Biology subjects

Moore, B.

Publications and source records attributed to Moore, B..

24 records · Page 2Linked to original sources

bioRxiv2020

Deep whole genome sequencing of multiple proband tissues and parental blood reveals the complex genetic etiology of congenital diaphragmatic hernias

The diaphragm is a mammalian muscle critical for respiration and separation of the thoracic and abdominal cavities. Defects in the development of the diaphragm are the cause of congenital diaphragmatic hernia (CDH), a common birth defect. In CDH, weaknesses in the developing diaphragm allow abdominal contents to herniate into the thoracic cavity and impair lung development, leading to a high neonatal mortality. The genetic etiology of CDH is complex. Single nucleotide variants (SNVs), insertion/deletions (indels), and structural/copy number variants in more than 150 genes have been associated with CDH, although few genes are recurrently mutated in multiple patients and recurrently mutated genes can be incompletely penetrant. This suggests that multiple genetic variants in combination, other not yet investigated classes of variants, and/or nongenetic factors contribute to CDH susceptibility. However, to date no studies have comprehensively investigated the contribution of all possible classes of variants throughout the genome to the etiology of CDH. In our study, we used a unique cohort of four patients with isolated CDH with samples from blood, skin, and diaphragm connective tissue and parental blood samples and deep whole genome sequencing to assess germline and somatic de novo and inherited variants of various sizes (SNVs, indels, and structural variants) in exons, introns, UTRs, and intergenic regions. In each patient we found a different mutational landscape that included germline de novo, and inherited SNVs and indels in multiple genes. We also found in two patients an inherited 343 bp deletion interrupting an annotated enhancer of the CDH associated gene, GATA4, and we hypothesize that this common deletion (found in 1-2% of the population) acts as a sensitizing allele for CDH. Overall, our comprehensive reconstruction of the genetic architecture of four CDH individuals demonstrates that the etiology of CDH is heterogeneous and multifactorial. AUTHOR SUMMARYDeep whole genome sequencing of family trios shows that etiology of congenital diaphragmatic hernias is heterogeneous and multifactorial.

genetics↗

bioRxiv2020

Noise Correlation is Modulated by Reward Expectation in the Primary Motor Cortex Bilaterally During Manual and Observational Tasks in Primates

Reward modulation is represented in the motor cortex (M1) and could be used to implement more accurate decoding models to improve brain computer interfaces (BCIs) (Zhao et al. 2018). Analyzing trial-to-trial noise-correlations between neural units in the presence of rewarding (R) and non-rewarding (NR) stimuli adds to our understanding of cortical network dynamics. We utilized Pearsons correlation coefficient to measure shared variability between simultaneously recorded units (32 - 112) and found significantly higher noise-correlation and positive correlation between the populations signal- and noise-correlation during NR trials as compared to R trials. This pattern is evident in data from two non-human primates (NHPs) during single-target center out reaching tasks, both manual and action observation versions. We conducted mean matched noise-correlation analysis in order to decouple known interactions between event triggered firing rate changes and neural correlations. Isolated reward discriminatory units demonstrated stronger correlational changes than units unresponsive to reward firing rate modulation, however the qualitative response was similar, indicating correlational changes within the network as a whole can serve as another information channel to be exploited by BCIs that track the underlying cortical state, such as reward expectation, or attentional modulation. Reward expectation and attention in return can be utilized with reinforcement learning towards autonomous BCI updating.

neuroscience↗

bioRxiv2019

Cariogenic Streptococcus mutans produces strain-specific antibiotics that impair commensal colonization

Streptococcus mutans is a common constituent of dental plaque and an etiologic agent of dental caries (tooth decay). Here we elucidate a biosynthetic pathway, encoded by globally distributed strains of S. mutans, which produces a series of bioactive small molecules including reutericyclin and two N-acyl tetramic acid analogues active against oral commensal bacteria. This pathway may provide S. mutans with a competitive advantage, promoting dysbiosis and caries pathogenesis.

microbiology↗

bioRxiv2019

Computer-assisted EEG diagnostic review for idiopathic generalized epilepsy

Epilepsy diagnosis can be costly, time-consuming and not uncommonly inaccurate. The reference standard diagnostic monitoring is continuous video-EEG monitoring, ideally capturing all events or concordant interictal discharges. Automating EEG data review would save time and resources, thus enabling more people to receive reference standard monitoring and also potentially herald a more quantitative approach to therapeutic outcomes. There is substantial research into automated detection of seizures and epileptic activity from EEG. However, automated detection software is not widely used in the clinic; and, despite numerous published algorithms, few methods have regulatory approval for detecting epileptic activity from EEG.\n\nThis study reports on a deep learning algorithm for computer-assisted EEG review. Deep, convolutional neural networks were trained to detect epileptic discharges using a pre-existing dataset of over 6000 labelled events in a cohort of 103 patients with idiopathic generalized epilepsy (IGE). Patients underwent 24-hour ambulatory outpatient EEG, and all data was curated and confirmed independently by two epilepsy specialists (Seneviratne et al, 2016). The resulting automated detection algorithm was then used to review diagnostic scalp-EEG for seven patients (four with IGE and three with events mimicking seizures) to validate performance in a clinical setting.\n\nThe automated detection algorithm showed state-of-the-art performance for detecting epileptic activity from clinical EEG, with mean sensitivity of >95% and corresponding mean false positive rate of 1 detection per minute. Importantly, diagnostic case studies showed that the automated detection algorithm reduced human review time by 80%-99%, without compromising event detection or diagnostic accuracy. The presented results demonstrate that computer-assisted review can increase the speed and accuracy of EEG assessment and has the potential to greatly improve therapeutic outcomes.

neuroscience↗

bioRxiv2019

Macrocyclic colibactin induces DNA double-strand breaks via copper-mediated oxidative cleavage

Colibactin is an as-yet-uncharacterized human gut bacterial genotoxin, whose biosynthesis is linked to clb genomic island that distributes widespread in pathogenic and commensal human enterobacteria. Colibactin-producing gut microbes promote colon tumor formation and enhance progression of colorectal cancer (CRC) via DNA double-strand breaks (DSBs)-induced cellular senescence and death; however, the chemical basis contributing to the pathogenesis at the molecular level remains elusive. Here we report the discovery and the mechanism of action of colibactin-645 as the highly sought final colibactin metabolite with a novel molecular scaffold. Colibactin-645 recapitulates its previously assumed genotoxicity and cytotoxicity, exhibiting a strong DNA DSBs activity in vitro and in human cell cultures via a unique copper-mediated oxidative mechanism. We also present a complete model for colibactin biosynthesis, revealing an unprecedented dual function of the aminomalonate-utilizing polyketide synthases. This work thus provides the first molecular basis for colibactins genotoxic activity and facilitates further mechanistic study of colibactin-related CRC incidence and prevention.

microbiology↗

bioRxiv2018

Natural Secretory Immunoglobulins Enhance Norovirus Infection

Secretory immunoglobulins (SIg) are a first line of mucosal defense by the host. They are secreted into the gut lumen via the polymeric immunoglobulin receptor (pIgR) where they bind to antigen and are transported back across the FAE via M cells. Noroviruses are highly prevalent, enteric pathogens that cause significant morbidity, mortality and economic losses worldwide. Murine norovirus (MNV) exploits microfold (M) cells to cross the lymphoid follicle-associated epithelium (FAE) and infect the underlying population of immune cells. However, whether natural, innate SIg can protect against norovirus infection remains unknown. To investigate the role of natural SIg during murine norovirus pathogenesis, we used pIgR-deficient animals, which lack SIg in the intestinal lumen. Contrary to other enteric pathogens, acute MNV replication was significantly reduced in the gastrointestinal tract of pIgR-deficient animals compared to controls, despite increased numbers of dendritic cells, macrophages, and B cells in the Peyers patch, established MNV target cell types. Also, natural SIg did not alter MNV FAE binding or FAE crossing into the lymphoid follicle. Instead, further analysis revealed enhanced baseline levels of the antiviral molecules interferon gamma (IFN{gamma}) and inducible nitric oxide synthase (iNOS) in the small intestine of naive pIgR-deficient animals compared to controls. Removing the microbiota equalized IFN{gamma} and iNOS transcript levels as well as MNV viral loads in germ-free pIgR KO mice compared to germ-free controls. These data are consistent with a model whereby SIg sensing reduces pro-inflammatory, antiviral molecules, which facilitates intestinal homeostasis but thereby promotes MNV infection. In conclusion, these findings demonstrate that natural SIg are not protective during norovirus infection in mice and represent another example of indirect modulation of enteric virus pathogenesis by the microbiota.

microbiology↗