EFHC1 variants in juvenile myoclonic epilepsy: reanalysis according to NHGRI and ACMG guidelines for assigning disease causality

Peer reviewe

The Effects of Governmental Protected Areas and Social Initiatives for Land Protection on the Conservation of Mexican Amphibians

Traditionally, biodiversity conservation gap analyses have been focused on governmental protected areas (PAs). However, an increasing number of social initiatives in conservation (SICs) are promoting a new perspective for analysis. SICs include all of the efforts that society implements to conserve biodiversity, such as land protection, from private reserves to community zoning plans some of which have generated community-protected areas. This is the first attempt to analyze the status of conservation in Latin America when some of these social initiatives are included. The analyses were focused on amphibians because they are one of the most threatened groups worldwide. Mexico is not an exception, where more than 60% of its amphibians are endemic. We used a niche model approach to map the potential and real geographical distribution (extracting the transformed areas) of the endemic amphibians. Based on remnant distribution, all the species have suffered some degree of loss, but 36 species have lost more than 50% of their potential distribution. For 50 micro-endemic species we could not model their potential distribution range due to the small number of records per species, therefore the analyses were performed using these records directly. We then evaluated the efficiency of the existing set of governmental protected areas and established the contribution of social initiatives (private and community) for land protection for amphibian conservation. We found that most of the species have some proportion of their potential ecological niche distribution protected, but 20% are not protected at all within governmental PAs. 73% of endemic and 26% of micro-endemic amphibians are represented within SICs. However, 30 micro-endemic species are not represented within either governmental PAs or SICs. This study shows how the role of land conservation through social initiatives is therefore becoming a crucial element for an important number of species not protected by governmental PAs

AHR2 Mutant Reveals Functional Diversity of Aryl Hydrocarbon Receptors in Zebrafish

The aryl hydrocarbon receptor (AHR) is well known for mediating the toxic effects of TCDD and has been a subject of intense research for over 30 years. Current investigations continue to uncover its endogenous and regulatory roles in a wide variety of cellular and molecular signaling processes. A zebrafish line with a mutation in ahr2 (ahr2hu3335), encoding the AHR paralogue responsible for mediating TCDD toxicity in zebrafish, was developed via Targeting Induced Local Lesions IN Genomes (TILLING) and predicted to express a non-functional AHR2 protein. We characterized AHR activity in the mutant line using TCDD and leflunomide as toxicological probes to investigate function, ligand binding and CYP1A induction patterns of paralogues AHR2, AHR1A and AHR1B. By evaluating TCDD-induced developmental toxicity, mRNA expression changes and CYP1A protein in the AHR2 mutant line, we determined that ahr2hu3335 zebrafish are functionally null. In silico modeling predicted differential binding of TCDD and leflunomide to the AHR paralogues. AHR1A is considered a non-functional pseudogene as it does not bind TCCD or mediate in vivo TCDD toxicity. Homology modeling, however, predicted a ligand binding conformation of AHR1A with leflunomide. AHR1A-dependent CYP1A immunohistochemical expression in the liver provided in vivo confirmation of the in silico docking studies. The ahr2hu3335 functional knockout line expands the experimental power of zebrafish to unravel the role of the AHR during development, as well as highlights potential activity of the other AHR paralogues in ligand-specific toxicological responses

Uptake of genetic testing and long-term tumor surveillance in von Hippel-Lindau disease

<p>Abstract</p> <p>Background</p> <p>von Hippel-Lindau (VHL) disease is a hereditary cancer syndrome caused by germline mutations in the <it>VHL </it>gene. Patients have significant morbidity and mortality secondary to vascular tumors. Disease management is centered on tumor surveillance that allows early detection and treatment. Presymptomatic genetic testing is therefore recommended, including in at-risk children.</p> <p>Methods</p> <p>We tested 17 families (n = 109 individuals) for <it>VHL </it>mutations including 43 children under the age of 18. Personalized genetic counseling was provided pre and post-test and the individuals undergoing presymptomatic testing filled out questionnaires gathering socio-demographic, psychological and psychiatric data. Mutation analysis was performed by direct sequencing of the <it>VHL </it>gene. Mutation-carriers were screened for VHL disease-related tumors and were offered follow-up annual examinations.</p> <p>Results</p> <p>Mutations were identified in 36 patients, 17 of whom were asymptomatic. In the initial screening, we identified at least one tumor in five of 17 previously asymptomatic individuals. At the end of five years, only 38.9% of the mutation-carriers continued participating in our tumor surveillance program. During this time, 14 mutation carriers developed a total of 32 new tumors, three of whom died of complications. Gender, education, income, marital status and religiosity were not found to be associated with adherence to the surveillance protocol. Follow-up adherence was also independent of pre-test depression, severity of disease, or number of affected family members. The only statistically significant predictor of adherence was being symptomatic at the time of testing (OR = 5; 95% CI 1.2 - 20.3; p = 0.02). Pre-test anxiety was more commonly observed in patients that discontinued follow-up (64.7% vs. 35.3%; p = 0.01).</p> <p>Conclusions</p> <p>The high initial uptake rate of genetic testing for VHL disease, including in minors, allowed the discontinuation of unnecessary screening procedures in non mutation-carriers. However, mutation-carriers showed poor adherence to long-term tumor surveillance. Therefore, many of them did not obtain the full benefit of early detection and treatment, which is central to the reduction of morbidity and mortality in VHL disease. Studies designed to improve adherence to vigilance protocols will be necessary to improve treatment and quality of life in patients with hereditary cancer syndromes.</p

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

Search for direct pair production of the top squark in all-hadronic final states in proton-proton collisions at s√=8 TeV with the ATLAS detector

The results of a search for direct pair production of the scalar partner to the top quark using an integrated luminosity of 20.1fb−1 of proton–proton collision data at √s = 8 TeV recorded with the ATLAS detector at the LHC are reported. The top squark is assumed to decay via t˜→tχ˜01 or t˜→ bχ˜±1 →bW(∗)χ˜01 , where χ˜01 (χ˜±1 ) denotes the lightest neutralino (chargino) in supersymmetric models. The search targets a fully-hadronic final state in events with four or more jets and large missing transverse momentum. No significant excess over the Standard Model background prediction is observed, and exclusion limits are reported in terms of the top squark and neutralino masses and as a function of the branching fraction of t˜ → tχ˜01 . For a branching fraction of 100%, top squark masses in the range 270–645 GeV are excluded for χ˜01 masses below 30 GeV. For a branching fraction of 50% to either t˜ → tχ˜01 or t˜ → bχ˜±1 , and assuming the χ˜±1 mass to be twice the χ˜01 mass, top squark masses in the range 250–550 GeV are excluded for χ˜01 masses below 60 GeV