The circadian molecular clock creates epidermal stem cell heterogeneity

Murine epidermal stem cells undergo alternate cycles of dormancy and activation, fuelling tissue renewal. However, only a subset of stem cells becomes active during each round of morphogenesis, indicating that stem cells coexist in heterogeneous responsive states. Using a circadian-clock reporter-mouse model, here we show that the dormant hair-follicle stem cell niche contains coexisting populations of cells at opposite phases of the clock, which are differentially predisposed to respond to homeostatic cues. The core clock protein Bmal1 modulates the expression of stem cell regulatory genes in an oscillatory manner, to create populations that are either predisposed, or less prone, to activation. Disrupting this clock equilibrium, through deletion of Bmal1 (also known as Arntl) or Per1/2, resulted in a progressive accumulation or depletion of dormant stem cells, respectively. Stem cell arrhythmia also led to premature epidermal ageing, and a reduction in the development of squamous tumours. Our results indicate that the circadian clock fine-tunes the temporal behaviour of epidermal stem cells, and that its perturbation affects homeostasis and the predisposition to tumorigenesis.     

MULTIPLE CRITERIA DECISION MAKING： DISCORDANT PREFERENCES AND PROBLEM DESCRIPTION

There are many practical decision problems where decision makers＇ preferences may be inconsistent and contradictory. In this paper, new methods for ordering and classifying multi-attribute objects by discordant collective preferences are suggested. These methods are based on the theory of multiset metric spaces. The proposed techniques are applied to ranking companies and a competitive selection of projects, which are estimated by several experts upon multiple qualitative criteria.     

The annexins: spatial and temporal coordination of signaling events during cellular stress

Annexins are a family of structurally related, Ca²⁺-sensitive proteins that bind to negatively charged phospholipids and establish specific interactions with other lipids and lipid microdomains. They are present in all eukaryotic cells and share a common folding motif, the “annexin core”, which incorporates Ca²⁺- and membrane-binding sites. Annexins participate in a variety of intracellular processes, ranging from the regulation of membrane dynamics to cell migration, proliferation, and apoptosis. Here we focus on the role of annexins in cellular signaling during stress. A chronic stress response triggers the activation of different intracellular pathways, resulting in profound changes in Ca²⁺ and pH homeostasis and the production of lipid second messengers. We review the latest data on how these changes are sensed by the annexins, which have the ability to simultaneously interact with specific lipid and protein moieties at the plasma membrane, contributing to stress adaptation via regulation of various signaling pathways.     

Rock-magnetic investigation of Siberia loess and its implication

Multiple-rock magnetic investigations conducted on the loess-paleosol sequences at Kurtak in Southwestern Siberia reveal that the mass-normalized low-field magnetic susceptibility profiles reflect changes in lithology between relatively unweathered primary loess of glacial periods and the interglacial paleosols. Maxima in susceptibility values correspond with the least-weathered loess horizons, and minima with the humic horizons of soils. Frequency-dependent susceptibility of the loess-paleosol sequences at Kurtak is very low and practically uniform, indicating the dominance of non-SP ferrimagnetic minerals and negligible pedogenesis. The history of temperature-dependence of susceptibility (TDS) and stepwise acquisition of the isothermal remanent magnetization (SIRM) have confirmed that magnetite is predominant magnetic mineral, and only few maghemite and probably hematite are present within the studied section. Anisotropy of the magnetic susceptibility (AMS) can be used to monitor tilt and disturbance of the sedimentary layers, and also to provide information about the paleo-transport direction for Siberia loess.     

西伯利亚南部黄土沉积物的磁学性质

对西伯利亚南部Ｋｕｒｔａｋ剖在末次间冰期以来黄土－古土壤进行了较为详细的岩石磁学研究。实验结果表明该剖面磁化率变化特征与阿拉斯加风成沉积物相同,与中国黄土完全相反,Ｋｕｒｔａｋ剖面黄土和古土壤的频率磁化率值基本一致,这表明其成土作用较弱,磁化率随温度的变化特征以及等温剩磁测定结果揭示出黄土和古土壤的磁性的都是以磁铁矿为主,只含有极少的磁赤铁矿和赤铁矿,磁化率各向异性研究表明,Ｋｕｒｔａｋ地区黄土沉     

The ‘Popperian Programme’ and mathematics: Part II: From quasi-empiricism to mathematical research Programmes

In the first part of this article I investigated the Popperian roots of Lakatos's Proofs and Refutations, which was an attempt to apply, and thereby to test, Popper's theory of knowledge in a field—mathematics—to which it had not primarily been intended to apply. While Popper's theory of knowledge stood up gloriously to this test, the new application gave rise to new insights into the heuristic of mathematical development, which necessitated further clarification and improvement of some Popperian methodological maxims. In the present part I analyze this second phase in the development of Lakatos's Popperian programme in mathematics, and its connection to the methodology of scientific research programmes.     

Reduction of disulphide bonds unmasks potent antimicrobial activity of human β-defensin 1

Human epithelia are permanently challenged by bacteria and fungi, including commensal and pathogenic microbiota. In the gut, the fraction of strict anaerobes increases from proximal to distal, reaching 99% of bacterial species in the colon. At colonic mucosa, oxygen partial pressure is below 25% of airborne oxygen content, moreover microbial metabolism causes reduction to a low redox potential of -200?mV to -300?mV in the colon. Defensins, characterized by three intramolecular disulphide-bridges, are key effector molecules of innate immunity that protect the host from infectious microbes and shape the composition of microbiota at mucosal surfaces. Human β-defensin 1 (hBD-1) is one of the most prominent peptides of its class but despite ubiquitous expression by all human epithelia, comparison with other defensins suggested only minor antibiotic killing activity. Whereas much is known about the activity of antimicrobial peptides in aerobic environments, data about reducing environments are limited. Herein we show that after reduction of disulphide-bridges hBD-1 becomes a potent antimicrobial peptide against the opportunistic pathogenic fungus Candida albicans and against anaerobic, Gram-positive commensals of Bifidobacterium and Lactobacillus species. Reduced hBD-1 differs structurally from oxidized hBD-1 and free cysteines in the carboxy terminus seem important for the bactericidal effect. In vitro, the thioredoxin (TRX) system is able to reduce hBD-1 and TRX co-localizes with reduced hBD-1 in human epithelia. Hence our study indicates that reduced hBD-1 shields the healthy epithelium against colonisation by commensal bacteria and opportunistic fungi. Accordingly, an intimate interplay between redox-regulation and innate immune defence seems crucial for an effective barrier protecting human epithelia.