Widespread genomic influences on phenotype in Dravet syndrome, a 'monogenic' condition

Dravet syndrome is an archetypal rare severe epilepsy, considered "monogenic", typically caused by loss-of-function SCN1A variants. Despite a recognisable core phenotype, its marked phenotypic heterogeneity is incompletely explained by differences in the causal SCN1A variant or clinical factors. In 34 adults with SCN1A-related Dravet syndrome, we show additional genomic variation beyond SCN1A contributes to phenotype and its diversity, with an excess of rare variants in epilepsy-related genes as a set and examples of blended phenotypes, including one individual with an ultra-rare DEPDC5 variant and focal cortical dysplasia. Polygenic risk scores for intelligence are lower, and for longevity, higher, in Dravet syndrome than in epilepsy controls. The causal, major-effect, SCN1A variant may need to act against a broadly compromised genomic background to generate the full Dravet syndrome phenotype, whilst genomic resilience may help to ameliorate the risk of premature mortality in adult Dravet syndrome survivors

Whole genome sequence and manual annotation of Clostridium autoethanogenum, an industrially relevant bacterium

Clostridium autoethanogenum is an acetogenic bacterium capable of producing high value commodity chemicals and biofuels from the C1 gases present in synthesis gas. This common industrial waste gas can act as the sole energy and carbon source for the bacterium that converts the low value gaseous components into cellular building blocks and industrially relevant products via the action of the reductive acetyl-CoA (Wood-Ljungdahl) pathway. Current research efforts are focused on the enhancement and extension of product formation in this organism via synthetic biology approaches. However, crucial to metabolic modelling and directed pathway engineering is a reliable and comprehensively annotated genome sequence

Widespread genomic influences on phenotype in Dravet syndrome, a ‘monogenic’ condition

Dravet syndrome is an archetypal rare severe epilepsy, considered “monogenic”, typically caused by loss-of-function SCN1A variants. Despite a recognisable core phenotype, its marked phenotypic heterogeneity is incompletely explained by differences in the causal SCN1A variant or clinical factors. In 34 adults with SCN1A-related Dravet syndrome, we show additional genomic variation beyond SCN1A contributes to phenotype and its diversity, with an excess of rare variants in epilepsy-related genes as a set and examples of blended phenotypes, including one individual with an ultra-rare DEPDC5 variant and focal cortical dysplasia. Polygenic risk scores for intelligence are lower, and for longevity, higher, in Dravet syndrome than in epilepsy controls. The causal, major-effect, SCN1A variant may need to act against a broadly compromised genomic background to generate the full Dravet syndrome phenotype, whilst genomic resilience may help to ameliorate the risk of premature mortality in adult Dravet syndrome survivors

The SIB Swiss Institute of Bioinformatics' resources: focus on curated databases

The SIB Swiss Institute of Bioinformatics (www.isb-sib.ch) provides world-class bioinformatics databases, software tools, services and training to the international life science community in academia and industry. These solutions allow life scientists to turn the exponentially growing amount of data into knowledge. Here, we provide an overview of SIB's resources and competence areas, with a strong focus on curated databases and SIB's most popular and widely used resources. In particular, SIB's Bioinformatics resource portal ExPASy features over 150 resources, including UniProtKB/Swiss-Prot, ENZYME, PROSITE, neXtProt, STRING, UniCarbKB, SugarBindDB, SwissRegulon, EPD, arrayMap, Bgee, SWISS-MODEL Repository, OMA, OrthoDB and other databases, which are briefly described in this article

Phenotypic Analysis of Dengue Virus with Different Epidemic Capacities in Primary Human Cells and Vector Contribution to Infectivity

Dengue virus (DENV) is the leading cause of arthropod transmitted disease worldwide, with an estimated 2.5 billion individuals at risk for infection each year in tropical and subtropical areas. There are four serotypes of DENV which are transmitted by the mosquito Aedes aegypti and Aedes albopictus. Although DENV infections are asymptomatic, dengue disease can present as dengue fever (DF), dengue hemorrhagic fever (DHF), and dengue shock syndrome (DSS). There are several hypotheses as to explain differences in disease severity. This thesis investigates the contribution of intrinsic viral factors to the innate immune response in primary immune cells utilizing clinical isolates of DENV-3 from Sri Lanka before and after the emergence of DHF in 1989. Using these clinical isolates we analyzed their replication and innate immune phenotype in a primary human system. Our data shows an increase in interferon (IFN) and IFN-stimulated gene induction only in dendritic cells (DCs) infected with post-DHF DENV-3, compared to the pre-DHF DENV-3. Co-culture experiments reveal that DCs infected with post-DHF DENV-3 prime T cells more efficiently towards Th1 responses than DCs infected with pre-DHF DENV-3. DCs infected with post-DHF DENV-3 also undergo apoptosis at higher levels in an IFN dependent manner compared with DCs infected with pre-DHF DENV-3. Current work investigates specific mutations in the DENV NS2B3 and NS5 genes may correspond to some of the observed differences in virulence between the viruses. Secondly, as human-to-human transmission is very rare, this thesis examines the contribution of the vector to the immune response against DENV. We investigated the innate immune response in primary cells to DENV grown in a variety of mammalian cells (primary and cell lines) in addition to DENV grown in mosquito cells and whole mosquitos. Although we do not observe a significant difference in DENV grown in mammalian cells, dendritic cells infected with mosquito DENV express higher levels of pro-inflammatory cytokines at early time points after infection. Dendritic cells treated with mosquito homogenate also upregulated these cytokines suggesting that upregulation of proinflammatory cytokines could be caused by a mosquito factor. Future experiments will examine immune responses to individual mosquito salivary factor proteins

Turks and Caicos rock iguana (Cyclura carinata) : conservation and management plan 2020–2024

The Endangered Turks and Caicos rock iguana, Cyclura carinata, is found only on the islands and cays of Turks and Caicos Islands (TCI), and on Booby Cay in The Bahamas, northwest of Providenciales. These iguanas now occupy less than 10 percent of their historic range largely due to the impact of invasive mammalian predators. Although conservation efforts have led to stabilisation of the population resulting in the 2020 down-listing of this species from Critically Endangered to Endangered on the IUCN Red List of Threatened Species, threats persist and management efforts are needed. This document presents a comprehensive four-year plan for the conservation and management actions considered essential to ensuring the long-term survival of Cyclura carinata in the wild. This document combines knowledge and expertise from local government, local and international NGOs, the tourism industry, educators, homeowners, private island managers, civil society, and members of the IUCN SSC Iguana Specialist Group working in the TCI

Integrating student feedback during “Dental Curriculum Hack-A-thon”

Abstract Background The future of dental education is at crossroads. This study used the parameter of the 2016 Dental Curriculum Hack-a-Thon to assess intra- and inter-institutional agreement between student and faculty views regarding dental curriculums to determine if there is an impact in student perceptions towards dental education from before and after the event. Methods This exploratory, cross-sectional study involved two surveys, with Survey 1 being distributed among four faculty-student pairs of the four participating dental schools answering 14 questions. Survey 2 assessed the views of 20 participating dental students through 26 questions in a pre- and post- event survey design. Descriptive statistics were used to explore differences in perceptions towards dental education across both instrument surveys. Results The results revealed valuable student insights regarding intra- and inter-institutional agreement relevant for the change in dental curriculum that needs to occur. Survey 2 revealed that mandatory attendance in didactic courses, electronic based examination preferences, and the preference of preclinical courses being held in the first and second years of a four-year dental curriculum were of particular importance to student participants. Conclusions The results of this study indicate that exposure and participation in subjects pertaining to dental education can be influential on student preferences and opinions on how dental education should be delivered in a four-year curriculum

Lifetime evolution of ADHD treatment

7noIn corso di stampareservedAttention-deficit hyperactivity disorder (ADHD), has been traditionally considered a neurodevelopmental disorder affecting children and adolescents characterized by inattention, hyperactivity, disruptive behavior, and impulsivity. Although still debated, it is evident that ADHD is also present in adulthood, but this diagnosis is rarely carried out, mainly for the frequent comorbidity with other psychiatric and/or substance abuse disorders. Given the need to shed more light on the pharmacological treatment of ADHD, we performed a naturalistic review to review and comment on the available literature of ADHD treatment across the lifespan. Indeed, stimulants are endowed of a prompt efficacy and safety, whilst non-stimulants, although requiring some weeks to be fully effective, are useful when a substance abuse history is detected. In any case, the pharmacological management of ADHD appears to be still largely influenced by the individual experience of the clinicians. Further longitudinal studies with a careful and detailed characterization of participants across different phases of the lifespan are also required to provide relevant confirmations (or denials) regarding pharmacological treatments amongst the different age groups. © 2021, The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.mixedFederico Mucci; Barbara Carpita; Giovanni Pagni; Alessandra Della Vecchia; Sarah Bjedov; Andrea Pozza; Donatella MarazzitiMucci, Federico; Carpita, Barbara; Pagni, Giovanni; Della Vecchia, Alessandra; Bjedov, Sarah; Pozza, Andrea; Marazziti, Donatell

Oral health conditions and correlates: a National Oral Health Survey of Rwanda

Background: Dental diseases are chronic, lifelong and preventable yet affect over half the world’s population. Personal oral hygiene practices and socio-economic factors contribute to oral health outcomes affecting oral health quality of life. Integrating basic oral care within community level health systems increases accessibility and availability of oral health resources. Objective: National Oral Health Survey of Rwanda (NOHSR) data were investigated for associations of socio-demographic characteristics, personal oral hygiene practices, oral health outcomes, and oral health quality of life indicators. Methods: Data were analyzed and descriptive statistics calculated. Multivariable logistic regression models were developed to assess associations between untreated caries, calculus, and pain with various independent variables (demographics and personal oral hygiene practices). Additional logistic regression models examined associations between quality of life indicators and the aforementioned independent variables as well as untreated caries and pain. Results: Those who did not use a toothbrush (62.7%), or toothpaste (70.0%), and cleaned their teeth less than once per day (55.3%) had a higher prevalence of untreated caries. Approximately one-third of those in rural areas cleaned their teeth once per day or more compared to two-thirds of those in urban areas (35.4% vs. 71.2%). Those cleaning their teeth less than once daily were estimated to have 56.0% higher odds of caries than those who cleaned their teeth once a day or more (OR = 1.56, [95% CI 1.25–1.95]). Those with secondary education or higher and those with skilled jobs demonstrated more frequent teeth cleaning and higher toothbrush and toothpaste use. Quality-of-life indicators varied significantly with untreated caries and pain. Conclusion: Socio-economic, individual, and workforce characteristics are important considerations when assessing oral health outcomes. This study investigated social demographic disparities in relation to oral health related behaviors and outcomes. This information can help guide oral health care programming in Rwanda

Building oral health research infrastructure: the first national oral health survey of Rwanda

Background: Oral health affects quality of life and is linked to overall health. Enhanced oral health research is needed in low- and middle-income countries to develop strategies that reduce the burden of oral disease, improve oral health and inform oral health workforce and infrastructure development decisions. Objective: To implement the first National Oral Health Survey of Rwanda to assess the oral disease burden and inform oral health promotion strategies. Methods: In this cross-sectional study, sample size and site selection were based on the World Health Organization (WHO) Oral Health Surveys Pathfinder stratified cluster methodologies. Randomly selected 15 sites included 2 in the capital city, 2 other urban centers and 11 rural locations representing all provinces and rural/urban population distribution. A minimum of 125 individuals from each of 5 age groups were included at each site. A Computer Assisted Personal Instrument (CAPI) was developed to administer the study instrument. Results: Nearly two-thirds (64.9%) of the 2097 participants had caries experience and 54.3% had untreated caries. Among adults 20 years of age and older, 32.4% had substantial oral debris and 60.0% had calculus. A majority (70.6%) had never visited an oral health provider. Quality-of-life challenges due to oral diseases/conditions including pain, difficulty chewing, self-consciousness, and difficulty participating in usual activities was reported at 63.9%, 42.2% 36.2%, 35.4% respectively. Conclusion: The first National Oral Health Survey of Rwanda was a collaboration of the Ministry of Health of Rwanda, the University of Rwanda Schools of Dentistry and Public Health, the Rwanda Dental Surgeons and Dental (Therapists) Associations, and Tufts University and Harvard University Schools of Dental Medicine. The international effort contributed to building oral health research capacity and resulted in a national oral health database of oral disease burden. This information is essential for developing oral disease prevention and management strategies as well as oral health workforce and infrastructure