Human SNP links differential outcomes in inflammatory and infectious disease to a FOXO3-regulated pathway.

The clinical course and eventual outcome, or prognosis, of complex diseases varies enormously between affected individuals. This variability critically determines the impact a disease has on a patient's life but is very poorly understood. Here, we exploit existing genome-wide association study data to gain insight into the role of genetics in prognosis. We identify a noncoding polymorphism in FOXO3A (rs12212067: T > G) at which the minor (G) allele, despite not being associated with disease susceptibility, is associated with a milder course of Crohn's disease and rheumatoid arthritis and with increased risk of severe malaria. Minor allele carriage is shown to limit inflammatory responses in monocytes via a FOXO3-driven pathway, which through TGFß1 reduces production of proinflammatory cytokines, including TNFα, and increases production of anti-inflammatory cytokines, including IL-10. Thus, we uncover a shared genetic contribution to prognosis in distinct diseases that operates via a FOXO3-driven pathway modulating inflammatory responses.

Interference of nuclear wavepackets in a pair of proton transfer reactions.

Quantum mechanics revolutionized chemists' understanding of molecular structure. In contrast, the kinetics of molecular reactions in solution are well described by classical, statistical theories. To reveal how the dynamics of chemical systems transition from quantum to classical, we study femtosecond proton transfer in a symmetric molecule with two identical reactant sites that are spatially apart. With the reaction launched from a superposition of two local basis states, we hypothesize that the ensuing motions of the electrons and nuclei will proceed, conceptually, in lockstep as a superposition of probability amplitudes until decoherence collapses the system to a product. Using ultrafast spectroscopy, we observe that the initial superposition state affects the reaction kinetics by an interference mechanism. With the aid of a quantum dynamics model, we propose how the evolution of nuclear wavepackets manifests the unusual intersite quantum correlations during the reaction.

Network Meta-Analysis: Effect of Cold Stress on the Gene Expression of Swine Adipocytes ATGL, CIDEA, UCP2, and UCP3.

Cold stress significantly affects gene expression in adipocytes; studying this phenomenon can help reveal the pathogeneses of conditions such as obesity and insulin resistance. Adipocyte triglyceride lipase (ATGL); cell death-inducing deoxyribonucleic acid (DNA) fragmentation factor subunit alpha (DFFA)-like effector (CIDEA); and uncoupling protein genes UCP1, UCP2, and UCP3 are the most studied genes in pig adipose tissues under cold stress. However, contradictory results have been observed in gene expression changes to UCP3 and UCP2 when adipose tissues under cold stress were examined. Therefore, we conducted a meta-analysis of 32 publications in total on the effect of cold stress on the expression of ATGL, CIDEA, UCP2, and UCP3. Our results showed that cold stress affected the expression of swine adipocyte genes; specifically, it was positively correlated with the expression of UCP3 in swine adipocytes. Conversely, expression of ATGL was negatively affected under cold stress conditions. In addition, the loss of functional UCP1 in pigs likely triggered a compensatory increase in UCP3 activity. We also simulated the docking results of UCP2 and UCP3. Our results showed that UCP2 could strongly bind to adenosine triphosphate (ATP), meaning that UCP3 played a more significant role in pig adipocytes.

Uncovering the mechanisms of host mitochondrial cardiolipin release in syphilis: Insights from human microvascular endothelial cells.

The release of host mitochondrial cardiolipin is believed to be the main factor that contributes to the production of anti-cardiolipin antibodies in syphilis. However, the precise mechanism by which mitochondria release cardiolipin in this context remains elusive. This study aimed to elucidate the mechanisms underlying mitochondrial cardiolipin release in syphilis. We conducted a cardiolipin quantitative assay and immunofluorescence analysis to detect mitochondrial cardiolipin release in human microvascular endothelial cells (HMEC-1), with and without Treponema pallidum (Tp) infection. Furthermore, we explored apoptosis, a key mechanism for mitochondrial cardiolipin release. The potential mediator molecules were then analyzed through RNA-sequence and subsequently validated using in vitro knockout techniques mediated by CRISPR-Cas9 and pathway-specific inhibitors. Our findings confirm that live-Tp is capable of initiating the release of mitochondrial cardiolipin, whereas inactivated-Tp does not exhibit this capability. Additionally, apoptosis detection further supports the notion that the release of mitochondrial cardiolipin occurs independently of apoptosis. The RNA-sequencing results indicated that microtubule-associated protein2 (MAP2), an axonogenesis and dendrite development gene, was up-regulated in HMEC-1 treated with Tp, which was further confirmed in syphilitic lesions by immunofluorescence. Notably, genetic knockout of MAP2 inhibited Tp-induced mitochondrial cardiolipin release in HMEC-1. Mechanically, Tp-infection regulated MAP2 expression via the MEK-ERK-HES1 pathway, and MEK/ERK phosphorylation inhibitors effectively block Tp-induced mitochondrial cardiolipin release. This study demonstrated that the infection of live-Tp enhanced the expression of MAP2 via the MEK-ERK-HES1 pathway, thereby contributing to our understanding of the role of anti-cardiolipin antibodies in the diagnosis of syphilis.

LncRNA PVT1 promotes strong stemness and endothelial progenitor cell characteristics in renal carcinoma stem cells.

Renal cancer stem cells (RCSCs) derived from clear cell renal cell carcinoma (ccRCC) tissues with higher microvessel density (MVD) have strong stemness and endothelial progenitor cells-like (EPCs-like) characteristics. A high level of lncRNA PVT1 expression is essential for simultaneously retaining strong RCSC stemness and EPCs-like characteristics. PVT1 binds with TAZ protein and prevents its phosphorylation, which promotes RCSC stemness. Moreover, RCSCs support endothelial differentiation and angiogenesis, which are mediated via the PVT1/miR-15b/KDR axis. This report provides insight into the determinants of RCSC impact on stemness and highlights the critical role of RCSC in angiogenesis. The presented findings suggest that targeting RCSC through PVT1 expression may be a new treatment strategy for ccRCC.

Sustained exposure to Helicobacter pylori induces immune tolerance by desensitizing TLR6.

Helicobacter pylori (H. pylori, Hp) has been designated a class I carcinogen and is closely associated with severe gastric diseases. During colonization in the gastric mucosa, H. pylori develops immune escape by inducing host immune tolerance. The gastric epithelium acts as the first line of defense against H. pylori, with Toll-like receptors (TLRs) in gastric epithelial cells being sensitive to H. pylori components and subsequently activating the innate immune system. However, the mechanism of immune tolerance induced by H. pylori through the TLR signalling pathway has not been fully elucidated. In this research, we detected the expression of TLRs and inflammatory cytokines in GES-1 cells upon sustained exposure to H. pylori or H. pylori lysate from 1 to 30 generations and in Mongolian gerbils infected with H. pylori for 5 to 90 weeks. We found that the levels of TLR6 and inflammatory cytokines first increased and then dropped during the course of H. pylori treatment in vitro and in vivo. The restoration of TLR6 potentiated the expression of IL-1ß and IL-8 in GES-1 cells, which recruited neutrophils and reduced the colonization of H. pylori in the gastric mucosa of gerbils. Mechanistically, we found that persistent infection with H. pylori reduces the sensitivity of TLR6 to bacterial components and regulates the expression of inflammatory cytokines in GES-1 cells through TLR6/JNK signaling. The TLR6 agonist obviously alleviated inflammation in vitro and in vivo. Promising results suggest that TLR6 may be a potential candidate immunotherapy drug for H. pylori infection.

The contributions of individual countries and regions to the global radiative forcing.

Knowing the historical relative contribution of greenhouse gases (GHGs) and short-lived climate forcers (SLCFs) to global radiative forcing (RF) at the regional level can help understand how future GHGs emission reductions and associated or independent reductions in SLCFs will affect the ultimate purpose of the Paris Agreement. In this study, we use a compact Earth system model to quantify the global RF and attribute global RF to individual countries and regions. As our evaluation, the United States, the first 15 European Union members, and China are the top three contributors, accounting for 21.9 ± 3.1%, 13.7 ± 1.6%, and 8.6 ± 7.0% of global RF in 2014, respectively. We also find a contrast between developed countries where GHGs dominate the RF and developing countries where SLCFs including aerosols and ozone are more dominant. In developing countries, negative RF caused by aerosols largely masks the positive RF from GHGs. As developing countries take measures to improve the air quality, their negative contributions from aerosols will likely be reduced in the future, which will in turn enhance global warming. This underlines the importance of reducing GHG emissions in parallel to avoid any detrimental consequences from air quality policies.

Strain-modulated Ru-O Covalency in Ru-Sn Oxide Enabling Efficient and Stable Water Oxidation in Acidic Solution.

RuO2 is one of the benchmark electrocatalysts used as the anode material in proton exchange membrane water electrolyser. However, its long-term stability is compromised due to the participation of lattice oxygen and metal dissolution during oxygen evolution reaction (OER). In this work, weakened covalency of Ru-O bond was tailored by introducing tensile strain to RuO6 octahedrons in a binary Ru-Sn oxide matrix, prohibiting the participation of lattice oxygen and the dissolution of Ru, thereby significantly improving the long-term stability. Moreover, the tensile strain also optimized the adsorption energy of intermediates and boosted the OER activity. Remarkably, the RuSnOx electrocatalyst exhibited excellent OER activity in 0.1 M HClO4 and required merely 184 mV overpotential at a current density of 10 mA cm-2 . Moreover, it delivered a current density of 10 mA cm-2 for at least 150 h with negligible potential increase. This work exemplifies an effective strategy for engineering Ru-based catalysts with extraordinary performance toward water splitting.

Superb Energy Storage Capability for NaNbO3 -Based Ceramics Featuring Labyrinthine Submicro-Domains with Clustered Lattice Distortions.

Designing superb dielectric capacitors is valuable but challenging since achieving simultaneously large energy-storage (ES) density and high efficiency is difficult. Herein, the synergistic effect of grain refining, bandgap widening, and domain engineering is proposed to boost comprehensive ES properties by incorporating CaTiO3 into 0.92NaNbO3 -0.08BiNi0.67 Ta0.33 O3 matrix (as abbreviated NN-BNT-xCT). Apart from grain refining and bandgap widening, multiple local distortions embedded in labyrinthine submicro-domains, as indicated by diffraction-freckle splitting and ½-type superlattices, produce slush-like polar clusters for the NN-BNT-0.2CT ceramic, which should be ascribed to the coexisting P4bm, P21 ma, and Pnma2 phases. Consequently, a high recoverable ES density Wrec of ≈ 7.1 J cm-3 and a high efficiency η of ≈ 90% at 646 kV cm-1 is achieved for the NN-BNT-0.2CT ceramic. Such hierarchically polar structure is favorable to superb comprehensive ES properties, which provide a strategy for developing high-performance dielectric capacitors.

Azvudine therapy of common COVID-19 in hemodialysis patients.

There is no antiviral study on hemodialysis patients infected with coronavirus disease 2019 (COVID-19), especially on the application of 2'-deoxy-2'-ß -fluoro-4'-azidocytidine (Azvudine, FNC) antiviral therapy. We conducted a multicenter observational study involving 1008 hemodialysis patients. After matching for age, sex, and other factors, 182 patients in the basic treatment group and 182 in the FNC group were included. The negative nucleic acid conversion rate of the FNC group was significantly higher than that of the basic treatment group, and viral loads, interleukin-6, and C-reactive protein were significantly lower than those of the basic treatment group (p < 0.05). There were no significant differences in liver function, renal function, or the number of adverse events between the two groups (p > 0.05). In conclusion, our study has provided novel evidence suggesting that the FNC scheme may be safe and effective compared to the basic treatment of hemodialysis patients with common COVID-19.

Buildup of multiple spatiotemporal nonlinear dynamics in an all-fiber multimode laser.

Ultrafast lasers based on multimode fibers have attracted extensive attention owing to the large mode-field area and nonlinear tolerance. The high spatial degree of freedom of multimode fibers is significant for spatiotemporal pulses locked both in transverse and longitudinal modes, where the energy of output pulses can be remarkably improved. Herein, the 1.5-µm all-fiber spatiotemporal mode-locked laser was realized based on carbon nanotubes as a saturable absorber. Moreover, by tuning the polarization controller and the pump power carefully, the output wavelengths can be ranged from 1529 to 1565 nm based on the multimode interference filter. In addition, Q-switched mode-locking and spatiotemporal mode-locked dual combs were also observed by further adjusting the polarization controller. Such a kind of an all-fiber multimode laser offers a crucial insight into the spatiotemporal nonlinear dynamics, which is of great significance in scientific research and practical applications.

Early-life noise exposure causes cognitive impairment in a sex-dependent manner by disrupting homeostasis of the microbiota-gut-brain axis.

Epidemiological investigations show that noise exposure in early life is associated with health and cognitive impairment. The gut microbiome established in early life plays a crucial role in modulating developmental processes that subsequently affect brain function and behavior. Here, we examined the impact of early-life exposure to noise on cognitive function in adolescent rats by analyzing the gut microbiome and metabolome to elucidate the underlying mechanisms. Chronic noise exposure during early life led to cognitive deficits, hippocampal injury, and neuroinflammation. Early-life noise exposure showed significant difference on the composition and function of the gut microbiome throughout adolescence, subsequently causing axis-series changes in fecal short-chain fatty acid (SCFA) metabolism and serum metabolome profiles, as well as dysregulation of endothelial tight junction proteins, in both intestine and brain. We also observed sex-dependent effects of microbiota depletion on SCFA-related beneficial bacteria in adolescence. Experiments on microbiota transplantation and SCFA supplementation further confirmed the role of intestinal bacteria and related SCFAs in early-life noise-exposure-induced impairments in cognition, epithelial integrity, and neuroinflammation. Overall, these results highlight the homeostatic imbalance of microbiota-gut-brain axis as an important physiological response toward environmental noise during early life and reveals subtle differences in molecular signaling processes between male and female rats.

Structural Change and Radical Generation of a Cadmium-Based Metal-Organic Framework Induced by an Electric Field.

Herein we report the structural change and radical generation of a cadmium-based metal-organic framework (Cd-MOF) induced by external electric fields. Under a weaker single electric field, different coordination modes of Cd-L lead to 3D → 2D structural change. Under stronger superposed electric fields, Cd-MOF was excited to produce a stable free radical. This study will provide a new avenue for the controlled assembly of MOFs.

Wavelength-tunable broadband lasers based on nanomaterials.

Nanomaterials are widely used in the fields of sensors, optoelectronics, biophotonics and ultrafast photonics due to their excellent mechanical, thermal, optical, electrical and magnetic properties. Particularly, owing to their nonlinear optical properties, fast response time and broadband operation, nanomaterials are ideal saturable absorption materials in ultrafast photonics, which contribute to the improvement of laser performance. Therefore, nanomaterials are of great importance to applications in wavelength-tunable broadband pulsed lasers. Herein, we review the integration and applications of nanomaterials in wavelength-tunable broadband ultrafast photonics. Firstly, the two integration methods, which are direct coupling and evanescent field coupling, and their characteristics are introduced. Secondly, the applications of nanomaterials in wavelength-tunable broadband lasers are summarized. Finally, the development of nanomaterials and broadband tunable lasers is reviewed and discussed.

EGR-1 Contributes to Pulmonary Edema by Regulating the Epithelial Sodium Channel in Lipopolysaccharide-Induced Acute Lung Injury.

Acute lung injury (ALI) is a common lung disease with increasing morbidity and mortality rates due to the lack of specific drugs. Impaired alveolar fluid clearance (AFC) is a primary pathological feature of ALI. Epithelial sodium channel (ENaC) is a primary determinant in regulating the transport of Na+ and the clearance of alveolar edema fluid. Therefore, ENaC is an important target for the development of drugs for ALI therapy. However, the role of ENaC in the progression of ALI remains unclear. Inhibition of early growth response factor (EGR-1) expression has been reported to induce a protective effect on ALI; therefore, we evaluated whether EGR-1 participates in the progression of ALI by regulating ENaC-α in alveolar epithelium. We investigated the potential mechanism of EGR-1-mediated regulation of ENaC in ALI. We investigated whether EGR-1 aggravates the pulmonary edema response in ALI by regulating ENaC. ALI mouse models were established by intrabronchial injection of lipopolysaccharides (LPS). Lentiviruses with EGR-1 knockdown were transfected into LPS-stimulated A549 cells. We found that EGR-1 expression was upregulated in the lung tissues of ALI mice and in LPS-induced A549 cells, and was negatively correlated with ENaC-α expression. Knockdown of EGR-1 increased ENaC-α expression and relieved cellular edema in ALI. Moreover, EGR-1 regulated ENaC-α expression at the transcriptional level, and correspondingly promoted pulmonary edema and aggravated ALI symptoms. In conclusion, our study demonstrated that EGR-1 could promote pulmonary edema by downregulating ENaC-α at the transcriptional level in ALI. Our study provides a new potential therapeutic strategy for treatment of ALI.

EGR-1 expression was increased in LPS-induced ALI mice and associated with aggravated pulmonary edemaEGR-1 induced pulmonary edema relying on regulating the expression of ENaC-α at the transcriptional level by manipulating the promoter.

Divergent Energy-Climate Nexus in the Global Fuel Combustion Processes.

Fuel combustion provides basic energy for the society but also produces CO2 and incomplete combustion products that threaten human survival, climate change, and global sustainability. A variety of fuels burned in different facilities expectedly have distinct impacts on climate, which remains to be quantitatively assessed. This study uses updated emission inventories and an earth system model to evaluate absolute and relative contributions in combustion emission-associated climate forcing by fuels, sectors, and regions. We showed that, from 1970 to 2014, coal burned in the energy sector and oil used in the transportation sector contributed comparable energies consumed (24 and 20% of the total) but had distinct climate forcing (1 and 40%, respectively). Globally, coal burned for energy production had negative impacts on climate forcing but positive effects in the residential sector. In many developing countries, coal combustion in the energy sector had negative radiative forcing (RF) per unit energy consumed due to insufficient controls on sulfur and scattering aerosol levels, but oils in the transportation sector had high positive RF values. These results had important implications on the energy transition and emission reduction actions in response to climate change. Distinct climate efficiencies of energies and the spatial heterogeneity implied differentiated energy utilization strategies and pollution control policies by region and sector.

14-3-3ζ inhibits maladaptive repair in renal tubules by regulating YAP and reduces renal interstitial fibrosis.

Acute kidney injury (AKI) refers to a group of common clinical syndromes characterized by acute renal dysfunction, which may lead to chronic kidney disease (CKD), and this process is called the AKI-CKD transition. The transcriptional coactivator YAP can promote the AKI-CKD transition by regulating the expression of profibrotic factors, and 14-3-3 protein zeta (14-3-3ζ), an important regulatory protein of YAP, may prevent the AKI-CKD transition. We established an AKI-CKD model in mice by unilateral renal ischemia-reperfusion injury and overexpressed 14-3-3ζ in mice using a fluid dynamics-based gene transfection technique. We also overexpressed and knocked down 14-3-3ζ in vitro. In AKI-CKD model mice, 14-3-3ζ expression was significantly increased at the AKI stage. During the development of chronic disease, the expression of 14-3-3ζ tended to decrease, whereas active YAP was consistently overexpressed. In vitro, we found that 14-3-3ζ can combine with YAP, promote the phosphorylation of YAP, inhibit YAP nuclear translocation, and reduce the expression of fibrosis-related proteins. In an in vivo intervention experiment, we found that the overexpression of 14-3-3ζ slowed the process of renal fibrosis in a mouse model of AKI-CKD. These findings suggest that 14-3-3ζ can affect the expression of fibrosis-related proteins by regulating YAP, inhibit the maladaptive repair of renal tubular epithelial cells, and prevent the AKI-CKD transition.

Laser ablation on vascular diseases: mechanisms and influencing factors.

Vascular diseases, such as venous insufficiency and coronary artery diseases, have been threatening the health of people. Efficient treatment with proper postoperative care is required to relieve the pain of the patients. Traditionally, venous insufficiency is treated with ligation and stripping, an open surgery whose complication rate cannot be ignored. Coronary artery disease is often treated with balloon angioplasty during which undilatable lesions may be encountered, limiting the efficacy of this approach. With advances in laser photonics and percutaneous coronary intervention procedure, laser ablation is emerging as an alternative and adjunctive therapy for these diseases. Endovenous laser ablation has the advantages of high success rate, low complication risk, and fast postoperative recovery. Laser ablation in arteries can handle uncrossable or undilatable lesions with a low incidence of serious complications. In this review, previously published research concerning vascular diseases and their therapies are analyzed in order to provide a clear explanation of the mechanisms and merits of laser ablation. For endovenous laser ablation, the main mechanisms are steam bubbles, heat conduction, and heat pipe, and three main influencing factors are wavelength, fiber types, and laser energy density. For excimer laser coronary atherectomy, the main mechanisms are photochemical, photothermal, and photomechanical effects, and three main influencing factors are catheter, medium, and laser parameters.

Bolt Installation Defect Detection Based on a Multi-Sensor Method.

With the development of industrial automation, articulated robots have gradually replaced labor in the field of bolt installation. Although the installation efficiency has been improved, installation defects may still occur. Bolt installation defects can considerably affect the mechanical properties of structures and even lead to safety accidents. Therefore, in order to ensure the success rate of bolt assembly, an efficient and timely detection method of incorrect or missing assembly is needed. At present, the automatic detection of bolt installation defects mainly depends on a single type of sensor, which is prone to mis-inspection. Visual sensors can identify the incorrect or missing installation of bolts, but it cannot detect torque defects. Torque sensors can only be judged according to the torque and angel information, but cannot accurately identify the incorrect or missing installation of bolts. To solve this problem, a detection method of bolt installation defects based on multiple sensors is proposed. The trained YOLO (You Only Look Once) v3 network is used to judge the images collected by the visual sensor, and the recognition rate of visual detection is up to 99.75%, and the average confidence of the output is 0.947. The detection speed is 48 FPS, which meets the real-time requirement. At the same time, torque and angle sensors are used to judge the torque defects and whether bolts have slipped. Combined with the multi-sensor judgment results, this method can effectively identify defects such as missing bolts and sliding teeth. Finally, this paper carried out experiments to identify bolt installation defects such as incorrect, missing torque defects, and bolt slips. At this time, the traditional detection method based on a single type of sensor cannot be effectively identified, and the detection method based on multiple sensors can be accurately identified.

Threshold-Responsive Colorimetric Sensing System for the Continuous Monitoring of Gases.

Colorimetric sensors are widely used because of their inherent advantages including accuracy, rapid response, ease-of-use, and low costs; however, they usually lack reusability, which precludes the continuous use of a single sensor. We have developed a threshold-responsive colorimetric system that enables repeated analyte measurements by a single colorimetric sensor. The threshold responsive algorithm automatically adjusts the sensor exposure time to the analyte and measurement frequency according to the sensor response. The system registers the colorimetric sensor signal change rate, prevents the colorimetric sensor from reaching saturation, and allows the sensor to fully regenerate before the next measurement is started. The system also addresses issues common to colorimetric sensors, including the response time and range of detection. We demonstrate the benefits and feasibility of this novel system, using colorimetric sensors for ammonia and carbon dioxide gases for continuous monitoring of up to (at least) 60 detection cycles without signs of analytical performance degradation of the sensors.