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Haploinsufficiency of the progranulin (PGRN)-encoding gene (GRN) causes frontotemporal lobar degeneration (GRN-FTLD) and results in microglial hyperactivation, TREM2 activation, lysosomal dysfunction, and TDP-43 deposition. To und...
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Haploinsufficiency of the progranulin (PGRN)-encoding gene (GRN) causes frontotemporal lobar degeneration (GRN-FTLD) and results in microglial hyperactivation, TREM2 activation, lysosomal dysfunction, and TDP-43 deposition. To understand the contribution of microglial hyperactivation to pathology, we used genetic and pharmacological approaches to suppress TREM2-dependent transition of microglia from a homeostatic to a disease-associated state. Trem2 deficiency in Grn KO mice reduced microglia hyperactivation. To explore antibody-mediated pharmacological modulation of TREM2-dependent microglial states, we identified antagonistic TREM2 antibodies. Treatment of macrophages from GRN-FTLD patients with these antibodies led to reduced TREM2 signaling due to its enhanced shedding. Furthermore, TREM2 antibody-treated PGRN-deficient microglia derived from human-induced pluripotent stem cells showed reduced microglial hyperactivation, TREM2 signaling, and phagocytic activity, but lysosomal dysfunction was not rescued. Similarly, lysosomal dysfunction, lipid dysregulation, and glucose hypometabolism of Grn KO mice were not rescued by TREM2 ablation. Synaptic loss and neurofilament light-chain (NfL) levels, a biomarker for neurodegeneration, were further elevated in the Grn/Trem2 KO cerebrospinal fluid (CSF). These findings suggest that TREM2-dependent microglia hyperactivation in models of GRN deficiency does not promote neurotoxicity, but rather neuroprotection.
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Context. Demoralization can be understood as a condition that results from existential conflict. It presents with symptoms of hopelessness and helplessness caused by a loss of purpose and meaning in life. It is a significant menta...
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Context. Demoralization can be understood as a condition that results from existential conflict. It presents with symptoms of hopelessness and helplessness caused by a loss of purpose and meaning in life. It is a significant mental health concern given there can be an associated desire for hastened death.
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Biochemical and genetic evidence implicate soluble oligomeric amyloid-beta(A beta o) in triggering Alzheimer's disease (AD) pathophysiology. Moreover, constitutive deletion of the A beta o-binding cellular prion protein (PrPC) pre...
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Biochemical and genetic evidence implicate soluble oligomeric amyloid-beta(A beta o) in triggering Alzheimer's disease (AD) pathophysiology. Moreover, constitutive deletion of the A beta o-binding cellular prion protein (PrPC) prevents development of memory deficits in APP(swe)/PS1 Delta E9 mice, a model of familial AD. Here, we define the role of PrPC to rescue or halt established AD endophenotypes in a therapeutic disease-modifying time window after symptom onset. Deletion of Prnp at either 12 or 16 months of age fully reverses hippocampal synapse loss and completely rescues preexisting behavioral deficits by 17 months. In contrast, but consistent with a neuronal function for A beta o/PrPC signaling, plaque density, microgliosis, and astrocytosis are not altered. Degeneration of catecholaminergic neurons remains unchanged by PrPC reduction after disease onset. These results define the potential of targeting PrPC as a disease-modifying therapy for certain AD-related phenotypes after disease onset.
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Background: Cognitive-motor step training can improve stepping, balance and mobility in people with multiple sclerosis (MS), but effectiveness in preventing falls has not been demonstrated.Objectives: This multisite randomised con...
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Background: Cognitive-motor step training can improve stepping, balance and mobility in people with multiple sclerosis (MS), but effectiveness in preventing falls has not been demonstrated.Objectives: This multisite randomised controlled trial aimed to determine whether 6 months of home-based step exergame training could reduce falls and improve associated risk factors compared with usual care in people with MS.Methods: In total, 461 people with MS aged 22-81 years were randomly allocated to usual care (control) or unsupervised home-based step exergame training (120 minutes/week) for 6 months. The primary outcome was rate of falls over 6 months from randomisation. Secondary outcomes included physical, cognitive and psychosocial function at 6 months and falls over 12 months.Results: Mean (standard deviation (SD)) weekly training duration was 70 (51) minutes over 6 months. Fall rates did not differ between intervention and control groups (incidence rates (95% confidence interval (CI)): 2.13 (1.57-2.69) versus 2.24 (1.35-3.13), respectively, incidence rate ratio: 0.96 (95% CI: 0.69-1.34, p = 0.816)). Intervention participants performed faster in tests of choice-stepping reaction time at 6 months. No serious training-related adverse events were reported.Conclusion: The step exergame training programme did not reduce falls among people with MS. However, it significantly improved choice-stepping reaction time which is critical to ambulate safely in daily life environment.
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Nitrogen deposition was experimentally increased on a Scottish peatbog over a period of 13 years (2002-2015). Nitrogen was applied in three forms, NH3 gas, NH4Cl solution, and NaNO3 solution, at rates ranging from 8 (ambient) to 6...
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Nitrogen deposition was experimentally increased on a Scottish peatbog over a period of 13 years (2002-2015). Nitrogen was applied in three forms, NH3 gas, NH4Cl solution, and NaNO3 solution, at rates ranging from 8 (ambient) to 64 kgNha(-1) yr(-1), and higher near the NH3 fumigation source. An automated system was used to apply the nitrogen, such that the deposition was realistic in terms of rates and high frequency of deposition events. We measured the response of nitrous oxide (N2O) flux to the increased nitrogen input. Prior expectations, based on the IPCC default emission factor, were that 1% of the added nitrogen would be emitted as N2O. In the plots treated with NH4+ and NO3- solution, no response was seen, and there was a tendency for N2O fluxes to be reduced by additional nitrogen, though this was not significant. Areas subjected to high NH3 emitted more N2O than expected, up to 8.5% of the added nitrogen. Differences in the response are related to the impact of the nitrogen treatments on the vegetation. In the NH4+ and NO3- treatments, all the additional nitrogen is effectively immobilised in the vegetation and top 10 cm of peat. In the NH3 treatment, much of the vegetation was killed off by high doses of NH3, and the nitrogen was presumably more available to denitrifying bacteria. The design of the wet and dry experimental treatments meant that they differed in statistical power, and we are less likely to detect an effect of the NH4+ and NO3- treatments, though they avoid issues of pseudo-replication.
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Nitrogen deposition was experimentally increased on a Scottish peatbog over a period of 13?years (2002–2015). Nitrogen was applied in three forms, NH3 gas, NH4Cl solution, and NaNO3 solution, at rates ranging from 8 (ambient) to ...
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Nitrogen deposition was experimentally increased on a Scottish peatbog over a period of 13?years (2002–2015). Nitrogen was applied in three forms, NH3 gas, NH4Cl solution, and NaNO3 solution, at rates ranging from 8 (ambient) to 64?kg?N?ha?1?yr?1, and higher near the NH3 fumigation source. An automated system was used to apply the nitrogen, such that the deposition was realistic in terms of rates and high frequency of deposition events. We measured the response of nitrous oxide (N2O) flux to the increased nitrogen input. Prior expectations, based on the IPCC default emission factor, were that 1?% of the added nitrogen would be emitted as N2O. In the plots treated with NH4+ and NO3? solution, no response was seen, and there was a tendency for N2O fluxes to be reduced by additional nitrogen, though this was not significant. Areas subjected to high NH3 emitted more N2O than expected, up to 8.5?% of the added nitrogen. Differences in the response are related to the impact of the nitrogen treatments on the vegetation. In the NH4+ and NO3? treatments, all the additional nitrogen is effectively immobilised in the vegetation and top 10?cm of peat. In the NH3 treatment, much of the vegetation was killed off by high doses of NH3, and the nitrogen was presumably more available to denitrifying bacteria. The design of the wet and dry experimental treatments meant that they differed in statistical power, and we are less likely to detect an effect of the NH4+ and NO3? treatments, though they avoid issues of pseudo-replication.
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Nitrogen deposition was experimentally increased on a Scottish peatbog over a period of 13?years (2002–2015). Nitrogen was applied in three forms, NH<sub>3</sub> gas, NH<sub>4</sub>Cl solution, and NaNO<sub>3</sub> solution, at r...
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Nitrogen deposition was experimentally increased on a Scottish peatbog over a period of 13?years (2002–2015). Nitrogen was applied in three forms, NH<sub>3</sub> gas, NH<sub>4</sub>Cl solution, and NaNO<sub>3</sub> solution, at rates ranging from 8 (ambient) to 64?kg?N?ha<sup>?1</sup>?yr<sup>?1</sup>, and higher near the NH<sub>3</sub> fumigation source. An automated system was used to apply the nitrogen, such that the deposition was realistic in terms of rates and high frequency of deposition events. We measured the response of nitrous oxide (N<sub>2</sub>O) flux to the increased nitrogen input. Prior expectations, based on the IPCC default emission factor, were that 1?% of the added nitrogen would be emitted as N<sub>2</sub>O. In the plots treated with NH<sub>4</sub><sup>+</sup> and NO<sub>3</sub><sup>?</sup> solution, no response was seen, and there was a tendency for N<sub>2</sub>O fluxes to be reduced by additional nitrogen, though this was not significant. Areas subjected to high NH<sub>3</sub> emitted more N<sub>2</sub>O than expected, up to 8.5?% of the added nitrogen. Differences in the response are related to the impact of the nitrogen treatments on the vegetation. In the NH<sub>4</sub><sup>+</sup> and NO<sub>3</sub><sup>?</sup> treatments, all the additional nitrogen is effectively immobilised in the vegetation and top 10?cm of peat. In the NH<sub>3</sub> treatment, much of the vegetation was killed off by high doses of NH<sub>3</sub>, and the nitrogen was presumably more available to denitrifying bacteria. The design of the wet and dry experimental treatments meant that they differed in statistical power, and we are less likely to detect an effect of the NH<sub>4</sub><sup>+</sup> and NO<sub>3</sub><sup>?</sup> treatments, though they avoid issues of pseudo-replication.
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We have sequenced miRNA libraries from human embryonic, neural and foetal mesenchymal stem cells. We report that the majority of miRNA genes encode mature isomers that vary in size by one or more bases at the 3' and/or 5' end of t...
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We have sequenced miRNA libraries from human embryonic, neural and foetal mesenchymal stem cells. We report that the majority of miRNA genes encode mature isomers that vary in size by one or more bases at the 3' and/or 5' end of the miRNA. Northern blotting for individual miRNAs showed that the proportions of isomiRs expressed by a single miRNA gene often differ between cell and tissue types. IsomiRs were readily co-immunoprecipitated with Argonaute proteins in vivo and were active in luciferase assays, indicating that they are functional. Bioinformatics analysis predicts substantial differences in targeting between miRNAs with minor 5' differences and in support of this we report that a 5' isomiR-9-1 gained the ability to inhibit the expression of DNMT3B and NCAM2 but lost the ability to inhibit CDH1 in vitro. This result was confirmed by the use of isomiR-specific sponges. Our analysis of the miRGator database indicates that a small percentage of human miRNA genes express isomiRs as the dominant transcript in certain cell types and analysis of miRBase shows that 5' isomiRs have replaced canonical miRNAs many times during evolution. This strongly indicates that isomiRs are of functional importance and have contributed to the evolution of miRNA genes.
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We have sequenced miRNA libraries from human embryonic, neural and foetal mesenchymal stem cells. We report that the majority of miRNA genes encode mature isomers that vary in size by one or more bases at the 3' and/or 5' end of t...
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We have sequenced miRNA libraries from human embryonic, neural and foetal mesenchymal stem cells. We report that the majority of miRNA genes encode mature isomers that vary in size by one or more bases at the 3' and/or 5' end of the miRNA. Northern blotting for individual miRNAs showed that the proportions of isomiRs expressed by a single miRNA gene often differ between cell and tissue types. IsomiRs were readily co-immunoprecipitated with Argonaute proteins in vivo and were active in luciferase assays, indicating that they are functional. Bioinformatics analysis predicts substantial differences in targeting between miRNAs with minor 5' differences and in support of this we report that a 5' isomiR-9-1 gained the ability to inhibit the expression of DNMT3B and NCAM2 but lost the ability to inhibit CDH1 in vitro. This result was confirmed by the use of isomiR-specific sponges. Our analysis of the miRGator database indicates that a small percentage of human miRNA genes express isomiRs as the dominant transcript in certain cell types and analysis of miRBase shows that 5' isomiRs have replaced canonical miRNAs many times during evolution. This strongly indicates that isomiRs are of functional importance and have contributed to the evolution of miRNA genes.
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The manufacturer of olaratumab (Lartruvo(A (R))), Eli Lilly & Company Limited, submitted evidence for the clinical and cost effectiveness of this drug, in combination with doxorubicin, for untreated advanced soft tissue sarcoma (STS) not amenable to surgery or radiotherapy, as part of the National Institute for Health and Care Excellence (NICE) Single Technology Appraisal process. The Peninsula Technology Assessment Group, commissioned to act as the Evidence Review Group (ERG), critically reviewed the company's submission. Clinical effectiveness evidence for the company's analysis was derived from an open-label, randomised controlled trial, JGDG. The analysis was based on a partitioned survival model with a time horizon of 25 years, and the perspective was of the UK National Health Service (NHS) and Personal Social Services. Costs and benefits were discounted at 3.5% per year. Given the available evidence, olaratumab is likely to meet NICE's end-of-life criteria. To improve the cost effectiveness of olaratumab, the company offered a discount through a Commercial Access Agreement (CAA) with the NHS England. When the discount was applied, the mean base-case and probabilistic incremental cost-effectiveness ratios (ICERs) for olaratumab plus doxorubicin versus the standard-of-care doxorubicin were A 46,076 pound and A 47,127 pound per quality-adjusted life-year (QALY) gained, respectively; the probability of this treatment being cost effective at the willingness-to-pay threshold of A 50,000 pound per QALY gained, applicable to end-of-life treatments, was ...
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The manufacturer of olaratumab (Lartruvo(A (R))), Eli Lilly & Company Limited, submitted evidence for the clinical and cost effectiveness of this drug, in combination with doxorubicin, for untreated advanced soft tissue sarcoma (STS) not amenable to surgery or radiotherapy, as part of the National Institute for Health and Care Excellence (NICE) Single Technology Appraisal process. The Peninsula Technology Assessment Group, commissioned to act as the Evidence Review Group (ERG), critically reviewed the company's submission. Clinical effectiveness evidence for the company's analysis was derived from an open-label, randomised controlled trial, JGDG. The analysis was based on a partitioned survival model with a time horizon of 25 years, and the perspective was of the UK National Health Service (NHS) and Personal Social Services. Costs and benefits were discounted at 3.5% per year. Given the available evidence, olaratumab is likely to meet NICE's end-of-life criteria. To improve the cost effectiveness of olaratumab, the company offered a discount through a Commercial Access Agreement (CAA) with the NHS England. When the discount was applied, the mean base-case and probabilistic incremental cost-effectiveness ratios (ICERs) for olaratumab plus doxorubicin versus the standard-of-care doxorubicin were A 46,076 pound and A 47,127 pound per quality-adjusted life-year (QALY) gained, respectively; the probability of this treatment being cost effective at the willingness-to-pay threshold of A 50,000 pound per QALY gained, applicable to end-of-life treatments, was 0.54. The respective ICERs from the ERG's analysis were approximately A 60,000 pound/QALY gained, and the probability of the treatment being cost effective was 0.21. In August 2017, the NICE Appraisal Committee recommended olaratumab in combination with doxorubicin for this indication for use via the UK Cancer Drugs Fund under the agreed CAA until further evidence being collected in the ongoing phase III trial-ANNOUNCE-becomes available in December 2020.
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