Inhibition of de novo ceramide synthesis by sirtuin-1 improves beta-cell function and glucose metabolism in type 2 diabetes.

Aims: Obesity and type 2 diabetes (T2D) are major risk factors for cardiovascular (CV) diseases. Dysregulated pro-apoptotic ceramide synthesis reduces β-cell insulin secretion, thereby promoting hyperglycaemic states that may manifest as T2D. Pro-apoptotic ceramides modulate insulin sensitivity and glucose tolerance while being linked to poor CV outcomes.

Sphingosine-1-phosphate receptor 3 regulates the transendothelial transport of high-density lipoproteins and low-density lipoproteins in opposite ways.

Aims: The entry of lipoproteins from blood into the arterial wall is a rate-limiting step in atherosclerosis. It is controversial whether this happens by filtration or regulated transendothelial transport.Because sphingosine-1-phosphate (S1P) preserves the endothelial barrier, we investigated in vivo and in vitro, whether S1P and its cognate S1P-receptor 3 (S1P3) regulate the transendothelial transport of lipoproteins.

Treatment with recombinant Sirt1 rewires the cardiac lipidome and rescues diabetes-related metabolic cardiomyopathy.

Background: Metabolic cardiomyopathy (MCM), characterized by intramyocardial lipid accumulation, drives the progression to heart failure with preserved ejection fraction (HFpEF). Although evidence suggests that the mammalian silent information regulator 1 (Sirt1) orchestrates myocardial lipid metabolism, it is unknown whether its exogenous administration could avoid MCM onset. We investigated whether chronic treatment with recombinant Sirt1 (rSirt1) could halt MCM progression.

Chronic SIRT1 supplementation in diabetic mice improves endothelial function by suppressing oxidative stress.

Aims: Enhancing SIRT1 activity exerts beneficial cardiovascular effects. In diabetes, plasma SIRT1 levels are reduced. We aimed to investigate the therapeutic potential of chronic recombinant murine SIRT1 (rmSIRT1) supplementation to alleviate endothelial and vascular dysfunction in diabetic mice (db/db).

Pulmonary Embolism Readmission Trend Over the Years (from a National Readmission Database).

With the evolution of pulmonary embolism (PE) management, the outcomes of PE-related complications and the need for readmission have not been well studied. The aim of this study is to see the trend in readmissions in patients with PE from 2010 to 2018. We used the National Readmission Database from 2010 to 2018 to identify hospitalized patients with a principal diagnosis of acute PE.

The Youngest Case of Metachronous Bilateral Acinic Cell Carcinoma of the Parotid Gland: A Case Report and Literature Review.

Introduction: Acinic cell carcinoma (ACC) is a low-grade malignant salivary neoplasm that represents 17% of all salivary gland malignancies. It has a tendency to affect young individuals, especially females. ACC mainly originates in the parotid gland and has a potential for recurrence and metastases.

Comparison of In-Hospital Mortality and Clinical Outcomes Between Patients Aged More Than and Less Than 80 Years Undergoing Transcatheter Aortic Valve Replacement.

Background The transcatheter aortic valve replacement (TAVR) procedure has been increasingly utilized in the management of aortic stenosis among the elderly. In this study, we sought to assess the hospital outcomes and major adverse events (MAEs) associated with TAVR in patients aged ≥80 years compared to those aged <80 years. Methodology We performed a retrospective observational study using the National Inpatient Sample in 2018.

Association of hypocalcemia with in-hospital mortality and complications in patients with acute pulmonary embolism: results from the 2017 Nationwide Inpatient Sample.

Background: Acute pulmonary embolism (PE) is a common cause for hospitalization associated with significant mortality and morbidity. Disorders of calcium metabolism are a frequently encountered medical problem. The effect of hypocalcemia is not well defined on the outcomes of patients with PE.

Posttranscriptional Regulation of the Human LDL Receptor by the U2-Spliceosome.

Background: The LDLR (low-density lipoprotein receptor) in the liver is the major determinant of LDL-cholesterol levels in human plasma. The discovery of genes that regulate the activity of LDLR helps to identify pathomechanisms of hypercholesterolemia and novel therapeutic targets against atherosclerotic cardiovascular disease.

Methods: We performed a genome-wide RNA interference screen for genes limiting the uptake of fluorescent LDL into Huh-7 hepatocarcinoma cells.

Apolipoprotein M and Sphingosine-1-Phosphate Receptor 1 Promote the Transendothelial Transport of High-Density Lipoprotein.

Objective: ApoM enriches S1P (sphingosine-1-phosphate) within HDL (high-density lipoproteins) and facilitates the activation of the S1P1 (S1P receptor type 1) by S1P, thereby preserving endothelial barrier function. Many protective functions exerted by HDL in extravascular tissues raise the question of how S1P regulates transendothelial HDL transport. Approach and Results: HDL were isolated from plasma of wild-type mice, Apom knockout mice, human apoM transgenic mice or humans and radioiodinated to trace its binding, association, and transport by bovine or human aortic endothelial cells.

Supraclavicular Solitary Hybrid Schwannoma/Neurofibroma: A Case Report.

Peripheral nerve sheath tumors (PNSTs) are benign lesions arising from the connective tissue sheath surrounding the neurons and are labeled schwannoma, perineurioma, or neurofibroma according to their histopathological characteristics. Lesions with a mixture of two or more of the aforementioned tumors are known as hybrid peripheral nerve sheath tumors (HPNSTs). These hybrid tumors have been described as rare entities.

Translation of the intrinsically disordered protein α-synuclein is inhibited by a small molecule targeting its structured mRNA.

Many proteins are refractory to targeting because they lack small-molecule binding pockets. An alternative to drugging these proteins directly is to target the messenger (m)RNA that encodes them, thereby reducing protein levels. We describe such an approach for the difficult-to-target protein α-synuclein encoded by the gene.

Maffucci Syndrome with Clival Enchondroma in Nasopharynx: A Case Report.

Maffucci syndrome is an extremely rare sporadic disease, characterized by multiple enchondromas and associated with multiple hemangiomas and/or lymphangiomas. First case was reported in 1881, and fewer than 200 case have been reported to date. Potential sarcomatous malignant transformation have been noticed in previous cases.

The Influence of Static Factors on Seating Comfort of Motorcycles: An Initial Investigation.

Objective: The aim of the current study is to examine the influence of static factors on overall seating comfort in motorcycles and validate the use of static lab-based setups for evaluating seating comfort in motorcycles.

Background: Seating comfort in automobiles has two factors, static and dynamic. Research on seating comfort of passenger cars has shown that when the magnitude of vibration reaching the seat is low, comfort is largely determined by static factors.

Macrophage NCOR1 protects from atherosclerosis by repressing a pro-atherogenic PPARγ signature.

Aims: Nuclear receptors and their cofactors regulate key pathophysiological processes in atherosclerosis development. The transcriptional activity of these nuclear receptors is controlled by the nuclear receptor corepressors (NCOR), scaffolding proteins that form the basis of large corepressor complexes. Studies with primary macrophages demonstrated that the deletion of Ncor1 increases the expression of atherosclerotic molecules.

Identifying and validating small molecules interacting with RNA (SMIRNAs).

High throughput sequencing has revolutionized our ability to identify aberrant RNA expression and mutations that cause or contribute to disease. These data can be used directly to design oligonucleotide-based modalities using Watson-Crick pairing to target unstructured regions in an RNA. A complementary, although more difficult, strategy to deactivate a malfunctioning RNA is to target highly structured regions with small molecules.

A cross-linking approach to map small molecule-RNA binding sites in cells.

Methods to identify RNAs bound by small molecules in cells are sparse. Herein, an advance to identify the direct RNA targets of small molecules in cells is described. The approach, dubbed Chemical Cross-Linking and Isolation by Pull-down to Map Small Molecule-RNA Binding Sites (Chem-CLIP-Map-Seq), appends a cross-linker and a purification tag onto a small molecule.

A Designed Small Molecule Inhibitor of a Non-Coding RNA Sensitizes HER2 Negative Cancers to Herceptin.

A small molecule (1) with overlapping affinity for two microRNA (miRNA) precursors was used to inform design of a dimeric compound (2) selective for one of the miRNAs. In particular, 2 selectively targets the microRNA(miR)-515 hairpin precursor to inhibit production of miR-515 that represses sphingosine kinase 1 (SK1), a key enzyme in the biosynthesis of sphingosine 1-phosphate (S1P). Application of 2 to breast cancer cells enhanced SK1 and S1P levels, triggering a migratory phenotype.

A Massively Parallel Selection of Small Molecule-RNA Motif Binding Partners Informs Design of an Antiviral from Sequence.

Many RNAs cause disease; however, RNA is rarely exploited as a small-molecule drug target. Our programmatic focus is to define privileged RNA motif small-molecule interactions to enable the rational design of compounds that modulate RNA biology starting from only sequence. We completed a massive, library-versus-library screen that probed over 50 million binding events between RNA motifs and small molecules.

Negative-Ion Mode Capillary Isoelectric Focusing Mass Spectrometry for Charge-Based Separation of Acidic Oligosaccharides.

Glycosaminoglycans (GAGs) are biologically and pharmacologically important linear, anionic polysaccharides containing various repeating disaccharides sequences. The analysis of these polysaccharides generally relies on their chemical or enzymatic breakdown to disaccharide units that are separated, by chromatography or electrophoresis, and detected, by UV, fluorescence, or mass spectrometry (MS). Isoelectric focusing (IEF) is an important analytical technique with high resolving power for the separation of analytes exhibiting differences in isoelectric points.

Approved Anti-cancer Drugs Target Oncogenic Non-coding RNAs.

Potential RNA drug targets for small molecules are found throughout the human transcriptome, yet small molecules known to elicit a pharmacological response by directly targeting RNA are limited to antibacterials. Herein, we describe AbsorbArray, a small molecule microarray-based approach that allows for unmodified compounds, including FDA-approved drugs, to be probed for binding to RNA motif libraries in a massively parallel format. Several drug classes bind RNA including kinase and topoisomerase inhibitors.

Scavenger receptor BI promotes cytoplasmic accumulation of lipoproteins in clear-cell renal cell carcinoma.

Clear-cell renal cell carcinomas (ccRCCs) are characterized by inactivation of the von Hippel-Lindau (VHL) gene and intracellular lipid accumulation by unknown pathomechanisms. The immunochemical analysis of 356 RCCs revealed high abundance of apoA-I and apoB, as well as scavenger receptor BI (SR-BI) in the ccRCC subtype. Given the characteristic loss of VHL function in ccRCC, we used VHL-defective and VHL-proficient cells to study the potential influence of VHL on lipoprotein uptake.

Endocytosis of lipoproteins.

During their metabolism, all lipoproteins undergo endocytosis, either to be degraded intracellularly, for example in hepatocytes or macrophages, or to be re-secreted, for example in the course of transcytosis by endothelial cells. Moreover, there are several examples of internalized lipoproteins sequestered intracellularly, possibly to exert intracellular functions, for example the cytolysis of trypanosoma. Endocytosis and the subsequent intracellular itinerary of lipoproteins hence are key areas for understanding the regulation of plasma lipid levels as well as the biological functions of lipoproteins.

Small Molecule Targeted Recruitment of a Nuclease to RNA.

The choreography between RNA synthesis and degradation is a key determinant in biology. Engineered systems such as CRISPR have been developed to rid a cell of RNAs. Here, we show that a small molecule can recruit a nuclease to a specific transcript, triggering its destruction.