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Abstract: Adult hippocampal neurogenesis is a multistage mechanism that continues throughout the lifespan of human and non-human mammals. These adult-born neurons in the central nervous system (CNS) play a significant role in various hippocampus-dependent processes, including learning, mood regulation, pattern recognition, etc. Reduction of adult hippocampal neurogenesis, caused by multiple factors such as neurological disorders and aging, would impair neuronal proliferation and differentiation and result in memory loss. Accumulating studies have indicated that functional neuron impairment could be restored by promoting adult hippocampal neurogenesis. In this review, we summarized the small molecules that could efficiently promote the process of adult neurogenesis, particularly the agents that have the capacity of crossing the blood-brain barrier (BBB), and showed in vivo efficacy in mammalian brains. This may pave the way for the rational design of drugs to treat human neurodegenerative disorders in the future.

Sucrose synthase (SUS) plays an important role in carbohydrate metabolism in plants. The SUS genes in licorice remain unknown. To reveal the sucrose metabolic pathway in licorice, all the 12 putative SUS genes of Glycyrrhiza uralensis were systematically identified by genome mining, and two novel SUSs (GuSUS1 and GuSUS2) were isolated and characterized for the first time. Furthermore, we found that the flexible N-terminus was responsible for the low stability of plant SUSs, and deletion of redundant N-terminus improved the stability of GuSUS1 and GuSUS2. The half-life of both GuSUS1 and GuSUS2 mutants was increased by 2-fold. Finally, the GuSUS1 mutant was coupled with UGT73C11 for the glycosylation of glycyrrhetinic acid (GA) with uridine 5'-diphosphate disodium salt hydrate (UDP) in situ recycling, and GA conversion was increased by 7-fold. Our study not only identified the SUS genes in licorice but also provided a stable SUS mutant for the construction of an efficient UDP-recycling system for GA glycosylation.

In general, potent non-ketolide versions of erythromycin possessed conformationally constricted two- or three-atom-length sidechains at 3-OH. Novel 14-membered non-ketolides possessing long spacers beyond three-atom length were evaluated for antibacterial activity. The most potent one is 34a, featuring a five-atom-length flexible linker from of a pyridine ring to the aglycone. Conversion of the pyridine of 34a to other aryl groups, changing the linker's length of 34a to longer or shorter ones, and variation of the linker flexibility to a rigid olefin or alkyne led to decreased antibacterial activity. The hybrids of macrolides and quinolones 28b, 31 and 34b possessing various sidechains, unlike their 15-membered counterparts, were ineffective compared to 34a. Similar to the marketed ketolide telithromycin, the non-ketolide 34a proved to be a time-dependent bactericidal agent, but it exhibited superior in vivo pharmacokinetic properties such as longer half-life, higher plasma concentration, lower clearance and shorter time to reach the highest drug concentration relative to telithromycin. Molecular docking suggested 34a might π - π interact with the bacterial ribosomal RNA base G2505Ec. This study suggested that the bacteriostatic agent erythromycin can be structurally modified to afford a new bactericidal chemotype that targets the ribosome and is superior to ciprofloxacin with regard to its minimum bactericidal concentration.

Resistance to telithromycin and off-target effects associated with the metabolic instability present serious and challenging problems for the development of novel macrolides. Herein, studies of hybrids of macrolides and quinolones (termed macrolones) bridged with linkers from 11,12-cyclic carbamate of macrolides revealed different structure-activity relationships from the previously reported macrolones bridged with linkers derived from 6-, 9- and 4''-positions of macrolides. The optimized macrolone 34 g with a longer and rigid sidechain than telithromycin had improved metabolic stability compared to telithromycin (t

Major depressive disorder (MDD) is one of the most common psychiatric disorders. However, the effective drugs for MDD have not yet been developed. WS6 is originally designed with a similar structure as Resveratrol and Pterostilbene. The present study aims to investigate the neuroprotective and ameliorating effects of WS6 treatment in a rat model of chronic unpredictable mild stress (CUMS) induced depression. The results show that CUMS is effective in producing depressive-like behavior in rats as indicated by decreased responses in the locomotor activity, sucrose preference test and increased immobility time. However, WS6 treatment significantly ameliorated these behavioral alterations associated with CUMS-induced depression. Moreover, the reduction in neurogenesis, GABAergic neurons, dendrite complexity, spine density and synaptic plasticity-associate protein 95 (PSD95) by CUMS can be reversed by treatment with WS6. Taken together, this study highlights the neuroprotective and antidepressant-like effects of WS6 against CUMS-induced depression, and suggest a possible mechanism for this protection via changes in neurogenesis within the hippocampus. These finding reveal the therapeutic protection of WS6 for use in clinical trials in the treatment of neuronal deterioration in MDD.

In the search for novel hybrid molecules by fusing two biologically active scaffolds into one heteromeric chemotype, we found that hybrids of azithromycin and ciprofloxacin/gatifloxacin 26j and 26l can inhibit the supercoiling activity of E. coli gyrase by poisoning it in a way similar to fluoroquinolones. This may modestly contribute to their potencies, which are equal to ciprofloxacin against constitutively resistant Staphylococcus aureus, whose growth is not inhibited by the presence of macrolides. In contrast, introduction of quinolines (the 3-quinoline 26b and the 6-quinoline 26o) with an optimized rigid spacer at the 6-OH of azithromycin acylides did not exert significant potency against constitutively resistant S. aureus, despite the fact that the quinoline-containing compounds, exemplified by 26o, were as active as telithromycin against susceptible, inducibly- and efflux-resistant pathogens. The novel dual modes of action involving protein synthesis inhibition and poisoning DNA replication may pave the way for restoration of antibacterial activities of the current macrolides against constitutively resistant clinical isolates.

This study examines the power of cognitive and noncognitive variables to predict students’ performance in algebra. We investigated students’ prior year’s assessment scores and demographic characteristics to predict eighth-grade algebra scores. Using California statewide assessment data, we explored predictive factors in three regression models. These analyses reveal that the seventh-grade mathematics test scores account for 61% of the variance in eighth graders’ algebra test scores. Analyzing subscores of the seventh-grade mathematics test, the assessment content focus of rational numbers is a major predictor, contributing 48% of the variance in eighth graders’ algebra test scores. On the other hand, students’ demographic variables show little predictive power for eighth-grade algebra scores. This study provides empirical evidence for understanding the factors that impact a student’s success in learning algebra.

The urban wastewater treatment industry produces a large amount of excess activated sludge which is mainly composed of microbial biomass and costly to be disposed. In this research, a comprehensive utilization of activated sludge was developed by sequentially extracting hydrolytic enzymes and polyhydroxyalkanoates (PHAs), and the residue was used to prepare water-retaining organic fertilizer. The sludge was extracted with fourfold H2O-containing 1% Triton X-100 with the yield of 66.7% protease activity. The enzyme solution was precipitated in 80% acetone and vacuum dried at 40°C at the dried enzyme yield of 2.4 g/kg wet sludge. The enzyme product contains collagenase, lipase, amylase, and cellulase activities, which are good compound enzymes to feed. The PHAs were extracted with 30% sodium hypoclorite:chloroform (1:3). The PHA solution was decolored and dried, and pure white PHAs were obtained at the yield of 70.1 g/kg wet sludge. The residue was used to prepare water-retaining organic fertilizer ...

Cytokine-induced killer (CIK) cells are a group of heterogeneous immune cells which can be isolated from human peripheral blood mononuclear cells and have demonstrated therapeutic benefit both in hematologic malignancies and solid tumors, including colorectal cancer. However, poor tumor-targeted migration has limited the clinical efficacy of CIK cell treatment. The chemokine-chemokine receptor (CK-CKR) axis serves a role in the tumor-directed trafficking capacity of immune cells. Investigating the relationship between CKR profiles on the surface of CIK cells and chemokine expression levels in the tumor microenvironment may improve CIK cell therapy. In the present study, the spectrum of chemokine expression levels in tumor tissues from patients with colorectal cancer (CRC) and CKR expression profiles in CIK cells obtained from the same individuals with CRC were investigated. The results showed that chemokine expression levels in tumor tissues exhibited variability and cell line heterogeneity. However, the expression levels of a number of chemokines were similar in different CRC donors and cell lines. Expression levels of CXCLL10, CXCL11 and CCL3 were significantly higher in most tumor tissues compared with adjacent normal tissues and highly expressed in most CRC cell lines. In accordance with chemokine expression levels, CKR profiles on the surface of CIK cells also showed donor-to-donor variability. However, concordant expression profiles of CKRs were identified in different patients with CRC. CXCR3 and CXCR4 were highly expressed on the surface of CIK cells through the culture process. Importantly, the expression levels of all CKRs, especially CCR4, CXCR4 and CXCR3, were notably decreased during the course of CIK cell expansion. The changing trend of CKR profiles were not correlated with the chemokine expression profiles in CRC tissues (CCL3, CXCL12 and CXCL10/CXCL11 were highly expressed in CRC tissue). Re-stimulating CIK cells using chemokines (CCL21 and CXCL11) at the proper time point increased corresponding CKR expression levels on the surface of CIK cells and enhance tumor-targeted trafficking in vitro. These results demonstrated that modification of the CK-CKR axis using exogenous recombinant chemokines at the proper time point enhanced CIK cell trafficking ability and improved CIK antitumor effects.

Constitutively erythromycin-resistant apathogens are more difficult to address than inducibly resistant and efflux-resistant strains. Three series of the 4th generation 2-fluoro 9-oxime erythromycin ketolides were synthesized and evaluated. Incorporation of substituted heteroaryl groups (a - m), in contrast to previously reported the unsubstituted heteroaryl groups, proved to the beneficial for enhancement of the activities of the 9-propgargyl ketolide 8 series and the 9-allyl ketolide 14 series. But these aryl groups (a - m) cannot supply the resulting compounds 8 and 14, unlike corresponding the 6-allyl ketolide 20 series, with activity against constitutively resistant Streptococcus pneumoniae. However, hybrids of macrolides and quinolones (8, 14 and 20, Ar = n - t) exhibited not only high activities against susceptible, inducibly erm-mediated resistant, and efflux-mediated resistant strains, but also significantly improved potencies against constitutively resistant Streptococcus pneumoniae and Streptococcus pyogenes. The capacity was highlighted by introduction of newly designed carbamoyl quinolones (q, r, s and t) rather than commonly seen carboxy quinolones (o and p) as the pharmacophores. Structure-activity relationships and molecular modelling indicated that 8r, 14r and 20q may have different binding sites compared to current erythromycins. Moreover, 8r, 14r and 20q have 2.5–3.6 times prolonged half-life and 2.3- to 2.6-fold longer mean residence time in vivo over telithromycin. These findings pave the way for rational design of novel non-telithromycin macrolides that target new binding sites within bacterial ribosomes.

To achieve the object of NIF ignition , it is required to prepare high density fuel targets . For DD layer, IR-layering can be used to improve its surface roughness. In this paper, glow discharge polymer (GDP) flat films and capsules were synthesized. The IR absorptive properties of GDP were thoroughly studied by using infrared spectrometer and microscopy while the extinction coefficients of GDP flat film at specific wavelengths were obtained. By comparing absorption properties of flat films and capsules, it is found that thermal treatments can lower the OH content of GDP and thus improve IR layering of DD ice. Finally, the needed IR power of integration sphere were estimated by using data obtained for future DD layering experiments in this paper. The results have laid a solid foundation for the implementation of DD IR layering.

With the increasing size of aging population all over the world, the incidence of Alzheimer’s disease has reached to the highest level in many developed countries. However, the etiology of Alzheimer’s disease remains largely unknown especially in the biological mechanism. Up to now, it is still a challenge that the disease can’t be controlled by the approved clinical medicines. As a result, new therapeutic strategies are urgently needed to prevent and cure Alzheimer’s disease. The hippocampus area is associated with learning, memory, cognitive regulation in the central nervous system, which is closely related to Alzheimer’s disease. Adult neurogenesis in hippocampal area allows new neuronal cells to emerge in the central nervous system. The brain’s plasticity is achieved in some sense. This review focuses on the progress in the study of variety of compounds in promotion of neurogenesis in adult hippocampal area in recent years. The potential of these compounds may shed a light on postponing the occurring of Alzheimer’s disease or even curing it.

Hippocampal neurogenesis has been widely considered as one of the potential biological mechanisms for the treatment of depression caused by chronic stress. Many natural products have been reported to be beneficial for neurogenesis. The present study is designed to investigate the effect of dragon’s blood extract (DBE) and its biologically active compound, pterostilbene (PTE), on hippocampal neurogenesis. The male Sprague-Dawley (SD) rats were used in this study, which were maintained on the normal, DBE and PTE diet groups for 4 weeks before dissection in the normal rat model and behavioral testing in the CUS depression rat model. Meanwhile, DMI-treated rats are subcutaneously injected with DMI (10 mg/kg, i.p.). Results revealed that DBE and PTE have the ability to promote hippocampal neurogenesis. DBE and PTE also promoted the proliferation of neural stem cells isolated from the brain of suckling rats. Oral administration of DBE and PTE induced the proliferation, migration, and differentiation of neural progenitor cells (NPCs) in chronic unexpected stressed (CUS) model rats, and improved the behavioral ability and alleviated depress-like symptoms of CUS rats. It was also observed that PTE treatment significantly induced the expression of neurogenesis-related factors, including BDNF, pERK, and pCREB. Oral administration of PTE could affect neurogenesis and it is likely to be achieved via BDNF/ERK/CREB-associated signaling pathways.

We aim to investigate the correlations of hypoxia inducible factor-1α (HIF-1α) C1772T (rs11549465) and G1790A (rs11549467) gene polymorphisms with digestive tract cancers. A sum of 267 digestive tract cancers patients were hospitalized in Taizhou Central Hospital of Zhejiang Province as case group between December 2012 and December 2014. Additionally, 275 healthy people who had a physical examination in our hospital at the same time were selected as control group. Polymerase chain reaction-restriction fragment length polymorphism was utilized for detecting allele and genotype frequency of different locus in case and control group. Meta-analysis was performed using Comprehensive Meta-analysis 2.0 (Biostat Inc., Englewood, New Jersey, USA). Our result showed statistical significance only exists in family history of cancer between case and control group (P

Reduction of hippocampal neurogenesis caused by aging and neurological disorders would impair neural circuits and result in memory loss. A new lead compound (N-trans-3',4'-methylenedioxystilben-4-yl acetamide 27) has been discovered to efficiently stimulate adult rats' neurogenesis. In-depth structure-activity relationship studies proved the necessity of a stilbene scaffold that is absent in highly cytotoxic analogs such as chalcones and heteroaryl rings and inactive analogs such as diphenyl acetylene and diphenyl ethane, and validated the importance of an NH in the carboxamide and a methylenedioxy substituent on the benzene ring. Immunohistochemical staining and biochemical analysis indicate, in contrast to previously reported neuroprotective chemicals, N-stilbenyl carboxamides have extra capacity for neuroproliferation-type neurogenesis, thereby providing a foundation for improving the plasticity of the adult mammalian brain.

Since the National Expanded Program on Immunization was implemented in China, considerable progress has been made in reducing the incidence of measles. However, the incidence of measles increased again in 2004. Few post-marketing studies on measles vaccine effectiveness were reported in China. In this study, we aimed to describe the measles epidemic and to evaluate the effectiveness of the measles vaccine in Guangzhou, southern China.Based on the surveillance data for measles, we investigated the epidemiology during different periods between 1951 and 2012. We analyzed the clinical characteristics of laboratory-confirmed cases of measles between 2009 and 2012 and conducted a case-control study using test-negative cases as controls. We determined the protective effect of measles vaccine.The highest annual incidence in Guangzhou was 2187.15/100,000 in 1964, and the lowest was 0.32/100,000 in 2011. The average incidence of measles from 1951 to 2012 was 306.27/100,000. There was a significant tendency of decline in recent years. From 2009 to 2012, there are 700 laboratory-confirmed cases were reported with an average onset age of 2.5 (median) years. The non-vaccinated target population (age8 months and ≥ 15 years) accounted for 56.7% of the cases. The transient (non-resident) population accounted for 51.3% of the cases. Fewer cases were observed in the population targeted for measles vaccine (aged 8 months to 14 years). The effectiveness of a single dose of the measles vaccine was 89.1% (95% confidence interval (CI), 44.5-97.9), and the effectiveness of ≥ 2 doses of the measles vaccine was 97.8% (95% CI, 88.3-99.6) in children aged 8 months to 14 years old.There is a significant overall decline in the incidence of measles (including clinical and laboratory confirmed cases) in the measles vaccine targeted population in Guangzhou. Two doses of measles vaccine are more effective than one dose in preventing measles in China. In order to accelerate the elimination of measles, vaccination should also be given to the transient and the non-vaccine targeted population.

Erythromycin was long viewed as a bacteriostatic agent. The erythromycin derivatives, 9-oxime ketolides have a species-specific bactericidal profile. Among them, the 3'-allyl version of the 9-oxime ketolide 1 (Ar=3-quinolyl; 17a) is bactericidal against Streptococcus pneumoniae and Streptococcus pyogenes. In contrast, the 2-fluoro analogs of 1, 13a (Ar=6-quinolyl), 13b (Ar=3-quinolyl) and 24a (Ar=4-isoquinolyl), show bactericidal activities against S. pneumoniae, Staphylococcus aureus and Moraxella catarrhalis, while the 2-fluoro analogs 13c (Ar=3-aminopyridyl) and 24b (Ar=3-carbamoylpyridyl) are only bactericidal against S. pneumoniae and Haemophilus influenzae. Reduction of the ketolides led to novel epiacylides, the 3-O-epimers of the acylides. Alteration of linker length (30b vs. 30a), 2-fluorination (33 vs. 30a) and incorporation of additional spacers at the 9-oxime or 6-OH (35, 40 vs. 30a) did not restore the epiacylides back to be as active as the acylide 31. Molecular docking suggested that epimerization at the 3-position reshapes the orientation of the 3-O-sidechain and leads to considerably weaker binding with bacterial ribosomes.

Enormous efforts were focused on the 3-descladinosyl erythromycin derivatives which led to 3-keto (ketolides), 3-O-acyl (acylides), 3-O-carbamate (carbamolides), and 3-O-alkyl (alkylides) and cladinosyl-containing erythromycin derivatives such as 4"-O-acyl, 4"-O-carbamate, and 4"-O-alkyl derivatives as recently exemplified by macrolones (macrolide-quinolone hybrids). Ketolides acquire activity against MLSB-resistant pathogens via a featured arylalkyl extension suspended on the macrolide core, which interacts with a base pair formed by A752Ec and U2609Ec located in the nascent peptide release tunnel of the bacterial rRNA. A base pair formed by C2610Ec and G2505Ec probably is another novel binding site for 3-descladinosyl non-ketolides. It is believed that 4"-derived compounds perhaps interfere with the formation of polypeptide because the extension oriented into peptidyl transferase center (PTC) region. Although macrolones are hybrids of macrolides and quinolones, they do not have dual modes of action, and serve only as protein synthesis inhibitors.

We report a series of new 9-oxime ether non-ketolides, including 3-hydroxyl, 3- O -acyl and 3- O -alkyl clarithromycin derivatives, and thiophene-containing ketolides 1b–1d . Unlike previously reported ketolide 1a , none of them is comparable to telithromycin. A molecular modeling study was performed to gain insight into the binding mode of alkylides 17 – 20 with bacterial rRNA and to rationalize the great disparity of their SAR. The 3- O -sidechains of 19 and 20 point to the so-called hydrophilic side of the macrolide ring, as seen in clarithromycin. In contrast, the 3- O -sidechains of 17 and 18 bend to the backside, the so-called hydrophobic side of the macrolide ring. The results clearly indicated the alkylides with improved antibacterial activity might possess a novel binding mode, which is different from clarithromycin and the alkylides with poor activity.

The permanent magnet synchronous motor take place under certain conditions chaotic phenomenon, according to the differential geometry theory, using the method of linear completely accurate, to design the control chaotic control law, and then through the experiments to verify its validity.

Yu-Jie Wu, Hui Wang, Jian-Hua Liang, Yi Miao, Lu Liu, Hai-Rong Qiu, Chun Qiao, Rong Wang, Jian-Yong Li Department of Hematology, First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, People’s Republic of China Abstract: Expression of ζ-chain-associated protein kinase 70 kDa (ZAP-70) in chronic lymphocytic leukemia (CLL) is associated with more aggressive disease and can help differentiate CLL from cases expressing mutated or unmutated immunoglobulin heavy chain variable region (IgHV) genes. However, standardizing ZAP-70 expression by flow cytometric analysis has proved unsatisfactory. The key point is that ZAP-70 is weakly expressed with a continuous expression pattern rather than a clear discrimination between positive and negative CLL cells, which means that the resulting judgment is subjective. Thus, in this study, we aimed at assessing the reliability and repeatability of ZAP-70 expression using the geometric mean fluorescence intensity (geo MFI) index method based on flow cytometry with 256-channel resolution in a series of 402 CLL patients and to compare ZAP-70 with other biological and clinical prognosticators. According to IgHV mutational status, we were able to confirm that the optimal cut-off point for the geo MFI index was 3.5 in the test set. In multivariate analyses that included the major clinical and biological prognostic markers for CLL, the prognostic impact of ZAP-70 expression appeared to have stronger discriminatory power when the geo MFI index method was applied. In addition, we found that ZAP-70-positive patients according to the geo MFI index method had shorter time to first treatment or overall survival (P=0.0002, P=0.0491). This is the first report showing that ZAP-70 expression can be evaluated by a new approach, the geo MFI index, which could be a useful prognostic method as it is more reliable, less subjective, and therefore better associated with improvement of CLL prognostication and prediction of clinical course. Keywords: chronic lymphocytic leukemia, ZAP-70, flow cytometry, prognosis, geometric mean fluorescence intensity index

In California, an increasing number of 8th graders have taken algebra courses since 2003. This study examines students’ California Standards Test (CST) results in grades 7 through 11, aiming to reveal who took the CST for Algebra I in 8th grade and whether the increase has led to a rise in students’ taking higher-level mathematics CSTs and an improved performance in following years. Results show that the pipeline of 8th-grade algebra and following years’ higher-level mathematics CSTs has a significant leak in it. Furthermore, the longitudinal analysis reveals that 9th-grade students have a 69% greater chance of succeeding in algebra if they passed the CST for General Mathematics in 8th grade compared to those who failed the CST for Algebra I.

Since 2003, California has enacted a policy through its education accountability system that encourages schools and districts to place all 8th grade students into algebra courses and therefore, be tested in algebra in the statewide assessment program. Ten years later, there are a great many more 8th graders taking algebra now. However, there are also many students repeating algebra, instead of going on taking higher level mathematics tests. This article aims to provide the historic context of this policy, previous and recent studies on 8th grade algebra, and our study based on the California Standardized Testing and Reporting (STAR) data. We analyzed 8th grade algebra test-taking and the following years� higher level mathematics test-taking to examine the college preparation course taking pipeline. Our longitudinal study compared two groups of students� performance on 9th grade algebra between those who previously scored below proficient on algebra at 8th grade and those who scored proficient or above on general mathematics at 8th grade. Further, another longitudinal study linked 7th grade mathematics sub-scores to 8th grade algebra achievement. The results show that �algebra for all� policy increased the number of students taking algebra at 8th grade and subsequently, taking higher level mathematics tests. However, the pipeline of the college preparation course taking has a significant leak because the number of students taking higher level mathematics decreased dramatically after algebra. Longitudinal study shows that students who pass the general mathematics test at 8th grade have a 69% greater chance to pass the algebra test at 9th grade compared to their peers who failed the algebra test at 8th grade. We also find that the sub-score rational numbers is a strong predictor of 8th grade algebra achievement. Alternatives to help all students achieve in mathematics learning are also discussed in addition to recommendations for future research.

A series of novel alkylides, possessing 3-O-arylalkyl group instead of 3-O-cladinose, were designed, synthesized and evaluated for in vitro antibacterial activities. The increased potency clearly ranked by the order of 3-O-(3-aryl-2-propargyl), 3-O-(3-aryl-E-prop-2-enyl), 3-O-(3-aryl-propyl), and 3-O-(3-aryl-Z-prop-1-enyl) groups. Some alkylides, exemplified by 7a, 10a, 21, 22, 26, 27 and 33, showed improved activities against inducible MLS(B) resistance and efflux resistance compared to the second-generation macrolides. Among them, 26 possessed comparable activities against erythromycin-susceptible Staphylococcus aureus, Streptococcus pneumoniae and Streptococcus pyogenes (MICs of 0.016-0.5 μg/mL). Moreover, 26 displayed dramatically enhanced potency against both efflux resistant and inducibly MLS(B) resistant strains (MICs of 0.125-0.5 μg/mL) resistant to clarithromycin and azithromycin (MICs of 1- >254 μg/mL), independent of methicillin-susceptible and methicillin-resistant phenotypes.

An allyl group was attached to 3-keto function of ketolides in the presence of allyl bromide and KOtBu. Consequently, the Heck reaction of the resulting 2, 3-dehydro-3-O-allyl-10, 11-anhydroclarithromycin derivatives, in the presence of palladium (II) acetate and tri(o-tolyl)phosphine, afforded a 3-O-(3-aryl-E-prop-2-enyl) sidechain, not the previously reported 3-O-(3-aryl-Z-prop-1-enyl) sidechain. The results suggested that some steric factors in β-hydrogen elimination might regulate the isomerization. The activity of 2, 3-dehydro-3-O-(3-aryl-E-prop-2-enyl)-10, 11-anhydroclarithromycin derivatives was low.

A facile and efficient route was presented to achieve 3-keto-clarithromycin 9-O-(3-aryl-E-2-propenyl) oxime derivatives 8, 2,3-dehydro-3-O-allyl-clarithromycin 9-O-(3-aryl-E-2-propenyl) oxime derivatives 11, and 3-O-allyl-clarithromycin 9-O-(3-aryl-E-2-propenyl) oxime derivatives 12. Among them, compound 8, particularly 8d (Ar = 6-quinolyl), exhibited improved antibacterial activities against erythromycin-susceptible Staphylococcus aureus and Streptococcus pneumoniae, and greatly enhanced activities against the resistant strains encoded by erm and mef genes, as compared to clarithromycin and azithromycin.

It has been reported that catalpol, an iridoid glucoside, isolated from the root of Rehmannia glutinosa, protected cells from damage induced by a variety of toxic stimulus such as LPS, MPP(+) and rotenone. Here, we further evaluated the effect of catalpol against Abeta(1-42)-induced apoptosis in primary cortical neuron cultures. In the present study, the primary cortical neuron culture treated with Abeta(1-42) was severed as cell model of Alzheimer's disease (AD) in vitro. By exposure to Abeta(1-42) (5 microM) for 72 h in cultures, neuronal apoptosis occurred characterized by enhancement of activities of caspases and reactive oxygen species (ROS) as well as Bax increase, loss of mitochondrial membrane potential and cytochrome c release. Pretreatment with catalpol (0.5mM) for 30 min prior to Abeta(1-42) treatment attenuated neuronal apoptosis not only by reversing intracellular ROS accumulation, Bax level, mitochondrial membrane potential and, cytochrome c release to some extent, but also through regulating the activity and cleavage of caspase-3 and caspase-9. Thus, catalpol protects primary cultured cortical neurons induced by Abeta(1-42) through a mitochondrial-dependent caspase pathway.

A new crystal structure of clarithromycin single acetonitrile solvate designated “Form III” was first determined by single crystal X-ray diffraction. The compound crystallized in the monoclinic system, P2 1 space group with a = 10.644(2) A, b = 18.099(4) A, c = 11.628(2) A, α = γ = 90°, β = 95.38(3)°, V = 2230.1(8) A3, Z = 2, D c = 1.175 g/cm3, μ = 0.087 mm−1, F(000) = 860, R 1 = 0.034, wR 2 = 0.062, S = 0.875, (Δ/σ)max = 0.001 for 2,709 observed reflections (I > 2σ (Ι)). Form III of clarithromycin, contrary to Form I, is more thermodynamically stable than Form II used currently on the market. A New Crystal Structure of Clarithromycin Jian-Hua Liang, Guo-Wei Yao A crystal structure of clarithromycin single acetonitrile solvate was first determined by single crystal X-ray diffraction.

9-Oxime acylides have different SAR and binding modes from 9-oxime ketolides. An aminopyridyl or carbamoylpyridyl group anchored at the end of the 9-oxime 2-propargyl group is beneficial for antimicrobial activity. Both the 2-pyridyl and 3-pyridyl groups derived from 3-OH have stacking interactions with the base pair G2505/C2610 (Escherichia coli numbering) of the bacterial rRNA. Compounds 3 presented characteristic features that belong to bactericidal agents when used against constitutive-erm resistant Staphylococcus aureus, susceptible and mef-encoded Streptococcus pneumoniae, inducible-erm resistant Streptococcus pyogenes, and Moraxella catarrhalis. A docking model indicated that the carbamoylpyridyl group of 3h may hydrogen bond to G2061 in addition to π-π stacking over the adenine of A2062 that proved to gate the tunnel for the egress of the nascent peptide. This study suggests that the 9-oxime acylides possess a bactericidal mechanism that is different from the traditional near-complete inhibition of protein synthesis. These studies provide a foundation for the rational design of macrolide antibiotics.

Three crystal structures of 2′, 4″-O-bis(trimethylsilyl) erythromycin A oxime ketal derivatives were determined and compared. Analogous protective groups on 9-oxime possessed various conformations, which resulted in very different steric congestion around 11-OH. The study on the conformations revealed the origin of the difference of regioselectivity as well as the reversal of selectivity from 11-OH to 6-OH.

Infections caused by antibiotic-resistant bacteria pose an increasing risk for clinical treatment. Macrolide-lincosamide-streptogramin B is becoming increasingly ineffective due to the methylation at the binding site of bacteria. Despite great efforts on the natural product, erythromycin, only one derivative, that is, telithromycin, capable of fighting against resistant bacteria has so far been marketed. However, the 3'-dimethylamino group is readily metabolized to a nitroso group, which would inhibit CYP3A4, a very important metabolic enzyme responsible for nearly half of all marketed drugs.Modifications at C-10 of erythromycin were seldom reported. This invention disclosed novel ketolides that had a side chain comprising additional nitrogen atoms in place of the original 10-methyl group. Surprisingly, introduction of the side chain at C-10 led to reduced cytochrome inhibition and increased metabolic stability. As a result, the limited ability to inhibit CYP3A4 would relieve the drug-drug interaction and improve the safety of drug co-administration.This invention opens a new avenue for future modifications to the erythromycin family. It remains unclear how the side chain effected on reduction of CYP inhibition. To fully identify structure-activity relationships, the MIC data of the derivatives on gram-negative bacteria is desirable.

The aim of this research was to investigate the variations of P50 auditory sensory gating (P50) in normal healthy adults and the first onset schizophrenics. By using the American Nicolet Bravo electromyography/evoked potential (EMG/EP) system, P50 was measured with conditioning-testing paradigm (paired-click stimuli S1 and S2 were used) in 58 first onset schizophrenics and 108 healthy adults, and the Positive and Negative Syndrome Scale (PANSS) was applied. The following three conclusions have been reached. (1) In normal control (NC) group, measured from central, anterior and posterior zone (Cz, Fz and Pz respectively), there were no statistical differences (P0.05) between S1 and S2 evoked P50 peak latencies (S1-P50 and S2-P50); the amplitudes of S2-P50 [(2.2 ± 1.4), (2.3 ± 1.5) and (2.1 ± 1.4) μV respectively] reduced significantly as compared with S1-P50 [(5.6 ± 3.3), (5.6 ± 3.9) and (4.9 ± 2.8) μV respectively] (P0.01); the S2/S1 ration, S1-S2 difference, and 100 (1-S2/S1) had no statistical differences (P0.05). (2) Compared with NC, the schizophrenic group significantly showed lower S1-P50 amplitudes (P0.01, except at Pz in which Z = 2.030, P = 0.042), higher S2-P50 amplitudes, higher S2/S1 ratio, lower S1-S2 difference, and more decreased 100 (1-S2/S1) (P0.01) at Cz, Fz and Pz. (3) No significant correlations were found among S2/S1 ratio, S1-S2, 100 (1-S2/S1) of sensory gating and PANSS (P0.05) in schizophrenic group. The first onset schizophrenics had sensory gating deficits, which could be quantified by P50.

Few characteristic changes of linear electroencephalograph (EEG) have been reported in schizophrenia. The aim of the present study was to investigate the changes in temporal-spatial dimensional properties of EEG under different cognitive tasks in patients with schizophrenia.EEG was recorded by using EEG-1518K system and mapping system (Nihon Kohden Tomioka Corporation, Japan) in 45 schizophrenic patients and 47 healthy adults (normal control, NC) under five states: eyes closed, eyes open, mental arithmetic test with eyes closed, memory test with eyes open, and number cancellation test. Correlation dimension (D2) and point-wise correlation dimension (PD2) were calculated for all EEG analyses.(1) There were no significant differences of D2 and PD2 between NC and schizophrenic patients under states of eyes open and closed. (2) Compared with NC, schizophrenic patients showed decreased performance of D2 in mental arithmetic test with eyes closed and number cancellation test (mental arithmetic test with eyes closed: Nc 5.9 ± 0.6, Sch 3.0 ± 0.8; number cancellation test: Nc 6.0 ± 0.6, Sch 4.4 ± 0.7; P0.05 or P0.01). (3) Schizophrenic patients also showed decrease performance of PD2 in mental arithmetic test with eyes closed, memory test with eyes open, and number cancellation test (mental arithmetic test with eyes closed: Nc 6.9 ± 0.7, Sch 4.0 ± 0.8; memory test with eyes open: Nc 6.6 ± 0.8, Sch 5.0 ± 0.9; number cancellation test: Nc 7.1 ± 0.7, Sch 4.8 ± 0.9; P0.05 or P0.01).Nonlinear dynamic analysis provided a new approach in clinical investigation of EEG signals. It was helpful to further understand the cerebral mechanism in schizophrenic cognitive process.

Raman spectroscopy was used for experimental research on D2 signal to noise ratio (SNR) under different conditions. The 32 mW Ar+ laser was injected into the Raman quartz glass cells to study the effect of grating, laser power, exposure time and the gas pressure on D2 Raman spectra SNR. D2 Raman spectral signal to noise ratio is proportional to the laser power, exposure time and gas pressure. The standard curve of the pressure and SNR for this experimental apparatus was obtained. Three sets of random samples were used to verify the formula SNR(J 2 --2) = 10.6 x 10(-4) p+1.271 34. When the deuterium pressure is 21 280 Pa, the relative error is 4.8%. When the pressure increases to 67 235 Pa, the relative error is down to 1.46%.

To explore whether the case of acute disseminated encephalomyelitis (ADEM) who had been inoculated with rabies vaccination reported in domestic literatures were related to the vaccination. Data on 1368 cases of ADEM (from 99 papers) were collected by computer from the Chinese Journal Full-text Database in CNKI and Wanfang database with the key words of acute disseminated encephalomyelitis/rabies vaccination/abnormal reaction in preventive vaccination during 1995 and 2011. All the cases were divided into the two queues according to the situation of rabies vaccination. Cohort study was used to analyze the relations between ADEM and vaccination. The incidence of ADEM, standardized by age that having received immunization with rabies vaccine, was 9.41/1 million person year, higher than 0.29/1 million person year (u = 428.35, P0.01) among those who had not. Among people who had been inoculated, the adjusted RR value of cause ADEM was 31.05 (95%CI: 26.33 - 36.62). RR values increased along with the times of rabies vaccine injection. Correlation was seen between inoculated rabies vaccine and ADEM.

Hydroxylated analogues of the anticancer topoisomerase I (Top1) inhibitors indotecan (LMP400) and indimitecan (LMP776) have been prepared because (1) a variety of potent Top1 poisons are known that contain strategically placed hydroxyl groups, which provides a clear rationale for incorporating them in the present case, and (2) the hydroxylated compounds could conceivably serve as synthetic standards for the identification of metabolites. Indeed, incubating LMP400 and LMP776 with human liver microsomes resulted in two major metabolites of each drug, which had HPLC retention times and mass fragmentation patterns identical to those of the synthetic standards. The hydroxylated indotecan and indimitecan metabolites and analogues were tested as Top1 poisons and for antiproliferative activity in a variety of human cancer cell cultures and in general were found to be very potent. Differences in activity resulting from the placement of the hydroxyl group are explained by molecular modeling analyses.

To study the clinical value of gastric tube esophagoplasty for complicated corrosive stricture of the esophagus in children.A retrospective analysis was performed to study 7 patients with complicated corrosive stricture of the esophagus who were treated with gastric tube esophagoplasty via retrosternal route between March 2010 and October 2011.Three patients had a stricture longer than 2.5 cm, and 4 patients had more than one stricture. All the operations went well. The average time for mechanical ventilation postoperatively was 6 hours. No patients showed insufficient ventilation after withdraw of ventilator. There was 1 patient developed anastomotic leak which was healed a week later. One patient had anastomotic leak with pyloric obstruction, and the leak was healed 3 weeks after intraoperative placement of duodenal feeding tube and pyloric obstruction became patent 4 weeks later. There were 2 patients developed anastomotic stricture and they resumed normal diet after balloon dilatation. The average follow-up duration was 10.5 months. The quality of life was improved and no other complications were found.Gastric tube esophagoplasty is a effective alternative for complicated corrosive stricture of the esophagus and the short-term outcomes are favorable.

A series of 9-O-(3-aryl-2-propargyl)oxime ketolides 8 was synthesized and evaluated for in vitro antibacterial activity. Among 8, 8b–8d, and 8h–8l displayed dramatically improved potency against inducibly MLSB-resistant and efflux-resistant pathogens as compared to clarithromycin and azithromycin. Especially, 8i (Ar 4-isoquinolyl) possessed an MIC of 0.064 μg/mL against constitutively MLSB-resistant Streptococcus pneumoniae, and MICs of 0.032–0.064 μg/mL against methicillin-resistant Staphylococcus aureus and methicillin-resistant Staphylococcus hominis. The analog 10 with a propyl linker was less effective than both the corresponding 8 and 9 containing propynyl and propenyl linkers. A docking study was performed to gain insight into the binding mode of series 8 and 9 and to rationalize the disparity found in the SAR of 8 and 9.

To explore the variations and their activated brain areas of error-related negativity (ERN) in first episode schizophrenics.ERN was tested by an ERP device and their activated brain areas were compared in 58 first episode schizophrenics (FES) and 62 normal controls (NC) from March 2010 to February 2011.(1) The ERN latencies in the FES group were significantly longer on Cz (58 ± 14 ms), Fz (60 ± 11 ms), C3 (57 ± 17 ms) and C4 (60 ± 13 ms) electrodes compared with those in the NC group (49 ± 13 ms, 47 ± 13 ms, 50 ± 14 ms, 51 ± 12 ms). And the ERN amplitudes were significantly lower than those in the controls in Cz (5.0 ± 2.8 µV; 7.5 ± 3.1 µV, P0.01), C3 (5.5 ± 4.0 µV; 8.0 ± 3.7 µV, P0.01), Fz (5.0 ± 3.1 µV; 7.7 ± 3.8 µV, P0.01) and Pz (4.5 ± 3.3 µV: 7.5 ± 3.0 µV, P0.01) electrodes.(2) The variations of ERN latencies and amplitudes showed an insignificant correlation with the positive symptom scores and total scores of PANSS. (3) The activation levels of insula, superior temporal gyrus, middle temporal gyrus and inferior parietal lobule were obviously lower in the FES group than those in the NC group.The anomalies of ERN latencies and amplitudes in first episode schizophrenics may reflect the deficient error-monitoring functions. Further studies are warranted. And such brain areas as insular may contribute pathogenically to the dysfunctions of error-monitoring in schizophrenics.

To study the immunization coverage and immune effects of hepatitis B vaccine (HepB) among people who were immunized later than at birth in Guangzhou city.A multistage randomized cluster sampling was used and the subjects were at age 20 to 59 years old, from the families of twelve districts in Guangzhou. Cross sectional analysis was carried out. Every study subject's HepB immunization history and main risk were investigated through questionnaire. Venous blood samples were collected and then tested for HBsAg and anti-HBs by means of ELISA. The immunization coverage rate of HepB, prevalence rates of HBsAg and anti-HBs among every age group were valuated by sampling weights. The protective efficacy of the people with immunization of HepB was assessed by case-control study.The overall immunization rate of HepB was 24.71% (95%CI: 20.86%-28.56%) in the 20-59 age group. HBsAg prevalence rate was 14.91% (95%CI: 12.73%-17.08%), and 8.52% in vaccinated group while 18.15% in the non-vaccinated group. Results from case-control study showed that HepB had good protective efficacy to HBV in people of 20-59 years old. The protective rate of HepB against HBV was 62.6%.Vaccinating HepB on people after the neonatal period also non-newborn could provide good immune effect to HBV.

To understand the variations of sensory gating P50 in naïve schizophrenia during follow-up and the relations with positive and negative symptom scale (PANSS).The data of auditory evoked potential P50 were recorded by USA Nicolet Brova instrument from 58 naïve schizophrenia patients (Sch) and 108 normal controls (NC) at baseline, Months 1, 2 and 3 after treatment. And a simultaneous assessment of PANSS was made.(1) At baseline, as compared with NC, Sch group had a sensory gating deficit, reflected by a higher S2/S1 (Cz: NC: 0.43 (0.27, 0.58); Sch: 0.77 (0.58, 1.04); Z = -9.23, P0.01), lower S1-S2 (Cz: NC: 2.65 (1.55, 4.79) microV; Sch: 0.92(-0.13, 2.32) microV; Z = -6.01, P0.01) and decreased more (1-S2/S1) (Cz: NC: 0.57 (0.43, 0.73); Sch: 0.23 (-0.04, 0.42); Z = -10.61, P0.01). (2) During follow-up, Sch group still had a sensory gating deficit. Compared with NC, Sch group had a more elevated S2-P50 amplitude, higher S2/S1, lower S1-S2 and (1-S2/S1) at Cz, Fz and Pz brain sites (P0.05 - 0.01), and no significantly differences with S2-P50 amplitude, S2/S1, S1-S2 and (1-S2/S1) during follow-up (P0.05). At baseline, Sch group had a much lowered S1-P50 amplitude than NC group at Cz and Fz brain sites (Cz: Sch: 4.1 microV +/- 2.1 microV, NC: 5.6 microV +/- 3.3 microV, t = -1.47, P = 0.001; Fz: Sch: 3.9 microV +/- 2.1 microV, NC: 5.6 microV +/- 3.9 microV, t = -1.63, P = 0.003). At Month 3, Sch group showed an improved S1-P50 amplitude to normal level at Cz brain site, but S1-P50 amplitude improved at Fz brain site but it was lower than NC group (Sch: 3.9 microV +/- 1.9 microV, NC: 5.6 microV +/- 3.9 microV, t = -1.62, P = 0.03). (3) At Month 3, Sch group showed a much lowered PANSS scale, positive symptom scale, negative symptom scale and general psychiatric symptoms scale than that at baseline (baseline: 138 +/- 15, 33 +/- 7, 41 +/- 5, 65 +/- 8; Month 3: 80 +/- 15, 17 +/- 4, 24 +/- 4, 38 +/- 9 respectively, P0.01). Spearman correlation revealed that P50 was not correlated with PANSS at baseline (P0.05). After treatment S2/S1 and (1-S2/S1) correlated with positive symptom scale and thought disorder and S1-S2 positively with thought disorder in schizophrenia (P0.05).Sensory gating deficit is closely related with thought disorder in naïve schizophrenia. And it may be an important pathogenesis of naïve schizophrenia. P50 sensory gating deficit is probably a diathesis marker in schizophrenia.

A series of novel 3-O-(3-aryl-propenyl)clarithromycin derivatives were designed, synthesized and evaluated for their in vitro antibacterial activities. Regioselective allylation at 3-OH was efficiently achieved in the presence of 9-oxime ether, compared with 9-keto. Most of the side chains were identified as the 3-O-(3-aryl-Z-prop-1-enyl) group, not the expected 3-O-(3-aryl-E-prop-2-enyl) group. Some derivatives of this series showed improved activities against erythromycin-resistant Staphylococcus aureus and Staphylococcus pneumoniae compared with the reference compound, clarithromycin, but weaker activities against susceptible strains.

A series of novel 3-O-(3-aryl-E-2-propenyl)clarithromycin derivatives 8 and 3-O-(3-aryl-2-propargyl)clarithromycin derivatives 11 were designed, synthesized, and evaluated for their in vitro antibacterial activities. Compared with 8c and 11c (Ar was 5-pyrimidyl), 3-O-(3-(5′-pyrimidyl)-Z-1-propenyl) counterpart 6c displayed 4- to 64-fold more potent activities against erythromycin-susceptible Staphylococcus aureus and Streptococcus pneumoniae. Moreover, the activities of 6c, 8c, and 11c against erythromycin-resistant S. aureus and S. pneumoniae were in general 4-fold higher than those of the reference compound, clarithromycin and azithromycin.