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Banerji J.,Center for Computational and Integrative Biology
International Journal of Molecular Medicine | Year: 2015

The present treatment of childhood T-cell leukemias involves the systemic administration of prokaryotic L-asparaginase (ASNase), which depletes plasma Asparagine (Asn) and inhibits protein synthesis. The mechanism of therapeutic action of ASNase is poorly understood, as are the etiologies of the side-effects incurred by treatment. Protein expression from genes bearing Asn homopolymeric coding regions (N-hCR) may be particularly susceptible to Asn level fluctuation. In mammals, N-hCR are rare, short and conserved. In humans, misfunctions of genes encoding N-hCR are associated with a cluster of disorders that mimic ASNase therapy side-effects which include impaired glycemic control, dislipidemia, pancreatitis, compromised vascular integrity, and neurological dysfunction. This paper proposes that dysregulation of Asn homeostasis, potentially even by ASNase produced by the microbiome, may contribute to several clinically important syndromes by altering expression of N-hCR bearing genes. By altering amino acid abundance and modulating ribosome translocation rates at codon repeats, the microbiomic environment may contribute to genome decoding and to shaping the proteome. We suggest that impaired translation at poly Asn codons elevates diabetes risk and severity.

Xiong Y.,Chinese Academy of Sciences | Sheen J.,Harvard University | Sheen J.,Center for Computational and Integrative Biology
Current Opinion in Plant Biology | Year: 2015

Nutrient and energy sensing and signaling mechanisms constitute the most ancient and fundamental regulatory networks to control growth and development in all life forms. The target of rapamycin (TOR) protein kinase is modulated by diverse nutrient, energy, hormone and stress inputs and plays a central role in regulating cell proliferation, growth, metabolism and stress responses from yeasts to plants and animals. Recent chemical, genetic, genomic and metabolomic analyses have enabled significant progress toward molecular understanding of the TOR signaling network in multicellular plants. This review discusses the applications of new chemical tools to probe plant TOR functions and highlights recent findings and predictions on TOR-mediate biological processes. Special focus is placed on novel and evolutionarily conserved TOR kinase effectors as positive and negative signaling regulators that control transcription, translation and metabolism to support cell proliferation, growth and maintenance from embryogenesis to senescence in the plant system. © 2015 Elsevier Ltd.

Ananthakrishnan A.N.,Massachusetts General Hospital | Ananthakrishnan A.N.,Harvard University | Oxford E.C.,Tulane University | Nguyen D.D.,Massachusetts General Hospital | And 9 more authors.
Alimentary Pharmacology and Therapeutics | Year: 2013

Background Patients with inflammatory bowel disease (IBD) are at higher risk for Clostridium difficile infection (CDI). Disruption of gut microbiome and interaction with the intestinal immune system are essential mechanisms for pathogenesis of both CDI and IBD. Whether genetic polymorphisms associated with susceptibility to IBD are also associated with risk of CDI is unknown. Aims To use a well-characterised and genotyped cohort of patients with UC to (i) identify clinical risk factors for CDI; (ii) examine if any of the IBD genetic risk loci were associated with CDI; and (iii) to compare the performance of predictive models using clinical and genetic risk factors in determining risk of CDI. Methods We used a prospective registry of patients from a tertiary referral hospital. Medical record review was performed to identify all ulcerative colitis (UC) patients within the registry with a history of CDI. All patients were genotyped on the Immunochip. We examined the association between the 163 risk loci for IBD and risk of CDI using a dominant genetic model. Model performance was examined using receiver operating characteristics curves. Results The study included 319 patients of whom 29 developed CDI (9%). Female gender and pancolitis were associated with increased risk, while use of anti-TNF was protective against CDI. Six genetic polymorphisms including those at TNFRSF14 [Odds ratio (OR) 6.0, P-value 0.01] were associated with increased risk while 2 loci were inversely associated. On multivariate analysis, none of the clinical parameters retained significance after adjusting for genetics. Presence of at least one high-risk locus was associated with an increase in risk for CDI (20% vs. 1%) (P = 6 × 10-9). Compared to 11% for a clinical model, the genetic loci explained 28% of the variance in CDI risk and had a greater AUROC. Conclusion Host genetics may influence susceptibility to Clostridium difficile infection in patients with ulcerative colitis. © 2013 John Wiley & Sons Ltd.

"Modern cells are constantly regulating what they are doing—synthesizing, degrading and exporting a whole suite of RNAs and proteins—depending on the cell's particular needs at the time," says Aaron Engelhart, PhD, of the MGH Department of Molecular Biology and the Center for Computational and Integrative Biology, lead author of the paper. "One would expect that the earliest cells weren't nearly as complex as today's cells, but they still had the need to regulate their internal environment. The sort of regulation we've shown here—switching on enzymes during growth—is perhaps the simplest form of the internal regulation that a primitive cell might have needed." Engelhart is a postdoctoral fellow in the laboratory of Jack Szostak, PhD, senior author of the report. A co-recipient of the 2009 Nobel Prize in Physiology or Medicine for his contribution to the discovery of the enzyme telomerase, Szostak and his team have been investigating the origins of life for more than 15 years, and much of their work has focused on developing a model protocell—a primitive, synthetic cell consisting of nucleic acid strands enclosed by a membrane that would be capable of growth, replication and evolution. Previous studies have shown that simple membranes comprised of fatty acids and lacking the complex molecular components of modern cells would still be permeable to small nutrient molecules, including those needed to assemble nucleic acids, such as RNA or DNA. A 2013 study showed it was possible to copy molecules of RNA—which many believe was the genetic blueprint of the first cells—without the complex enzymes used by today's cells, even within small sacs or vesicles formed from fatty acid membranes. Szostak's team has also found that such vesicles will expand under certain conditions, raising the question of how vesicles' internal environment can be maintained, since their contents would become diluted as the enclosing membranes expand. To investigate this question, Engelhart and his colleagues examined how the concentration of a protocell's contents might affect the activity of RNA enzymes, called ribozymes. They hypothesized that high levels of small nucleic acid strands within a cell might bind to corresponding sequences on a ribozyme, suppressing its activity. They first tested this in free solution—not within vesicles—and found that short RNA strands could totally shut down ribozyme activity at high concentrations but had little effect at low concentrations. Experiments with vesicles containing both ribozymes and short strands of RNA specifically designed to bind to the ribozymes showed that enzymatic activity remained steady as the vesicles expanded; but in vesicles containing the enzymes alone, activity dropped as the vesicles grew. The researchers also observed this regulatory effect when the short strands of RNA contained random sequences. "Without some sort of regulatory mechanism like we've shown here, cellular growth would be accompanied by some loss of function, since active enzymes would be present at a lower concentration in larger cells," says Engelhart. "We haven't extended this work to dividing vesicles yet, but a key long-term goal of the lab is developing a full, chemically based primitive cell cycle, including both growth and replication. A number of people in the lab are working on the next step towards that—systems that will allow us to make many copies of a single strand of RNA—and it will be very exciting to see how systems like the one we've explored in this paper work in such a cycle." Explore further: The search for life's stirrings

Huett A.,Center for Computational and Integrative Biology | Huett A.,Harvard University | Goel G.,Center for Computational and Integrative Biology | Xavier R.J.,Center for Computational and Integrative Biology | And 3 more authors.
Current Opinion in Gastroenterology | Year: 2010

Purpose of review: The field of autophagy is rapidly expanding to encompass many important areas of cell biology, physiology and disease. Recent discoveries and tools allow the connection of the autophagy pathway to other cellular signals and processes, thus beginning a systematic approach to elucidation of autophagy components, functions and connections. Recent findings: We outline recent discoveries illustrating the role of autophagy in Parkinson's disease, inflammatory bowel disease (IBD) and cancer. Recently important details of the mechanisms by which autophagy operates in these contexts have been elucidated. We illustrate how autophagy can be triggered by diverse stimuli and how cell fate is determined by the responses to many signals and stresses. We discuss the known links between autophagy and apoptosis and present a working model of the current interactions between autophagy components, apoptosis and cell cycle control at different stages of autophagic vesicle progression. Summary: Autophagy represents not only an essential metabolic process, but a hub which responds to diverse stresses and signals to aid cell survival or control cell fate. There are currently many known links between autophagy and disease states, and the pace of discovery appears to be accelerating. Thus an understanding of autophagy is likely to be crucial to current and future approaches to therapy. Here we give a systems biology view of the autophagy field and how it is being connected to other pathways, such as apoptosis and responses to reactive oxygen damage. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.

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