Effectiveness of Different Agricultural Management Styles as Insect Biological Corridors: A comparison of insect populations in fragmented Chocó cloud forest, Ecuador

Insects are part of the most diverse class of animals on the planet and are essential to various ecological functions such as pollination, nutrient cycling, providing a food source for other taxa, and more. The diversity and ecological services of insects are necessary to the operation of agriculture because of pest control and pollination of crops. However, the diversity of insects is severely reduced due to fragmentation. It is currently not well understood if certain types of agriculture can lessen the impact of fragmentation on natural and crop-based insect communities. In this study, insect populations in four different agricultural management styles and their borders were analyzed to understand the difference in insect populations not only within different cultivated areas, but to also understand the potential for different agricultural management styles to function as biological corridors for insects. Two types of sampling were done to observe the soil insect population as well as the winged insect population found in each study area. A 20cm3 sample of soil was taken from each quadrant to collect the soil insects present. Additionally, within a 10m by 5m quadrant a netting collection was done for two hours. All insects were persevered and identified to family level with a microscope. It was found that the traditional organic polyculture contained the highest diversity of both soil and winged insects and had the most similar insect community to its border according to β diversity calculations. Agricultural systems that focus on mimicking components of natural ecosystems such as increased biodiversity, absence of pesticides, and minimum soil disturbance are most likely to function as relatively effective biological corridors for insects between forest fragments. Insectos son una parte de la clase más diversa de animales en el planeta y son esenciales a varias funciones ecológicas, por ejemplo, polinización, el ciclo de nutrientes, provenir una fuente de comida para otros taxones y más. La diversidad y los servicios ecológicos de insectos son necesarios a la operación del sistema agrícola a causa de control de las plagas y la polinización de los cultivos. Sin embargo, la diversidad de insectos es reducida severamente debido a la fragmentación. En este momento, no se entiende bien si algunos tipos de agricultura pueden reducir el impacto de fragmentación en comunidades de insectos naturales y en cultivos. En esta investigación, poblaciones de insectos de cuatro estilos diferentes del manejo agrícola y sus bordes fueron analizados para entender la diferencia en poblaciones de insectos no solo dentro de las áreas cultivadas, sino entender la potencial para estilos diferentes del manejo agrícola para funcionar como corredores biológicos por insectos también. Dos tipos diferentes de muestras fueron tomados para observar la población de los insectos del suelo además de la población de los insectos alados encontrados en cada área de investigación. Una muestra de 20cm3 fue tomada de cada cuadrante para colectar los insectos de suelo presentes. Además, dentro de un cuadrante de 10m por 5m una colección de la red fue hecha por dos horas. Todos de los insectos fueron preservados e identificados al nivel de familia con un microscopio. Fue encontrado que el policultivo orgánico tradicional contuvo la diversidad más alta de insectos del suelo y alados y tuvo la comunidad de insectos más similar a su borde según calculaciones de diversidad β. Los sistemas de agricultura que enfocan en el mimetismo de los componentes de ecosistemas naturales como biodiversidad aumentada, ausencia de las pesticidas, y la perturbación mínima del suelo son más probable que funcionar como corredores biológicos efectivos relativamente para insectos entre fragmentos del bosque

Development, behaviour and autism in individuals with SMC1A variants

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Phenotypes and genotypes in individuals with SMC1A variants

SMC1A encodes one of the proteins of the cohesin complex. SMC1A variants are known to cause a phenotype resembling Cornelia de Lange syndrome (CdLS). Exome sequencing has allowed recognizing SMC1A variants in individuals with encephalopathy with epilepsy who do not resemble CdLS. We performed an international, interdisciplinary study on 51 individuals with SMC1A variants for physical and behavioral characteristics, and compare results to those in 67 individuals with NIPBL variants. For the Netherlands all known individuals with SMC1A variants were studied, both with and without CdLS phenotype. Individuals with SMC1A variants can resemble CdLS, but manifestations are less marked compared to individuals with NIPBL variants: growth is less disturbed, facial signs are less marked (except for periocular signs and thin upper vermillion), there are no major limb anomalies, and they have a higher level of cognitive and adaptive functioning. Self-injurious behavior is more frequent and more severe in the NIPBL group. In the Dutch group 5 of 13 individuals (all females) had a phenotype that shows a remarkable resemblance to Rett syndrome: epileptic encephalopathy, severe or profound intellectual disability, stereotypic movements, and (in some) regression. Their missense, nonsense, and frameshift mutations are evenly spread over the gene. We conclude that SMC1A variants can result in a phenotype resembling CdLS and a phenotype resembling Rett syndrome. Resemblances between the SMC1A group and the NIPBL group suggest that a disturbed cohesin function contributes to the phenotype, but differences between these groups may also be explained by other underlying mechanisms such as moonlighting of the cohesin gene

HNRNPC haploinsufficiency affects alternative splicing of intellectual disability-associated genes and causes a neurodevelopmental disorder

Heterogeneous nuclear ribonucleoprotein C (HNRNPC) is an essential, ubiquitously abundant protein involved in mRNA processing. Genetic variants in other members of the HNRNP family have been associated with neurodevelopmental disorders. Here, we describe 13 individuals with global developmental delay, intellectual disability, behavioral abnormalities, and subtle facial dysmorphology with heterozygous HNRNPC germline variants. Five of them bear an identical in-frame deletion of nine amino acids in the extreme C terminus. To study the effect of this recurrent variant as well as HNRNPC haploinsufficiency, we used induced pluripotent stem cells (iPSCs) and fibroblasts obtained from affected individuals. While protein localization and oligomerization were unaffected by the recurrent C-terminal deletion variant, total HNRNPC levels were decreased. Previously, reduced HNRNPC levels have been associated with changes in alternative splicing. Therefore, we performed a meta-analysis on published RNA-seq datasets of three different cell lines to identify a ubiquitous HNRNPC-dependent signature of alternative spliced exons. The identified signature was not only confirmed in fibroblasts obtained from an affected individual but also showed a significant enrichment for genes associated with intellectual disability. Hence, we assessed the effect of decreased and increased levels of HNRNPC on neuronal arborization and neuronal migration and found that either condition affects neuronal function. Taken together, our data indicate that HNRNPC haploinsufficiency affects alternative splicing of multiple intellectual disability-associated genes and that the developing brain is sensitive to aberrant levels of HNRNPC. Hence, our data strongly support the inclusion of HNRNPC to the family of HNRNP-related neurodevelopmental disorders. [Display omitted] We identified genetic variants of HNRNPC in 13 individuals with intellectual disability and global developmental delay. Through a meta-analysis of multiple cell types, we found that loss of HNRNPC affects alternative splicing, in particular of intellectual disability-associated genes. In vivo assays confirmed that neurodevelopment was affected by aberrant HNRNPC levels

Long-term safety and efficacy of tezacaftor–ivacaftor in individuals with cystic fibrosis aged 12 years or older who are homozygous or heterozygous for Phe508del CFTR (EXTEND): an open-label extension study

Background: Tezacaftor-ivacaftor is an approved cystic fibrosis transmembrane conductance regulator (CFTR) modulator shown to be efficacious and generally safe and well tolerated over 8-24 weeks in phase 3 clinical studies in participants aged 12 years or older with cystic fibrosis homozygous for the Phe508del CFTR mutation (F/F; study 661-106 [EVOLVE]) or heterozygous for the Phe508del CFTR mutation and a residual function mutation (F/RF; study 661-108 [EXPAND]). Longer-term (>24 weeks) safety and efficacy of tezacaftor-ivacaftor has not been assessed in clinical studies. Here, we present results of study 661-110 (EXTEND), a 96-week open-label extension study that assessed long-term safety, tolerability, and efficacy of tezacaftor-ivacaftor in participants aged 12 years or older with cystic fibrosis who were homozygous or heterozygous for the Phe508del CFTR mutation. Methods: Study 661-110 was a 96-week, phase 3, multicentre, open-label study at 170 clinical research sites in Australia, Europe, Israel, and North America. Participants were aged 12 years or older, had cystic fibrosis, were homozygous or heterozygous for Phe508del CFTR, and completed one of six parent studies of tezacaftor-ivacaftor: studies 661-103, 661-106, 661-107, 661-108, 661-109, and 661-111. Participants received oral tezacaftor 100 mg once daily and oral ivacaftor 150 mg once every 12 h for up to 96 weeks. The primary endpoint was safety and 'tolerability. Secondary endpoints were changes in lung function, nutritional parameters, and respiratory symptom scores; pulmonary exacerbations; and pharmacokinetic parameters. A post-hoc analysis assessed the rate of lung function decline in F/F participants who received up to 120 weeks of tezacaftor-ivacaftor in studies 661-106 (F/F) and/or 661-110 compared with a matched cohort of CFTR modulator-untreated historical F/F controls from the Cystic Fibrosis Foundation Patient Registry. Primary safety analyses were done in all participants from all six parent studies who received at least one dose of study drug during this study. This study was registered at ClinicalTrials.gov (NCT02565914). Findings: Between Aug 31, 2015, to May 31, 2019, 1044 participants were enrolled in study 661-110 from the six parent studies of whom 1042 participants received at least one dose of study drug and were included in the safety set. 995 (95%) participants had at least one TEAE; 22 (2%) had TEAEs leading to discontinuation; and 351 (34%) had serious TEAEs. No deaths occurred during the treatment-emergent period; after the treatment-emergent period, two deaths occurred, which were both deemed unrelated to study drug. F/F (106/110; n=459) and F/RF (108/110; n=226) participants beginning tezacaftor-ivacaftor in study 661-110 had improvements in efficacy endpoints consistent with parent studies; improvements in lung function and nutritional parameters and reductions in pulmonary exacerbations observed in the tezacaftor-ivacaftor groups in the parent studies were generally maintained in study 661-110 for an additional 96 weeks. Pharmacokinetic parameters were also similar to those in the parent studies. The annualised rate of lung function decline was 61·5% (95% CI 35·8 to 86·1) lower in tezacaftor-ivacaftor-treated F/F participants versus untreated matched historical controls. Interpretation: Tezacaftor-ivacaftor was generally safe, well tolerated, and efficacious for up to 120 weeks, and the safety profile of tezacaftor-ivacaftor in study 661-110 was consistent with cystic fibrosis manifestations and with the safety profiles of the parent studies. The rate of lung function decline was significantly reduced in F/F participants, consistent with cystic fibrosis disease modification. Our results support the clinical benefit of long-term tezacaftor-ivacaftor treatment for people aged 12 years or older with cystic fibrosis with F/F or F/RF genotypes. Funding: Vertex Pharmaceuticals Incorporated