Differentiate and switch,a tale of two heads of a lipid

Neuronal differentiation is an intricate process involving many factors and programs. One notable “curiosity” has been the observation that upon neuronal differentiation, stem cells switch the expression of their surface glycosphingolipids (GSLs) by substituting one class (the globo‐series) of GSLs by another (the ganglio‐series). Russo and colleagues show that there is an intricate dance between these two lipid series such that the globo products suppress neuronal differentiation via the master regulator AUTS2, which in turn suppresses the formation of the ganglio‐series. These findings open the door for further mechanistic studies on the roles of various GSLs in neuronal differentiation.     

Novel glucocorticoids containing a 6,5-bicyclic core fused to a pyrazole ring: synthesis, in vitro profile, molecular modeling studies, and in vivo experiments

Chemistry was developed to synthesize the title series of compounds. The ability of these novel ligands to bind to the glucocorticoid receptor was investigated. These compounds were also tested in a series of functional assays and some were found to display the profile of a dissociated glucocorticoid. The SAR of the 6,5-bicyclic series differed markedly from the previously reported 6,6-series. Molecular modeling studies were employed to understand the conformational differences between the two series of compounds, which may explain their divergent activity. Two compounds were profiled in vivo and shown to reduce inflammation in a mouse model. An active metabolite is suspected in one case.     

3-Imidazolylmethylaminophenylsulfonyltetrahydroquinolines, a novel series of farnesyltransferase inhibitors

Design, synthesis and structure-activity relationship of a series of 3-imidazolylmethylaminophenylsulfonyltetrahydroquinolines as farnesyltransferase inhibitors are presented. A working pharmacophore of inhibiting farnesyltransferase by this series of inhibitors is proposed.     

Drug design, synthesis, and evaluation of a non-sugar-based selectin antagonist

We have designed a series of simple rigid compounds (2) having a phenyl ring attached to three essential groups necessary for selectin binding, i.e., a fucose unit, a carboxylic acid, and the hydrophobic part. In this series of compound 2, 2a exhibited strong inhibitory activity in in vitro P-selectin mediated cell adhesion assay. The novel type of compound 2a would be a potential lead compound for selectin antagonist.     

Discovery of a substituted 8-arylquinoline series of PDE4 inhibitors: structure-activity relationship, optimization, and identification of a highly potent, well tolerated, PDE4 inhibitor

The discovery and SAR of a new series of substituted 8-arylquinoline PDE4 inhibitors are herein described. This work has led to the identification of several compounds with excellent in vitro and in vivo profiles, including a good therapeutic window of emesis to efficacy in several animal models. Typical optimized compounds from this series are potent inhibitors of PDE4 (IC(50)<1nM) and also of LPS-induced TNF-alpha release in human whole blood (IC(50)<0.5microM). The same compounds are potent inhibitors of ovalbumin-induced bronchoconstriction in conscious guinea pigs (EC(50)<0.1mg/kg ip) but require a dose of about 10mg/kg po in the squirrel monkey to produce an emetic response. From this series of compounds, 23a (L-454,560) was identified as an optimized compound.     

Comparison of ivermectin, doramectin, selamectin, and eleven intermediates in a nematode larval development assay.

Chemical substitutions at pharmacologically relevant sites such as C-5, C-13, C-22,23, and C-25 were examined in ivermectin, doramectin, selamectin, and a series of 11 other intermediates using a larval development assay with Haemonchus contortus. A range of activities spanning 5 orders of magnitude were manifest with small changes in the substituents to the 14 avermectins. Within this compound series, there was no major potency advantage or disadvantage to a disaccharide over a monosaccharide substituent at C-13. Ivermectin and doramectin were each fully effective at a concentration of 0.001 microg/ml, and both were similar to their respective monosaccharide homologs. Specific patterns emerged among the analogs with substituents at C-5. Analogs possessing hydroxyl groups at C-5 were superior in activity by several orders of magnitude over those with oxo substituents. Replacement of the oxo with an oxime (NOH) restored activity to some degree but did not restore it to the level of those possessing the hydroxyl substituent. Consequently, ivermectin and doramectin that possess hydroxyl moieties at C-5 were superior against H. contortus to those like selamectin that have oxime substituents. There was no advantage for analogs with a single or double bond at C-22,23 within the cyclohexyl series, and these analogs had equivalent activity as those with a single bond at C-22,23 in the sec-butyl/isopropyl series. However, there was superior activity for the analog series that possessed the combination of a double-bond at C-22,23 and a sec-butyl/isopropyl substituent at C-25. As a result, the most potent compound in this test was not any of the 3 commercialized avermectins but was a monosaccharide with a double bond at C-22,23, an hydroxyl at C-5, and a sec-butyl/isopropyl moiety at C-25.     

Design, synthesis, and conformational analysis of a novel series of HIV protease inhibitors

A combination of structure-based design and both solution, and solid-phase synthesis were utilized to derive a potent (nM) series of HIV-1 protease inhibitors bearing a structurally novel backbone. Detailed structural analysis of several inhibitors prepared in this series has suggested that rigidification of the P₁/P₂ region of this class of molecules may result in compounds with improved potency.     

Brachydactyly, a possible inherited anomaly at prehistoric Prince Rupert Harbour

Disproportionately short metacarpals or metatarsals in eight burial skeletons and three unusually short metapodials recovered as disturbed bones were identified in a 1500 B.C. to A.D. 500 skeletal series from eight archeological sites of the north mainland coast of British Columbia, Canada. At least ten people were affected from four sites for a minimum series frequency of 5.2%. Various factors clinically implicated in the occurrence of brachymetapody were investigated to account for the anomaly. Context-sensitive information suggested that trauma, infarction or infection, and individual or family-related malformation syndromes were unlikely possibilities. Some modern population data suggest that the series frequency was unusually high, particularly for fourth metatarsal involvement, the most commonly affected bone. Modern pedigree interpretations, ethnohistoric inferences, and the archeological contexts of the affected burial skeletons and site samples provide a framework for concluding that brachymetapody in the series was more likely due to the inheritance of an essentially isolated anomaly.     

HODGKIN'S DISEASE,a Clinical-Pathological Review of 150 Cases

One hundred and fifty cases of Hodgkin''s disease were analyzed in an effort to detect significant clinical-pathological correlations and to elucidate any possible factors of prognostic or etiological importance.A relatively long survival for patients with Hodgkin''s paragranuloma was not noted in this series. Instead the survival rate among them was closely parallel to that of patients with classical granuloma. Hodgkin''s sarcoma is a more malignant disease with a patient survival rate not more than half that of patients with the granuloma variety. It is not necessarily a disease of older age groups. Great caution must be exercised to avoid including non-Hodgkin''s disease tumors under the heading of Hodgkin''s sarcoma or paragranuloma.The series reported corresponds with many other reported series of Hodgkin''s disease as regards greater incidence in males and longer survival in females. In this series the cases in patients under the age of 15 were all in males. The predominance of initial enlargement of the cervical nodes was again noted in this series, as was the high proportion of negative reaction to tuberculin tests. The incidence of tuberculous lesions in patients who died of Hodgkin''s disease was only slightly greater than in those who died of other lymphoma. Site of origin of the disease apparently affects survival time. There was statistical evidence that gonadal activity might influence the equilibrium of the disease.Lymph node bacteriological cultures were not remarkable. Brucella organisms were absent. Fertile egg passages for detecting possible viral agents revealed increased egg mortality and cutaneous sensitivity reactions to the harvested amniotic fluid.     

An allotypic specificity presumably of the a series in rabbit immunoglobulins, different from a1, a2, and a3

From the serum of a wild rabbit lacking all the known allotypic specificities of the a series, IgG showing an allotypic specificity named. A100 has been isolated and antisera against it prepared in domestic rabbits. The determinants responsible for the A100 allotypic specificity are present both on IgG and IgM. They are located on the heavy chain and the Fab fragment of IgG.Evidence for the genetic determinism of A100 suggests that it is the product of a new allele at the $\text{a}$ locus.     

面向土系调查制图的小尺度区域景观分类——以宁镇丘陵区中一小区域为例

土系是中国土壤系统分类的基层分类单元,与所处微域景观联系密切,对小尺度样区进行景观分类研究有助于对研究区景观建立系统的认识。以宁镇丘陵区一小尺度样区为例,结合景观生态分类理论及土系特点,探讨了面向土系调查制图的景观分类的原则与方法,建立了包括景观区、景观类、景观亚类和景观相的四级景观分类系统,并借助3S技术进行了景观制图,并以此为基础对样区开展土系调查,对景观分类体系进行了验证。结果表明,景观相与土系有较好相关性,对土系分布具有指示作用,此景观分类体系有助于对土壤所处景观条件形成深入系统认识,可为土系调查制图工作提供参考。     

Vestolide,a guaianolide from vicoa vestita

A new sesquiterpene lactone, vestolide, of the guaiane series was isolated from the aerial parts of Vicoa vestita. Its structure was established on the basis of chemical and spectral evidence.     

Structure-activity relationship analysis of a novel necroptosis inhibitor, Necrostatin-5

Necrostatin-5 (Nec-5) is a novel potent small-molecule inhibitor of necroptosis structurally distinct from previously described Necrostatin-1 (Nec-1), and therefore, represents a new direction for the inhibition of this cellular caspase-independent necrotic cell death mechanism. Here, we describe a series of structural modifications of Nec-5 and the structure-activity relationship (SAR) of Nec-5 series in inhibiting necroptosis.     

Structure-activity relationship study of a novel necroptosis inhibitor, necrostatin-7

Necroptosis is a regulated caspase-independent cell death mechanism characterized by morphological features resembling non-regulated necrosis. Necrotatin-7 (Nec-7), a novel potent small-molecule inhibitor of necroptosis, is structurally distinct from previously described necrostatins (Nec-1, Nec-3, Nec-4 and Nec-5). Here, we describe a series of structural modifications and the structure-activity relationship (SAR) of the Nec-7 series for inhibiting necroptosis.     

Studies on a series of potent, orally bioavailable, 5-HT(1) receptor ligands

A series of 5-(piperidinylethyloxy)quinoline 5-HT(1) receptor ligands have been studied by elaboration of the series of dual 5-HT(1)-SSRIs reported previously. These new compounds display a different pharmacological profile with potent affinity across the 5-HT(1A), 5-HT(1B) and 5-HT(1D) receptors and selectivity against the serotonin transporter. Furthermore, they have improved pharmacokinetic profiles and CNS penetration.     

Design,Synthesis, and Biological Evaluation of a Novel Series of Pirfenidone Derivatives

Russian Journal of Bioorganic Chemistry - In this study, a series of novel pirfenidone derivatives were designed and synthesized, and their activities against pulmonary fibrosis were evaluated. The...     

Embryogenic staging of fugu, Takifugu rubripes, and expression profiles of aldh1a2, aldh1a3 and cyp26a1

Fugu (Takifugu rubripes) has contributed as an ideal model organism for understanding the structure and evolution of vertebrate genomes, but also has potential as a good model organism for developmental biology because of the availability of the genome information. However, there is no comprehensive report describing the developmental stages, which is fundamental data for developmental biology. Here we describe a series of stages of the embryonic development of fugu during the first 8 days after fertilization, i.e. from fertilization to hatching. We define seven periods of embryogenesis – the zygote, cleavage, blastula, gastrula, segmentation, pharyngula, and hatching periods. Stages subdividing these periods are defined based on morphological characteristics. In addition, as a model experiment of gene expression analysis using this staging series, we performed in situ hybridization of aldh1a2, aldh1a3 and cyp26a1 that play regulatory roles in retinoic acid (RA) metabolism essential for embryogenesis. This report provides fundamental information on fugu embryogenesis, which is anticipated to facilitate the use of fugu as a model organism for developmental studies.     

Computer-aided simulation of a dendrimer with a protoporphyrinic core as potential,novel hemoprotein mimic

In this work, we have inserted the ion-heme group characterizing human blood in a class of synthetic, dendrimeric macromolecules, to evaluate a series of structural and physico-chemical properties related to the possible biological activity of these polymers. To this purpose, we have performed a complete series of investigations of five dendrimer generations both in vacuum and in water by molecular mechanics/dynamics simulations. To mimic oxygen binding, we have studied the same molecules in which the protoporphyrinic core was complexed to a Fe(II)-O(2)-hystidine residue. The main results of this study have led us to conclude that all dendrimer generations can bind oxygen stably, the fifth generation being the most affine to the myoglobin molecule, the natural carrier of blood oxygen.     

Bovista sclerocystis, a new species from Mexico

Bovista sclerocystis is described as a new species. It was found in Mexico, growing on rich soil of a tropical forest. It belongs to section Globaria, series Albosquamosa. The most striking character of this taxon is the exoperidium composed of polymorphous mycosclereids.