Cohomology for infinitesimal unipotent algebraic and quantum groups

In this paper we study the structure of cohomology spaces for the Frobenius kernels of unipotent and parabolic algebraic group schemes and of their quantum analogs. Given a simple algebraic group $G$, a parabolic subgroup $P_J$, and its unipotent radical $U_J$, we determine the ring structure of the cohomology ring $H^\bullet((U_J)_1,k)$. We also obtain new results on computing $H^\bullet((P_J)_1,L(\lambda))$ as an $L_J$-module where $L(\lambda)$ is a simple $G$-module with high weight $\lambda$ in the closure of the bottom $p$-alcove. Finally, we provide generalizations of all our results to the quantum situation.Comment: 18 pages. Some proofs streamlined over previous version. Additional details added to some proofs in Section

The age-dependent associations of white matter hyperintensities and neurofilament light in early- and late-stage Alzheimer's disease

Neurofilament light (NFL) is an emerging marker of axonal degeneration. This study investigated the relationship between white matter hyperintensities (WMHs) and plasma NFL in a large elderly cohort with, and without, cognitive impairment. We used the Alzheimer's Disease Neuroimaging Initiative and included 163 controls, 103 participants with a significant memory concern, 279 with early mild cognitive impairment (EMCI), 152 with late mild cognitive impairment (LMCI), and 130 with Alzheimer's disease, with 3T MRI and plasma NFL data. Multiple linear regression models examined the relationship between WMHs and NFL, with and without age adjustment. We used smoking status, history of hypertension, history of diabetes, and BMI as additional covariates to examine the effect of vascular risk. We found increases of between 20% and 41% in WMH volume per 1SD increase in NFL in significant memory concern, early mild cognitive impairment, late mild cognitive impairment, and Alzheimer's disease groups (p < 0.02). Marked attenuation of the positive associations between WMHs and NFL were seen after age adjustment, suggesting that a significant proportion of the association between NFL and WMHs is age-related. No effect of vascular risk was observed. These results are supportive of a link between WMH and axonal degeneration in early to late disease stages, in an age-dependent, but vascular risk-independent manner

Recurrent delirium over 12 months predicts dementia: results of the Delirium and Cognitive Impact in Dementia (DECIDE) study.

BACKGROUND: Delirium is common, distressing and associated with poor outcomes. Previous studies investigating the impact of delirium on cognitive outcomes have been limited by incomplete ascertainment of baseline cognition or lack of prospective delirium assessments. This study quantified the association between delirium and cognitive function over time by prospectively ascertaining delirium in a cohort aged ≥ 65 years in whom baseline cognition had previously been established. METHODS: For 12 months, we assessed participants from the Cognitive Function and Ageing Study II-Newcastle for delirium daily during hospital admissions. At 1-year, we assessed cognitive decline and dementia in those with and without delirium. We evaluated the effect of delirium (including its duration and number of episodes) on cognitive function over time, independently of baseline cognition and illness severity. RESULTS: Eighty two of 205 participants recruited developed delirium in hospital (40%). One-year outcome data were available for 173 participants: 18 had a new dementia diagnosis, 38 had died. Delirium was associated with cognitive decline (-1.8 Mini-Mental State Examination points [95% CI -3.5 to -0.2]) and an increased risk of new dementia diagnosis at follow up (OR 8.8 [95% CI 1.9-41.4]). More than one episode and more days with delirium (>5 days) were associated with worse cognitive outcomes. CONCLUSIONS: Delirium increases risk of future cognitive decline and dementia, independent of illness severity and baseline cognition, with more episodes associated with worse cognitive outcomes. Given that delirium has been shown to be preventable in some cases, we propose that delirium is a potentially modifiable risk factor for dementia

Patterns of progressive atrophy vary with age in Alzheimer's disease patients

Age is not only the greatest risk factor for Alzheimer's disease (AD) but also a key modifier of disease presentation and progression. Here, we investigate how longitudinal atrophy patterns vary with age in mild cognitive impairment (MCI) and AD. Data comprised serial longitudinal 1.5-T magnetic resonance imaging scans from 153 AD, 339 MCI, and 191 control subjects. Voxel-wise maps of longitudinal volume change were obtained and aligned across subjects. Local volume change was then modeled in terms of diagnostic group and an interaction between group and age, adjusted for total intracranial volume, white-matter hyperintensity volume, and apolipoprotein E genotype. Results were significant at p < 0.05 with family-wise error correction for multiple comparisons. An age-by-group interaction revealed that younger AD patients had significantly faster atrophy rates in the bilateral precuneus, parietal, and superior temporal lobes. These results suggest younger AD patients have predominantly posterior progressive atrophy, unexplained by white-matter hyperintensity, apolipoprotein E, or total intracranial volume. Clinical trials may benefit from adapting outcome measures for patient groups with lower average ages, to capture progressive atrophy in posterior cortices

Use of low-dose oral theophylline as an adjunct to inhaled corticosteroids in preventing exacerbations of chronic obstructive pulmonary disease: study protocol for a randomised controlled trial.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is associated with high morbidity, mortality, and health-care costs. An incomplete response to the anti-inflammatory effects of inhaled corticosteroids is present in COPD. Preclinical work indicates that 'low dose' theophylline improves steroid responsiveness. The Theophylline With Inhaled Corticosteroids (TWICS) trial investigates whether the addition of 'low dose' theophylline to inhaled corticosteroids has clinical and cost-effective benefits in COPD. METHOD/DESIGN: TWICS is a randomised double-blind placebo-controlled trial conducted in primary and secondary care sites in the UK. The inclusion criteria are the following: an established predominant respiratory diagnosis of COPD (post-bronchodilator forced expiratory volume in first second/forced vital capacity [FEV1/FVC] of less than 0.7), age of at least 40 years, smoking history of at least 10 pack-years, current inhaled corticosteroid use, and history of at least two exacerbations requiring treatment with antibiotics or oral corticosteroids in the previous year. A computerised randomisation system will stratify 1424 participants by region and recruitment setting (primary and secondary) and then randomly assign with equal probability to intervention or control arms. Participants will receive either 'low dose' theophylline (Uniphyllin MR 200 mg tablets) or placebo for 52 weeks. Dosing is based on pharmacokinetic modelling to achieve a steady-state serum theophylline of 1-5 mg/l. A dose of theophylline MR 200 mg once daily (or placebo once daily) will be taken by participants who do not smoke or participants who smoke but have an ideal body weight (IBW) of not more than 60 kg. A dose of theophylline MR 200 mg twice daily (or placebo twice daily) will be taken by participants who smoke and have an IBW of more than 60 kg. Participants will be reviewed at recruitment and after 6 and 12 months. The primary outcome is the total number of participant-reported COPD exacerbations requiring oral corticosteroids or antibiotics during the 52-week treatment period. DISCUSSION: The demonstration that 'low dose' theophylline increases the efficacy of inhaled corticosteroids in COPD by reducing the incidence of exacerbations is relevant not only to patients and clinicians but also to health-care providers, both in the UK and globally. TRIAL REGISTRATION: Current Controlled Trials ISRCTN27066620 was registered on Sept. 19, 2013, and the first subject was randomly assigned on Feb. 6, 2014

Predicting consumer biomass, size-structure, production, catch potential, responses to fishing and associated uncertainties in the world's marine ecosystems

Existing estimates of fish and consumer biomass in the world’s oceans are disparate. This creates uncertainty about the roles of fish and other consumers in biogeochemical cycles and ecosystem processes, the extent of human and environmental impacts and fishery potential. We develop and use a size-based macroecological model to assess the effects of parameter uncertainty on predicted consumer biomass, production and distribution. Resulting uncertainty is large (e.g. median global biomass 4.9 billion tonnes for consumers weighing 1 g to 1000 kg; 50% uncertainty intervals of 2 to 10.4 billion tonnes; 90% uncertainty intervals of 0.3 to 26.1 billion tonnes) and driven primarily by uncertainty in trophic transfer efficiency and its relationship with predator-prey body mass ratios. Even the upper uncertainty intervals for global predictions of consumer biomass demonstrate the remarkable scarcity of marine consumers, with less than one part in 30 million by volume of the global oceans comprising tissue of macroscopic animals. Thus the apparently high densities of marine life seen in surface and coastal waters and frequently visited abundance hotspots will likely give many in society a false impression of the abundance of marine animals. Unexploited baseline biomass predictions from the simple macroecological model were used to calibrate a more complex size- and trait-based model to estimate fisheries yield and impacts. Yields are highly dependent on baseline biomass and fisheries selectivity. Predicted global sustainable fisheries yield increases ≈4 fold when smaller individuals (< 20 cm from species of maximum mass < 1kg) are targeted in all oceans, but the predicted yields would rarely be accessible in practice and this fishing strategy leads to the collapse of larger species if fishing mortality rates on different size classes cannot be decoupled. Our analyses show that models with minimal parameter demands that are based on a few established ecological principles can support equitable analysis and comparison of diverse ecosystems. The analyses provide insights into the effects of parameter uncertainty on global biomass and production estimates, which have yet to be achieved with complex models, and will therefore help to highlight priorities for future research and data collection. However, the focus on simple model structures and global processes means that non-phytoplankton primary production and several groups, structures and processes of ecological and conservation interest are not represented. Consequently, our simple models become increasingly less useful than more complex alternatives when addressing questions about food web structure and function, biodiversity, resilience and human impacts at smaller scales and for areas closer to coasts

Use of an Outbred Rat Hepacivirus Challenge Model for Design and Evaluation of Efficacy of Different Immunization Strategies for Hepatitis C Virus

BACKGROUND AND AIMS: The lack of immunocompetent small animal models for hepatitis C virus (HCV) has greatly hindered the development of effective vaccines. Using rodent hepacivirus (RHV), a homolog of HCV that shares many characteristics of HCV infection, we report the development and application of an RHV outbred rat model for HCV vaccine development. APPROACH AND RESULTS: Simian adenovirus (ChAdOx1) encoding a genetic immune enhancer (truncated shark class II invariant chain) fused to the nonstructural (NS) proteins NS3-NS5B from RHV (ChAd-NS) was used to vaccinate Sprague-Dawley rats, resulting in high levels of cluster of differentiation 8-positive (CD8+ ) T-cell responses. Following RHV challenge (using 10 or 100 times the minimum infectious dose), 42% of vaccinated rats cleared infection within 6-8 weeks, while all mock vaccinated controls became infected with high-level viremia postchallenge. A single, 7-fold higher dose of ChAd-NS increased efficacy to 67%. Boosting with ChAd-NS or with a plasmid encoding the same NS3-NS5B antigens increased efficacy to 100% and 83%, respectively. A ChAdOx1 vector encoding structural antigens (ChAd-S) was also constructed. ChAd-S alone showed no efficacy. Strikingly, when combined with ChAd-NS, ChAD-S produced 83% efficacy. Protection was associated with a strong CD8+ interferon gamma-positive recall response against NS4. Next-generation sequencing of a putative RHV escape mutant in a vaccinated rat identified mutations in both identified immunodominant CD8+ T-cell epitopes. CONCLUSIONS: A simian adenovirus vector vaccine strategy is effective at inducing complete protective immunity in the rat RHV model. The RHV Sprague-Dawley rat challenge model enables comparative testing of vaccine platforms and antigens and identification of correlates of protection and thereby provides a small animal experimental framework to guide the development of an effective vaccine for HCV in humans

Serotonin and corticosterone rhythms in mice exposed to cigarette smoke and in patients with COPD:implication for COPD-associated neuropathogenesis

The circadian timing system controls daily rhythms of physiology and behavior, and disruption of clock function can trigger stressful life events. Daily exposure to cigarette smoke (CS) can lead to alteration in diverse biological and physiological processes. Smoking is associated with mood disorders, including depression and anxiety. Patients with chronic obstructive pulmonary disease (COPD) have abnormal circadian rhythms, reflected by daily changes in respiratory symptoms and lung function. Corticosterone (CORT) is an adrenal steroid that plays a considerable role in stress and anti-inflammatory responses. Serotonin (5-hydroxytryptamine; 5HT) is a neurohormone, which plays a role in sleep/wake regulation and affective disorders. Secretion of stress hormones (CORT and 5HT) is under the control of the circadian clock in the suprachiasmatic nucleus. Since smoking is a contributing factor in the development of COPD, we hypothesize that CS can affect circadian rhythms of CORT and 5HT secretion leading to sleep and mood disorders in smokers and patients with COPD. We measured the daily rhythms of plasma CORT and 5HT in mice following acute (3 d), sub-chronic (10 d) or chronic (6 mo) CS exposure and in plasma from non-smokers, smokers and patients with COPD. Acute and chronic CS exposure affected both the timing (peak phase) and amplitude of the daily rhythm of plasma CORT and 5HT in mice. Acute CS appeared to have subtle time-dependent effects on CORT levels but more pronounced effects on 5HT. As compared with CORT, plasma 5HT was slightly elevated in smokers but was reduced in patients with COPD. Thus, the effects of CS on plasma 5HT were consistent between mice and patients with COPD. Together, these data reveal a significant impact of CS exposure on rhythms of stress hormone secretion and subsequent detrimental effects on cognitive function, depression-like behavior, mood/anxiety and sleep quality in smokers and patients with COPD