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Genetics
Discovery and fine-mapping of adiposity loci using high density imputation of genome-wide association studies in individuals of African ancestry: African ancestry anthropometry genetics consortium
Apr 21, 2017   PLoS Genetics
Ng MCY, Graff M, Lu Y, Justice AE, Mudgal P,   . . . . . .   , Bowden DW, Cupples LA, Haiman CA, Loos RJF, North KE
Discovery and fine-mapping of adiposity loci using high density imputation of genome-wide association studies in individuals of African ancestry: African ancestry anthropometry genetics consortium
Apr 21, 2017
PLoS Genetics
Genome-wide association studies (GWAS) have identified >300 loci associated with measures of adiposity including body mass index (BMI) and waist-to-hip ratio (adjusted for BMI, WHRadjBMI), but few have been identified through screening of the African ancestry genomes. We performed large scale meta-analyses and replications in up to 52,895 individuals for BMI and up to 23,095 individuals for WHRadjBMI from the African Ancestry Anthropometry Genetics Consortium (AAAGC) using 1000 Genomes phase 1 imputed GWAS to improve coverage of both common and low frequency variants in the low linkage disequilibrium African ancestry genomes. In the sex-combined analyses, we identified one novel locus (TCF7L2/HABP2) for WHRadjBMI and eight previously established loci at P < 5×10-8: seven for BMI, and one for WHRadjBMI in African ancestry individuals. An additional novel locus (SPRYD7/DLEU2) was identified for WHRadjBMI when combined with European GWAS. In the sex-stratified analyses, we identified three novel loci for BMI (INTS10/LPL and MLC1 in men, IRX4/IRX2 in women) and four for WHRadjBMI (SSX2IP, CASC8, PDE3B and ZDHHC1/HSD11B2 in women) in individuals of African ancestry or both African and European ancestry. For four of the novel variants, the minor allele frequency was low (
Utility of the new Movement Disorder Society clinical diagnostic criteria for Parkinson's disease applied retrospectively in a large cohort study of recent onset cases
Apr 22, 2017   Parkinsonism & Related Disorders
Malek N, Lawton MA, Grosset KA, Bajaj N, Barker RA, Ben-Shlomo Y, Burn DJ, Foltynie T, Hardy J, Morris HR, Williams NM, Wood N, Grosset DG, PRoBaND clinical consortium
Utility of the new Movement Disorder Society clinical diagnostic criteria for Parkinson's disease applied retrospectively in a large cohort study of recent onset cases
Apr 22, 2017
Parkinsonism & Related Disorders
To examine the utility of the new Movement Disorder Society (MDS) diagnostic criteria in a large cohort of Parkinson's disease (PD) patients. Recently diagnosed (
Identifying Genetic Sources of Phenotypic Heterogeneity in Orofacial Clefts by Targeted Sequencing
Apr 22, 2017   Birth Defects Research
Carlson JC, Taub MA, Feingold E, Beaty TH, Murray JC, Marazita ML, Leslie EJ
Identifying Genetic Sources of Phenotypic Heterogeneity in Orofacial Clefts by Targeted Sequencing
Apr 22, 2017
Birth Defects Research
Orofacial clefts (OFCs), including nonsyndromic cleft lip with or without cleft palate (NSCL/P), are common birth defects. NSCL/P is highly heterogeneous with multiple phenotypic presentations. Two common subtypes of NSCL/P are cleft lip (CL) and cleft lip with cleft palate (CLP) which have different population prevalence. Similarly, NSCL/P can be divided into bilateral and unilateral clefts, with unilateral being the most common. Individuals with unilateral NSCL/P are more likely to be affected on the left side of the upper lip, but right side affection also occurs. Moreover, NSCL/P is twice as common in males as in females. The goal of this study is to discover genetic variants that have different effects in case subgroups. We conducted both common variant and rare variant analyses in 1034 individuals of Asian ancestry with NSCL/P, examining four sources of heterogeneity within CL/P: cleft type, sex, laterality, and side. We identified several regions associated with subtype differentiation: cleft type differences in 8q24 (p = 1.00 × 10-4 ), laterality differences in IRF6, a gene previously implicated with wound healing (p = 2.166 × 10-4 ), sex differences and side of unilateral CL differences in FGFR2 (p = 3.00 × 10-4 ; p = 6.00 × 10-4 ), and sex differences in VAX1 (p < 1.00 × 10-4 ) among others. Many of the regions associated with phenotypic modification were either adjacent to or overlapping functional elements based on ENCODE chromatin marks and published craniofacial enhancers. We have identified multiple common and rare variants as potential phenotypic modifiers of NSCL/P, and suggest plausible elements responsible for phenotypic heterogeneity, further elucidating the complex genetic architecture of OFCs. Birth Defects Research, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.
Molecular control of gut formation in the spider parasteatoda tepidariorum
Apr 22, 2017   Genesis (New York, N.Y. : 2000)
Feitosa NM, Pechmann M, Schwager EE, Tobias-Santos V, McGregor AP, Damen WGM, Nunes da Fonseca R
Molecular control of gut formation in the spider parasteatoda tepidariorum
Apr 22, 2017
Genesis (New York, N.Y. : 2000)
The development of a digestive system is an essential feature of bilaterians. Studies of the molecular control of gut formation in arthropods have been studied in detail in the fruit fly Drosophila melanogaster. However, little is known in other arthropods, especially in noninsect arthropods. To better understand the evolution of arthropod alimentary system, we investigate the molecular control of gut development in the spider Parasteatoda tepidariorum (Pt), the primary chelicerate model species for developmental studies. Orthologs of the ectodermal genes Pt-wingless (Pt-wg) and Pt-hedgehog (Pt-hh), of the endodermal genes, Pt-serpent (Pt-srp) and Pt-hepatocyte-nuclear factor-4 (Pt-hnf4) and of the mesodermal gene Pt-twist (Pt-twi) are expressed in the same germ layers during spider gut development as in D. melanogaster. Thus, our expression data suggest that the downstream molecular components involved in gut development in arthropods are conserved. However, Pt-forkhead (Pt-fkh) expression and function in spiders is considerably different from its D. melanogaster ortholog. Pt-fkh is expressed before gastrulation in a cell population that gives rise to endodermal and mesodermal precursors, suggesting a possible role for this factor in specification of both germ layers. To test this hypothesis, we knocked down Pt-fkh via RNA interference. Pt-fkh RNAi embryos not only fail to develop a proper gut, but also lack the mesodermal Pt-twi expressing cells. Thus, in spiders Pt-fkh specifies endodermal and mesodermal germ layers. We discuss the implications of these findings for the evolution and development of gut formation in Ecdysozoans. © 2017 Wiley Periodicals, Inc.
A rare variant in TOR1A exon 5 associated with isolated dystonia in southwestern Chinese
Apr 22, 2017   Movement Disorders : Official Journal Of The Movement Disorder Society
Long Y, Chen Y, Qian Y, Wang J, Luo L, Huang X, Li L, Chu J, Yang Z, Sun H
A rare variant in TOR1A exon 5 associated with isolated dystonia in southwestern Chinese
Apr 22, 2017
Movement Disorders : Official Journal Of The Movement Disorder Society
TOR1A has been proposed as an important genetic factor in early-onset isolated dystonia. Variants located in the 3' untranslated region of TOR1A are of particular importance because they may influence gene expression, although related studies are limited. The objectives of the present study focused on variants in the TOR1A 3' untranslated region. The last exon of TOR1A was sequenced in 229 cases with isolated dystonia and in 210 controls. In addition, 471 controls were tested to determine the frequency of the variants in the 3' untranslated region. Except for c.904_906delGAG, 3 rare sequence variants (NM_000113.2:c.*454T>A, NM_000113.2:c.860C>A [rs766483672], and NM_000113.2:c.*302T>A [rs563498119]) were found only in the patients. The c.*302T>A variant was located in the conserved region of the human microRNA (hsa-miR-494) binding site. A luciferase reporter assay showed that c.*302T>A significantly altered gene expression. Population frequencies, computational analyses, and function experiments in this study implied that c.*302T>A is associated with dystonia. © 2017 International Parkinson and Movement Disorder Society. © 2017 International Parkinson and Movement Disorder Society.
Novel 3q27.2-qter deletion in a patient with Diamond-Blackfan anemia and immunodeficiency: Case report and review of literature
Apr 22, 2017   American Journal Of Medical Genetics. Part A
Alkhunaizi E, Schrewe B, Alizadehfar R, Vézina C, Stewart GS, Braverman N
Novel 3q27.2-qter deletion in a patient with Diamond-Blackfan anemia and immunodeficiency: Case report and review of literature
Apr 22, 2017
American Journal Of Medical Genetics. Part A
3q27.2-qter deletion syndromes feature an overlapping set of terminal and interstitial deletions with variable congenital malformations. Diamond-Blackfan anemia (DBA) is etiologically heterogeneous disorder in which one cause is dominant mutations of the RPL35A gene on 3q29. We report a child with a 3q27.2-qter deletion that contains the RPL35A gene. She had clinical and laboratory features consistent with DBA and as well, an unexplained immunodeficiency disorder. Given these unusual findings, we reviewed other patients in the literature with overlapping genomic deletions. In addition, we evaluated our patient for the immunodeficiency disorder, RIDDLE syndrome, due to recessive mutations in the RNF168 gene on 3q29. A PubMed search for case reports of 3q27.2-qter overlapping deletions was performed. To determine if RPL35A was in the deletion region, the chromosomal regions reported were mapped to genomic regions using the UCSC Genome Browser. We identified 85 overlapping deletions, of which six included the RPL35A gene and all should be had DBA. Interestingly, none of the reported cases had immunodeficiency. To evaluate RIDDLE syndrome (radiosensitivity, immunodeficiency, dysmorphic features, and learning difficulties), we sequenced the remaining RNF168 gene and examined her fibroblast culture for a DNA double strand break repair deficiency. These results were normal, indicating that the immunodeficiency is unlikely to result from a RNF168 deficiency. We show that RPL35A haploinsufficiency is a cause of DBA and we report a novel case with 3q27.2-qter deletion and immunodeficiency. The etiology for the immunodeficiency remains unsolved and could be caused by an unknown gene effect or consequent to the DBA phenotype. © 2017 Wiley Periodicals, Inc.
Expansion of the clinical phenotype of the distal 10q26.3 deletion syndrome to include ataxia and hyperemia of the hands and feet
Apr 22, 2017   American Journal Of Medical Genetics. Part A
Lacaria M, Srour M, Michaud JL, Doja A, Miller E, Schwartzentruber J, Goldsmith C, Majewski J, FORGE Canada Consortium, Boycott KM
Expansion of the clinical phenotype of the distal 10q26.3 deletion syndrome to include ataxia and hyperemia of the hands and feet
Apr 22, 2017
American Journal Of Medical Genetics. Part A
Distal deletion of the long arm of chromosome 10 is associated with a dysmorphic craniofacial appearance, microcephaly, behavioral issues, developmental delay, intellectual disability, and ocular, urogenital, and limb abnormalities. Herein, we present clinical, molecular, and cytogenetic investigations of four patients, including two siblings, with nearly identical terminal deletions of 10q26.3, all of whom have an atypical presentation of this syndrome. Their prominent features include ataxia, mild-to-moderate intellectual disability, and hyperemia of the hands and feet, and they do not display many of the other features commonly associated with deletions of this region. These results point to a novel gene locus associated with ataxia and highlight the variability of the clinical presentation of patients with deletions of this region. © 2017 Wiley Periodicals, Inc.
The spacing effect for structural synaptic plasticity provides specificity and precision in plastic changes
Apr 22, 2017   The Journal Of Neuroscience : The Official Journal Of The Society For Neuroscience
San MA, Rela L, Gelb BD, Pagani MR
The spacing effect for structural synaptic plasticity provides specificity and precision in plastic changes
Apr 22, 2017
The Journal Of Neuroscience : The Official Journal Of The Society For Neuroscience
In contrast to trials of training without intervals (massed training), training trials spaced over time (spaced training) induce a more persistent memory identified as long-term memory (LTM). This phenomenon known as "the spacing effect for memory" is poorly understood. LTM is supported by structural synaptic plasticity; however, how synapses integrate spaced stimuli remains elusive. Here, we analyzed events of structural synaptic plasticity at the single synapse level after distinct patterns of stimulation in motoneurons of Drosophila We found that the spacing effect is a phenomenon detected at synaptic level, which determine the specificity and the precision in structural synaptic plasticity. Whereas a single pulse of stimulation (massed) induced structural synaptic plasticity, the same amount of stimulation divided in three spaced stimuli completely prevented it. This inhibitory effect was determined by the length of the inter-stimulus intervals. The inhibitory effect of the spacing was lost by suppressing the activity of Ras or MAPK, while the overexpression of Ras-WT enhanced it. Moreover, dividing the same total time of stimulation into five or more stimuli produced a higher precision in the number of events of plasticity. Ras mutations associated with intellectual disability abolish the spacing effect and made that neurons decoded distinct stimulation patterns as massed stimulation. This evidence suggests that the spacing effect for memory may results from the effect of the spacing in synaptic plasticity, which appear to be a property not limited to neurons involved in learning and memory. We propose a model of spacing-dependent structural synaptic plasticity.SIGNIFICANCE STATEMENTLong-term memory (LTM) induced by repeated trials spaced over time is known as the spacing effect, a common property in the animal kingdom. Altered mechanisms in the spacing effect have been found in animal models of disorders with intellectual disability, such as Noonan syndrome. Although LTM is sustained by structural synaptic plasticity, how synapses integrate spaced stimuli and decode them into specific plastic changes remains elusive. Here, we show that the spacing effect is a phenomenon detected at synaptic level, which determines the properties of the response in structural plasticity, including precision of such response. Whereas suppressing or enhancing Ras/MAPK signaling changed how synapses decode a pattern of stimuli, a disease-related Ras allele abolished the spacing effect for plastic changes. Copyright © 2017 the authors.
Glucose tolerance and insulin responsiveness in Gitelman syndrome patients
Apr 22, 2017   Endocrine Connections
Yuan T, Jiang L, Chen C, Peng X, Nie M, Li X, Xing X, Li X, Chen L
Glucose tolerance and insulin responsiveness in Gitelman syndrome patients
Apr 22, 2017
Endocrine Connections
Objective Impaired glucose metabolism and insulin sensitivity have been reported in patients with Gitelman syndrome (GS), but insulin secretion and the related mechanisms are not well understood. Design and Methods The serum glucose levels, insulin secretion and insulin sensitivity were evaluated in patients with GS (n=28), patients with type 2 diabetes mellitus (DM) and healthy individuals (n=20 in both groups) using an oral glucose tolerance test. Serum and urine sodium, potassium and creatinine levels were measured at 0, 30, 60, 120 and 180 min after an oral glucose load was administered. Results The areas under the serum glucose curves were higher in the GS patients than in the healthy controls (17.4±5.1 mmol•h/l vs 14.5±2.8 mmol•h/l, P=0.02) but lower than in the DM patients (24.8±5.3 mmol•h/l, P
NINJ2- A novel regulator of endothelial inflammation and activation
Apr 22, 2017   Cellular Signalling
Wang J, Fa J, Wang P, Jia X, Peng H, Chen J, Wang Y, Wang C, Chen Q, Tu X, Wang QK, Xu C
NINJ2- A novel regulator of endothelial inflammation and activation
Apr 22, 2017
Cellular Signalling
Previous genetic studies suggested that variants in NINJ2 (encode ninjurin2) confer risk to ischemic stroke or large artery atherosclerotic stroke. However, the underlying mechanisms of NINJ2 in ischemic stroke or atherosclerosis are still unknown. In this study, we hypothesized that NINJ2 may play a role in endothelial inflammation and activation, and regulate the process of atherosclerosis. Here, we demonstrated that NINJ2 can regulate the expression of a panel of genes that are associated with inflammation and atherosclerosis (e.g. IL-1β, TNF-α, IL-8, IL-6, ICAM-1 and E-selectin) in human vascular endothelial cells (HUVECs). Moreover, we found the expression of ninjurin2 is upregulated in LPS stimulated HUVECs and mouse aorta, and it can regulate LPS-induced endothelial activation and the adhesion of monocytes to endothelial cells. We also found that NINJ2 can regulate NF-κB and c-jun through interacting with TLR4. In conclusion, our study suggests that ninjurin2 is a novel regulator of endothelia inflammation and activation through TLR4 signaling pathways, and these data provided new insights into the mechanisms between NINJ2 and atherosclerosis. Copyright © 2017. Published by Elsevier Inc.
Transcriptome comparison reveals insights into muscle response to hypoxia in blunt snout bream (Megalobrama amblycephala)
Apr 22, 2017   Gene
Chen BX, Yi SK, Wang WF, He Y, Huang Y, Gao ZX, Liu H, Wang WM, Wang HL
Transcriptome comparison reveals insights into muscle response to hypoxia in blunt snout bream (Megalobrama amblycephala)
Apr 22, 2017
Gene
The economic and biological significance of blunt snout bream (Megalobrama amblycephala) makes this species important to explore the underlying molecular mechanism of hypoxia response. In the present study, we compared the transcriptional responses to serious hypoxia in skeletal muscle among hypoxia tolerant (MT), sensitive (MS) and control (without hypoxia treatment, MC) M. amblycephala obtained according to the time difference of losing balance after hypoxia treatment. A total of 88,200,889 clean reads were generated and assembled into 44,493 unigenes. Transcriptomic comparison revealed 463 genes differentially expressed among different groups. A similar hypoxia-induced transcription patterns suggested a common hypoxia response involved in cell cycle, p53 signaling pathway, apoptosis, heart contraction and blood circulation. Interesting, four genes, heat shock protein beta-8 (hspb8), cysteine/serine-rich nuclear protein 1 (csrnp1), salt-inducible kinase 1 (sik1), and visinin-like 1a (vsnl1a) were up-regulated in MT Vs MC but down-regulated in MS Vs MC. Additionally, FoxO signaling pathway was significantly enriched only in MT Vs MC. These results not only provided the first insights into the mechanism that muscle tissue coped with the hypoxia stress in cyprinid species, but offered a theory base for breeding of M. amblycephala with hypoxia-resistant traits. Copyright © 2017. Published by Elsevier B.V.
Multiple repair pathways mediate cellular tolerance to resveratrol-induced DNA damage
Apr 22, 2017   Toxicology In Vitro : An International Journal Published In Association With BIBRA
Liu Y, Wu X, Hu X, Chen Z, Liu H, Takeda S, Qing Y
Multiple repair pathways mediate cellular tolerance to resveratrol-induced DNA damage
Apr 22, 2017
Toxicology In Vitro : An International Journal Published In Association With BIBRA
Resveratrol (RSV) has been reported to exert health benefits for the prevention and treatment of many diseases, including cancer. The anticancer mechanisms of RSV seem to be complex and may be associated with genotoxic potential. To better understand the genotoxic mechanisms, we used wild-type (WT) and a panel of isogenic DNA-repair deficient DT40 cell lines to identify the DNA damage effects and molecular mechanisms of cellular tolerance to RSV. Our results showed that RSV induced significant formation of γ-H2AX foci and chromosome aberrations (CAs) in WT cells, suggesting direct DNA damage effects. Comparing the survival of WT with isogenic DNA-repair deficient DT40 cell lines demonstrated that single strand break repair (SSBR) deficient cell lines of Parp1-/-, base excision repair (BER) deficient cell lines of Polβ-/-, homologous recombination (HR) mutants of Brca1-/- and Brca2-/- and translesion DNA synthesis (TLS) mutants of Rev3-/- and Rad18-/- were more sensitive to RSV. The sensitivities of cells were associated with enhanced DNA damage comparing the accumulation of γ-H2AX foci and number of CAs of isogenic DNA-repair deficient DT40 cell lines with WT cells. These results clearly demonstrated that RSV-induced DNA damage in DT40 cells, and multiple repair pathways including BER, SSBR, HR and TLS, play critical roles in response to RSV- induced genotoxicity. Copyright © 2017. Published by Elsevier Ltd.
Heterogeneous ribonuclear protein A3 (hnRNP A3) is present in dipeptide repeat protein containing inclusions in Frontotemporal Lobar Degeneration and Motor Neurone disease associated with expansions in C9orf72 gene
Apr 22, 2017   Acta Neuropathologica Communications
Davidson YS, Flood L, Robinson AC, Nihei Y, Mori K, Rollinson S, Richardson A, Benson BC, Jones M, Snowden JS, Pickering-Brown S, Haass C, Lashley T, Mann DMA
Heterogeneous ribonuclear protein A3 (hnRNP A3) is present in dipeptide repeat protein containing inclusions in Frontotemporal Lobar Degeneration and Motor Neurone disease associated with expansions in C9orf72 gene
Apr 22, 2017
Acta Neuropathologica Communications
Frontotemporal Lobar Degeneration (FTLD) encompasses certain related neurodegenerative disorders which alter behaviour, personality and language. Heterogeneous ribonuclear proteins (hnRNPs) maintain RNA metabolism and changes in their function may underpin the pathogenesis of FTLD. Immunostaining for hnRNP A1, A2/B1 and A3 was performed on sections of temporal cortex with hippocampus from 61 patients with FTLD, stratified by pathological hallmarks into FTLD-tau and FTLD-TDP type A, B and C subtypes, and by genetics into patients with C9orf72 expansions, MAPT or GRN mutations, or those without known mutation. Four patients with Motor Neurone Disease (MND) with C9orf72 expansions and 10 healthy controls were also studied. Semi-quantitative analysis assessed hnRNP staining intensity in dentate gyrus (DG) and CA4 region of hippocampus, and temporal cortex (Tcx) in the different pathological and genetic groups.Immunostaining for hnRNP A1, A2/B1 and A3 revealed no consistent changes in pattern or amount of physiological staining across any of the pathological or genetic groups. No immunostaining of any inclusions resembling TDP-43 immunoreactive neuronal cytoplasmic inclusions or dystrophic neurites, was seen in either Tcx or DG of the hippocampus in any of the FTLD cases investigated for hnRNP A1, A2/B1 and A3. However, immunostaining for hnRNP A3 showed that inclusion bodies, resembling those TDP-43 negative, p62-immunopositive structures containing dipeptide repeat proteins (DPR) were variably observed in hippocampus and cerebellum. The proportion of cases showing hnRNP A3-immunoreactive DPR, and the number of hnRNP A3-positive inclusions within cases, was significantly greater in DG than in cells of CA4 region and cerebellum, but the latter was significantly less in all three regions compared to that detected by p62 immunostaining.
Emerging evidence for the role of differential tumor microenvironment in breast cancer racial disparity: a closer look at the surroundings
Apr 21, 2017   Carcinogenesis
Deshmukh SK, Srivastava SK, Tyagi N, Ahmad A, Singh AP, Ghadhban AA, Dyess DL, Carter JE, Dugger K, Singh S
Emerging evidence for the role of differential tumor microenvironment in breast cancer racial disparity: a closer look at the surroundings
Apr 21, 2017
Carcinogenesis
Although increased awareness leading to early detection and prevention, as well as advancements in treatment strategies, have resulted in superior clinical outcomes, African American women with breast cancer continue to have greater mortality rates, compared to Caucasian American counterparts. Moreover, African American women are more likely to have breast cancer at a younger age and be diagnosed with aggressive tumor sub-types. Such racial disparities can be attributed to socioeconomic differences, but it is increasingly being recognized that these disparities may indeed be due to certain genetic and other non-genetic biological differences. Tumor microenvironment, which provides a favorable niche for the growth of tumor cells, is comprised of several types of stromal cells and the various proteins secreted as a consequence of bi-directional tumor-stromal cross-talk. Emerging evidence suggests inherent biological differences in the tumor microenvironment of breast cancer patients from different racial backgrounds. Tumor microenvironment components, affected by the genetic make-up of the tumor cells as well as other non-tumor-associated factors, may also render patients more susceptible to the development of aggressive tumors and faster progression of disease resulting in early onset, thus adversely affecting patients' survival. This review provides an overview of breast cancer racial disparity and discusses the existence of race-associated differential tumor microenvironment and its underlying genetic and non-genetic causal factors. A better understanding of these aspects would help further research on effective cancer management and improved approaches for reducing the racial disparities gaps in breast cancer patients. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
Reduction of pulmonary toxicity of metal oxide nanoparticles by phosphonate-based surface passivation
Apr 22, 2017   Particle And Fibre Toxicology
Cai X, Lee A, Ji Z, Huang C, Chang CH, Wang X, Liao YP, Xia T, Li R
Reduction of pulmonary toxicity of metal oxide nanoparticles by phosphonate-based surface passivation
Apr 22, 2017
Particle And Fibre Toxicology
The wide application of engineered nanoparticles has induced increasing exposure to humans and environment, which led to substantial concerns on their biosafety. Some metal oxides (MOx) have shown severe toxicity in cells and animals, thus safe designs of MOx with reduced hazard potential are desired. Currently, there is a lack of a simple yet effective safe design approach for the toxic MOx. In this study, we determined the key physicochemical properties of MOx that lead to cytotoxicity and explored a safe design approach for toxic MOx by modifying their hazard properties. THP-1 and BEAS-2B cells were exposed to 0-200 μg/mL MOx for 24 h, we found some toxic MOx including CoO, CuO, Ni2O3 and Co3O4, could induce reactive oxygen species (ROS) generation and cell death due to the toxic ion shedding and/or oxidative stress generation from the active surface of MOx internalized into lysosomes. We thus hypothesized that surface passivation could reduce or eliminate the toxicity of MOx. We experimented with a series of surface coating molecules and discovered that ethylenediamine tetra (methylene phosphonic acid) (EDTMP) could form stable hexadentate coordination with MOx. The coating layer can effectively reduce the surface activity of MOx with 85-99% decrease of oxidative potential, and 65-98% decrease of ion shedding. The EDTMP coated MOx show negligible ROS generation and cell death in THP-1 and BEAS-2B cells. The protective effect of EDTMP coating was further validated in mouse lungs exposed to 2 mg/kg MOx by oropharyngeal aspiration. After 40 h exposure, EDTMP coated MOx show significant decreases of neutrophil counts, lactate dehydrogenase (LDH) release, MCP-1, LIX and IL-6 in bronchoalveolar lavage fluid (BALF), compared to uncoated particles. The haematoxylin and eosin (H&E) staining results of lung tissue also show EDTMP coating could significantly reduce the pulmonary inflammation of MOx. The surface reactivity of MOx including ion shedding and oxidative potential is the dominated physicochemical property that is responsible for the cytotoxicity induced by MOx. EDTMP coating could passivate the surface of MOx, reduce their cytotoxicity and pulmonary hazard effects. This coating would be an effective safe design approach for a broad spectrum of toxic MOx, which will facilitate the safe use of MOx in commercial nanoproducts.
Macrophages Facilitate Electrical Conduction in the Heart
Apr 21, 2017   Cell
Hulsmans M, Clauss S, Xiao L, Aguirre AD, King KR,   . . . . . .   , Kohl P, Vinegoni C, Milan DJ, Ellinor PT, Nahrendorf M
Macrophages Facilitate Electrical Conduction in the Heart
Apr 21, 2017
Cell
Organ-specific functions of tissue-resident macrophages in the steady-state heart are unknown. Here, we show that cardiac macrophages facilitate electrical conduction through the distal atrioventricular node, where conducting cells densely intersperse with elongated macrophages expressing connexin 43. When coupled to spontaneously beating cardiomyocytes via connexin-43-containing gap junctions, cardiac macrophages have a negative resting membrane potential and depolarize in synchrony with cardiomyocytes. Conversely, macrophages render the resting membrane potential of cardiomyocytes more positive and, according to computational modeling, accelerate their repolarization. Photostimulation of channelrhodopsin-2-expressing macrophages improves atrioventricular conduction, whereas conditional deletion of connexin 43 in macrophages and congenital lack of macrophages delay atrioventricular conduction. In the Cd11bDTR mouse, macrophage ablation induces progressive atrioventricular block. These observations implicate macrophages in normal and aberrant cardiac conduction. Copyright © 2017 Elsevier Inc. All rights reserved.
The Ubiquitin Ligase CHIP Integrates Proteostasis and Aging by Regulation of Insulin Receptor Turnover
Apr 21, 2017   Cell
Tawo R, Pokrzywa W, Kevei É, Akyuz ME, Balaji V, Adrian S, Höhfeld J, Hoppe T
The Ubiquitin Ligase CHIP Integrates Proteostasis and Aging by Regulation of Insulin Receptor Turnover
Apr 21, 2017
Cell
Aging is attended by a progressive decline in protein homeostasis (proteostasis), aggravating the risk for protein aggregation diseases. To understand the coordination between proteome imbalance and longevity, we addressed the mechanistic role of the quality-control ubiquitin ligase CHIP, which is a key regulator of proteostasis. We observed that CHIP deficiency leads to increased levels of the insulin receptor (INSR) and reduced lifespan of worms and flies. The membrane-bound INSR regulates the insulin and IGF1 signaling (IIS) pathway and thereby defines metabolism and aging. INSR is a direct target of CHIP, which triggers receptor monoubiquitylation and endocytic-lysosomal turnover to promote longevity. However, upon proteotoxic stress conditions and during aging, CHIP is recruited toward disposal of misfolded proteins, reducing its capacity to degrade the INSR. Our study indicates a competitive relationship between proteostasis and longevity regulation through CHIP-assisted proteolysis, providing a mechanistic concept for understanding the impact of proteome imbalance on aging. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.
AKT/PKB Signaling: Navigating the Network
Apr 21, 2017   Cell
Manning BD, Toker A
AKT/PKB Signaling: Navigating the Network
Apr 21, 2017
Cell
The Ser and Thr kinase AKT, also known as protein kinase B (PKB), was discovered 25 years ago and has been the focus of tens of thousands of studies in diverse fields of biology and medicine. There have been many advances in our knowledge of the upstream regulatory inputs into AKT, key multifunctional downstream signaling nodes (GSK3, FoxO, mTORC1), which greatly expand the functional repertoire of AKT, and the complex circuitry of this dynamically branching and looping signaling network that is ubiquitous to nearly every cell in our body. Mouse and human genetic studies have also revealed physiological roles for the AKT network in nearly every organ system. Our comprehension of AKT regulation and functions is particularly important given the consequences of AKT dysfunction in diverse pathological settings, including developmental and overgrowth syndromes, cancer, cardiovascular disease, insulin resistance and type 2 diabetes, inflammatory and autoimmune disorders, and neurological disorders. There has also been much progress in developing AKT-selective small molecule inhibitors. Improved understanding of the molecular wiring of the AKT signaling network continues to make an impact that cuts across most disciplines of the biomedical sciences. Copyright © 2017 Elsevier Inc. All rights reserved.
Combining Human Epigenetics and Sleep Studies in C. elegans: A Cross-species Approach for Finding Conserved Genes Regulating Sleep
Apr 21, 2017   Sleep
Huang H, Zhu Y, Eliot MN, Knopik VS, McGeary JE, Carskadon MA, Hart AC
Combining Human Epigenetics and Sleep Studies in C. elegans: A Cross-species Approach for Finding Conserved Genes Regulating Sleep
Apr 21, 2017
Sleep
We aimed to test a combined approach to identify conserved genes regulating sleep and to explore the association between DNA methylation and sleep length. We identified candidate genes associated with shorter versus longer sleep duration in college students based on DNA methylation using Illumina Infinium HumanMethylation450 BeadChip arrays. Orthologous genes in Caenorhabditiselegans were identified and we examined whether their loss of function affected C. elegans sleep. For genes whose perturbation affected C. elegans sleep, we subsequently undertook a small pilot study to re-examine DNA methylation in an independent set of human subjects with shorter versus longer sleep durations. Eighty-seven out of 485,577 CpG sites had significant differential methylation in young adults with shorter versus longer sleep duration, corresponding to 52 candidate genes. We identified 34 C. elegans orthologs, including NPY/flp-18 and flp-21, which are known to affect sleep. Loss of 5 additional genes alter developmentally-timed C. elegans sleep (B4GALT6/bre-4, DOCK180/ced-5, GNB2L1/rack-1, PTPRN2/ida-1, ZFYVE28/lst-2). For one of these genes, ZFYVE28 (also known as hLst2), the pilot replication study again found decreased DNA methylation associated with shorter sleep duration at the same two CpG sites in the first intron of ZFYVE28. Using an approach that combines human epigenetics and C. elegans sleep studies, we identified 5 genes that play previously unidentified roles in C. elegans sleep. We suggest sleep duration in humans may be associated with differential DNA methylation at specific sites and that the conserved genes identified here likely play roles in C. elegans sleep and in other species.
Cis-regulatory divergence in gene expression between two thermally divergent yeast species
Apr 21, 2017   Genome Biology And Evolution
Li XC, Fay JC
Cis-regulatory divergence in gene expression between two thermally divergent yeast species
Apr 21, 2017
Genome Biology And Evolution
Gene regulation is a ubiquitous mechanism by which organisms respond to their environment. While organisms are often found to be adapted to the environments they experience, the role of gene regulation in environmental adaptation is not often known. In this study, we examine divergence in cis-regulatory effects between two Saccharomyces species, S. cerevisiae and S. uvarum, that have substantially diverged in their thermal growth profile. We measured allele specific expression (ASE) in the species' hybrid at three temperatures, the highest of which is lethal to S. uvarum but not the hybrid or S. cerevisiae. We find that S. uvarum alleles can be expressed at the same level as S. cerevisiae alleles at high temperature and most cis-acting differences in gene expression are not dependent on temperature. While a small set of 136 genes show temperature-dependent ASE, we find no indication that signatures of directional cis-regulatory evolution are associated with temperature. Within promoter regions we find binding sites enriched upstream of temperature responsive genes, but only weak correlations between binding site and expression divergence. Our results indicate that temperature divergence between S. cerevisiae and S. uvarum has not caused widespread divergence in cis-regulatory activity, but point to a small subset of genes where the species' alleles show differences in magnitude or opposite responses to temperature. The difficulty of explaining divergence in cis-regulatory sequences with models of transcription factor binding sites and nucleosome positioning highlights the importance of identifying mutations that underlie cis-regulatory divergence between species. © The Author(s) 2017. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.
Genomic data for 78 chickens from 14 populations
Apr 21, 2017   GigaScience
Li D, Che T, Chen B, Tian S, Zhou X,   . . . . . .   , Yang M, Zhou R, Li R, Zhu Q, Li M
Genomic data for 78 chickens from 14 populations
Apr 21, 2017
GigaScience
Since the domestication of the red jungle fowls ( Gallus gallus ) (dating back to ∼10,000 B.P.) in Asia, domestic chickens ( Gallus gallus domesticus ) have been subjected to the combined effects of natural selection and human-driven artificial selection; this has resulted in marked phenotypic diversity in a number of traits, including behavior, body composition, egg production and skin color. Population genomic variations through diversifying selection have not been fully investigated. The whole genomes of 78 domestic chickens were sequenced to an average of 18-fold coverage for each bird. By combining this data with publicly available genomes of 5 wild red jungle fowls and 8 Xishuangbanna game fowls, we conducted a comprehensive comparative genomics analysis of 91 chickens from 17 populations. After aligning ∼21.30 gigabases (Gb) of high quality data from each individual to the reference chicken genome, we identified ∼6.44 million (M) SNPs for each population. These SNPs included 1.10 M novel SNPs in 17 populations that were absent in the current chicken dbSNP (Build 145) entries. The current data is important for population genetics and further studies in chicken, and will serve as a valuable resource for investigating diversifying selection and candidate genes for selective breeding in chicken.
Patterns of genome-wide diversity and population structure in the Drosophila athabasca species complex
Apr 21, 2017   Molecular Biology And Evolution
Wong Miller KM, Bracewell RR, Eisen MB, Bachtrog D
Patterns of genome-wide diversity and population structure in the Drosophila athabasca species complex
Apr 21, 2017
Molecular Biology And Evolution
The Drosophila athabasca species complex contains three recently diverged, prezygotically isolated semispecies (Western-Northern, Eastern-A, and Eastern-B) that are distributed across North America and share zones of sympatry. Inferences based on a handful of loci suggest that this complex might be an ideal system for studying the genetics of incipient speciation and the evolution of prezygotic isolating mechanisms, but patterns of differentiation have not been characterized systematically. Here, we assembled a draft genome for D. athabasca and analyze whole-genome re-sequencing data for 28 individuals from across the species range to characterize genome-wide patterns of diversity and population differentiation among semispecies. Patterns of differentiation on the X-chromosome vs. autosomes vary, with the X-chromosome showing better phylogenetic resolution and increased levels of between semispecies divergence. Despite low levels of overall differentiation and a lack of phylogenetic resolution of the autosomes for the most closely related semispecies, individuals do exhibit distinct genetic clustering. Demographic analyses provide some support for a model of isolation with migration within D. athabasca, with divergence times
Long non-coding RNA exchange during the oocyte-to-embryo transition in mice
Apr 21, 2017   DNA Research : An International Journal For Rapid Publication Of Reports On Genes And Genomes
Karlic R, Ganesh S, Franke V, Svobodova E, Urbanova J, Suzuki Y, Aoki F, Vlahovicek K, Svoboda P
Long non-coding RNA exchange during the oocyte-to-embryo transition in mice
Apr 21, 2017
DNA Research : An International Journal For Rapid Publication Of Reports On Genes And Genomes
Inhibition of the P2X7-PANX1 complex suppresses spreading depolarization and neuroinflammation
Apr 21, 2017   Brain : A Journal Of Neurology
Chen SP, Qin T, Seidel JL, Zheng Y, Eikermann M, Ferrari MD, van den Maagdenberg AMJM, Moskowitz MA, Ayata C, Eikermann-Haerter K
Inhibition of the P2X7-PANX1 complex suppresses spreading depolarization and neuroinflammation
Apr 21, 2017
Brain : A Journal Of Neurology
Spreading depolarization is a wave of neuronal and glial depolarization. Within minutes after spreading depolarization, the neuronal hemichannel pannexin 1 (PANX1) opens and forms a pore complex with the ligand-gated cation channel P2X7, allowing the release of excitatory neurotransmitters to sustain spreading depolarization and activate neuroinflammation. Here, we explore the hypothesis that the P2X7-PANX1 pore complex is a critical determinant of spreading depolarization susceptibility with important consequences for neuroinflammation and trigeminovascular activation. We found that genetic loss of function or ablation of the P2x7 gene inhibits spreading depolarization. Moreover, pharmacological suppression of the P2X7-PANX1 pore complex inhibits spreading depolarization in mice carrying the human familial hemiplegic migraine type 1 R192Q missense mutation as well as in wild-type mice and rats. Pore inhibitors elevate the electrical threshold for spreading depolarization, and reduce spreading depolarization frequency and amplitude. Pore inhibitors also suppress downstream consequences of spreading depolarization such as upregulation of interleukin-1 beta, inducible nitric oxide synthase and cyclooxygenase-2 in the cortex after spreading depolarization. In addition, they inhibit surrogates for trigeminovascular activation, including expression of calcitonin gene-related peptide in the trigeminal ganglion and c-Fos in the trigeminal nucleus caudalis. Our results are consistent with the hypothesis that the P2X7-PANX1 pore complex is a critical determinant of spreading depolarization susceptibility and its downstream consequences, of potential relevance to its signature disorders such as migraine. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
miR-24-3p Is Overexpressed in Hodgkin Lymphoma and Protects Hodgkin and Reed-Sternberg Cells from Apoptosis
Apr 22, 2017   The American Journal Of Pathology
Yuan Y, Kluiver J, Koerts J, de Jong D, Rutgers B, Razak FRA, Terpstra M, Plaat B, Nolte IM, Diepstra A, Visser L, Kok K, van den Berg A
miR-24-3p Is Overexpressed in Hodgkin Lymphoma and Protects Hodgkin and Reed-Sternberg Cells from Apoptosis
Apr 22, 2017
The American Journal Of Pathology
miRNAs play important roles in biological processes, such as proliferation, metabolism, differentiation, and apoptosis, whereas altered expression levels contribute to diseases, such as cancers. We identified miRNAs with aberrant expression in Hodgkin lymphoma (HL) and investigated their role in pathogenesis. Small RNA sequencing revealed 84 significantly differentially expressed miRNAs in HL cell lines as compared to germinal center B cells. Three up-regulated miRNAs-miR-23a-3p, miR-24-3p, and miR-27a-3p-were derived from one primary miRNA transcript. Loss-of-function analyses for these miRNAs and their seed family members resulted in decreased growth on miR-24-3p inhibition in three and of miR-27a/b-3p inhibition in one HL cell line. Apoptosis analysis indicated that the effect of miR-24-3p on cell growth is at least in part caused by an increase of apoptotic cells. Argonaute 2 immunoprecipitation revealed 1142 genes consistently targeted by miRNAs in at least three of four HL cell lines. Furthermore, 52 of the 1142 genes were predicted targets of miR-24-3p. Functional annotation analysis revealed a function related to cell growth, cell death, and/or apoptosis for 15 of the 52 genes. Western blotting of the top five genes showed increased protein levels on miR-24-3p inhibition for CDKN1B/P27kip1 and MYC. In summary, we showed that miR-24-3p is up-regulated in HL and its inhibition impairs cell growth possibly via targeting CDKN1B/P27kip1 and MYC. Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

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