Mesoscopic Model of Neuronal System Deficits in Multiple Sclerosis.

J Theor Biol. 2016 Jul 12;

Authors: Safarbali B, Hadaeghi F, Gharibzadeh S

Abstract
Multiple Sclerosis (MS) is a devastating autoimmune disease which deteriorates the connections in central nervous system (CNS) through the attacks to oligodendrocytes. Studying its origin and progression, in addition to clinical developments such as MRI brain images, cerebrospinal fluid (CSF) variation and quantitative measures of disability (EDSS), which sought to early diagnosis and efficient therapy, there is an increasing interest in developing computational models using the experimental data obtained from MS patients. From the perspective of mathematical modelling, although the origin of systemic symptoms might be attributed to cellular phenomena in microscopic level such as axonal demyelination, symptoms mainly are observed in macroscopic levels. How to fill the gap between these two levels of system modelling, however, remains as a challenge in systems biology studies. Trying to provide a conceptual framework to bridge between these two levels of modelling in systems biology, we have suggested a mesoscopic model composed of interacting neuronal population, which successfully replicates the changes in neuronal population synchrony due to MS progression.

PMID: 27422137 [PubMed - as supplied by publisher]

6 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

("orphan disease" OR "rare disease" OR "orphan diseases" OR "rare diseases")

These pubmed results were generated on 2016/07/16

PubMed comprises more than 24 million citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Suppressive effects of methylthiouracil on polyphosphate-mediated vascular inflammatory responses.

J Cell Mol Med. 2016 Jul 15;

Authors: Min G, Ku SK, Jeong S, Baek MC, Bae JS

Abstract
Drug repositioning is used to discover drug candidates to treat human diseases, through the application of drugs or compounds that are approved for the treatment of other diseases. This method can significantly reduce the time required and cost of discovering new drug candidates for human diseases. Previous studies have reported pro-inflammatory responses of endothelial cells to the release of polyphosphate (PolyP). In this study, we examined the anti-inflammatory responses and mechanisms of methylthiouracil (MTU), which is an antithyroid drug, and its effects on PolyP-induced septic activities in human umbilical vein endothelial cells (HUVECs) and mice. The survival rates, septic biomarker levels, behaviour of human neutrophils and vascular permeability were determined in PolyP-activated HUVECs and mice. MTU suppressed the PolyP-mediated vascular barrier permeability, up-regulation of inflammatory biomarkers, adhesion/migration of leucocytes, and activation and/or production of nuclear factor-κB, tumour necrosis factor-α and interleukin-6. Furthermore, MTU demonstrated protective effects on PolyP-mediated lethal death and the levels of the related septic biomarkers. Therefore, these results indicated the therapeutic potential of MTU on various systemic inflammatory diseases, such as sepsis or septic shock.

PMID: 27421058 [PubMed - as supplied by publisher]

Angiotensin II type 1 receptor blocker telmisartan induces apoptosis and autophagy in adult T-cell leukemia cells.

FEBS Open Bio. 2016 May;6(5):442-60

Authors: Kozako T, Soeda S, Yoshimitsu M, Arima N, Kuroki A, Hirata S, Tanaka H, Imakyure O, Tone N, Honda S, Soeda S

Abstract
Adult T-cell leukemia/lymphoma (ATL), an aggressive T-cell malignancy that develops after long-term infection with human T-cell leukemia virus (HTLV-1), requires new treatments. Drug repositioning, reuse of a drug previously approved for the treatment of another condition to treat ATL, offers the possibility of reduced time and risk. Among clinically available angiotensin II receptor blockers, telmisartan is well known for its unique ability to activate peroxisome proliferator-activated receptor-γ, which plays various roles in lipid metabolism, cellular differentiation, and apoptosis. Here, telmisartan reduced cell viability and enhanced apoptotic cells via caspase activation in ex vivo peripheral blood monocytes from asymptomatic HTLV-1 carriers (ACs) or via caspase-independent cell death in acute-type ATL, which has a poor prognosis. Telmisartan also induced significant growth inhibition and apoptosis in leukemia cell lines via caspase activation, whereas other angiotensin II receptor blockers did not induce cell death. Interestingly, telmisartan increased the LC3-II-enriched protein fraction, indicating autophagosome accumulation and autophagy. Thus, telmisartan simultaneously caused caspase activation and autophagy. A hypertension medication with antiproliferation effects on primary and leukemia cells is intriguing. Patients with an early diagnosis of ATL are generally monitored until the disease progresses; thus, suppression of progression from AC and indolent ATL to acute ATL is important. Our results suggest that telmisartan is highly effective against primary cells and leukemia cell lines in caspase-dependent and -independent manners, and its clinical use may suppress acute transformation and improve prognosis of patients with this mortal disease. This is the first report demonstrating a cell growth-inhibitory effect of telmisartan in fresh peripheral blood mononuclear cells from leukemia patients.

PMID: 27419050 [PubMed]

Rapid and ultra-rapid metabolizers with CYP2C19*17 polymorphism do not respond to standard therapy with proton pump inhibitors.

Meta Gene. 2016 Sep;9:159-64

Authors: Deshpande N, V S, V V RK, H V V M, M S, Banerjee R, Tandan M, D NR

Abstract
INTRODUCTION AND OBJECTIVE: Polymorphisms in genes encoding drug metabolizing enzymes may lead to varied enzyme activity and inter-individual variability in drug efficacy and/or toxicity. Since CYP2C19 and CYP3A4 genes code for enzymes involved in metabolizing wide variety of drugs including proton pump inhibitors, we sought to identify polymorphisms in these genes in order to study their impact on drug metabolism in subjects.
METHODS: DNA was isolated from healthy individuals including tribals and genotyped for 11 single nucleotide polymorphisms in CYP2C19 and 6 polymorphisms in CYP3A4. Individuals were categorized into different phenotypes based on their drug metabolizing genotype. Volunteers from each group were administered proton pump inhibitors (Esomeprazole, Pantoprazole; 40 mg/day) for 5 days followed by pharmacokinetic studies and measurement of intra-gastric pH.
RESULTS: Of the 17 polymorphisms studied, only CYP2C19*2,*3,*17 and CYP3A4*1B polymorphisms were observed. In comparison to urban individuals, a significantly (p = 0.0003) higher number of poor metabolizers were noted in the tribal individuals. Pantoprazole was found to be most effective in poor metabolizers in terms of area under the curve and Tmax. No significant difference was observed in the intra-gastric pH at baseline and day 6 in rapid and ultra-rapid metabolizers.
CONCLUSION: Our study has demonstrated that 19.7% of our subjects are carriers of the CYP2C19*17 allele who did not respond to the standard dose of proton pump inhibitors. Genetic screening to identify subjects with variant alleles would thus be useful for personalization of therapy with proton pump inhibitors.

PMID: 27419077 [PubMed]

Human Immunodeficiency Virus and Allergic Bronchopulmonary Aspergillosis: Case Report and Review of Literature.

Open Forum Infect Dis. 2016 Apr;3(2):ofw116

Authors: Galiatsatos P, Melia MT, Silhan LL

Abstract
Allergic bronchopulmonary aspergillosis (ABPA) results from a hypersensitivity response to airways colonization with Aspergillus fumigatus, and it occurs most often in individuals with asthma or cystic fibrosis. Allergic bronchopulmonary aspergillosis is an indolent, but potentially progressive, disease in patients. In patients infected with human immunodeficiency virus (HIV), ABPA is rare, and its description in the literature is limited to case reports. We describe the occurrence of ABPA in a 37-year-old woman with well controlled HIV infection. This represents the first documented case of ABPA in an HIV-infected patient whose only pulmonary comorbidity included the ramifications of prior acute respiratory distress syndrome due to Pneumocystis jirovecii pneumonia. We also review prior case reports of ABPA in HIV-infected patients and consider risk factors for its development.

PMID: 27419184 [PubMed]

Is it feasible to radiologically monitor the evolution of non-CF bronchiectasis?

Respirology. 2016 Aug;21(6):1137

Authors: Crivelli P, Sverzellati N, Sotgiu G, Aliberti S

PMID: 27416880 [PubMed - in process]

When communities collide.

Elife. 2016;5

Authors: Merritt J, Kuehn S

Abstract
A new model demonstrates how microbial communities can survive encounters with other communities as a cohesive group, even in the complete absence of cooperation.

PMID: 27420812 [PubMed - as supplied by publisher]

Optimizing cyanobacterial product synthesis: Meeting the challenges.

Bioengineered. 2016 Jul 15;:0

Authors: Zavřel T, Červený J, Knoop H, Steuer R

Abstract
The synthesis of renewable bioproducts using photosynthetic microorganisms holds great promise. Sustainable industrial applications, however, are still scarce and the true limits of phototrophic production remain unknown. One of the limitations of further progress is our insufficient understanding of the quantitative changes in photoautotrophic metabolism that occur during growth in dynamic environments. We argue that a proper evaluation of the intra- and extracellular factors that limit phototrophic production requires the use of highly-controlled cultivation in photobioreactors, coupled to real-time analysis of production parameters and their evaluation by predictive computational models. In this addendum, we discuss the importance and challenges of systems biology approaches for the optimization of renewable biofuels production. As a case study, we present the utilization of a state-of-the-art experimental setup together with a stoichiometric computational model of cyanobacterial metabolism for quantitative evaluation of ethylene production by a recombinant cyanobacterium Synechocystis sp. PCC 6803.

PMID: 27420605 [PubMed - as supplied by publisher]

Developmentally regulated long non-coding RNAs in Xenopus tropicalis.

Dev Biol. 2016 Jul 11;

Authors: Forouzmand E, Owens ND, Blitz IL, Paraiso KD, Khokha MK, Gilchrist MJ, Xie X, Cho KW

Abstract
Advances in RNA sequencing technologies have led to the surprising discovery that a vast number of transcripts emanate from regions of the genome that are not part of coding genes. Although some of the smaller ncRNAs such as microRNAs have well-characterized functions, the majority of long ncRNA (lncRNA) functions remain poorly understood. Understanding the significance of lncRNAs is an important challenge facing biology today. A powerful approach to uncovering the function of lncRNAs is to explore temporal and spatial expression profiling. This may be particularly useful for classes of lncRNAs that have developmentally important roles as the expression of such lncRNAs will be expected to be both spatially and temporally regulated during development. Here, we take advantage of our ultra-high frequency (temporal) sampling of Xenopus embryos to analyze gene expression trajectories of lncRNA transcripts over the first 3 days of development. We computationally identify 5689 potential single- and multi-exon lncRNAs. These lncRNAs demonstrate clear dynamic expression patterns. A subset of them displays highly correlative temporal expression profiles with respect to those of the neighboring genes. We also identified spatially localized lncRNAs in the gastrula stage embryo. These results suggest that lncRNAs have regulatory roles during early embryonic development.

PMID: 27418388 [PubMed - as supplied by publisher]

A roadmap for biocatalysis - functional and spatial orchestration of enzyme cascades.

Microb Biotechnol. 2016 Jul 15;

Authors: Schmidt-Dannert C, Lopez-Gallego F

Abstract
Advances in biological engineering and systems biology have provided new approaches and tools for the industrialization of biology. In the next decade, advanced biocatalytic systems will increasingly be used for the production of chemicals that cannot be made by current processes and/or where the use of enzyme catalysts is more resource efficient with a much reduced environmental impact. We expect that in the future, manufacture of chemicals and materials will utilize both biocatalytic and chemical synthesis synergistically. The realization of such advanced biomanufacturing processes currently faces a number of major challenges. Ready-to-deploy portfolios of biocatalysts for design to production must be created from biological diverse sources and through protein engineering. Robust and efficient multi-step enzymatic reaction cascades must be developed that can operate simultaneously in one-pot. For this to happen, bio-orthogonal strategies for spatial and temporal control of biocatalyst activities must be developed. Promising approaches and technologies are emerging that will eventually lead to the design of in vitro biocatalytic systems that mimic the metabolic pathways and networks of cellular systems which will be discussed in this roadmap.

PMID: 27418373 [PubMed - as supplied by publisher]

11 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

("orphan disease" OR "rare disease" OR "orphan diseases" OR "rare diseases")

These pubmed results were generated on 2016/07/15

PubMed comprises more than 24 million citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

6 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Cystic Fibrosis"

These pubmed results were generated on 2016/07/15

PubMed comprises more than 24 million citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Genetic polymorphisms study of pharmacogenomic VIP variants in Han ethnic of China's Shaanxi province.

Environ Toxicol Pharmacol. 2016 Jun 27;46:27-35

Authors: Jin T, Zhao R, Shi X, He N, He X, Ouyang Y, Wang H, Wang B, Kang L, Yuan D

Abstract
BACKGROUND: Multiple factors include genetic and non-genetic interactions induce to different drug response among different individuals. Lots of researches proved that different frequencies of genetic variants exists different ethnic groups. The aim of this study was to screen Han volunteers in Shaanxi for VIP gene polymorphisms.
MATERIALS AND METHODS: We genotyped 80 Very Important Pharmacogenes (VIP) (selected from the PharmGKB database) in 192 unrelated, healthy Han ethnic adults from Shaanxi, the northwest of China, and then analyzed genotyping data wtih Structure and F-statistics (Fst) analysis.
RESULTS: We compared our data with 15 other populations (Deng, Kyrgyz, Tajik, Uygur and 11 HapMap populations), and found the frequency distribution of Han population in Shaanxi is most similar with CHB. Also, Structure and Fst showed that Shaanxi Han has a closest genetic background with CHB.
CONCLUSIONS: Our study have supplemented the Han Chinese data related to pharmacogenomics and illustrated differences in genotypic frequencies of selected VIP variants' among the Han population and 15 other populations.

PMID: 27414743 [PubMed - as supplied by publisher]

Chemotherapy induced neutropenia at 1-month mark is a predictor of overall survival in patients receiving TAS-102 for refractory metastatic colorectal cancer: a cohort study.

BMC Cancer. 2016;16:467

Authors: Kasi PM, Kotani D, Cecchini M, Shitara K, Ohtsu A, Ramanathan RK, Hochster HS, Grothey A, Yoshino T

Abstract
BACKGROUND: TAS-102 (trifluridine and tipiracil hydrochloride; a novel combination oral nucleoside anti-tumor agent) has recently received regulatory approval for patients with refractory metastatic colorectal cancer (mCRC). Internal review of data at a single-institution showed a trend towards better overall survival (OS) for patients who experienced chemotherapy-induced neutropenia at 1-month (CIN-1-month). To explore this finding further, a cohort study was designed based on outcome data from three centers in United States and one from Japan.
METHODS: CIN-1-month after starting TAS-102 was defined by the Common Terminology Criteria for Adverse Events (CTCAE), version 4.03 as a neutrophil count decrease of ≥ grade 2 (absolute neutrophil count < 1500/mm(3)). Patients had confirmed mCRC that was refractory to standard therapies. Patient demographics and clinical characteristics were compared between patients with CIN-1-month (CIN-1-month positive) versus those who did not have CIN-1-month (CIN-1-month negative); with the median progression-free survival (PFS) and OS were calculated using the Kaplan-Meier method, and differences evaluated using the Log-rank test.
RESULTS: Our cohort study had a total of 149 patients with data regarding their neutrophil assessment at 1-month mark. Patients who developed ≥ grade 2 CIN-1-month had a both longer PFS (median 3.0 months versus 2.4 months; Log-rank P-value = 0.01), as well as OS (14.0 versus 5.6 months; Log-rank P-value < 0.0001). Only CIN-1-month (adjusted HR: 0.21 (95 % CI: 0.11-0.38) and higher baseline CEA levels (adjusted HR: 2.00 (95 % CI: 1.22-3.35) were noted to be independent predictors of OS. Furthermore, the CIN-1-month was noted to be a statistically significantly predictor of OS over a wide range of cutoffs.
CONCLUSIONS: Our observations are novel and hypothesis generating. Neutropenia after starting TAS-102 was associated with better prognosis in patients with refractory mCRC. It can be postulated that the dosage of TAS-102 potentially may need to be increased to achieve better outcomes in patients not experiencing any neutropenia. Further pharmacologic investigations should help elucidate these issues.

PMID: 27412464 [PubMed - in process]

Topological Small-World Organization of the Fibroblastic Reticular Cell Network Determines Lymph Node Functionality.

PLoS Biol. 2016 Jul;14(7):e1002515

Authors: Novkovic M, Onder L, Cupovic J, Abe J, Bomze D, Cremasco V, Scandella E, Stein JV, Bocharov G, Turley SJ, Ludewig B

Abstract
Fibroblastic reticular cells (FRCs) form the cellular scaffold of lymph nodes (LNs) and establish distinct microenvironmental niches to provide key molecules that drive innate and adaptive immune responses and control immune regulatory processes. Here, we have used a graph theory-based systems biology approach to determine topological properties and robustness of the LN FRC network in mice. We found that the FRC network exhibits an imprinted small-world topology that is fully regenerated within 4 wk after complete FRC ablation. Moreover, in silico perturbation analysis and in vivo validation revealed that LNs can tolerate a loss of approximately 50% of their FRCs without substantial impairment of immune cell recruitment, intranodal T cell migration, and dendritic cell-mediated activation of antiviral CD8+ T cells. Overall, our study reveals the high topological robustness of the FRC network and the critical role of the network integrity for the activation of adaptive immune responses.

PMID: 27415420 [PubMed - as supplied by publisher]

Network analysis and juvenile idiopathic arthritis (JIA): a new horizon for the understanding of disease pathogenesis and therapeutic target identification.

Pediatr Rheumatol Online J. 2016;14(1):40

Authors: Donn R, De Leonibus C, Meyer S, Stevens A

Abstract
Juvenile idiopathic arthritis (JIA) is a clinically diverse and genetically complex autoimmune disease. Currently, there is very limited understanding of the potential underlying mechanisms that result in the range of phenotypes which constitute JIA.The elucidation of the functional relevance of genetic associations with phenotypic traits is a fundamental problem that hampers the translation of genetic observations to plausible medical interventions. Genome wide association studies, and subsequent fine-mapping studies in JIA patients, have identified many genetic variants associated with disease. Such approaches rely on 'tag' single nucleotide polymorphisms (SNPs). The associated SNPs are rarely functional variants, so the extrapolation of genetic association data to the identification of biologically meaningful findings can be a protracted undertaking. Integrative genomics aims to bridge the gap between genotype and phenotype.Systems biology, principally through network analysis, is emerging as a valuable way to identify biological pathways of relevance to complex genetic diseases. This review aims to highlight recent findings in systems biology related to JIA in an attempt to assist in the understanding of JIA pathogenesis and therapeutic target identification.

PMID: 27411317 [PubMed - in process]

Overview of major molecular alterations during progression from Barrett's esophagus to esophageal adenocarcinoma.

Ann N Y Acad Sci. 2016 Jul 14;

Authors: Kalatskaya I

Abstract
Esophageal adenocarcinoma (EAC) develops in the sequential transformation of normal epithelium into metaplastic epithelium, called Barrett's esophagus (BE), then to dysplasia, and finally cancer. BE is a common condition in which normal stratified squamous epithelium of the esophagus is replaced with an intestine-like columnar epithelium, and it is the most prominent risk factor for EAC. This review aims to impartially systemize the knowledge from a large number of publications that describe the molecular and biochemical alterations occurring over this progression sequence. In order to provide an unbiased extraction of the knowledge from the literature, a text-mining methodology was used to select genes that are involved in the BE progression, with the top candidate genes found to be TP53, CDKN2A, CTNNB1, CDH1, GPX3, and NOX5. In addition, sample frequencies across analyzed patient cohorts at each stage of disease progression are summarized. All six genes are altered in the majority of EAC patients, and accumulation of alterations correlates well with the sequential progression of BE to cancer, indicating that the text-mining method is a valid approach for gene prioritization. This review discusses how, besides being cancer drivers, these genes are functionally interconnected and might collectively be considered a central hub of BE progression.

PMID: 27415609 [PubMed - as supplied by publisher]

Muscle Logic: New Knowledge Resource for Anatomy Enables Comprehensive Searches of the Literature on the Feeding Muscles of Mammals.

PLoS One. 2016;11(2):e0149102

Authors: Druzinsky RE, Balhoff JP, Crompton AW, Done J, German RZ, Haendel MA, Herrel A, Herring SW, Lapp H, Mabee PM, Muller HM, Mungall CJ, Sternberg PW, Van Auken K, Vinyard CJ, Williams SH, Wall CE

Abstract
BACKGROUND: In recent years large bibliographic databases have made much of the published literature of biology available for searches. However, the capabilities of the search engines integrated into these databases for text-based bibliographic searches are limited. To enable searches that deliver the results expected by comparative anatomists, an underlying logical structure known as an ontology is required.
DEVELOPMENT AND TESTING OF THE ONTOLOGY: Here we present the Mammalian Feeding Muscle Ontology (MFMO), a multi-species ontology focused on anatomical structures that participate in feeding and other oral/pharyngeal behaviors. A unique feature of the MFMO is that a simple, computable, definition of each muscle, which includes its attachments and innervation, is true across mammals. This construction mirrors the logical foundation of comparative anatomy and permits searches using language familiar to biologists. Further, it provides a template for muscles that will be useful in extending any anatomy ontology. The MFMO is developed to support the Feeding Experiments End-User Database Project (FEED, https://feedexp.org/), a publicly-available, online repository for physiological data collected from in vivo studies of feeding (e.g., mastication, biting, swallowing) in mammals. Currently the MFMO is integrated into FEED and also into two literature-specific implementations of Textpresso, a text-mining system that facilitates powerful searches of a corpus of scientific publications. We evaluate the MFMO by asking questions that test the ability of the ontology to return appropriate answers (competency questions). We compare the results of queries of the MFMO to results from similar searches in PubMed and Google Scholar.
RESULTS AND SIGNIFICANCE: Our tests demonstrate that the MFMO is competent to answer queries formed in the common language of comparative anatomy, but PubMed and Google Scholar are not. Overall, our results show that by incorporating anatomical ontologies into searches, an expanded and anatomically comprehensive set of results can be obtained. The broader scientific and publishing communities should consider taking up the challenge of semantically enabled search capabilities.

PMID: 26870952 [PubMed - indexed for MEDLINE]

13 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

("orphan disease" OR "rare disease" OR "orphan diseases" OR "rare diseases")

These pubmed results were generated on 2016/07/14

PubMed comprises more than 24 million citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.