Neuroinflammation in Multiple System Atrophy: Response to and Cause of α-Synuclein Aggregation

Multiple system atrophy (MSA) is a progressive neurodegenerative disease presenting with combinations of autonomic dysfunction, parkinsonism, cerebellar ataxia and/or pyramidal signs. Oligodendroglial cytoplasmic inclusions (GCIs) rich in α-synuclein (α-syn) constitute the disease hallmark, accompanied by neuronal loss and activation of glial cells which indicate neuroinflammation. Recent studies demonstrate that α-syn may be released from degenerating neurons to mediate formation of abnormal inclusion bodies and to induce neuroinflammation which, interestingly, might also favor the formation of intracellular α-syn aggregates as a consequence of cytokine release and the shift to a pro-inflammatory environment. Here, we critically review the relationships between α-syn and astrocytic and microglial activation in MSA to explore the potential of therapeutics which target neuroinflammation.9 page(s

Multi-level Contextual Type Theory

Contextual type theory distinguishes between bound variables and meta-variables to write potentially incomplete terms in the presence of binders. It has found good use as a framework for concise explanations of higher-order unification, characterize holes in proofs, and in developing a foundation for programming with higher-order abstract syntax, as embodied by the programming and reasoning environment Beluga. However, to reason about these applications, we need to introduce meta^2-variables to characterize the dependency on meta-variables and bound variables. In other words, we must go beyond a two-level system granting only bound variables and meta-variables. In this paper we generalize contextual type theory to n levels for arbitrary n, so as to obtain a formal system offering bound variables, meta-variables and so on all the way to meta^n-variables. We obtain a uniform account by collapsing all these different kinds of variables into a single notion of variabe indexed by some level k. We give a decidable bi-directional type system which characterizes beta-eta-normal forms together with a generalized substitution operation.Comment: In Proceedings LFMTP 2011, arXiv:1110.668

Ultralight vector dark matter search using data from the KAGRA O3GK run

Among the various candidates for dark matter (DM), ultralight vector DM can be probed by laser interferometric gravitational wave detectors through the measurement of oscillating length changes in the arm cavities. In this context, KAGRA has a unique feature due to differing compositions of its mirrors, enhancing the signal of vector DM in the length change in the auxiliary channels. Here we present the result of a search for U(1)B−L gauge boson DM using the KAGRA data from auxiliary length channels during the first joint observation run together with GEO600. By applying our search pipeline, which takes into account the stochastic nature of ultralight DM, upper bounds on the coupling strength between the U(1)B−L gauge boson and ordinary matter are obtained for a range of DM masses. While our constraints are less stringent than those derived from previous experiments, this study demonstrates the applicability of our method to the lower-mass vector DM search, which is made difficult in this measurement by the short observation time compared to the auto-correlation time scale of DM

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570