Abstract Increasing evidence indicates that inflammatory responses could play a critical role in the pathogenesis of motor neuron injury in amyotrophic lateral sclerosis (ALS). Recent findings have ...underlined the role of Toll-like receptors (TLRs) and the receptor for advanced glycation endproducts (RAGE) in the regulation of both innate and adaptive immunity in different pathologies associated with neuroinflammation. In the present study we investigated the expression and cellular distribution of TLR2, TLR4, RAGE and their endogenous ligand high mobility group box 1 (HMGB1) in the spinal cord of control ( n =6) and sporadic ALS ( n =12) patients. The immunohistochemical analysis of TLR2, TLR4 and RAGE showed increased expression in reactive glial cells in both gray (ventral horn) and white matter of ALS spinal cord. TLR2 was predominantly detected in cells of the microglia/macrophage lineage, whereas the TLR4 and RAGE was strongly expressed in astrocytes. Real-time quantitative PCR analysis confirmed the increased expression of both TLR2 and TLR4 and HMGB1 mRNA level in ALS patients. In ALS spinal cord, HMGB1 signal is increased in the cytoplasm of reactive glia, indicating a possible release of this molecule from glial cells. Our findings show increased expression of TLR2, TLR4, RAGE and HMGB1 in reactive glia in human ALS spinal cord, suggesting activation of the TLR/RAGE signaling pathways. The activation of these pathways may contribute to the progression of inflammation, resulting in motor neuron injury. In this context, future studies, using animal models, will be important to achieve a better understanding of these signaling pathways in ALS in view of the development of new therapeutic strategies.
A
bstract
The kaon sector is characterised by several processes which are under active investigation across different experiments. In this work, we present the global picture that emerges from a ...study of the different decay modes. We begin by revisiting the theoretical component of these decays and providing up-to-date predictions of the Standard Model as well as the corresponding uncertainties. Several new features emerge, in particular for
K
S,L
→
μ
μ
¯
, and are presented in considerable detail. This offers an ideal platform for extracting the parameter space supported by the existing data. Motivated by possible lepton flavour universality violation in
B
decays, we investigate such Beyond the Standard Model effects also in rare kaon decays. Without loss of generality, our primary analyses correspond to the paradigm where the Wilson coefficients for operators involving tau leptons are chosen to be equal to that involving the muon, i.e.
δC
τ
=
δC
μ
. We conclude by presenting the possible picture that can be achieved towards the end of the run of data accumulation in the planned experiments. This includes assumptions on possible sensitivity goals that the experiments can aim to achieve, in order to extract the kind of physics highlighted in this paper.
A
bstract
We consider a color octet scalar particle and its exotic decay in the channel gluon-
γ
using an effective Lagrangian description for its strong and electromagnetic interactions. Such a ...state is present in many extensions of the Standard Model, and in particular in composite Higgs models with top partial compositeness, where couplings to photons arise via the Wess-Zumino-Witten term. We find that final states with one or two photons allow for a better reach at the LHC, even for small branching ratios. Masses up to 1
.
2 TeV can be probed at the HL-LHC by use of all final states. Finally, we estimate the sensitivity of the hadronic FCC.
We investigate the production of heavy colored scalars and vectors and their relevance at the LHC for the study of vectorlike quarks (T). These colored states (C) are present in a large number of ...extensions of the standard model, in particular, in composite models and in extradimensional models. Assuming that these bosonic states are heavier than the vectorlike quarks (VLQ), we consider their production through the process pp→C→tT. Large QCD production cross sections for C enable us to probe heavier masses for the VLQ, thereby allowing us to put stronger limits on the vectorlike quarks which are produced in their decay chain. We adopt a universal analysis strategy by including leptons under the classification of “jets,” thereby limiting the bias towards a specific combination of final state. We also study the possibility of disentangling these scenarios from supersymmetric extensions of the standard model by using simple discriminants based on jet multiplicity and missing energy. We demonstrate that a simple set of cuts is sufficient to disentangle the VLQ signal from the backgrounds. In models with a moderate B.R.(C→Tt), the analysis enables one to get a hint of VLQ masses as heavy as 3 TeV.
The Tera-Z phase of future e+e− colliders, FCC-ee and CEPC, is a gold mine for exploring Z portal physics. We focus on axionlike particles (ALPs) that can be produced via Z decays with a ...monochromatic photon. As a template model, we consider composite Higgs models with a light pseudoscalar that couples through the Wess-Zumino-Witten term to the electroweak gauge bosons. For both photophilic and photophobic cases, we show that the Tera-Z can probe composite scales up to 100s of TeV, well beyond the capability of the LHC and current precision physics. Our results also apply to generic ALPs and, in particular, severely constrain models that explain the muon g−2 anomaly.
Indirect searches have the potential to probe scales beyond the realm of direct searches. In this paper, we consider the implications of two parity violating experiments: weak charge of proton QWp ...and the Caesium atom QWCs on the solutions to lepton flavor nonuniversality violations in the decay of B mesons. Working in a generic implementation of a minimal Z′ model, we assume the primary contribution being due to the electron to facilitate comparison with the low q2 parity violating experiments. We demonstrate that the conclusion is characterized by different limiting behavior depending on the chirality of the lepton current. The correlation developed in this study demonstrates the effectiveness in studying the synergy between different experiments leading to a deeper understanding of the interpretation of the existing data. It is shown that a possible future improvement in the parity violating experiments can have far reaching implications in the context of direct searches. We also comment on the prospect of addition of the muon to the fits and the role it plays in ameliorating the constraints on models of Z′. This offers a complimentary understanding of the pattern of the coupling of the new physics to the leptons, strongly suggesting either a muon only or a combination of solutions to the anomalies.
Alpha synuclein (αS) is a ~14 kDa intrinsically disordered protein. Decades of research have increased our knowledge on αS yet its physiological function remains largely elusive. The conversion of ...monomeric αS into oligomers and amyloid fibrils is believed to play a central role of the pathology of Parkinson's disease (PD). It is becoming increasingly clear that the interactions of αS with cellular membranes are important for both αS's functional and pathogenic actions. Therefore, understanding interactions of αS with membranes seems critical to uncover functional or pathological mechanisms. This review summarizes our current knowledge of how physicochemical properties of phospholipid membranes affect the binding and aggregation of αS species and gives an overview of how post-translational modifications and point mutations in αS affect phospholipid membrane binding and protein aggregation. We discuss the disruptive effects resulting from the interaction of αS aggregate species with membranes and highlight current approaches and hypotheses that seek to understand the pathogenic and/or protective role of αS in PD.
•Many different mechanisms have been proposed to contribute to the membrane disrupting properties of αS (aggregates).•The physicochemical membrane properties that support functional αS interactions also enable disruptive toxic interactions.•How combinations of PTMs and PD related αS modifications affect function and aggregate toxicity is underinvestigated.
Life-Space mobility and clinical outcomes in COPD Iyer, Anand S; Wells, James M; Bhatt, Surya P ...
International journal of chronic obstructive pulmonary disease,
01/2018, Letnik:
13
Journal Article
Recenzirano
Odprti dostop
Social isolation is a common experience in patients with COPD but is not captured by existing patient-reported outcomes, and its association with clinical outcomes is unknown.
We prospectively ...enrolled adults with stable COPD who completed the University of Alabama at Birmingham Life Space Assessment (LSA) (range: 0-120, restricted Life-Space mobility: ≤60 and a marker of social isolation in older adults); six-minute walk test (6MWT), and the University of California at San Diego Shortness of Breath Questionnaire, COPD Assessment Test, and Hospital Anxiety and Depression Scale. The occurrence of severe exacerbations (emergency room visit or hospitalization) was recorded by review of the electronic record up to 1 year after enrollment. We determined associations between Life-Space mobility and clinical outcomes using regression analyses.
Fifty subjects had a mean ± SD %-predicted FEV
of 42.9±15.5, and 23 (46%) had restricted Life-Space mobility. After adjusting for age, gender, %-predicted FEV
, comorbidity count, inhaled corticosteroid/long-acting beta
-agonist use, and prior cardiopulmonary rehabilitation, subjects with restricted Life-Space had an increased risk for severe exacerbations (adjusted incidence rate ratio 4.65, 95% CI 1.19-18.23,
=0.03). LSA scores were associated with 6MWD (
=0.50,
<0.001), dyspnea (
=-0.58,
<0.001), quality of life (
=-0.34,
=0.02), and depressive symptoms (
=-0.39,
=0.005).
Restricted Life-Space mobility predicts severe exacerbations and is associated with reduced exercise tolerance, more severe dyspnea, reduced quality of life, and greater depressive symptoms.
Abstract Recent data support the involvement of the endocannabinoid signaling in early brain development, as well as a key role of cannabinoid receptors (CBR) in pathological conditions associated ...with unbalanced neuronal excitability and inflammation. Using immunocytochemistry, we explored the expression and cellular pattern of CBR 1 and 2 (CB1 and CB2) during prenatal human cortical development, as well as in focal malformations of cortical development associated with intractable epilepsy (focal cortical dysplasia; cortical tubers in patients with the tuberous sclerosis complex and glioneuronal tumors). Strong CB1 immunoreactivity was detected in the cortical plate in developing human brain from the earliest stages tested (gestational week 9) and it persisted throughout prenatal development. Both cannabinoid receptors were not detected in neural progenitor cells located in the ventricular zone. Only CB1 was expressed in the subventricular zone and in Cajal–Retzius cells in the molecular zone of the developing neocortex. CB2 was detected in cells of the microglia/macrophage lineage during development. In malformations of cortical development, prominent CB1 expression was demonstrated in dysplastic neurons. Both CBR were detected in balloon/giant cells, but CB2 appeared to be more frequently expressed than CB1 in these cell types. Reactive astrocytes were mainly stained with CB1, whereas cells of the microglia/macrophage lineage were stained with CB2. These findings confirm the early expression pattern of cannabinoid receptors in the developing human brain, suggesting a function for CB1 in the early stages of corticogenesis. The expression patterns in malformations of cortical development highlight the role of cannabinoid receptors as mediators of the endocannabinoid signaling and as potential pharmacological targets to modulate neuronal and glial cell function in epileptogenic developmental pathologies.
miR-146a and miR-155 are key regulators of the innate immune response. We hypothesized that an inflammation-mediated dysregulation of these miRNAs may occur in patients with Down syndrome (DS) and ...Alzheimer's disease (AD).
The miRNA expression patterns were investigated by in situ hybridization in developing hippocampus from controls, patients with DS and in adults with AD pathology (DS and sporadic AD; sAD). Quantitative real-time PCR was employed to evaluate the miRNA levels in the hippocampus of sAD and in mouse models of DS and AD. Both miRNAs were expressed in prenatal human hippocampus. In DS we detected increased miR-146a expression in reactive astrocytes. Increased expression of miR-146a was found in the hippocampus of sAD and negatively correlated with its target IRAK-1. APP/PS1 mice showed a significant increase in the expression of both miRNAs at 11-13 months of age as compared to WT and mice at 3 months. A negative correlation between miR-146a levels and its target TRAF6 was observed in both Ts65Dn and APP/PS1 mice.
These findings suggest a possible involvement of miR-146a and miR-155 in brain development and neurodegeneration. In particular, we provide evidence of a dysregulation of these two immunomodulatory miRNAs in AD with a potential therapeutical implication, deserving further investigation.
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