Effects of cholinergic stimulation with pyridostigmine bromide on chronic chagasic cardiomyopathic mice

The aim of the present study was to assess the effects of an anticholinesterase agent, pyridostigmine bromide (Pyrido), on experimental chronic Chagas heart disease in mice. To this end, male C57BL/6J mice noninfected (control:Con) or chronically infected (5 months) with Trypanosoma cruzi (chagasic:Chg) were treated or not (NT) with Pyrido for one month. At the end of this period, electrocardiogram (ECG); cardiac autonomic function; heart histopathology; serum cytokines; and the presence of blood and tissue parasites by means of immunohistochemistry and PCR were assessed. In NT-Chg mice, significant changes in the electrocardiographic, autonomic, and cardiac histopathological profiles were observed confirming a chronic inflammatory response. Treatment with Pyrido in Chagasic mice caused a significant reduction of myocardial inflammatory infiltration, fibrosis, and hypertrophy, which was accompanied by a decrease in serum levels of IFN\u3b3 with no change in IL-10 levels, suggesting a shift of immune response toward an anti-inflammatory profile. Lower nondifferent numbers of parasite DNA copies were observed in both treated and nontreated chagasic mice. In conclusion, our findings confirm the marked neuroimmunomodulatory role played by the parasympathetic autonomic nervous system in the evolution of the inflammatory-immune response to T. cruzi during experimental chronic Chagas heart disease in mice

Multi-year characterisation of the broad-band emission from the intermittent extreme BL Lac 1ES 2344+514

Aims. The BL Lac 1ES 2344+514 is known for temporary extreme properties characterised by a shift of the synchrotron spectral energy distribution (SED) peak energy νsynch, p above 1 keV. While those extreme states have only been observed during high flux levels thus far, additional multi-year observing campaigns are required to achieve a coherent picture. Here, we report the longest investigation of the source from radio to very high energy (VHE) performed so far, focussing on a systematic characterisation of the intermittent extreme states. Methods. We organised a monitoring campaign covering a 3-year period from 2019 to 2021. More than ten instruments participated in the observations in order to cover the emission from radio to VHE. In particular, sensitive X-ray measurements by XMM-Newton, NuSTAR, and AstroSat took place simultaneously with multi-hour MAGIC observations, providing an unprecedented constraint of the two SED components for this blazar. Results. While our results confirm that 1ES 2344+514 typically exhibits νsynch, p > 1 keV during elevated flux periods, we also find periods where the extreme state coincides with low flux activity. A strong spectral variability thus happens in the quiescent state, and is likely caused by an increase in the electron acceleration efficiency without a change in the electron injection luminosity. On the other hand, we also report a strong X-ray flare (among the brightest for 1ES 2344+514) without a significant shift of νsynch, p. During this particular flare, the X-ray spectrum is among the softest of the campaign. It unveils complexity in the spectral evolution, where the common harder-when-brighter trend observed in BL Lacs is violated. By combining Swift-XRT and Swift-UVOT measurements during a low and hard X-ray state, we find an excess of the UV flux with respect to an extrapolation of the X-ray spectrum to lower energies. This UV excess implies that at least two regions significantly contribute to the infrared/optical/ultraviolet/X-ray emission. Using the simultaneous MAGIC, XMM-Newton, NuSTAR, and AstroSat observations, we argue that a region possibly associated with the 10 GHz radio core may explain such an excess. Finally, we investigate a VHE flare, showing an absence of simultaneous variability in the 0.3−2 keV band. Using time-dependent leptonic modelling, we show that this behaviour, in contradiction to single-zone scenarios, can instead be explained by a two-component model.publishedVersio

The variability patterns of the TeV blazar PG 1553 + 113 from a decade of MAGIC and multiband observations

PG 1553 + 113 is one of the few blazars with a convincing quasi-periodic emission in the gamma-ray band. The source is also a very high energy (VHE; >100 GeV) gamma-ray emitter. To better understand its properties and identify the underlying physical processes driving its variability, the MAGIC Collaboration initiated a multiyear, multiwavelength monitoring campaign in 2015 involving the OVRO 40-m and Medicina radio telescopes, REM, KVA, and the MAGIC telescopes, Swift and Fermi satellites, and the WEBT network. The analysis presented in this paper uses data until 2017 and focuses on the characterization of the variability. The gamma-ray data show a (hint of a) periodic signal compatible with literature, but the X-ray and VHE gamma-ray data do not show statistical evidence for a periodic signal. In other bands, the data are compatible with the gamma-ray period, but with a relatively high p-value. The complex connection between the low- and high-energy emission and the non-monochromatic modulation and changes in flux suggests that a simple one-zone model is unable to explain all the variability. Instead, a model including a periodic component along with multiple emission zones is required.publishedVersio

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele