Untangling Genetic Risk for Alzheimer's Disease.

Biol Psychiatry. 2017 May 22;:

Authors: Pimenova AA, Raj T, Goate AM

Abstract
Alzheimer's disease (AD) is a genetically heterogeneous neurodegenerative disorder caused by fully penetrant single gene mutations in a minority of cases, while the majority of cases are sporadic or show modest familial clustering. These cases are of late onset and likely result from the interaction of many genes and the environment. More than 30 loci have been implicated in AD by a combination of linkage, genome-wide association, and whole genome/exome sequencing. We have learned from these studies that perturbations in endolysosomal, lipid metabolism, and immune response pathways substantially contribute to sporadic AD pathogenesis. We review here current knowledge about functions of AD susceptibility genes, highlighting cells of the myeloid lineage as drivers of at least part of the genetic component in late-onset AD. Although targeted resequencing utilized for the identification of causal variants has discovered coding mutations in some AD-associated genes, a lot of risk variants lie in noncoding regions. Here we discuss the use of functional genomics approaches that integrate transcriptomic, epigenetic, and endophenotype traits with systems biology to annotate genetic variants, and to facilitate discovery of AD risk genes. Further validation in cell culture and mouse models will be necessary to establish causality for these genes. This knowledge will allow mechanism-based design of novel therapeutic interventions in AD and promises coherent implementation of treatment in a personalized manner.

PMID: 28666525 [PubMed - as supplied by publisher]

Evolution of Gene Expression in the Uterine Cervix related to Steroid Signaling: Conserved features in the regulation of cervical ripening.

Sci Rep. 2017 Jun 30;7(1):4439

Authors: Wagner GP, Nnamani MC, Chavan AR, Maziarz J, Protopapas S, Condon J, Romero R

Abstract
The uterine cervix is the boundary structure between the uterus and the vagina and is key for the maintenance of pregnancy and timing of parturition. Here we report on a comparative transcriptomic study of the cervix of four placental mammals, mouse, guinea pig, rabbit and armadillo, and one marsupial, opossum. Our aim is to investigate the evolution of cervical gene expression as related to putative mechanisms for functional progesterone withdrawal. Our findings are: 1) The patterns of gene expression in eutherian (placental) mammals are consistent with the notion that an increase in the E/P4 signaling ratio is critical for cervical ripening. How the increased E/P4 ratio is achieved, however, is variable between species. 2) None of the genes related to steroid signaling, that are modulated in eutherian species, change expression during opossum gestation. 3) A tendency for decreased expression of progesterone receptor co-activators (NCOA1, -2 and -3, and CREBBP) towards term is a shared derived feature of eutherians. This suggests that parturition is associated with broad scale histone de-acetylation. Western-blotting on mouse cervix confirmed large scale histone de-acetylation in labor. This finding may have important implications for the control of premature cervical ripening and prevention of preterm birth in humans.

PMID: 28667298 [PubMed - in process]

Tuberculosis infection in rural labor migrants in Shenzhen, China: Emerging challenge to tuberculosis control during urbanization.

Sci Rep. 2017 Jun 30;7(1):4457

Authors: Li X, Yang Q, Feng B, Xin H, Zhang M, Deng Q, Deng G, Shan W, Yue J, Zhang H, Li M, Li H, Jin Q, Chen X, Gao L

Abstract
During China's urbanization process, rural labor migrants have been suggested to be one important bridge population to change urban-rural distribution on tuberculosis (TB) burden. Aiming to estimate the prevalence of TB infection and to track the active disease development in rural labor migrants, a prospective study was conducted in Shenzhen city, southern China. TB infection was detected using interferon-γ release assay (IGRA). Here we mainly report the characteristics of TB infection in the study population based on the baseline survey. A total of 4,422 eligible participants completed baseline survey in July 2013. QuantiFERON (QFT) positivity rates 17.87% (790/4,422) and was found to be consistent with the local TB epidemic of the areas where the participants immigrated from. Age, smoking, residence registered place, and present of BCG scars were found to be independently associated with QFT positivity. Additionally, evidence for interaction between smoking and age was observed (p for likelihood ratio test < 0.001). Our results suggested that the development of TB control strategy including latent TB infection management should pay more attention to the rural flowing population due to their high mobility and higher prevalence of TB infection.

PMID: 28667275 [PubMed - in process]

Response of microbial community function to fluctuating geochemical conditions within a legacy radioactive waste trench environment.

Appl Environ Microbiol. 2017 Jun 30;:

Authors: Vázquez-Campos X, Kinsela AS, Bligh MW, Harrison JJ, Payne TE, Waite TD

Abstract
During the 1960s, small quantities of radioactive materials were co-disposed with chemical waste at the Little Forest Legacy Site (Sydney, Australia) in three-metre-deep, unlined trenches. Chemical and microbial analyses, including functional and taxonomic information derived from shotgun metagenomics, were collected across a six-week period immediately after a prolonged rainfall event to assess how changing water levels impact upon the microbial ecology and contaminant mobility. Collectively, results demonstrated that oxygen-laden rainwater rapidly altered the redox balance in the trench water, strongly impacting microbial functioning as well as the radiochemistry. Two contaminants of concern, plutonium and americium, were shown to transition from solid-iron-associated species immediately after the initial rainwater pulse, to progressively more soluble moieties as reducing conditions were enhanced. Functional metagenomics revealed the potentially important role that the taxonomically-diverse microbial community played in this transition. In particular, aerobes dominated in the first day followed by an increase of facultative anaerobes/denitrifiers at day four. Towards the mid-end of the sampling period, the functional and taxonomic profiles depicted an anaerobic community distinguished by a higher representation of dissimilatory sulfate reduction and methanogenesis pathways. Our results have important implications to similar near-surface environmental systems in which redox cycling occurs.Importance The role of chemical and microbiological factors in mediating the biogeochemistry of groundwaters from trenches used to dispose of radioactive materials during the 1960s is examined in this study. Specifically, chemical and microbial analyses, including functional and taxonomic information derived from shotgun metagenomics, were collected across a six-week period immediately after a prolonged rainfall event to assess how changing water levels influence microbial ecology and contaminant mobility.Results demonstrate that oxygen-laden rainwater rapidly altered the redox balance in the trench water, strongly impacting microbial functioning as well as the radiochemistry. Two contaminants of concern, plutonium and americium, were shown to transition from solid-iron-associated species immediately after the initial rainwater pulse, to progressively more soluble moieties as reducing conditions were enhanced. Functional metagenomics revealed the important role that the taxonomically-diverse microbial community played in this transition. Our results have important implications to similar near-surface environmental systems in which redox cycling occurs.

PMID: 28667104 [PubMed - as supplied by publisher]

Control of serine integrase recombination directionality by fusion with the directionality factor.

Nucleic Acids Res. 2017 Jun 28;:

Authors: Olorunniji FJ, McPherson AL, Rosser SJ, Smith MCM, Colloms SD, Stark WM

Abstract
Bacteriophage serine integrases are extensively used in biotechnology and synthetic biology for assembly and rearrangement of DNA sequences. Serine integrases promote recombination between two different DNA sites, attP and attB, to form recombinant attL and attR sites. The 'reverse' reaction requires another phage-encoded protein called the recombination directionality factor (RDF) in addition to integrase; RDF activates attL × attR recombination and inhibits attP × attB recombination. We show here that serine integrases can be fused to their cognate RDFs to create single proteins that catalyse efficient attL × attR recombination in vivo and in vitro, whereas attP × attB recombination efficiency is reduced. We provide evidence that activation of attL × attR recombination involves intra-subunit contacts between the integrase and RDF moieties of the fusion protein. Minor changes in the length and sequence of the integrase-RDF linker peptide did not affect fusion protein recombination activity. The efficiency and single-protein convenience of integrase-RDF fusion proteins make them potentially very advantageous for biotechnology/synthetic biology applications. Here, we demonstrate efficient gene cassette replacement in a synthetic metabolic pathway gene array as a proof of principle.

PMID: 28666339 [PubMed - as supplied by publisher]

Inferring transcriptional logic from multiple dynamic experiments.

Bioinformatics. 2017 Jun 28;:

Authors: Minas G, Jenkins DJ, Rand DA, Finkenstädt B

Abstract
Motivation: The availability of more data of dynamic gene expression under multiple experimental conditions provides new information that makes the key goal of identifying not only the transcriptional regulators of a gene but also the underlying logical structure attainable.
Results: We propose a novel method for inferring transcriptional regulation using a simple, yet biologically interpretable, model to find the logic by which a set of candidate genes and their associated transcription factors (TFs) regulate the transcriptional process of a gene of interest. Our dynamic model links the mRNA transcription rate of the target gene to the activation states of the TFs assuming that these interactions are consistent across multiple experiments and over time. A trans-dimensional Markov Chain Monte Carlo (MCMC) algorithm is used to efficiently sample the regulatory logic under different combinations of parents and rank the estimated models by their posterior probabilities. We demonstrate and compare our methodology with other methods using simulation examples and apply it to a study of transcriptional regulation of selected target genes of Arabidopsis Thaliana from microarray time series data obtained under multiple biotic stresses. We show that our method is able to detect complex regulatory interactions that are consistent under multiple experimental conditions.
Availability: Programs are written in MATLAB and Statistics Toolbox Release 2016b, The MathWorks, Inc., Natick, Massachusetts, United States and are available on GitHub https://github.com/giorgosminas/TRS .
Contact: giorgos.minas@warwick.ac.uk , B.F.Finkenstadt@warwick.ac.uk.
Supplementary information: Supplementary data are available at Bioinformatics online.

PMID: 28666320 [PubMed - as supplied by publisher]

GPU-powered model analysis with PySB/cupSODA.

Bioinformatics. 2017 Jun 28;:

Authors: Harris LA, Nobile MS, Pino JC, Lubbock ALR, Besozzi D, Mauri G, Cazzaniga P, Lopez CF

Abstract
Summary: A major barrier to the practical utilization of large, complex models of biochemical systems is the lack of open-source computational tools to evaluate model behaviors over high-dimensional parameter spaces. This is due to the high computational expense of performing thousands to millions of model simulations required for statistical analysis. To address this need, we have implemented a user-friendly interface between cupSODA, a GPU-powered kinetic simulator, and PySB, a Python-based modeling and simulation framework. For three example models of varying size, we show that for large numbers of simulations PySB/cupSODA achieves order-of-magnitude speedups relative to a CPU-based ordinary differential equation integrator.
Availability and Implementation: The PySB/cupSODA interface has been integrated into the PySB modeling framework (version 1.4.0), which can be installed from the Python Package Index (PyPI) using a Python package manager such as pip . cupSODA source code and precompiled binaries (Linux, Mac OS/X, Windows) are available at github.com/aresio/cupSODA (requires an Nvidia GPU; developer.nvidia.com/cuda-gpus ). Additional information about PySB is available at pysb.org.
Contact: c.lopez@vanderbilt.edu ; paolo.cazzaniga@unibg.it.
Supplementary information: Supplementary data are available at Bioinformatics online.

PMID: 28666314 [PubMed - as supplied by publisher]

Effects of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on cardiovascular events and residual renal function in dialysis patients: a meta-analysis of randomised controlled trials.

BMC Nephrol. 2017 Jun 30;18(1):206

Authors: Liu Y, Ma X, Zheng J, Jia J, Yan T

Abstract
BACKGROUND: The role of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) reducing risk of cardiovascular events (CVEs) and preserving kidney function in patients with chronic kidney disease is well-documented. However, the efficacy and safety of these agents in dialysis patients is still a controversial issue.
METHODS: We systematically searched MEDLINE, Embase, Cochrane Library and Wanfang for randomized trials. The relative risk (RR) reductions were calculated with a random-effects model. Major cardiovascular events, changes in GFR and drug-related adverse events were analyzed.
RESULTS: Eleven trials included 1856 participants who were receiving dialysis therapy. Compared with placebo or other active agents groups, ARB therapy reduced the risk of heart failure events by 33% (RR 0.67, 95% CI 0.47 to 0.93) with similar decrement in blood pressure in dialysis patients. Indirect comparison suggested that fewer cardiovascular events happened during treatment with ARB (0.77, 0.63 to 0.94). The results indicated no significant differences between the two treatment regimens with regard to frequency of myocardial infarction (1.0, 0.45 to 2.22), stroke (1.16, 0.69 to 1.96), cardiovascular death (0.89, 0.64 to 1.26) and all-cause mortality (0.94, 0.75 to 1.17). Five studies reported the renoprotective effect and revealed that ACEI/ARB therapy significantly slowed the rate of decline in both residual renal function (MD 0.93 mL/min/1.73 m(2), 0.38 to 1.47 mL/min/1.73 m(2)) and urine volume (MD 167 ml, 95% CI 21 ml to 357 ml). No difference in drug-related adverse events was observed in both treatment groups.
CONCLUSIONS: This study demonstrates that ACE-Is/ARBs therapy decreases the loss of residual renal function, mainly for patients with peritoneal dialysis. Overall, ACE-Is and ARBs do not reduce cardiovascular events in dialysis patients, however, treatment with ARB seems to reduce cardiovascular events including heart failure. ACE-Is and ARBs do not induce an extra risk of side effects.

PMID: 28666408 [PubMed - in process]

New drugs or alternative therapy to blurring the symptoms of fibromyalgia - a patent review.

Expert Opin Ther Pat. 2017 Jun 30;:

Authors: Oliveira MA, Guimarães AG, Araújo AAS, Quintans-Júnior LJ, Quintans JSS

Abstract
INTRODUCTION: Fibromyalgia (FM) is a musculoskeletal condition characterized by chronic widespread pain, tenderness and often accompanied by other comorbid conditions such as depression, anxiety, chronic fatigue, among others. Now we aimed to survey the recent patents describing new drugs or alternative therapy for FM. Areas covered: This review covers the therapeutic patents published between 2010 and 2017 from specialized search databases (WIPO, DERWENT, INPI, ESPANET and USPTO) that report the discovery of new drugs or pharmacologic alternative for the treatment of FM. Expert opinion: New therapeutic substances have been proposed in the last seven years. At least as it has been found in our survey, most are still in the pre-clinical phase of the study and its clinical applicability is unclear. However, other therapeutic approaches were found in patents such as well-established drugs in the market in combination or drug repositioning that combines the "new analgesic" effects with the old side-effects. Hence, it is a safe approach for pharmaceutical market, but poorer to patients who need a radical innovation. So, there is the emerging need for further studies on the safety and efficacy of such therapeutic measures and the search for improvement of side-effects, as well as the development of new drugs that are unorthodox for different FM symptoms.

PMID: 28665159 [PubMed - as supplied by publisher]

Bacoside A Induces Tumor Cell Death in Human Glioblastoma Cell Lines through Catastrophic Macropinocytosis.

Front Mol Neurosci. 2017;10:171

Authors: John S, Sivakumar KC, Mishra R

Abstract
Glioblastoma multiforme (GBM) is a highly aggressive type of brain tumor with an extremely poor prognosis. Recent evidences have shown that the "biomechanical imbalances" induced in GBM patient-derived glioblastoma cells (GC) and in vivo via the administration of synthetic small molecules, may effectively inhibit disease progression and prolong survival of GBM animal models. This novel concept associated with de novo anti-GBM drug development has however suffered obstacles in adequate clinical utility due to the appearance of unrelated toxicity in the prolonged therapeutic windows. Here, we took a "drug repurposing approach" to trigger similar physico-chemical disturbances in the GBM tumor cells, wherein, the candidate therapeutic agent has been previously well established for its neuro-protective roles, safety, efficacy, prolonged tolerance and excellent brain bioavailability in human subjects and mouse models. In this study, we show that the extracts of an Indian traditional medicinal plant Bacopa monnieri (BM) and its bioactive component Bacoside A can generate dosage associated tumor specific disturbances in the hydrostatic pressure balance of the cell via a mechanism involving excessive phosphorylation of calcium/calmodulin-dependent protein kinase IIA (CaMKIIA/CaMK2A) enzyme that is further involved in the release of calcium from the smooth endoplasmic reticular networks. High intracellular calcium stimulated massive macropinocytotic extracellular fluid intake causing cell hypertrophy in the initial stages, excessive macropinosome enlargement and fluid accumulation associated organellar congestion, cell swelling, cell rounding and membrane rupture of glioblastoma cells; with all these events culminating into a non-apoptotic, physical non-homeostasis associated glioblastoma tumor cell death. These results identify glioblastoma tumor cells to be a specific target of the tested herbal medicine and therefore can be exploited as a safe anti-GBM therapeutic.

PMID: 28663722 [PubMed - in process]

The PAPI-1 pathogenicity island-encoded small RNA PesA influences Pseudomonas aeruginosa virulence and modulates pyocin S3 production.

PLoS One. 2017;12(6):e0180386

Authors: Ferrara S, Falcone M, Macchi R, Bragonzi A, Girelli D, Cariani L, Cigana C, Bertoni G

Abstract
Small non-coding RNAs (sRNAs) are post-transcriptional regulators of gene expression that have been recognized as key contributors to bacterial virulence and pathogenic mechanisms. In this study, we characterized the sRNA PesA of the opportunistic human pathogen Pseudomonas aeruginosa. We show that PesA, which is transcribed within the pathogenicity island PAPI-1 of P. aeruginosa strain PA14, contributes to P. aeruginosa PA14 virulence. In fact, pesA gene deletion resulted in a less pathogenic strain, showing higher survival of cystic fibrosis human bronchial epithelial cells after infection. Moreover, we show that PesA influences positively the expression of pyocin S3 whose genetic locus comprises two structural genes, pyoS3A and pyoS3I, encoding the killing S3A and the immunity S3I proteins, respectively. Interestingly, the deletion of pesA gene results in increased sensitivity to UV irradiation and to the fluoroquinolone antibiotic ciprofloxacin. The degree of UV sensitivity displayed by the PA14 strain lacking PesA is comparable to that of a strain deleted for pyoS3A-I. These results suggest an involvement of pyocin S3 in DNA damage repair and a regulatory role of PesA on this function.

PMID: 28665976 [PubMed - in process]

Primary Ciliary Dyskinesia Diagnosis. Is Color Better Than Black and White?

Am J Respir Crit Care Med. 2017 Jul 01;196(1):9-10

Authors: Knowles MR, Leigh MW

PMID: 28665204 [PubMed - in process]

A semiquantitative MRI-Score can predict loss of lung function in patients with cystic fibrosis: Preliminary results.

Eur Radiol. 2017 Jun 29;:

Authors: Schaefer JF, Hector A, Schmidt K, Teufel M, Fleischer S, Graepler-Mainka U, Riethmueller J, Gatidis S, Schaefer S, Nikolaou K, Hartl D, Tsiflikas I

Abstract
OBJECTIVES: To evaluate the applicability of a semiquantitative MRI scoring system (MR-CF-S) as a prognostic marker for clinical course of cystic fibrosis (CF) lung disease.
METHODS: This observational study of a single-centre CF cohort included a group of 61 patients (mean age 12.9 ± 4.7 years) receiving morphological and functional pulmonary MRI, pulmonary function testing (PFT) and follow-up of 2 years. MRI was analysed by three raters using MR-CF-S. The inter-rater agreement, correlation of score categories with forced expiratory volume in 1 s (FEV1) at baseline, and the predictive value of clinical parameters, and score categories was assessed for the whole cohort and a subgroup of 40 patients with moderately impaired lung function.
RESULTS: The inter-rater agreement of MR-CF-S was sufficient (mean intraclass correlation coefficient 0.92). MR-CF-S (-0.62; p < 0.05) and most of the categories significantly correlated with FEV1. Differences between patients with relevant loss of FEV1 (>3%/year) and normal course were only significant for MR-CF-S (p < 0.05) but not for clinical parameters. Centrilobular opacity (CO) was the most promising score category for prediction of a decline of FEV1 (area under curve: whole cohort 0.69; subgroup 0.86).
CONCLUSIONS: MR-CF-S is promising to predict a loss of lung function. CO seems to be a particular finding in CF patients with an abnormal course.
KEY POINTS: • Lung imaging is essential in the diagnostic work-up of CF patients • MRI serves as a powerful, radiation-free modality in paediatric CF patients • Observational single-centre study showed significant correlation of MR-CF score and FEV 1 • MR-CF score is promising in predicting a loss of lung function.

PMID: 28664245 [PubMed - as supplied by publisher]

Bacteraemia and fungaemia in cystic fibrosis patients with febrile pulmonary exacerbation: a prospective observational study.

BMC Pulm Med. 2017 Jun 29;17(1):96

Authors: Grosse-Onnebrink J, Stehling F, Tschiedel E, Olivier M, Mellies U, Schmidt R, Buer J, Rath PM, Steinmann J

Abstract
BACKGROUND: Bloodstream pathogens can be identified by multiplex PCR (SeptiFast (SF)) or blood culture (BC); whether these pathogens are present in cystic fibrosis (CF) patients during febrile pulmonary exacerbations (FPE) has not been sufficiently studied.
METHODS: In this prospective observational study, blood from CF patients experiencing FPE was tested with SF and BC before the initiation of antibiotic treatment.
RESULTS: After contaminants had been excluded, 9 of 72 blood samples tested positive by BC or SF. SF exclusively detected four pathogens; BC, one. Pulmonary pathogen transmission was likely in all cases except for 2 cases of candidaemia, which were believed to be caused by catheter-related infections. For three cases, test results caused us to change the antibiotic regimen. Sensitivity (85.7% vs. 42.9%) and negative predictive value (98.4% vs. 87.0%) tended to be higher for SF than for BC.
CONCLUSIONS: The results of SF and BC show that bacteraemia and fungaemia are present in CF patients during FPE and may affect antibiotic therapy. SF can help rule out catheter-related bloodstream infections.

PMID: 28662657 [PubMed - in process]

Immune Mechanisms in Pulmonary Fibrosis.

Am J Respir Cell Mol Biol. 2016 Sep;55(3):309-22

Authors: Kolahian S, Fernandez IE, Eickelberg O, Hartl D

Abstract
Pulmonary fibrosis, particularly idiopathic pulmonary fibrosis, represents a chronic and progressive disease with high mortality and limited therapeutic options. Excessive deposition of extracellular matrix proteins results in fibrotic remodeling, alveolar destruction, and irreversible loss of lung function. Both innate and adaptive immune mechanisms contribute to fibrogenesis at several cellular and noncellular levels. Here, we summarize and discuss the role of immune cells (T cells, neutrophils, macrophages, and fibrocytes) and soluble mediators (cytokines and chemokines) involved in pulmonary fibrosis, pointing toward novel immune-based therapeutic strategies in the field.

PMID: 27149613 [PubMed - indexed for MEDLINE]

Multimodal nonlinear optical microscopy reveals critical role of kinesin-1 in cartilage development.

Biomed Opt Express. 2017 Mar 01;8(3):1771-1782

Authors: He S, Xue W, Duan Z, Sun Q, Li X, Gan H, Huang J, Qu JY

Abstract
We developed a multimodal nonlinear optical (NLO) microscope system by integrating stimulated Raman scattering (SRS), second harmonic generation (SHG) and two-photon excited fluorescence (TPEF) imaging. The system was used to study the morphological and biochemical characteristics of tibial cartilage in a kinesin-1 (Kif5b) knockout mouse model. The detailed structure of fibrillar collagen in the extracellular matrix of cartilage was visualized by the forward and backward SHG signals, while high resolution imaging of chondrocytes was achieved by capturing endogenous TPEF and SRS signals of the cells. The results demonstrate that collagen fibrils in the superficial surface of the articular cartilage decreased significantly in the absence of Kif5b. The distorted morphology along with accumulated intracellular collagen was observed in the Kif5b-deficient chondrocytes, indicating the critical roles of kinesin-1 in the chondrocyte morphogenesis and collagen secretion. The study shows that multimodal NLO imaging method is an effective approach to investigate early development of cartilage.

PMID: 28663865 [PubMed]

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