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Emerging evidence indicates that gut dysbiosis may play a regulatory role in the onset and progression of Huntington’s disease (HD). However, any alterations in the fecal microbiome of HD patients and its relation to the host cytokine response remain unknown. The present study investigated alterations and host cytokine responses in patients with HD. We enrolled 33 HD patients and 33 sex- and age- matched healthy controls. Fecal microbiota communities were determined through 16S ribosomal DNA gene sequencing, from which we analyzed fecal microbial richness, evenness, structure, and differential abundance of individual taxa between HD patients and healthy controls. HD patients were evaluated for their clinical characteristics, and the relationships of fecal microbiota with these clinical characteristics were analyzed. Plasma concentrations of interferon gamma (IFN-γ), interleukin 1 beta (IL-1β), IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, and tumor necrosis factor alpha were measured by Meso Scale Discovery (MSD) assays, and relationships between microbiota and cytokine levels were analyzed in the HD group. HD patients showed increased α-diversity (richness), β-diversity (structure), and altered relative abundances of several taxa compared to those in healthy controls. HD-associated clinical characteristics correlated with the abundances of components of fecal microbiota at the genus level. Genus Intestinimonas was correlated with total functional capacity scores and IL-4 levels. Our present study also revealed that genus Bilophila were negatively correlated with proinflammatory IL-6 levels. Taken together, our present study represents the first to demonstrate alterations in fecal microbiota and inflammatory cytokine responses in HD patients. Further elucidation of interactions between microbial and host immune responses may help to better understand the pathogenesis of HD.

The failure in some direct synthesis of hierarchical zeolite with a hard- or soft-templating method would be caused by the brittle binding forces between the templates and zeolite precursors or frameworks. In present work, high-quality hierarchically porous ZSM-5 with crystalline pore walls is synthesized by using hydroxylated carbon nanotubes (CNTs) as templates. Mesopores structure with a size of about 10–35 nm similar to the diameters of the CNTs template is successfully fabricated in the as-synthesized ZSM-5 zeolite. The structural and textural properties of the as-synthesized samples are revealed by characterization of X-ray powder diffraction, scanning electron microscopy, transmission electron microscopy, in situ infrared spectroscopy of pyridine, temperature-programmed desorption of ammonia (NH3-TPD), N2 adsorption–desorption, and nuclear magnetic resonance spectroscopy in details. Catalytic cracking of tri-isopropylbenzene is chosen as a probe reaction so as to explore the catalytic performances of the hierarchical zeolite because of its notably increased external surfaces resulted from the created hierarchical pore system. A hierarchically cracking manner of bulky reactants is found over the as-synthesized the meso-zeolite ZSM-5.

Background Stem cell-based therapy is a promising strategy for treating Parkinson’s disease (PD) characterized by the loss of dopaminergic neurons. Recently, induced neural stem cell-derived dopaminergic precursor cells (iNSC-DAPs) have been emerged as a promising candidate for PD cell therapy because of a lower tumor-formation ability. Designer receptors exclusively activated by designer drugs (DREADDs) are useful tools for examining functional synaptic connections with host neurons. Methods DREADD knock-in human iNSCs to express excitatory hM3Dq and inhibitory hM4Di receptors were engineered by CRISPR. The knock-in iNSCs were differentiated into midbrain dopaminergic precursor cells (DAPs) and transplanted into PD mice. The various behavior test such as the Apomorphine-induced rotation test, Cylinder test, Rotarod test, and Open field test were assessed at 4, 8, or 12 weeks post-transplantation with or without the administration of CNO. Electrophysiology were performed to assess the integrated condition and modulatory function to host neurons. Results DREADD expressing iNSCs were constructed with normal neural stem cells characteristics, proliferation ability, and differentiation potential into dopaminergic neuorns. DAPs derived from DREADD expressing iNSC showed matched function upon administration of clozapine N-oxide (CNO) in vitro. The results of electrophysiology and behavioral tests of transplanted PD mouse models revealed that the grafts established synaptic connections with downstream host neurons and exhibited excitatory or inhibitory modulation in response to CNO in vivo. Conclusion iNSC-DAPs are a promising candidate for cell replacement therapy for Parkinson’s disease. Remote DREADD-dependent activation of iNSC-DAP neurons significantly enhanced the beneficial effects on transplanted mice with Parkinson’s disease.

A long-standing mystery shrouds the mechanism by which catalytically repressed receptor tyrosine kinase domains accomplish transphosphorylation of activation loop (A-loop) tyrosines. Here we show that this reaction proceeds via an asymmetric complex that is thermodynamically disadvantaged because of an electrostatic repulsion between enzyme and substrate kinases. Under physiological conditions, the energetic gain resulting from ligand-induced dimerization of extracellular domains overcomes this opposing clash, stabilizing the A-loop-transphosphorylating dimer. A unique pathogenic fibroblast growth factor receptor gain-of-function mutation promotes formation of the complex responsible for phosphorylation of A-loop tyrosines by eliminating this repulsive force. We show that asymmetric complex formation induces a more phosphorylatable A-loop conformation in the substrate kinase, which in turn promotes the active state of the enzyme kinase. This explains how quantitative differences in the stability of ligand-induced extracellular dimerization promotes formation of the intracellular A-loop-transphosphorylating asymmetric complex to varying extents, thereby modulating intracellular kinase activity and signaling intensity. X-ray crystallography, solution NMR and biochemical and cell-based analyses reveal a model where catalytically repressed receptor tyrosine kinases accomplish activation loop (A-loop) tyrosine transphosphorylation.

Endocannabinoid (eCB), 2 -arachidonoyl-glycerol (2-AG), the most abundant eCB in the brain, regulates diverse neural functions. Here we linked multiple homozygous loss-of-function mutations in 2-AG synthase diacylglycerol lipase β ( DAGLB ) to an early onset autosomal recessive Parkinsonism. DAGLB is the main 2-AG synthase in human and mouse substantia nigra (SN) dopaminergic neurons (DANs). In mice, the SN 2-AG levels were markedly correlated with motor performance during locomotor skill acquisition. Genetic knockdown of Daglb in nigral DANs substantially reduced SN 2-AG levels and impaired locomotor skill learning, particularly the across-session learning. Conversely, pharmacological inhibition of 2-AG degradation increased nigral 2-AG levels, DAN activity and dopamine release and rescued the locomotor skill learning deficits. Together, we demonstrate that DAGLB -deficiency contributes to the pathogenesis of Parkinsonism, reveal the importance of DAGLB-mediated 2-AG biosynthesis in nigral DANs in regulating neuronal activity and dopamine release, and suggest potential benefits of 2-AG augmentation in alleviating Parkinsonism. 2- arachidonoylglycerol (2-AG), an abundant endocannabinoid in the brain, regulates diverse neural functions. Here, the authors identified four loss-of-function mutations in dicylglycerol lipase β (DAGLB) from six patients with early onset Parkinsonism. In mice, loss of DAGLB in dopamine neurons reduced neuronal activity and impaired locomotor function and augmentation of 2-AG levels boosted neuronal activity and rescued locomotor deficits.

Background Lower urinary tract symptoms are one of the most common groups of non-movement symptoms in patients with Parkinson’s disease (PD). Storage symptoms are well-acknowledged, but neurogenic voiding dysfunction caused by PD remains a knowledge gap. This study aimed to evaluate the neurogenic bladder outlet obstruction in male patients with PD and its clinical significance. Methods Male patients who were diagnosed with PD and underwent urodynamic studies were retrospectively reviewed. The patients with prostate size < 30 ml and bladder outlet obstruction index ≥40 were included in the study. Lower urinary tract symptoms were evaluated by International Prostate Symptom Score (IPSS). Free flowmetry was performed and post void residual (PVR) volume was measured by ultrasound at follow-up. Results Six patients were included in the final analysis. The mean age was 68.2 and the mean movement symptom duration was 70.7 months. The patients had a mean IPSS of 12.5 and mean PVR volume of 70.8 ml. All patients had slow stream but none of them reported significant voiding difficulty. Urodynamic studies showed the delayed urinary sphincter relaxation and the special trace pattern. After a mean follow-up of 20 months, they had a mean IPSS of 12.5 and mean PVR volume of 73.3 ml. None of them complained of significant voiding difficulty at follow-up. Conclusion The delayed urinary sphincter relaxation is a rare but repeatable phenomenon in male patients with PD. It is unlikely to cause disturbing voiding dysfunction, as reported by the patients, and does not progress prominently during the course of PD. Further studies are needed to investigate the nature of this special type of neurogenic BOO and whether it is peculiar to PD in a larger patient cohort.

Semantic fluency is the ability to name items from a given category within a limited time, which relies on semantic memory, working memory, and executive function. Semantic disfluency is a common problem in Parkinson’s disease (PD) and Alzheimer’s disease (AD). We demonstrated a graph theoretical analysis of semantic fluency in patients with PD (N=86), patients with AD (N=40), and healthy controls (HC, N=88). All participants completed a standard animal fluency test. Their verbal responses were recorded, transcripted, and transformed into directed speech graphs. Patients with PD generated fewer correct words than HC and more correct words than patients with AD. Patients with PD showed higher density, shorter diameter, and shorter average shortest path length than HC, but lower density, longer diameter, and longer average shortest path length than patients with AD. It suggests that patients with PD produced relatively smaller and denser speech graphs. Moreover, in PD, the densities of speech graphs correlated with the severity of non-motor symptoms, but not the severity of motor symptoms. The graph theoretical analysis revealed new features of semantic disfluency in patients with PD.

PurposeTo evaluate whether neurogenic lower urinary tract dysfunction and urodynamic parameters predict the outcomes of patients with multiple system atrophy (MSA).MethodsA retrospective study was performed in patients who were diagnosed with MSA and underwent urodynamic studies simultaneously from September 2014 to July 2018. The urodynamic traces were reviewed by urologists. Detrusor contractility was evaluated by the bladder contractility index (BCI) and Schäfer nomogram. Telephone follow-up was conducted in July 2019 to acquire survival data. Clinical and urodynamic parameters were analyzed for survival using Cox regression analysis.ResultsOverall, 70 MSA patients were eligible for analysis, and 61 of them underwent urodynamic study within 3 years of initial symptom onset. The parkinsonian subtype of MSA (MSA-P) had a smaller proportion of men as well as longer motor and lower urinary tract symptom durations than the cerebellar subtype (MSA-C). MSA-P also had a lower mean BCI than MSA-C (32.0 ± 27.0 versus 53.6 ± 33.4, p = 0.025). The mean MSA survival time was 5.4 [95% confidence interval (CI) 4.8–6.3] years. Cox regression analysis showed that survival from baseline was correlated only with BCI [hazard ratio (HR) 0.983, 95% CI 0.969–0.997, p = 0.020]. Overall survival was correlated with BCI (HR 0.982, 95% CI 0.966–0.999, p = 0.039) and the presence of urinary incontinence (HR 3.007, 95% CI 0.993–9.220, p = 0.052).ConclusionDetrusor contractility can be a prognostic marker in MSA patients. A high BCI value is a protective factor for survival from baseline and overall survival. The presence of urinary incontinence predicts shortened overall survival.

To improve the catalytic performance of zeolite catalysts in reactions involving bulky molecules, a series of mesoporous Beta zeolite were prepared using organic functionalized fumed silica as the silicon source, which were thoroughly characterized in terms of porosity and acidity. The peaks in X-ray diffraction (XRD) patterns showed broadening, and the external surface area and mesoporosity increased progressively when the content of organic functionalization increased. An infrared (IR) spectroscopy study of adsorbed probe molecules, including pyridine (Py-IR), 2,6-ditertbutylpyridine (DTBPy-IR) and pivalonitrile (Pn-IR), showed that the improvement of mesoporosity increased the accessibility of acidic sites. In the catalytic benzylation of naphthalene with benzyl chloride (BC) over the mesoporous Beta zeolite catalysts, the conversion of BC was significantly increased when the accessibility of Brönsted acid sites improved. The increase of mesoporosity not only improved the diffusion ability of the reactants and products, but also increased the accessibility of acid sites, which greatly enhanced the activity of the mesoporous Beta zeolite catalysts. It is highlighted that the interdependence of mesoporosity, acid type, acid concentration, and strength of the mesoporous Beta zeolites on the catalytic performance in the benzylation of naphthalene with BC was comprehensively studied.

Asymptomatic Leucine-Rich Repeat Kinase 2 Gene (LRRK2) carriers are at risk for developing Parkinson's disease (PD). We studied presymptomatic substantia nigra pars compacta (SNc) regional neurodegeneration in asymptomatic LRRK2 carriers compared to idiopathic PD patients using neuromelanin-sensitive MRI technique (NM-MRI). Fifteen asymptomatic LRRK2 carriers, 22 idiopathic PD patients, and 30 healthy controls (HCs) were scanned using NM-MRI. We computed volume and contrast-to-noise ratio (CNR) derived from the whole SNc and the sensorimotor, associative, and limbic SNc regions. An analysis of covariance was performed to explore the differences of whole and regional NM-MRI values among the groups while controlling the effect of age and sex. In whole SNc, LRRK2 had significantly lower CNR than HCs but non-significantly higher volume and CNR than PD patients, and PD patients significantly lower volume and CNR compared to HCs. Inside SNc regions, there were significant group effects for CNR in all regions and for volumes in the associative region, with a trend in the sensorimotor region but no significant changes in the limbic region. PD had reduced volume and CNR in all regions compared to HCs. Asymptomatic LRRK2 carriers showed globally decreased SNc volume and CNR suggesting early nigral neurodegeneration in these subjects at risk of developing PD.