Proximal improvement and higher-order resting state network change after multidomain cognitive training intervention in healthy older adults

GeroScience - Prior randomized control trials have shown that cognitive training interventions resulted in improved proximal task performance, improved functioning of activities of daily living,...     

Recessive ACTA1 variant causes congenital muscular dystrophy with rigid spine

Variants in ACTA1, which encodes α-skeletal actin, cause several congenital myopathies, most commonly nemaline myopathy. Autosomal recessive variants comprise approximately 10% of ACTA1 myopathy. All recessive variants reported to date have resulted in loss of skeletal α-actin expression from muscle and severe weakness from birth. Targeted next-generation sequencing in two brothers with congenital muscular dystrophy with rigid spine revealed homozygous missense variants in ACTA1. Skeletal α-actin expression was preserved in these patients. This report expands the clinical and histological phenotype of ACTA1 disease to include congenital muscular dystrophy with rigid spine and dystrophic features on muscle biopsy. This represents a new class of recessive ACTA1 variants, which do not abolish protein expression.     

Pathway analysis with next-generation sequencing data

Although pathway analysis methods have been developed and successfully applied to association studies of common variants, the statistical methods for pathway-based association analysis of rare variants have not been well developed. Many investigators observed highly inflated false-positive rates and low power in pathway-based tests of association of rare variants. The inflated false-positive rates and low true-positive rates of the current methods are mainly due to their lack of ability to account for gametic phase disequilibrium. To overcome these serious limitations, we develop a novel statistic that is based on the smoothed functional principal component analysis (SFPCA) for pathway association tests with next-generation sequencing data. The developed statistic has the ability to capture position-level variant information and account for gametic phase disequilibrium. By intensive simulations, we demonstrate that the SFPCA-based statistic for testing pathway association with either rare or common or both rare and common variants has the correct type 1 error rates. Also the power of the SFPCA-based statistic and 22 additional existing statistics are evaluated. We found that the SFPCA-based statistic has a much higher power than other existing statistics in all the scenarios considered. To further evaluate its performance, the SFPCA-based statistic is applied to pathway analysis of exome sequencing data in the early-onset myocardial infarction (EOMI) project. We identify three pathways significantly associated with EOMI after the Bonferroni correction. In addition, our preliminary results show that the SFPCA-based statistic has much smaller P-values to identify pathway association than other existing methods.     

Further delineation of the KBG syndrome caused by ANKRD11 aberrations

Loss-of-function variants in ANKRD11 were identified as the cause of KBG syndrome, an autosomal dominant syndrome with specific dental, neurobehavioural, craniofacial and skeletal anomalies. We present the largest cohort of KBG syndrome cases confirmed by ANKRD11 variants reported so far, consisting of 20 patients from 13 families. Sixteen patients were molecularly diagnosed by Sanger sequencing of ANKRD11, one familial case and three sporadic patients were diagnosed through whole-exome sequencing and one patient was identified through genomewide array analysis. All patients were evaluated by a clinical geneticist. Detailed orofacial phenotyping, including orthodontic evaluation, intra-oral photographs and orthopantomograms, was performed in 10 patients and revealed besides the hallmark feature of macrodontia of central upper incisors, several additional dental anomalies as oligodontia, talon cusps and macrodontia of other teeth. Three-dimensional (3D) stereophotogrammetry was performed in 14 patients and 3D analysis of patients compared with controls showed consistent facial dysmorphisms comprising a bulbous nasal tip, upturned nose with a broad base and a round or triangular face. Many patients exhibited neurobehavioural problems, such as autism spectrum disorder or hyperactivity. One-third of patients presented with (conductive) hearing loss. Congenital heart defects, velopharyngeal insufficiency and hip anomalies were less frequent. On the basis of our observations, we recommend cardiac assessment in children and regular hearing tests in all individuals with a molecular diagnosis of KBG syndrome. As ANKRD11 is a relatively common gene in which sequence variants have been identified in individuals with neurodevelopmental disorders, it seems an important contributor to the aetiology of both sporadic and familial cases.     

Evolution of bacterial steroid biosynthesis and its impact on eukaryogenesis

Steroids are components of the eukaryotic cellular membrane and have indispensable roles in the process of eukaryotic endocytosis by regulating membrane fluidity and permeability. In particular, steroids may have been a structural prerequisite for the acquisition of mitochondria via endocytosis during eukaryogenesis. While eukaryotes are inferred to have evolved from an archaeal lineage, there is little similarity between the eukaryotic and archaeal cellular membranes. As such, the evolution of eukaryotic cellular membranes has limited our understanding of eukaryogenesis. Despite evolving from archaea, the eukaryotic cellular membrane is essentially a fatty acid bacterial-type membrane, which implies a substantial bacterial contribution to the evolution of the eukaryotic cellular membrane. Here, we address the evolution of steroid biosynthesis in eukaryotes by combining ancestral sequence reconstruction and comprehensive phylogenetic analyses of steroid biosynthesis genes. Contrary to the traditional assumption that eukaryotic steroid biosynthesis evolved within eukaryotes, most steroid biosynthesis genes are inferred to be derived from bacteria. In particular, aerobic deltaproteobacteria (myxobacteria) seem to have mediated the transfer of key genes for steroid biosynthesis to eukaryotes. Analyses of resurrected steroid biosynthesis enzymes suggest that the steroid biosynthesis pathway in early eukaryotes may have been similar to the pathway seen in modern plants and algae. These resurrected proteins also experimentally demonstrate that molecular oxygen was required to establish the modern eukaryotic cellular membrane during eukaryogenesis. Our study provides unique insight into relationships between early eukaryotes and other bacteria in addition to the well-known endosymbiosis with alphaproteobacteria.

The emergence of modern eukaryotic cells from their archaeal ancestor requires multiple evolutionary steps, most notably the acquisition of mitochondria, nucleus, endomembrane system, and bacterial-like cellular membranes. The acquisition of mitochondria by early eukaryotes before the last eukaryotic common ancestor (LECA) would have been a key step to exploit new resources within an aerobic environment (1). Similarly, the transformation of the eukaryotic cellular membrane system from an archaeal-type to bacterial-type membrane would have also been crucial to develop the dynamic cellular membrane system observed in modern eukaryotes (2). Such a dynamic membrane may have been the prerequisite for a pre-LECA cell to perform endocytosis and, hence, later acquire organelles such as mitochondria and chloroplasts. While the tetraether monolayer membrane in archaea is more rigid and is advantageous to harsh environments, such as high temperature and low pH conditions, the diester bilayer membrane found in bacteria and eukaryotes has been suggested to be adaptable to more general environments (3). Recent phylogenomic analyses of archaea and eukaryotes suggest that eukaryotes evolved from within the archaeal domain (4, 5). However, there is little similarity between the archaeal and the bacterial/eukaryotic cellular membranes. Both the stereochemistry of lipid molecules (i.e., phospholipids) and their lipid composition (e.g., fatty acid chain versus isoprenoid chain and the presence of sphingolipids and steroids) are fundamentally different between the two types of membranes. As such, the evolutionary history of the eukaryotic cellular membrane is a major gap in our understanding of eukaryogenesis (6).Here, we focus on the evolution of the steroid component of the eukaryotic cellular membrane. Steroids have indispensable roles in the process of eukaryotic endocytosis because they are embedded in the cellular membrane and are known to regulate membrane fluidity and permeability (7–9). Thus, steroids may also have been integral for the endocytic process to acquire mitochondria during eukaryogenesis. Steroids would also function as hormones to control various cellular processes, including differentiation, morphogenesis, and homeostasis to enable multicellularity (10). In addition to the vital biochemical role in modern eukaryotes, steroids also have a geobiological importance. They can serve as unique biological markers (biomarkers) for eukaryotes in the geological record and thus provide clues to trace the evolutionary history of eukaryotes on a geological time scale. Membrane-bound steroids are modified in a unique manner within each eukaryotic taxon. For instance, cholesterol is a major component of cellular membrane in metazoans, whereas stigmasterol is a major component in plants (11, 12). These taxon-specific modifications can be used as taxonomic markers in the geological record (13–15). No analogous steroid biosynthesis pathway has been observed in archaea and thus steroid biosynthesis is generally inferred to have evolved de novo within eukaryotes (16). Despite this inference, some bacteria are known to produce hopanoids that are structurally similar to steroids (17). Indeed, several genes that are involved in hopanoid and steroid biosynthesis are suggested to have been horizontally transferred from bacteria to eukaryotes (18, 19). These recent observations suggest a more complex evolutionary history of steroid biosynthesis in eukaryotes. Ancestral sequence reconstruction (ASR) enables us to experimentally analyze resurrected enzymes (20, 21) and thus infer evolutionary histories of steroid biosynthesis and their impacts on eukaryogenesis.     

Absence of human papillomavirus DNA detected by polymerase chain reaction in French patients with esophageal carcinoma

Recent studies have suggested that esophageal human papillomavirus infection could be a risk factor for esophageal squamous cell carcinoma. The aim of this study was to evaluate the prevalence of human papillomavirus DNA sequences in the esophagus of French patients with esophageal squamous cell carcinoma. Multiplex polymerase chain reactions with consensus primers directed to the L1 gene or specific primers for human papillomavirus types 6, 11, 16, 18, 31, and 33 directed to E6 gene (40 cycles followed by restriction mapping of the amplified products) were used to determine the presence of human papillomavirus DNA sequences in esophageal squamous cell carcinoma (n = 75), normal adjacent mucosa (n = 49), and metastatic lymphadenopathies (n = 5). As an internal control, a target located in the embryonic myosin heavy-chain gene was used in each reaction. Human papillomavirus DNA sequences could not be detected in any of the tumoral samples, the normal adjacent mucosa, or the metastatic lymphadenopathies. Human papillomavirus seems not to be implicated in esophageal carcinogenesis, at least in French patients, because the viral genomes are not associated with esophageal squamous cell carcinomas.