bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical Application of aCGH for Prenatal Diagnosis: Experience with >350 Cases
Authors: Cheung Sau Wai 
Published: June 2021

We report our experience in using a targeted clinical aCGH for prenatal diagnosis including assessment of variants of uncertain significance and the ability to detect abnormalities not detected by karyotype.Women who underwent amniocentesis or chorionic villus sampling (CVS) were offered aCGH as an adjunct test. Fetal DNA was analyzed on targeted BAC or oligonucleotide arrays, optimized for detection of genomic disorders with reduced detection of polymorphic copy number variants (CNV).We analyzed 350 samples, most were amniotic fluid (82 %) and CVS (17%). The most common indications were advanced maternal age (N=123) and abnormal ultrasound findings (N=84). We detected 58 CNVs (19.3 %). Of these, 40 (13.3 %) were interpreted as likely benign, fifteen (5.0%) were of defined pathological significance while three (1.0 %) were of uncertain clinical significance. For seven (~2.3% or 1/43), aCGH contributed important new information. For two of these (1 % or ~1/150), the abnormality would not have been detected without aCGH analysis. We conclude that aCGH is an important new diagnostic tool for prenatal diagnosis of submicroscopic and larger unbalanced genomic rearrangements and for identification of the genomic content of marker chromosomes. Although aCGH detected benign inherited variants in 13% of cases, these did not present major counseling difficulties.
Anatomy of Human Life: Moving Ahead From Considering An Embalmed Cadaver As Your First Patient
Authors: Gannon Patrick John , Metzger Keith A , Moser Eileen M , Kheck Nancy , Wallach Paul M , Stagnaro‐Green Alex 
Published: June 2021

First exposure to a deceased person for many medical students is the cadaver in gross anatomy. This can give rise to a myriad of anxiety provoking experiences from confronting mortality to humanistic concerns. Further, students know they are likely expected to dissect and dismember the body. To assuage these concerns it is commonly suggested "consider this body your first patient". Since anxieties might persist, does this approach really engender comfort and promote clinical skills? Here we present a new approach in a new school that might help bridge any gaps.Students can be exposed to surface anatomy of the body before they meet the face of death in lab. We propose students become familiar with body surface phenomena such as pulses, reflexes, bony & muscular landmarks and auscultation. Experiences serve as living links to systems and deep structures. The "first patients" will be themselves, their peers and live simulation models. Further, the nature of a living individual's body is welcoming, realistic and distinct.We conclude that our new approach will have students initiate their lifelong journey of learning human anatomy as physicians with fond memories of an unforgettable founding experience.
Midbrain Neurons Integrate Information From Different Senses To Produce Adaptive Behaviors
Authors: Stein Barry Edward 
Published: June 2021

Midbrain Neurons Integrate Information From Different Senses To Produce Adaptive Behaviors. Barry E. Stein. Department of Neurobiology & Anatomy, Wake Forest University, School of Medicine, Winston‐Salem, North Carolina, 27157, USAMidbrain neurons in the superior colliculus (SC) are able to synthesize information from different senses, thereby substantially altering their responses to external stimuli (visual, auditory and somatosensory) and the behaviors that depend on them. Cross‐modal stimuli whose spatial and temporal properties make them likely to be associated with common events enhance physiological responses, and also enhance behavioral performance on orientation and localization tasks. Often, these performance benefits are quite striking, substantially increasing the probability of responding appropriately to biologically relevant events. In contrast, cross‐modal stimuli that are more likely to be associated with different external events either yield no multisensory integration or degrade physiological responses and overt behavior. Using the cat and monkey SC as models, we have found that neither these properties of SC neurons nor their behavioral benefits are present in the neonatal brain. Their maturation was studied in cat and found to be gradual and to be dependent on two factors: the development of a cooperative interaction between the descending projections to the SC from different sensory subdivisions of association cortex (e.g., visual and auditory), and the acquisition of extensive postnatal experience with the relevant cross‐modal cues. The biological significance of this circuit for underlying adaptive behavior, its developmental antecedents, and the likely component of the circuit that acquires the relevant cross‐modal experience will be discussed. This research was supported by NIH grants EY016716 and NS36916.
Initiation at the human Fragile X (FMR1) origin of chromosomal replication
Authors: Fanning Ellen , Gerhardt Jeannine , Gray Steven J , Guler Gulfem D 
Published: June 2021

Eukaryotic chromosomal DNA replication begins at origins marked by pre‐replication complexes (pre‐RCs) containing ORC, MCM2‐7, and other proteins. However, understanding of mammalian origins and their possible role in maintenance of genomic stability remains incomplete. We have mapped a replication origin 5' of the FMR1 gene, a heritable fragile site on the human X chromosome. As expected, the FMR1 origin binds to pre‐RC proteins in vivo. FMR1 alleles with heritable CGG repeat expansions suffer chromosome breaks and gaps when cells experience folate deficiency, but how the expansion leads to chromosome fragility is not clear.Recent clues from the human DNA helicase HDHB may lead to one answer for this question. In late M/G1, HDHB assembles in pre‐RCs at the laminB2, MCM4, and FMR1 origins, but not in flanking sequences. Based on siRNA and dominant negative approaches, HDHB is important for initiation. At G1/S, HDHB is released from the laminB2 and MCM4 origins and much of it is exported from the nucleus. However, a low level of HDHB is retained on bulk chromatin during S phase and this fraction is increased in cells exposed to agents that stall fork progression. To ask whether HDHB may localize at stalled replication forks even in unperturbed cells, we used ChIP to study the FMR1 origin region and the common fragile site FRA16D. HDHB was strongly enriched in S phase at both sites and not in flanking regions. Taken together, the data suggest that HDHB functions in initiation of replication at origins and in preventing or repairing stalled replication forks that arise in specific regions even in unperturbed cells.
Effect of non‐oil seed pulses on glycemic control: a meta‐analysis of randomized controlled experimental trials in humans.
Authors: Sievenpiper John L , Esfahani Amin , Wong Julia MW , Carleton Amanda J , Jiang Henry Y , Bazinet Richard P , Jenkins David JA , Kendall Cyril WC 
Published: June 2021

BackgroundDietary pulses (beans, lentils, chickpeas, etc.) are a good source of viscous fibre and a valuable means for lowering the glycemic‐index (GI) of the diet.ObjectiveTo assess the effect of pulses on glycemic control, we conducted a meta‐analysis of experimental trials investigating the effect of pulses alone or in low‐GI or high‐fibre diets on indices of glycemic control.MethodsWe searched MEDLINE, EMBASE, CINAHL, and Cochrane Library for relevant controlled trials of =7d in humans. Two independent reviewers extracted information on study design, participants, treatments, and outcomes. Generic inverse variance models were used for pooled analyses. Heterogeneity was assessed by Chi2 and quantified by I2.ResultsForty‐four trials were included. Pulses alone (12 trials) lowered fasting blood glucose (FBG) (standardized mean difference [SMD] ‐0.81 [95% CI ‐1.32,‐0.29]) and insulin (‐0.61[‐1.07,‐0.14]). Pulses in low‐GI‐diets (19 trials) lowered glycosylated proteins (GPs) (‐0.28[‐0.42, ‐0.14]). Pulses in high‐fibre diets (12 trials) lowered FBG (‐0.22[‐0.43,‐0.00]) and GPs (‐0.33[‐0.59,‐0.06]). Inter‐study heterogeneity was significant in all cases.ConclusionsThese data demonstrate that pulses alone or in low‐GI or high‐fibre diets improve markers of glycemic control in humans. Subgroup analyses are planned to explore sources of heterogeneity.Funding sourcePulse Canada.
Mediterranean diet and incidence and mortality of coronary heart disease and stroke in women
Authors: Fung Teresa , Rexrode Kathryn , Mantzoros Christos , Manson JoAnn , Willett Walter , Hu Frank 
Published: June 2021

In this study, we prospectively assessed the association between adherence to the Mediterranean diet and risk of incident coronary heart disease (CHD) and stroke. 74,886 women aged 38‐63 in the Nurses' Health Study, without a history of cardiovascular disease (CVD) and diabetes were followed from 1984 to 2004. We computed an alternate Mediterranean diet score from dietary data collected through validated food frequency questionnaires administered 6 times during follow‐up. Relative risks for incident CHD, stroke, and combined fatal CVD were estimated using Cox proportional hazards models adjusted for CVD risk factors. During 20 years of follow‐up, 2391 incident cases of CHD, 1763 incident cases of stroke, and 1077 CVD deaths (fatal CHD and strokes combined) were ascertained. Women in the top aMed quintile were at lower risk for both CHD and stroke compared with the bottom quintile (RR=0.71 (95%CI=0.62‐0.82; p trend< 0.0001) for CHD; RR=0.87 (95% CI=0.73‐1.02; p trend=0.03) for stroke). CVD mortality was significantly lower among women in the top quintile of the aMed (RR=0.61, 95g% CI=0.49‐0.76, p trend<0.0001).ConclusionGreater adherence to the Mediterranean diet was associated with a lower risk of incident CHD and stroke in women. Funded by NIH grants CA87969, HL60712, HL34594, HL88521.
Anti carcinogenic effects of Citrus auraptene in N‐methyl nitrosourea (MNU) induced mammary carcinogenesis in rats
Authors: Krishnan Prasad , Windler David , McLarty Jerry , Yan Karen , Li Benjamin , Kleiner Heather 
Published: June 2021

Our goal was to determine the anticarcinogenic effects of auraptene against breast cancer. In human breast carcinoma, MDA‐MB‐231 cells, auraptene inhibited cell proliferation by 50% at 12 μM and by 85% at 25 μM. In the in vivo study using the N‐methylnitrosourea (MNU) induced rat mammary carcinogenesis model, female Sprague‐Dawley rats were fed control diet, or diets containing auraptene (200 or 500 ppm) , at 42 days of age till the end of the study. Since eIF4E is over expressed in human breast cancer, another group with rapamaycin, an inhibitor of eIF4E was included (3.33 ppm in the diet). Auraptene (500 ppm) significantly delayed median time to tumor by 39 days compared to MNU only group. Analysis of rat mammary glands by HPLC with fluorescence detection indicated auraptene reaching the mammary glands in micromolar concentrations. In the analysis of human breast cancer samples in a tissue micro array (TMA) format, expression of cyclin D1, c‐Myc, and ODC (ornithine decarboxylase)the downstream effector molecules of eIF4E of showed an upregulation in the cancer samples.We studied the expressionof ODC in the mammary tumors in the auraptene‐fed groups and saw a significant reduction (p<0.05) in the expression of ODC. Recent studies in MCF‐7 cells showed that auraptene and rapamycin reduced the expression of cyclin‐D1.These results point to the potential chemopreventive effects of auraptene in mammary carcinogenesis.This study was supported by NCI: 1K22 CA102005‐01A2
Resolvin E1‐induced Intestinal Alkaline Phosphatase contributes to inflammation resolution via LPS detoxification
Authors: Campbell Eric , Keely Simon , MacManus Christopher , Scully Melanie , Colgan Sean P 
Published: June 2021

Inflammatory bowel diseases are disorders of unknown etiology characterized by inappropriate inflammation. There is recent intense interest in understanding mechanisms of inflammatory resolution. Resolvin‐E1 (RvE1) has been demonstrated to promote resolution in numerous disease models. Given the importance of epithelial cells in coordinating mucosal inflammation, we hypothesized that RvE1 elicits an epithelial inflammatory resolution signature.Microarray profiling of epithelial cells exposed to RvE1, revealed transcriptional induction of numerous inflammatory response genes. Notably, RvE1 induced intestinal alkaline phosphatase (ALPI) expression and enhanced epithelial ALPI enzymatic activity. ALPI was recently demonstrated to detoxify bacterial LPS. In our studies, both purified ALPI and "conditioned" LPS‐containing media derived from RvE1‐exposed epithelia were demonstrated to detoxify LPS. To define these features in vivo, we employed a murine DSS model of colitis. Compared to vehicle controls, administration of RvE1 resulted in significant improvement of disease activity indices. RvE1 treatment resulted in significantly increased ALPI expression in murine intestinal epithelial cells. Moreover, disease severity inversely correlated with ALPI expression. Taken together, these data implicate a previously unappreciated role for ALPI in RvE1 mediated inflammatory resolution.
Overpressure‐induced brain injury at the cellular level
Authors: Leung Lai Yee , VandeVord Pamela 
Published: June 2021

Veterans returning from wars exposed to blast with no visible wounds were diagnosed with mild traumatic brain injury (Warden 2006). Animal studies revealed the effects of primary blast wave on central nervous system. These studies mainly focused on systemic effect (Kaur et al 1995‐97; Cernak et al 2001). The molecular mechanism of blast wave‐induced brain injury is still unclear. We conducted a series of in vitro experiments to examine the cellular responses of astrocytes and neurons after exposing to overpressure (OP). A barochamber was designed and fabricated to generate a pressure with magnitude ranged from 17 to 58 psi and duration of 10 msec. Individual cell types were cultured on Petri dish, sealed and then exposed to OP. Viability assays and total RNA extraction for quantitative real‐time PCR were carried out at 24, 48 and 72 hours. Results of astrocytic response were published, which showed that astrocytes survived the OP and became reactive (VandeVord et al 2008). In rat cortical neuron cultures, Bcl‐2/BAX expression ratios were less than 1 (indicating apoptosis) in all groups except controls at 24 hour post‐exposure, followed by a significant increase (ratios>1, indicating survival) at 48 hour. The expression level of apoptosis‐related gene Caspase‐8 reached the peak at 72 hour. Neurons exhibited both apoptotic and survival processes after OP insult.Grant Funding SourceVA RR&D Career Development Award
A model for the investigation of regenerative or degenerative motoneurons and neuropil: Relevance to injury and ALS
Authors: Mesnard Nichole A , Haulcomb Melissa M , Sanders Virginia M , Jones Kathryn J 
Published: June 2021

Amyotrophic lateral sclerosis (ALS) involves progressively fatal neurodegeneration, specifically targeting motoneurons (MN). In the SOD1 transgenic mouse model of ALS, recent evidence has shown that disease progression results in two populations of MN, one compensatory and one degenerative. Using facial nerve axotomy to investigate MN survival, we have also discovered two populations of MN, one regenerative and one degenerative, resulting from an uneven distribution of survival across the six facial nucleus subnuclei in wild‐type (WT) mice. Facial nerve axotomy is used in this study to examine the injury‐induced molecular response of diseased MN in pre‐symptomatic SOD1 mice compared to WT. The regenerative ventromedial (VM) subnucleus maintains the highest level of MN survival following axotomy in WT (100%) and SOD1 (60%), while the degenerative ventrolateral (VL) elicits a significant MN survival decrease in WT (70%) and SOD1 (20%). WT and SOD1 subnuclei were characterized via laser microdissection with RT PCR (PACAP, GAP‐43, ?II tubulin, BDNF, Hn1, CX3CL1, GFAP, caspase 8, TNFá, IFNã, IL‐10, IL‐4), and in situ hybridization. The axotomized WT and SOD1 neuronal response is similar. However, differences in the SOD1 neuropil may lead to the increased cell death observed in the VM and VL compared to WT.Supported by the Les Turner ALS Foundation (NAM and KJJ).Grant Funding SourceLes Turner ALS Foundation & NIH
G Protein‐Coupled Receptor (GPCR) Signaling Pathways in Beta‐Cells
Authors: Wess Jürgen , Ruiz de Azua Inigo , Gautam Dinesh , Scarselli Marco , Rosemond Erica , Cui Yinghong , Guettier Jean‐Marc 
Published: June 2021

G protein‐coupled receptors regulate many aspects of beta‐cell function. To assess the physiological relevance of the different beta‐cell G protein signaling pathways in vivo, we generated a series of mutant M3 muscarinic acetylcholine (ACh) receptors (M3 mAChRs) which are unable to bind the endogenous ligand, ACh, but can activate different classes of G proteins when treated with the pharmacologically inert compound, clozapine‐N‐oxide. Studies with transgenic mice selectively expressing these modified M3 mAChRs in pancreatic beta‐cells have shed new light on the in vivo roles of distinct G protein signaling pathways in beta‐cell function.The M3 mAChR is a prototypic Gq‐coupled receptor. Recent data suggest that strategies aimed at enhancing signaling through beta‐cell M3 mAChRs may be beneficial for the treatment of type 2 diabetes by promoting glucose‐stimulated insulin secretion. To identify regulatory proteins that reduce M3 mAChR signaling in pancreatic beta‐cells, we used the MIN6 murine insulinoma cell line as an in vitro model system. By using siRNA technology, we identified several proteins, including different receptor kinases and RGS proteins, that acted as negative regulators of M3 mAChR function in MIN6 cells. Given the key role of M3 mAChR signaling in beta‐cell function, it is likely that this approach will lead to promising new targets for the treatment of type 2 diabetes.
n‐3 Fatty Acids Are Neuroprotective After Cerebral Hypoxia‐Ischemia In Rodent Models
Authors: WILLIAMS JILL J , Bazan Nicolas , Ten Vadim S , Vannucci Susan J , Mastropietro Christopher , Deckelbaum Richard J 
Published: June 2021

We questioned if acute administration of n‐3 FA decreases brain injury after hypoxia‐ischemia (H/I), and if so, what mechanisms are involved. Juvenile Wistar rats and adult and neonatal C57/BL6 mice underwent right carotid artery ligation followed by exposure to 8% O2, and received n‐3‐rich FA emulsion or saline (controls). 72h (rats) and up to 48h (mice) post H/I, animals were euthanized. Brain sections were stained with TTC, H&E, and Fluoro Jade to analyze injury. FA content was determined by GLC. Mouse brains were analyzed by GC mass spectrophotometry for neuroprotectin D1 (NPD1). Cerebral blood flow (CBF) was measured using Laser‐Doppler flowmetry.Injury scores were 0.42±0.62 (n‐3) vs. 2.00±0.83 (control rats) (p < 0.005) with similar results in adult and neonatal mice. In controls, but not in n‐3, there was a ~25% decrease in each FA/g rat brain in right hemispheres, indicating brain edema. Injured areas display cell loss, pyknotic nuclei and degenerating neurons. In whole mouse brain, NPD1 increased at 8h post H/I in n‐3 compared to controls (2.0±0.4 vs. 0.9±0.4 pmole/mg protein, p<0.05). There were no n‐3 related differences in CBF. Thus, acute administration of n‐3 FA is protective against H/I induced brain infarction in 3 rodent models. Neuroprotection relates to an early response to cerebral H/I by NPD1 and to prevention of brain edema.Grant Funding SourceNIH‐NHLBI
Potato consumption reduced oxidative stress and inflammatory damage in humans
Authors: Kaspar Kerrie L , Park Jean Soon , Mathison Bridget , Brown Charles R , Navarre Roy , Chew Boon P 
Published: June 2021

Potatoes contain phenolic acids, anthocyanins and carotenoids; however, their potential benefits in immune modulation and against oxidative stress and inflammation are unknown. Free‐living healthy male participants (18‐40 yr; n=12/group) ate 150 g of cooked White (WP), Yellow (YP) or Purple (PP) flesh potatoes once a day for 6 wk in a single‐blinded study. A 3‐day dietary recall was obtained. Blood was collected at baseline and wk 6 to analyze total antioxidant capacity, 8‐hydroxydeoxyguanosine (8‐OHdG), protein oxidation, lipid peroxidation, C‐reactive protein, IL‐6, TNF‐α, IFN‐γ, lymphoproliferation, NK cytotoxicity and phenotypes. Compared to participants fed WP, those fed PP (P<0.1) or YP (P<0.05) had lower plasma 8‐OHdG while subjects fed PP had lower (P<0.1) C‐reactive protein. Plasma IL‐6 also was lower (P<0.07) in PP. The population of total Tc cells was lower (P<0.05) in PP, while subjects fed YP tended to have lower (P>0.1) B and NK cell subpopulations and higher total T cell populations than those fed WP. Similarly compared, subjects fed PP tended (P>0.1) to have higher B and NK cell, and lower total T cell populations. Therefore, consumption of pigmented potatoes reduced inflammation and DNA damage, and modulated immune cell phenotype in male subjects. Support: Washington State Potato Comm.Grant Funding SourceWashington State Potato Commission
Over‐expression of Peroxisome‐Proliferator‐Activated Receptor‐Gamma Co‐Activator 1 Beta decreases cellular triglyceride content and secretion in HepG2 Cells
Authors: Johnson Diana Roshek , Brinker Anita M , Dixon Joseph L 
Published: June 2021

The Peroxisome‐Proliferator‐Activated Receptor‐Gamma Co‐Activator 1 Beta (PGC1β) is a co‐activator of several transcription factors involved in lipid metabolism and very low density lipoprotein (VLDL) secretion. Therefore, PGC1β may be a master regulator of lipid metabolism in liver. To study this hypothesis, human liver HepG2 cells were infected with adenoviruses containing PGC1β or β‐galactosidase (control), and cells and medium were extracted to determine changes in cellular lipids. A wide array of lipids was measured using liquid chromatography/mass spectrometry (LC/MS/MS) using an Applied Biosystems 4000Q Trap. PGC1β over‐expression caused significant decreases in liver cellular neutral lipids. There was a 61.5±3.9% decrease in triacylglycerides (TAG), 40.9±6.7% decrease in diacylglycerides (DAG), and 52.9±3.8% decrease in monoacylglycerides (MAG). During this period, over‐expression of cellular PGC1β decreased the secretion of neutral lipids: 39.7±4.9% decrease in TAG, 60.2±4.1% decrease in DAG; MAG were not detectable in HepG2 medium. There were no significant changes in any of the cellular phospholipid concentrations or species between control cells and cells treated with PGC1β. Our studies show that over‐expression of PGC1β greatly influences neutral lipid metabolism in human liver HepG2 cells.Grant Funding SourceNIH, Rutgers University