Discovery and functional prioritization of Parkinson's disease candidate genes from large-scale whole exome sequencing.

BACKGROUND: Whole-exome sequencing (WES) has been successful in identifying genes that cause familial Parkinson's disease (PD). However, until now this approach has not been deployed to study large cohorts of unrelated participants. To discover rare PD susceptibility variants, we performed WES in 1148 unrelated cases and 503 control participants. Candidate genes were subsequently validated for functions relevant to PD based on parallel RNA-interference (RNAi) screens in human cell culture and Drosophila and C. elegans models. RESULTS: Assuming autosomal recessive inheritance, we identify 27 genes that have homozygous or compound heterozygous loss-of-function variants in PD cases. Definitive replication and confirmation of these findings were hindered by potential heterogeneity and by the rarity of the implicated alleles. We therefore looked for potential genetic interactions with established PD mechanisms. Following RNAi-mediated knockdown, 15 of the genes modulated mitochondrial dynamics in human neuronal cultures and four candidates enhanced α-synuclein-induced neurodegeneration in Drosophila. Based on complementary analyses in independent human datasets, five functionally validated genes-GPATCH2L, UHRF1BP1L, PTPRH, ARSB, and VPS13C-also showed evidence consistent with genetic replication. CONCLUSIONS: By integrating human genetic and functional evidence, we identify several PD susceptibility gene candidates for further investigation. Our approach highlights a powerful experimental strategy with broad applicability for future studies of disorders with complex genetic etiologies

Relações entre a adubação nitrogenada e a qualidade de grãos e de sementes em aveia branca Relationships between nitrogen fertility and grain and seeds quality in oats

Com o objetivo de avaliar o efeito da adubação nitrogenada sobre atributos qualitativos dos grãos e das sementes em aveia branca, foi conduzido experimento envolvendo os cultivares, CTC 5, UFRGS 15, UFRGS 19 e UPF 18, e 0, 24, 48 e 73kg ha-1 de N como doses de adubação, em Argissolo Amarelo eutrófico típico, com 26,7g dm-3 de matéria orgânica. A qualidade industrial dos grãos foi avaliada através do peso do hectolitro de grãos (PH), do teor de proteína e do rendimento industrial; a qualidade das sementes foi estimada pelos testes de germinação e de envelhecimento acelerado. Independentemente do cultivar considerado, o incremento, nas doses de adubação nitrogenada reduz o peso do hectolitro, eleva a concentração de proteína nas cariopses e a produção de proteína e não afeta o rendimento industrial e a qualidade fisiológica das sementes.<br>With the objective of evaluating the effect of nitrogen (N) fertilization on grain and seeds quality parameters in oat, a field experiment was conducted with the cultivars CTC5, UFRGS 15, UFRGS 19 and UPF 18, and levels of N fertilization, 0, 24, 48 and 73kg ha-1 in a Typic Hapludalf soil, with 26.7g dm-3 of organic matter. The grain quality was evaluated trough the test weight, protein concentration and groat percentage; the seed quality was estimated by the germination test and accelerated aging test. Independently of the considered cultivar the increase on level of N, decrease the test weight results, increase the protein concentration in the caryopsis and the protein yield, and does not affect the caryopsis percentage and physiological quality seeds

Consensus practice guidelines on interventions for cervical spine (facet) joint pain from a multispecialty international working group

Background. The past two decades have witnessed a surge in the use of cervical spine joint procedures including joint injections, nerve blocks and radiofrequency ablation to treat chronic neck pain, yet many aspects of the procedures remain controversial. Methods. In August 2020, the American Society of Regional Anesthesia and Pain Medicine and the American Academy of Pain Medicine approved and charged the Cervical Joint Working Group to develop neck pain guidelines. Eighteen stakeholder societies were identified, and formal request-for-participation and member nomination letters were sent to those organizations. Participating entities selected panel members and an ad hoc steering committee selected preliminary questions, which were then revised by the full committee. Each question was assigned to a module composed of 4-5 members, who worked with the Subcommittee Lead and the Committee Chairs on preliminary versions, which were sent to the full committee after revisions. We used a modified Delphi method whereby the questions were sent to the committee en bloc and comments were returned in a non-blinded fashion to the Chairs, who incorporated the comments and sent out revised versions until consensus was reached. Before commencing, it was agreed that a recommendation would be noted with >50% agreement among committee members, but a consensus recommendation would require >= 75% agreement. Results. Twenty questions were selected, with 100% consensus achieved in committee on 17 topics. Among participating organizations, 14 of 15 that voted approved or supported the guidelines en bloc, with 14 questions being approved with no dissensions or abstentions. Specific questions addressed included the value of clinical presentation and imaging in selecting patients for procedures, whether conservative treatment should be used before injections, whether imaging is necessary for blocks, diagnostic and prognostic value of medial branch blocks and intra-articular joint injections, the effects of sedation and injectate volume on validity, whether facet blocks have therapeutic value, what the ideal cut-off value is for designating a block as positive, how many blocks should be performed before radiofrequency ablation, the orientation of electrodes, whether larger lesions translate into higher success rates, whether stimulation should be used before radiofrequency ablation, how best to mitigate complication risks, if different standards should be applied to clinical practice and trials, and the indications for repeating radiofrequency ablation. Conclusions. Cervical medial branch radiofrequency ablation may provide benefit to well-selected individuals, with medial branch blocks being more predictive than intra-articular injections. More stringent selection criteria are likely to improve denervation outcomes, but at the expense of false-negatives (ie, lower overall success rate). Clinical trials should be tailored based on objectives, and selection criteria for some may be more stringent than what is ideal in clinical practice