Notes

Practical heterogeneity regarding POMC neurons relies upon mTORC1 signaling.
Childhood trauma (CT) is known to be a vulnerability factor for schizophrenia, but the specific impact of different trauma subtypes on the prognosis of these patients remains unclear.

To assess the relationship between the occurrence of overall CT and its subtypes with factors of known prognostic impact to schizophrenia, such as age of symptoms onset, global functioning and cognitive impairment in a sample of Brazilian patients.

A hundred and five stable patients diagnosed with schizophrenia, in accordance with DSM-5 criteria, were evaluated using the ILSS scale (self-report global functioning), SCoRS (subjective cognitive impairment), and CTQ (perceived overall CT, Emotional Neglect, Physical Neglect, Physical Abuse, Emotional and Sexual Abuse). SB431542 Statistical analysis through multivariable linear regression was performed.

After controlling for educational level and age, subjective cognitive impairment was directly correlated with perceived overall CT occurrence, Emotional Abuse and Sexual Abuse. Self-report global functioning was inversely correlated with perceived overall CT occurrence, Emotional Abuse and Sexual Abuse. Emotional Abuse and Physical Abuse was also inversely correlated with the age of symptoms onset.

CT can be related to more severe prognostic in schizophrenia, impacting on the early onset of symptoms, less global functioning and greater cognitive impairment. Subtypes of trauma can be associated with different prognostic risks.
CT can be related to more severe prognostic in schizophrenia, impacting on the early onset of symptoms, less global functioning and greater cognitive impairment. Subtypes of trauma can be associated with different prognostic risks.
Sphingosine-1-phosphate (S1P) is a signalling lipid involved in embryonic development, physiological homeostasis, and pathogenic processes in multiple organ systems. Disturbance of S1P homeostasis has been associated with various human diseases in which the immune response and vascular integrity are severely compromised. Up-to-date, no study has analyzed S1P levels in neonates. link2 The objective of this study was to determine S1P serum concentrations in neonates and establish S1P reference ranges.

S1P levels in the umbilical cord blood of 460 term and preterm neonates were compared to a previously described cohort of healthy adult blood donors. S1P levels were further correlated with demographic characteristics, cellular sources of S1P, and inflammatory markers.

The median S1P serum level in neonates was 1.70μmol/L (IQR 1.41-1.97μmol/L) and significantly higher than normal values reported in adults. S1P levels correlated positively with the number of red blood cells (p<0.001) and negatively with neutrophil precursors (p=0.028).

Elevated S1P levels in neonates compared to adults possibly result from higher S1P content in its cellular sources due to the essential role of S1P during embryogenesis. link3 Generated S1P ranges may be used as reference ranges for future studies in neonates.
Elevated S1P levels in neonates compared to adults possibly result from higher S1P content in its cellular sources due to the essential role of S1P during embryogenesis. Generated S1P ranges may be used as reference ranges for future studies in neonates.Mtr4 is a Ski2-like RNA helicase that plays a central role in RNA surveillance and degradation pathways as an activator of the RNA exosome. Multiple crystallographic and cryo-EM studies over the past 10 years have revealed important insight into the Mtr4 structure and interactions with protein and nucleic acid binding partners. These structures place Mtr4 at the center of a dynamic process that recruits RNA substrates and presents them to the exosome. In this review, we summarize the available Mtr4 structures and highlight gaps in our current understanding.RNA helicases are enzymes that exist in all domains of life whose canonical functions include ATP-dependent remodeling of RNA structures and displacement of proteins from ribonucleoprotein complexes (RNPs). These enzymes play roles in virtually all processes of RNA metabolism, including pre-mRNA splicing, rRNA processing, nuclear mRNA export, translation and RNA decay. Here we review emerging noncanonical substrates of RNA helicases including RNA-DNA hybrids (R-loops) and RNA and DNA G-quadruplexes and discuss their biological significance.DHX36 is a eukaryotic DEAH/RHA family helicase that disrupts G-quadruplex structures (G4s) with high specificity, contributing to regulatory roles of G4s. Here we used a DHX36 truncation to examine the roles of the 13-amino acid DHX36-specific motif (DSM) in DNA G4 recognition and disruption. We found that the DSM promotes G4 recognition and specificity by increasing the G4 binding rate of DHX36 without affecting the dissociation rate. Further, for most of the G4s measured, the DSM has little or no effect on the G4 disruption step by DHX36, implying that contacts with the G4 are maintained through the transition state for G4 disruption. This result suggests that partial disruption of the G4 from the 3' end is sufficient to reach the overall transition state for G4 disruption, while the DSM remains unperturbed at the 5' end. Interestingly, the DSM does not contribute to G4 binding kinetics or thermodynamics at low temperature, indicating a highly modular function. Together, our results animate recent DHX36 crystal structures, suggesting a model in which the DSM recruits G4s in a modular and flexible manner by contacting the 5' face early in binding, prior to rate-limiting capture and disruption of the G4 by the helicase core.RNA helicases of the DEAH/RHA family form a large and conserved class of enzymes that remodel RNA protein complexes (RNPs) by translocating along the RNA. Driven by ATP hydrolysis, they exert force to dissociate hybridized RNAs, dislocate bound proteins or unwind secondary structure elements in RNAs. The sub-cellular localization of DEAH-helicases and their concomitant association with different pathways in RNA metabolism, such as pre-mRNA splicing or ribosome biogenesis, can be guided by cofactor proteins that specifically recruit and simultaneously activate them. Here we review the mode of action of a large class of DEAH-specific adaptor proteins of the G-patch family. Defined only by their eponymous short glycine-rich motif, which is sufficient for helicase binding and stimulation, this family encompasses an immensely varied array of domain compositions and is linked to an equally diverse set of functions. G-patch proteins are conserved throughout eukaryotes and are even encoded within retroviruses. They are involved in mRNA, rRNA and snoRNA maturation, telomere maintenance and the innate immune response. Only recently was the structural and mechanistic basis for their helicase enhancing activity determined. We summarize the molecular and functional details of G-patch-mediated helicase regulation in their associated pathways and their involvement in human diseases.
Transforming growth factor-β (TGF-β) pathway presents dysregulation in pathological scarring and mediates hypertrophic scar (HS) formation.

The study aims to analyze the potential mechanism of long non-coding RNA NORAD (LncRNA NORAD) and microRNA (miR-26a) regulation of the TGF-β pathway in hypertrophic scar fibroblasts (HSFs).

Hypertrophic scar tissues were collected and assayed for LncRNA NORAD, miR-26a, transforming growth factor β receptor I (TGF-βR1) and TGF-βR2, with enzyme-linked immunosorbent assay (ELISA) or qualitative polymerase chain reaction (qPCR). LncRNA NORAD interfering plasmids were transfected into HSFs and induced with TGF-β1. Cell Counting Kit-8 (CCK-8) assays were performed to assess HSF proliferation, and flow cytometry to analyze apoptosis and the cell cycle. TGF-βR1, TGF-βR2, Smad2, and p-Smad2 levels were detected using western blot (WB). The related proteins (p21, cyclin D1 and cyclin-dependent kinase 4 (CDK4)) regulating the cell cycle, and apoptosis-related proteins (caspaseLncRNA NORAD regulates HSF proliferation via miR-26a mediating the regulation of TGF-βR2/R1. LncRNA NORAD/miR-26a could be a potential target for treating HS.
LncRNA NORAD regulates HSF proliferation via miR-26a mediating the regulation of TGF-βR2/R1. LncRNA NORAD/miR-26a could be a potential target for treating HS.Metastatic breast cancer is one of the deadliest forms of malignancy, primarily driven by its characteristic micro-environment comprising cancer cells interacting with stromal components. These interactions induce genetic and metabolic alterations creating a conducive environment for tumor growth. In this study, a physiologically relevant 3D vascularized breast cancer micro-environment is developed comprising of metastatic MDA-MB-231 cells and human umbilical vein endothelial cells loaded in human dermal fibroblasts laden fibrin, representing the tumor stroma. The matrix, as well as stromal cell density, impacts the transcriptional profile of genes involved in tumor angiogenesis and cancer invasion, which are hallmarks of cancer. Cancer-specific canonical pathways and activated upstream regulators are also identified by the differential gene expression signatures of these composite cultures. Additionally, a tumor-associated vascular bed of capillaries is established exhibiting dilated vessel diameters, representative of in vivo tumor physiology. Further, employing aspiration-assisted bioprinting, cancer-endothelial crosstalk, in the form of collective angiogenesis of tumor spheroids bioprinted at close proximity, is identified. Overall, this bottom-up approach of tumor micro-environment fabrication provides an insight into the potential of in vitro tumor models and enables the identification of novel therapeutic targets as a preclinical drug screening platform.
To investigate the impact of transcatheter heart valve (THV) sizing on procedural results and clinical outcomes following transcatheter aortic valve implantation (TAVI).

The impact of individual THV sizing for patients with borderline aortic annulus anatomy remains unclear.

In the prospective BernTAVI registry, THV sizing conditions were retrospectively evaluated, and patients were categorized into three groups based on the recommendations and the sizing chart of the manufacturers optimal sizing, borderline sizing (THV size located within 5% to each border of the optimal sizing recommendation), and suboptimal sizing (THV size outside the recommended range). The latter two groups were further subcategorized into THV-oversizing and THV-undersizing. The primary endpoint was a composite of all-cause death and unplanned repeat intervention at 1 year.

Out of a total of 1,638 patients who underwent TAVI, 9.5 and 15.6% of patients were categorized into the borderline and suboptimal sizing group, respectively. Device success was achieved in 87.4, 88.9, and 83.6% of patients with optimal, borderline, and suboptimal sizing, respectively. The primary endpoint occurred in 12.3% of patients with optimal sizing, 14.9% of patients with borderline sizing (HR
1.35, 95%CI 0.87-2.09), and in 17.4% of patients with suboptimal sizing (HR
1.42, 95%CI 1.01-1.99). Within the suboptimal sizing cohort, unfavorable outcomes were mainly associated with THV undersizing (device success 76.4%, primary endpoint 23.9%, HR
1.98, 95%CI 1.36-2.87).

Suboptimal TAVI prosthesis sizing is associated with an increased risk of all-cause death and unplanned repeat intervention within 1 year largely attributable to undersized THV prostheses.
Suboptimal TAVI prosthesis sizing is associated with an increased risk of all-cause death and unplanned repeat intervention within 1 year largely attributable to undersized THV prostheses.
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