bluuebunny/crossref_metadata_2025_split huggingface dataset:
Exploring the Role of Immunological Biomarkers in the Association Between Mental Health Status and Executive Function in Early Adulthood
Authors: Moore Jessy , Maguire Aindriu R. R. , Dempster Kylie S. , Gagnon Madison K. , Henry Megan A. , O’Leary Deborah D. , MacNeil Adam J. , Wade Terrance J. 
Published: April 2020

By the time Canadians reach 40 years of age almost 50% have, or have had, a mental illness, with the majority of mental health problems first manifesting in adolescence and early adulthood. Poor mental health is the leading cause of disability in Canada and the disease burden is higher than all cancers put together, highlighting the importance of understanding this condition. People with higher levels of depressive and anxiety symptomatology, as measures of mental health status tend to have lower life satisfaction, feel less able to handle daily stresses and have a shorter life expectancy. Poor mental health is most prevalent in working‐age Canadians and is known to affect mood, thinking, and behavior. Recent evidence suggests an altered immunological state among individuals with higher depressive symptoms. It has also been found that there may be a link between an altered immune state and cognitive functioning as many cytokines play a role in communicating with the brain. The aim of the current study was to explore a potential immunological link between depressive and anxiety symptomatology with executive function in early adulthood. This study included a sample of young adults from the Niagara Longitudinal Heart Study (NLHS). Participants completed a self‐reported questionnaire that included questions about depression, anxiety, and executive function. Blood samples were collected, and serum was used to analyze levels of various immune biomarkers. Several immune markers, including interleukins and interferons were found to be associated with changes in depression and anxiety from childhood to early adulthood. These same immune biomarkers were strongly correlated with measures of executive function in early adulthood. Furthermore, participants who reported feeling depressed or anxious reported lower levels of executive function. Thus, we propose an association between mental health status, executive function, and an altered immunological state in early adulthood. This represents a potential physiological state which could help explain both poor mental health status and lower levels of executive function. These immune biomarkers may also represent a new target for research aimed at reducing the burden of mental illness and poor mental health status in early adulthood.Support or Funding InformationThe NLHS is funded by the Canadian Institutes of Health Research (CIHR #s 363774, 399332). ARRM is supported by the Ontario Graduate Scholarship (OGS) program. KSD is funded by a CIHR Doctoral Research Award – Frederick Banting and Charles Best Canada Graduate Scholarship (RFN#167014).
Effect of Range of Motion in the Various Eccentric Exercise Intensities – A Preliminary Study
Authors: Sadacharan Chakravarthy Marx 
Published: April 2020

Purpose of the studyTo assess the functional limitations in the activities of daily living (ADL) and the level of muscle pain in individuals after completing small range of motion eccentric exercises with and without yoga poses.Methods and MaterialsTwelve research participants (untrained active healthy men and women) aged between 18 and 30 years were recruited from the students of the University of New England and were randomly assigned into groups 1 and 2. Four muscle groups (elbow and knee flexors and extensors) were selected (one muscle group per limb) from each participant and maximal voluntary isometric contraction (MVIC) were calculated using a hand‐held dynamometer. Participants performed eccentric exercises protocol (5 × 10 repetitions) with 60° of active range of motion (AROM) using their 15% of MVIC on day 1 of first week, 25% of MVIC on day 1 of third week, and 35% of MVIC on day 1 of fifth week in the elbow and knee joints. To control the initial 60‐degrees of AROM in the elbow and knee joints, dynamic adjustable AROM controlled splints were used. Participants did not perform any exercise protocol during the weeks 2 and 4. In weeks 1, 3, and 5, after the eccentric exercise protocol (day 1), from day 2 to 6, the subjective ADL difficulty scale, visual analogue scale (VAS)) and objective assessments (pain pressure threshold (PPT), arm and thigh circumference, and AROM were carried out. Group 1 performed only exercise protocol whereas group 2 performed prior yoga poses for upper and lower limbs along with exercise protocol. Linear regression and two‐way variance of ANOVA statistical analysis were used.ResultsGroup 2 had a minimal pain and ADL difficulty when compared to group 1. Group 1 that performed exercise protocol at week 5 with 35% MVIC had a mild pain (pain scale ranged 1–2 out of 10) in the elbow extensors and knee flexors and ADL difficulty (scale ranged 1–2 out of 10) in pull a heavy object, carry an object with arm above shoulder, washing opposite armpit and back, ascending stairs, bend to pick up from the floor when compared to group 2. There was no significant difference in the AROM and, arm and thigh circumference between both groups during entire exercise protocol.ConclusionThe small range of motion eccentric exercise with low intensity and yoga poses may have great effect in reducing muscle pain. Current preliminary study can be used as an essential research for sedentary older adults with chronic conditions.Support or Funding InformationFunded by the Biology Department, College of Arts and Sciences (CAS), University of New England, ME, USA ‐04005
Sleep homeostasis in the rat following the induction of a torpor‐like state
Authors: Hitrec Timna , Cerri Matteo , Del Vecchio Flavia , Luppi Marco , Martelli Davide , Occhinegro Alessandra , Piscitiello Emiliana , Squarcio Fabio , Tupone Domenico , Amici Roberto 
Published: April 2020

Soon after the exit from a state of torpor/hibernation, a non‐REM sleep (NREMS) bout with high Delta electroencephalographic activity (EEG) power occurs, suggesting that the time passed in torpor/hibernation is a period of sleep deprivation (Deboer et al., J Comp Physiol A., 1994). The homeostatic nature of the after‐torpor Delta rebound has been challenged (Strijkstra & Daan, Am J Physiol. R, 1998) in the past. According to this alternative view, the Delta enhancement is a consequence of a non‐specific reactivation of cortical activity.We recently found that in the rat, a non‐hibernator, the induction of a torpor‐like state, achieved by multiple injections of muscimol (GABA‐A agonist) into the rostral ventromedial medulla (RVMM), is also followed by a Delta rebound, when the animal recovers from the hypothermic state (Cerri et al., J Neurosci., 2013). The aim of the study was to understand whether the Delta rebound observed in our rats is homeostatically driven or unspecific.We used twelve male Sprague Dawley rats (300–350 g) implanted, under general anaesthesia (Diazepam, 5mg/kg, i.m., Ketamine, 100 mg/kg, i.p.) with: i) electrodes for
EEG, and nuchal (nEMG) and diaphragm (dEMG) electromyogram recording, for Wake‐Sleep states scoring; ii) a thermistor for deep brain temperature (Tbrain) recording; iii) a wireless catheter for arterial pressure (AP) and heart rate (HR) recording; iv) a microcannula in the RVMM for drug delivery. Animals were induced into a torpor‐like state by multiple injections of muscimol (1mM, 120 nl) into the RVMM at an ambient temperature (Ta) of 15°C starting at 11 AM. At 5 PM, after 6h of torpor‐like condition, the animals were placed at Ta 28°C in order to favor the rewarming process. After the return to normothermia (8 PM) the animals were either sleep deprived by gentle handling for 6h or left undisturbed (n=6 each).In comparison to their baseline, animals exposed to sleep deprivation showed a powerful increase in Delta power during NREMS soon after the end of the deprivation period. This increase was significantly larger in sleep deprived rats (281±13%) than in non‐deprived animals (237±19%, p<0.05).The size of the Delta rebound in sleep deprived rats indicates that such rebound is not only the consequence of the previous sleep deprivation period, but also of the sleep debt accumulated during the torpor‐like state. Thus, t
he Delta rebound which immediately follows a torpor‐like condition is not due to a non‐specific reactivation of cortical activity, but is the expression of a sleep need.
Effects of a mitochondria targeted antioxidant on skeletal muscle mitochondrial function with cigarette smoke exposure and Chronic Obstructive Pulmonary Disease
Authors: Layec Gwenael , Thurston Taylor S. , Decker Stephen , Huecksteadt Thomas , Hoidal John R. , Sanders Karl , Kwon Oh Sung 
Published: April 2020

Reactive oxygen species (ROS) are important signaling molecules in cells. However, the exaggerated free radical production accompanying mitochondrial dysfunction with Chronic Obstructive Pulmonary Disease (COPD) has been suggested to play a crucial role in the development of metabolic abnormalities in these patients. Consequently, selective inhibition of mitochondrial ROS could be a potential therapeutic strategy to restore mitochondrial function and subsequently attenuate exercise‐induced metabolic disturbance during exercise in COPD patients. The goal of this study was therefore to determine the effects of a mitochondria targeted antioxidant, MitoQ, on free radical levels, mitochondrial function, and skeletal muscle metabolism in six patients with moderate to very‐severe COPD and a smoking mouse model (C57/Bl6 exposed to cigarette smoke for 8 months) using electron paramagnetic spectroscopy (EPR), 31P/1H magnetic resonance spectroscopy (1H/31P MRS), high‐resolution respirometry in permeabilized skeletal muscle fiber. 4 weeks of MitoQ supplementation (MQ) decreased blood free radical levels measured by EPR (control, CTL: 4.3 ± 3.3 a.u.; MQ: 1.8 ± 1.7 a.u.; P<0.05). Nevertheless, the exercise‐induced changes in intracellular O2 partial pressure, high‐energy phosphate, and pH measured by 1H/31P MRS in the plantar flexor muscles of patients with COPD were not significantly altered with MitoQ. Also, the peak rate of oxidative ATP synthesis measured by 31P‐MRS was lower with MitoQ (CTL: 19 ± 6 mM.min−1; MQ: 14 ± 4 mM.min−1, P<0.05), suggesting an impaired mitochondrial function in vivo. This finding was further supported by the lower muscle respiratory capacity measured in permeabilized skeletal muscle fibers incubated with MitoQ (−43%, P<0.05) from a smoking mouse model. Specifically, complex I (−42%) and free‐fatty acid (−51%) linked respiration were significantly decreased with MitoQ (P<0.05). Together, these findings suggest that decreasing ROS levels using a mitochondria targeted antioxidant may, in fact, be detrimental to oxidative phosphorylation capacity in the skeletal muscle of COPD patients.Support or Funding InformationThis work was funded in part by grants from the Flight Attendant Medical Research Institute (FAMRI), NIH National Heart, Lung, and Blood Institute (HL125756)
Vascular Endothelial Growth Factor Production by Interleukin‐17C‐Stimulated Colorectal Cancer Cells Is Dependent on the STAT3/miR‐23a‐3p Signaling
Authors: Im Eunok , Lee Yunna , Kim Su Jin , Choo Jieun , Heo Gwangbeom , Rhee Sang Hoon 
Published: April 2020

Recent studies have shown that interleukin‐17C (IL‐17C) is associated with tumor initiation and progression of colorectal cancer (CRC). However, the detailed mechanism of action remains to be elucidated. We aimed to investigate the effect of IL‐17C on angiogenesis and delineate the direct target genes of IL‐17C signaling in CRC. Aims were tested by using angiogenesis assays, murine xenograft experiments, immunohistochemical staining, gene silencing, quantitative real time PCR, ELISA, and western blot analysis. IL‐17C induced angiogenesis of intestinal endothelial cells, subsequently enhancing cell invasion and migration of DLD‐1 cells. IL‐17C‐conditioned DLD‐1 cells enhanced angiogenesis by secreting vascular endothelial growth factor (VEGF). Moreover, IL‐17C significantly increased xenograft tumor growth via VEGF production, but treatment with the VEGF receptor 2 inhibitor Ki8751 ameliorated its tumor promoting activity. IL‐17C also increased levels of PECAM and VE‐cadherin in tumor tissues, which was suppressed by Ki8751. Furthermore, IL‐17C increased miR‐23a‐3p expression via STAT3 phosphorylation. Accordingly, miR‐23a‐3p suppressed semaphorin 6D (SEMA6D) expression, enabling VEGF induction. Therefore, our data showed that IL‐17C promotes tumorigenesis and angiogenesis through VEGF production via the STAT3/miR‐23a‐3p/SEMA6D axis, suggesting its potential as a novel target for anti‐CRC therapy.Support or Funding InformationThis work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (No. 2019R1A2C1010536 to E.I.).
The existence of a Cryptic Allosteric Site on Plasmodium falciparum Malate Dehydrogenase
Authors: Botros Natalie , Bell Ellis , Bell Jessica 
Published: April 2020

Approximately one million people die from malaria each year, and thus this disease is a prevalent and pressing matter. Plasmodium falciparum, the protozoan parasite responsible for malaria has been subject to intensive study with the goal of developing specific drugs for malaria treatment. Plasmodium falciparum has a distinctive Malate Dehydrogenase (MDH), being tetrameric compared to the canonical dimeric forms of MDH, yet shares the same catalytic and substrate binding site motives as human mitochondrial and cytosolic forms. To investigate the possible existence of a cryptic allosteric site in the P falciparum enzyme, we have used sequence and structural bioinformatics and identified several short sequences,(G175‐L176, Q211‐M216) each containing highly conserved (in Plasmodium and related species) amino acids that are different in the Plasmodium falciparum enzyme than the human mitochondrial or cytosolic forms. To investigate the possibility that these regions form a cryptic allosteric site in Plasmodium falciparum we expressed, purified, using NiNTA Affinity chromatography, and characterized all three forms (Plasmodium falciparum, human cytosolic and human mitochondrial malate dehydrogenases). In terms of kinetic parameters the Plasmodium falciparum enzyme resembled the mammalian mitochondrial isoform, exhibiting similar substrate inhibition with oxaloacetate and weaker affinity for NADH than the mammalian cytosolic isoform. To determine the potential that the Plasmodium falciparum enzyme had a cryptic allosteric site we designed two mutations, one in each of the two significant sequence differences between the human isoforms and the Plasmodium falciparum enzyme (.D176N and R214E ). Each mutation was constructed using Quikchange mutagenesis, transformed into XL Gold cells and expressed. The purified mutant proteins were characterized using enzyme kinetics and size exclusion chromatography and their overall secondary structures compared to the wildtype enzyme using circular dichroism spectroscopy. Stability was compared using CD thermal melts at 222nm and a Fluorescence based Thermal Shift assay. While both mutations showed altered specific activities compared to wildtype, the D176N mutant showed a 90% lower activity than wildtype Plasmodium falciparum malate dehydrogenase. Both mutations significantly lowered affinity for the cofactor NADH, >20fold decrease in affinity. Taken together these results suggest that Plasmodium falciparum malate dehydrogenase may have a highly conserved cryptic allosteric site distinct from any such site in the mammalian isoforms. This Cryptic Allosteric Site could be exploited to develop inhibitors of Plasmodium falciparum malate dehydrogenase that would not impact the human isoforms.Support or Funding InformationThis work was supported by NSF Grants 1726932 and 0448905.
Flow regulation of WNK1 localization in the cortical collecting duct (CCD)
Authors: Carrisoza-Gaytan Rolando , Subramanya Arohan R. , Ray Evan C. , Kleyman Thomas R. , Satlin Lisa M. 
Published: April 2020

A high K diet (HKD) x 10 d increases (i) luminal flow rate in the distal nephron and (ii) expression of apical immunodetectable L‐WNK1 in CCD intercalated cells (IC), which we propose enhances apical BK channel activity measured as flow‐induced K+ secretion (FIKS) (Webb et al, 2015). We previously demonstrated that fluid shear stress (FSS) x 30 min induces expression of ERK and p‐38, both BK channel modulators, in a CCD principal cell (PC) model (Carrisoza‐Gaytan et al, 2014). The objective of this study was to test the hypothesis that an increase in tubular fluid flow rate rapidly induces apical localization of L‐WNK1 in the CCD.CCDs isolated from NZW rabbits fed a HKD x 10 d were microperfused at slow (n=4) or fast (n=4) luminal flow rates x 1 hr, fixed on the rig, immunoperfused with antibodies (Abs) directed against L‐WNK1 (+ A488‐fluorescent 2o Abs) and rhodamine‐conjugated peanut lectin (PNA) or Dolichus biflorus lectin (DBA), which bind to apical surfaces of IC and PC, respectively, and examined by confocal microscopy. MDCK cells were subject to no (static), low or high FSS x 1 hr (n=2 each condition) and fixed for immunodetection of L‐WNK1 and BKα in situ or harvested for semi quantitative immunoblotting of isolated plasma membranes.The expression of IC apical L‐WNK1 relative to that in the total cell was 40.0±1.1 % greater in CCDs perfused at fast flow compared to those perfused at slow flow rates (p<0.001). In plasma membrane preparations of MDCK cells subject to low and high FSS, L‐WNK1 abundance was 6.0±0.8 and 11.9±2.5 fold greater, respectively, to that measured in the absence of flow. In static MDCK cells, BKα did not colocalize with L‐WNK1 at the apical membrane; however, the two proteins colocalized in cells subject to low or high FSS.In conclusion, (i) apical expression of L‐WNK1 in the microperfused CCD IC is rapidly stimulated by increases in luminal flow rate and (ii) FSS favors apical colocalization of L‐WNK1 with BKα, responses that may facilitate BK channel‐mediated FIKS in the CCD.Support or Funding InformationNIH NIDDK: R01 DK038470‐27A1, P30 DK079307, R01 DK119252, R01 DK098145; NIH NHLBI R01 HL147818.
Dimerization of the Transmembrane Domain of Mucin 16
Authors: Murphy Robert James , Butch Nicole , Li Edwin 
Published: April 2020

Mucin 16 (MUC16) is a transmembrane protein produced by epithelial cells, and its main role is to contribute to the formation of a protective mucous barrier to inhibit debris, pathogens and viruses from entering the cells. However, when overexpressed, MUC16 can lead to cancers of the breast and ovary. Recent studies have shown that in cancer cells, MUC16 is trafficked to the nucleus, but little is known regarding the mechanism of this trafficking. One possible explanation may involve dimerization of MUC16, as shown in the case of mucin 1 (MUC1). Overexpression of the transmembrane MUC1 is also associated with various forms of cancer. Recent studies have shown that MUC1 is trafficked to the nucleus, where it may act as a transcription factor regulating the expression of genes associated with cell growth. The nuclear trafficking of MUC1 is dependent on the formation of MUC1 dimers, formed through inter‐disulfide bonds by two cysteine residues near the end of the transmembrane domain (TMD) of MUC1.The TMD of MUC16 (FWAVILIGLAGLLGVIT
CLI
C) has two cysteine residues that reside in the end of the TMD, which led us to the hypothesis that MUC16 may also form cysteine‐mediated dimers. The ToxR assay, a technique to measure transmembrane domain dimerization, was used to investigate the roles of the cysteine residues in MUC16 TMD dimerization. Our preliminary results show that the cysteine residues in the TMD play a role in dimerization, but not as significant as in the case of MUC1 TMD. These results suggest that noncovalent interactions may be important for MUC16 TMD dimerization. Understanding the formation of MUC16 dimers, similar to MUC1, is important because dimerization may serve as a precursor to the nuclear trafficking of MUC16.
Regulation of Junctophilin‐2 Expression by Triiodothyronine in Adult Rat Cardiomyocytes
Authors: Gilani Nimra , Wang Kaihao , Muncan Adam , Peter Jerrin , Gerdes A. Martin , Stout Randy , Ojamaa Kaie Martin 
Published: April 2020

IntroductionCardiac junctophilin‐2 (Jph2) plays a central role in myocardial contractility by anchoring transverse tubules (TT) to the junctional sarcoplasmic reticulum (jSR), essential for excitation‐contraction (EC) coupling and calcium signaling. Decreases in the expression levels of Jph2 have been observed in a variety of pathological conditions including hypertrophic cardiomyopathy, arrhythmias, and progression of disease in failing hearts. Studies have shown that T3 regulates SR Ca2+ ATPase (SERCa2), phospholamban (PLN), L‐type Ca2+ channels and ryanodine receptors (RyR2), that are responsible for regulating intracellular Ca2+ and maintaining normal systolic and diastolic function. We previously reported that T3 improves cardiac contractile function after induction of myocardial infarction (MI) by maintaining TT network integrity and by regulating expression of myofibrillar and Ca2+ handling proteins. We hypothesize that T3 regulates Jph2 expression and its localization within the jSR‐TT complex to maintain functional TT structures and thus normal Ca2+ transients and contractility.MethodsThyroid deficiency was induced in female Sprague Dawley rats (~220g) by ingestion of 0.025% PTU (propylthiouracil) in drinking water. Control (EU) rats had access to untreated water. After 8 weeks, a subgroup of PTU treated rats received T3 (10ug/kg/d) in PTU‐containing water for an additional 2 weeks. RNA was extracted from left ventricular (LV) tissue to measure Jph2, SERCa2, PLN, LTCC and RyR2 mRNA by RT‐qPCR. RNAseq analysis interrogated 15,000 genes. LV myocytes were isolated by collagenase digestion and cultured with and without T3 (10−7 M). Cells were harvested at 24, 48, and 72 hrs for RT‐qPCR analysis of Jph2, SERCa2, and Bridging Integrator‐1 (Bin1). Isolated myocytes from all study groups were immunolabeled with RyR2, Cav1.2 and Jph2 for nanoimaging using STORM.ResultsRT‐PCR analysis showed significant upregulation of Jph2 expression compared to thyroid deficiency (1.404±0.73 vs 0.322±0.17 fold change). RNAseq revealed 567 differentially expressed genes with 377 genes up‐regulated and 190 down‐regulated in T3‐treated hearts compared to TH deficient hearts. Results showed up‐regulation of Jph2 (p<0.001) and SERCa2 by >1.5‐fold (p<0.00001). Cultured EU and PTU cardiomyocytes similarly showed significantly (p<0.05) increased Jph2 expression in T3 treatment vs non‐treated cells at 48 and 72 hr time points. STORM imaging showed increased clustering of LTCC (Cav1.2) within the RyR/Cav1.2 clusters of TT‐jSR complexes in the T3‐treated vs TH deficient cardiomyocytes (0.53±0.13 vs 0.36±0.03).ConclusionsT3 regulates expression of Jph2 which in turn is a critical regulator of the jSR‐TT organization in cardiomyocytes allowing for optimal calcium transients and contractile function.