The annotation of GBA1 has been concealed by its protein-coding pseudogene GBAP1.

Mutations in GBA1 cause Gaucher disease and are the most important genetic risk factor for Parkinson's disease. However, analysis of transcription at this locus is complicated by its highly homologous pseudogene, GBAP1. We show that >50% of short RNA-sequencing reads mapping to GBA1 also map to GBAP1. Thus, we used long-read RNA sequencing in the human brain, which allowed us to accurately quantify expression from both GBA1 and GBAP1. We discovered significant differences in expression compared to short-read data and identify currently unannotated transcripts of both GBA1 and GBAP1. These included protein-coding transcripts from both genes that were translated in human brain, but without the known lysosomal function-yet accounting for almost a third of transcription. Analyzing brain-specific cell types using long-read and single-nucleus RNA sequencing revealed region-specific variations in transcript expression. Overall, these findings suggest nonlysosomal roles for GBA1 and GBAP1 with implications for our understanding of the role of GBA1 in health and disease.

"I'm Not Only a Body": Change in Thoughts about the Body after Mirror Exposure Treatment in Women with Obesity-An Exploratory Study.

Nowadays, obesity (OB) is one of the most important health problems in population-wide health. In addition to its physical consequences, it is a risk factor for the development of psychological problems, including body dissatisfaction (BD). This is why the treatment of BD is essential for its prevention. However, this has mostly been studied from a quantitative perspective, without focusing on the discomfort experienced by the person and the accompanying thoughts and emotions. In this study, 26 women with obesity (BMI > 30 kg/m2) participated, of whom 16 had high BD and 10 had low BD, as measured by the BSQ questionnaire. The women with high BD underwent six sessions of exposure to their own body in front of a mirror, recording the discomfort experienced with this vision during the session. In addition, all participants recorded positive and negative thoughts towards their body before and after these sessions. After the exposure treatment sessions, a reduction in symptomatology (BD, discomfort when visualizing one's own body) was observed, as well as a change in the thoughts expressed by the participants, both in quantity (fewer negative thoughts) and in quality (a more positive self-perception and/or in more respectful terms used towards themselves). In conclusion, such treatments prove to be effective in reducing subjective discomfort and body-related thoughts in women with obesity.

Risk of Type 2 Diabetes in University Students at the University of Extremadura: A Cross-Sectional Study.

The prevalence of type 2 diabetes is increasing worldwide. The aim of our study was to detect people susceptible to DM among a university population aged 18 to 45 years and analyze the existence of modifiable risk factors in order to implement prevention programs, in addition to analyzing BMI data related to the variables under study. We proposed a descriptive, cross-sectional study following the recommendations of cross-sectional studies (STROBE), with a sample of 341 subjects, students enrolled at the University of Extremadura, carried out by two researchers. The research protocol was approved by the Bioethics Committee of the University of Extremadura (165/2021). The study considered the Findrisk questionnaire in Spanish, validated by the Blackboard Study, a stadiometer to measure height, a bioimpedance meter to evaluate weight and body composition parameters, and a blood pressure monitor to measure blood pressure. The results indicated that the participants had a low risk of suffering T2DM. The highest Findrisk test scores were found in those with a BMI value above 25, lower physical activity, poor dietary intake of fruits and vegetables, and increased fat mass. Our future research will be the implementation of T2DM prevention programs, acting on modifiable factors.

Comparative evaluation of the dentoalveolar effects of three Class II correctors: A finite element analysis study.

OBJECTIVE: To compare the stress distribution and total strain applied to the dentition, periodontal ligament (PDL) and cortical and trabecular bones by three Class II correctors using finite element analysis. DESIGN: Three-dimensional analysis of stresses and total strain of the dentition with three Class II correctors. SETTING: Computational study. METHODS: Three-dimensional finite element models of Class II elastics, the Forsus Fatigue Resistant Device (FRD) and the Carriere Motion Appliance (CMA) were constructed from a cone-beam computed tomography (CBTC) image of an orthodontic Class II patient. The distribution of stress (von Mises and principal stress) and the total strain (mm) in maxillo-mandibular dentition, PDL, cortical and trabecular bone were analysed. RESULTS: The highest von Mises yield and the maximum principal stress in the three models were found at the teeth, followed by the cortical bone, trabecular bone and PDL. The maximum stress and total deformation were located at the upper canines and lower molars in the Class II elastics and CMA models, in the upper first molars in the Forsus FRD and CMA, and in the lower first premolars in the Forsus FRD. In addition, stress was distributed in the anterior and posterior regions of the teeth, and the total deformation was found in the distal direction in the upper arch and in the mesial direction in the lower arch. CONCLUSION: The stress concentrations in the three models were located close to the active components of each appliance, producing specific patterns of stress distribution and displacement that should be taken into account when planning the type of appliance to be used for the correction of the Class II malocclusion.

Impact of letermovir prophylaxis in CMV reactivation and disease after allogenic hematopoietic cell transplantation: a real-world, observational study.

Letermovir for CMV prevention in CMV-seropositive adults undergoing allo-HCT was implemented at our program in 2021. This study investigates the results from the use of letermovir. The study includes all the 140 CMV-seropositive patients who underwent an allo-HCT during the years 2020, 2021, and 2022 at our institution. Thirty-eight (27.4%) of these patients received letermovir, administered from day + 7 to day + 100 and restarted if patients were on treatment with steroids. The day + 180 and 1-year cumulative incidences of CMV reactivation were 5.3% and 12.1% for patients who received letermovir and 52.9% and 53.9% for those who did not (P < 0.001) (HR 0.19, P < 0.001). Four (10.5%) of these thirty-eight patients had a CMV reactivation, but only 2 (5.3%) cases occurred during the administration of letermovir. During the first year after allo-HCT, 13 (9.2%) patients had CMV disease; the day + 180 and 1-year cumulative incidences were 2.6% and 6.0% for patients who received letermovir and 9.9% and 12.3% for those who did not (P = 0.254) (HR 1.01, P = 0.458). Two (4.2%) of the patients included in the letermovir group had CMV disease, but both of them after letermovir discontinuation. Letermovir induced a protective effect on CMV reactivation risk, but its use was not associated with a significant reduction of CMV disease. The fact that the CMV disease in patients who received letermovir occurred after the discontinuation of the drug, questions whether CMV prophylaxis should be used in patients with high risk for CMV reactivation or disease.

Development of Neural Mechanisms Underlying Threat Processing: Associations With Childhood Social Reticence and Adolescent Anxiety.

Background: Social reticence in early childhood is characterized by shy and anxiously avoidant behavior, and it confers risk for pediatric anxiety disorders later in development. Aberrant threat processing may play a critical role in this association between early reticent behavior and later psychopathology. The goal of this longitudinal study is to characterize developmental trajectories of neural mechanisms underlying threat processing and relate these trajectories to associations between early-childhood social reticence and adolescent anxiety. Methods: In this 16-year longitudinal study, social reticence was assessed from 2 to 7 years of age; anxiety symptoms and neural mechanisms during the dot-probe task were assessed at 10, 13, and 16 years of age. The sample included 144 participants: 71 children provided data at age 10 (43 girls, meanage = 10.62), 85 at age 13 (46 girls, meanage = 13.25), and 74 at age 16 (36 girls, meanage = 16.27). Results: A significant interaction manifested among social reticence, anxiety symptoms, and time, on functional connectivity between the left amygdala and the left dorsolateral prefrontal cortex, voxelwise p < .001, clusterwise familywise error p < .05. Children with high social reticence showed a negative association between amygdala-dorsolateral prefrontal cortex connectivity and anxiety symptoms with age, compared to children with low social reticence, suggesting distinct neurodevelopmental pathways to anxiety. Conclusions: These findings were present across all conditions, suggesting task-general effects in potential threat processing. Additionally, the timing of these neurodevelopmental pathways differed for children with high versus low social reticence, which could affect the timing of effective preventive interventions.

ensemblQueryR: fast, flexible and high-throughput querying of Ensembl LD API endpoints in R.

We present ensemblQueryR, an R package for querying Ensembl linkage disequilibrium (LD) endpoints. This package is flexible, fast and user-friendly, and optimised for high-throughput querying. ensemblQueryR uses functions that are intuitive and amenable to custom code integration, familiar R object types as inputs and outputs as well as providing parallelisation functionality. For each Ensembl LD endpoint, ensemblQueryR provides two functions, permitting both single- and multi-query modes of operation. The multi-query functions are optimised for large query sizes and provide optional parallelisation to leverage available computational resources and minimise processing time. We demonstrate improved computational performance of ensemblQueryR over an exisiting tool in terms of random access memory (RAM) usage and speed, delivering a 10-fold speed increase whilst using a third of the RAM. Finally, ensemblQueryR is near-agnostic to operating system and computational architecture through Docker and singularity images, making this tool widely accessible to the scientific community.

aws-s3-integrity-check: an open-source bash tool to verify the integrity of a dataset stored on Amazon S3.

Amazon Simple Storage Service (Amazon S3) is a widely used platform for storing large biomedical datasets. Unintended data alterations can occur during data writing and transmission, altering the original content and generating unexpected results. However, no open-source and easy-to-use tool exists to verify end-to-end data integrity. Here, we present aws-s3-integrity-check, a user-friendly, lightweight, and reliable bash tool to verify the integrity of a dataset stored in an Amazon S3 bucket. Using this tool, we only needed ∼114 min to verify the integrity of 1,045 records ranging between 5 bytes and 10 gigabytes and occupying ∼935 gigabytes of the Amazon S3 cloud. Our aws-s3-integrity-check tool also provides file-by-file on-screen and log-file-based information about the status of each integrity check. To our knowledge, this tool is the only open-source one that allows verifying the integrity of a dataset uploaded to the Amazon S3 Storage quickly, reliably, and efficiently. The tool is freely available for download and use at https://github.com/SoniaRuiz/aws-s3-integrity-check and https://hub.docker.com/r/soniaruiz/aws-s3-integrity-check.

Poly-l-glutamic acid modification modulates the bio-nano interface of a therapeutic anti-IGF-1R antibody in prostate cancer.

Modifying biological agents with polymers such as polyethylene glycol (PEG) has demonstrated clinical benefits; however, post-market surveillance of PEGylated derivatives has revealed PEG-associated toxicity issues, prompting the search for alternatives. We explore how conjugating a poly-l-glutamic acid (PGA) to an anti-insulin growth factor 1 receptor antibody (AVE1642) modulates the bio-nano interface and anti-tumor activity in preclinical prostate cancer models. Native and PGA-modified AVE1642 display similar anti-tumor activity in vitro; however, AVE1642 prompts IGF-1R internalization while PGA conjugation prompts higher affinity IGF-1R binding, thereby inhibiting IGF-1R internalization and altering cell trafficking. AVE1642 attenuates phosphoinositide 3-kinase signaling, while PGA-AVE1642 inhibits phosphoinositide 3-kinase and mitogen-activated protein kinase signaling. PGA conjugation also enhances AVE1642's anti-tumor activity in an orthotopic prostate cancer mouse model, while PGA-AVE1642 induces more significant suppression of cancer cell proliferation/angiogenesis than AVE1642. These findings demonstrate that PGA conjugation modulates an antibody's bio-nano interface, mechanism of action, and therapeutic activity.

Orthodontic treatment need, the types of brackets and the oral health-related quality of life.

BACKGROUND: Malocclusion can affect the oral health-related quality of life (OHRQoL). The influence of the orthodontic treatment need (OTN) and the type of brackets on OHRQOL is not clear. OBJECTIVES: The aim of the present study was to determine the relationships between OTN and the bracket type and OHRQoL during the first 6 months of orthodontic treatment (OT) in adult patients. MATERIAL AND METHODS: This cohort study was conducted at the Department of Orthodontics of a private university. A total of 216 patients aged ≥18 years participated in the study (106 patients with conventional brackets and 110 with self-ligating brackets). The OHRQoL was evaluated using the 14-item Oral Health Impact Profile (OHIP-14) at 5 time points - before OT (T0), and at 24/48 h (T1), 1 month (T2), 3 months (T3), and 6 months (T4) after the installation of the orthodontic appliance. The OTN was evaluated with the dental aesthetic index (DAI) by 2 previously calibrated operators. For the statistical analysis, the χ2 test and the Mann-Whitney U test were used. Additionally, Poisson regression models were performed. RESULTS: The evidence of an association between OHRQoL and OTN was found only at T3 (p = 0.0095). No association was found between OHRQoL and the bracket type. However, in the regression models, OHRQoL was statistically significantly worse at T3 in the group with a greater OTN (IRR (incidence rate ratio) = 1.34; 95% CI (confidence interval): 1.21;1.48) and at T4 in the self-ligation group (IRR = 1.23; 95% CI: 1.12;1.36). CONCLUSIONS: The OHRQoL was affected in the same way at the beginning of OT, regardless of OTN and the bracket type used. However, a worse OHRQoL was observed at 3 months in subjects with greater OTN and at 6 months in patients with self-ligating brackets.

The non-specific lethal complex regulates genes and pathways genetically linked to Parkinson's disease.

Genetic variants conferring risks for Parkinson's disease have been highlighted through genome-wide association studies, yet exploration of their specific disease mechanisms is lacking. Two Parkinson's disease candidate genes, KAT8 and KANSL1, identified through genome-wide studies and a PINK1-mitophagy screen, encode part of the histone acetylating non-specific lethal complex. This complex localizes to the nucleus, where it plays a role in transcriptional activation, and to mitochondria, where it has been suggested to have a role in mitochondrial transcription. In this study, we sought to identify whether the non-specific lethal complex has potential regulatory relationships with other genes associated with Parkinson's disease in human brain. Correlation in the expression of non-specific lethal genes and Parkinson's disease-associated genes was investigated in primary gene co-expression networks using publicly-available transcriptomic data from multiple brain regions (provided by the Genotype-Tissue Expression Consortium and UK Brain Expression Consortium), whilst secondary networks were used to examine cell type specificity. Reverse engineering of gene regulatory networks generated regulons of the complex, which were tested for heritability using stratified linkage disequilibrium score regression. Prioritized gene targets were then validated in vitro using a QuantiGene multiplex assay and publicly-available chromatin immunoprecipitation-sequencing data. Significant clustering of non-specific lethal genes was revealed alongside Parkinson's disease-associated genes in frontal cortex primary co-expression modules, amongst other brain regions. Both primary and secondary co-expression modules containing these genes were enriched for mainly neuronal cell types. Regulons of the complex contained Parkinson's disease-associated genes and were enriched for biological pathways genetically linked to disease. When examined in a neuroblastoma cell line, 41% of prioritized gene targets showed significant changes in mRNA expression following KANSL1 or KAT8 perturbation. KANSL1 and H4K8 chromatin immunoprecipitation-sequencing data demonstrated non-specific lethal complex activity at many of these genes. In conclusion, genes encoding the non-specific lethal complex are highly correlated with and regulate genes associated with Parkinson's disease. Overall, these findings reveal a potentially wider role for this protein complex in regulating genes and pathways implicated in Parkinson's disease.

Distinct neurocognitive fingerprints reflect differential associations with risky and impulsive behavior in a neurotypical sample.

Engagement in risky and impulsive behavior has long been associated with deficits in neurocognition. However, we have a limited understanding of how multiple subfunctions of neurocognition co-occur within individuals and which combinations of neurocognitive subfunctions are most relevant for risky and impulsive behavior. Using the neurotypical Nathan Kline Institute Rockland Sample (N = 673), we applied a Bayesian latent feature learning model-the Indian Buffet Process-to identify nuanced, individual-specific profiles of multiple neurocognitive subfunctions and examine their relationship to risky and impulsive behavior. All features were within a relatively normative range of neurocognition; however, there was subtle variability related to risky and impulsive behaviors. The relatively overall poorer neurocognition feature correlated with greater affective impulsivity and substance use patterns/problems. The poorer episodic memory and emotion feature correlated with greater trait externalizing and sensation-seeking. The poorer attention feature correlated with increased trait externalizing and negative urgency but decreased positive urgency and substance use. Finally, the average or mixed features negatively correlated with various risky and impulsive behaviors. Estimating nuanced patterns of co-occurring neurocognitive functions can inform our understanding of a continuum of risky and impulsive behaviors.

Alignment efficiency of heat activated and superelastic nickel-titanium archwires in orthodontic patients over three months: A Single-center, randomized clinical trial.

OBJECTIVE: The aim of this 2-arm parallel study was to evaluate the alignment efficiency of heat-activated nickel-titanium (NiTi-TE) and superelastic nickel titanium (NiTi-PSE) archwires over the first 3 months of orthodontic treatment and compare these groups. SETTING AND SAMPLE POPULATION: Randomized, double-blind, controlled, single-center trial in 52 patients with fixed orthodontic appliances from an orthodontic graduate program in the permanent dentition and moderate crowding in the lower arch. MATERIAL AND METHODS: Patients were randomly allocated to one of two interventions: NiTi-TE and NiTi-PSE archwires, 0.014-inch (3M Unitek™, CA, USA) with a follow-up period of 3 months. The primary outcome was the alignment efficiency determined by the reduction in Little's irregularity index (mm), measured in three points, T0: before the start of orthodontic treatment, T1: 1 month later, T2: 2 months later, T3: 3 months later. Data were analyzed using independent sample t tests and repeated measures ANOVA. RESULTS: 52 patients (NiTi-TE n = 26; NiTi-PSE n = 26) were randomized and analyzed (average age: 21.73; standard deviation (SD): 6.07; average lower anterior irregularity: 5.20; SD: 0.76) for intention-to-treat (ITT) analysis. No statistically significant differences between the groups were found (mean of the differences: T1: 0.20; 95% CI: -0.558; 0.958; T2: 0.49: 95% CI: -0.339; 1.319; T3: 0.33; 95% CI: -0.308; 0.968). The resolution of crowding with each of the wires was significant (P < 0.0001) at all times. Twelve participants (2 treated with NiTi-TE and 10 treated with NiTi-PSE) lost follow-up due to face-to-face dental-procedures restrictions during the COVID-19 pandemic, the missing data was imputed. CONCLUSIONS: NiTi-TE and NiTi-PSE wires of 0.014-inch were similar in their clinical efficiency for the resolution of crowding during the first 3 months of orthodontic treatment. REGISTRATION: Clinical Trials NCT03256279.

Impact of Suspected Preterm Labor during Pregnancy on Cardiometabolic Profile and Neurodevelopment during Childhood: A Prospective Cohort Study Protocol.

INTRODUCTION: Suspected preterm labor (SPL), defined as the presence of regular and painful uterine contractions and cervical shortening, represents a prenatal insult with potential long-term consequences. However, despite recent evidence demonstrating suboptimal neurodevelopment at 2 years in this population, it remains underestimated as a significant risk factor for neurodevelopmental disorders or other chronic diseases. The aim of this study is to assess the impact of suspected preterm labor during pregnancy on cardiometabolic profile and neurodevelopment during childhood (6-8 years). METHODS AND ANALYSIS: Prospective cohort study including children whose mothers suffered suspected preterm labour during pregnancy and paired controls. Neurodevelopmental, cardiovascular, and metabolic assessments will be performed at 6-8 years of age. A trained psychologist will carry out the neurodevelopment assessment including intelligence, visual perception, and behavioral assessment. Body composition and physical fitness assessment will be performed by one trained pediatrician and nurse. Finally, cardiovascular evaluation, including echocardiography and blood pressure, will be performed by two pediatric cardiologists. Data regarding perinatal and postnatal characteristics, diet, lifestyle, and weekly screen time of the child will be obtained from medical history and direct interviews with families. Primary outcome measures will include body mass index and adiposity, percentage of fat mass and total and regional lean mass, bone mineral content and density, cardiorespiratory resistance, isometric muscle strength, dynamic lower body strength, systolic and diastolic blood pressure, left ventricle (LV) systolic and diastolic function, general intelligence index, visuospatial working memory span, oculomotor control test, index of emotional, and behavioral problems.

Functional genomics provide key insights to improve the diagnostic yield of hereditary ataxia.

Improvements in functional genomic annotation have led to a critical mass of neurogenetic discoveries. This is exemplified in hereditary ataxia, a heterogeneous group of disorders characterised by incoordination from cerebellar dysfunction. Associated pathogenic variants in more than 300 genes have been described, leading to a detailed genetic classification partitioned by age-of-onset. Despite these advances, up to 75% of patients with ataxia remain molecularly undiagnosed even following whole genome sequencing, as exemplified in the 100 000 Genomes Project. This study aimed to understand whether we can improve our knowledge of the genetic architecture of hereditary ataxia by leveraging functional genomic annotations, and as a result, generate insights and strategies that raise the diagnostic yield. To achieve these aims, we used publicly-available multi-omics data to generate 294 genic features, capturing information relating to a gene's structure, genetic variation, tissue-specific, cell-type-specific and temporal expression, as well as protein products of a gene. We studied these features across genes typically causing childhood-onset, adult-onset or both types of disease first individually, then collectively. This led to the generation of testable hypotheses which we investigated using whole genome sequencing data from up to 2182 individuals presenting with ataxia and 6658 non-neurological probands recruited in the 100 000 Genomes Project. Using this approach, we demonstrated a high short tandem repeat (STR) density within childhood-onset genes suggesting that we may be missing pathogenic repeat expansions within this cohort. This was verified in both childhood- and adult-onset ataxia patients from the 100 000 Genomes Project who were unexpectedly found to have a trend for higher repeat sizes even at naturally-occurring STRs within known ataxia genes, implying a role for STRs in pathogenesis. Using unsupervised analysis, we found significant similarities in genomic annotation across the gene panels, which suggested adult- and childhood-onset patients should be screened using a common diagnostic gene set. We tested this within the 100 000 Genomes Project by assessing the burden of pathogenic variants among childhood-onset genes in adult-onset patients and vice versa. This demonstrated a significantly higher burden of rare, potentially pathogenic variants in conventional childhood-onset genes among individuals with adult-onset ataxia. Our analysis has implications for the current clinical practice in genetic testing for hereditary ataxia. We suggest that the diagnostic rate for hereditary ataxia could be increased by removing the age-of-onset partition, and through a modified screening for repeat expansions in naturally-occurring STRs within known ataxia-associated genes, in effect treating these regions as candidate pathogenic loci.

Assessment of Diabetic Foot Prevention by Nurses.

Diabetic foot is a severe complication of diabetes, with serious consequences such as amputations and high mortality rates as well as elevated economic costs. To evaluate whether or not nursing staff follow the recommendations of national and international organizations regarding diabetic foot prevention, a cross-sectional and observational descriptive study was carried out using an ad hoc self-administered questionnaire validated by seven experts, with a Cronbach's alpha of 0.731. Of the total 164 participants, 157 met the inclusion criteria. Findings showed that 96.58% asked their patients to remove their footwear, 78.34% performed thorough examinations, and 80.25% assessed the risk of developing diabetic foot. Participants educated their patients in self-care and evaluated skills related to diabetic foot control either frequently (84.07%) or very frequently (62.42%), and only 19.11% of them carried out group activity workshops. Significant statistical differences were found in the performance of activities in the groups by participant age intervals, whether working in primary health care or a hospital, having specific training, and the participant's DM patient ratio. We obtained high percentages of compliance in the assessed activities in comparison to other studies. Nevertheless, we believe it is necessary to encourage screening in specialized care, skills testing, and the implementation of educational group activities and workshops.

Fear-potentiated startle reveals diminished threat extinction in pathological anxiety.

BACKGROUND: Major theories propose that perturbed threat learning is central to pathological anxiety, but empirical support is inconsistent. Failures to detect associations with anxiety may reflect limitations in quantifying conditioned responses to anticipated threat, and hinder translation of theory into empirical work. In prior work, we could not detect threat-specific anxiety effects on states of conditioned threat using psychophysiology in a large sample of patients and healthy comparisons. Here, we examine the utility of an alternative fear potentiated startle (FPS) scoring in revealing associations between anxiety and threat conditioning and extinction in this dataset. Secondary analyses further explored associations among conditioned threat responses, subcortical morphometry, and treatment outcomes. METHODS: Youths and adults with anxiety disorders and healthy comparisons (n = 306; 178 female participants; 8-50 years) previously completed a well-validated differential threat learning paradigm. FPS and skin conductance response (SCR) quantified psychophysiological responses during threat conditioning and extinction. In this report, we examined normalizing raw FPS scores to intertrial intervals (ITI) to address challenges in more common approaches to FPS scoring which could mask group effects. Secondary analyses examined associations between FPS and subcortical morphometry and with response to exposure-based cognitive behavioral therapy in a subsample of patients. RESULTS: Patients and comparisons showed comparable differential threat conditioning using FPS and SCR. While SCR suggested comparable extinction between groups, FPS revealed stronger retention of threat contingency during extinction in individuals with anxiety disorders. Extinction indexed with FPS was not associated with age, morphometry, or anxiety treatment outcome. CONCLUSION: ITI-normalized FPS may have utility in detecting difficulties in extinguishing conditioned threat responses in anxiety. These findings provide support for extinction theories of anxiety and encourage continued research on aberrant extinction in pathological anxiety.

IntroVerse: a comprehensive database of introns across human tissues.

Dysregulation of RNA splicing contributes to both rare and complex diseases. RNA-sequencing data from human tissues has shown that this process can be inaccurate, resulting in the presence of novel introns detected at low frequency across samples and within an individual. To enable the full spectrum of intron use to be explored, we have developed IntroVerse, which offers an extensive catalogue on the splicing of 332,571 annotated introns and a linked set of 4,679,474 novel junctions covering 32,669 different genes. This dataset has been generated through the analysis of 17,510 human control RNA samples from 54 tissues provided by the Genotype-Tissue Expression Consortium. IntroVerse has two unique features: (i) it provides a complete catalogue of novel junctions and (ii) each novel junction has been assigned to a specific annotated intron. This unique, hierarchical structure offers multiple uses, including the identification of novel transcripts from known genes and their tissue-specific usage, and the assessment of background splicing noise for introns thought to be mis-spliced in disease states. IntroVerse provides a user-friendly web interface and is freely available at https://rytenlab.com/browser/app/introverse.

Rare disease gene association discovery from burden analysis of the 100,000 Genomes Project data.

To discover rare disease-gene associations, we developed a gene burden analytical framework and applied it to rare, protein-coding variants from whole genome sequencing of 35,008 cases with rare diseases and their family members recruited to the 100,000 Genomes Project (100KGP). Following in silico triaging of the results, 88 novel associations were identified including 38 with existing experimental evidence. We have published the confirmation of one of these associations, hereditary ataxia with UCHL1 , and independent confirmatory evidence has recently been published for four more. We highlight a further seven compelling associations: hypertrophic cardiomyopathy with DYSF and SLC4A3 where both genes show high/specific heart expression and existing associations to skeletal dystrophies or short QT syndrome respectively; monogenic diabetes with UNC13A with a known role in the regulation of ß cells and a mouse model with impaired glucose tolerance; epilepsy with KCNQ1 where a mouse model shows seizures and the existing long QT syndrome association may be linked; early onset Parkinson's disease with RYR1 with existing links to tremor pathophysiology and a mouse model with neurological phenotypes; anterior segment ocular abnormalities associated with POMK showing expression in corneal cells and with a zebrafish model with developmental ocular abnormalities; and cystic kidney disease with COL4A3 showing high renal expression and prior evidence for a digenic or modifying role in renal disease. Confirmation of all 88 associations would lead to potential diagnoses in 456 molecularly undiagnosed cases within the 100KGP, as well as other rare disease patients worldwide, highlighting the clinical impact of a large-scale statistical approach to rare disease gene discovery.

Relación entre la inclinación de los incisivos con la estabilidad en la alineación del sector anterior según criterios del índice PAR

Introducción : el objetivo de este estudio fue el evaluar la relación entre la inclinación de los incisivos al finalizar tratamiento de ortodoncia con la estabilidad de la alineación de dientes anteriores usando índice PAR. Métodos: estudio analítico de corte transversal, en 47 pacientes que finalizaron ortodoncia, con radiografía lateral inicial y final, se evaluó el ángulo formado entre plano (Silla-Nasion) (U1-NS) e inclinación del incisivo superior y el ángulo entre inclinación axial del incisivo inferior y plano mandibular (Go-Gn). Se aplicó el índice PAR del sector anterior a modelos pretratamiento (T0), postratamiento (T1) y de seguimiento (T2). El análisis estadístico se realizó mediante distribuciones de frecuencias y porcentuales, prueba T, Anova I, Anova II y Manova; significancia P= 0.05. Resultados: no se encontró asociación entre la inclinación del incisivo superior e inferior, la estabilidad en alineación y el puntaje ponderado del PAR entre T2-T1 (P>0.05). El PAR disminuyó 75.29% de T0 a T1 y 58.79% de T0 aT2, con recidiva de 16,5%. No hubo asociación entre tipo de retenedor y puntaje ponderado del PAR. De T0 a T2 hubo asociación entre la interacción de la inclinación del incisivo superior (P=0.03) e inferior (P=0.04), con el puntaje total ponderado del índice PAR. Conclusión: no hubo asociación entre la modificación de la inclinación de los incisivos con la estabilidad del sector anterior. Al terminar ortodoncia se presentó un nivel de corrección alto en el sector antero-superior e inferior, sin embargo, hubo recidiva de 16.5%.

Introduction: the objective of this study was to evaluate the relationship between incisor inclination at the end of orthodontic treatment with the anterior teeth alignment stability using PAR index. Methods: analytical cross-sectional study, the angle formed between the plane (Silla-Nasion) (U1-NS) and the inclination of the upper incisor and the angle between axial inclination of the lower incisor and mandibular plane (Go-Gn), were measured in 47 initial and final lateral radiographs of patients who finished orthodontic treatment. The anterior sector PAR index was applied to pretreatment (T0), posttreatment (T1) and follow-up (T2) casts. Statistical analysis was performed using frequency and percentage distributions, T test, Anova I, Anova II and Manova; significance p = 0,05. Results: no association was found between upper and lower incisor inclination, alignment stability and PAR weighted score between T2-T1 (p> 0,05). The PAR decreased 75,29% from T0 to T1 and 58,79% from T0 to T2, with a recurrence of 16,5%. There was no association between retainer type and PAR weighted score. From T0 to T2 there was an association between the interaction of the incisor inclination of upper (p = 0,03) and lower (p = 0,04), with the weighted total score of the PAR index. Conclusion: there was no association between the modification of the incisor inclination with the stability of the anterior sector. At the end of orthodontic treatment there was a high level of correction in the anterior-superior and inferior sector, however, there was a recurrence of 16,5%.