Fluorescent small molecule donors.

Small molecule donors (SMDs) play subtle roles in the signaling mechanism and disease treatments. While many excellent SMDs have been developed, dosage control, targeted delivery, spatiotemporal feedback, as well as the efficiency evaluation of small molecules are still key challenges. Accordingly, fluorescent small molecule donors (FSMDs) have emerged to meet these challenges. FSMDs enable controllable release and non-invasive real-time monitoring, providing significant advantages for drug development and clinical diagnosis. Integration of FSMDs with chemotherapeutic, photodynamic or photothermal properties can take full advantage of each mode to enhance therapeutic efficacy. Given the remarkable properties and the thriving development of FSMDs, we believe a review is needed to summarize the design, triggering strategies and tracking mechanisms of FSMDs. With this review, we compiled FSMDs for most small molecules (nitric oxide, carbon monoxide, hydrogen sulfide, sulfur dioxide, reactive oxygen species and formaldehyde), and discuss recent progress concerning their molecular design, structural classification, mechanisms of generation, triggered release, structure-activity relationships, and the fluorescence response mechanism. Firstly, from the large number of fluorescent small molecular donors available, we have organized the common structures for producing different types of small molecules, providing a general strategy for the development of FSMDs. Secondly, we have classified FSMDs in terms of the respective donor types and fluorophore structures. Thirdly, we discuss the mechanisms and factors associated with the controlled release of small molecules and the regulation of the fluorescence responses, from which universal guidelines for optical properties and structure rearrangement were established, mainly involving light-controlled, enzyme-activated, reactive oxygen species-triggered, biothiol-triggered, single-electron reduction, click chemistry, and other triggering mechanisms. Fourthly, representative applications of FSMDs for trackable release, and evaluation monitoring, as well as for visible in vivo treatment are outlined, to illustrate the potential of FSMDs in drug screening and precision medicine. Finally, we discuss the opportunities and remaining challenges for the development of FSMDs for practical and clinical applications, which we anticipate will stimulate the attention of researchers in the diverse fields of chemistry, pharmacology, chemical biology and clinical chemistry. With this review, we hope to impart new understanding thereby enabling the rapid development of the next generation of FSMDs.

EMC10 modulates hepatic ER stress and steatosis in an isoform-specific manner.

BACKGROUND & AIMS: Endoplasmic reticulum (ER) membrane protein complex subunit 10 (EMC10) has been implicated in obesity. Here we investigated the roles of the two isoforms of EMC10, including a secreted isoform (scEMC10) and an ER membrane-bound isoform (mEMC10), in metabolic dysfunction-associated steatotic liver disease (MASLD). METHODS: Manifold steatotic mouse models and HepG2 cells were employed to investigate the role of EMC10 in the regulation of hepatic PERK-eIF2α-ATF4 signaling and hepatosteatosis. The therapeutic effect of scEMC10-neutralizing antibody on mouse hepatosteatosis was explored. Associations of MASLD with serum scEMC10 and hepatic mEMC10 were determined in two cohorts of participants with MASLD. RESULTS: scEMC10 promoted, while mEMC10 suppressed, the activation of hepatic PERK-eIF2α-ATF4 signaling. Emc10 gene knockout exacerbated, while hepatic overexpression of mEMC10 ameliorated, hepatic ER stress and steatosis in mice challenged with either a methionine- and choline-deficient diet or tunicamycin, highlighting a direct, suppressive role of mEMC10 in MASLD via modulation of hepatic ER stress. Overexpression of scEMC10 promoted, whereas neutralization of circulating scEMC10 prevented, hepatosteatosis in mice with fatty liver, suggesting a role of scEMC10 in MASLD development. Clinically, serum scEMC10 was increased, while hepatic mEMC10 was decreased, in participants with MASLD. Correlative analysis indicated that serum scEMC10 positively, whereas hepatic mEMC10 negatively, correlated with liver fat content and serum ALT, AST, and GGT. CONCLUSIONS: These findings demonstrate a novel isoform-specific role for EMC10 in the pathogenesis of MASLD and identify the secreted isoform as a tractable therapeutic target for MASLD via antibody-based neutralization. IMPACT AND IMPLICATIONS: We have shown the role of EMC10 in the regulation of energy homeostasis and obesity. In this study, we determine the distinct roles of the two isoforms of EMC10 in the regulation of hepatic endoplasmic reticulum stress and steatosis in mice, and report on the associations of the different EMC10 isoforms with metabolic dysfunction-associated steatotic liver disease in humans. Our findings delineate a novel regulatory axis for hepatosteatosis and identify EMC10 as a modulator of the PERK-eIF2α-ATF4 signaling cascade that may be of broad physiological significance. Moreover, our pre-clinical and clinical studies provide evidence of the therapeutic potential of targeting scEMC10 in MASLD.

Research Progress on the Assembly of Large DNA Fragments.

Synthetic biology, a newly and rapidly developing interdisciplinary field, has demonstrated increasing potential for extensive applications in the wide areas of biomedicine, biofuels, and novel materials. DNA assembly is a key enabling technology of synthetic biology and a central point for realizing fully synthetic artificial life. While the assembly of small DNA fragments has been successfully commercialized, the assembly of large DNA fragments remains a challenge due to their high molecular weight and susceptibility to breakage. This article provides an overview of the development and current state of DNA assembly technology, with a focus on recent advancements in the assembly of large DNA fragments in Escherichia coli, Bacillus subtilis, and Saccharomyces cerevisiae. In particular, the methods and challenges associated with the assembly of large DNA fragment in different hosts are highlighted. The advancements in DNA assembly have the potential to facilitate the construction of customized genomes, giving us the ability to modify cellular functions and even create artificial life. It is also contributing to our ability to understand, predict, and manipulate living organisms.

Developing NIR xanthene-chalcone fluorophores with large Stokes shifts for fluorescence imaging.

A series of novel near-infrared (NIR) xanthene-chalcone fluorophores were constructed through a modular synthesis with the electron-donating xanthene moiety and the electron-withdrawing chalcone moiety. These fluorophores are convenient for fluorescence imaging in living cells, benefiting from their NIR emissions (650-710 nm), large Stokes shifts (>100 nm), moderate quantum yields and low cytotoxicity. The substituted hydroxyl group of the xanthene-chalcone fluorophore HCA-E facilitates the development of multifunctional fluorescent probes. As an example, a highly sensitive and selective probe N-HCA-E for glutathione (GSH) detection was developed based on the fluorophore HCA-E. A 4-nitrobenzenesulfonyl (4-Ns) group was introduced to cage the hydroxyl group of HCA-E, which was used as a selective recognition site for the thiol of GSH and an effective fluorescence quencher. Probe N-HCA-E revealed NIR "turn-on" fluorescence (709 nm) for endogenous and exogenous GSH detection in lysosomes with a large Stokes shift (129 nm) and high anti-interference ability.

Tunable Ultralong Room Temperature Phosphorescence Based on Zn(II)-Niacin Metal-Organic Complex: Accessible and Low-Cost.

Long persistent luminescence (LPL) materials open up a new avenue for information security, anticounterfeiting technology, and bioimaging thanks to their unique luminescence characteristics like ultralong exciton migration distances and multiple-colored light emission. As materials that have value for commercial applications, they attract much attention. In this paper, inexpensive, accessible, and eco-friendly niacin is used as a ligand to combine with the universally used metal ion Zn(II) to form a crystallized metal-organic complex dubbed Zn-NA. The named material possesses an ultralong room-temperature phosphorescence (RTP) with a lifetime of up to 265 ms under the atmosphere and up to 446 ms at 77 K. Notably, it exhibits a bright and multimode (excitation- and temperature-dependent) color-tunable LPL that changes from blue to cyan and then to yellow-green upon removal of the irradiation sources. Depending on its photoluminescence and theoretical calculations, the observed long-lived RTP of Zn-NA can be attributed to the coexistence of a single-molecule state induced by the heavy atom effect and an aggregated state within a dense crystalline structure.

Paramagnetic Chemical Probes for Studying Biological Macromolecules.

Paramagnetic chemical probes have been used in electron paramagnetic resonance (EPR) and nuclear magnetic resonance (NMR) spectroscopy for more than four decades. Recent years witnessed a great increase in the variety of probes for the study of biological macromolecules (proteins, nucleic acids, and oligosaccharides). This Review aims to provide a comprehensive overview of the existing paramagnetic chemical probes, including chemical synthetic approaches, functional properties, and selected applications. Recent developments have seen, in particular, a rapid expansion of the range of lanthanoid probes with anisotropic magnetic susceptibilities for the generation of structural restraints based on residual dipolar couplings and pseudocontact shifts in solution and solid state NMR spectroscopy, mostly for protein studies. Also many new isotropic paramagnetic probes, suitable for NMR measurements of paramagnetic relaxation enhancements, as well as EPR spectroscopic studies (in particular double resonance techniques) have been developed and employed to investigate biological macromolecules. Notwithstanding the large number of reported probes, only few have found broad application and further development of probes for dedicated applications is foreseen.

Myocd regulates airway smooth muscle cell remodeling in response to chronic asthmatic injury.

Abnormal growth of airway smooth muscle cells is one of the key features in asthmatic airway remodeling, which is associated with asthma severity. The mechanisms underlying inappropriate airway smooth muscle cell growth in asthma remain largely unknown. Myocd has been reported to act as a key transcriptional coactivator in promoting airway-specific smooth muscle development in fetal lungs. Whether Myocd controls airway smooth muscle remodeling in asthma has not been investigated. Mice with lung mesenchyme-specific deletion of Myocd after lung development were generated, and a chronic asthma model was established by sensitizing and challenging the mice with ovalbumin for a prolonged period. Comparison of the asthmatic pathology between the Myocd knockout mice and the wild-type controls revealed that abrogation of Myocd mitigated airway smooth muscle cell hypertrophy and hyperplasia, accompanied by reduced peri-airway inflammation, decreased fibrillar collagen deposition on airway walls, and attenuation of abnormal mucin production in airway epithelial cells. Our study indicates that Myocd is a key transcriptional coactivator involved in asthma airway remodeling. Inhibition of Myocd in asthmatic airways may be an effective approach to breaking the vicious cycle of asthmatic progression, providing a novel strategy in treating severe and persistent asthma. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Atorvastatin-induced intracerebral hemorrhage is inhibited by berberine in zebrafish.

Intracerebral hemorrhage (ICH), for which there are currently no effective preventive or treatment methods, has a very high fatality rate. Statins, such as atorvastatin (ATV), are the first-line drugs for regulating blood lipids and treating hyperlipidemia-related cardiovascular diseases. However, ATV-associated ICH has been reported, although its incidence is rare. In this study, we aimed to investigate the protective action and mechanisms of berberine (BBR) against ATV-induced brain hemorrhage. We established an ICH model in zebrafish induced by ATV (2 µM) and demonstrated the effects of BBR (10, 50, and 100 µM) on ICH via protecting the vascular network using hemocyte staining and three transgenic zebrafish. BBR was found to reduce brain inflammation and locomotion injury in ICH-zebrafish. Mechanism research showed that ATV increased the levels of VE-cadherin and occludin proteins but disturbed their localization at the cell membrane by abnormal phosphorylation, which decreased the number of intercellular junctions between vascular endothelial cells (VECs), disrupting the integrity of vascular walls. BBR reversed the effects of ATV by promoting autophagic degradation of phosphorylated VE-cadherin and occludin in ATV-induced VECs examined by co-immunoprecipitation (co-IP). These findings provide crucial insights into understanding the BBR mechanisms involved in the maintenance of vascular integrity and in mitigating adverse reactions to ATV.

Estimating the loss-reduction effects of disaster preparedness and mitigation: An empirical study of US coastal states.

As extreme weather events like floods and storms continue to increase, it is crucial to examine the degree to which various disaster preparedness and mitigation investments can lower these risks. In this research, we empirically examine the effects of multiple federal disaster aid programs on reducing subsequent flood- and storm-related damages across US coastal states. Our analysis distinguishes aid programs and their funded projects targeting different emergency management functions, including preparedness, nonstructural and structural mitigation, emergency response and protective measures, and rehabilitation of public infrastructure. We construct panel data of more than 1800 US counties over the years 2000-2019 and estimate a fixed-effects model with time-varying county-level socioeconomic and demographic characteristics. We find that disaster aid generally helps mitigate property damages, although this loss-reduction effect varies by program. Among all aid programs, the Emergency Management Performance Grant results in the largest reduction of future flood damages. The Public Assistance grants supporting emergency work are also found to exert a strong effect on risk reduction. We also find that the impacts of disaster aid are higher in coastal counties. Our study is one of the first few examining the resilience implication of disaster aid in coastal counties, and our results underscore the importance of investing in capacity building, contingency planning, and consistency in maintenance.

A training program for improving the capacity of infection high-throughput sequencing and diagnosis in China.

BACKGROUND: Infectious diseases are a serious threat to human especially since the COVID-19 outbreak has proved the importance and urgency of their diagnosis and treatment again. Metagenomic next-generation sequencing (mNGS) has been widely used and recognized in clinical and carried out localized testing in hospitals. Increasing the training of mNGS detection technicians can enhance their professional quality and more effectively realize the application value of the hospital platform. METHODS: Based on the initial theoretical understanding and practice of the mNGS platform for localization construction, we have designed a training program to enhance the ability of technicians to detect pathogens by utilizing mNGS, and hence to conduct training practices nationwide. RESULTS: Until August 30, 2022, the page views of online classes have reached 51,500 times and 6 of offline small-scale training courses have been conducted. A total of 67 trainees from 67 hospitals have participated in the training with a qualified rate of 100%. After the training course, the localization platform of 1 participating hospital has been put into use, 2 have added the mNGS localization platform for admission, among which 3 have expressed strong intention of localization. CONCLUSIONS: This study focuses on the training procedures and practical experience of the project which is the first systematic standardized program of mNGS in the world. It solves the training difficulties in the current industry, and effectively promotes the localization construction and application of mNGS in hospitals. It has great development potential in the future and is worth further promotion.