Longitudinal identification of clinically distinct neurophenotypes in young children with fragile X syndrome

Fragile X syndrome (FXS), due to mutations of the FMR1 gene, is the most common known inherited cause of developmental disability. The cognitive, behavioral, and neurological phenotypes observed in affected individuals can vary considerably, making it difficult to predict outcomes and determine the need for interventions. We sought to examine early structural brain growth as a potential marker for identification of clinically meaningful subgroups. Participants included 42 very young boys with FXS who completed a T1-weighted anatomical MRI and cognitive/behavioral assessment at two longitudinal time points, with mean ages of 2.89 y and 4.91 y. Topological data analysis (TDA), an unsupervised approach to multivariate pattern analysis, was applied to the longitudinal anatomical data to identify coherent but heretofore unknown subgroups. TDA revealed two large subgroups within the study population based solely on longitudinal MRI data. Post hoc comparisons of cognition, adaptive functioning, and autism severity scores between these groups demonstrated that one group was consistently higher functioning on all measures at both time points, with pronounced and significant unidirectional differences (P < 0.05 for time point 1 and/or time point 2 for each measure). These results support the existence of two longitudinally defined, neuroanatomically distinct, and clinically relevant phenotypes among boys with FXS. If confirmed by additional analyses, such information may be used to predict outcomes and guide design of targeted therapies. Furthermore, TDA of longitudinal anatomical MRI data may represent a useful method for reliably and objectively defining subtypes within other neuropsychiatric disorders

Topological methods reveal high and low functioning neuro-phenotypes within fragile X syndrome: Topology Finds Fragile X Syndrome Phenotypes

Fragile X syndrome (FXS), due to mutations of the FMR1 gene, is the most common known inherited cause of developmental disability as well as the most common single-gene risk factor for autism. Our goal was to examine variation in brain structure in FXS with topological data analysis (TDA), and to assess how such variation is associated with measures of IQ and autism-related behaviors. To this end, we analyzed imaging and behavioral data from young boys (n=52; aged 1.57-4.15 years) diagnosed with FXS. Application of topological methods to structural MRI data revealed two large subgroups within the study population. Comparison of these subgroups showed significant between-subgroup neuroanatomical differences similar to those previously reported to distinguish children with FXS from typically developing controls (e.g., enlarged caudate). In addition to neuroanatomy, the groups showed significant differences in IQ and autism severity scores. These results suggest that despite arising from a single gene mutation, fragile X syndrome may encompass two biologically and clinically separable phenotypes. In addition, these findings underscore the potential of TDA as a powerful tool in the search for biological phenotypes of neuropsychiatric disorders

Search for Gravitational Waves from Galactic and Extra-Galactic Binary Neutron Stars

We use 373 hours (≈15 days) of data from the second science run of the LIGO gravitational-wave detectors to search for signals from binary neutron star coalescences within a maximum distance of about 1.5 Mpc, a volume of space which includes the Andromeda Galaxy and other galaxies of the Local Group of galaxies. This analysis requires a signal to be found in data from detectors at the two LIGO sites, according to a set of coincidence criteria. The background (accidental coincidence rate) is determined from the data and is used to judge the significance of event candidates. No inspiral gravitational-wave events were identified in our search. Using a population model which includes the Local Group, we establish an upper limit of less than 47 inspiral events per year per Milky Way equivalent galaxy with 90% confidence for nonspinning binary neutron star systems with component masses between 1 and 3M⊙

Insights into the cultured bacterial fraction of corals

Bacteria associated with coral hosts are diverse and abundant, with recent studies suggesting involvement of these symbionts in host resilience to anthropogenic stress. Despite their putative importance, the work dedicated to culturing coral-associated bacteria has received little attention. Combining published and unpublished data, here we report a comprehensive overview of the diversity and function of culturable bacteria isolated from corals originating from tropical, temperate, and cold-water habitats. A total of 3,055 isolates from 52 studies were considered by our metasurvey. Of these, 1,045 had full-length 16S rRNA gene sequences, spanning 138 formally described and 12 putatively novel bacterial genera across the Proteobacteria, Firmicutes, Bacteroidetes, and Actinobacteria phyla. We performed comparative genomic analysis using the available genomes of 74 strains and identified potential signatures of beneficial bacterium-coral symbioses among the strains. Our analysis revealed \u3e 400 biosynthetic gene clusters that underlie the biosynthesis of antioxidant, antimicrobial, cytotoxic, and other secondary metabolites. Moreover, we uncovered genomic features-not previously described for coral-bacterium symbioses-potentially involved in host colonization and host-symbiont recognition, antiviral defense mechanisms, and/or integrated metabolic interactions, which we suggest as novel targets for the screening of coral probiotics. Our results highlight the importance of bacterial cultures to elucidate coral holobiont functioning and guide the selection of probiotic candidates to promote coral resilience and improve holistic and customized reef restoration and rehabilitation efforts

Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead.

Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety 'Mode of Action' framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology

Characterizing Gravitational Wave Detector Networks: From A♯^\sharp to Cosmic Explorer

Gravitational-wave observations by the Laser Interferometer Gravitational-Wave Observatory (LIGO) and Virgo have provided us a new tool to explore the universe on all scales from nuclear physics to the cosmos and have the massive potential to further impact fundamental physics, astrophysics, and cosmology for decades to come. In this paper we have studied the science capabilities of a network of LIGO detectors when they reach their best possible sensitivity, called A#, and a new generation of observatories that are factor of 10 to 100 times more sensitive (depending on the frequency), in particular a pair of L-shaped Cosmic Explorer observatories (one 40 km and one 20 km arm length) in the US and the triangular Einstein Telescope with 10 km arms in Europe. We use a set of science metrics derived from the top priorities of several funding agencies to characterize the science capabilities of different networks. The presence of one or two A# observatories in a network containing two or one next generation observatories, respectively, will provide good localization capabilities for facilitating multimessenger astronomy and precision measurement of the Hubble parameter. A network of two Cosmic Explorer observatories and the Einstein Telescope is critical for accomplishing all the identified science metrics including the nuclear equation of state, cosmological parameters, growth of black holes through cosmic history, and make new discoveries such as the presence of dark matter within or around neutron stars and black holes, continuous gravitational waves from rotating neutron stars, transient signals from supernovae, and the production of stellar-mass black holes in the early universe. For most metrics the triple network of next generation terrestrial observatories are a factor 100 better than what can be accomplished by a network of three A# observatories.Comment: 45 pages, 20 figure