Patient-derived iPSCs show premature neural differentiation and neuron type-specific phenotypes relevant to neurodevelopment.

Ras/MAPK pathway signaling is a major participant in neurodevelopment, and evidence suggests that BRAF, a key Ras signal mediator, influences human behavior. We studied the role of the mutation BRAFQ257R, the most common cause of cardiofaciocutaneous syndrome (CFC), in an induced pluripotent stem cell (iPSC)-derived model of human neurodevelopment. In iPSC-derived neuronal cultures from CFC subjects, we observed decreased p-AKT and p-ERK1/2 compared to controls, as well as a depleted neural progenitor pool and rapid neuronal maturation. Pharmacological PI3K/AKT pathway manipulation recapitulated cellular phenotypes in control cells and attenuated them in CFC cells. CFC cultures displayed altered cellular subtype ratios and increased intrinsic excitability. Moreover, in CFC cells, Ras/MAPK pathway activation and morphological abnormalities exhibited cell subtype-specific differences. Our results highlight the importance of exploring specific cellular subtypes and of using iPSC models to reveal relevant human-specific neurodevelopmental events

Simvastatin inhibits TLR8 signaling in primary human monocytes and spontaneous TNF production from rheumatoid synovial membrane cultures

Simvastatin has been shown to have anti-inflammatory effects that are independent of its serum cholesterol lowering action, but the mechanisms by which these anti-inflammatory effects are mediated have not been elucidated. To explore the mechanism involved, the effect of simvastatin on Toll-like receptor (TLR) signalling in primary human monocytes was investigated. A short pre-treatment with simvastatin dose-dependently inhibited the production of tumor necrosis factor-α (TNF) in response to TLR8 (but not TLRs 2, 4, or 5) activation. Statins are known inhibitors of the cholesterol biosynthetic pathway, but intriguingly TLR8 inhibition could not be reversed by addition of mevalonate or geranylgeranyl pyrophosphate; downstream products of cholesterol biosynthesis. TLR8 signalling was examined in HEK 293 cells stably expressing TLR8, where simvastatin inhibited IKKα/β phosphorylation and subsequent NF-κB activation without affecting the pathway to AP-1. Since simvastatin has been reported to have anti-inflammatory effects in RA patients and TLR8 signalling contributes to TNF production in human RA synovial tissue in culture, simvastatin was tested in these cultures. Simvastatin significantly inhibited the spontaneous release of TNF in this model which was not reversed by mevalonate. Together, these results demonstrate a hitherto unrecognized mechanism of simvastatin inhibition of TLR8 signalling that may in part explain its beneficial anti-inflammatory effects

Design of a pulse power supply unit for micro-ECM

Electrochemical micro-machining (μECM) requires a particular pulse power supply unit (PSU) to be developed in order to achieve desired machining performance. This paper summarises the development of a pulse PSU meeting the requirements of μECM. The pulse power supply provides tens of nanosecond pulse duration, positive and negative bias voltages and a polarity switching functionality. It fulfils the needs for tool preparation with reversed pulsed ECM on the machine. Moreover, the PSU is equipped with an ultrafast overcurrent protection which prevents the tool electrode from being damaged in case of short circuits. The developed pulse PSU was used to fabricate micro-tools out of 170 μm WC-Co alloy shafts via micro-electrochemical turning and drill deep holes via μECM in a disk made of 18NiCr6. The electrolyte used for both processes was a mixture of sulphuric acid and NaNO3 aqueous solutions.The research reported in this paper is supported by the European Commission within the project “Minimizing Defects in Micro-Manufacturing Applications (MIDEMMA)” (FP7-2011-NMP-ICT-FoF-285614

Self-Reported Occupational Exposure to HIV and Factors Influencing its Management Practice: A Study of Healthcare Workers in Tumbi and Dodoma Hospitals, Tanzania.

Blood borne infectious agents such as hepatitis B virus (HBV), hepatitis C virus (HCV) and human immune deficiency virus (HIV) constitute a major occupational hazard for healthcare workers (HCWs). To some degree it is inevitable that HCWs sustain injuries from sharp objects such as needles, scalpels and splintered bone during execution of their duties. However, in Tanzania, there is little or no information on factors that influence the practice of managing occupational exposure to HIV by HCWs. This study was conducted to determine the prevalence of self-reported occupational exposure to HIV among HCWs and explore factors that influence the practice of managing occupational exposure to HIV by HCWs in Tanzania. Self-administered questionnaire was designed to gather information of healthcare workers' occupational exposures in the past 12 months and circumstances in which these injuries occurred. Practice of managing occupational exposure was assessed by the following questions: Nearly half of the HCWs had experienced at least one occupational injury in the past 12 months. Though most of the occupational exposures to HIV were experienced by female nurses, non-medical hospital staff received PEP more frequently than nurses and doctors. Doctors and nurses frequently encountered occupational injuries in surgery room and labor room respectively. HCWs with knowledge on the possibility of HIV transmission and those who knew whom to contact in event of occupational exposure to HIV were less likely to have poor practice of managing occupational exposure. Needle stick injuries and splashes are common among HCWs at Tumbi and Dodoma hospitals. Knowledge of the risk of HIV transmission due to occupational exposure and knowing whom to contact in event of exposure predicted practice of managing the exposure. Thus provision of health education on occupational exposure may strengthen healthcare workers' practices to manage occupational exposure

Impact of inhaled corticosteroids on growth in children with asthma: systematic review and meta-analysis

Background: Long-term inhaled corticosteroids (ICS) may reduce growth velocity and final height of children with asthma. We aimed to evaluate the association between ICS use of >12 months and growth. Methods: We initially searched MEDLINE and EMBASE in July 2013, followed by a PubMed search updated to December 2014. We selected RCTs and controlled observational studies of ICS use in patients with asthma. We conducted random effects meta-analysis of mean differences in growth velocity (cm/year) or final height (cm) between groups. Heterogeneity was assessed using the I2 statistic. Results: We found 23 relevant studies (twenty RCTs and three observational studies) after screening 1882 hits. Meta-analysis of 16 RCTs showed that ICS use significantly reduced growth velocity at one year follow-up (mean difference -0.48 cm/year (95% CI -0.66 to -0.29)). There was evidence of a dose-response effect in three RCTs. Final adult height showed a mean reduction of -1.20 cm (95% CI -1.90 cm to -0.50 cm) with budesonide versus placebo in a high quality RCT. Meta-analysis of two lower quality observational studies revealed uncertainty in the association between ICS use and final adult height, pooled mean difference -0.85 cm (95% CI -3.35 to 1.65). Conclusion: Use of ICS for >12 months in children with asthma has a limited impact on annual growth velocity. In ICS users, there is a slight reduction of about a centimeter in final adult height, which when interpreted in the context of average adult height in England (175 cm for men and 161 cm for women), represents a 0.7% reduction compared to non-ICS users

A Chinese cave links climate change, social impacts, and human adaptation over the last 500 years.

The collapse of some pre-historical and historical cultures, including Chinese dynasties were presumably linked to widespread droughts, on the basis of synchronicities of societal crises and proxy-based climate events. Here, we present a comparison of ancient inscriptions in Dayu Cave from Qinling Mountains, central China, which described accurate times and detailed impacts of seven drought events during the period of 1520-1920 CE, with high-resolution speleothem records from the same cave. The comparable results provide unique and robust tests on relationships among speleothem δ(18)O changes, drought events, and societal unrest. With direct historical evidences, our results suggest that droughts and even modest events interrupting otherwise wet intervals can cause serious social crises. Modeling results of speleothem δ(18)O series suggest that future precipitation in central China may be below the average of the past 500 years. As Qinling Mountain is the main recharge area of two large water transfer projects and habitats of many endangered species, it is imperative to explore an adaptive strategy for the decline in precipitation and/or drought events.We gratefully acknowledge the NBRPC (2013CB955902), NSFC (41372192; 41290254; 41230524; 41023006), and the WLF-CAS for funding this research. This study was also partially supported by Taiwan MOST (103-2119-M-002-022) and NTU (101R7625) grants. H.C. and R.L.E. received financial support from the U.S. NSF (EAR-0908792 and EAR-1211299), and S.F.M.B. received support from the Swiss NSF (CRSI22_132646/1).This is the final version. It was first published by NPG at http://www.nature.com/srep/2015/150717/srep12284/full/srep12284.html#author-information

Clinical-pathological study on β-APP, IL-1β, GFAP, NFL, Spectrin II, 8OHdG, TUNEL, miR-21, miR-16, miR-92 expressions to verify DAI-diagnosis, grade and prognosis

Traumatic brain injury (TBI) is one of the most important death and disability cause, involving substantial costs, also in economic terms, when considering the young age of the involved subject. Aim of this paper is to report a series of patients treated at our institutions, to verify neurological results at six months or survival; in fatal cases we searched for βAPP, GFAP, IL-1β, NFL, Spectrin II, TUNEL and miR-21, miR-16, and miR-92 expressions in brain samples, to verify DAI diagnosis and grade as strong predictor of survival and inflammatory response. Concentrations of 8OHdG as measurement of oxidative stress was performed. Immunoreaction of β-APP, IL-1β, GFAP, NFL, Spectrin II and 8OHdG were significantly increased in the TBI group with respect to control group subjects. Cell apoptosis, measured by TUNEL assay, were significantly higher in the study group than control cases. Results indicated that miR-21, miR-92 and miR-16 have a high predictive power in discriminating trauma brain cases from controls and could represent promising biomarkers as strong predictor of survival, and for the diagnosis of postmortem traumatic brain injury

Regulation of the water status in three co-occurring phreatophytes at the southern fringe of the Taklamakan Desert

Aims We investigated the regulation of the water status in three predominant perennial C3 phreatophytes (Alhagi sparsifolia, Populus euphratica, Tamarix ramosissima) at typical sites of their occurrence at the Southern fringe of the hyperarid Taklamakan Desert (north-west China). Methods In the foreland of the river oasis of Qira (Cele), we determined meteorological variables, plant biomass production, plant water potentials (psi(l)) and the water flux through the plants. We calculated the hydraulic conductance on the flow path from the soil to the leaves (k(SL)) and tested the effects of k(SL) psi(L) and the leaf-to-air difference in the partial pressure of water vapour (Delta w) on stomatal regulation using regression analyses. Important Findings Despite high values of plant water potential at the point of turgor loss, all plants sustained psi(L) at levels that were high enough to Maintain transpiration throughout the growing season. In A. sparsitolia, stomatal resistance (r(s); related to leaf area or leaf mass) was most closely correlated with k(SL);. whereas in P. euphratica, similar to 70%, of the variation in r(s) was explained by Delta w. In T. ramosissima, leaf area-related r(s) was significantly correlated with psi(L) and k(SL). The regulation mechanisms are in accordance with the growth patterns and the Occurrence of the species in relation to their distance to the ground water

The All-Data-Based Evolutionary Hypothesis of Ciliated Protists with a Revised Classification of the Phylum Ciliophora (Eukaryota, Alveolata)

This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ The file attached is the published version of the article

TGFβR2 is a major target of miR-93 in nasopharyngeal carcinoma aggressiveness.

BACKGROUND: MiR-17-92 cluster and its paralogues have emerged as crucial regulators of many oncogenes and tumor suppressors. Transforming growth factor-β receptor II (TGFβR2), as an important tumor suppressor, is involved in various cancer types. However, it is in cancer that only two miRNAs of this cluster and its paralogues have been reported so far to regulate TGFβR2. MiR-93 is oncogenic, but its targetome in cancer has not been fully defined. The role of miR-93 in nasopharyngeal carcinoma (NPC) still remains largely unknown. METHODS: We firstly evaluated the clinical signature of TGFβR2 down-regulation in clinical samples, and next used a miRNA expression profiling analysis followed by multi-validations, including Luciferase reporter assay, to identify miRNAs targeting TGFβR2 in NPC. In vitro and in vivo studies were performed to further investigate the effects of miRNA-mediated TGFβR2 down-regulation on NPC aggressiveness. Finally, mechanism studies were conducted to explore the associated pathway and genes influenced by this miRNA-mediated TGFβR2 down-regulation. RESULTS: TGFβR2 was down-regulated in more than 50% of NPC patients. It is an unfavorable prognosis factor contributing to clinical NPC aggressiveness. A cluster set of 4 TGFβR2-associated miRNAs was identified; they are all from miR-17-92 cluster and its paralogues, of which miR-93 was one of the most significant miRNAs, directly targeting TGFβR2, promoting cell proliferation, invasion and metastasis in vitro and in vivo. Moreover, miR-93 resulted in the attenuation of Smad-dependent TGF-β signaling and the activation of PI3K/Akt pathway by suppressing TGFβR2, further promoting NPC cell uncontrolled growth, invasion, metastasis and EMT-like process. Impressively, the knockdown of TGFβR2 by siRNA displayed a consentaneous phenocopy with the effect of miR-93 in NPC cells, supporting TGFβR2 is a major target of miR-93. Our findings were also substantiated by investigation of the clinical signatures of miR-93 and TGFβR2 in NPC. CONCLUSION: The present study reports an involvement of miR-93-mediated TGFβR2 down-regulation in NPC aggressiveness, thus giving extended insights into molecular mechanisms underlying cancer aggressiveness. Approaches aimed at blocking miR-93 may serve as a promising therapeutic strategy for treating NPC patients