Biology subjects

Morgan, J.

Publications and source records attributed to Morgan, J..

6 recordsLinked to original sources

bioRxiv2018

Regenerative capacity in the lamprey spinal cord is not altered after a repeated transection

The resilience of regeneration in vertebrate tissues is not well understood. Yet understanding how well tissues can regenerate after repeated insults, and identifying any limitations, is an important step towards elucidating the underlying mechanisms of tissue plasticity. This is particularly challenging in tissues such as the nervous system, which contain a large number of terminally differentiated cells (i.e. neurons) and that often exhibits limited regenerative potential in the first place. However, unlike mammals that exhibit very little spinal cord regeneration, many non-mammalian vertebrate species, including lampreys, fishes, amphibians and reptiles, regenerate their spinal cords and functionally recover even after a complete spinal cord transection. It is well established that lampreys undergo full functional recovery of swimming behaviors after a single spinal cord transection, which is accompanied by tissue repair at the lesion as well as axon and synapse regeneration. Here, using the lamprey model, we begin to explore resilience of spinal cord regeneration after a second spinal re-transection. We report that by all functional and anatomical measures tested, the lampreys regenerated after spinal re-transection just as robustly as after single transections. Recovery of swimming behaviors, axon regeneration, synapse and cytoskeletal distributions, and neuronal survival were nearly identical after a single spinal transection or a repeated transection. Thus, regenerative potential in the lamprey spinal cord is largely unaffected by spinal re-transection, indicating a greater persistent regenerative potential than exists in some other highly-regenerative models. These findings establish a new path for uncovering pro-regenerative targets that could be deployed in non-regenerative conditions.

neuroscience↗

bioRxiv2018

Disrupting folate metabolism alters the capacity of bacteria in exponential growth to develop persisters to antibiotics

Bacteria can survive high doses of antibiotics through stochastic phenotypic diversification.We present initial evidence that folate metabolism could be involved with the formation of persisters. The aberrant expression of the folate enzyme gene fau seems to reduce the incidence of persisters to antibiotics. Folate impaired bacteria had a lower generation rate for persisters to both antibiotics ampicillin and ofloxacin. Persister bacteria were detectable from the outset of the exponential growth phase in the complex media. Gene expression analyses showed tentatively distinctive profiles in exponential growth at times when bacteria persisters were observed. Levels of persisters were assessed in bacteria with altered, genetically and pharmacologically, folate metabolism. This work shows that by disrupting folate biosynthesis and usage, bacterial tolerance to antibiotics seems to be diminished. Based on these findings there is a possibility that bacteriostatic antibiotics such as antifolates could have a role to play in clinical settings where the incidence of antibiotic persisters seem to drive recalcitrant infections.

microbiology↗

bioRxiv2018

Interim impact evaluation of the hepatitis C virus elimination program in Georgia

Background and AimsGeorgia has one of the highest hepatitis C virus (HCV) prevalence rates in the world, with >5% of the adult population (~150,000 people) chronically infected. In April 2015, the Georgian government, in collaboration with CDC and other partners, launched a national program to eliminate HCV through scaling up HCV treatment and prevention interventions, with the aim of achieving a 90% reduction in prevalence by 2020. We evaluate the interim impact of the HCV treatment program as of 31 October 2017, and assess the feasibility of achieving the elimination goal by 2020.\n\nMethodWe developed a dynamic HCV transmission model to capture the current and historical epidemic dynamics of HCV in Georgia, including the main drivers of transmission. Using the 2015 national sero-survey and prior surveys conducted among people who inject drugs (PWID) from 1997-2015, the model was calibrated to data on HCV prevalence by age, gender and PWID status, and the age distribution of PWID. We use the model to project the interim impact of treatment strategies currently being undertaken as part of the ongoing Georgia HCV elimination program, while accounting for treatment failure/loss to follow up, in order to determine whether they are on track to achieving their HCV elimination target by 2020, or whether strategies need to be modified to ensure success.\n\nResultsA treatment rate of 2,050 patients/month was required from the beginning of the national program to achieve a 90% reduction in prevalence by the end of 2020, with equal treatment rates of PWID and the general population. From May 2015 to October 2017, 40,420 patients were treated, an average of ~1,350 per month; although the treatment rate has recently declined from a peak of 4,500/month in September 2016 to 2100/month in November-December 2016, and 1000/month in August-October 2017, with a sustained virological response rate (SVR) of 98% per-protocol or 78% intent to treat. The model projects that the treatments undertaken up to October 2017 have reduced adult chronic prevalence by 26% (18-35%) to 3.7% (2.9-5.1%), reduced total incidence by 25% (15-35%), and prevented 1845 (751-3969) new infections and 93 (31-177) HCV-related deaths. If the treatment rate of 1000 patients initiated per month continues, prevalence will have halved by 2020, and reduce by 90% by 2026. In order to reach a 90% reduction by 2020, the treatment rate must increase 3.5-fold to 4000/month.\n\nConclusionThe Georgia HCV elimination program has accomplished an impressive scale up of treatment, which has already impacted on prevalence and incidence, and averted deaths due to HCV. However, extensive scale up is needed to achieve a 90% reduction in prevalence by 2020.

epidemiology↗

bioRxiv2018

Association between schizophrenia and both loss of function and missense mutations in paralog conserved sites of voltage-gated sodium channels

Sequencing studies have highlighted candidate sets of genes involved in schizophrenia, including activity-regulated cytoskeleton-associated protein (ARC) and N-methyl-d-aspartate receptor (NMDAR) complexes. Two genes, SETD1A and RBM12, have also been associated with robust statistical evidence. Larger samples and novel methods for identifying disease-associated missense variants are needed to reveal novel genes and biological mechanisms associated with schizophrenia. We sequenced 187 genes, selected for prior evidence of association with schizophrenia, in a new dataset of 5,207 cases and 4,991 controls. Included were members of ARC and NMDAR post-synaptic protein complexes, as well as voltage-gated sodium and calcium channels. We observed a significant case excess of rare (<0.1% in frequency) loss-of-function (LoF) mutations across all 187 genes (OR = 1.36; Pcorrected = 0.0072) but no individual gene was associated with schizophrenia after correcting for multiple testing. We found novel evidence that LoF and missense variants at paralog conserved sites were enriched in sodium channels (OR = 1.26; P = 0.0035). Meta-analysis of our new data with published sequencing data (11,319 cases, 15,854 controls and 1,136 trios) supported and refined this association to sodium channel alpha subunits (P = 0.0029). Meta-analysis also confirmed association between schizophrenia and rare variants in ARC (P = 4.0 x 10-4) and NMDAR (P = 1.7 x 10-5) synaptic genes. No association was found between rare variants in calcium channels and schizophrenia.\n\nIn one of the largest sequencing studies of schizophrenia to date, we provide novel evidence that multiple voltage-gated sodium channels are involved in schizophrenia pathogenesis, and increase the evidence for association between rare variants in ARC and NMDAR post-synaptic complexes and schizophrenia. Larger samples are required to identify specific genes and variants driving these associations.\n\nAuthor SummaryCommon and rare genetic variations are known to play a substantial role in the development of schizophrenia. Recently, sequencing studies have started to highlight specific sets of genes that are enriched for rare variation in schizophrenia, such as the synaptic gene sets ARC and NMDAR, as well as voltage-gated sodium and calcium channels. To confirm the role of these gene sets in schizophrenia, and identify specific risk genes, we sequenced 187 genes in a new sample of 5,207 schizophrenia cases and 4,991 controls. We find an excess of protein truncating mutations with a frequency <0.1% in all 187 targeted genes, and provide novel evidence that mutations altering amino acids conserved across sodium channel proteins are risk factors for schizophrenia. Through meta-analysing our new data with previously published sequencing data sets, for a total of 11,319 cases, 15,854 controls and 1,136 trios, we increase the evidence for association between rare coding variants and schizophrenia in voltage-gated sodium channels, as well as in synaptic gene sets ARC and NMDAR. Although no individual gene was associated with schizophrenia, these findings suggest larger studies will identify the specific genes driving these associations.

genetics↗

bioRxiv2017

Programmable transport of micro- and nanoparticles by Paramecium caudatum

We exploit chemo- and galvanotactic behaviour of Paramecium caudatum to design a hybrid device that allows for controlled uptake, transport and deposition of environmental micro- and nanoparticulates in an aqueous medium. Manipulation of these objects is specific, programmable and parallel. We demonstrate how device operation and output interpretation may be automated via a DIY low-cost fluorescence spectrometer, driven by a microprocessor board. The applications of the device presented range from collection and detoxification of environmental contaminants (e.g. nanoparticles), to micromixing, to natural expressions of computer logic.

microbiology↗

bioRxiv2017

High-risk Autism Spectrum Disorder Utah pedigrees: a novel Shared Genomic Segments analysis.

Progress in gene discovery for Autism Spectrum Disorder (ASD) has been rapid over the past decade, with major successes in validation of risk of predominantly rare, penetrant, de novo and inherited mutations in over 100 genes (de Rubies et al., 2015; Sanders et al., 2015). However, the majority of individuals with ASD diagnoses do not carry a rare, penetrant genetic risk factor. In fact, recent estimates suggest that most of the genetic liability of ASD is due to as yet undiscovered common, less penetrant inherited variation (Gaugler et al., 2014) which is much more difficult to detect. The study of extended, high-risk families adds significant information in our search for these common inherited risk factors. Here, we present results of a new, powerful pedigree analysis method (Shared Genomic Segments--SGS) on three large families from the Utah Autism Research Program. The method improves upon previous methods by allowing for within-family heterogeneity, and identifying exact region boundaries and subsets of cases who share for targeted follow-up analyses. Our SGS analyses identified one genome-wide significant shared segment on chromosome 17 (q21.32, p=1.47x10-8). Additional regions with suggestive evidence were identified on chromosomes 3, 4, 6, 8, 11, 13, 14, 15, and 18. Several of these segments showed evidence of sharing across families. Genes of interest in these regions include ATP8A1, DOCK3, CACNA2D2, ITGB3, AMBRA1, FOLH1, DGKZ, MTHFS, ARNT2, BTN2A2, BTN3A1, BTN3A3, BTN2A1, and BTN1A1. We are exploring multiple other lines of evidence to follow up these implicated regions and genes.

genetics↗