Calcium Oxalate Crystallization in Urine of Healthy Men and Women: A Comparative Study

This study aimed to compare calcium oxalate (CaOx) crystallization in undiluted urine from healthy men and women with the object of clarifying the difference in stone incidence between the two sexes. Twenty-four hour urine specimens were collected from 37 men and 28 women. Urinary pH, and concentrations of Ca, oxalate and urate were measured, and indices of crystallization determined by Coulter Counter particle analysis following induction of CaOx crystallization by addition of oxalate. The amount of oxalate required to induce crystallization was significantly (p \u3c 0.01) higher in females than in males, as was the overall particle volume deposited after 90 minutes incubation (p \u3c 0 .006). Scanning electron microscopy revealed larger individual crystals in female urine, and a greater degree of crystal aggregation in male urine, although the average overall size of the precipitated crystal particles did not differ between the two sexes. There were no significant differences between men and women with regard to median pH, or Ca and oxalate concentrations, but the median urate concentrations were slightly, but significantly, higher (p \u3c 0.05) in the women\u27s urines than in the men\u27s. It was concluded that the greater risk of CaOx stones in men is related to an increased propensity to nucleate CaOx crystals per se, rather than to a tendency to form larger crystalline particles

Polymorphism and selection of rpoS in pathogenic Escherichia coli

<p>Abstract</p> <p>Background</p> <p>Though RpoS is important for survival of pathogenic <it>Escherichia coli </it>in natural environments, polymorphism in the <it>rpoS </it>gene is common. However, the causes of this polymorphism and consequential physiological effects on gene expression in pathogenic strains are not fully understood.</p> <p>Results</p> <p>In this study, we found that growth on non-preferred carbon sources can efficiently select for loss of RpoS in seven of ten representative verocytotoxin-producing <it>E. coli </it>(VTEC) strains. Mutants (Suc⁺⁺) forming large colonies on succinate were isolated at a frequency of 10^-8mutants per cell plated. Strain O157:H7 EDL933 yielded mainly mutants (about 90%) that were impaired in catalase expression, suggesting the loss of RpoS function. As expected, inactivating mutations in <it>rpoS </it>sequence were identified in these mutants. Expression of two pathogenicity-related phenotypes, cell adherence and RDAR (red dry and rough) morphotype, were also attenuated, indicating positive control by RpoS. For the other Suc⁺⁺mutants (10%) that were catalase positive, no mutation in <it>rpoS </it>was detected.</p> <p>Conclusion</p> <p>The selection for loss of RpoS on poor carbon sources is also operant in most pathogenic strains, and thus is likely responsible for the occurrence of <it>rpoS </it>polymorphisms among <it>E. coli </it>isolates.</p

Mechanism of Cyclophosphamide-Induced Ovarian Follicle Loss in the Prepubertal Mouse

Background: Cancer therapies cause serious side effects, affecting the quality of life for young cancer survivors. The ovary is affected by cancer therapies, causing premature ovarian insufficiency, leading to endocrine dysfunction, infertility, and ovarian aging. Thus, maintaining ovarian function against cancer treatment is an unmet need for female cancer patients. Cyclophosphamide (CPA), a common chemotherapeutic agent, forms DNA crosslinks to induce apoptosis in rapidly proliferating tumor cells. However, the underlying mechanism of the CPA-induced oocyte death in ovarian reserve remains unclear. Experimental design: This study aims to investigate the mechanism of oocyte death in primordial follicles by generating oocyte-specific Abl1 and p63 knockout and Pik3ca* knockin mouse models using Gdf9-iCre+. Prepubertal day 7 female mice were utilized for further analysis. Results: The quantification of surviving follicles validated that 90% of the primordial follicles from oocyte-specific Abl1 knockout mice were lost following CPA treatment in vivo and in vitro. Concurrently, high expression of CHK2 was detected in the oocytes of the ovary cultured with CPA metabolite in vitro. Most importantly, p63 knockout oocytes were rescued after CPA treatment and maintained functional fertility in the mating trials. To better understand the CPA-induced primordial follicle loss, Pik3ca* mice were examined with or without CPA administration. As expected, ovarian primordial follicles with constitutive PI3K expression inside of oocytes in the Pik3ca* mice survived against CPA. Accordingly, the apoptosis markers, BAX and cleaved PARP were highly induced with CPA injection in a time-dependent manner in the ovaries of wild-type female mice but not from the p63 knockout. The double-strand break also occurred in the nucleus of oocytes post CPA administration as γH2AX was detected. Interestingly, OPA1, a protein required for mitochondrial fusion, was highly induced inside the oocyte cytoplasm of the p63 knockout, while oocytes in wild-type mice time-dependently lost the OPA1 expression by CPA treatment. This indicates that oocytes without p63 in the nucleus survive and induce mitochondrial fusion to escape apoptosis by mitochondrial damage. Conclusion: cAbl is dispensable for primordial follicle depletion caused by CPA. However, TAp63 is the key regulator in CPA-induced apoptosis in oocytes. Furthermore, CHK2 is upregulated in the oocytes of primordial follicles post CPA exposure. Activated follicles resist gonadotoxic agents, even though p63 is expressed inside their oocytes. Therefore, CPA induces depletion of oocytes in primordial follicles through the CHK2-TAp63 apoptotic pathway.https://digitalcommons.unmc.edu/chri_forum/1054/thumbnail.jp

Early Virological and Immunological Events in Asymptomatic Epstein-Barr Virus Infection in African Children

Epstein-Barr virus (EBV) infection often occurs in early childhood and is asymptomatic. However, if delayed until adolescence, primary infection may manifest as acute infectious mononucleosis (AIM), a febrile illness characterised by global CD8+ T-cell lymphocytosis, much of it reflecting a huge expansion of activated EBV-specific CD8+ T-cells. While the events of AIM have been intensely studied, little is known about how these relate to asymptomatic primary infection. Here Gambian children (14–18 months old, an age at which many acquire the virus) were followed for the ensuing six months, monitoring circulating EBV loads, antibody status against virus capsid antigen (VCA) and both total and virus-specific CD8+ T-cell numbers. Many children were IgG anti-VCA-positive and, though no longer IgM-positive, still retained high virus loads comparable to AIM patients and had detectable EBV-specific T-cells, some still expressing activation markers. Virus loads and the frequency/activation status of specific T-cells decreased over time, consistent with resolution of a relatively recent primary infection. Six children with similarly high EBV loads were IgM anti-VCA-positive, indicating very recent infection. In three of these donors with HLA types allowing MHC-tetramer analysis, highly activated EBV-specific T-cells were detectable in the blood with one individual epitope response reaching 15% of all CD8+ T-cells. That response was culled and the cells lost activation markers over time, just as seen in AIM. However, unlike AIM, these events occurred without marked expansion of total CD8+ numbers. Thus asymptomatic EBV infection in children elicits a virus-specific CD8+ T-cell response that can control the infection without over-expansion; conversely, in AIM it appears the CD8 over-expansion, rather than virus load per se, is the cause of disease symptoms

More than 50 years of successful continuous temperature section measurements by the global expendable bathythermograph network, its integrability, societal benefits, and future

The first eXpendable BathyThermographs (XBTs) were deployed in the 1960s in the North Atlantic Ocean. In 1967 XBTs were deployed in operational mode to provide a continuous record of temperature profile data along repeated transects, now known as the Global XBT Network. The current network is designed to monitor ocean circulation and boundary current variability, basin-wide and trans-basin ocean heat transport, and global and regional heat content. The ability of the XBT Network to systematically map the upper ocean thermal field in multiple basins with repeated trans-basin sections at eddy-resolving scales remains unmatched today and cannot be reproduced at present by any other observing platform. Some repeated XBT transects have now been continuously occupied for more than 30 years, providing an unprecedented long-term climate record of temperature, and geostrophic velocity profiles that are used to understand variability in ocean heat content (OHC), sea level change, and meridional ocean heat transport. Here, we present key scientific advances in understanding the changing ocean and climate system supported by XBT observations. Improvement in XBT data quality and its impact on computations, particularly of OHC, are presented. Technology development for probes, launchers, and transmission techniques are also discussed. Finally, we offer new perspectives for the future of the Global XBT Network

Circuit-wide Transcriptional Profiling Reveals Brain Region-Specific Gene Networks Regulating Depression Susceptibility

Depression is a complex, heterogeneous disorder and a leading contributor to the global burden of disease. Most previous research has focused on individual brain regions and genes contributing to depression. However, emerging evidence in humans and animal models suggests that dysregulated circuit function and gene expression across multiple brain regions drive depressive phenotypes. Here we performed RNA-sequencing on 4 brain regions from control animals and those susceptible or resilient to chronic social defeat stress at multiple time points. We employed an integrative network biology approach to identify transcriptional networks and key driver genes that regulate susceptibility to depressive-like symptoms. Further, we validated in vivo several key drivers and their associated transcriptional networks that regulate depression susceptibility and confirmed their functional significance at the levels of gene transcription, synaptic regulation and behavior. Our study reveals novel transcriptional networks that control stress susceptibility and offers fundamentally new leads for antidepressant drug discovery

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment