Microcephaly Proteins Wdr62 and Aspm Define a Mother Centriole Complex Regulating Centriole Biogenesis, Apical Complex, and Cell Fate.

Neuron. 2016 Nov 23;92(4):813-828

Authors: Jayaraman D, Kodani A, Gonzalez DM, Mancias JD, Mochida GH, Vagnoni C, Johnson J, Krogan N, Harper JW, Reiter JF, Yu TW, Bae BI, Walsh CA

Abstract
Mutations in several genes encoding centrosomal proteins dramatically decrease the size of the human brain. We show that Aspm (abnormal spindle-like, microcephaly-associated) and Wdr62 (WD repeat-containing protein 62) interact genetically to control brain size, with mice lacking Wdr62, Aspm, or both showing gene dose-related centriole duplication defects that parallel the severity of the microcephaly and increased ectopic basal progenitors, suggesting premature delamination from the ventricular zone. Wdr62 and Aspm localize to the proximal end of the mother centriole and interact physically, with Wdr62 required for Aspm localization, and both proteins, as well as microcephaly protein Cep63, required to localize CENPJ/CPAP/Sas-4, a final common target. Unexpectedly, Aspm and Wdr62 are required for normal apical complex localization and apical epithelial structure, providing a plausible unifying mechanism for the premature delamination and precocious differentiation of progenitors. Together, our results reveal links among centrioles, apical proteins, and cell fate, and illuminate how alterations in these interactions can dynamically regulate brain size.

PMID: 27974163 [PubMed - in process]

Clinical presentation, pathological features, and natural course of metastatic uveal melanoma (MUM) as an orphan and commonly fatal disease.

J Clin Oncol. 2009 May 20;27(15_suppl):e20005

Authors: Cerbone L, Van Ginderdeuren R, Van den Oord J, Fieuws S, Spileers W, Van Eenoo L, Wozniak A, Sternberg CN, Schöffski P

Abstract
e20005 Background: Uveal melanoma (UM) is a rare disease characterized by an unpredictable course and variable outcome ranging from cure by local treatment to the occurrence of untreatable metastasis. The current project analyzed patients with the metastatic phenotype.
METHODS: We performed data collection in 76 pts with MUM treated in Leuven between 1957-2008. Statistical analysis involved nonparametric tests, Kaplan Meyer and log rank test.
RESULTS: The med. age at diagnosis of UM was 58 yrs (range 30-94). Common initial treatments were surgery (71%), brachytherapy (20%) and external beam RT (7%). MUM was more common in women (F:M ratio 48:28) and independent from the side of the primary tumor (left vs. right eye). Synchronous metastasis was found in 9% of cases, all others had metachronous disease after a med. interval of 40 mos (range, 7-420). Statistical analysis failed to identify predisposing factors for MUM with the exception of a significant negative correlation between age at diagnosis of UM and time until metastatic disease (Spearman ρ = -0.4, p<0.001). Metastasis in >1 organ, usually liver plus another site, was seen in 47% of cases. The most frequent sites were liver (96%), lung (23%), subcutaneous (13%), bone (11%) and brain (3%).The med. OS from diagnosis of UM was 46 mos (range, 2-182), and 4,5 mos after diagnosis of metastasis (range, 1-128). 65% of MUM pts qualified for further treatment, including systemic therapy (60%), radiotherapy (7%) and surgery (7%). Systemic therapy (45 pts) included mainly chemo- (50%), chemo- plus hormones (12%), immuno- (3%) or hormonal therapy (3%). The most common drugs given were DTIC (43%), cisplatin (27%), tamoxifen (10%) or phase I agents (8%). Patient benefit (PR+SD) was seen in 16/45 pts (36%), including 2 PR.
CONCLUSIONS: In this orphan disease with female predominance metastasis occurs late, is mainly found but not confined to the liver, and is associated with high morbidity, as >1/3 of pts do not qualify for further therapy. Advances in MUM can only be achieved by networking of sites interested in this tumor with systematic collection of data and tissue to improve our understanding of the molecular biology of the disease. No significant financial relationships to disclose.

PMID: 27962598 [PubMed - in process]

Clinical presentation, treatment and outcome of anaplastic thyroid carcinoma: results of a multicenter study in Germany.

Eur J Endocrinol. 2016 Dec;175(6):521-529

Authors: Wendler J, Kroiss M, Gast K, Kreissl MC, Allelein S, Lichtenauer U, Blaser R, Spitzweg C, Fassnacht M, Schott M, Führer D, Tiedje V

Abstract
CONTEXT: Anaplastic thyroid carcinoma (ATC) is an orphan disease and confers a dismal prognosis. Standard treatment is not established.
OBJECTIVE: The aim of this study is to describe clinical characteristics, current treatment regimens and outcome of ATC and to identify clinical prognostic markers and treatment factors associated with improved prognosis.
DESIGN: Retrospective cohort study at five German tertiary care centers.
PATIENTS AND METHODS: Totally 100 ATC patients diagnosed between 2000 and 2015 were included in the analysis. Disease-specific overall survival (OS) was compared with the Kaplan-Meier method and log-rank test; Cox proportional hazard model was used to identify risk factors.
RESULTS: The 6-month, 1-year and 5-year disease-specific OS rates were 37, 28 and 5%, respectively. Stage-dependent OS at 6 months was 78, 54 and 18% for stage IVA, B and C, respectively. 29% patients survived >1 year. Multivariate analysis of OS identified age ≥70 years, incomplete local resection status and the presence of distant metastasis as significant risk factors associated with shorter survival. Radical surgery (hazard ratio [HR] 2.20, 95% confidence interval (CI) 1.19-4.09, P = 0.012), external beam radiation therapy (EBRT) ≥40 Gy (HR = 0.34, 0.15-0.76, P = 0.008) and any kind of chemotherapy (CTX) (HR = 11.64, 2.42-60.39, P = 0.003) were associated with longer survival in multivariate analyses adjusted for age and tumor stage. A multimodal treatment regimen was significantly associated with a survival benefit (HR = 1.04, 1.01-1.08, P < 0.0001) only in IVC patients.
CONCLUSION: Disease-specific OS is still poor in ATC. Treatment factors associated with improved OS provide a rationale to devise treatment pathways for routine care. Collaborative research structures should be aimed to advance treatment of ATC.

PMID: 27926471 [PubMed - in process]

The Coupling of Peripheral Blood Pressure and Ventilatory Responses during Exercise in Young Adults with Cystic Fibrosis.

PLoS One. 2016;11(12):e0168490

Authors: Van Iterson EH, Wheatley CM, Baker SE, Olson TP, Morgan WJ, Snyder EM

Abstract
PURPOSE: Cystic fibrosis (CF) is commonly recognized as a pulmonary disease associated with reduced airway function. Another primary symptom of CF is low exercise capacity where ventilation and gas-exchange are exacerbated. However, an independent link between pathophysiology of the pulmonary system and abnormal ventilatory and gas-exchange responses during cardiopulmonary exercise testing (CPET) has not been established in CF. Complicating this understanding, accumulating evidence suggests CF demonstrate abnormal peripheral vascular function; although, the clinical implications are unclear. We hypothesized that compared to controls, relative to total work performed (WorkTOT), CF would demonstrate increased ventilation accompanied by augmented systolic blood pressure (SBP) during CPET.
METHODS: 16 CF and 23 controls (age: 23±4 vs. 27±4 years, P = 0.11; FEV1%predicted: 73±14 vs. 96±5, P<0.01) participated in CPET. Breath-by-breath oxygen uptake ([Formula: see text]), ventilation ([Formula: see text]), and carbon dioxide output ([Formula: see text]) were measured continuously during incremental 3-min stage step-wise cycle ergometry CPET. SBP was measured via manual sphygmomanometry. Linear regression was used to calculate [Formula: see text] slope from rest to peak-exercise.
RESULTS: Compared to controls, CF performed less WorkTOT during CPET (90±19 vs. 43±14 kJ, respectively, P<0.01). With WorkTOT as a covariate, peak [Formula: see text] (62±8 vs. 90±4 L/min, P = 0.76), [Formula: see text] (1.8±0.3 vs. 2.7±0.1 L/min, P = 0.40), and SBP (144±13 vs. 152±6 mmHg, P = 0.88) were similar between CF and controls, respectively; whereas CF demonstrated increased [Formula: see text] slope (38±4 vs. 28±2, P = 0.02) but lower peak [Formula: see text] versus controls (22±5 vs. 33±4 mL/kg/min, P<0.01). There were modest-to-moderate correlations between peak SBP with [Formula: see text] (r = 0.30), [Formula: see text] (r = 0.70), and [Formula: see text] (r = 0.62) in CF.
CONCLUSIONS: These data suggest that relative to WorkTOT, young adults with mild-to-moderate severity CF demonstrate augmented [Formula: see text] slope accompanied by increased SBP during CPET. Although the underlying mechanisms remain unclear, the coupling of ventilatory inefficiency with increased blood pressure suggest important contributions from peripheral pathophysiology to low exercise capacity in CF.

PMID: 27997623 [PubMed - in process]

Intracellular Chloride Concentration Changes Modulate IL-1β Expression and Secretion in Human Bronchial Epithelial Cultured Cells.

J Cell Biochem. 2016 Dec 20;:

Authors: Clauzure M, Valdivieso ÁG, Massip-Copiz MM, Mori C, Dugour AV, Figueroa JM, Coloma TA

Abstract
Cystic fibrosis (CF) is caused by mutations in the CFTR gene, which encodes a cAMP-regulated chloride channel. Several cellular functions are altered in CF cells. However, it is not clear how the CFTR failure induces those alterations. We have found previously several genes differentially expressed in CF cells, including c-Src, MUC1, MTND4 and CISD1 (CFTR-dependent genes). Recently, we also reported the existence of several chloride-dependent genes, among them GLRX5 and RPS27. Here, varying the intracellular chloride concentration [Cl(-) ]i of IB3-1 CF bronchial epithelial cells, we show that IL-1β mRNA expression and secretion are also under Cl(-) modulation. The response to Cl(-) is biphasic, with maximal effects at 75 mM Cl(-) . The regulation of the IL-1β mRNA expression involves an IL-1β autocrine effect, since in the presence of the IL-1β receptor antagonist IL1RN or anti-IL-1β blocking antibody, the mRNA response to Cl(-) disappeared. Similar effects were obtained with the JNK inhibitor SP600125, the c-Src inhibitor PP2 and the IKK inhibitor III (BMS-345541). On the other hand, the IL-1β secretion is still modulated by Cl(-) in the presence of IL-1RN, IL-1β blocking antibody or cycloheximide, suggesting that Cl(-) is affecting the IL-1β maturation/secretion, which in turn starts an autocrine positive feedback loop. In conclusion, the Cl(-) anion acts as a second messenger for CFTR, modulating the IL-1β maturation/secretion. The results also imply that, depending on its intracellular concentration, Cl(-) could be a pro-inflammatory mediator. This article is protected by copyright. All rights reserved.

PMID: 27996167 [PubMed - as supplied by publisher]

Gene therapy for haemophilia.

Cochrane Database Syst Rev. 2016 Dec 20;12:CD010822

Authors: Sharma A, Easow Mathew M, Sriganesh V, Reiss UM

Abstract
BACKGROUND: Haemophilia is a genetic disorder characterized by spontaneous or provoked, often uncontrolled, bleeding into joints, muscles and other soft tissues. Current methods of treatment are expensive, challenging and involve regular administration of clotting factors. Gene therapy has recently been prompted as a curative treatment modality. This is an update of a published Cochrane Review.
OBJECTIVES: To evaluate the safety and efficacy of gene therapy for treating people with haemophilia A or B.
SEARCH METHODS: We searched the Cochrane Cystic Fibrosis & Genetic Disorders Group's Coagulopathies Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched the reference lists of relevant articles and reviews.Date of last search: 18 August 2016.
SELECTION CRITERIA: Eligible trials include randomised or quasi-randomised clinical trials, including controlled clinical trials comparing gene therapy (with or without standard treatment) with standard treatment (factor replacement) or other 'curative' treatment such as stem cell transplantation for individuals with haemophilia A or B of all ages who do not have inhibitors to factor VIII or IX.
DATA COLLECTION AND ANALYSIS: No trials of gene therapy for haemophilia were found.
MAIN RESULTS: No trials of gene therapy for haemophilia were identified.
AUTHORS' CONCLUSIONS: No randomised or quasi-randomised clinical trials of gene therapy for haemophilia were identified. Thus, we are unable to determine the safety and efficacy of gene therapy for haemophilia. Gene therapy for haemophilia is still in its nascent stages and there is a need for well-designed clinical trials to assess the long-term feasibility, success and risks of gene therapy for people with haemophilia.

PMID: 27996087 [PubMed - as supplied by publisher]

Intragenic CFTR Duplication and 5T/12TG Variant in a Patient with Non-Classic Cystic Fibrosis.

Sci Rep. 2016 Dec 20;6:38776

Authors: Celestino-Soper PB, Simpson E, Tumbleson Brink D, Lynnes TC, Dlouhy S, Vatta M, Yeley J, Brown C, Bai S

Abstract
Cystic fibrosis (CF) is an autosomal recessive disorder characterized by the accumulation of sticky and heavy mucus that can damage several organs. CF shows variable expressivity in affected individuals, but it typically causes respiratory and digestive complications as well as congenital bilateral absence of the vas deferens in males. Individuals with classic CF usually have variants that produce a defective protein from both alleles of the CFTR gene. Individuals with other variants may present with classic, non-classic, or milder forms of CF due to lower levels of functional CFTR protein. This article reports the genetic analysis of a female with features of asthma and mild or non-classic CF. CFTR sequencing demonstrated that she is a carrier for a maternally derived 5T/12TG variant. Deletion/duplication analysis by multiplex ligation-dependent probe amplification (MLPA) showed the presence of an intragenic paternally derived duplication involving exons 7-11 of the CFTR gene. This duplication is predicted to result in the production of a truncated CFTR protein lacking the terminal part of the nucleotide-binding domain 1 (NBD1) and thus is likely to be a non-functioning allele. The combination of this large intragenic duplication and 5T/12TG is the probable cause of the mild or non-classic CF features in this individual.

PMID: 27996019 [PubMed - in process]

Ralstonia mannitolilytica in cystic fibrosis: A new predictor of worse outcomes.

Respir Med Case Rep. 2017;20:48-50

Authors: Coman I, Bilodeau L, Lavoie A, Carricart M, Tremblay F, Zlosnik JE, Berthiaume Y

Abstract
BACKGROUND: Patients with Cystic Fibrosis are subject to repeated respiratory tract infections, with recent increasing isolation of unusual pathogens. Ralstonia species have lately been isolated at our institution, an organism historically frequently misidentified as Burkholderia or Pseudomonas. The prevalence of Ralstonia spp. in cystic fibrosis populations has yet to be determined, along with its clinical implications.
CASE PRESENTATIONS: Seven patients out of the 301 followed at our cystic fibrosis clinic have had Ralstonia strains identified in their respiratory tract. Most strains identified were multi-drug resistant. After aquisition of Ralstonia spp., the patients' clinical course was characterized by more frequent and more severe respiratory infections along with prolonged hospitalizations, greater decline of lung function, and greater mortality. The mortality rate in this group of patients was 86%. No other factor that could explain such a dramatic evolution was identified upon review of patient data. Some of the strains involved were recognized as clones on Pulse Field Electrophoresis Gel, raising the question of person-to-person transmission.
CONCLUSION: New pathogens are identified with the evolution of the microbiota in cystic fibrosis respiratory tracts. In our cohort of patients, acquisition of Ralstonia spp. was associated with dramatic outcomes in terms of disease acceleration and raised mortality rates. It is of critical importance to continue to better define the prevalence and clinical impact of Ralstonia in cystic fibrosis populations.

PMID: 27995056 [PubMed]

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Pharmacogenomics[Title/Abstract] AND ("2005/01/01"[PDAT] : "3000"[PDAT])

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Next generation metronomic chemotherapy-report from the Fifth Biennial International Metronomic and Anti-angiogenic Therapy Meeting, 6-8 May 2016, Mumbai.

Ecancermedicalscience. 2016;10:689

Authors: Pantziarka P, Hutchinson L, André N, Benzekry S, Bertolini F, Bhattacharjee A, Chiplunkar S, Duda DG, Gota V, Gupta S, Joshi A, Kannan S, Kerbel R, Kieran M, Palazzo A, Parikh A, Pasquier E, Patil V, Prabhash K, Shaked Y, Sholler GS, Sterba J, Waxman DJ, Banavali S

Abstract
The 5(th) Biennial Metronomic and Anti-angiogenic Therapy Meeting was held on 6(th) - 8(th) May in the Indian city of Mumbai. The meeting brought together a wide range of clinicians and researchers interested in metronomic chemotherapy, anti-angiogenics, drug repurposing and combinations thereof. Clinical experiences, including many from India, were reported and discussed in three symposia covering breast cancer, head and neck cancers and paediatrics. On the pre-clinical side research into putative mechanisms of action, and the interactions between low dose metronomic chemotherapy and angiogenesis and immune responses, were discussed in a number of presentations. Drug repurposing was discussed both in terms of clinical results, particularly with respect to angiosarcoma and high-risk neuroblastoma, and in pre-clinical settings, particularly the potential for peri-operative interventions. However, it was clear that there remain a number of key areas of challenge, particularly in terms of definitions, perceptions in the wider oncological community, mechanisms of action and predictive biomarkers. While the potential for metronomics and drug repurposing in low and middle income countries remains a key theme, it is clear that there is also considerable potential for clinically relevant improvements in patient outcomes even in high income economies.

PMID: 27994645 [PubMed]

Repurposing toremifene for the treatment of oral bacterial infections.

Antimicrob Agents Chemother. 2016 Dec 19;:

Authors: Gerits E, Defraine V, Vandamme K, De Cremer K, De Brucker K, Thevissen K, Cammue BP, Beullens S, Fauvart M, Verstraeten N, Michiels J

Abstract
The spread of antibiotic resistance and the challenges associated with antiseptics such as chlorhexidine have necessitated the search for new antibacterial agents against oral bacterial pathogens. As a result of failing traditional approaches, drug repurposing has emerged as a novel paradigm to find new antibacterial agents. In this study, we examined the effect of the FDA-approved anticancer agent toremifene against oral bacteria Porphyromonas gingivalis and Streptococcus mutans. We found that the drug was able to inhibit growth of both pathogens as well as prevent biofilm formation at concentrations ranging from 12.5 to 25 μM. Moreover, toremifene was shown to eradicate preformed biofilms at concentrations ranging from 25 to 50 μM. In addition, we found that toremifene prevents P. gingivalis and S. mutans biofilm formation on titanium surfaces. A time-kill study indicated that toremifene acts bactericidal against S. mutans Macromolecular synthesis assays revealed that treatment with toremifene does not cause preferential inhibition of DNA, RNA, or protein synthesis pathways, indicating membrane-damaging activity. Biophysical studies using fluorescent probes and fluorescence microscopy further confirmed the membrane-damaging mode of action. Taken together, our results suggest that the anti-cancer agent toremifene is a suitable candidate for further investigation for the development of new treatment strategies for oral bacterial infections.

PMID: 27993858 [PubMed - as supplied by publisher]

Predict Drug Permeability to Blood-Brain-Barrier from Clinical Phenotypes: Drug Side Effects and Drug Indications.

Bioinformatics. 2016 Dec 19;:

Authors: Gao Z, Chen Y, Cai X, Xu R

Abstract
MOTIVATION: Blood-Brain-Barrier (BBB) is a rigorous permeability barrier for maintaining homeostasis of Central Nervous System (CNS). Determination of compound's permeability to BBB is prerequisite in CNS drug discovery. Existing computational methods usually predict drug BBB permeability from chemical structure and they generally apply to small compounds passing BBB through passive diffusion. As abundant information on drug side effects and indications has been recorded over time through extensive clinical usage, we aim to explore BBB permeability prediction from a new angle and introduce a novel approach to predict BBB permeability from drug clinical phenotypes (drug side effects and drug indications). This method can apply to both small compounds and macro-molecules penetrating BBB through various mechanisms besides passive diffusion.
RESULTS: We composed a training dataset of 213 drugs with known brain and blood steady-state concentrations ratio and extracted their side effects and indications as features. Next, we trained SVM models with polynomial kernel and obtained accuracy of 76.0%, AUC 0.739, and F1 score (macro weighted) 0.760 with Monte Carlo cross validation. The independent test accuracy was 68.3%, AUC 0.692, F1 score 0.676. When both chemical features and clinical phenotypes were available, combining the two types of features achieved significantly better performance than chemical feature based approach (accuracy 85.5% vs 72.9%, AUC 0.854 vs 0.733, F1 score 0.854 vs 0.725; p < e(-90)). We also conducted de novo prediction and identified 110 drugs in SIDER database having the potential to penetrate BBB, which could serve as start point for CNS drug repositioning research.
AVAILABILITY: https://github.com/bioinformatics-gao/CASE-BBB-prediction-Data CONTACT: rxx@case.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

PMID: 27993785 [PubMed - as supplied by publisher]

Comparative genetic screens in human cells reveal new regulatory mechanisms in WNT signaling.

Elife. 2016 Dec 20;5:

Authors: Lebensohn AM, Dubey R, Neitzel LR, Tacchelly-Benites O, Yang E, Marceau CD, Davis EM, Patel BB, Bahrami-Nejad Z, Travaglini KJ, Ahmed Y, Lee E, Carette JE, Rohatgi R

Abstract
The comprehensive understanding of cellular signaling pathways remains a challenge due to multiple layers of regulation that may become evident only when the pathway is probed at different levels or critical nodes are eliminated. To discover regulatory mechanisms in canonical WNT signaling, we conducted a systematic forward genetic analysis through reporter-based screens in haploid human cells. Comparison of screens for negative, sensitizing and positive regulators of WNT signaling, mediators of R-spondin-dependent signaling and suppressors of constitutive signaling induced by loss of the tumor suppressor APC or casein kinase 1α uncovered new regulatory features at many levels of the pathway. These include a requirement for the transcription factor TFAP4, a role for the DAX domain of AXIN2 in controlling β-catenin activity, a contribution of GPI anchor biosynthetic enzymes and glypicans to R-spondin-potentiated signaling, and two different mechanisms that regulate signaling when distinct components of the β-catenin destruction complex are lost.

PMID: 27996937 [PubMed - as supplied by publisher]

AraQTL - Workbench and Archive for systems genetics in Arabidopsis thaliana.

Plant J. 2016 Dec 20;:

Authors: Nijveen H, Ligterink W, Keurentjes JJ, Loudet O, Long J, Sterken MG, Prins P, Hilhorst HW, de Ridder D, Kammenga JE, Snoek BL

Abstract
Genetical genomics studies uncover genome-wide genetic interactions between genes and their transcriptional regulators. High-throughput measurement of gene expression in recombinant inbred line populations enabled the investigation of the genetic architecture of gene expression variation. This has the potential to enrich the understanding of the molecular mechanisms affected by and underlying natural variation. Moreover, it contributes to the systems biology of natural variation, as a substantial number of experiments have resulted in a valuable amount of interconnectable phenotypic, molecular and genotypic data. For Arabidopsis thaliana a number of genetical genomics studies have been published, uncovering many expression quantitative trait loci (eQTLs). Yet, this complex data is not easily accessible to the plant research community, leaving most of the valuable genetic interactions unexplored as cross-analysis of these studies is a major effort. We address this with AraQTL www.bioinformatics.nl/AraQTL/, an easily accessible workbench and database for comparative analysis and meta-analysis of all published Arabidopsis eQTL datasets. AraQTL provides a workbench for comparing, re-using and extending upon the results of these experiments. For example, one can easily screen a physical region for specific local-eQTLs that could harbour candidate genes for phenotypic QTL, or detect gene-by-environment interactions by comparing eQTLs under different conditions. This article is protected by copyright. All rights reserved.

PMID: 27995664 [PubMed - as supplied by publisher]

Probabilistic adaptation in changing microbial environments.

PeerJ. 2016;4:e2716

Authors: Katz Y, Springer M

Abstract
Microbes growing in animal host environments face fluctuations that have elements of both randomness and predictability. In the mammalian gut, fluctuations in nutrient levels and other physiological parameters are structured by the host's behavior, diet, health and microbiota composition. Microbial cells that can anticipate environmental fluctuations by exploiting this structure would likely gain a fitness advantage (by adapting their internal state in advance). We propose that the problem of adaptive growth in structured changing environments, such as the gut, can be viewed as probabilistic inference. We analyze environments that are "meta-changing": where there are changes in the way the environment fluctuates, governed by a mechanism unobservable to cells. We develop a dynamic Bayesian model of these environments and show that a real-time inference algorithm (particle filtering) for this model can be used as a microbial growth strategy implementable in molecular circuits. The growth strategy suggested by our model outperforms heuristic strategies, and points to a class of algorithms that could support real-time probabilistic inference in natural or synthetic cellular circuits.

PMID: 27994963 [PubMed]

ReconMap: an interactive visualization of human metabolism.

Bioinformatics. 2016 Dec 19;:

Authors: Noronha A, Daníelsdóttir AD, Gawron P, Jóhannsson F, Jónsdóttir S, Jarlsson S, Gunnarsson JP, Brynjólfsson S, Schneider R, Thiele I, Fleming RM

Abstract
MOTIVATION: A genome-scale reconstruction of human metabolism, Recon 2, is available but no interface exists to interactively visualize its content integrated with omics data and simulation results.
RESULTS: We manually drew a comprehensive map, ReconMap 2.0, that is consistent with the content of Recon 2. We present it within a web interface that allows content query, visualization of custom datasets and submission of feedback to manual curators.
AVAILABILITY AND IMPLEMENTATION: ReconMap can be accessed via http://vmh.uni.lu, with network export in a Systems Biology Graphical Notation compliant format released under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. A Constraint-Based Reconstruction and Analysis (COBRA) Toolbox extension to interact with ReconMap is available via https://github.com/opencobra/cobratoolbox CONTACT: : ronan.mt.fleming@gmail.com.

PMID: 27993782 [PubMed - as supplied by publisher]

Recon2Neo4j: Applying graph database technologies for managing comprehensive genome-scale networks.

Bioinformatics. 2016 Dec 19;:

Authors: Balaur I, Mazein A, Saqi M, Lysenko A, Rawlings CJ, Auffray C

Abstract
The goal of this work is to offer a computational framework for exploring data from the Recon2 human metabolic reconstruction model. Advanced user access features have been developed using the Neo4j graph database technology and this paper describes key features such as efficient management of the network data, examples of the network querying for addressing particular tasks, and how query results are converted back to the Systems Biology Markup Language (SBML) standard format. The Neo4j-based metabolic framework facilitates exploration of highly-connected and comprehensive human metabolic data and identification of metabolic subnetworks of interest. A Java-based parser component has been developed to convert query results (available in the JSON format) into SBML and SIF formats in order to facilitate further results exploration, enhancement or network sharing.
AVAILABILITY: The Neo4j-based metabolic framework is freely available from: https://diseaseknowledgebase.etriks.org/metabolic/browser/ The java code files developed for this work are available from the following url: https://github.com/ibalaur/MetabolicFramework CONTACT: ibalaur@eisbm.org SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

PMID: 27993779 [PubMed - as supplied by publisher]

Current Experimental Methods for Characterizing Protein-Protein Interactions.

ChemMedChem. 2016 Apr 19;11(8):738-56

Authors: Zhou M, Li Q, Wang R

Abstract
Protein molecules often interact with other partner protein molecules in order to execute their vital functions in living organisms. Characterization of protein-protein interactions thus plays a central role in understanding the molecular mechanism of relevant protein molecules, elucidating the cellular processes and pathways relevant to health or disease for drug discovery, and charting large-scale interaction networks in systems biology research. A whole spectrum of methods, based on biophysical, biochemical, or genetic principles, have been developed to detect the time, space, and functional relevance of protein-protein interactions at various degrees of affinity and specificity. This article presents an overview of these experimental methods, outlining the principles, strengths and limitations, and recent developments of each type of method.

PMID: 26864455 [PubMed - indexed for MEDLINE]