADAM17 is needed for EGF-R-mediated induction of IL-6 synthesis, which via IL-6 trans-signaling induces β-catenin-dependent tumorigenesis. Our data reveal the possibility of a novel strategy for treatment of colorectal cancer that could circumvent intrinsic and acquired resistance to EGF-R blockade.
Adaptive immune cells with regulatory function reportedly mediate immune escape in a variety of tumors. Little is known regarding the relevance of the most prominent regulatory cell populations, ...namely Foxp3+ T regulatory cells (Tregs) and CD19+IL‐10+ B regulatory cells (Bregs), for neuroblastoma (NB) survival. After establishing a novel immunocompetent syngeneic NB mouse model where orthotopic tumors can be generated after intrarenal injection of NB975A cells, we studied the importance of Tregs and Bregs in Foxp3‐DTR mice whose Tregs can be depleted by diphtheria toxin (DT) application as well as in CD19‐specific IL‐10 deficient mice that lack IL‐10+ Bregs (CD19cre+/− × IL‐10fl/fl mice). We observed Foxp3 Treg cells in tumors from wild type mice. On the contrary, Bregs or B cells were scarce. Specific depletion of Tregs in Foxp3‐DTR mice resulted in an 85% reduction of tumor volume and weight compared to DT‐treated wild type mice and untreated Foxp3‐DTR mice. In contrast, NB tumor growth was not affected in CD19‐specific IL‐10 deficient mice. Similarly, mice lacking mature B cells (μMT mice) and CD19 deficient mice (CD19cre mice) showed no change in growth pattern of NB tumors. In Treg‐depleted mice, reduced tumor growth was associated with an increased concentration of IFN‐gamma, TNF‐alpha, IL‐4, IL‐6, and IL‐10 in isolated splenocytes. In summary, transient ablation of Tregs but not absence of Bregs hindered the growth of NB, strongly suggesting the therapeutic potential of targeting Tregs for this aggressive childhood tumor.
What's new?
While regulatory adaptive immune cells mediate immune escape in a variety of tumors, little is known about their role in neuroblastoma. In a newly‐developed syngeneic orthotopic mouse model, the authors observed that the specific depletion of regulatory T cells in Foxp3DTR knock‐in mice hindered tumor growth and stimulated systemic cytokine production. Neuroblastoma growth was not affected by absence of mature B cells in μMT mice or IL‐10‐producing B cells in CD19cre+/− × IL‐10fl/fl mice. The findings identified Treg, but not Breg, as a key regulator of tolerance induced by neuroblastoma and an important potential therapeutic target.
The acid stress response is an important factor influencing the transmission of intestinal microbes such as the enterobacterium Escherichia coli. E. coli activates three inducible acid resistance ...systems - the glutamate decarboxylase, arginine decarboxylase, and lysine decarboxylase systems to counteract acid stress. Each system relies on the activity of a proton-consuming reaction catalyzed by a specific amino acid decarboxylase and a corresponding antiporter. Activation of these three systems is tightly regulated by a sophisticated interplay of membrane-integrated and soluble regulators. Using a fluorescent triple reporter strain, we quantitatively illuminated the cellular individuality during activation of each of the three acid resistance (AR) systems under consecutively increasing acid stress. Our studies highlight the advantages of E. coli in possessing three AR systems that enable division of labor in the population, which ensures survival over a wide range of low pH values.
Abstract Objective We aimed to prospectively derive and validate a novel 1h-algorithm using high-sensitivity cardiac troponin I (hs-cTnI) for early rule-out and rule-in of acute myocardial ...infarction. Methods We performed a prospective multicenter diagnostic study enrolling 1811 patients with suspected acute myocardial infarction. The final diagnosis was centrally adjudicated by 2 independent cardiologists using all available information, including coronary angiography, echocardiography, follow-up data, and serial measurements of hs-cTnT (but not hs-cTnI). The hs-cTnI 1h-algorithm, incorporating measurements performed at baseline and absolute changes within 1 hour, was derived in a randomly selected sample of 906 patients (derivation cohort), and then validated in the remaining 905 patients (validation cohort). Results Acute myocardial infarction was the final diagnosis in 18% of patients. After applying the hs-cTnI 1h-algorithm developed in the derivation cohort to the validation cohort, 50.5% of patients could be classified as “rule-out,” 19% as “rule-in,” 30.5% as “observe.” In the validation cohort, the negative predictive value for acute myocardial infarction in the “rule-out” zone was 99.6% (95% confidence interval, 98.4%-100%), and the positive predictive value for acute myocardial infarction in the “rule-in” zone was 73.9% (95% confidence interval, 66.7%-80.2%). Negative predictive value of the 1h-algorithm was higher compared with the classical dichotomous interpretation of hs-cTnI and to the standard of care combining hs-cTnI with the electrocardiogram (both P < .001). Positive predictive value also was higher compared with the standard of care ( P < .001). Conclusion Using a simple algorithm incorporating baseline hs-cTnI values and the absolute change within the first hour allows safe rule-out as well as accurate rule-in of acute myocardial infarction in 70% of patients presenting with suspected acute myocardial infarction.
The design and development of dye-sensitized solar cells (DSCs) is currently often realized on an empirical basis. In view of assisting in this optimization process, we present the framework of a ...model which consists in a coupled optical and electrical model of the DSC. The experimentally validated optical model, based on a ray-tracing algorithm, allows accurate determination of the internal quantum efficiency of devices, an important parameter that is not easily estimated. Coupling the output of the optical modelthe dye absorption rateto an electrical model for charge generation, transport, and first-order (linear) recombination allows extraction of a set of intrinsic parameters from steady-state photocurrent measurements, such as the diffusion length or the dye electron injection efficiency. Importantly, the sources of optical and electric losses in the device can be separated and quantified (i.e., transmittance, reflectance, absorptance, charge injection, recombination, and potential losses). The model has been validated for two dye systems (Z907 and C101) and the strong effect of the presence of Li+ ions in the electrolyte on intrinsic parameters is confirmed. This optoelectronic model of the DSC is a significant step toward a future systematic model-assisted optimization of DSC devices.
Abstract Understanding the expression level and evolutionary rate of associated genes with human polygenic diseases provides crucial insights into their disease-contributing roles. In this work, we ...leveraged genome-wide association studies to investigate the relationship between the genetic association and both the evolutionary rate (dN/dS) and expression level of human genes associated with the two polygenic diseases of schizophrenia and coronary artery disease. Our findings highlight a distinct variation in these relationships between the two diseases. Genes associated with both diseases exhibit a significantly greater variance in evolutionary rate compared to those implicated in monogenic diseases. Expanding our analyses to 4,756 complex traits in the GWAS atlas database, we unraveled distinct trait categories with a unique interplay among the evolutionary rate, expression level, and genetic association of human genes. In most polygenic traits, highly expressed genes were more associated with the polygenic phenotypes compared to lowly expressed genes. About 69% of polygenic traits displayed a negative correlation between genetic association and evolutionary rate, while approximately 30% of these traits showed a positive correlation between genetic association and evolutionary rate. Our results demonstrate the presence of a spectrum among complex traits, shaped by natural selection. Notably, at opposite ends of this spectrum, we find metabolic traits being more likely influenced by purifying selection, and immunological traits that are more likely shaped by positive selection. We further established the polygenic evolution portal (evopolygen.de) as a resource for investigating relationships and generating hypotheses in the field of human polygenic trait evolution.
Metastasis is the major cause of death in cancer patients. Circulating tumor cells need to migrate through the endothelial layer of blood vessels to escape the hostile circulation and establish ...metastases at distant organ sites. Here, we identified the membrane-bound metalloprotease ADAM17 on endothelial cells as a key driver of metastasis. We show that TNFR1-dependent tumor cell-induced endothelial cell death, tumor cell extravasation, and subsequent metastatic seeding is dependent on the activity of endothelial ADAM17. Moreover, we reveal that ADAM17-mediated TNFR1 ectodomain shedding and subsequent processing by the γ-secretase complex is required for the induction of TNF-induced necroptosis. Consequently, genetic ablation of ADAM17 in endothelial cells as well as short-term pharmacological inhibition of ADAM17 prevents long-term metastases formation in the lung. Thus, our data identified ADAM17 as a novel essential regulator of necroptosis and as a new promising target for antimetastatic and advanced-stage cancer therapies.
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