bluuebunny/crossref_metadata_2025_split huggingface dataset:
The female menstrual cycle: impact on cardiovascular, ventilatory and neuromuscular responses to whole body exercise
Authors: Georgescu Vincent P. , Thurston Taylor S. , Jarrett Catherine L. , Weavil Josh C. , Richardson Russell S. , Amann Markus 
Published: April 2020

BACKGROUNDThe female menstrual cycle (MC) is characterized by varying levels of endogenous sex hormones. Previous investigations have indicated that fluctuating levels of estrogen and progesterone may influence vascular function, ventilatory chemosensitivity, and exercise‐induced fatigue throughout the MC. However, a comprehensive analysis of the role of these sex hormones on determining cardiovascular, ventilatory, and neuromuscular responses during whole body exercise is currently lacking. Therefore, the purpose of this study was to investigate cardiovascular, ventilatory and neuromuscular responses to submaximal cycling exercise of eumenorrheic females throughout the MC.METHODSFemales were studied during three MC phases: early follicular (EF; days 1–4), late follicular (LF; days 8–12), and mid luteal (ML; days 8–10 post LH peak). Prior to exercise, venous blood was collected each visit to characterize endogenous hormone concentrations. Subjects cycled at 50 W, 75 W, 100 W, and 80% Wpeak (129 ± 12 W) for 4 min per stage. Heart rate (HR), mean arterial pressure (MAP), femoral artery blood flow (QL, Doppler ultrasound), minute ventilation (VE), oxygen consumption (VO2), carbon dioxide production (VCO2), and estimated arterial hemoglobin saturation (SpO2) were quantified throughout all cycling trials. Preto post‐exercise changes in potentiated quadriceps twitches (ΔQtw) were used to quantify peripheral locomotor muscle fatigue.RESULTSHR, MAP, and QL were not different at any intensity throughout the MC (P > 0.4). VE, VO2, VCO2 were also not different throughout the MC (P > 0.2). Furthermore, neither hemoglobin content, nor SpO2 and arterial oxygen content changed significantly across the MC (P > 0.1). Consequently, leg O2 delivery during exercise at all intensities were similar during the MC. Finally, exercise‐induced peripheral fatigue was not different throughout the MC (ΔQtw: ~47%; P = 0.2).CONCLUSIONFluctuating endogenous female sex hormones do not significantly influence central or peripheral hemodynamics or the ventilatory response to submaximal whole‐body exercise. Similarly, the exercise‐induced development of peripheral fatigue also remains unaltered across the MC during submaximal cycling exercise of the same duration and intensity. Although depending on the research question, these data suggest that controlling for MC phase may not be necessary when examining cardioventailtory or neuromuscular responses to whole body exercise in females, and should encourage the participation of more females in these types of studies.Support or Funding InformationNational Heart, Lung, and Blood Institute (HL‐116579)
Understanding the Cellular Functions Polyamines Play in Proliferation, Replication, and Survival of Leishmania donovani
Authors: Perdeh Jasmine , Love Quintin , Leizorek Yvette , Berioso Brandon , Le Linh , Roberts Sigrid 
Published: April 2020

Leishmaniasis, a neglected tropical disease, affects an estimated billion people worldwide. A better understanding of parasite biology is vital for the development of much needed new therapeutic strategies. Our research addresses this critical need by focusing on the role of polyamines for growth and survival of Leishmania parasites. The main polyamine biosynthetic enzymes in Leishmania are ornithine decarboxylase (ODC) and spermidine synthase (SPDSYN), which sequentially convert ornithine to the polyamines, putrescine and spermidine. With generated gene deletion mutants, Δodc and Δspdsyn, we have demonstrated in vitro that the metabolite putrescine is essential beyond its function as the precursor for spermidine formation. Additionally, we observed that putrescine‐depleted Δodc parasites immediately ceased proliferation and died within two weeks. In contrast, putrescine‐rich Δspdsyn mutants showed an intermediate growth phenotype and entered a quiescent‐like state with cell death occurring after six weeks. Furthermore, putrescine‐depleted cells were unable to synthesize DNA and stopped replicating. We also observed two hallmarks of programmed cell death in the putrescine‐depleted cells: cell‐rounding and phosphatidylserine exposure. To reduce the variability associated with working with two cell lines and to further understand the functions polyamines play, we are in the process of generating a double gene deletion mutant, ΔodcΔspdsyn.Support or Funding InformationPacific University School of Pharmacy Research Incentive Grant
Elevated miR‐125b inhibits trophoblast invasion by directly targeting KCNA1 in preeclampsia
Authors: Li Qinghua , Yin Lingxuan , Si Yanru , Meng Yuhan , Yang Weiwei 
Published: April 2020

Preeclampsia (PE) is a pregnancy‐specific syndrome of human pregnancy associated with poor trophoblast invasion, which attributed to 63 000 maternal and 500 000 infant deaths annually worldwide. The incidence of PE has increased by 40% over the last several decades. Elevated miR‐125b in the placenta has been reported to be linked with the risk of PE. Our bioinformatic analysis showed that voltage‐gated potassium channel subfamily A member 1 (KCNA1) is a predicted target for miR‐125b. However, roles of miR‐125b in the pathogenesis of PE is not fully explored. Here we test the hypothesis that miR‐125b is involved in the development of PE by targeting KCNA1 in human trophoblast cells. We found that expression of miR‐125b was upregulated on first trimester in patients who later developed preeclampsia(p=0.0009<0.01), while KCNA1 levels were significantly decreased and negatively correlated with miR‐125b levels in the PE placentas (r2=0.6099, p<0.01). We validated that KCNA1 is a direct target of miR‐125b using luciferase assay and western blotting(p<0.05). We then conducted transwell invasion assay and found that miR‐125b significantly inhibited trophoblast cell invasion by 58.67±3.48% (compared to mock, p<0.05), knockout of KCNA1 significantly attenuated the invasion‐inhibitory effect of miR‐125b (p<0.05) while overexpression of KCNA1 reversed the effect of miR‐125b (p<0.05). In conclusion, these data suggest that elevated miR‐125b impaired trophoblast invasion via directly targeting KCNA1 in the pathology of PE. The findings highlight the function of KCNA1 in human placental cells and provide new insight of how miR‐125b is involved in the pathogenesis of preeclampsia.Support or Funding InformationThis research was supported by the National Natural Science Foundation of China (81601318) and Shandong Province Health and Medical Science and Technology Program (2016WS0668), Weifang Medical University (No. 2017BSQD11).
Acute Cervical Spinal Cord Injury Alters Swallow Motor Patterns
Authors: Iceman Kimberly , Strecker Courtney , Greene Clint , Howland Dena , Pitts Teresa 
Published: April 2020

Cervical spinal cord injuries (cSCIs) can cause swallow disorder (dysphagia), potentially resulting in aspiration and pneumonia. Dysphagia is characterized by disruption of the swallow motor pattern, which involves sequential activation of muscles that propels the bolus into the esophagus while avoiding the airway. Normal swallow includes diaphragm activity that generates negative pressure, drawing the bolus into the esophagus. Centers in the brainstem control the swallow patterns. Thus, despite reports of dysphagia in some patients with cSCI, little consideration has been given to the potential contributions of spinal circuitry to swallow. We aim to characterize swallow dysfunction in cats with cSCI. Using EMG to record breathing patterns, water‐induced swallow in pentobarbital‐anesthetized spontaneously breathing cats is captured before and after acute high cervical hemisections (at C2 or C3). EMGs are recorded from the mylohyoid, thyrohyoid, thyroarytenoid, thyropharyngeus, cricopharyngeus (upper esophageal sphincter), and diaphragm muscles, and trans‐diaphragmatic pressure is measured by monitoring esophageal and stomach pressures. After hemisection, swallow is dramatically altered, as indicated by a dysfunctional swallow motor pattern. Coordinated, sequential muscle activation necessary for proper movement of a bolus through the pharynx is lost, esophageal pressure is positive rather than negative due to reduced activation of the diaphragm, and upper airway EMG activity increases. These alterations in behavior‐specific muscle recruitment patterns are profoundly dysphagic, indicating that disruption of spinal circuits in the high cervical spinal region can produce major dysfunction in swallow motor patterns. This work may inform screening and treatment protocols of the cSCI patient population, in which dysphagia is likely to be underdiagnosed.Support or Funding InformationNIH grants HL 111215, NS 110169 and OT20D001983, the Craig H. Neilsen Foundation Pilot Research Grant 546714, Kentucky Spinal Cord and Head Injury Research Trust, the Commonwealth of Kentucky Challenge for Excellence, VA RR&D B9249S and the Rebecca F. Hammond Endowment.
Crystalizing Structured RNAs Using a Surface‐Entropy‐Reduced Fab as a Crystallization Chaperone
Authors: Roman Christina Alexandra , Koirala Deepak , Piccirilli Joseph 
Published: April 2020

Our lab studies the molecular mechanisms of regulatory RNAs elements by determining their atomic resolution structure using x‐ray crystallography. However, RNA crystallization presents many challenges. One strategy to meet these challenges is the use of a protein chaperone to assist RNA crystallization. Antibody fragments (Fabs) provide one type of crystallization chaperone, and we have used these successfully for RNA crystallization in two ways. In one approach, a Fab‐binding‐RNA epitope is grafted into the RNA of interest to create a binding site for the cognate Fab crystallization chaperone. To improve this method, I performed surface entropy reduction on the Fab framework to make a version of our crystallization chaperone that is more suited to well‐ordered crystal packing. Using structural analysis software as a guide, I made twelve surface‐entropy‐reduced (SER) mutant versions of the Fab framework, in which patches of bulky, flexible residues are mutated to alanine. To test the performance of these mutants, I carried out crystallization trials of their complexes with the yjdF RNA, a novel bacterial riboswitch that binds to aza‐aromatic compounds. The wild type Fab (wt BL3‐6) and many of the mutants were able to crystalize with the riboswitch and gave diffraction datasets with 3.5 – 3 angstrom resolution range, and the structure is currently being solved. Using the mutants, I have also crystalized a second RNA target, PEMV2, which is a viral cap‐independent‐translation‐element. This RNA crystalized with wild type but could only diffract to 2.75 angstrom resolution with the aid of a mutant. I am in the process of solving this structure which will give valuable hints to the mechanism of action of this class of viral cap‐independent‐translation‐elements. As I refine this crystallization chaperone technology, I will also apply it to a notoriously difficult crystallization target, domain V of the human polio virus IRES.Support or Funding InformationNIH, HHMI, The University of Chicago
ETB Receptor Function is Modulated by Estradiol in Young Women
Authors: Shoemaker Leena N. , Haigh Katherine M. , Kuczmarski Andrew V. , McGinty Shane J. , Welti Laura M. , Edwards David G. , Feinberg Ronald , Wenner Megan M. 
Published: April 2020

It is well known that vascular endothelial function declines in women after menopause. Our laboratory has recently shown that impaired endothelial function in postmenopausal women is due in part to a loss of endothelin‐B (ETB) receptor mediated dilation. However, it is unclear whether these changes in ETB function are due to aging or menopause‐related declines in ovarian hormones. Therefore, the purpose of this study was to test the hypothesis that short‐term estradiol (E2) administration would enhance the contribution of ETB receptor mediated dilation during local heating in young women. Twelve young women (24 ± 4 years, 24 ± 3 kg/m2, mean arterial blood pressure: 84 ± 6 mm Hg) participated in this study. Endogenous sex hormone production was suppressed with daily administration of a gonadotropin‐releasing hormone antagonist (GnRHant; Ganirelix) for 10 days. E2 (0.1 mg/day, Vivelle dot patch) was added back on days 4–10. We measured cutaneous vasodilation to local heating (42°C) on day 4 (GnRHant) and day 10 (GnRHant+E2) via laser Doppler flowmetry coupled with intradermal microdialysis for the perfusion of lactated Ringer’s (control) and ETB receptor antagonist (BQ‐788, 300 nM). Cutaneous vascular conductance (CVC) was calculated as cutaneous red blood cell flux/mean arterial blood pressure, and expressed as a percent of maximal vasodilation (CVC %max) achieved with local heating to 43°C and perfusion of sodium nitroprusside (28 mM). E2 administration improved cutaneous vasodilation by 8 ± 10% (control site; P = 0.02) compared to GnRHant. ETB receptor blockade increased cutaneous vasodilation to local heating during hormone suppression with GnRHant (control: 84 ± 7 vs. BQ‐788: 89 ± 5 CVC %max, P = 0.02). However, ETB receptor blockade tended to reduce cutaneous vasodilation to local heating during short duration E2 administration (control: 90 ± 7 vs. BQ‐788: 85 ± 8 CVC %max, P = 0.08). These data indicate that suppression of endogenous ovarian hormone production alters ETB receptor responses in young women, mimicking the response profile in postmenopausal women observed in our previous data. Furthermore, these data suggest that E2 modulates ETB receptor function. Additional data are needed to determine ETB receptor function and sensitivity to E2 in postmenopausal women.Support or Funding InformationResearch supported by AHA Award 16SDG30700015 (MMW), NIH Grant U54‐GM104941 (PI: Binder‐Macleod), and P20 GM113125 (DGE).
Effects of Acclimatization on Cognitive Function at High Altitude
Authors: Oeung Britney , Heinrich Erica C. , Puvvula Nikhil , Pham Kathy , Frost Shyleen , Brena Rebbecca , DeYoung Pamela N. , Orr Jeremy E. , Malhotra Atul 
Published: April 2020

Acute high‐altitude exposure can lead to impaired neurocognitive function. However, it remains unclear if the duration of exposure impacts the degree of impairment or if acclimatization improves performance over time. We hypothesized that measures of sustained attention and reaction time would be impaired by acute high‐altitude exposure and would improve over three days of acclimatization. 14 participants (n=9 men; n=5 women) were included in the study. Participants completed a 30 minute cognitive function test battery (Cognition by Joggle Research) at sea level and each morning over three days at 3800 m elevation. Half of the participant group completed baseline sea‐level cognitive function testing before ascent to high altitude and half completed baseline tests at least 2 days after returning to sea level. The cognitive test battery evaluated sensory motor speed, visual learning, working memory and spatial working memory, abstraction, spatial orientation, complex scanning and visual tracking, risk decision making, and vigilant attention. Mean reaction time on the Psychomotor Vigilance Task (PVT) was higher at high‐altitude compared to sea level (SL: 199 ± 27 ms; Day 1 Alt: 224 ± 33 ms; p=0.005) and did not improve over three days of acclimatization. However, mean reaction time on the Line Orientation Task (LOT) was lower at high‐altitude compared to sea level (SL: 6076 ± 1831 ms; Day 1 Alt: 5173 ± 988 ms; p=0.02) and remained lower throughout acclimatization. The number of correct responses on the LOT did not change significantly upon ascent. Reaction times on the Digit Symbol Substitution Task (DSST) decreased (R=‐0.33, p=0.04) and the number of correct responses increased (R=0.32, p=0.04) throughout acclimatization. Mean reaction time on the Balloon Analog Risk Task (BART) decreased throughout acclimatization (R=‐0.35, p=0.02). These data suggest that while some cognitive domains including complex scanning and visual tracking (DSST) improve with acclimatization, behavioral alertness and sustained attention (PVT) remain impaired. Furthermore, spatial orientation measured by the LOT was improved at high altitude, consistent with studies showing no change, or improvements in visuospatial perception, under mild stress. Further work is required to determine the mechanisms underlying the effects of acclimatization on cognitive function, the domains in which improvement occurs, the time course of these changes, and whether interventions can impact these processes.Support or Funding InformationThis work was funded by the University of California, Riverside, School of Medicine.
Influenza A Virus Escape Mutations and their Effects on Binding Affinity
Authors: Burke Lucas S. , Kalyanaraman Karshana , Flores Stephanie , Khong Trang , Selover Danielle , Rusch-Salazar Laura 
Published: April 2020

The Influenza A virus (IAV) causes a common and potentially fatal infection. The Center for Disease Control reports that 3–11% of the U.S. population is affected annually by IAV. The 2017–2018 burden of influenza led to over 950,000 patient hospitalizations and almost 80,000 deaths. The surface of IAV contains two proteins essential for infection: hemagglutinin (HA) and neuraminidase (NA). HA binds to a receptor on an epithelial host cell surface, and helps IAV penetrate the cell and release the viral RNA genome. As newly formed IAV particles leave the infected cell, NA assists in viral release and driving the infection of neighboring cells. Due to frequent, natural mutations in the IAV genome, annual IAV vaccines are engineered but are not always effective. The Schiffer Lab propagated IAV in vitro in the presence of an antibody to identify mutations of IAV that can escape immune detection. A critical asparagine located in the binding pocket of HA (N203HA) facilitates a hydrogen bond to sialic acid on LSTc (a human receptor analog). The N203VHA escape mutation disrupts the virus‐ligand interaction; however, an allosteric mutation on NA (E329KNA) can compensate for the HA mutation. Our 3‐D printed model of the HA active site visually depicts the binding of the N203 residue with the LSTc. This model further illustrates that viruses can use allosteric mutations to circumvent the immune system. Physically modeling the active site of HA allows students to investigate how substrates fit into active sites and visualize mutations within proteins.Support or Funding InformationThe CREST Program is funded through DUE‐IUSE #1725940 awarded to Milwaukee School of Engineering Center for BioMolecular Modeling.
Small‐Molecule Sigma1 Modulator Suppresses PD‐L1‐Mediated Cancer Cell Adaptive Immune Resistance in Response to Interferon‐Gamma
Authors: Haas Derick A. , Kim Felix J. 
Published: April 2020

BackgroundSigma1 (also known as sigma‐1 receptor) is a unique ligand‐regulated integral membrane protein enriched in the endoplasmic reticulum (ER) of cancer cells. Sigma1 acts as a multi‐functional scaffolding or chaperone protein to maintain protein and lipid homeostasis in the secretory pathway of these cells. Programmed Death‐Ligand 1 (PD‐L1) is a type I integral membrane glycoprotein that is processed through the secretory pathway. Upon reaching the cell surface, PD‐L1 acts as an inhibitory immune checkpoint molecule by binding to its cognate receptor, programmed death‐1 (PD‐1), on activated T cells, resulting in T cell inactivation, thus suppressing the anti‐tumor immune response. PD‐L1 protein expression and transport to the cell surface can be upregulated by interferon‐gamma (IFN‐γ). This mechanism is known as adaptive immune resistance, whereby cancer cells change their phenotype in response to a proinflammatory immune response. PD‐L1 is also incorporated onto cancer cell‐derived extracellular vesicles called exosomes, which can inactivate T cells within the tumor microenvironment and at distant sites. We previously reported that Sigma1 associates with PD‐ L1 and that small molecule Sigma1 inhibitors (Sigma1i) can trigger lysosomal degradation of PD‐L1.ObjectiveThe purpose of our present study is to examine the role of Sigma1 in the PD‐L1 life cycle, including interferon gamma (IFN‐γ) signal transduction, upregulation of PD‐L1 mRNA, post‐translational modification of PD‐L1, transport to the cell surface, and incorporation onto exosomes.MethodsSix cancer cell lines from multiple cancer types were assessed for PD‐L1 protein expression by immunoblot and PD‐L1 mRNA by qRT‐PCR. PD‐L1 surface expression was assessed by flow cytometry and biotinylation assays. Exosomes were isolated by ultracentrifugation and concentrations and particle size profiles were determined using nanoparticle tracking. We used Sigma1i to examine the role of Sigma1 in the PD‐L1 life cycle.ResultsWe found that Sigma1i blocks IFN‐γ induced PD‐L1 at a post‐translational step. Cotreatment of Sigma1i with IFN‐γ results in accumulation of Endoglycosidase H (EndoH) sensitive PD‐L1 in the ER and thus prevents cell‐surface expression of PD‐L1. Furthermore, Sigma1i blocked IFN‐γ‐induced incorporation of PD‐L1 on cancer cell exosomes.ConclusionWe have found that Sigma1i causes nascent PD‐L1 to be retained in the ER, preventing it from progressing through the secretory pathway, reaching the cell surface, and from being packaged onto exosomes. By reducing cell surface PD‐L1 and exosomal PD‐L1, Sigma1 lation could provide a novel approach to enhancing anti‐tumor immunity.
The Incidence and Anatomical Characteristic of Anterior and Posterior Meniscofemoral Ligaments. A Meta‐Analysis.
Authors: Paziewski Mateusz Paweł , Pękala Przemysław Andrzej , Pękala Jakub Radosław , Mann Mitch , Pasieka Paweł Melchior , Tomaszewski Krzysztof Andrzej , Walocha Jerzy Andrzej 
Published: April 2020

IntroductionThe meniscofemoral ligament consists of two divisions ‐ anterior (aMFL) and posterior (pMFL). MFL plays a role as a knee stabilizator and supports the posterior cruciate ligament (PCL). The main purpose of this study was to summarize the anatomic features of the meniscofemoral ligament in the field of arthroscopic surgery, to update current clinical guidelines.Materials and methodsA comprehensive search was conducted through the largest medical databases. Two reviewers were involved in search and data extraction. Both AQUA tool and PRISMA guidelines were strictly followed during the research.ResultsThe study enrolled 61 articles into the analysis. The prevalence of aMFL was 56.2% (95%CI: 46.7–65.4%) of 4366 knees. It was more common in males than in females (37.2% vs. 29.1%) and occured more often in right than in left knees (53.4% vs 46.6%). Mean length and thickness of aMFL equaled 23.00 mm (95%CI 22.8–23.5mm) and 1.7mm (95%CI 1.6–1.8mm) respectively. The incidence of pMFL, was 7 1.0% (95%CI 64.3–77.2%) out of 5056 lower limbs. The pMFL was more likely to appear among females than males (81.1% vs. 76.7%) and in right legs (56.1% vs. 43.9%). Mean length and thickness was 27.4mm (95%CI 27.1–27.7mm) and 2.5mm (95%CI 2.4–2.5mm) respectively. Both aMFL and pMFL occurred together in 33.4% (95%CI 22.1–38.6%), but both were absent in 7.2% (95%CI 2.7–11.8) of cases.ConclusionsAnterior and posterior meniscofemoral ligaments are very common structures of knee joint. Clinicians should take it under attention during arthroscopic surgery to avoid its damage. MFLs high prevalence develop a high demand to expound its function and relevance in knee surgery.