Inhibitors of the Cdc34 acidic loop:a computational investigation integrating molecular dynamics, virtual screening and docking approaches

AbstractAmong the different classes of enzymes involved in the ubiquitin pathway, E2 ubiquitin-conjugating enzymes occupy a central role in the ubiquitination cascade. Cdc34-like E2 enzymes are characterized by a 12–14 residue insertion in the proximity of the catalytic site, known as the acidic loop. Cdc34 ubiquitin-charging activity is regulated by CK2-dependent phosphorylation and the regulatory mechanism involves the acidic loop. Indeed, the phosphorylation stabilizes the loop in an open conformation that is competent for ubiquitin charging.Cdc34 is associated with a variety of diseases, such as hepatocellular carcinomas and prostatic adenocarcinomas. In light of its role, the discovery of potential inhibitory compounds would provide the mean to effectively modulate its activity.Here, we carried out a computational study based on molecular dynamics, virtual screening and docking to identify potential inhibitory compounds of Cdc34, modulating the acidic loop conformation. The molecules identified in this study have been designed to act as molecular hinges that can bind the acidic loop in its closed conformation, thus inhibiting the Cdc34-mediated ubiquitination cascade at the ubiquitin-charging step. In particular, we proposed a pharmacophore model featuring two amino groups in the central part of the model and two lateral aromatic chains, which respectively establish electrostatic interactions with the acidic loop (Asp 108 and Glu 109) and a hydrogen bond with Ser 139, which is one of the key residues for Cdc34 activity

Severe FMF Presentation with Rare Association of MEFV Variants (p.Pro369Ser/p.Glu148Gln)

We report the case of a 28-year-old man who presented with recurring episodes of high fever, pleural and pericardial effusions and bilateral hydrocele. He was diagnosed with familial Mediterranean fever (FMF) and responded well to colchicine therapy. Genetic testing showed variants of the MEFV gene (p.Pro369Ser and p.Glu148Gln) previously independently described as having a more benign course of the disease. Their association is very rarely reported. Our patient and our review of the literature suggest that these genetic variants are associated with indolent courses but might also trigger the classic symptoms seen in severe FMF, probably in a compound heterozygous fashion. The combination of these variants should be taken into consideration in the diagnosis and management of patients

LTE Adaptation for Mobile Broadband Satellite Networks

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Fatal Septic Shock Associated with Herpes Simplex Virus Hepatitis: A Case Report

Herpes simplex viruses are endemic worldwide, with an estimated seroprevalence of approximately 70% in developed countries. However, it is less well known that they are one of the viral causes of fulminant hepatitis (<2%) and constitute <1% of all causes of acute liver failure. We describe the case of an 89-year-old man who developed sepsis caused by a urinary tract infection due to drug-sensitive Escherichia coli. After empirical treatment with piperacillin-tazobactam was initiated, the patient’s condition worsened with shock, acute liver and renal failure, encephalopathy and persistent fever, that led to admission to the intensive care unit. The emergence of an acute abdomen prompted exploratory laparotomy but the patient died soon after surgery from abdominal haemorrhage. Immunohistochemical analysis of a liver biopsy specimen identified herpes simplex virus (HSV) hepatitis. The authors emphasize the need for better understanding of this rare condition in order to more precisely identify patients at risk who need more aggressive evaluation and empirical treatment, especially patients presenting with marked hepatic cytolysis with a rapidly worsening clinical evolution

Genetic characterisation of PPARG, CEBPA and RXRA, and their influence on meat quality traits in cattle

Background: Peroxisome proliferator-activated receptor gamma (PPARG), CCAAT/enhancer binding protein alpha (CEBPA) and retinoid X receptor alpha (RXRA) are nuclear transcription factors that play important roles in regulation of adipogenesis and fat deposition. The objectives of this study were to characterise the variability of these three candidate genes in a mixed sample panel composed of several cattle breeds with different meat quality, validate single nucleotide polymorphisms (SNPs) in a local crossbred population (Angus - Hereford - Limousin) and evaluate their effects on meat quality traits (backfat thickness, intramuscular fat content and fatty acid composition), supporting the association tests with bioinformatic predictive studies. Results: Globally, nine SNPs were detected in the PPARG and CEBPA genes within our mixed panel, including a novel SNP in the latter. Three of these nine, along with seven other SNPs selected from the Single Nucleotide Polymorphism database (SNPdb), including SNPs in the RXRA gene, were validated in the crossbred population (N = 260). After validation, five of these SNPs were evaluated for genotype effects on fatty acid content and composition. Significant effects were observed on backfat thickness and different fatty acid contents (P < 0.05). Some of these SNPs caused slight differences in mRNA structure stability and/or putative binding sites for proteins. Conclusions: PPARG and CEBPA showed low to moderate variability in our sample panel. Variations in these genes, along with RXRA, may explain part of the genetic variation in fat content and composition. Our results may contribute to knowledge about genetic variation in meat quality traits in cattle and should be evaluated in larger independent populations.Instituto de Genética Veterinari

Characterization of the bovine gene LIPE and possible influence on fatty acid composition of meat

LIPE is an intracellular neutral lipase, which is capable of hydrolyzing a variety of esters and plays a key role in the mobilization of fatty acids from diacylglycerols. The objectives of this study were to characterize the genetic polymorphism of bovine LIPE gene and to evaluate the possible association between three SNPs in the coding regions of this gene with the fatty acid composition of meat in a cattle population. Forty-three unrelated animals from different cattle breeds were re-sequenced and 21 SNPs were detected over approximately 2600. bp, five of these SNPs were novel. Three SNPs were selected, on the basis of evolutionary conservation, to perform validation and association studies in a crossbred cattle population. Our results may suggest a possible association of SNP1 with contents of oleic acid and total monounsaturated fatty acids (p < 0.01), and SNP2 and SNP3 with Heneicosylic acid content (p < 0.01), may be helpful to improve the quality of meat and improve health.Instituto de Genética Veterinari

Precocidad sexual de corderas Texel, Corriedate, Highlander y Poll Dorset en el Sudeste de Buenos Aires

La provincia de Buenos Aires posee el 17% del total de ovinos de la Argentina. La mayoría de las majadas están constituidas por razas de doble propósito (carne y lana) y se crían predominantemente en forma extensiva sobre campo natural. Tradicionalmente, el primer servicio se realiza en el segundo otoño de vida de las borregas, cuando tienen 18-20 meses de edad. Sin embargo, en la actualidad existen razas que permiten adelantar el primer servicio al primer otoño de vida, cuando las corderas tienen 7-9 meses de vida. El objetivo del presente trabajo fue comparar el desempeño reproductivo de 4 razas ovinas servidas a los 8-9 meses de edad para evaluar su precocidad sexualEEA BalcarceFil: Gual, Ignacio. Universidad Nacional de mar del Plata. Facultad de Ciencias Agrarias; ArgentinaFil: Hozbor Federico A. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Balcarce; ArgentinaFil: Papaleo Mazzucco, Juliana. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Balcarce; ArgentinaFil: Jaimes, Florencia. Universidad Nacional de Mar del Plata. Facultad de Ciencias Agrarias; ArgentinaFil: Dininno, José Sergio. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Balcarce; ArgentinaFil: Nieto, Carlos Alberto. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Balcarce; ArgentinaFil: Burges, Julio Cesar. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Balcarce; Argentin

Radiomics and artificial intelligence in prostate cancer: new tools for molecular hybrid imaging and theragnostics

In prostate cancer (PCa), the use of new radiopharmaceuticals has improved the accuracy of diagnosis and staging, refined surveillance strategies, and introduced specific and personalized radioreceptor therapies. Nuclear medicine, therefore, holds great promise for improving the quality of life of PCa patients, through managing and processing a vast amount of molecular imaging data and beyond, using a multi-omics approach and improving patients' risk-stratification for tailored medicine. Artificial intelligence (AI) and radiomics may allow clinicians to improve the overall efficiency and accuracy of using these "big data" in both the diagnostic and theragnostic field: from technical aspects (such as semi-automatization of tumor segmentation, image reconstruction, and interpretation) to clinical outcomes, improving a deeper understanding of the molecular environment of PCa, refining personalized treatment strategies, and increasing the ability to predict the outcome. This systematic review aims to describe the current literature on AI and radiomics applied to molecular imaging of prostate cancer

Characterization of the bovine gene LIPE and possible influence on fatty acid composition of meat

LIPE is an intracellular neutral lipase, which is capable of hydrolyzing a variety of esters and plays a key role in the mobilization of fatty acids from diacylglycerols. The objectives of this study were to characterize the genetic polymorphism of bovine LIPE gene and to evaluate the possible association between three SNPs in the coding regions of this gene with the fatty acid composition of meat in a cattle population. Forty-three unrelated animals from different cattle breeds were re-sequenced and 21 SNPs were detected over approximately 2600. bp, five of these SNPs were novel. Three SNPs were selected, on the basis of evolutionary conservation, to perform validation and association studies in a crossbred cattle population. Our results may suggest a possible association of SNP1 with contents of oleic acid and total monounsaturated fatty acids (p < 0.01), and SNP2 and SNP3 with Heneicosylic acid content (p < 0.01), may be helpful to improve the quality of meat and improve health.Instituto de Genética Veterinari

NEMO-SN1 Abyssal Cabled Observatory in the Western Ionian Sea

The NEutrinoMediterranean Observatory—Submarine Network 1 (NEMO-SN1) seafloor observatory is located in the central Mediterranean Sea, Western Ionian Sea, off Eastern Sicily (Southern Italy) at 2100-m water depth, 25 km from the harbor of the city of Catania. It is a prototype of a cabled deep-sea multiparameter observatory and the first one operating with real-time data transmission in Europe since 2005. NEMO-SN1 is also the first-established node of the European Multidisciplinary Seafloor Observatory (EMSO), one of the incoming European large-scale research infrastructures included in the Roadmap of the European Strategy Forum on Research Infrastructures (ESFRI) since 2006. EMSO will specifically address long-term monitoring of environmental processes related to marine ecosystems, marine mammals, climate change, and geohazards