Two unusual cases of Gitelman's syndrome with a complex inheritance: how the phenotype can help interpret the genotype: lesson for the clinical nephrologist

Bartter\u2019s syndrome (BS) and Gitelman\u2019s syndrome (GS) are autosomal recessive disorders with overlapping features, caused by biallelic variants in six genes encoding proteins involved in renal electrolyte homeostasis in different districts of the nephron. Here we describe two patients with a clinical diagnosis of GS with a complex inheritance whose clinical interpretation and treatment proved challenging. In one patient, compound heterozygosity for two known pathogenic variant in the SLC12A3 gene was associated with an uncommon variant in the KCNJ1 gene (one of the known BS genes). The unusual severity of GS phenotype encountered in this patient led us to hypothesize that the missense variant can act as a genetic modifier by exacerbating the severity of the disease and by inducing BS-like clinical manifestations. In the other patient, two novel likely pathogenic variants in the SLC12A3 gene were coupled with a hitherto unreported rare variant in the SLC4A1 gene; the latter\u2019s disease-causing variants have been associated with both dominant and recessive forms of distal renal tubular acidosis (dRTA). Patient\u2019s medical history (he was clinically diagnosed with incomplete hypokalemic dRTA at 10 years old) supports the hypothesis of a dual molecular diagnosis and hence of a blended phenotype

Maturation signatures of conventional dendritic cell subtypes in COVID‐19 suggest direct viral sensing

Growing evidence suggests that conventional dendritic cells (cDCs) undergo aberrant maturation in COVID-19, which negatively affects T-cell activation. The presence of effector T cells in patients with mild disease and dysfunctional T cells in severely ill patients suggests that adequate T-cell responses limit disease severity. Understanding how cDCs cope with SARS-CoV-2 can help elucidate how protective immune responses are generated. Here, we report that cDC2 subtypes exhibit similar infection-induced gene signatures, with the upregulation of interferon-stimulated genes and interleukin (IL)-6 signaling pathways. Furthermore, comparison of cDCs between patients with severe and mild disease showed severely ill patients to exhibit profound downregulation of genes encoding molecules involved in antigen presentation, such as MHCII, TAP, and costimulatory proteins, whereas we observed the opposite for proinflammatory molecules, such as complement and coagulation factors. Thus, as disease severity increases, cDC2s exhibit enhanced inflammatory properties and lose antigen presentation capacity. Moreover, DC3s showed upregulation of anti-apoptotic genes and accumulated during infection. Direct exposure of cDC2s to the virus in vitro recapitulated the activation profile observed in vivo. Our findings suggest that SARS-CoV-2 interacts directly with cDC2s and implements an efficient immune escape mechanism that correlates with disease severity by downregulating crucial molecules required for T-cell activation

Genotype-phenotype correlation in Gordon's syndrome: report of two cases carrying novel heterozygous mutations

Gordon's syndrome, known also as Pseudohypoaldosteronism type II is a rare inherited dominant form of low-renin hypertension associated with hyperkalemia and metabolic acidosis. Four genes related to the regulation of the NaCl co-symporter NCC have been discovered associated to Gordon phenotypes: WINK 1 and WINK4, which, along with WNK2 and WNK3, encode a family of WNK-kinases, and KLHL3 and CUL3 encoding respectively, Kelch-like 3 protein and cullin. Heterozygous mutations in these genes constitutively activate NCC leading to abnormally increased salt reabsorption and salt-sensitive hypertension. Thiazide diuretic is the recognized treatment for this condition. We report and discuss phenotypic and genetic heterogeneity of two patients with Gordon's syndrome carrying novel heterozygous mutations in the WNK1 and KLHL3 genes. A very rare variant in the SCNN1G gene encoding the gamma subunit of epithelial sodium channel ENaC was also identified in one patient

A Label-Free Proteomic Approach for the Identification of Biomarkers in the Exosome of Endometrial Cancer Serum

Endometrial cancers (ECs) are mostly adenocarcinomas arising from the inner part of the uterus. The identification of serum biomarkers, either soluble or carried in the exosome, may be useful in making an early diagnosis. We used label-free quantification mass spectrometry (LFQ-MS)-based proteomics to investigate the proteome of exosomes in the albumin-depleted serum from 12 patients with EC, as compared to 12 healthy controls. After quantification and statistical analysis, we found significant changes in the abundance (p < 0.05) of 33 proteins in EC vs. control samples, with a fold change of ≥1.5 or ≤0.6. Validation using Western blotting analysis in 36 patients with EC as compared to 36 healthy individuals confirmed the upregulation of APOA1, HBB, CA1, HBD, LPA, SAA4, PF4V1, and APOE. A multivariate logistic regression model based on the abundance of these proteins was able to separate the controls from the EC patients with excellent sensitivity levels, particularly for stage 1 ECs. The results show that using LFQ-MS to explore the specific proteome of serum exosomes allows for the identification of biomarkers in EC. These observations suggest that PF4V1, CA1, HBD, and APOE represent biomarkers that are able to reach the clinical stage, after a validation phase

Previsione della fauna ittica mediante reti neurali artificiali.

Predicting the structure of fish assemblages in rivers is a very interesting goal in ecological research, both from a purely theoretical point of view and from an applied one, for instance when river management strategies are to be defined or when the implementation of the Directive 2000/60/EC is taken into account. Models for estimating the abundance or the probability of presence of fish species have been developed using different approaches. Although some conventional statistical tools provided interesting results, the application of artificial neural networks has recently outperformed those techniques in terms of accuracy and ease of development. Artificial neural networks are especially effective in reproducing the complex, non-linear relationships that link fish species to environmental variables. Recent developments of the artificial neural network training procedures, specifically aimed at solving ecological problems, allowed to optimize the prediction of species assemblages. The improvement in prediction involves not only the accuracy of the models, but also their ecological consistency. Some results about models for fish assemblages in the rivers of the Veneto region (Northern Italy) are presented and their potential applications are discussed

Ultrathin InAlN/GaN heterostructures on sapphire for high on/off current ratio high electron mobility transistors

We report on InAlN/GaN high electron mobility transistors (HEMTs) grown by metal organic vapor phase epitaxy on sapphire with ultrathin buffers. Two dimensional electron gas (2DEG) exhibiting high mobility (1100 cm(2) /V s) and low sheet resistivity (356 Omega/square) is achieved at room temperature for a buffer thickness as low as similar to 0.1 mu m. It is shown that despite a huge dislocation density imposed by this thin buffer, surface roughness is the main factor which affects the transport properties. In addition, sapphire surface nitridation is found to drastically affect the properties of the InAlN/GaN 2DEG. Eventually, HEMTs are processed from these heterostructures. Maximum current densities of 0.35 A/mm and current on-off ratios higher than 10(9) are measured, which make them suitable for high performance GaN based sensing in harsh environments. (C) 2013 AIP Publishing LLC

Defective excitation-contraction coupling and mitochondrial respiration precede mitochondrial Ca2+ accumulation in spinobulbar muscular atrophy skeletal muscle

: Polyglutamine expansion in the androgen receptor (AR) causes spinobulbar muscular atrophy (SBMA). Skeletal muscle is a primary site of toxicity; however, the current understanding of the early pathological processes that occur and how they unfold during disease progression remains limited. Using transgenic and knock-in mice and patient-derived muscle biopsies, we show that SBMA mice in the presymptomatic stage develop a respiratory defect matching defective expression of genes involved in excitation-contraction coupling (ECC), altered contraction dynamics, and increased fatigue. These processes are followed by stimulus-dependent accumulation of calcium into mitochondria and structural disorganization of the muscle triads. Deregulation of expression of ECC genes is concomitant with sexual maturity and androgen raise in the serum. Consistent with the androgen-dependent nature of these alterations, surgical castration and AR silencing alleviate the early and late pathological processes. These observations show that ECC deregulation and defective mitochondrial respiration are early but reversible events followed by altered muscle force, calcium dyshomeostasis, and dismantling of triad structure