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 construct curcumin pyrazole derivative by the reaction of diketone of curcumin and benzylhydrazine based on the above structure-activity relationship,and to explore its antioxidant activity to provide experimental basis for the development of curcumin antioxidant derivative.Methods Curcumin-N-substituted pyrazole derivative was synthesized from curcumin and benzylhydrazine.The structures of the derivative were confirmed by infrared spectroscopy(IR),nuclear magnetic resonance spectroscopy(1H-NMR,13C-NMR)and LC-MS.The antioxidant activity in vitro of the derivative was evaluated by determination of curcumin and its pyrazole derivative scavenging ability for 2,2-diphenyl-1-picrylhydrazyl(DPPH)free radical and 2,2'-azino-bis-3-ethylbenzothiazoline-6-sulfonic acid(ABTS)free radical.Results Curcumin pyrazole derivative was successfully synthesized.Curcumin and its pyrazole derivative showed good free radical scavenging effects in the range of 4.6-73.6,6.25-100 μg·mL-1,respectively,with a significant dose-effect relationship.The half-maximal inhibition(IC50)values of curcumin and its pyrazole derivatives determined by DPPH method were 14.24,40.37 μg·mL-1,respectively,while the IC50 values of curcumin and its pyrazole derivatives determined by ABTS method were 36.65,19.26 μg·mL-1,respectively.Conclusion The antioxidant activity of β-dione of curcumin was retained through the substitution of the pyrazole ring,and the curcumin pyrazole derivative deserves further investigation as a potential antioxidant.

The pathogenesis of the nephrotic syndrome is complex and the pathological types are diverse, so the minor symptoms in its early phases are difficult to detect. Renal biopsy is the gold indicator for the diagnosis of renal pathology and progression, but poor patient compliance shows, and the optimal treatment time is often delayed. Therefore, the discovery of biomarkers for early diagnosis and disease progression monitoring is of great clinical significance. In this study, doxorubicin-injured podocyte models were used to simulate human kidney disease at different stages of progression. LC-MS-based metabolomic technology combined with statistical methods was used to screen and identify the potential biomarkers associated with early injury or progression of podocytes. The results of cell viability, apoptosis tests and podocyte structural protein analysis showed that the model was successfully constructed, and the degree of podocyte injury was significantly different between the two modeling methods. According to VIP > 1 and P < 0.05 based on the orthogonal partial least squares discriminant analysis (OPLS-DA) model, nine differential metabolites reflecting early podocyte injury and twelve differential metabolites reflecting the injury progression were screened, respectively. ROC analysis was adopted to focus on the potential biomarkers that can reflecting the early podocyte injury including L-tryptophan, guanosine triphosphate (GTP), 5′-thymidylic acid (dTMP) and thymidine, and the biomarkers reflecting the injury progression of podocytes composed of L-phenylalanine, L-tyrosine acid, uridine 5′-diphosphate (UDP) and guanosine 5′-diphosphate (GDP) AUC > 0.85. It indicated that these eight metabolites may have high sensitivity and diagnostic ability. This study provides a reference for the research on biomarkers of progressive diseases.

OBJECTIVE: To explore the effects of different administration methods of tranexamic acid(TXA) on the perioperative blood loss, hidden blood loss, transfusion rate and adverse reactions in lumbar spinal decompression and fusion. METHODS: Sixty patients who received lumbar spinal canal decompression and fusion from July 2019 to July 2020 were enrolled and divided into observation group and control group, with 30 cases in each group. The observation group was given 2 g TXA orally at 2 hours before operation, control group was given 1 g TXA for 5-10 min before skin incision and 6 hours after operation intravenously. The intraoperative blood loss, postoperative drainage, total blood loss, hidden blood loss, drainage tube removal time, blood transfusion rate, venous thrombosis rate, adverse event rate were recorded respectively. The changes of hemoglobin(Hb) and hematocrit (HCT) were observed before operation and 1, 3 days after operation. RESULTS: Hb and HCT at 1 and 3 days after operation were significantly improved compared with those before operation(P<0.01). However, there was no significant difference between the groups(P>0.05). There were no significant difference in amount of blood loss, postoperative drainage, total blood loss, intraoperative blood loss, hidden blood loss, postoperative drainage time, and blood transfusion rate between two groups (P>0.05). There were no venous thrombosis and adverse events occurred in both groups. CONCLUSION During the perioperative period of lumbar spinal decompression and fusion, oral TXA and intravenous TXA have the same effect in reducing perioperative blood loss and are safe and reliable. It is recommended that oral TXA be used to save medical costs and convenience.
Antifibrinolytic Agents/therapeutic use* ; Blood Loss, Surgical/prevention & control* ; Decompression ; Humans ; Postoperative Hemorrhage ; Spinal Canal ; Spinal Fusion/methods* ; Tranexamic Acid/therapeutic use* ; Venous Thrombosis/etiology*

Cephalosporins are widely used in the treatment of infectious diseases. The structural differences in cephalosporin drugs mainly lie in the C-7 amino side chain and the C-3 substituent. In this study, twenty-five haloacylated cephalosporins of five series were designed by using a strategy of introducing simple substituents at the C-7 amino group in four cephalosporin parent nucleus with different C-3 substituents and efficiently synthesized under optimized conditions. Their activities against human pathogenic bacteria, Pichia pastoris, citrus canker and citrus pathogenic fungi were evaluated. The results showed that most of the molecules had activity against human pathogenic bacteria, of which seven compounds including TM1f had stronger or equivalent inhibitory activities against eight human pathogens than the marketed drugs cefalotin, cefoxitin sodium and ceftizoxime sodium. The inhibitory activity of TM1s against Alternaria alternate Al.6 was stronger than that of cephalosporins and comparable to that of the positive control prochloraz. TM1f and TM1s are worthy of further study.

Drynariae Rhizoma is warm in nature and bitter in taste, mainly acting on liver and kidney systems. It is a common Chinese herbal medicine for the treatment of fracture and bone injury. The chemical compositions of Drynariae Rhizoma mainly include flavonoids, triterpenoids, phenylpropanoids and lignans. At present, modern pharmacological and clinical studies have shown that Drynariae Rhizoma has the effects of anti osteoporosis, promoting fracture healing, kidney protection, anti-inflammatory, promoting tooth growth, preventing and treating aminoglycoside ototoxicity and lowering blood lipid. In addition, the toxicity evaluation experiment of Drynariae Rhizoma has also shown that it has no obvious toxic and side effects. Naringin is a kind of dihydroflavone in Drynariae Rhizoma. Many studies have shown that naringin and other total flavonoids play an important role in anti-osteoporosis, promoting fracture healing, anti-inflammation, promoting tooth growth and lowering blood lipid. In this study, the research progresses on chemical consti-tuents and pharmacological activities of Drynariae Rhizoma in recent years were reviewed, and some mechanisms of action were summarized, to provide references for the further research and development of Drynariae Rhizoma.
Drugs, Chinese Herbal/pharmacology* ; Flavonoids ; Humans ; Osteoporosis/drug therapy* ; Polypodiaceae ; Rhizome

Objective:To investigate the effect of Weiwei Tongtiao decoction on gastric mucosal pathology and the expression level of inhibitor kappa B kinase β（IKKβ） and B-cell lymphoma-2（Bcl-2）in rats with chronic atrophic gastritis （CAG） precancerous lesion. Method:SD rats were randomly divided into normal group， model group， positive drug Weifuchun group， Weiwei Tongtiao decoction high， medium and low dose treatment groups. The rat model of CAG precancerous lesion was prepared by N-methyl-N'-nitro-N-nitrosoguanidine （MNNG）compound modeling method. weiwei Tongtiao decoction high， medium and low dose treatment groups received intragastric administration of 24， 12， 6 g·kg^-1 Weiwei Tongtiao decoction respectively， while Weifuchun group received 0.45 g·kg^-1 Weifuchun suspension， once per day for 12 weeks. The pathological changes of gastric mucosa of rats were observed by hematoxylin-eosin（HE）staining， and the mRNA and protein levels of IKKβ and Bcl-2 in gastric mucosa of rats were detected by Real-time quantitative polymerase chain reaction （Real-time PCR）， immunohistochemistry（IHC）and Western blot. Result:Compared with the normal group， 100% inherent gland atrophy， mild to severe intestinal metaplasia， and 25% low-grade intraepithelial neoplasia were observed under microscope in model group. All Weifuchun group and Weiwei Tongtiao decoction groups could improve the atrophy of gastric glands， moderate to severe intestinal metaplasia and pathological injury of low-grade intraepithelial neoplasia， especially at high dose group. Compared with the normal group， IKKβ， Bcl-2 mRNA and protein expressions in the gastric mucosa of the model group were up-regulated （P<0.01）. Compared with the model group， the mRNA and protein expressions of IKKβ and Bcl-2 in gastric mucosa of rats in the Weifuchun group and the Weiwei Tongtiao decoction high， medium and low dose groups were down-regulated （P<0.05，P<0.01）， showing a dose-dependent relationship， and such levels in the Weiwei Tongtiao decoction high-dose intervention group were similar to those in normal group. Conclusion:Weiwei Tongtiao decoction can improve and even reverse gastric mucosa with CAG precancerous lesions in rats， and its intervention mechanism may be related to down-regulating the expressions of IKKβ and Bcl-2 in gastric mucosa.

Altitude ; China/epidemiology* ; Community-Acquired Infections/epidemiology* ; Humans ; Pneumonia/etiology* ; Tibet

Objective:To investigate any effect of different environments on the levels of adrenocorticotropic hormone (ACTH), cortisol and testosterone using SAMP8 senescence-accelerated mice.Methods:Thirty SAMP8 mice were randomly divided into an enriched environment (EE) group, an impoverished environment (IE) group and a standard environment (SE) group, each of 10. The serum levels of ACTH, cortisol and testosterone were measured in all of the mice after they had lived in their respective environments for 8 weeks.Results:The average ACTH concentrations of the IE, EE and SE groups were (60.54±16.22), (48.98±15.30) and (28.49±8.24)pg/ml respectively. The average cortisol concentrations were (5.37±0.81), (4.09±0.92) and (3.19±0.88)ng/ml. The average testosterone concentrations being (2.35±0.90), (7.07±1.57) and (3.16±1.10)ng/ml. The average ACTH and cortisol levels were significantly different between the SE and IE groups. The average ACTH and testosterone levels differed significantly between the SE and EE groups and between the EE and IE groups.Conclusions:An impoverished environment can increase the secretion of ACTH and cortisol and activate the hypothalamic-pituitary-adrenal axis, at least in SAMP8 mice. An enriched environment can promote the secretion of ACTH and testosterone, but not that of cortisol.

Background:Transcranial alternating current stimulation (tACS) offers a new approach for adult patients with major depressive disorder (MDD).The study is to evaluate the efficacy and safety of tACS treating MDD.Methods:This is an 8-week,double-blind,randomized,placebo-controlled study.Ninety-two drug-naive patients with MDD aged 18 to 65 years will receive 20 daily 40-min,77.5-Hz,15-mA sessions of active or sham tACS targeting the forehead and both mastoid areas on weekdays for 4 consecutive weeks (week 4),following a 4-week observation period (week 8).The primary outcome is the remission rate defined as the 17-item Hamilton depression rating scale (HDRS-17) score ≤7 at week 8.Secondary outcomes are the rates of response at weeks 4 and 8 and rate of remission at week 4 based on HDRS-17,the proportion of participants having improvement in the clinical global impression-improvement,the change in HDRS-17 score (range,0-52,with higher scores indicating more depression) over the study,and variations of brain imaging and neurocognition from baseline to week 4.Safety will be assessed by vital signs at weeks 4 and 8,and adverse events will be collected during the entire study.Discussion:The tACS applied in this trial may have treatment effects on MDD with minimal side effects.