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Latest Ebola data rule out rapid mutation

news@nature - Tue, 05/19/2015 - 9:21am

Genetic-sequence haul shows that the virus evolved differently — but no faster — than in previous epidemics.

Nature News doi: 10.1038/nature.2015.17554

When Patient Is Ms. -- Not Mr. -- Celiac Diagnosis Is Delayed

Headlines from MedPage Today® - Tue, 05/19/2015 - 9:00am
(MedPage Today) -- Swiss study suggests that physicians are slower to act on women's symptoms.

RNA Interference in Caenorhabditis elegans

eScholarship@UMMS - Tue, 05/19/2015 - 8:51am

RNAi has become an essential tool in C. elegans research. This unit describes procedures for RNAi in C. elegans by microinjecting with dsRNA, feeding with bacteria expressing dsRNA, and soaking in dsRNA solution, as well as high-throughput methods for RNAi-based screens. (c) 2015 by John Wiley and Sons, Inc.

Let a hundred flowers bloom: the role of context dependence in creating phenotypic diversity following targeted therapy

eScholarship@UMMS - Tue, 05/19/2015 - 8:51am

Using a newly developed computational platform, COSPER, Litvin et al. (2015) identify context-dependent interactions between MEK and interferon signaling that underlie sensitivity and resistance to MEK inhibition in melanoma.

Spatial enhancer clustering and regulation of enhancer-proximal genes by cohesin

eScholarship@UMMS - Tue, 05/19/2015 - 8:51am

In addition to mediating sister chromatid cohesion during the cell cycle, the cohesin complex associates with CTCF and with active gene regulatory elements to form long-range interactions between its binding sites. Genome-wide chromosome conformation capture had shown that cohesin's main role in interphase genome organization is in mediating interactions within architectural chromosome compartments, rather than specifying compartments per se. However, it remains unclear how cohesin-mediated interactions contribute to the regulation of gene expression. We have found that the binding of CTCF and cohesin is highly enriched at enhancers and in particular at enhancer arrays or "super-enhancers" in mouse thymocytes. Using local and global chromosome conformation capture, we demonstrate that enhancer elements associate not just in linear sequence, but also in 3D, and that spatial enhancer clustering is facilitated by cohesin. The conditional deletion of cohesin from noncycling thymocytes preserved enhancer position, H3K27ac, H4K4me1, and enhancer transcription, but weakened interactions between enhancers. Interestingly, approximately 50% of deregulated genes reside in the vicinity of enhancer elements, suggesting that cohesin regulates gene expression through spatial clustering of enhancer elements. We propose a model for cohesin-dependent gene regulation in which spatial clustering of enhancer elements acts as a unified mechanism for both enhancer-promoter "connections" and "insulation."

Widespread macromolecular interaction perturbations in human genetic disorders

eScholarship@UMMS - Tue, 05/19/2015 - 8:51am

How disease-associated mutations impair protein activities in the context of biological networks remains mostly undetermined. Although a few renowned alleles are well characterized, functional information is missing for over 100,000 disease-associated variants. Here we functionally profile several thousand missense mutations across a spectrum of Mendelian disorders using various interaction assays. The majority of disease-associated alleles exhibit wild-type chaperone binding profiles, suggesting they preserve protein folding or stability. While common variants from healthy individuals rarely affect interactions, two-thirds of disease-associated alleles perturb protein-protein interactions, with half corresponding to "edgetic" alleles affecting only a subset of interactions while leaving most other interactions unperturbed. With transcription factors, many alleles that leave protein-protein interactions intact affect DNA binding. Different mutations in the same gene leading to different interaction profiles often result in distinct disease phenotypes. Thus disease-associated alleles that perturb distinct protein activities rather than grossly affecting folding and stability are relatively widespread.

Human gene-centered transcription factor networks for enhancers and disease variants

eScholarship@UMMS - Tue, 05/19/2015 - 8:51am

Gene regulatory networks (GRNs) comprising interactions between transcription factors (TFs) and regulatory loci control development and physiology. Numerous disease-associated mutations have been identified, the vast majority residing in non-coding regions of the genome. As current GRN mapping methods test one TF at a time and require the use of cells harboring the mutation(s) of interest, they are not suitable to identify TFs that bind to wild-type and mutant loci. Here, we use gene-centered yeast one-hybrid (eY1H) assays to interrogate binding of 1,086 human TFs to 246 enhancers, as well as to 109 non-coding disease mutations. We detect both loss and gain of TF interactions with mutant loci that are concordant with target gene expression changes. This work establishes eY1H assays as a powerful addition to the toolkit of mapping human GRNs and for the high-throughput characterization of genomic variants that are rapidly being identified by genome-wide association studies.

Australia takes university cash to pay for research facilities

news@nature - Tue, 05/19/2015 - 5:21am

But overall flat science funding in latest budget is seen as a reprieve after last year’s heavy cuts.

Nature News doi: 10.1038/nature.2015.17556

How Hospitals Nab High Ratings: HealthLeaders Media

Headlines from MedPage Today® - Mon, 05/18/2015 - 7:00pm
(MedPage Today) -- Also, clinical registry shortcomings and unscheduled care.

Harvoni Safe and Effective for Cirrhotic Patients (CME/CE)

Headlines from MedPage Today® - Mon, 05/18/2015 - 6:00pm
(MedPage Today) -- Perfect response rates with 24 weeks Harvoni plus ribavirin.

IBS: Peppermint Oil May Be a Treatment Option (CME/CE)

Headlines from MedPage Today® - Mon, 05/18/2015 - 5:33pm
(MedPage Today) -- Slow-release formula offers relief within an hour.

GI Events Do Not Explain Weight Loss With Saxenda (CME/CE)

Headlines from MedPage Today® - Mon, 05/18/2015 - 5:30pm
(MedPage Today) -- No difference in weight loss between patients who had nausea and vomiting with diet drug, and those who didn't.

Populations at Risk: Hepatitis C

Headlines from MedPage Today® - Mon, 05/18/2015 - 5:29pm
(MedPage Today) -- 10 days, 10 questions: Day 1 -- Who is at risk and how can they be reached?

NASH: First Cut on Comparative Effectiveness; Dire Outcomes in Pediatric Cases (CME/CE)

Headlines from MedPage Today® - Mon, 05/18/2015 - 5:00pm
(MedPage Today) -- Two studies illustrate how much remains to be learned about treating NASH.

ATS: Combo Tx Cuts Admissions in PAH

Headlines from MedPage Today® - Mon, 05/18/2015 - 4:30pm
(MedPage Today) -- Initial therapy with ambrisentan plus tadalafil lowered the rate of hospitalization.

E-Cigs Hamper Ability to Cough

Headlines from MedPage Today® - Mon, 05/18/2015 - 3:30pm
(MedPage Today) -- Just one exposure significantly diminished cough reflex sensitivity.

A laminin 511 matrix is regulated by TAZ and functions as the ligand for the alpha6Bbeta1 integrin to sustain breast cancer stem cells

eScholarship@UMMS - Mon, 05/18/2015 - 3:06pm

Understanding how the extracellular matrix impacts the function of cancer stem cells (CSCs) is a significant but poorly understood problem. We report that breast CSCs produce a laminin (LM) 511 matrix that promotes self-renewal and tumor initiation by engaging the alpha6Bbeta1 integrin and activating the Hippo transducer TAZ. Although TAZ is important for the function of breast CSCs, the mechanism is unknown. We observed that TAZ regulates the transcription of the alpha5 subunit of LM511 and the formation of a LM511 matrix. These data establish a positive feedback loop involving TAZ and LM511 that contributes to stemness in breast cancer.

Orphan nuclear receptor TR3/Nur77 improves wound healing by upregulating the expression of integrin beta4

eScholarship@UMMS - Mon, 05/18/2015 - 3:06pm

Tissue repair/wound healing, in which angiogenesis plays an important role, is a critical step in many diseases including chronic wound, myocardial infarction, stroke, cancer, and inflammation. Recently, we were the first to report that orphan nuclear receptor TR3/Nur77 is a critical mediator of angiogenesis and its associated microvessel permeability. Tumor growth and angiogenesis induced by VEGF-A, histamine, and serotonin are almost completely inhibited in Nur77 knockout mice. However, it is not known whether TR3/Nur77 plays any roles in wound healing. In these studies, skin wound-healing assay was performed in 3 types of genetically modified mice having various Nur77 activities. We found that ectopic induction of Nur77 in endothelial cells of mice is sufficient to improve skin wound healing. Although skin wound healing in Nur77 knockout mice is comparable to the wild-type control mice, the process is significantly delayed in the EC-Nur77-DN mice, in which a dominant negative Nur77 mutant is inducibly and specifically expressed in mouse endothelial cells. By a loss-of-function assay, we elucidate a novel feed-forward signaling pathway, integrin beta4 --> PI3K --> Akt --> FAK, by which TR3 mediates HUVEC migration. Furthermore, TR3/Nur77 regulates the expression of integrin beta4 by targeting its promoter activity. In conclusion, expression of TR3/Nur77 improves wound healing by targeting integrin beta4. TR3/Nur77 is a potential candidate for proangiogenic therapy. The results further suggest that TR3/Nur77 is required for pathologic angiogenesis but not for developmental/physiologic angiogenesis and that Nur77 and its family members play a redundant role in normal skin wound healing.

Deletion of the gene encoding G0/G 1 switch protein 2 (G0s2) alleviates high-fat-diet-induced weight gain and insulin resistance, and promotes browning of white adipose tissue in mice

eScholarship@UMMS - Mon, 05/18/2015 - 3:06pm

AIMS/HYPOTHESIS: Obesity is a global epidemic resulting from increased energy intake, which alters energy homeostasis and results in an imbalance in fat storage and breakdown. G0/G1 switch gene 2 (G0s2) has been recently characterised in vitro as an inhibitor of adipose triglyceride lipase (ATGL), the rate-limiting step in fat catabolism. In the current study we aim to functionally characterise G0s2 within the physiological context of a mouse model.

METHODS: We generated a mouse model in which G0s2 was deleted. The homozygous G0s2 knockout (G0s2 (-/-)) mice were studied over a period of 22 weeks. Metabolic variables were measured including body weight and body composition, food intake, glucose and insulin tolerance tests, energy metabolism and thermogenesis.

RESULTS: We report that G0s2 inhibits ATGL and regulates lipolysis and energy metabolism in vivo. G0s2 (-/-) mice are lean, resistant to weight gain induced by a high-fat diet and are glucose tolerant and insulin sensitive. The white adipose tissue of G0s2 (-/-) mice has enhanced lipase activity and adipocytes showed enhanced stimulated lipolysis. Energy metabolism in the G0s2 (-/-) mice is shifted towards enhanced lipid metabolism and increased thermogenesis. G0s2 (-/-) mice showed enhanced cold tolerance and increased expression of thermoregulatory and oxidation genes within white adipose tissue, suggesting enhanced 'browning' of the white adipose tissue.

CONCLUSIONS/INTERPRETATION: Our data show that G0s2 is a physiological regulator of adiposity and energy metabolism and is a potential target in the treatment of obesity and insulin resistance.

Development of a prognostic genetic signature to predict the metastatic risk associated with cutaneous melanoma

eScholarship@UMMS - Mon, 05/18/2015 - 3:06pm

PURPOSE: The development of a genetic signature for the identification of high-risk cutaneous melanoma tumors would provide a valuable prognostic tool with value for stage I and II patients who represent a remarkably heterogeneous group with a 3% to 55% chance of disease progression and death 5 years from diagnosis.

EXPERIMENTAL DESIGN: A prognostic 28-gene signature was identified by analysis of microarray expression data. Primary cutaneous melanoma tumor tissue was evaluated by RT-PCR for expression of the signature, and radial basis machine (RBM) modeling was performed to predict risk of metastasis.

RESULTS: RBM analysis of cutaneous melanoma tumor gene expression reports low risk (class 1) or high risk (class 2) of metastasis. Metastatic risk was predicted with high accuracy in development (ROC = 0.93) and validation (ROC = 0.91) cohorts of primary cutaneous melanoma tumor tissue. Kaplan-Meier analysis indicated that the 5-year disease-free survival (DFS) rates in the development set were 100% and 38% for predicted classes 1 and 2 cases, respectively (P < 0.0001). DFS rates for the validation set were 97% and 31% for predicted classes 1 and 2 cases, respectively (P < 0.0001). Gene expression profile (GEP), American Joint Committee on Cancer stage, Breslow thickness, ulceration, and age were independent predictors of metastatic risk according to Cox regression analysis.

CONCLUSIONS: The GEP signature accurately predicts metastasis risk in a multicenter cohort of primary cutaneous melanoma tumors. Preliminary Cox regression analysis indicates that the signature is an independent predictor of metastasis risk in the cohort presented.

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