Genetic Basis of Nonsyndromic Sensorineural Hearing Loss in the Sub-Saharan African Island Population of São Tomé and Príncipe: The Role of the DFNB1 Locus?

Hearing loss (HL) is a common condition with both genetic and environmental causes, and it greatly impacts global health. The prevalence of HL is reportedly higher in developing countries such as the Sub-Saharan African island of São Tomé and Príncipe, where the deaf community is estimated to be less than 1% of the population. We investigated the role of the DFNB1 locus (GJB2 and GJB6 genes) in the etiology of nonsyndromic sensorineural hearing loss (NSSHL) in São Tomé and Príncipe. A sample of 316 individuals, comprising 136 NSSHL patients (92 bilateral, 44 unilateral) and 180 controls, underwent a clinical and audiological examination. Sequencing of the GJB2 coding region and testing for the (GJB6-D13S1830) and del(GJB6-D13S1854) GJB6 deletions were performed. A total of 311 out of 316 individuals were successfully analyzed regarding the GJB2 and GJB6 genetic variations, respectively. The frequency of the GJB2 coding mutations in patients and controls was low. Some of those coding mutations are the most commonly found in Eurasian and Mediterranean populations and have also been identified in Portugal. None of the GJB6 deletions was present. The presence of certain coding variants in São Tomé and Príncipe suggests a non-Sub-Saharan genetic influx and supports the previously reported genetic influx from European (mainly Portuguese) ancestors. In summary, DFNB1 locus does not appear to be a major contributor to NSSHL in São Tomé and Príncipe. However, the presence of both pathogenic and likely pathogenic mutations in GJB2 suggests that GJB2-related NSSHL might still occur in this population, warranting further research on GJB2 testing in NSSHL cases

Cardiac afferent activity modulates the expression of racial stereotypes

Negative racial stereotypes tend to associate Black people with threat. This often leads to the misidentification of harmless objects as weapons held by a Black individual. Yet, little is known about how bodily states impact the expression of racial stereotyping. By tapping into the phasic activation of arterial baroreceptors, known to be associated with changes in the neural processing of fearful stimuli, we show activation of race-threat stereotypes synchronized with the cardiovascular cycle. Across two established tasks, stimuli depicting Black or White individuals were presented to coincide with either the cardiac systole or diastole. Results show increased race-driven misidentification of weapons during systole, when baroreceptor afferent firing is maximal, relative to diastole. Importantly, a third study examining the positive Black-athletic stereotypical association fails to demonstrate similar modulations by cardiac cycle. We identify a body–brain interaction wherein interoceptive cues can modulate threat appraisal and racially biased behaviour in context-dependent ways

Does Habitual Physical Activity Increase the Sensitivity of the Appetite Control System? A Systematic Review.

BACKGROUND: It has been proposed that habitual physical activity improves appetite control; however, the evidence has never been systematically reviewed. OBJECTIVE: To examine whether appetite control (e.g. subjective appetite, appetite-related peptides, food intake) differs according to levels of physical activity. DATA SOURCES: Medline, Embase and SPORTDiscus were searched for articles published between 1996 and 2015, using keywords pertaining to physical activity, appetite, food intake and appetite-related peptides. STUDY SELECTION: Articles were included if they involved healthy non-smoking adults (aged 18-64 years) participating in cross-sectional studies examining appetite control in active and inactive individuals; or before and after exercise training in previously inactive individuals. STUDY APPRAISAL AND SYNTHESIS: Of 77 full-text articles assessed, 28 studies (14 cross-sectional; 14 exercise training) met the inclusion criteria. RESULTS: Appetite sensations and absolute energy intake did not differ consistently across studies. Active individuals had a greater ability to compensate for high-energy preloads through reductions in energy intake, in comparison with inactive controls. When physical activity level was graded across cross-sectional studies (low, medium, high, very high), a significant curvilinear effect on energy intake (z-scores) was observed. LIMITATIONS: Methodological issues existed concerning the small number of studies, lack of objective quantification of food intake, and various definitions used to define active and inactive individuals. CONCLUSION: Habitually active individuals showed improved compensation for the energy density of foods, but no consistent differences in appetite or absolute energy intake, in comparison with inactive individuals. This review supports a J-shaped relationship between physical activity level and energy intake. Further studies are required to confirm these findings. PROSPERO REGISTRATION NUMBER: CRD42015019696

The role of multiple marks in epigenetic silencing and the emergence of a stable bivalent chromatin state

We introduce and analyze a minimal model of epigenetic silencing in budding yeast, built upon known biomolecular interactions in the system. Doing so, we identify the epigenetic marks essential for the bistability of epigenetic states. The model explicitly incorporates two key chromatin marks, namely H4K16 acetylation and H3K79 methylation, and explores whether the presence of multiple marks lead to a qualitatively different systems behavior. We find that having both modifications is important for the robustness of epigenetic silencing. Besides the silenced and transcriptionally active fate of chromatin, our model leads to a novel state with bivalent (i.e., both active and silencing) marks under certain perturbations (knock-out mutations, inhibition or enhancement of enzymatic activity). The bivalent state appears under several perturbations and is shown to result in patchy silencing. We also show that the titration effect, owing to a limited supply of silencing proteins, can result in counter-intuitive responses. The design principles of the silencing system is systematically investigated and disparate experimental observations are assessed within a single theoretical framework. Specifically, we discuss the behavior of Sir protein recruitment, spreading and stability of silenced regions in commonly-studied mutants (e.g., sas2, dot1) illuminating the controversial role of Dot1 in the systems biology of yeast silencing.Comment: Supplementary Material, 14 page

Integrating genetic maps in bambara groundnut [Vigna subterranea (L) Verdc.] and their syntenic relationships among closely related legumes

Background Bambara groundnut [Vigna subterranea (L) Verdc.] is an indigenous legume crop grown mainly in subsistence and small-scale agriculture in sub-Saharan Africa for its nutritious seeds and its tolerance to drought and poor soils. Given that the lack of ex ante sequence is often a bottleneck in marker-assisted crop breeding for minor and underutilised crops, we demonstrate the use of limited genetic information and resources developed within species, but linked to the well characterised common bean (Phaseolus vulgaris) genome sequence and the partially annotated closely related species; adzuki bean (Vigna angularis) and mung bean (Vigna radiata). From these comparisons we identify conserved synteny blocks corresponding to the Linkage Groups (LGs) in bambara groundnut genetic maps and evaluate the potential to identify genes in conserved syntenic locations in a sequenced genome that underlie a QTL position in the underutilised crop genome. Results Two individual intraspecific linkage maps consisting of DArTseq markers were constructed in two bambara groundnut (2n = 2x = 22) segregating populations: 1) The genetic map of Population IA was derived from F2 lines (n = 263; IITA686 x Ankpa4) and covered 1,395.2 cM across 11 linkage groups; 2) The genetic map of Population TD was derived from F3 lines (n = 71; Tiga Nicuru x DipC) and covered 1,376.7 cM across 11 linkage groups. A total of 96 DArTseq markers from an initial pool of 142 pre-selected common markers were used. These were not only polymorphic in both populations but also each marker could be located using the unique sequence tag (at selected stringency) onto the common bean, adzuki bean and mung bean genomes, thus allowing the sequenced genomes to be used as an initial ‘pseudo’ physical map for bambara groundnut. A good correspondence was observed at the macro synteny level, particularly to the common bean genome. A test using the QTL location of an agronomic trait in one of the bambara groundnut maps allowed the corresponding flanking positions to be identified in common bean, mung bean and adzuki bean, demonstrating the possibility of identifying potential candidate genes underlying traits of interest through the conserved syntenic physical location of QTL in the well annotated genomes of closely related species. Conclusions The approach of adding pre-selected common markers in both populations before genetic map construction has provided a translational framework for potential identification of candidate genes underlying a QTL of trait of interest in bambara groundnut by linking the positions of known genetic effects within the underutilised species to the physical maps of other well-annotated legume species, without the need for an existing whole genome sequence of the study species. Identifying the conserved synteny between underutilised species without complete genome sequences and the genomes of major crops and model species with genetic and trait data is an important step in the translation of resources and information from major crop and model species into the minor crop species. Such minor crops will be required to play an important role in future agriculture under the effects of climate change

Gene therapy restores dopamine transporter expression and ameliorates pathology in iPSC and mouse models of infantile parkinsonism

Most inherited neurodegenerative disorders are incurable, and often only palliative treatment is available. Precision medicine has great potential to address this unmet clinical need. We explored this paradigm in dopamine transporter deficiency syndrome (DTDS), caused by biallelic loss-of-function mutations in SLC6A3, encoding the dopamine transporter (DAT). Patients present with early infantile hyperkinesia, severe progressive childhood parkinsonism, and raised cerebrospinal fluid dopamine metabolites. The absence of effective treatments and relentless disease course frequently leads to death in childhood. Using patient-derived induced pluripotent stem cells (iPSCs), we generated a midbrain dopaminergic (mDA) neuron model of DTDS that exhibited marked impairment of DAT activity, apoptotic neurodegeneration associated with TNFα-mediated inflammation, and dopamine toxicity. Partial restoration of DAT activity by the pharmacochaperone pifithrin-μ was mutation-specific. In contrast, lentiviral gene transfer of wild-type human SLC6A3 complementary DNA restored DAT activity and prevented neurodegeneration in all patient-derived mDA lines. To progress toward clinical translation, we used the knockout mouse model of DTDS that recapitulates human disease, exhibiting parkinsonism features, including tremor, bradykinesia, and premature death. Neonatal intracerebroventricular injection of human SLC6A3 using an adeno-associated virus (AAV) vector provided neuronal expression of human DAT, which ameliorated motor phenotype, life span, and neuronal survival in the substantia nigra and striatum, although off-target neurotoxic effects were seen at higher dosage. These were avoided with stereotactic delivery of AAV2.SLC6A3 gene therapy targeted to the midbrain of adult knockout mice, which rescued both motor phenotype and neurodegeneration, suggesting that targeted AAV gene therapy might be effective for patients with DTDS

Hospital deaths and adverse events in Brazil

<p>Abstract</p> <p>Background</p> <p>Adverse events are considered a major international problem related to the performance of health systems. Evaluating the occurrence of adverse events involves, as any other outcome measure, determining the extent to which the observed differences can be attributed to the patient's risk factors or to variations in the treatment process, and this in turn highlights the importance of measuring differences in the severity of the cases. The current study aims to evaluate the association between deaths and adverse events, adjusted according to patient risk factors.</p> <p>Methods</p> <p>The study is based on a random sample of 1103 patient charts from hospitalizations in the year 2003 in 3 teaching hospitals in the state of Rio de Janeiro, Brazil. The methodology involved a retrospective review of patient charts in two stages - screening phase and evaluation phase. Logistic regression was used to evaluate the relationship between hospital deaths and adverse events.</p> <p>Results</p> <p>The overall mortality rate was 8.5%, while the rate related to the occurrence of an adverse event was 2.9% (32/1103) and that related to preventable adverse events was 2.3% (25/1103). Among the 94 deaths analyzed, 34% were related to cases involving adverse events, and 26.6% of deaths occurred in cases whose adverse events were considered preventable. The models tested showed good discriminatory capacity. The unadjusted odds ratio (OR 11.43) and the odds ratio adjusted for patient risk factors (OR 8.23) between death and preventable adverse event were high.</p> <p>Conclusions</p> <p>Despite discussions in the literature regarding the limitations of evaluating preventable adverse events based on peer review, the results presented here emphasize that adverse events are not only prevalent, but are associated with serious harm and even death. These results also highlight the importance of risk adjustment and multivariate models in the study of adverse events.</p