bluuebunny/crossref_metadata_2025_split huggingface dataset:
A comparison of efficacy of a 5‐day versus 10‐day zinc therapy for acute childhood diarrhoea (ACD) on the incidence of diarrhoea in subsequent three months
Authors: Shamsul Alam Dewan , Yunus Mohammad , El Arifeen Shams , Rahman Chowdhury Hafizur , Larson Charles P , Allen Sack David , Baqui Abdullah H , Black Robert E 
Published: June 2021

Design Randomised, double‐blind, placebo controlled community trial.Seeting Rural BangladeshSubjects and Methods: Children (n=1622) aged 4 – 59 months with acute diarrhea, detected by daily community surveillance, were randomly allocated either to 5‐ or 10‐days of zinc treatment. Those allocated to the 5‐day course received an indistinguishable placebo for the remaining 5 days. Female field workers visited each individual child daily and supervised the administration of zinc.Result: The two groups were comparable in terms of age, sex, nutritional status and selected SES variables. Adherence to the treatment was 99% for the 1st five days and 97% for 2nd five days. The mean (±SD) incidence of diarrhoea over 90 days did not differ significantly between 5‐d vs 10‐d groups (1.08±1.38 vs 1.02±1.35; p=0.35; respectively). Children in both groups spent a comparable days with diarrhoea (3.1±5.6 d vs 2.9±5.6 d; p=0.64; 5‐d vs 10‐d respectively). Time to onset of the first episode during 90 d period did not differ significantly between groups. The proportion of children suffering from diarrhoea over the 90‐day period did not differ significantly between groups. The diarrhea incidence and prevalence in the two groups were also comparable.Conclusions: These findings suggest that a 5‐day zinc treatment for ACD is as efficacious as 10 days of therapy in preventing diarrhoea in the subsequent three months.
Resistant starch is effective in lowering body fat in a rat model of human endocrine obesity
Authors: Robert Julina A. , Zhou Jun , Raggio Anne M. , Tulley Richard T. , McCutcheon Kathleen L. , Martin Roy J. , Keenan Michael J. 
Published: June 2021

Endocrine obesity is a problem among females in the United States. Our previous studies show that resistant starch (RS) is effective in reducing body weight and fat in normal rats and mice. This study examined the effects of RS on abdominal fat and body weight in ovariectomized (OVX) and sham‐operated (sham) rats. Twenty OVX and 20 sham 10‐week old virgin female Sprague‐Dawley rats were purchased from Harlan. Rats were fed an energy control diet (EC, 3.27 kcal/g) for 6 wk prior to dietary treatment for measurement of energy intake and weight gain in the hyperphagic period after surgery. A 2x2 factorial was used as rats were then blocked by weight into diet treatment groups, and spent 13 wk on either an RS or EC diet. Data comparisons were significant at p < 0.05. OVX rats consumed more energy and gained more weight than sham rats in the pretrial period. For OVX and sham rats, energy intake, total gastrointestinal weight, large intestine/cecum weight (indicator of increased fermentation), and small intestine weight were higher in RS rats compared to EC rats. All abdominal fat pads were lower in RS rats compared to EC rats. RS rats had a lower disemboweled body weight compared to EC rats (p<0.06). This data indicate that RS was effective in lowering abdominal fat in an endocrine form of obesity compared to rats fed the EC diet, despite greater energy intakes for RS rats.Grant Funding Source: NIH and LSU AgCenter
The Effects of Pistachios on Postprandial Glucose and Insulin Levels, Gut Satiety Hormones and Measures of Oxidative Stress
Authors: Kendall Cyril WC , Josse Andrea R , Jenkins David JA 
Published: June 2021

Background: Nuts are associated with a reduced risk of CHD and Type 2 Diabetes possibly relating to their favorable fat, protein and antioxidant profiles. Moreover, nuts have also been shown to reduce serum LDL‐C. Previous studies have demonstrated that pistachios decreased the postprandial glycemic response of white bread in a dose‐dependent manner and attenuated the glucose excursions of common carbohydrate foods when consumed with 2oz of pistachios.Objective: To assess the effect of pistachios on postprandial serum insulin levels, gut satiety hormone responses and measures of tissue oxidative stress.Methods: After an overnight fast, 15 healthy subjects consumed 2 iso‐caloric test meals and 1 control meal in a randomized fashion, each separated by 1 week. Test meals, with similar macronutrient profiles, consisted of white bread (97g) plus 2oz of pistachios; white bread (97g) plus butter (14g) and cheese (68g). The control meal was white bread. Capillary finger‐prick and venous blood samples were taken and subjective satiety measures via a visual analogue scale were assessed over 3 hours. The relative glycemic and insulinemic responses were assessed by calculating the incremental area under the 3h curve (IAUC).Results: Differences are assessed by least squares means with a Tukey adjustment for multiple comparisons. To be presented.Funding Support: Western Pistachio Association
Rosenthal fiber‐rich glioblastoma: A case report
Authors: Takei Hidehiro , Powell Suzanne Z 
Published: June 2021

Background: Rosenthal fibers (RFs) are thick, elongated, brightly eosinophilic structures occurring within astrocytic processes. Although the presence of numerous RFs in brain tumor is most closely associated with a low‐grade astrocytoma, particularly pilocytic astrocytoma, a few RFs are recognized to occur, although rarely, in glioblastoma (GBM). We report a very rare case of GBM with abundant RFs.Case Report: A 60‐year‐old woman presented with a six‐month history of difficulty coordinating her right hand, occasional intermittent diplopia, and occasional dizzy spells. An MRI showed a heterogeneously enhancing, infiltrating mass with cystic component involving left midbrain, thalamus, and posterior basal ganglia. Biopsy was performed. Cytologic touch imprints revealed fibrillary astrocytic cells possessing oval nuclei and long delicate processes with abundant RFs. Histologic sections showed diffusely infiltrating astrocytoma with prominent RFs diffusely distributed throughout the tumor, brisk mitotic activity, vascular proliferation, and small areas of necrosis, as seen in GBM. MIB‐1 labeling index was 7.1%. P53 immunoreactivity was not seen.Discussion: This is a case of RF‐rich GBM, most likely de novo GBM. For the histological diagnosis, infiltrating astrocytoma with abundant RFs should be carefully examined in light of clinical information (e.g., patient age) and neuroimaging studies.
Eosinophilic intracytoplasmic inclusions within the cerebral cortex in chronic seizure disorder ‐ a report of two cases and a review of the literature
Authors: Cunliffe Clare Helen , Fischer Ingeborg , Zagzag David , Miller Douglas C 
Published: June 2021

Brightly eosinophilic inclusions within astrocytes have been reported 6 times in the literature, occurring in maldevelopmental disorders, Aicardi Syndrome, and once in seizure disorder. We report 2 more cases of this histologic finding within the cortex in patients with chronic seizure disorder.One of the cases was a 3 year old boy who developed seizures following routine vaccinations. The other was a 14 year old woman with seizures since infancy. The cortical inclusions were similar in both cases: rope‐like or globular and brightly eosinophilic on H&E stain, some resembling Rosenthal fibers, and bright red on Azocarmine and Masson‐Trichrome stains, labeled by an S‐100 immunostain, but not labeled by GFAP, synaptophysin, neurofilament protein, Neu‐N, alpha‐B‐crystallin, and alpha‐synuclein immunostains. Ultrastructurally, the inclusions in one of the cases consisted of granular osmiophilic material within the cytoplasm of astrocytes.The nature and significance of the inclusions is unclear. The tinctorial and immunohistochemical properties of these inclusions is similar to those described in the literature. Whether these inclusions represent a reactive process to seizure activity, or are causative in nature remains to be elucidated. However, they represent an unusual change which may be present in resected seizure foci, and as such, it is helpful for neuropathologists to be aware of this phenomenon.
Identification of residues lining the entrance of the human serotonin transporter substrate permeation pathway using homology modeling
Authors: Torres‐Altoro Melissa I. , Nichols David E. , Barker Eric L. 
Published: June 2021

Appropriate removal of monoamine neurotransmitters after release into the synapse is mediated by presynaptic transporters. Many neurological disorders have been implicated in the dysfunction of these important drug targets. A high‐resolution crystal structure for the monoamine transporters is yet to be resolved. We have developed a homology model for the serotonin transporter (SERT) based on the crystal structure of the leucine transporter (LeuTAa) from Aquifex aeolicus. The objective of my studies is to identify the structural determinants to the entrance into the substrate permeation pathway based on predictions drawn from the homology model. Taking advantage of the substituted cysteine accessibility method (SCAM), we identified residues that were sensitive and accessible to different MTS (methanethiosulfonate) reagents. These residues were protected against MTS reactivity with different SERT ligands. Moreover, those residues with significant changes in MTS reactivity after ligand protection were further analyzed by determining their rate of inactivation. Furthermore, bifunctional MTS cross‐linkers were used to assess the proximity of the helices predicted to be forming the entrance into the protein pore. Our studies provide the opportunity to refine the model and further extend SERT structural characterization.This research supported by NIH grant R01DA018682.
Role of Toll‐like receptors in ischemic stroke induced endothelial cell dysfunction
Authors: Tiwari Samata , Mattson Mark P , Arumugam Thiruma V 
Published: June 2021

Toll‐like receptors (TLRs) regulate host responses to pathogens and inflammatory responses. Activation of TLRs initiates signal transduction cascades involving kinases and transcription factors activator protein‐1 and NF‐kappa B. Recently studies have shown that TLR2 and −4 may play a role in ischemic stroke induced brain injury. Our recent findings showed that TLR2 and −4 are expressed in cerebral cortical neurons where their levels and downstream signaling via JNK are increased in response to energy deprivation in cell culture and ischemia in vivo. Here we use human microvascular endothelial cells (HMECs), mouse brain endothelial cells (MBECs) and in vivo models of ischemic stroke to elucidate roles of endothelial TLR2, −3 and −4 signaling in ischemic stroke induced endothelial dysfunction. Preliminary data shows that TLR2, −3 and −4 mRNA expression were increased during the first few hours in glucose deprivation (GD) and oxygen and glucose deprivation (OGD) conditions in both HMECs and MBECs. We also observed increased levels of TLR signaling adaptor molecule MYD88 mRNA in response to GD and OGD. Immunoblot analysis also showed increased expression of TLR proteins and MyD88 in response to OGD in MBECs. Preliminary results indicate a role for endothelial TLR signaling in pathogenesis of stroke.Research Support: TTUHSC School of Pharmacy Start up Fund.
Validation of effect of Pioglitazone on acute phase changes induced by partial global cerebral ischemia in mice
Authors: Medhi Bikash , Aggrawal Raman , Chakrabarty Amitava 
Published: June 2021

Objective: Present study was carried out to investigate the possible neuroprotective effect of pioglitazone on acute phase changes in mice model of cerebral ischemia.Materials and Methods: Male mice weighing 20–30 gm were used in the study. BCCAO model was used to induce partial global cerebral ischemia. Animals were divided into 3 groups and following parameters were assessed (infarct size, brain edema, MDA, SOD, Catalase, GPx &TNF (). Postischemic seizure susceptibility was assessed using subconvulsive dose of PTZ (30 mg/kg i.p.).Results: BCCAO induced significant brain infarct size and edema in control group with increase oxidative stress. Pioglitazone (20 mg/kg orally) has shown neuroprotective effects by reducing cerebral infarct size significantly as compared to control group. Postischemic seizure susceptibility was also reduced as number of positive responders decreased to a significant number. Brain edema was subsided to a significant level. Pioglitazone has reduced the plasma TNF‐ a and improved antioxidant parameters levels as compared to ischemia group significantly.Conclusion: Pioglitazone showed neuroprotection against ischemic insult suggesting the role of PPAR ? agonist as neuroprotective agents. (Supported by PGIMER, Chandigarh, India.) Key words: Cerebral ischemia, pioglitazone, PPAR‐gamma, neuroprotection
PEGylated phospholipid nanomicelles protect Swedish mutants APP695 and sweΔ9 N2a mouse neuroblastoma cells from β‐amyloid induced apoptosis
Authors: Pai Ashwini S. , Onyuksel Hayat , Rubinstein Israel 
Published: June 2021

The purpose of this study was to determine whether β‐amyloid evokes cell death in Swedish mutants APP695 and sweΔ9 mouse N2a neuroblastoma cells and, if so, whether sterically stabilized phospholipid nanomicelles (SSM) inhibit this process. Mouse N2a neuroblastoma cells stably expressing Swedish mutant APP695 and exon‐9 deletion mutant PS1 (sweΔ9) (2 × 103cells/well) were incubated in the absence or presence of SSM (10–100 μM) overnight. Thereafter, LDH release from and caspase3/7 activity in these cells were determined. We found that β‐amyloid had no significant effects on LDH release from N2a cells either in the absence or presence of SSM (n=3; p>0.5). By contrast, exposure to β‐amyloid was associated with significantly higher caspase 3/7 activity in comparison to control that was significantly attenuated in the presence of SSM in a concentration‐dependent fashion (n=3; p<0.05). Collectively, these data indicate that SSM protect Swedish mutants APP695 and sweΔ9 N2a mouse neuroblastoma cells from β‐amyloid induced apoptosis. W e suggest that SSM should be further developed as a novel nanomedicine for Alzheimer's disease.Supported by IDPH # 73280001, NIH RO1 5R01CA121797, AG024026, VA merit Review and was conducted in a facility supported from NIH RFIP 06RR15482.Ashwini S. Pai is a recipient of Deans Scholar Award UIC 2007–2008 and American Foundation For Aging research (AFAR) fellowship 2007–2008.
Prostacyclin receptor regulates contraction‐associated proteins and contractile proteins in pregnant human myometrium via PKA/cAMP and the transcription factors GATA‐6 and myocardin
Authors: Fetalvero Kristina , Zhang Pei‐Sheng , Shyu Maureen , Young Benjamin , Hwa John , Young Roger C. , Martin Kathleen A. 
Published: June 2021

Objective: Levels of the smooth muscle relaxant prostacyclin increase prior to labor. We investigated the role of prostacyclin in myometrial activation.Methods: Myometrial tissue was obtained from term pregnant women during cesarean delivery and treated with vehicle or the prostacyclin receptor (IP) agonist iloprost in organ or cell culture models. siRNA was transfected using a Nucleofector. Contraction‐associated protein (CAP) and contractile protein expression were analyzed by immunoblotting or RT‐PCR.Results: Iloprost induced expression of the CAPs COX‐2 and connexin‐43, and the contractile proteins smooth muscle‐myosin heavy chain, h‐caldesmon, and calponin in organ culture and/or cell culture. COX‐2 activity increased as measured by PGF2αrelease. Iloprost activated cAMP/PKA, and siRNA against PKA reduced iloprost‐induced CAP and contractile protein expression, while 8‐Br‐cAMP mimicked the effect. siRNA against the transcription factors GATA‐6 or myocardin inhibited iloprost‐induced SM‐MHC and COX‐2.Conclusions: IP activation of cAMP/PKA induces CAPs and contractile proteins in human myometrium, perhaps by regulating GATA‐6 and myocardin. Prostacyclin may provide positive feedback, linking CAPs and contractile proteins, by increasing COX‐2 activity. These mechanisms may be involved in the conversion of the human uterus from quiescent to an actively contracting labor phenotype.This work was supported by grants from the NIH NHLBI and an NIH NCI training grant
Direct detection of intracellular superoxide generation from freshly isolated rat aorta: a novel approach
Authors: Goel Aditya , Matkar Smita , Rahimian Roshanak 
Published: June 2021

Although superoxide (O2−) plays an important role in vascular diseases, direct measurement of O2− in viable tissue remains a challenge. The aim of this study was to design and validate a procedure to measure O2− generation using freshly isolated aorta.Method:The 8 mm fresh aortic segments from male and female rats were cut longitudinally in Krebs buffer at 37°C and mounted on the silicon elastomer surface with the lumenal surface facing upward. The segments were incubated with the nitric oxide probe 4,5‐diaminofluorescein diacetate (DAF‐2DA, 5 μM) or O2− probe dihydroethidium (DHE, 2.5 μM), followed by fluorescent recoding at longitudinal edge using Leica DMIRE2 microscope. Acetylcholine‐induced increased DAF fluorescence was taken as evidence for the endothelial integrity. To examine the effect of O2− generator, DHE fluorescence was quantified before and after incubation of segments with phorbol myristate acetate (PMA, 0.1 μM), or PMA in the presence of O2− scavenger (tempol, 100 μM) for 30 min.Results:The extent of PMA‐induced O2− increase was greater in female tissues (9.2 fold) than that in males (2.8 fold), and this was prevented by the presence of tempol. This data was comparable to our recent report on gender difference in PMA‐induced O2− production in rat aorta using isometric tension study.Conclusion:This procedure will allow us to detect O2− generation in translucent viable vessels. (Supported by NHLBI)
Advances in structure based drug design and virtual screening
Authors: Abagyan Ruben 
Published: June 2021

The rapid growth of the number of structures in the Protein Data Bank and the emergence of the chemogenomics databases combined with the advances in computational methods created a unique opportunity for a wider application of rational drug design and structure based virtual screening. Another factor is the determination of the three dimensional structure of beta 2 adrenergic receptor. The main challenge, however, remains to be the understanding and treatment of the receptor induced fit effects.We built the largest structural chemogenomic database and presented a docking algorithm that reliably docks ligands to their pockets despite the induced fit effect. The new GPCR structure and its implications for rational design and screening of potent and specific GPCR agonists and antagonists are reviewed.The success of the ligand guided models is demonstrated on several cases studies including drug repurposing.This work was supported by NIH grants 5R01‐GM074832‐02 and 5R01‐GM071872‐02.
Agonist and antagonist activation of signalling pathways in CHO‐K1 cells stably expressing the human β3‐adrenoceptor
Authors: Summers Roger J , Hutchinson Dana S , Evans Bronwyn A , Sato Masaaki 
Published: June 2021

The human β3‐adrenoceptor (hβ3‐AR) couples to Gs to activate adenylyl cyclase, leading to lipolysis or thermogenesis in adipose tissue. hβ3‐AR also couple to Gi, to modulate adenylyl cyclase and activate mitogen‐activated protein kinase (MAPK) pathways. Here, we have examined the action of the β2‐AR agonist zinterol, the selective hβ3‐AR agonist L755507 and the selective hβ3‐AR antagonist L748337 on hβ3‐AR stably expressed in CHO‐K1 cells. Zinterol and L755507 caused dose‐dependent cAMP accumulation (pEC50′ 8.47±0.11 and 12.28±0.03) while L748337 had little effect in this assay. In contrast, in the cytosensor microphysiometer, the maximum extracellular acidification rate (ECAR) responses elicited by L748337 (pEC50 7.14±0.03) were almost identical to those obtained with zinterol and L755507 (pEC50 8.13±0.03 and 8.63±0.10 respectively). This suggested that L748337 can selectively activate pathways other than cAMP. Western blots of p38 MAPK and Erk1/2 phosphorylation showed strong activation in response to both L748337 and to L755507. Activation in response to L748337 was almost completely abolished by PTX pre‐treatment that only slightly affected responses to L755507. We conclude that L755507 and L748337 utilize discrete pathways to activate p38 MAPK and Erk1/2; L755507 by signalling through Gs and L748337 by signalling through Gi.This research was supported by National Health and Medical Research Council Project Grants 236884 and 491190.
S1P receptor localization confers selectivity for Gi mediated signaling pathways
Authors: Means Chris , Miyamoto Shigeki , Chun Jerold , Brown Joan Heller 
Published: June 2021

Adult mouse ventricular myocytes (AMVMs) express S1P1, S1P2, and S1P3 receptors. S1P activates Akt and ERK in AMVMs through a pertussis toxin (PTX)‐sensitive (Gi‐mediated) pathway. S1P‐mediated activation of ERK and Akt is partially reduced in both S1P2 and S1P3 receptor null AMVMs and abolished in S1P2,3 receptor null AMVMs. In addition S1P treatment leads to PTX‐sensitive inhibition of isoproterenol (iso)‐stimulated cAMP accumulation in WT myocytes, and this response in unchanged in S1P2,3 null myocytes, demonstrating that the S1P1 receptor also couples to Gi. Similarly an S1P1 receptor selective agonist, SEW2871, also decreased iso‐stimulated cAMP accumulation but failed to activate either ERK or Akt. To determine whether localization of the S1P1 receptor and its effectors is important in mediating this signaling specificity, the caveolae disrupting agent methyl‐β‐cyclodextrin (MβCD) was used. The S1P1 receptor was concentrated in caveolar fractions and this localization was disrupted by MβCD treatment. MβCD did not prevent S1P‐mediated activation of ERK or Akt, but fully abolished the inhibition of cAMP accumulation and negative inotropic effects of both S1P and SEW2871. Together, the data indicate that localization of S1P1 receptors to caveolae is required for this receptor to inhibit adenylyl cyclase and decrease contractility, yet compromises the coupling of this receptor to Akt and ERK pathways.This work was supported by National Institutes of Health Grants HL28143 and HL46345 (to J.H. Brown), NS048478 and DA019674 (to J. Chun), and by an American Heart Association predoctoral fellowship (to C.K. Means)
The pleiotropic physiological effects of relaxin are determined by the signalling pathway profile activated in target cells
Authors: Halls Michelle L , Bathgate Ross A , Summers Roger J 
Published: June 2021

Relaxin is a two‐chain hormone, related to insulin, that mediates pleiotropic effects in physiological systems. The relaxin receptor RXFP1, is a G‐protein coupled receptor that increases cAMP accumulation via a biphasic pathway when expressed in HEK293T cells: initially RXFP1 couples to Gαs and GαoB, to increase and modulate cAMP respectively, but with time recruits coupling to Gαi3 and activates a Gβγ‐PI3K‐PKCζ pathway to further increase cAMP. However, the signalling transduction mechanisms activated by this hormone in physiological target cells and tissues are unclear. This study examines the signalling pathways activated by relaxin in cells that endogenously express RXFP1 using an α‐screen cAMP accumulation assay. RXFP1 expression was identified in three cell lines and two primary cell cultures: THP‐1, T‐47D, Colo16, rat cardiac fibroblasts and rat renal fibroblasts from obstructed kidneys. Only in THP‐1 cells and rat cardiac fibroblasts was there activation of the delayed Gαi3 pathway. In all other cells there was activation of a combination of the initial pathways. T‐47D cells could only activate Gαs, whereas Colo16 and rat renal fibroblasts could activate both Gαs and GαoB. Thus the signalling pathways activated by relaxin are highly dependent upon the cell under investigation, and may help explain the varied physiological responses exerted by relaxin in different target tissues.This research was supported by National Health and Medical Research Council Project Grants 436713 and 454375.