Future medicine: from molecular pathways to the collective intelligence of the body

The remarkable anatomical homeostasis exhibited by complex living organisms suggests that they are inherently reprogrammable information-processing systems that offer numerous interfaces to their physiological and anatomical problem-solving capacities. We briefly review data suggesting that the multiscale competency of living forms affords a new path for biomedicine that exploits the innate collective intelligence of tissues and organs. The concept of tissue-level allostatic goal-directedness is already bearing fruit in clinical practice. We sketch a roadmap towards 'somatic psychiatry' by using advances in bioelectricity and behavioral neuroscience to design methods that induce self-repair of structure and function. Relaxing the assumption that cellular control mechanisms are static, exploiting powerful concepts from cybernetics, behavioral science, and developmental biology may spark definitive solutions to current biomedical challenges.     

Regulation of lipid metabolism: a tale of two yeasts

Eukaryotic cells synthesize multiple classes of lipids by distinct metabolic pathways in order to generate membranes with optimal physical and chemical properties. As a result, complex regulatory networks are required in all organisms to maintain lipid and membrane homeostasis as well as to rapidly and efficiently respond to cellular stress. The unicellular nature of yeast makes it particularly vulnerable to environmental stress and yeast has evolved elaborate signaling pathways to maintain lipid homeostasis. In this article we highlight the recent advances that have been made using the budding and fission yeasts and we discuss potential roles for the unfolded protein response (UPR) and the SREBP-Scap pathways in coordinate regulation of multiple lipid classes.     

New insights into the function of Atg9

Autophagy is a lysosomal degradation pathway that is essential for cellular homeostasis. Identification of more than 30 autophagy related proteins including a multi-spanning membrane protein, Atg9, has increased our understanding of the molecular mechanisms involved in autophagy. Atg9 is required for autophagy in several eukaryotic organisms although its function is unknown. Recently, we identified a novel interacting partner of mAtg9, p38 MAPK interacting protein, p38IP. We summarise recent data on the role of Atg9 trafficking in yeast and mammalian autophagy and discuss the role of p38IP and p38 MAPK in regulation of mAtg9 trafficking and autophagy.     

The secret life of extracellular vesicles in metal homeostasis and neurodegeneration

Biologically active metals such as copper, zinc and iron are fundamental for sustaining life in different organisms with the regulation of cellular metal homeostasis tightly controlled through proteins that coordinate metal uptake, efflux and detoxification. Many of the proteins involved in either uptake or efflux of metals are localised and function on the plasma membrane, traffic between intracellular compartments depending upon the cellular metal environment and can undergo recycling via the endosomal pathway. The biogenesis of exosomes also occurs within the endosomal system, with several major neurodegenerative disease proteins shown to be released in association with these vesicles, including the amyloid‐β (Aβ) peptide in Alzheimer's disease and the infectious prion protein involved in Prion diseases. Aβ peptide and the prion protein also bind biologically active metals and are postulated to play important roles in metal homeostasis. In this review, we will discuss the role of extracellular vesicles in Alzheimer's and Prion diseases and explore their potential contribution to metal homeostasis.     

Claudin-based barrier in simple and stratified cellular sheets

For homeostasis in multicellular organisms, isolation and compartmentalisation of the internal environment are essential, and are established by various cellular sheets. For these cellular sheets to function as barriers, the intercellular route must be sealed. Recent advances reveal that claudins - major cell adhesion molecules in tight junctions - are directly involved in this intercellular sealing, not only in simple but also in stratified cellular sheets in vertebrates.     

PIKfyve: Partners, significance, debates and paradoxes

Key components of membrane trafficking and signaling machinery in eukaryotic cells are proteins that bind or synthesize phosphoinositides. PIKfyve, a product of an evolutionarily conserved single-copy gene has both these features. It binds to membrane phosphatidylinositol (PtdIns)3P and synthesizes PtdIns(3,5)P2 and PtdIns5P. Molecular functions of PIKfyve are elusive but recent advances are consistent with a key role in the course of endosomal transport. PIKfyve dysfunction induces endosome enlargement and profound cytoplasmic vacuolation, likely as a result of impaired normal endosome processing and membrane exit out of endosomes. Multicellular organisms with genetically impaired function of PIKfyve or that of the PIKfyve protein partners regulating PtdIns(3,5)P2 homeostasis display severe disorders, including embryonic/perinatal death. This review describes recent advances on PIKfyve functionality in higher eukaryotes, with particular reference to biochemical and genetic insights in PIKfyve protein partners.     

Mechanisms of mammalian iron homeostasis

Iron is vital for almost all organisms because of its ability to donate and accept electrons with relative ease. It serves as a cofactor for many proteins and enzymes necessary for oxygen and energy metabolism, as well as for several other essential processes. Mammalian cells utilize multiple mechanisms to acquire iron. Disruption of iron homeostasis is associated with various human diseases: iron deficiency resulting from defects in the acquisition or distribution of the metal causes anemia, whereas iron surfeit resulting from excessive iron absorption or defective utilization causes abnormal tissue iron deposition, leading to oxidative damage. Mammals utilize distinct mechanisms to regulate iron homeostasis at the systemic and cellular levels. These involve the hormone hepcidin and iron regulatory proteins, which collectively ensure iron balance. This review outlines recent advances in iron regulatory pathways as well as in mechanisms underlying intracellular iron trafficking, an important but less studied area of mammalian iron homeostasis.     

The concept of the organism in physiology

Summary The growth of physiology in the 19^th and 20^th centuries was accompanied by the development of disciplinary boundaries between physiology and other biological sciences. Physiology became the study of the mechanisms that underlie the functions of organisms and their component parts. Concern with the internal workings of organisms has led physiologists to focus on the maintenance of homeostasis in the internal environment rather than on the interactions of organisms with their external environments. Moreover, interest in the cellular or biochemical mechanisms that underlie organismal function has resulted in the use of inbred populations of laboratory animals in which these mechanisms can be most rigorously studied. Finally, emphasis on the function of fully developed or adult organisms has been accompanied by a relative neglect of developmental processes. Disregard for the environment, for variation, and for development has made possible major advances in our knowledge of physiological mechanisms but has led to an impoverished concept of organisms. Incorporation of evolutionary, ecological, and developmental perspectives into the study of organisms might help to unite physiology more closely with the other biological sciences and lead to a richer and fuller understanding of organisms.     

Dynamics of receptor trafficking in tumorigenicity

The transport and sorting of cell surface receptors into membrane-bound intracellular compartments is crucial for cellular homeostasis. Defects in receptor trafficking are associated with several diseases, including cancer. Recent advances in our understanding of mechanisms that control receptor trafficking have highlighted the involvement of membrane trafficking in cell signaling, as well as in biological processes, including cell migration and invasion. In this review, we summarize current knowledge of how cargos, focusing on receptor tyrosine kinases (RTKs) and integrins, are dynamically transported through the endosomal pathway for recycling, and how this promotes spatially restricted signaling microdomains associated with distinct biological responses. We discuss mechanisms through which dysregulation of membrane trafficking contributes to tumorigenesis and potential therapeutic approaches.     

The dynamic roles of intracellular lipid droplets: from archaea to mammals

During the past decade, there has been a paradigm shift in our understanding of the roles of intracellular lipid droplets (LDs). New genetic, biochemical and imaging technologies have underpinned these advances, which are revealing much new information about these dynamic organelles. This review takes a comparative approach by examining recent work on LDs across the whole range of biological organisms from archaea and bacteria, through yeast and Drosophila to mammals, including humans. LDs probably evolved originally in microorganisms as temporary stores of excess dietary lipid that was surplus to the immediate requirements of membrane formation/turnover. LDs then acquired roles as long-term carbon stores that enabled organisms to survive episodic lack of nutrients. In multicellular organisms, LDs went on to acquire numerous additional roles including cell- and organism-level lipid homeostasis, protein sequestration, membrane trafficking and signalling. Many pathogens of plants and animals subvert their host LD metabolism as part of their infection process. Finally, malfunctions in LDs and associated proteins are implicated in several degenerative diseases of modern humans, among the most serious of which is the increasingly prevalent constellation of pathologies, such as obesity and insulin resistance, which is associated with metabolic syndrome.     

植物Na+/H+逆向转运蛋白功能及调控的研究进展

Na+/H+逆向转运蛋白是一种调控Na+、H+跨膜转运的膜蛋白,对细胞内Na+的平衡和pH值的调控等活动具有重要作用。该文主要对近年来Na+/H+逆向转运蛋白功能及其调控的研究进展进行概述,着重讨论其在调控离子稳态平衡,液泡pH值大小与花色显现,以及在影响细胞,器官(叶片)发育,盐胁迫信号转导等方面的可能作用。     

环境污染物对水生生物产生氧化压力的分子生物标志物

为了能够建立一种简单、快速、准确的环境污染监测预警体系,人们进行了广泛的研究,其中有关环境污染物对分子生物标志物的影响已成为研究热点。生物体内的氧自由基和其它活性氧分子（ROS）对组织和细胞成分造成的伤害,称之为氧化压力,环境中的有毒物质能够对生物体产生不同程度的氧化压力。生物体内的强氧化剂或体外因素（如环境污染物）引起的强氧化物与抗氧化防御系统之间的平衡能够用于评估环境压力对生物体产生影响的程度,尤其适合于评估不同种化学物质引起氧化损伤的程度。这些抗氧化防御系统及其对氧化压力的敏感性在环境毒物学研究中占有非常重要的地位,大量研究结果表明：过渡金属、多环芳烃、有机氯和有机磷农药、多氯联苯、二氧芑和其它异型物质都能够对生物体产生氧化压力。这些有毒物质能够引起各种有害影响,如对膜脂、DNA和蛋白产生损伤;改变抗氧化酶的活性等。总结了这种氧化压力的研究进展情况,并讨论了这些分子生物标志物在水生生物中的应用。     

Autophagy and aging: keeping that old broom working

Autophagy, a highly conserved mechanism of quality control inside cells, is essential for the maintenance of cellular homeostasis and for the orchestration of an efficient cellular response to stress. The decrease in autophagic activity observed in almost all cells and tissues as organisms age was proposed to contribute to different aspects of the aging phenotype and to the aggravation of detrimental age-related diseases. The recent advances in our understanding of the molecular mechanisms underlying autophagy and the identification of the subset of genes involved in this process has enabled the use of genetic manipulations to start testing this hypothesis. Here, I review the recent genetic evidence in support of tight connections between autophagy, health span and aging.     

Molecular landmarks along the axonal route: axonal transport in health and disease

Axonal transport of organelles has emerged as a key process in the regulation of neuronal differentiation and survival. Several components of this specialised transport machinery, their regulators and vesicular cargoes are mutated or altered in many neurodegenerative conditions. The molecular characterisation of these mechanisms has furthered our understanding of neuronal homeostasis, providing insights into the spatio-temporal control of membrane traffic and signalling in neurons with a precision not achievable in other cellular systems. Here, we summarise the recent advances in the field of axonal trafficking of different organelles, and the essential role of motor and adaptor proteins in this process.     

Comparing methods for metabolic network analysis and an application to metabolic engineering

Bioinformatics tools have facilitated the reconstruction and analysis of cellular metabolism of various organisms based on information encoded in their genomes. Characterization of cellular metabolism is useful to understand the phenotypic capabilities of these organisms. It has been done quantitatively through the analysis of pathway operations. There are several in silico approaches for analyzing metabolic networks, including structural and stoichiometric analysis, metabolic flux analysis, metabolic control analysis, and several kinetic modeling based analyses. They can serve as a virtual laboratory to give insights into basic principles of cellular functions. This article summarizes the progress and advances in software and algorithm development for metabolic network analysis, along with their applications relevant to cellular physiology, and metabolic engineering with an emphasis on microbial strain optimization. Moreover, it provides a detailed comparative analysis of existing approaches under different categories.