NMD3 regulates both mRNA and rRNA nuclear export in African trypanosomes via an XPOI-linked pathway

Trypanosomes mostly regulate gene expression through post-transcriptional mechanisms, particularly mRNA stability. However, much mRNA degradation is cytoplasmic such that mRNA nuclear export must represent an important level of regulation. Ribosomal RNAs must also be exported from the nucleus and the trypanosome orthologue of NMD3 has been confirmed to be involved in rRNA processing and export, matching its function in other organisms. Surprisingly, we found that TbNMD3 depletion also generates mRNA accumulation of procyclin-associated genes (PAGs), these being co-transcribed by RNA polymerase I with the procyclin surface antigen genes expressed on trypanosome insect forms. By whole transcriptome RNA-seq analysis of TbNMD3-depleted cells we confirm the regulation of the PAG transcripts by TbNMD3 and using reporter constructs reveal that PAG1 regulation is mediated by its 5′UTR. Dissection of the mechanism of regulation demonstrates that it is not dependent upon translational inhibition mediated by TbNMD3 depletion nor enhanced transcription. However, depletion of the nuclear export factors XPO1 or MEX67 recapitulates the effects of TbNMD3 depletion on PAG mRNAs and mRNAs accumulated in the nucleus of TbNMD3-depleted cells. These results invoke a novel RNA regulatory mechanism involving the NMD3-dependent nuclear export of mRNA cargos, suggesting a shared platform for mRNA and rRNA expor

Prospectus, January 20, 1987

https://spark.parkland.edu/prospectus_1987/1001/thumbnail.jp

Effects of canagliflozin on initiation of insulin and other antihyperglycaemic agents in the CANVAS program

This study compared initiation of insulin and other AHAs with canagliflozin versus placebo for participants with type 2 diabetes and a history/high risk of cardiovascular disease in the CANagliflozin cardioVascular Assessment Study (CANVAS) Program. After 1 year fewer participants treated with canagliflozin versus placebo initiated any AHA (7% vs 16%), insulin (3% vs 9%;) or any non-insulin AHA (5% vs 12%; p<0.001 for all); overall AHA initiation rates increased over time but were consistently lower with canagliflozin compared with placebo. During the study, the likelihood of initiating insulin was 2.7 times lower for participants treated with canagliflozin compared with placebo (hazard ratio, 0.37; 95% CI: 0.31,0.43; p<0.001). The time difference between 10% of patients in the canagliflozin and placebo groups being initiated on insulin from the beginning of the trial was about two years. Time to initiation of other AHAs, including metformin, dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists and sulphonylureas, was also delayed for canagliflozin versus placebo (p<0.001 for each). Compared with placebo, canagliflozin delayed the need for initiation of other AHAs and delayed time to insulin therapy, an outcome that is important to many people with diabetes. Trial registration: ClinicalTrials.gov identifiers NCT01032629, NCT01989754. This article is protected by copyright. All rights reserved

Atypical scrapie in sheep from a UK research flock which is free from classical scrapie

Background: In the wake of the epidemic of bovine spongiform encephalopathy the British government established a flock of sheep from which scrapie-free animals are supplied to laboratories for research. Three breeds of sheep carrying a variety of different genotypes associated with scrapie susceptibility/resistance were imported in 1998 and 2001 from New Zealand, a country regarded as free from scrapie. They are kept in a purpose-built Sheep Unit under strict disease security and are monitored clinically and post mortem for evidence of scrapie. It is emphasised that atypical scrapie, as distinct from classical scrapie, has been recognised only relatively recently and differs from classical scrapie in its clinical, neuropathological and biochemical features. Most cases are detected in apparently healthy sheep by post mortem examination.Results: The occurrence of atypical scrapie in three sheep in (or derived from) the Sheep Unit is reported. Significant features of the affected sheep included their relatively high ages (6 y 1 mo, 7 y 9 mo, 9 y 7 mo respectively), their breed (all Cheviots) and their similar PRNP genotypes (AFRQ/AFRQ, AFRQ/ALRQ, and AFRQ/AFRQ, respectively). Two of the three sheep showed no clinical signs prior to death but all were confirmed as having atypical scrapie by immunohistochemistry and Western immunoblotting. Results of epidemiological investigations are presented and possible aetiologies of the cases are discussed.Conclusion: By process of exclusion, a likely explanation for the three cases of atypical scrapie is that they arose spontaneously and were not infected from an exterior source. If correct, this raises challenging issues for countries which are currently regarded as free from scrapie. It would mean that atypical scrapie is liable to occur in flocks worldwide, especially in older sheep of susceptible genotypes. To state confidently that both the classical and atypical forms of scrapie are absent from a population it is necessary for active surveillance to have taken place

Identification of improved IL28B SNPs and haplotypes for prediction of drug response in treatment of hepatitis C using massively parallel sequencing in a cross-sectional European cohort

BACKGROUND: The hepatitis C virus (HCV) infects nearly 3% of the World's population, causing severe liver disease in many. Standard of care therapy is currently pegylated interferon alpha and ribavirin (PegIFN/R), which is effective in less than half of those infected with the most common viral genotype. Two IL28B single nucleotide polymorphisms (SNPs), rs8099917 and rs12979860, predict response to (PegIFN/R) therapy in treatment of HCV infection. These SNPs were identified in genome wide analyses using Illumina genotyping chips. In people of European ancestry, there are 6 common (more than 1%) haplotypes for IL28B, one tagged by the rs8099917 minor allele, four tagged by rs12979860. METHODS: We used massively parallel sequencing of the IL28B and IL28A gene regions generated by polymerase chain reaction (PCR) from pooled DNA samples from 100 responders and 99 non-responders to therapy, to identify common variants. Variants that had high odds ratios and were validated were then genotyped in a cohort of 905 responders and non-responders. Their predictive power was assessed, alone and in combination with HLA-C. RESULTS: Only SNPs in the IL28B linkage disequilibrium block predicted drug response. Eighteen SNPs were identified with evidence for association with drug response, and with a high degree of confidence in the sequence call. We found that two SNPs, rs4803221 (homozygote minor allele positive predictive value (PPV) of 77%) and rs7248668 (PPV 78%), predicted failure to respond better than the current best, rs8099917 (PPV 73%) and rs12979860 (PPV 68%) in this cross-sectional cohort. The best SNPs tagged a single common haplotype, haplotype 2. Genotypes predicted lack of response better than alleles. However, combination of IL28B haplotype 2 carrier status with the HLA-C C2C2 genotype, which has previously been reported to improve prediction in combination with IL28B, provides the highest PPV (80%). The haplotypes present alternative putative transcription factor binding and methylation sites. CONCLUSIONS: Massively parallel sequencing allowed identification and comparison of the best common SNPs for identifying treatment failure in therapy for HCV. SNPs tagging a single haplotype have the highest PPV, especially in combination with HLA-C. The functional basis for the association may be due to altered regulation of the gene. These approaches have utility in improving diagnostic testing and identifying causal haplotypes or SNPs

Identifying diagnostic criteria for upper- and lower-limb lymphoedema

BACKGROUND Bioimpedance spectroscopy (BIS) assesses resistance (impedance) to the flow of an electrical current. Through the measurement of impedance to currents at low (R0) and high (Rinf) frequencies, extracellular fluid (ECF) and total body fluid (TBF) can be measured, respectively, and intracellular fluid (Ri = ICF) subsequently extrapolated (TBW = ECF + ICF). Measuring bilateral upper-limb or lower-limb secondary lymphoedema following cancer is complicated by the unavailability of a comparable, unaffected limb. Availability of normative BIS data for all 4 limb segments would enable an extension of BIS in the diagnosis of bilateral upper-, as well as lower-limb lymphoedema. The purpose of this study was to describe normative arm to leg, arm to arm and leg to leg impedance ratios and to determine optimal cut-off thresholds for diagnosing lymphoedema by testing the accuracy of cut-offs based on normative means plus or minus 0.5 to 3 SDs to diagnose known cases of lymphoedema

Eastern Mediterranean hydroclimate over the late glacial and Holocene, reconstructed from the sediments of Nar lake, central Turkey, using stable isotopes and carbonate mineralogy

There is a lack of high-resolution records of hydroclimate variability in the Eastern Mediterranean from the late glacial and early Holocene. More knowledge of the speed of climate shifts and the degree to which they were synchronous with changes in the North Atlantic or elsewhere is required to understand better the controls on Eastern Mediterranean climate. Using endogenic carbonate from a sediment sequence from Nar Gölü, a maar lake in central Turkey, dated by varve counting and uranium-thorium methods, we present high-resolution (∼25 years) oxygen (δ18O) and carbon isotope records, supported by carbonate mineralogy data, spanning the late glacial and Holocene. δ18Ocarbonate at Nar Gölü has been shown previously to be a strong proxy for regional water balance. After a dry period (i.e. evaporation far exceeding precipitation) in the Younger Dryas, the data show a transition into the relatively wetter early Holocene. In the early Holocene there are two drier periods that appear to peak at ∼9.3 ka and ∼8.2 ka, coincident with cooling ‘events’ seen in North Atlantic records. After this, and as seen in other records from the Eastern Mediterranean, there is a millennial-scale drying trend through the Mid Holocene Transition. The relatively dry late Holocene is punctuated by centennial-scale drought intervals, at the times of 4.2 ka ‘event’ and Late Bronze Age societal ‘collapse’. Overall, we show that central Turkey is drier when the North Atlantic is cooler, throughout this record and at multiple timescales, thought to be due to a weakening of the westerly storm track resulting from reduced cyclogenesis in the North Atlantic. However, some features, such as the Mid Holocene Transition and the fact the early Holocene dry episodes at Nar Gölü are of a longer duration than the more discrete ‘events’ seen in North Atlantic records, imply there are additional controls on Eastern Mediterranean hydroclimate

Physiotherapy for functional motor disorders: a consensus recommendation.

BACKGROUND: Patients with functional motor disorder (FMD) including weakness and paralysis are commonly referred to physiotherapists. There is growing evidence that physiotherapy is an effective treatment, but the existing literature has limited explanations of what physiotherapy should consist of and there are insufficient data to produce evidence-based guidelines. We aim to address this issue by presenting recommendations for physiotherapy treatment. METHODS: A meeting was held between physiotherapists, neurologists and neuropsychiatrists, all with extensive experience in treating FMD. A set of consensus recommendations were produced based on existing evidence and experience. RESULTS: We recommend that physiotherapy treatment is based on a biopsychosocial aetiological framework. Treatment should address illness beliefs, self-directed attention and abnormal habitual movement patterns through a process of education, movement retraining and self-management strategies within a positive and non-judgemental context. We provide specific examples of these strategies for different symptoms. CONCLUSIONS: Physiotherapy has a key role in the multidisciplinary management of patients with FMD. There appear to be specific physiotherapy techniques which are useful in FMD and which are amenable to and require prospective evaluation. The processes involved in referral, treatment and discharge from physiotherapy should be considered carefully as a part of a treatment package