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Genetic modifiers of multiple sclerosis progression, severity and onset.

Clin Immunol. 2017 May 10;:

Authors: Dessa Sadovnick A, Traboulsee AL, Zhao Y, Bernales CQ, Encarnacion M, Ross JP, Yee IM, Criscuoli MG, Vilariño-Güell C

Abstract
The genetic contribution to clinical outcomes for multiple sclerosis (MS) has yet to be defined. We performed exome sequencing analysis in 100 MS patients presenting opposite extremes of clinical phenotype (discovery cohort), and genotyped variants of interest in 2016 MS patients (replication cohort). Linear and logistic regression analyses were used to identify significant associations with disease course, severity and onset. Our analysis of the discovery cohort nominated 38 variants in 21 genes. Replication analysis identified PSMG4 p.W99R and NLRP5 p.M459I to be associated with disease severity (p=0.002 and 0.008). CACNA1H p.R1871Q was found associated with patients presenting relapsing remitting MS at clinical onset (p=0.028) whereas NLRP5 p.M459I and EIF2AK1 p.K558R were associated with primary progressive disease (p=0.031 and 0.023). In addition, PSMG4 p.W99R and NLRP5 p.R761L were found to correlate with an earlier age at MS clinical onset, and MC1R p.R160W with delayed onset of clinical symptoms (p=0.010-0.041).

PMID: 28501589 [PubMed - as supplied by publisher]

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Free chlorine and monochloramine inactivation kinetics of Aspergillus and Penicillium in drinking water.

Water Res. 2017 Apr 29;120:265-271

Authors: Ma X, Bibby K

Abstract
Fungi are near-ubiquitous in potable water distribution systems, but the disinfection kinetics of commonly identified fungi are poorly studied. In the present study, laboratory scale experiments were conducted to evaluate the inactivation kinetics of Aspergillus fumigatus, Aspergillus versicolor, and Penicillium purpurogenum by free chlorine and monochloramine. The observed inactivation data were then fit to a delayed Chick-Watson model. Based on the model parameter estimation, the Ct values (integrated product of disinfectant concentration C and contact time t over defined time intervals) for 99.9% inactivation of the tested fungal strains ranged from 48.99 mg min/L to 194.7 mg min/L for free chlorine and from 90.33 mg min/L to 531.3 mg min/L for monochloramine. Fungal isolates from a drinking water system (Aspergillus versicolor and Penicillium purpurogenum) were more disinfection resistant than Aspergillus fumigatus type and clinical isolates. The required 99.9% inactivation Ct values for the tested fungal strains are higher than E. coli, a commonly monitored indicator bacteria, and within a similar range for bacteria commonly identified within water distribution systems, such as Mycobacterium spp. and Legionella spp.

PMID: 28501787 [PubMed - as supplied by publisher]

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PROBer Provides a General Toolkit for Analyzing Sequencing-Based Toeprinting Assays.

Cell Syst. 2017 May 09;:

Authors: Li B, Tambe A, Aviran S, Pachter L

Abstract
A number of sequencing-based transcriptase drop-off assays have recently been developed to probe post-transcriptional dynamics of RNA-protein interaction, RNA structure, and RNA modification. Although these assays survey a diverse set of epitranscriptomic marks, we use the term toeprinting assays since they share methodological similarities. Their interpretation is predicated on addressing a similar computational challenge: how to learn isoform-specific chemical modification profiles in the face of complex read multi-mapping. We introduce PROBer, a statistical model and associated software, that addresses this challenge for the analysis of toeprinting assays. PROBer takes sequencing data as input and outputs estimated transcript abundances and isoform-specific modification profiles. Results on both simulated and biological data demonstrate that PROBer significantly outperforms individual methods tailored for specific toeprinting assays. Since the space of toeprinting assays is ever expanding and these assays are likely to be performed and analyzed together, we believe PROBer's unified data analysis solution will be valuable to the RNA community.

PMID: 28501650 [PubMed - as supplied by publisher]

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

Funding Opportunity RFA-DK-17-009 from the NIH Guide for Grants and Contracts. The purpose of this Funding Opportunity Announcement (FOA) is to support an ancillary study grant application(s) to add psychological, behavioral, and/or neurocognitive assessments to the data collection in adults ( 18 years of age) enrolled at the clinical sites in the Molecular Transducers of Physical Activity in Humans Consortium (MoTrPAC) supported by the NIH Common Fund. This ancillary study FOA complements the parent MoTrPAC study by supporting research to elucidate the individual level psychological, behavioral, and neurocognitive characteristics that explain variation in individual response and adherence to a program of physical activity. The ultimate goal of the research supported by this FOA is to characterize individual differences in response to exercise over the course of the MoTrPAC protocol in order to identify novel treatment targets and inform personalized physical activity intervention approaches in the future.

Funding Opportunity RFA-ES-17-004 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) encourages Small Business Innovation Research (SBIR) grant applications from small business concerns (SBCs) that propose to further the development of Advanced Technology Training (ATT) products for the health and safety training of hazardous materials (HAZMAT) workers; skilled support personnel; emergency responders in biosafety response, infectious disease training and cleanup; emergency responders in disasters and resiliency training; and for ATT tools to assist in research into the acute and long-term health effects of environmental disasters. ATT as defined by the Worker Training Program (WTP) includes, but is not limited to, online training, virtual reality, and serious gaming, which complement all aspects of training from development to evaluation including advance technologies that enhance, supplement, improve, and provide health and safety training for hazardous materials workers. These products must complement the goals and objectives of the WTP http://www.niehs.nih.gov/careers/hazmat/about_wetp/. The major objective of the NIEHS WTP is to prevent work related harm by assisting in the training of workers in how best to protect themselves and their communities from exposure to hazardous materials. The financial support for this initiative comes directly from NIEHS Worker Education and Training Branch SBIR funds.

Funding Opportunity RFA-MH-18-400 from the NIH Guide for Grants and Contracts. This funding opportunity announcement (FOA) seeks to leverage data from existing basic, clinical, and intervention research on suicide risk and behaviors as well as social media and healthcare records data, by encouraging the integration of existing data sets for novel secondary analyses aimed at identifying potential biological, experiential, and other predictors and moderators of suicide risk. The use of dimensional variables and inclusion of multiple levels of analyses is particularly encouraged. A secondary goal of this FOA is to support innovative projects that will generate foundational work for research studies on suicide-related behaviors that inform a Research Domain Criteria (RDoC) approach in this area. Projects supported by this FOA will help address gaps identified in the 2014 Prioritized Research Agenda for Suicide Prevention.

Notice NOT-DE-17-009 from the NIH Guide for Grants and Contracts

Notice NOT-DA-17-039 from the NIH Guide for Grants and Contracts

Funding Opportunity PAR-17-287 from the NIH Guide for Grants and Contracts. The objective of the NIA Academic Leadership Career Award (K07) is to provide support for senior investigators who have the expertise and leadership skills to enhance aging and geriatric research capacity within their academic institution.

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

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HLA-A 31:01 is not associated with the development of methotrexate pneumonitis in the UK population: results from a genome-wide association study.

Ann Rheum Dis. 2017 May 12;:

Authors: Bluett J, Owen SA, Massey J, Alfirevic A, Pirmohamed M, Plant D, Verstappen SMM, Barton A, Pneumonitis Study Consortium

PMID: 28500057 [PubMed - as supplied by publisher]

Interventions for preventing silent cerebral infarcts in people with sickle cell disease.

Cochrane Database Syst Rev. 2017 May 13;5:CD012389

Authors: Estcourt LJ, Fortin PM, Hopewell S, Trivella M, Doree C, Abboud MR

Abstract
BACKGROUND: Sickle cell disease (SCD) is one of the commonest severe monogenic disorders in the world, due to the inheritance of two abnormal haemoglobin (beta globin) genes. SCD can cause severe pain, significant end-organ damage, pulmonary complications, and premature death. Silent cerebral infarcts are the commonest neurological complication in children and probably adults with SCD. Silent cerebral infarcts also affect academic performance, increase cognitive deficits and may lower intelligence quotient.
OBJECTIVES: To assess the effectiveness of interventions to reduce or prevent silent cerebral infarcts in people with SCD.
SEARCH METHODS: We searched for relevant trials in the Cochrane Library, MEDLINE (from 1946), Embase (from 1974), the Transfusion Evidence Library (from 1980), and ongoing trial databases; all searches current to 19 September 2016. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register: 06 October 2016.
SELECTION CRITERIA: Randomised controlled trials comparing interventions to prevent silent cerebral infarcts in people with SCD. There were no restrictions by outcomes examined, language or publication status.
DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodological procedures.
MAIN RESULTS: We included five trials (660 children or adolescents) published between 1998 and 2016. Four of the five trials were terminated early. The vast majority of participants had the haemoglobin (Hb)SS form of SCD. One trial focused on preventing silent cerebral infarcts or stroke; three trials were for primary stroke prevention and one trial dealt with secondary stroke prevention.Three trials compared the use of regular long-term red blood cell transfusions to standard care. Two of these trials included children with no previous long-term transfusions: one in children with normal transcranial doppler (TCD) velocities; and one in children with abnormal TCD velocities. The third trial included children and adolescents on long-term transfusion.Two trials compared the drug hydroxyurea and phlebotomy to long-term transfusions and iron chelation therapy: one in primary prevention (children), and one in secondary prevention (children and adolescents).The quality of the evidence was moderate to very low across different outcomes according to GRADE methodology. This was due to trials being at high risk of bias because they were unblinded; indirectness (available evidence was only for children with HbSS); and imprecise outcome estimates. Long-term red blood cell transfusions versus standard care Children with no previous long-term transfusions and higher risk of stroke (abnormal TCD velocities or previous history of silent cerebral infarcts) Long-term red blood cell transfusions may reduce the incidence of silent cerebral infarcts in children with abnormal TCD velocities, risk ratio (RR) 0.11 (95% confidence interval (CI) 0.02 to 0.86) (one trial, 124 participants, low-quality evidence); but make little or no difference to the incidence of silent cerebral infarcts in children with previous silent cerebral infarcts on magnetic resonance imaging and normal or conditional TCDs, RR 0.70 (95% CI 0.23 to 2.13) (one trial, 196 participants, low-quality evidence).No deaths were reported in either trial.Long-term red blood cell transfusions may reduce the incidence of: acute chest syndrome, RR 0.24 (95% CI 0.12 to 0.49) (two trials, 326 participants, low-quality evidence); and painful crisis, RR 0.63 (95% CI 0.42 to 0.95) (two trials, 326 participants, low-quality evidence); and probably reduces the incidence of clinical stroke, RR 0.12 (95% CI 0.03 to 0.49) (two trials, 326 participants, moderate-quality evidence).Long-term red blood cell transfusions may improve quality of life in children with previous silent cerebral infarcts (difference estimate -0.54; 95% confidence interval -0.92 to -0.17; one trial; 166 participants), but may have no effect on cognitive function (least squares means: 1.7, 95% CI -1.1 to 4.4) (one trial, 166 participants, low-quality evidence). Transfusions continued versus transfusions halted: children and adolescents with normalised TCD velocities (79 participants; one trial)Continuing red blood cell transfusions may reduce the incidence of silent cerebral infarcts, RR 0.29 (95% CI 0.09 to 0.97 (low-quality evidence).We are very uncertain whether continuing red blood cell transfusions has any effect on all-cause mortality, Peto odds ratio (OR) 8.00 (95% CI 0.16 to 404.12); or clinical stroke, RR 0.22 (95% CI 0.01 to 4.35) (very low-quality evidence).The trial did not report: comparative numbers for SCD-related adverse events; quality of life; or cognitive function. Hydroxyurea and phlebotomy versus transfusions and chelation Primary prevention, children (121 participants; one trial)We are very uncertain whether switching to hydroxyurea and phlebotomy has any effect on: silent cerebral infarcts (no infarcts); all-cause mortality (no deaths); risk of stroke (no strokes); or SCD-related complications, RR 1.52 (95% CI 0.58 to 4.02) (very low-quality evidence). Secondary prevention, children and adolescents with a history of stroke (133 participants; one trial)We are very uncertain whether switching to hydroxyurea and phlebotomy has any effect on: silent cerebral infarcts, Peto OR 7.28 (95% CI 0.14 to 366.91); all-cause mortality, Peto OR 1.02 (95%CI 0.06 to 16.41); or clinical stroke, RR 14.78 (95% CI 0.86 to 253.66) (very low-quality evidence).Switching to hydroxyurea and phlebotomy may increase the risk of SCD-related complications, RR 3.10 (95% CI 1.42 to 6.75) (low-quality evidence).Neither trial reported on quality of life or cognitive function.
AUTHORS' CONCLUSIONS: We identified no trials for preventing silent cerebral infarcts in adults, or in children who do not have HbSS SCD.Long-term red blood cell transfusions may reduce the incidence of silent cerebral infarcts in children with abnormal TCD velocities, but may have little or no effect on children with normal TCD velocities. In children who are at higher risk of stroke and have not had previous long-term transfusions, long-term red blood cell transfusions probably reduce the risk of stroke, and other SCD-related complications (acute chest syndrome and painful crises).In children and adolescents at high risk of stroke whose TCD velocities have normalised, continuing red blood cell transfusions may reduce the risk of silent cerebral infarcts. No treatment duration threshold has been established for stopping transfusions.Switching to hydroxyurea with phlebotomy may increase the risk of silent cerebral infarcts and SCD-related serious adverse events in secondary stroke prevention.All other evidence in this review is of very low-quality.

PMID: 28500860 [PubMed - as supplied by publisher]

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Ciprofloxacin-loaded lipid-core nanocapsules as mucus penetrating drug delivery system intended for the treatment of bacterial infections in cystic fibrosis.

Int J Pharm. 2017 May 09;:

Authors: Torge A, Wagner S, Chaves PS, Oliveira EG, Guterres SS, Pohlmann AR, Titz A, Schneider M, Beck RCR

Abstract
Treatment of bacterial airway infections is essential for cystic fibrosis therapy. However, effectiveness of antibacterial treatment is limited as bacteria inside the mucus are protected from antibiotics and immune response. To overcome this biological barrier, ciprofloxacin was loaded into lipid-core nanocapsules (LNC) for high mucus permeability, sustained release, and antibacterial activity. Ciprofloxacin-loaded LNC with a mean size of 180nm showed a by 50% increased drug permeation through mucus. In antibacterial growth assays, the drug in the LNC had similar minimum inhibitory concentrations as the free drug in P. aeruginosa and S. aureus. Interestingly, formation of biofilm-like aggregates, which were observed for S. aureus treated with free ciprofloxacin, was avoided by exposure to LNC. With the combined advantages over the non-encapsulated drug, ciprofloxacin-loaded LNC represent a promising drug delivery system with the prospect of an improved antibiotic therapy in cystic fibrosis.

PMID: 28499793 [PubMed - as supplied by publisher]

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Cystic fibrosis carriership and tuberculosis: hints toward an evolutionary selective advantage based on data from the Brazilian territory.

BMC Infect Dis. 2017 May 12;17(1):340

Authors: Bosch L, Bosch B, De Boeck K, Nawrot T, Meyts I, Vanneste D, Le Bourlegat CA, Croda J, da Silva Filho LVRF

Abstract
BACKGROUND: The reason why Cystic Fibrosis (CF) is the most common fatal genetic disease among Caucasians has been incompletely studied. We aimed at deepening the hypothesis that CF carriers have a relative protection against Mycobacterium tuberculosis (Mtb) infection.
METHODS: Applying spatial epidemiology, we studied the link between CF carriership rate and tuberculosis (TB) incidence in Brazil. We corrected for 5 potential environmental and 2 immunological confounders in this relation: monthly income, sanitary provisions, literacy rates, racial composition and population density along with AIDS incidence rates and diabetes mellitus type 2. Smoking data were incomplete and not available for analysis.
RESULTS: A significant, negative correlation between CF carriership rate and TB incidence, independent of any of the seven confounders was found.
CONCLUSION: We provide exploratory support for the hypothesis that carrying a single CFTR mutation arms against Mtb infections.

PMID: 28499359 [PubMed - in process]

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HLAscan: genotyping of the HLA region using next-generation sequencing data.

BMC Bioinformatics. 2017 May 12;18(1):258

Authors: Ka S, Lee S, Hong J, Cho Y, Sung J, Kim HN, Kim HL, Jung J

Abstract
BACKGROUND: Several recent studies showed that next-generation sequencing (NGS)-based human leukocyte antigen (HLA) typing is a feasible and promising technique for variant calling of highly polymorphic regions. To date, however, no method with sufficient read depth has completely solved the allele phasing issue. In this study, we developed a new method (HLAscan) for HLA genotyping using NGS data.
RESULTS: HLAscan performs alignment of reads to HLA sequences from the international ImMunoGeneTics project/human leukocyte antigen (IMGT/HLA) database. The distribution of aligned reads was used to calculate a score function to determine correctly phased alleles by progressively removing false-positive alleles. Comparative HLA typing tests using public datasets from the 1000 Genomes Project and the International HapMap Project demonstrated that HLAscan could perform HLA typing more accurately than previously reported NGS-based methods such as HLAreporter and PHLAT. In addition, the results of HLA-A, -B, and -DRB1 typing by HLAscan using data generated by NextGen were identical to those obtained using a Sanger sequencing-based method. We also applied HLAscan to a family dataset with various coverage depths generated on the Illumina HiSeq X-TEN platform. HLAscan identified allele types of HLA-A, -B, -C, -DQB1, and -DRB1 with 100% accuracy for sequences at ≥ 90× depth, and the overall accuracy was 96.9%.
CONCLUSIONS: HLAscan, an alignment-based program that takes read distribution into account to determine true allele types, outperformed previously developed HLA typing tools. Therefore, HLAscan can be reliably applied for determination of HLA type across the whole-genome, exome, and target sequences.

PMID: 28499414 [PubMed - in process]

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Higher viral load and genetic diversity of HIV-1 in the seminal compartments than in the blood of seven Chinese homosexual men with early HIV-1 infection.

Microbiol Immunol. 2017 May 13;:

Authors: Jiao YM, Chen GL, Zhu WJ, Huang HH, Fu JL, Chen WW, Shi M, Zhang T, Wu H, Wang FS

Abstract
To date, there have been no reports characterizing the Human Immunodeficiency Virus-1 (HIV-1) in the semen of Chinese men having sex with men (MSM) with early infection of HIV-1.We examined genetic diversity and viral load of HIV-1 in the seminal compartments and blood of Chinese MSM with early HIV-1 infection in this study. Viral load and genetic diversity of HIV-1 in paired samples of semen and blood were analyzed in seven homosexual patients who were with early HIV-1 infection. Levels of HIV-1 RNA and DNA were tested by real-time PCR assays. Through sequencing the C2-V5 region of the HIV-1 env gene we determined the HIV-1 genotype and genetic diversity based on V3 loop amino acid sequences by using Geno2pheno and PSSM programs theco-receptor usage was predicated. We found that in seminal plasma the HIV-1 RNA levels were higher compared with those in blood plasma and total, the levels of 2-LTR circular and integrated HIV-1 DNA were higher in seminal cells compared with those in peripheral blood mononuclear cells from all seven early HIV-infected patients. There was higher HIV-1 genetic diversity in seminal compartments as compared to blood compartments. HIV-1 in plasma displayed higher genetic diversity than in cells from the blood and semen, respectively. In addition, the V3 loop central motifs, which present some key neutralizing antibodies epitopes, varied between the blood and the semen. So virological parameters in semen may be more representative to evaluate the transmission risk in early HIV infection.

PMID: 28500746 [PubMed - as supplied by publisher]

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Intranasal drug delivery of small interfering RNA targeting Beclin1 encapsulated with polyethylenimine (PEI) in mouse brain to achieve HIV attenuation.

Sci Rep. 2017 May 12;7(1):1862

Authors: Rodriguez M, Lapierre J, Ojha CR, Kaushik A, Batrakova E, Kashanchi F, Dever SM, Nair M, El-Hage N

Abstract
We previously reported that activation of the host autophagic protein, Beclin1, by HIV-1 infection represents an essential mechanism in controlling HIV replication and viral-induced inflammatory responses in microglial cells. Existing antiretroviral therapeutic approaches have been limited in their ability to cross the blood-brain barrier effectively and recognize and selectively eliminate persistent HIV-infected brain reservoirs. In the present study and for the first time, the bio-distribution and efficacy of noninvasive intranasal delivery of small interfering RNA (siRNA) against the Beclin1 gene using the cationic linear polyethylenimines (PEI) as a gene carrier was investigated in adult mouse brain. Fluorescein isothiocyanate (FITC)-labeled control siRNA delivered intranasally was found in the cytoplasm of neurons and glial cells of the prefrontal cortex at 4 and 24 hours post-delivery, with no major adverse immune reaction encountered. Intranasal delivery of the siRNA targeting Beclin1 significantly depleted the target protein expression levels in brain tissues with no evidence of toxicity. Binding of siRNA to PEI-polymer was characterized and confirmed by Raman spectroscopy. These results indicate that the intranasal drug delivery allows for the direct delivery of the PEI-siRNA nano-complex to the central nervous system, which could potentially offer an efficient means of gene silencing-mediated therapy in the HIV-infected brain.

PMID: 28500326 [PubMed - in process]

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Combined HMG-COA reductase and prenylation inhibition in treatment of CCM.

Proc Natl Acad Sci U S A. 2017 May 12;:

Authors: Nishimura S, Mishra-Gorur K, Park J, Surovtseva YV, Sebti SM, Levchenko A, Louvi A, Gunel M

Abstract
Cerebral cavernous malformations (CCMs) are common vascular anomalies that develop in the central nervous system and, more rarely, the retina. The lesions can cause headache, seizures, focal neurological deficits, and hemorrhagic stroke. Symptomatic lesions are treated according to their presentation; however, targeted pharmacological therapies that improve the outcome of CCM disease are currently lacking. We performed a high-throughput screen to identify Food and Drug Administration-approved drugs or other bioactive compounds that could effectively suppress hyperproliferation of mouse brain primary astrocytes deficient for CCM3. We demonstrate that fluvastatin, an inhibitor of 3-hydroxy-3-methyl-glutaryl (HMG)-CoA reductase and the N-bisphosphonate zoledronic acid monohydrate, an inhibitor of protein prenylation, act synergistically to reverse outcomes of CCM3 loss in cultured mouse primary astrocytes and in Drosophila glial cells in vivo. Further, the two drugs effectively attenuate neural and vascular deficits in chronic and acute mouse models of CCM3 loss in vivo, significantly reducing lesion burden and extending longevity. Sustained inhibition of the mevalonate pathway represents a potential pharmacological treatment option and suggests advantages of combination therapy for CCM disease.

PMID: 28500274 [PubMed - as supplied by publisher]

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ZBTB48 is both a vertebrate telomere-binding protein and a transcriptional activator.

EMBO Rep. 2017 May 12;:

Authors: Jahn A, Rane G, Paszkowski-Rogacz M, Sayols S, Bluhm A, Han CT, Draškovič I, Londoño-Vallejo JA, Kumar AP, Buchholz F, Butter F, Kappei D

Abstract
Telomeres constitute the ends of linear chromosomes and together with the shelterin complex form a structure essential for genome maintenance and stability. In addition to the constitutive binding of the shelterin complex, other direct, yet more transient interactions are mediated by the CST complex and HOT1/HMBOX1, while subtelomeric variant repeats are recognized by NR2C/F transcription factors. Recently, the Kruppel-like zinc finger protein ZBTB48/HKR3/TZAP has been described as a novel telomere-associated factor in the vertebrate lineage. Here, we show that ZBTB48 binds directly both to telomeric and to subtelomeric variant repeat sequences. ZBTB48 is found at telomeres of human cancer cells regardless of the mode of telomere maintenance and it acts as a negative regulator of telomere length. In addition to its telomeric function, we demonstrate through a combination of RNAseq, ChIPseq and expression proteomics experiments that ZBTB48 acts as a transcriptional activator on a small set of target genes, including mitochondrial fission process 1 (MTFP1). This discovery places ZBTB48 at the interface of telomere length regulation, transcriptional control and mitochondrial metabolism.

PMID: 28500257 [PubMed - as supplied by publisher]