Seroprevalence of 34 Human Papillomavirus Types in the German General Population

The natural history of infections with many human papillomavirus (HPV) types is poorly understood. Here, we describe for the first time the age- and sex-dependent antibody prevalence for 29 cutaneous and five mucosal HPV types from 15 species within five phylogenetic genera (alpha, beta, gamma, mu, nu) in a general population. Sera from 1,797 German adults and children (758 males and 1,039 females) between 1 and 82 years (median 37 years) were analysed for antibodies to the major capsid protein L1 by Luminex-based multiplex serology. The first substantial HPV antibody reactions observed already in children and young adults are those to cutaneous types of the genera nu (HPV 41) and mu (HPV 1, 63). The antibody prevalence to mucosal high-risk types, most prominently HPV 16, was elevated after puberty in women but not in men and peaked between 25 and 34 years. Antibodies to beta and gamma papillomaviruses (PV) were rare in children and increased homogeneously with age, with prevalence peaks at 40 and 60 years in women and 50 and 70 years in men. Antibodies to cutaneous alpha PV showed a heterogeneous age distribution. In summary, these data suggest three major seroprevalence patterns for HPV of phylogenetically distinct genera: antibodies to mu and nu skin PV appear early in life, those to mucosal alpha PV in women after puberty, and antibodies to beta as well as to gamma skin PV accumulate later in life

De Novo and Bi-allelic Pathogenic Variants in NARS1 Cause Neurodevelopmental Delay Due to Toxic Gain-of-Function and Partial Loss-of-Function Effects

Aminoacyl-tRNA synthetases (ARSs) are ubiquitous, ancient enzymes that charge amino acids to cognate tRNA molecules, the essential first step of protein translation. Here, we describe 32 individuals from 21 families, presenting with microcephaly, neurodevelopmental delay, seizures, peripheral neuropathy, and ataxia, with de novo heterozygous and bi-allelic mutations in asparaginyl-tRNA synthetase (NARS1). We demonstrate a reduction in NARS1 mRNA expression as well as in NARS1 enzyme levels and activity in both individual fibroblasts and induced neural progenitor cells (iNPCs). Molecular modeling of the recessive c.1633C>T (p.Arg545Cys) variant shows weaker spatial positioning and tRNA selectivity. We conclude that de novo and bi-allelic mutations in NARS1 are a significant cause of neurodevelopmental disease, where the mechanism for de novo variants could be toxic gain-of-function and for recessive variants, partial loss-of-function

De Novo and Bi-allelic Pathogenic Variants in NARS1 Cause Neurodevelopmental Delay Due to Toxic Gain-of-Function and Partial Loss-of-Function Effects.

Aminoacyl-tRNA synthetases (ARSs) are ubiquitous, ancient enzymes that charge amino acids to cognate tRNA molecules, the essential first step of protein translation. Here, we describe 32 individuals from 21 families, presenting with microcephaly, neurodevelopmental delay, seizures, peripheral neuropathy, and ataxia, with de novo heterozygous and bi-allelic mutations in asparaginyl-tRNA synthetase (NARS1). We demonstrate a reduction in NARS1 mRNA expression as well as in NARS1 enzyme levels and activity in both individual fibroblasts and induced neural progenitor cells (iNPCs). Molecular modeling of the recessive c.1633C>T (p.Arg545Cys) variant shows weaker spatial positioning and tRNA selectivity. We conclude that de novo and bi-allelic mutations in NARS1 are a significant cause of neurodevelopmental disease, where the mechanism for de novo variants could be toxic gain-of-function and for recessive variants, partial loss-of-function

Bi-allelic variants in SPATA5L1 lead to intellectual disability, spastic-dystonic cerebral palsy, epilepsy, and hearing loss

Spermatogenesis-associated 5 like 1 (SPATA5L1) represents an orphan gene encoding a protein of unknown function. We report 28 bi-allelic variants in SPATA5L1 associated with sensorineural hearing loss in 47 individuals from 28 (26 unrelated) families. In addition, 25/47 affected individuals (53%) presented with microcephaly, developmental delay/intellectual disability, cerebral palsy, and/or epilepsy. Modeling indicated damaging effect of variants on the protein, largely via destabilizing effects on protein domains. Brain imaging revealed diminished cerebral volume, thin corpus callosum, and periventricular leukomalacia, and quantitative volumetry demonstrated significantly diminished white matter volumes in several individuals. Immunofluorescent imaging in rat hippocampal neurons revealed localization of Spata5l1 in neuronal and glial cell nuclei and more prominent expression in neurons. In the rodent inner ear, Spata5l1 is expressed in the neurosensory hair cells and inner ear supporting cells. Transcriptomic analysis performed with fibroblasts from affected individuals was able to distinguish affected from controls by principal components. Analysis of differentially expressed genes and networks suggested a role for SPATA5L1 in cell surface adhesion receptor function, intracellular focal adhesions, and DNA replication and mitosis. Collectively, our results indicate that bi-allelic SPATA5L1 variants lead to a human disease characterized by sensorineural hearing loss (SNHL) with or without a nonprogressive mixed neurodevelopmental phenotype

Analogrechneranalyse über den Einfluß des Insulins auf den Galaktosestoffwechsel des Menschen

Peer Reviewe

Disaccharidasenaktivität und Monosaccharidabsorption bei genetisch adipösen Mäusen

Peer Reviewe

Gauging the Performance of Density Functionals for Lanthanide-Containing Molecules

Several density functional approaches have been considered for their ability to predict enthalpies of formation and bond dissociation energies for lanthanide-containing molecules. To enable comparison with experiment, the Ln54 set, introduced here, is compiled to include lanthanides both in the common 3+ oxidation state as well as in more exotic oxidation states. Due to the magnitude of the experimental uncertainties a “lanthanide chemical accuracy” of 5.0 kcal mol^–1 is proposed. The density functionals considered span the full range of complexity from LDA through double hybrids. The performance of the density functionals is assessed for each class of lanthanide-containing molecules and for the Ln54 molecule set overall. In general, hybrid functionals perform worse than functionals without exact exchange, and TPSS performs the best overall for the Ln54 set with a MAD of 19.2 kcal mol^–1 and MSD of −1.9 kcal mol^–1

Parent-child relationship quality and child psychological adjustment in families created using egg donation: children's perspectives at age 5 years.

STUDY QUESTION: What are children's perspectives of the quality of their relationships with their parents and their own psychological well-being in families created using egg donation? SUMMARY ANSWER: Children's scores indicated good parent-child relationship quality and high levels of psychological well-being, with children in families created using egg donation rating their relationships with their mothers as higher in warmth/enjoyment than children in a comparison group of families created using IVF. WHAT IS KNOWN ALREADY: Little is known about how children in families created through egg donation view their family relationships and their own psychological well-being. Research with 7-and-10-year-olds in anonymous egg donation families has indicated good parent-child relationship quality from children's perspectives, but studies have not involved younger children or those conceived following identity-release egg donation. STUDY DESIGN, SIZE, DURATION: This study included 50 children who had been born through egg donation and a comparison group of 43 children conceived through IVF with the parents' own gametes. Data were collected between April 2018 and December 2019. The sample forms part of a larger longitudinal study examining family functioning in families created through fertility treatment. PARTICIPANTS/MATERIALS, SETTING, METHODS: Children were aged 5 years old and had been born into families with different-sex couple parents. All families were visited at home. Children were administered the Berkeley Puppet Interview, a standardized assessment of parent-child relationship quality and psychological well-being. MAIN RESULTS AND THE ROLE OF CHANCE: Children in egg donation families rated their relationships with their mothers as higher in warmth and enjoyment than did children in IVF families. No differences were found between the two family types in children's ratings of the father-child relationship, or in children's ratings of their own psychological well-being. LIMITATIONS, REASONS FOR CAUTION: It is possible that children who did not consent to take part in the research had less positive perceptions of their family and themselves than children who participated. WIDER IMPLICATIONS OF THE FINDINGS: The findings are relevant to UK clinics offering identity-release egg donation, to parents who have used egg donation to create their family and to individuals and couples considering their fertility treatment options. That children in egg donation families were more similar than different to children in IVF families in their self-concept and perception of their family relationships should prove reassuring. STUDY FUNDING/COMPETING INTEREST(S): This research was supported by a Wellcome Trust Collaborative Award [208013/Z/17]. The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A