Deficiency in Nucleotide Excision Repair Family Gene Activity, Especially ERCC3, Is Associated with Non-Pigmented Hair Fiber Growth

We conducted a microarray study to discover gene expression patterns associated with a lack of melanogenesis in non-pigmented hair follicles (HF) by microarray. Pigmented and non-pigmented HFs were collected and micro-dissected into the hair bulb (HB) and the upper hair sheaths (HS) including the bulge region. In comparison to pigmented HS and HBs, nucleotide excision repair (NER) family genes ERCC1, ERCC2, ERCC3, ERCC4, ERCC5, ERCC6, XPA, NTPBP, HCNP, DDB2 and POLH exhibited statistically significantly lower expression in non- pigmented HS and HBs. Quantitative PCR verified microarray data and identified ERCC3 as highly differentially expressed. Immunohistochemistry confirmed ERCC3 expression in HF melanocytes. A reduction in ERCC3 by siRNA interference in human melanocytes in vitro reduced their tyrosinase production ability. Our results suggest that loss of NER gene function is associated with a loss of melanin production capacity. This may be due to reduced gene transcription and/or reduced DNA repair in melanocytes which may eventually lead to cell death. These results provide novel information with regard to melanogenesis and its regulation

Worm Grunting, Fiddling, and Charming—Humans Unknowingly Mimic a Predator to Harvest Bait

Background: For generations many families in and around Florida’s Apalachicola National Forest have supported themselves by collecting the large endemic earthworms (Diplocardia mississippiensis). This is accomplished by vibrating a wooden stake driven into the soil, a practice called ‘‘worm grunting’’. In response to the vibrations, worms emerge to the surface where thousands can be gathered in a few hours. Why do these earthworms suddenly exit their burrows in response to vibrations, exposing themselves to predation? Principal Findings: Here it is shown that a population of eastern American moles (Scalopus aquaticus) inhabits the area where worms are collected and that earthworms have a pronounced escape response from moles consisting of rapidly exiting their burrows to flee across the soil surface. Recordings of vibrations generated by bait collectors and moles suggest that ‘‘worm grunters’ ’ unknowingly mimic digging moles. An alternative possibility, that worms interpret vibrations as rain and surface to avoid drowning is not supported. Conclusions: Previous investigations have revealed that both wood turtles and herring gulls vibrate the ground to elicit earthworm escapes, indicating that a range of predators may exploit the predator-prey relationship between earthworms and moles. In addition to revealing a novel escape response that may be widespread among soil fauna, the results sho

High-performance and scalable metal-chalcogenide semiconductors and devices via chalco-gel routes

We report a general strategy for obtaining high-quality, large-areametal-chalcogenide semiconductor films from precursors combining chelated metal salts with chalcoureas or chalcoamides. Using conventional organic solvents, such precursors enable the expeditious formation of chalco-gels,which are easily transformed into the corresponding highperformance metal-chalcogenide thin films with large, uniform areas. Diverse metal chalcogenides and their alloys (MQx: M = Zn, Cd, In, Sb, Pb; Q = S, Se, Te) are successfully synthesized at relatively low processing temperatures (<400°C). The versatility of this scalable route is demonstrated by the fabrication of large-area thin-film transistors (TFTs), optoelectronic devices, and integrated circuits on a 4-inch Si wafer and 2.5-inch borosilicate glass substrates in ambient air using CdS, CdSe, and In2Se3 active layers. The CdSe TFTs exhibit a maximum field-effect mobility greater than 300 cm2 V-1 s-1 with an on/off current ratio of >107 and good operational stability (threshold voltage shift < 0.5 V at a positive gate bias stress of 10 ks). In addition,metal chalcogenide-based phototransistors with a photodetectivity of >1013 Jones and seven-stage ring oscillators operating at a speed of ∼2.6 MHz (propagation delay of < 27 ns per stage) are demonstrated. © 2018 The Authors.1

A Functional Nuclear Localization Sequence in the C. elegans TRPV Channel OCR-2

The ability to modulate gene expression in response to sensory experience is critical to the normal development and function of the nervous system. Calcium is a key activator of the signal transduction cascades that mediate the process of translating a cellular stimulus into transcriptional changes. With the recent discovery that the mammalian Cav1.2 calcium channel can be cleaved, enter the nucleus and act as a transcription factor to control neuronal gene expression, a more direct role for the calcium channels themselves in regulating transcription has begun to be appreciated. Here we report the identification of a nuclear localization sequence (NLS) in the C. elegans transient receptor potential vanilloid (TRPV) cation channel OCR-2. TRPV channels have previously been implicated in transcriptional regulation of neuronal genes in the nematode, although the precise mechanism remains unclear. We show that the NLS in OCR-2 is functional, being able to direct nuclear accumulation of a synthetic cargo protein as well as the carboxy-terminal cytosolic tail of OCR-2 where it is endogenously found. Furthermore, we discovered that a carboxy-terminal portion of the full-length channel can localize to the nucleus of neuronal cells. These results suggest that the OCR-2 TRPV cation channel may have a direct nuclear function in neuronal cells that was not previously appreciated

Investigating the Willingness to Pay for a Contributory National Health Insurance Scheme in Saudi Arabia:A Cross-sectional Stated Preference Approach

Background: The Saudi Healthcare System is universal, financed entirely from government revenue principally derived from oil, and is ‘free at the point of delivery’ (non-contributory). However, this system is unlikely to be sustainable in the medium to long term. This study investigates the feasibility and acceptability of healthcare financing reform by examining households’ willingness to pay (WTP) for a contributory national health insurance scheme. Methods: Using the contingent valuation method, a pre-tested interviewer-administered questionnaire was used to collect data from 1187 heads of household in Jeddah province over a 5-month period. Multi-stage sampling was employed to select the study sample. Using a double-bounded dichotomous choice with the follow-up elicitation method, respondents were asked to state their WTP for a hypothetical contributory national health insurance scheme. Tobit regression analysis was used to examine the factors associated with WTP and assess the construct validity of elicited WTP. Results: Over two-thirds (69.6%) indicated that they were willing to participate in and pay for a contributory national health insurance scheme. The mean WTP was 50 Saudi Riyal (US$13.33) per household member per month. Tobit regression analysis showed that household size, satisfaction with the quality of public healthcare services, perceptions about financing healthcare, education and income were the main determinants of WTP. Conclusions: This study demonstrates a theoretically valid WTP for a contributory national health insurance scheme by Saudi people. The research shows that willingness to participate in and pay for a contributory national health insurance scheme depends on participant characteristics. Identifying and understanding the main influencing factors associated with WTP are important to help facilitate establishing and implementing the national health insurance scheme. The results could assist policy-makers to develop and set insurance premiums, thus providing an additional source of healthcare financing

Pitfalls in Using Electrophysiological Studies to Diagnose Neuromuscular Disorders

Electrodiagnostic testing is used widely for the full characterization of neuromuscular disorders and for providing unique information on the processes underlying the pathology of peripheral nerves and muscles. However, such testing should be considered as an extension of anamnesis and physical examination, not as pathognomonic of a specific disease entity. There are many pitfalls that could lead to erroneous interpretation of electrophysiological study results when the studies are not performed properly or if they are performed in the presence of anatomical aberrations. The diagnostic reliability of electrodiagnostic studies can be improved and the associated pitfalls overcome if the physician is familiar with all of those possible pitfalls. In this article we discuss the most common and important pitfalls associated with electrodiagnostic medicine

What Works to Improve and Manage Fecal Incontinence in Care Home Residents Living With Dementia? A Realist Synthesis of the Evidence.

The prevalence of fecal incontinence (FI) in care homes is estimated to range from 30% to 50%. There is limited evidence of what is effective in the reduction and management of FI in care homes. Using realist synthesis, 6 potential program theories of what should work were identified. These addressed clinician-led support, assessment, and review; the contribution of teaching and support for care home staff on how to reduce and manage FI; addressing the causes and prevention of constipation; how cognitive and physical capacity of the resident affects outcomes; how the potential for recovery, reduction, and management of FI is understood by those involved; and how the care of people living with dementia and FI is integral to the work patterns of the care home and its staff. Dementia was a known risk factor for fecal incontinence (FI), but how it affected uptake of different interventions or the dementia specific continence and toileting skills staff require, were not addressed in the literature. There was a lack of dementia-specific evidence on continence aids. Most care home residents with FI will be doubly incontinent; there is, therefore, limited value in focusing solely on FI or single causes, such as constipation. Medical and nursing support for continence care is an important resource, but it is unhelpful to create a distinction between what is continence care and what is personal or intimate care. Prompted toileting is an approach that may be particularly beneficial for some residents. Valuing the intimate and personal care work unqualified and junior staff provide to people living with dementia and reinforcement of good practice in ways that are meaningful to this workforce are important clinician-led activities. Providing dementia-sensitive continence care within the daily work routines of care homes is key to helping to reduce and manage FI for this population

Exacerbated fires in Mediterranean Europe due to anthropogenic warming projected with non-stationary climate-fire models

The observed trend towards warmer and drier conditions in southern Europe is projected to continue in the next decades, possibly leading to increased risk of large fires. However, an assessment of climate change impacts on fires at and above the 1.5 °C Paris target is still missing. Here, we estimate future summer burned area in Mediterranean Europe under 1.5, 2, and 3 °C global warming scenarios, accounting for possible modifications of climate-fire relationships under changed climatic conditions owing to productivity alterations. We found that such modifications could be beneficial, roughly halving the fire-intensifying signals. In any case, the burned area is robustly projected to increase. The higher the warming level is, the larger is the increase of burned area, ranging from ~40% to ~100% across the scenarios. Our results indicate that significant benefits would be obtained if warming were limited to well below 2 °C

Intestinal Epithelial Stem/Progenitor Cells Are Controlled by Mucosal Afferent Nerves

Background: The maintenance of the intestinal epithelium is of great importance for the survival of the organism. A possible nervous control of epithelial cell renewal was studied in rats and mice. Methods: Mucosal afferent nerves were stimulated by exposing the intestinal mucosa to capsaicin (1.6 mM), which stimulates intestinal external axons. Epithelial cell renewal was investigated in the jejunum by measuring intestinal thymidine kinase (TK) activity, intestinal H-3-thymidine incorporation into DNA, and the number of crypt cells labeled with BrdU. The influence of the external gut innervation was minimized by severing the periarterial nerves. Principal Findings: Luminal capsaicin increased all the studied variables, an effect nervously mediated to judge from inhibitory effects on TK activity or H-3-thymidine incorporation into DNA by exposing the mucosa to lidocaine (a local anesthetic) or by giving four different neurotransmitter receptor antagonists i.v. (muscarinic, nicotinic, neurokinin1 (NK1) or calcitonin gene related peptide (CGRP) receptors). After degeneration of the intestinal external nerves capsaicin did not increase TK activity, suggesting the involvement of an axon reflex. Intra-arterial infusion of Substance P (SP) or CGRP increased intestinal TK activity, a response abolished by muscarinic receptor blockade. Immunohistochemistry suggested presence of M3 and M5 muscarinic receptors on the intestinal stem/progenitor cells. We propose that the stem/progenitor cells are controlled by cholinergic nerves, which, in turn, are influenced by mucosal afferent neuron(s) releasing acetylcholine and/or SP and/or CGRP. In mice lacking the capsaicin receptor, thymidine incorporation into DNA and number of crypt cells labeled with BrdU was lower than in wild type animals suggesting that nerves are important also in the absence of luminal capsaicin, a conclusion also supported by the observation that atropine lowered thymidine incorporation into DNA by 60% in control rat segments. Conclusion: Enteric nerves are of importance in maintaining the intestinal epithelial barrier.Original Publication:Ove Lundgren, Mats Jodal, Madeleine Jansson, Anders T Ryberg and Lennart Svensson, Intestinal Epithelial Stem/Progenitor Cells Are Controlled by Mucosal Afferent Nerves, 2011, PLOS ONE, (6), 2, 16295.http://dx.doi.org/10.1371/journal.pone.0016295Copyright: Public Library of Science (PLoS)http://www.plos.org

Why Are Clinicians Not Embracing the Results from Pivotal Clinical Trials in Severe Sepsis? A Bayesian Analysis

BACKGROUND: Five pivotal clinical trials (Intensive Insulin Therapy; Recombinant Human Activated Protein C [rhAPC]; Low-Tidal Volume; Low-Dose Steroid; Early Goal-Directed Therapy [EGDT]) demonstrated mortality reduction in patients with severe sepsis and expert guidelines have recommended them to clinical practice. Yet, the adoption of these therapies remains low among clinicians. OBJECTIVES: We selected these five trials and asked: Question 1--What is the current probability that the new therapy is not better than the standard of care in my patient with severe sepsis? Question 2--What is the current probability of reducing the relative risk of death (RRR) of my patient with severe sepsis by meaningful clinical thresholds (RRR >15%; >20%; >25%)? METHODS: Bayesian methodologies were applied to this study. Odds ratio (OR) was considered for Question 1, and RRR was used for Question 2. We constructed prior distributions (enthusiastic; mild, moderate, and severe skeptic) based on various effective sample sizes of other relevant clinical trials (unfavorable evidence). Posterior distributions were calculated by combining the prior distributions and the data from pivotal trials (favorable evidence). MAIN FINDINGS: Answer 1--The analysis based on mild skeptic prior shows beneficial results with the Intensive Insulin, rhAPC, and Low-Tidal Volume trials, but not with the Low-Dose Steroid and EGDT trials. All trials' results become unacceptable by the analyses using moderate or severe skeptic priors. Answer 2--If we aim for a RRR>15%, the mild skeptic analysis shows that the current probability of reducing death by this clinical threshold is 88% for the Intensive Insulin, 62-65% for the Low-Tidal Volume, rhAPC, EGDT trials, and 17% for the Low-Dose Steroid trial. The moderate and severe skeptic analyses show no clinically meaningful reduction in the risk of death for all trials. If we aim for a RRR >20% or >25%, all probabilities of benefits become lower independent of the degree of skepticism. CONCLUSIONS: Our clinical threshold analysis offers a new bedside tool to be directly applied to the care of patients with severe sepsis. Our results demonstrate that the strength of evidence (statistical and clinical) is weak for all trials, particularly for the Low-Dose Steroid and EGDT trials. It is essential to replicate the results of each of these five clinical trials in confirmatory studies if we want to provide patient care based on scientifically sound evidence