The Alzheimer’s disease (AD) susceptibility gene, CD2-associated protein (CD2AP), encodes an actin binding adaptor protein, but its function in the nervous system is largely unknown. Loss of the ...Drosophila ortholog cindr enhances neurotoxicity of human Tau, which forms neurofibrillary tangle pathology in AD. We show that Cindr is expressed in neurons and present at synaptic terminals. cindr mutants show impairments in synapse maturation and both synaptic vesicle recycling and release. Cindr associates and genetically interacts with 14-3-3ζ, regulates the ubiquitin-proteasome system, and affects turnover of Synapsin and the plasma membrane calcium ATPase (PMCA). Loss of cindr elevates PMCA levels and reduces cytosolic calcium. Studies of Cd2ap null mice support a conserved role in synaptic proteostasis, and CD2AP protein levels are inversely related to Synapsin abundance in human postmortem brains. Our results reveal CD2AP neuronal requirements with relevance to AD susceptibility, including for proteostasis, calcium handling, and synaptic structure and function.
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•cindr, fly homolog of the Alzheimer’s risk gene CD2AP, encodes a synaptic protein•cindr mutants disrupt synaptic vesicle recycling and release and impair plasticity•Cindr and 14-3-3ζ regulate the proteasome and presynaptic calcium homeostasis•Cd2ap mouse and human brain studies support a conserved role in synapse proteostasis
CD2AP is an Alzheimer’s disease susceptibility gene with uncertain brain function. Ojelade et al. discover that mutation of the Drosophila homolog cindr disrupts ubiquitin-proteasome system activity, causing calcium dyshomeostasis and impaired synaptic vesicle recycling and release. Cd2ap null mice and human brain proteomic studies support a conserved role in synaptic proteostasis.
The post-natal heart adapts to stress and overload through hypertrophic growth, a process that may be pathologic or beneficial （physiologic hypertrophy）. Physiologic hypertrophy improves cardiac ...performance in both healthy and diseased individuals, yet the mechanisms that propagate this f~vorable adaptation remain poorly defined. We identify the cytokine cardiotrophin 1 （CT1） as a factor capable of recapitulating the key features of physiologic growth of the heart including transient and reversible hypertrophy of the myocardium, and stimulation of cardiomyocyte-derived angiogenic signals leading to increased vascularity. The capacity of CT1 to induce physiologic hypertrophy originates from a CK2-mediated restraining of caspase activation, preventing the transition to unrestrained pathologic growth. Exogenous CT1 protein delivery attenuated pathology and restored contractile function in a severe model of right heart failure, suggesting a novel treatment option for this intractable cardiac disease.
This study used several informatics techniques to analyze consumer-driven social media data from four cities (Paris, Milan, New York, and London) during the 2019 Fall/Winter (F/W) Fashion Week. ...Analyzing keywords using a semantic network analysis method revealed the main characteristics of the collections, celebrities, influencers, fashion items, fashion brands, and designers connected with the four fashion weeks. Using topic modeling and a sentiment analysis, this study confirmed that brands that embodied similar themes in terms of topics and had positive sentimental reactions were also most frequently mentioned by the consumers. A semantic network analysis of the tweets showed that social media, influencers, fashion brands, designers, and words related to sustainability and ethics were mentioned in all four cities. In our topic modeling, the classification of the keywords into three topics based on the brand collection’s themes provided the most accurate model. To identify the sentimental evaluation of brands participating in the 2019 F/W Fashion Week, we analyzed the consumers’ sentiments through positive, neutral, and negative reactions. This quantitative analysis of consumer-generated social media data through this study provides insight into useful information enabling fashion brands to improve their marketing strategies.
In multicellular organisms, glycosylation regulates various developmental signaling pathways including the Notch pathway. One of the O-linked glycans added to epidermal growth factor-like (EGF) ...repeats in animal proteins including the Notch receptors is the xylose-xylose-glucose-O oligosaccharide. Drosophila glucoside xylosyltransferase (Gxylt) Shams negatively regulates Notch signaling in specific contexts. Since Shams adds the first xylose residue to O-glucose, its loss-of-function phenotype could be due to the loss of the first xylose, the second xylose or both. To examine the contribution of the second xylose residues to Drosophila Notch signaling, we have performed biochemical and genetic analysis on CG11388, which is the Drosophila homolog of human xyloside xylosyltransferase 1 (XXYLT1). Experiments in S2 cells indicated that similar to human XXYLT1, CG11388 can add the second xylose to xylose-glucose-O glycans. Flies lacking both copies of CG11388 (Xxylt) are viable and fertile and do not show gross phenotypes indicative of altered Notch signaling. However, genetic interaction experiments show that in sensitized genetic backgrounds with decreased or increased Notch pathway components, loss of Xxylt promotes Delta-mediated activation of Notch. Unexpectedly, we find that in such sensitized backgrounds, even loss of one copy of the fly Gxylt shams enhances Delta-mediated Notch activation. Taken together, these data indicate that while the first xylose plays a key role in tuning the Delta-mediated Notch signaling in Drosophila, the second xylose has a fine-tuning role only revealed in sensitized genetic backgrounds.
The last decade has seen phenomenal growth of electronic commerce in Asia. An important driving force has been the parallel rise of social media, enabling pervasive interactions among consumers and ...between consumers and firms. This article provides an overview of the current state of development of social media in Asia. We also survey the literature on social media that has been produced by authors in this region. The research covers a variety of topics and issues, including: user behavior with social media, the impacts of social media, and the issues arising from its use. It also identifies a number of future research opportunities that fall into these areas. The Asia region is filled with high potential for promising research regarding how social media may be leveraged for e-commerce. This article calls for more research attention to be given to social media-related e-commerce research, and the discovery of new knowledge related to the connections between social media and e-commerce that are unique to the Asia region.
Unlike tumor biopsies that can be constrained by problems such as sampling bias, circulating tumor cells (CTCs) are regarded as the “liquid biopsy” of the tumor, providing convenient access to all ...disease sites, including primary tumor and fatal metastases. Although enumerating CTCs is of prognostic significance in solid tumors, it is conceivable that performing molecular and functional analyses on CTCs will reveal much significant insight into tumor biology to guide proper therapeutic intervention. We developed the Thermoresponsive NanoVelcro CTC purification system that can be digitally programmed to achieve an optimal performance for purifying CTCs from non-small cell lung cancer (NSCLC) patients. The performance of this unique CTC purification system was optimized by systematically modulating surface chemistry, flow rates, and heating/cooling cycles. By applying a physiologically endurable stimulation (i.e., temperature between 4 and 37 °C), the mild operational parameters allow minimum disruption to CTCs’ viability and molecular integrity. Subsequently, we were able to successfully demonstrate culture expansion and mutational analysis of the CTCs purified by this CTC purification system. Most excitingly, we adopted the combined use of the Thermoresponsive NanoVelcro system with downstream mutational analysis to monitor the disease evolution of an index NSCLC patient, highlighting its translational value in managing NSCLC.
A two-axis scanning catheter was developed for 3D endoscopic imaging with spectral domain optical coherence tomography (SD-OCT). The catheter incorporates a micro-mirror scanner implemented with ...microelectromechanical systems (MEMS) technology: the micro-mirror is mounted on a two-axis gimbal comprised of folded flexure hinges and is actuated by magnetic field. The scanner can run either statically in both axes or at the resonant frequency (>= 350Hz) for the fast axis. The assembled catheter has an outer diameter of 2.8 mm and a rigid part of 12 mm in length. Its scanning range is +/- 20 in optical angle in both axes with low voltages (1 approximately 3V), resulting in a scannable length of approximately 1 mm at the surface in both axes, even with the small catheter size. The catheter was incorporated with a multi-functional SD-OCT system for 3D endoscopic imaging. Both intensity and polarization-sensitive images could be acquired simultaneously at 18.5K axial scans/s. In vivo 3D images of human fingertips and oral cavity tissue are presented as a demonstration.
Circulating fetal nucleated cells (CFNCs) in maternal blood offer an ideal source of fetal genomic DNA for noninvasive prenatal diagnostics (NIPD). We developed a class of nanoVelcro microchips to ...effectively enrich a subcategory of CFNCs, i.e., circulating trophoblasts (cTBs) from maternal blood, which can then be isolated with single-cell resolution by a laser capture microdissection (LCM) technique for downstream genetic testing. We first established a nanoimprinting fabrication process to prepare the LCM-compatible nanoVelcro substrates. Using an optimized cTB-capture condition and an immunocytochemistry protocol, we were able to identify and isolate single cTBs (Hoechst+/CK7+/HLA-G+/CD45–, 20 μm > sizes > 12 μm) on the imprinted nanoVelcro microchips. Three cTBs were polled to ensure reproducible whole genome amplification on the cTB-derived DNA, paving the way for cTB-based array comparative genomic hybridization (aCGH) and short tandem repeats analysis. Using maternal blood samples collected from expectant mothers carrying a single fetus, the cTB-derived aCGH data were able to detect fetal genders and chromosomal aberrations, which had been confirmed by standard clinical practice. Our results support the use of nanoVelcro microchips for cTB-based noninvasive prenatal genetic testing, which holds potential for further development toward future NIPD solution.
Ubiquitin-mediated inactivation of caspases has long been postulated to contribute to the regulation of apoptosis. However, detailed mechanisms and functional consequences of caspase ubiquitylation ...have not been demonstrated. Here we show that the
Drosophila Inhibitor of Apoptosis 1, DIAP1, blocks effector caspases by targeting them for polyubiquitylation and nonproteasomal inactivation. We demonstrate that the conjugation of ubiquitin to drICE suppresses its catalytic potential in cleaving caspase substrates. Our data suggest that ubiquitin conjugation sterically interferes with substrate entry and reduces the caspase's proteolytic velocity. Disruption of drICE ubiquitylation, either by mutation of DIAP1's E3 activity or drICE's ubiquitin-acceptor lysines, abrogates DIAP1's ability to neutralize drICE and suppress apoptosis in vivo. We also show that DIAP1 rests in an “inactive” conformation that requires caspase-mediated cleavage to subsequently ubiquitylate caspases. Taken together, our findings demonstrate that effector caspases regulate their own inhibition through a negative feedback mechanism involving DIAP1 “activation” and nondegradative polyubiquitylation.
Target nomination for drug development has been a major challenge in the path to finding a cure for several neurological disorders. Comprehensive transcriptome profiles have revealed brain gene ...expression changes associated with many neurological disorders, and the functional validation of these changes is a critical next step. Model organisms are a proven approach for the elucidation of disease mechanisms, including screening of gene candidates as therapeutic targets. Frequently, multiple models exist for a given disease, creating a challenge to select the optimal model for validation and functional follow-up. To help in nominating the best mouse models for studying neurological diseases, we developed a web portal to visualize mouse transcriptomic data related to neurological disorders: http://mmad.nrihub.org. Users can examine gene expression changes across mouse model studies to help select the optimal mouse model for further investigation. The portal provides access to mouse studies related to Alzheimer's diseases (AD), Parkinson's disease (PD), Huntington's disease (HD), Amyotrophic Lateral Sclerosis (ALS), Spinocerebellar ataxia (SCA), and models related to aging.
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