Inflammatory agents partially explain associations between cortical thickness, surface area, and body mass in adolescents and young adulthood

Background/objectives Excessive body mass index (BMI) has been linked to a low-grade chronic inflammation state. Unhealthy BMI has also been related to neuroanatomical changes in adults. Research in adolescents is relatively limited and has produced conflicting results. This study aims to address the relationship between BMI and adolescents'brain structure as well as to test the role that inflammatory adipose-related agents might have over this putative link. Methods We studied structural MRI and serum levels of interleukin-6, tumor necrosis factor alpha (TNF-α), C-reactive protein and fibrinogen in 65 adolescents (aged 12-21 years). Relationships between BMI, cortical thickness and surface area were tested with a vertex-wise analysis. Subsequently, we used backward multiple linear regression models to explore the influence of inflammatory parameters in each brain-altered area. Results We found a negative association between cortical thickness and BMI in the left lateral occipital cortex (LOC) and the right precentral gyrus as well as a positive relationship between surface area and BMI in the left rostral middle frontal gyrus and the right superior frontal gyrus. In addition, we found that higher fibrinogen serum concentrations were related to thinning within the left LOC (β=−0.45,p< 0.001), while higher serum levels of TNF-αwere associated to a greater surface area in the right superior frontal gyrus (β=0.32,p=0.045). Besides, we have also identified a trend that negatively correlates the cortical thickness of the left fusiform gyrus with the increases in BMI. It was also associated to fibrinogen(β=−0.33,p=0.035). Conclusions These results suggest that adolescents'body mass increases are related with brain abnormalities in areas that could play a relevant role in some aspects of feeding behavior. Likewise, we have evidenced that these cortical changes were partially explained by inflammatory agents such as fibrinogen and TNF-α

Basal ganglia volume predicts speed processing performance in obese adolescents

La obesidad se ha relacionado con cambios estructurales en los ganglios basales y alteraciones en dominios transversales como la velocidad de procesamiento. El objetivo del presente estudio es investigar la relación entre velocidad de procesamiento y volumen de los ganglios basales en adolescentes con y sin obesidad. Treinta y tres participantes obesos y treinta y tres con peso normal fueron resonados (Siemens 3T Trio) y evaluados neuropsicológicamente. Se compararon los resultados de un índice de velocidad y la ratio de los ganglios basales controlando por edad, sexo y tamaño de la cabeza. Se realizaron regresiones lineales con las estructuras relacionadas con este índice. Se encontraron diferencias en el índice de velocidad, pero no en la ratio de los ganglios basales. El grupo con obesidad mostró una correlación positiva entre velocidad y ratio del globo pálido derecho (r= .41; p= .021). No hallamos relaciones significativas en el grupo normopeso. La ratio del globo pálido derecho predijo parte del rendimiento en velocidad en adolescentes obesos. Las diferencias en velocidad de procesamiento entre adolescentes con y sin obesidad podrían estar moderadas por el tamaño de estructuras subcorticales como el globo pálido.Obesity is related to structural changes in basal ganglia and alterations among transversal domains such as speed processing. The aim of the study is to address the relationship between speed processing and basal ganglia volumes in adolescents with and without obesity. Thirty-three obese and 33 normal-weight participants underwent MRI acquisition (Siemens 3T Trio) and neuropsychological assessment to obtain an index of speed processing. Speed processing index and basal ganglia ratios (VolBrain software) were compared controlling for age, sex and head size. Linear regressions were conducted in the structures related to such index. Groups differed for speed processing index, but did not differ for basal ganglia ratios. The obese group showed positive correlations between speed processing index and the right globus pallidum ratio (r= .41; p= .021). None relationship was found among normal-weight adolescents. Concretely, the right globus pallidum ratio predicted part of the performance in speed in obese participants. The differences in speed processing between adolescents with and without obesity might be mediated by the size of subcortical structures such as the globus pallidum

Implementation and first results of the KM3NeT real-time core-collapse supernova neutrino search

The KM3NeT research infrastructure is unconstruction in the Mediterranean Sea. KM3NeT will study atmospheric and astrophysical neutrinos with two multi-purpose neutrino detectors, ARCA and ORCA, primarily aimed at GeV–PeV neutrinos. Thanks to the multi-photomultiplier tube design of the digital optical modules, KM3NeT is capable of detecting the neutrino burst from a Galactic or near-Galactic core-collapse supernova. This potential is already exploitable with the first detection units deployed in the sea. This paper describes the real-time implementation of the supernova neutrino search, operating on the two KM3NeT detectors since the first months of 2019. A quasi-online astronomy analysis is introduced to study the time profile of the detected neutrinos for especially significant events. The mechanism of generation and distribution of alerts, as well as the integration into the SNEWS and SNEWS 2.0 global alert systems, are described. The approach for the follow-up of external alerts with a search for a neutrino excess in the archival data is defined. Finally, an overview of the current detector capabilities and a report after the first two years of operation are given.Acknowledgements The authors acknowledge the financial support of the funding agencies: Agence Nationale de la Recherche (contract ANR-15-CE31-0020), Centre National de la Recherche Scientifique (CNRS), Commission Européenne (FEDER fund and Marie Curie Program), Institut Universitaire de France (IUF), LabEx UnivEarthS (ANR-10-LABX-0023 and ANR-18-IDEX-0001), Paris Île-de-France Region, France; Shota Rustaveli National Science Foundation of Georgia (SRNSFG, FR-18-1268), Georgia; Deutsche Forschungsgemeinschaft (DFG), Germany; The General Secretariat of Research and Technology (GSRT), Greece; Istituto Nazionale di Fisica Nucleare (INFN), Ministero dell’Università e della Ricerca (MIUR), PRIN 2017 program (Grant NAT-NET 2017W4HA7S) Italy; Ministry of Higher Education Scientific Research and Professional Training, ICTP through Grant AF-13, Morocco; Nederlandse organisatie voor Wetenschappelijk Onderzoek (NWO), the Netherlands; The National Science Centre, Poland (2015/18/E/ST2/00758); National Authority for Scientific Research (ANCS), Romania; Ministerio de Ciencia, Innovación, Investigación y Universidades (MCIU): Programa Estatal de Generación de Conocimiento (refs. PGC2018-096663-B-C41, -A-C42, -B-C43, -B-C44) (MCIU/FEDER), Generalitat Valenciana: Prometeo (PROMETEO/2020/019), Grisolía (ref. GRISOLIA/2018/119) and GenT (refs. CIDEGENT/2018/034, /2019/043, /2020/049) programs, Junta de Andalucía (ref. A-FQM-053-UGR18), La Caixa Foundation (ref. LCF/BQ/IN17/11620019), EU: MSC program (ref. 101025085), Spain

The Lsm1-7/Pat1 complex binds to stress-activated mRNAs and modulates the response to hyperosmotic shock

RNA-binding proteins (RBPs) establish the cellular fate of a transcript, but an understanding of these processes has been limited by a lack of identified specific interactions between RNA and protein molecules. Using MS2 RNA tagging, we have purified proteins associated with individual mRNA species induced by osmotic stress, STL1 and GPD1. We found members of the Lsm1-7/Pat1 RBP complex to preferentially bind these mRNAs, relative to the non-stress induced mRNAs, HYP2 and ASH1. To assess the functional importance, we mutated components of the Lsm1-7/Pat1 RBP complex and analyzed the impact on expression of osmostress gene products. We observed a defect in global translation inhibition under osmotic stress in pat1 and lsm1 mutants, which correlated with an abnormally high association of both non-stress and stress-induced mRNAs to translationally active polysomes. Additionally, for stress-induced proteins normally triggered only by moderate or high osmostress, in the mutants the protein levels rose high already at weak hyperosmosis. Analysis of ribosome passage on mRNAs through co-translational decay from the 5' end (5P-Seq) showed increased ribosome accumulation in lsm1 and pat1 mutants upstream of the start codon. This effect was particularly strong for mRNAs induced under osmostress. Thus, our results indicate that, in addition to its role in degradation, the Lsm1-7/Pat1 complex acts as a selective translational repressor, having stronger effect over the translation initiation of heavily expressed mRNAs. Binding of the Lsm1-7/Pat1p complex to osmostress-induced mRNAs mitigates their translation, suppressing it in conditions of weak or no stress, and avoiding a hyperresponse when triggered

Mutational spectrum of GNAL, THAP1 and TOR1A genes in isolated dystonia: study in a population from Spain and systematic literature review

[Objective] We aimed to investigate the prevalence of TOR1A, GNAL and THAP1 variants as the cause of dystonia in a cohort of Spanish patients with isolated dystonia and in the literature.[Methods] A population of 2028 subjects (including 1053 patients with different subtypes of isolated dystonia and 975 healthy controls) from southern and central Spain was included. The genes TOR1A, THAP1 and GNAL were screened using a combination of high-resolution melting analysis and direct DNA resequencing. In addition, an extensive literature search to identify original articles (published before 10 August 2020) reporting mutations in TOR1A, THAP1 or GNAL associated to dystonia was performed.[Results] Pathogenic or likely pathogenic variants in TOR1A, THAP1 and GNAL were identified in 0.48%, 0.57% and 0.29% of our patients, respectively. Five patients carried the variation p.Glu303del in TOR1A. A very rare variant in GNAL (p.Ser238Asn) was found as a putative risk factor for dystonia. In the literature, variations in TOR1A, THAP1 and GNAL accounted for about 6%, 1.8% and 1.1% of published dystonia patients, respectively.[Conclusions] There is a different genetic contribution to dystonia of these three genes in our patients (about 1.3% of patients) and in the literature (about 3.6% of patients), probably due the high proportion of adult-onset cases in our cohort. As regards age at onset, site of dystonia onset, and final distribution, in our population there is a clear differentiation between DYT-TOR1A and DYT-GNAL, with DYT-THAP1 likely to be an intermediate phenotype.This work was supported by the Carlos III Health Institute-European Regional Development Fund (ISCIII-FEDER) [PI14/01823, PI16/01575, PI18/01898, PI19/01576], the Andalusian Regional Ministry of Economics, Innovation, Science and Employment [CVI-02526, CTS-7685], the Andalusian Regional Ministry of Health and Welfare [PI-0741-2010, PI-0471-2013, PE-0210-2018, PI-0459-2018, PE-0186-2019], and the Alicia Koplowitz and Mutua Madrileña Foundations. Pilar Gómez-Garre was supported by the "Miguel Servet" program [MSII14/00018] (from ISCIII-FEDER) and “Nicolás Monardes” program [C-0048-2017] (from the Andalusian Regional Ministry of Health). Silvia Jesús was supported by the "Juan Rodés" program [B-0007-2019] and Daniel Macías-García by the “Río Hortega” program [CM18/00142] (both from ISCIII-FEDER). María Teresa Periñán was supported by the Spanish Ministry of Education [FPU16/05061]. Cristina Tejera was supported by VPPI-US from the University of Seville.Peer reviewe

Non-motor symptom burden in patients with Parkinson's disease with impulse control disorders and compulsive behaviours : results from the COPPADIS cohort

The study was aimed at analysing the frequency of impulse control disorders (ICDs) and compulsive behaviours (CBs) in patients with Parkinson's disease (PD) and in control subjects (CS) as well as the relationship between ICDs/CBs and motor, nonmotor features and dopaminergic treatment in PD patients. Data came from COPPADIS-2015, an observational, descriptive, nationwide (Spain) study. We used the validated Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease-Rating Scale (QUIP-RS) for ICD/CB screening. The association between demographic data and ICDs/CBs was analyzed in both groups. In PD, this relationship was evaluated using clinical features and treatment-related data. As result, 613 PD patients (mean age 62.47 ± 9.09 years, 59.87% men) and 179 CS (mean age 60.84 ± 8.33 years, 47.48% men) were included. ICDs and CBs were more frequent in PD (ICDs 12.7% vs. 1.6%, p < 0.001; CBs 7.18% vs. 1.67%, p = 0.01). PD patients had more frequent previous ICDs history, premorbid impulsive personality and antidepressant treatment (p < 0.05) compared with CS. In PD, patients with ICDs/CBs presented younger age at disease onset, more frequent history of previous ICDs and premorbid personality (p < 0.05), as well as higher comorbidity with nonmotor symptoms, including depression and poor quality of life. Treatment with dopamine agonists increased the risk of ICDs/CBs, being dose dependent (p < 0.05). As conclusions, ICDs and CBs were more frequent in patients with PD than in CS. More nonmotor symptoms were present in patients with PD who had ICDs/CBs compared with those without. Dopamine agonists have a prominent effect on ICDs/CBs, which could be influenced by dose

Heterozygous aggrecan variants are associated with short stature and brachydactyly: Description of 16 probands and a review of the literature.

OBJECTIVE: Mutations in the aggrecan gene (ACAN) have been identified in two autosomal dominant skeletal dysplasias, spondyloepiphyseal dysplasia, Kimberley type (SEDK), and osteochondritis dissecans, as well as in a severe recessive dysplasia, spondyloepimetaphyseal dysplasia, aggrecan type. Next-generation sequencing (NGS) has aided the identification of heterozygous ACAN mutations in individuals with short stature, minor skeletal defects and mild facial dysmorphisms, some of whom have advanced bone age (BA), poor pubertal spurt and early growth cessation as well as precocious osteoarthritis. DESIGN AND METHODS: This study involves clinical and genetic characterization of 16 probands with heterozygous ACAN variants, 14 with short stature and mild skeletal defects (group 1) and two with SEDK (group 2). Subsequently, we reviewed the literature to determine the frequency of the different clinical characteristics in ACAN-positive individuals. RESULTS: A total of 16 ACAN variants were located throughout the gene, six pathogenic mutations and 10 variants of unknown significance (VUS). Interestingly, brachydactyly was observed in all probands. Probands from group 1 with a pathogenic mutation tended to be shorter, and 60% had an advanced BA compared to 0% in those with a VUS. A higher incidence of coxa valga was observed in individuals with a VUS (37% vs 0%). Nevertheless, other features were present at similar frequencies. CONCLUSIONS: ACAN should be considered as a candidate gene in patients with short stature and minor skeletal defects, particularly those with brachydactyly, and in patients with spondyloepiphyseal dysplasia. It is also important to note that advanced BA and osteoarticular complications are not obligatory conditions for aggrecanopathies/aggrecan-associated dysplasias

Heterozygous aggrecan variants are associated with short stature and brachydactyly: Description of 16 probands and a review of the literature

[EN]Objective: Mutations in the aggrecan gene (ACAN) have been identified in two autosomal dominant skeletal dysplasias, spondyloepiphyseal dysplasia, Kimberley type (SEDK), and osteochondritis dissecans, as well as in a severe recessive dysplasia, spondyloepimetaphyseal dysplasia, aggrecan type. Next-generation sequencing (NGS) has aided the identification of heterozygous ACAN mutations in individuals with short stature, minor skeletal defects and mild facial dysmorphisms, some of whom have advanced bone age (BA), poor pubertal spurt and early growth cessation as well as precocious osteoarthritis

Identification of novel risk loci, causal insights, and heritable risk for Parkinson's disease: a meta-analysis of genome-wide association studies

Background: Genome-wide association studies (GWAS) in Parkinson's disease have increased the scope of biological knowledge about the disease over the past decade. We aimed to use the largest aggregate of GWAS data to identify novel risk loci and gain further insight into the causes of Parkinson's disease. / Methods: We did a meta-analysis of 17 datasets from Parkinson's disease GWAS available from European ancestry samples to nominate novel loci for disease risk. These datasets incorporated all available data. We then used these data to estimate heritable risk and develop predictive models of this heritability. We also used large gene expression and methylation resources to examine possible functional consequences as well as tissue, cell type, and biological pathway enrichments for the identified risk factors. Additionally, we examined shared genetic risk between Parkinson's disease and other phenotypes of interest via genetic correlations followed by Mendelian randomisation. / Findings: Between Oct 1, 2017, and Aug 9, 2018, we analysed 7·8 million single nucleotide polymorphisms in 37 688 cases, 18 618 UK Biobank proxy-cases (ie, individuals who do not have Parkinson's disease but have a first degree relative that does), and 1·4 million controls. We identified 90 independent genome-wide significant risk signals across 78 genomic regions, including 38 novel independent risk signals in 37 loci. These 90 variants explained 16–36% of the heritable risk of Parkinson's disease depending on prevalence. Integrating methylation and expression data within a Mendelian randomisation framework identified putatively associated genes at 70 risk signals underlying GWAS loci for follow-up functional studies. Tissue-specific expression enrichment analyses suggested Parkinson's disease loci were heavily brain-enriched, with specific neuronal cell types being implicated from single cell data. We found significant genetic correlations with brain volumes (false discovery rate-adjusted p=0·0035 for intracranial volume, p=0·024 for putamen volume), smoking status (p=0·024), and educational attainment (p=0·038). Mendelian randomisation between cognitive performance and Parkinson's disease risk showed a robust association (p=8·00 × 10−7). / Interpretation: These data provide the most comprehensive survey of genetic risk within Parkinson's disease to date, to the best of our knowledge, by revealing many additional Parkinson's disease risk loci, providing a biological context for these risk factors, and showing that a considerable genetic component of this disease remains unidentified. These associations derived from European ancestry datasets will need to be followed-up with more diverse data. / Funding: The National Institute on Aging at the National Institutes of Health (USA), The Michael J Fox Foundation, and The Parkinson's Foundation (see appendix for full list of funding sources)

Identification of Candidate Parkinson Disease Genes by Integrating Genome-Wide Association Study, Expression, and Epigenetic Data Sets

Importance Substantial genome-wide association study (GWAS) work in Parkinson disease (PD) has led to the discovery of an increasing number of loci shown reliably to be associated with increased risk of disease. Improved understanding of the underlying genes and mechanisms at these loci will be key to understanding the pathogenesis of PD. / Objective To investigate what genes and genomic processes underlie the risk of sporadic PD. / Design and Setting This genetic association study used the bioinformatic tools Coloc and transcriptome-wide association study (TWAS) to integrate PD case-control GWAS data published in 2017 with expression data (from Braineac, the Genotype-Tissue Expression [GTEx], and CommonMind) and methylation data (derived from UK Parkinson brain samples) to uncover putative gene expression and splicing mechanisms associated with PD GWAS signals. Candidate genes were further characterized using cell-type specificity, weighted gene coexpression networks, and weighted protein-protein interaction networks. / Main Outcomes and Measures It was hypothesized a priori that some genes underlying PD loci would alter PD risk through changes to expression, splicing, or methylation. Candidate genes are presented whose change in expression, splicing, or methylation are associated with risk of PD as well as the functional pathways and cell types in which these genes have an important role. / Results Gene-level analysis of expression revealed 5 genes (WDR6 [OMIM 606031], CD38 [OMIM 107270], GPNMB [OMIM 604368], RAB29 [OMIM 603949], and TMEM163 [OMIM 618978]) that replicated using both Coloc and TWAS analyses in both the GTEx and Braineac expression data sets. A further 6 genes (ZRANB3 [OMIM 615655], PCGF3 [OMIM 617543], NEK1 [OMIM 604588], NUPL2 [NCBI 11097], GALC [OMIM 606890], and CTSB [OMIM 116810]) showed evidence of disease-associated splicing effects. Cell-type specificity analysis revealed that gene expression was overall more prevalent in glial cell types compared with neurons. The weighted gene coexpression performed on the GTEx data set showed that NUPL2 is a key gene in 3 modules implicated in catabolic processes associated with protein ubiquitination and in the ubiquitin-dependent protein catabolic process in the nucleus accumbens, caudate, and putamen. TMEM163 and ZRANB3 were both important in modules in the frontal cortex and caudate, respectively, indicating regulation of signaling and cell communication. Protein interactor analysis and simulations using random networks demonstrated that the candidate genes interact significantly more with known mendelian PD and parkinsonism proteins than would be expected by chance. / Conclusions and Relevance Together, these results suggest that several candidate genes and pathways are associated with the findings observed in PD GWAS studies