Nipah virus (NiV) and related viruses form a distinct henipavirus genus within the Paramyxoviridae family. NiV continues to spillover into the humans causing deadly outbreaks with increasing human-bat interaction. NiV encodes the large protein (L) and phosphoprotein (P) to form the viral RNA polymerase machinery. Their sequences show limited homologies to those of non-henipavirus paramyxoviruses. We report two cryo-electron microscopy (cryo-EM) structures of the Nipah virus (NiV) polymerase L-P complex, expressed and purified in either its full-length or truncated form. The structures resolve the RNA-dependent RNA polymerase (RdRp) and polyribonucleotidyl transferase (PRNTase) domains of the L protein, as well as a tetrameric P protein bundle bound to the L-RdRp domain. L-protein C-terminal regions are unresolved, indicating flexibility. Two PRNTase domain zinc-binding sites, conserved in most Mononegavirales, are confirmed essential for NiV polymerase activity. The structures further reveal anchoring of the P protein bundle and P protein X domain (XD) linkers on L, via an interaction pattern distinct among Paramyxoviridae. These interactions facilitate binding of a P protein XD linker in the nucleotide entry channel and distinct positioning of other XD linkers. We show that the disruption of the L-P interactions reduces NiV polymerase activity. The reported structures should facilitate rational antiviral-drug discovery and provide a guide for the functional study of NiV polymerase.
Nipah Virus/chemistry* ; Cryoelectron Microscopy ; Viral Proteins/genetics* ; RNA-Dependent RNA Polymerase/genetics* ; Phosphoproteins/genetics* ; Humans ; Models, Molecular ; Protein Binding

Objective:To understand the molecular characteristics of the mutant strain of polymerase basic protein 2 (PB2) gene of influenza A (H1N1pdm) in Guangdong province, and to explore its specific molecular sites, so as to provide scientific basis for the prevention and control of influenza virus.Methods:Throat swab samples were collected from 2 cases infected with PB2 gene variant strains for virus isolation, and 23 influenza virus strains were selected from Guangdong province for sequencing analysis. The reference sequences and vaccine strain sequences provided by GISAID were used to perform evolutionary analysis on hemagglutinin (HA) and PB2 genes. Virus strain antigen analysis and neuraminidase (NA) inhibition test were carried out. PB2 protein model was constructed and polymerase activity was analyzed.Results:H399N amino acid mutation occurred in the HA gene of PB2-D701N and PB2-A271S variant strains, both of which belonged to the branch of 6B.1A.5a.2a. They belonged to the same big branch and different small branches as the vaccine strain A/Victoria/4897/2022, and they are all vaccine-like strains. In the three-dimensional structure, the mutations of PB2-D701N and PB2-A271S change charge and hydrophobicity.Conclusions:PB2-D701 and A271 were highly conserved, and PB2 mutant strains were not the dominant strains. The PB2 mutant had high antigenicity with the vaccine. The PB2 mutant strain is sensitive to NA inhibitors. The three-dimensional model predicted that PB2-D701N mutation could enhance virulence and affect transmissibility of influenza virus, while PB2-A271S mutation could affect polymerase activity and polymerase complex synthesis of influenza virus.

AIM:The study aimed to explore the effect of curcumin(Cur)on lipopolysaccharide(LPS)-in-duced RAW264.7 cell-derived osteoclasts,together with its underlying mechanism.METHODS:An osteoclast model was established by treating RAW264.7 cells with LPS.The viability of the cells was assessed by CCK-8 assays and osteo-clast formation was evaluated by tartrate-resistant acid phosphatase(TRAP)activity.The levels of reactive oxygen species(ROS),Fe2+,glutathione(GSH),and malondialdehyde(MDA)were examined by biochemical assays.Mitochondrial morphology was assessed by transmission electron microscopy.The mRNA and protein levels of p53,glutathione peroxi-dase 4(GPX4),and solute carrier family 7 member 11(SLC7A11)were determined by RT-qPCR and Western blot,re-spectively.RESULTS:Treatment with LPS successfully induced osteoclasts formation in RAW264.7 cells.The TRAP results showed that compared with the LPS-treated group,the number of osteoclasts and TRAP activity in the curcumin-treated group decreased dose-dependently(P<0.01).Compared with the control group,the LPS+Erastin group showed significantly increased TRAP activity(P<0.01),while after curcumin treatment,the TRAP activity declined in a dose-de-pendent manner(P<0.01).The results of the biochemical tests showed that compared with the control group,the LPS+Erastin group had significantly elevated levels of ROS,Fe2+,and MDA,while the GSH level was significantly reduced(P<0.01),and compared with the LPS+Erastin group,the ROS,Fe2+,and MDA levels in the curcumin group decreased(P<0.01)and GSH levels increased(P<0.01).These effects were all dose-dependent.Transmission electron microscopy showed that compared with the LPS group,the LPS+Erastin group had reduced mitochondrial cristae and increased mem-brane density,while after treatment with curcumin,both these effects were reversed.The RT-qPCR and Western blot re-sults showed that compared with the control group,the mRNA and protein levels of p53 in the LPS+Erastin group were sig-nificantly increased,while those of of SLC7A11 and GPX4 were significantly reduced(P<0.01).After curcumin treat-ment,the p53 mRNA and protein levels were reduced while the levels of SLC7A11 and GPX4 were increased(P<0.01).CONCLUSION:Curcumin can inhibit lipopolysaccharide-induced differentiation of RAW264.7 cells into osteoclasts,and its mechanism may be related to the inhibition of the p53/SLC7A11/GPX4 signaling pathway.

BACKGROUND: Biliary tract carcinomas (BTCs) are relatively rare but lethal primary malignant tumors derived from the biliary tract system. The burden of BTCs varies according to sex, age, region, and country, but limited attention has been paid to the burden of BTCs. We sought to explore the up-to-date data from the Global Burden of Disease Study (GBD) and expand findings by accessing the demographic features of BTC disease burden. METHODS: Using the latest data from the GBD 2021, we evaluated and analyzed the distributions and patterns of BTC disease burden in various age groups, sexes, regions, and countries. RESULTS: The number of incident cases, deaths, and disability-adjusted life-years (DALYs) tended to increase and peaked at 216,770 (95% uncertainty interval [UI]: 181,890-245,240), 171,960 (95% UI: 142,350-194,240), and 3,732,100 (95% UI: 3,102,900-4,317,000) person-years, respectively, in 2021. However, the average global age-standardized rates (ASRs) of incident cases, deaths, and DALYs shrunk by -11.46% (95% UI: -21.91 to 3.35%), -24.09% (95% UI: -33.19 to 16.88%), and -26.25% (95% UI: -35.53 to 18.36%), respectively, from 1990 to 2021. Meanwhile, the male/female ratio (male per 100 female) of incidence, deaths, and DALYs changed from 76.40, 75.41, and 74.72 to 86.89, 79.11, and 82.29, respectively. In 2021, the highest number of incident cases, deaths, and DALYs occurred in East Asia. The top three highest incidences, deaths, and DALYs were observed in China, India, and Japan, and the highest ASRs were observed in Chile in 2021. Analysis of the Human Development Index along with disease burden estimates of BTCs also suggests that the burden of the disease is related to the level of comprehensive development of the society. CONCLUSION This study provided a comprehensive comparison of differences in the burden of disease across populations and over time, and further presented evidence concerning the formulation of prevention and control policies and etiologic studies for BTCs and proposed logical hypotheses to investigate.
Humans ; Global Burden of Disease ; Biliary Tract Neoplasms/epidemiology* ; Male ; Female ; Disability-Adjusted Life Years ; Middle Aged ; Aged ; Adult ; Incidence ; Aged, 80 and over ; Quality-Adjusted Life Years ; Cost of Illness

Acute pancreatitis-associated ascites fluid (PAAF) is a common complication in patients with acute pancreatitis (AP) and is closely associated with the severity of AP, the development of local and systemic complications, and prognosis. PAAF may originate from the leakage of abdominal blood vessels, lymphatic vessels, and pancreatic duct. Recent studies have found that early removal of PAAF by abdominal paracentesis drainage can help to reduce systemic inflammation and alleviate pancreatitis-associated organ injury, thereby improving the conditions of patients with severe AP and reducing mortality. However, it is still not completely clear how PAAF aggravates systemic inflammatory response, participates in pancreatic injury and damage of distal organs, and leads to the aggravation of disease conditions in patients with AP. Therefore, this article gives an overview of PAAF and summarizes related studies in recent years, so as to provide directions for exploring the pathophysiological process and treatment of AP.

Surgical operation is the main treatment method for pancreatic cancer, and in clinical practice, radical surgery for pancreatic cancer is often combined with superior mesenteric-portal vein confluence pancreaticoduodenectomy to achieve R0 resection. However, severe left-sided portal hypertension (LSPH) may occur after splenic vein dissection, resulting in a series of pathological changes such as congestive splenomegaly, thrombocytopenia, backflow obstruction of splenic vein, and gastrointestinal varices, and in some cases, it can lead to fatal gastrointestinal hemorrhage and hemorrhagic shock. Therefore, in order to better manage LSPH in clinical practice, this article systematically analyzes and reviews the pathogenesis, treatment regimens, and control strategies of LSPH after combined superior mesenteric-portal vein confluence pancreaticoduodenectomy and put forward corresponding suggestions based on current studies.

Objective:To translate the health literacy-sensitive communication scale into Chinese and examine its reliability and validity.Methods:Following Brislin′s translation principles, the HL-COM was translated and culturally adapted into Chinese. This cross-sectional study surveyed 434 outpatients and inpatients from three tertiary hospitals in Hubei Province using a questionnaire. Cronbach′s α coefficient and split half reliability were used to evaluate the reliability of the scale. Scale-level content validity index (S-CVI) and item-level content validity index (I-CVI) were used to evaluate the content validity. Exploratory factor analysis and confirmatory factor analysis were used to test the structural validity, while measurement equivalence across gender was examined.Results:The Chinese version of HL-COM contains 9 items, which was consistent with the original English version. Reliability of the scale: Cronbach′s ɑ Coefficient=0.938, Spearman-Brown half coefficient=0.926; Content validity: Scale-level content validity index (S-CVI)=0.926, Item-level content validity index (I-CVI) was 0.833-1.000; only one factor was extracted based on exploratory factor analysis, with a cumulative variance contribution rate of 68.541%. Confirmatory factor analysis indicated a good fit, with the fitting indexes of ?χ2/df=2.794, Normed Fit Index (NFI)=0.974, Standardized Root Mean Square Residual (SRMR)=0.025, Goodness-of-Fit Index (GFI)=0.962, Root Mean Square Error of Approximation (RMSEA)=0.089, Comparative Fit Index (CFI)=0.983. Multigroup confirmatory factor analysis indicated measurement invariance of the Chinese version of HL-COM across gender. Conclusion:The Chinese version of HL-COM demonstrates good reliability and validity, and serves as a valuable tool for assessing health literate in health care organization in China.

Objective:To discuss the procedure for correction of inverted nipple using tiny incision with primary breast ducts reserved.Methods:A total of 35 patients (63 sides) with primary inverted nipples from January 2006 to March 2019 were reviewed retrospectively. Tiny radial incisions were made on the areola around the base of the inverted nipple which had been pulled out. Without skin removed, shorten fiber bundles which caused nipple inverted were totally cut and released. While the primary breast ducts were preserved, purse-string suture was taken around the base of the nipple. The nipple protector was prepared by ourselves, and the nipple was pulled and suspended for 2-6 months.Results:Sixty-three sides of 35 patients with inverted nipples were successfully corrected by this minimally invasive surgery. There was no nipple necrosis. One patient developed mild swelling 3 weeks after operation, and the swelling subsided after symptomatic anti-inflammatory treatment. The average follow-up period was 39 months. After removing the nipple protector, 2 sides (2/63) had a certain degree of recurrence. The rest of the nipples had ideal shape, no obvious scar, good nipple feeling, and retained the possibility of lactation.Conclusions:The procedure for correction of inverted nipple using tiny incision with primary breast ducts reserved has advantages of minimal invasion, safety, less pain, while retaining the possibility of lactation in the future. The clinical effect is satisfactory. It is especially suitable for the correction of type Ⅰ and type Ⅱ inverted nipples.

OBJECTIVE: To review antibacterial/osteogenesis dual-functional surface modification strategy of titanium-based implants, so as to provide reference for subsequent research. METHODS: The related research literature on antibacterial/osteogenesis dual-functional surface modification strategy of titanium-based implants in recent years was reviewed, and the research progress was summarized based on different kinds of antibacterial substances and osteogenic active substances. RESULTS: At present, the antibacterial/osteogenesis dual-functional surface modification strategy of titanium-based implants includes: ① Combined coating strategy of antibiotics and osteogenic active substances. It is characterized in that antibiotics can be directly released around titanium-based implants, which can improve the bioavailability of drugs and reduce systemic toxicity. ② Combined coating strategy of antimicrobial peptides and osteogenic active substances. The antibacterial peptides have a wide antibacterial spectrum, and bacteria are not easy to produce drug resistance to them. ③ Combined coating strategy of inorganic antibacterial agent and osteogenic active substances. Metal ions or metal nanoparticles antibacterial agents have broad-spectrum antibacterial properties and various antibacterial mechanisms, but their high-dose application usually has cytotoxicity, so they are often combined with substances that osteogenic activity to reduce or eliminate cytotoxicity. In addition, inorganic coatings such as silicon nitride, calcium silicate, and graphene also have good antibacterial and osteogenic properties. ④ Combined coating strategy of metal organic frameworks/osteogenic active substances. The high specific surface area and porosity of metal organic frameworks can effectively package and transport antibacterial substances and bioactive molecules. ⑤ Combined coating strategy of organic substances/osteogenic active substancecs. Quaternary ammonium compounds, polyethylene glycol, N-haloamine, and other organic compounds have good antibacterial properties, and are often combined with hydroxyapatite and other substances that osteogenic activity. CONCLUSION The factors that affect the antibacterial and osteogenesis properties of titanium-based implants mainly include the structure and types of antibacterial substances, the structure and types of osteogenesis substances, and the coating process. At present, there is a lack of clinical verification of various strategies for antibacterial/osteogenesis dual-functional surface modification of titanium-based implants. The optimal combination, ratio, dose-effect mechanism, and corresponding coating preparation process of antibacterial substances and bone-active substances are needed to be constantly studied and improved.
Anti-Bacterial Agents/pharmacology* ; Coated Materials, Biocompatible/chemistry* ; Metal-Organic Frameworks/pharmacology* ; Osteogenesis ; Surface Properties ; Titanium/pharmacology* ; Prostheses and Implants

Objective:To analyze and reveal the genetic evolution and variation of influenza viruses in cases of co-infection in Guangdong Province.Methods:Throat swab samples were collected from four cases of H1N1pdm and H3N2 co-infection for viral isolation. The isolated strains were subjected to antigen analysis and neuraminidase inhibitor susceptibility test. High-throughput sequencing was used to detect the sequences of strains in three throat swab samples and one virus strain, and then genetic variations were analyzed.Results:Four influenza viruses were isolated with one strain of H1N1pdm and three of H3N2 subtype, and all of them were genetically similar to the vaccine strain in 2022-2023. The HA genes of H1N1pdm and H3N2 strains belonged to clade 6B.1A.5a.2a and 2a.3a.1, respectively. The isolated strains belonged to the same clade as the strains prevalent in Guangdong during the same period. No drug-resistant variations were detected in N1 or N2 gene, and the isolated strains were sensitive to oseltamivir and zanamivir.Conclusions:H1pdm subtype had stronger replication ability than H3 subtype in the influenza viruses isolated from co-infected cases. H1N1pdm and H3N2 subtype influenza viruses were genetically similar to the strains circulating in Guangdong at the same time. The isolated H1N1pdm and H3N2 strains were sensitive to both oseltamivir and zanamivir, indicating that they could continue to be used in the treatment of influenza virus infections caused by one or two genotypes.