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The current need for novel antibiotics is especially acute for drug-resistant Gram-negative pathogens.sup.1,2. These microorganisms have a highly restrictive permeability barrier, which limits the penetration of most compounds.sup.3,4. As a result, the last class of antibiotics that acted against Gram-negative bacteria was developed in the 1960s.sup.2. We reason that useful compounds can be found in bacteria that share similar requirements for antibiotics with humans, and focus on Photorhabdus symbionts of entomopathogenic nematode microbiomes. Here we report a new antibiotic that we name darobactin, which was obtained using a screen of Photorhabdus isolates. Darobactin is coded by a silent operon with little production under laboratory conditions, and is ribosomally synthesized. Darobactin has an unusual structure with two fused rings that form post-translationally. The compound is active against important Gram-negative pathogens both in vitro and in animal models of infection. Mutants that are resistant to darobactin map to BamA, an essential chaperone and translocator that folds outer membrane proteins. Our study suggests that bacterial symbionts of animals contain antibiotics that are particularly suitable for development into therapeutics. Bacterial symbionts of animals may contain antibiotics that are particularly suitable for development into therapeutics; one such compound, darobactin, is active against important Gram-negative pathogens both in vitro and in animal models of infection., Author(s): Yu Imai [sup.1] , Kirsten J. Meyer [sup.1] , Akira Iinishi [sup.1] , Quentin Favre-Godal [sup.1] , Robert Green [sup.1] , Sylvie Manuse [sup.1] , Mariaelena Caboni [sup.1] , [...]

The three-dimensional organization of a genome plays a critical role in regulating gene expression, yet little is known about the machinery and mechanisms that determine higher-order chromosome structure. Here we perform genome-wide chromosome conformation capture analysis, fluorescent in situ hybridization (FISH), and RNA-seq to obtain comprehensive three-dimensional (3D) maps of the Caenorhabditis elegans genome and to dissect X chromosome dosage compensation, which balances gene expression between XX hermaphrodites and XO males. The dosage compensation complex (DCC), a condensin complex, binds to both hermaphrodite X chromosomes via sequence-specific recruitment elements on X (rex sites) to reduce chromosome-wide gene expression by half. Most DCC condensin subunits also act in other condensin complexes to control the compaction and resolution of all mitotic and meiotic chromosomes. By comparing chromosome structure in wild-type and DCC-defective embryos, we show that the DCC remodels hermaphrodite X chromosomes into a sex-specific spatial conformation distinct from autosomes. Dosage-compensated X chromosomes consist of self-interacting domains (∼1 Mb) resembling mammalian topologically associating domains (TADs). TADs on X chromosomes have stronger boundaries and more regular spacing than on autosomes. Many TAD boundaries on X chromosomes coincide with the highest-affinity rex sites and become diminished or lost in DCC-defective mutants, thereby converting the topology of X to a conformation resembling autosomes. rex sites engage in DCC-dependent long-range interactions, with the most frequent interactions occurring between rex sites at DCC-dependent TAD boundaries. These results imply that the DCC reshapes the topology of X chromosomes by forming new TAD boundaries and reinforcing weak boundaries through interactions between its highest-affinity binding sites. As this model predicts, deletion of an endogenous rex site at a DCC-dependent TAD boundary using CRISPR/Cas9 greatly diminished the boundary. Thus, the DCC imposes a distinct higher-order structure onto X chromosomes while regulating gene expression chromosome-wide.

Ageing and lifespan of organisms are determined by complicated interactions between their genetics and the environment, but the cellular mechanisms remain controversial. There have been a number of studies suggesting that cellular energy metabolism and free radical dynamics affect lifespan, implicating mitochondrial function. Recently, Shen et al. provided apparent mechanistic insight by reporting that mitochondrial oscillations of ‘free radical production’, called ‘mitoflashes’, in the pharynx of 3-day old Caenorhabditis elegans correlated inversely with lifespan. The interpretation of ‘mitoflashes’ as ‘bursts of superoxide’ radicals assumes that circularly permuted yellow fluorescent protein (cpYFP) is a reliable indicator of mitochondrial superoxide. This interpretation has been criticised because experiments and theoretical considerations both show that changes in cpYFP fluorescence are due to alterations in pH, not superoxide-. We now provide direct evidence that purified cpYFP is completely unresponsive to superoxide. Therefore ‘mitoflashes’ do not reflect superoxide generation and are not evidence for a link between mitochondrial free radical dynamics and lifespan.

Crossover recombination events between homologous chromosomes are required to form chiasmata, temporary connections between homologues that ensure their proper segregation at meiosis I. Despite this requirement for crossovers and an excess of the double-strand DNA breaks that are the initiating events for meiotic recombination, most organisms make very few crossovers per chromosome pair. Moreover, crossovers tend to inhibit the formation of other crossovers nearby on the same chromosome pair, a poorly understood phenomenon known as crossover interference. Here we show that the synaptonemal complex, a meiosis-specific structure that assembles between aligned homologous chromosomes, both constrains and is altered by crossover recombination events. Using a cytological marker of crossover sites in Caenorhabditis elegans, we show that partial depletion of the synaptonemal complex central region proteins attenuates crossover interference, increasing crossovers and reducing the effective distance over which interference operates, indicating that synaptonemal complex proteins limit crossovers. Moreover, we show that crossovers are associated with a local 0.4-0.5-micrometre increase in chromosome axis length. We propose that meiotic crossover regulation operates as a self-limiting system in which meiotic chromosome structures establish an environment that promotes crossover formation, which in turn alters chromosome structure to inhibit other crossovers at additional sites.

Epitaxy is a process by which a thin layer of one crystal is deposited in an ordered fashion onto a substrate crystal. The direct epitaxial growth of semiconductor heterostructures on top of crystalline superconductors has proved challenging. Here, however, we report the successful use of molecular beam epitaxy to grow and integrate niobium nitride (NbN)-based superconductors with the wide-bandgap family of semiconductorssilicon carbide, gallium nitride (GaN) and aluminium gallium nitride (AlGaN). We apply molecular beam epitaxy to grow an AlGaN/GaN quantum-well heterostructure directly on top of an ultrathin crystalline NbN superconductor. The resulting high-mobility, two-dimensional electron gas in the semiconductor exhibits quantum oscillations, and thus enables a semiconductor transistoran electronic gain elementto be grown and fabricated directly on a crystalline superconductor. Using the epitaxial superconductor as the source load of the transistor, we observe in the transistor output characteristics a negative differential resistancea feature often used in amplifiers and oscillators. Our demonstration of the direct epitaxial growth of high-quality semiconductor heterostructures and devices on crystalline nitride superconductors opens up the possibility of combining the macroscopic quantum effects of superconductors with the electronic, photonic and piezoelectric properties of the group III/nitride semiconductor family., Author(s): Rusen Yan (corresponding author) [1]; Guru Khalsa [2]; Suresh Vishwanath [1]; Yimo Han [3]; John Wright [2]; Sergei Rouvimov [4]; D. Scott Katzer [5]; Neeraj Nepal [5]; Brian P. [...]

Gibbons are small arboreal apes that display an accelerated rate of evolutionary chromosomal rearrangement and occupy a key node in the primate phylogeny between Old World monkeys and great apes. Here we present the assembly and analysis of a northern white-cheeked gibbon (Nomascus leucogenys) genome. We describe the propensity for a gibbon-specific retrotransposon (LAVA) to insert into chromosome segregation genes and alter transcription by providing a premature termination site, suggesting a possible molecular mechanism for the genome plasticity of the gibbon lineage. We further show that the gibbon genera (Nomascus, Hylobates, Hoolock and Symphalangus) experienced a near-instantaneous radiation ~5 million years ago, coincident with major geographical changes in southeast Asia that caused cycles of habitat compression and expansion. Finally, we identify signatures of positive selection in genes important for forelimb development (TBX5) and connective tissues (COL1A1) that may have been involved in the adaptation of gibbons to their arboreal habitat. The genome of the gibbon, a tree-dwelling ape from Asia positioned between Old World monkeys and the great apes, is presented, providing insights into the evolutionary history of gibbon species and their accelerated karyotypes, as well as evidence for selection of genes such as those for forelimb development and connective tissue that may be important for locomotion through trees. Gibbon genome reflects the high life The many species of gibbons are small, tree-living apes from Southeast Asia, most of them listed as 'endangered' or 'critically endangered' on the IUCN list. In their presentation of the genome of the northern white-cheeked gibbon (Nomascus leucogenys) , Lucia Carbone and colleagues provide intriguing insights into the biology and evolutionary history of a group that straddles the divide between Old World monkeys and the great apes. The authors investigate how a novel gibbon-specific retrotransposon might be the source of gibbons' genome plasticity. Rapid karyotype evolution combined with multiple episodes of climate and environmental change might explain the almost instantaneous divergence of the four gibbon genera. Positive selection on genes involved in forelimb development and connective tissue might have been related to gibbons' unique mode of locomotion in the tropical canopy., Author(s): Lucia Carbone [sup.1] [sup.2] [sup.3] [sup.4] , R. Alan Harris [sup.5] , Sante Gnerre [sup.6] , Krishna R. Veeramah [sup.7] [sup.8] , Belen Lorente-Galdos [sup.9] , John Huddleston [sup.10] [...]

The Drosophila tumour suppressors Scribbled and Discs large 1 are found to be essential regulators of planar spindle alignment during epithelial cell division; aberrant effects of spindle alignment are shown to be corrected through apoptosis, and the suppression of this mechanism can result in epithelial dysplasia and tumorigenesis. Discs large, Scribbled involved in spindle alignment Mitotic spindle formation is a key step towards the segregation of chromosomes into two daughter cells during mitosis, and the precise alignment of mitotic spindles to the plane of the epithelium is thought to be important in maintaining tissue integrity. The in vivo determinants of planar spindle orientation remain unknown. Here Matthew Gibson and colleagues demonstrate that the actomyosin cortex and junction-localized tumour suppressors Scribbled and Discs large 1 are essential regulators of planar spindle alignment. Defective alignment of the mitotic spindle correlates with cell delamination and apoptotic death, and furthermore, blocking death of misaligned cells is sufficient to drive the formation of tumour-like cell masses. The authors propose that the deleterious effects of aberrant spindle alignment are corrected by apoptosis and that suppression of this mechanism could result in epithelial dysplasia and tumorigenesis. During epithelial cell proliferation, planar alignment of the mitotic spindle coordinates the local process of symmetric cell cleavage with the global maintenance of polarized tissue architecture.sup.1,2. Although the disruption of planar spindle alignment is proposed to cause epithelial to mesenchymal transition and cancer.sup.3,4,5,6, the in vivo mechanisms regulating mitotic spindle orientation remain elusive. Here we demonstrate that the actomyosin cortex and the junction-localized neoplastic tumour suppressors Scribbled and Discs large 1 have essential roles in planar spindle alignment and thus the control of epithelial integrity in the Drosophila imaginal disc. We show that defective alignment of the mitotic spindle correlates with cell delamination and apoptotic death, and that blocking the death of misaligned cells is sufficient to drive the formation of basally localized tumour-like masses. These findings indicate a key role for junction-mediated spindle alignment in the maintenance of epithelial integrity, and also reveal a previously unknown cell-death-mediated tumour-suppressor function inherent in the polarized architecture of epithelia., Author(s): Yu-ichiro Nakajima [sup.1] , Emily J. Meyer [sup.1] , Amanda Kroesen [sup.1] , Sean A. McKinney [sup.1] , Matthew C. Gibson [sup.1] [sup.2] Author Affiliations: (1) Stowers Institute for [...]

Autism spectrum disorders (ASDs) are childhood neurodevelopmental disorders with complex genetic origins(1-4). Previous studies focusing on candidate genes or genomic regions have identified several copy number variations (CNVs) that are associated with an increased risk of ASDs(5-9). Here we present the results from a whole-genome CNV study on a cohort of 859 ASD cases and 1,409 healthy children of European ancestry who were genotyped with 550,000 single nucleotide polymorphism markers, in an attempt to comprehensively identify CNVs conferring susceptibility to ASDs. Positive findings were evaluated in an independent cohort of 1,336 ASD cases and 1,110 controls of European ancestry. Besides previously reported ASD candidate genes, such as NRXNI (ref. 10) and CNTN4 (refs 11, 12), several new susceptibility genes encoding neuronal cell-adhesion molecules, including NLGNI and ASTN2, were enriched with CNVs in ASD cases compared to controls (P = 9.5 x [10.sup.-3]). Furthermore, CNVs within or surrounding genes involved in the ubiquitin pathways, including UBE3A, PARKZ RFWD2 and FBX040, were affected by CNVs not observed in controls (P= 3.3 x [10.sup.-3]). We also identified duplications 55 kilobases upstream of complementary DNA AK123120 (P=3.6 x [10.sup.-6]). Although these variants may be individually rare, they target genes involved in neuronal cell-adhesion or ubiquitin degradation, indicating that these two important gene networks expressed within the central nervous system may contribute to the genetic susceptibility of ASD., ASDs, including autism, are neurodevelopmental disorders characterized by impairments in social and communication skills, as well as stereotyped and repetitive behaviours and/or a restricted range of interests. Current prevalence estimates [...]

Author(s): Diana S. Chu (corresponding author) [1]; Hongbin Liu [2, 3]; Paola Nix [4, 5]; Tammy F. Wu [1]; Edward J. Ralston [4, 5]; John R. Yates III [2]; Barbara [...]

An amendment to this paper has been published and can be accessed via a link at the top of the paper., Author(s): Yu Imai [sup.1] , Kirsten J. Meyer [sup.1] , Akira Iinishi [sup.1] , Quentin Favre-Godal [sup.1] , Robert Green [sup.1] , Sylvie Manuse [sup.1] , Mariaelena Caboni [sup.1] , [...]

Author(s): Raymond C. Chan [1]; Annette Chan [1]; Mili Jeon [2]; Tammy F. Wu [1]; Danielle Pasqualone [1]; Ann E. Rougvie [3]; Barbara J. Meyer (corresponding author) [1] Faithful transmission [...]

Caenorhabditis elegans was used as a model organism to dissect an x-chromosome-counting mechanism. Several genes control the activity of the sex-determination gene xol-1. A nuclear-hormone-receptor homologue SEX-1 has been identified as regulating the transcription of xol-1. It is critical to x-chromosome counting, acting directly on xol-1 and linking with its promoter in vivo, repressing xol-1 transcription in XX embryos.

Rapid post-transcriptional changes in gene expression could be mediated by repositioning of translational components to sites of signal reception. These movements may be guided by mechanical tension. Research into whether cell binding to the extracellular matrix (ECM) encourages the formation of a cytoskeletal microcompartment specialized for translational control at the site of integrin binding indicates that mRNA and ribosomes localize to focal adhesion complexes that arise when cells bind to ECM-coated microbeads.

Scientists have identified two molecular mechanisms which work together to repress the X-chromosome in the sex determination process of the nematode worm Caenorhabditis elegans. The first represses the transcription of xol-1 protein in XX types. The second effectively lowers the xol-1 protein level in situ. Both mechanisms allow the x-chromosome counting process to determine whether the organism is male or hermaphrodite.

Photosynthesis in plants underpins the existence of many life-forms on Earth. At its heart is a remarkable chemical reaction: the light-powered conversion of water and carbon dioxide into oxygen and [...]