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Chronic mitochondrial stress associates with major neurodegenerative diseases. Recovering stressed mitochondria constitutes a critical step of mitochondrial quality control and thus energy maintenance in early stages of neurodegeneration. Here, we reveal Mul1-Mfn2 pathway that maintains neuronal mitochondrial integrity under stress conditions. Mul1 deficiency increases Mfn2 activity that triggers the first phasic mitochondrial hyperfusion and also acts as an ER-Mito tethering antagonist. Reduced ER-Mito coupling leads to increased cytoplasmic Ca 2+ load that activates calcineurin and induces the second phasic Drp1-dependent mitochondrial fragmentation and mitophagy. Overexpressing Mfn2, but not Mfn1, mimics Mul1-deficient phenotypes, while expressing PTPIP51, an ER-Mito anchoring protein, suppresses Parkin-mediated mitophagy. Thus, by regulating mitochondrial morphology and ER-Mito contacts, Mul1-Mfn2 pathway plays an early checkpoint role in maintaining mitochondrial integrity. Our study provides new mechanistic insights into neuronal mitochondrial maintenance under stress conditions, which is relevant to several major neurodegenerative diseases associated with mitochondrial dysfunction and altered ER-Mito interplay. Little is known about the pathways that maintain mitochondrial structure and function under neuronal stress conditions. Here, authors demonstrate that the Mul1-Mfn2 pathway plays a checkpoint role in maintaining mitochondrial integrity and energy maintenance by ensuring ER-mitochondrial tethering and preventing mitophagy.

Accessing and exploring large-scale genomics data sets remains a significant challenge to researchers without specialist bioinformatics training. We present the integrated PlantGenIE.org platform for exploration of Populus, conifer and Arabidopsis genomics data, which includes expression networks and associated visualization tools. Standard features of a model organism database are provided, including genome browsers, gene list annotation, BLAST homology searches and gene information pages. Community annotation updating is supported via integration of WebApollo. We have produced an RNA-sequencing (RNA-Seq) expression atlas for Populus tremula and have integrated these data within the expression tools. An updated version of the COMPLEX resource for performing comparative plant expression analyses of gene coexpression network conservation between species has also been integrated. The PlantGenIE.org platform provides intuitive access to large-scale and genome-wide genomics data from model forest tree species, facilitating both community contributions to annotation improvement and tools supporting use of the included data resources to inform biological insight.

Many complex networks in the real world have community structures – groups of well-connected nodes with important functional roles. It has been well recognized that the identification of communities bears numerous practical applications. While existing approaches mainly apply statistical or graph theoretical/combinatorial methods for community detection, in this paper, we present a novel geometric approach which  enables us to borrow powerful classical geometric methods and properties. By considering networks as geometric objects and communities in a network as a geometric decomposition, we apply curvature and discrete Ricci flow, which have been used to decompose smooth manifolds with astonishing successes in mathematics, to break down communities in networks. We  tested our method on networks with ground-truth community structures, and experimentally confirmed the effectiveness of this geometric approach.

Sepsis is a lethal syndrome with multiple organ failure caused by an inappropriate host response to infection. Cardiac dysfunction is one of the important complications of sepsis, termed sepsis-induced myocardial dysfunction (SIMD), which is characterized by systolic and diastolic dysfunction of both sides of the heart. Mechanisms that contribute to SIMD include an excessive inflammatory response, altered circulatory, microvascular status, nitric oxide (NO) synthesis impairment, endothelial dysfunction, disorders of calcium regulation, cardiac autophagy anomaly, autonomic nervous system dysregulation, metabolic reprogramming, and mitochondrial dysfunction. The role of mitochondrial dysfunction, which is characterized by structural abnormalities, increased oxidative stress, abnormal opening of the mitochondrial permeability transition pore (mPTP), mitochondrial uncoupling, and disordered quality control systems, has been gaining increasing attention as a central player in the pathophysiology of SIMD. The disruption of homeostasis within the organism induced by mitochondrial dysfunction may also be an important aspect of SIMD development. In addition, an emerging therapy strategy targeting mitochondria, namely, metabolic resuscitation, seems promising. The current review briefly introduces the mechanism of SIMD, highlights how mitochondrial dysfunction contributes to SIMD, and discusses the role of metabolic resuscitation in the treatment of SIMD.

Achieving the activation of drugs within cellular systems may provide targeted therapies. Here we construct a tumour-selective cascade activatable self-detained system (TCASS) and incorporate imaging probes and therapeutics. We show in different mouse models that the TCASS system accumulates in solid tumours. The molecules show enhanced accumulation in tumour regions via the effect of recognition induced self-assembly. Analysis of the molecular penetration in tumour tissue shows that in vivo self-assembly increases the penetration capability compared to typical soft or hard nanomaterials. Importantly, the in vivo self-assembled molecules exhibit a comparable clearance pathway to that of small molecules, which are excreted from organs of the reticuloendothelial system (liver and kidney), while are relatively slowly eliminated from tumour tissues. Finally, this system, combined with the NIR probe, shows high specificity and sensitivity for detecting bladder cancer in isolated intact patient bladders. The activation of drugs within cellular systems may provide targeted therapies for cancer. Here, the authors make a drug delivery system that is activated within the cell and exploits XIAP expression to cleave a linker region, resulting in the self-assembly of the system and drug release within cancer cells.

RNA molecules (e.g., siRNA, microRNA, and mRNA) have shown tremendous potential for immunomodulation and cancer immunotherapy. They can activate both innate and adaptive immune system responses by silencing or upregulating immune-relevant genes. In addition, mRNA-based vaccines have recently been actively pursued and tested in cancer patients, as a form of treatment. Meanwhile, various nanomaterials have been developed to enhance RNA delivery to the tumor and immune cells. In this review article, we summarize recent advances in the development of RNA-based therapeutics and their applications in cancer immunotherapy. We also highlight the variety of nanoparticle platforms that have been used for RNA delivery to elicit anti-tumor immune responses. Finally, we provide our perspectives of potential challenges and opportunities of RNA-based nanotherapeutics in clinical translation towards cancer immunotherapy.

In the digital economy era, small service business struggle to compete in a rapidly changing and dynamic market. Therefore, through digital transformation (DT), small service business seek to increase their competitive advantage, improve business performance, and achieve business growth. Having limited resources and capabilities, small service business must deal with several barriers and challenges. This study aims to discover the barriers, and the roles of government, for digital transformation in small service business. This study applied a qualitative approach involving semi-structured in-depth interviews with top management of small service business. Then, we employed the content analysis method to examine interview data and construct a model. This research reveals four main barriers to digital transformation in small service business: lack of funding, lack of digital capability, lack of human resources, and technical barriers. We found there are four government roles for supporting digital transformation in small service business: build a digital platform for small service business, promote mobile/digital payment, provide digital training, and build a digital collaboration ecosystem. Additionally, based on this study’s findings, a model for barriers and government support of digital transformation in small service business is presented. This study contributes to the conceptual framework and management implications in the digital transformation field. The study’s findings provide insights to practitioners and suggest that the government could alter the current policies and programs to support digital transformation in small service business.

Random laser with intrinsically uncomplicated fabrication processes, high spectral radiance, angle-free emission, and conformal onto freeform surfaces is in principle ideal for a variety of applications, ranging from lighting to identification systems. In this work, a white random laser (White-RL) with high-purity and high-stability is designed, fabricated, and demonstrated via the cost-effective materials ( e.g ., organic laser dyes) and simple methods ( e.g ., all-solution process and self-assembled structures). Notably, the wavelength, linewidth, and intensity of White-RL are nearly isotropic, nevertheless hard to be achieved in any conventional laser systems. Dynamically fine-tuning colour over a broad visible range is also feasible by on-chip integration of three free-standing monochromatic laser films with selective pumping scheme and appropriate colour balance. With these schematics, White-RL shows great potential and high application values in high-brightness illumination, full-field imaging, full-colour displays, visible-colour communications, and medical biosensing.

Targeting PD-L1 and PD-1 interactions is a relatively new therapeutic strategy used to treat cancer. Inhibitors of PD-1/PD-L1 include peptides, small molecule chemical compounds, and antibodies. Several approved antibodies targeting PD-1 or PD-L1 have been patented with good curative effect in various cancer types in clinical practices. While the current antibody therapy is facing development bottleneck, some companies have tried to develop PD-L1 companion tests to select patients with better diagnosis potential. Meanwhile, many companies have recently synthesized small molecule inhibitors of PD-1/PD-L1 interactions and focused on searching for novel biomarker to predict the efficacy of anti-PD-1/PD-L1 drugs. This review summarized clinical studies and patent applications related to PD-1/PD-L1 targeted therapy and also discussed progress in inhibitors of PD-1/PD-L1.