The energy-transducing NADH: quinone oxidoreductase,complex I

The energy-transducing NADH: quinone (Q) oxidoreductase (complex I) is the largest and most complicated enzyme complex in the oxidative phosphorylation system. Complex I is a redox pump that uses the redox energy to translocate H(+) (or Na(+)) ions across the membrane, resulting in a significant contribution to energy production. The need to elucidate the molecular mechanisms of complex I has greatly increased. Many devastating neurodegenerative disorders have been associated with complex I deficiency. The structural and functional complexities of complex I have already been established. However, intricate biogenesis and activity regulation functions of complex I have just been identified. Based upon these recent developments, it is apparent that complex I research is entering a new era. The advancement of our knowledge of the molecular mechanism of complex I will not only surface from bioenergetics, but also from many other fields as well, including medicine. This review summarizes the current status of our understanding of complex I and sheds light on new theories and the future direction of complex I studies.     

Governing stem cell banks and registries: Emerging Issues

The expansion of national and international research efforts in stem cell research is increasingly paired with the trend of establishing stem cell banks and registries. In jurisdictions crossing the spectrum of restrictive to liberal stem cell policies, banks and registries are emerging as an essential resource for transnational access to quality-controlled and ethically sourced stem cell lines. In this study, we report the preliminary findings of a survey of stem cell banks participating in the International Stem Cell Forum's International Stem Cell Banking Initiative (ISCBI). The questionnaire circulated to all ISCBI members addressed both general issues surrounding research policies (e.g., national policies regulating the permissibility of conducting embryonic stem cell research (hESCR)) and, more specifically, issues relating to the governance of stem cell banking projects. The results of the questionnaire were complemented by scholarly research conducted by the authors. This article provides an overview of the current international hESC banking landscape (I). For this purpose, the policy and governance approaches adopted in the surveyed stem cell banks at the national level will be analyzed and areas of convergence and variance will be identified (II). It is beyond the scope of this paper to provide a comprehensive analysis of the wide range of possible governance approaches, policy responses, and their implications. However, we want to provide a starting point for discussion surrounding key questions and challenges as concerns provenance, access, and deposit of hESC lines (III). Finally, while our analysis is focused on research grade hESCs, the lessons to be gleaned from this examination will encourage further thought, analysis, and research into the issues raised in the banking and governance of other sources of stem cell lines (e.g., SCNT, parthenogenesis, iPs) (IV).     

Mechanisms of metal resistance in plants: aluminum and heavy metals

Plants have evolved sophisticated mechanisms to deal with toxic levels of metals in the soil. In this paper, an overview of recent progress with regards to understanding fundamental molecular and physiological mechanisms underlying plant resistance to both aluminum (Al) and heavy metals is presented. The discussion of plant Al resistance will focus on recent advances in our understanding of a mechanism based on Al exclusion from the root apex, which is facilitated by Al-activated exudation of organic acid anions. The consideration of heavy metal resistance will focus on research into a metal hyperaccumulating plant species, the Zn/Cd hyperaccumulator, Thlaspi caerulescens, as an example for plant heavy metal research. Based on the specific cases considered in this paper, it appears that quite different strategies are used for Al and heavy metal resistance. For Al, our current understanding of a resistance mechanism based on excluding soil-borne Al from the root apex is presented. For heavy metals, a totally different strategy based on extreme tolerance and metal hyperaccumulation is described for a hyperaccumulator plant species that has evolved on naturally metalliferous soils. The reason these two strategies are the focus of this paper is that, currently, they are the best understood mechanisms of metal resistance in terrestrial plants. However, it is likely that other mechanisms of Al and/or heavy metal resistance are also operating in certain plant species, and there may be common features shared for dealing with Al and heavy resistance. Future research may uncover a number of novel metal resistance mechanisms in plants. Certainly the complex genetics of Al resistance in some crop plant species, such as rice and maize, suggests that a number of presently unidentified mechanisms are part of an overall strategy of metal resistance in crop plants.     

Glutamate receptor genes

Schizophrenia, depression, and bipolar disorder are three major neuropsychiatric disorders that are among the leading causes of disability and have enormous economic impacts on our society. Although several neurotransmitter systems have been suggested to play a role in their etiology, we still have not identified any gene or molecular mechanism that might lead to genetic susceptibility for or protection against these neuropsychiatric disorders. The glutamatergic receptor system, and in particular the N-methyl-D-aspartate (NMDA) receptor complex, has long been implicated in their etiology. I review the current molecular evidence that supports a critical role for the glutamatergic receptor system in schizophrenia and the potential involvement of this receptor system in depression and bipolar disorder. It is likely that mutations in glutamate receptor genes might alter the risk of developing one of these disorders. Potential future research directions designed to identify these mutations and to elucidate their effect on mental health will be discussed.     

Causal Drift,Robust Signaling,and Complex Disease

The phenotype of many regulatory circuits in which mutations can cause complex, polygenic diseases is to some extent robust to DNA mutations that affect circuit components. Here I demonstrate how such mutational robustness can prevent the discovery of genetic disease determinants. To make my case, I use a mathematical model of the insulin signaling pathway implicated in type 2 diabetes, whose signaling output is governed by 15 genetically determined parameters. Using multiple complementary measures of a parameter’s importance for this phenotype, I show that any one disease determinant that is crucial in one genetic background will be virtually irrelevant in other backgrounds. In an evolving population that drifts through the parameter space of this or other robust circuits through DNA mutations, the genetic changes that can cause disease will vary randomly over time. I call this phenomenon causal drift. It means that mutations causing disease in one (human or non-human) population may have no effect in another population, and vice versa. Causal drift casts doubt on our ability to infer the molecular mechanisms of complex diseases from non-human model organisms.     

Is an archaeon the ancestor of eukaryotes?

The origin of complex cellular life is a key puzzle in evolutionary research, which has broad implications for various neighbouring scientific disciplines. Naturally, views on this topic vary widely depending on the world view and context from which this topic is approached. In the following, I will share my perspective about our current scientific knowledge on the origin of eukaryotic cells, that is, eukaryogenesis, from a biological point of view focusing on the question as to whether an archaeon was the ancestor of eukaryotes.     

Will technology trample peer review in ecology? Ongoing issues and potential solutions

The classical view of peer review is that it is our primary process for assessing and judging whether research results should be published in a scholarly journal. However, the increased pressure to publish and technological developments are transforming peer review such that it is becoming a system that judges where work is published rather than whether the research is publishable (a ‘where rather than if’ process). Ecology is a field in which publication numbers puts a particular pressure on the review system. In this forum piece, I summarize the issues with the current publication system and discuss how technology is changing it, while suggesting solutions for important prior and ongoing issues with the peer review system. The view explored here is that technological developments (e.g. ease of creating journals, internet sites, storage, data generation, sharing of data and analytical code) will not eliminate peer review per se but will allow for a new set of parameters in which ethics and the optimal use of public funding will play a vital role in the evolution of the review process. Synthesis The number of papers and journals in Ecology has increased dramatically in the past decade. I present a critical overview of our review system and proposes that pressure to publish and technological developments have transformed peer review into a system that decides “where rather than if” papers are publishable. While reviewing the current pressures and factors playing a vital role in the evolution of the review and publication systems, I propose potential solutions to deal with current and future challenges to the peer review and publication systems.     

“山水林田湖草沙生命共同体”耦合框架、模型与展望

“山水林田湖草沙生命共同体”系统保护与修复是我国生态文明建设的重要内容。明确生命共同体的耦合机制,是科学地进行生态保护和修复工作的关键。针对当前生命共同体耦合机制不清、理论和方法不健全的问题,从耦合的视角出发,在小流域尺度上单一生态系统内部生态要素的耦合、流域尺度上不同生态系统之间的耦合、区域尺度上人与自然的耦合三个方面进行整合,在此基础上探讨了多尺度山水林田湖草沙耦合理论,提出了一般性的山水林田湖草沙耦合理论框架。梳理并比较了当前主要的生态系统模型、景观模型、统计学模型以及复合生态系统的多模型耦合方法,综合提出了一个适用于"山水林田湖草沙生命共同体"耦合研究方法。对进一步完善山水林田湖草沙一体化保护修复提出了建议,包括：一是构建多源信息数据库,推进定量化耦合机制研究;二是开展全生命周期监测与评估,探索适应性治理路径;三是强化多元主体参与,完善协同保护机制。     

Looking back, looking beyond: revisiting the ethics of genome generation

This paper will explore some of the ethical imperatives that have shaped strategic and policy frameworks for the use of new genetic technologies and how these play a role in shaping the nature of research and changing attitudes; with an attempt to conceptualize some theories of genetic determinism. I analyse why there is a need to put bioethical principles within a theoretical framework in the context of new technologies, and how, by doing so, their practical applications for agriculture, environment medicine and health care can be legitimized. There are several theories in favour of and against the use of genetic technologies that focus on genes and their role in our existence. In particular the theory of geneticisation is commonly debated. It highlights the conflicting interests of science, society and industry in harnessing genetic knowledge when the use of such knowledge could challenge ethical principles. Critics call it a ‘reductionist’ approach, based on arguments that are narrowed down to genes, often ignoring other factors including biological, social and moral ones. A parallel theory is that there is something special about genes, and it is this “genetic exceptionalism” that creates hopes and myths. Either way, the challenging task is to develop a common ground for understanding the importance of ethical sensitivities. As research agendas become more complex, ethical paradigms will need to be more influential. New principles are needed to answer the complexities of ethical issues as complex technologies develop. This paper reflects on global ethical principles and the tensions between ethical principles in legitimizing genetic technologies at the social and governance level.     

Structure of respiratory complex I – An emerging blueprint for the mechanism

Complex I is one of the major respiratory complexes, conserved from bacteria to mammals. It oxidises NADH, reduces quinone and pumps protons across the membrane, thus playing a central role in the oxidative energy metabolism. In this review we discuss our current state of understanding the structure of complex I from various species of mammals, plants, fungi, and bacteria, as well as of several complex I-related proteins. By comparing the structural evidence from these systems in different redox states and data from mutagenesis and molecular simulations, we formulate the mechanisms of electron transfer and proton pumping and explain how they are conformationally and electrostatically coupled. Finally, we discuss the structural basis of the deactivation phenomenon in mammalian complex I.     

Our flawed approach to undue inducement in medical research

Some worry that offering too much money to participate in medical research can seduce people into participating against their better judgment. These overly attractive offers that impair judgment are often referred to as ‘undue inducements’. The current approach to prevent undue inducement is to limit the size of such offers. The hope is that smaller offers will not be attractive enough to impair judgment. Even if this is true, I argue that we should reject this solution. In Section 1, I go over the problem of undue inducement, and our current approach to preventing it, in more detail. In Section 2, I argue that, like money, therapeutic benefits of medical research may also unduly induce. In Section 3, I argue that the current approach to preventing undue inducement is absurd in the case of therapeutic inducements. In Section 4, I argue that our current approach is analogously problematic in the case of monetary inducements.     

Defining dysbiosis and its influence on host immunity and disease

Mammalian immune system development depends on instruction from resident commensal microorganisms. Diseases associated with abnormal immune responses towards environmental and self antigens have been rapidly increasing over the last 50 years. These diseases include inflammatory bowel disease (IBD), multiple sclerosis (MS), type I diabetes (T1D), allergies and asthma. The observation that people with immune mediated diseases house a different microbial community when compared to healthy individuals suggests that pathogenesis arises from improper training of the immune system by the microbiota. However, with hundreds of different microorganisms on our bodies it is hard to know which of these contribute to health and more importantly how? Microbiologists studying pathogenic organisms have long adhered to Koch's postulates to directly relate a certain disease to a specific microbe, raising the question of whether this might be true of commensal–host relationships as well. Emerging evidence supports that rather than one or two dominant organisms inducing host health, the composition of the entire community of microbial residents influences a balanced immune response. Thus, perturbations to the structure of complex commensal communities (referred to as dysbiosis) can lead to deficient education of the host immune system and subsequent development of immune mediated diseases. Here we will overview the literature that describes the causes of dysbiosis and the mechanisms evolved by the host to prevent these changes to community structure. Building off these studies, we will categorize the different types of dysbiosis and define how collections of microorganisms can influence the host response. This research has broad implications for future therapies that go beyond the introduction of a single organism to induce health. We propose that identifying mechanisms to re‐establish a healthy complex microbiota after dysbiosis has occurred, a process we will refer to as rebiosis, will be fundamental to treating complex immune diseases.     

Global change,biodiversity, and ecosystem services: What can we learn from studies of pollination?

The study of global environmental change and its effect on biodiversity and ecosystem function is at an exciting crossroads, at which ideas developed largely through theory and small-scale experiments are now being tested with ecosystem services as they are delivered to people in real-world landscapes. Pollinators and pollination are emerging as a model system for exploring these questions, which inherently required working large spatio-temporal scales. In this Invited View, I discuss current questions that are at the leading edge of this research. I first point out some surprising knowledge gaps in our understanding of pollinators’ response to global change. I then outline several ways in which current understanding of the biodiversity-ecosystem functioning relationship might be transformed by studies conducted at large spatio-temporal scales. Specifically, I propose two hypotheses that relate to the number of species required to saturate ecosystem function, and to the mechanisms through which biodiversity stabilizes ecosystem function over space or time.     

SNARE proteins and schizophrenia: linking synaptic and neurodevelopmental hypotheses

Much of the focus of neurobiological research into schizophrenia is based on the concept that disrupted synaptic connectivity underlies the pathology of the disorder. Disruption of synaptic connectivity is proposed to be a consequence of both disrupted synaptic transmission in adulthood and abnormalities in the processes controlling synaptic connectivity during development of the central nervous system. This synaptic hypothesis fits with neurodevelopmental models of schizophrenia and our understanding of the mechanisms of antipsychotic medication. This conceptual model has fostered efforts to define the exact synaptic pathology further. Synaptic proteins are obvious candidates for such studies, and the integral role of the SNARE complex, and SNARE-associated proteins, in synaptic transmission will ensure that it is the focus of much of this research. Significant new insights into the role of this complex are arising from new mouse models of human disease. Here the evidence from both animal and human clinical studies showing that the SNARE complex has a key role to play in the aetiology and pathogenesis of schizophrenia is discussed.     

NADH Dehydrogenases: From Basic Science to Biomedicine

This review article is concerned with two on-going research projects in our laboratory, both of which are related to the study of the NADH dehydrogenase enzyme complexes in the respiratory chain. The goal of the first project is to decipher the structure and mechanism of action of the proton-translocating NADH-quinone oxidoreductase (NDH-1) from two bacteria, Paracoccus denitrificans and Thermus thermophilus HB-8. These microorganisms are of particular interest because of the close resemblance of the former (P. denitrificans) to a mammalian mitochondria, and because of the thermostability of the enzymes of the latter (T. thermophilus). The NDH-1 enzyme complex of these and other bacteria is composed of 13 to 14 unlike subunits and has a relatively simple structure relative to the mitochondrial proton-translocating NADH-quinone oxidoreductase (complex I), which is composed of at least 42 different subunits. Therefore, the bacterial NDH-1 is believed to be a useful model for studying the mitochondrial complex I, which is understood to have the most intricate structure of all the membrane-associated enzyme complexes. Recently, the study of the NADH dehydrogenase complex has taken on new urgency as a result of reports that complex I defects are involved in many human mitochondrial diseases. Thus the goal of the second project is to develop possible gene therapies for mitochondrial diseases caused by complex I defects. This project involves attempting to repair complex I defects in the mammalian system using Saccharomyces cerevisiae NDI1 genes, which code for the internal, rotenone-insensitive NADH–quinone oxidoreductase. In this review, we will discuss our progress and the data generated by these two projects to date. In addition, background information and the significance of various approaches employed to pursue these research objectives will be described.     

Current perspectives on NMDA-type glutamate signalling in bone

Bone is a complex, evolving tissue, architecturally defined by the activities of osteoclasts and osteoblasts that continually resorb and replace the mineralised matrix. Numerous regulatory mechanisms exist to control bone remodelling and the maintenance of bone mass. The consequences of inappropriate or uncoupled bone resorption and formation are significant and invariably lead to different disease states, the most prevalent being osteoporosis. In recent years, much attention has focused on unravelling the systemic and local signalling interactions that influence the differentiation and function of bone cells with a view to developing our understanding of bone biology and identifying potential new targets for therapeutic intervention. Several lines of evidence indicate that neurotransmitters and neuromodulators have influential roles to play in the regulation of bone remodelling and much of this research has involved analysis of the excitatory amino acid glutamate. This review will summarise current understanding of glutamate signalling in bone cells, addressing specifically the function of N-methyl-D-aspartate (NMDA)-type glutamate receptor signalling mechanisms, and will address the functional significance and future prospects for this area of research.     

There's more than one frog in the pond: a survey of the Amphibia and their contributions to developmental biology

The study of developmental biology has benefited greatly from the insights gained using amphibians as experimental models. Although Xenopus is currently the predominant model, much of our embryological knowledge derives from research on other amphibians. I will review some of these discoveries, made through astute choice of model organism, and I will examine the reasons behind the adoption of Xenopus as the standard for amphibian research. Additionally, I will discuss the diversity in developmental and reproductive strategies that exists within the Amphibia, and consider some of the recent advances in our understanding of the mechanisms underlying this developmental diversity.     

Keystone species and food webs

Different species are of different importance in maintaining ecosystem functions in natural communities. Quantitative approaches are needed to identify unusually important or influential, ‘keystone’ species particularly for conservation purposes. Since the importance of some species may largely be the consequence of their rich interaction structure, one possible quantitative approach to identify the most influential species is to study their position in the network of interspecific interactions. In this paper, I discuss the role of network analysis (and centrality indices in particular) in this process and present a new and simple approach to characterizing the interaction structures of each species in a complex network. Understanding the linkage between structure and dynamics is a condition to test the results of topological studies, I briefly overview our current knowledge on this issue. The study of key nodes in networks has become an increasingly general interest in several disciplines: I will discuss some parallels. Finally, I will argue that conservation biology needs to devote more attention to identify and conserve keystone species and relatively less attention to rarity.     

中国国家公园体制改革: 回顾与前瞻

自2013年提出建立国家公园体制, 我国国家公园体制改革已取得了重要进展, 成为整个生态文明体制改革任务中进展最快、成果最显著的综合性改革。过去5年, 通过国家公园体制改革试点, 初步完成了国家公园的顶层设计、明确了管理体制、启动了相关立法程序, 筑就了国家公园建设的基本框架。改革的主要经验可以总结为四个方面: 一是高层引领与改革创新, 二是试点先行和动态调整, 三是问题导向和顶层设计, 四是利益相关方参与和改善治理体系。然而, 未来国家公园体制建设仍然任重道远, 面临众多挑战和困难, 包括国家公园建设区通常人口众多、土地权属复杂、利益相关者众多、缺乏多方参与机制、地方管理能力薄弱等。今后, 应在总结国家公园体制改革经验的基础上, 坚持正确的改革取向, 进一步扩大开放和创新思维, 坚持法治优先、系统推进、分类指导、分阶段实施的基本原则, 采取顶层设计加试点先行的方式, 实现依法办园、科学办园、民主办园、开放办园; 加快推动国家公园和自然保护地立法, 建立国家公园现代化治理体系, 探索建立国家公园生态产品价值实现机制; 最终使以国家公园为主体的自然保护地体系得到整体保护, 人民利益得以最大化, 真正实现人与自然和谐发展。