bluuebunny/crossref_metadata_2025 huggingface dataset:
Sexually Dimorphic Epigenetic Regulation of Brain-Derived Neurotrophic Factor in Fetal Brain in the Valproic Acid Model of Autism Spectrum Disorder
Authors: Konopko Melissa A. , Densmore Allison L. , Krueger Bruce K.
Published: October 2017

Prenatal exposure to the antiepileptic, mood-stabilizing drug, valproic acid (VPA), increases the incidence of autism spectrum disorders (ASDs); in utero administration of VPA to pregnant rodents induces ASD-like behaviors such as repetitive, stereotyped activity, and decreased socialization. In both cases, males are more affected than females. We previously reported that VPA, administered to pregnant mice at gestational day 12.5, rapidly induces a transient, 6-fold increase in BDNF (brain-derived neurotrophic factor) protein and mRNA in the fetal brain. Here, we investigate sex differences in the induction of Bdnf expression by VPA as well as the underlying epigenetic mechanisms. We found no sex differences in the VPA stimulation of total brain Bdnf mRNA as indicated by probing for the BDNF protein coding sequence (exon 9); however, stimulation of individual transcripts containing two of the nine 5′-untranslated exons (5′UTEs) in Bdnf (exons 1 and 4) by VPA was greater in female fetal brains. These Bdnf transcripts have been associated with different cell types or subcellular compartments within neurons. Since VPA is a histone deacetylase inhibitor, covalent histone modifications at Bdnf 5′UTEs in the fetal brain were analyzed by chromatin immunoprecipitation. VPA increased the acetylation of multiple H3 and H4 lysine residues in the vicinity of exons 1, 2, 4, and 6; minimal differences between the sexes were observed. H3 lysine 4 trimethylation (H3K4me3) at those exons was also stimulated by VPA. Moreover, the VPA-induced increase in H3K4me3 at exons 1, 4, and 6 was significantly greater in females than in males, i.e., sexually dimorphic stimulation of H3K4me3 by VPA correlated with Bdnf transcripts containing exons 1 and 4, but not 6. Neither H3K27me3 nor cytosine methylation at any of the 117 CpGs in the vicinity of the transcription start sites of exons 1, 4, and 6 was affected by VPA. Thus, of the 6 epigenetic marks analyzed, only H3K4me3 can account for the sexually dimorphic expression of Bdnf transcripts induced by VPA in the fetal brain. Preferential expression of exon 1- and exon 4-Bdnf transcripts in females may contribute to sex differences in ASDs by protecting females from the adverse effects of genetic variants or environmental factors such as VPA on the developing brain.
Modulation of the Proteasome Pathway by Nano-Curcumin and Curcumin in Retinal Pigment Epithelial Cells
Authors: Ramos de Carvalho J. Emanuel , Verwoert Milan T. , Vogels Ilse M.C. , Schipper-Krom Sabine , Van Noorden Cornelis J.F. , Reits Eric A. , Klaassen Ingeborg , Schlingemann Reinier O.
Published: October 2017

Introduction: Curcumin has multiple biological effects including the modulation of protein homeostasis by the ubiquitin-proteasome system. The purpose of this study was to assess the in vitro cytotoxic and oxidative effects of nano-curcumin and standard curcumin and characterize their effects on proteasome regulation in retinal pigment epithelial (RPE) cells. Methods: Viability, cell cycle progression, and reactive oxygen species (ROS) production were determined after treatment with nano-curcumin or curcumin. Subsequently, the effects of nano-curcumin and curcumin on proteasome activity and the gene and protein expression of proteasome subunits PA28α, α7, β5, and β5i were assessed. Results: Nano-curcumin (5-100 μM) did not show significant cytotoxicity or anti-oxidative effects against H2O2-induced oxidative stress, whereas curcumin (≥10 μM) was cytotoxic and a potent inducer of ROS production. Both nano-curcumin and curcumin induced changes in proteasome-mediated proteolytic activity characterized by increased activity of the proteasome subunits β2 and β5i/β1 and reduced activity of β5/β1i. Likewise, nano-curcumin and curcumin affected mRNA and protein levels of household and immunoproteasome subunits. Conclusions: Nano-curcumin is less toxic to RPE cells and less prone to induce ROS production than curcumin. Both nano-curcumin and curcumin increase proteasome-mediated proteolytic activity. These results suggest that nano-curcumin may be regarded as a proteasome-modulating agent of limited cytotoxicity for RPE cells.
Temporal Associations between Fatigue, Depression, and Apathy after Stroke: Results of the Cognition and Affect after Stroke, a Prospective Evaluation of Risks Study
Authors: Douven Elles , Köhler Sebastian , Schievink Syenna H.J. , van Oostenbrugge Robert J. , Staals Julie , Verhey Frans R.J. , Aalten Pauline
Published: October 2017

Background: Poststroke fatigue (PSF) is a form of pathological fatigue that can develop after stroke and has a negative impact on functional outcome. PSF is associated with poststroke depression (PSD), which in turn shows similarities with poststroke apathy (PSA). This study aimed at disentangling the temporal associations between PSF and PSD and between PSF and PSA. Methods: A total of 250 stroke patients were included, of which 243 completed the Fatigue Severity Scale, Montgomery-Åsberg Depression Rating Scale, and Apathy Evaluation Scale at 3 months poststroke, with follow-up measurements at 6 and 12 months after initial testing. Linear mixed models and linear regressions were performed to evaluate the temporal associations between PSF and PSD, and between PSF and PSA. Results: PSF was present in 119 patients (49%), of whom 62 patients also had PSD (26%), and 21 patients (9%) also had PSA. At baseline, PSF patients showed higher depression levels, which remained stable at follow-up. PSD patients had higher fatigue levels compared with no-PSD patients at baseline, which remained stable at follow-up. No association between apathy and fatigue was found at baseline and no interaction with time was found. Change in fatigue from baseline to 12-month follow-up was associated with change in depression and with change in apathy. Conclusions: Bidirectional associations were found between PSF and PSD. In treatment and rehabilitation programs, early focus on the presence of PSD and PSF is important, since these conditions tend to persist. As there are currently more treatment options for PSD, attention for PSD is important and might also have a beneficial effect on PSF.
Genomic Characterization of Chromosomal Insertions: Insights into the Mechanisms Underlying Chromothripsis
Authors: Kato Takema , Ouchi Yuya , Inagaki Hidehito , Makita Yoshio , Mizuno Seiji , Kajita Mitsuharu , Ikeda Toshiro , Takeuchi Kazuhiro , Kurahashi Hiroki
Published: October 2017

Chromosomal insertions are rare structural rearrangements, and the molecular mechanisms underlying their origin are unknown. In this study, we used whole genome sequencing to analyze breakpoints and junction sequences in 4 patients with chromosomal insertions. Our analysis revealed that none of the 4 cases involved a simple insertion mediated by a 3-chromosomal breakage and rejoining events. The inserted fragments consisted of multiple pieces derived from a localized genomic region, which were shuffled and rejoined in a disorderly fashion with variable copy number alterations. The junctions were blunt ended or with short microhomologies or short microinsertions, suggesting the involvement of nonhomologous end-joining. In one case, analysis of the parental origin of the chromosomes using nucleotide variations within the insertion revealed that maternal chromosomal segments were inserted into the paternal chromosome. This patient also carried both maternal alleles, suggesting the presence of zygotic trisomy. These data indicate that chromosomal shattering may occur in association with trisomy rescue in the early postzygotic stage.
Sodium Chloride Supplementation Is Not Routinely Performed in the Majority of German and Austrian Infants with Classic Salt-Wasting Congenital Adrenal Hyperplasia and Has No Effect on Linear Growth and Hydrocortisone or Fludrocortisone Dose
Authors: Bonfig Walter , Roehl Friedhelm , Riedl Stefan , Brämswig Jürgen , Richter-Unruh Annette , Fricke-Otto Susanne , Hübner Angela , Bettendorf Markus , Schönau Eckhard , Dörr Helmut , Holl Reinhard W. , Mohnike Klaus
Published: October 2017

Introduction: Sodium chloride supplementation in salt-wasting congenital adrenal hyperplasia (CAH) is generally recommended in infants, but its implementation in routine care is very heterogeneous. Objective: To evaluate oral sodium chloride supplementation, growth, and hydrocortisone and fludrocortisone dose in infants with salt-wasting CAH due to 21-hydroxylase in 311 infants from the AQUAPE CAH database. Results: Of 358 patients with classic CAH born between 1999 and 2015, 311 patients had salt-wasting CAH (133 females, 178 males). Of these, 86 patients (27.7%) received oral sodium chloride supplementation in a mean dose of 0.9 ± 1.4 mmol/kg/day (excluding nutritional sodium content) during the first year of life. 225 patients (72.3%) were not treated with sodium chloride. The percentage of sodium chloride-supplemented patients rose from 15.2% in children born 1999–2004 to 37.5% in children born 2011–2015. Sodium chloride-supplemented and -unsupplemented infants did not significantly differ in hydrocortisone and fludrocortisone dose, target height-corrected height-SDS, and BMI-SDS during the first 2 years of life. Conclusion: In the AQUAPE CAH database, approximately one-third of infants with salt-wasting CAH receive sodium chloride supplementation. Sodium chloride supplementation is performed more frequently in recent years. However, salt supplementation had no influence on growth, daily fludrocortisone and hydrocortisone dose, and frequency of adrenal crisis.
Mechanisms of Resistance to CDK4/6 Inhibitors in Breast Cancer and Potential Biomarkers of Response
Authors: Guarducci Cristina , Bonechi Martina , Boccalini Giulia , Benelli Matteo , Risi Emanuela , Di Leo Angelo , Malorni Luca , Migliaccio Ilenia
Published: October 2017

Randomized clinical trials demonstrated that CDK4/6 inhibitors are highly effective in patients with hormone receptor-positive (HR+), HER2-negative (HER2-) metastatic breast cancer in combination with endocrine therapy. The use of CDK4/6 inhibitors in clinics is becoming common for patients with HR+/HER2- metastatic breast cancer and will certainly increase in the near future. However, patients might show de novo or acquired resistance to these drugs. Molecular alterations have been suggested as determinants for de novo resistance to CDK4/6 inhibitors, but have never been validated in a clinical setting. In addition, molecular mechanisms of acquired resistance to palbociclib have been analyzed only in preclinical studies. Here we review the current knowledge on the available preclinical data about the mechanisms of de novo and acquired resistance to CDK4/6 inhibitors in breast cancer, and clinical data about potential biomarkers of response.
Epigenetically-Regulated MicroRNA-9-5p Suppresses the Activation of Hepatic Stellate Cells via TGFBR1 and TGFBR2
Authors: Yu Fujun , Chen BiCheng , Fan XuFei , Li Guojun , Dong Peihong , Zheng Jianjian
Published: October 2017

Background/Aims: Recently, microRNAs (miRNAs) have been demonstrated to act as regulators of activation of hepatic stellate cells (HSCs). It is well known that the main profibrogenic inducer transforming growth factor-β1 (TGF-β1) contributes to HSC activation, which is a key event in liver fibrosis. Increasing studies show that miR-9-5p is down-regulated in liver fibrosis and restoration of miR-9-5p limits HSC activation. However, the role of miR-9-5p in TGF-β1-induced HSC activation is still not clear. Methods: miR-9-5p expression was quantified using real-time PCR in chronic hepatitis B (CHB) patients and TGF-β1-treated LX-2 cells. In CHB patients, histological activity index (HAI) and fibrosis stages were assessed using the Ishak scoring system. Effects of miR-9-5p on liver fibrosis in vivo and in vitro were analyzed. Luciferase activity assays were performed to examine the binding of miR-9-5p to the 3′-untranslated region of type I TGF-β receptor (TGFBR1) as well as TGFBR2. Results: Compared with healthy controls, miR-9-5p was reduced in CHB patients. There was a lower miR-9-5p expression in CHB patients with higher fibrosis scores or HAI scores. miR-9-5p was down-regulated by TGF-β1 in a dose-dependent manner. TGF-β1-induced HSC activation including cell proliferation, α-SMA and collagen expression was blocked down by miR-9-5p. Notably, miR-9-5p ameliorates carbon tetrachloride-induced liver fibrosis. As determined by luciferase activity assays, TGFBR1 and TGFBR2 were targets of miR-9-5p. Further studies demonstrated that miR-9-5p inhibited TGF-β1/Smads pathway via TGFBR1 and TGFBR2. Interestingly, promoter methylation was responsible for miR-9-5p down-regulation in liver fibrosis. The relationship between miR-9-5p expression and methylation was confirmed in CHB patients and TGF-β1-treated cells. Conclusion: Our results demonstrate that miR-9-5p could inhibit TGF-β1-induced HSC activation through TGFBR1 and TGFBR2. Loss of miR-9-5p is associated with its methylation status in liver fibrosis.
Preimplantation Factor (PIF) Promotes HLA-G, -E, -F, -C Expression in JEG-3 Choriocarcinoma Cells and Endogenous Progesterone Activity
Authors: Hakam Miya Soukaina , Miranda-Sayago Jose Maria , Hayrabedyan Soren , Todorova Krassimira , Spencer Patrick Simon , Jabeen Asma , Barnea Eytan R. , Fernandez Nelson
Published: October 2017

Background/Aims: Pregnancy success requires mandatory maternal tolerance of the semi/ allogeneic embryo involving embryo-derived signals. Expression levels of PreImplantation Factor (PIF), a novel peptide secreted by viable embryos, correlate with embryo development, and its early detection in circulation correlates with a favourable pregnancy outcome. PIF enhances endometrial receptivity to promote embryo implantation. Via the p53 pathway, it increases trophoblast invasion, improving cell survival / immune privilege. PIF also reduces spontaneous and LPS-induced foetal death in immune naïve murine model. We examined PIF effect on gene expression of human leukocyte antigen (HLA-G, -E -F and –C) and the influence of PIF on local progesterone activity in JEG-3 choriocarcinoma cells. Methods: PIF and progesterone (P4) effects on JEG-3 cells surface and intracellular HLA molecules was tested using monoclonal antibodies, flow cytometry, and Western blotting. PIF and IL17 effects on P4 and cytokines secretion was determined by ELISA. PIF and P4 effects on JEG-3 cells proteome was examined using 2D gel staining followed by spot analysis, mass spectrometry and bioinformatic analysis. Results: In cytotrophoblastic JEG-3 cells PIF increased intracellular expression of HLA-G, HLA-F, HLA-E and HLA-C and surface expression of HLA-G, HLA-E and HLA-C in dose and time dependent manner. In case of HLA-E, -F results were confirmed also by Western blot. Proteome analysis confirmed an increase in HLA-G, pro-tolerance FOXP3+ regulatory T cells (Tregs), coagulation factors and complement regulator. In contrast, PIF reduced PRDX2 and HSP70s to negate oxidative stress and protein misfolding. PIF enhanced local progesterone activity, increasing steroid secretion and the receptor protein. It also promoted the secretion of the Th1/Th2 cytokines (IL-10, IL-1β, IL-8, GM-CSF and TGF-β1), resulting in improved maternal signalling. Conclusion: PIF can generate a pro-tolerance milieu by enhancing the expression of HLA molecules and by amplifying endogenous progesterone activity. A Fast-Track clinical trial for autoimmune disease has been satisfactorily completed. The acquired data warrants PIF use for the treatment of early pregnancy disorders.
Combination of Solamargine and Metformin Strengthens IGFBP1 Gene Expression Through Inactivation of Stat3 and Reciprocal Interaction Between FOXO3a and SP1
Authors: Tang Qing , Zheng Fang , Wu JingJing , Xiao Qian , Li Liuning , Hann Swei Sunny
Published: October 2017

Background/Aims: Solamargine, one natural photochemical component from traditional plants, has been shown to have anti-cancers properties. We previously showed that solamargine inhibited the growth of non-small-cell lung cancer (NSCLC) cells through suppression of prostaglandin E2 (PGE2) receptor EP4 gene and regulation of downstream signaling pathways. However, the detailed mechanism underlying this, especially in combination of metformin, a known AMPK activator, still remained to be determined. Methods: Cell viability was measured using a 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) and colorimetric 5-bromo-2-deoxyuridine (BrdU) ELISA methods, respectively. Western blot analysis and immunohistochemistry were performed to examine the phosphorylation and protein expressions of signal transducer and activator of transcription 3 (Stat3), SP1, forkhead box O3a (FOXO3a), and insulin-like growth factor (IGF)-IGF binding protein 1 (IGFBP1). The expression of IGFBP1 mRNA was measured by quantitative real time PCR (qRT-PCR). Silencing of FOXO3a and IGFBP1 were examined by siRNA procedures. Exogenously expression of SP1, FOXO3a, and IGFBP1 were carried out by transient transfection assays. The promoter activity of IGFBP1 was tested using Secrete-PairTM Dual Luminescence Assay Kit. A xenografted tumor model was used to further test the effect of solamargine in combining with metformin in vivo. Results: We further demonstrated that solamargine inhibited growth and induced cell cycle arrest in other NSCLC cell lines. Through mechanism-based approaches, we showed that solamargine decreased the phosphorylation of Stat3; In addition, solamargine induced FOXO3a, whereas reduced SP1 protein levels; all of which were abrogated in cells with overexpressed Stat3 gene. Interestingly, there is interaction between FOXO3a and SP1. Moreover, solamargine increased mRNA, protein expression and promoter activity of IGFBP1, which was not observed in cells with overexpressed SP1 or with silenced FOXO3a genes. Finally, ablation of IGFBP1 expression by siRNA blocked the effect of solamargine on cell growth inhibition. More importantly, there was a synergy of combination of solamargine and metformin. Similar findings were also observed in vivo. Conclusion: Our results show that solamargine increases IGFBP1 gene expression through inactivation of Stat3, followed by regulation and reciprocal interaction of FOXO3a and SP1 in vitro and in vivo. This ultimately leads to suppression of human lung cancer cell growth. Moreover, this is a synergy of solamargine in combination with metformin in this process. This study unravels a novel mechanism underlying the anti-lung cancer effects of solamargine in combination of metformin, and suggests a potential new lung cancer associated therapy.
A new distribution report of the Critically Endangered Amomum kingii Baker (Zingiberaceae) outside Sikkim, India
Authors: Bhadra Sreetama , Bandyopadhyay Maumita
Published: October 2017

In this correspondence, the distribution of a population of Amomum kingii Baker, a Critically Endangered species of Zingiberaceae, is reported from Darjeeling District, West Bengal, India.  Previously, this plant was described only from Sikkim, India and no other population of this endemic plant has ever been found outside this distributional range.  In the present study, the plant was morphologically described and molecular characterization was done for the first time using three DNA regions- ITS, matK and rbcL.  The urgency and necessity of conservation of this plant has also been discussed.
New butterfly records from the Jammu Shiwaliks, Jammu & Kashmir, India
Authors: Sharma Shakha , Sharma Neeraj
Published: October 2017

The Himalayan state of Jammu and Kashmir, owing to variety of habitats, different climatic regimes and a wide range of altitude offers conducive habitats to butterflies ranging from low level hills of Shiwaliks to Trans-Himalayan landscapes of Ladakh through mighty Pir-Panjal and Valley of Kashmir.   It is noteworthy that these mountainous landscapes though rich in insect diversity are the least known for butterfly fauna. The present note describes the new records based on opportunistic surveys of butterflies on the sidelines of avian surveys conducted in Jammu Shiwaliks during the years 2015 and 2016.
The Odonata (Insecta) of northern and central Oman
Authors: Cowan Elaine M. , Cowan Peter J.
Published: October 2017

Oman is largely a desert country with a mainly arid climate.  We summarise published records of Odonata (Insecta) for northern and central Oman, present our photographic records of the same there for 50 sites and give an apparent-status statement for most species (the more afrotropical Dhofar governorate is excluded).  Highlights are photographed Orthetrum ransonnetii, Macrodiplax cora (ovipositing in tandem) and Urothemis thomasi.  Of the 44 species for Oman, 36 have been recorded in northern and central Oman (eight zygopteran and 28 anisopteran species).  All are Least Concern except Arabineura khalidi and Urothemis thomasi, both Endangered, and Paragomphus sinaiticus, Near Threatened.
New records of the subfamily Stratiomyinae (Diptera: Stratiomyidae) from Pakistan
Authors: Hassan Muhammad Asghar , Bodlah Imran , Iqbal Zafar , Jabeen Rubina
Published: October 2017

Based on collected specimens from the Narowal, Rawalpindi and Jhelum districts of (Punjab Province) Pakistan, three species were recognised in two genera, under the subfamily Stratiomyinae (Diptera: Stratiomyidae).  Odontomyia ochropa Thomson, 1869, Oplodontha minuta (Fabricius, 1794) and Oplodontha rubrithorax (Macquart, 1838) are recorded for the first time from Pakistan.  Photographs, diagnostic characters, descriptions, geographical distributions and identification keys of the described species are provided.
Feeding habits and behaviour of Bagre bagre and Genidens barbus, two ariid catfishes (Pisces: Siluriformes) from southeastern Brazil
Authors: Tavares Maria Thereza Manhães , Di Beneditto Ana Paula Madeira
Published: October 2017

The feeding habits and behaviour of adult specimens of Bagre bagre (Linnaeus, 1766) and Genidens barbus (Lacepède, 1803), both targets of commercial fisheries in coastal southeastern Brazil, were evaluated through stomach content analysis.  These catfish are generalistic benthophagous feeders and daytime consumers, and the analysis points to fish and crustaceans as their primary prey.  The fish Trichiurus lepturus and the shrimp Xiphopenaeus kroyeri were the main prey species, indicating that both catfish species prey upon the most abundant resources available in the study area.
Δ-5 Fatty Acid Desaturase
FADS1
Impacts Metabolic Disease by Balancing Proinflammatory and Proresolving Lipid Mediators
Authors: Gromovsky Anthony D. , Schugar Rebecca C. , Brown Amanda L. , Helsley Robert N. , Burrows Amy C. , Ferguson Daniel , Zhang Renliang , Sansbury Brian E. , Lee Richard G. , Morton Richard E. , Allende Daniela S. , Parks John S. , Spite Matthew , Brown J. Mark
Published: October 2017

Objective—

Human genetic variants near the FADS (fatty acid desaturase) gene cluster (
FADS1-2
-
3
) are strongly associated with cardiometabolic traits including dyslipidemia, fatty liver, type 2 diabetes mellitus, and coronary artery disease. However, mechanisms underlying these genetic associations are unclear.

Approach and Results—

Here, we specifically investigated the physiological role of the Δ-5 desaturase FADS1 in regulating diet-induced cardiometabolic phenotypes by treating hyperlipidemic LDLR (low-density lipoprotein receptor)-null mice with antisense oligonucleotides targeting the selective knockdown of
Fads1
.
Fads1
knockdown resulted in striking reorganization of both ω-6 and ω-3 polyunsaturated fatty acid levels and their associated proinflammatory and proresolving lipid mediators in a highly diet-specific manner. Loss of
Fads1
activity promoted hepatic inflammation and atherosclerosis, yet was associated with suppression of hepatic lipogenesis.
Fads1
knockdown in isolated macrophages promoted classic M1 activation, whereas suppressing alternative M2 activation programs, and also altered systemic and tissue inflammatory responses in vivo. Finally, the ability of
Fads1
to reciprocally regulate lipogenesis and inflammation may rely in part on its role as an effector of liver X receptor signaling.

Conclusions—

These results position
Fads1
as an underappreciated regulator of inflammation initiation and resolution, and suggest that endogenously synthesized arachidonic acid and eicosapentaenoic acid are key determinates of inflammatory disease progression and liver X receptor signaling.
Deletion of AT2 Receptor Prevents SHP-1–Induced VEGF Inhibition and Improves Blood Flow Reperfusion in Diabetic Ischemic Hindlimb
Authors: Paquin-Veillette Judith , Lizotte Farah , Robillard Stéphanie , Béland Raphaël , Breton Marc-André , Guay Andréanne , Despatis Marc-Antoine , Geraldes Pedro
Published: October 2017

Objective—

Ischemia caused by narrowing of femoral artery is a major cause of peripheral arterial disease and morbidity affecting patients with diabetes mellitus. We have previously reported that the inhibition of the angiogenic response to VEGF (vascular endothelial growth factor) in diabetic mice was associated with the increased expression of SHP-1 (SH2 domain–containing phosphatase 1), a protein that can be activated by the AT2 (angiotensin II type 2) receptor. Deletion of AT2 receptor has been shown to promote angiogenesis within the ischemic muscle. However, the relative impact of AT2 receptor in diabetic condition remains unknown.

Approach and Results—

Nondiabetic and diabetic AT2 null (
Atgr2
−
/Y
) mice underwent femoral artery ligation after 2 months of diabetes mellitus. Blood perfusion was measured every week ≤4 weeks post-surgery. Expression of the VEGF, SHP-1, and renin–angiotensin pathways was evaluated. Blood flow in the ischemic muscle of diabetic
Atgr2
−
/Y
mice recovered faster and ≤80% after 4 weeks compared with 51% recovery in diabetic control littermates. Diabetic
Atgr2
−
/Y
had reduced apoptotic endothelial cells and elevated small vessel formation compared with diabetic
Atgr2
+/Y
mice, as well as increased SHP-1 expression and reduced VEGF receptor activity. In endothelial cells, high glucose levels and AT2 agonist treatment did not change SHP-1, VEGF, and VEGF receptor expression. However, the activity of SHP-1 and its association with the VEGF receptors were increased, causing inhibition of the VEGF action in endothelial cell proliferation and migration.

Conclusions—

Our results suggest that the deletion of AT2 receptor reduced SHP-1 activity and restored VEGF actions, leading to an increased blood flow reperfusion after ischemia in diabetes mellitus.
Relationship Between Total Serum Bilirubin Levels and Carotid and Femoral Atherosclerosis in Familial Dyslipidemia
Authors: Amor Antonio J. , Ortega Emilio , Perea Verónica , Cofán Montserrat , Sala-Vila Aleix , Nuñez Isabel , Gilabert Rosa , Ros Emilio
Published: October 2017

Objective—

Bilirubin is a potent antioxidant that has been inversely related to cardiovascular disease. There is little information on serum total bilirubin (TB) in relation to atherosclerosis in familial dyslipidemia. We assessed the association between TB and carotid and femoral atherosclerosis in this high-risk group.

Approach and Results—

We evaluated 464 individuals with familial dyslipidemia (56% men; median age, 48 years), 322 with familial hypercholesterolemia, and 142 with familial combined hyperlipidemia. Carotid and femoral arteries were imaged bilaterally with a standardized ultrasonographic protocol. Mean and maximum intima-media thickness and plaque presence (≥1.2 mm) and height were recorded. Cross-sectional associations between TB and atherosclerosis variables were investigated in multivariable-adjusted models, including lipid values and hypolipidemic drug use. Inflammatory markers (C-reactive protein, total leukocyte count, and lipoprotein[a]) were also determined. Increasing TB levels were associated with decreasing intima-media thickness of all carotid segments (
P
<0.05, all). TB also related to carotid plaque, present in 78% of individuals, and to plaque burden (≥3 plaques), with odds ratios (95% confidence interval) 0.59 (0.36–0.98) and 0.57 (0.34–0.96) for each increase of 0.5 mg in TB, respectively. Findings were confirmed in a validation cohort of 177 subjects with nonfamilial dyslipidemia. Only the familial combined hyperlipidemia group, with higher inflammation-related markers, showed an inverse association between TB and femoral plaque height (β=−0.183;
P
=0.030).

Conclusions—

TB was inversely and independently associated with carotid plaque burden in familial and nonfamilial dyslipidemia. These findings support the use of TB as a biomarker of atherosclerosis in this high-risk group.
GLP-1 Elicits an Intrinsic Gut–Liver Metabolic Signal to Ameliorate Diet-Induced VLDL Overproduction and Insulin Resistance
Authors: Khound Rituraj , Taher Jennifer , Baker Christopher , Adeli Khosrow , Su Qiaozhu
Published: October 2017

Objective—

Perturbations in hepatic lipid and very-low–density lipoprotein (VLDL) metabolism are involved in the pathogenesis of obesity and hepatic insulin resistance. The objective of this study is to delineate the mechanism of subdiaphragmatic vagotomy in preventing obesity, hyperlipidemia, and insulin resistance.

Approach and Results—

By subjecting the complete subdiaphragmatic vagotomized mice to various nutritional conditions and investigating hepatic de novo lipogenesis pathway, we found that complete disruption of subdiaphragmatic vagal signaling resulted in a significant decrease of circulating VLDL–triglyceride compared with the mice obtained sham procedure. Vagotomy further prevented overproduction of VLDL–triglyceride induced by an acute fat load and a high-fat diet–induced obesity, hyperlipidemia, hepatic steatosis, and glucose intolerance. Mechanistic studies revealed that plasma glucagon-like peptide-1 was significantly raised in the vagotomized mice, which was associated with significant reductions in mRNA and protein expression of SREBP-1c (sterol regulatory element-binding protein 1c), SCD-1 (stearoyl-CoA desaturase-1), and FASN (fatty acid synthase), as well as enhanced hepatic insulin sensitivity. In vitro, treating mouse primary hepatocytes with a glucagon-like peptide-1 receptor agonist, exendin-4, for 48 hours inhibited free fatty acid, palmitic acid treatment induced de novo lipid synthesis, and VLDL secretion from hepatocytes.

Conclusions—

Elevation of glucagon-like peptide-1 in vagotomized mice may prevent VLDL overproduction and insulin resistance induced by high-fat diet. These novel findings, for the first time, delineate an intrinsic gut–liver regulatory circuit that is mediated by glucagon-like peptide-1 in regulating hepatic energy metabolism.
PLUMBER Study (Prevalence of Large Vessel Occlusion Strokes in Mecklenburg County Emergency Response)
Authors: Dozois Adeline , Hampton Lorrie , Kingston Carlene W. , Lambert Gwen , Porcelli Thomas J. , Sorenson Denise , Templin Megan , VonCannon Shellie , Asimos Andrew W.
Published: October 2017

Background and Purpose—

The recently proposed American Heart Association/American Stroke Association EMS triage algorithm endorses routing patients with suspected large vessel occlusion (LVO) acute ischemic strokes directly to endovascular centers based on a stroke severity score. The predictive value of this algorithm for identifying LVO is dependent on the overall prevalence of LVO acute ischemic stroke in the EMS population screened for stroke, which has not been reported.

Methods—

We performed a cross-sectional study of patients transported by our county’s EMS agency who were dispatched as a possible stroke or had a primary impression of stroke by paramedics. We determined the prevalence of LVO by reviewing medical record imaging reports based on a priori specified criteria.

Results—

We enrolled 2402 patients, of whom 777 (32.3%) had an acute stroke–related diagnosis. Among 485 patients with acute ischemic stroke, 24.1% (n=117) had an LVO, which represented only 4.87% (95% confidence interval, 4.05%–5.81%) of the total EMS population screened for stroke.

Conclusions—

Overall, the prevalence of LVO acute ischemic stroke in our EMS population screened for stroke was low. This is an important consideration for any EMS stroke severity-based triage protocol and should be considered in predicting the rates of overtriage to endovascular stroke centers.
Statins and the Risk of Intracerebral Hemorrhage in Patients With Previous Ischemic Stroke or Transient Ischemic Attack
Authors: Gaist David , Goldstein Larry B. , Cea Soriano Lucía , García Rodríguez Luis Alberto
Published: October 2017

Background and Purpose—

Although there is no overall association between statin use and intracerebral hemorrhage (ICH), whether there is an increased risk among those with a history of ischemic stroke (IS) or transient ischemic attack (TIA) remains controversial. We evaluated the relationship of preadmission statin use with the risk of ICH in patients with a history of IS or TIA in a population-based cohort.

Methods—

The Health Improvement Network primary care database in the United Kingdom was used to identify new users of low-dose aspirin and a matched comparison. Both cohorts were followed to identify incident cases of ICH, with validation by manual review of patient records and linkage to hospitalization data. In a nested case–control study, we compared the adjusted odds ratios (ORs) with 95% confidence intervals (CIs) for ICH based on statin use in the subgroup of individuals with history of IS/TIA.

Results—

Last statin use within 1 year of ICH (OR, 0.92; 95% CI [confidence interval], 0.60–1.4), last use between 8 days and 1 year (OR, 1.81; 95% CI, 0.99–3.28), and statin use at the time of ICH (OR, 0.77; 95% CI, 0.49–1.21) were not associated with the overall ICH risk among 157 patients with ICH and 884 controls with a history of IS/TIA. There was also no difference in 30-day rates of fatal (OR, 0.82; 95% CI, 0.41–1.64) or nonfatal (OR, 0.90; 95% CI, 0.51–1.57) ICH.

Conclusions—

Statin use was not associated with an increased risk of ICH among patients with a previous history of IS/TIA.
Fair Chance and not a Blunt Refusal
Authors: Bergman Yoel
Published: October 2017

Newly found documents demonstrate that Alfred Nobel’s 1887 patented smokeless Ballistite gunpowder was tested by the French Army in 1889, yielding unimpressive results. This and other technical reasons were the basis for final 1889 French rejection rather than political motives, as claimed by Nobel, repeated by an influential 1962 biography, and echoed on a current Nobel website. Nobel offered Ballistite to the French military in late 1887, but was refused by 1888 since the French smokeless poudre B of 1884 was already employed and Ballistite was considered erosive and unsafe to produce. However, letters from French officials (and the intervention of the French Minister of War) confirm that Ballistite was indeed tested by the French military in 1889. Ballistic results in the 8 mm Lebel rifle were unfavorable and this seems the final technical reason for the rejection, rather than French interests in promoting their supposedly inferior propellant. This case study highlights the question of balance between technical and social history of military technology. The latter, examining social factors often ignored in various past military technological histories, have shown to shape inventions. In this case, though, the author of the influential Nobel biography has missed the complex technical history of the issue, relying on the personal and political for explaining the decisions.
Taxonomic revision of the Andean harvestman genus Rhaucus Simon, 1879 (Arachnida, Opiliones, Cosmetidae)
Authors: GARCÍA ANDRÉS F. , KURY ADRIANO B.
Published: October 2017

The Andean genus Rhaucus Simon 1879 is revised. Five valid species are recognized, including Rhaucus florezi sp. nov. The following nomenclatural acts are proposed. At genus level: Megarhaucus Mello-Leitão, 1941, Neorhaucus Pickard-Cambridge, 1905 and Pararhaucus Pickard-Cambridge, 1905 are considered junior subjective synonyms of Rhaucus. At species level: Neorhaucus aurolineatus Pickard-Cambridge, 1905 is considered a junior subjective synonym of Rhaucus vulneratus Simon, 1879; Rhaucus (Rhaucus) tristis Sørensen, 1932, Rhaucus (Rhaucus) muticus Sørensen, 1932 and Pararhaucus obscurus Pickard-Cambridge, 1905 are considered junior subjective synonyms of Rhaucus quinquelineatus Simon, 1879 (the latter combination is restored from current combination Flirtea quinquelineata); Flirtea paucimaculata Roewer, 1963, Rhaucus (Rhaucus) geographicus Sørensen, 1932, Metarhaucus reticulatus Roewer, 1912 and Metarhaucus fuscus Pickard-Cambridge, 1905 are considered junior subjective synonyms of Erginus serripes Simon, 1879 (that is here combined as Rhaucus serripes comb. rest.). Megarhaucus robustus Mello-Leitão, 1941 is newly combined as Rhaucus robustus (Mello-Leitão, 1941) comb. nov. Distribution maps of the species are provided. The new term multicapitate apophysis (mca) is introduced here for a special type of apophysis on coxa IV of males.
A second species of the genus Martensolasma (Opiliones, Dyspnoi, Nemastomatidae) from Mexico
Authors: CRUZ-LÓPEZ JESÚS A.
Published: October 2017

A second species of the previously monotypic genus Martensolasma Shear, 2006 is described: Martensolasma catrina sp. n., based on specimens collected in Metztitlán, Hidalgo, Mexico. The taxonomy the genus is briefly discussed.
A review of North American Elonus species, with description of E. gruberi n. sp. (Coleoptera: Tenebrionoidea: Aderidae)
Authors: GOMPEL NICOLAS
Published: October 2017

This work provides a taxonomic survey of the North American species of the genus Elonus Casey, 1895 (Coleoptera: Tenebrionoidea: Aderidae). It includes the description of a new species, Elonus gruberi n. sp. from the United States, related to E. hesperus Werner, 1990 and to E. basalis (LeConte, 1855). A review and key to the North American species is provided.
Assimilation of Radar Radial Velocity and Reflectivity, Satellite Cloud Water Path, and Total Precipitable Water for Convective-Scale NWP in OSSEs
Authors: Pan Sijie , Gao Jidong , Stensrud David J. , Wang Xuguang , Jones Thomas A.
Published: October 2017

In this study, the ensemble of three-dimensional variational data assimilation (En3DVar) method for convective-scale weather is adopted and evaluated using an idealized supercell storm simulated by the Weather Research and Forecasting (WRF) Model. Synthetic radar radial velocity, reflectivity, satellite-derived cloud water path (CWP), and total precipitable water (TPW) data are produced from the simulated supercell storm and then these data are assimilated into another WRF Model run that starts with no convection. Two types of experiments are performed. The first assimilates radar and satellite CWP data using a perfect storm environment. The second assimilates additional TPW data using a storm environment with dry bias. The first set of experiments indicates that incorporating CWP and radar data into the assimilation leads to a much faster initiation of supercell storms than found using radar data alone. Assimilating CWP data primarily improves the analyses of nonprecipitating hydrometeor variables. The results from the second set of experiments demonstrate the critical importance of the storm environment. When using the biased storm environment, assimilation of CWP and radar data enhances the analyses, but the forecast skill rapidly decreases over the subsequent 1-h forecast. Further experiments show that assimilating the TPW data has a large impact on storm environment that is essential to the accuracy of the storm forecasts. In general, the combination of radar data and satellite data within the En3DVar results in better analyses and forecasts than when only radar data are used, especially for an imperfect storm environment.
A Talent for Tinkering: Developing Talents in Children From Low-Income Households Through Engineering Curriculum
Authors: Robinson Ann , Adelson Jill L. , Kidd Kristy A. , Cunningham Christine M.
Published: October 2017

Guided by the theoretical framework of curriculum as a platform for talent development, this quasi-experimental field study investigated an intervention focused on engineering curriculum and curriculum based on a biography of a scientist through a comparative design implemented in low-income schools. Student outcome measures included science content achievement, engineering knowledge, and engineering engagement. The sample comprised 1,387 Grade 1 students across 62 classrooms. Multilevel modeling was used separately for each of the three student outcome measures. The intervention resulted in an effect size of 0.28 on an out-of-level science content assessment and effect size of 0.66 for the engineering knowledge measure. Students in the intervention group reported a high level of engineering engagement. General education teachers were trained to implement the curricula through a summer institute and received coaching throughout the subsequent academic year. Evidence suggests the intervention functioned as a talent-spotting tool as teachers reported they would nominate a substantial portion of low-income and culturally diverse students for subsequent gifted and talented services. Discussion focused on the match between the needs and preferences of students from low-income households for hands-on design experiences and the curricular affordances in the engineering domain as a talent development pathway for young, poor children.
Selective Role of Discoidin Domain Receptor 2 in Murine Temporomandibular Joint Development and Aging
Authors: Ge C. , Mohamed F. , Binrayes A. , Kapila S. , Franceschi R.T.
Published: October 2017

Temporomandibular joint (TMJ) disorders are often associated with development of osteoarthritis-like changes in the mandibular condyle. Discoidin domain receptor 2 (DDR2), a collagen receptor preferentially activated by type I and III collagen found in the TMJ and other fibrocartilages, has been associated with TMJ degeneration, but its role in normal joint development has not been previously examined. Using Ddr2 LacZ-tagged mice and immunohistochemistry, we found that DDR2 is preferentially expressed and activated in the articular zone of TMJs but not knee joints. To assess the requirement for Ddr2 in TMJ development, studies were undertaken to compare wild-type and smallie ( slie) mice, which contain a spontaneous deletion in Ddr2 to produce an effective null allele. Analysis of TMJs from newborn Ddr2slie/slie mice revealed a developmental delay in condyle mineralization, as measured by micro–computed tomography and histologic analysis. In marked contrast, knee joints of Ddr2slie/slie mice were normal. Analysis of older Ddr2slie/slie mice (3 and 10 mo) revealed that the early developmental delay led to a dramatic and progressive loss of TMJ articular integrity and osteoarthritis-like changes. Mutant condyles had a rough and flattened bone surface, accompanied by a dramatic loss of bone mineral density. Mankin scores showed significantly greater degenerative changes in the TMJs of 3- and 10-mo-old Ddr2slie/slie mice as compared with wild-type controls. No DDR2-dependent degenerative changes were seen in knees. Analysis of primary cultures of TMJ articular chondrocytes from wild-type and Ddr2slie/slie mice showed defects in chondrocyte maturation and mineralization in the absence of Ddr2. These studies demonstrate that DDR2 is necessary for normal TMJ condyle development and homeostasis and that these DDR2 functions are restricted to TMJ fibrocartilage and not seen in the hyaline cartilage of the knee.
Propagation modeling and performance analysis of intelligent drilling communication system based on capacitance coupling approach
Authors: Liu Feng , Liu Yajun , Yang Debin , Xu Jinwu
Published: October 2017

A new type of intelligent drilling communication system is proposed based on capacitance coupling in order to realize signal transmission in the downhole environment. A system model is established and the dispersion equation is derived. Group velocity, propagation constant, attenuation factor, and the terminal matching condition of the system are discussed according to theoretical derivations. Simulations of a large number of drill pipe units in the time domain, based on the fourth-order Runge–Kutta method, are described to verify the mathematical derivations. An experimental system of lumped parameter components has been established, which verifies the effectiveness of the simulation. Analytical and simulation results show that the carrier frequency can be as high as 0.843 MHz, and that the bandwidth of the proposed system can reach up to about 406 kHz. The results can provide a theoretical basis and comprehensive design guidance for the frequency, communication rate, and bandwidth budget of intelligent drilling communication systems.
Mind the gaps! A research agenda for urban interstices
Authors: Phelps Nicholas A , Silva Cristian
Published: October 2017

Processes of urbanisation can hardly be considered without reference to the spaces that lie between developments. However, the literature on such interstitial spaces is fragmentary. In this paper we draw together insights from the extant literature into a research agenda on urban interstices. We propose a research agenda centred on four themes: the multiple geographic scales at which the interstitial spaces of urban sprawl might be analysed; the pending nature of such spaces; their planned or unplanned character and their relational properties. We develop these themes, briefly illustrating them with reference to the case of metropolitan area of Santiago de Chile. In conclusion, we emphasise some of the implications of interstitial spaces for theories of urban politics and their value in forcing inter-disciplinarity in urban studies.
Solitude as an Approach to Affective Self-Regulation
Authors: Nguyen Thuy-vy T. , Ryan Richard M. , Deci Edward L.
Published: October 2017

In this research, we showed that solitude generally has a deactivation effect on people’s affective experiences, decreasing both positive and negative high-arousal affects. In Study 1, we found that the deactivation effect occurred when people were alone, but not when they were with another person. Study 2 showed that this deactivation effect did not depend on whether or not the person was engaged in an activity such as reading when alone. In Study 3, high-arousal positive affect did not drop in a solitude condition in which participants specifically engaged in positive thinking or when they actively chose what to think about. Finally, in Study 4, we found that solitude could lead to relaxation and reduced stress when individuals actively chose to be alone. This research thus shed light on solitude effects in the past literature, and on people’s experiences when alone and the different factors that moderate these effects.
Societal Sentience
Authors: Hobson-West Pru , Davies Ashley
Published: October 2017

The use of nonhuman animals as models in research and drug testing is a key route through which contemporary scientific knowledge is certified. Given ethical concerns, regulation of animal research promotes the use of less “sentient” animals. This paper draws on a documentary analysis of legal documents and qualitative interviews with Named Veterinary Surgeons and others at a commercial laboratory in the UK. Its key claim is that the concept of animal sentience is entangled with a particular imaginary of how the general public or wider society views animals. We call this imaginary societal sentience. Against a backdrop of increasing ethnographic work on care encounters in the laboratory, this concept helps to stress the wider context within which such encounters take place. We conclude that societal sentience has potential purchase beyond the animal research field, in helping to highlight the affective dimension of public imaginaries and their ethical consequences. Researching and critiquing societal sentience, we argue, may ultimately have more impact on the fate of humans and nonhumans in the laboratory than focusing wholly on ethics as situated practice.