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Pseudomonas aeruginosa Regulated Intramembrane Proteolysis (RIP): Protease MucP can Overcome Mutations in the AlgO Periplasmic Protease to Restore Alginate Production in Nonmucoid Revertants.

J Bacteriol. 2018 May 21;:

Authors: Delgado C, Florez L, Lollett I, Lopez C, Kangeyan S, Kumari H, Stylianou M, Smiddy RJ, Schneper L, Sautter RT, Szatmari G, Mathee K

Abstract
The progression of cystic fibrosis (CF) from an acute to a chronic disease is often associated with the conversion of the opportunistic pathogen Pseudomonas aeruginosa from a nonmucoid form to a mucoid form in the lung. This conversion involves the overproduction of the exopolysaccharide alginate, whose production is under control of the AlgT/U sigma factor. This factor is regulated posttranslationally by an extremely unstable process and has been commonly attributed to mutations in the algT/U gene. By exploiting this unstable phenotype, we isolated 34 spontaneous nonmucoid variants arising from the mucoid strain PDO300, a PAO1 derivative containing the mucA22 allele commonly found in mucoid CF isolates. Complementation analysis using a minimal tiling path cosmid library revealed that most of these mutants mapped to two protease-encoding genes, algO also known as prc or PA3257, and mucP. Interestingly, our algO mutations were complemented by both mucP and algO, leading us to delete, clone and overexpress mucP, algO, mucE and mucD in both wild-type PAO1 and in PDO300 backgrounds to better understand the regulation of this complex regulatory mechanism. Our findings suggest the regulatory proteases follow two pathways for regulated intramembrane proteolysis (RIP), where both the AlgO/MucP pathway and MucE/AlgW pathway are required in the wild type strain, but where the AlgO/MucP pathway can bypass the MucE/AlgW pathway in mucoid strains with membrane-associated forms of MucA with shortened C-termini, such as the MucA22 variant. This work gives us a better understanding of how alginate production is regulated in the clinically important mucoid variants of Pseudomonas aeruginosa.IMPORTANCE: Infection by the opportunistic pathogen Pseudomonas aeruginosa is the leading cause of morbidity and mortality seen in cystic fibrosis (CF) patients. Poor patient prognosis correlates with the genotypic and phenotypic change of the bacteria from a typical nonmucoid to a mucoid form in the CF lung, characterized by the overproduction of alginate. The expression of this exopolysaccharide is under the control an alternate sigma factor, AlgT/U, that is regulated post translationally by a series of proteases. A better understanding of this regulatory phenomenon will help in the development of therapies targeting alginate production, ultimately leading to an increase in the length and quality of life for those suffering from CF.

PMID: 29784885 [PubMed - as supplied by publisher]

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Cystic Fibrosis and Lower-Extremity Edema: A Case of Intraoperative Diagnosis of Acute Deep Venous Thrombosis and Pulmonary Embolism in a Double-Lung Transplant Recipient Using Point-of-Care Ultrasound.

J Cardiothorac Vasc Anesth. 2018 Apr 21;:

Authors: Melnyk V, Phillips D, Schisler T, Subramaniam K

PMID: 29784497 [PubMed - as supplied by publisher]

Umbilical Cord Blood Transplantation Corrects Very Early-Onset Inflammatory Bowel Disease in Chinese Patients With IL10RA-Associated Immune Deficiency.

Inflamm Bowel Dis. 2018 May 18;:

Authors: Peng K, Qian X, Huang Z, Lu J, Wang Y, Zhou Y, Wang H, Wu B, Wang Y, Chen L, Zhai X, Huang Y

Abstract
Background: Hematopoietic stem cell transplantation is considered the only curative therapy for very early-onset inflammatory bowel disease with specific immune defects, such as interleukin-10 receptor deficiency. We performed reduced-intensity conditioning before umbilical cord blood transplantation in patients with interleukin-10 receptor-A deficiency.
Methods: We enrolled 9 very early-onset inflammatory bowel disease patients with typical manifestations. We diagnosed the patients with interleukin-10 receptor-A deficiency by whole-exome sequencing. Umbilical cord blood transplantation was performed in all 9 patients. Eight patients received the reduced-intensity conditioning regimen, and 1 patient received the myeloablative conditioning regimen.
Results: All 9 patients received transplantation between the ages of 6 months to 43 months (average, 16.8 months) with body weights ranging from 3 to 10.4 kg (average, 6.6 kg). The patients displayed complete chimerism at 2-8 weeks after transplantation; 6 patients achieved complete remission without evidence of graft-vs-host disease or infections; 1 patient died of chronic lung graft-vs-host disease at 6 months post-transplantation; and the other 2 patients died of sepsis post-transplantation because of unsuccessful engraftments. Severe malnutrition and growth retardation associated with interleukin-10 receptor-A deficiency were significantly improved post-transplantation.
Conclusions: We recommend umbilical cord blood transplantation as a potential treatment for very early-onset inflammatory bowel disease with a defined monogenic immunodeficiency, and we suggest that reduced-intensity conditioning chemotherapy is more suitable than myeloablative conditioning for patients with severe malnutrition and bowel disease. We have demonstrated success with reduced-intensity conditioning for interleukin-10 receptor-A deficiency in pediatric patients with severe clinical conditions. 10.1093/ibd/izy028_video1izy028.video15786489183001.

PMID: 29788474 [PubMed - as supplied by publisher]

Infantile Onset Intractable Inflammatory Bowel Disease Due to Novel Heterozygous Mutations in TNFAIP3 (A20).

Inflamm Bowel Dis. 2018 May 17;:

Authors: Zheng C, Huang Y, Ye Z, Wang Y, Tang Z, Lu J, Wu J, Zhou Y, Wang L, Huang Z, Yang H, Xue A

Abstract
Background : Mutations in tumor necrosis factor alpha-induced protein 3 (TNFAIP3), a key player in the negative feedback regulation of nuclear factor-κB signaling, have recently been recognized as leading to early onset autoinflammatory and autoimmune syndrome. Here, we have reported the phenotypes of 3 infantile onset intractable inflammatory bowel disease (IBD) patients with TNFAIP3 mutations and reviewed previously reported cases to establish phenotypic features associated with TNFAIP3 monogenicity.
Methods: From January 1, 2015, to December 31, 2017, we recruited 58 infantile-onset IBD patients. Targeted sequencing and whole-exome sequencing were performed. Sanger sequencing confirmed the variants and determined the parental origin. We followed all the patients with TNFAIP3 mutations in our cohort and analyzed their clinical data.
Results: Genetic screening in all 58 patients with infantile-onset IBD revealed 44 (75.9%) cases of monogenic disorders, and 3 de novo TNFAIP3 mutations were identified, including 1 nonsense and 2 frame shift mutations. All the mutations resulted in premature stop codon. All 3 patients had multiple systemic involvements, with predominant gastrointestinal diseases.
Conclusions: Most infantile-onset IBD was associated with monogenetic mutation, and in addition to the 50 reported genes, other rare genetic variants need to be determined. TNFAIP3 may be an important candidate gene. The treatment of TNFAIP3-associated infantile-onset-IBD was challenging.

PMID: 29788367 [PubMed - as supplied by publisher]

Nonsynonymous Polymorphism in Guanine Monophosphate Synthetase Is a Risk Factor for Unfavorable Thiopurine Metabolite Ratios in Patients With Inflammatory Bowel Disease.

Inflamm Bowel Dis. 2018 May 16;:

Authors: Roberts RL, Wallace MC, Seinen ML, van Bodegraven AA, Krishnaprasad K, Jones GT, van Rij AM, Baird A, Lawrance IC, Prosser R, Bampton P, Grafton R, Simms LA, Studd C, Bell SJ, Kennedy MA, Halliwell J, Gearry RB, Radford-Smith G, Andrews JM, McHugh PC, Barclay ML

Abstract
Background : Up to 20% of patients with inflammatory bowel disease (IBD) who are refractory to thiopurine therapy preferentially produce 6-methylmercaptopurine (6-MMP) at the expense of 6-thioguanine nucleotides (6-TGN), resulting in a high 6-MMP:6-TGN ratio (>20). The objective of this study was to evaluate whether genetic variability in guanine monophosphate synthetase (GMPS) contributes to preferential 6-MMP metabolizer phenotype.
Methods: Exome sequencing was performed in a cohort of IBD patients with 6-MMP:6-TGN ratios of >100 to identify nonsynonymous single nucleotide polymorphisms (nsSNPs). In vitro assays were performed to measure GMPS activity associated with these nsSNPs. Frequency of the nsSNPs was measured in a cohort of 530 Caucasian IBD patients.
Results: Two nsSNPs in GMPS (rs747629729, rs61750370) were detected in 11 patients with very high 6-MMP:6-TGN ratios. The 2 nsSNPs were predicted to be damaging by in silico analysis. In vitro assays demonstrated that both nsSNPs resulted in a significant reduction in GMPS activity (P < 0.05). The SNP rs61750370 was significantly associated with 6-MMP:6-TGN ratios ≥100 (odds ratio, 5.64; 95% confidence interval, 1.01-25.12; P < 0.031) in a subset of 264 Caucasian IBD patients.
Conclusions: The GMPS SNP rs61750370 may be a reliable risk factor for extreme 6MMP preferential metabolism.

PMID: 29788244 [PubMed - as supplied by publisher]

Diagnostic Yield of Next-Generation Sequencing in Very Early-Onset Inflammatory Bowel Diseases: A Multicenter Study.

J Crohns Colitis. 2018 May 18;:

Authors: Charbit-Henrion F, Parlato M, Hanein S, Duclaux-Loras R, Nowak J, Begue B, Rakotobe S, Bruneau J, Fourrage C, Alibeu O, Rieux-Laucat F, Lévy E, Stolzenberg MC, Mazerolles F, Latour S, Lenoir C, Fischer A, Picard C, Aloi M, Amil Dias J, Ben Hariz M, Bourrier A, Breuer C, Breton A, Bronski J, Buderus S, Cananzi M, Coopman S, Crémilleux C, Dabadie A, Dumant-Forest C, Egritas Gurkan O, Fabre A, Fischer A, German Diaz M, Gonzalez-Lama Y, Goulet O, Guariso G, Gurcan N, Homan M, Hugot JP, Jeziorski E, Karanika E, Lachaux A, Lewindon P, Lima R, Magro F, Major J, Malamut G, Mas E, Mattyus I, Mearin LM, Melek J, Navas-Lopez VM, Paerregaard A, Pelatan C, Pigneur B, Pinto Pais I, Rebeuh J, Romano C, Siala N, Strisciuglio C, Tempia-Caliera M, Tounian P, Turner D, Urbonas V, Willot S, Ruemmele FM, Cerf-Bensussan N

Abstract
Background and Aims: An expanding number of monogenic defects have been identified as causative of severe forms of very early-onset inflammatory bowel diseases (VEO-IBD). The present study aimed at defining how next-generation sequencing (NGS) methods can be used to improve identification of known molecular diagnosis and adapt treatment.
Methods: 207 children were recruited in 45 Paediatric centres through an international collaborative network (ESPGHAN GENIUS working group) with a clinical presentation of severe VEO-IBD (n=185) or an anamnesis suggestive of a monogenic disorder (n=22). Patients were divided at inclusion into three phenotypic subsets: predominantly small bowel inflammation, colitis with perianal lesions, and colitis only. Methods to obtain molecular diagnosis included functional tests followed by specific Sanger sequencing, custom-made targeted NGS, and in selected cases whole exome sequencing (WES) of parents-child trios. Genetic findings were validated clinically and/or functionally.
Results: Molecular diagnosis was achieved in 66/207 children (32%): 61% with small bowel inflammation, 39% with colitis and perianal lesions and 18% with colitis only. Targeted NGS pinpointed gene mutations causative of atypical presentations and identified large exonic copy number variations previously missed by WES.
Conclusions: Our results lead us to propose an optimised diagnostic strategy to identify known monogenic causes of severe IBD.

PMID: 29788237 [PubMed - as supplied by publisher]

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CoDE-seq, an augmented whole-exome sequencing, enables the accurate detection of CNVs and mutations in Mendelian obesity and intellectual disability.

Mol Metab. 2018 May 16;:

Authors: Montagne L, Derhourhi M, Piton A, Toussaint B, Durand E, Vaillant E, Thuillier D, Gaget S, De Graeve F, Rabearivelo I, Lansiaux A, Lenne B, Sukno S, Desailloud R, Cnop M, Nicolescu R, Cohen L, Zagury JF, Amouyal M, Weill J, Muller J, Sand O, Delobel B, Froguel P, Bonnefond A

Abstract
OBJECTIVE: The molecular diagnosis of extreme forms of obesity, in which accurate detection of both copy number variations (CNVs) and point mutations, is crucial for an optimal care of the patients and genetic counseling for their families. Whole-exome sequencing (WES) has benefited considerably this molecular diagnosis, but its poor ability to detect CNVs remains a major limitation. We aimed to develop a method (CoDE-seq) enabling the accurate detection of both CNVs and point mutations in one step.
METHODS: CoDE-seq is based on an augmented WES method, using probes distributed uniformly throughout the genome. CoDE-seq was validated in 40 patients for whom chromosomal DNA microarray was available. CNVs and mutations were assessed in 82 children/young adults with suspected Mendelian obesity and/or intellectual disability and in their parents when available (ntotal = 145).
RESULTS: CoDE-seq not only detected all of the 97 CNVs identified by chromosomal DNA microarrays but also found 84 additional CNVs, due to a better resolution. When compared to CoDE-seq and chromosomal DNA microarrays, WES failed to detect 37% and 14% of CNVs, respectively. In the 82 patients, a likely molecular diagnosis was achieved in >30% of the patients. Half of the genetic diagnoses were explained by CNVs while the other half by mutations.
CONCLUSIONS: CoDE-seq has proven cost-efficient and highly effective as it avoids the sequential genetic screening approaches currently used in clinical practice for the accurate detection of CNVs and point mutations.

PMID: 29784605 [PubMed - as supplied by publisher]

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A homozygous loss-of-function CAMK2A mutation causes growth delay, frequent seizures and severe intellectual disability.

Elife. 2018 May 22;7:

Authors: Chia PH, Zhong FL, Niwa S, Bonnard C, Utami KH, Zeng R, Lee H, Eskin A, Nelson SF, Xie WH, Al-Tawalbeh S, El-Khateeb M, Shboul M, Pouladi MA, Al-Raqad M, Reversade B

Abstract
Calcium/calmodulin-dependent protein kinase II (CAMK2) plays fundamental roles in synaptic plasticity that underlies learning and memory. Here, we describe a new recessive neurodevelopmental syndrome with global developmental delay, seizures and intellectual disability. Using linkage analysis and exome sequencing, we found that this disease maps to chromosome 5q31.1-q34 and is caused by a biallelic germline mutation in CAMK2A. The missense mutation, p.His477Tyr is located in the CAMK2A association domain that is critical for its function and localization. Biochemically, the p.His477Tyr mutant is defective in self-oligomerization and unable to assemble into the multimeric holoenzyme.In vivo, CAMK2AH477Y failed to rescue neuronal defects in C. elegans lacking unc-43, the ortholog of human CAMK2A. In vitro, neurons derived from patient iPSCs displayed profound synaptic defects. Together, our data demonstrate that a recessive germline mutation in CAMK2A leads to neurodevelopmental defects in humans and suggest that dysfunctional CAMK2 paralogs may contribute to other neurological disorders.

PMID: 29784083 [PubMed - in process]

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Severe hepatopathy and neurological deterioration after start of valproate treatment in a 6-year-old child with mitochondrial tryptophanyl-tRNA synthetase deficiency.

Orphanet J Rare Dis. 2018 May 21;13(1):80

Authors: Vantroys E, Smet J, Vanlander AV, Vergult S, De Bruyne R, Roels F, Stepman H, Roeyers H, Menten B, Van Coster R

Abstract
BACKGROUND: The first subjects with deficiency of mitochondrial tryptophanyl-tRNA synthetase (WARS2) were reported in 2017. Their clinical characteristics can be subdivided into three phenotypes (neonatal phenotype, severe infantile onset phenotype, Parkinson-like phenotype).
RESULTS: Here, we report on a subject who presented with early developmental delay, motor weakness and intellectual disability and who was considered during several years as having a non-progressive encephalopathy. At the age of six years, she had an epileptic seizure which was treated with sodium valproate. In the months after treatment was started, she developed acute liver failure and severe progressive encephalopathy. Although valproate was discontinued, she died six months later. Spectrophotometric analysis of the oxidative phosphorylation complexes in liver revealed a deficient activity of complex III and low normal activities of the complexes I and IV. Activity staining in the BN-PAGE gel confirmed the low activities of complex I, III and IV and, in addition, showed the presence of a subcomplex of complex V. Histochemically, a mosaic pattern was seen in hepatocytes after cytochrome c oxidase staining. Using Whole Exome Sequencing two known pathogenic variants were detected in WARS2 (c.797delC, p.Pro266ArgfsTer10/ c.938 A > T, p.Lys313Met).
CONCLUSION: This is the first report of severe hepatopathy in a subject with WARS2 deficiency. The hepatopathy occurred soon after start of sodium valproate treatment. In the literature, valproate-induced hepatotoxicity was reported in the subjects with pathogenic mutations in POLG and TWNK. This case report illustrates that the course of the disease in the subjects with a mitochondrial defect can be non-progressive during several years. The subject reported here was first diagnosed as having cerebral palsy. Only after a mitochondriotoxic medication was started, the disease became progressive, and the diagnosis of a mitochondrial defect was made.

PMID: 29783990 [PubMed - in process]

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Effects of antipsychotic drugs on neurites relevant to schizophrenia treatment.

Med Res Rev. 2018 May 22;:

Authors: Huang XF, Song X

Abstract
Although antipsychotic drugs are mainly used for treating schizophrenia, they are widely used for treating various psychiatric diseases in adults, the elderly, adolescents and even children. Today, about 1.2% of the worldwide population suffers from psychosis and related disorders, which translates to about 7.5 million subjects potentially targeted by antipsychotic drugs. Neurites project from the cell body of neurons and connect neurons to each other to form neural networks. Deficits in neurite outgrowth and integrity are implicated in psychiatric diseases including schizophrenia. Neurite deficits contribute to altered brain development, neural networking and connectivity as well as symptoms including psychosis and altered cognitive function. This review revealed that (1) antipsychotic drugs could have profound effects on neurites, synaptic spines and synapse, by which they may influence and regulate neural networking and plasticity; (2) antipsychotic drugs target not only neurotransmitter receptors but also intracellular signaling molecules regulating the signaling pathways responsible for neurite outgrowth and maintenance; (3) high doses and chronic administration of antipsychotic drugs may cause some loss of neurites, synaptic spines, or synapsis in the cortical structures. In addition, confounding effects causing neurite deficits may include elevated inflammatory cytokines and antipsychotic drug-induced metabolic side effects in patients on chronic antipsychotic therapy. Unraveling how antipsychotic drugs affect neurites and neural connectivity is essential for improving therapeutic outcomes and preventing aversive effects for patients on antipsychotic drug treatment.

PMID: 29785841 [PubMed - as supplied by publisher]

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[Relationship between hepatic drug-metabolizing enzymes CYP450 and traditional Chinese medicine-induced hepatotoxicity].

Zhongguo Zhong Yao Za Zhi. 2016 Aug;41(15):2774-2780

Authors: Hou J, Sun E, Song J, Yang L, Zhang ZH, Ning Q, Jia XB

Abstract
In recent years, with the emergence of new methods and technologies in traditional Chinese medicines metabolism, the relationship between medicine metabolism and cytochrome P450 has gradually been revealed. The research on P450 drug metabolizing enzymes can be used to predict the side effects of traditional Chinese medicines and explore the relationship between compatibility of medicines and toxicity reducing and efficacy enhancing. This paper aims to summarize the progress of CYP450 research, the mechanism of hepatic drug-metabolizing enzymes in the process of drug-metabolism and the relationship between CYP450 and medicine hepatotoxicity. Furthermore, we set out the regulation effects of typical traditional Chinese medicines on CYP450 to provide a reliable basis for the rational use of Chinese medicines.

PMID: 28914015 [PubMed - indexed for MEDLINE]

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Deaths from acute drug reactions in Galician (Spain) Prisons (2001-2010).

Rev Esp Sanid Penit. 2017 Dec;19(2):49-56

Authors: Miguel-Arias D, Pereiro-Gómez C, Bermejo-Barrera AM, Vázquez-Ventoso C, Rodríguez-Barca T

Abstract
INTRODUCTION AND OBJECTIVES: drug use is associated with multiple complications with an increase in morbidity, with death by acute drugs reactions (ADR) being the most serious. A large percentage of the prison population has problems associated with drug additions, and substance abuse is also a common internal problem of penal institutions, despite their control measures. The goal of this study is to analyse the prevalence of ADR in penitentiaries, deceased sociodemographic characteristics as well as the circumstances in which they are produced.
MATERIAL AND METHODS: All deaths by ADR between 2001-2010 in Galicia are studied, in particular, those deaths that took place inside prisons.
RESULTS: In the whole sample (n=510) male (90.6%), single (46.1%) with an average age of 35.8 and with a prevalent factor of long experience in drug abuse. Thirty seven of them died in Penal/Correctional Institutions, representing 7.3% of the total sample. The characteristics of this population subtype were similar to the total sample (average age: 34.7 years; 89.2% were males) but we found significant differences regarding the substances detected.
DISCUSSION: ADR is the most frequent cause of death among drug addict convicts in prisons. The pattern of the detected substances in the toxicological analysis as well as the socio-demographic characteristics can help to establish a higher risk profile and preventive measures.

PMID: 28748984 [PubMed - indexed for MEDLINE]

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[Direct mechanism of action in toxic myopathies].

Ann Pharm Fr. 2017 Sep;75(5):323-343

Authors: Khelfi A, Azzouz M, Abtroun R, Reggabi M, Alamir B

Abstract
Toxic myopathies are a large group of disorders generated by surrounding agents and characterized by structural and/or functional disturbances of muscles. The most recurrent are those induced by commonly used medications. Illicit drugs, environmental toxins from animals, vegetables, or produced by micro-organisms as well as chemical products commonly used are significant causes of such disorders. The muscle toxicity results from multiple mechanisms at different biological levels. Many agents can induce myotoxicity through a direct mechanism in which statins, glucocorticoids and ethyl alcohol are the most representative. Diverse mechanisms were highlighted as interaction with macromolecules and induction of metabolic and cellular dysfunctions. Muscle damage can be related to amphiphilic properties of some drugs (chloroquine, hydroxychloroquine, etc.) leading to specific lysosomal disruptions and autophagic dysfunctions. Some agents affect the whole muscle fiber by inducing oxidative stress (ethyl alcohol and some statins) or triggering cell death pathways (apoptosis or necrosis) resulting in extensive alterations. More studies on these mechanisms are needed. They would allow a better knowledge of the intracellular mediators involved in these pathologies in order to develop targeted therapies of high efficiency.

PMID: 28526123 [PubMed - indexed for MEDLINE]

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An Evaluation of Indian Consumers' Reporting of Suspected Adverse Drug Reactions with a Designated Reporting Form.

Curr Drug Saf. 2017;12(1):51-56

Authors: Rehan HS, Sah R, Gupta A, Nagar P

Abstract
BACKGROUND: The Pharmacovigilance Program of India recently initiated a process for direct patient reporting of Adverse Drug Reactions (ADRs) with a designated form.
PATIENTS AND METHODS: A survey of 200 patients reporting ADRs filling the form. Forms were analysed for patient data, the suspected medication(s), ADRs and possible causality.
RESULTS: 54.3% of respondents provided their contact information; the implicated medicine was mentioned in 60% and the description of ADRs in 80% although 46.2% were not interpretable. The severity of ADRs was mentioned in 73.5%. No responder filled the expiry date component of the implicated modification and a causality assessment from most forms was unclassifiable (57%) or unclassified (26%). Details of concomitant drugs were missing.
CONCLUSION: Missing information was a deterrent in analysing the consumer ADR reports for signal detection. It is recommended that the following fields are highlighted in the form: consumer's initials, address, date suspected reaction started, description of event, name, dose, and the reason for the use the medication as well as its expiry date. These should be mandatory in the existing form and new fields added for weight and height, batch number for vaccines and biological products, de challenge and rechallenge results to the suspected medicine and concomitantly used medicines. To improve the quality of information in the consumer reporting form an awareness campaign is also suggested.

PMID: 27188794 [PubMed - indexed for MEDLINE]

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Funding Opportunity RFA-RM-18-008 from the NIH Guide for Grants and Contracts. The NIH Directors New Innovator Award supports early stage investigators of exceptional creativity who propose highly innovative new research approaches with the potential to produce a major impact on broad, important problems in biomedical or behavioral research. Applications from individuals with diverse backgrounds and in any topic relevant to the broad mission of NIH are welcome. The NIH Director's New Innovator Award complements ongoing efforts by NIH and its Institutes and Centers to fund early stage investigators through R01 grants, which continue to be the major sources of NIH support for early stage investigators. The NIH Directors New Innovator Award is a component of the High-Risk, High-Reward Research program of the NIH Common Fund.

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