Microtubule stabilization reduces amyloid pathology and improves synaptic/memory deficits in APP/PS1 mice

Aims: Cognitive decline in Alzheimer's disease (AD) is highly related to synaptic/neuronal loss. Tau hyperphosphorylation destabilizes microtubules leading to axonal transport failure and generation of dystrophic neurites, thus contributing to synaptic dysfunction. The effect of microtubule stabilization on amyloid-beta pathology has not been assessed in vivo yet. This study evaluated the effect of the microtubule-stabilizing agent, Epothilone D (EpoD) in the pathology of an amyloidogenic mouse model. Methods: APP751SL/PS1M146L mice (3-month-old) were treated weekly with intraperitoneal injections of EpoD (2 mg/kg) or vehicle for 3 months. For memory performance, animals were tested on the objectrecognition, Y-maze and Morris water maze. Hippocampal proteinopathies were quantified by image analysis after immunostaining. Somatostatin (SOM)-numerical density was calculated by stereology. APPswe-N2a cells were treated with EpoD 100nM for 12/24 hours. Protein levels were analysed by Western/dot-blot. Results: EpoD-treated mice improved their performance of cognitive tests, while hippocampal phospho-tau and Ab (especially oligomers) accumulation decreased, together with synaptic/neuritic pathology. Remarkably, EpoD exerted a neuroprotective effect on SOM-interneurons, a highly AD-vulnerable GABAergic subpopulation. Conclusions: EpoD improved microtubule dynamics and axonal transport in an AD-like context, reducing tau and Ab accumulation and promoting neuronal and cognitive protection, underlining the cross-talk between cytoskeleton pathology and proteinopathy. Therefore, microtubule-stabilizing drugs could be candidates for slowing AD at both tau and Ab pathologies.Supported by PI18/01557 (to AG) and PI18/01556 (to JV) grants from ISCiii of Spain, co-financed by FEDER funds (European Union), CIBERNED collaborative grant (to AG and JV), and by PPIT.UMA.B1.2017/26 grant (to RSV). Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Campus source to sink wastewater surveillance of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)

Wastewater-based surveillance (WBS) offers an aggregate, and cost-effective approach for tracking infectious disease outbreak prevalence within communities, that provides data on community health complementary to individual clinical testing. This study reports on a 16-month WBS initiative on a university campus in England, UK, assessing the presence of SARS-CoV-2 in sewers from large buildings, downstream sewer locations, raw wastewater, partially treated and treated effluents. Key findings include the detection of the Alpha (B.1.1.7) variant in wastewater, with 70 % of confirmed campus cases correlating with positive wastewater samples. Notably, ammonium nitrogen (NH4-N) levels showed a positive correlation (ρ = 0.543, p < 0.01) with virus levels at the large building scale, a relationship not observed at the sewer or wastewater treatment works (WWTW) levels due to dilution. The WWTW was compliant to wastewater standards, but the secondary treatment processes were not efficient for virus removal as SARS-CoV-2 was consistently detected in treated discharges. Tools developed through WBS can also be used to enhance traditional environmental monitoring of aquatic systems. This study provides a detailed source-to-sink evaluation, emphasizing the critical need for the widespread application and improvement of WBS. It showcases WBS utility and reinforces the ongoing challenges posed by viruses to receiving water quality

Monitoring occurrence of SARS-CoV-2 in school populations: A wastewater-based approach

Clinical testing of children in schools is challenging, with economic implications limiting its frequent use as a monitoring tool of the risks assumed by children and staff during the COVID-19 pandemic. Here, a wastewater-based epidemiology approach has been used to monitor 16 schools (10 primary, 5 secondary and 1 post-16 and further education) in England. A total of 296 samples over 9 weeks have been analysed for N1 and E genes using qPCR methods. Of the samples returned, 47.3% were positive for one or both genes with a detection frequency in line with the respective local community. WBE offers a low cost, non-invasive approach for supplementing clinical testing and can provide longitudinal insights that are impractical with traditional clinical testing

Wastewater monitoring for detection of public health markers during the COVID-19 pandemic: Near-source monitoring of schools in England over an academic year

Background Schools are high-risk settings for infectious disease transmission. Wastewater monitoring for infectious diseases has been used to identify and mitigate outbreaks in many near-source settings during the COVID-19 pandemic, including universities and hospitals but less is known about the technology when applied for school health protection. This study aimed to implement a wastewater surveillance system to detect SARS-CoV-2 and other public health markers from wastewater in schools in England. Methods A total of 855 wastewater samples were collected from 16 schools (10 primary, 5 secondary and 1 post-16 and further education) over 10 months of school term time. Wastewater was analysed for SARS-CoV-2 genomic copies of N1 and E genes by RT-qPCR. A subset of wastewater samples was sent for genomic sequencing, enabling determination of the presence of SARS-CoV-2 and emergence of variant(s) contributing to COVID-19 infections within schools. In total, >280 microbial pathogens and >1200 AMR genes were screened using RT-qPCR and metagenomics to consider the utility of these additional targets to further inform on health threats within the schools. Results We report on wastewater-based surveillance for COVID-19 within English primary, secondary and further education schools over a full academic year (October 2020 to July 2021). The highest positivity rate (80.4%) was observed in the week commencing 30th November 2020 during the emergence of the Alpha variant, indicating most schools contained people who were shedding the virus. There was high SARS-CoV-2 amplicon concentration (up to 9.2x106 GC/L) detected over the summer term (8th June - 6th July 2021) during Delta variant prevalence. The summer increase of SARS-CoV-2 in school wastewater was reflected in age-specific clinical COVID-19 cases. Alpha variant and Delta variant were identified in the wastewater by sequencing of samples collected from December to March and June to July, respectively. Lead/lag analysis between SARS-CoV-2 concentrations in school and WWTP data sets show a maximum correlation between the two-time series when school data are lagged by two weeks. Furthermore, wastewater sample enrichment coupled with metagenomic sequencing and rapid informatics enabled the detection of other clinically relevant viral and bacterial pathogens and AMR. Conclusions Passive wastewater monitoring surveillance in schools can identify cases of COVID-19. Samples can be sequenced to monitor for emerging and current variants of concern at the resolution of school catchments. Wastewater based monitoring for SARS-CoV-2 is a useful tool for SARS-CoV-2 passive surveillance and could be applied for case identification and containment, and mitigation in schools and other congregate settings with high risks of transmission. Wastewater monitoring enables public health authorities to develop targeted prevention and education programmes for hygiene measures within undertested communities across a broad range of use cases

Distinct Microglial Responses in Two Transgenic Murine Models of TAU Pathology

Microglial cells are crucial players in the pathological process of neurodegenerative diseases, such as Alzheimer’s disease (AD). Microglial response in AD has been principally studied in relation to amyloid-beta pathology but, comparatively, little is known about inflammatory processes associated to tau pathology. In the hippocampus of AD patients, where tau pathology is more prominent than amyloid-beta pathology, a microglial degenerative process has been reported. In this work, we have directly compared the microglial response in two different transgenic tau mouse models: ThyTau22 and P301S. Surprisingly, these two models showed important differences in the microglial profile and tau pathology. Where ThyTau22 hippocampus manifested mild microglial activation, P301S mice exhibited a strong microglial response in parallel with high phospho-tau accumulation. This differential phospho-tau expression could account for the different microglial response in these two tau strains. However, soluble (S1) fractions from ThyTau22 hippocampus presented relatively high content of soluble phospho-tau (AT8-positive) and were highly toxic for microglial cells in vitro, whereas the correspondent S1 fractions from P301S mice displayed low soluble phospho-tau levels and were not toxic for microglial cells. Therefore, not only the expression levels but the aggregation of phospho-tau should differ between both models. In fact, most of tau forms in the P301S mice were aggregated and, in consequence, forming insoluble tau species. We conclude that different factors as tau mutations, accumulation, phosphorylation, and/or aggregation could account for the distinct microglial responses observed in these two tau models. For this reason, deciphering the molecular nature of toxic tau species for microglial cells might be a promising therapeutic approach in order to restore the deficient immunological protection observed in AD hippocampus

Effectiveness and Safety of the Switch from Remicade® to CT-P13 in Patients with Inflammatory Bowel Disease

BACKGROUND AND AIMS: To evaluate the clinical outcomes in patients with IBD after switching from Remicade® to CT-P13 in comparison with patients who maintain Remicade®. METHODS: Patients under Remicade® who were in clinical remission with standard dosage at study entry were included. The ''switch cohort'' [SC] comprised patients who made the switch from Remicade® to CT-P13, and the ''non-switch'' cohort [NC] patients remained under Remicade®. RESULTS: A total of 476 patients were included: 199 [42%] in the SC and 277 [58%] in the NC. The median follow-up was 18 months in the SC and 23 months in the NC [p < 0.01]. Twenty-four out of 277 patients relapsed in the NC; the incidence of relapse was 5% per patient-year. The cumulative incidence of relapse was 2% at 6 months and 10% at 24 months in this group. Thirty-eight out of 199 patients relapsed in the SC; the incidence rate of relapse was 14% per patient-year. The cumulative incidence of relapse was 5% at 6 months and 28% at 24 months. In the multivariate analysis, the switch to CT-P13 was associated with a higher risk of relapse (HR = 3.5, 95% confidence interval [CI] = 2-6). Thirteen percent of patients had adverse events in the NC, compared with 6% in the SC [p < 0.05]. CONCLUSIONS: Switching from Remicade® to CT-P13 might be associated with a higher risk of clinical relapse, although this fact was not supported in our study by an increase in objective markers of inflammation. The nocebo effect might have influenced this result. Switching from Remicade® to CT-P13 was safe

Rapidity and centrality dependence of proton and antiproton production from 197Au + 197Au collisions at √SNN = 130 GeV

We report on the rapidity and centrality dependence of proton and antiproton transverse mass distributions from 197Au + 197Au collisions at sqrt[sNN ]=130 GeV as measured by the STAR experiment at the Relativistic Heavy Ion Collider (RHIC). Our results are from the rapidity and transverse momentum range of |y| <0.5 and 0.35< pt <1.00 GeV/c . For both protons and antiprotons, transverse mass distributions become more convex from peripheral to central collisions demonstrating characteristics of collective expansion. The measured rapidity distributions and the mean transverse momenta versus rapidity are flat within |y| <0.5 . Comparisons of our data with results from model calculations indicate that in order to obtain a consistent picture of the proton (antiproton) yields and transverse mass distributions the possibility of prehadronic collective expansion may have to be taken into account

Pion-Xi correlations in Au-Au collisions at STAR

We present pion-Xi correlation analysis in Au-Au collisions at sqrt(s_NN)= 200 GeV and sqrt(s_NN) = 62.4 GeV, performed using the STAR detector at RHIC. A Xi*(1530) resonance signal is observed for the first time in Au-Au collisions. Experimental data are compared with theoretical predictions. The strength of the Xi* peak is reproduced in the correlation function assuming that pions and Xis emerge from a system in collective expansion.Comment: To appear in the proceedings of 18th Nuclear Physics Division Conference of the EPS (NPDC18),Prague, 23.8.-29.8. 200

Transverse momentum and collision energy dependence of high pTp_{T} hadron suppression in Au+Au collisions at ultrarelativistic energies

We report high statistics measurements of inclusive charged hadron production in Au+Au and p+p collisions at \sqrtsNN=200 GeV. A large, approximately constant hadron suppression is observed in central Au+Au collisions for 5\lt\pT\lt12 GeV/c. The collision energy dependence of the yields and the centrality and \pT dependence of the suppression provide stringent constraints on theoretical models of suppression. Models incorporating initial-state gluon saturation or partonic energy loss in dense matter are largely consistent with observations. We observe no evidence of \pT-dependent suppression, which may be expected from models incorporating jet attentuation in cold nuclear matter or scattering of fragmentation hadrons.Comment: Final journal version. Data tables for figures may be downloaded from the STAR home page: http://www.star.bnl.gov --> Publications --> Access to STAR published dat

Particle-type dependence of azimuthal anisotropy and nuclear modification of particle production in Au+Au collisions at s(NN)**(1/2) = 200-GeV

We present STAR measurements of the azimuthal anisotropy parameter $v_2$ and the binary-collision scaled centrality ratio $R_{CP}$ for kaons and lambdas ($\Lambda+\bar{\Lambda}$) at mid-rapidity in Au+Au collisions at $\sqrt{s_{_{NN}}}=200$ GeV. In combination, the $v_2$ and $R_{CP}$ particle-type dependencies contradict expectations from partonic energy loss followed by standard fragmentation in vacuum. We establish $p_T \approx 5$ GeV/c as the value where the centrality dependent baryon enhancement ends. The $K_S^0$ and $\Lambda+\bar{\Lambda}$ $v_2$ values are consistent with expectations of constituent-quark-number scaling from models of hadron fromation by parton coalescence or recombination.Comment: 6 pages, 4 figures, 1 table. As published in PRL on Feb. 2, 2004; Significant revisions have been made to the text and color has been added to plot