bluuebunny/crossref_metadata_2025_split huggingface dataset:
Zinc Deficiency‐Induced Renal NFkB Activation drives Sodium Chloride Co‐transporter Upregulation.
Authors: Wenegieme Tara-Yesomi , Waite Aston , Naraine Meagan , Murta Cindellynn , Schindele Dylan , Sonner Martha , Williams Clintoria 
Published: April 2020

BackgroundZn2+ deficiency (ZnD) is a worldwide problem. In the United States, 14% of Americans are Zn2+ deficient, which represents 1 out of 7 people. In ZnD populations, the prevalence of hypertension is higher. In our recent studies, we demonstrated that ZnD induces hypertension by promoting renal Na+ reabsorption by the sodium chloride co‐transporter (NCC). However, the exact molecular mechanisms involved in NCC upregulation were undefined. Nuclear factor‐κB (NFκB) is a transcription factor found to play a role in ZnD‐mediated detrimental effects throughout the body.HypothesisAs such, we hypothesized that ZnD drives renal NFκB activation.Experimental DesignTo examine the effects of ZnD on renal NFκB activation, adult, male C57Bl/6 mice were fed a ZnA‐ or ZnD‐diet for 6 weeks. NFκB expression and nuclear translocation were examined by immunohistochemistry. To confirm the role of Zn2+ in NFκB regulation, mouse distal convoluted tubular (mDCT) cells were treated with the Zn2+ chelator ‐ N,N,N′,N′‐tetrakis(2‐pyridylmethyl)ethane‐1,2‐diamine (TPEN) or vehicle ± Zn2+ supplementation.ResultsIn ZnD mice, NFκB protein expression and nuclear localization were increased compared to ZnA mice. Consistently, in mDCT cells, TPEN‐induced ZnD stimulated NFκB expression and nuclear translocation. However, Zn2+ supplementation reversed TPEN‐induced NFκB upregulation.ConclusionThese results indicate that 1) NFκB is a Zn2+‐regulated nuclear transcription factor, and 2) ZnD drives renal NFkB activation.SignificanceNFκB represents a potential mediator that drives ZnD‐induced NCC upregulation and consequently renal Na+ reabsorption and hypertension.Support or Funding InformationAmerican Heart Association ‐ Scientist Development Grant #16SDG27080009 National Institutes of Health ‐ R21 Exploratory/Development Grant #R21DK119879
Effect of Vancomycin on Cytoplasmic Peptidoglycan Intermediate Levels in Vancomycin Resistant Enterococci.
Authors: Gargvanshi Shivani , Gutheil William 
Published: April 2020

Vancomycin is a natural glycopeptide antibiotic and is used for the treatment of multi‐drug resistant Gram positive bacteria. However, resistance to vancomycin has emerged. Vancomycin resistance in VanA‐type Enterococcus faecium is due to a vancomycin resistance cassette comprised of vanH, vanX, vanY, vanZ, vanR and vanS genes. These genes encode for an alternative peptidoglycan biosynthesis pathway in which D‐Ala‐D‐Ala is replaced with D‐Ala‐D‐Lac. Vancomycin binds with a lower affinity to D‐Ala‐D‐Lac as it does to the nomal dipeptide. In this study, several of the unique UDP‐linked intermediates from VanA‐type vancomycin resistant Enterococcus faecium (VRE) were preparatively purified from vancomycin treated cultures and used to optimize their LC‐MS/MS quantification. Cytoplasmic pool levels were then measured in VRE before and after vancomycin exposure. VRE in the absence of vancomycin had low but readily detectible basal levels of VanA pathway intermediates. After a 15 min vancomycin exposure, normal pathway intermediates were only modestly affected, whereas alternative pathway intermediates increased substantially. Alternative pathway intermediates then decreased back toward unexposed levels after longer vancomycin exposure. A vancomycin concentration profile demonstrated a midpoint of vancomycin effect between 1 and 4 μg/mL. Time course experiments revealed a complex response to vancomycin exposure, with most normal pathway intermediates responding rapidly (minutes) to vancomycin exposure, and alternative pathway intermediates increasing for 15–20 min and then decreasing partially back toward normal levels. qRT‐PCR study also demonstrated that mRNA levels of VanA pathway genes also took about 15 min to reach their maximal level of induction.Support or Funding InformationNIH R15
Western diet promotes renal injury, inflammation, and fibrosis in a murine model of Alström syndrome
Authors: Kim Young Chul , Ganguly Souradipta , Nespoux Josselin , Freeman Brent , Zhang Haiyan , Brenner David , Dhar Debanjan , Vallon Volker 
Published: April 2020

Alström syndrome is a rare recessive genetic disease caused by mutations in ALMS1, which encodes a protein that is related to cilia function and intracellular endosome trafficking. The syndrome has been linked to impaired glucose metabolism and chronic kidney disease (CKD). Polymorphisms in ALMS1 have likewise been linked to CKD, but little is known about the modification of the phenotype by environmental factors. To gain further insights, the fat aussie (foz) mouse strain, a genetic murine model of Alström syndrome, was exposed to a normal chow (NC) or to a Western diet (WD, 20% fat, 34% sucrose by weight and 0.2% cholesterol). Body weight was 50% higher in foz vs WT mice on NC, and WD enhanced the difference to 64% (Pinteraction=0.0002, two‐way ANOVA). Kidney weight to body weight ratio was not different between groups. Plasma creatinine was lower in foz vs WT mice independent of diet, potentially indicating glomerular hyperfiltration in foz mice. Renal mRNA expression of injury marker Kim1 was not affected by WD in WT and was not different between foz and WT mice on NC (P=0.9995), but it was 26‐fold higher in foz vs WT mice on WD (P<0.0001). Likewise, other renal injury markers (Ngal mRNA; histology assessment) and renal markers of inflammation (Tnf, Il6, Il10 and Ccl2 mRNA; CD68‐positive cells) and fibrosis (Col1A1, Timp1 and Tgf‐beta mRNA; Masson’s trichrome staining) were similar in both genotypes on NC, but significantly greater in foz vs WT mice fed a WD. Albuminuria was higher in foz vs WT mice on both diets but WD significantly increased the difference (Pinteraction=0.0019, two‐way ANOVA). A glucose tolerance test performed in foz and WT mice on a WD revealed similar basal blood glucose levels and subsequent blood glucose profiles. These results indicate that a Western diet sensitizes a murine model of Alström syndrome to kidney injury, inflammation and fibrosis, an effect that may not be solely due to effects on glucose metabolism. Polymorphisms in ALMS1 may induce CKD in part by modulating the deleterious effects of high dietary fat and sucrose on the kidney.Support or Funding InformationThe authors were supported by NIH grants R01DK112042, R01DK106102 (VV), the UAB/UCSD O’Brien Center of Acute Kidney Injury NIH‐P30DK079337 (VV), the Department of Veterans Affairs (VV), and by an investigator‐initiated research project by Janssen (DB, VV). DD was supported by NIH/CTRI 1KL2TR001444 and the American Liver Foundation (ALF) “Liver Scholar” grants.
Lysine Acetylation in Granulosa Cells of PCOS Women Regulated by Carbohydrate Metabolism
Authors: Pei Wendi , Min Zheying , Yu Yang 
Published: April 2020

ContextLower‐quality embryos are often found in Polycystic Ovary Syndrome (PCOS) women during assisted reproductive technology treatment; however, there is still a lack of a reliable marker to predict the outcomes of fertilization and embryo development in the clinic.ObjectiveThe aims of this study were to comparatively profile protein lysine acetylation in ovarian granulosa cells, to understand its potential effect on ovarian function at the posttranslational modification level and to establish a reliable marker to predict embryo quality in women with PCOS.DesignThis study recruited 47 PCOS patients and 55 non‐PCOS controls. Mural granulosa cells were collected during oocyte retrieval surgery. A quantitative analysis of acetylated proteomics was carried out by mass spectrometry. The clinical presentations and outcomes of the patients with different acetylation levels in their granulosa cells were analyzed.ResultsIn the granulosa cells, there was widespread lysine acetylation of proteins, of which 265 proteins had increased levels of acetylation and 68 proteins had decreased levels of acetylation in the PCOS group. Most notably, differentially acetylated proteins were significantly enriched in the metabolic pathways of glycolysis/gluconeogenesis, fatty acid degradation and amino acid biosynthesis. In addition, women with PCOS with enhanced acetylation in their granulosa cells had markedly reduced 2 pronuclear (2PN) rates, numbers of available embryos and rates of available embryos.ConclusionThe dynamic levels of lysine acetylation in the granulosa cells of women with PCOS might alter ovarian metabolic homeostasis and can be a marker to reflect embryo quality in the clinic.Support or Funding InformationThis work was supported in part by the National Key R&D Program of China (2016YFC1000601) and the National Natural Science Funds (81571400, 81771580, and 81971381).
Role Of SDF:CXCR4 In Diet‐Induced Cardiac Injury
Authors: Dong Feng , Patel Karishma , Kiedrowski Matthew , Penn Marc 
Published: April 2020

IntroductionDiabetic cardiomyopathy (DCM) is a major cardiovascular complication in patients with diabetes and is defined as ventricular dysfunction (in diabetes) independent of coronary artery disease. In this study, we define a novel role for the SDF‐1: CXCR4 axis in diabetes‐associated myocardial dysfunction.MethodsWild‐type mice were randomly assigned to a high fat high sugar diet (HFHS) or control diet (LF) for 14 months. Serial echocardiography was used to assess cardiac function. The hSDF‐1 plasmid was injected into the LV wall of HFHS mice 7 months and 14 months after HFHS diet. The mRNA levels in the hearts were quantified by qPCR.ResultsHFHS‐fed mice (vs. control diet) showed significantly increased deceleration time (diastolic dysfunction) 7 months after HFHS diet and decreased Ejection Fraction (EF) (systolic dysfunction) 14 months after the HFHS diet. We observed a significant increase in cardiac myocytes surface area and a decrease in vascular density in the hearts of HFHS mice. HFHS‐fed mice showed decreased P‐selectin, E‐selectin expression and increased CXCR4, Resistin, and DDR2 expression in the heart. There is no significant improvement in diastolic function after the SDF‐1 injection at 7 month. However, direct myocardial injection of hSDF‐1 plasmid led to a significant improvement in EF compared to the control group. To determine the role of CM CXCR4 in hyperglycemia associated cardiac injury, we quantified cardiac function and survival rate in HFHS‐fed CM‐CXCR4 null mice. We observed a significantly increased mortality rate before 14 months on HFHS fed CM‐CXCR4 null mice compare to HFHS‐fed control mice.ConclusionHFHS diet induces diastolic dysfunction in the short term then systolic dysfunction after a long term. SDF‐1 treatment ameliorates systolic dysfunction but not diastolic dysfunction. Our data suggest that cardiac myocyte expression of CXCR4 has an important role in diabetes‐associated cardiac injury.
Expression of Kv11.1 Channels in Lungs and Role in Pulmonary Hypertension
Authors: Shults Nataliia V. , Rybka Vladyslava , Suzuki Yuichiro , Brelidze Tinatin 
Published: April 2020

BackgroundWhile Kv11.1 potassium selective channels are well known for their contribution to the heart repolarization little is known about their importance for the lung function. Here we show that Kv11.1 channels are abundantly expressed in the human and rat lung tissues.Methods & ResultsWe found that, in the lungs of healthy humans and rats, Kv11.1 channel expression was limited to the large pulmonary arteries (PAs). In the lungs of human patients with chronic obstructive pulmonary disease (COPD) and of rats with pulmonary arterial hypertension (PAH), Kv11.1 channels were expressed not only in the large PAs, but also in the small PAs with the diameter <100 micrometers. The increase in the Kv11.1 channel expression followed the time course of the development of pulmonary vascular remodeling in PAH rats. Administration of dofetilide, a Kv11.1 blocker, to rats with PAH inhibited PAH‐associated pulmonary vascular remodeling.ConclusionsOur study indicates that Kv11.11 channels are expressed in the lung and that these channels mediate the development of pulmonary vascular remodeling. Dofetilide is an FDA approved drug used for treatment of atrial fibrillation. Thus, our findings raise a possibility of repurposing this antiarrhythmic drug for the treatment of pulmonary hypertension.Support or Funding InformationSupported by NIH
LC‐MS‐based urine metabolomics analyses for early diagnosis of medulloblastoma
Authors: Li Jing , Hao Xiaolei , Guo zhengguang , Sun Haidan , Liu Xiaoyan , Zhang Yang , Zhang liwei , Tian Yongji Yongji , Sun Wei 
Published: April 2020

(MB) is the most common type of brain cancer in pediatric patients. In present study, we applied liquid chromatography ‐ mass spectrometry (LC‐MS) based metabolomics to analyze a cohort including 425 urine samples (118 healthy controls, 112 medulloblastoma patients, 33 patients with brain malignant cancers and 53 patients with brain benign diseases, 29 MB patients with surgery after a week and 80 MB patients with surgery after a month). Differential metabolites were analyzed to investigate if urine metabolites could differentiate MB from non‐MB. Apparent separation was observed between MB urine samples and healthy controls, brain benign diseases, other brain malignant tumor. The AUC in discovery group respectively were 0.94, 0.938, 0.808, and the AUC of external validation dataset were 0.913, 0.889, 0.822. According to the comparisons, 14 metabolites were found to be the specific metabolites of MB. Among 14 metabolites, two metabolites were validated in postoperative samples and with high AUC values (0.858 compare to non‐MB). Our data showed that urine metabolomics could be used for MB diagnosis and would provide candidates for the potential biomarkers of MB.Support or Funding InformationNational Basic Research Program of China (No. 2013CB530805, 2014CBA02005)
Protein‐Tyrosine Kinase, Syk Accelerates Phagosome Maturation by Depolymerizing F‐Actin in Complement‐Mediated Phagocytosis
Authors: Tabata Hiroyuki , Tohyama Yumi 
Published: April 2020

Syk is a non‐receptor protein‐tyrosine kinase and primarily expressed in hematopoietic cells. We previously reported that Syk plays an essential role in complement‐mediated phagocytosis, especially in engulfment process. In the current study, we aimed at clarifying the role of Syk in phagosome maturation process in complement‐mediated phagocytosis. To reveal the role of Syk in the phagocytosis, we established various Syk‐knockout (Syk‐KO) cell lines by using CRISPR/Cas9 system in HL60 cells. Using these parental and mutant HL60 cells, we performed complement‐mediated phagocytosis assay after macrophage‐like differentiation. As a result, we found that Syk‐KO macrophages permitted escape of C. albicans from the phagosomes because of the insufficient phagosome acidification. Additionally, we found that fusion of phagosomes with lysosomes did not occur in Syk‐KO cells and phagosomes of Syk‐KO cells still remained surrounded by thick F‐actin structure after engulfment process. These results demonstrate that Syk accelerates phagosome acidification by facilitating the collapse of F‐actin surrounding phagosomes and resultant fusion of lysosomes to the phagosomes in complement‐mediated phagocytosis. In conclusion, our results indicate that actin‐remodeling is essential not only for phagosome formation but also for phagosome maturation process in complement‐mediated phagocytosis.Support or Funding InformationThis work was supported by JSPS KAKENHI Grant Number JP 18K07432.
Unfolded Protein Response Regulates Pulmonary P53 Expression
Authors: Akhter Mohammad Shohel , Kubra Khadeja-Tul , Uddin Mohammad Afaz , Barabutis Nektarios 
Published: April 2020

INTRODUCTIONLung endothelial barrier dysfunction leads to severe pathologies, including the lethal Acute Respiratory Distress Syndrome. P53 has been associated with anti‐inflammatory activities. The current study employs a variety of Unfolded Protein Response (UPR) activators and inhibitors to investigate the regulation of P53 by UPR in lung cells. The outcomes of our investigation reveal a positive regulation between UPR and P53. Since it has been shown that a mild induction of UPR opposes inflammation, we suggest that P53 is involved in those protective activities in the lung.METHODSBovine Pulmonary Arterial Endothelial Cells (BPAEC) were maintained at 37°C in a humidified atmosphere of 5% CO2 – 21% O2, and were cultured in DMEM medium supplemented with 10% FBS and 1X penicillin/streptomycin. Protein levels were measured by Western Blot analysis, and were quantified using Image J software. All antibodies were purchased from Cell Signaling (Danvers, MA), and the chemicals from VWR (Radnor, PA).BPAECs were purchased from Genlantis (San Diego, CA).RESULTSBPAEC exposed to the UPR inductors Brefeldin (2 μg/ml), Dithiothreitol (1mM), or Thapsigargin (1μM) for 4, 8 and 24 hours exerted increased expression of the UPR marker Binding Immunoglobulin Protein (BiP); as well as P53. On the other hand, treatment of those cells with the UPR suppressors N‐acetyl Cysteine (1mM), Kifunensine (5μM), or the ATP‐competitive IRE1α kinase inhibiting RNase attenuator (1μM) for the same periods (4, 8, 24 hours) exerted the opposite effects. Thus, those suppressors reduced both BiP and P53 abundance in the intracellular niche.CONCLUSIONSOur study suggests that UPR is directly associated with P53 expression, and that UPR induction induces P53. Since this protein supports the endothelium function, future studies may delineate the exact components of the UPR machinery in charge of that regulation, and reveal whether those effects are associated with lung endothelium integrity.Support or Funding InformationThis work was supported by 1) R&D, Research Competitiveness Subprogram of the Louisiana Board of Regents through the Board of Regents Support Fund (LEQSF(2019‐22)‐RD‐A‐26) II) NIGMS/NIH (5P20GM103424‐15, 3P20GM103424‐15S1).
The Marine Pharmacology and Pharmaceuticals Pipeline in 2020
Authors: Le Henry M , Newman David J , Glaser Keith B , Mayer Alejandro M 
Published: April 2020

The ocean’s organisms continue to deliver a chemical biodiversity that contributes to both the global preclinical and clinical pharmaceutical pipelines. Thus, in November 2019, the clinical marine pharmaceutical pipeline consisted of 9 approved marine‐derived drugs: for Herpes Simplex Virus, vidarabine (Vira‐A®, FDA‐approved 1976); for pain, ziconotide (Prialt®, FDA‐approved 2004); for hypertriglyceridemia, omega‐3‐acid ethyl esters (Lovaza®, FDA‐approved 2004); and for cancer, cytarabine (Cytosar‐U®, Depocyt®, FDA‐approved 1969);, eribulin mesylate (Halaven®, FDA‐approved 2010), brentuximab vedotin (Adcetris®, FDA‐approved 2011), trabectedin (Yondelis®, EU approved 2008, FDA‐approved 2015), plitidepsin (Aplidine®) approved in Australia in 2018 and polatuzumab vedotin (POLIVY®, FDA‐approved 2019). The website www.clinicaltrials.gov was researched for marine‐derived compounds in Phase I, Phase II and Phase III: Our research determined that there were 31 marine‐derived compounds in active clinical trials: 5 marine‐derived compounds were in Phase III, 13 compounds in Phase II, and at least 9 compounds in Phase I, several auristatin‐containing antibody drug conjugates or ADCs. Regular updates on the clinical marine pharmaceutical pipeline are posted on: https://www.midwestern.edu/departments/marinepharmacology.xmlFurthermore, it is important to note that the global preclinical marine pharmacology pipeline continues to generate considerable data on multiple pharmacological classes. We thus conclude that in November 2019, both the marine pharmacology preclinical and clinical pharmaceutical pipelines remained very active.Support or Funding InformationCollege of Pharmacy, Vicki Sears, Pharmacology Department, College of Graduate Studies and Office of Research and Sponsored Programs, Midwestern University
Autonomic Reactivity to Acute Mental Stress Differs Between Women and Men with Post Traumatic Stress Disorder (PTSD)
Authors: Jones Toure N. , Fonkoue Ida T. , Vemulapalli Monica , Dacosta Dana , Park Jeanie 
Published: April 2020

Over 7 million Americans are affected by post‐traumatic stress disorder (PTSD), a debilitating mental illness that is associated with significant cardiovascular disease risk. Women are twice as likely as men to develop PTSD after a traumatic event. A prior study from our laboratory showed that sympathetic nervous system reactivity during combat related and non‐combat related stress is heightened in PTSD; however, this study was conducted in a predominantly male cohort and did not consider the potential influence of sex on neural cardiovascular function in PTSD. The aim of the current study was to determine if women with PTSD have heightened blood pressure (BP), heart rate (HR), and sympathetic reactivity to acute mental stress than men with PTSD. We recruited 15 women and 18 men clinically diagnosed with PTSD and confirmed using the Clinician Administered PTSD Scale (CAPS) and PTSD Checklist‐Military (PCL‐M) surveys. We measured muscle sympathetic nerve activity (MSNA), continuous BP, HR and heart rate variability (HRV) at baseline and during 3 minutes of mental arithmetic. Women and men were matched for race, age (41±2 vs 38±2 years, p=0.191), body mass index (31±2 vs 29±2 kg/m2, p=0.368), CAPS (71 ±9 vs 74 ±4, p=0.732) and PCLM (57 ±5 vs 68 ±4, p=0.129) scores. Likewise, baseline systolic BP (131±5 vs 128±4 mmHg), diastolic BP (76±4 vs 74±2 mmHg) and HR (70±3 vs 64±2 beats/min) were comparable (P>0.05) between women and men. Although resting HRV measures were not different between groups (p>0.05), resting MSNA was higher (p=0.008) in women compared to men (27±3 vs 16±3 bursts/min). In response to mental arithmetic, systolic BP reactivity was higher in women compared to men (Δ+5.1±1 versus Δ+2.2±1 mm Hg, p<0.001). Diastolic BP (p=0.366) and HR (p=0.170) responses were not different. However, MSNA reactivity was higher (p=0.04) in women compared to men (Δ15.2±5 versus Δ6.4±3 bursts/min), suggesting an exaggerated sympathetic response to acute stress. Although RMSSD reactivity was similar between both groups (p=0.347), HF response to mental stress was blunted (p=0.05) in women compared to men, suggesting a greater withdrawal of parasympathetic control of the heart during acute stress. In summary, women with PTSD show an exaggerated blood pressure and sympathetic response to acute mental stress coupled with a blunted parasympathetic control of the heart. These results provide important insight into the physiological mechanisms linking the high risk of PTSD in women and the associated cardiovascular disease and hypertension risk.Support or Funding InformationThis work was supported by National Institutes of Health (NIH) Grant R01 HL135183; NIH R61 AT010457, VA Merit I01CX001065, the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Decatur, Georgia, and the APS STRIDE Undergraduate Summer Research Fellowship, grant program number NHLBI; 1 R25 HL115473‐01.