Alkaloids Used as Medicines: Structural Phytochemistry Meets Biodiversity—An Update and Forward Look

Selecting candidates for drug developments using computational design and empirical rules has resulted in a broad discussion about their success. In a previous study, we had shown that a species’ abundance [as expressed by the GBIF (Global Biodiversity Information Facility)] dataset is a core determinant for the development of a natural product into a medicine. Our overarching aim is to understand the unique requirements for natural product-based drug development. Web of Science was queried for research on alkaloids in combination with plant systematics/taxonomy. All alkaloids containing species demonstrated an average increase of 8.66 in GBIF occurrences between 2014 and 2020. Medicinal Species with alkaloids show higher abundance compared to non-medicinal alkaloids, often linked also to cultivation. Alkaloids with high biodiversity are often simple alkaloids found in multiple species with the presence of ’driver species‘ and are more likely to be included in early-stage drug development compared to ‘rare’ alkaloids. Similarly, the success of an alkaloid containing species as a food supplement (‘botanical’) is linked to its abundance. GBIF is a useful tool for assessing the druggability of a compound from a certain source species. The success of any development programme from natural sources must take sustainable sourcing into account right from the start

Atypical PKC-iota Controls Stem Cell Expansion via Regulation of the Notch Pathway

SummaryThe number of stem/progenitor cells available can profoundly impact tissue homeostasis and the response to injury or disease. Here, we propose that an atypical PKC, Prkci, is a key player in regulating the switch from an expansion to a differentiation/maintenance phase via regulation of Notch, thus linking the polarity pathway with the control of stem cell self-renewal. Prkci is known to influence symmetric cell division in invertebrates; however a definitive role in mammals has not yet emerged. Using a genetic approach, we find that loss of Prkci results in a marked increase in the number of various stem/progenitor cells. The mechanism used likely involves inactivation and symmetric localization of NUMB, leading to the activation of NOTCH1 and its downstream effectors. Inhibition of atypical PKCs may be useful for boosting the production of pluripotent stem cells, multipotent stem cells, or possibly even primordial germ cells by promoting the stem cell/progenitor fate

Spatiotemporal perspectives on urban energy transitions: a comparative study of three cities in China

This paper develops an integrated framework to study the socio-spatial and temporal dimensions of urban energy transitions to investigate the development and spread of solar energy technologies in urban China. A comparative analysis of three case studies of solar energy transitions in the cities of Foshan (in Guangdong), Rizhao (in Shandong), and Wuxi (in Jiangsu) demonstrates the framework’s applicability. The results map each city’s trajectory towards low carbon energy. Transitions result from dynamic interactions among central and local governments, solar manufacturers, solar installers, and residents. Alongside industrial strategies, locally-specific factors have a determining influence on the eventual outcomes

Reduced neonatal regulatory T cell response to microbial stimuli associates with subsequent eczema in high risk infants

Background: Regulatory T cells (Treg) play an essential role in early immune programming and shaping the immune response towards a pro‐allergic or tolerant state. We evaluated cord blood Treg and cytokine responses to microbial and non‐microbial stimuli in infants at high risk of allergic disease and their associations with development of allergic disease in the first year. Methods: Cord blood mononuclear cells from 72 neonates were cultured with toll‐like receptors (TLR2) ligands: lipoteichoic acid (LTA) and heat‐killed Lactobacillus rhamnosus GG (HKL); TLR4 ligand: lipopolysaccharide (LPS); ovalbumin (OVA); anti‐CD3; or media for 48 h. Treg numbers and Treg cytokines were assessed in relation to allergic disease outcomes during the first year of life (eczema and atopic sensitization). Results: Infants with eczema (n = 24) had reduced percentages of FoxP3hiCD25hi Treg in LTA (p = 0.01, adj p = 0.005) and HKL (p = 0.04, adj p = 0.02) stimulated cultures as well as reduced IL‐10 (p = 0.01) production following HKL stimulation compared to those without eczema (n = 48). No differences in Treg or cytokine responses to LPS, OVA or anti‐CD3 were seen. Infants who developed sensitization had lower percentages of Treg following TLR2 stimulation (but not other stimuli) compared to non‐sensitized infants. Conclusions: High‐risk children who develop allergic disease in the first year of life have deficient Treg responses to microbial stimuli but not allergen from the time of birth, which may contribute to failure of immune tolerance development in infancy

Anomalies de l’électro-encéphalogramme en neurologie pédiatrique: à propos de 500 enregistrements à l’Hôpital Gynéco-Obstétrique et Pédiatrique de Yaoundé (Cameroun)

Introduction: Cette étude dont le but était d'évaluer la contribution de l'électroencéphalogramme (EEG) en neurologie pédiatrique et de déterminer les indications pertinentes chez l'enfant de 0 à 15ans. Méthodes: Il s'agit d'une étude rétrospective et descriptive réalisée au laboratoire d'électroencéphalographie de l'Hôpital Gynéco-Obstétrique et Pédiatrique de Yaoundé du 1er novembre 2011 au 15 mars 2012.Résultats: L'âge moyen des patients était de 70.2 mois avec des extrêmes de 0 et 180 mois. Le sexe ratio était de 1.04. Cent quatre vingt treize des 500 tracés de veille étaient anormaux 41 des 114 tracés de sommeil étaient anormaux et 78 des 500 tracés réalisés présentaient un rythme de fond ralenti pour l'âge. Cent cinquante tracés présentaient des anomalies épileptiques dont 81 focales, 35 multifocales et 34 des anomalies généralisées. Sur les 137 patients dont l'EEG était compatible avec une épilepsie, le lobe temporal était le plus souvent le siège d'anomalies épileptiques avec des épilepsies temporales et des épilepsies à pointes centro-temporales, venaient ensuite le lobe frontal, les épilepsies généralisées, les épilepsies du lobe occipital et l'hypsarythmie. Chez 13 des 150 patients avec des anomalies épileptiques à l'EEG, les anomalies retrouvées ne rentraient pas dans le cadre d'un syndrome épileptique particulier. Lorsque l'épilepsie était connue, la probabilité d'avoir un tracé EEG anormal était 1,44 fois plus élevée (OR=1.44 (0.83-2.52) même si la corrélation n'était pas statistiquement significative (p=0.1). En revanche lorsque l'épilepsie était suspectée, il y avait 3.43 fois plus de risques d'avoir un tracé anormal (OR=3.43 (2.27-5.18) avec une corrélation statistiquement significative (p< ;0.05). Les convulsions fébriles, les mouvements anormaux, le retard psychomoteur, les troubles déficitaires de l'attention avec hyperinésie, la perte de connaissance et les troubles du langage n'étaient pas significativement corrélés avec un risque accru d'avoir un EEG anormal. Conclusion: L'EEG a un rôle aussi bien dans la confirmation et la caractérisation de divers syndromes épileptiques et suspicions d'épilepsie que dans la discrimination des manifestations paroxystiques non épileptiques chez l'enfant. Les renseignements cliniques sont indispensables pour une lecture optimale du tracé.Key words: Enfants, épilepsies, électro-encéphalogramme, Camerou

Design of an electrochemical micromachining machine

Electrochemical micromachining (μECM) is a non-conventional machining process based on the phenomenon of electrolysis. μECM became an attractive area of research due to the fact that this process does not create any defective layer after machining and that there is a growing demand for better surface integrity on different micro applications including microfluidics systems, stress-free drilled holes in automotive and aerospace manufacturing with complex shapes, etc. This work presents the design of a next generation μECM machine for the automotive, aerospace, medical and metrology sectors. It has three axes of motion (X, Y, Z) and a spindle allowing the tool-electrode to rotate during machining. The linear slides for each axis use air bearings with linear DC brushless motors and 2-nm resolution encoders for ultra precise motion. The control system is based on the Power PMAC motion controller from Delta Tau. The electrolyte tank is located at the rear of the machine and allows the electrolyte to be changed quickly. This machine features two process control algorithms: fuzzy logic control and adaptive feed rate. A self-developed pulse generator has been mounted and interfaced with the machine and a wire ECM grinding device has been added. The pulse generator has the possibility to reverse the pulse polarity for on-line tool fabrication.The research reported in this paper is supported by the European Commission within the project “Minimizing Defects in Micro-Manufacturing Applications (MIDEMMA)” (FP7-2011-NMPICT- FoF-285614)

Distribution of Matrix Cracks in a Uniaxial Ceramic Composite

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65596/1/j.1151-2916.1992.tb08181.x.pd

The cerebellum ages slowly according to the epigenetic clock

Studies that elucidate why some human tissues age faster than others may shed light on how we age, and ultimately suggest what interventions may be possible. Here we utilize a recent biomarker of aging (referred to as epigenetic clock) to assess the epigenetic ages of up to 30 anatomic sites from supercentenarians (subjects who reached an age of 110 or older) and younger subjects. Using three novel and three published human DNA methylation data sets, we demonstrate that the cerebellum ages more slowly than other parts of the human body. We used both transcriptional data and genetic data to elucidate molecular mechanisms which may explain this finding. The two largest superfamilies of helicases (SF1 and SF2) are significantly over-represented (p=9.2x10-9) among gene transcripts that are over-expressed in the cerebellum compared to other brain regions from the same subject. Furthermore, SNPs that are associated with epigenetic age acceleration in the cerebellum tend to be located near genes from helicase superfamilies SF1 and SF2 (enrichment p=5.8x10-3). Our genetic and transcriptional studies of epigenetic age acceleration support the hypothesis that the slow aging rate of the cerebellum is due to processes that involve RNA helicases

Genotoxic agents promote the nuclear accumulation of annexin A2: role of annexin A2 in mitigating DNA damage

Annexin A2 is an abundant cellular protein that is mainly localized in the cytoplasm and plasma membrane, however a small population has been found in the nucleus, suggesting a nuclear function for the protein. Annexin A2 possesses a nuclear export sequence (NES) and inhibition of the NES is sufficient to cause nuclear accumulation. Here we show that annexin A2 accumulates in the nucleus in response to genotoxic agents including gamma-radiation, UV radiation, etoposide and chromium VI and that this event is mediated by the nuclear export sequence of annexin A2. Nuclear accumulation of annexin A2 is blocked by the antioxidant agent N-acetyl cysteine (NAC) and stimulated by hydrogen peroxide (H2O2), suggesting that this is a reactive oxygen species dependent event. In response to genotoxic agents, cells depleted of annexin A2 show enhanced phospho-histone H2AX and p53 levels, increased numbers of p53-binding protein 1 nuclear foci and increased levels of nuclear 8-oxo-2'-deoxyguanine, suggesting that annexin A2 plays a role in protecting DNA from damage. This is the first report showing the nuclear translocation of annexin A2 in response to genotoxic agents and its role in mitigating DNA damage.Natural Sciences and Engineering Research Council of Canada (NSERC); European Union [PCOFUND-GA-2009-246542]; Foundation for Science and Technology of Portugal; Beatrice Hunter Cancer Research Institute; Terry Fox Foundationinfo:eu-repo/semantics/publishedVersio