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.     

An outline of a revised classification of Saxifraga L.

GORNALL, R. J., 1987. An outline of a revised classification of Saxifraga. A revised classification of Saxifraga is presented in which 15 sections, 19 subsections and 34 series are recognized. A total of 394 names are accounted for, including the following new taxa, combinations and names: series Hirculoideae (Engler & Irmscher) Gornall, stat. nov.; series Lychnitidae (Engler & Irmscher) Gornall, stat. nov.; series Nulanles (Engler & Irmscher) Gornall, stat. nov.; series Cinctae (H. Sm.) Gornall, stat. nov.; series Gemmiparae (Engler & Irmscher) Gornall, stat. nov.; series Spinulosae (C. B. Clarke) Gornall, stat. nov.; subsection Rosulares Gornall, nom. nov.; subsection Serpyllifoliae Gornall, subscct. nov.; subsection Hemisphaericae (Engler & Irmscher) Gornall, stat. nov.; section Merkianae (Engler & Irmscher) Gornall, stat. nov.; subsection Stellares (Engler & Irmscher) Gornall, stat. nov.; series Birostres Gornall, ser. nov.; series Melanocentrae (Engler & Irmscher) Gornall, stat. nov.; series Astasianlhes (Sternberg) Gornall, stat. nov.; subsection Micranthes (Haworth) Gornall, stat. nov.; series Aulaxis (Haworth) Gornall, stat. nov.; series Dermasea (Haworth) Gornall, stat. nov.; series Micranthes (Haworth) Gornall, stat. nov.; scries Aretioideae (Engler & Irmscher) Gornall, stat. nov.; series Juniperifoliae (Engler & Irmscher) Gornall, stat. nov.; series Lilacinae Gornall, ser. nov.; series Marginatae (Engler & Irmscher) Gornall, stat. nov.; series Squarrosae (Engler & Irmscher) Gornall, stat. nov.; series Rigidae (Engler & Irmscher) Gornall, stat. nov.; subsection Engleria (Siindermann) Gornall, stat. nov; series Subsessiliflorae Gornall, ser. nov.; series Oppositiofoliae (Hayek) Gornall, stat. nov.; series Tetrameridium (Engler) Gornall, stat. nov.; subsection Mutatae (Engler & Irmscher) Gornall, stat. nov.; subsection Florulentae (Engler & Irmscher) Gornall, stat. nov.; section Odontophyllae Gornall, sect, nov.; series Biternatae (Engler & Irmscher) Gornall, stat. nov.; subsection Triplinervium (Gaudin) Gornall, stat. nov.; series Arachnoideae (Engler & Irmscher) Gornall, stat. nov.; subsection Tridactylites (Haworth) Gornall, stat. nov.     

Horseradish peroxidase-catalyzed oligomerization of ferulic acid on a template of a tyrosine-containing tripeptide

Ferulic acid (FA) is an abundantly present phenolic constituent of plant cell walls. Kinetically controlled incubation of FA and the tripeptide Gly-Tyr-Gly (GYG) with horseradish peroxidase and H2O2 yielded a range of new cross-linked products. Two predominant series of hetero-oligomers of FA linked by dehydrogenation to the peptidyl tyrosine were characterized by electrospray ionization (tandem) mass spectrometry. One series comprises GYG coupled with 4-7 FA moieties linked by dehydrogenation, of which one is decarboxylated. In the second series 4-9 FA moieties linked by dehydrogenation, of which two are decarboxylated, are coupled to the tripeptide. A third series comprises three hetero-oligomers in which the peptidyl tyrosine is linked to 1-3 FA moieties of which none is decarboxylated. Two mechanisms for the formation of the FA-Tyr oligomers that result from the dualistic, concentration-dependent chemistry of FA and their possible role in the regulation of plant cell wall tissue growth are presented.     

MARK inhibitors: Declaring a No-Go decision on a chemical series based on extensive DMPK experimentation

Attempts to optimize pharmacokinetic properties in a promising series of pyrrolopyrimidinone MARK inhibitors for the treatment of Alzheimer’s disease are described. A focus on physical properties and ligand efficiency while prosecuting this series afforded key tool compounds that revealed a large discrepancy in the rat in vitro–in vivo DMPK (Drug Metabolism/Pharmacokinetics) correlation. These differences prompted an in vivo rat disposition study employing a radiolabeled representative of the series, and the results from this experiment justified the termination of any further optimization efforts.     

Phenmetrazine hydrochloride; a clinical evaluation of a new anoretic agent

Phenmetrazine hydrochloride appeared to be a safe anoretic agent and was effective in weight control in 80 per cent of a series of 49 obese patients. Tolerance to the drug did not develop in periods up to 18 weeks of continued treatment. Phenmetrazine was most effective in patients under 45 years of age in this series. Side effects were minimal and easily controlled. No allergic or toxic effects were noted.     

Discovery of a new binding mode for a series of liver X receptor agonists

Structural modification of a series of dual LXRα/β agonists led to the identification of a new class of LXRβ partial agonists. An X-ray co-crystal structure shows that a representative member of this series, pyrrole 5, binds to LXRβ with a reversed orientation compared to 1.     

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。     

Conditional heteroscedasticity as a leading indicator of ecological regime shifts

Regime shifts are massive, often irreversible, rearrangements of nonlinear ecological processes that occur when systems pass critical transition points. Ecological regime shifts sometimes have severe consequences for human well-being, including eutrophication in lakes, desertification, and species extinctions. Theoretical and laboratory evidence suggests that statistical anomalies may be detectable leading indicators of regime shifts in ecological time series, making it possible to foresee and potentially avert incipient regime shifts. Conditional heteroscedasticity is persistent variance characteristic of time series with clustered volatility. Here, we analyze conditional heteroscedasticity as a potential leading indicator of regime shifts in ecological time series. We evaluate conditional heteroscedasticity by using ecological models with and without four types of critical transition. On approaching transition points, all time series contain significant conditional heteroscedasticity. This signal is detected hundreds of time steps in advance of the regime shift. Time series without regime shifts do not have significant conditional heteroscedasticity. Because probability values are easily associated with tests for conditional heteroscedasticity, detection of false positives in time series without regime shifts is minimized. This property reduces the need for a reference system to compare with the perturbed system.     

Identification of a methoxynaphthalene scaffold as a core replacement in quinolizidinone amide M1 positive allosteric modulators

A series of methoxynaphthalene amides were prepared and evaluated as alternatives to quinolizidinone amide M₁ positive allosteric modulators. A methoxy group was optimal for M₁ activity and addressed key P-gp issues present in the aforementioned quinolizidinone amide series.     

Discovery of a novel series of quinoxalines as inhibitors of c-Met kinase

A series of quinoxaline inhibitors of c-Met kinase is described. The postulated binding mode was confirmed by an X-ray crystal structure and optimisation of the series was performed on the basis of this structure. Future directions for development of the series are discussed together with the identification of a novel quinoline scaffold.     

Structure-activity relationship studies on a series of cyclohexylpiperazines bearing a phanylacetamide as ligands of the human melanocortin-4 receptor

Synthesis and structure-activity relationship studies of a series of cyclohexylpiperazines bearing an amide side chain as ligands of the MC4 receptor are discussed. Compounds such as 11i from this series are potent agonists (EC(50)=33nM, IA=96%).     

Thrombin inhibitors based on a propargylglycine template

A series of novel arylsulfonylpropargylglycinamide derivatives was investigated as thrombin inhibitors in which the SAR was focused on substituents at the acetylenic terminus. Several compounds in this series were identified as potent thrombin inhibitors (Ki up to 5 nM) that are highly selective over trypsin and other serine proteases as well.     

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.     

Bounded random walks as a null model for evaluating population trends

Management of wildlife and protection of endangered species depend on determination of population trends. Because population changes are stochastic and autoregressive, there is reason to believe that population trends might not be properly determined by simple regression over short time periods. A bounded random walk (BRW) model is introduced as a null model for evaluating population trends. The BRW model shows long-term stability but rising and falling sequences of up to many decades. For a given variability and survey length, there will be an expected probability of finding a greater than X% slope simply by chance. This false positive probability needs to be considered when evaluating trends. Breeding Bird Survey data for 128 species over 46 years for two states were analyzed for trends for different series lengths. Trends estimated from short series were likely to not agree with the 46-year trends. Very short series (e.g., 5 years) tended to indicate no trend due to loss of statistical power. A 101-year series for sandwich term (Sterna sandvicensis) revealed that even for 40 year-long series, 33% of subset series had a negative trend compared to the strong 101 year full series positive trend. The BRW model simulations and both data sets pointed to 20 years as a minimum time period for estimating trends reliably, though this can be longer for species that tend to cycle. Proper inference should thus consider the implications of inherent time series variability.     

Reflections on a journey: a retrospective of the ISCB Student Council symposium series

This article describes the motivation, origin and evolution of the student symposia series organised by the ISCB Student Council. The meeting series started thirteen years ago in Madrid and has spread to four continents. The article concludes with the highlights of the most recent edition of annual Student Council Symposium held in conjunction with the 25th Conference on Intelligent Systems for Molecular Biology and the 16th European Conference on Computational Biology, in Prague, in July 2017.     

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.     

Lead optimization of a sulfonylurea-based piperazine pyridazinone series of glucan synthase inhibitors

The structure-activity relationship studies of a novel sulfonylurea series of piperazine pyridazine-based small molecule glucan synthase inhibitors is described. The optimization of PK profiles within the series led to the discovery of several compounds with improved pharmacokinetic profiles which demonstrated in vitro potency against clinically relevant strains. However, the advancement of compounds from this series into a non-lethal systemic fungal infection model failed to show in vivo efficacy.     

Intraperitoneal injection induces a delayed preconditioning-like effect in mice

We hypothesized that intraperitoneal injections of anaesthetics or fluid per se might evoke a delayed preconditioning-like response in mice hearts isolated and Langendorff perfused 24 h later. To test this, mice were given opioid anaesthesia by intraperitoneal injections or sham treated and the hearts were harvested and subjected to global ischaemia and reperfusion 24 h later in series 1. In series 2, mice were subjected to intraperitoneal injection of Ringer, sham needle prick procedure, or no intervention 24 h before heart isolation. In series 3, intraperitoneal Ringer injection 24 h earlier was compared with the effects of classic preconditioning or no pretreatment of the isolated heart or no treatment. Heart function was measured in all series. At the end of reperfusion, hearts in series 1 and 2 were frozen and infarct size was estimated by triphenyltetrazolium chloride solution. In series 3, separate hearts were frozen for immunoblotting to detect phosphorylation of mitogen-activated protein (MAP) kinases. Cardiac activation of nuclear factor kappa B (NFkappaB) was measured using a NFkappaB luciferase firefly reporter mouse. The ischaemia-induced impairment of left ventricular function was attenuated by opioid anaesthesia injected 24 h earlier, which also reduced infarct size. Injection of fluid, but not the sham needle prick procedure, reduced infarct size. The functional protection afforded by classic preconditioning and Ringer pretreatment was comparable. Neither cardiac MAP kinases nor NFkappaB were influenced by the interventions. In conclusion, this study demonstrates a delayed preconditioning-like effect of the heart caused by intraperitoneal administration of opioid anaesthetics and of fluid only in the mouse. The mechanism of protection remains to be determined.     

The role of signal and motivational links of a conditioned reflex in the initiation of instrumental movements in dogs

Alimentary instrumental conditioned reflex (CR) was elaborated in dogs to light flashes (I series), electrostimulation (ES) of the hippocampus (II series) and the hypothalamus (III series). Nonreinforced ES of the hypothalamus, amygdala, hippocampus and septum reproduced pressings on the pedal to the least extent in the I series (17-40% of trials), increasing in the II-nd one up to 40-87% during stimulation of the lateral hypothalamus, medial amygdala and contralateral hippocampus. In the III-rd series the number of pressings increased statistically significantly in comparison with the I-st series for most structures. Probably, besides the artificial increase of motivation during ES of the limbic structures which took place in all series, in the II-nd and III-rd series significance for movement reproduction was acquired by CR generalization appearing due to close interconnection of the structures. In this phenomenon connections (evaluated by the EPs) from the tested structures to the initially signal one are important.     

Arylsulfonamides: a study of the relationship between activity and conformational preferences for a series of factor Xa inhibitors

Torsional scans of sulfonamide S-C bonds in small model systems of a series of arylsulfonamide factor Xa inhibitors were performed in order to investigate if conformational effects can help to rationalise the observed SAR. Computational results were in good agreement with the experimental data indicating that the sulfonamide conformation plays an important role in determining the activity in this particular series of factor Xa inhibitors.