Establishing the precise evolutionary history of a gene improves prediction of disease-causing missense mutations

PURPOSE: Predicting the phenotypic effects of mutations has become an important application in clinical genetic diagnostics. Computational tools evaluate the behavior of the variant over evolutionary time and assume that variations seen during the course of evolution are probably benign in humans. However, current tools do not take into account orthologous/paralogous relationships. Paralogs have dramatically different roles in Mendelian diseases. For example, whereas inactivating mutations in the NPC1 gene cause the neurodegenerative disorder Niemann-Pick C, inactivating mutations in its paralog NPC1L1 are not disease-causing and, moreover, are implicated in protection from coronary heart disease. METHODS: We identified major events in NPC1 evolution and revealed and compared orthologs and paralogs of the human NPC1 gene through phylogenetic and protein sequence analyses. We predicted whether an amino acid substitution affects protein function by reducing the organism’s fitness. RESULTS: Removing the paralogs and distant homologs improved the overall performance of categorizing disease-causing and benign amino acid substitutions. CONCLUSION: The results show that a thorough evolutionary analysis followed by identification of orthologs improves the accuracy in predicting disease-causing missense mutations. We anticipate that this approach will be used as a reference in the interpretation of variants in other genetic diseases as well. Genet Med 18 10, 1029–1036

The influence of semantic and phonological factors on syntactic decisions: An event-related brain potential study

During language production and comprehension, information about a word's syntactic properties is sometimes needed. While the decision about the grammatical gender of a word requires access to syntactic knowledge, it has also been hypothesized that semantic (i.e., biological gender) or phonological information (i.e., sound regularities) may influence this decision. Event-related potentials (ERPs) were measured while native speakers of German processed written words that were or were not semantically and/or phonologically marked for gender. Behavioral and ERP results showed that participants were faster in making a gender decision when words were semantically and/or phonologically gender marked than when this was not the case, although the phonological effects were less clear. In conclusion, our data provide evidence that even though participants performed a grammatical gender decision, this task can be influenced by semantic and phonological factors

Litter size components in a full diallel cross of four maternal lines of rabbits

[EN] A crossbreeding experiment between 4 Spanish maternal lines of rabbits was performed to estimate crossbreeding effects on litter size components. The experiment was designed as a complete diallel cross involving 4 lines selected for litter size at weaning (A, V, H, and LP [L]) and their 12 simple crosses. Does from these 16 genetic groups were distributed among 4 Spanish farms, but only V line was present in all farms, allowing connectivity of the data. A total of 2,015 does in the third, fourth, or fifth gestations were subjected to laparoscopy. The recorded traits were ovulation rate (OR), number of implanted embryos (IE), total born (TB), embryo survival (ES), foetal survival (FS), and prenatal survival (PS). The differences in direct genetic effects, maternal genetic effects, and individual heterosis between the lines were estimated according to Dickerson s model. Line A was significantly inferior to lines V and H, whereas line LP was similar to A line, but for FS and PS, line A showed the best values, followed by line LP. Comparing crossbred groups to line V, significant differences were shown favoring crossbred groups for OR and IE. The crossbred groups presented high implantation rate, but the foetal survival was lower than in V line. Important values for commercial production were presented by some crosses for OR (HV, 1.26 ova), IE (AH, 1.50 embryos; HV, 1.41 embryos), and TB (AH, 0.82 rabbits; HV, 0.78 rabbits). Relevant and significant reciprocal effects were found, especially for OR in all cases except the LV and VL crosses. These differences become nonsignificant in most of the other traits. Regarding direct genetic effects, line A presented lower estimates than the other lines with important values for OR, but the opposite was observed for FS. The maternal effects were significant only for some contrasts in OR and revealed that the LP line was inferior to the others (1.08 ova compared to the A line, 1.23 compared to the H line, and 0.38 compared to the V line). In general, high positive values for heterosis were found in crossbred does for OR and IE. The crosses, where lines A and H were involved, showed significant heterosis. The highest values were obtained by crossing lines A and H (1.18 ova for OR, 1.87 embryos for IE) followed by the cross between lines H and V. Crosses between line LP and the other lines had a negative heterosis for FS and PS.This work was supported by the Spanish project AGL2011-30170 from the Spanish National Research Plan.Mohamed Ragab, M.; Sánchez Serrano, JP.; Mínguez Balaguer, C.; Vicente Antón, JS.; Baselga Izquierdo, M. (2014). Litter size components in a full diallel cross of four maternal lines of rabbits. Journal of Animal Science. 92(8):3231-3236. https://doi.org/10.2527/jas.2013-7286S3231323692

Therapeutic trial design for frontotemporal dementia and related disorders

The frontotemporal dementia (FTD) spectrum is a heterogeneous group of neurodegenerative syndromes with overlapping clinical, molecular and pathological features, all of which challenge the design of clinical trials in these conditions. To date, no pharmacological interventions have been proven effective in significantly modifying the course of these disorders. This study critically reviews the construct and methodology of previously published randomised controlled trials (RCTs) in FTD spectrum disorders in order to identify limitations and potential reasons for negative results. Moreover, recommendations based on the identified gaps are elaborated in order to guide future clinical trial design. A systematic literature review was carried out and presented in conformity with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses criteria. A total of 23 RCTs in cohorts with diagnoses of behavioural and language variants of FTD, corticobasal syndrome and progressive supranuclear palsy syndrome were identified out of the 943 citations retrieved and were included in the qualitative review. Most studies identified were early-phase clinical trials that were small in size, short in duration and frequently underpowered. Diagnoses of populations enrolled in clinical trials were based on clinical presentation and rarely included precision-medicine tools, such as genetic and molecular testing. Uniformity and standardisation of research outcomes in the FTD spectrum are essential. Several elements should be carefully considered and planned in future clinical trials. We anticipate that precision-medicine approaches will be crucial to adequately address heterogeneity in the FTD spectrum research

Experiences and attitudes of Dutch rheumatologists and oncologists with regard to their patients’ health-related Internet use

The objective of this study is to explore the experiences and attitudes of rheumatologists and oncologists with regard to their patients’ health-related Internet use. In addition, we explored how often physicians referred their patients to health-related Internet sites. We sent a questionnaire to all the rheumatologists and oncologists in the Netherlands. The questionnaire included questions concerning demographics, experiences with patients’ health-related Internet use, referral behavior, and attitudes to the consequences of patients’ health-related Internet use (for patients themselves, the physician-patient relationship and the health care). The response rate was 46% (N = 238). Of these respondents, 134 practiced as a rheumatologist and 104 as an oncologist. Almost all physicians encountered their patients raising information from the Internet during a consultation. They were not, however, confronted with their patients’ health-related Internet use on a daily basis. Physicians had a moderately positive attitude towards the consequences of patients’ health-related Internet use, the physician-patient relationship and the health care. Oncologists were significantly less positive than rheumatologists about the consequences of health-related Internet use. Most of the physicians had never (32%) or only sometimes (42%) referred a patient to a health-related Internet site. Most physicians (53%) found it difficult to stay up-to-date with reliable Internet sites for patients. Physicians are moderately positive about their patients’ health-related Internet use but only seldom refer them to relevant sites. Offering an up-to-date site with accredited websites for patients might help physicians refer their patients

The pore-forming subunit MCU of the mitochondrial Ca2+ uniporter is required for normal glucose-stimulated insulin secretion in vitro and in vivo in mice

Aims/hypothesis Mitochondrial oxidative metabolism is central to glucose-stimulated insulin secretion (GSIS). Whether Ca2+ uptake into pancreatic beta cell mitochondria potentiates or antagonises this process is still a matter of debate. Although the mitochondrial Ca2+ importer (MCU) complex is thought to represent the main route for Ca2+ transport across the inner mitochondrial membrane, its role in beta cells has not previously been examined in vivo. Methods Here, we inactivated the pore-forming subunit of the MCU, encoded by Mcu, selectively in mouse beta cells using Ins1Cre-mediated recombination. Whole or dissociated pancreatic islets were isolated and used for live beta cell fluorescence imaging of cytosolic or mitochondrial Ca2+ concentration and ATP production in response to increasing glucose concentrations. Electrophysiological recordings were also performed on whole islets. Serum and blood samples were collected to examine oral and i.p. glucose tolerance. Results Glucose-stimulated mitochondrial Ca2+ accumulation (p< 0.05), ATP production (p< 0.05) and insulin secretion (p< 0.01) were strongly inhibited in beta cell-specific Mcu-null (βMcu-KO) animals, in vitro, as compared with wild-type (WT) mice. Interestingly, cytosolic Ca2+ concentrations increased (p< 0.001), whereas mitochondrial membrane depolarisation improved in βMcu-KO animals. βMcu-KO mice displayed impaired in vivo insulin secretion at 5 min (p< 0.001) but not 15 min post-i.p. injection of glucose, whilst the opposite phenomenon was observed following an oral gavage at 5 min. Unexpectedly, glucose tolerance was improved (p< 0.05) in young βMcu-KO (<12 weeks), but not in older animals vs WT mice. Conclusions/interpretation MCU is crucial for mitochondrial Ca2+ uptake in pancreatic beta cells and is required for normal GSIS. The apparent compensatory mechanisms that maintain glucose tolerance in βMcu-KO mice remain to be established

Mental Health and Substance Abuse Characteristics Among a Clinical Sample of Urban American Indian/Alaska Native Youths in a Large California Metropolitan Area: a Descriptive Study

This study analyzes descriptive data among a clinical sample of American Indian/Alaska Native (AI/AN) youths receiving mental health services in a large California metropolitan area. Among 118 urban AI/AN youths, mood disorders (41.5%) and adjustment disorder (35.4%) were the most common mental health diagnoses. Alcohol (69.2%) and marijuana (50.0%) were the most commonly used substances. Witnessing domestic violence (84.2%) and living with someone who had a substance abuse problem (64.7%) were reported. The majority of patients demonstrated various behavior and emotional problems. Enhancing culturally relevant mental health and substance abuse treatment and prevention programs for urban AI/AN youth is suggested

An allosteric role for receptor activity-modifying proteins in defining GPCR pharmacology

G protein-coupled receptors are allosteric proteins that control transmission of external signals to regulate cellular response. Although agonist binding promotes canonical G protein signalling transmitted through conformational changes, G protein-coupled receptors also interact with other proteins. These include other G protein-coupled receptors, other receptors and channels, regulatory proteins and receptor-modifying proteins, notably receptor activity-modifying proteins (RAMPs). RAMPs have at least 11 G protein-coupled receptor partners, including many class B G protein-coupled receptors. Prototypic is the calcitonin receptor, with altered ligand specificity when co-expressed with RAMPs. To gain molecular insight into the consequences of this protein–protein interaction, we combined molecular modelling with mutagenesis of the calcitonin receptor extracellular domain, assessed in ligand binding and functional assays. Although some calcitonin receptor residues are universally important for peptide interactions (calcitonin, amylin and calcitonin gene-related peptide) in calcitonin receptor alone or with receptor activity-modifying protein, others have RAMP-dependent effects, whereby mutations decreased amylin/calcitonin gene-related peptide potency substantially only when RAMP was present. Remarkably, the key residues were completely conserved between calcitonin receptor and AMY receptors, and between subtypes of AMY receptor that have different ligand preferences. Mutations at the interface between calcitonin receptor and RAMP affected ligand pharmacology in a RAMP-dependent manner, suggesting that RAMP may allosterically influence the calcitonin receptor conformation. Supporting this, molecular dynamics simulations suggested that the calcitonin receptor extracellular N-terminal domain is more flexible in the presence of receptor activity-modifying protein 1. Thus, RAMPs may act in an allosteric manner to generate a spectrum of unique calcitonin receptor conformational states, explaining the pharmacological preferences of calcitonin receptor-RAMP complexes. This provides novel insight into our understanding of G protein-coupled receptor-protein interaction that is likely broadly applicable for this receptor class

Cigarette Smoking and Cognitive Function in Chinese Male Schizophrenia: A Case-Control study

Schizophrenic patients have higher smoking rates than the general population. Studies show that smoking may be a form of self-medication in an attempt to alleviate cognitive deficits in schizophrenic patients of European background. This study examined the relationships between smoking and cognitive deficits in Chinese schizophrenic patients, which have previously received little systemic study. We recruited 580 male chronic patients meeting DSM-IV criteria for schizophrenia and 175 male control subjects who were matched on age and education. The subjects completed a detailed cigarette smoking questionnaire, the Fagerstrom Test for Nicotine Dependence (FTND), and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Patients also were rated on the Positive and Negative Symptom Scale (PANSS), the Simpson and Angus Extrapyramidal Symptom Rating Scale (SAES), and the Abnormal Involuntary Movement Scale (AIMS). All five RBANS subscales except for the Visuospatial/Constructional index showed significantly lower cognitive performance for schizophrenics than normal controls. The schizophrenic smokers scored lower than the schizophrenic non-smokers on the RBANS total score and the Visuospatial/Constructional and Immediate Memory indices. Similarly, the control smokers scored lower than the control non-smokers on the RBANS total score and the Immediate Memory index . Also, the schizophrenic smokers consistently performed the poorest on the cognitive domains of the RBANS. Among the schizophrenic patients, smokers displayed significantly fewer negative symptoms than non-smokers. Using multivariate regression analysis the following variables were independently associated with the RBANS total score: years of education, PANSS negative symptom score, age at schizophrenia onset, and number of hospitalizations. Our results show that smoking is associated with significant cognitive impairment in both schizophrenic patients and normal controls, but the smokers with schizophrenia had a reduced level of negative symptoms, suggesting that the benefits of smoking for those with schizophrenia may be limited to certain aspects of a given clinical phenotype

Early Alterations in Hippocampal Circuitry and Theta Rhythm Generation in a Mouse Model of Prenatal Infection: Implications for Schizophrenia

Post-mortem studies suggest that GABAergic neurotransmission is impaired in schizophrenia. However, it remains unclear if these changes occur early during development and how they impact overall network activity. To investigate this, we used a mouse model of prenatal infection with the viral mimic, polyriboinosinic–polyribocytidilic acid (poly I∶C), a model based on epidemiological evidence that an immune challenge during pregnancy increases the prevalence of schizophrenia in the offspring. We found that prenatal infection reduced the density of parvalbumin- but not somatostatin-positive interneurons in the CA1 area of the hippocampus and strongly reduced the strength of inhibition early during postnatal development. Furthermore, using an intact hippocampal preparation in vitro, we found reduced theta oscillation generated in the CA1 area. Taken together, these results suggest that redistribution in excitatory and inhibitory transmission locally in the CA1 is associated with a significant alteration in network function. Furthermore, given the role of theta rhythm in memory, our results demonstrate how a risk factor for schizophrenia can affect network function early in development that could contribute to cognitive deficits observed later in the disease