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Abstract Eastern equine encephalitis virus (EEEV) is the most virulent alphavirus that infects humans, and many survivors develop neurological sequelae, including paralysis and intellectual disability. Alphavirus spike proteins comprise trimers of heterodimers of glycoproteins E2 and E1 that mediate binding to cellular receptors and fusion of virus and host cell membranes during entry. We recently identified very-low density lipoprotein receptor (VLDLR) and apolipoprotein E receptor 2 (ApoER2) as cellular receptors for EEEV and a distantly related alphavirus, Semliki Forest virus (SFV). Here, we use single-particle cryo-electron microscopy (cryo-EM) to determine structures of the EEEV and SFV spike glycoproteins bound to the VLDLR ligand-binding domain and found that EEEV and SFV interact with the same cellular receptor through divergent binding modes. Our studies suggest that the ability of LDLR-related proteins to interact with viral spike proteins through very small footprints with flexible binding modes results in a low evolutionary barrier to the acquisition of LDLR-related proteins as cellular receptors for diverse sets of viruses.

Abstract Background Additional resection for invasive cancer at perihilar cholangiocarcinoma (pCCA) resection margins has become a consensus. However, controversy still exists regarding whether additional resection is necessary for residual biliary intraepithelial neoplasia (BilIN). Method Consecutive patients with pCCA from two hospitals were enrolled. The incidence and pattern of resection margin BilIN were summarized. Prognosis between patients with negative margins (R0) and BilIN margins were analyzed. Cox regression with a forest plot was used to identify independent risk factors associated with overall survival (OS) and recurrence-free survival (RFS). Subgroup analysis was performed based on BilIN features and tumor characteristics. Results 306 pCCA patients receiving curative resection were included. 255 had R0 margins and 51 had BilIN margins. There was no significant difference in OS (P = 0.264) or RFS (P = 0.149) between the two group. Specifically, 19 patients with BilIN at distal bile ducts and 32 at proximal bile ducts. 42 patients showed low-grade BilIN, and 9 showed high-grade. Further analysis revealed no significant difference in long-term survival between different locations (P = 0.354), or between different grades (P = 0.772). Portal vein invasion, poor differentiation and lymph node metastasis were considered independent risk factors for OS and RFS, while BilIN was not. Subgroup analysis showed no significant difference in long-term survival between the lymph node metastasis subgroup, or between the portal vein invasion subgroup. Conclusion For pCCA patients underwent curative resection, residual BilIN at resection margin is acceptable. Additional resection is not necessary for such patients to achieve absolute R0 margin.

Geological conditions and rainfall intensity are two primary factors that can induce changes in groundwater level, which are one of the major triggering causes of geological disasters, such as collapse, landslides, and debris flow. In view of this, an improved TANK model is developed based on the influence of rainfall intensity, terrain, and geological conditions on the groundwater level in order to effectively predict the groundwater level evolution of rainfall landslides. A trapezoidal structure is used instead of the traditional rectangular structure to define the nonlinear change in a water level section to accurately estimate the storage of groundwater in rainfall landslides. Furthermore, big data are used to extract effective features from large-scale monitoring data. Here, we build prediction models to accurately predict changes in groundwater levels. Monitoring data of the Taziping landslide are taken as the reference for the study. The simulation results of the traditional TANK model and the improved TANK model are compared with the actual monitoring data, which proves that the improved TANK model can effectively simulate the changing trend in the groundwater level with rainfall. The study can provide a reliable basis for predicting and evaluating the change in the groundwater state in rainfall-type landslides.

Background: Comorbid chronic neuropathic pain (NPP) and anxio-depressive disorders (ADD) have become a serious global public-health problem. The SLIT and NTRK-like 1 (SLITRK1) protein is important for synaptic remodeling and is highly expressed in the amygdala, an important brain region involved in various emotional behaviors. We examined whether SLITRK1 protein in the amygdala participates in NPP and comorbid ADD. Methods: A chronic NPP mouse model was constructed by L5 spinal nerve ligation; changes in chronic pain and ADD-like behaviors were measured in behavioral tests. Changes in SLITRK1 protein and excitatory synaptic functional proteins in the amygdala were measured by immunofluorescence and Western blot. Adeno-associated virus was transfected into excitatory synaptic neurons in the amygdala to up-regulate the expression of SLITRK1. Results: Chronic NPP-related ADD-like behavior was successfully produced in mice by L5 ligation. We found that chronic NPP and related ADD decreased amygdalar expression of SLITRK1 and proteins important for excitatory synaptic function, including Homer1, postsynaptic density protein 95 (PSD95), and synaptophysin. Virally-mediated SLITRK1 overexpression in the amygdala produced a significant easing of chronic NPP and ADD, and restored the expression levels of Homer1, PSD95, and synaptophysin. Conclusion: Our findings indicated that SLITRK1 in the amygdala plays an important role in chronic pain and related ADD, and may prove to be a potential therapeutic target for chronic NPP-ADD comorbidity.

Objective To investigate the establishment of a competitive performance evaluation management program for blood centers to ensure the blood supply. Methods A competitive performance evaluation system for Blood Donor Service Department of blood centers in eastern Shenzhen was established. The data concerning blood collection after (May to October 2021, the experiment group) and before (the corresponding period in 2020, the control) the launch of evaluation system was compared, including the proportion of total/novel blood donors in fixed donation sites, the donation rate of 400 mL and pre-collection deferral rate; collected units per shift, the average collection volume of staff, and the growth rate of per capita donation; the proportion of first-time/repeated/double-dose platelet apheresis donors; the proportion of transfer-in/transfer-out of red blood cells; the ratio of group to street blood donors. Results The proportion of total/novel blood donors in fixed donation sites(81.13% vs 75.87%), the donation rate of 400 mL(58.14% vs 57.91%) and pre-collection deferral rate(76.55% vs 65.92%) in the experimental group was higher than that of the control, while the proportion of pre-collection deferral was lower(18.87% vs 24.13%) (P

Objective To explore the application effect of target management combined with intelligent display system on apheresis platelet donor recruitment. Methods Control group: 317 apheresis platelet donors were recruited according to the conventional appointment mode of intelligent display system from October 2020 to March 2021, with a total of 1 073 donations. Experimental group: 404 apheresis platelet donors were recruited using quantitative target management plus the intelligent display system from April 2021 to September 2021, with a total of 1 308 donations. The number of first-time donors, repeated donors, recalled donors after first-time donation, and their corresponding donations, as well as the double-dose collection rate, and the transfer-in/-out of platelet product were analyzed and compared. Results The number of first-time donors increased from 89 (28.08%) to 179 (44.31%) while repeated donors decreased from 228 (71.92%) to 225 (55.69%), all P0.05.The cumulative number of first-time and repeated platelet donors increased from 149 (13.89%) to 331 (25.31%), and 924 (86.11%) to 977 (74.69%), respectively(all P0.05). The double-dose collection rate decreased from 24.70% (265/1 073) to 13.46% (176/1 308)(P

A hydrogel system loaded with mesenchymal stem cell–derived exosome (MSC-Exos) is an attractive new tool for tissue regeneration. However, the effect of the stiffness of exosome-loaded hydrogels on tissue regeneration is unclear. Here, the role of exosome-loaded hydrogel stiffness, during the regeneration of injured nerves, was assessed in vivo. The results showed that the photocrosslinkable hyaluronic acid methacrylate hydrogel stiffness plays an important role in repairing nerve injury. Compared with the stiff hydrogels loaded with exosomes, soft hydrogels loaded with exosomes showed better repair of injured peripheral nerves. The soft hydrogel promoted nerve repair by quickly releasing exosomes to inhibit the infiltration of macrophages and the expression of the proinflammatory factors IL-1β and TNF-α in injured nerves. Our work revealed that exosome-loaded hydrogel stiffness plays an important role in tissue regeneration by regulating exosome release behavior and provided important clues for the clinical application of biological scaffold materials.

The severity of a landslide-debris flow is determined by such factors as the speed, deposition morphology and impact force of the sliding body. Differences in the lithological characteristics and structural distribution of the sliding source area lead to differences in the particle order distribution and particle size of the sliding body. During the movement, the collision, friction, and jumping between the particles affect the degree of hazard of the landslide-debris flow. Based on the physical model test, the dimensional discrete element software PFC3D is used to explore the influence of the particle order distribution and particle size on the speed, stacking morphology and impact force. The results show that the average velocity of particles in the debris flow is affected by both the particle size and the initial particle order in the slip source region, and the initial particle order has a greater effect on the average velocity of particles. The particle size has a greater effect on the particle order arrangement in the thickness direction, while the particle order distribution in the slip source area has a greater effect on the deposition morphology. Under the effect of particle-size segregation, the particle size becomes the main factor controlling the peak impact force and the slip source. The particle sequence distribution in the slip source area determines the accumulation morphology, which controls the impact force of the debris flow in the quasi-static accumulation stage.

The spike (S) protein of coronaviruses is responsible for receptor recognition and the fusion between the viral membrane and the of cell host membrane. Here the authors report a cryo-EM structure of SARS-CoV post-fusion S2 trimer, providing insights into the fusion mechanism that could be useful for therapeutic development against coronaviruses.

Abstract Background MicroRNA-125b (miR-125b) is downregulated in human cutaneous squamous cell carcinoma (CSCC). However, its function in CSCC has yet to be extensively explored. Here, we analyze the relationship between signal transducer and activator of transcription 3 (STAT3) and miR-125b in CSCC. Methods Western blotting and quantitative RT-PCR were used to determine the expression of the miR-125b–STAT3 axis in human CSCC tissues and cell lines. The direct regulatory effect of miR-125b on STAT3 expression was assessed using a luciferase reporter gene assay and RNA immunoprecipitation assay. The MTT assay and flow cytometry were used to determine the role of the miR-125b–STAT3 axis in CSCC cell proliferation and apoptosis. Results MiR-125b expression levels were significantly lower in CSCC cell lines and tissues than in normal cell lines and tissues. STAT3 was identified as the direct target of miR-125b. Upregulation of miR-125b and downregulation of STAT3 suppressed cell proliferation and promoted cell apoptosis. Cyclin D1 and Bcl2 were identified as the downstream targets of the miR-125–STAT3 axis. Conclusions Our findings indicate that miR-125b acts as a tumor suppressor in CSCC by targeting the STAT3 pathway. This observation increases our understanding of the molecular mechanisms of CSCC. Therapies aimed at activating miR-125b or inhibiting STAT3 signaling should be explored as potential treatments for CSCC.

Chronic pain, such as persistent inflammatory pain, remains a public health problem that has no effective treatment at present. Bromodomain-containing protein 4 (BRD4) inhibition, induced by JQ1 injection or BRD4 knockdown, has been used to attenuate inflammatory pain; However, it remains elusive whether BRD4 aggravates inflammatory pain by regulating inflammasome. Western blot and immunofluorescence staining showed that BRD4 expression increased after administration of complete Freund’s adjuvant (CFA) and reached its peak on day 3. Immunofluorescence staining showed that BRD4 was mainly colocalized with NeuN-positive neurons in the spinal cord, which was accompanied by upregulation of inflammasome component proteins, such as NLRP3, gasdermin D, and caspase-1. JQ1 was intrathecally injected into mice 1 h before CFA administration, and the mechanical and thermal hyperalgesia levels were measured on days 1, 3, and 7 after CFA administration. CFA-induced inflammatory pain, paw inflammation, and swelling were attenuated by pre-treatment with JQ1. To our knowledge, this study was the first to prove that NLRP3 inflammasome-induced neuronal pyroptosis participates in inflammatory pain. BRD4 inhibition decreased the expression of pyroptosis-related proteins by inhibiting the activation of NF-κB signaling pathway, both in vivo and in vitro. Taken together, BRD4 inhibition exerted analgesic and anti-inflammatory effects against inflammatory pain by inhibiting NF-κB and inflammasome activation, which protected neural cells from pyroptosis.

Water pollution deteriorates ecosystems and is a great threat to the environment. The environmental benefits of wastewater treatment are extremely important to minimize pollutants. Here, the oxalic acid used as reductant was used to treat the wastewater which contained high concentration of vanadium (V). Nearly 100% of vanadium was efficiently reduced at selected reaction conditions. The optimization results simulated by response surface methodology (RSM) analysis indicated the parameters all had significant effects on the reduction process, and followed the order: dosage of oxalic acid > reaction temperature > reaction time > initial pH of vanadium-containing wastewater. The reduction behavior analysis indicated that the pseudo first-order kinetics model could describe well the reduction process with Ea = 42.14 kJ/mol, and was described by the equation as followed: −LnC=K0·[pH]0.1016·[n(O)/n(V)]2.4569·[T]2.2588·exp(−42.14/T)·t.

Combining powerful sensors and near ubiquitous distribution, the smartphone has become an irreplaceable part of modern day life. Using its pervasive sensing capabilities, the smart-phone guides us to our destination with precise step-by-step directions, advises us on what to have for lunch, and improves our photography skills through stabilizing our camera. Using the popular augmented reality (AR) smartphone app Pokemon Go as a case study, we explore the world of pervasive sensing. In this paper, we show both the current state of the art that enable applications such as Pokemon Go to thrive, as well as the limitations and opportunities inherent in current pervasive sensing applications.

How to mitigate such pressure has become a critical challenge for global grid enterprises.Empowered by the development of IoT techniques,high-speed communications,and AI-chips,traditional grid enterprises are trying to adopt these new techniques to solve the challenge,especially in heterogeneous data collection,energy scheduling,and AI-enabled monitoring.Firstly,the background of smart grid and the history of edge computing were introduced.Then,edge computing enabled solutions were illustrated in three typical grid scenarios.Finally,two edge computing platforms at home and abroad were introduced.The main technologies and application scenarios of them were also analyzed.