Mutational mechanism for DAB1 (ATTTC) n insertion in SCA37: ATTTT repeat lengthening and nucleotide substitution

Dynamic mutations by microsatellite instability are the molecular basis of a growing number of neuromuscular and neurodegenerative diseases. Repetitive stretches in the human genome may drive pathogenicity, either by expansion above a given threshold, or by insertion of abnormal tracts in nonpathogenic polymorphic repetitive regions, as is the case in spinocerebellar ataxia type 37 (SCA37). We have recently established that this neurodegenerative disease is caused by an (ATTTC)n insertion within an (ATTTT)n in a noncoding region of DAB1. We now investigated the mutational mechanism that originated the (ATTTC)n insertion within an ancestral (ATTTT)n . Approximately 3% of nonpathogenic (ATTTT)n alleles are interspersed by AT-rich motifs, contrarily to mutant alleles that are composed of pure (ATTTT)n and (ATTTC)n stretches. Haplotype studies in unaffected chromosomes suggested that the primary mutational mechanism, leading to the (ATTTC)n insertion, was likely one or more T>C substitutions in an (ATTTT)n pure allele of approximately 200 repeats. Then, the (ATTTC)n expanded in size, originating a deleterious allele in DAB1 that leads to SCA37. This is likely the mutational mechanism in three similar (TTTCA)n insertions responsible for familial myoclonic epilepsy. Because (ATTTT)n tracts are frequent in the human genome, many loci could be at risk for this mutational process.We are grateful to the families and individuals who participated in this work. We thank Patricia Ribeiro for technical assistance. This study was financed by Fundo Europeu de Desenvolvimento Regional (FEDER), through the COMPETE 2020 Operational Pro- gram for Competitiveness and Internationalization (POCI) of Portugal 2020, and by the Fundacão para a Ciência e a Tecnologia (FCT) and Ministério da Ciência, Tecnologia e Ensino Superior (Portugal), in the framework of the project POCI-01-0145-FEDER-029255; (PTDC/MED-GEN/29255/2017) to I.S. J.R.L. and C.L.O. were sup- ported by scholarships from PEst-C/SAU/LA0002/2013. S.M. is funded by the project IF/00930/2013/ CP1184/CT0002 from FCT. This work was also funded by the Porto Neurosciences and Neurologic Disease Research Initiative at the Instituto de Investigação e Inovação em Saúde (Norte-01-0145-FEDER- 000008), supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTU- GAL 2020 Partnership Agreement with FEDER

Molecular identification of Coccidioides spp. in soil samples from Brazil

<p>Abstract</p> <p>Background</p> <p>Since 1991 several outbreaks of acute coccidioidomycosis (CM) were diagnosed in the semi-arid Northeast of Brazil, mainly related to disturbance of armadillo burrows caused by hunters while digging them for the capture of these animals. This activity causes dust contaminated with arthroconidia of <it>Coccidioides posadasii</it>, which, once inhaled, cause the mycosis. We report on the identification of <it>C. posadasii </it>in soil samples related to outbreaks of CM.</p> <p>Results</p> <p>Twenty four soil samples had their DNA extracted and subsequently submitted to a semi-nested PCR technique using specific primers. While only 6 (25%) soil samples were positive for <it>C. posadasii </it>by mice inoculation, all (100%) were positive by the molecular tool.</p> <p>Conclusion</p> <p>This methodology represents a simple, sensitive and specific molecular technique to determine the environmental distribution of <it>Coccidioides </it>spp. in endemic areas, but cannot distinguish the species. Moreover, it may be useful to identify culture isolates. Key-words: 1. Coccidioidomycosis. 2. <it>Coccidioides </it>spp. 3. <it>C. posadasii</it>. 4. Semi-arid. 5. Semi-nested PCR</p

Culture Matters in Communicating the Global Response to COVID-19.

Current communication messages in the COVID-19 pandemic tend to focus more on individual risks than community risks resulting from existing inequities. Culture is central to an effective community-engaged public health communication to reduce collective risks. In this commentary, we discuss the importance of culture in unpacking messages that may be the same globally (physical/social distancing) yet different across cultures and communities (individualist versus collectivist). Structural inequity continues to fuel the disproportionate impact of COVID-19 on black and brown communities nationally and globally. PEN-3 offers a cultural framework for a community-engaged global communication response to COVID-19

Block of NMDA receptor channels by endogenous neurosteroids: implications for the agonist induced conformational states of the channel vestibule

N-methyl-D-aspartate receptors (NMDARs) mediate synaptic plasticity, and their dysfunction is implicated in multiple brain disorders. NMDARs can be allosterically modulated by numerous compounds, including endogenous neurosteroid pregnanolone sulfate. Here, we identify the molecular basis of the use-dependent and voltage-independent inhibitory effect of neurosteroids on NMDAR responses. The site of action is located at the extracellular vestibule of the receptor's ion channel pore and is accessible after receptor activation. Mutations in the extracellular vestibule in the SYTANLAAF motif disrupt the inhibitory effect of negatively charged steroids. In contrast, positively charged steroids inhibit mutated NMDAR responses in a voltage-dependent manner. These results, in combination with molecular modeling, characterize structure details of the open configuration of the NMDAR channel. Our results provide a unique opportunity for the development of new therapeutic neurosteroid-based ligands to treat diseases associated with dysfunction of the glutamate system

IFNAR1-Signalling Obstructs ICOS-mediated Humoral Immunity during Non-lethal Blood-Stage Plasmodium Infection

Funding: This work was funded by a Career Development Fellowship (1028634) and a project grant (GRNT1028641) awarded to AHa by the Australian National Health & Medical Research Council (NHMRC). IS was supported by The University of Queensland Centennial and IPRS Scholarships. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewedPublisher PD

Association between neighborhood safety and overweight status among urban adolescents

<p>Abstract</p> <p>Background</p> <p>Neighborhood safety may be an important social environmental determinant of overweight. We examined the relationship between perceived neighborhood safety and overweight status, and assessed the validity of reported neighborhood safety among a representative community sample of urban adolescents (who were racially and ethnically diverse).</p> <p>Methods</p> <p>Data come from the 2006 Boston Youth Survey, a cross-sectional study in which public high school students in Boston, MA completed a pencil-and-paper survey. The study used a two-stage, stratified sampling design whereby schools and then 9^th–12^thgrade classrooms within schools were selected (the analytic sample included 1,140 students). Students reported their perceptions of neighborhood safety and several associated dimensions. With self-reported height and weight data, we computed body mass index (BMI, kg/m²) for the adolescents based on CDC growth charts. Chi-square statistics and corresponding <it>p</it>-values were computed to compare perceived neighborhood safety by the several associated dimensions. Prevalence ratios (PRs) and 95% confidence intervals (CI) were calculated to examine the association between perceived neighborhood safety and the prevalence of overweight status controlling for relevant covariates and school site.</p> <p>Results</p> <p>More than one-third (35.6%) of students said they always felt safe in their neighborhood, 43.9% said they sometimes felt safe, 11.6% rarely felt safe, and 8.9% never felt safe. Those students who reported that they rarely or never feel safe in their neighborhoods were more likely than those who said they always or sometimes feel safe to believe that gang violence was a serious problem in their neighborhood or school (68.0% vs. 44.1%, <it>p </it>< 0.001), and to have seen someone in their neighborhood assaulted with a weapon (other than a firearm) in the past 12 months (17.8% vs. 11.3%, <it>p </it>= 0.025). In the fully adjusted model (including grade and school) stratified by race/ethnicity, we found a statistically significant association between feeling unsafe in one's own neighborhood and overweight status among those in the Other race/ethnicity group [(PR = 1.56, (95% CI: 1.02, 2.40)].</p> <p>Conclusion</p> <p>Data suggest that perception of neighborhood safety may be associated with overweight status among urban adolescents in certain racial/ethnic groups. Policies and programs to address neighborhood safety may also be preventive for adolescent overweight.</p

Atividade física, qualidade de vida e depressão durante a gravidez

This study examines physical activity patterns among women, from pre-pregnancy to the second trimester of pregnancy, and the relationship between physical activity status based on physical activity guidelines and health-related quality of life (HRQoL) and depression over pregnancy. 56 healthy pregnant women self reported physical activity, HRQoL and depression at 10-15 and 19-24 weeks of pregnancy and physical activity before pregnancy. Whereas vigorous leisure physical activity decreased after conception, moderate leisure physical activity and work related physical activity remained stable over time. The prevalence of recommended physical activity was 39.3% and 12.5% in the 1st and 2nd trimesters of pregnancy respectively, and 14.3% pre-pregnancy. From the 1st to the 2nd pregnancy trimester, most physical HRQoL dimensions scores decreased and only mental component increased, independently of physical activity status. No changes in mean depression scores were observed. These data suggest that physical activity patterns change with pregnancy and that physical and mental components are differentially affected by pregnancy course, independently of physical activity status.Este estudo examina os padrões de atividade física antes da concepção até o segundo trimestre de gravidez e a relação entre o nível de atividade física, com base nas recomendações de atividade física, a qualidade de vida relacionada à saúde (QVRS) e depressão ao longo da gravidez. Cinquenta e seis grávidas saudáveis reportaram nível de atividade física, QVRS e depressão às 10-15 e 19-24 semanas de gravidez, além de atividade física antes da concepção. Enquanto a atividade física vigorosa no lazer diminuiu depois da concepção, as atividades físicas moderadas no lazer e no trabalho mantiveram-se estáveis. A prevalência de atividade fí- sica recomendada foi de 39,3%, 12,5% e 14,3% antes, no primeiro e no segundo trimestres de gravidez, respectivamente. Independentemente do estatuto de atividade física, a maior parte dos escores nas dimensões físicas da QVRS diminui do primeiro para o segundo trimestre de gestação, e apenas o componente mental aumenta. Não se verificaram alterações nos escores médios de depressão. Estes dados sugerem que, com a gravidez, há alteração nos padrões de atividade física; além disso, os componentes físico e mental são diferentemente afetados pelo curso da gestação, independentemente do nível de atividade física

Clinical practice: neonatal resuscitation. A Dutch consensus

The updated Dutch guidelines on Neonatal Resuscitation assimilate the latest evidence in neonatal resuscitation. Important changes with regard to the 2004 guidelines and controversial issues concerning neonatal resuscitation are reviewed, and recommendations for daily practice are provided and argued in the context of the ILCOR 2005 consensus