Huntington's disease (HD) is a neurodegenerative disorder that manifests with movement dysfunction. The expression of mutant Huntingtin (mHTT) disrupts the functions of brain cells. Galectin-3 (Gal3) ...is a lectin that has not been extensively explored in brain diseases. Herein, we showed that the plasma Gal3 levels of HD patients and mice correlated with disease severity. Moreover, brain Gal3 levels were higher in patients and mice with HD than those in controls. The up-regulation of Gal3 in HD mice occurred before motor impairment, and its level remained high in microglia throughout disease progression. The cell-autonomous up-regulated Gal3 formed puncta in damaged lysosomes and contributed to inflammation through NFκB- and NLRP3 inflammasome-dependent pathways. Knockdown of Gal3 suppressed inflammation, reduced mHTT aggregation, restored neuronal DARPP32 levels, ameliorated motor dysfunction, and increased survival in HD mice. Thus, suppression of Gal3 ameliorates microglia-mediated pathogenesis, which suggests that Gal3 is a novel druggable target for HD.
Tissues and cells in organism are continuously exposed to complex mechanical cues from the environment. Mechanical stimulations affect cell proliferation, differentiation, and migration, as well as ...determining tissue homeostasis and repair. By using a specially designed skin-stretching device, we discover that hair stem cells proliferate in response to stretch and hair regeneration occurs only when applying proper strain for an appropriate duration. A counterbalance between WNT and BMP-2 and the subsequent two-step mechanism are identified through molecular and genetic analyses. Macrophages are first recruited by chemokines produced by stretch and polarized to M2 phenotype. Growth factors such as HGF and IGF-1, released by M2 macrophages, then activate stem cells and facilitate hair regeneration. A hierarchical control system is revealed, from mechanical and chemical signals to cell behaviors and tissue responses, elucidating avenues of regenerative medicine and disease control by demonstrating the potential to manipulate cellular processes through simple mechanical stimulation.
Highly adjustable photonic modules were constructed based on the heterostructures crystals of a new series of donor‐acceptor metal–organic framework (D‐A MOF) featuring highly tunable thermally ...activated delayed fluorescence (TADF). By introducing N‐phenylcarbazole and derivatives as donor guests into the acceptor host NKU‐111, highly tunable through‐space charge transfer based TADF could be achieved through the engineering of heavy atom effect, which result in modulatable emission wavelength (540 to 600 nm) and enhanced quantum yield (up to 30.86 %). Furthermore, by rationally integrating the D‐A MOFs with distinctive emissions, rod‐like heterostructures crystals featuring excitation position dependent tip emissions in wide wavelength range (495 to 598 nm) could be fabricated, which could serve as highly potential photonic modules for photonic circuit applications.
A new series of donor‐acceptor metal–organic framework (D‐A MOF) featuring highly tunable through‐space charge transfer (TSCT) based thermally activated delayed fluorescence (TADF) were realized. Furthermore, heterostructures crystals featuring highly adjustable emissions in wide wavelength range was fabricated, illustrating its potential as photonic modules for photonic integrated circuit applications.
Studies on the relationship between osteoporosis and intervertebral disc degeneration (IVDD) are inconsistent. Therefore, we assessed whether IVDD is affected by vertebral osteoporosis in ...ovariectomized mice and investigated the underlying pathogenesis of IVDD related to osteoporosis.
Thirty healthy female C57BL/6 J mice aged 8 weeks were randomly divided into two groups: a control group (sham operation, n = 15) and an ovariectomy group (OVX; bilateral ovariectomy, n = 15). At 12 weeks after surgery, the bone quantity and microstructure in the lumbar vertebra and endplate as well as the volume of the L4/5 disc space were evaluated by microcomputed tomography (micro-CT). The occurrence and characteristic alterations of IVDD were identified via histopathological staining. The osteoclasts were detected using tartrate-resistant acid phosphatase (TRAP) staining. Type II collagen (Col II), osterix (OSX), osteopontin (OPN), and vascular endothelial growth factor (VEGF) expression in the intervertebral disc were detected by immunohistochemical analysis.
OVX significantly increased the body weight and decreased the uterus weight. Micro-CT analysis showed that osteoporosis of the vertebra and osteochondral remodeling of the endplate were accompanied by an increase in the endplate porosity and a decrease in the disc volume in the OVX group. Likewise, histological evaluation revealed that IVDD occurred at 12 weeks after ovariectomy, with features of endochondral ossification of the endplate, loose and broken annulus fibrosus, and degeneration of nucleus pulposus. TRAP staining showed that numerous active osteoclasts appeared in the subchondral bone and cartilaginous endplate of OVX mice, whereas osteoclasts were rarely detected in control mice. Immunohistochemical analysis demonstrated that the expression of osterix was significantly increased, notably in the endplate of OVX mice. In addition, Col II was decreased in the ossification endplate and the degenerative annulus fibrosus, where OPN and VEGF expressions were elevated in OVX mice.
OVX induced vertebral osteoporosis and osteochondral remodeling of the cartilaginous endplate contributing to the angiogenesis and an increase in porosity of the bone-cartilage surface, and also affected the matrix metabolism which consequently had detrimental effects on the intervertebral disc. Our study suggests that preserving the structural integrity and the function of the adjacent structures, including the vertebrae and endplates, may protect the disc against degeneration.
•Using machine learning to assess a large-scale environment is feasible.•Road and terrain are crucial elements for perceived walkability.•Auditing urban socio-spatial justice of walkability is ...crucial.
Walkability is an important issue in urban planning equity, which is primarily influenced by the objective environment and subjective perception. However, assessing the objective environment of the city on a large scale or obtaining the general public’s perceptual evaluation of the urban environment with less cost is challenging. This research adopted two-stage studies to identify the relationship between streetscape elements and perceived walkability using Google Street View images with machine learning in Taipei City. In Study I, the Zhongzheng District in Taipei was selected as the sample area and successfully developed a walkability prediction model that integrates street elements segmented by semantic segmentation technique, with the perceived walkability. Roads and terrains were identified as key predictors that affect perceived walkability in this random forest regression model. Based on this prediction model, we expanded the walkability assessment citywide with semantic segmentation in Study II, and the citywide walkability maps were produced. Accordingly, the socio-spatial equality of walkability was further audited. We further adopted spatial linear regression analysis to examine the relationship between neighborhood socioeconomic indicators (individual income, elderly %, and less educated %) and perceived walkability. Through the geographically weighted regression analysis, the results indicated that situated in peripheral areas were more sensitive to local socioeconomic indicators. This highlights the significant presence of social-spatial vulnerability in the walkability of Taipei City. Our research demonstrated the feasibility of using machine learning to audit urban socio-spatial justice from urban micro-to-macro scales.
Background
Coping strategies are a potential way to improve interventions designed to manage the caregiver burden of dementia. The purpose of this study was to develop an intervention targeted ...towards improving coping strategies and to examine its effectiveness on reducing caregiver burden.
Methods
A controlled study design was used. Fifty‐seven caregivers of dementia patients were enrolled. Coping strategies were assessed with the Revised Ways of Coping Checklist (WCCL‐R) and caregiver burden was assessed with the Chinese version of the Caregiver Burden Inventory. The participants were randomly divided into two groups. The intervention group was offered a series of five interventions in which problem‐solving skills, knowledge of dementia, social resources, and emotional support were taught every 2 weeks, and the control group was telephoned every 2 weeks for the usual clinical management. Two weeks after the end of the intervention, we again administered the WCCL‐R and the Caregiver Burden Inventory. Two‐way repeated‐measure anova was used to evaluate the changes in coping strategies and caregiver burden.
Results
Forty‐six participants completed the study. No statistically significant differences were noted in the demographic data between the two groups. On the problem‐focused coping subscale on the WCCL‐R, the intervention group's mean score increased by 3.8 points, and the control group's decreased by 5.1 points (F = 7.988, P = 0.007). On the seeking social support coping subscale on the WCCL‐R, the intervention group's mean score increased by 3.8 points, and the control group's decreased by 3.1 points (F = 4.462, P = 0.04). On the Caregiver Burden Inventory, the intervention group's mean score decreased by 7.2 points, and the control group's increased by 2.2 points (F = 6.155, P = 0.017).
Conclusions
Psychosocial intervention can help caregivers to adopt more problem‐focused and social support coping strategies, which are beneficial in terms of reducing the caregiver burden.
Mammalian innate immune sensor STING (STimulator of INterferon Gene) was recently found to originate from bacteria. During phage infection, bacterial STING sense c-di-GMP generated by the CD-NTase ...(cGAS/DncV-like nucleotidyltransferase) encoded in the same operon and signal suicide commitment as a defense strategy that restricts phage propagation. However, the precise binding mode of c-di-GMP to bacterial STING and the specific recognition mechanism are still elusive. Here, we determine two complex crystal structures of bacterial STING/c-di-GMP, which provide a clear picture of how c-di-GMP is distinguished from other cyclic dinucleotides. The protein-protein interactions further reveal the driving force behind filament formation of bacterial STING. Finally, we group the bacterial STING into two classes based on the conserved motif in β-strand lid, which dictate their ligand specificity and oligomerization mechanism, and propose an evolution-based model that describes the transition from c-di-GMP-dependent signaling in bacteria to 2'3'-cGAMP-dependent signaling in eukaryotes.
Patients with chronic kidney disease (CKD) are more readily prone to have impaired physical activity than the general population. The aim of this study is to examine the relationship between physical ...activity and adverse clinical outcomes and quality of life (QOL) in CKD. One hundred and sixty-one patients with CKD stages 1-5 was enrolled from February 2013 to September 2013 and followed up until June 2016. Physical activity was measured using high handgrip strength, 30-second chair stand, and 2-minute step. The QOL was assessed using the Taiwan version of the World Health Organization Quality of Life-BREF. Clinical outcomes included commencing dialysis, major adverse cardiovascular events (MACEs), and first hospitalization. Of all participants, 1 kgf increase in handgrip strength was significantly associated with 0.13 score increase in total scores of QOL and 0.05 score increase in physical domain of QOL in adjusted analysis. One time increase in 30-second chair stand was significantly correlated with 0.14 score increase in psychological domain of QOL. Over a mean follow-up period of 29.1±11.2 months, 37 (23.0%) reached commencing dialysis, 11(6.8%) had MACEs, and 50(31.1%) had first hospitalization. High handgrip strength (hazard ratio (HR): 0.89, 95% CI: 0.84-0.96) and high 2-minute step (HR: 0.04, 95% CI: 0.01-0.95) were significantly associated with decreased risk for commencing dialysis in multivariate analysis. Thirty-second chair-stand was negatively associated with MACEs (HR: 0.65, 95%CI: 0.47-0.89) and first hospitalization (HR: 0.84, 95%CI: 0.74-0.95). In conclusion, physical activity is a potential predictor of QOL and adverse clinical outcomes in patients with CKD.
Objective
Huntington disease (HD) is an inherited neurodegenerative disease caused by the mutant huntingtin gene (mHTT), which harbors expanded CAG repeats. We previously reported that the brain ...vessel density is higher in mice and patients with HD than in controls. The present study determines whether vascular function is altered in HD and characterizes the underlying mechanism.
Methods
The brain vessel density and vascular reactivity (VR) to carbogen challenge of HD mice were monitored by 3D ΔR2‐mMRA and blood oxygenation level–dependent (BOLD)/flow‐sensitive alternating inversion recovery (FAIR) magnetic resonance imaging (MRI), respectively. The amount of vascular endothelial growth factor (VEGF)‐A and the pericyte coverage were determined by immunohistochemistry and enzyme‐linked immunosorbent assay in human and mouse brain sections, primary mouse astrocytes and pericytes, and human astrocytes derived from induced pluripotent stem cells.
Results
Expression of mHTT in astrocytes and neurons is sufficient to increase the brain vessel density in HD mice. BOLD and FAIR MRI revealed gradually impaired VR to carbogen in HD mice. Astrocytes from HD mice and patients contained more VEGF‐A, which triggers proliferation of endothelial cells and may be responsible for the augmented neurovascular changes. Moreover, an astrocytic inflammatory response, which reduces the survival of pericytes through an IκB kinase–dependent pathway, mediates the low pericyte coverage of blood vessels in HD brains.
Interpretation
Our findings suggest that the inflammation‐prone HD astrocytes provide less pericyte coverage by promoting angiogenesis and reducing the number of pericytes and that these changes can explain the inferior VR in HD mice. The resultant impaired VR might hinder cerebral hemodynamics and increase brain atrophy during HD progression. Ann Neurol 2015;78:178–192
The primary objective of this paper is to examine the associations among managerial ability, political connections and enforcement actions for financial reporting misrepresentation (hereafter ...financial reporting fraud) in China. Using a sample of listed firms in China during 2007–2012, we first find that increased managerial ability leads to less financial reporting fraud. Second, political connections of firms can weaken or limit the effect of managerial ability on the likelihood of financial statement fraud. Further analyses indicate that the results are primarily driven by non-state-owned firms, rather than state-owned firms. Finally, we further find that firms with capable managers face less severe penalties by the regulatory agencies relative to those without capable managers.
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