C-terminal calcium binding of α-synuclein modulates synaptic vesicle interaction.

Alpha-synuclein is known to bind to small unilamellar vesicles (SUVs) via its N terminus, which forms an amphipathic alpha-helix upon membrane interaction. Here we show that calcium binds to the C terminus of alpha-synuclein, therewith increasing its lipid-binding capacity. Using CEST-NMR, we reveal that alpha-synuclein interacts with isolated synaptic vesicles with two regions, the N terminus, already known from studies on SUVs, and additionally via its C terminus, which is regulated by the binding of calcium. Indeed, dSTORM on synaptosomes shows that calcium mediates the localization of alpha-synuclein at the pre-synaptic terminal, and an imbalance in calcium or alpha-synuclein can cause synaptic vesicle clustering, as seen ex vivo and in vitro. This study provides a new view on the binding of alpha-synuclein to synaptic vesicles, which might also affect our understanding of synucleinopathies

Analysis of IFT74 as a candidate gene for chromosome 9p-linked ALS-FTD

BACKGROUND: A new locus for amyotrophic lateral sclerosis – frontotemporal dementia (ALS-FTD) has recently been ascribed to chromosome 9p. METHODS: We identified chromosome 9p segregating haplotypes within two families with ALS-FTD (F476 and F2) and undertook mutational screening of candidate genes within this locus. RESULTS: Candidate gene sequencing at this locus revealed the presence of a disease segregating stop mutation (Q342X) in the intraflagellar transport 74 (IFT74) gene in family 476 (F476), but no mutation was detected within IFT74 in family 2 (F2). While neither family was sufficiently informative to definitively implicate or exclude IFT74 mutations as a cause of chromosome 9-linked ALS-FTD, the nature of the mutation observed within F476 (predicted to truncate the protein by 258 amino acids) led us to sequence the open reading frame of this gene in a large number of ALS and FTD cases (n = 420). An additional sequence variant (G58D) was found in a case of sporadic semantic dementia. I55L sequence variants were found in three other unrelated affected individuals, but this was also found in a single individual among 800 Human Diversity Gene Panel samples. CONCLUSION: Confirmation of the pathogenicity of IFT74 sequence variants will require screening of other chromosome 9p-linked families

Comparative ecology of the European eel, Anguilla anguilla (L.1758), in a large Iberian river

A total of 1,816 eels were sampled in 1988, from seven sampling areas. Four areas were located in brackish water and the remaining three were located in freshwater reaches of the Tagus river basin. Eels were more abundant in the middle estuary and decreased both in the upstream and in the downstream directions, with a predominance of males in higher density areas. Smaller individuals preferred more peripheral areas, such as margins and upper reaches in the brackish water zone, and the tributaries of the freshwater habitats. It was assumed that this distribution pattern resulted from three main factors: (i) the dominance of larger specimens; (ii) the need to avoid predators and; (iii) the search for better trophic conditions. The condition of the individuals generally decreased toward the upper reaches, apparently due to a corresponding decrease in feeding intensity. The presence of the Belver dam in the main river, 158 km upstream from the sea, seemed to impose major alterations to the described patterns. The concentration of specimens below this impassable obstacle yielded a reduction in the proportion of females and a decrease in the condition and survival of the eels, contributing to a reduction in the spawning success of this population. Suggestions to diminish the effects of the dam, and to preserve the fishery are also presente

Analysis of shared heritability in common disorders of the brain

ience, this issue p. eaap8757 Structured Abstract INTRODUCTION Brain disorders may exhibit shared symptoms and substantial epidemiological comorbidity, inciting debate about their etiologic overlap. However, detailed study of phenotypes with different ages of onset, severity, and presentation poses a considerable challenge. Recently developed heritability methods allow us to accurately measure correlation of genome-wide common variant risk between two phenotypes from pools of different individuals and assess how connected they, or at least their genetic risks, are on the genomic level. We used genome-wide association data for 265,218 patients and 784,643 control participants, as well as 17 phenotypes from a total of 1,191,588 individuals, to quantify the degree of overlap for genetic risk factors of 25 common brain disorders. RATIONALE Over the past century, the classification of brain disorders has evolved to reflect the medical and scientific communities' assessments of the presumed root causes of clinical phenomena such as behavioral change, loss of motor function, or alterations of consciousness. Directly observable phenomena (such as the presence of emboli, protein tangles, or unusual electrical activity patterns) generally define and separate neurological disorders from psychiatric disorders. Understanding the genetic underpinnings and categorical distinctions for brain disorders and related phenotypes may inform the search for their biological mechanisms. RESULTS Common variant risk for psychiatric disorders was shown to correlate significantly, especially among attention deficit hyperactivity disorder (ADHD), bipolar disorder, major depressive disorder (MDD), and schizophrenia. By contrast, neurological disorders appear more distinct from one another and from the psychiatric disorders, except for migraine, which was significantly correlated to ADHD, MDD, and Tourette syndrome. We demonstrate that, in the general population, the personality trait neuroticism is significantly correlated with almost every psychiatric disorder and migraine. We also identify significant genetic sharing between disorders and early life cognitive measures (e.g., years of education and college attainment) in the general population, demonstrating positive correlation with several psychiatric disorders (e.g., anorexia nervosa and bipolar disorder) and negative correlation with several neurological phenotypes (e.g., Alzheimer's disease and ischemic stroke), even though the latter are considered to result from specific processes that occur later in life. Extensive simulations were also performed to inform how statistical power, diagnostic misclassification, and phenotypic heterogeneity influence genetic correlations. CONCLUSION The high degree of genetic correlation among many of the psychiatric disorders adds further evidence that their current clinical boundaries do not reflect distinct underlying pathogenic processes, at least on the genetic level. This suggests a deeply interconnected nature for psychiatric disorders, in contrast to neurological disorders, and underscores the need to refine psychiatric diagnostics. Genetically informed analyses may provide important "scaffolding" to support such restructuring of psychiatric nosology, which likely requires incorporating many levels of information. By contrast, we find limited evidence for widespread common genetic risk sharing among neurological disorders or across neurological and psychiatric disorders. We show that both psychiatric and neurological disorders have robust correlations with cognitive and personality measures. Further study is needed to evaluate whether overlapping genetic contributions to psychiatric pathology may influence treatment choices. Ultimately, such developments may pave the way toward reduced heterogeneity and improved diagnosis and treatment of psychiatric disorders

Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture

The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia, and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA. Genetic risk scores demonstrate that LBD shares risk profiles and pathways with Alzheimer's disease and Parkinson's disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition

Mendelian randomization implies no direct causal association between leukocyte telomere length and amyotrophic lateral sclerosis

Funder: QingLan Research Project of Jiangsu for Outstanding Young TeachersFunder: Project funded by Postdoctoral Science Foundation of Xuzhou Medical UniversityFunder: Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD) for Xuzhou Medical UniversityAbstract: We employed Mendelian randomization (MR) to evaluate the causal relationship between leukocyte telomere length (LTL) and amyotrophic lateral sclerosis (ALS) with summary statistics from genome-wide association studies (n = ~ 38,000 for LTL and ~ 81,000 for ALS in the European population; n = ~ 23,000 for LTL and ~ 4,100 for ALS in the Asian population). We further evaluated mediation roles of lipids in the pathway from LTL to ALS. The odds ratio per standard deviation decrease of LTL on ALS was 1.10 (95% CI 0.93–1.31, p = 0.274) in the European population and 0.75 (95% CI 0.53–1.07, p = 0.116) in the Asian population. This null association was also detected between LTL and frontotemporal dementia in the European population. However, we found that an indirect effect of LTL on ALS might be mediated by low density lipoprotein (LDL) or total cholesterol (TC) in the European population. These results were robust against extensive sensitivity analyses. Overall, our MR study did not support the direct causal association between LTL and the ALS risk in neither population, but provided suggestive evidence for the mediation role of LDL or TC on the influence of LTL and ALS in the European population

Longitudinal variation in the composition of the benthic macroinvertebrate fauna of a typical North coast Jamaican river

Benthic macroinvertebrate fauna plays a major role in river ecosystems, especially those of tropical islands. Since there is no information on the distribution of benthic invertebrates along a Jamaican river, we report here on the composition of the benthic fauna of the Buff Bay river, on the Northern coast of Jamaica. A total of 14 samples were collected from five sites, using kick nets and a Surber sampler, between May 1997 and October 1998. We also examined the applicability of the rhithron/potamon model, and some of the premises of the River Continuum Concept (RCC) in relation to the distribution of invertebrate taxa. The results showed a total of 38 taxa of identified invertebrates. A group of dominant taxa, composed mainly of immature stages of insects, occurred at all sites. Two notable characteristics of the river were the absence of a true potamonic fauna and the low representation of the shredder functional feeding group in the community We conclude that, while there was minor variation in the composition of the benthic macroinvertebrate fauna among the sites, this was a response to local conditions within the river system. The characteristics of the community did not conform to either of the models.<br>La fauna bentónica de macroinvertebrados juega un papel importante en los ecosistemas fluviales, especialmente los de las islas tropicales. En vista de que hay poca información disponible para los ríos de Jamaica, presentamos la composición de la fauna bentónica de la bahía riverina Buff, en la costa norte de Jamaica. Para ello, recolectamos un total de 14 muestras en cinco sitios, mediante el uso de redes de golpe y trampa Surber, entre mayo 1997 y octubre 1998. También se examinó la aplicabilidad del modelo de subdivisión de ríos ritrón/potamón y algunas de las premisas del concepto de Río como un Continuo, en relación con la distribución de los táxones de invertebrados. Los resultados mostraron un total de 38 táxones de invertebrados identificados, hay un grupo de taxones dominantes, compuesto principalmente por los estadios inmaduros de insectos, que se presentaron en todos los sitios. Dos características notables del río fueron la ausencia de una fauna de potamón verdadera y la escasa representación del grupo funcional alimenticio triturador en la comunidad. Llegamos a la conclusión de que, si bien hay una variación de menor importancia en la composición de la fauna de macroinvertebrados bentónicos entre los sitios, esto fue una respuesta a las condiciones locales dentro del sistema fluvial y las características de la comunidad que no se ajusta a ninguno de los modelos. Este estudio representa la primera publicación de una descripción longitudinal de la fauna bentónica de macroinvertebrados de un sistema fluvial de Jamaica

Proposed Anti-Seizure Medication Combinations With Rufinamide in the Treatment of Lennox-Gastaut Syndrome: Narrative Review and Expert Opinion

Lennox-Gastaut syndrome (LGS) is a severe, chronic, complex form of early childhood-onset epilepsy characterized by multiple seizure types, generalized slow (≤2.5 Hz) spike-and-wave activity and other electroencephalography abnormalities, and cognitive impairment. A key treatment goal is early seizure control, and several anti-seizure medications (ASMs) are available. Due to the low success rate in achieving seizure control with monotherapy and an absence of efficacy data supporting any particular combination of ASMs for treating LGS, a rational approach to selection of appropriate polytherapy should be applied to maximize benefit to patients. Such rational polytherapy involves consideration of factors including safety (including boxed warnings), potential drug-drug interactions, and complementary mechanisms of action. Based on the authors\u27 clinical experience, rufinamide offers a well-considered first adjunctive therapy for LGS, particularly in combination with clobazam and other newer agents for LGS, and may be particularly useful for reducing the frequency of tonic-atonic seizures associated with LGS