Evaluation of Mineralocorticoid Receptor Antagonism on Changes in NT-proBNP Among Persons With HIV

Subclinical myocardial dysfunction is prevalent among well-treated persons with HIV (PWH). We have previously demonstrated unique renin-angiotensin-aldosterone system physiology among PWH with metabolic dysregulation. Mineralocorticoid receptor blockade may be a targeted treatment strategy for subclinical heart disease in PWH. Forty-six PWH were randomized to receive either eplerenone 50 mg daily or placebo in a 6-month randomized, double-blinded, placebo-controlled trial. We assessed changes in N-terminal pro-B-type natriuretic peptide (NT-proBNP), a biomarker of cardiac stretch, under controlled posture and dietary conditions. The eplerenone- and placebo-treated groups demonstrated a long duration of HIV with good immunological control. NT-proBNP levels were similar between the groups at baseline (41.1 [20.2, 97.9] vs 48.9 [29.2, 65.4] ng/L, P = .80) and decreased significantly more in the eplerenone- vs placebo-treated groups after 6 months (change NT-proBNP -9.6 [-46.8, 0.3] vs -3.0 [-17.0, 39.9] ng/L, P = .02 for comparison of change between groups). Decreases in NT-proBNP were independent of changes in systolic and diastolic blood pressure, and related to decreases in high-sensitivity C-reactive protein (ρ = 0.32, P = .05) and inversely to increases in serum aldosterone (ρ = -0.33, P = .04) among all participants. Treatment with eplerenone for 6 months vs placebo significantly decreases NT-proBNP levels among PWH, independent of eplerenone’s known blood pressure-lowering effects. Further studies should elucidate whether lowering NT-proBNP in this at-risk metabolic population with subclinical heart disease will offer cardioprotection. Clinical Trial Registration NCT01405456

Perception about Teaching and Learning Methodologies Applied in Physiology: A study on Medical Students of Pakistan

Background: The study of physiology is an essential part of the medical school curriculum. Medical teachers have identified the preference for a specific mode of content delivery to communicate knowledge to students in a rational, strategic, coherent, and sequential manner. In comparison to the focus on systems-based didactic lectures, more emphasis is now put on the developing critical thinking skills. Physiology is widely acknowledged as a difficult subject for medical students to grasp, incorporate, and apply in clinical sciences. Aim: To learn about students’ perceptions of teaching, learning, and assessment approaches used in the physiology. Method A quantitative cross-sectional survey was conducted online on 533 medical students from first to final year and also post grate students. After the approval of Ethical review committee, a questionnaire to determine the various aspects of Physiology as a subject being taught. The survey was conducted online via “Google forms''. Participants answered anonymously with informed consent, and the survey was conducted for a period of two months. Data was analyzed using SPSS version 23. Results: A total number of 533 students participated in this research and responding to Physiology learning and teaching. When students were asked about that which subject is most interesting in first Year MBBS, majority of the students that is 46.2% of the responses claimed that Physiology is the most interesting subject. 33.6% students were from 1st Year. 9.2% students were Postgraduates. 63.4% of the students preferred studying physiology from Guyton and Hall as reference book for Physiology. Majority of students that is 25.5% of the students found Blood Physiology to be the most interesting. Whereas 19.8% found Heart or Cardio Vascular System Physiology as the most interesting subject.15.6% found cell and nerve muscle as an interesting topic in Physiology.9.6% found Endocrinology and reproduction physiology as interesting as compared to 7.7% who found central Nervous system Physiology interesting. 43.9% of the students responded that they perfeer face to face interactive lectures.23.3% of the students perfered small group discussion.10.9% students prefered learing by tutorilas.Interestingly, 20.4% of the participants replied that they would definitely pursue physiology as their career. Conclusion: Physiology is the most interesting subject preferred by majority of students. Keywords: Perception, learning methodologies, medical students

NR0B2 regulation during Primary Sclerosing Cholangitis defines a metabolic and pre-malignant reprogramming of Cholangiocyte

SUMMARYPrimary Sclerosing Cholangitis (PSC) is an idiopathic, cholestatic liver disease that is characterized by persistent, progressive, biliary inflammation leading to cirrhosis. These patients present higher risk for developing bile duct cancers.Biomedical text-mining related to PSC symptoms like: biliary inflammation, biliary fibrosis, biliary cholestasis was initiated to collect gene associations with this pathophysiology. The text mining work was integrated in distinct omics data such as human transcriptome of PSC liver, Farnesoid X receptor (FXR) functional liver transcriptome and liver single cell transcriptome of the Abcb4-/- model of PSC. A molecular network implicated in abnormal hepatobiliary system physiology was built and confirming a major implication of Nr0b2 and its associated nuclear receptors like FXR in a metabolic cascade that could influence immune response. TNFRSF12A/TWEAK receptor, was found up regulated in PSC liver independently of FXR regulation and TWEAK signaling is known for its implication in pre-conditioning niche of cholangiocarcinoma. NR0B2 deregulation in PSC liver was found independent of gender, age and body mass index surrogates. At single cell level, Nr0b2 up regulation was found in cholangiocytes but not in hepatocytes. In affected cholangiocytes, the cell trajectory built on Nr0b2 expression, revealed implication of several metabolic pathways for detoxification like sulfur, glutathione derivative and monocarboxylic acid metabolisms. On this cell trajectory it was discovered some molecules potentially implicated in carcinogenesis like: GSTA3, ID2 and mainly TMEM45A a transmembrane molecule from golgi apparatus considered as oncogene in several cancers. All together, these observations found in humanPSC liver and in its murine models allowed to highlight an independent deregulation of NR0B2 with a metabolic and premalignant reprogramming of cholangiocytes.

Tuning the Reduction of Graphene Oxide Nanoflakes Differently Affects Neuronal Networks in the Zebrafish

The increasing engineering of biomedical devices and the design of drug-delivery platforms enriched by graphene-based components demand careful investigations of the impact of graphene-related materials (GRMs) on the nervous system. In addition, the enhanced diffusion of GRM-based products and technologies that might favor the dispersion in the environment of GRMs nanoparticles urgently requires the potential neurotoxicity of these compounds to be addressed. One of the challenges in providing definite evidence supporting the harmful or safe use of GRMs is addressing the variety of this family of materials, with GRMs differing for size and chemistry. Such a diversity impairs reaching a unique and predictive picture of the effects of GRMs on the nervous system. Here, by exploiting the thermal reduction of graphene oxide nanoflakes (GO) to generate materials with different oxygen/carbon ratios, we used a high-throughput analysis of early-stage zebrafish locomotor behavior to investigate if modifications of a specific GRM chemical property influenced how these nanomaterials affect vertebrate sensory-motor neurophysiology—exposing zebrafish to GO downregulated their swimming performance. Conversely, reduced GO (rGO) treatments boosted locomotor activity. We concluded that the tuning of single GRM chemical properties is sufficient to produce differential effects on nervous system physiology, likely interfering with different signaling pathways.

KCNE4-dependent functional consequences of Kv1.3-related leukocyte physiology

The voltage-dependent potassium channel Kv1.3 plays essential roles in the immune system, participating in leukocyte activation, proliferation and apoptosis. The regulatory subunit KCNE4 acts as an ancillary peptide of Kv1.3, modulates K+ currents and controls channel abundance at the cell surface. KCNE4-dependent regulation of the oligomeric complex fine-tunes the physiological role of Kv1.3. Thus, KCNE4 is crucial for Ca2+-dependent Kv1.3-related leukocyte functions. To better understand the role of KCNE4 in the regulation of the immune system, we manipulated its expression in various leukocyte cell lines. Jurkat T lymphocytes exhibit low KCNE4 levels, whereas CY15 dendritic cells, a model of professional antigen-presenting cells, robustly express KCNE4. When the cellular KCNE4 abundance was increased in T cells, the interaction between KCNE4 and Kv1.3 affected important T cell physiological features, such as channel rearrangement in the immunological synapse, cell growth, apoptosis and activation, as indicated by decreased IL-2 production. Conversely, ablation of KCNE4 in dendritic cells augmented proliferation. Furthermore, the LPS-dependent activation of CY15 cells, which induced Kv1.3 but not KCNE4, increased the Kv1.3-KCNE4 ratio and increased the expression of free Kv1.3 without KCNE4 interaction. Our results demonstrate that KCNE4 is a pivotal regulator of the Kv1.3 channelosome, which fine-tunes immune system physiology by modulating Kv1.3-associated leukocyte functions.

Novelty of Sphingolipids in the Central Nervous System Physiology and Disease: Focusing on the Sphingolipid Hypothesis of Neuroinflammation and Neurodegeneration

For decades, lipids were confined to the field of structural biology and energetics as they were considered only structural constituents of cellular membranes and efficient sources of energy production. However, with advances in our understanding in lipidomics and improvements in the technological approaches, astounding discoveries have been made in exploring the role of lipids as signaling molecules, termed bioactive lipids. Among these bioactive lipids, sphingolipids have emerged as distinctive mediators of various cellular processes, ranging from cell growth and proliferation to cellular apoptosis, executing immune responses to regulating inflammation. Recent studies have made it clear that sphingolipids, their metabolic intermediates (ceramide, sphingosine-1-phosphate, and N-acetyl sphingosine), and enzyme systems (cyclooxygenases, sphingosine kinases, and sphingomyelinase) harbor diverse yet interconnected signaling pathways in the central nervous system (CNS), orchestrate CNS physiological processes, and participate in a plethora of neuroinflammatory and neurodegenerative disorders. Considering the unequivocal importance of sphingolipids in CNS, we review the recent discoveries detailing the major enzymes involved in sphingolipid metabolism (particularly sphingosine kinase 1), novel metabolic intermediates (N-acetyl sphingosine), and their complex interactions in CNS physiology, disruption of their functionality in neurodegenerative disorders, and therapeutic strategies targeting sphingolipids for improved drug approaches.

Calmodulin-dependent KCNE4 dimerization controls membrane targeting

The voltage-dependent potassium channel Kv1.3 participates in the immune response. Kv1.3 is essential in different cellular functions, such as proliferation, activation and apoptosis. Because aberrant expression of Kv1.3 is linked to autoimmune diseases, fine-tuning its function is crucial for leukocyte physiology. Regulatory KCNE subunits are expressed in the immune system, and KCNE4 specifically tightly regulates Kv1.3. KCNE4 modulates Kv1.3 currents slowing activation, accelerating inactivation and retaining the channel at the endoplasmic reticulum (ER), thereby altering its membrane localization. In addition, KCNE4 genomic variants are associated with immune pathologies. Therefore, an in-depth knowledge of KCNE4 function is extremely relevant for understanding immune system physiology. We demonstrate that KCNE4 dimerizes, which is unique among KCNE regulatory peptide family members. Furthermore, the juxtamembrane tetraleucine carboxyl-terminal domain of KCNE4 is a structural platform in which Kv1.3, Ca2+/calmodulin (CaM) and dimerizing KCNE4 compete for multiple interaction partners. CaM-dependent KCNE4 dimerization controls KCNE4 membrane targeting and modulates its interaction with Kv1.3. KCNE4, which is highly retained at the ER, contains an important ER retention motif near the tetraleucine motif. Upon escaping the ER in a CaM-dependent pattern, KCNE4 follows a COP-II-dependent forward trafficking mechanism. Therefore, CaM, an essential signaling molecule that controls the dimerization and membrane targeting of KCNE4, modulates the KCNE4-dependent regulation of Kv1.3, which in turn fine-tunes leukocyte physiology.