肥胖症易感基因——FTO的研究进展

FTO（fat mass and obesity associated）是肥胖症易感基因,表达于人体各组织,且在下丘脑中高表达。它能编码核酸去甲基化酶,通过去甲基化作用影响其他相关基因表达。FTO的基因多态性与体重指数（BMI）及肥胖症密切相关。FTO能够影响能量摄入及能量消耗,并通过多种途径诱导人群中肥胖症及2型糖尿病等相关疾病的发生,而FTO失活的小鼠能够避免肥胖发生。主要综述了FTO基因多态性与肥胖等疾病易感性的相关性、FTO可能的作用机制和FTO对人群中能量平衡的影响。     

Multilocus selection in subdivided populations II. Maintenance of polymorphism under weak or strong migration

The potential of maintaining multilocus polymorphism by migration-selection balance is studied. A large population of diploid individuals is distributed over finitely many demes connected by migration. Generations are discrete and nonoverlapping, selection may vary across demes, and loci are multiallelic. It is shown that if migration and recombination are strong relative to selection, then with weak or no epistasis and intermediate dominance at every locus and in every deme, arbitrarily many alleles can be maintained at arbitrarily many loci at a stable equilibrium. If migration is weak relative to selection and recombination, then with weak or no epistasis and intermediate dominance at every locus and in every deme, as many alleles as there are demes can be maintained at arbitrarily many loci at equilibrium. In both cases open sets of such parameter combinations are constructed, thus the results are robust with respect to small, but arbitrary, perturbations in the parameters. For weak migration, the number of demes is, in fact, a generic upper bound to the number of alleles that can be maintained at any locus. Thus, several scenarios are identified under which multilocus polymorphism can be maintained by migration-selection balance when this is impossible in a panmictic population.      

Evolution of the control of sexual identity in nematodes

Most animals are male/female species and reproduce sexually. Variation in this pattern of reproduction has arisen many times during animal evolution, particularly in nematodes. Little is known about the evolutionary forces and constraints that influenced the origin of self-fertilization, for instance, a type of reproduction that seems to have evolved many times in the phylum Nematoda. Caenorhabditis elegans, a very well known nematode, provides the framework for comparative studies of sex determination. The relative ease with which nematodes can be studied in the laboratory and the fact that many recently developed techniques can be applied to many species make them attractive for comparative research. It is relatively poorly understood how the evolution of new types of sex determination and mode of reproduction results in changes in genome structure, ecology and population genetics. Here, I review the evolution of sex determination and mating types in the phylum Nematoda with the objective of providing a framework for future research.     

Chemoenzymatic synthesis of classical and non-classical anticoagulant heparan sulfate polysaccharides

Heparan sulfate (HS) polysaccharides interact with numerous proteins at the cell surface and orchestrate many different biological functions. Though many functions of HS are well established, only a few specific structures can be attributed to HS functions. The extreme diversity of HS makes chemical synthesis of specific bioactive HS structures a cumbersome and tedious undertaking that requires laborious and careful functional group manipulations. Now that many of the enzymes involved in HS biosynthesis are characterized, we show in this study how one can rapidly and easily assemble bioactive HS structures with a set of cloned enzymes. We have demonstrated the feasibility of this new approach to rapidly assemble antithrombin III-binding classical and non-classical anticoagulant polysaccharide structures for the first time.     

Optimal analysis of complex protein mass spectra

Due to physical and chemical phenomena, a simple sample can give rise to a complex mass spectrum with many more peaks than the number of molecular species present in the sample. We link peaks within and between different spectra, and come up with an advanced analysis approach to produce reliable estimates of the molecule masses and abundances. By linking peaks, we can locate multiple‐charge peaks at the correct position in the spectrum, we can deconvolute complex regions with many overlapping peaks by including information from related regions with lower complexity and higher resolution, and we reduce the total number of observed peaks in a spectrum to a much smaller number of underlying molecular species. In this paper we properly model 29 952 peaks in 64 spectra, using only 39 location parameters and one shape parameter. This major reduction from many different molecules to a limited set of molecular species reduces the statistical test multiplicity for biomarker discovery and therefore we imply that the reduction should eventually increase the biomarker discovery power significantly, too.     

The conservation value of small, isolated fragments of lowland tropical rain forest

Deforestation is occurring at an alarming rate in the lowland tropics. In many tropical regions, rain forest is restricted to small (<100 ha), isolated fragments. While only the preservation of large areas of tropical rain forest can safeguard the complete biota, recent research has shown that a substantial number of forest species can persist for decades in fragmented forest, though large vertebrates are susceptible to habitat fragmentation. Inevitably, small fragments will become the last refuges of many rainforest species that are on the brink of extinction. In areas with little rain forest remaining, fragments can be the 'seeds' from which to re-establish extensive forest.     

Influence of grain size on the distribution of tubificid oligochaete species

The grain size fraction less than 63 µm is an important environmental factor affecting the distribution and abundance of many of the tubificid species of Lake Constance. In substrates with a heterogeneous grain size where tubificids can be selective many species occur almost exclusively in their particle size preference range, which is highly species specific.     

Spiritual aspects of death and dying.

Dying is an event beyond our comprehension, an experience that can only be imagined. Patients with cancer have a gift denied many others: some time to prepare for the approaching end of life. This time can be used to bring old conflicts to a close, to say goodbye and seek forgiveness from others, to express love and gratitude for the gifts of a life. Physicians can help patients by being aware of the spiritual dimensions to life that many patients have. In major religious traditions, death is accepted as the natural end of the gift of life and as a point of transition to another, yet unknown, existence. For many patients, it is not death that is feared, but abandonment. The physician's awareness of the spiritual needs of patients can make care of the dying more rewarding and fulfilling for all concerned.     

X-ray and neutron scattering studies of the hydration structure of alkali ions in concentrated aqueous solutions

The presence of ions in water provides a rich and varied environment in which many natural processes occur with important consequences in biology, geology and chemistry. This article will focus on the structural properties of ions in water and it will be shown how the 'difference' methods of neutron diffraction with isotopic substitution (NDIS) and anomalous X-ray diffraction (AXD) can be used to obtain direct information regarding the radial pair distribution functions of many cations and anions in solution. This information can subsequently be used to calculate coordination numbers and to determine ion-water conformation in great detail. As well as enabling comparisons to be made amongst ions in particular groups in the periodic table, such information can also be contrasted with results provided by molecular dynamics (MD) simulation techniques. To illustrate the power of these 'difference' methods, reference will be made to the alkali group of ions, all of which have been successfully investigated by the above methods, with the exception of the radioactive element francium. Additional comments will be made on how NDIS measurements are currently being combined with MD simulations to determine the structure around complex ions and molecules, many of which are common in biological systems.     

Metabolism of fluoroorganic compounds in microorganisms: impacts for the environment and the production of fine chemicals

Incorporation of fluorine into an organic compound can favourably alter its physicochemical properties with respect to biological activity, stability and lipophilicity. Accordingly, this element is found in many pharmaceutical and industrial chemicals. Organofluorine compounds are accepted as substrates by many enzymes, and the interactions of microorganisms with these compounds are of relevance to the environment and the fine chemicals industry. On the one hand, the microbial transformation of organofluorines can lead to the generation of toxic compounds that are of environmental concern, yet similar biotransformations can yield difficult-to-synthesise products and intermediates, in particular derivatives of biologically active secondary metabolites. In this paper, we review the historical and recent developments of organofluorine biotransformation in microorganisms and highlight the possibility of using microbes as models of fluorinated drug metabolism in mammals.     

Structure based design of protein linkers for zinc finger nuclease

Zinc finger nucleases are a promising tool to edit DNA in many biological applications, in particular for gene knockout. Despite many efforts the number of genes that can be effectively targeted with ZFNs remains severely limited, as available constructs cannot address arbitrary gene sequences. Here, we develop a novel concept to significantly enhance the number of DNA sequences that can be targeted by ZFN. Using an efficient computational model, we provide an extensive library of possible linker molecules between individual zinc finger motifs in the construct that can skip up to 10 base pairs between adjacent zinc finger recognition sites in the DNA sequence, which increases the number of genes that can be efficiently targeted by more than an order of magnitude.     

大肠杆菌表达的戊型肝炎病毒ORF2片段的聚合现象研究

在大肠杆菌中表达了戊型肝炎病毒（HEV）ORF2的a.a.394～a.a.604片段,得到的重组蛋白NE2在SDSPAGE中主要以可被尿素解聚的二聚体形式存在,二聚体对病人血清的反应性明显强于单体;质谱分析表明NE2可形成从二聚体到至少六聚体的多种聚体;动态光散射测定表明平均分子半径约4nm,相当于四聚体,但分散度较大,提示为多种大小不一的聚合体的混合物。这些证据表明NE2蛋白可形成以同源二聚体为基本单位的多种聚合体形式,其中以二聚体间的结合最为紧密,并且以二聚体为基础可进一步装配出多种更高级结构,从而具有作为HEV疫苗及诊断试剂抗原的良好前景。      

More than Just a Phase: Prions at the Crossroads of Epigenetic Inheritance and Evolutionary Change

A central tenet of molecular biology is that heritable information is stored in nucleic acids. However, this paradigm has been overturned by a group of proteins called “prions.” Prion proteins, many of which are intrinsically disordered, can adopt multiple conformations, at least one of which has the capacity to self-template. This unusual folding landscape drives a form of extreme epigenetic inheritance that can be stable through both mitotic and meiotic cell divisions. Although the first prion discovered—mammalian PrP—is the causative agent of debilitating neuropathies, many additional prions have now been identified that are not obviously detrimental and can even be adaptive. Intrinsically disordered regions, which endow proteins with the bulk property of “phase-separation,” can also be drivers of prion formation. Indeed, many protein domains that promote phase separation have been described as prion-like. In this review, we describe how prions lie at the crossroads of phase separation, epigenetic inheritance, and evolutionary adaptation.     

Assay technologies facilitating drug discovery for ADP-ribosyl writers,readers and erasers

ADP-ribosylation is a post-translational modification catalyzed by writer enzymes – ADP-ribosyltransferases. The modification is part of many signaling events, can modulate the function and stability of target proteins, and often results in the recruitment of reader proteins that bind to the ADP-ribosyl groups. Erasers are integral actors in these signaling events and reverse the modification. ADP-ribosylation can be targeted with therapeutics and many inhibitors against writers exist, with some being in clinical use. Inhibitors against readers and erasers are sparser and development of these has gained momentum only in recent years. Drug discovery has been hampered by the lack of specific tools, however many significant advances in the methods have recently been reported. We discuss assays used in the field with a focus on methods allowing efficient identification of small molecule inhibitors and profiling against enzyme families. While human proteins are focused, the methods can be also applied to bacterial toxins and virus encoded erasers that can be targeted to treat infectious diseases in the future.     

Marine Birds as Sentinels of Environmental Pollution

Marine birds are useful as bioindicators of environmental pollution in estuarine and marine environments because they are often at the top of the food chain, ubiquitous, and many are abundant and common, making collecting possible. Seabirds have the advantage of being large, wide-ranging, conspicuous, abundant, long-lived, easily observed, and important to people. Many species are at the top of the food chain where they bioaccumulate contaminants with age. One disadvantage is that many species are migratory, making it difficult to determine where exposure occurred. This can be eliminated by using sedentary species or young birds that obtain all their food from parents. Further, noninvasive collection of feathers can be used to assess heavy metal levels, both from current collections and from historical collections in museums dating back centuries. Marine birds can be used as bioindicators in many ways, including tissue levels of contaminants, epidemiological field studies of effects, and experimental and laboratory studies of dose and effects. Examples from our research indicate some of the ways marine birds can be useful as indicators and sentinels of contamination, particularly by using young birds and feathers.     

树鼩在医学实验研究中的新进展

树鼩的许多生物学特性近似于人类,人们利用树鼩成功建立了多种人类病毒感染的动物模型,并在肿瘤、内分泌、神经、视觉等方面有相当广泛和深入的应用和研究。本文概述了树鼩在医学实验研究中的新进展。     

Role of cofactors in metalloprotein folding

Metals are commonly found as natural constituents of proteins. Since many such metals can interact specifically with their corresponding unfolded proteins in vitro , cofactor-binding prior to polypeptide folding may be a biological path to active metalloproteins. By interacting with the unfolded polypeptide, the metal may create local structure that initiates and directs the polypeptide-folding process. Here, we review recent literature that addresses the involvement of metals in protein-folding reactions in vitro . To date, the best characterized systems are simple one such as blue-copper proteins, heme-binding proteins, iron-sulfur-cluster proteins and synthetic metallopeptides. Taken together, the available data demonstrates that metals can play diverse roles: it is clear that many cofactors bind before polypeptide folding and influence the reaction; yet, some do not bind until a well-structured active site is formed. The significance of characterizing the effects of metals on protein conformational changes is underscored by the many human diseases that are directly linked to anomalous protein-metal interactions.     

Separation of optical isomers of scopolamine, cocaine, homatropine, and atropine

Different drug stereoisomers can have different physiological and therapeutic effects. Difficulties in separating optical isomers often make it impractical to market stereochemically pure products or to monitor isomeric contamination. This is not thought to be a problem with drugs isolated from biological sources (the alkaloids, for example). However, small amounts of isomeric impurities also exist in many biological systems. More importantly the isolation and purification process can cause partial or complete racimization in some cases. Great care must be taken in the handling of some drugs and an efficient, sensitive means to monitor racimization is important. Liquid chromatographic separation on a chiral beta-cyclodextrin bonded phase can be an effective technique in many cases. Its use in separating optical isomers of dl-scopolamine, dl-hyoscyamine, dl-homatropine, and dl-cocaine is discussed.     

Ion-selective Microelectrodes: Their Use and Importance in Modern Plant Cell Biology

The exact ion gradients across cellular membranes and their changes due to metabolic or transport processes can be best studied with the use of ion-selective microelectrodes. The last decade of research using ion-selective microelectrodes in intact cells has proven this technique to be indispensable for the investigation of a variety of physiological questions of regulatory processes, membrane transport, cellular signalling, developmental biology and plant nutrition. Their application to selected problems has led to numerous exciting observations, many of which have changed our view concerning cellular responses to environmental stimuli and in many instances have led to a new understanding of plant cell physiology. Since, with these electrodes, intracellular as well as extracellular free ion concentrations can be simultaneously detected with electrical transport parameters such as membrane potential and membrane conductance, they can be powerful tools in the hands of many plant cell biologists.     

Biochemical aspects of free radicals

Toxic free radicals can be produced by many reactions required for the maintenance of normal metabolism and the production of energy in the cell. The reactivity of both primary and secondary radicals with biomolecules and in whole tissue systems is of interest, not only because of their importance in radiobiology but also because of the role these species play in toxicity and various disorders. Oxidant stress is known to increase the production of free radicals. In the presence of metals, especially iron, these radicals are converted into more damaging species. Trace elements play an important role in many systems that have evolved to deal with free radicals. The dietary status of the cell can affect the preventative antioxidant constituents of the cell. The chain-breaking antioxidant status can clearly be influenced by the dietary content of substances such as vitamins E and C.