bluuebunny/crossref_metadata_2025_split huggingface dataset:
New method for systemic sclerosis, systemic lupus erythematosus and vascular angiopathy diagnosis
Authors: Cattaruzzi Giacomo , Vitrani Francesco , Moretti Massimo , Scorza Raffaella , Curcio Francesco 
Published: June 2021

Systemic sclerosis (SSc) is characterized by skin thickening and abnormalities of many visceral organs. Vascular damage, immune activation and extracellular matrix excessive synthesis and deposition are SSc features. Serum autoantibodies are strong predictors of disease outcome and organ complication pattern but their pathogenetic role is unclear, although there is evidence that they also have a role in pathogenesis. Angiogenesis is strongly disturbed: as demonstrated by capillaroscopy, vessels damage evolves progressively and is characterized by different morphological aspects. Almost all patients develop Raynaud's phenomenon which, together with structural vasculopathy, results in ulceration and critical digital ischemia.Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the production of antibodies to cell nucleus and a diverse array of clinical manifestations. The primary pathological findings in patients with SLE are inflammation, immune complex deposition and vasculopathy.We developed a cell‐extract based method which is capable of identify SSc and SLE patients. The results of a study involving 340 individuals indicated that our method is highly specific. Our method can identify, within SSc (limited cutaneous and diffuse forms), subjects showing vascular damages at early stages; it also correlates with the Raynaud's phenomenon in SLE subjects.
Aeroallergen‐induced hypoxic bradycardia in spontaneously breathing house dust mite‐sensitive nonhuman primates
Authors: Wardle Robert L , Ellis Stuart R , Gaddis J Leslie , Olmstead Stephen G , Putnam Benjamin D , Reece Shaun P , Fick Robert B , Van Scott Michael R 
Published: June 2021

RATIONALEA small number of house dust mite (HDM)‐sensitive nonhuman primates (NHP) exhibit life‐threatening bradycardia after aero‐HDM challenge. Retrospective analysis was performed to elucidate conditions associated with the adverse cardiac response.METHODSData recorded for 71 NHP over 4 years was screened for a >25% decrease in HR and minimum HR <100 bpm following HDM challenge. Prior to data acquisition, NHP were anesthetized, intubated, and instrumented to record SpO2 & HR, lung resistance (RL), and dynamic compliance (Cdyn).RESULTSHypoxic bradycardia was observed in 10 of 71 NHP. It was associated with airway sensitivity to HDM and was preceded by rapid‐shallow breathing and often apnea. HR decreased 50% to 76±6 bpm and was associated with an SpO2 of 71±4%, increase in RL of 139±37%, and decrease in Cdyn of 59±5%. Bradycardia was also observed during methacholine provocation performed 24 hours after HDM challenge. Bradycardia was reversed by mechanical ventilation or atropine.CONCLUSIONSHypoxic bradycardia during respiratory stasis has been described in humans and canines. Our data indicate that HDM‐allergy can lower O2 and tidal volume thresholds for the reflex in susceptible subjects.
Biomarker of whole grain wheat intake associated lower BMI in older adults
Authors: Ma Jiantao , Ross Alastair , Bruce Stephen J , Jacques Paul , Lichtenstein Alice H , Saltzman Edward , Booth Sarah , McKeown Nicola 
Published: June 2021

Alkylresorcinols (AR) are phenolic lipids in the bran fraction of some whole grains (wheat, rye and barley). Plasma AR reflect recent intake of these whole grains. We examined the cross‐sectional associations between plasma AR (measured by LCMS/MS), whole wheat intake, and body mass index (BMI) in 407 free‐living older adults (166 men and 241 women; 60–81y; mean BMI 27.9 kg/m2). After adjustment for total cholesterol and triglyceride, median plasma AR across quartile categories of AR were 5, 13, 28, and 62 nmol/L, respectively. Whole grain wheat (servings/d) and bran (g/d) intakes were estimated using a semi‐quantitative FFQ. Spearman correlation coefficients between plasma AR and whole grain wheat and bran were 0.34 and 0.28, respectively. Age and sex adjusted geometric mean daily whole wheat intakes in the lowest and highest quartile categories of plasma AR were 0.4 and 1.1 servings (P‐trend <0.0001). Without inclusion of added bran, whole grain intake (g/d) was weakly correlated with plasma AR (r = 0.12, P<0.0001). After adjustment for lifestyle and dietary covariates, mean BMI values in the lowest and highest quartile category of plasma AR were 27.8 and 26.7 kg/m2, respectively (P‐trend 0.03). Our study confirms the observed inverse relationship between whole grain intake and BMI using an independent biomarker of whole grain wheat intake.Grant Funding Source: U.S. Department of Agriculture, Agricultural Research Service, under Cooperative Agreement 58‐1950‐7‐707, the National Institutes of Health (AG14759 and HL69272)
Body composition in achondroplasia
Authors: Schulze Kerry , Henry Bobbie , Koerner Celide , Alade Yewande , McGready John , Collop Nancy , Silber Harry , Germain-Lee Emily , Hoover-Fong Julie 
Published: June 2021

BackgroundThe major components of body composition are fat and lean mass, quantifiable via dual energy X‐ray absorptiometry (DXA), bioelectrical impedance (BIA) and anthropometry. Average stature normative body composition values are not applicable because of extreme disproportionate short stature in achondroplasia. Obesity is a major concern in the general population, yet little has been done to validate methods for determining body composition in short stature skeletal dysplasias.MethodsBody composition was determined by DXA, BIA and anthropometry in a cross‐sectional study of 20 adults with achondroplasia.ResultsMean % body fat by DXA was 33.1%(F 42.7%, M 25.2%) and by BIA was 33.4% (F 43.2%, M 25.4%), r=0.94(p<0.0001). Mean estimated arm fat area was 35.3 cm2 (F 51.1 cm2, M 22.4 cm2). DXA % body fat was highly correlated with umbilical waist (M r=0.93, F r=0.72), maximal hip (M r=0.85, F r=0.77), and neck circumferences (M r=0.89, F r=0.73) and estimated arm fat area(M r=0.84, F r=0.86); all p<0.05 except the female umbilical. BIA % body fat was highly correlated with the same measures, all p<0.05 except female neck.DiscussionBasic anthropometry is highly correlated to DXA and BIA and more accessible for future investigation of health outcomes. Supported by Greenberg Center for Skeletal Dysplasias
Age associated change in biomarkers of bone metabolism in cats
Authors: Yu Shiguang 
Published: June 2021

Age associated change in bone metabolism in cats was investigated by measuring biomarkers of bone metabolism in a cross sectional study. Serum and urine samples were collected from 96 healthy American domestic shorthair cats (29 males and 67 females) with ages ranging from 1.7 to 15.9 years old after they were fed a dry cat food for at least 3 weeks. Following biomarkers were measured: procollagen type II C‐propeptide (PIICP), C‐terminal cleavage products of type II collagen (C2C), C‐terminal telopeptide of type II collagen fragments (CTX II), Type IIA collagen N‐propeptide (PIIANP), N‐terminal cross‐linked telopeptide of type I collegen (NTx), keratan sulfate (KS), chondroitin sulfate epitope 846 (CS846), and bone specific alkaline phosphatase (BAP). Linear correlation coefficient between age and measured biomarkers was calculated.Serum BAP (r=−0.19, p=0.01) and urine CTX II (r=−0.47, p<0.01) were negatively and serum C2C (r=0.37, p<0.01) and KS (r=0.35, p<0.01) were positively associated with age. Both serum BAP and urine CTX II were significantly higher in cats < 2 years old, suggesting that bone metabolism does not attain maturity in cats until they are 2 years old. No association between age and other measured biomarkers was observed in cats > 1 year old.
Differential expression of insulin receptor isoforms A and B in highly proliferative stem and tumor cells vs. differentiated intestinal epithelial cells
Authors: Bortvedt Sarah F , Mah Amanda T , Van Landeghem Laurianne , Santoro M. Agostina , Magness Scott , Lund P. Kay 
Published: June 2021

Little is known about expression and roles of insulin receptor (IR) in the intestinal epithelium despite emerging links between obesity, hyperinsulinemia, and intestinal dysfunction or cancer risk. IR exists as an IR‐B isoform that mediates insulin's metabolic actions and an IR‐A isoform implicated in fetal growth and recently, cancer. This study used Sox9‐EGFP reporter mice, ApcMin/+ mice, and human colorectal cancer cell lines (CRC) to test the hypothesis that IR‐A and IR‐B have distinct expression profiles in highly proliferative vs differentiated normal intestinal epithelial cells (IEC) or CRC.ResultsIR‐A predominates in highly proliferative intestinal epithelial stem cells and progenitors, while IR‐B predominates in differentiated lineages. In ApcMin/+ mice, the IR‐B:IR‐A ratio is dramatically decreased in tumor vs non‐tumor tissue in small intestine (0.65 ± 0.02 vs 1.3 ± 0.03) and colon (0.63 ± 0.1 vs 1.27 ± 0.9). The IR‐B:IR‐A ratio is higher in CRC with the ability to differentiate vs undifferentiated, aggressively growing CRC. The ratio of IR‐B:IR‐A is significantly increased in differentiated vs undifferentiated Caco2 cells (2.2 ± 0.2 vs 1.5 ± 0.1). We conclude that relative expression levels of IR‐B:IR‐A may be critical determinants of normal IEC or CRC differentiation. Grants: F31AG040943 (SFB) and NIH DK040247‐19 (PKL).
Recruitment of the Vascular Endothelium into Neurovascular Coupling
Authors: Longden Thomas , Nelson Mark 
Published: June 2021

In neurovascular coupling (NVC), neuronal activity in the brain leads to elevated local blood flow to satisfy the increased metabolic demands of the active tissue. The vascular endothelium has a major role in the modulation of blood flow, and here we explore the hypothesis that the endothelium has an important role in NVC.Brain slices were prepared from male C57 Bl/6 mice. Intraparenchymal arterioles were pre‐constricted with U46619 (125 nM). Neurons were depolarized with electrical field stimulation (EFS) to induce NVC and arteriolar dilation. In some experiments, the endothelium was loaded with di‐8‐ANEPPS (20 μM).EFS‐evoked arteriolar dilation was accompanied by endothelial hyperpolarization, as indicated by a 1.4% increase in the fluorescence ratio of di‐8‐ANEPPS (n=7). Blockade of I prostanoid receptors with 1 μM R01138452 had no effect on NVC (n=4). Blockade of neuronal nitric oxide synthase (NOS) with 7‐NI (100 μM) reduced the magnitude of vasodilation by 63% (n=7) with no effect on vessel tone (n=5). Blockade of both neuronal and endothelial NOS with L‐NNA (100 μM) caused a tonic constriction (17%, n=5) and reduced vasodilation by 89% (n=7). In the absence of U46619, L‐NNA constricted arterioles by 28% and reduced vasodilation by 90% (n=5).These data are consistent with the concept that the vascular endothelium is actively engaged during neurovascular coupling. Supported by NIH award P01 HL095489.
Angiotensin II decreases the levels of PKA‐mediated NHE3 phosphorylation in renal proximal tubule
Authors: Rossetto Silmara Larissa , Queiroz-Leite Gabriella Duarte , Crajoinas Renato Oliveira , Omae Samantha V , Malnic Gerhard , Girardi Adriana C 
Published: June 2021

NHE3 transport function is inhibited by PKA. Binding of angiotensin II (ANG II) to AT1 receptor has been reported to activate Gi‐protein signaling pathway, resulting in the inhibition of adenylyl cyclase, and consequently, in decreased PKA activation. We therefore tested the hypothesis that decrement of PKA‐mediated NHE3 phosphorylation is one of the mechanisms by which ANG II acutely stimulates NHE3 activity in renal proximal tubule. To this end, OKP cells were treated with 100 μM Dopamine (DOP) for 30 min in the presence or absence of 10−10 M ANG II for 5, 15, and 30 min; or only with ANG II for 30 min. Extrusion of H+ from OKP cells was measured. DOP significantly inhibited NHE3 activity (0.2013 ± 0.009 vs. 0.3036 ± 0.0019 pH units/min in control). Simultaneous incubation of DOP with ANG II for 15 (0.2347 ± 0.044 pH units/min) and 30 min (0.3295 ± 0.032 pH units/min) completely blocked this inhibitory effect. As expected, ANG II stimulated NHE3 activity. DOP increased the levels of NHE3 phosphorylated at the PKA consensus phosphorylation sites [serines 552 and 605] by 64 ± 8% and 288 ± 37% respectively vs. control. ANG II treatment for 15 and 30 min prevented this increase. PKA activity was also measured in these groups of cells. We found that PKA activity was significantly increased in cells treated with DOP for 30 min and in cells treated with DOP plus ANG II for 5 min. Longer incubation times with ANG II (15 and 30 min) in the presence of DOP restored PKA activity near to control levels. Losartan blocked all the effects of ANG II here reported. Collectively, these data suggest that inhibition of PKA activity leading to lower levels of endogenous phosphorylation of NHE3 is one of the mechanisms by which ANG II stimulates NHE3 activity in the proximal tubule.Supported by FAPESP
The use of human embryonic kidney (HEK 293) cells to enhance characterization of the LMX1B pathway
Authors: Stump Robert Patrick , Feenstra Jennifer M , Castillo Michael A , Soriano Salvador , Oberg Kerby C 
Published: June 2021

LMX1B is a homeodomain transcription factor critical to kidney development and glomerular filtration. In humans, LMX1B haploinsufficiency causes a condition known as Nail Patella syndrome (NPS). Individuals with NPS typically have under developed nails, absent patellae, and impaired kidney function. In <I/>Lmx1b knockout mice, the absence of Lmx1b function disrupts glomerular filtration and abates urine production. The molecules targeted by LMX1B that regulate glomerular development and function, however, are poorly characterized. Immortalized human embryonic kidney (HEK 293) cells provide a potential tool for high‐throughput identification of LMX1B targets and an <I/>in vitro system for dissecting the functional role of targets. Thus, we characterized the known LMX1B pathway in HEK 293 cells and evaluated sites of LMX1B binding. We demonstrate the expression of <I/>LMX1B and its renal targets, <I/>COLLAGEN 4 ALPHA 4 and <I/>PODICIN in HEK 293 cells by RT‐PCR. Protein expression of LMX1B was verified by western blot analysis. In addition, using Chromatin immunoprecipitation we determined that LMX1B binds to regulatory sequences associated with both target genes. Further characterization of the LMX1B pathway in HEK 293 cells is underway and will likely enhance the identification of relevant downstream targets and the molecular cascade that regulates glomerular development and function.Grant Funding Source: (NICHD) HD 39421
Proliferation, osteogenic and chrondrogenic differentiation of equine‐derived bone marrow mesenchymal stem cells on bacterial cellulose scaffolds
Authors: Favi Pelagie M. , Stephens Christopher , Neilsen Nancy , Hammonds Ryan , Benson Roberto , Dhar Madhu 
Published: June 2021

The purpose of this study was to evaluate the cell proliferation and viability, osteocyte and chondrocyte differentiation of equine‐derived bone marrow mesenchymal stem cells (Eq‐MSCs) when seeded onto biocompatible bacterial cellulose (BC) scaffolds. BC was synthesized using the bacterium Gluconacetobacter sucrofermentans. Previously isolated, expanded and characterized Eq‐MSCs were seeded on the BC scaffolds and fluorescence microscopy confirmed adherence and expansion. Confocal imaging confirmed the cells positively stained for CD90 antibody, a common surface marker for mesenchymal stem cells. MTS assay demonstrated increasing proliferation and viability with time (days 2, 7 and14). Cell‐scaffold constructs were cultured for 14 days under osteogenic and chondrogenic conditions. Osteocytes were positive for alizarin red and chondrogenesis was confirmed by alcian blue staining of the chondrocytes. In summary, biocompatible BC scaffolds support the proliferation and viability, osteogenic and chondrogenic differentiation of Eq‐MSCs cultured onto its surface in‐vitro, allowing for future potential use for tissue engineering therapies. This research is sponsored by the Physicians Medical and Education Research Foundation Grant, the Cardiothoracic Surgery Gift Fund, and the National Institute of Health Training Grant.Grant Funding Source: Physicians Medical and Education Research Foundation Grant, the Cardiothoracic Surgery Gift Fund, and the National Institute of Health Training Grant
Tumor‐Derived IDO Affects the Lifespan in a Mouse Model of Glioblastoma
Authors: Wainwright Derek Alan , Lesniak Maciej S. 
Published: June 2021

Glioblastoma multiforme (GBM) is a malignant brain tumor with an average survival time of one year. Our laboratory previously demonstrated that a subset of T cells, known as Tregs, infiltrate both human‐ and mouse models of‐GBM. Importantly, depleting Tregs leads to increased survival in a mouse model of GBM. Indoleamine 2,3 dioxygenase (IDO) has emerged as a molecule that controls Treg recruitment and/or activation and has recently been shown to be expressed in human GBM. Based on this association, we hypothesized that IDO is involved in GBM progression. Thus, this work set out to establish: 1) if IDO expression affected survival and, 2) where IDO is required to affect survival, in a mouse model of GBM. To determine if and where IDO is required to affect lifespan, we used wild‐type (WT) and IDO‐deficient (IDO−/−) mice, intracranial injections of the GBM‐like cell line, GL261, histological quantification of tumor size, immunofluorescence for IDO expression, small hairpin RNA knockdown for IDO, as well as mouse survival analysis. Here, we demonstrate that both WT and IDO−/− mice intracranially‐injected with GL261 cells and knocked‐down for IDO (GL261Kd) live significantly longer than WT and IDO−/− mice intracranially‐injected GL261 cells transduced with a scrambled control shRNA (GL261Vc) (p < 0.001). Histology confirms that the GL261Kd GBM grows significantly slower, when compared to the GL261Vc GBM (p < 0.001). This is co‐incident with a significant decrease in immunofluorescence for IDO expression in the GL261Kd‐, when compared to the GL261Vc‐GBM (p < 0.001). By using a pre‐clinical mouse model of GBM whereby IDO is deficient or knocked‐down in different anatomical compartments, this work demonstrates that IDO is an important molecule, required and sufficient for promoting brain tumor growth, supporting the future investigation of pharmacological inhibitors of IDO in patients with GBM.Grant Funding Source: 5R01CA138587‐03; 1F32NS073366‐ 01A1
Switch in amyloid clearance mechanisms leads to vascular fragility in cerebral amyloid angiopathy
Authors: Zabel Matthew K , Schrag Matthew , Crofton Andrew , Tung Spencer , Vinters Harry V , Kirsch Wolff M 
Published: June 2021

Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA) are two very common pathologies associated with amyloid accumulation and inflammatory processes, which are not well understood. The objective of this study was to evaluate human post mortem brains of cases with pure AD, those with AD and either concomitant mild, moderate or severe CAA and age matched controls (all n=4) for differing expression of microglia‐associated Aβ clearance receptors and complement activation. We used brain parenchymal homogenate and an enriched microvessel fraction from the occipital lobe for western blot analysis to measure the levels of C3b and C6. Immunoprecipitation was used to pull down microglial CD11b to look for binding complex levels with C3b and Aβ. Confocal microscopy was used to visualize these interactions and light microscopy to visualize late complement deposition. C3b was significantly increased in all CAA severities compared to AD and controls. Co‐IP showed significantly increased CD11b/C3b complexes with Aβ. Additionally, C6 was significantly increased on isolated CAA blood vessels compared to AD and control vessels. These findings suggest an Aβ clearance mechanism via microglial CD11b that delivers Aβ and complement factors to the blood vessels in CAA, which leads to Aβ deposition and vascular fragility due to the lysing effects of late complement.Grant Funding Source : NIH grant AG20948, NSF‐MRI 0619774 and by Loma Linda University School of Medicine.
Valproic acid attenuates neuronal apoptosis in APP/PS1 transgenic Alzheimer′s disease mice model
Authors: He Guiqiong , Zhao Lei 
Published: June 2021

One of the hallmarks of Alzheimer's disease (AD) is the accumulation of senile plaques(SP) composed of extracellular aggregates of amyloid ¦Â peptides (A¦Â). It is proved that A¦Â triggers apoptotic cell death via the activation of caspase‐dependent and ‐independent cell death effectors, respectively. Valproic acid (VPA) is a widely used mood stabilizer and antiepileptic drug. Our previous study showed that VPA treatment significantly reduced SP formation and improved memory deficits in AD model mice. The present study intended to explore the protective effect of VPA on neuronal apoptosis in transgenic AD model mice and the possible mechanisms involved. Immunohistochemical staining showed that VPA reduced the number of swollen neurons and promoted neurite outgrowth in AD mice. MTT assay and Tunel staining showed that VPA increased cell viability and reduced the number of apoptotic cells. Western blot revealed that VPA downregulated the expression of Caspase‐ 3, Caspase‐9 and Caspase‐12, reduced cytochrome C level. The expression of Bcl‐2 was increased by VPA treatment. Flow cytometry revealed that VPA decreased intracellular level of Ca2+ and elevated mitochondrial membrane potential. Our results indicate that VPA protected AD mice model via inhibition of both mitochondrial and endoplasmic reticulum pathway of apoptosis.This work was supported by National Natural Science Foundation of China (30970986).
Mobilization of endothelial progeitor cells in patents with acute ischemic stroke
Authors: Zheng Min , Wang Jian 
Published: June 2021

ObjectivesTo observe the mobilization of Endothelial Progenitor cell (EPCs) following acute ischemic stroke (AIS) and the possible mechanism involved.MethodsLevel of circulating EPCs(CD34+/KDR+) of patients with AIS were examined by flow cytometry at day1, 7, 14 and 21 after acute stroke. Infarct volume was checked by MRI. Stromal derived factor‐1(SDF‐1) content was determined by ELISA. The change rate of EPCs was defined as (EPC14d‐EPC1d)/EPC1d.Results1. The number of circulating EPCs began to increase at day 7 after AIS, reached peak level at day 14 and decreased at day 21. EPCs change rate was significantly correlated with infarct volume (r = 0.692; P<0.01). 2. The content of SDF‐1 significantly increased at day 7 after AIS, reached peak level at day 14 and decreased at day 21. SDF‐1 content at day 14 was significantly correlated with infarct volume (r = 0.774; P<0.01). 3. EPCs change rate in patients with AIS was significantly correlated with SDF‐1 content at day 14(r = 0.682; P<0.01).ConclusionThe increased circulating EPCs may result from the mobilization of EPCs in response to stroke stress. The mechanism of EPCs mobilization may be associated with an increased expression of SDF‐1.This work was supported by National Scientific Foundation Committee of China ( 31100985)