Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Who Actually Read Exner? Returning to the Source of the Frontal "Writing Centre" Hypothesis

International audienceWe have translated the most famous text of Sigmund Exner (1846-1926), the one relating to the existence of a localised "writing centre" in the brain. We discuss its relevance to the modern study and understanding of writing and agraphia. In Exner's most famous text, he hypothesised about the eponymous "Exner's Area", a discrete area within the brain that was located in the left middle frontal gyrus, which was dedicated to the function of writing. This text in German, included in a book published in 1881 "Untersuchungen über die Lokalisation der Functionen in der Grosshirnrinde des Menschen" (Studies on the localization of functions in the cerebral cortex of humans), lent itself to passionate debates during the following decades on the possibility of finding a specific writing centre in left middle frontal gyrus. Modern authors still refer back to the evidence cited in this seminal text. However, over the 281 pages of Exner's book, only a few chapters dealt with agraphia. Only four of the 167 case reports in the book explicitly mention agraphia. Although Exner describes the anatomical details of these lesions (from autopsies), none of them had pure agraphia, and only one case had an isolated lesion of the posterior part of the middle frontal gyrus. The small number of patients, the absence of pure agraphia symptoms, and the variation in the anatomy of these lesions are the main reasons why Exner's hypothesis of a writing centre in left middle frontal gyrus has been continually debated until now. More than the seminal publication of Sigmund Exner on agraphia, the diffusion of his theory was partly due to the influence that Exner and his family had within the scientific community at the turn of the 20th century

The neural basis for writing from dictation in the temporoparietal cortex

Cortical electrical stimulation mapping was used to study neural substrates of the function of writing in the temporoparietal cortex. We identified the sites involved in oral language (sentence reading and naming) and writing from dictation, in order to spare these areas during removal of brain tumours in 30 patients (23 in the left, and 7 in the right hemisphere). Electrostimulation of the cortex impaired writing ability in 62 restricted cortical areas (.25 cm2). These were found in left temporoparietal lobes and were mostly located along the superior temporal gyrus (Brodmann's areas 22 and 42). Stimulation of right temporoparietal lobes in right-handed patients produced no writing impairments. However there was a high variability of location between individuals. Stimulation resulted in combined symptoms (affecting oral language and writing) in fourteen patients, whereas in eight other patients, stimulation-induced pure agraphia symptoms with no oral language disturbance in twelve of the identified areas. Each detected area affected writing in a different way. We detected the various different stages of the auditory-to-motor pathway of writing from dictation: either through comprehension of the dictated sentences (word deafness areas), lexico-semantic retrieval, or phonologic processing. In group analysis, barycentres of all different types of writing interferences reveal a hierarchical functional organization along the superior temporal gyrus from initial word recognition to lexico-semantic and phonologic processes along the ventral and the dorsal comprehension pathways, supporting the previously described auditory-to-motor process. The left posterior Sylvian region supports different aspects of writing function that are extremely specialized and localized, sometimes being segregated in a way that could account for the occurrence of pure agraphia that has long-been described in cases of damage to this region

The graphemic/motor frontal area Exner's area revisited

International audienceObjectiveIn 1881, Exner first described a “graphic motor image center” in the middle frontal gyrus. Current psycholinguistic models of handwriting involve the conversion of abstract, orthographic representations into motor representations before a sequence of appropriate hand movements is produced. Direct cortical stimulation and functional magnetic resonance imaging (fMRI) were used to study the human frontal areas involved in writing.MethodsCortical electrical stimulation mapping was used intraoperatively in 12 patients during the removal of brain tumors to identify the areas involved in oral language (sentence reading and naming) and writing, and to spare them during surgery. The fMRI activation experiment involved 12 right-handed and 12 left-handed healthy volunteers using word dictation (without visual control) and 2 control tasks.ResultsDirect cortical electrical stimulation of restricted areas rostral to the primary motor hand area (Brodmann area [BA] 6) impaired handwriting in 6 patients, without disturbing hand movements or oral language tasks. In 6 other patients, stimulation of lower frontal regions showed deficits combining handwriting with other language tasks. fMRI also revealed selective activation during word handwriting in left versus right BA6 depending on handedness. This area was anatomically matched to those areas that affected handwriting on electrical stimulation.InterpretationAn area in middle frontal gyrus (BA6) that we have termed the graphemic/motor frontal area supports bridging between orthography and motor programs specific to handwriting. Ann Neurol 2009;66:537–54

Modular capsid decoration boosts adenovirus vaccine-induced humoral immunity against SARS-CoV-2

Adenovirus vector vaccines have been widely and successfully deployed in response to coronavirus disease 2019 (COVID-19). However, despite inducing potent T cell immunity, improvement of vaccine-specific antibody responses upon homologous boosting is modest compared with other technologies. Here, we describe a system enabling modular decoration of adenovirus capsid surfaces with antigens and demonstrate potent induction of humoral immunity against these displayed antigens. Ligand attachment via a covalent bond was achieved using a protein superglue, DogTag/DogCatcher (similar to SpyTag/SpyCatcher), in a rapid and spontaneous reaction requiring only co-incubation of ligand and vector components. DogTag was inserted into surface-exposed loops in the adenovirus hexon protein to allow attachment of DogCatcher-fused ligands on virus particles. Efficient coverage of the capsid surface was achieved using various ligands, with vector infectivity retained in each case. Capsid decoration shielded particles from vector neutralizing antibodies. In prime-boost regimens, adenovirus vectors decorated with the receptor-binding domain of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) spike induced >10-fold higher SARS-CoV-2 neutralization titers compared with an undecorated vector encoding spike. Importantly, decorated vectors achieved equivalent or superior T cell immunogenicity against encoded antigens compared with undecorated vectors. We propose capsid decoration using protein superglues as a novel strategy to improve efficacy and boostability of adenovirus-based vaccines and therapeutics

A Minimal Information Model for Potential Drug-Drug Interactions

espite the significant health impacts of adverse events associated with drug-drug interactions, no standard models exist for managing and sharing evidence describing potential interactions between medications. Minimal information models have been used in other communities to establish community consensus around simple models capable of communicating useful information. This paper reports on a new minimal information model for describing potential drug-drug interactions. A task force of the Semantic Web in Health Care and Life Sciences Community Group of the World-Wide Web consortium engaged informaticians and drug-drug interaction experts in in-depth examination of recent literature and specific potential interactions. A consensus set of information items was identified, along with example descriptions of selected potential drug-drug interactions (PDDIs). User profiles and use cases were developed to demonstrate the applicability of the model. Ten core information items were identified: drugs involved, clinical consequences, seriousness, operational classification statement, recommended action, mechanism of interaction, contextual information/modifying factors, evidence about a suspected drug-drug interaction, frequency of exposure, and frequency of harm to exposed persons. Eight best practice recommendations suggest how PDDI knowledge artifact creators can best use the 10 information items when synthesizing drug interaction evidence into artifacts intended to aid clinicians. This model has been included in a proposed implementation guide developed by the HL7 Clinical Decision Support Workgroup and in PDDIs published in the CDS Connect repository. The complete description of the model can be found at https://w3id.org/hclscg/pdd

The effectiveness of Early Head Start for 3-year-old children and their parents

Early Head Start, a federal program begun in 1995 for low-income pregnant women and families with infants and toddlers, was evaluated through a randomized trial of 3,001 families in 17 programs. Interviews with primary caregivers, child assessments, and observations of parent-child interactions were completed when children were 3 years old. Caregivers were diverse in race-ethnicity, language, and other characteristics. Regression-adjusted impact analyses showed that 3-year-old program children performed better than did control children in cognitive and language development, displayed higher emotional engagement of the parent and sustained attention with play objects, and were lower in aggressive behavior. Compared with controls, Early Head Start parents were more emotionally supportive, provided more language and learning stimulation, read to their children more, and spanked less. The strongest and most numerous impacts were for programs that offered a mix of home-visiting and center-based services and that fully implemented the performance standards early