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Abstract The incidence of autoimmune diseases has significantly increased over the past 20 years. Excessive host immunoreactions and disordered immunoregulation are at the core of the pathogenesis of autoimmune diseases. The traditional anti-tumor chemotherapy drug CPT-11 is associated with leukopenia. Considering that CPT-11 induces leukopenia, we believe that it is a promising drug for the control of autoimmune diseases. Here, we show that CPT-11 suppresses T cell proliferation and pro-inflammatory cytokine production in healthy C57BL/6 mice and in complete Freund’s adjuvant-challenged mice. We found that CPT-11 effectively inhibited T cell proliferation and Th1 and Th17 cell differentiation by inhibiting glycolysis in T cells. We also assessed CPT-11 efficacy in treating autoimmune diseases in models of experimental autoimmune encephalomyelitis and psoriasis. Finally, we proved that treatment of autoimmune diseases with CPT-11 did not suppress long-term immune surveillance for cancer. Taken together, these results show that CPT-11 is a promising immunosuppressive drug for autoimmune disease treatment.

Abstract Heterotopic ossification (HO) is the abnormal formation of bone in extraskeletal sites. However, the mechanisms linking HO pathogenesis with bone mass dysfunction remain unclear. Here, we showed that mice harboring injury-induced and BMP4-dependent HO exhibit bone mass loss similar to that presented by patients with HO. Moreover, we found that injury-induced hyperinflammatory responses at the injury site triggered HO initiation but did not result in bone mass loss at 1 day post-injury (dpi). In contrast, a suppressive immune response promoted HO propagation and bone mass loss by 7 dpi. Correcting immune dysregulation by PD1/PDL1 blockade dramatically alleviated HO propagation and bone mass loss. We further demonstrated that fetuin-A (FetA), which has been frequently detected in HO lesions but rarely observed in HO-adjacent normal bone, acts as an immunomodulator to promote PD1 expression and M2 macrophage polarization, leading to immunosuppression. Intervention with recombinant FetA inhibited hyperinflammation and prevented HO and associated bone mass loss. Collectively, our findings provide new insights into the osteoimmunological interactions that occur during HO formation and suggest that FetA is an immunosuppressor and a potential therapeutic option for the treatment of HO.

Check dams on the Chinese Loess Plateau (CLP) have captured billions of tons of eroded sediment, substantially reducing sediment load in the Yellow River. However, uncertainties persist regarding the precise sediment capture and the role of these dams in Yellow River flow and sediment dynamics due to the lack of available spatial distribution datasets. We produced the first vectorized dataset of silted land formed by check dams on the CLP, combining high-resolution and easily accessible Google Earth images with object-based classification methods. The accuracy of the dataset was verified by 1947 collected test samples, and the producer's accuracy and user's accuracy of the dam lands were 88.9% and 99.5%, respectively. Our dataset not only provides fundamental information for accurately assessing the ecosystem service functions of check dams, but also helps to interpret current changes in sediment delivery of the Yellow River and plan future soil and water conservation projects., (© 2024. The Author(s).)

Mounting evidence has proposed the importance of the Wnt/β-catenin pathway and tripartite motif 31 (TRIM31) in certain malignancies. Our research aimed to clarify the correlation between aberrant TRIM31 expression and the Wnt/β-catenin pathway during gastric cancer (GC) oncogenesis and development. TRIM31 was drastically elevated in GC tissues and was closely associated with aggressive clinical outcomes and poor prognosis. Moreover, TRIM31 downregulation attenuated GC cell proliferation and invasion in vitro. Mechanistically, TRIM31 could bind and ubiquitinate Axin1 protein, thereby facilitating the activation of the Wnt/β-catenin pathway. Additionally, Axin1 knockdown partially abrogated the inhibitory effects on the proliferative, invasive and migratory abilities of GC cells induced by TRIM31 silencing. Furthermore, TRIM31 was negatively correlated with Axin1 protein expression in GC tissues. In summary, we revealed a new TRIM31-Axin1-Wnt/β-catenin axis that contributed greatly to the progression of GC, and targeting this regulatory axis may represent an effective treatment for GC patients., (© 2023. The Author(s).)

Adaptation based on social resilience is proposed as an effective measure to mitigate hunger and avoid food shocks caused by climate change. But these have not been investigated comprehensively in climate-sensitive regions. North Korea (NK) and its neighbours, South Korea and China, represent three economic levels that provide us with examples for examining climatic risk and quantifying the contribution of social resilience to rice production. Here our data-driven estimates show that climatic factors determined rice biomass changes in NK from 2000 to 2017, and climate extremes triggered reductions in production in 2000 and 2007. If no action is taken, NK will face a higher climatic risk (with continuous high-temperature heatwaves and precipitation extremes) by the 2080s under a high-emissions scenario, when rice biomass and production are expected to decrease by 20.2% and 14.4%, respectively, thereby potentially increasing hunger in NK. Social resilience (agricultural inputs and population development for South Korea; resource use for China) mitigated climate shocks in the past 20 years (2000-2019), even transforming adverse effects into benefits. However, this effect was not significant in NK. Moreover, the contribution of social resilience to food production in the undeveloped region (15.2%) was far below the contribution observed in the developed and developing regions (83.0% and 86.1%, respectively). These findings highlight the importance of social resilience to mitigate the adverse effects of climate change on food security and human hunger and provide necessary quantitative information., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

G-protein-coupled receptors (GPCRs) are a target for over 34% of current drugs. The calcium-sensing receptor (CaSR), a family C GPCR, regulates systemic calcium (Ca 2+ ) homeostasis that is critical for many physiological, calciotropical, and noncalciotropical outcomes in multiple organs. However, the mechanisms by which extracellular Ca 2+ (Ca 2+ ex ) and the CaSR mediate networks of intracellular Ca 2+ -signaling and players involved throughout the life cycle of CaSR are largely unknown. Here we report the first CaSR protein-protein interactome with 94 novel putative and 8 previously published interactors using proteomics. Ca 2+ ex promotes enrichment of 66% of the identified CaSR interactors, pertaining to Ca 2+ dynamics, endocytosis, degradation, trafficking, and primarily to protein processing in the endoplasmic reticulum (ER). These enhanced ER-related processes are governed by Ca 2+ ex -activated CaSR which directly modulates ER-Ca 2+ (Ca 2+ ER ), as monitored by a novel ER targeted Ca 2+ -sensor. Moreover, we validated the Ca 2+ ex dependent colocalizations and interactions of CaSR with ER-protein processing chaperone, 78-kDa glucose regulated protein (GRP78), and with trafficking-related protein. Live cell imaging results indicated that CaSR and vesicle-associated membrane protein-associated A (VAPA) are inter-dependent during Ca 2+ ex induced enhancement of near-cell membrane expression. This study significantly extends the repertoire of the CaSR interactome and reveals likely novel players and pathways of CaSR participating in Ca 2+ ER dynamics, agonist mediated ER-protein processing and surface expression., (© 2021. The Author(s).)

Novel coronavirus pneumonia (NCP) has been widely spread in China and several other countries. Early finding of this pneumonia from huge numbers of suspects gives clinicians a big challenge. The aim of the study was to develop a rapid screening model for early predicting NCP in a Zhejiang population, as well as its utility in other areas. A total of 880 participants who were initially suspected of NCP from January 17 to February 19 were included. Potential predictors were selected via stepwise logistic regression analysis. The model was established based on epidemiological features, clinical manifestations, white blood cell count, and pulmonary imaging changes, with the area under receiver operating characteristic (AUROC) curve of 0.920. At a cut-off value of 1.0, the model could determine NCP with a sensitivity of 85% and a specificity of 82.3%. We further developed a simplified model by combining the geographical regions and rounding the coefficients, with the AUROC of 0.909, as well as a model without epidemiological factors with the AUROC of 0.859. The study demonstrated that the screening model was a helpful and cost-effective tool for early predicting NCP and had great clinical significance given the high activity of NCP.

The prevalence of HIV-1 in Guangxi is very high, and the rate of HIV-1 infection among men who have sex with men (MSM) has been increasing. Therefore, it is necessary to explore the patterns and risk factors of HIV transmission in Guangxi. For this purpose, individuals diagnosed with HIV-1 during 2013-2018 in Guangxi were recruited. Phylogenetic relationship, transmission clusters, and genotypic drug resistance analyses were performed based on HIV-1 pol sequences. Related factors were analysed to assess for their association with HIV-1 transmission. CRF07_BC (50.4%) and CRF01_AE (33.4%) were found to be the predominant subtypes. The analysed 1633 sequences (50.15%, Guangxi; 49.85%, other provinces) were segregated into 80 clusters (size per cluster, 2-704). We found that 75.3% of the individuals were in three clusters (size ˃ 100), and 73.8% were high-risk spreaders (links ≥ 4). Infection time, marital status, and subtype were significantly associated with HIV-1 transmission. Additionally, 80.2% of recent infections were linked to long-term infections, and 46.2% were linked to other provinces. A low level of transmitted drug resistance was detected (4.8%). Our findings indicated superclusters and high-risk HIV-1 spreaders among the MSM in Guangxi. Effective strategies blocking the route of transmission should be developed.

Although the Guangxi region accounts for 10% of all HIV-1 cases new reported in 2011 in China, the sources of the transmitted HIV-1 strains are virtually unknown. To determine the extent to which recent HIV infections were derived from already circulating local strains as opposed to recently introduced strains, we performed a cross-sectional molecular epidemiological investigation of recent infections across Guangxi during 2012-2013. HIV-1 nucleotide sequences were amplified and sequenced. Phylogenetic analyses of pol gene regions were used to determine HIV-1 transmission source strains. Based on 229 sequences generated, the subtype/CRF distribution was as follows: CRF01&#95;AE (61.1%), CRF07&#95;BC (18.8%), CRF08&#95;BC (16.6%), CRF55&#95;01B (3.1%), and subtype B' (0.4%). In total, 213 of 229 (93.0%) sequenced transmission strains were derived from already-circulating local strains. Multivariate logistic regression analysis showed that only an age of 18-25 years was significantly associated with transmission from outside Guangxi (compared to >25 years, AOR: 5.15, 95% CI: 1.18-22.48, p < 0.01). This is the first study to use a Bayesian discrete phylogeographic approach to analyze transmission source strains in China. Our results provide useful data for designing evidence-based prevention strategies and methods for combating the rapid spread of sexually transmitted HIV in Guangxi.

The debate over whether soil erosion is a carbon (C) sink or atmospheric CO 2 source remains highly controversial. For the first time, we report the magnitude of C stabilization associated with soil erosion control for an entire large river basin. The soil erosion of the Yellow River basin in northern China is among the most severe worldwide. Progressive soil conservation has been implemented by the Chinese government since the 1970s, including the largest ever revegetation programme, the Grain-for-Green Project, which began in 1999. Based on compiled hydrological records and organic carbon (OC) data, together with primary production estimates, we evaluated the sequestered OC resulting from soil conservation. Compared with that at baseline in 1950-1970, in which significant soil conservation did not occur, the fate of erosion-induced OC was substantially altered in the period from 2000-2015. Approximately 20.6 Tg of OC were effectively controlled per year by soil conservation efforts. Simultaneously, the decomposition of erosion-induced soil organic carbon (SOC) declined from 8 Tg C yr -1 to current 5.3 Tg C yr -1 . The reduced C emissions (2.7 Tg C yr -1 ) within the Yellow River basin alone account for 12.7% of the mean C accumulation acquired via forest expansion throughout all of China previously assessed. If the accumulated C in restored plants and soils was included, then 9.7 Tg C yr -1 was reduced from the atmospheric C pool during this period, which represents a tremendous C-capturing benefit. Thus, the increased C storage obtained via soil conservation should be considered in future C inventories.

Insect pheromone-binding proteins (PBPs) have been proposed to capture and transport hydrophobic sex pheromone components emitted by con-specific insects to pheromone receptors in the hemolymph of male antennal sensilla. In this study, field trapping results indicate that a mixture of E11-16: Ald and Z11-16: Ald can effectively attract a great number of male Tryporyza intacta. Real-time PCR results suggest that the transcript levels of three TintPBP1-3 genes are mainly expressed in the adult antennae. Fluorescence competitive binding experiments show that TintPBP1-3 proteins have great binding affinities to their major sex pheromones. Moreover, TintPBPs clearly cannot bind to other four kinds of sex pheromone components released by another sugarcane borer, Chilo venosatus and Chilo infuscatellu, which have the same host plant and live in similar habitats like T. intacta. The molecular docking results demonstrate that six amino acid residues of the three TintPBPs are crucial for the specific perception of the sex pheromone components. These results will provide a foundation for the development of novel sex pheromone analogues and blocking agents for biological control of sugarcane pests, improving their efficient monitoring and integrated management strategies in the sugarcane field.

Studies on serum alkaline phosphatase (ALP) and mortality risk in patients with end-stage renal disease (ESRD) undergoing dialysis have yielded conflicting results. This meta-analysis was designed to assess the association of serum ALP levels with cardiovascular or all-cause mortality risk among patients on dialysis. PubMed and Embase databases were searched until March 2017 for studies evaluating the association of serum ALP levels and cardiovascular or all-cause mortality risk in adult patients with ESRD undergoing maintenance hemodialysis or chronic peritoneal dialysis. Twelve studies enrolling 393,200 patients on dialysis were included. Compared with the reference low serum ALP category, pooled adjusted hazard risk (HR) of all-cause mortality was 1.46 (95% confidence interval [CI] 1.30-1.65) for patients on hemodialysis and 1.93 (95% CI 1.71-2.17) for peritoneal patients on dialysis. In addition, elevated serum ALP significantly increased cardiovascular mortality among patients on peritoneal dialysis (HR 2.39; 95% CI 1.23-4.65) but not in patients on hemodialysis (HR 1.08; 95% CI 0.84-1.40). Elevated serum ALP was an independent risk factor for all-cause mortality among patients on hemodialysis or peritoneal dialysis. Further well-designed prospective studies are needed to investigate the association of high serum ALP levels with cardiovascular mortality among patients on dialysis.

Although clinical antibiotic-resistant bacteria have attracted tremendous attention in the microbiology community, the resistant bacteria that persist in natural environments have been overlooked for a longtime. We previously proposed a new species Paramesorhizobium desertii, isolated from the soil of the Taklimakan Desert in China that is highly resistant to most β-lactam antibiotics. To identify potential β-lactamase(s) in this bacteria, we first confirmed the carbapenemase activity in the freeze-thawed supernatant of a P. desertii A-3-E T culture using the modified Hodge assay. We then identified a novel chromosome-encoded carbapenemase (PAD-1) in strain A-3-E T , using a shotgun proteomic analysis of the supernatant and genomic information. The bioinformatics analysis indicated that PAD-1 is a class A carbapenemase. Subsequent enzyme kinetic assays with purified PAD-1 confirmed its carbapenemase activity, which is similar to that of clinically significant class A carbapenemases, including BKC-1 and KPC-2. Because the location in which A-3-E T was isolated is not affected by human activity, PAD-1 is unlikely to be associated with the selection pressures exerted by modern antibiotics. This study confirmed the diversity of antibiotic-resistant determinants in the environmental resistome.

We aimed to conduct an up-to-date meta-analysis to comprehensively assess the renoprotective effect of remote ischemic preconditioning (RIPC) in patients undergoing adult cardiac surgery. 21 randomized controlled trials (RCTs) with a total of 6302 patients were selected and identified. Compared with controls, RIPC significantly reduced the incidence of acute kidney injury (AKI) [odds ratio (OR) = 0.79; P = 0.02; I 2  = 38%], and in particular, AKI stage I (OR = 0.65; P = 0.01; I 2  = 55%). RIPC significantly shortened mechanical ventilation (MV) duration [weighted mean difference (WMD) = -0.79 hours; P = 0.002; I 2  = 53%), and reduced intensive care unit (ICU) stay (WMD = -0.23 days; P = 0.07; I 2  = 96%). Univariate meta-regression analyses showed that the major sources of heterogeneity for AKI stage I were age (coefficient = 0.06; P = 0.01; adjusted R2 = 0.86) and proportion of complex surgery (coefficient = 0.02; P = 0.03; adjusted R2 = 0.81). Subsequent multivariate regression and subgroup analyses also confirmed these results. The present meta-analysis suggests that RIPC reduces the incidence of AKI in adults undergoing cardiac surgery and this benefit was more pronounced in younger patients undergoing non-complex cardiac surgery. RIPC may also shorten MV duration and ICU stay. Future RCTs tailored for those most likely to benefit from RIPC warrants further investigation.

Augmented three-dimensional (3D) subdiffraction-limited resolution of fluorescence-free single-nanoparticles was achieved with wavelength-dependent enhanced dark-field (EDF) illumination and a least-cubic algorithm. Various plasmonic nanoparticles on a glass slide (i.e., gold nanoparticles, GNPs; silver nanoparticles, SNPs; and gold nanorods, GNRs) were imaged and sliced in the z-direction to a thickness of 10 nm. Single-particle images were then compared with simulation data. The 3D coordinates of individual GNP, SNP, and GNR nanoparticles (x, y, z) were resolved by fitting the data with 3D point spread functions using a least-cubic algorithm and collation. Final, 3D super-resolution microscopy (SRM) images were obtained by resolving 3D coordinates and their Cramér-Rao lower bound-based localization precisions in an image space (530 nm × 530 nm × 300 nm) with a specific voxel size (2.5 nm × 2.5 nm × 5 nm). Compared with the commonly used least-square method, the least-cubic method was more useful for finding the center in asymmetric cases (i.e., nanorods) with high precision and accuracy. This novel 3D fluorescence-free SRM technique was successfully applied to resolve the positions of various nanoparticles on glass and gold nanospots (in vitro) as well as in a living single cell (in vivo) with subdiffraction limited resolution in 3D.

New techniques are urgently needed to replace conventional long and costly pre-clinical testing in the new drug administration process. In this study, a laminated microfluidic device was fabricated to mimic the drug ADME response test in vivo. This proposed device was loaded and cultured with functional cells for drug response investigation and organ tissues that are involved in ADME testing. The drug was introduced from the top of the device and first absorbed by the Caco-2 cell layer, and then metabolized by the primary hepatocyte layer. It subsequently interacted with the MCF-7 cell layer, distributed in the lung, heart and fat tissues, and was finally eliminated through the dialysis membrane. Throughout this on-chip ADME process, the proposed device can be used as a reliable tool to simultaneously evaluate the drug anti-tumor activity, hepatotoxicity and pharmacokinetics. Furthermore, this device was proven to be able to reflect the hepatic metabolism of a drug, drug distribution in the target tissues, and the administration method of a drug. Furthermore, this microdevice is expected to reduce the number of drug candidates and accelerate the pre-clinical testing process subject to animal testing upon adaptation in new drug discovery.

Bi-phase dispersible core-shell FeAu@ZnO magneto-opto-fluorescent nanoparticles were synthesized by a modified nanoemulsion process using poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) (PEO-PPO-PEO) as the surfactant. The morphology and crystal structure of the nanoparticles were studied by TEM/HRTEM and XRD. The nanoparticles manifest soft ferromagnetic and/or near superparamagnetic behavior with a small coercivity of ~19 Oe at room temperature. The corresponding magnetic hysteresis curves were elucidated by the modified Langevin equation. The FTIR study confirms the PEO-PPO-PEO molecules on the surface of the nanoparticles. The UV-vis and PL results reveal the well-behaved absorption bands including surface plasmon resonance and multiple visible fingerprint photoluminescent emissions of the nanoparticles dispersed in both hydrophilic and hydrophobic solvents. Moreover, the processes of solvent dispersion-collection of the nanoparticles were demonstrated for application readiness of such core-shell nanostructures.

Super-resolution fluorescence microscopy has generated tremendous success in revealing detailed subcellular structures in animal cells. However, its application to plant cell biology remains extremely limited due to numerous technical challenges, including the generally high fluorescence background of plant cells and the presence of the cell wall. In the current study, stochastic optical reconstruction microscopy (STORM) imaging of intact Arabidopsis thaliana seedling roots with a spatial resolution of 20-40 nm was demonstrated. Using the super-resolution images, the spatial organization of cortical microtubules in different parts of a whole Arabidopsis root tip was analyzed quantitatively, and the results show the dramatic differences in the density and spatial organization of cortical microtubules in cells of different differentiation stages or types. The method developed can be applied to plant cell biological processes, including imaging of additional elements of the cytoskeleton, organelle substructure, and membrane domains.

Super-resolution imaging of fluorescence-free plasmonic nanoparticles (NPs) was achieved using enhanced dark-field (EDF) illumination based on wavelength-modulation. Indistinguishable adjacent EDF images of 103-nm gold nanoparticles (GNPs), 40-nm gold nanorods (GNRs), and 80-nm silver nanoparticles (SNPs) were modulated at their wavelengths of specific localized surface plasmon scattering. The coordinates (x, y) of each NP were resolved by fitting their point spread functions with a two-dimensional Gaussian. The measured localization precisions of GNPs, GNRs, and SNPs were 2.5 nm, 5.0 nm, and 2.9 nm, respectively. From the resolved coordinates of NPs and the corresponding localization precisions, super-resolution images were reconstructed. Depending on the spontaneous polarization of GNR scattering, the orientation angle of GNRs in two-dimensions was resolved and provided more elaborate localization information. This novel fluorescence-free super-resolution method was applied to live HeLa cells to resolve NPs and provided remarkable sub-diffraction limit images.

We describe two experiments demonstrating that a cylindrical cloak formerly introduced for linear surface liquid waves works equally well for sound and electromagnetic waves. This structured cloak behaves like an acoustic cloak with an effective anisotropic density and an electromagnetic cloak with an effective anisotropic permittivity, respectively. Measured forward scattering for pressure and magnetic fields are in good agreement and provide first evidence of broadband cloaking. Microwave experiments and 3D electromagnetic wave simulations further confirm reduced forward and backscattering when a rectangular metallic obstacle is surrounded by the structured cloak for cloaking frequencies between 2.6 and 7.0 GHz. This suggests, as supported by 2D finite element simulations, sound waves are cloaked between 3 and 8 KHz and linear surface liquid waves between 5 and 16 Hz. Moreover, microwave experiments show the field is reduced by 10 to 30 dB inside the invisibility region, which suggests the multi-wave cloak could be used as a protection against water, sonic or microwaves.

Biofilm formation in flea gut is important for flea-borne transmission of Yersinia pestis. There are enhancing factors (HmsHFRS, HmsCDE, and HmsT) and inhibiting one (HmsP) for Yersinia pestis biofilm formation. The RcsAB regulatory complex acts as a repressor of Yesinia biofilm formation, and adaptive pseudogenization of rcsA promotes Y. pestis to evolve the ability of biofilm formation in fleas. In this study, we constructed a set of isogenic strains of Y. pestis biovar Microtus, namely WT (RscB+ and RcsA-), c-rcsA (RscB+ and RcsA+), ΔrcsB (RscB- and RcsA-), and ΔrcsB/c-rcsA (RscB- and RcsA+). The phenotypic assays confirmed that RcsB alone (but not RcsA alone) had an inhibiting effect on biofilm/c-di-GMP production whereas assistance of RcsA to RcsB greatly enhanced this inhibiting effect. Further gene regulation experiments showed that RcsB in assistance of RcsA tightly bound to corresponding promoter-proximal regions to achieve transcriptional repression of hmsCDE, hmsT and hmsHFRS and, meanwhile, RcsAB positively regulated hmsP most likely in an indirect manner. Data presented here disclose that pseudogenization of rcsA leads to dramatic remodeling of RcsAB-dependent hms gene expression between Y. pestis and its progenitor Y. pseudotuberculosis, enabling potent production of Y. pestis biofilms in fleas.