bluuebunny/crossref_metadata_2025_split huggingface dataset:
Infant feeding support strategy reduces growth faltering in late infancy among infants of HIV‐infected mothers in urban Haiti
Authors: Heidkamp Rebecca A , Stoltzfus Rebecca J , Fitzgerald Daniel , Pape Jean W 
Published: June 2021

There is growing consensus about strategies to reduce mother‐to‐child transmission of HIV through breastmilk during early infancy (0–5 mo) in low‐income countries, but less research on feeding in late infancy (6–12 mo) when risk of growth faltering is high. We evaluated a program strategy to support infant nutrition at GHESKIO, a clinic serving poor HIV‐infected mothers in Port‐au‐Prince, Haiti. In 2008–09, 82 six‐mo‐old non‐breastfed HIV‐exposed infants were enrolled in a 6‐month intervention that included a daily ration of micronutrient‐fortified ready‐to‐use supplementary food, monthly “mothers club” sessions for infant feeding education, and monthly individualized growth monitoring/counseling. Data was collected on growth, anemia, dietary intake, morbidity, compliance, caregiver knowledge, satisfaction and program feasibility. Outcomes in participants were compared to infants seen at GHESKIO in the previous year (n=174). At age 6 months, stunting (LAZ<−2 WHO 2006) prevalence was slightly higher in intervention group than in controls (NS). Among 12‐mo‐olds, stunting was 9.6% in the intervention cohort vs. 20.8% in controls (p<.05) and wasting (WLZ<−2) 2.7% vs. 8.7% in controls (p=.074). The program was highly acceptable to mothers and feasible to implement in the clinical context. Research support was provided by Cornell's Einaudi Center, Weill Cornell Center for Global Health, and PEFPAR.Grant Funding Source: NIH
Differential effect of white botton and shiitake mushroom‐fortified diets on liver fat content in C57BL/6 female mice
Authors: Christopher Lawrance , Traore Djibril , Kuvibidila Solo 
Published: June 2021

Shiitake (SM) are frequently used in Asia for treatment/prevention of chronic diseases and reduction of blood cholesterol. The mechanisms of reduced blood cholesterol are unknown and may involve impaired synthesis or release to blood. We previously observed that 5% SM‐fortified diet increased IL‐6 plasma levels in DBA mice. Considering IL‐6 plasma levels are usually elevated in fatty liver disease, we sought to assess the effect of SM‐fortified diet on liver fat content. Two month‐old C57BL/6 female mice were fed control, SM or button mushrooms (WBM)‐fortified diets (5%) for 6 weeks (n=9). At euthanasia, livers were removed and stained with Hematoxyline & Eosin. Oil O Red, PAS staining and Trichrome staining were done to demonstrate the presence of fat droplet, glycogen content and fibrosis respectively. SM and WBM had no effect on liver weights. Compared to WBM and control groups, mice fed the SM‐fortified diet showed significant increased number of vacuolated hepatocytes suggesting fatty liver (p<0.05). Oil O red staining confirmed the presence of fat droplets. SM did not induce fibrosis or affect glycogen content. WBM increased glycogen but not fat content. Data suggest that one of the mechanisms by which SM decrease blood lipid is likely by blocking liver fat release. The long term health implication of increased liver fat by SM requires further investigation.Grant Funding Source: Mushroom Council; Oklahoma State University
Calorie restriction increases fatty acid synthesis and whole body fat oxidation rates
Authors: Bruss Matthew Douglas , Khambatta Cyrus F , Aggarwal Ishita , Hellerstein Marc K 
Published: June 2021

Calorie restriction (CR) increases longevity and retards the development of many chronic diseases, but the underlying metabolic signals are poorly understood. Increased fatty acid (FA) oxidation and reduced FA synthesis have been hypothesized to be important metabolic adaptations to CR. However at steady state, FA oxidation must match FA intake plus synthesis; FA intake is low, not high, during CR. It is therefore not clear how FA dynamics are altered during CR. Accordingly, we measured food intake patterns, whole‐body fuel selection, endogenous FA synthesis and gene expression in mice on CR. Within two days of starting CR, a shift occurred to a cyclic pattern of whole‐body FA metabolism, with an initial phase of elevated endogenous FA synthesis (respiratory exchange ratio [RER]>1.10, lasting 4–6 hours after food provision), followed by a prolonged phase of FA oxidation (RER=0.70, lasting 18–20 hours). CR mice oxidized four times as much fat per day as ad libitum fed (AL) controls (367 vs 97 mg/d) despite reduced fat intake. This increase in FA oxidation was balanced by a 3‐fold increase in adipose tissue FA synthesis. We conclude that CR induces a surprising metabolic pattern characterized by periods of elevated FA synthesis alternating with periods of FA oxidation disproportionate to dietary FA intake. This pattern may have implications for understanding the reduced oxidative damage and disease risk in CR animals.Grant Funding Source: NIH
Potential Role of Toll‐like Receptor 4 in Obesity‐Induced Adipose Tissue Remodeling
Authors: Adapala Venkata Jitendra Kumar , Adedokun Sunday Adetayo , Adeola Olayiwola , Ward Meliza G , Ajuwon Kolapo Matthew 
Published: June 2021

Obesity is a state of chronic inflammation which contributes to insulin resistance. Toll‐like receptor (TLR) 4 is involved in adipose tissue (AT) inflammation, but its role in the regulation of extracellular matrix (ECM) genes in AT is unknown. We conducted a study on the effect of high fat diet (HFD) and acute TLR4 activation with lipopolysaccharide (LPS) on ECM gene expression. We also investigated the impact of chronic TLR4 activation by HFD on ECM genes in a wild type (WT) C3H/HeOuJ and TLR4 deficient (KO) C3H/HeJ mice. In the subcutaneous (SC) AT, apart from induction of inflammatory cytokines, there was no effect of LPS challenge on the expression of ECM genes. However, HFD results in significant induction of COL1A1 and COL6A1 (P < 0.05). In the epididymal depot, LPS challenge results in the upregulation of biglycan but a down regulation of lumican and COL6A1 (P < 0.05). Higher expression of biglycan, lumican and COL1A1 (P < 0.05) was induced by HFD. The WT mice had higher ECM gene expression than the KO. Limited effect of HFD was observed in the WT. Significant induction of ECM genes by HFD was observed in both the epididymal and the SC depot of the KO mice. Although HFD leads to induction of transcripts of ECM genes, our results suggest a limited role for TLR4 activation in HFD‐induced AT remodeling. However, the WT has a higher basal expression of the ECM mRNA. This indicates a non‐dietary connection to ECM gene regulation by TLR4.Grant Funding Source: Purdue University
C‐reactive protein (CRP) exclusion cutoffs and serum zinc, ferritin, and copper status in children: a cross sectional study among 6–11 y healthy children in Guatemala
Authors: Bui Vinh Quang , Ramakrishnan Usha , Stein Aryeh D. , Flores‐Ayala Rafael C. , Ramirez‐Zea Manuel , Villalpando Salvador , Martorell Reynaldo , DiGirolamo Ann M. 
Published: June 2021

Infections can affect markers of micronutrient status such as serum vitamin A and ferritin but less is known about effects on other micronutrients. C‐Reactive Protein (CRP), a marker of acute inflammation, has been used to correct for the effects of infection but the appropriate cutoffs for excluding subjects are unclear. We assessed the prevalence of low zinc, iron and copper status in children using a range of CRP cutoffs. Serum CRP (by laser nephelometry), Zn, ferritin, and Cu were measured in 720 healthy 6–11 y Guatemalan children. The proportion of samples with CRP ≤0.5, 1, 3, 5, and 10mg/L was 44.8%, 65.5%, 84.9%, 92.5% and 97.6%, respectively. The prevalence of serum Zn <65μg/dL, ferritin <15μg/dL, and Cu <90μg/dL was 21.7%, 2.3%, and 23.8%, respectively. Serum CRP was correlated with serum ferritin (r=0.24, p<0.01) and Cu (r=0.29, p<0.01), but not Zn (r=0.04, p=0.3). Subjects with CRP levels > 1, 3, and 5 mg/L had a reduced risk of low iron and Cu status (all p<0.05). For example, the prevalence of Cu<90μg/dL was 23.8% and 28.7% with and without exclusion of subjects with CRP >1mg/L, respectively. Markers of iron and copper status, but not of zinc, were associated with inflammation.Funding: National Institute of Health (R01 MH067981).Grant Funding Source: NIH R01 MH067981
Epigenetic Placental Programming of Preeclampsia
Authors: Uthus Eric O. , Anderson Cindy M. 
Published: June 2021

Preeclampsia (PE) affects 8–10% of women in the US and long‐term consequences include development of maternal hypertension and hypertension in offspring. As methylation patterns are established during fetal life, we focused on epigenetic alterations as a plausible explanation of the heritable development of hypertension resulting from maternal PE. In this proof‐of‐principle study we determined genome‐wide CpG DNA methylation patterns in placental tissue from women with normotensive pregnancy and PE (n=3/group) by using 2.1M microarrays (NimbleGen). These arrays tile 7000 bp upstream and 3000 bp downstream a promoter in 100 bp segments and cover 28000 CpG islands. Criteria for gene selection included methylation +/−1000 bp of the respective gene's transcription start site. We identified 163 genes methylated only in PE and uploaded them to DAVID (http://david.abcc.ncifcrf.gov) where we used a classification stringency of high to determine functional annotation clusters. Cluster 1had an enrichment score of 5.59; this cluster contains the GO Terms of anatomical structure formation, angiogenesis, blood vessel development, vasculature development, and blood vessel morphogenesis. There are 12 genes total in this cluster 10 of which are common to all 5 GO Terms. This work suggests that an epigenetic mechanism may be involved in PE.Robert Wood Johnson Nurse Faculty Scholar, Sigma Theta Tau International, ARS
PKA prevents mitochondrial pathology induced by loss of PINK1 function
Authors: Dagda Ruben K. , Cherra Salvatore J , Strack Stefan , Green Steven , Chu Charleen T. 
Published: June 2021

PTEN‐induced kinase 1 (PINK1) and mitochondrial PKA targeted to mitochondria via AKAP121 are two ser/thr kinases that regulate neuronal survival and mitochondrial function. We have previously shown that stable loss of PINK1 leads to increased generation of mitochondrial ROS, fission, and protective mitophagy (Dagda et al, 2009). Given that these two protective ser/thr kinases have the ability to localize to mitochondria, we hypothesized that PKA and PINK1 regulate common mitochondrial pathways in neurons.We transiently expressed multiple GFP fusion constructs of PKA in stable PINK1 knockdown SH‐SY5Y cell lines. Confocal analysis of transfected cells showed that treating cells with analogues of cyclic AMP or transient expression of mitochondrially targeted PKA but not of untargeted GFP, reverses mitochondrial fission induced by stable loss of PINK1. Moreover, cell survival assays showed that transient expression of cytosolic PKA or that cyclic AMP treatment significantly increased survival against cell death induced by stable loss of PINK1 in SH‐SY5Y cells or cell death induced by transient expression of PINK1 mutants in primary cortical neurons. Overall, our studies support a PKA‐PINK1 signaling pathway to reverse mitochondrial fission and increase survival of PINK1 deficient cells.This study was supported by NIH (AG026389 and DC009120, CTC)and RKD was supported by F32 AG030821.
Potential hepatoprotective role for CXC Chemokine Receptor‐1 after Liver Ischemia/Reperfusion in Mice
Authors: Clarke Callisia N , Sakai Nozomu , Tevar Amit D , Edwards Michael J , Lentsch Alex B 
Published: June 2021

BACKGROUNDCXC chemokines and their receptors, CXCR1 and CXCR2, have been implicated as key mediators of inflammation following hepatic I/R. We have recently shown that signaling through CXCR2 is detrimental to liver recovery and regeneration after hepatic I/R. However, the role of CXCR1 signaling is unknown. Here we investigated the function of CXCR1 after liver I/R.METHODSMale wild‐type and CXCR2−/− mice underwent partial hepatic ischemia for 90 minutes and were reperfused up to 96 hours. Sham operations used the same protocol without vascular occlusion. Repertaxin (CXCR1 and 2 antagonist) was used to inhibit CXCR1 in CXCR2−/− mice.RESULTSLiver CXCR1 expression was increased in all mice after 24 hrs of reperfusion and was maximal after 96 hrs of reperfusion. Expression was hepatocyte‐specific by Western blot and immunohistochemistry. CXCR1 signaling blockade with repertaxin in CXCR2−/− mice at the time of reperfusion showed no difference in hepatocellular injury or inflammation when compared to control. However, when repertaxin was administered 24 hrs post‐reperfusion there was significant increase in hepatocellular injury and delayed recovery. There was no difference in hepatocyte proliferation between control‐ and repertaxin‐treated mice.CONCLUSIONCXCR1 has divergent effects from CXCR2 and may have hepatoprotective effects during liver recovery and regeneration after I/R.
Detecting phenotypical subtypes of breast cancer with multiplexed immunohistochemistry
Authors: Mansfield James , Hoyt Clifford 
Published: June 2021

Treatment for breast cancer has benefited significantly from advances in molecular biology. IHC tests for protein receptors ER, PR, and Her2 have lead to a new patient classification system. Traditional approaches to assessing multiple proteins use serial sections, staining for one protein per serial section. Multiple proteins can be assessed in the same tissue section, determining phenotype on a per‐cell basis, possibly revealing significant subtypes and leading to more targeted and more effective treatments and therapies.Multispectral imaging (MSI) was performed on two sets of a 712‐core TMA (356 patients, in duplicate). One set was stained for ER and ki67, the second for ER, PR and Her2 (both plus counterstain). IHC signals were spectrally unmixed from each other and counterstain. Machine‐learning‐based automated image analysis was performed to locate cancer cells, segment subcellular compartments, and extract IHC signals on a per‐cell basis. Per‐cell co‐expression subtypes were detected using flow‐cytometry data analysis software. Percent double and triple positivity were determined, revealing subtypes. Correlation between subtypes and clinical outcomes will be the topic of future publications.MSI and analysis software, coupled with flow‐cytometry analysis tools, can be used to reveal molecular subtypes, which may lead to new targeted strategies for breast cancer research and clinical care.
Expression Profiles of Metastasis‐Related Genes in a Cohort of Childhood and Adult Adrenocortical Tumors
Authors: Lin Chin Jia , Lerario Antonio Marcondes , Fragoso Maria Candida , Mendonca Berenice Bilharinho 
Published: June 2021

BackgroudAdrenocortical carcinoma (ACC) is a rare neoplasm with a poor prognosis. Although molecular studies have uncovered many aspects of ACC tumorigenesis, little is known about molecular pathways involved in metastatic spread. The objective of our study is to analyze the expression profile of metastasis‐related genes in a cohort of metastatic and non‐metastatic adrenocortical tumors in order to identify genes involved in the metastatic spread.MethodsThe expression profiles of 27 adrenocortical tumors from 15 adults (8 ACC and 7 adenomas) and from 12 children (5 metastatic and 7 non‐metastatic) were evaluated by an array of 113 genes known to be involved in human metastasis.ResultsThe comparison of adult adenoma and ACC identified 13 differentially expressed genes. In the pediatric group, 6 genes were found to be differentially expressed between metastatic and non‐metastatic tumors. Most of the differentially expressed genes are involved in processes of cell cycle control and extracellular matrix remodeling.Conclusionthe expression profiles of metastasis‐relatad genes identified important aspects of involved in metastatic spread of adrenocortical tumors. Distinctive patterns of gene expression between metastatic and non‐metastatic tumors may be useful in prognosis prediction.
Lack of TGF‐beta signaling in dendritic cells leads to systemic autoimmunity
Authors: Ramalingam Rajalakshmy , Larmonier Claire B , Bommireddy Ramireddy , Ghishan Fayez K , Kiela Pawel R 
Published: June 2021

ObjectiveTGF‐β is an immunoregulatory cytokine that has a pivotal function in maintenance of tolerance via lymphocyte proliferation, differentiation and survival. Defects in TGF‐β1 expression or its signaling in T cells correlate with the onset of several autoimmune diseases. However, the early effects of the cytokine on the innate component of the immune system, particularly the dendritic cells (DCs) which play an equally important role in development of immune tolerance, are not well documented.MethodsTo address the role of TGF‐β signaling in DCs, we have generated two lines of conditional knockout mice with TGF‐β receptor deleted specifically in DCs using Cre‐Lox recombination system.ResultsPreliminary observations of DC‐TGFβRII knock‐out mice indicate development of systemic autoimmunity, spontaneous DC and T cell activation and premature death. The TGFβRII‐deficient DCs also demonstrated an impaired ability to drive tolerogenic reponses and in vitro conversion of regulatory T cells.ConclusionsThe phenotype of this novel mouse model clearly indicates the importance of TGF‐β signaling in DCs in the maintenance of immune homeostasis and prevention of autoimmunity and provides an opportunity to study the pathogenesis of complex disorders such as autoimmune gastritis, hepatitis and inflammatory bowel diseases.
Nutrition, Epigenetics and Complex Birth Defects
Authors: Finnell Richard 
Published: June 2021

Birth defects are a global problem that affects ~6% of births worldwide. In the U.S., birth defects are the leading cause of pediatric hospitalizations, medical expenditures, and death in the first year of life. Globally, at least 3.3 million children <5 years die each year because of a birth defect. Indeed, birth defects are one of, if not the leading healthcare concern for the youngest members of society. Neural tube defects (NTDs) are the 2nd most common of all human birth defects, annually affecting approximately 324,000 births worldwide and 3,000 pregnancies in the U.S.We have explored the potential role of environmental factors that alter maternal epigenetic homeostasis and contributes to birth defects. We believe that environmental exposures or nutritional status can impact production of reactive oxidative molecules, the availability of methyl groups, methyltransferase activity, inflammation and endocrine disruption which all have epigenetic implications during the process of neural tube closure. Such exposures may modify multiple biological processes that affect epigenetic mechanisms, including DNA methylation, histone codes, and miRNA expression. These changes may, in turn, modify chromatin organization and condensation, gene expression, and adversely affect pathogenetic processes in the developing embryo. Such factors may interact and act synergistically, such as a nutritional folate deficiency may create altered immune responses that compromise neural tube closure. An in depth exploration of the epigenetic relationship between environmental toxicants, nutritional status and the developmental impact on the embryo will be the focus of this presentation.Supported by NIH grants DE016315 and NS050249
Development of gender‐specific cardiac hypertrophy: role of the nitric oxide synthase system
Authors: Wong Philip G , Brander Emily PA , Tse M Yat , Armstrong David WJ , Pang Stephen C. 
Published: June 2021

IntroductionGender‐specific differences in hormonal regulation may influence susceptibility to cardiac hypertrophy (CH). The nitric oxide synthase (NOS) and natriuretic peptide (NP) systems are homeostatic regulators of blood pressure; ablation of either system increases predisposition to hypertension and CH.ObjectiveTo elucidate how the NOS and NP systems work in concert, as well as the impact of estrogen on these systems using the atrial natriuretic peptide gene‐disrupted (ANP−/−) mouse model.MethodsAt 13–16 weeks, female ANP+/+ and ANP−/− mice were euthanized during either the estrus (high estrogen) or proestrus (low estrogen) phases of their estrus cycle. Organs were harvested and left ventricle tissue gene expression of NOS system components were assessed using real‐time quantitative RT‐PCR.ResultsFemale ANP+/+ at estrus had a decreased expression of iNOS, eNOS, sGCα1 and sGCβ1 as compared to female ANP+/+ at proestrus. Female ANP−/− at estrus had an increased expression of iNOS, eNOS, sGCα1 and sGCβ1 as compared to female ANP−/− at proestrus.ConclusionsHigh estrogen levels led to a downregulation of the NOS system in ANP+/+ mice, and an upregulation of the NOS system in ANP−/− mice. Whether alteration in NOS system gene expression is a result of hypertension or reduction in circulating ANP levels remains to be determined. (Support from the Heart & Stroke Foundation of Ontario)Grant Funding Source: Heart and Stroke Foundation of Ontario
Loss of nNOS Signaling Exacerbates Dystrophic Pathology, but not Skeletal Muscle Fatigue in the mdx Mouse Model of Duchenne Muscular Dystrophy
Authors: Percival Justin , Reed Sarah , Bible Ken , Froehner Stanley 
Published: June 2021

Debilitating fatigue is common in muscle wasting diseases such as Duchenne Muscular Dystrophy (DMD). NO produced by nNOSμ and nNOSβ is a critical regulator of skeletal muscle fatigue. Levels of NOSμ are depleted in the skeletal muscles of DMD patients and may contribute to their fatigue. Increased nitric oxide (NO) levels in the mdx mouse (a model for DMD) significantly reduced dystrophic pathology; however, it is unclear whether the anti‐dystrophic effects of exogenous NO are due to activation of downstream targets of nNOSμ or nNOSβ or both. To address nNOS function in mdx muscle, mdx mice were engineered to lack residual nNOSμ and all nNOSβ nNOS‐deficient mdx muscles were smaller in size and showed evidence of increased inflammation. Tibialis anterior (TA) muscles from nNOS‐deficient mdx mice exhibited reduced maximal tetanic and specific force capacity. Unexpectedly, nNOS‐deficient mdx muscle exhibited increased susceptibility to injury by eccentric contractions. Also surprisingly, absence of both nNOS isozymes from mdx muscle did not affect muscle fatigue. In conclusion, the absence of fatigue in nNOS‐deficient mdx muscle suggests the existence of mechanisms that compensate for absent nNOS signaling. This novel compensatory mechanism may contribute to the mild phenotype of the mdx mouse compared to its DMD homologue. These data support the hypothesis that nNOS, particularly nNOSβ, modulates clinically relevant features of dystrophin‐deficient muscle.Funding sources: PPMD, MDA, NIH.