Capsular Typing Method for Streptococcus agalactiae Using Whole-Genome Sequence Data.

Group B streptococcus (GBS) capsular serotypes are major determinants of virulence and affect potential vaccine coverage. Here we report a whole-genome-sequencing-based method for GBS serotype assignment. This method shows strong agreement (kappa of 0.92) with conventional methods and increased serotype assignment (100%) to all 10 capsular types

Spectroscopic Discovery of the Broad-Lined Type Ic Supernova 2010bh Associated with the Low-Redshift GRB 100316D

We present the spectroscopic discovery of a broad-lined Type Ic supernova (SN 2010bh) associated with the nearby long-duration gamma-ray burst (GRB) 100316D. At z = 0.0593, this is the third-nearest GRB-SN. Nightly optical spectra obtained with the Magellan telescopes during the first week after explosion reveal the gradual emergence of very broad spectral features superposed on a blue continuum. The supernova features are typical of broad-lined SNe Ic and are generally consistent with previous supernovae associated with low-redshift GRBs. However, the inferred velocities of SN 2010bh at 21 days after explosion are a factor of ~2 times larger than those of the prototypical SN 1998bw at similar epochs, with v ~ 26,000 km/s, indicating a larger explosion energy or a different ejecta structure. A near-infrared spectrum taken 13.8 days after explosion shows no strong evidence for He I at 1.083 microns, implying that the progenitor was largely stripped of its helium envelope. The host galaxy is of low luminosity (M_R ~ -18.5 mag) and low metallicity (Z < 0.4 Z_solar), similar to the hosts of other low-redshift GRB-SNe.Comment: 6 pages, 4 figures, 1 table, submitted to ApJ Letter

Mechanism of KMT5B haploinsufficiency in neurodevelopment in humans and mice

KMT5B gene; Neurodevelopment; MiceGen KMT5B; Neurodesenvolupament; RatolinsGen KMT5B; Neurodesarrollo; RatonesPathogenic variants in KMT5B, a lysine methyltransferase, are associated with global developmental delay, macrocephaly, autism, and congenital anomalies (OMIM# 617788). Given the relatively recent discovery of this disorder, it has not been fully characterized. Deep phenotyping of the largest (n = 43) patient cohort to date identified that hypotonia and congenital heart defects are prominent features that were previously not associated with this syndrome. Both missense variants and putative loss-of-function variants resulted in slow growth in patient-derived cell lines. KMT5B homozygous knockout mice were smaller in size than their wild-type littermates but did not have significantly smaller brains, suggesting relative macrocephaly, also noted as a prominent clinical feature. RNA sequencing of patient lymphoblasts and Kmt5b haploinsufficient mouse brains identified differentially expressed pathways associated with nervous system development and function including axon guidance signaling. Overall, we identified additional pathogenic variants and clinical features in KMT5B-related neurodevelopmental disorder and provide insights into the molecular mechanisms of the disorder using multiple model systems.This work was supported by LB692 Nebraska Tobacco Settlement Biomedical Research Development Program (to H.A.F.S.); The Simons Foundation Autism Research Initiative–Bridge to Independence Award SFARI 381192 (to H.A.F.S.); The A*STAR, Singapore, IAF-PP Program H17/01/a0/004 (to C.Y.L.); The Wong Boon Hock Society research program Yong Loo Lin School of Medicine (to Z.X.C.); NIH training grant 2T32GM008638-25 (L.B.); The Intramural Research Program of the National Human Genome Research Institute (to W.G.); The National Center for Advancing Translational Sciences of the NIH award number TL1TR001880 (to S.E.S.); The Eunice Kennedy Shriver National Institute of Child Health and Human Development award number HD009003-01 (to S.E.S.); Institute for Translational Medicine and Therapeutics of the Perelman School of Medicine at the University of Pennsylvania (to S.E.S.); and Swiss National Science Foundation (SNSF) grant 320020_179547 and funds from the University of Zurich Research Priority Programs (URPP) AdaBD: Adaptive Brain Circuits in Developments (to A.Rau.). F.J.K. was funded by the Deutsche Forschungsgemeinschaft grant number FOR 2488. In silico modeling was supported by the Spanish Ministerio de Ciencia e Innovación grant number PID2019-111217RB-I00 (to X.d.l.C.). This study used data from the DDD study. The DDD study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003). This study makes use of DECIPHER (www.deciphergenomics.org), which is funded by Wellcome (grant number 223718/Z/21/Z). See Nature PMID: 25533962 or www.ddduk.org/access.html for full acknowledgement

Integrated chromosomal and plasmid sequence analyses reveal diverse modes of carbapenemase gene spread among Klebsiella pneumoniae.

Molecular and genomic surveillance systems for bacterial pathogens currently rely on tracking clonally evolving lineages. By contrast, plasmids are usually excluded or analyzed with low-resolution techniques, despite being the primary vectors of antibiotic resistance genes across many key pathogens. Here, we used a combination of long- and short-read sequence data of Klebsiella pneumoniae isolates (n = 1,717) from a European survey to perform an integrated, continent-wide study of chromosomal and plasmid diversity. This revealed three contrasting modes of dissemination used by carbapenemase genes, which confer resistance to last-line carbapenems. First, blaOXA-48-like genes have spread primarily via the single epidemic pOXA-48-like plasmid, which emerged recently in clinical settings and spread rapidly to numerous lineages. Second, blaVIM and blaNDM genes have spread via transient associations of many diverse plasmids with numerous lineages. Third, blaKPC genes have transmitted predominantly by stable association with one successful clonal lineage (ST258/512) yet have been mobilized among diverse plasmids within this lineage. We show that these plasmids, which include pKpQIL-like and IncX3 plasmids, have a long association (and are coevolving) with the lineage, although frequent recombination and rearrangement events between them have led to a complex array of mosaic plasmids carrying blaKPC Taken altogether, these results reveal the diverse trajectories of antibiotic resistance genes in clinical settings, summarized as using one plasmid/multiple lineages, multiple plasmids/multiple lineages, and multiple plasmids/one lineage. Our study provides a framework for the much needed incorporation of plasmid data into genomic surveillance systems, an essential step toward a more comprehensive understanding of resistance spread

Instability of Plastid DNA in the Nuclear Genome

Functional gene transfer from the plastid (chloroplast) and mitochondrial genomes to the nucleus has been an important driving force in eukaryotic evolution. Non-functional DNA transfer is far more frequent, and the frequency of such transfers from the plastid to the nucleus has been determined experimentally in tobacco using transplastomic lines containing, in their plastid genome, a kanamycin resistance gene (neo) readymade for nuclear expression. Contrary to expectations, non-Mendelian segregation of the kanamycin resistance phenotype is seen in progeny of some lines in which neo has been transferred to the nuclear genome. Here, we provide a detailed analysis of the instability of kanamycin resistance in nine of these lines, and we show that it is due to deletion of neo. Four lines showed instability with variation between progeny derived from different areas of the same plant, suggesting a loss of neo during somatic cell division. One line showed a consistent reduction in the proportion of kanamycin-resistant progeny, suggesting a loss of neo during meiosis, and the remaining four lines were relatively stable. To avoid genomic enlargement, the high frequency of plastid DNA integration into the nuclear genome necessitates a counterbalancing removal process. This is the first demonstration of such loss involving a high proportion of recent nuclear integrants. We propose that insertion, deletion, and rearrangement of plastid sequences in the nuclear genome are important evolutionary processes in the generation of novel nuclear genes. This work is also relevant in the context of transgenic plant research and crop production, because similar processes to those described here may be involved in the loss of plant transgenes

Drawing firmer conclusions: autistic children show no evidence of a local processing bias in a controlled copying task

Drawing tasks are frequently used to test competing theories of visuospatial skills in autism. Yet, methodological differences between studies have led to inconsistent findings. To distinguish between accounts based on local bias or global deficit, we present a simple task that has previously revealed dissociable local/global impairments in neuropsychological patients. Autistic and typical children copied corner elements, arranged in a square configuration. Grouping cues were manipulated to test whether global properties affected the accuracy of reproduction. All children were similarly affected by these manipulations. There was no group difference in the reproduction of local elements, although global accuracy was negatively related to better local processing for autistic children. These data speak against influential theories of visuospatial differences in autism

Supported Intermetallic PdZn Nanoparticles as Bifunctional Catalysts for the Direct Synthesis of Dimethyl Ether from CO-Rich Synthesis Gas

The single-step syngas-to-dimethyl ether (STD) process entails economic and technical advantages over the current industrial two-step process. Pd/ZnO-based catalysts have recently emerged as interesting alternatives to currently used Cu/ZnO/Al2O3 catalysts, but the nature of the active site(s), the reaction mechanism, and the role of Pd and ZnO in the solid catalyst are not well established. Now, Zn-stabilized Pd colloids with a size of 2 nm served as the key building blocks for the methanol active component in bifunctional Pd/ZnO-gamma-Al2O3 catalysts. The catalysts were characterized by combining high-pressure operando X-ray absorption spectroscopy and DFT calculations. The enhanced stability, longevity, and high dimethyl ether selectivity observed makes Pd/ZnO-gamma-Al2O3 an effective alternative system for the STD process compared to Cu/ZnO/gamma-Al2O3

CpG-free plasmids confer reduced inflammation and sustained pulmonary gene expression.

Pulmonary delivery of plasmid DNA (pDNA)/cationic liposome complexes is associated with an acute unmethylated CG dinucleotide (CpG)-mediated inflammatory response and brief duration of transgene expression. We demonstrate that retention of even a single CpG in pDNA is sufficient to elicit an inflammatory response, whereas CpG-free pDNA vectors do not. Using a CpG-free pDNA expression vector, we achieved sustained (≥56 d) in vivo transgene expression in the absence of lung inflammation

Gain and loss of function variants in EZH1 disrupt neurogenesis and cause dominant and recessive neurodevelopmental disorders.

Genetic variants in chromatin regulators are frequently found in neurodevelopmental disorders, but their effect in disease etiology is rarely determined. Here, we uncover and functionally define pathogenic variants in the chromatin modifier EZH1 as the cause of dominant and recessive neurodevelopmental disorders in 19 individuals. EZH1 encodes one of the two alternative histone H3 lysine 27 methyltransferases of the PRC2 complex. Unlike the other PRC2 subunits, which are involved in cancers and developmental syndromes, the implication of EZH1 in human development and disease is largely unknown. Using cellular and biochemical studies, we demonstrate that recessive variants impair EZH1 expression causing loss of function effects, while dominant variants are missense mutations that affect evolutionarily conserved aminoacids, likely impacting EZH1 structure or function. Accordingly, we found increased methyltransferase activity leading to gain of function of two EZH1 missense variants. Furthermore, we show that EZH1 is necessary and sufficient for differentiation of neural progenitor cells in the developing chick embryo neural tube. Finally, using human pluripotent stem cell-derived neural cultures and forebrain organoids, we demonstrate that EZH1 variants perturb cortical neuron differentiation. Overall, our work reveals a critical role of EZH1 in neurogenesis regulation and provides molecular diagnosis for previously undefined neurodevelopmental disorders