REM sleep behavior disorder (RBD) Hu, Michele T.
Neurobiology of disease,
September 2020, 2020-09-00, 20200901, 2020-09-01, Letnik:
143
Journal Article
Recenzirano
Odprti dostop
Since its first description in 1986 by Dr. Carlos Schenck, and his group's subsequent report of the delayed emergence of a Parkinsonian disorder in idiopathic RBD patients one decade later, RBD has ...emerged in recent years as one of the most promising markers of prodromal Parkinson's (References 2, 3). RBD is present in 25–58% of patients with Parkinson's disease and up to 90% of those with Dementia with Lewy Bodies (DLB) or Multiple System Atrophy (MSA). In a substantial proportion of these patients RBD onset occurs before motor symptoms. Critically, when seen in isolation, RBD is a highly specific marker of future synucleinopathy: long-term cohort studies indicate that more than 80% of people who develop isolated RBD will go on to develop an alpha-synuclein related neurodegenerative disorder. Recently, the largest ever study of 1280 polysomnographically-diagnosed RBD subjects from 24 International RBD Study Group sleep centres by a single author group, found an overall conversion rate from iRBD to an overt neurodegenerative syndrome of 6.3% per year. RBD is therefore common, representative of a large proportion of sporadic disease, and provides a unique window for the study of prodromal neurodegeneration, whether it be Parkinson's or Dementia.
The VicRK 2-component system of Streptococcus mutans regulates genes associated with cell wall biogenesis and biofilm formation. A putative RNase III–encoding gene (rnc) is located downstream from ...the vicRKX operon. The goals of this study were to investigate the potential role of VicR in the regulation of adjacent downstream genes and evaluate transcription levels of vicR during planktonic and biofilm growth. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to investigate whether vicRKX and adjacent downstream genes were cotranscribed. Binding of purified recombinant VicR protein to promoter regions of vicR, rnc, and syfA genes was confirmed by electrophoretic mobility shift assay and by chromatin immunoprecipitation analyses. VicR antisense (ASvicR) RNA was detected by Northern blotting and qRT-PCR assays. ASvicR overexpression mutants were constructed, and the biofilm biomass was determined by crystal violet microtiter assay. Adjacent downstream genes rnc, smc, syfA, smu.1511, and syfB were cotranscribed with vicRKX. The predicted promoter regions of vicR, rnc, and syfA genes were directly regulated by VicR. An ASvicR RNA transcript was detected upstream of the rnc gene. Expression of the ASvicR RNA transcript was elevated in planktonic cultures and repressed during biofilm growth. In addition, Western blot data showed that expression of the VicR protein decreased by 35% in planktonic as compared with biofilm cultures. Furthermore, we show that overexpression of ASvicR led to a reduction in biofilm formation. The downstream genes rnc, smc, syfA, smu.1511, and syfB are cotranscribed with vicRKX. VicR is autophosphorylated, and rnc and syfA are directly regulated by VicR. Expression of VicR protein correlated inversely with different levels of ASvicR RNA transcript and growth conditions. The biofilm biomass decreased in the ASvicR overexpression mutant. These data suggest a role for the ASvicR RNA transcript in posttranscriptional regulation of VicR protein production in S. mutans.
Background
IL‐25 has been proposed to play a key role in the pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP). This study aimed to evaluate the association of IL‐25 with the ...Th2‐biased inflammatory profiles in CRSwNP.
Methods
Nasal polyp (NP) tissues and control uncinate process tissues were collected from 92 patients with CRSwNP, 20 patients with chronic rhinosinusitis without nasal polyps (CRSsNP), and 16 normal control subjects. IL‐25 expression was examined using immunohistochemistry and immunofluorescence staining, flow cytometry, RT‐qPCR, and ELISA. The inflammatory profiles and clinical characteristics of 2 NP subtypes (IL‐25high and IL‐25low) were evaluated, and the effects of IL‐25 on Th2 cytokine production in cultured dispersed polyp cells were examined in vitro.
Results
The mRNA and protein levels of IL‐25 were significantly increased in the polyp tissues compared with the control uncinate process tissues. The IL‐25high subtype showed greater computed tomography scores, endoscopic scores, and Th2 response. Exposure to IL‐25 activated type 2 innate lymphoid cells and Th2 cells in NP simultaneously which further increased Th2 cytokine production in vitro.
Conclusions
Local IL‐25 plays a crucial role in promoting Th2‐biased inflammatory profiles in NP and may serve as a promising therapeutic target in CRSwNP patients.
The area of thin-film photovoltaics has been overwhelmed by organometal halide perovskites. Unfortunately, serious stability concerns arise with perovskite solar cells. For example, methyl-ammonium ...lead iodide is known to decompose in the presence of water and, more severely, even under inert conditions at elevated temperatures. Here, we demonstrate inverted perovskite solar cells, in which the decomposition of the perovskite is significantly mitigated even at elevated temperatures. Specifically, we introduce a bilayered electron-extraction interlayer consisting of aluminium-doped zinc oxide and tin oxide. We evidence tin oxide grown by atomic layer deposition does form an outstandingly dense gas permeation barrier that effectively hinders the ingress of moisture towards the perovskite and-more importantly-it prevents the egress of decomposition products of the perovskite. Thereby, the overall decomposition of the perovskite is significantly suppressed, leading to an outstanding device stability.
In spite of the immense potential of biodegradable magnesium alloys, the fast degradation rates of Mg-based biomedical implants in the physiological environment impose severe limitations in many ...clinical applications. Consequently, extensive in vitro studies have been carried out to investigate the materials’ performance and fathom the associated mechanisms. Here, an up-to-date review of the in vitro studies on biomedical magnesium alloys in a simulated physiological environment is provided. This review focuses on four topics: (1) materials selection and in vitro biocompatibility of biomedical magnesium alloys; (2) in vitro degradation of biomedical magnesium alloys in simulated physiological environments, specifically discussing corrosion types, degradation rates, corrosion products and impact of the constituents in body fluids on materials degradation; (3) selection of suitable test media for in vitro assessment; and (4) future research trends.
In little more than 30 years, Lyme disease, which is caused by the spirochaete Borrelia burgdorferi, has risen from relative obscurity to become a global public health problem and a prototype of an ...emerging infection. During this period, there has been an extraordinary accumulation of knowledge on the phylogenetic diversity, molecular biology, genetics and host interactions of B. burgdorferi. In this Review, we integrate this large body of information into a cohesive picture of the molecular and cellular events that transpire as Lyme disease spirochaetes transit between their arthropod and vertebrate hosts during the enzootic cycle.
The Lyme disease bacterial pathogen, Borrelia burgdorferi, establishes a long-term infection inside its mammalian hosts. Despite the continued presence of the bacteria in animal models of disease, ...inflammation is transitory and resolves spontaneously. T cells with limited effector functions and the inability to become activated by antigen, termed exhausted T cells, are present in many long-term infections. These exhausted T cells mediate a balance between pathogen clearance and preventing tissue damage resulting from excess inflammation. Exhausted T cells express a variety of immunoinhibitory molecules, including the molecule PD-1. Following B. burgdorferi infection, we found that PD-1 and its ligand PD-L1 are significantly upregulated on CD4+ T cells and antigen presenting cell subsets, respectively. Using mice deficient in PD-1, we found that the PD-1/PD-L1 pathway did not impact bacterial clearance but did impact T cell expansion and accumulation in the ankle joint and popliteal lymph nodes without affecting B cell populations or antibody production, suggesting that the PD-1/PD-L1 pathway may play a role in shaping the T cell populations present in affected tissues.
The cognitive mechanisms underlying apathy in Parkinson's disease are poorly understood. Le Heron et al. report that apathetic patients make decisions about effortful actions differently, and that ...dopamine does not correct this change. This finding sheds light on the causes of apathy, and suggests the importance of non-dopaminergic treatment strategies.
Abstract
Effort-based decision-making is a cognitive process crucial to normal motivated behaviour. Apathy is a common and disabling complication of Parkinson's disease, but its aetiology remains unclear. Intriguingly, the neural substrates associated with apathy also subserve effort-based decision-making in animal models and humans. Furthermore, the dopaminergic system plays a core role in motivating effortful behaviour for reward, and its dysfunction has been proposed to play a crucial role in the aetiology of apathy in Parkinson's disease. We hypothesized that disrupted effort-based decision-making underlies the syndrome of apathy in Parkinson's disease, and that this disruption may be modulated by the dopaminergic system. An effort-based decision-making task was administered to 39 patients with Parkinson's disease, with and without clinical apathy, ON and OFF their normal dopaminergic medications across two separate sessions, as well as 32 healthy age- and gender-matched controls. On a trial-by-trial basis, participants decided whether to accept or reject offers of monetary reward in return for exerting different levels of physical effort via handheld, individually calibrated dynamometers. Effort and reward were manipulated independently, such that offers spanned the full range of effort/reward combinations. Apathy was assessed using the Lille apathy rating scale. Motor effects of the dopamine manipulation were assessed using the Unified Parkinson's Disease Rating Scale part three motor score. The primary outcome variable was choice (accept/decline offer) analysed using a hierarchical generalized linear mixed effects model, and the vigour of squeeze (Newtons exerted above required force). Both apathy and dopamine depletion were associated with reduced acceptance of offers. However, these effects were driven by dissociable patterns of responding. While apathy was characterized by increased rejection of predominantly low reward offers, dopamine increased responding to high effort, high reward offers, irrespective of underlying motivational state. Dopamine also exerted a main effect on motor vigour, increasing force production independently of reward offered, while apathy did not affect this measure. The findings demonstrate that disrupted effort-based decision-making underlies Parkinson's disease apathy, but in a manner distinct to that caused by dopamine depletion. Apathy is associated with reduced incentivization by the rewarding outcomes of actions. In contrast, dopamine has a general effect in motivating behaviour for high effort, high reward options without altering the response pattern that characterizes the apathetic state. Thus, the motivational deficit observed in Parkinson's disease appears not to be simply secondary to dopaminergic depletion of mesocorticolimbic pathways, suggesting non-dopaminergic therapeutic strategies for apathy may be important future targets.
Translation and mRNA degradation are intimately connected, yet the mechanisms that link them are not fully understood. Here, we studied these mechanisms in embryonic stem cells (ESCs). Transcripts ...showed a wide range of stabilities, which correlated with their relative translation levels and that did not change during early ESC differentiation. The protein DHH1 links translation to mRNA stability in yeast; however, loss of the mammalian homolog, DDX6, in ESCs did not disrupt the correlation across transcripts. Instead, the loss of DDX6 led to upregulated translation of microRNA targets, without concurrent changes in mRNA stability. The
knockout cells were phenotypically and molecularly similar to cells lacking all microRNAs (
knockout ESCs). These data show that the loss of DDX6 can separate the two canonical functions of microRNAs: translational repression and transcript destabilization. Furthermore, these data uncover a central role for translational repression independent of transcript destabilization in defining the downstream consequences of microRNA loss.
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