Retardation of cochlear maturation and impaired hair cell function caused by deletion of all known thyroid hormone receptors

The deafness caused by early onset hypothyroidism indicates that thyroid hormone is essential for the development of hearing. We investigated the underlying roles of the TRa1 and TRß thyroid hormone receptors in the auditory system using receptor-deficient mice. TRa1 and TRß, which act as hormone-activated transcription factors, are encoded by the Thra and Thrb genes, respectively, and both are expressed in the developing cochlea. TRß is required for hearing because TRß-deficient (Thrb tm1/tm1) mice have a defective auditory-evoked brainstem response and retarded expression of a potassium current (I K,f) in the cochlear inner hair cells. Here, we show that although TRa1 is individually dispensable, TRa1 and TRß synergistically control an extended array of functions in postnatal cochlear development. Compared with Thrb tm1/tm1 mice, the deletion of all TRs inThra tm1/tm1 Thrb tm1/tm1mice produces exacerbated and novel phenotypes, including delayed differentiation of the sensory epithelium, malformation of the tectorial membrane, impairment of electromechanical transduction in outer hair cells, and a low endocochlear potential. The induction ofI K,f in inner hair cells was not markedly more retarded than in Thrb tm1/tm1mice, suggesting that this feature of hair cell maturation is primarily TRß-dependent. These results indicate that distinct pathways mediated by TRß alone or by TRß and TRa1 together facilitate control over an extended range of functions during the maturation of the cochlea

Investigation on mechanical and thermal properties of 3D-printed polyamide 6, graphene oxide and glass-fibre-reinforced composites under dry, wet and high temperature conditions.

This study is focused on 3D printing of polyamide 6 (PA6), PA6/graphene oxide (PA6/GO) and PA6/glass-fibre-reinforced (PA6/GF) composites. The effect of graphene oxide and glass-fibre reinforcement on 3D-printed PA6 is explored for improvement of the interfacial bond and interlaminar strength in ambient, wet and high temperature conditions relating to electric car battery box requirements. The influence of environmental conditions and process parameters on the 3D printed polymer composites quality is also examined. Commercial PA6 filament was modified with GO to investigate the thermal and mechanical properties. The modified composites were melt-compounded using a twin-feed extruder to produce an improved 3D-printing filament. The improved filaments were then used to 3D-print test samples for tensile and compression mechanical testing using universal testing machines and thermal characterisation was performed following condition treatment in high temperature and water for correlation to dry/ambient samples. The study results show the studied materials were mostly suitable in dry/ambient conditions. PA6/GF samples demonstrated the highest strength of all three samples in ambient and high-temperature conditions, but the least strength in wet conditions due to osmotic pressure at the fibre/matrix interface that led to fibre breakage. The introduction of 0.1% GO improved the tensile strength by 33%, 11% and 23% in dry/ambient, dry/high temperature and wet/ambient conditions, respectively. The wet PA6/GO samples demonstrated the least strength in comparison to the ambient and high temperature conditions. Notwithstanding this, PA6/GO exhibited the highest tensile strength in the wet condition, making it the most suitable for a high-strength, water-exposed engineering application

Patients' Perception of Quality of Pre-Operative Informed Consent in Athens, Greece: A Pilot Study

BACKGROUND: We sought to perform a study to record and evaluate patients' views of the way surgeons communicate informed consent (IC) in Greece. METHODOLOGY/PRINCIPAL FINDINGS: A prospective pilot study was carried out in Athens from 9/2007 to 4/2008. The study sample was extracted from patients, operated by eight different surgeons, who volunteered to fill in a post-surgery self-report questionnaire on IC. A composite delivered information index and a patient-physician relationship index were constructed for the purposes of the analysis. In total, 77 patients (42 males) volunteered to respond to the questionnaire. The delivered information index scores ranged from 3 to 10, the mean score was 8, and the standard deviation (SD) was 1.9. All patients were aware of their underlying diagnosis and reason for surgery. However, a considerable proportion of the respondents (14.3%) achieved a score below or equal to 5. The patient-physician relationship scores ranged from 0 to 20, the mean score was 16 and the standard deviation (SD) was 4.3. The better the patient-physician relationship, the more information was finally delivered to the patient from the physician (Spearman's rank-order correlation coefficient was 0.4 and p<0.001). Delivered information index was significantly higher among participants who comprehended the right to informed consent, compared to participants who did not (p<0.001), and among participants who were given information regarding other possible therapeutic options (p = 0.001). 43% of the respondents answered that less than 10 minutes were spent on the consent process, 58.4% of patients stated that they had not been informed about other possible therapeutic choices and 28.6% did not really comprehend their legal rights to IC. CONCLUSIONS: Despite the inherent limitations and the small sample size that do not permit to draw any firm conclusions, results indicate that a successful IC process may be associated with specific elements such as the patient-physician relationship, the time spent by the physician to inform the patient, a participant's comprehension of the right to IC and the provision of information regarding other possible therapeutic options

Multifunctional cytokine production reveals functional superiority of memory CD4 T cells

T cell protective immunity is associated with multifunctional memory cells that produce several different cytokines. Currently, our understanding of when and how these cells are generated is limited. We have used an influenza virus mouse infection model to investigate whether the cytokine profile of memory T cells is reflective of primary responding cells or skewed towards a distinct profile. We found that, in comparison to primary cells, memory T cells tended to make multiple cytokines simultaneously. Analysis of the timings of release of cytokine by influenza virus‐specific T cells, demonstrated that primary responding CD4 T cells from lymphoid organs were unable to produce a sustained cytokine response. In contrast CD8 T cells, memory CD4 T cells, and primary responding CD4 T cells from the lung produced a sustained cytokine response throughout the restimulation period. Moreover, memory CD4 T cells were more resistant than primary responding CD4 T cells to inhibitors that suppress T cell receptor signalling. Together, these data suggest that memory CD4 T cells display superior cytokine responses compared to primary responding cells. These data are key to our ability to identify the cues that drive the generation of protective memory CD4 T cells following infection

Testing robustness of CPUE standardization and inclusion of environmental variables with simulated longline catch datasets

Environmental variability changes the distribution, migratory patterns, and susceptibility to various fishing gears for highly migratory marine fish. These changes become especially problematic when they affect the indices of abundance (such as those based on catch-per-unit-effort: CPUE) used to assess the status of fish stocks. The use of simulated CPUE data sets with known values of underlying population trends has been recommended by ICCAT (International Commission for the Conservation of Atlantic Tunas) to test the robustness of CPUE standardization methods. A longline CPUE data simulator was developed to meet this objective and simulate fisheries data from a population with distinct habitat preferences. The simulation was used to test several statistical hypotheses regarding best practices for index standardization aimed at accurate estimation of population trends. Effort data from the US pelagic longline fleet was paired with a volume-weighted habitat suitability model for blue marlin (Makaira nigricans) to derive a simulated time series of blue marlin catch and effort from 1986 to 2015 with four different underlying population trends. The simulated CPUE data were provided to stock assessment scientists to determine if the underlying population abundance trend could accurately be detected with different methods of CPUE standardization that did or did not incorporate environmental data. While the analysts’ approach to the data and the modeling structure differed, the underlying population trends were captured, some more successfully than others. In general, the inclusion of environmental and habitat variables aided the standardization process. However, differences in approaches highlight the importance of how explanatory variables are categorized and the criteria for including those variables. A set of lessons learned from this study was developed as recommendations for best practices for CPUE standardization.FCT IF/00253/2014info:eu-repo/semantics/publishedVersio

Secondary school smartphone policies in England:a descriptive analysis of how schools rationalize, design, and implement restrictive and permissive phone policies

This study provides a descriptive analysis of the content and implementation of smartphone policies across 30 secondary schools in England, comparing schools that do (permissive) or do not (restrictive) allow phone use during recreational time. School policy documents were collected, along with survey data from pupil (n = 1198), teacher (n = 53), and SLT (n = 30) participants. Phones were positioned as benefitting safety, learning, and communication. However, most schools adopted restrictive policies, aiming to improve attainment, behavior, and safeguarding. Significant differences were found between pupils and teachers, and between pupils at permissive vs restrictive schools, regarding their support for the rules. Implications are discussed

The HicA toxin from Burkholderia pseudomallei has a role in persister cell formation

© 2014 The Authors Journal compilation. ©2014 Biochemical Society.This is an open access article that is freely available in ORE or from the publisher's website. Please cite the published version.Published by Portland Press on behalf of the Biochemical SocietyTA (toxin-antitoxin) systems are widely distributed amongst bacteria and are associated with the formation of antibiotic tolerant (persister) cells that may have involvement in chronic and recurrent disease. We show that overexpression of the Burkholderia pseudomallei HicA toxin causes growth arrest and increases the number of persister cells tolerant to ciprofloxacin or ceftazidime. Furthermore, our data show that persistence towards ciprofloxacin or ceftazidime can be differentially modulated depending on the level of induction of HicA expression. Deleting the hicAB locus from B. pseudomallei K96243 significantly reduced persister cell frequencies following exposure to ciprofloxacin, but not ceftazidime. The structure of HicA(H24A) was solved by NMR and forms a dsRBD-like (dsRNA-binding domain-like) fold, composed of a triple-stranded β-sheet, with two helices packed against one face. The surface of the protein is highly positively charged indicative of an RNA-binding protein and His24 and Gly22 were functionality important residues. This is the first study demonstrating a role for the HicAB system in bacterial persistence and the first structure of a HicA protein that has been experimentally characterized.Wellcome Trus

BRF1 accelerates prostate tumourigenesis and perturbs immune infiltration

BRF1 is a rate-limiting factor for RNA Polymerase III-mediated transcription and is elevated in numerous cancers. Here, we report that elevated levels of BRF1 associate with poor prognosis in human prostate cancer. In vitro studies in human prostate cancer cell lines demonstrated that transient overexpression of BRF1 increased cell proliferation whereas the transient downregulation of BRF1 reduced proliferation and mediated cell cycle arrest. Consistent with our clinical observations, BRF1 overexpression in a Pten-deficient mouse (Pten BRF1 ) prostate cancer model accelerated prostate carcinogenesis and shortened survival. In Pten BRF1 tumours, immune and inflammatory processes were altered, with reduced tumoral infiltration of neutrophils and CD4 positive T cells, which can be explained by decreased levels of complement factor D (CFD) and C7 components of the complement cascade, an innate immune pathway that influences the adaptive immune response. We tested if the secretome was involved in BRF1-driven tumorigenesis. Unbiased proteomic analysis on BRF1-overexpresing PC3 cells confirmed reduced levels of CFD in the secretome, implicating the complement system in prostate carcinogenesis. We further identify that expression of C7 significantly correlates with expression of CD4 and has the potential to alter clinical outcome in human prostate cancer, where low levels of C7 associate with poorer prognosis

Clonal analyses and gene profiling identify genetic biomarkers of human brown and white preadipocyte thermogenic potential

Targeting brown adipose tissue (BAT) content or activity has therapeutic potential for treating obesity and the metabolic syndrome by increasing energy expenditure. Both inter- and intra-individual differences contribute to heterogeneity in human BAT and potentially to differential thermogenic capacity in human populations. Here, we demonstrated the generated clones of brown and white preadipocytes from human neck fat of four individuals and characterized their adipogenic differentiation and thermogenic function. Combining an uncoupling protein 1(UCP1) reporter system and expression profiling, we defined novel sets of gene signatures in human preadipocytes that could predict the thermogenic potential of the cells once they were maturated in culture. Knocking out the positive UCP1 regulators identified by this approach, PREX1 and EDNRB in brown preadipocytes using CRISPR/Cas9 markedly abolished the high level of UCP1 in brown adipocytes differentiated from the preadipocytes. Finally, we were able to prospectively isolate adipose progenitors with great thermogenic potential using cell surface marker CD29. These data provide new insights into the cellular heterogeneity in human fat and offer the identification of possible biomarkers of thermogenically competent preadipocytes