HSV-1 antigens and DNA in the corneal explant buttons of patients with non-herpetic or clinically atypical herpetic stromal keratitis

Background: Little is known about the role of HSV-1 in keratitis not primarily attributed to herpetic origin. This study therefore aimed to prospectively evaluate the corneal explant buttons of patients with non-herpetic or clinically atypical herpetic stromal keratitis (experimental group: non-HSK) for the presence of HSV-1 antigens and DNA, and to compare the findings with those from individuals with typical herpetic stromal keratitis (positive control group: HSK) or non-inflammatory degenerative keratopathy (negative control group). Methods: Corneal buttons derived from 51 patients with HSK, from 72 with non-HSK and from 30 with degenerative keratopathy were prospectively collected and subjected to immunohistochemical analysis for HSV-1 antigens and to HSV-1 DNA amplification. Results: In corneal buttons derived from patients with non-HSK, viral antigens were detected immunohistochemically in 8/72 cases and DNA amplified in 16/72. Corresponding values for the HSK group were 16/51 and 11/51. Taking viral antigen and DNA findings together, HSV-1 was detected in 18/72 (25%) patients with non-HSK and in 19/51 (37%) with HSK (p=0.2), but in only 2/30 (6%) individuals with non-inflammatory degenerative keratopathy. Conclusion: Since the detection frequencies for HSV-1 antigens and DNA were comparable in the HSK and non-HSK groups, Herpes may play an underestimated and as yet undefined role in non-herpetic and clinically atypical herpetic stromal keratitis, either as a primary trigger of the disease or as a secondary contributor to it. In this category of individuals, early anti-herpetic therapy should be considered if patients do not respond in the expected manner to treatment for non-herpetic stromal keratiti

Replication confers β cell immaturity.

Pancreatic β cells are highly specialized to regulate systemic glucose levels by secreting insulin. In adults, increase in β-cell mass is limited due to brakes on cell replication. In contrast, proliferation is robust in neonatal β cells that are functionally immature as defined by a lower set point for glucose-stimulated insulin secretion. Here we show that β-cell proliferation and immaturity are linked by tuning expression of physiologically relevant, non-oncogenic levels of c-Myc. Adult β cells induced to replicate adopt gene expression and metabolic profiles resembling those of immature neonatal β that proliferate readily. We directly demonstrate that priming insulin-producing cells to enter the cell cycle promotes a functionally immature phenotype. We suggest that there exists a balance between mature functionality and the ability to expand, as the phenotypic state of the β cell reverts to a less functional one in response to proliferative cues

Crossing the Communication Chasm: Challenges and Opportunities in Transitions of Care from the Hospital to the Primary Care Clinic

Background Transitions of care from specialty and acute settings to primary care abound. Compared to the continuity in end-of-shift handoffs, care transitions involve provider communication between practices and facilities with their own cultures and bureaucracies. Using the transition from acute care to outpatient primary care for stroke/transient ischemic attack (TIA) patients as a case study, this qualitative research explored communication practices and institutional arrangements among clinical providers responsible for longitudinal management of hypertension. In this study, researchers investigated the barriers and facilitators of effective communication between acute stroke/TIA inpatient and primary care providers at a Veterans Affairs Medical Center. Methods A multidisciplinary team conducted consensus-based coding and thematic analysis of semistructured interviews with 21 clinical providers (9 with primary responsibilities for inpatient care and 12 with primary responsibilities in outpatient, primary care). Results Thematic analysis of responses identified three factors that influenced communication between clinical providers: (1) consistent, concise but complete medication and treatment plans; (2) reliable, standardized discharge documentation; (3) use of multiple modes of communication. Participants identified cultural barriers, including challenges with rotating providers at a teaching hospital and local discharge practices. Conclusion Ambiguity about who is being handed off to and time pressures in the acute setting may lead inpatient providers to give lower priority to discharge communication, leaving outpatient providers with low-quality information. While electronic templates have standardized key components of discharge documentation, improvement opportunities remain. Increased awareness of the challenges and opportunities on each side of the care transfer could foster communication practices that systematically account for the information needs of inpatient and outpatient providers

Mitigating Ischemic Injury of Stem Cell-Derived Insulin-Producing Cells after Transplant.

The advent of large-scale in vitro differentiation of human stem cell-derived insulin-producing cells (SCIPC) has brought us closer to treating diabetes using stem cell technology. However, decades of experiences from islet transplantation show that ischemia-induced islet cell death after transplant severely limits the efficacy of the therapy. It is unclear to what extent human SCIPC are susceptible to ischemia. In this study, we show that more than half of SCIPC die shortly after transplantation. Nutrient deprivation and hypoxia acted synergistically to kill SCIPC in vitro. Amino acid supplementation rescued SCIPC from nutrient deprivation, likely by providing cellular energy. Generating SCIPC under physiological oxygen tension of 5% conferred hypoxia resistance without affecting their differentiation or function. A two-pronged strategy of physiological oxygen acclimatization during differentiation and amino acid supplementation during transplantation significantly improved SCIPC survival after transplant

Systematic interaction network filtering identifies CRMP1 as a novel suppressor of huntingtin misfolding and neurotoxicity

Assemblies of huntingtin (HTT) fragments with expanded polyglutamine (polyQ) tracts are a pathological hallmark of Huntington's disease (HD). The molecular mechanisms by which these structures are formed and cause neuronal dysfunction and toxicity are poorly understood. Here, we utilized available gene expression data sets of selected brain regions of HD patients and controls for systematic interaction network filtering in order to predict disease-relevant, brain region-specific HTT interaction partners. Starting from a large protein-protein interaction (PPI) data set, a step-by-step computational filtering strategy facilitated the generation of a focused PPI network that directly or indirectly connects 13 proteins potentially dysregulated in HD with the disease protein HTT. This network enabled the discovery of the neuron-specific protein CRMP1 that targets aggregation-prone, N-terminal HTT fragments and suppresses their spontaneous self-assembly into proteotoxic structures in various models of HD. Experimental validation indicates that our network filtering procedure provides a simple but powerful strategy to identify disease-relevant proteins that influence misfolding and aggregation of polyQ disease proteins.DFG [SFB740, 740/2-11, SFB618, 618/3-09, SFB/TRR43 A7]; BMBF(NGFN-Plus) [01GS08169-73, 01GS08150, 01GS08108]; HDSA Coalition for the Cure; EU (EuroSpin) [Health-F2-2009-241498, HEALTH-F2-2009-242167]; Helmholtz Association (MSBN, HelMA) [HA-215]; FCT [IF/00881/2013]info:eu-repo/semantics/publishedVersio

Recommendations on the development, use and provision of Research Software

These recommendations describe challenges relating to research software and provide recommendations for the development, use and provision of this type of software. The relevance of research software to modern research should be clearly underlined, especially in the context of political debate on digital transformation in the sciences and humanities. This document was prepared by the Research Software Working Group, established in 2016, within the Alliance initiative

On the nature of long-range contributions to pair interactions between charged colloids in two dimensions

We perform a detailed analysis of solutions of the inverse problem applied to experimentally measured two-dimensional radial distribution functions for highly charged latex dispersions. The experiments are carried out at high colloidal densities and under low-salt conditions. At the highest studied densities, the extracted effective pair potentials contain long-range attractive part. At the same time, we find that for the best distribution functions available the range of stability of the solutions is limited by the nearest neighbour distance between the colloidal particles. Moreover, the measured pair distribution functions can be explained by purely repulsive pair potentials contained in the stable part of the solution.Comment: 6 pages, 5 figure

Comparison and consolidation of microarray data sets of human tissue expression

<p>Abstract</p> <p>Background</p> <p>Human tissue displays a remarkable diversity in structure and function. To understand how such diversity emerges from the same DNA, systematic measurements of gene expression across different tissues in the human body are essential. Several recent studies addressed this formidable task using microarray technologies. These large tissue expression data sets have provided us an important basis for biomedical research. However, it is well known that microarray data can be compromised by high noise level and various experimental artefacts. Critical comparison of different data sets can help to reveal such errors and to avoid pitfalls in their application.</p> <p>Results</p> <p>We present here the first comparison and integration of four freely available tissue expression data sets generated using three different microarray platforms and containing a total of 377 microarray hybridizations. When assessing the tissue expression of genes, we found that the results considerably depend on the chosen data set. Nevertheless, the comparison also revealed statistically significant similarity of gene expression profiles across different platforms. This enabled us to construct consolidated lists of platform-independent tissue-specific genes using a set of complementary measures. Follow-up analyses showed that results based on consolidated data tend to be more reliable.</p> <p>Conclusions</p> <p>Our study strongly indicates that the consolidation of the four different tissue expression data sets can increase data quality and can lead to biologically more meaningful results. The provided compendium of platform-independent gene lists should facilitate the identification of novel tissue-specific marker genes.</p

Three-body interactions in colloidal systems

We present the first direct measurement of three-body interactions in a colloidal system comprised of three charged colloidal particles. Two of the particles have been confined by means of a scanned laser tweezers to a line-shaped optical trap where they diffused due to thermal fluctuations. Upon the approach of a third particle, attractive three-body interactions have been observed. The results are in qualitative agreement with additionally performed nonlinear Poissson-Boltzmann calculations, which also allow us to investigate the microionic density distributions in the neighborhood of the interacting colloidal particles

<em>CYP2D6 </em>genotype and adjuvant tamoxifen:meta-analysis of heterogeneous study populations

The International Tamoxifen Pharmacogenomics Consortium was established to address the controversy regarding cytochrome P450 2D6 (CYP2D6) status and clinical outcomes in tamoxifen therapy. We performed a meta-analysis on data from 4,973 tamoxifen-treated patients (12 globally distributed sites). Using strict eligibility requirements (postmenopausal women with estrogen receptor-positive breast cancer, receiving 20 mg/day tamoxifen for 5 years, criterion 1), CYP2D6 poor metabolizer status was associated with poorer invasive disease-free survival (IDFS: hazard ratio = 1.25; 95% confidence interval = 1.06, 1.47; P = 0.009). However, CYP2D6 status was not statistically significant when tamoxifen duration, menopausal status, and annual follow-up were not specified (criterion 2, n = 2,443; P = 0.25) or when no exclusions were applied (criterion 3, n = 4,935; P = 0.38). Although CYP2D6 is a strong predictor of IDFS using strict inclusion criteria, because the results are not robust to inclusion criteria (these were not defined a priori), prospective studies are necessary to fully establish the value of CYP2D6 genotyping in tamoxifen therapy.</p