Pharmacogenetics and application in pediatrics.

Therapie. 2018 Feb 16;:

Authors: Neyro V, Jacqz-Aigrain E, Adam de Beaumais T

Abstract
Identification of markers involved in drug disposition is crucial for drugs with a narrow therapeutic index. Individual genomic differences can affect the pharmacology of some drugs and participate to inter-individual variability in drug response. Pharmacogenetics is a useful tool in clinical practice for dosage adjustment and to limit drug toxicities. In pediatrics, physiological changes can also influence the disposition of drugs in infants, children and adolescents. The importance of ontogeny translates into different responses to the same drug in children and adults. Thus, interactions between the maturation of metabolism enzymes or transporters and genetics have a major impact on drug exposure leading to age-specific dosage requirements. This review aims to describe implementation of pharmacogenetics in personalized medicine and specifies pediatric characteristics with ethical considerations.

PMID: 29530313 [PubMed - as supplied by publisher]

Changing rates of chronic Pseudomonas aeruginosa infections in cystic fibrosis: a population-based cohort study.

Clin Infect Dis. 2018 Mar 09;:

Authors: Crull MR, Somayaji R, Ramos KJ, Caldwell E, Mayer-Hamblett N, Aitken ML, Nichols DP, Rowhani-Rahbar A, Goss CH

Abstract
Rationale: Chronic Pseudomonas aeruginosa lung infection is common and associated with significant morbidity and mortality in cystic fibrosis (CF). Whether recent advances in care have affected the rates of chronic infection is unknown.
Objectives: Determine if the rates of developing new chronic P. aeruginosa infection among adolescents and adults with CF has significantly changed between 2003 and 2012.
Methods: The cohort consisted of individuals with CF followed in the CF Foundation Patient Registry who were 13 years of age and older without chronic Pseudomonas aeruginosa at baseline. Multivariable regression models accounting for within patient correlation were used to assess the change in rate of developing chronic Pseudomonas aeruginosa infection between 2003 and 2012.
Measurements and Main Results: During the observation period, 15,504 individuals were followed for a median of 5 (IQR 2-9) years. The annual rates of developing new chronic P. aeruginosa decreased from 14.3% in 2003 to 6.4% in 2012. After adjusting for potential confounders, relative risk (RR) of developing chronic P. aeruginosa infection decreased significantly over time compared to 2003 (P value test of trend < 0.001). Compared with 2003, the RR of developing chronic P. aeruginosa infection in 2012 was 0.33 (95% CI: 0.30-0.37). No significant increases in risk of chronic infections with other major CF bacterial pathogens relative to 2003 were identified.
Conclusions: Among individuals with CF, a significant decrease in the risk and rates of developing chronic P. aeruginosa infection between 2003 and 2012 was observed. Whether this decline results in changes in clinical outcomes warrants further exploration.

PMID: 29534149 [PubMed - as supplied by publisher]

Transcriptome analysis of a Pseudomonas aeruginosasn-glycerol-3-phosphate dehydrogenase mutant reveals a disruption in bioenergetics.

Microbiology. 2018 Mar 13;:

Authors: Shuman J, Giles TX, Carroll L, Tabata K, Powers A, Suh SJ, Silo-Suh L

Abstract
Pseudomonas aeruginosa causes acute and chronic human infections and is the major cause of morbidity and mortality in cystic fibrosis (CF) patients. We previously determined that the sn-glycerol-3-phosphate dehydrogenase encoded by glpD plays a larger role in P. aeruginosa physiology beyond its role in glycerol metabolism. To better understand the effect of a glpD mutation on P. aeruginosa physiology we compared the transcriptomes of P. aeruginosa strain PAO1 and the PAO1ΔglpD mutant using RNA-seq analysis. We determined that a null mutation of glpD significantly altered amino acid metabolism in P. aeruginosa and affected the production of intermediates that are channelled into the tricarboxylic acid cycle. Moreover, the loss of glpD induced a general stress response mediated by RpoS in P. aeruginosa. Several other phenotypes observed for the P. aeruginosa glpD mutant include increased persister cell formation, reduced extracellular ATP accumulation and increased heat output. Taken together, these findings implicate sn-glycerol-3-phosphate dehydrogenase as a key player in energy metabolism in P. aeruginosa.

PMID: 29533746 [PubMed - as supplied by publisher]

ΔF508-CFTR Modulator Screen Based on Cell Surface Targeting of a Chimeric Nucleotide Binding Domain 1 Reporter.

SLAS Discov. 2018 Mar 01;:2472555218763310

Authors: Phuan PW, Veit G, Tan JA, Roldan A, Finkbeiner WE, Haggie PM, Lukacs GL, Verkman AS

Abstract
The most common cystic fibrosis-causing mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) is deletion of phenylalanine at residue 508 (∆F508). The ∆F508 mutation impairs folding of nucleotide binding domain 1 (NBD1) and interfacial interactions of NBD1 and the membrane spanning domains. Here, we report a domain-targeted screen to identify ∆F508-CFTR modulators that act on NBD1. A biochemical screen for ΔF508-NBD1 cell surface expression was done in Madin-Darby canine kidney cells expressing a chimeric reporter consisting of ΔF508-NBD1, the CD4 transmembrane domain, and an extracellular horseradish peroxidase (HRP) reporter. Using a luminescence readout of HRP activity, the screen was robust with a Z' factor of 0.7. The screening of ~20,000 synthetic small molecules allowed the identification of compounds from four chemical classes that increased ∆F508-NBD1 cell surface expression by up to 4-fold; for comparison, a 12-fold increased cell surface expression was found for a wild-type NBD1 chimera. While the compounds were inactive as correctors of full-length ΔF508-CFTR, several carboxamide-benzothiophenes had potentiator activity with low micromolar EC50. Interestingly, the potentiators did not activate G551D or wild-type CFTR. Our results provide a proof of concept for a cell-based NBD1 domain screen to identify ∆F508-CFTR modulators that target the NBD1 domain.

PMID: 29533733 [PubMed - as supplied by publisher]

Gap Junctions Are Involved in the Rescue of CFTR-Dependent Chloride Efflux by Amniotic Mesenchymal Stem Cells in Coculture with Cystic Fibrosis CFBE41o- Cells.

Stem Cells Int. 2018;2018:1203717

Authors: Carbone A, Zefferino R, Beccia E, Casavola V, Castellani S, Di Gioia S, Giannone V, Seia M, Angiolillo A, Colombo C, Favia M, Conese M

Abstract
We previously found that human amniotic mesenchymal stem cells (hAMSCs) in coculture with CF immortalised airway epithelial cells (CFBE41o- line, CFBE) on Transwell® filters acquired an epithelial phenotype and led to the expression of a mature and functional CFTR protein. In order to explore the role of gap junction- (GJ-) mediated intercellular communication (GJIC) in this rescue, cocultures (hAMSC : CFBE, 1 : 5 ratio) were studied for the formation of GJIC, before and after silencing connexin 43 (Cx43), a major component of GJs. Functional GJs in cocultures were inhibited when the expression of the Cx43 protein was downregulated. Transfection of cocultures with siRNA against Cx43 resulted in the absence of specific CFTR signal on the apical membrane and reduction in the mature form of CFTR (band C), and in parallel, the CFTR-dependent chloride channel activity was significantly decreased. Cx43 downregulation determined also a decrease in transepithelial resistance and an increase in paracellular permeability as compared with control cocultures, implying that GJIC may regulate CFTR expression and function that in turn modulate airway epithelium tightness. These results indicate that GJIC is involved in the correction of CFTR chloride channel activity upon the acquisition of an epithelial phenotype by hAMSCs in coculture with CF cells.

PMID: 29531530 [PubMed]

Retraction: "Haemophilus influenzae responds to glucocorticoids used in asthma therapy by modulation of biofilm formation and antibiotic resistance".

EMBO Mol Med. 2018 Mar 12;:

Authors:

Abstract
Chris S Earl, Teh Wooi Keong, Shi-qi An, Sarah Murdoch, Yvonne McCarthy, Junkal Garmendia, Joseph Ward, J Maxwell Dow, Liang Yang, George A O'Toole & Robert P RyanThe above article, published May 20 2015 in EMBO Molecular Medicine, has been retracted by agreement between the authors of the study, CSE, TWK, SQA, SM, YMcC, JG, JW, JMD, LY, RPR, the journal Chief Editor and the EMBO Head of Scientific Publications in accordance with the outcomes of independent investigations conducted by the University of Dundee and University College Cork.GAO'T disagrees with the text of this retraction notice, albeit not with the retraction.The following issues are noted: Table 1 contains clinical data described in the paper as being derived from a cohort of asthma patients. However, the provenance of this data is unclear. Based on the evidence available, the University of Dundee investigation concluded that the majority of the patient cohort is likely to be a subset of a cohort of cystic fibrosis patients reported in PLoS One 8(12): e82432 (https://doi.org/10.1371/journal.pone.0082432), although in a number of cases the patient's gender is at odds between the two reports.The RNAseq data are unavailable on the European Nucleotide Archive under the reported accession number ERG003569. RNAseq data were uploaded with accession number ERS654066 before publication.The paper describes use of both prednisolone and prednisone, yet only the latter was used in the study.

PMID: 29531022 [PubMed - as supplied by publisher]

The apical anion exchanger Slc26a6 promotes oxalate secretion by murine submandibular gland acinar cells.

J Biol Chem. 2018 Mar 12;:

Authors: Mukaibo T, Munemasa T, George AT, Tran DT, Gao X, Herche J, Masaki C, Shull GE, Soleimani M, Melvin JE

Abstract
The solute carrier family 26 (SLC26) gene family encodes at least 10 different anion exchangers. SLC26 member 6 (SLC26A6 or CFEX/PAT-1) and cystic fibrosis transmembrane conductance regulator (CFTR) co-localize to the apical membrane of pancreatic duct cells where they act in concert to drive HCO3- and fluid secretion. By contrast, in the small intestine, SLC26A6 serves as the major pathway for oxalate secretion. However, little is known about the function of Slc26a6 in murine salivary glands. Here, RNA-Seq-based transcriptional profiling and Western blots revealed that Slc26a6 is highly expressed in mouse submandibular and sublingual salivary glands. Slc26a6 localized to the apical membrane of salivary gland acinar cells with no detectable immunostaining in the ducts. CHO-K1 cells transfected with mouse Slc26a6 exchanged Cl- for oxalate and HCO3-, while two other anion exchangers known to be expressed in salivary gland acinar cells, Slc4a4 and Slc4a9, mediated little if any Cl-/oxalate exchange. Of note, both Cl-/oxalate exchange and Cl-/HCO3- exchange were significantly reduced in acinar cells isolated from the submandibular glands of Slc26a6-/- mice. Oxalate secretion in submandibular saliva decreased significantly in Slc26a6-/- mice, but HCO3- secretion was unaffected. Taken together, our findings indicate that Slc26a6 is located at the apical membrane of salivary gland acinar cells where it mediates Cl-/oxalate exchange and plays a critical role in the secretion of oxalate into saliva.

PMID: 29530983 [PubMed - as supplied by publisher]

Can resveratrol, a quorum sensing inhibitor, function as an aminoglycoside antibiotic-accelerant against Pseudomonas aeruginosa?

Int J Antimicrob Agents. 2018 Mar 09;:

Authors: Zhou JW, Chen TT, Tan XJ, Sheng JY, Jia AQ

Abstract
Pseudomonas aeruginosa infection is a serious disease in cystic fibrosis (CF) patients and is difficult to cure due to biofilm persistence and emerging multidrug resistance. Considering the essential role of quorum sensing (QS) in P. aeruginosa infections, the enhanced effects between quorum sensing inhibitor (QSI) resveratrol and several antibiotics against P. aeruginosa PAO1 were investigated. Crystal violet staining assay revealed that the biofilms of P. aeruginosa PAO1 grown in the presence of resveratrol were more susceptible to aminoglycoside antibiotics. Scanning electron and fluorescence microscopy showed architectural disruption of the biofilms when treated with resveratrol and aminoglycoside antibiotics. Furthermore, qRT-PCR analysis demonstrated that the expressions of lasI and rhlI, two genes that encode enzymes to synthesize signal molecules in QS systems, were inhibited in the P. aeruginosa PAO1 biofilms by resveratrol. These results indicate that QSI resveratrol can significantly enhance the effects of aminoglycoside antibiotics (i.e., tobramycin, gentamycin, amikacin, and netilmicin) on P. aeruginosa PAO1 biofilms. Our findings suggest that resveratrol is a potential accelerant in the treatment of P. aeruginosa biofilms and can restore or enhance the efficacy of aminoglycoside antibiotics.

PMID: 29530588 [PubMed - as supplied by publisher]

Genetic variants in the LAMA5 gene in pediatric nephrotic syndrome.

Nephrol Dial Transplant. 2018 Mar 09;:

Authors: Braun DA, Warejko JK, Ashraf S, Tan W, Daga A, Schneider R, Hermle T, Jobst-Schwan T, Widmeier E, Majmundar AJ, Nakayama M, Schapiro D, Rao J, Schmidt JM, Hoogstraten CA, Hugo H, Bakkaloglu SA, Kari JA, El Desoky S, Daouk G, Mane S, Lifton RP, Shril S, Hildebrandt F

Abstract
Background: Nephrotic syndrome (NS), a chronic kidney disease, is characterized by significant loss of protein in the urine causing hypoalbuminemia and edema. In general, ∼15% of childhood-onset cases do not respond to steroid therapy and are classified as steroid-resistant NS (SRNS). In ∼30% of cases with SRNS, a causative mutation can be detected in one of 44 monogenic SRNS genes. The gene LAMA5 encodes laminin-α5, an essential component of the glomerular basement membrane. Mice with a hypomorphic mutation in the orthologous gene Lama5 develop proteinuria and hematuria.
Methods: To identify additional monogenic causes of NS, we performed whole exome sequencing in 300 families with pediatric NS. In consanguineous families we applied homozygosity mapping to identify genomic candidate loci for the underlying recessive mutation.
Results: In three families, in whom mutations in known NS genes were excluded, but in whom a recessive, monogenic cause of NS was strongly suspected based on pedigree information, we identified homozygous variants of unknown significance (VUS) in the gene LAMA5. While all affected individuals had nonsyndromic NS with an early onset of disease, their clinical outcome and response to immunosuppressive therapy differed notably.
Conclusion: We here identify recessive VUS in the gene LAMA5 in patients with partially treatment-responsive NS. More data will be needed to determine the impact of these VUS in disease management. However, familial occurrence of disease, data from genetic mapping and a mouse model that recapitulates the NS phenotypes suggest that these genetic variants may be inherited factors that contribute to the development of NS in pediatric patients.

PMID: 29534211 [PubMed - as supplied by publisher]

IKBKG (NEMO) 5' untranslated splice mutations lead to severe, chronic disseminated mycobacterial infections.

Clin Infect Dis. 2018 Mar 09;:

Authors: Hsu AP, Zerbe CS, Foruraghi L, Iovine NM, Mushatt DM, Wild L, Kuhns DB, Holland SM

Abstract
4 patients with adult-onset, disseminated mycobacterial infection had 5' UTR mutations in IKBKG without clear physical stigmata of NEMO deficiency. These mutations caused decreased levels of NEMO protein and Toll-like receptor driven cytokine production. 3 patients died from disseminated disease. These mutations may be missed by whole exome sequencing.

PMID: 29534156 [PubMed - as supplied by publisher]

Hypercalciuria and nephrolithiasis: Expanding the renal phenotype of Donnai-Barrow syndrome.

Clin Genet. 2018 Mar 13;:

Authors: Anglani F, Terrin L, Brugnara M, Battista M, Cantaluppi V, Ceol M, Bertoldi L, Valle G, Joy MP, Pober BR, Longoni M

Abstract
Whole exome sequencing detected novel likely pathogenic variants in LRP2 gene in 2 patients presenting with hearing and vision loss, and the Dent disease (DD) classical renal phenotype, that is, low molecular weight proteinuria (LMWP), hypercalciuria and nephrocalcinosis/nephrolithiasis. We propose that a subset of patients presenting as DD may represent unrecognized cases or mild forms of Donnai-Barrow/facio-oculo-acustico-renal (DB/FOAR) syndrome or be on the phenotypic continuum between the 2 conditions.

PMID: 29532936 [PubMed - as supplied by publisher]

Phenotypic and genotypic characterization of inflammatory bowel disease in children under six years of age in China.

World J Gastroenterol. 2018 Mar 07;24(9):1035-1045

Authors: Fang YH, Luo YY, Yu JD, Lou JG, Chen J

Abstract
AIM: To analyze clinical differences between monogenic and nonmonogenic very-early-onset inflammatory bowel disease (VEO-IBD) and to characterize monogenic IBD phenotypically and genotypically via genetic testing.
METHODS: A retrospective analysis of children aged 0 to 6 years diagnosed with VEO-IBD in a tertiary hospital in southern China from 2005 to 2017 was performed. Clinical data for VEO-IBD patients were collected, and genetic characteristics were analyzed using whole exome sequencing or target gene panel sequencing.
RESULTS: A total of 54 VEO-IBD patients were included in this study. A diagnosis of Crohn's disease (CD) or CD-like intestinal manifestations accounted for 72.2% of the VEO-IBD cases. Nine patients (16.7%) were identified by genetic testing as having monogenic IBD. The median age of diagnosis in the monogenic group was younger than that of the nonmonogenic IBD group, at 18 mo (interquartile range (IQR): 4 to 78) and 43.5 mo (IQR: 3 to 173), respectively; the P-value was 0.021. The incidence of perianal disease in the monogenic group was higher than that in the nonmonogenic group (P = 0.001). However, there were no significant differences between weight-for-age and height-for-age Z-scores between the two groups, and similar laboratory results were obtained for the two groups. Five patients were found to have IL10 receptor mutation, two patients had chronic granulomatous disease, one patient had common variable immunodeficiency disease, and one patient had X-linked inhibitor of apoptosis protein deficiency.
CONCLUSION: A high proportion of monogenic IBD was observed in the VEO-IBD group, especially with disease onset before the age of 6 mo. Monogenic IBD and nonmonogenic IBD exhibited similar clinical features. Furthermore, next-generation sequencing played an important role in the diagnosis of monogenic IBD, and IL10 receptor mutation was predominant in this cohort.

PMID: 29531467 [PubMed - in process]

Genome-wide association analysis identifies new candidate risk loci for familial intracranial aneurysm in the French-Canadian population.

Sci Rep. 2018 Mar 12;8(1):4356

Authors: Zhou S, Gan-Or Z, Ambalavanan A, Lai D, Xie P, Bourassa CV, Strong S, Ross JP, Dionne-Laporte A, Spiegelman D, Dupré N, Foroud TM, Xiong L, Dion PA, Rouleau GA

Abstract
Intracranial Aneurysm (IA) is a common disease with a worldwide prevalence of 1-3%. In the French-Canadian (FC) population, where there is an important founder effect, the incidence of IA is higher and is frequently seen in families. In this study, we genotyped a cohort of 257 mostly familial FC IA patients and 1,992 FC controls using the Illumina NeuroX SNP-chip. The most strongly associated loci were tested in 34 Inuit IA families and in 32 FC IA patients and 106 FC controls that had been exome sequenced (WES). After imputation, one locus at 3p14.2 (FHIT, rs1554600, p = 4.66 × 10-9) reached a genome-wide significant level of association and a subsequent validation in Nunavik Inuit cohort further confirmed the significance of the FHIT variant association (rs780365, FBAT-O, p = 0.002839). Additionally, among the other promising loci (p < 5 × 10-6), the one at 3q13.2 (rs78125721, p = 4.77 × 10-7), which encompasses CCDC80, also showed an increased mutation burden in the WES data (CCDC80, SKAT-O, p = 0.0005). In this study, we identified two new potential IA loci in the FC population: FHIT, which is significantly associated with hypertensive IA, and CCDC80, which has potential genetic and functional relevance to IA pathogenesis, providing evidence on the additional risk loci for familial IA. We also replicated the previous IA GWAS risk locus 18q11.2, and suggested a potential locus at 8p23.1 that warrants further study.

PMID: 29531279 [PubMed - in process]

Related Articles

Discordant congenital Zika syndrome twins show differential in vitro viral susceptibility of neural progenitor cells.

Nat Commun. 2018 02 02;9(1):475

Authors: Caires-Júnior LC, Goulart E, Melo US, Araujo BSH, Alvizi L, Soares-Schanoski A, de Oliveira DF, Kobayashi GS, Griesi-Oliveira K, Musso CM, Amaral MS, daSilva LF, Astray RM, Suárez-Patiño SF, Ventini DC, Gomes da Silva S, Yamamoto GL, Ezquina S, Naslavsky MS, Telles-Silva KA, Weinmann K, van der Linden V, van der Linden H, de Oliveira JMR, Arrais NRM, Melo A, Figueiredo T, Santos S, Meira JCG, Passos SD, de Almeida RP, Bispo AJB, Cavalheiro EA, Kalil J, Cunha-Neto E, Nakaya H, Andreata-Santos R, de Souza Ferreira LC, Verjovski-Almeida S, Ho PL, Passos-Bueno MR, Zatz M

Abstract
Congenital Zika syndrome (CZS) causes early brain development impairment by affecting neural progenitor cells (NPCs). Here, we analyze NPCs from three pairs of dizygotic twins discordant for CZS. We compare by RNA-Seq the NPCs derived from CZS-affected and CZS-unaffected twins. Prior to Zika virus (ZIKV) infection the NPCs from CZS babies show a significantly different gene expression signature of mTOR and Wnt pathway regulators, key to a neurodevelopmental program. Following ZIKV in vitro infection, cells from affected individuals have significantly higher ZIKV replication and reduced cell growth. Whole-exome analysis in 18 affected CZS babies as compared to 5 unaffected twins and 609 controls excludes a monogenic model to explain resistance or increased susceptibility to CZS development. Overall, our results indicate that CZS is not a stochastic event and depends on NPC intrinsic susceptibility, possibly related to oligogenic and/or epigenetic mechanisms.

PMID: 29396410 [PubMed - indexed for MEDLINE]

Related Articles

Whole exome sequencing in neurogenetic odysseys: An effective, cost- and time-saving diagnostic approach.

PLoS One. 2018;13(2):e0191228

Authors: Córdoba M, Rodriguez-Quiroga SA, Vega PA, Salinas V, Perez-Maturo J, Amartino H, Vásquez-Dusefante C, Medina N, González-Morón D, Kauffman MA

Abstract
BACKGROUND: Diagnostic trajectories for neurogenetic disorders frequently require the use of considerable time and resources, exposing patients and families to so-called "diagnostic odysseys". Previous studies have provided strong evidence for increased diagnostic and clinical utility of whole-exome sequencing in medical genetics. However, specific reports assessing its utility in a setting such as ours- a neurogeneticist led academic group serving in a low-income country-are rare.
OBJECTIVES: To assess the diagnostic yield of WES in patients suspected of having a neurogenetic condition and explore the cost-effectiveness of its implementation in a research group located in an Argentinean public hospital.
METHODS: This is a prospective study of the clinical utility of WES in a series of 40 consecutive patients selected from a Neurogenetic Clinic of a tertiary Hospital in Argentina. We evaluated patients retrospectively for previous diagnostic trajectories. Diagnostic yield, clinical impact on management and economic diagnostic burden were evaluated.
RESULTS: We demonstrated the clinical utility of Whole Exome Sequencing in our patient cohort, obtaining a diagnostic yield of 40% (95% CI, 24.8%-55.2%) among a diverse group of neurological disorders. The average age at the time of WES was 23 (range 3-70). The mean time elapsed from symptom onset to WES was 11 years (range 3-42). The mean cost of the diagnostic workup prior to WES was USD 1646 (USD 1439 to 1853), which is 60% higher than WES cost in our center.
CONCLUSIONS: WES for neurogenetics proved to be an effective, cost- and time-saving approach for the molecular diagnosis of this heterogeneous and complex group of patients.

PMID: 29389947 [PubMed - indexed for MEDLINE]

Related Articles

Genetics of Schizophrenia: Ready to Translate?

Curr Psychiatry Rep. 2017 Sep;19(9):61

Authors: Foley C, Corvin A, Nakagome S

Abstract
PURPOSE OF REVIEW: This is an era where we have significantly advanced the understanding of the genetic architecture of schizophrenia. In this review, we consider how this knowledge may translate into advances that will improve patient care.
RECENT FINDINGS: Large-scale genome-wide association studies (GWAS) have identified more than a hundred loci each making a small contribution to illness risk. Meta-analysis of copy number variants (CNVs) in the Psychiatric Genomics Consortium (PGC) dataset has confirmed that some variants have a moderate or large impact on risk, although these are rare in the population. Genome sequencing advances allow a much more comprehensive evaluation of genomic variation. We describe the key findings from whole exome studies to date. These studies are happening against a backdrop of growing understanding of the regulation and expression of genes and better functional tools to investigate molecular mechanisms in model systems. We provide an overview of how recent approaches in schizophrenia genetics are converging and consider how they could impact on diagnostics, the development of personalized medicine, and drug discovery.

PMID: 28741255 [PubMed - indexed for MEDLINE]

Funding Opportunity PAR-18-700 from the NIH Guide for Grants and Contracts. The purpose of the NIDCD Research Dissertation Fellowship for Au.D. Audiologists (F32) program is to support a comprehensive, rigorous biomedical research training, and dissertation research leading to a research doctorate (i.e., Ph.D.) in the biomedical, behavioral, or clinical sciences.

Notice NOT-AR-18-020 from the NIH Guide for Grants and Contracts

Notice NOT-AR-18-019 from the NIH Guide for Grants and Contracts

Notice NOT-ES-18-008 from the NIH Guide for Grants and Contracts