Notice NOT-MH-17-038 from the NIH Guide for Grants and Contracts

Notice NOT-MH-17-037 from the NIH Guide for Grants and Contracts

GPR37L1 modulates seizure susceptibility: Evidence from mouse studies and analyses of a human GPR37L1 variant.

Neurobiol Dis. 2017 Jul 05;:

Authors: Giddens MM, Wong JC, Schroeder JP, Farrow EG, Smith BM, Owino S, Soden SE, Meyer RC, Saunders C, LePichon JB, Weinshenker D, Escayg A, Hall RA

Abstract
Progressive myoclonus epilepsies (PMEs) are disorders characterized by myoclonic and generalized seizures with progressive neurological deterioration. While several genetic causes for PMEs have been identified, the underlying causes remain unknown for a substantial portion of cases. Here we describe several affected individuals from a large, consanguineous family presenting with a novel PME in which symptoms begin in adolescence and result in death by early adulthood. Whole exome analyses revealed that affected individuals have a homozygous variant in GPR37L1 (c.1047G>T [Lys349Asp]), an orphan G protein-coupled receptor (GPCR) expressed predominantly in the brain. In vitro studies demonstrated that the K349N substitution in GPR37L1 did not grossly alter receptor expression, surface trafficking or constitutive signaling in transfected cells. However, in vivo studies revealed that a complete loss of GPR37L1 function in mice results in increased seizure susceptibility. Mice lacking the related receptor Gpr37 also exhibited an increase in seizure susceptibility, while genetic deletion of both receptors resulted in an even more dramatic increase in vulnerability to seizures. These findings provide evidence linking GPR37L1 and GPR37 to seizure etiology and demonstrate an association between a GPR37L1 variant and a novel progressive myoclonus epilepsy.

PMID: 28688853 [PubMed - as supplied by publisher]

Apoptotic and genotoxic effects of low-intensity ultrasound on healthy and leukemic human peripheral mononuclear blood cells.

J Med Ultrason (2001). 2017 Jul 08;:

Authors: Saliev T, Begimbetova D, Baiskhanova D, Abetov D, Kairov U, Gilman CP, Matkarimov B, Tachibana K

Abstract
PURPOSE: To scrutinize the apoptotic and genotoxic effects of low-intensity ultrasound and an ultrasound contrast agent (SonoVue; Bracco Diagnostics Inc., EU) on human peripheral mononuclear blood cells (PMBCs).
METHODS: PMBCs were subjected to a low-intensity ultrasound field (1-MHz frequency; spatial peak temporal average intensity 0.18 W/cm2) followed by analysis for apoptosis and DNA damage (single-strand breaks + double-strand breaks). The comet assay was then repeated after 2 h to examine the ability of cells to repair DNA breaks.
RESULTS: The results demonstrated that low-intensity ultrasound was capable of selectively inducing apoptosis in leukemic PMBCs, but not in healthy cells. The introduction of ultrasound contrast agent SonoVue resulted in an increase in apoptosis in both groups. DNA analysis after ultrasound exposure indicated that ultrasound triggered DNA damage in leukemic PMBCs (66.05 ± 13.36%), while the damage was minimal (7.01 ± 0.89%) in control PMBCs. However, both cell lines demonstrated an ability to repair DNA single- and double-strand breaks 2 h after sonication.
CONCLUSIONS: The study demonstrated that low-intensity ultrasound selectively induced apoptosis in cancer PMBCs. Ultrasound-induced DNA damage was observed primarily in leukemic PMBCs. Nevertheless, both cell lines were able to repair ultrasound-mediated DNA strand breaks.

PMID: 28689300 [PubMed - as supplied by publisher]

Notice NOT-OD-17-085 from the NIH Guide for Grants and Contracts

Notice NOT-DK-17-014 from the NIH Guide for Grants and Contracts

Notice NOT-NR-17-022 from the NIH Guide for Grants and Contracts

Notice NOT-CA-17-054 from the NIH Guide for Grants and Contracts

Funding Opportunity PA-17-325 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) invites Research Project Grant (R01) applications that propose to study the ethical, legal and social implications (ELSI) of human genome research. Applications may propose studies using either single or mixed methods. Proposed approaches may include but are not limited to data-generating qualitative and quantitative approaches, legal, economic and normative analyses, and other types of analytical and conceptual research methodologies, such as those involving the direct engagement of stakeholders.

Funding Opportunity PA-17-324 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) invites Small Research Grant (R03) applications to study the ethical, legal and social implications (ELSI) of human genome research. These applications should be for small, self-contained research projects, such as those that involve single investigators. Of particular interest are projects that propose normative or conceptual analyses, including focused legal, economic, philosophical, anthropological, or historical analyses of new or emerging issues. This mechanism can also be used for the collection of preliminary data and the secondary analysis of existing data.

Funding Opportunity PA-17-323 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) invites Exploratory/Developmental Research Grant (R21) applications that propose to study the ethical, legal and social implications (ELSI) of human genome research. These applications should propose single or mixed methods studies that break new ground, extend previous discoveries in new directions or develop preliminary data in preparation for larger studies. Of particular interest are studies that explore the implications of new or emerging genomic technologies or novel uses of genomic information.

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A Framework for the Targeted Selection of Herbs with Similar Efficacy by Exploiting Drug Repositioning Technique and Curated Biomedical Knowledge.

J Ethnopharmacol. 2017 Jul 04;:

Authors: Yea SJ, Kim BY, Kim C, Yi MY

Abstract
ETHNO PHARMACOLOGICAL RELEVANCE: Plants have been the most important natural resources for traditional medicine and for the modern pharmaceutical industry. They have been in demand in regards to finding alternative medicinal herbs with similar efficacy. Due to the very low probability of discovering useful compounds by random screening, researchers have advocated for using targeted selection approaches. Furthermore, because drug repositioning can speed up the process of drug development, an integrated technique that exploits chemical, genetic, and disease information has been recently developed. Building upon these findings, in this paper, we propose a novel framework for the targeted selection of herbs with similar efficacy by exploiting drug repositioning technique and curated modern scientific biomedical knowledge, with the goal of improving the possibility of inferring the traditional empirical ethno-pharmacological knowledge.
MATERIALS AND METHODS: To rank candidate herbs on the basis of similarities against target herb, we proposed and evaluated a framework that is comprised of the following four layers: links, extract, similarity, and model. In the framework, multiple databases are linked to build an herb-compound-protein-disease network which was composed of one tripartite network and two bipartite networks allowing comprehensive and detailed information to be extracted. Further, various similarity scores between herbs are calculated, and then prediction models are trained and tested on the basis of theses similarity features.
RESULTS: The proposed framework has been found to be feasible in terms of link loss. Out of the 50 similarities, the best one enhanced the performance of ranking herbs with similar efficacy by about 120-320% compared with our previous study. Also, the prediction model showed improved performance by about 180-480%. While building the prediction model, we identified the compound information as being the most important knowledge source and structural similarity as the most useful measure.
CONCLUSIONS: In the proposed framework, we took the knowledge of herbal medicine, chemistry, biology, and medicine into consideration to rank herbs with similar efficacy in candidates. The experimental results demonstrated that the performances of framework outperformed the baselines and identified the important knowledge source and useful similarity measure.

PMID: 28687508 [PubMed - as supplied by publisher]

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Angioedema: An Orphan Symptom with Its Own Orphan Disease.

Immunol Allergy Clin North Am. 2017 Aug;37(3):xiii-xiv

Authors: Tilles SA

PMID: 28687114 [PubMed - in process]

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Pharmacoeconomics of Orphan Disease Treatment with a Focus on Hereditary Angioedema.

Immunol Allergy Clin North Am. 2017 Aug;37(3):617-628

Authors: Lumry WR

Abstract
This article discusses orphan diseases, their prevalence, legislative incentives to encourage development of therapies, and the impact of treatment on health care payment systems. Specifically, the cost burden of hereditary angioedema on patients, health care systems, and society is reviewed. The impact of availability of and access to novel and specific therapies on morbidity, mortality, and overall burden of disease is explored. Changes in treatment paradigms to improve effect and reduce cost of treatment are presented.

PMID: 28687113 [PubMed - in process]

Rivaroxaban non-responders: do plasma measurements have a place?

Clin Chem Lab Med. 2017 Jul 08;:

Authors: Dideriksen D, Damkier P, Nybo M

PMID: 28688225 [PubMed - as supplied by publisher]

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Pneumocystis jirovecii and Cystic Fibrosis in Brittany, France.

Mycopathologia. 2017 Jul 07;:

Authors: Nevez G, Robert-Gangneux F, Pougnet L, Virmaux M, Belleguic C, Deneuville E, Rault G, Chevrier S, Ramel S, Le Bihan J, Guillaud-Saumur T, Calderon E, Le Govic Y, Gangneux JP, Le Gal S

Abstract
Pneumocystis jirovecii is a transmissible fungus with a high pulmonary tropism. The prevalence of P. jirovecii in patients with cystic fibrosis (CF) has been estimated in Germany at 7.4%, in Spain at 21.5% and in Brazil at 38.2%. Data on the prevalence of P. jirovecii in CF patients in France remain scarce, particularly in Brittany, where the prevalence of CF is high (from 1/1600 to 1/4500). Our objectives were to determine the prevalence of colonization of the airways by P. jirovecii in Brittany in CF patients monitored at the "Centre de Ressources et de Compétences de la Mucoviscidose (CRCM)" of Rennes compared to that previously observed at the CRCM of Roscoff-Brest. Sputa from 86 patients (178 specimens) followed in Rennes were analyzed retrospectively. The detection of P. jirovecii was performed using real-time PCR targeting the gene encoding the mitochondrial large subunit of ribosomal RNA. Pneumocystis jirovecii DNA was detected in 3/86 patients (3.5%) monitored at Rennes, whereas it had previously been detected in 1/76 patients (1.3%) monitored at Roscoff-Brest, thus showing an overall prevalence of 2.5% in Brittany. These results obtained from two Breton centers taken together show that P. jirovecii prevalence in patients with CF in Brittany is lower than those observed in Germany, Spain, Brazil or in other regions of France. This study is a preliminary step in determining the risk factors for P. jirovecii acquisition, its epidemiological and clinical significance in CF patients through a prospective multicenter study.

PMID: 28688008 [PubMed - as supplied by publisher]

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Germline Loss-of-Function Mutations in EPHB4 Cause a Second Form of Capillary Malformation-Arteriovenous Malformation (CM-AVM2) Deregulating RAS-MAPK Signaling.

Circulation. 2017 Jul 07;:

Authors: Amyere M, Revencu N, Helaers R, Pairet E, Baselga E, Cordisco MR, Chung WK, Dubois J, Lacour JP, Martorell L, Mazereeuw-Hautier J, Pyeritz RE, Amor DJ, Bisdorff A, Blei F, Bombei H, Dompmartin A, Brooks DG, Dupont J, González-Enseñat MA, Frieden IJ, Gérard M, Kvarnung M, Hanson-Kahn AK, Hudgins L, Léauté-Labrèze C, McCuaig C, Metry D, Parent P, Paul C, Petit F, Phan A, Quéré I, Salhi A, Turner AM, Vabres P, Vicente A, Wargon O, Watanabe S, Weibel L, Wilson A, Willing M, Mulliken JB, Boon LM, Vikkula M

Abstract
Background -Most AVMs are localized and occur sporadically; however they also can be multifocal in autosomal dominant disorders, such as Hereditary Hemorrhagic Telangiectasia (HHT) and Capillary Malformation-Arteriovenous Malformation (CM-AVM). Previously, we identified RASA1 mutations in 50% of patients with CM-AVM. Herein we studied non-RASA1 patients to further elucidate the pathogenicity of CMs and AVMs. Methods -We conducted a genome-wide linkage study on a CM-AVM family. Whole exome sequencing was also performed on 9 unrelated CM-AVM families. We identified a candidate-gene and screened it in a large series of patients. The influence of several missense variants on protein function was also studied in vitroResults -We found evidence for linkage in two loci. Whole-exome sequencing data unraveled four distinct damaging variants in EPHB4 in five families that co-segregated with CM-AVM. Overall, screening of EPHB4 detected 47 distinct mutations in 54 index patients: 27 lead to a premature stop codon or splice-site alteration, suggesting loss of function. The other 20 are non-synonymous variants that result in amino-acid substitutions. In vitro expression of several mutations confirmed loss of function of EPHB4. The clinical features included multifocal CMs, telangiectasias, and AVMs. Conclusions -We found EPHB4 mutations in patients with multifocal CMs associated with AVMs. The phenotype, CM-AVM2, mimics RASA1-related CM-AVM1 and also HHT. RASA1 encoded p120RASGAP is a direct effector of EPHB4. Our data highlights the pathogenetic importance of this interaction and indicts EPHB4-RAS-ERK signaling pathway as a major cause for arterio-venous malformations.

PMID: 28687708 [PubMed - as supplied by publisher]

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Recessive mutation in EXOSC3 associates with mitochondrial dysfunction and pontocerebellar hypoplasia.

Mitochondrion. 2017 Jul 04;:

Authors: Schottmann G, Picker-Minh S, Schwarz JM, Gill E, Rodenburg RJT, Stenzel W, Kaindl AM, Schuelke M

Abstract
Recessive mutations in EXOSC3, encoding a subunit of the human RNA exosome complex, cause pontocerebellar hypoplasia type 1b (PCH1B). We report a boy with severe muscular hypotonia, psychomotor retardation, progressive microcephaly, and cerebellar atrophy. Biochemical abnormalities comprised mitochondrial complex I and pyruvate dehydrogenase complex (PDHc) deficiency. Whole exome sequencing uncovered a known EXOSC3 mutation p.(D132A) as the underlying cause. In patient fibroblasts, a large portion of the EXOSC3 protein was trapped in the cytosol. MtDNA copy numbers in muscle were reduced to 35%, but mutations in the mtDNA and in nuclear mitochondrial genes were ruled out. RNA-Seq of patient muscle showed highly increased mRNA copy numbers, especially for genes encoding structural subunits of OXPHOS complexes I, III, and IV, possibly due to reduced degradation by a dysfunctional exosome complex. This is the first case of mitochondrial dysfunction associated with an EXOSC3 mutation, which expands the phenotypic spectrum of PCH1B. We discuss the links between exosome and mitochondrial dysfunction.

PMID: 28687512 [PubMed - as supplied by publisher]

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Evaluating Amber force fields using computed NMR chemical shifts.

Proteins. 2017 Jul 08;:

Authors: Koes DR, Vries JK

Abstract
NMR chemical shifts can be computed from molecular dynamics (MD) simulations using a template matching approach and a library of conformers containing chemical shifts generated from ab initio quantum calculations. This approach has potential utility for evaluating the force fields that underlie these simulations. Imperfections in force fields generate flawed atomic coordinates. Chemical shifts obtained from flawed coordinates have errors that can be traced back to these imperfections. We use this approach to evaluate a series of AMBER force fields that have been refined over the course of two decades (ff94, ff96, ff99SB, ff14SB, ff14ipq and ff15ipq). For each force field a series of MD simulations are carried out for eight model proteins. The calculated chemical shifts for the (1) H, (15) N and (13) C(a) atoms are compared with experimental values. Initial evaluations are based on root mean squared (RMS) errors at the protein level. These results are further refined based on secondary structure and the types of atoms involved in non-bonded interactions. The best chemical shift for identifying force field differences is the shift associated with peptide protons. Examination of the model proteins on a residue by residue basis reveals that force field performance is highly dependent on residue position. Examination of the time course of non-bonded interactions at these sites provides explanations for chemical shift differences at the atomic coordinate level. Results show that the newer ff14ipq and ff15ipq force fields developed with the implicitly polarized charge method perform better than the older force fields. This article is protected by copyright. All rights reserved.

PMID: 28688107 [PubMed - as supplied by publisher]

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CCM111, the water extract of Antrodia cinnamomea, regulates immune-related activity through STAT3 and NF-κB pathways.

Sci Rep. 2017 Jul 07;7(1):4862

Authors: Lin IY, Pan MH, Lai CS, Lin TT, Chen CT, Chung TS, Chen CL, Lin CH, Chuang WC, Lee MC, Lin CC, Ma N

Abstract
Antrodia cinnamomea (AC) exhibits many bioactivities, including anti-inflammatory, anti-cancer, and hepatoprotection activities. Many researchers have studied the functions of the components or fractions of AC, but the functions of the original extractions of AC have not been studied. In addition, the detailed relationship between AC and immune-related signaling pathways is unclear. In this study, we screened the effects of CCM111, which is the extract of AC, on seven immune-related signaling pathways and further investigated whether CCM111 can influence inflammation. Interestingly, our results showed that CCM111 significantly inhibited the IL-6-stimulated STAT3 pathway and the LPS-stimulated NF-κB pathway in macrophages. CCM111 also decreased the phosphorylation of STAT3, Tyk2 and the nuclear translocation of p65. Moreover, CCM111 and F4, a fraction of CCM111, down-regulated nitric oxide (NO) production, the protein levels of iNOS and COX-2, and inflammatory cytokines in macrophage cells. Therefore, our study suggested that CCM111 has the potential to be developed as an effective anti-inflammatory agent.

PMID: 28687744 [PubMed - in process]