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A-Long Cui,1,* Wen-Fang Sun,1,2,* Zhao-Jin Zhong,1 Jie Jin,1 Si-Tu Xue,1 Shuo Wu,1,2 Yu-Huan Li,1,2 Zhuo-Rong Li1 1Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, People’s Republic of China; 2CAMS Key Laboratory of Antiviral Drug Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, People’s Republic of China*These authors contributed equally to this workCorrespondence: Si-Tu Xue; Shuo Wu Tel +86-10-63027185; +86-10-63010984Email xuesitu@imb.pumc.edu.cn; wushuoimb@126.comIntroduction: Hepatitis B virus (HBV) is a global health concern that can cause acute and chronic liver diseases. Thus, there is an urgent need to research novel anti-HBV agents. Our previous reports show that N-phenylbenzamide derivatives exert broad-spectrum antiviral effects against HIV-1, HCV, and EV71 by increasing intracellular levels of APOBEC3G (A3G). As A3G is capable of inhibiting the replication of HBV, we screened the N-phenylbenzamide derivatives against HBV.Methods: In this study, a new derivative, N-(4-chlorophenyl)-4-methoxy-3-(methylamino) benzamide (IMB-0523), was synthesized and its anti-HBV activity was evaluated in vitro and in vivo. The acute toxicity and pharmacokinetic profiles of IMB-0523 were also investigated.Results: Our results show that IMB-0523 has higher anti-HBV activity in both wild-type HBV (IC50: 1.99 μM) and drug-resistant HBV (IC50: 3.30 μM) than lamivudine (3TC, IC50: 7.37 μM in wild-type HBV, IC50: > 440 μM in drug-resistant HBV). The antiviral effect of IMB-0523 against HBV may be due to an increased level of intracellular A3G. IMB-0523 also showed low acute toxicity (LD50: 448 mg/kg) in mice and promising PK properties (AUC0-t: 7535.10± 2226.73 μg·h/L) in rats. Further, IMB-0523 showed potent anti-HBV activity in DHBV-infected ducks.Conclusion: Thus, IMB-0523 may be a potential anti-HBV agent with different mechanisms than current anti-HBV treatment options.Keywords: anti-HBV activity, APOBEC3G, hepatitis B virus, IMB-0523, PK, toxicity

Objectives: Polymyxins are the last-line therapy for top-priority multidrug-resistant (MDR) gram-negative bacteria. However, polymyxin nephrotoxicity impedes its clinical application. This study aimed to design, synthesize, and identify a novel and promising polymyxin derivative with high efficacy and low toxicity., Methods: To design polymyxin derivatives, we reduced the hydrophobicity of the two hydrophobic domains (fatty acyl chain and D-Phe 6 -L-Leu 7 ) and modified the positive charged L-2,4-diaminobutyric acid (Dab) residues. Twenty-five derivatives were synthesized, and their antibacterial activities in vitro and renal cytotoxicities were determined. The nephrotoxicity and pharmacokinetic parameters of compound 12 were examined in rats. Antibacterial efficacy in vivo was evaluated using a mouse systemic infection model. Surface plasmon resonance analysis, compound 12-rifampicin combination therapy, and scanning electron microscopy were used to study the mechanism of action of compound 12., Results: This research found a new compound, identified as compound 12, which showed similar or increased antibacterial activity against all tested sensitive and carbapenem-resistant gram-negative bacteria. It exhibited reduced renal cytotoxicity and nephrotoxicity, a favorable pharmacokinetic profile, and maintained or improved antibacterial efficacy in vivo. Importantly, its anti-Pseudomonas aeruginosa activity significantly improved. Compound 12, when combined with rifampicin, enhanced the activity of rifampin against gram-negative bacteria. Compound 12 also showed a high affinity for lipopolysaccharide and disrupted cell membrane integrity., Conclusion: Reducing the hydrophobicity of the two domains reduced renal cytotoxicity and nephrotoxicity. Shortening the side chain of Dab 3 by one carbon maintained or increased its antibacterial activity both in vitro and in vivo. Furthermore, only the length of the side chain of Dab 9 could be shortened by one carbon among the Dab 1,5 and Dab 8,9 residues. The bactericidal effects of compound 12 were related to the disruption of cell membrane integrity. Compound 12 may be a promising candidate for combating sensitive and carbapenem-resistant gram-negative bacterial infections, especially Pseudomonas aeruginosa., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Objective: To understand the epidemiological characteristics of human respiratory syncytial virus (HRSV) among acute respiratory infection (ARI) cases in 16 provinces of China from 2009 to 2023. Methods: The data of this study were collected from the ARI surveillance data from 16 provinces in China from 2009 to 2023, with a total of 28 278 ARI cases included in the study. The clinical specimens from ARI cases were screened for HRSV nucleic acid from 2009 to 2023, and differences in virus detection rates among cases of different age groups, regions, and months were analyzed. Results: A total of 28 278 ARI cases were enrolled from January 2009 to September 2023. The age of the cases ranged from<1 month to 112 years, and the age M ( Q 1 , Q 3 ) was 3 years (1 year, 9 years). Among them, 3 062 cases were positive for HRSV nucleic acid, with a total detection rate of 10.83%. From 2009 to 2019, the detection rate of HRSV was 9.33%, and the virus was mainly prevalent in winter and spring. During the Corona Virus Disease 2019 (COVID-19) pandemic, the detection rate of HRSV fluctuated between 6.32% and 18.67%. There was no traditional winter epidemic peak of HRSV from the end of 2022 to the beginning of 2023, and an anti-seasonal epidemic of HRSV occurred from April to May 2023. About 87.95% (2 693/3 062) of positive cases were children under 5 years old, and the difference in the detection rate of HRSV among different age groups was statistically significant ( P <0.001), showing a decreasing trend of HRSV detection rate with the increase of age ( P <0.001). Among them, the HRSV detection rate (25.69%) was highest in children under 6 months. Compared with 2009-2019, the ranking of HRSV detection rates in different age groups changed from high to low between 2020 and 2023, with the age M (Q 1 , Q 3 ) of HRSV positive cases increasing from 1 year (6 months, 3 years) to 2 years (11 months, 3 years). Conclusion: Through 15 years of continuous HRSV surveillance analysis, children under 5 years old, especially infants under 6 months old, are the main high-risk population for HRSV infection. During the COVID-19 pandemic, the prevalence and patterns of HRSV in China have changed.

Objective: To investigate the genotype and epidemiological characteristics of human metapneumovirus (HMPV) among hospitalized cases with acute respiratory infections (ARI) in children in Changchun City, Jilin Province, China. Methods: From June 2019 to June 2023, throat swabs of ARI inpatients in Changchun Children's Hospital were collected, and their epidemiological and clinical information were also collected. Quantitative reverse transcription-PCR was used to identify HMPV-positive cases, followed by the amplification of the G gene and genetic analysis in the HMPV-positive cases. Results: A total of 3 311 children hospitalized with ARI were included in this study. Their age ranged from 0 to 17 years old, and the M ( Q 1 , Q 3 ) of age was 2 (1, 3) years. About 1 811 (54.70%) cases were males. A total of 167 HMPV-positive cases were detected with a positive rate of 5.04%, of which 92.81% (155/167) were children under 5 years old. The positive rate of HMPV in 2019 was 6.37% (30/471), which dropped to the lowest in 2020 (2.31%, 10/432). The HMPV-positive rate was then rebounded in 2021 (4.70%, 60/1 277) and 2022 (4.56%, 21/461), which increased to 6.87% (46/670) in 2023. The difference in HMPV-positive rate among each year was statistically significant ( P <0.05). The prevalence peak of HMPV varied in different years, showing either a unimodal or bimodal distribution in one year. A total of 79 HMPV G gene sequences were obtained, of which subtype A and subtype B accounted for 48.10% and 51.90%, respectively. All of the subtype A sequences were clarified as A2c duplicated variants, and subtype B was mainly B2 genotype. Besides, subtypes A and B were prevalent alone or co-circulated in different years, and there was a subtype replacement pattern in HMPV. Conclusion: The positive rate of HMPV in hospitalized ARI cases in children is significantly different from 2019 to 2023 in Changchun City. Notably, there are certain switch patterns of HMPV subtypes A and B in different years.

Hereditary hearing loss (HHL), a genetic disorder that impairs auditory function, significantly affects quality of life and incurs substantial economic losses for society. To investigate the underlying causes of HHL and evaluate therapeutic outcomes, appropriate animal models are necessary. Pigs have been extensively used as valuable large animal models in biomedical research. In this review, we highlight the advantages of pig models in terms of ear anatomy, inner ear morphology, and electrophysiological characteristics, as well as recent advancements in the development of distinct genetically modified porcine models of hearing loss. Additionally, we discuss the prospects, challenges, and recommendations regarding the use pig models in HHL research. Overall, this review provides insights and perspectives for future studies on HHL using porcine models.

Herein, we first prepared a novel anti-TROP2 antibody-drug conjugate (ADC) hIMB1636-MMAE using hIMB1636 antibody chemically coupled to monomethyl auristatin E (MMAE) via a Valine-Citrulline linker and then reported its characteristics and antitumor activity. With a DAR of 3.92, it binds specifically to both recombinant antigen ( K D ∼ 0.687 nM) and cancer cells and could be internalized by target cells and selectively kill them with IC 50 values at nanomolar/subnanomolar levels by inducing apoptosis and G2/M phase arrest. hIMB1636-MMAE also inhibited cell migration, induced ADCC effects, and had bystander effects. It displayed significant tumor-targeting ability and excellent tumor-suppressive effects in vivo, resulting in 5/8 tumor elimination at 12 mg/kg in the T3M4 xenograft model or complete tumor disappearance at 10 mg/kg in BxPc-3 xenografts in nude mice. Its half-life in mice was about 87 h. These data suggested that hIMB1636-MMAE was a promising candidate for the treatment of pancreatic cancer with TROP2 overexpression.

Reliable diagnostic approaches especially those targeting critical Gram-negative bacteria are urgently needed for the prevention of antimicrobial resistance. Polymyxin B (PMB) which specifically targets the outer membrane of Gram-negative bacteria is the last-line antibiotic against life-threatening multidrug-resistant Gram-negative bacteria. However, increasing number of studies have reported the spread of PMB-resistant strains. With the aim to specifically detect Gram-negative bacteria and potentially reduce the irrational use of antibiotics, we herein rationally designed two Gram-negative bacteria specific fluorescent probes based on our previous activity-toxicity optimization of PMB. The in vitro probe PMS-Dns showed fast and selective labeling of Gram-negative pathogens in complex biological cultures. Subsequently, we constructed the caged in vivo fluorescent probe PMS-Cy-NO 2 by conjugating bacterial nitroreductase (NTR)-activatable positive charged hydrophobic near-infrared (NIR) fluorophore with polymyxin scaffold. Significantly, PMS-Cy-NO 2 exhibited excellent Gram-negative bacterial detection capability with the differentiation between Gram-positive and Gram-negative in a mouse skin infection model., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The current global issue of antibiotic resistance is serious, and there is an urgent requirement of developing novel antibiotics. Octapeptins have recently regained interest because of their activities against resistant Gram-negative bacteria. We synthesized four natural octapeptins and 33 derivatives with diverse polarity, amphiphilicity, and acid-base properties by solid-phase synthesis and investigated their in vitro antibacterial activity and renal cytotoxicity. We also assessed the structure-activity relationship and structure-toxicity relationship of the cyclic lipopeptide compounds. Some compounds showed increased activity against Gram-negative and/or Gram-positive bacteria, with improved renal cytotoxicity. C-02 showed remarkable in vitro antibacterial activity and low renal cytotoxicity. We found that C-02 showed high antibacterial activity against Escherichia coli in vivo and manifested its effects preliminarily by increasing outer membrane permeability. Therefore, C-02 might be a new antibiotic lead compound with not only high efficacy but also low renal cytotoxicity.

Background: Given the benzimidazole derivatives have anti-ovarian cancer effects, the authors aimed to determine whether benzimidazole-2-substituted pyridine and phenyl propenone derivatives exert anti-ovarian cancer activity. Materials & methods: 21 derivatives were synthesized and assayed for their antiproliferative activities. Western blotting in A2780 cells was used to detect the effects of compound A-6 on apoptosis-related proteins. Invasion, migration and apoptosis were assayed in SKOV3 cells treated with A-6. The in vivo activity was also examined. Results: A-6 could inhibit proliferation, invasion and migration and induce apoptosis in SKOV3 cells. Additionally, A-6 had potent inhibitory activity in a xenograft mouse model. Conclusion: A-6 shows potent efficacy in the treatment of ovarian cancer and may be a potential antitumor agent.

Objective: To understand the common viral infection among the surveillance cases of fever respiratory syndrome (FRS) in nine provinces in China. Methods: The research data were obtained from nine provinces (Anhui, Beijing, Guangdong, Hebei, Hunan, Jilin, Shandong, Shaanxi and Xinjiang) in the "Infectious Disease Surveillance Technology Platform Information Management System" of the Chinese Center for Disease Control and Prevention from January 2009 to June 2021. Finally, 8 243 FRS cases with nucleic acid detection results of eight viruses [human influenza virus (HIFV), human respiratory syncytial virus (HRSV), human adenovirus (HAdV), human parainfluenza virus (HPIV), human rhinovirus (HRV), human metapneumovirus (HMPV), human coronavirus (HCoV) and human Boca virus (HBoV)] were included in the study. The χ 2 test/Fisher exact probability method was used to analyze the difference of virus detection rate in different age groups, regions and seasons. Result s The M ( Q 1 , Q 3 ) age of 8 243 FRS cases was 4 (1, 18) years old, and 56.56% (4 662 cases) were children under 5 years old. Males accounted for 58.1% (4 792 cases) of all cases. All cases were from outpatient/emergency department (2 043 cases) and inpatient department (6 200 cases). The virus detection rates of FRS cases from high to low were HRSV, HIFV, HPIV, HRV, HAdV, HMPV, HCoV and HBoV. Two or more viruses were detected simultaneously in 524 cases, accounting for 15.66% of virus-positive cases. The difference of the virus detection rate in different age groups was statistically significant (all P values<0.05), and the virus detection rate in children<5 years old was higher (49.96%). The positive rate of any virus in south China was higher than that in north China ( P <0.001). The virus-positive FRS cases were detected throughout the year. The detection rate of HRSV was higher in autumn and winter. The detection rate of HIFV was higher in winter. The detection rate of HMPV was higher in winter and spring. The detection rates of HPIV, HRV, HCoV and HBoV were higher in summer and autumn, while there was no significant difference in the detection rate of HAdV in different seasons. Compared with 2009-2019, the detection rate of any virus in 2020-2021 decreased from 41.37% to 37.86%. The detection rate of HIFV decreased sharply from 10.62% to 1.37%. The detection rate of HPIV decreased from 8.24% to 5.88%. The detection rate of HRV and HBoV increased from 5.43% and 1.79% to 9.67% and 3.19%, respectively. Conclusion: HRSV and HIFV infections are more common among FRS cases in nine provinces in China from 2009 to 2021, and the epidemiological characteristics of eight common respiratory viruses vary in different age groups, regions and seasons.

Background: Acute meningitis or encephalitis (AME) results from a neurological infection causing high case fatality and severe sequelae. AME lacked comprehensive surveillance in China., Methods: Nation-wide surveillance of all-age patients with AME syndromes was conducted in 144 sentinel hospitals of 29 provinces in China. Eleven AME-causative viral and bacterial pathogens were tested with multiple diagnostic methods., Findings: Between 2009 and 2018, 20,454 AME patients were recruited for tests. Based on 9,079 patients with all-four-virus tested, 28.43% (95% CI: 27.50%‒29.36%) of them had at least one virus-positive detection. Enterovirus was the most frequently determined virus in children <18 years, herpes simplex virus and Japanese encephalitis virus were the most frequently determined in 18-59 and ≥60 years age groups, respectively. Based on 6,802 patients with all-seven-bacteria tested, 4.43% (95% CI: 3.94%‒4.91%) had at least one bacteria-positive detection, Streptococcus pneumoniae and Neisseria meningitidis were the leading bacterium in children aged <5 years and 5-17 years, respectively. Staphylococcus aureus was the most frequently detected in adults aged 18-59 and ≥60 years. The pathogen spectrum also differed statistically significantly between northern and southern China. Joinpoint analysis revealed age-specific positive rates, with enterovirus, herpes simplex virus and mumps virus peaking at 3-6 years old, while Japanese encephalitis virus peaked in the ≥60 years old. As age increased, the positive rate for Streptococcus pneumoniae and Escherichia coli statistically significantly decreased, while for Staphylococcus aureus and Streptococcus suis it increased., Interpretation: The current findings allow enhanced identification of the predominant AME-related pathogen candidates for diagnosis in clinical practice and more targeted application of prevention and control measures in China, and a possible reassessment of vaccination strategy., Funding: China Mega-Project on Infectious Disease Prevention and the National Natural Science Funds., Competing Interests: We declare no competing interests., (© 2021 The Author(s).)

Objective: To investigate the efficacy of radiofrequency ablation (RFA) as a treatment option for primary hyperparathyroidism (pHPT) and risk factors for postablative eucalcemic parathyroid hormone elevation (ePTH)., Methods: This retrospective study included 51 patients with pHPT who underwent RFA. The patients were divided into the ePTH and normal PTH groups, based on the serum intact parathyroid hormone (iPTH) level one month after ablation. Serum iPTH, calcium, and phosphorus levels, and the volume reduction rates (VRR) of the parathyroid glands were compared between the groups at each follow-up point. Risk factors for ePTH at one month after ablation were examined., Results: After RFA, one (2%) patient had persistent pHPT, and 50 (98%) patients were cured. The incidence rates of ePTH at 1, 3, 6, and 12 months were 48%, 30%, 20%, and 16%, respectively. Serum iPTH levels in the ePTH group were higher than those in the normal PTH group at each follow-up point (all p  < 0.05), except 1 day after ablation ( p  > 0.05). Serum calcium and phosphorus levels, and the VRR of the glands were comparable in both groups at each follow-up point (all p  > 0.05), except for calcium levels 3 days after RFA ( p  < 0.05). Baseline iPTH (odds ratio, 1.067; p  = 0.045) and calcium (odds ratio, 3.923; p  = 0.038) levels were independent risk factors for ePTH 1 month after RFA., Conclusions: RFA is safe and effective for the treatment of pHPT. Moreover, ePTH occurrence after RFA was associated with baseline iPTH and calcium levels and did not increase the risk of recurrent pHPT.

Nationwide prospective surveillance of all-age patients with acute respiratory infections was conducted in China between 2009‒2019. Here we report the etiological and epidemiological features of the 231,107 eligible patients enrolled in this analysis. Children <5 years old and school-age children have the highest viral positivity rate (46.9%) and bacterial positivity rate (30.9%). Influenza virus, respiratory syncytial virus and human rhinovirus are the three leading viral pathogens with proportions of 28.5%, 16.8% and 16.7%, and Streptococcus pneumoniae, Mycoplasma pneumoniae and Klebsiella pneumoniae are the three leading bacterial pathogens (29.9%, 18.6% and 15.8%). Negative interactions between viruses and positive interactions between viral and bacterial pathogens are common. A Join-Point analysis reveals the age-specific positivity rate and how this varied for individual pathogens. These data indicate that differential priorities for diagnosis, prevention and control should be highlighted in terms of acute respiratory tract infection patients' demography, geographic locations and season of illness in China., (© 2021. The Author(s).)

Polymyxin B and colistin (polymyxin E) are increasingly used as the last line of therapy for infections caused by multidrug-resistant (MDR) gram-negative pathogens. However, nephrotoxicity is still a limiting factor for the use of polymyxin. Therefore, better tolerated and more effective polymyxin derivatives are urgently needed. In this study, we aimed to evaluate the activity of the low-alkalinity polymyxin derivative, AL-6, against MDR Acinetobacter baumannii (Ab) clinical isolates in vitro and A. baumannii ATCC 19606 in vivo . Additionally, we performed a preliminarily study of the antibacterial mechanism. AL-6 showed much higher activity (0.125-0.25 μg/mL) against MDR A. baumannii clinical isolates than polymyxin E 2 (PE 2 , 0.5-1 μg/mL). AL-6 also showed much higher activity (0.5-256 μg/mL) against polymyxin-resistant strains than PE 2 (16-1024 μg/mL). Additionally, AL-6 showed slow resistance against A. baumannii . AL-6 also increased the survival rates of mice by 10% at 48 h compared with PE 2 (5 mg/kg). AL-6 could be used at a dose of up to 10 mg/kg, increasing the survival rate to 30% at 72 h after infection. A preliminary study of the antibacterial mechanism showed that AL-6 permeabilized the outer membrane and destroyed cell membrane integrity. Moreover, there was a substantial increase in zeta potential ( i.e ., less negative) upon AL-6 exposure for A. baumannii . Overall, AL-6 carrying only four positive charges showed high activity against A. baumannii in vitro by disrupting cell membrane integrity. Higher doses of AL-6 could increase survival rates of mice. Thus, AL-6 may have potential applications as a bactericidal agent.

Objective: To study the prevalence and genetic characteristics of human respiratory syncytial virus (HRSV) in Quanzhou city, from 2018 to 2019. Methods: A total of 141 throat swabs were collected from children patients of lower respiratory tract infection in Quanzhou children Hospital, Fujian Province from November 2018 to May 2019. RT-PCR was used to amplify the 3 'end of G gene HRSV. Sequencer 5.0 and MEGA5.05 softwares were used for sequence editing, phylogenetic tree construction and genotyping analysis. Results: Twenty-five samples were positive for HRSV. Seventeen samples succeeded to obtain the target gene, including 13 of HRSVA and 4 of HRSVB. Two genotypes were identified: ON1 genotype (13 samples, HRSVA) and BA9 genotype (4 samples, HRSVB). Five strains of ON1 genotype sequences were clustered with the ON1 sequences prevalent in Beijing, Changchun and Zhejiang from 2012 to 2015 (cluster1); one strain (FJ19-02) was clustered with the sequences of ON1 genotype circulating in many regions of China from 2012 to 2015 (cluster2); Seven strains were clustered independently (cluster FJ). FJ18-02, FJ19-14 and FJ19-15 of HRSVB were clustered with the BA9 genotype sequences prevalent in Changchun, Jilin Province in 2015, while FJ19-13 was closely related to the BA9 genotype sequences prevalent in Guangzhou and Zhejiang Province in 2013. Both the ON1 and BA9 genotypes showed variations of nucleotide and amino acid in 72 and 60 insertion segments. Amino acid mutation (H266L) only occurred among the sequence of cluster-FJ, and the mutations of H261Q and Q265L only appeared in strain FJ19-13. Conclusion: BA9 and ON1 genotypes were prevalent in Quanzhou city, from 2018 to 2019. Cluster-FJ was a newly discovered independent transmission chain, which may continue to circulate in local Quanzhou area.

National-based prospective surveillance of all-age patients with acute diarrhea was conducted in China between 2009‒2018. Here we report the etiological, epidemiological, and clinical features of the 152,792 eligible patients enrolled in this analysis. Rotavirus A and norovirus are the two leading viral pathogens detected in the patients, followed by adenovirus and astrovirus. Diarrheagenic Escherichia coli and nontyphoidal Salmonella are the two leading bacterial pathogens, followed by Shigella and Vibrio parahaemolyticus. Patients aged <5 years had higher overall positive rate of viral pathogens, while bacterial pathogens were more common in patients aged 18‒45 years. A joinpoint analysis revealed the age-specific positivity rate and how this varied for individual pathogens. Our findings fill crucial gaps of how the distributions of enteropathogens change across China in patients with diarrhea. This allows enhanced identification of the predominant diarrheal pathogen candidates for diagnosis in clinical practice and more targeted application of prevention and control measures.

Twenty-three polymyxin analogs with variations at nine amino acid positions were synthesized and assessed for antimicrobial activity and renal cytotoxicity. Compounds M 2 , 14 , S 2 , and 16 (MIC = 0.125-4 μg/mL) had similar or stronger activities against susceptible and drug-resistant strains of Escherichia coli , Klebsiella pneumoniae , Pseudomonas aeruginosa , and Acinetobacter baumannii compared to polymyxin B (MIC = 1-2 μg/mL). Most synthesized compounds (50% cytotoxic concentration, CC 50 ≥ 200 μg/mL) exhibited lower cytotoxicity than polymyxin B (CC 50 = 99 ± 6 μg/mL). Polymyxin S 2 showed high plasma stability in vitro and strong efficacy in a mouse systemic infection model (ED 50 = 0.9 mg/kg) against NDM-1-producing Klebsiella pneumoniae , suggesting that it is a potential candidate for drug development. The activity and cytotoxicity results indicated that the amino acids at positions 2, 3, 6, and 7 might be replaced. Effects on activity and cytotoxicity linked to changes in the number of positively charged amino acids varied among different cyclopeptide skeletons, but the underlying mechanisms are unknown.

RAS protein activator like-1 (RASAL1) exists in numerous human tissues and has been commonly demonstrated to act as a tumor suppressor in several cancers. This study aimed to identify the functional characteristics of RASAL1 in ovarian adenocarcinoma and a potential mechanism of action. We analyzed RASAL1 gene expression in ovarian adenocarcinoma samples and normal samples gained from the GEO and Oncomine databases respectively. Then the relationship between RASAL1 expression and overall survival (OS) was assessed using the Kaplan-Meier method. Furthermore, the biological effect of RASAL1 in ovarian adenocarcinoma cell lines was assessed by Quantitative real time-PCR (qRT-PCR), Cell Counting Kit-8 (CCK-8), western blot, wound healing and transwell assay. The statistical analysis showed patients with higher RASAL1 expression correlated with worse OS. The in vitro assays suggested knockdown of RASAL1 could inhibit cell proliferation, cell invasion and migration of ovarian adenocarcinoma. Moreover, the key proteins in the mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK/ERK) signaling pathway were also decreased in ovarian adenocarcinoma cells with RASAL1 silencing. These findings provide promising evidence that RASAL1 may be not only a powerful biomarker but also an effective therapeutic target of ovarian adenocarcinoma., Competing Interests: Conflict of interest Authors state no conflict of interest, (© 2019 Rui-Xia Chang et al.,published by De Gruyter.)

The tumor suppressor bridging integrator 1 (BIN1) is a corepressor of the transcription factor E2F1 and inhibits cell-cycle progression. BIN1 also curbs cellular poly(ADP-ribosyl)ation (PARylation) and increases sensitivity of cancer cells to DNA-damaging therapeutic agents such as cisplatin. However, how BIN1 deficiency, a hallmark of advanced cancer cells, increases cisplatin resistance remains elusive. Here, we report that BIN1 inactivates ataxia telangiectasia-mutated (ATM) serine/threonine kinase, particularly when BIN1 binds E2F1. BIN1 + 12A (a cancer-associated BIN1 splicing variant) also inhibited cellular PARylation, but only BIN1 increased cisplatin sensitivity. BIN1 prevented E2F1 from transcriptionally activating the human ATM promoter, whereas BIN1 + 12A did not physically interact with E2F1. Conversely, BIN1 loss significantly increased E2F1-dependent formation of MRE11A/RAD50/NBS1 DNA end-binding protein complex and efficiently promoted ATM autophosphorylation. Even in the absence of dsDNA breaks (DSBs), BIN1 loss promoted ATM-dependent phosphorylation of histone H2A family member X (forming γH2AX, a DSB biomarker) and mediator of DNA damage checkpoint 1 (MDC1, a γH2AX-binding adaptor protein for DSB repair). Of note, even in the presence of transcriptionally active ( i.e. proapoptotic) TP53 tumor suppressor, BIN1 loss generally increased cisplatin resistance, which was conversely alleviated by ATM inactivation or E2F1 reduction. However, E2F2 or E2F3 depletion did not recapitulate the cisplatin sensitivity elicited by E2F1 elimination. Our study unveils an E2F1-specific signaling circuit that constitutively activates ATM and provokes cisplatin resistance in BIN1-deficient cancer cells and further reveals that γH2AX emergence may not always reflect DSBs if BIN1 is absent., (© 2019 Folk et al.)

Epidermal growth factor receptor (EGFR) is a rational target for cancer therapy, because its overexpression plays an important oncogenic role in a variety of solid tumors; however, EGFR-targeted antibody-drug conjugate (ADC) therapy for esophageal squamous cell carcinoma (ESCC) is exceedingly rare. LR004 is a novel anti-EGFR antibody with the advantages of improved safety and fewer hypersensitivity reactions. It may be of great value as a carrier in ADCs with high binding affinity and internalization ability. Here, we prepared an EGFR-targeting ADC, LR004-VC-MMAE, and evaluated its antitumor activities against ESCC and EGFR-positive cells. LR004 was covalently conjugated with monomethyl auristatin E (MMAE) via a VC linker by antibody interchain disulfide bond reduction. VC-MMAE was conjugated with LR004 with approximately 4.0 MMAE molecules per ADC. LR004-VC-MMAE showed a potent antitumor effect against ESCC and other EGFR-positive cells with IC 50 values of nM concentrations in vitro. The in vivo antitumor effects of LR004-VC-MMAE were investigated in ESCC KYSE520 and A431 xenograft nude mice models. Significant activity was seen at 5 mg·kg -1 , and complete tumor regression was observed at 15 mg·kg -1 in the KYSE520 xenograft nude mice after four injections, while the naked antibody LR004 had little effect on inhibiting tumor growth. Similar promising results were obtained in the A431 models. In addition, the tumors also remained responsive to LR004-VC-MMAE for large tumor experiments (tumor volume 400-500 mm 3 ). The study results demonstrated that LR004-VC-MMAE could be a potential therapeutic agent for ESCC and other EGFR-expressing malignancies. We also evaluated PK profile of LR004-VC-MMAE ADC in the mice model, which would provide qualitative guiding significance for the further research., (© 2018 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.)

In this paper, 26 natural polymyxin components and a new derivative S 2 were synthesized, and their differences in efficacy and toxicity have been investigated. Almost all of the synthesized components showed strong activity against both susceptible and resistant strains of E. coli, K. pneumoniae, P. aeruginosa, and A. baumannii. The toxicities were obviously different between the components. Only some of the components were tested for toxicity in vivo. Compounds E 2 , E 2 -Val, A 2 , M 2 , D 2 , and S 2 showed obviously lower renal cytotoxicity and acute toxicity than polymyxins B and E. The in vivo nephrotoxicity of E 2 , M 2 , and S 2 was similar to that of polymyxin E. Compound S 2 , with four positive charges, was especially interesting as it possessed both increased efficacy and decreased toxicity. The SAR and toxicity studies indicated that further structural modification could concentrate on polymyxin S. The results also indicated that S 2 could be a new drug candidate.

We herein report the synthesis, crystal structure and magnetic properties of nine new heterotrimetallic complexes. [Ni(Me 2 valpn)] (H 2 Me 2 valpn = N,N'-bis(3-methoxysalicylidene)-2,2-dimethyl-1,3-diaminopropane) was used as the precursor to construct phenoxo-bridged [Ni 2 Ln] 3+ (Ln 3+ = Dy, Tb, Gd and Y) species that were respectively connected by two [M(CN) 6 ] 3- (M = Cr, Fe or Co) anions to form octanuclear cyclic complexes, i.e. {[Ni(Me 2 valpn)] 2 Ln(H 2 O)M(CN) 6 } 2 in which Ln = Y, Gd, Tb and Dy and M = Cr, Fe or Co (1-9). Each of the complexes contains many lattice-bound molecules of solvation. The Ni(ii) ions are penta-coordinate, while the Ln(iii) ions are nine coordinated with a muffin geometry. The fitting to the χ m T vs. T curves of complexes 6-9 gave the parameters of J NiCr = 11.82 cm -1 , J NiGd = 0.94 cm -1 and g = 2.04 for complex 6, J NiFe = 10.58 cm -1 , J NiGd = 1.24 cm -1 and g = 2.03 for complex 7, J NiCr = 9.4(1) cm -1 , zJ' = -0.050(2) cm -1 and g = 2.06(1) for complex 8 and J NiFe = 4.9(7) cm -1 , zJ' = -0.35(2) cm -1 and g = 2.24(1) for complex 9, respectively. The dynamic magnetic investigations demonstrate that complexes 1-5 display single-molecule magnet properties with an effective energy barrier (U eff ) of 38.9 K (1, M1 = Dy, M2 = Cr), 37.2 K (2, M1 = Dy, M2 = Cr), 24.4 K (3, M1 = Dy, M2 = Co), 21.9 K (4, M1 = Tb, M2 = Cr) and 29.6 K (5, M1 = Tb, M2 = Fe), respectively. Complex 1 shows the highest energy barrier among the octanuclear [Ni 4 LnM 2 ] (Ln = Dy or Tb, M = Fe, Cr, Co or W) system. Although the [Ni 4 Dy 2 Cr 2 ] complexes have U eff higher than that of [Ni 4 Dy 2 Fe 2 ], complex [Ni 4 TbCr 2 ] shows lower U eff than that of [Ni 4 TbFe 2 ]. The results indicate that besides the M-C[triple bond, length as m-dash]N-Ni magnetic coupling the lanthanide ions can significantly affect the magnetic performances of heterotrimetallic SMMs as well. Moreover, the SMMs are achieved when diamagnetic Co(iii) was substituted by paramagnetic Cr(iii) or Fe(iii) in the [Ni 4 Tb 2 M 2 ] system, suggesting that the trimetallic strategy is effective in the construction of new 3d-4f SMMs.

N -methyl-D-aspartate (NDMA) receptor-mediated excitotoxicity has been implicated in a variety of pathological situations such as Alzheimer's disease (AD) and Parkinson's disease. However, no effective treatments for the same have been developed so far. Humanin (HN) is a 24-amino acid peptide originally cloned from the brain of patients with AD and it prevents stress-induced cell death in many cells/tissues. In our previous study, HN was found to effectively rescue rat cortical neurons. It is still not clear whether HN protects the neurons through the attenuation of mitochondrial dysfunction. In this study, excitatory toxicity was induced by NMDA, which binds the NMDA receptor in primarily cultured rat cortical neurons. We found that NMDA (100 μmol/L) dramatically induced the decrease of cell viability and caused mitochondrial dysfunction. Pretreatment of the neurons with HN (1 μmol/L) led to significant increases of mitochondrial succinate dehydrogenase (SDH) activity and membrane potential. In addition, HN pretreatment significantly reduced the excessive production of both reactive oxygen species (ROS) and nitric oxide (NO). Thus, HN could attenuate the excitotoxicity caused by the overactivation of the NMDA receptor through the alleviation of mitochondrial dysfunction., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Objective: To clarify the genotype of wild-type strains of varicella zoster virus (VZV) in Jilin province in 2014, and to discriminate between v-Oka vaccine strains and wild-type strains., Methods: Vesicle fluid and throat swab samples were collected from 13 individuals with suspected VZV in Jilin province from January to December 2014. Viral DNA was extracted, the fragments of 15 open reading fragments (ORFs) were amplified by polymerase chain reaction (PCR), and viral genotypes were determined by single nucleotide polymorphisms (SNP). PCR restriction fragment length polymorphism (RFLP) was used to distinguish between wild-type strains and v-Oka vaccine strains. The results were analyzed with MEGA5 software, using the VZV reference strain sequences from GenBank., Results: The 13 suspected samples included 5 males and 8 females, aged 11-27 years (mean: (16.69±5.48) years). Sampling was performed on days 0 to 3 of suspected infection. VZV strains were detected in 8 samples, all belonging to Clade 2. There was a synonymous mutation (T>C) in SNP18082 compared with the v-Oka vaccine strain. Analysis of PCR-RFLPs showed that all 8 positive samples were wild-type strains (PstⅠ(+)BglⅠ(+)SmaⅠ(-))., Conclusions: The study revealed that the VZV strains circulating in Jilin province in 2014 were wild-type strains belonging to Clade 2.

Two cyano- and phenoxo-bridged octanuclear complexes ZnDyCo (complex ) and ZnDyCr (complex ) with diamagnetic Zn(ii) and Co(iii) are reported. Dy(iii) is surrounded by nine oxygen atoms of two [Zn(Me2valpn)] (Me2valpn(2-) = dianion of N,N'-2,2-dimethylpropylenebis(3-methoxysalicylideneimine)) and one water molecule. Magnetic studies reveal that both exhibit single-ion magnet (SIM) behavior with the energy barrier of 85.9 K for complex and 100.9 K for complex .

Two cyano- and phenoxo-bridged hexanuclear Ni(II)2Dy(III)2Fe(III)2 (1) and octanuclear Ni(II)4Dy(III)2Fe(III)2 (2) trimetallic cyclic complexes have been obtained. They are the first trimetallic metallocycles. Magnetic studies reveal that 1 and 2 exhibit single-molecule-magnet behavior with an energy barrier of 17.9 K for complex 1 in a 2000 Oe static field and 25.0 K for complex 2 in a zero static field.

The synthesis and characterization of four dinuclear 3d-4f complexes [M(II)Ln(III)(L)(DBM)3] (ZnDy = 1, CoY = 2, CoDy = 3·3.5CH3CN, CoGd = 4·3.5CH3CN) are reported (H2L = N,N'-dimethyl-N,N'-(2-hydroxy-3-methoxy-5-methyl-benzyl)ethylenediamine, DBM(-) = anion of 1,3-diphenyl-propane-1,3-dione). In each of the four complexes, the M(II) ion occupies the internal N2O2 site whereas the Ln(III) ion occupies the external O4 site. There are diphenoxo bridges between the M(II) and Ln(III) ions in these complexes. The remaining coordination sites are occupied by three DBM(-) anions. Direct current (dc) magnetic susceptibility measurements indicate the presence of intramolecular ferromagnetic interactions in complexes 3 and 4. The magnetic coupling constant, JCoGd, of complex 4 is estimated to be 0.26 cm(-1) (H = -2JCoGdSCoSGd). Alternating current (ac) magnetic susceptibility studies reveal that complexes 1 and 2 show field-induced single molecule magnet behavior, with ΔE values of 36.5 K and 8.56 K, respectively. Complex 3 shows frequency dependent out-of-phase signals, indicating the presence of a slow relaxation of the magnetization, whereas complex 4 does not display slow magnetization relaxation.

Supramolecular strategy was employed to achieve the highest nuclearity Co(II) cluster exhibiting spin-crossover (SCO) behavior. Magnetic susceptibility characterization of the Co4(II) complex shows that two different spin-transition processes occur. The SCO behavior is directed by the partially deprotonated polydentate ligand, which favors the structural distortion required by the spin transition.

The chains in complex [Mn(TPP)][Mn(TPP)(CN)2] (H2TPP = meso-tetra(4-phenyl)-porphyrin) demonstrate perfect linearity, and are well isolated with the nearest interchain Mn-Mn separation of 12.95 Å. Ferromagnetic coupling is present among adjacent Mn(III) ions, and single-chain magnet (SCM) behaviour is verified.

Five Cu II complexes of trinuclear [Cu 3 (L 1 ) 2 (N 3 ) 6 ] (1), one-dimensional chain [Cu 5 (L 2 ) 2 (N 3 ) 10 ] n  (2), trinuclear [Cu 3 (L 3 ) 2 (N 3 ) 6 ] (3) and dinuclear [Cu 2 (L 4 ) 2 (N 3 ) 2 Cl 2 ] (4) and [Cu 2 (L 5 ) 2 (N 3 ) 2 Cl 2 ] (5) (L 1-5 =RCH 2 OR', R=substituted pyrazole or imidazole, R'=Me, Et or nPr) were synthesized by the reaction of CuCl 2 ⋅2 H 2 O, sodium azide with RCH 2 Cl in CH 3 OH, C 2 H 5 OH or n-C 3 H 7 OH. The ether ligands L 1 and L 2 can be alternatively prepared by the alcoholysis of RCH 2 Cl in the presence of sodium azide, whereas the ligands L 3-5 form in corresponding alcohols without azide. For complexes 1-5, the oxygen atom of the ether ligands is located at the Jahn-Teller axis of Cu II with the long CuO separations of 2.377(3)-2.830(3) Å. The nitrogen atoms of bridging azides are located in the equatorial or basal planes of Cu II ions, favoring strong magnetic coupling. The Cu-N azido -Cu bridging angles in complexes 1-3 are 98.8(2)°-101.6(1)°, leading to ferromagnetic coupling, whereas the Cu-N azido -Cu angles in complexes 4 and 5 are close to 103°, leading to antiferromagnetic coupling., (Copyright © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Excitatory neurotoxicity has been implicated in many pathological situations and there is no effective treatment available. Humanin is a 24-aa peptide cloned from the brain of patients with Alzheimer's disease (AD). In the present study, excitatory toxicity was induced by N-methyl-D-aspartate (NMDA) in primarily cultured rat cortical neurons. MTT assessment, lactate dehydrogenase (LDH) release, and calcein staining were employed to evaluate the protective activity of humanin on NMDA induced toxicity. The results suggested that NMDA (100 μmol/L, 2.5 hr) triggered neuronal morphological changes, lactate dehydrogenase (LDH) release (166% of the control), reduction of cell viability (about 50% of the control), and the decrease of living cell density (about 50% of the control). When pretreated with humanin, the toxicity was suppressed. The living cells' density of humanin treated group was similar to that of control. The cell viability was attenuated dose-dependently (IC50 = 0.132 nmol/L). The LDH release was also neutralized in a dose-dependent manner. In addition, the intracellular Ca(2+) overloading triggered by NMDA reverted quickly and humanin could not inhibit it. These findings indicate that humanin can rescue cortical neurons from NMDA-induced toxicity in rat but not through interfering with NMDA receptor directly.

Mumps virus strains of genotype F have been circulating in China for decades. To identify genetic variation of mumps virus based on the complete genome sequence of a mumps isolate of genotype F, the complete genome of the genotype F reference strain, MuVi/Shandong. CHN/4.05 [F] was sequenced. Genetic characteristics of this virus were analyzed and compared with the complete genome sequences of others genotypes available in GenBank. The genetic differences in antigenic sites were also compared between the genotype F strain and the vaccine strains. The nucleotide differences between MuVi/Shandong. CHN/4.05 [F] and other genotypes of mumps virus based on the whole genome ranged between 3.8% and 6.5%. The maximum and minimum difference was found between MuVi/Shandong. CHN/4.05 [F] and genotype A (the vaccine strains), and genotype B-N strains, respectively. There were 26 N-glycosylation sites in the strain MuVi/Shandong. CHN/4.05 [F] and all other genotypes of mumps virus, however, one N-glycosylation site was absent from the vaccine strains, which was at the aa position 464-466 of the HN gene. Variation was detected at some of the known antigenic sites of mumps virus strain MuVi/Shandong. CHN/4.05 [F] and the vaccine strains. Genetic variations were detected in the epidemic mumps virus strain in China as well as in other genotypes of mumps virus strains and the vaccine strains across the complete genome. These results indicate the need to further strengthen the surveillance of genetic variation of wild type mumps virus.

To investigate the genetic characterization of Human parainfluenza virus-3 (HPIV-3) circulating in Gansu and Shaanxi Provinces of China, 719 throat swabs were collected from pediatric patients with acute respiratory infections from 2009-2011. Multiplex RT-PCR was used to screen common respiratory viral pathogens. For HPIV-3-positive specimens, nested RT-PCR was used to amplify the HN gene of HPIV-3. The nucleotides of Hemagglutinin-neuraminidase(HN)gene of 13 HPIV-3 positive strains identified in Gansu and Shaanxi Provinces were successfully sequenced and compared with those downloaded from GenBank. The phylogenetic analysis based on the nucleotides sequence of HN gene showed that 13 HPIV-3 strains belonged to sub-cluster C3 with little sequence variation (overall nucleotide divergence of 0.2%-2.3% and amino acid divergence at 0-1.1%). Compared with the complete gene of HPIV-3 strains from U.S.A., Canada, and Australia, the biggest divergence of the nucleotide and amino acid lovels was 6.0% and 3.4%, respectively. The nucleotide divergence between shaanxi09-2 and shaanxi10-H0091 was 0.9%, while the nucleotide divergence between shaanxi10-H005 and gansull-62110372 was 0.5%, between shaanxi09-2 and BJ/291/09 was 0.6%. However, there was no amino acid divergence among them. It is likely that HPIV-3 virus had been transmitting in Gansu and Shaanxi Provinces for several years. Human parainfluenza virus-3 (HPIV-3) circulated in Gansu and Shaanxi Provinces from 2009 to 2011 belonged to sub-cluster C3.

To rapidly identify the cross-contamination problems caused by the positive control in the process of mumps virus nucleic acid detection, a new mumps virus RNA positive control was developed in this study. Using the same primers and reaction conditions, the cross-contamination problems caused by the positive control could be readily identified by comparing the fragments lengths of the PCR products between the positive control and the samples. This new RNA positive control of mumps virus can be widely used in the diagnosis and genotyping of mumps virus as a better laboratory quality control.

The synthesis and characterization of three isomorphous complexes [NiII(L)LnIII(DBM)₃] (Ln = Gd (1·2.5CH₃CN·0.5H₂O), Tb (2·2CH₃CN·0.5MeOH), and Dy (3·2CH₃CN·0.5MeOH·0.5H₂O)) are reported (H₂L = N,N'-dimethyl-N,N'-(2-hydroxy-3-methoxy-5-methylbenzyl)ethylenediamine, DBM⁻ = anion of 1,3-diphenylpropane-1,3-dione). The flexible ligand L²⁻ contains an N₂O₂-inner and an O₄-outer coordination site. There are diphenoxo bridges between NiII and LnIII ions in these complexes. The remaining coordination sites are occupied by DBM⁻ anions. Direct current (dc) magnetic susceptibility measurements indicate the presence of intramolecular ferromagnetic interactions in desolvated complexes 1-3. The magnetic coupling constant JNiGd in complex 1 is estimated to be 1.11 cm⁻¹ (H = -2JNiGdSNiSGd). Alternating current (ac) magnetic susceptibility studies reveal that complexes 2 and 3 show frequency-dependent out-of-phase signals, which indicate that they exhibit SMM behavior. The energy barriers for complexes 2 and 3 under a 2 kOe applied direct current (dc) magnetic field are estimated from Arrhenius plots to be 14.4 and 11.3 K, respectively.

To study the epidemic characteristics of human rhinovirus (HRV) in children with acute respiratory infections in Gansu Province. 286 throat swabs were collected from children with acute respiratory in fections in Gansu Province during 2011. Multiplex reverse transcription-PCR (multiplex RT-PCR) assay was used to screen those specimens for detection of common respiratory tract pathogens. For HRV-positive samples, nested reverse transcription polymerase chain reaction (nested RT-PCR) was performed to amplify VP1 and VP4/VP2 gene fragments of HRV. The VP4/VP2 and VP1 regions of HRV-positive samples were sequenced and performed genotype analysis. Of 286 specimens fested, 27 were positive for HRV by multiplex RT-PCR and nested RT-PCR, of which 16 children were made (16/185), 8.64%) and 11 female (11/101,10.89%). The positive rate was 9.44% (27/286). The mean age of HRV-positive children was 3 years in this study, children less than one year old had the highest proportion 44.4% (12/ 27, 44.4%). The highest HRV positive rate fell on May, 2011 (6/27, 22.2%). Common cold accounted for the highest proportion, 12.24% (12/98) followed by pneumonia, 8.50% (13/153). The remaining 2 cases were bronchitis. Sequence analysis showed HRV A was the predominant genotype in Gansu Province in 2011, accounting for 84.62% (22/26) of positive cases, followed by HRV C (11.54%, 3/26) and only one HRV B was detected (3.85%, 1/26). HRV could be detected throughout the year in Gansu Province and primarily infected children under one year old. The group A was the epidemic genotype of HRV and move than one genotype existed in Gansu Province during 2011.

Two bis(tridentate) Schiff base ligands H2L(x) were used to construct three 2×2 grid-type tetranuclear Fe(II) complexes 1-3 to obtain polynuclear spin-crossover materials. Magnetic susceptibility measurements show that the spin states of the complexes are related to the substituents of H2L(x), and that spin transition occurs only in complexes 1 and 2, which are derived from a bulky ligand, whereas complex 3 is diamagnetic. The transition temperatures of complexes 1 and 2 are close to room temperature and are dependent on counteranions. The spin transition of complex 1 can be reversibly tuned by the dehydration and hydration process.

A supramolecular strategy has been applied to construct two tetranuclear lanthanide complexes for investigating the magnetic properties of individual lanthanide ions. The Ln(III) complexes (Ln = Dy, Tb) display field-induced slow magnetization relaxation, typical of single-molecule magnet behavior. The four lanthanide ions in the molecules are well separated by distances of ca. 9 Å, and thus the slow magnetization relaxation should be assigned to single-ion magnet (SIM) behavior. Therefore, the present complexes are novel supramolecular aggregates of four isolated SIMs.

To reveal the epidemiological and pathogenic characteristics of Hand-foot-and-mouth disease (HFMD) in Hainan province in 2010, epidemiology data of HFMD reporting cases were analyzed, clinical specimens from 1346 HFMD cases were collected for enterovirus (EV) detection. Viral isolation was performed for EV nucleic acid positive samples. Complete VP1 encoding region of EV71 were sequenced and analyzed with Sequencher (version 5.0) and MEGA software (version 5.0). The epidemiology data showed that all 18 prefectures in Hainan had reporting cases during 2010, with higher incidence in the northeast; and the children less than 4 years old accounted for the majority of the suffered; the epidemic reached peak during September to October, which was different from other Provinces in China. The laboratory results indicated that EV71 and CA16 were identified as the major causative pathogens in Hainan in 2010, however, EV71 infection was absolutely dominant among severe and fatal cases. In addition, some HFMD cases were identified associated with other serotypes of EV infections. Molecular epidemiological analysis showed that all the EV71 strains belonged to C4a evolutionary branch, which is the dominant evolutionary branch in China in recent years, and at least three transmission chains existed. This study has an important information in clarifying the characteristics of epidemics and transmission of HFMD in Hainan, and to provide the guidance for HFMD prevention and control in the future.

Objective: Analysis the viral pathogenic spectrum for patients with fever and respiratory tract infection syndrome in Shaanxi province during 2010 and investigate the molecular epidemiology characteristics of respiratory syncytial virus., Methods: A total of 208 patients' pharyngeal swabs were collected based on surveillance definition from January 2010 to January 2011 and screened for sixteen human respiratory virus types/subtypes by Qiaxcel-based multiplex reverse transcription-PCR assay, including HRV,HCoV, Flu, HPIV, ADV, HRSV, HMPV and HBoV and investigate molecular epidemiology of HRSV by sequencing and phylogenetic analysis of the C-terminal second hypervariable region of the G gene., Results: 109 out of 208 specimens (53%) were positive for one or more viruses. HRSV(42. 2%) was the dominant pathogen detected, followed by Flu(24. 5%), PIV(20%), HRV(13.6%) and ADV( 10.9%),there were also 8 strains of HCoV, 5 strains of HMPV and 3 strains of HBoV detected. The results showed that 22 specimens were positive for two or more viruses, PIV (14/22) was the most frequently detected viral agent among co-infection specimens, and the highest incidence of mixed infection is aged 15-39 years group (P < 0.05). The overall viral detection rate was no related to age. In addition to Flu, HMPV and PIV, other viruses (HRV, HBoV, HCoV, ADV, RSV) mainly infected 0 to 4 years old children. Among 46 HRSV positive specimens, 42 HRSV-A strains clustered into NA1 genotype and two HRSV-B strains clustered into two genotypes, BA9 and GB2., Conclusion: HRSV is the dominate pathogen collected from patients with fever and respiratory tract infection syndrome in Shaanxi and HRSV A is the predominant subtype. For most viruses, infection was most prevalent among children aged <4 years. PIV was the most common pathogen in co-infection.

Objective: To be acquainted with genetic characteristics and variation of mumps virus strains circulating in Hunan province., Methods: Mumps virus (MV) strains were isolated using Vero/ SLAM cells. The small hydrophobic protein (SH) genes of MV isolates were sequenced, and the sequences were analysed phylogenetically between the isolated strains and other reference mumps strains., Results: 4 mumps virus strains were isolated from 16 specimens collected in 2011 from different regions of Hunan province. The genotype of isolated strains were supposed to be F type., Conclusion: Genotype F is the main genotype of circulating strains in Hunan province in 2011 and there is no variation between genotype.

The compartmental Schiff base ligands N,N'-ethylenebis(3-hydroxysalicylidene) (H(4)L) and N,N'-propylenebis(3-hydroxysalicylidene) (H(4)L') have been employed in the synthesis of a cyclic tetranuclear Cu(II) complex [Cu(4)(L')(2)(MeOH)(3)(H(2)O)]·[Cu(4)(L')(2)(MeOH)(3)] (1), a novel octanuclear Cu(II) complex [Cu(8)(L-L)(2)(H(2)O)(4)(μ(2)-H(2)O)]·3DMF·3H(2)O (2) and a hetero-octanuclear Cu(II)-Fe(III) complex [Cu(4)Fe(4)(L)(4)(H(2)O)(3)(μ(3)-O)(2)]·3DMF·3H(2)O (3). During the formation of the Cu(8) complex (2), a new bis-Schiff base ligand (L-L)(8-) forms via the ortho-para C-C coupling of two H(4)L ligands. The bicyclic complex (2) is comprised of two cyclic Cu(4) units that are similar to that of complex 1. In the Cu(4) unit, the alternate Cu(II) ions are singly bridged by phenoxo groups. The three complexes display overall antiferromagnetic coupling, and the Cu(II)-Cu(II) magnetic coupling constant falls in the range -117.2 to -473.6 cm(-1) for complexes 1 and 2 corresponding to the bridging Cu-O(phenoxide)-Cu bond angles of 124.3-131.0°.

Objective: To understand the evolutionary relationship between the C4a evolutionary lineage of human enterovirus 71 (HEV71) strains circulating in mainland of China during 2008-2010 and 2008 Fuyang strains and study the prevalence and transmission patterns of 2008 Fuyang strains., Methods: Download all the complete VP1 ( > or = 891 bp) or approximate complete VP1 (> or = 876 bp) gene nucleotide sequences from GenBank of HEV71 strains circulating in Mainland of China during 2008-2010. And analyze the phylogenetic relationship between Fuyang strains and other provinces' strains using the MEGA software, version 5.0., Results: All of the HEV71 isolates circulating in Mainland of China during 2008-2010 were clustered into evolutionary lineage C4a except for eight strains grouped in the genotype A and one isolate belongs to evolutionary lineage C4b; the homology analysis showed there were 96.5%-100% identity between C4a viruses circulating in mainland China during 2008-2010 and 2008 Fuyang strains, and they were evolved from C4b viruses of 1998. The transmission chains of Fuyang strains were mainly transmitted in Guangdong, Jiangsu, Shanghai, Hunan, Shandong provinces., Conclusion: The predominant viruses circulating in Mainland of China during 2008-2010 were evolutionary lineage C4a of human Enterovirus 71; Fuyang transmission chains mainly distributed in southern of China and the Central China around Anhui provinces.

The synthesis and characterizations of a family of isomorphous [Mn(III)(2)M(III)(4)L(2)(μ(4)-O)(2)(N(3))(2)(CH(3)O)(2)(CH(3)OH)(4)(NO(3))(2)]·2H(2)O (M = Y(1), Gd(2), Tb(3), Dy(4)) are reported, where H(4)L = N,N'-dihydroxyethyl-N,N'-(2-hydroxy-4,5-dimethylbenzyl)ethylenediamine. They were obtained from the reactions of H(4)L with M(NO(3))(3)·6H(2)O, Mn(ClO(4))(2)·6H(2)O, NaN(3) and NEt(3) in a 1:1:1:2:2 molar ratio. The core structure consists of a Mn(2)M(4) unit. The four M(III) ions that are held together by two μ(4)-bridging oxygen atoms form a butterfly M(4) moiety. The M(4) core is further connected to the two five-coordinate trigonal-bipyramidal Mn(III) ions via one μ(4)-O(2-), two alkyloxo and one methoxo triple bridges. Magnetic susceptibility measurements indicate the presence of intramolecular antiferromagnetic interactions in complex 2, and overall intramolecular ferromagnetic interactions in complexes 3 and 4. The alternating current (AC) magnetic susceptibility studies revealed that complexes 3 and 4 showed frequency-dependent out-of-phase signals, which indicates that they exhibit slow relaxation of the magnetization.

Tetranuclear [Ni(4)(Hpzaox)(2)(pzaox)(2)(py)(4)](ClO(4))(2)·2py (1), [Ni(4)(Hpzaox)(2)(pzaox)(2)(py)(4)](NO(3))(2)·4py (2), and two-dimensional (2D) [Ni(4)(Hpzaox)(2)(pzaox)(2)(H(2)O)(2)](NO(3))(2)·2H(2)O (3) are prepared via the reaction of NiX(2)·6H(2)O and pyrazine-2-amidoxime (H(2)pzaox). All compounds contain [Ni(4)(Hpzaox)(2)(pzaox)(2)](2+) fragments, which assemble to form a tetranuclear or polymeric network. Magnetic studies show that the tetranuclear compounds display usual ferromagnetic coupling via the oxime N-O bridges, and the 2D compound displays unusual antiferromagnetic behavior.

Single-, double- and triple-decker oximato-bridged Ni(ii) clusters based on pyridine-2-amidoxime (H(2)pyaox) have been synthesized and characterized. The decks have the same tetranuclear cationic units [Ni(4)(Hpyaox)(2)(pyaox)(2)](2+) that are stably present in the reaction solution. Magnetic studies show that uncommon ferromagnetic exchange between the adjacent Ni(ii) ions through the oxime bridges is operative in the compounds with the magnetic coupling constant (J) in the range 0.6-6.3 cm(-1) (H = -2JS(Ni1)S(Ni2)). Density function theoretical (DFT) calculations and the experimental data confirm that the N-O bond distances of the bridging oxime group have a decisive effect in magnetic coupling. For the present Ni(ii) species, the elongation of N-O bond distances are responsible for the switching from antiferromagnetic to ferromagnetic exchange with the critical bond distance of 1.394 Å.

Novel tetranuclear Cu(ii)-Ln(iii)-Cr(iii) complexes with oxamidate and oxalate bridges have been prepared using [Cu(L)], LnCl(3).6H(2)O and K(3)[Cr(ox)(3)] components (ox(2-) = oxalate) during the development of new multimetallic complexes as molecular magnets. Overall ferromagnetic properties have been observed in the Cu(2)GdCr compound, and no single-magnet behavior has been found in the Cu(2)TbCr and Cu(2)DyCr compounds.

Objective: To understand the epidemiological and genetic characteristics of rubella viruses in China (excluded Hongkong, Macao and Taiwan areas, the same below) from 2007 to 2008, and to provide the basis for the development of rubella immunization strategy., Methods: Both rubella epidemiology data from rubella disease surveillance information management system and rubella virology data from National measles Laboratory surveillance data base were analyzed., Results: The reported rubella incidence rate was 5.70/100,000 in 2007 and 9.11/100,000 in 2008 and the reported cases distributed in the whole country. The predominant proportions of rubella cases were <15-years-old children which accounted for 80.94% and 81.85% of total cases in 2007 and 2008 respectively. And the highest number of cases belong to 6-10 age groups, which accounted for 43.24% and 44.13% of total cases in 2007 and 2008 respectively. 1E genotype was the predominant genotype of rubella viruses in China during 2007-2008, and the nucleotide homology of the rubella isolates was 98.1%-100%., Conclusion: The rubella Serology diagnosis, virological and serological surveillance should be strengthened. Practicable vaccine immunization strategy for different age groups should be established to achieve the goal of prevention and control of rubella and congenital rubella syndrome.