256 research outputs found
Leigh syndrome: One disorder, more than 75 monogenic causes
Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/137543/1/ana24551_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/137543/2/ana24551.pd
Paddock scale modelling to assess effectiveness of agricultural management practice in improving water quality in the Great Barrier Reef Catchments
Agriculture in the catchment areas adjacent to the World Heritage listed Great Barrier Reef (GBR) Marine Park generates pollutants that are a concern for the health of the Reef. Under the Paddock to Reef Integrated Monitoring, Modelling and Reporting program (P2R) of the Reef Plan, the impacts of improved agricultural management practices on water quality entering the GBR are modelled to evaluate the effectiveness of Government water quality improvement policies. The Source Catchments modelling framework estimates loads of pollutants entering the GBR lagoon from rivers. However, Source Catchments does not have the capacity to represent the collection of management practices available to farmers that affect water quality in runoff and drainage at a paddock scale. Therefore, paddock scale agricultural systems models were used to demonstrate the effects of management practice adoption and to provide input to the catchment scale models. Paddock scale models were used because they represent a level of process detail compatible with the management practice investments and implementation on-ground. A fit-for-purpose modelling approach was used, where the paddock model most suited to a given land use and/or water quality pollutant was applied. Three one-dimensional agricultural systems models were employed; HowLeaky in grains, APSIM in sugarcane with HowLeaky post-processing for herbicides and phosphorous and GRASP in grazing lands. These models share similar soil water balance, ground cover and runoff sub-models. However, they vary in the level of detail, particularly in terms of representing crop growth and in the processes considered, such as pesticide degradation and export. In grains and sugarcane cropping, the pollutant time-series (e.g. load per day per unit area) in the Source Catchments models was replaced with an output time-series from HowLeaky or APSIM for each soil-climate spatial combination. Management practices were grouped into systems classed as A, B, C or D. The proportion of each of these management systems contributing to the modelled loads was adjusted to reflect data on the prevalence of adoption of improved management practices in the GBR catchment. In grazing lands, GRASP pasture utilisation and ground cover time-series outputs were interrogated to derive relationships between changes in grazing system management and changes in the USLE C-factors. The USLE is used to predict hillslope erosion in the Source Catchments model. Scaling indices derived from GRASP outputs were used to adjust the USLE C-factors applied in Source Catchments where management practices had changed. The P2R program has demonstrated the effectiveness of linking paddock scale models or emergent models derived from them with catchment scale models. This has enabled detailed management options to be simulated to investigate broad scale water quality impacts of the adoption of improved agricultural practices
Biochemical and molecular diagnosis of mitochondrial respiratory chain disorders
AbstractBiochemical diagnosis of mitochondrial respiratory chain disorders requires caution to avoid misdiagnosis of secondary enzyme defects, and can be improved by the use of conservative diagnostic criteria. Pathogenic mutations causing mitochondrial disorders have now been identified in more than 30 mitochondrial DNA (mtDNA) genes encoding respiratory chain subunits, ribosomal- and t-RNAs. mtDNA mutations appear to be responsible for most adult patients with mitochondrial disease and approximately a quarter of paediatric patients. A family history suggesting maternal inheritance is the exception rather than the norm for children with mtDNA mutations, many of whom have de novo mutations. Prenatal diagnosis and pre-implantation genetic diagnosis can be offered to some women at risk of transmitting a mtDNA mutation, particularly those at lower recurrence risk. Mutations in more than 30 nuclear genes, including those encoding for respiratory chain subunits and assembly factors, have now been shown to cause mitochondrial disorders, creating difficulties in prioritising which genes should be studied by mutation analysis in individual patients. A number of approaches offer promise to guide the choice of candidate genes, including Blue Native-PAGE immunoblotting and microarray expression analysis
Chalk cliff retreat in East Sussex and Kent 1870s to 2001
The retreat of chalk cliffs fringing the eastern English Channel contributes shingle to the beaches which helps to protect the cliffs and slow down erosion. Conversely, cliff retreat endangers settlements and infrastructure on the clifftop. Rates of retreat have been calculated by a variety of methods over the past century, but no attempt has been made to provide a complete coverage that allows for a true comparison of retreat rates over the entire coastline. Using historic maps and recent orthophotos, cliff retreat rates have been calculated for consecutive 50 m sections of chalk cliff along the English side of the entire eastern English Channel for a period of 125 years. The chalk cliffs of East Sussex erode at an average rate of 0.25 - 0.3 m y−1 while those in Kent at a rate of 0.1 m y−1
Ontogenetic Variation in Movements and Depth Use, and Evidence of Partial Migration in a Benthopelagic Elasmobranch
Tope (Galeorhinus galeus) is a highly mobile elasmobranch in the temperate to subtropical northeast Atlantic. It is highly migratory and has been shown to display complex movement patterns, such as partial migration, in the southern hemisphere. In the northeast Atlantic, previous mark-recapture studies have struggled to identify movement patterns and the species behavior is poorly described, yet identification of migratory behaviors and habitats of importance for the species is of paramount importance for effective management. Here, we combined fisheries independent survey data with mark-recapture (MR) data to investigate the distribution of different age classes of tope across the northeast Atlantic. We further investigated depth use in detail with archival electronic tags and a pop-up satellite archival tag (PSAT). We suggest previous studies struggling to find consistent movement patterns using MR data were confounded by a combination of site fidelity, partial migration by females, and increasing depth and home range of juveniles. Survey and MR data showed immature tope <40 cm were caught exclusively in continental shelf waters <45 m deep, showing a significant relationship between habitat depth and total length. Immature individuals seemed to remain on the continental shelf, while mature tope of both genders were caught in both shelf and offshore waters. This use of deeper water habitats by mature tope was further supported by archival tags, which indicated individuals use both shallow (<200 m depth) and deep-water habitats, diving to depths of 826 m; the deepest record for this species. The PSAT tag tracked the horizontal movements of an adult male, which confirmed utilization of both shallow inshore and deep offshore habitats. Most tope remained within 500 km of their tagging site, although some mature females had a larger, more southerly range, including connectivity with the Mediterranean. This study clearly demonstrates the highly migratory habits of tope, and suggests larger individuals divide their time between shallow and deep-water habitats. It shows the northeast Atlantic tope population should benefit from consistent management throughout its range
Bacterial and metabolic phenotypes associated with inadequate response to ursodeoxycholic acid treatment in primary biliary cholangitis
Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease with ursodeoxycholic acid (UDCA) as first-line treatment. Poor response to UDCA is associated with a higher risk of progressing to cirrhosis, but the underlying mechanisms are unclear. UDCA modulates the composition of primary and bacterial-derived bile acids (BAs). We characterized the phenotypic response to UDCA based on BA and bacterial profiles of PBC patients treated with UDCA. Patients from the UK-PBC cohort (n = 419) treated with UDCA for a minimum of 12-months were assessed using the Barcelona dynamic response criteria. BAs from serum, urine, and feces were analyzed using Ultra-High-Performance Liquid Chromatography-Mass Spectrometry and fecal bacterial composition measured using 16S rRNA gene sequencing. We identified 191 non-responders, 212 responders, and a subgroup of responders with persistently elevated liver biomarkers (n = 16). Responders had higher fecal secondary and tertiary BAs than non-responders and lower urinary bile acid abundances, with the exception of 12-dehydrocholic acid, which was higher in responders. The sub-group of responders with poor liver function showed lower alpha-diversity evenness, lower abundance of fecal secondary and tertiary BAs than the other groups and lower levels of phyla with BA-deconjugation capacity (Actinobacteriota/Actinomycetota, Desulfobacterota, Verrucomicrobiota) compared to responders. UDCA dynamic response was associated with an increased capacity to generate oxo-/epimerized secondary BAs. 12-dehydrocholic acid is a potential biomarker of treatment response. Lower alpha-diversity and lower abundance of bacteria with BA deconjugation capacity might be associated with an incomplete response to treatment in some patients
MPV17 Loss Causes Deoxynucleotide Insufficiency and Slow DNA Replication in Mitochondria
MPV17 is a mitochondrial inner membrane protein whose dysfunction causes mitochondrial DNA abnormalities and disease by an unknown mechanism. Perturbations of deoxynucleoside triphosphate (dNTP) pools are a recognized cause of mitochondrial genomic instability; therefore, we determined DNA copy number and dNTP levels in mitochondria of two models of MPV17 deficiency. In Mpv17 ablated mice, liver mitochondria showed substantial decreases in the levels of dGTP and dTTP and severe mitochondrial DNA depletion, whereas the dNTP pool was not significantly altered in kidney and brain mitochondria that had near normal levels of DNA. The shortage of mitochondrial dNTPs in Mpv17-/- liver slows the DNA replication in the organelle, as evidenced by the elevated level of replication intermediates. Quiescent fibroblasts of MPV17-mutant patients recapitulate key features of the primary affected tissue of the Mpv17-/- mice, displaying virtual absence of the protein, decreased dNTP levels and mitochondrial DNA depletion. Notably, the mitochondrial DNA loss in the patients’ quiescent fibroblasts was prevented and rescued by deoxynucleoside supplementation. Thus, our study establishes dNTP insufficiency in the mitochondria as the cause of mitochondrial DNA depletion in MPV17 deficiency, and identifies deoxynucleoside supplementation as a potential therapeutic strategy for MPV17-related disease. Moreover, changes in the expression of factors involved in mitochondrial deoxynucleotide homeostasis indicate a remodeling of nucleotide metabolism in MPV17 disease models, which suggests mitochondria lacking functional MPV17 have a restricted purine mitochondrial salvage pathway
UK-Wide Multicenter Evaluation of Second-line Therapies in Primary Biliary Cholangitis
Background & aims: thirty-to-forty percent of patients with primary biliary cholangitis inadequately respond to ursodeoxycholic acid. Our aim was to assemble national, real-world data on the effectiveness of obeticholic acid (OCA) as a second-line treatment, alongside non-licensed therapy with fibric acid derivatives (bezafibrate or fenofibrate).Methods: this was a nationwide observational cohort study conducted from August 2017 until June 2021.Results: we accrued data from 457 patients; 349 treated with OCA and 108 with fibric acid derivatives. At baseline/pre-treatment, individuals in the OCA group manifest higher risk features compared with those taking fibric acid derivatives, evidenced by more elevated alkaline phosphatase values, and a larger proportion of individuals with cirrhosis, abnormal bilirubin, prior non-response to ursodeoxycholic acid, and elastography readings >9.6kPa (P < .05 for all). Overall, 259 patients (OCA) and 80 patients (fibric acid derivatives) completed 12 months of second-line therapy, yielding a dropout rate of 25.7% and 25.9%, respectively. At 12 months, the magnitude of alkaline phosphatase reduction was 29.5% and 56.7% in OCA and fibric acid groups (P < .001). Conversely, 55.9% and 36.4% of patients normalized serum alanine transaminase and bilirubin in the OCA group (P < .001). The proportion with normal alanine transaminase or bilirubin values in the fibric acid group was no different at 12 months compared with baseline. Twelve-month biochemical response rates were 70.6% with OCA and 80% under fibric acid treatment (P = .121). Response rates between treatment groups were no different on propensity-score matching or on sub-analysis of high-risk groups defined at baseline.Conclusion: across the population of patients with primary biliary cholangitis in the United Kingdom, rates of biochemical response and drug discontinuation appear similar under fibric acid and OCA treatment.</p
Assessing Big-Bang Nucleosynthesis
Systematic uncertainties in the light-element abundances and their evolution
make a rigorous statistical assessment difficult. However, using Bayesian
methods we show that the following statement is robust: the predicted and
measured abundances are consistent with 95\% credibility only if the
baryon-to-photon ratio is between and
and the number of light neutrino species is less than 3.9. Our analysis
suggests that the He abundance may have been systematically underestimated.Comment: 7 pages, LaTeX(2.09), 6 postscript figures (attached). A postscript
version with figures can be found at
ftp://astro.uchicago.edu/pub/astro/copi/assessing_BBN . (See the README file
for details
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