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En Europe, la liste des saints sauroctones, tueurs de dragons, est longue : depuis l’archange Michel, saint Georges, saint Marcel jusqu’au capitaine Nemo du célèbre roman de Jules Verne. Il en va différemment en Asie continentale et spécialement en Chine, où le dragon jouit d’une valorisation extrêmement positive. Quelles sont les causes d’un tel renversement symbolique ? C’est ce que nous tentons d’élucider dans cet article. Le dragon, si chargé de malignité en Occident et nécessitant un héros pour le combattre et restaurer, contre la perversité multiple, la solidité de l’être, est, en Orient chinois, une image bénéfique qui s’enrichit de toutes les richesses de la multiplicité : assimilé au « Fils du Ciel », empereur de l’ici-bas terrestre, au moyeu du monde changeant, il assure la bonne ordonnance des pluralités politiques, géographiques, calendaires et anthropologiques. Deux visions du monde se trouvent dressées face à face : l’une qui sauve l’être-un en pourfendant le dragon, l’autre qui reconnaît la valeur des changements et transformations.

Lead-free piezoelectric ceramics (1−x)(Na0.5K0.5)NbO3-xBiFeO3 (x=0~0.07) were synthesized by the solid-state reaction. Differential scanning calorimetry (DSC) measurements revealed that an increase in the amount of BiFeO3 dopant resulted in a decrease in the orthorhombic-tetragonal and tetragonal-cubic phase transition temperature of the material. One percent BiFeO3 additive suppressed grain growth, which not only benefits the sintering of ceramics but also enhances the piezoelectric and ferroelectric properties, where d33=145pC/N, kp=0.31, Qm=80, Pr=11.3 μC cm−2 and Ec=16.5 kV cm−1. As xBF>0.01, both piezoelectric and ferroelectric properties decreased rapidly with an increasing amount of dopant.

Discusses the morphology and discharge parameter dependence of property and structure of radio frequency (RF) sputter-deposited fluorocarbon coatings on polyethylene (PET) fibers. Effect of power on properties; Effect of pressure on properties; Effect of deposition time on properties; Effects of TSD on properties.

Objective: To investigate the molecular mechanism and distribution characteristics of RhD negative phenotypes in Han population of blood donors in Wuhu city., Methods: A total of 210 RhD - samples from August 2021 to August 2022 were screened by serological test and collected from Wuhu Central Blood Station for the voluntary blood donor population. Exons 1 and 10 of the RHD gene were amplificated by PCR to determine whether the samples had the RHD gene. Exons 1-10 of the RHD gene were amplificated by PCR and zygosity analysis were performed in 82 samples containing D gene, and Sanger sequencing was performed on 55 samples containing all RHD exons to determine the genotype., Results: Among 210 RhD - specimens, 128 cases (60.38%) had RHD gene deletion. 27 cases had partial exons of RHD , including 2 cases with RHD*DVI.3/RHD*01N.01 , 24 cases with RHD*01N.04/RHD*01N.01 , and 1 case with RHD-CE(2-10)/RHD*01N.01 . 55 cases had retained all of 10 exons, including 4 cases with RHD*01/RHD*01N.01 , 6 cases with RHD*15/RHD*01N.01 , 1 case with RHD*01W.72/RHD*01N.01 , 1 case with RHD*15/RHD*01EL.01 , 39 cases with RHD*01EL.01/RHD*01N.01 , and the remaining 4 cases were determined to have no RHD gene deletion by zygosity analysis and sequencing showed the presence of 1227G>A mutation loci., Conclusion: There is polymorphism in the molecular mechanism of RhD - D gene in Wuhu blood donor population, among which RHD*01EL.01 and RHD*15 are the main variants in this region. The results of this study provide a theoretical basis for RhD blood group identification and clinical blood transfusion in this region.

Background: Although autologous fat grafting is a feasible surgical technique to improve facial deformity in patients with localized scleroderma, its success is limited by the low graft retention induced by the local inflammatory environment. This study investigated the potential effect of adipose-derived stem cells (ASCs) on skin fibrosis and fat retention in a localized scleroderma mouse model., Methods: BALB/C nude mice that were induced by bleomycin to establish a localized scleroderma model were divided randomly into five groups: blank control; fat grafting; and low, moderate, and high doses of ASC-assisted fat grafting. The backs of the mice were subcutaneously injected with phosphate-buffered saline or fat, or fat with low, moderate, and high doses of ASCs (1 × 10 5 /mL, 5 × 10 5 /mL, and 25 × 10 5 /mL, respectively). The skin fibrosis and fat retention were analyzed after 1 month or 3 months, respectively., Results: Compared to the disease model group, the fat-grafting group, and the low- and moderate-dose ASC-enriched groups, the high-dose ASCs significantly attenuated skin fibrosis, inhibited the production of type III collagen and transforming growth factor-β1, increased fat graft retention, enhanced the expression of angiogenesis-related cytokines and angiogenesis, and increased the expression of adipogenesis-related cytokines., Conclusions: The results demonstrated that high-dose ASCs attenuated skin fibrosis and improved fat retention in a localized scleroderma model by reducing inflammation and by promoting angiogenesis and adipogenesis. The authors further demonstrated that ASCs enhanced adipogenesis through the AKT/ERK signaling pathway., Clinical Relevance Statement: Fat grafting has been used to treat localized scleroderma patients but with low fat retention. In this study, ASC attenuated skin fibrosis and improved fat retention in the localized scleroderma model, providing evidence for cell therapy in future application of localized scleroderma treatment., (Copyright © 2022 by the American Society of Plastic Surgeons.)

Objective: To investigate the bacterial community diversity in Dermatophagoides farinae., Methods: Laboratory-cultured D. farinae was collected, and the composition of microbial communities was determined by sequence analyses of the V4 region in the bacterial 16S ribosomal RNA (16S rRNA) gene on an Illumina PE250 high-throughput sequencing platform. Following quality control and filtering of the raw sequence files, valid reads were obtained and subjected to operational taxonomic units (OTU) clustering and analysis of the composition of microbial communities and alpha diversity index using the Usearch software, Silva database, and Mothur software., Results: A total of 187 616 valid reads were obtained, and 469 OTUs were clustered based on a sequence similarity of more than 97%. OTU annotation showed that the bacteria in D. farinae belonged to 26 phyla, 43 classes, 100 orders, 167 families and 284 genera. The bacteria in D. farinae were mainly annotated to five phyla of Proteobacteria, Firmicutes, Bacteroidota, Actinobacteriota, and Acidobacteriota, with Proteobacteria as the dominant phylum, and mainly annotated to five dominant genera of Ralstonia, norank-f-Mitochondria, Staphylococcus and Sphingomonas, with Wolbachia identified in the non-dominant genus., Conclusions: A high diversity is identified in the composition of the bacterial community in D. farinae, and there are differences in bacterial community diversity and abundance among D. farinae.

Astigmatid mites are economically significant pests of stored products and sources of inhalant allergens causing allergic rhinitis and asthma worldwide. The morphological identification of astigmatid mites at the species level is often a difficult task due to their small size, phenotypic similarity and lack of diagnostic characters. We used multiplex polymerase chain reaction (PCR) to identify astigmatid mite species, which could complement the morphological data for the species-specific identification of mites. Internal ribosomal transcribed spacer (ITS) sequences (i.e., partial 18S, the full length of ITS1-5.8S-ITS2 and partial 28S) from eight astigmatid species ( Acarus siro , Tyrophagus putrescentiae , Suidasia nesbitti , Dermatophagoides pteronyssinus , Dermatophagoides farinae , Lepidoglyphus destructor , Chortoglyphus arcuatus and Gohieria fuscus ) were obtained by DNA extraction and then sequenced after PCR amplification. Specific primers were designed in the ITS2 region manually. Results revealed that an identification method for eight common astigmatid species was established based on multiplex PCR, which should be effective for the identification of other species of mites by redesigning species-specific primers in future experiments., Competing Interests: The authors declare that there are no conflicts of interest., (© 2022 Urmia University. All rights reserved.)

Background: Localized scleroderma (LoS) is an autoimmune connective tissue disorder leading to serious long-term aesthetic impairment on patients. Objective evaluation methods are badly needed to facilitate the evaluation of the surgical treatment on individual patients and clinical studies., Objective: To develop and assess the reliability and validity of Peking Union Medical College LoS facial aesthetic index (PUMC LoSFAI)., Methods: Twelve experts devoted their time and resources in the development and validation. LoS patients in the stable phase were recruited. Reliability and validity was then assessed. LoS patients were evaluated by two plastic surgeons using PUMC LoSFAI and LoS skin damage index (LoSDI). The PUMC LoSFAI comprises 4 domains for the local assessment (surface area of lesion, dyspigmentation, skin thickness and soft tissue atrophy) and 3 domains for the overall assessment (facial symmetry, proportion and profile) to describe LoS facial aesthetic impairment. Face-Q was completed by patients at each visit., Results: Thirty-two LoS patients had 96 visits, during which 138 lesions were assessed. PUMC LoSFAI and 7 domains demonstrated substantial to excellent inter- and intra-rater reliability (ICC 0.995, κ w 0.72-0.91, r 0.85-0.99, respectively). Seven domains considered to be important to extremely important variables (mean rank 3.2-3.8) had high I-CVI (> 0.78) and S-CVI (0.93). PUMC LoSFAI correlated excellently with LoSDI (r = 0.933, P < 0.001), and correlated fairly with Face-Q (r = - 0.399, P = 0.001)., Conclusions: PUMC LoSFAI was developed and evaluated to play as a tool of aesthetic impairment assessment for LoS patients, which may facilitate the evaluation of the treatment on individual patients and clinical studies. PUMC LoSFAI demonstrated high reliability and validity, and further study in larger patient samples is needed to confirm these preliminary findings., Level of Evidence Iv: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine Ratings, please refer to Table of Contents or online Instructions to Authors www.springer.com/00266 ., (© 2021. Springer Science+Business Media, LLC, part of Springer Nature and International Society of Aesthetic Plastic Surgery.)

Background: The mitochondrial (mt) genomes of Sarcoptiformes mites typically contain 37 genes. Although the loss of genes is rare in Sarcoptiformes mite mitogenomes, two of the six previously reported oribatid mites (Acariforms: Sarcoptiformes) are reported to have lost parts of their tRNA genes. To confirm whether the tRNA genes were indeed lost and whether the loss is universal, we re-annotated the available oribatid mite sequences and sequenced the mitogenome of Oribatula sakamorii., Methods: The mitogenome of O. sakamorii was sequenced using an Illumina HiSeq sequencer. The mt tRNA gene was annotated using multi-software combined with a manual annotation approach. Phylogenetic analyses were performed using the maximum likelihood and Bayesian inference methods with concatenated nucleotide and amino acid sequences., Results: The mitogenomes of O. sakamorii contained 37 genes, including 22 tRNA genes. We identified all mt tRNA genes that were reported as "lost" in Steganacarus magnus and Paraleius leontonychus and revealed certain atypical tRNA annotation errors in oribatid mite sequences. Oribatid mite mitogenomes are characterized by low rates of genetic rearrangement, with six or seven gene blocks conserved between the mitogenome of all species and that of ancestral arthropods. Considering the relative order of the major genes (protein-coding genes and rRNAs), only one or two genes were rearranged with respect to their positions in the ancestral genome. We explored the phylogenetic relationships among the available oribatid mites, and the results confirmed the systematic position of Hermannia in the Crotonioidea superfamily. This was also supported by the synapomorphic gene-derived boundaries., Conclusions: The tRNA "lost" phenomenon is not universal in oribatid mites. Rather, highly atypical secondary structure of the inferred mt tRNA genes made them unidentifiable using a single type of tRNA search program. The use of multi-software combined with a manual annotation approach can improve the accuracy of tRNA gene annotation. In addition, we identified the precise systematic position of Hermannia and validated that Astigmata is nested in Oribatida.

Objective: To analyze the sequences of mitochondrial cytochrome C oxidase subunit I gene ( COI ) and 18S ribosomal RNA gene ( 18S rRNA ), so as to identify the feasible DNA barcodes for 4 species of cheyletid mites and improve the DNA barcoding database for cheyletid mites., Methods: Cheyletid mite samples were collected from small-scale flour mills in Fuyang, Wuhu and Tongling cities of Anhui Province from May 2018 to July 2019, extracted and morphologically identified. Then, genomic DNA was extracted from a single cheyletid mite, and the COI and 18S rRNA gene sequences were obtained by PCR amplification, cloning and sequencing. The obtained sequences were aligned using the BLAST software. Multiple sequence alignment was done using the software ClustalX version 1.83 using the known gene sequences from cheyletid mites. The genetic distance was calculated using the software MEGA X, and the phylogenetic tree was created using the maximum likelihood method., Results: The DNA barcoding results of Cheyletus malaccensis , C. carnifex and Cheletomorpha lepidopterorum were consistent with the morphological identification, while no sequences pertaining to Eucheyletia reticulate were retrieved in the GenBank database. The proportions of A + T were 69.6% and 55.1% in the COI and 18S rRNA sequences of 4 cheyletid mites species, respectively, and the numbers of base substitutions were 137 and 46, respectively. There were 154 to 321 and 58 to 99 inter-species variation loci in the COI and 18S rRNA gene sequences of 4 cheyletid mites species, respectively, and the intra-species genetic distance was all 0.020 or less in the COI and 18S rRNA gene sequences of 4 cheyletid mites species, with inter-species genetic distance of 0.235 to 0.583 and 0.078 to 0.114, respectively. Phylogenetic analysis based on COI and 18S rRNA genes showed that all four species of cheyletid mites were clustered into a branch with a 100% supportive rate, which was consistent with the morphological identification., Conclusions: Mitochondrial COI gene is superior to 18S rRNA gene as DNA barcodes for 4 species of cheyletid mites, which is more suitable to be used to investigate the phylogenetic relationship of at genus and species levels.

In this study, we de novo sequenced and analyzed the circular mitochondrial genome (mitogenome) of Tyrophagus putrescentiae. It was 14,156 bp long and contained a complete set of 37 genes, contrary to the initial published sequences; it included 22 tRNA sequences and the largest non-coding region. The mtDNA gene order of T. putrescentiae was found to be identical to that of Aleuroglyphus ovatus, Caloglyphus berlesei, and Rhizoglyphus robini (all Acaroidea). Most tRNAs of T. putrescentiae lack at least a D-arm or T-arm. Tyrophagus putrescentiae tRNAs also shared considerable structural and sequence similarity with the tRNAs of other reported Acaroidea species that have the full set of tRNAs. The largest non-coding region was located between trnF and trnS1, and it contained a microsatellite-like (AT) n sequence, short palindromic sequences, and several hairpin loops, as observed in other reported Acaroidea species (excepting Tyrophagus longior).

BACKGROUND Presently, studies of factors associated with drug-resistant tuberculosis (TB) focus on patients' socio-demographic characteristics and living habits, to the exclusion of biochemical indicators, especially immune factors. This study was carried out to determine whether immune factors are associated with drug-resistant TB. MATERIAL AND METHODS A total of 227 drug-resistant pulmonary TB patients and 225 drug-susceptible pulmonary TB patients were enrolled in this study. Information on socio-demographic characteristics and biochemical indicators were obtained through their clinical records. Non-conditional logistic regression was used to analyze the association of these indicators with drug-resistant TB. RESULTS There were significant differences in re-treatment, marital status, alanine aminotransferase (ALT), blood uric acid (BUA), carcino-embryonic antigen (CEA), T-spot, and CD3 and CD4 counts between the 2 groups. In multivariable analysis, re-treatment [Odds Ratio (OR)=5.290, 95% Confidence Interval [CI]=2.652-10.551); CD3 (OR=1.034, 95% CI=1.001-1.068); CD4 (OR=1.035, 95% CI =1.001-1.070) and IgM (OR=1.845, 95% CI=1.153-2.952) were associated with drug-resistant TB. CONCLUSIONS These results suggest the need for greater attention to re-treatment cases and immune function when treating drug-resistant TB.

Objective: To study the species and density of Acaroid mites breeding in stored dry fruits., Methods: The samples from the dried fruit stores and warehouses were collected, and the mites breeding in them were separated, then the slides with mites were prepared and observed by a light microscope for species identification and counting. The indexes such as the breeding density, species richness index, diversity index and evenness index were calculated., Results: Totally 12 species of Acaroid mites belonging to 6 families and 10 genera were obtained from the total 49 samples. The dominant mite species were Carpoglyphus lactis, Tyrophagus putrescentiae, Acarus siro, and Caloglyphus berlesei. The breeding densities of mites in longans, filberts and plum candies were 79.78, 48.91, 35.73 mites/g, respectively, which were higher than those in other dry fruits. The seasonal variation experiment of mites found that the average breeding density of acaroid mites was higher in July and October, the richness index and diversity index reached the highest value in July, and the evenness index was higher in January and April. The observation of the growth and decline of Acaroid mites under the artificial condition found the number of Caloglyphus berlesei declined sharply and Tyrophagus putrescentiae first increased and then decreased., Conclusion: The pollution of Acaroid mites is serious in the stored dried fruits, for which the positive prevention and control measures to the mite breeding should be taken to reduce the harm.

Objective: To understand the breeding situation of Acaroid mites in indoor environments of kindergartens in Wuhu City, so as to provide the evidence for its prevention and control., Methods: From March to June and September to December in 2014, dust samples were collected from 15 kindergartens of 3 ranks every month. Acaroid mites in the samples were isolated, identified and counted., Results: Totally 360 samples were selected, and 169 samples (46.94%) had mite infestation. Pyroglyphidae accounted for the most in the population, with the breeding rate of 45.00%. Totally 18 504 mites were found, and Dermatophagoides farina and Dermatophagoides pteronyssinus were the dominant species, with the composition ratios of 30.21% (5 590 mites) and 17.83% (3 300 mites), respectively. The third-ranked kindergartens were in the most serious situation concerning with 81.67% (98/120) of the breeding rate of Acaroid mites. The differences were statistically significant among the kindergartens with different ranks (F = 6.048, χ2 = 73.523, both P < 0.05). There were no significant differences about the Acaroid mite population among different grades in kindergartens (F = 0.132, χ2 = 2.377, both P > 0.05)., Conclusion: Acaroid mites in the kindergartens in Wuhu City were in serious condition, and the population and species composition of Acaroid mite community is influenced by the human behavior and indoors environments.

The circular mitochondrial genome (mitogenome) of Aleuroglyphus ovatus was sequenced. It was 14,328 bp long, and consisted of 37 coding genes including 13 protein-coding genes, two ribosomal RNA genes, and 22 transfer RNA genes. This is the first description of the complete mitogenome of a species in the Acaridae (Acari: Sarcoptiformes). The mtDNA gene order for A. ovatus is identical to those of Dermatophagoides farinae and D. pteronyssinus, but distinctly different from the mtDNA of other Acari. Most inferred tRNA genes of A. ovatus are extremely truncated (48-62 bp), lack stem-loops on either the T- or D-arm (except the trnK), and are unable to fold into the canonical tRNA cloverleaf structure. The largest non-coding region (378 bp) contained several conserved sequences involved in the regulation of mitogenome replication, including one core sequence (ACAT) associated with termination of the J-strand replication and several hypothetical stem-loop structures. The microsatellite-like (AT)n sequence in the largest non-coding region was observed in two other Astigmata species, but it has not been found in other Acari.

Objective: To understand the zoonotic trematode species identified in domestic animals from Huainan area, Anhui Province, so as to supply the evidence for the prevention of zoonoses., Methods: The livestock/definitive hosts were commercially available on category basis, and sacrificed for obtaining the parasitic samples via dissecting the viscera. The specimens were microscopically identified, with reference to the descriptions in the previous literature., Results: By identification, sorting and classification, 41 species of internal trematodes were found so far in the domestic animals fed in Huainan areas, in which 23 species were zoonotic trematodes and 18 were internally parasitic in livestock, belonging to 4 orders, 12 families and 21 genera, and occurred in 9 definitive hosts including chicken, ducks, geese, pigs, cattle, buffaloes, sheep, goats and dogs, respectively., Conclusion: The findings suggest that the zoonotic trematodes belong to many kinds and prevalent in the domestic animals in Huainan areas, and such prevalence should call for high attention since it is urgent risk factors for zoonoses in this geographic area.

Objective: To investigate the species of Cheyletoid mites breeding status in the stored traditional Chinese medicinal materials and the relationship between its community and habitats., Methods: A total of 60 samples of the traditional Chinese medicinal materials were collected from Huainan, Wuhu and Xuancheng in China. The mites were isolated with shakesieve shock, directicopy, Tullgren funnel, waternacopy and redricopy, and identified and counted under the light microscope., Results: Cheyletoid mites were represented in 48 of the 60 samples, and the breeding rate accounted for as high as 80.0% (48/60). Totally, 6 species of Cheyletoid mites were identified, which belonged to Cheyletus, Acaropsis, Cheletomorpha, Eucheyletic and Pseudocheyles genera under the family of Cheyletidae. In the three investigated areas, the average breeding density of Cheyletoid mites was 109.75 heads/g, and average richness index was 1.54. The index of species diversity was 2.55 and the number of evenness was 0.95., Conclusion: This result entails positive prevention and control of the mite breeding in storage and processing of herbal materials.

Herein, we describe the synthesis and SAR of a series of small molecule macrocycles that selectively inhibit JAK2 kinase within the JAK family and FLT3 kinase. Following a multiparameter optimization of a key aryl ring of the previously described SB1518 (pacritinib), the highly soluble 14l was selected as the optimal compound. Oral efficacy in the murine collagen-induced arthritis (CIA) model for rheumatoid arthritis (RA) supported 14l as a potential treatment for autoimmune diseases and inflammatory disorders such as psoriasis and RA. Compound 14l (SB1578) was progressed into development and is currently undergoing phase 1 clinical trials in healthy volunteers.

Herein, we describe the design, synthesis, and SAR of a series of unique small molecule macrocycles that show spectrum selective kinase inhibition of CDKs, JAK2, and FLT3. The most promising leads were assessed in vitro for their inhibition of cancer cell proliferation, solubility, CYP450 inhibition, and microsomal stability. This screening cascade revealed 26 h as a preferred compound with target IC(50) of 13, 73, and 56 nM for CDK2, JAK2 and FLT3, respectively. Pharmacokinetic (PK) studies of 26 h in preclinical species showed good oral exposures. Oral efficacy was observed in colon (HCT-116) and lymphoma (Ramos) xenograft studies, in line with the observed PK/PD correlation. 26h (SB1317/TG02) was progressed into development in 2010 and is currently undergoing phase 1 clinical trials in advanced leukemias and multiple myeloma.

Discovery of the activating mutation V617F in Janus Kinase 2 (JAK2(V617F)), a tyrosine kinase critically involved in receptor signaling, recently ignited interest in JAK2 inhibitor therapy as a treatment for myelofibrosis (MF). Herein, we describe the design and synthesis of a series of small molecule 4-aryl-2-aminopyrimidine macrocycles and their biological evaluation against the JAK family of kinase enzymes and FLT3. The most promising leads were assessed for their in vitro ADME properties culminating in the discovery of 21c, a potent JAK2 (IC(50) = 23 and 19 nM for JAK2(WT) and JAK2(V617F), respectively) and FLT3 (IC(50) = 22 nM) inhibitor with selectivity against JAK1 and JAK3 (IC(50) = 1280 and 520 nM, respectively). Further profiling of 21c in preclinical species and mouse xenograft and allograft models is described. Compound 21c (SB1518) was selected as a development candidate and progressed into clinical trials where it is currently in phase 2 for MF and lymphoma.

A series of 3-(1,2-disubstituted-1H-benzimidazol-5-yl)-N-hydroxyacrylamides (1) were designed and synthesized as HDAC inhibitors. Extensive SARs have been established for in vitro potency (HDAC1 enzyme and COLO 205 cellular IC(50)), liver microsomal stability (t(1/2)), cytochrome P450 inhibitory (3A4 IC(50)), and clogP, among others. These parameters were fine-tuned by carefully adjusting the substituents at positions 1 and 2 of the benzimidazole ring. After comprehensive in vitro and in vivo profiling of the selected compounds, SB939 (3) was identified as a preclinical development candidate. 3 is a potent pan-HDAC inhibitor with excellent druglike properties, is highly efficacious in in vivo tumor models (HCT-116, PC-3, A2780, MV4-11, Ramos), and has high and dose-proportional oral exposures and very good ADME, safety, and pharmaceutical properties. When orally dosed to tumor-bearing mice, 3 is enriched in tumor tissue which may contribute to its potent antitumor activity and prolonged duration of action. 3 is currently being tested in phase I and phase II clinical trials.

Thirty-six novel acylurea connected straight chain hydroxamates were designed and synthesized. Structure-activity relationships (SAR) were established for the length of linear chain linker and substitutions on the benzoylurea group. Compounds 5g, 5i, 5n, and 19 showed 10-20-fold enhanced HDAC1 potency compared to SAHA. In general, the cellular potency pIC(50) (COLO205) correlates with enzymatic potency pIC(50) (HDAC1). Compound 5b (SB207), a structurally simple and close analogue to SAHA, is more potent against HDAC1 and HDAC6 compared to the latter. As a representative example of this series, good in vitro enzymatic and cellular potency plus an excellent pharmacokinetic profile has translated into better efficacy than SAHA in both prostate cancer (PC3) and colon cancer (HCT116) xenograft models., (Copyright 2010 Elsevier Ltd. All rights reserved.)

A series of alkenyl indazoles were synthesized and evaluated in Aurora kinase enzyme assays. Several promising leads were optimized for selectivity towards Aurora B. Excellent binding affinity and good selectivity were achieved with optimized compounds in isolated Aurora subfamily assays., (Copyright 2010 Elsevier Ltd. All rights reserved.)

A series of N-hydroxy-1,2-disubstituted-1H-benzimidazol-5-yl acrylamides were designed and synthesized as novel HDAC inhibitors. General SAR has been established for the substituents at positions 1 and 2, as well as the importance of the ethylene group and its attachment to position 5. Optimized compounds are much more potent than SAHA in both enzymatic and cellular assays. A representative compound, 23 (SB639), has demonstrated antitumor activity in a colon cancer xenograft model.

A series of unusual fused tricyclic thiochromeno[2,3-b]pyridines were successfully synthesized by tandem [3 + 3] annulation and SNAr of beta-(2-chloroaroyl) thioacetanilides with activated 4-arylidene-2-phenyloxazol-5(4H)-ones or aromatic aldehydes and ethyl 2-cyanoacetate under microwave irradiation, respectively. Because of the existence of the o-chloro atom of beta-(2-chloroaroyl) thioacetanilides, these reactions were very mild, convenient, and ortho-selective to form new fused tricyclic target molecules. In the domino processes, at least seven reactive distinct chemical sites were involved and up to three new covalent bonds and one tricycle with only cis configuration were generated. A synthetic study and mechanistic proposal for these transformations are presented.

Gonadotropin releasing hormone (GnRH) plays an important role in the biology of reproduction. The use of GnRH receptor antagonists has been reported in the literature for the treatment of breast, ovarian, and prostate cancers. In this article, we report the synthesis, in vitro characterization, pharmacokinetics, and pharmacodynamics of an orally bioavailable, potent, small molecule GnRH receptor antagonist N-{4,6-dimethoxy-2-[(3-morpholin-4-ylpropyl)amino]pyrimidin-5-yl}-5-[3,3,6-trimthyl-2,3-dihydro-1H-inden-5-yl)oxy]-2-furamide (compound 1).

Parafossarulus striatulus, Pseudorasbora parva and brood ducks are involved in the lifecycle of Metorchis orientalis. Natural nidi of M. orientalis are confirmed in Huaihe River Basin.

In order to investigate the relationship between spleen and muscle, the changes of trace elements, enzyme activity, adenine nucleotides and energy charge (EC) in the skeletal muscle of rats with Syndrome of Spleen Qi Deficiency (SQD) were studied, the curative effects of Sijunzi Tang (SJZT) for SQD were observed too. Results showed that in comparing with normal rats, the levels of ATP and EC lowered significantly (ATP P < 0.01, EC P < 0.001), the enzyme activity of the anaerobic glycolysis increased significantly (P < 0.05), the zinc and iron concentrations were higher (P < 0.01) while the copper, potassium and sodium concentrations were lower than normal significantly (P < 0.05). These changes could be corrected after treatment with SJZT for strengthening spleen and tonifying qi. Above-mentioned results suggested that the mechanism of spleen qi deficiency is closely related to the abnormal energy metabolism, and the TCM theory of spleen dominating muscles might have its scientific basis.

We have mapped protein expression of the FMRFamide neuropeptide gene in Drosophila with polyclonal antisera against three small peptides whose sequences were derived from the Drosophila proFMRFamide precursor. One antiserum was affinity-purified and extensively characterized. The enriched antibodies labeled 15-21 bilaterally symmetric pairs of neurons in a pattern that corresponded very closely to the pattern of in situ hybridization that was determined previously (Schneider et al. [1991] J. Comp. Neurol. 304:608-622; O'Brien et al. [1991] J. Comp. Neurol. 304:623-638). The other antisera produced complementary results. These findings suggest that the antisera specifically label cells that express the FMRFamide gene. In larvae we consistently observed strong staining in identified interneurons and neuroendocrine cells, and moderate to weak staining in neurons of unknown function. The adult pattern of expression included both larval neurons whose immunoreactivity persisted through metamorphosis and adult-specific neurons. During metamorphosis, we observed transient staining in a small number of neurons and in specific neuropil regions that included the central body, the protocerebral bridge, and the optic ganglia. Based on these morphological features, we suggest that the FMRFamide-like neuropeptides in Drosophila play a number of functional roles, perhaps affecting both physiological and developmental phenomena. Such roles include general modulation throughout all post-embryonic stages, via the blood, and also more stage- and region-specific modulation within the CNS.

(+/-)-3-Carboxy-5-phosphono-1,2,3,4-tetrahydroisoquinoline (SC-48981), a conformationally restricted analog of the potent competitive N-methyl-D-aspartate (NMDA) antagonist, 2-amino-5-phosphonopentanoate (AP-5), potently inhibited the binding of [3H]glutamate to the N-methyl-D-aspartate (NMDA) receptors with a Ki of 1.6 mcM, but with minimal affinity for kaininate and quisqualate receptors (Ki greater than 50 mcM), in vitro. Consistent with its ability to antagonize the NMDA receptor, SC-48981 decreased the binding of [3H]glycine and [3H]TCP [1-(2-thienyl)cyclohexylpiperidine] to the NMDA-associated glycine and phencyclidine (PCP) recognition sites, in vitro. SC-48981 attenuated levels of basal cGMP and harmaline-induced increases in levels of cGMP in the mouse cerebellum, in vivo, in a competitive manner, with ED50 values of 5.5 and 8.7 mg/kg, i.p. Direct intracerebellar injection of SC-48981 (0.5 microgram) attenuated increases in levels of cGMP induced by central injection of the NMDA-associated glycine receptor agonist, D-serine and by NMDA itself. Parenteral administration of SC-48981 (25 mg/kg, s.c.) decreased basal levels of cGMP for up to 3 h. These results indicate that SC-48981 represents a novel bioavailable competitive NMDA antagonist with a long duration of action.

Following intravenous administration, 1-aminocyclobutane-1-carboxylate (ACBC, 100 mg/kg), a N-methyl-D-aspartate (NMDA)-associated glycine receptor antagonist, was eliminated with a T1/2 of 5 min in mouse brain and 4 min in rat cerebrospinal fluid (CSF). 1-Aminocyclopropane-1-carboxylate (ACC), a NMDA-associated glycine receptor agonist, was found to have a T1/2 of less than 5 min in mouse brain. ACC and ACBC did not alter basal cerebellar cGMP. Glycine and D-serine increased cGMP, and 1-hydroxy-3-aminopyrrolidone-2 (HA-966), a glycine antagonist, reversed the D-serine-induced increases in cGMP. In contrast, ACBC did not reverse the D-serine-induced increases in cGMP. These data suggest that despite their brain bioavailability and marked potency at the glycine receptor in vitro, ACC and ACBC are rapidly inactivated and thus have limited in vivo utility.

Analogues of the carboxyl protease inhibitor, pepstatin, were synthesized from optically pure forms of N-(tert-butoxycarbonyl)-4-amino-3-hydroxy-6-methylheptanoic acid (Boc-Sta), and the inhibition of pepsin and renin was determined. In addition, the new amino acid (3S,4S)-4-amino-3-hydroxy-5-phenylpentanoic acid [AHPPA] was synthesized and the stereochemistry of the 3 and 4 positions established. The tripeptides isovaleryl-L-valyl-(3S,4S)-4-amino-3-hydroxy-6-methylheptanoyl-L-alanine isoamylamide [Iva-Val-(3S,4S)-Sta-Ala-NHiC5H11] and Iva-Val-(3S,4S)-AHPPA-Ala-NHiC5H11 were found to be potent inhibitors of pepsin with Ki = 1 x 10(-9) and 0.9 x 10(-9) M, respectively. Changing the chirality of the (3S)-hydroxy group to 3R or shortening the peptide chain diminished binding to pepsin over 100-fold. Three structural requirements necessary for potent inhibition of pepsin are proposed.