Background
Although mental disorders and suicidal thoughts‐behaviors (suicidal thoughts and behaviors) are common among university students, the majority of students with these problems remain ...untreated. It is unclear what the barriers are to these students seeking treatment.
Aims
The aim of this study is to examine the barriers to future help‐seeking and the associations of clinical characteristics with these barriers in a cross‐national sample of first‐year college students.
Method
As part of the World Mental Health International College Student (WMH‐ICS) initiative, web‐based self‐report surveys were obtained from 13,984 first‐year students in eight countries across the world. Clinical characteristics examined included screens for common mental disorders and reports about suicidal thoughts and behaviors. Multivariate regression models adjusted for socio‐demographic, college‐, and treatment‐related variables were used to examine correlates of help‐seeking intention and barriers to seeking treatment.
Results
Only 24.6% of students reported that they would definitely seek treatment if they had a future emotional problem. The most commonly reported reasons not to seek treatment among students who failed to report that they would definitely seek help were the preference to handle the problem alone (56.4%) and wanting to talk with friends or relatives instead (48.0%). Preference to handle the problem alone and feeling too embarrassed were also associated with significantly reduced odds of having at least some intention to seek help among students who failed to report that they would definitely seek help. Having 12‐month major depression, alcohol use disorder, and suicidal thoughts and behaviors were also associated with significantly reduced reported odds of the latter outcome.
Conclusions
The majority of first‐year college students in the WMH‐ICS surveys report that they would be hesitant to seek help in case of future emotional problems. Attitudinal barriers and not structural barriers were found to be the most important reported reasons for this hesitation. Experimental research is needed to determine whether intention to seek help and, more importantly, actual help‐seeking behavior could be increased with the extent to which intervention strategies need to be tailored to particular student characteristics. Given that the preference to handle problems alone and stigma and appear to be critical, there could be value in determining if internet‐based psychological treatments, which can be accessed privately and are often build as self‐help approaches, would be more acceptable than other types of treatments to student who report hesitation about seeking treatment.
Background and aim: A genetically impaired intestinal barrier function has long been suspected to be a predisposing factor for Crohn’s disease (CD). Recently, mutations of the capsase recruitment ...domain family, member 15 (CARD15) gene have been identified and associated with CD. We hypothesise that a CARD15 mutation may be associated with an impaired intestinal barrier. Methods: We studied 128 patients with quiescent CD, 129 first degree relatives (CD-R), 66 non-related household members (CD-NR), and 96 healthy controls. The three most common CARD15 polymorphisms (R702W, G908R, and 3020insC) were analysed and intestinal permeability was determined by the lactulose/mannitol ratio. Results: Intestinal permeability was significantly increased in CD and CD-R groups compared with CD-NR and controls. Values above the normal range were seen in 44% of CD and 26% of CD-R but only in 6% of CD-NR, and in none of the controls. A household community with CD patients, representing a common environment, was not associated with increased intestinal permeability in family members. However, 40% of CD first degree relatives carrying a CARD15 3020insC mutation and 75% (3/4) of those CD-R with combined 3020insC and R702W mutations had increased intestinal permeability compared with only 15% of wild-types, indicating a genetic influence on barrier function. R702W and G908R mutations were not associated with high permeability. Conclusions: In healthy first degree relatives, high mucosal permeability is associated with the presence of a CARD15 3020insC mutation. This indicates that genetic factors may be involved in impairment of intestinal barrier function in families with IBD.
Postzygotic mosaicism (PZM) in NIPBL is a strong source of causality for Cornelia de Lange syndrome (CdLS) that can have major clinical implications. Here, we further delineate the role of somatic ...mosaicism in CdLS by describing a series of 11 unreported patients with mosaic disease-causing variants in NIPBL and performing a retrospective cohort study from a Spanish CdLS diagnostic center. By reviewing the literature and combining our findings with previously published data, we demonstrate a negative selection against somatic deleterious NIPBL variants in blood. Furthermore, the analysis of all reported cases indicates an unusual high prevalence of mosaicism in CdLS, occurring in 13.1% of patients with a positive molecular diagnosis. It is worth noting that most of the affected individuals with mosaicism have a clinical phenotype at least as severe as those with constitutive pathogenic variants. However, the type of genetic change does not vary between germline and somatic events and, even in the presence of mosaicism, missense substitutions are located preferentially within the HEAT repeat domain of NIPBL. In conclusion, the high prevalence of mosaicism in CdLS as well as the disparity in tissue distribution provide a novel orientation for the clinical management and genetic counselling of families.
To characterize the molecular genetics of autosomal recessive Noonan syndrome.
Families underwent phenotyping for features of Noonan syndrome in children and their parents. Two multiplex families ...underwent linkage analysis. Exome, genome, or multigene panel sequencing was used to identify variants. The molecular consequences of observed splice variants were evaluated by reverse-transcription polymerase chain reaction.
Twelve families with a total of 23 affected children with features of Noonan syndrome were evaluated. The phenotypic range included mildly affected patients, but it was lethal in some, with cardiac disease and leukemia. All of the parents were unaffected. Linkage analysis using a recessive model supported a candidate region in chromosome 22q11, which includes LZTR1, previously shown to harbor mutations in patients with Noonan syndrome inherited in a dominant pattern. Sequencing analyses of 21 live-born patients and a stillbirth identified biallelic pathogenic variants in LZTR1, including putative loss-of-function, missense, and canonical and noncanonical splicing variants in the affected children, with heterozygous, clinically unaffected parents and heterozygous or normal genotypes in unaffected siblings.
These clinical and genetic data confirm the existence of a form of Noonan syndrome that is inherited in an autosomal recessive pattern and identify biallelic mutations in LZTR1.
Recently antibodies with a wide range of binding specificities have been isolated from large repertoires of antibody fragments displayed on filamentous phage, including those that are difficult to ...raise by immunization. We have used this approach to isolate an antibody fragment against chicken very low density lipoprotein (VLDL) receptor. It binds to the receptor with good affinity (Kaff = 2 × 108M−1) as measured by plasmon surface resonance, and competes for binding of natural ligands (vitellogenin, VLDL, and receptor-associated protein). The antibody also binds to other members of the low density lipoprotein (LDL) receptor family including rat LDL receptor and human and rat low density lipoprotein receptor-related protein (LRP/α2MR), and it competes for binding of receptor-associated protein to LRP/α2MR. Moreover, the antibody fragment inhibits infection of human fibroblasts deficient in LDL-R but expressing LRP/α2MR by human rhinovirus. Binding of the antibody is abolished upon reduction of the receptors and is strictly Ca2+ dependent. The phage antibody thus recognizes the ligand binding site(s) of several members of the LDL receptor family, in contrast to antibodies produced by hybridoma technology.
Disease gene discovery on chromosome (chr) X is challenging owing to its unique modes of inheritance. We undertook a systematic analysis of human chrX genes. We observe a higher proportion of ...disorder-associated genes and an enrichment of genes involved in cognition, language, and seizures on chrX compared to autosomes. We analyze gene constraints, exon and promoter conservation, expression, and paralogues, and report 127 genes sharing one or more attributes with known chrX disorder genes. Using machine learning classifiers trained to distinguish disease-associated from dispensable genes, we classify 247 genes, including 115 of the 127, as having high probability of being disease-associated. We provide evidence of an excess of variants in predicted genes in existing databases. Finally, we report damaging variants in CDK16 and TRPC5 in patients with intellectual disability or autism spectrum disorders. This study predicts large-scale gene-disease associations that could be used for prioritization of X-linked pathogenic variants.
Hemipteran insects are well-known in their ability to establish symbiotic relationships with bacteria. Among them, heteropteran insects present an array of symbiotic systems, ranging from the most ...common gut crypt symbiosis to the more restricted bacteriome-associated endosymbiosis, which have only been detected in members of the superfamily Lygaeoidea and the family Cimicidae so far. Genomic data of heteropteran endosymbionts are scarce and have merely been analyzed from the Wolbachia endosymbiont in bed bug and a few gut crypt-associated symbionts in pentatomoid bugs. In this study, we present the first detailed genomic analysis of a bacteriome-associated endosymbiont of a phytophagous heteropteran, present in the seed bug Henestaris halophilus (Hemiptera: Heteroptera: Lygaeoidea). Using phylogenomics and genomics approaches, we have assigned the newly characterized endosymbiont to the Sodalis genus, named as Candidatus Sodalis baculum sp. nov. strain kilmister. In addition, our findings support the reunification of the Sodalis genus, currently divided into six different genera. We have also conducted comparative analyses between 15 Sodalis species that present different genome sizes and symbiotic relationships. These analyses suggest that Ca. Sodalis baculum is a mutualistic endosymbiont capable of supplying the amino acids tyrosine, lysine, and some cofactors to its host. It has a small genome with pseudogenes but no mobile elements, which indicates middle-stage reductive evolution. Most of the genes in Ca. Sodalis baculum are likely to be evolving under purifying selection with several signals pointing to the retention of the lysine/tyrosine biosynthetic pathways compared with other Sodalis.
Accurate modeling of the molecular environment is critical in condensed phase simulations of chemical reactions. Conventional quantum mechanical/molecular mechanical (QM/MM) simulations traditionally ...model non-electrostatic non-bonded interactions through an empirical Lennard-Jones (LJ) potential which, in violation of intuitive chemical principles, is bereft of any explicit coupling to an atom's local electronic structure. This oversight results in a model whereby short-ranged exchange-repulsion and long-ranged dispersion interactions are invariant to changes in the local atomic charge, leading to accuracy limitations for chemical reactions where significant atomic charge transfer can occur along the reaction coordinate. The present work presents a variational, charge-dependent exchange-repulsion and dispersion model, referred to as the charge-dependent exchange and dispersion (QXD) model, for hybrid QM/MM simulations. Analytic expressions for the energy and gradients are provided, as well as a description of the integration of the model into existing QM/MM frameworks, allowing QXD to replace traditional LJ interactions in simulations of reactive condensed phase systems. After initial validation against QM data, the method is demonstrated by capturing the solvation free energies of a series of small, chlorine-containing compounds that have varying charge on the chlorine atom. The model is further tested on the SN2 attack of a chloride anion on methylchloride. Results suggest that the QXD model, unlike the traditional LJ model, is able to simultaneously obtain accurate solvation free energies for a range of compounds while at the same time closely reproducing the experimental reaction free energy barrier. The QXD interaction model allows explicit coupling of atomic charge with many-body exchange and dispersion interactions that are related to atomic size and provides a more accurate and robust representation of non-electrostatic non-bonded QM/MM interactions.
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