bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of a comprehensive intervention to prevent iron deficiency during the first year of life
Authors: Martinez Homero , Duque Ximena , Flores Sergio , Ramos Rosa Isela , Martinez Gloria , Unzaga Marco A. 
Published: June 2021

We carried out a randomized, controlled clinical trial that included 1,699 healthy, term newborn infants who were recruited in clinical facilities in Mexico. Children were randomly assigned to receive weekly (7 mg/dose) or monthly iron (30 mg/dose) supplementation, with either ferrous sulphate or aminochelate iron. The intervention was delivered during one year, beginning on the first month of life. Mothers received counseling on proper feeding practices. Data were recorded monthly on the child's growth, health, morbidity, and diet. Blood samples to determine iron status were taken at 3, 6, 9 and 12 moths of life. The control group was drawn from a nationally representative sample of children with similar characteristics. Iron deficiency based on ferritin determination (deficiency < 10 ng/ml) and anemia was defined according to hemoglobin values, using age cutoffs.There were no statistically significant differences between any of the four arms of the intervention groups in terms of hemoglobin and ferritin concentrations, or the percent of children under the different categories of iron status, so their results are collapsed into a category of “study children”.The use of a comprehensive strategy to prevent iron deficiency and iron deficiency anemia proved effective in the study children, irrespective of the type of iron administered or the frequency of administration.
Satratoxin‐G from black mold induces rhinitis and apoptosis of olfactory sensory neurons in the nasal airways of rhesus monkeys
Authors: Carey Stephan , Plopper Charles , Islam Zahidul , Pestka James , Harkema Jack 
Published: June 2021

Satratoxin‐G (SG) is a macrocyclic trichothecene mycotoxin of Stachybotrys chartarum, a black mold suggested to contribute to adverse health effects associated with water‐damaged buildings. We recently reported that intranasal exposure to SG evokes apoptosis of olfactory sensory neurons (OSNs) and acute inflammation in the nose and brain of mice. To assess the potential human risk of nasal airway injury and neurotoxicity, we developed an in vivo model of SG exposure in monkeys, whose nasal airways more closely resemble those of humans. Male, 2–3 year‐old rhesus macaques received either a single intranasal instillation of 20μg SG (high‐dose, n=3), or daily instillation of 5μg SG for four days (repeated low‐dose, n=3) in one nasal passage. Saline vehicle alone was administered to the contralateral nasal passage. Animals were euthanized 24h post‐exposure. Nasal tissues were examined for SG‐induced injury in the olfactory epithelium (OE). In both groups, SG induced acute rhinitis in the OE, resulting in a 9‐fold increase in intraepithelial neutrophils versus controls. SG also induced olfactory epithelial atrophy and apoptosis of OSNs in both groups. OSN apoptosis was identified with immunohistochemistry for caspase‐3 and electron microscopy for ultrastructural changes. High‐dose and repeated low‐dose SG elicited a 13% and 66% reduction in OSN volume density, and a 14‐fold and 28‐fold increase in apoptotic cells of the OE, respectively. Caspase‐3 immunoreactivity was detected in the OE and the olfactory nerve bundles in the underlying nasal mucosa in both SG groups. This model provides new insight into the potential human risk of nasal airway injury and neurotoxicity caused by exposure to S. chartarum in water‐damaged buildings.Funded by: NIH P51 RR000169
The effects of acute phase phosphoplipids from patients with chronic fatigue syndrome on the sodium channel in tissue culture
Authors: Campora Cara Empey , Hara Cynthia , Kuribayashi Tina , Le Huynh Diana , Pires Amanda , Imada Brian , Hokama Yoshitsugi , Yabusaki Kenichi 
Published: June 2021

Acute phase phospholipids isolated from the sera of patients with clinically diagnosed chronic fatigue syndrome (CFS) were examined for effects on the sodium channel of mouse neuroblastoma cells in tissue culture after studies suggested a structural correlation between CFS lipids and the lipophilic marine toxin, ciguatoxin. The neuroblastoma cell bioassay is a directed cytotoxicity assay that records sensitive changes in the sodium channel of neuroblastoma cells in the presence of sodium channel activators or inhibitors. The ciguatoxins are characterized by their ability to cause the persistent activation of voltage‐sensitive sodium channels, leading to increased cell Na+ permeability. Ciguatera fish poisoning in humans is characterized by neurological, gastrointestinal, and cardiovascular manifestations that are similar to the symptoms of CFS.Several lipids were examined for sodium channel activity: ciguatoxin, cholesterol, cholesterol myristate, and the phospholipids isolated from CFS patients as well as antagonists gluconate, ursodeoxycholic acid, d‐ribose, and anti‐CTX antibody. Results indicate that cholesterol and cholesterol myristate have weak but observable interactions at the sodium channel as activators, and that CTX and CFS lipids both have strong activity as sodium channel activators. However, studies revealed that none of the potential antagonists evaluated were effective at blocking the activity of the lipids at the sodium channel.[Supported in part by National CFIDS Foundation, and the Hokama‐Yagawa Fund]
The forced‐swim test in juvenile rats: A model to screen antidepressant efficacy for childhood and adolescent depression
Authors: Reed Abbey L , Happe H Kevin , Petty Frederick , Bylund David B 
Published: June 2021

We tested 21‐day old male Sprague‐Dawley rats in the forced‐swim test (FST) to screen compounds for antidepressant efficacy. Selective serotonin reuptake inhibitors (SSRIs) prevented behavioral despair, similar to results obtained with adult rats. Treatment with tricyclic antidepressants (TCAs) did not prevent behavioral despair in day 21 rats. This is in contrast to adult studies which show TCAs as effective for decreasing behavioral despair in the FST. The drug response in juvenile rats for the FST is similar to the response of children and adolescents to antidepressant treatment, as they respond to SSRIs but not TCAs. Novel compounds shown to have antidepressant‐like effects in adult animal models of depression have been screened using this newly developed model for possible activity in childhood and adolescent depression. The monoamine oxidase inhibitor, tranylcypromine, was able to decrease immobility and increase swimming behavior in juveniles. In adults tranylcypromine decreases immobility but increases both swimming and climbing behaviors. Other compounds effective at decreasing immobility in the adult FST were not effective in the juvenile FST. Screening drugs for antidepressant effects in the juvenile FST can narrow the focus of further efforts to develop compounds that would be useful for treating childhood and adolescent depression.Support: MH66959(DBB); HFF(HKH).
Regulation of G‐protein coupled receptor activities by platelet‐endothelial cell adhesion molecule, PECAM‐1
Authors: Yeh Jiunn‐chern , Otte Laura , Frangos John A 
Published: June 2021

Previously, we have shown that G protein alpha subunit Gq/11 is rapidly activated in primary HUVEC upon fluid shear stress stimulation. Here we show that Gq/11 forms a complex with PECAM‐1. In order to understand the role of PECAM‐1 in this complex, we determined the critical regions of PECAM‐1 involved in this interaction. By expressing truncated forms of PECAM‐1 in HEK293 cells, we found that the cytoplasmic domain of PECAM‐1 is not required for its association with Gq/11. Domain swapping of PECAM‐1 with intracellular cell adhesion molecule 1 (ICAM‐1), a protein that does not form a complex with Gq/11, provides evidence that the extracellular domain of PECAM‐1 is critical for this interaction. This result also suggests that PECAM‐1 does not directly interact with Gq/11. Co‐expression of bradykinin receptor B2 (BKRB2), a Gq/11‐coupled receptor, with PECAM‐1 enhances PECAM‐1‐Gq/11 complex formation, suggesting an interaction between PECAM‐1 and BKRB2. Co‐immunoprecipitation experiments indicate that these two molecules indeed form a complex when expressed in HEK293 cells. Activation of ERK1/2 by bradykinin in HUVEC is enhanced when PECAM‐1 expression is inhibited by transfection of small interference RNA against PECAM‐1. Taken together, our results provide evidence of PECAM‐1 interaction with BKRB2 and of its possible role in regulating GPCR and G protein functions.Supported by NIH grant HL40696.
Epac is an integrator of pro‐and anti‐fibrotic signals in cardiac fibroblasts
Authors: Aroonsakool Nakon , Yokoyama Utako , Patel Hemal H , Lai N Chin , Jennings Michelle M , Roth David M 
Published: June 2021

Cyclic AMP (cAMP) regulates many biological processes but its role in tissue remodeling is not well understood. Actions of cAMP occur via protein kinase A (PKA) and by Exchange protein activated by cAMP (Epac). We hypothesized that Epac and PKA play distinct roles in cAMP‐mediated effects on cardiac fibroblasts (CF), which regulate repair and remodeling in the heart. We found that the Epac activator, Me‐cAMP, stimulated, while the PKA activator, Phe‐cAMP, inhibited CF migration, as assessed by a Boyden chamber method. siRNA‐mediated disruption of Epac1 blocked agonist‐induced migration of CF while a PKA inhibitor enhanced migration. Activation of either Epac or PKA inhibited collagen I and III mRNA expression. Pro‐fibrogenic agonists (TGFβ1, angiotensin II and endothelin) decreased Epac1 mRNA expression and Epac‐induced migration. Overexpression of Epac1 inhibited TGFβ1‐induced collagen synthesis and Epac1 protein expression decreased at the border zone of rats with myocardial infarction. In summary, 1) Epac promotes while PKA inhibits migration of CF; 2) Epac1 expression is decreased by pro‐fibrotic agonists and by myocardial infarction and 3) Increased expression of Epac1 decreases collagen synthesis. Thus, Epac1 appears to integrate pro‐and anti‐fibrotic signals in the heart.This work was supported by grants from NIH (2P01HL066941‐060005), AHA, VA and the Ellison Medical Foundation.
SHR exhibit greater ANG II induced release of Neuropeptide Y (NPY) from mesenteric bed preparations than normotensive controls
Authors: Byku Mirnela , Macarthur Heather , Westfall Thomas C 
Published: June 2021

NPY is a cotransmitter with NE and ATP in sympathetic nerves. There is evidence for increased activity of the sympathetic nervous system and the renin‐angiotensin system (RAS) as well as a role for NPY in the development and maintenance of hypertension in experimental animal models and in humans. Angiotensin II (Ang II) is known to facilitate sympathetic neurotransmission, and evoke the release of NE. This effect of Ang II is enhanced in blood vessels obtained from Spontaneously Hypertensive Rats (SHR). The objective of this study was to investigate the role of Ang II on the basal and nerve stimulated overflow of NPY from the perfused mesenteric arterial bed of SHR as hypertension develops.We observed that Ang II (0.01; 0.1 μM) facilitates basal and nerve stimulated overflow of NPY from the mesenteric arterial bed; an effect that is greater in preparations obtained from 4–6, 10–12 and 18–20 week old SHR than age matched normotensive Wistar‐Kyoto (WKY) or Sprague Dawley (SD) rats. Preparations obtained from prehypertensive (4–6 week old) SHR appear to behave similarly to those of 10–12 week old SHR with respect to Ang II induced changes in nerve stimulated NPY overflow. This facilitatory effect of Ang II appears to be mediated by the AT1 receptor. In addition, Captopril administration resulted in decreased NE overflow from SHR preparations, suggesting that the local RAS is active in this model. (Sponsored by NIH HL60260 and AHA)
Circulating oxidized low‐density lipoproteins are associated with overweight, obesity, and low serum carotenoids in older community‐dwelling women
Authors: Beck Justine C , Ferruci Luigi , Sun Kai , Linda Fried , Varadhan Ravi , Walston Jeremy , Guralnik Jack , Semba Richard 
Published: June 2021

Context:Oxidized low‐density lipoproteins (ox‐LDL) have been implicated in the pathogenesis of atherosclerosis and cardiovascular disease. The relationship between serum carotenoids, which are important components of low‐density lipoproteins, and obesity with ox‐LDL has not been well characterized.Objective:The objective of this study was to examine the independent relationships between total serum carotenoids and obesity with ox‐LDL in moderately to severely disabled older women living in the community.Methods:Serum carotenoids and oxLDL were measured in 543 women from the Women's Health and Aging Study I in Baltimore, Maryland.Results:Total serum carotenoids, smoking, overweight (BMI 25–29.9 kg/m2), and obesity (BMI ≥30 mg/kg2) were significantly associated with ox‐LDL/LDL‐cholesterol ratio after adjusting for age, C‐reactive protein, and chronic diseases. Alpha‐tocopherol and selenium were not significantly associated with ox‐LDL/LDL‐cholesterol ratio.Conclusions:Older women who are overweight or obese or who have low total serum carotenoids are more likely to have higher lipoprotein oxidation. Weight reduction in overweight/obese women and increased intake of carotenoid‐rich foods may potentially reduce lipoprotein oxidation.This work was supported by National Institute on Aging Grant R01 AG027012, AG11703‐01A1, NIH‐NCRR, OPD‐GCRC grant RR00722, R01 AI41956, NIA Contract N01‐AG12112, and the Intramural Research Program, National Institute on Aging, NIH.
Tissue Kallikrein increases perivascular cell coverage of angiogenic vessels via a Bradykinin‐2‐Receptor dependent mechanism
Authors: Stone Oliver Andrew , Emanueli Costanza , Harper Steven J. , Madeddu Paolo , Bates David O. 
Published: June 2021

We previously showed that Tissue Kallikrein (hTK) overexpression induces an increase in perivascular cell coverage of angiogenic vessels. To further investigate the mechanisms of hTK induced angiogenesis, hTK was overexpressed in the adult rat mesentery, and intravital and confocal imaging used to examine vessel morphology and histology following daily subcutaneous injection of the B2‐receptor antagonist Icatibant. B2R blockade caused no significant reduction in the hTK induced increase in functional vessel area (457±90% vs 420±74%). Angiogenesis in the presence of Icatibant was associated with a significant reduction in fractional pericyte coverage (64±4 vs 27±6 %, p<0.02) and smooth muscle cell recruitment was abolished (7.2±1.2% vs 0±0% p<0.001). Icatibant also caused an increase in sprout point density (7±2 vs 22±3mm−2, p<0.05) and was associated with haemorrhage of the microvasculature. Further investigation indicated the co‐localisation of pericytes and B2R expression in both control and treated animals. These data provide the first mechanistic explanation for the hTK induced increase in pericyte coverage, implicating a pivotal role for the B2 receptor in the recruitment/proliferation of perivascular cells and the stabilisation of the angiogenic microvasculature.All data presented mean±SEM, n = 6. Work funded by the BHF.
Nicotine‐induced up‐regulation of Wingless/Int signaling in human alveolar interstitial fibroblasts (AIFs)
Authors: Cerny Laura , Sakurai Reiko , Wang Ying , Guo Pinzheng , Torday John S , Rehan Virender K 
Published: June 2021

Nicotine induces AIF‐to‐myofibroblast (MYF) transdifferentiation. Since these phenotypes are determined by Peroxisome Proliferator‐Activated Receptor (PPAR)γ and Wnt signaling, respectively, we hypothesized that nicotine down‐regulates PPARγ signaling and up‐regulates Wnt signaling. And since nicotine activates PKC, we hypothesized nicotine up‐regulates Wnt signaling via PKC activation. WI38 cells were treated with nicotine 10−6M for 30 min or 24 hours +/− 30 minute pretreatment with calphostin C (10−7), a pan‐PKC inhibitor. Cell lysates were analyzed by Western blotting for activation of 1) PKC (p‐PKC) and 2) Wnt signaling (p‐GSK‐3β, β‐catenin, LEF‐1, and fibronectin); and 3) down‐regulation of PPARγ. We also examined activation of nicotinic acetylcholine receptors (nAChR)‐α3 and –α7, up‐stream regulators of Wnt signaling.Following 30 min of nicotine stimulation, nAChR‐α3 and –α7 were up‐regulated, accompanied by activation of PKC and Wnt signaling and significant changes in expression of down‐stream targets of Wnt signaling at 24h. All changes were blocked by calphostin C, indicating the central involvement of PKC in nicotine‐induced activation of Wnt signaling, and hence AIF‐to‐MYF transdifferentiation. Therefore PKC signaling plays a central role in nicotine‐induced activation of Wnt signaling, providing novel preventive/therapeutic targets. Funding‐NIH HL75405 & TRDRP 14RT‐0013.
Angiopoietin‐1 reverses protein permeability in an injury model of cultured human alveolar epithelial type II cells
Authors: Neyrinck Arne Pieter , Lee Jae‐Woo , Fang Xiaohui , Gupta Naveen , Matthay Michael A 
Published: June 2021

OBJECTIVE: We recently reported that acute lung injury (ALI) pulmonary edema and cytomix (IL1β, TNFα and IFNγ) increase epithelial protein permeability (JBC, 2007). Angiopoietin‐1 (Ang‐1) maintains vascular integrity and reduces endothelial activation in a model of ALI (AJRCCM 2007). In this study, we hypothesized that Ang‐1 could reverse increased protein permeability in cultured human alveolar epithelial type II cells (ATII) exposed to cytomix.METHODS: Isolated human ATII cells were cultured in an air‐liquid interface and protein permeability was measured. Cells were exposed to control medium, cytomix (50 ng/ml) and cytomix with recombinant human Ang‐1 (10,000 pg/ml).RESULTS: 1) Cytomix increased protein permeability in cultured ATII cells. 2) Recombinant human Ang‐1 decreased ATII protein permeability significantly after exposure to cytomix (Figure 1).CONCLUSIONS: Ang‐1 can reverse protein permeability across ATII cells exposed to cytomix. These results are the first results to show a potential role for Ang‐1 in regulation of alveolar epithelial permeability. The data support a further role of Ang‐1 in the treatment of ALI.Supported by NIH HL51856 and HL51854
Elucidating Conformational Changes in the γ‐Aminobutyric Acid (GABA)Transporter
Authors: Meinild Anne‐Kristine , Loo Donald , MacAulay Nanna 
Published: June 2021

In addition to the Na+‐coupled GABA transport, the Na+/Cl− dependent GABA transporter, GAT‐1, also has a Li+‐induced leak. Recently, the amino acids directly involved in the interaction with the Na+ and Li+ ions have been identified (Zhou et al, 2006, JBC Vol. 281). In the present study, we obtain insight into the structural dynamics of the two transport modes of GAT‐1 by applying the voltage clamp fluorometry method (VCF) to wild type GAT‐1 expressed in Xenopus oocytes. We have taken advantage of the only accessible cysteine in wild type rat GAT‐1, C74, and labeled this residue with a cysteine‐reactive fluorophor, tetramethyl rhodamine‐6‐maleinamide.Our fluorescent read‐outs show that the transporter undergoes different voltage dependent conformational changes in the presence of the different ions in the external solution: in Na+ buffer the V½ for fluorescence is −2 ± 9 mV whereas in Li+ buffer it is −71 ± 12 mV. The time courses of these fluorescent changes are also highly dependent on the cation: in Na+ the τmax is 120 ms and in Li+ it is 40 ms. The fluorescence data for Li+ correlates with the Li+ induced currents: these are highly voltage dependent and only present at hyperpolarized potentials (<−50 mV).The study demonstrates the advantage of applying the VCF method in combination with homology modeling of the neurotransmitter transporters to the newly crystallized bacterial homolog, LeuT.
Redox Regulation of Circulating NO Bioavailability & Post‐Exercise Hemodynamics in Hypertension
Authors: New Karl James , Bailey Damian , McEneny Jane , Templeton Catherine , Ellis Gethin , James Philip , Davies Bruce 
Published: June 2021

9 pre‐hypertensive males, MAP = 106 ± 5 mmHg were studied for 2‐hours following 30‐minutes of cycle exercise at 70% maximal oxygen consumption. Echocardiography determined cardiac output (CO) and systemic vascular resistance (SVR) by MABP/CO. Venous blood was sampled from an antecubital vein pre‐, immediately post‐, 1‐hour post‐ (P1) and 2‐hours post‐ (P2) exercise and corrected for plasma volume shifts. Plasma nitrate (NO−3) and nitrite (NO−2) was determined fluorometrically, S‐Nitrosothiol (RSNO) concentrations were assayed by the Saville reaction. Lipid hydroperoxides (LOOH) were determined spectrophotometrically whilst blood was also assayed for selective antioxidants. Upper (UL) and lower limb (LL) arterial pulse wave velocity (APWV) was determined pre and post‐exercise via oscillometry.Ascorbic acid, α‐tocopherol, RSNO and LL APWV were unchanged. UL APWV was 18% lower than baseline at post recovering by P2 being 9% elevated above baseline.Elevated oxidative stress in the recovery period coincides with a blunting of circulating NO, UL arterial compliance and a return of SVR towards baseline.
Skeletal muscle anabolic response to resistance exercise and essential amino acids is delayed with aging
Authors: Drummond Micah J , Dreyer Hans C , Pennings Bart , Fry Christopher S , Dhanani Shaheen , Dillon Edgar L , Sheffield‐Moore Melinda , Volpi Elena , Rasmussen Blake B 
Published: June 2021

The loss of skeletal muscle during aging (sarcopenia) leads to an increased risk of falls, fractures and eventually loss of independence. Resistance exercise (RE) is a useful intervention to prevent sarcopenia, however, the response to RE is less when compared to young subjects. Essential amino acids (EAA) increase muscle protein synthesis (MPS) equally in both young and old subjects. We hypothesized that EAA ingestion following RE would restore anabolic signaling and MPS in aging muscle. Young and old men ingested 20g of EAA 1hr following a bout of leg‐RE. Muscle biopsies were obtained before, 1, 3, and 6hr post‐exercise to measure MPS and signaling pathways which regulate translation initiation. MPS increased early in young (1–3hr post‐exercise) and later in old (3–6hr post‐exercise). RE activated ERK1/2 and eIF2α signaling only in the young 1hr post‐exercise. mTOR/S6K1 signaling was similar between groups at all time points and AMPKα phosphorylation was higher in old 1–3hr post‐exercise. We conclude that MPS after RE and EAA ingestion is similar between young and old but delayed with aging. Unresponsive ERK1/2 signaling and AMPK activation in aging may explain the delayed activation of MPS. Notwithstanding, the combination of RE and EAA should be a useful strategy to combat sarcopenia.Supported by NIH/NIAMS grant # R01 AR049877 and NIH/NIA P30 AG024832