bluuebunny/crossref_metadata_2025_split huggingface dataset:
Metabolomic responses in brain endothelial cells (CLU‐512‐hCMEC/D) to Angiotensin II and Angiotensin 1‐7
Authors: Pena‐Silva Ricardo A. , Ana Sierra , Cala‐Molina Monica P. 
Published: May 2022

Metabolomics is the discipline focused on the study of the dynamics, composition, interactions and responses to changes in metabolites in cells, tissues and biological fluids. Vasoactive peptides such as angiotensins cause multiple metabolic changes in vascular tissues, however these changes have not been characterized in detail. Angiotensin 1‐7 is a peptide derived from angiotensin II through the action of Angiotensin Converting Enzyme type II. This exploratory study seeks to understand the metabolic responses of a human cerebral microvascular endothelial endothelial cell line to stimulation with vasoactive peptides, in vitro (Angiotensin II, Angiotensin 1‐7).MethodsWe performed single cultures of the cell line (CLU‐512‐hCMEC/D), which was treated with Ang II, Ang 1‐7 or vehicle. Cells and culture medium were sampled before and after treatments. The samples were subjected to the process of extraction of metabolites with organic solvents. Each treatment was prepared in three biological replicates and was followed by metabolite extraction. Determination of metabolic profiles was performed by multiplatform, non‐targeted, metabolomic analysis, using liquid chromatography (LC) coupled to high resolution mass spectrometry (HRMS). To determine the differences in metabolic profiles between groups and to select statistically significant metabolites, multivariate statistical analysis was performed.ResultsWe found 122 metabolites that varied between groups. In general, Ang II‐induced changes were similar to those found for Ang 1‐7. In particular, we found a reduction in the levels of several types of lipids including some bile salts, sphingolipids, glycerophospholipids and fatty acids.This study is our first step in characterizing methods to study the impact of vasoactive peptides and inflammatory molecules on the blood‐brain barrier metabolome. Studying the modulation of the vascular tissue metabolome and endothelial cells could enhance our understanding of the effect of angiotensin 1‐7 and ACE2 in pathologies such as COVID‐19.
A Novel En Bloc Circulatory System Dissection: A Teaching Tool for Systems‐Based Medical School Curricula
Authors: Gustilo Katherine S. , Stabio Maureen , Goldberg Chelsea , Lohman Bonfiglio Chelsea 
Published: May 2022

Introduction and ObjectiveWith the transition to integrative, systems‐based anatomical instruction in medical school curricula, the use of traditional, regionally‐based, cadaveric dissection has decreased while the use of systems‐based prosections has increased. Recent studies have demonstrated the value of such prosections for the nervous system through an en bloc extraction of the central nervous system. However, comparable approaches for the circulatory system have not been reported, and there are currently no dissection instructions for an en bloc circulatory system extraction that do not require polymer injection into vessels prior to embalming. Thus, the goal of this project was to prosect, extract, and preserve the circulatory system en bloc for long‐term use in a systems‐based integrated medical curriculum.Materials and MethodsOne male cadaveric donor without documented vascular disease or pathology was used to extract the following structures in a single interconnected piece: the heart, more than 350 named arteries, 10 superficial veins, 21 veins of the portal system, the liver, and at least 27 major veins of the caval system. Vascular structures were carefully isolated from the surrounding tissues in each region of the body over the course of approximately 250 hours by a single dissector. Muscles, nerves and organ tissues were cleared from the vessels using common dissection tools, including scissors, forceps, probes, and scalpels. Extraction of vessels from bones required use of chisels, rib cutters, and an autopsy electric saw. Best approaches, challenges, and time‐saving strategies were recorded.Results & ConclusionThe circulatory system was successfully extracted from the limbs, torso and head in a single piece after embalming without the need for advanced polymer injection. A detailed dissection guide with instructions and images was developed, so this dissection could be replicated. The cadaveric specimen will be plastinated in approximate anatomical position with small tags placed on all named vessels to allow for easy identification of each structure and long‐term use.Significance and ImplicationThis prosection is a novel approach to meet the needs of changing medical school curricula by illustrating the complexity and continuity of the circulatory system as a whole system. The 3D display will allow students to access a real, anatomical model that comprehensively demonstrates the majority of important, named vessels, providing the necessary context to augment 2D images, vascular diagrams, and atlases. Subsequent investigations will evaluate the educational value of this model in a flipped‐classroom approach. Future plans also include surface scanning and 3D‐printing the model to reproduce a less time‐consuming replica. This reimagination of traditional dissection techniques has generated new avenues for illustrating the human body, even in an established field such as gross anatomy.
Change in Metabolomic Profile Associated with an Average Increase in Plain Water Intake of >+1 L/day, Sustained over 4 Weeks, in Healthy Young Men with Initial Total Water Intake below 2 L/day
Authors: Stookey Jodi , Paulweber Bernhard , Lang Florian , Ritter Markus 
Published: May 2022

Cells adapt to chronic extracellular hypotonicity by altering metabolism, such that cell‐level chronic disease risk factors are reduced. Corresponding effects of sustained whole‐body hydration are hypothesized but remain to be confirmed and translated into population‐level chronic disease prevention.This analysis aimed to 1) describe change in urine and serum metabolomic profiles associated with change in hydration, induced by four weeks of sustained higher intake of drinking water, 2) check if features recognized as key osmolytes in specific tissues changed in urine and/or serum, and 3) identify which metabolic pathways might potentially be impacted by sustained hypotonic hydration.Adapt Study [Stookey JD et al., Physiol Rep 2013;1(5)] data from for 4 healthy, normal weight men (20‐25 years) who transitioned from not meeting to meeting 3 osmolality criteria (urine:<800mmol/kg, serum:<295mmol/kg and saliva:<100mmol/kg) over 4 weeks of >+1L/d intake of drinking water were used for this analysis. Untargeted metabolomic assays were performed by the UC Davis West Coast Metabolomic Center on first‐morning urine collected after overnight food and water restriction and urine (t+60min) and serum (t+90min) collected after a 750 ml bolus of drinking water. Metaboanalyst 5.0 was used to compare Week 1 vs Week 6 metabolomic profiles, using heatmap, OPLS‐DA, fold‐change, and pathway analyses.In heatmap and OPLS‐DA plots, metabolomic profiles appeared more similar in Week 6.Over 350 metabolic features decreased by 2‐fold or more relative to creatinine for at least 3 out of 4 participants in first‐morning and post‐bolus urine. Over 200 features increased by 2‐fold or more relative to creatinine in serum. A wide variety of known compounds changed by 2‐fold or more in at least one specimen type, including alcohols, monosaccharides, disaccharides, sugar acids, polyols, azoline, lactone, nucleosides, phenols, purines, pyridines, pyrimidines, fatty acids, cholesterol, glycerolipids, amino acids, carboxylic acids, phosphate, and urea. Based on hypergeometric test p‐value <0.05 or pathway impact factor >0.2, sustained +1L/d of drinking water was associated with concurrent changes in carbohydrate, protein, lipid, and micronutrient metabolism, a ‘reverse’ Warburg‐like pattern favoring carbohydrate oxidation via the TCA cycle in Week 6.The results warrant further work to leverage cell hydration effects for chronic disease prevention.
Pyridoxine and cobalamin supplementation effect regarding cell death in a human glioblastoma cell line
Authors: Martínez‐Mendiola Carolina A. , Estrada Jose A. , Zapi‐Colín Luis Á. , Contreras Irazú 
Published: May 2022

Glioblastoma multiforme is the most common and aggressive form of brain tumor. Its treatment is challenging despite the use of combined treatments including surgery, chemotherapy, and radiotherapy. Mean survival rates after 5 years are usually around 5%. Recent advances in cancer therapy have focused on the use of adjuvant strategies to improve clinical outcomes. Among these, nutritional interventions have shown significant potential for preventing tumor development and enhancing response to standard treatments, improving life quality and expectancy in cancer patients.Vitamins are essential micronutrients required for cellular metabolism and homeostasis. B group vitamins are key for development of the nervous system, participating in de novo synthesis of nucleic acids, homocysteine and one‐carbon metabolism, as well as contributing to mitochondrial functions. B vitamins have been shown to possess significant properties relating to the prevention of tumor development in some types of cancer. However, their role in glioblastoma has not been determined.The aim of this study is to determine the effect of B group vitamin supplementation on the survival of the human glioblastoma cells. B6 (pyridoxine) and B12 (cobalamin) vitamins were administered directly to cultured U87MG human glioblastoma cells at different concentrations and exposure times. A crystal violet colorimetric assay was used to evaluate cell viability after vitamin supplementation. The results show a strong dose‐dependent effect of pyridoxine supplementation on glioblastoma cell viability at 2,000‐4,000 µM concentrations. Viability also decreased at longer exposure times. In contrast, cobalamin supplementation at 1‐100 µM concentrations does not appear to have any effect on glioblastoma cell viability at any exposure time.These data suggest that direct supplementation with pyridoxine, but not cobalamin, may affect glioblastoma cell viability. Additional experiments are underway to explore the molecular mechanisms responsible for the observed effects.
Assessment of Mitochondrial Respiratory Function in Isolated Nephron Segments of Dahl SS Rats in Salt Induced Hypertension
Authors: Yang Chun , Zheleznova Nadezhda N. , Dash Ranjan K. , Cowley Allen W. 
Published: May 2022

RationaleKidney nephrons actively reabsorb 99% of the filtrate to maintain body fluid and solute homeostasis. A large amount of ATP synthesis and O2 consumption must work coordinal to support this demand. We hypothesized that mitochondrial function of proximal tubules (PT) and medullary thick ascending limbs (mTAL) is altered during the development of salt induced hypertension in the Dahl salt‐sensitive (SS) rat.MethodThe mitochondrial oxygen consumption rates (OCR) were determined in freshly bulk isolated PT and mTAL segments from SS rats fed 0.4% NaCl diet (low salt; LS) or 4% NaCl diet (high salt; HS) for 7 days. A protocol was developed to determine basal levels of OCR and the effects of various key circulating substrates (glucose, lactate, pyruvate, glutamine, and palmitate) upon mitochondrial respiration (OCR) using the Agilent Seahorse XF96 Extracellular Flux Analyzer combined with the Agilent Seahorse XF Cell Mito Stress Test protocol.ResultsAnalysis of the renal tubular mitochondrial OCR data for five different circulating substrates confirmed that there were clear differences in the substrate preference between the PT and mTAL which were altered by HS feeding. It was found that PT preferred lactate and glutamine while mTAL preferred glucose and pyruvate and that both segments could effectively utilize palmitate as a mitochondrial substrate. PT isolated from SS rats fed HS displayed higher OCR levels compared to PT from LS fed rats, but HS diet did not result in significant differences in individual substrate effects. In contrast, isolated mTAL from HS fed rats exhibited increased OCR in response to glutamine and palmitate compared to mTAL from LS fed rats although no basal differences in OCR were observed.ConclusionThese observations demonstrated that renal tubular mitochondrial respiratory function is altered in SS rats during the development of salt‐induced hypertension and that both PT and mTAL exhibit an increased respiratory capacity in response to HS feeding. These changes in metabolism appear necessary to meet the increased tubular workloads and need for greater ATP production and O2 utilization in both PT and mTAL. We conclude, however, that different metabolic strategies are utilized by each of these tubular segments to meet these increased metabolic requirements.
Role of beetroots in oxidative stress and vascular relaxation in ovariectomized rats
Authors: Wang Hui Di , Nguyen David H. , Deng Arlinda , Longo Amanda , MacPherson Rebecca , Ward Wendy 
Published: May 2022

The onset of hypertension in women is known to peak dramatically after menopause, partly due to decreased estrogen levels. It is well known that postmenopausal estrogen therapy can cause many adverse effects, and there is growing interest in using dietary products as potential treatment options. Dietary nitrates in beetroot may raise blood nitric oxide levels. We tested the hypothesis that beetroot can improve the oxidative stress and vascular relaxation responses in a model of an ovariectomized rodent.Female ovariectomized Sprague‐Dawley rats were divided into four treatment groups: beetroot juice (nitrate content 18.75mg), nitroglycerin (0.2 mg/kg), estradiol replacement (1.5mg) or no treatment for 12 weeks (n=4 per group). The isometric contractile activities were measured in isolated aortic rings mounted in tissue baths. Phenylephrine (10‐6 M) was used to precontract the aortic rings. The contractile activities to various concentrations of acetylcholine and sodium nitroprusside were evaluated. The superoxide concentration was measured using chemiluminescence.The beetroot treatment significantly reduced superoxide production (P<0.05). However, it did not affect acetylcholine or sodium nitroprusside‐induced vascular relaxation at any of the concentrations used in the experiments (P>0.05). There were no significant differences in acetylcholine‐induced vascular relaxation curves among the different treatment groups (P>0.05).In conclusion, these experiments indicate that dietary beetroot does not improve acetylcholine‐mediated vascular relaxation while decreasing oxidative stress, contrary to expectations.
Virtual Screening Approach to Repurpose FDA‐approved Drugs for Targeting Acid Ceramidase‐1 in Pancreatic Cancer
Authors: Raval Nipam , Henrichs Grant 
Published: May 2022

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer‐related deaths in the US. Despite extensive research and advances in molecular pathogenesis, PDAC remains a major problem in the US. It is also projected to be the second leading cause of cancer‐related deaths in the US by 2030. PDAC is an aggressive disease and characterized by poor prognosis, rapid progression, drug resistance and recurrence. The current chemotherapy treatment only improved survival to <10%, hence there is a need to identify a novel target for drug discovery.Recently, altered sphingolipid metabolism was identified in PDAC patients. Sphingolipids are critical constituents of the cell membrane that regulate several signaling pathways related to cell survival. The major sphingolipid metabolites are ceramide and sphingosine which are interconvertible, while ceramide is pro‐apoptotic and sphingosine is anti‐apoptotic. Ceramidases are a heterogeneous enzyme family that convert ceramides into sphingosine and fatty acids. The five human ceramidases are identified are the acid ceramidase (ASAH1); neutral ceramidase (ASAH2); alkaline ceramidase 1 (ACER1); alkaline ceramidase 2 (ACER2); and alkaline ceramidase 3 (ACER3). To understand the role of ceramides in PDAC, we first interrogated the cancer genome atlas database and found that all ceramides are expressed in lower levels in PDAC except ASAH1 which is uniquely overexpressed in PDAC patients compared to normal individuals. Further, immunocytochemistry of PDAC patient tissue microarray showed higher expression of ASAH1 in PDAC tumors compared to normal pancreas. Western blot analysis also showed overexpression of ASAH1 protein in PDAC cell lines. Studies indicate that ASAH1 plays an important role in PDAC progression. Our data indicate that ASAH1 is a potential target for the treatment of PDAC. For faster translation of this target to the clinic, we used virtual screening and molecular docking approach to identify FDA‐approved drugs for targeting ASAH1. We have downloaded the 3D‐protein structure of ASAH1 from the protein data bank and currently screening a library of small molecular drugs against ASAH1 protein using multiple software programs such as Autodock vina and PyRx. We will select the top 10 drug candidates from virtual screening based on their binding energies and the ability to form hydrogen bonds with key amino acids. We will confirm these findings using a cellular thermal shift assay to analyze the binding of these drugs to ASAH1 in PDAC cell lines and test their anticancer activities in cell culture system and orthotopic PDAC mouse model.
Summing up 10 years in a new medical school: Per aspera ad astra
Authors: Barash Alon , Toledano Nadav , Maoz Eyla , Blumberg Yair , Dickman Nomy , Karasik David 
Published: May 2022

Opening a new medical school and introducing an anatomy course is a rare opportunity for medical anatomy educators. Here we sum our experience in an ongoing 10‐year anatomy program, emphasizing the challenges we endured, the hardships and successes in the hope that others can learn from our experience.In February 2010, Bar Ilan University was chosen by the Israeli Council for Higher Education to open a new, fifth, medical faculty. A mere eight months later, the school opened its gates to a class of 70 students in the northern city of Safed. This new faculty, dedicated to establishing connections to the local community, enabled us to develop and implement a new anatomy curriculum.The basic course incorporated frontal lectures, dissection labs, basic systematic physiology, clinical correlation lectures and imaging labs. The initial curriculum included trunk and Head & neck regions spanning 5 weeks. After the first couple of years, the length and contents of the course started to change and adapt according to the needs of our faculty, and by input from physicians as well as students. Over the years student number rose to 100, and the course expanded to 10 weeks to incorporate the entire body aside from neuroanatomy, which is taught in a separate course. Histology and embryology were included; ultrasound hands‐on labs were added; and virtual anatomy sessions were integrated to the program. Clinical and physiological correlate lectures were cut down, with the understating, backed by students’ evaluations, that this was too early for them, and focus should remain on basic normal anatomy. On the other hand, more time was added to imaging sessions and lectures, as most modern physicians use these techniques in their everyday clinical practice. While originally relaying on retired physicians to serve as dissection instructors, we initialed a near‐peer students dissection instructors’ program that was met with great success.In the last couple of years our program and indeed the entire medical school was heavily impacted by the ongoing Covid‐19 pandemic. While lectures were taken to virtual platform, we decided to continue dissection sessions as normally as possible, with strict mandatory regulations including personal protective gear and keeping students’ number within the lab to a minimum of 15, 7‐8 students per cadaver. Students were highly appreciative of our efforts, and course scoring was exceptionally high.The last 10 years has shown us that anatomy, a basic and important tradition, could be taught in many exceptional ways, and we should always strive to improve. But perhaps even more important is the understating that we are educators to whom our students look up to, and endurance, perseverance, resourcefulness, and professionalism are just as important as scholastic knowledge.
Facial dysmorphologies in genetic disorders: exploring the ancestry component in a Colombian population
Authors: Martínez Abadías Neus , Echeverry Luis Miguel , Gómez Eidith , Solís Paula , Candelo Estephania , Ramírez‐Montaño Diana , Ortiz Diana , González Alejandro , Sevillano Xavier , Cuéllar Juan Carlos , Pachajoa Harry 
Published: May 2022

Currently there are more than 10,000 rare diseases that affect about 7% of the world's population. Up to 40% of rare genetic disorders present craniofacial dysmorphologies, which can vary from subtle facial anomalies to severe malformations. Visual assessment of facial dysmorphology is commonly used for clinical diagnosis, patient management and treatment monitoring. However, qualitative descriptions are usually vague and quantitative approaches using craniofacial phenotypes for the diagnosis of rare diseases are based on North American and European populations, disregarding the influence of population ancestry on facial variation, as in Latin‐America. In this study, we assessed facial dysmorphologies associated to three different genetic disorders (Down (DS), Morquio (MS) and Noonan syndrome (NS)) in a Latin‐American population from Cali (Colombia). We recorded the coordinates of 18 facial landmarks in 2D images from 34 pediatric patients (19 DS, 8 MS, 6 NS) and 75 controls and quantified facial differences between patients and control groups using Euclidean Distance Matrix Analysis (EDMA).Comparisons between control and syndromic phenotypes indicated that individuals diagnosed with DS and MS presented the largest percentage of dysmorphologies, with respectively 56.2% and 54.9% of significantly different facial traits. In NS, the percentage decreased to 12.4%. Each syndrome presented a characteristic facial pattern. In DS, all facial structures were affected, with a 6% increase of relative distance between the eyes and a 7‐10% reduction in facial height. The eyes and nose were most affected in MS, but not the mouth, with higher hypertelorism and facial reduction than in DS (9% and 8‐17%). In NS, facial differences were more subtle and affected mainly the eyes and mouth, reducing the relative distance between them from 1 to 4% in patients as compared to controls. Our study provides a precise quantitative comparison of facial dysmorphologies in three genetic disorders that in the future can be compared with other world‐wide populations to test whether facial traits associated to disease are altered by different evolutionary and adaptive histories of human populations.