bluuebunny/crossref_metadata_2025_split huggingface dataset:
NLRP3 inflammasome activation in dopamine neurons contributes to neurodegeneration in Parkinson’s Disease
Authors: Panicker Nikhil , Kam Tae-In , Neifert Stewart , Hinkle Jared , Mao Xiaobo , Karuppagounder Senthilkumar , Wang Hu , Kumar Manoj , Pirooznia Sheila , Pletnikova Olga , Troncoso Juan , Dawson Valina L. , Dawson Ted M. 
Published: April 2020

Parkinson’s disease (PD) is a progressive neurodegenerative disorder that affects over a million people within the U.S. Underlying the clinical symptoms of PD is the degeneration of dopamine (DA) neurons located in the pars compacta of the substantia nigra (SNpc). Microglial activation of the NLRP3 inflammasome has been well‐documented in various neurodegenerative diseases, including PD. We report herein that adult onset conditional knockdown of Parkin in the mouse SNpc results in priming and activation of the NLRP3 inflammasome within dopamine neurons. These results were replicated in Parkin knockout generated human embryonic stem cell (hES) differentiated DA neurons (hDA neurons). Next, we utilized Nlrp3A350VneoR mice to demonstrate that dopamine neuron specific activation of the NLRP3 inflammasome is sufficient to elicit DA neuron death. Double transgenic Parkinflx/flx/Casp1KO mice were protected from adult onset Parkin deletion‐mediated DA neuron death. Finally, we demonstrate that Parkin is inactivated in alpha‐synuclein pre‐formed fibril (PFF)‐treated cortical neurons and in‐vivo, licensing neuronal NLRP3 inflammasome activation in sporadic PD mouse models as well. Taken together, our results indicate that atypical NLRP3 inflammasome activation within DA neurons may constitute a novel cell‐death mechanism that may contribute to neurodegeneration in PD.Support or Funding InformationThe first (and presenting) author is supported by a post‐doctoral fellowship from the Maryland Stem Cell Research Fund (MSCRF) Grant ID: 2017‐MSCRF‐3838
PAPSS2 ablation prevents acetaminophen‐induced hepatotoxicity in mice
Authors: Xu Pengfei , Wang Pengcheng , Xi Yue , An Yunqi , Xu Meishu , Ren Songrong , Ma Xiaochao , Xie Wen 
Published: April 2020

Sulfate plays an essential role in numerous biochemical and cellular processes in mammalian physiology. The PAPS synthase 2 (PAPSS2) is the primary enzyme to synthesize 3'‐phosphoadenosine 5'‐phosphosulfate (PAPS), which is the universal sulfonate donor for all sulfonation reactions in mammals. Acetaminophen (APAP) overdose is the leading cause of acute liver failure in the United States, and sulfation is widely believed to contribute to the detoxification of many drugs including APAP. The goal of this study is to determine whether PAPSS2 plays a role in APAP‐induced hepatotoxicity. Surprisingly, we found the PAPSS2 knockout mice were protected from APAP‐induced hepatotoxicity, and this protection was accompanied by increased antioxidant ability through the activation Nrf2‐Keap1 and p53 pathways. The hepatoprotective effect of PAPSS2 ablation was abolished when p53 was knocked down. In summary, we have uncovered a unique role of PAPSS2 in APAP‐induced hepatotoxicity.Support or Funding InformationThis work was supported in part by National Institutes of Health Grants DK083952, ES023438
LPAR3 Is Associated with Migration of NIH 3T3 Cells and Progression to Malignant Cell Transformation during Carcinogenesis
Authors: Lee Michael , Hwang Sung-Hee , Yeom Hojin 
Published: April 2020

We have previously identified that the LPAR3 gene is commonly hypermethylated in foci transformed by two non‐genotoxic carcinogens (NGTxC). In this study, we validated the down‐regulation of LPAR3 genes using qPCR analysis in both NGTxC‐induced transformed foci and another v‐Ha‐ras‐transformed NIH 3T3 cells (Ras‐NIH 3T3). We revealed that LPAR3 overexpression significantly increased migration of Ras‐NIH 3T3 whose migration capacity was much lower than that of their parental cells. However, LPAR3 overexpression in Ras‐NIH 3T3 cells resulted in the inhibition of cell survival concomitant with G2/M arrest. On the other hand, inhibition of LPAR3 signaling with Ki16425 had little effect on cell survival of Ras‐NIH 3T3 cells with low level of LPAR3 expression, whereas inhibiting cell survival of NIH 3T3 cells. These results imply that LPAR3 plays a positive role in proliferation of NIH 3T3 cells but not in that of its ras‐transformed cells. To further analyze the role of LPAR3 during carcinogenesis, LPAR3 knockout (KO) in NIH 3T3 cells was generated using the CRISPR/Cas9 genome editing. Four clones from nine initial clones were confirmed with sequencing for genomic editing at the target site. From this initial screen, one clone with biallelic homozygous fragments deletions was selected for further analysis. WST‐1 assay showed that LPAR3 KO greatly inhibited cell survival of NIH 3T3 cells. LPAR3 KO also reduced migration of NIH 3T3 cells. Taken together, our results indicate that LPAR3 might be functionally involved in malignant cell transformation. Further research will be required to understand the intrinsic relationships between cell survival and migration.Support or Funding InformationThis work was supported by the National Research Foundation of Korea (NRF) grant funded by the Ministry of Science and ICT (MIST) (NRF‐2019R1F1A1048733).
Variation in the origin of the first motor branch of the ulnar nerve to the flexor carpi ulnaris muscle
Authors: Dugan Sonja Hedblom , Lundgren Mary , Inouye Sandra , Molen Jonathan Vander , Freemyer-Brown Anna 
Published: April 2020

Introduction/PurposeSurgical decompression of the ulnar nerve in the treatment of cubital tunnel syndrome is performed in close proximity to the first motor branch of the ulnar nerve to flexor carpi ulnaris (FCU). Understanding the variability of this branch is important for improving surgical interventions. The purpose of this study was to determine the location and anatomical variation of the first motor branch to flexor carpi ulnaris.MethodsEmbalmed cadavers were dissected to expose the ulnar nerve as it courses past the medial epicondyle of the humerus. Digital calipers were used to measure the distance between the point of origin of the first motor branch of the ulnar nerve to FCU and the most prominent aspect of the medial epicondyle. The length of the ulna was also measured and correlated with data from ulnar nerve measurements. Statistical significance was defined as a p‐value < 0.05.OutcomesData was obtained from 113 cadaveric elbows. The location of the branch point was most consistently found (88.5% of specimens) distal to the medial epicondyle (average 19.42 mm, standard deviation 4.39, 95% confidence interval 18.54 – 20.29). In 11.5% of elbows, however, the branch point occurred proximal to the medial epicondyle (average 16.02 mm, standard deviation 4.53, 95% confidence interval 13.28 – 18.76 mm). The average distance was 18.42 mm distal to the medial epicondyle in females and 20.45 mm in males, with a statistically significant difference between genders (p‐value = 0.02). The correlation between the branch point of the first motor branch of the ulnar nerve to FCU and ulna body size was also explored.ConclusionThis study has demonstrated that the first motor branch of the ulnar nerve is most consistently located 18.54 to 20.29 mm distal to the medial epicondyle. Males had a significantly greater distance from the origin of the first motor branch of the ulnar nerve to FCU from the medial epicondyle compared to females. No statistically significant correlation was found related to laterality. Additionally, the prevalence of the anatomical variant in which branching of the first motor nerve from the ulnar nerve occurs proximal to the medial epicondyle was estimated. Prior to this study, the prevalence of this variant had not been reported.Support or Funding InformationThe authors would like to thank Midwestern University for the use of the specimens in this study.
Zinc Deficiency‐Induced NFkB Activation Promotes Hypertension by Driving Renal Na+ Reabsorption
Authors: Williams Clintoria R. , Schindele Dylan S. , Murta Cindellynn K. , Wenegieme Tara-Yesomi , Waite Aston , Sonner Martha J. 
Published: April 2020

BackgroundZinc deficiency (ZnD) is a common comorbidity with chronic disorders including diabetes and kidney disease. Patients with these diseases also have a higher incidence of hypertension. Recently, we reported that a zinc deficient diet is sufficient to induce hypertension in mice. Changes in blood pressure were accompanied by increased Na+ reabsorption via the renal sodium chloride cotransporter (NCC). Although our novel results indicate that zinc plays a critical role in NCC regulation and its downstream effects on blood pressure, the specific mechanisms involved are unknown.HypothesisSince nuclear factor‐kB (NFkB) is a key transcription factor implicated in ZnD‐mediated effects, we tested the hypothesis that ZnD stimulates renal NFκB activation which drives NCC upregulation and thereby promotes hypertension.Experimental DesignAdult, male C57BL/6 mice were fed a zinc adequate (ZnA; 50ppm) or a ZnD (1ppm) diet for 6 weeks. To examine the role of NFkB in ZnD‐induced hypertension, mice were switched from a ZnA‐diet to a ZnD‐diet for 5 weeks. After, ZnD mice were administered caffeic acid phenethyl ester (CAPE), an NFkB inhibitor, for 1 week. In mice, NCC expression (qRT‐PCR) and blood pressure (tail‐cuff) were measured. To further investigate the role of NFkB in NCC expression (qRT‐PCR and Western blot), mouse distal convoluted tubule (mDCT) cells were treated with TPEN (a zinc chelator) or vehicle (DMSO) ± CAPE.ResultsCompared to ZnA mice, NCC mRNA abundance was increased in ZnD mice (7.625 ± 1.747 vs 1.0 ± 0.127) and was accompanied by enhanced renal NFkB nuclear localization. In mDCT cells, TPEN‐induced ZnD stimulated NCC mRNA expression (3.152 ± 0.966 vs 1.0 ± 0.174) and NFkB upregulation (1.573 ± 0.117 vs 1.0 ± 0). However, NFkB inhibition by CAPE prevented TPEN‐induced NCC mRNA (0.636 ± 0.178 vs 3.152 ± 0.966) and protein (1.039 ± 0.018 vs 2.335 ± 0.062) expression in mDCT cells. Finally, CAPE administration lowered blood pressure (154.5 ± 5.42 vs 138.1 ± 1.97 mm Hg) in ZnD mice.SummaryThese results demonstrate that 1) renal NFkB is a Zn2+‐regulated transcription factor, 2) NFkB is involved in NCC regulation and 3) NFkB mediates ZnD‐induced blood pressure increases.SignificanceTaken together, these data indicate that ZnD stimulates NFkB activation thereby driving NCC upregulation and hypertension.Support or Funding InformationAHA‐16SDG27080009 and NIH‐R21DK119879
Mechanism of Acrolein Toxicity:The Effect on Epigenetic Changes
Authors: Nwaiwu Uchechi Grace , Yousefipour Zivar , Ranganna Kasturi , Joseph Mathew 
Published: April 2020

Acrolein, an alpha‐beta unsaturated aldehyde and a very reactive toxic compound, is released into the environment from different sources such as combustion of fossil fuel, cigarette smoke, overheating of frying oil, as well as endogenously being produced in body via lipid peroxidation. As a pervasive environmental pollutant, acrolein poses a serious environmental health threat acknowledged by investigators, health, and environmental government agencies.Epigenetics is the modifications in gene expression that do not alter the DNA sequence of a gene. This alteration could occur naturally or by factors such as age, environmental exposure, individual lifestyle, and disease condition. Phosphorylation, Methylations and acetylation are the most common epigenetic changes. N‐ Acetyl cysteine (NAC) is an antioxidant involved in the production of cellular glutathione.The aim of the study was to determine the effect of acrolein on histone phosphorylation, acetylation and methylation in vascular smooth muscle cells (VSMCs) and to establish the beneficial effect of NAC in prevention of acrolein toxicity through blockage of histones modification.VSMCs were treated with 3μg/ml acrolein for 6 hours in the presence and absence of 0.2 mM NAC. At the end of the treatment, cytotoxicity of acrolein was measured using tetrazolium‐calorimetric assay. Additionally, free radical generation was measured by fluorometric methods, histone H3 modification by ELISA kit, and protein expression by western blotting.Results indicated that six‐hour exposure of VSMC to 3μg/ml of acrolein resulted in 99% decrease in cell viability and addition of 0.2Mm of NAC provided complete protection of VSMCs from toxicity caused by acrolein. In the absence of NAC, acrolein increased level of reactive oxygen species (ROS) generation by 85%. Addition of NAC abolished high level of ROS by 75%.ELISA analysis showed acrolein‐induced modification of histones 3 (H3) at different lysine and serine residues including SER‐10P and SER‐28P, K4ME, K9ME, K27ME, K79ME, K9AC, K14AC, K18AC. Western blot analysis of two of these residues indicated 45% increase in Ser10P1, 59% increase in Ser28p1, and addition of NAC decreased these modifications by 86% and 76% respectively. Additionally, we observed a 66% increase in the expression of methylated H3K9 and 66% in acetylated H3k9 protein, which was attenuated by addition of NAC by 71% and 65% respectively.In conclusion, this study revealed that exposure of VSMCs to acrolein causes modification of H3 histones at different residues and NAC is effective in inhibiting the effects of acrolein.Support or Funding InformationNIH SC3GM103746‐04
New nonintrusive method of predicting adult stature from the age of 13 years using chronological age and maturity. Validation in adolescent basketball players
Authors: Duvallet Alain Louis , Pineau Jean-Claude , Duvallet Emilie , Lhuissier François , Beaudry Michele 
Published: April 2020

The purpose of this study was to define a new method to estimate the adult height of an individual from data recorded during a single and nonintrusive childhood examination. The data required are maturity stage and stature in a standing position. Specific growth curves were obtained from longitudinal data collected from 125 sedentary boys aged from 12 to 17.5 years, during 5 consecutive years. The sample comprise of 1234 measurements.The puberty stages were based on facial, axillary hair growth and changing voice with four stages: stage 1 (ST1, below the puberty), stage 2 (ST2, prepubescent), stage 3 (ST3, para pubescent), and stage 4 (ST4, pubescent). They were classified as early, standard, or late maturation.Between the different maturation groups, significant differences were found for the age of peak height velocity (APHV). From 160 to 164 months, we found a connection between the pubertal stages and the APHV without possible intersection. Significant differences were observed between APHV for each maturation group, which enable to model average curves of the stature for each puberty group.To validate the new model, we predicted young basketball players’ adult stature. First, data were collected (height and stage of puberty) a single time for age between 160 and 164 months. From our models of sedentary reference subjects we estimated the adult stature. In a second time, these estimations were compared to the real measured stature at 18 years old (216 months).For each basketball player we calculated the deviation from the average value obtained on the first population expressed as standard deviation (Z‐score).The relation between the predicted stature and the adult stature for overall basketball population shows a correlation with r = 0.98 and SEE = 1.65 cm. The predictions lie within +/− 0.3cm, 98% of the time.This study shows that the knowledge of biological maturation (peak of height velocity) and maturity (delayed, standard or advanced puberty) make possible to develop new stature growth curves, and to predict adult stature.This technique is a new valid nonintrusive and accurate method, which permits to predict adult stature. It was validated with a population of basketball players and constitutes an advance in the detection and the orientation of future basketball players.Support or Funding InformationMichele Beaudry
Reliability of Skin Blood Flow Measurement with Multiple Laser Doppler Probes
Authors: Cui Jian , Kunselman Allen R. , Herr Michael D. , Pai Samuel , Blaha Cheryl , Luck Jonathan Carter , Sinoway Lawrence I. 
Published: April 2020

Skin blood flow (SkBF) measurements with laser Doppler probe provide a continuous real‐time index for local microcirculatory blood flow under the probe. However, because the area detected by a single probe is very small, it is known that SkBF reading may vary significantly if the position of the probe is moved slightly. The possible low reliability after replacing the probe limits the application of this measurement in some experiments (e.g. prior and after outdoor exercise). In this study, we tested the hypothesis that using multiple laser Doppler probes could increase the reliability of the measurements. SkBF, local skin temperature (Tsk) and blood pressure were measured with 3 repeated trials in 11 subjects (6 M, 5 F, 42 ± 5 yrs) in a temperature controlled room. Seven laser Doppler probes were placed in a custom‐made holder (round shape, diameter 45 mm). Trial 1: after the probe holder was placed on a forearm, the position was marked. After ~5 min rest, SkBF and Tsk (under the holder) were recorded for 3 min. Then, the probe holder was removed from the forearm and placed on the side calf of a leg to measure leg SkBF. After dis‐instrumentation, subjects were released from the testing table for 10–15 min. Trial 2 and 3: the probe holder was carefully replaced as close as possible on the same positions according to the markers on the skin. The measurements on forearm and then leg as well as the intervals between the trials were repeated. In this Test‐Retest Reliability study, two‐way mixed‐effects models with absolute agreement were used to compute the intraclass correlation coefficient (ICC). There was no significant difference in blood pressure and Tsk between the trials. With the measurements from each single probe, the lowest ICCs were 0.68 (95% Confidence Interval: 0.35, 0.89) for SkBF and 0.76 (0.48, 0.92) for cutaneous vascular conductance (CVC) at leg. With the averaged values from 7 probes, the ICCs were 0.86 (0.62, 0.96) for SkBF and 0.91 (0.74, 0.97) for CVC at leg, and 0.95 (0.87, 0.99) for SkBF and 0.96 (0.88, 0.99) for CVC at forearm. Moreover, with the averaged values from 4 contiguous probes, the ICCs were greater than 0.84. These data suggest that SkBF measurement with multiple laser Doppler probes in a custom‐made holder has high reliability after replacing the probes on the same subjects.Support or Funding InformationSupported by NIH MPI R01 HL141198 (Li and Cui) and UL1 TR002014 (Sinoway)
DNA Replication Checkpoint Activates Respiration in Budding Yeast
Authors: Nagar Shreya , Kaur Pritpal , Bhagwat Madhura , Jassar Salony , Vancura Ales 
Published: April 2020

In addition to DNA damage checkpoint (DDC), eukaryotic cells have also DNA replication checkpoint (DRC) that is distinct from the DDC and specifically signals slowly progressing or arrested replication forks. We have showed previously that DDC activates respiration to increase ATP production and to elevate dNTP levels, which are required for efficient DNA repair and cell survival upon DNA damage. The underlying mechanism involves DNA damage‐induced downregulation of histone expression and altered chromatin structure, leading to increased transcription of genes encoding enzymes of tricarboxylic acid cycle, electron transport chain, and oxidative phosphorylation. Here we show that similarly to DDC, activation of DRC also induces respiration by a Mec1p‐ and Rad53p‐ dependent mechanism. However, unlike DDC, DRC induces respiration by a mechanism that is not dependent on histone gene expression and chromatin structure.Support or Funding InformationNIH GM120710
Regulation of Histone Gene Expression during DNA Damage Response in Budding Yeast
Authors: Bhagwat Madhura , Nagar Shreya , Kaur Pritpal , Vancura Ales 
Published: April 2020

The DNA damage response (DDR), a highly conserved process, senses and repairs damaged DNA. We have showed previously that DDR activates respiration to increase ATP production and to elevate dNTP levels, which are required for efficient DNA repair and cell survival upon DNA damage. The underlying mechanism involves DNA damage‐induced downregulation of histone expression and altered chromatin structure, leading to increased transcription of genes encoding enzymes of tricarboxylic acid cycle, electron transport chain, and oxidative phosphorylation. Here we show that the downregulation of histone gene expression during DDR requires Rad53p and occurs at the level of transcription and not at the level histone mRNA decay. The corresponding mechanism involves DDR‐mediated inhibition of assembly of the preinitiation complex and decreased recruitment of Spt10p and Spt21p to the promoters of histone genes.Support or Funding InformationNIH GM120710
Serum lead and cadmium exposure is an independent risk factor for acute ischemic stroke in a south Taiwan population
Authors: Chen Hsin-Hung , Yen Cheng-Chung , Hsu Yi-Ting , Cheng Pei-Wen , Tseng Ching-Jiunn , Lin Ching-Huang 
Published: April 2020

BackgroundAcute ischemic stroke (AIS) is among the major causes of disability and death worldwide. It is caused by thrombotic or embolic occlusion of a cerebral artery and has a higher prevalence than hemorrhagic stroke. Environmental exposure to heavy metals has been associated with AIS risk; however, this association is yet to be well established. We aimed to assess the effect of accumulation of heavy metals (e.g. arsenic, cadmium, lead, and mercury) in patients with AIS.MethodsWe enrolled 33 pairs of newly diagnosed patients with AIS. We used inductively coupled plasma mass spectrometry to measure heavy metal levels. We used Pearson’s correlation coefficient to assess the association between heavy metal levels and the variables. Between‐group differences in the heavy metal levels and variables were analyzed using an independent t‐test.ResultsSerum cadmium levels were significantly higher in patients with AIS who were smokers (mean ± SD: 1.0 ± 0.5 mg/L versus 0.6 ± 0.2 mg/L; P < 0.003). Similarly, serum lead levels were significantly higher in smokers (mean ± SD: 25.3 ± 8.5 mg/L versus 17.5 ± 6.3 mg/L; P < 0.006). Further, serum cadmium levels were significantly higher in alcohol drinking patients with AIS (mean ± SD: 1.2 ± 0.6 mg/L versus 0.6 ± 0.3 mg/L; P < 0.003). Similarly, serum lead levels were significantly higher in alcohol drinkers (mean ± SD: 29.5 ± 8.6 mg/L versus 18.5 ± 6.1 mg/L; P < 0.003).ConclusionsSerum cadmium and lead levels were associated with the incidence of AIS both independently and in association with smoking and drinking. This supports the hypothesis that smoking and drinking increases cadmium and lead exposure, and therefore increases the AIS risk.Support or Funding Information107‐2320‐B‐075B‐002‐MY2、107‐2320‐B‐075B‐001