Host adaptive mutations in the influenza A virus (IAV) PB2 protein are critical for human infection, but their molecular action is not well understood. We observed that when IAV containing avian PB2 infects mammalian cells, vRNP aggregates that localize to the microtubule-organizing center (MTOC) are formed. These vRNP aggregates resemble LC3-associated autophagosome structures, with aggresome-like properties, in that they cause re-distribution of vimentin. However, electron microscopy revealed that these LC3-associated aggregates are not canonical double-membrane autophagosomes. Compared to mammalian-PB2 virus, avian-PB2 virus induces higher autophagic flux in infected cells, indicating an increased rate of autophagosomes containing avian vRNPs fusing with lysosomes. We found that p62 is essential for the formation of vRNP aggregates and that the Raptor-interacting region of p62 is required for interaction with vRNPs through the PB2 polymerase subunit. Selective autophagic sequestration during late stage virus replication is thus an additional strategy for host restriction of avian-PB2 IAV.
Purpose: To describe the extent of delays in insulin initiation, analyze its impact on glycemic control, and explore factors influencing delayed insulin initiation among Chinese type 2 diabetes mellitus (T2DM) patients. Methods: A real-world, retrospective cohort study with regional electronic health records from Fuzhou, southeast China was conducted among T2DM patients. Adult patients uncontrolled with oral antidiabetic drugs (OADs; HbA 1c ≥ 7%) and initiated on insulin treatment were included. Time to insulin initiation was described. After propensity-score matching, Wilcoxon rank-sum test and chi-square test were used to compare follow-up HbA 1c (first HbA 1c 3 months after insulin initiation) between timely (initiated insulin within 6 months after OAD failure) and delayed (initiated after 6 months) insulin-initiation groups. Sensitivity analysis was also performed by linear and logistic regression. Factors associated with delayed insulin initiation were explored using logistic regression. Results: A total of 940 patients were included, with mean±SD age 66.3± 11.9 years. In sum, 328 had HbA 1c recorded 3 months after insulin initiation. After propensity-score matching (1:1 matching), 184 patients were included for further analysis. Median follow-up HbA 1c was lower in the timely-initiation group than the delayed-initiation group (7.25% vs 8.25%, P =0.009). Patients in the timely initiation group also had higher odds of achieving HbA 1c < 7% (OR=3.15, P =0.001). Results were confirmed by logistic regression. Hypertension, coronary artery disease, baseline HbA 1c , and hospital level at insulin initiation were associated with delays in insulin initiation. Conclusion: Timely insulin initiation after OAD failure is associated with better glycemic control. Keywords: type 2 diabetes mellitus, therapeutic inertia, delayed insulin initiation, glycemic control, HbA 1c
Significantly higher numbers of human infections with H5N1 virus have occurred in Indonesia and Egypt, compared with other affected areas, and it is speculated that there are specific viral factors for human infection with avian H5N1 viruses in these locations. We previously showed PB2-K526R is present in 80% of Indonesian H5N1 human isolates, which lack the more common PB2-E627K substitution. Testing the hypothesis that this mutation may prime avian H5N1 virus for human infection, we showed that: (1) K526R is rarely found in avian influenza viruses but was identified in H5N1 viruses 2⁻3 years after the virus emerged in Indonesia, coincident with the emergence of H5N1 human infections in Indonesia; (2) K526R is required for efficient replication of Indonesia H5N1 virus in mammalian cells in vitro and in vivo and reverse substitution to 526K in human isolates abolishes this ability; (3) Indonesian H5N1 virus, which contains K526R-PB2, is stable and does not further acquire E627K following replication in infected mice; and (4) virus containing K526R-PB2 shows no fitness deficit in avian species. These findings illustrate an important mechanism in which a host adaptive mutation that predisposes avian H5N1 virus towards infecting humans has arisen with the virus becoming prevalent in avian species prior to human infections occurring. A similar mechanism is observed in the Qinghai-lineage H5N1 viruses that have caused many human cases in Egypt; here, E627K predisposes towards human infections. Surveillance should focus on the detection of adaptation markers in avian strains that prime for human infection.
To assess the efficacy of Huangshukuihua (Flos Abelmoschi Manihot) on diabetic nephropathy (DN). Articles were retrieved from PubMed, EMBASE, the Cochrane Central Register of Controlled Trials, Web of Science, Chinese Biomedical Literature Database, and China National Knowledge Infrastructure Database, Chinese Evidence-Based Medicine Database, and Wanfang Database. Two reviewers independently reviewed the article. Only randomized controlled trials were included and 27 were identified involving 2239 patients (1143 in the treatment group and 1096 in the control group). Huangshukuihua (Flos Abelmoschi Manihot) had a significant effect on renal function by improving blood urea nitrogen and serum creatinine, reducing urine protein (24-h urine protein, and urinary albumin excretion rate), and improving serum albumin level, compared with the control group. Our findings suggest that, although the bioactive ingredients and mechanism underlying renal protection are unknown, the role of Huangshukuihua (Flos Abelmoschi Manihot) in the treatment of DN deserves further investigation.
Objective To discuss the clinical value of diagnosing aerobic vaginitis( AV) by aerobic vaginitis /bacterial vaginosis combined determination technology. Methods Detection 200 suspected AV patients by microscopic method and aerobic vaginitis / bacterial vaginosis combined determination technology. Results Among 200 suspected AV patients,there were 174 positive patients by microscopic method,there were 169 positive patients by aerobic vaginitis / bacterial vaginosis combined determination technology. With microscopic method as a standard,the sensitivity of aerobic vaginitis / bacterial vaginosis combined determination technology was 94. 83%,the specificity was 84. 62%. Conformity of two methods was 93. 50% [( 165 + 22) /200],and they also showed moderate consistency( Kappa = 0. 735,P 0. 05). Conclusion Aerobic vaginitis / bacterial vaginosis combined determination technology has high sensitivity and specificity for diagnosing AV,it has high coincidence rate compare to microscopic method used by clinic now,and this technology is simply practised and quick,it is worth that using widely by clinic.
Objective To investigate the effect of the selective cyclooxygenase-2 inhibitor celecoxib on the expression of PGE2 and VEGF induced by IL-1β in A549 cell lines.Methods A549 cells were incubated with IL-1β in the presence or absence of celecoxib.After indicated incubation time,cells were harvested to detect VEGFmRNA by reverse transcription-polymerase chain rection(RT-PCR),the medium was collected to determine the concentration of PGE2 and VEGF by enzyme-linked immunosorbent assay(ELISA).Results After Celecoxib intervention,the formation of PGE2 and VEGF expression decreased more than control group(IL-1β induced),the difference being significance(P0.05);with the concentration of Celecoxib stepping up,the formation of PGE2 and VEGF expression was decreased in dose-dependent manner,and the difference within different groups was significant(P0.05),the percent rate of decrease in the formation of PGE2 and VEGF expression being almost the same.Conclusion These results suggest celecoxib down-regulats interleukin-1β induced VEGF expression in dose-dependent manner in A549 cells,and the mechanism may be carried out by inhibiting PGE2 formation.
Objective:To compare the efficacy and safety of two different high dose chemoterapy protocols for advanced breast cancer.Methods: 47 patients with advanced breast cancer (stageⅢ-Ⅳ) were randomized into two groups: 23 patients were treated with epirubicin 90 mg/m 2,cyclophosphamide 600 mg/m 2 d 1;5 FU 900 mg/m 2 d 1,8 ,every 21 days (A group).The other 24 patients were treated with cisplatin 50 mg/m 2 d 2,8 ,epirubicin 40 mg/m 2 d 1,etopostide 70 mg/m 2 d 4～6 ,every 28 days (B group).A total of 168 cycles were administered with a median of 3,5 cycles per patient (range 2-6).Results:The response rate was 69.6% in the A group and 70.8% in the B group,respectively.The difference between the two groups was not statistically significant ( P 0.1) The therapeutic effect was slightly better in patients initially diagnosed than in patinents with recurrence (RR: 75.0%,78.6% vs 63.6%,60.0%).The major side effect was leukopenia.Mild to moderate GI tract side effects were observed.There was no significant cardiotoxicity.Conclusions:High dose EPI combined with CTX,5 FU and high dose DDP combined with Vp 16,EPI are safe and effective regimens for patients with advanced breast cancer,They could be considered as a first line treatment regiemen for refractory breast cancer.
Abstract SARS-CoV-2 is zoonotic origin and contains a PRRA polybasic cleavage motif which is considered critical for efficient infection and transmission in humans. We previously reported on a panel of attenuated SARS-CoV-2 variants with deletion at the S1/S2 junction of spike protein. Here we characterize pathogenicity, immunogenicity, and protective ability of a further cell-adapted SARS-CoV-2 variant, Ca-DelMut, in in vitro and in vivo systems. Ca-DelMut replicates more efficiently than wild type or parental virus in cells, but causes no apparent disease in hamsters, despite replicating in respiratory tissues. Unlike wild type virus, Ca-DelMut causes no apparent pathological changes and does not induce elevated proinflammatory cytokines in hamster infections, but still triggers a strong neutralizing antibody response in hamsters. Ca-DelMut immunized hamsters challenged with wild type SARS-CoV-2 are fully protected with no sign of virus replication in the upper or lower respiratory tract of challenged animals, demonstrating sterilizing immunity.
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