Osteoinductive micro-nano guided bone regeneration membrane for in situ bone defect repair.

BACKGROUND: Biomaterials used in bone tissue engineering must fulfill the requirements of osteoconduction, osteoinduction, and osseointegration. However, biomaterials with good osteoconductive properties face several challenges, including inadequate vascularization, limited osteoinduction and barrier ability, as well as the potential to trigger immune and inflammatory responses. Therefore, there is an urgent need to develop guided bone regeneration membranes as a crucial component of tissue engineering strategies for repairing bone defects. METHODS: The mZIF-8/PLA membrane was prepared using electrospinning technology and simulated body fluid external mineralization method. Its ability to induce biomimetic mineralization was evaluated through TEM, EDS, XRD, FT-IR, zeta potential, and wettability techniques. The biocompatibility, osteoinduction properties, and osteo-immunomodulatory effects of the mZIF-8/PLA membrane were comprehensively evaluated by examining cell behaviors of surface-seeded BMSCs and macrophages, as well as the regulation of cellular genes and protein levels using PCR and WB. In vivo, the mZIF-8/PLA membrane's potential to promote bone regeneration and angiogenesis was assessed through Micro-CT and immunohistochemical staining. RESULTS: The mineralized deposition enhances hydrophilicity and cell compatibility of mZIF-8/PLA membrane. mZIF-8/PLA membrane promotes up-regulation of osteogenesis and angiogenesis related factors in BMSCs. Moreover, it induces the polarization of macrophages towards the M2 phenotype and modulates the local immune microenvironment. After 4-weeks of implantation, the mZIF-8/PLA membrane successfully bridges critical bone defects and almost completely repairs the defect area after 12-weeks, while significantly improving the strength and vascularization of new bone. CONCLUSIONS: The mZIF-8/PLA membrane with dual osteoconductive and immunomodulatory abilities could pave new research paths for bone tissue engineering.

Protective effect of alizarin on vascular endothelial dysfunction via inhibiting the type 2 diabetes-induced synthesis of THBS1 and activating the AMPK signaling pathway.

BACKGROUND: In this study, we investigated the protective effects of alizarin (AZ) on endothelial dysfunction (ED). AZ has inhibition of the type 2 diabetes mellitus (T2DM)-induced synthesis of thrombospondin 1 (THBS1). Adenosine 5'-monophosphate- activated protein kinase (AMPK), particularly AMPKα2 isoform, plays a critical role in maintaining cardiac homeostasis. PURPOSE: The aim of this study was to investigate the ameliorative effect of AZ on vascular injury caused by T2DM and to reveal the potential mechanism of AZ in high glucose (HG)-stimulated human umbilical vein endothelial cells (HUVECs) and diabetic model rats. STUDY DESIGN: HUVECs, rats and AMPK-/- transgenic mice were used to investigate the mitigating effects of AZ on vascular endothelial dysfunction caused by T2DM and its in vitro and in vivo molecular mechanisms. METHODS: In type 2 diabetes mellitus rats and HUVECs, the inhibitory effect of alizarin on THBS1 synthesis was verified by immunohistochemistry (IHC), immunofluorescence (IF) and Western blot (WB) so that increase endothelial nitric oxide synthase (eNOS) content in vitro and in vivo. In addition, we verified protein interactions with immunoprecipitation (IP). To probe the mechanism, we also performed AMPKα2 transfection. AMPK's pivotal role in AZ-mediated prevention against T2DM-induced vascular endothelial dysfunction was tested using AMPKα2-/- mice. RESULTS: We first demonstrated that THBS1 and AMPK are targets of AZ. In T2DM, THBS1 was robustly induced by high glucose and inhibited by AZ. Furthermore, AZ activates the AMPK signaling pathway, and recoupled eNOS in stressed endothelial cells which plays a protective role in vascular endothelial dysfunction. CONCLUSIONS: The main finding of this study is that AZ can play a role in different pathways of vascular injury due to T2DM. Mechanistically, alizarin inhibits the increase in THBS1 protein synthesis after high glucose induction and activates AMPKα2, which increases NO release from eNOS, which is essential in the prevention of vascular endothelial dysfunction caused by T2DM.

Metformin alleviates cerebral ischemia/reperfusion injury aggravated by hyperglycemia via regulating AMPK/ULK1/PINK1/Parkin pathway-mediated mitophagy and apoptosis.

Stroke remains the main leading cause of death and disabilities worldwide, with diabetes mellitus being a significant independent risk factor for it. Metformin, as an efficient hypoglycemic drug in treating type 2 diabetes, has been reported to alleviate the risk of diabetes-related stroke. However, its underlying mechanisms remain unclear. This study aimed to investigate the role of mitophagy and its regulatory pathway in the neuroprotective mechanism of metformin against cerebral ischemia/reperfusion (I/R) injury aggravated by hyperglycemia. A hyperglycemic cerebral I/R animal model and a high glucose cultured oxygen-glucose deprivation/reperfusion (OGD/R) cell model were used in the experiment. The indexes of brain injury, cell activity, mitochondrial morphology and function, mitophagy, mitochondrial pathway apoptosis and the AMPK pathway were observed. In diabetic rats, metformin treatment decreased cerebral infarction volume and neuronal apoptosis, and improved neurological symptoms following I/R injury. Additionally, metformin induced activation of the AMPK/ULK1/PINK1/Parkin mitophagy pathway to have neuroprotective effects. In vitro, high glucose culture and OGD/R treatment impaired mitochondrial morphology and function, mitochondrial membrane potential, and induced apoptosis. However, metformin activated AMPK/ULK1/PINK1/Parkin mitophagy pathway, normalized mitochondrial injury. This protection was reversed by autophagy inhibitor 3-methyladenine (3MA) and AMPK inhibitor compound C. In conclusion, our present study validates the potential mechanism of metformin in alleviating hyperglycemia aggravated cerebral I/R injury by the activation of AMPK/ULK1/PINK1/Parkin mitophagy pathway.

Ancient Mitochondrial Genomes Provide New Clues to the Origin of Domestic Cattle in China.

Cattle are one of the six livestock species that have occupied an important place in Chinese history. Previous ancient DNA studies have indicated that Chinese taurine cattle (Bos taurus taurus) are exotic, but the exact route and diffusion by which they were introduced to China is unknown. In this study, we extracted the mitochondrial genomes of 34 cases of ancient taurine cattle (from the late Neolithic to Qin and Han dynasties) excavated from sites in northern China and the eastern Eurasian steppe, and successfully obtained 14 mitochondrial genome sequences. The results of ancient DNA analysis reveal that with cultural exchange and trade, there was close genetic exchange between domestic taurine cattle in different regions. The haplotypes shared by domestic cattle have genetic continuity, reflecting the strong cultural influence of the large capital city sites such as Taosi, Shimao and Erlitou on the surrounding areas. This study suggests that ancient northern Chinese taurine cattle may have accompanied the westward transmission of agricultural or painted pottery culture and thus had a maternal genetic contribution to modern Tibetan cattle.

A method for simulating spatial fates of chemicals in flowing lake systems: Application to phthalates in a lake.

In order to describe spatio-temporal distribution of chemicals in flowing lake systems, a dynamic multimedia fate model of chemicals with spatial differentiation was constructed by coupling the level IV fugacity model with lake hydrodynamics. It was successfully applied to four phthalates (PAEs) in a lake recharged by reclaimed water and its accuracy was verified. Results show that under the long-term influence of flow field, the distributions of PAEs in both lake water and sediment have significant spatial heterogeneity of 2∼5 orders of magnitude, but present different distribution rules, which was explained by analysis of PAE transfer fluxes. The spatial distribution of PAEs in the water column depends on hydrodynamic conditions and whether the primary source is reclaimed water or atmospheric input. Slow water exchange and flow speed promote the migration of PAEs from water to sediment, causing them to always accumulate in sediments far away from the recharging inlet. Uncertainty and sensitivity analysis show that the PAE concentrations in water phase are mainly affected by emission and physicochemical parameters, while those in sediment phase are also sensitive to environmental parameters. The model can provide important information and accurate data support for the scientific management of chemicals in flowing lake systems.

Pollution characteristics of typical ARGs in the sediments of the sea area adjacent to the Yangtze Estuary, China.

The pollution characteristics of the typical antibiotic resistance genes (ARGs) in the sediments of the sea area adjacent to the Yangtze Estuary, China were investigated with both seasonal and spatial insights. The positive rates of sulfonamides sul1, sul2, tetracycline tetW and quinolone gyrA resistance genes in the sediments of all sampling sites were 100%, indicating that the sea area adjacent to the Yangtze Estuary were extensively polluted by these ARGs. Occupying a dominance in most sampling sites, sul1 was found to be the dominant resistance gene in the sediments of the sea area adjacent to the Yangtze Estuary. In terms of seasonal variation characteristics, the absolute abundances of the ARGs in flood season were higher than those in dry season. In terms of spatial distribution characteristics, the absolute abundances of the ARGs in the southern sites were mostly higher than those in the northern sites, and the high abundance sites were mostly located near the coast. Different ARGs also showed different spatial distribution characteristics. The disclosure of the pollution characteristics of the typical ARGs in the sediments of the sea area adjacent to the Yangtze Estuary can provide valued information for protecting the environment of this area as well as the Yangtze River Basin.

Fate of phthalates in a river receiving wastewater treatment plant effluent based on a multimedia model.

Phthalic acid esters (PAEs) can enter environment media by secondary effluent discharge from wastewater treatment plants (WWTP) into receiving rivers, thus posing a threat to ecosystem health. A level III fugacity model was established to simulate the fate and transfer of four PAEs in a study area in Tianjin, China, and to evaluate the influence of WWTP discharge on PAEs levels in the receiving river. The results show that the logarithmic residuals of most simulated and measured values of PAEs are within one order of magnitude with a good agreement. PAEs in the study area were mainly distributed in soil and sediment phases, which accounted for 84.66%, 50.26%, 71.96% and 99.09% for dimethyl phthalate (DMP), diethyl phthalate (DEP), dibutyl phthalate (DBP) and di-(2-ethylhexyl) phthalate (DEHP), respectively. The upstream advection accounted for 77.90%, 93.20%, 90.21% and 90.93% of the total source of DMP, DEP, DBP and DEHP in the river water, respectively, while the contribution of secondary effluent discharge was much lower. Sensitivity analysis shows that emission and inflow parameters have greater influences on the multimedia distributions of PAEs than physicochemical and environmental parameters. Monte Carlo analysis quantifies the uncertainties and verifies the reliability of the simulation results.

Radiocarbon and genomic evidence for the survival of Equus Sussemionus until the late Holocene.

The exceptionally rich fossil record available for the equid family has provided textbook examples of macroevolutionary changes. Horses, asses, and zebras represent three extant subgenera of Equus lineage, while the Sussemionus subgenus is another remarkable Equus lineage ranging from North America to Ethiopia in the Pleistocene. We sequenced 26 archaeological specimens from Northern China in the Holocene that could be assigned morphologically and genetically to Equus ovodovi, a species representative of Sussemionus. We present the first high-quality complete genome of the Sussemionus lineage, which was sequenced to 13.4× depth of coverage. Radiocarbon dating demonstrates that this lineage survived until ~3500 years ago, despite continued demographic collapse during the Last Glacial Maximum and the great human expansion in East Asia. We also confirmed the Equus phylogenetic tree and found that Sussemionus diverged from the ancestor of non-caballine equids ~2.3-2.7 million years ago and possibly remained affected by secondary gene flow post-divergence. We found that the small genetic diversity, rather than enhanced inbreeding, limited the species' chances of survival. Our work adds to the growing literature illustrating how ancient DNA can inform on extinction dynamics and the long-term resilience of species surviving in cryptic population pockets.

Citronellal alleviate macro- and micro-vascular damage in high fat diet / streptozotocin - Induced diabetic rats via a S1P/S1P1 dependent signaling pathway.

Citronellal (CT) is an acyclic monoterpene aldehyde isolated from lemon citronella, which could ameliorate vascular endothelial dysfunction in atherosclerosis in our previous study, however, whether CT can alleviate vascular endothelial dysfunction related with type 2 diabetes (T2DM) is still unknown. So, we investigated the role of CT in vascular dysfunction related to T2DM and the mechanism involved. T2DM rat model was induced by a single intraperitoneal injection of low-dose streptozotocin (STZ) (60 mg/kg) to rats fed with high-fat diet (HFD) (4 weeks). After treated with CT (150 mg/kg/d), both the thoracic aorta injury and micro-vascular pathological injury in T2DM rats ex vivo were alleviated, and the oxidative stress in T2DM rats treated with CT were attenuated, manifested as increased content of endothelial nitric oxide synthase (eNOS) and superoxide dismutase (SOD), and decreased content of malondialdehyde (MDA). Furthermore, CT (15 µg/L) increased the migration capacity of human umbilical vein endothelial cells (HUVECs) under high glucose circumstance (30 mM), and increased the endothelial-dependent relaxation in thoracic aorta isolated from T2DM rats in vitro. Finally, all of these effects of CT were blocked by fingolimod (FTY720), a sphingosine-1-phosphate receptor agonist, and the expression of sphingosine-1-phosphate receptor 1 (S1P1) was increased by CT. In conclusion, CT improved vascular function through S1P/S1P1 signaling pathway.

Visual question answering model for fruit tree disease decision-making based on multimodal deep learning.

Visual Question Answering (VQA) about diseases is an essential feature of intelligent management in smart agriculture. Currently, research on fruit tree diseases using deep learning mainly uses single-source data information, such as visible images or spectral data, yielding classification and identification results that cannot be directly used in practical agricultural decision-making. In this study, a VQA model for fruit tree diseases based on multimodal feature fusion was designed. Fusing images and Q&A knowledge of disease management, the model obtains the decision-making answer by querying questions about fruit tree disease images to find relevant disease image regions. The main contributions of this study were as follows: (1) a multimodal bilinear factorized pooling model using Tucker decomposition was proposed to fuse the image features with question features: (2) a deep modular co-attention architecture was explored to simultaneously learn the image and question attention to obtain richer graphical features and interactivity. The experiments showed that the proposed unified model combining the bilinear model and co-attentive learning in a new network architecture obtained 86.36% accuracy in decision-making under the condition of limited data (8,450 images and 4,560k Q&A pairs of data), outperforming existing multimodal methods. The data augmentation is adopted on the training set to avoid overfitting. Ten runs of 10-fold cross-validation are used to report the unbiased performance. The proposed multimodal fusion model achieved friendly interaction and fine-grained identification and decision-making performance. Thus, the model can be widely deployed in intelligent agriculture.

Perillaldehyde improves cognitive function in vivo and in vitro by inhibiting neuronal damage via blocking TRPM2/NMDAR pathway.

BACKGROUND: Vascular cognitive dysfunction in patients with vascular dementia (VD) is a kind of severe cognitive dysfunction syndrome caused by cerebrovascular diseases. At present, effective drugs to improve the cognitive function of VD patients still need to be explored. Transient Receptor Potential Melastatin 2 (TRPM2) channel is a nonspecific cation channel that plays a key role in the toxic death of neurons. Perillaldehyde (PAE) has the protective effect of epilepsy and insomnia and other central nervous system diseases. The aim of this study is to explore whether PAE improves cognitive function in VD rats and to investigate the potential mechanisms in vivo and vitro. METHODS: VD rats were induced by bilateral common carotid arteries occlusion (2-vessel occlusion [2VO]) and treated with PAE for 4 weeks. The neuroprotective effects of PAE was subsequently assessed by the Morris water maze, hematoxylin-eosin (HE) staining, Golgi staining, electron microscopy, Neuron-specific nuclear protein (Neu N) staining, and TdT-mediated dUTP nick end labeling (TUNEL) staining. After primary hippocampal neurons were isolated, cell viability was detected by MTT assay and intracellular Ca2+ concentration was detected by calcium imaging assay. The content of Nitriteoxide (NO), Malondialdehyde (MDA) and Superoxide dismutase (SOD) activity in serum of rats were observed by Enzyme Linked Immunosorbent Assay (ELISA). Immunohistochemistry, Western blot, and Confocal laser scanning were used to detect the expression levels of N-methyl-D-asprtate receptor-2B (NR2B) and TRPM2. RESULTS: The results showed that PAE can improve the number and activity of neurons, increase the length and number of dendrites in hippocampus, decrease the Vv value and PE value of neuronal nucleus and mitochondrial structure significantly, increase the s value and L value in nucleus structure, decrease the s value and L value in mitochondrial structure, and improve the learning and memory ability of rats significantly. And PAE can strengthen the ability of antioxidant stress confirmed by increasing the activity of SOD and reducing the production of MDA. The results of western blot, immunohistochemistry and immunofluorescence showed that PAE could reduce the level of TRPM2 and increase the expression of NR2B. CONCLUSIONS: Taken together, our findings provide evidence that the neuroprotective effects of PAE in VD rats maybe through TRPM2 inhibition and subsequent activation of NMDAR signaling pathway.

NiCoP with Dandelion-like Arrays Anchored on Nanowires for Electrocatalytic Overall Water Splitting.

Although transition-metal-based phosphides as cost-effective catalysts have great potential for transforming water to hydrogen, their electrocatalytic property for industrial application is still limited. Herein, we focus on developing amorphous NiCoP with dandelion-like arrays anchored on nanowires through a universal strategy of hydrothermal and phosphorization. The hierarchical structure features in larger catalytic surface areas expedited reaction kinetics and improved structural stability. Benefiting from these merits, the NiCoP reaches 10 mA cm-2 at an overpotential of mere 57 mV for a hydrogen evolution reaction in standard solution. Also, a profound activity for the generation of oxygen is along with it, which requires 276 mV to attain 10 mA cm-2. Moreover, it demonstrates satisfying durability for both processes.

KLF2 Inhibits Chicken Preadipocyte Differentiation at Least in Part via Directly Repressing PPARγ Transcript Variant 1 Expression.

Peroxisome proliferator-activated receptor gamma (PPARγ) is the master regulatory factor of preadipocyte differentiation. As a result of alternative splicing and alternative promoter usage, PPARγ gene generates multiple transcript variants encoding two protein isoforms. Krüppel-like factor 2 (KLF2) plays a negative role in preadipocyte differentiation. However, its underlying mechanism remains incompletely understood. Here, we demonstrated that KLF2 inhibited the P1 promoter activity of the chicken PPARγ gene. Bioinformatics analysis showed that the P1 promoter harbored a conserved putative KLF2 binding site, and mutation analysis showed that the KLF2 binding site was required for the KLF2-mediated transcription inhibition of the P1 promoter. ChIP, EMSA, and reporter gene assays showed that KLF2 could directly bind to the P1 promoter regardless of methylation status and reduced the P1 promoter activity. Consistently, histone modification analysis showed that H3K9me2 was enriched and H3K27ac was depleted in the P1 promoter upon KLF2 overexpression in ICP1 cells. Furthermore, gene expression analysis showed that KLF2 overexpression reduced the endogenous expression of PPARγ transcript variant 1 (PPARγ1), which is driven by the P1 promoter, in DF1 and ICP1 cells, and that the inhibition of ICP1 cell differentiation by KLF2 overexpression was accompanied by the downregulation of PPARγ1 expression. Taken together, our results demonstrated that KLF2 inhibits chicken preadipocyte differentiation at least inpart via direct downregulation of PPARγ1 expression.

Status of insecticide resistance and biochemical characterization of chlorpyrifos resistance in Sogatella furcifera (Hemiptera:Delphacidae) in Sichuan Province, China.

The white-backed planthopper, Sogatella furcifera (Horváth) (Hemiptera, Delphacidae), is an energetic rice insect pest in rice production or rice-growing areas. Due to excessive use of the chemical insecticide, S. furcifera has produced the high resistance to some frequently used insecticides. In this paper, the resistance levels of S. furcifera from the eight different areas of Sichuan Province against the five chemicals were monitored by using the rice seedling dipping during 2017-2018 to understand the resistance levels. The results showed that most of all populations have developed low or moderate level of resistance for chlorpyrifos (3.4 to 44.3-fold) and thiamethoxam (3.9- to 15.5-fold), the populations in the LS (1.7 to 5.4- fold)and WS (1.6 to 5.0- fold) regions were still sensitive or low resistance levels compared with other local populations. Almost all populations displayed the susceptible to imidacloprid (0.9- to 5.0-fold), buprofezin (0.9- to 4.3-fold) or low levels of resistance to pymetrozine (1.5- to 6.8-fold). The synergism experiment indicated that P450 enzymes may be important contributed to the metabolic detoxification of chlorpyrifos. The cross-resistance bioassay showed that there was no cross-resistance between chlorpyrifos and triflumezopyrim, but for sulfoxaflor, in the XY17 population. The relative expression level of twelve insecticide resistant-related P450 genes were analyzed by using qRT-PCR and found that CYP4C77, CYP418A1, CYP418A2, CYP408A3 and CYP6ER4 were significantly more expressed in the 3rd-instar nymph of the XY17 and XY18 field populations. To determine the main resistant-related P450 gene for chlorpyrifos, the relative expression level of five P450 genes were detected by using qRT-PCR from the G2 and G4 generation of XY17 under the pressure with LC50 of chlorpyrifos. The results showed that CYP6ER4 was significantly up-regulated expression in XY17 G2 and G4 generations population over 700-fold (P < 0.01). The full length and proteins tertiary structure were also cloned and predicted. Meanwhile, the function of CYP6ER4 was analyzed by RNA interference and the results indicated that the relative expression of CYP6ER4 in the XY17 (G4) population after injected dsRNA was lower than that in the dsGFP injected group. Moreover, the mortality rates of the S. furcifera treated with the LC50 concentration of chlorpyrifos after dsRNA microinjection was significantly higher than that of the dsGFP injected group 72 h after treatment (P < 0.01). Therefore, the overexpression of CYP6ER4 may be one of the primary factors in the development of chlorpyrifos resistance in S. furcifera.

Peroxisome proliferator-activated receptor γ isoforms differentially regulate preadipocyte proliferation, apoptosis, and differentiation in chickens.

Peroxisome proliferator-activated receptor γ (PPARγ) has 2 protein isoforms (PPARγ1 and PPARγ2) generated by alternative promoter usage and alternative splicing. However, their functional uniqueness and similarity remain unclear. In the study, we investigated the effects of lentivirus-mediated overexpression of PPARγ1 and PPARγ2 on proliferation, apoptosis, and differentiation of the immortalized chicken preadipocytes. Cell Counting Kit-8 assay showed PPARγ1 and PPARγ2 overexpression markedly suppressed cell proliferation, and fluorescence activated cell sorting analysis showed that PPARγ1 and PPARγ2 overexpression caused cell cycle arrest at G0/G1 phase. Cell death detection ELISA analysis showed both PPARγ1 and PPARγ2 overexpression induced cell apoptosis. Oil red O staining and gene expression analysis showed both PPARγ1 and PPARγ2 overexpression promoted preadipocyte differentiation. In the presence of PPARγ ligand, rosiglitazone, PPARγ2 overexpression was more potent in inducing apoptosis, promoting adipogenesis, and suppressing cell proliferation than PPARγ1 overexpression. We further explored the molecular basis for their functional differences. Reporter gene assay showed that under ligand conditions, PPARγ2 overexpression resulted in 1.68-fold increase in transcription activity compared with PPARγ1. Electrophoretic mobility shift assay showed both PPARγ1 and PPARγ2 could bind to PPAR response element (PPRE) as heterodimer with retinoid X receptor alpha, and by comparison, PPARγ2 had a higher affinity for PPRE than PPARγ1. Reporter gene assay showed expression PPARγ1 and PPARγ2 similarly induced fatty acid synthase and adipocyte fatty acid-binding protein promoter activity but differentially induced lipoprotein lipase and perilipin 1 promoter activities. Coimmunoprecipitation analysis showed that PPARγ1 and PPARγ2 interacted similarly with the coactivators, Tat-interacting protein 60. Taken together, our results demonstrate that PPARγ1 and PPARγ2 differentially regulate preadipocyte proliferation, apoptosis, and differentiation as a result of their distinct and overlapping molecular functions.

Effect of initiation of renal replacement therapy on mortality in acute pancreatitis patients.

This study aims to explore effect of initiation of renal replacement therapy (RRT) on mortality in acute pancreatitis (AP) patients. In this study, a total of 92 patients from the surgical intensive care unit (SICU) of the Second Affiliated Hospital of Harbin Medical University who were diagnosed with AP and underwent RRT or not between January 2014 and December 2018 were included in this retrospective study. Demographic and clinical data were obtained on admission to SICU. Patients were divided into early initiation of RRT group (n = 44) and delayed initiation of RRT group (n = 48). Duration of mechanical ventilation (MV), intra-peritoneal pressure, vasopressors infusion, body temperature, procalcitonin, creatinine, platelet counts, length of hospital stay and prognosis were recorded during hospitalization, and then compared between groups. Patients with delayed initiation of RRT exhibited significantly higher APACHE II score, SOFA score and lower GCS score than those with early initiation of RRT (P < 0.001, <0.001,  = 0.04, respectively). No difference in the rest of the baseline data and vasopressors infusion was found. Dose of Norepinephrine, maximum and mean PCT, maximum and mean creatinine, maximum and mean intra-peritoneal pressure, length of hospital stay, prognosis of ICU and hospitalization showed significant difference between groups. Early initiation of RRT may be beneficial for AP patients, which can provide some insight and support for patients' treatment in clinic.

NIR-II Fluorescence Imaging of Skin Avulsion and Necrosis.

Skin avulsion is commonly seen in individuals exposed to heavy shearing forces. Subcutaneous tissue detachment and bone fractures usually accompany skin avulsion. Thus, the estimation of the extent of damaged tissue is very important. Currently, the viability of skin and subcutaneous tissue is determined by clinical observations, and these observations always underestimate the true extent of the avulsed skin. Herein, we synthesized an innovative probe, CH1055-GRRRDEVDK (CH1055-GK), which can specifically bind to caspase-3 so as to image skin avulsion and define necrotic regions. Our uptake and binding affinity tests in apoptotic cells and evaluation of the probe ex vivo and in vivo showed that the probe has a strong ability to bind caspase-3 in skin avulsion models and that it vividly detected the necrotic area in avulsed skins. Furthermore, the increased fluorescence intensity of the probe in the avulsed skin showed a larger affected area than that determined by clinical observations in live mice. Consequently, our results indicated that observation of the caspase-3-targeted probe CH1055-GK via NIR-II imaging allowed the clear detection of skin avulsion in subjects, indicating its potential as an imaging tool for the early diagnosis of skin avulsion and the determination of necrotic margins.

The Wnt/ß-Catenin/LEF1 Pathway Promotes Cell Proliferation at Least in Part Through Direct Upregulation of miR-17-92 Cluster.

The miR-17-92 cluster is involved in animal development and homeostasis, and its dysregulation leads to human diseases such as cancer. In the present study, we investigated the functional link between miR-17-92 cluster and Wnt/ß-catenin signaling pathway in ICP2 and DF1 cells. We demonstrated that ectopic expression of either LEF1 or ß-catenin increased the promoter activity of the miR-17-92 cluster host gene (MIR17HG) and combined ectopic expression of LEF1 and ß-catenin further enhanced the promoter activity; while knockdown of either LEF1 or ß-catenin reduced the MIR17HG promoter activity. Both LEF1 and ß-catenin could directly bind to the MIR17HG promoter. Furthermore, we demonstrated that low doses of lithium chloride (LiCl), an activator of Wnt/ß-catenin signaling pathway, increased MIR17HG promoter activity and the endogenous expression of the miR-17-92 cluster, while high doses of LiCl had the opposite effects. Treatment with XAV-939, an inactivator of the Wnt/ß-catenin pathway, reduced the endogenous expression of miR-17-92 cluster. Finally, we found that low doses of LiCl promoted the proliferation of ICP2 and DF1 cells, while high doses of LiCl inhibited the proliferation of ICP2 and DF1 cells. Taken together, our results reveal that MIR17HG is a target of LEF1 and the Wnt/ß-catenin pathway and suggest that the miR-17-92 cluster may, at least in part, mediate the proliferation-promoting effect of the Wnt/ß-catenin pathway in cell proliferation.

A NIR-II fluorescent probe for articular cartilage degeneration imaging and osteoarthritis detection.

Articular cartilage (AC) is a complex water-bearing tissue consisting of chondrocytes, proteoglycans, and collagen. AC degeneration, which occurs in the early stage and throughout the entire course of osteoarthritis (OA), is one of the main pathological changes of OA. However, current clinical approaches are unable to detect AC degradation during the early stage of OA. Herein, a novel NIR-II probe, CH1055-WL, was developed with an organic fluorophore (CH1055) and type II collagen-binding peptide (WYRGRL) for AC targeting and degeneration imaging. In vitro and in vivo imaging studies demonstrated that CH1055-WL specifically bound to AC and permitted sensitive detection of age-related or surgically induced AC degeneration in living mice. In vitro imaging of cartilage samples from pig knee joint and in vivo imaging of live mice with the probe administered via local injection in joint cavities demonstrated that CH1055-WL specifically and efficiently bound to AC. Further evaluation of CH1055-WL revealed sensitive detection of age-related AC degeneration and surgically induced AC degeneration in living mice. Our results indicated that the cartilage-targeting probe CH1055-WL allowed visual monitoring of AC degeneration in living subjects, thus displaying promise for early OA detection.