Spatial sensing of stimulus gradients can be superior to temporal sensing for free-swimming bacteria.

Predictions of the minimal size an organism must have to swim along stimulus gradients were used to compare the relative advantages of sensory systems employing spatial (simultaneous) and temporal (sequential) gradient detection mechanisms for small free-swimming bacteria, leading to the following conclusions: 1) there are environmental conditions where spatial detection mechanisms can function for smaller organisms than can temporal mechanisms, 2) temporal mechanisms are superior (have a smaller size limit) for the difficult conditions of low concentration and shallow gradients, but 3) observed bacterial chemotaxis occurs mostly under conditions where spatial mechanisms have a smaller size limit, and 4) relevant conditions in the natural environment favor temporal mechanisms in some cases and spatial mechanisms in others. Thus, sensory ecology considerations do not preclude free-swimming bacteria from employing spatial detection mechanisms, as has been thought, and microbiologists should be on the lookout for them. If spatial mechanisms do not occur, the explanation should be sought elsewhere.     

Do innate killing mechanisms activated by inflammasomes have a role in treating melanoma?

Melanoma, as for many other cancers, undergoes a selection process during progression that limits many innate and adaptive tumor control mechanisms. Immunotherapy with immune checkpoint blockade overcomes one of the escape mechanisms but if the tumor is not eliminated other escape mechanisms evolve that require new approaches for tumor control. Some of the innate mechanisms that have evolved against infections with microorganisms and viruses are proving to be active against cancer cells but require better understanding of how they are activated and what inhibitory mechanisms may need to be targeted. This is particularly so for inflammasomes which have evolved against many different organisms and which recruit a number of cytotoxic mechanisms that remain poorly understood. Equally important is understanding of where these mechanisms will fit into existing treatment strategies and whether existing strategies already involve the innate killing mechanisms.     

Mechanisms of pattern formation in development and evolution

We present a classification of developmental mechanisms that have been shown experimentally to generate pattern and form in metazoan organisms. We propose that all such mechanisms can be organized into three basic categories and that two of these may act as composite mechanisms in two different ways. The simple categories are cell autonomous mechanisms in which cells enter into specific arrangements ('patterns') without interacting, inductive mechanisms in which cell communication leads to changes in pattern by reciprocal or hierarchical alteration of cell phenotypes ('states') and morphogenetic mechanisms in which pattern changes by means of cell interactions that do not change cell states. The latter two types of mechanism can be combined either morphostatically, in which case inductive mechanisms act first, followed by the morphogenetic mechanism, or morphodynamically, in which case both types of mechanisms interact continuously to modify each other's dynamics. We propose that this previously unexplored distinction in the operation of composite developmental mechanisms provides insight into the dynamics of many developmental processes. In particular, morphostatic and morphodynamic mechanisms respond to small changes in their genetic and microenvironmental components in dramatically different ways. We suggest that these differences in 'variational properties' lead to morphostatic and morphodynamic mechanisms being represented to different extents in early and late stages of development and to their contributing in distinct ways to morphological transitions in evolution.     

Autophagy,anoikis, ferroptosis,necroptosis, and endoplasmic reticulum stress: Potential applications in melanoma therapy

Melanoma as the most major skin malignancy has attracted much attention, so far. Although a successful therapeutic strategy requires an accurate understanding of the precise mechanisms for the initiation and progression of the melanoma. Several types of cell death mechanisms have recently been identified along with conventional cell death mechanisms such as apoptosis and necrosis. Among those mechanisms, necroptosis, anoikis, ferroptosis, and autophagy may be considered to have remarkable modulatory impacts on melanoma. In the present review, we explain the mechanisms of cell death signaling pathways related to autophagy, ferroptosis, anoikis, necroptosis, and reticulum endoplasmic stress in cells and describe how those mechanisms transduce signals in melanoma cells. Meanwhile, we describe how we can modulate those mechanisms to eliminate melanoma.     

A three-dimensional computer model of four hypothetical mechanisms protecting biofilms from antimicrobials

Four hypothetical mechanisms for protection of biofilms against antimicrobials were incorporated into a three-dimensional model of biofilm growth and development. The model integrated processes of substrate utilization, diffusion, growth, cell migration, death, and detachment in a cellular automaton framework. Compared to simulations of unprotected biofilms, each of the protective mechanisms provided some tolerance to antimicrobial action. When the mechanisms were compared to each other, the behaviors of the four protective mechanisms produced distinct shapes of killing curves, nonuniform spatial patterns of survival and cell type distribution, and anticipated susceptibility patterns for dispersed biofilm cells. The differences between the protective mechanisms predicted in these simulations could guide the design of experiments to discriminate antimicrobial tolerance mechanisms in biofilms. Each of the mechanisms could be a plausible avenue of biofilm protection.     

Systems Neuroprotective Mechanisms in Ischemic Stroke

Ischemic stroke, although causing brain infarction and neurological deficits, can activate innate neuroprotective mechanisms, including regional mechanisms within the ischemic brain and distant mechanisms from non-ischemic organs such as the liver, spleen, and pancreas, supporting neuronal survival, confining brain infarction, and alleviating neurological deficits. Both regional and distant mechanisms are defined as systems neuroprotective mechanisms. The regional neuroprotective mechanisms involve release and activation of neuroprotective factors such as adenosine and bradykinin, inflammatory responses, expression of growth factors such as nerve growth factors and neurotrophins, and activation and differentiation of resident neural stem cells to neurons and glial cells. The distant neuroprotective mechanisms are implemented by expression and release of endocrine neuroprotective factors such as fibroblast growth factor 21, resistin like molecule γ, and trefoil factor 3 from the liver; brain-derived neurotrophic factor and nerve growth factor from the spleen; and neurotrophin 3 and vascular endothelial growth factor C from the pancreas. Furthermore, ischemic stroke induces mobilization of bone marrow hematopoietic stem cells and endothelial progenitor cells into the circulatory system and brain, contributing to neuroprotection. The regional and distant mechanisms may act in coordination and synergy to protect the ischemic brain from injury and death. This paper addresses these mechanisms and associated signaling networks.     

A Three-Dimensional Computer Model of Four Hypothetical Mechanisms Protecting Biofilms from Antimicrobials

Four hypothetical mechanisms for protection of biofilms against antimicrobials were incorporated into a three-dimensional model of biofilm growth and development. The model integrated processes of substrate utilization, diffusion, growth, cell migration, death, and detachment in a cellular automaton framework. Compared to simulations of unprotected biofilms, each of the protective mechanisms provided some tolerance to antimicrobial action. When the mechanisms were compared to each other, the behaviors of the four protective mechanisms produced distinct shapes of killing curves, nonuniform spatial patterns of survival and cell type distribution, and anticipated susceptibility patterns for dispersed biofilm cells. The differences between the protective mechanisms predicted in these simulations could guide the design of experiments to discriminate antimicrobial tolerance mechanisms in biofilms. Each of the mechanisms could be a plausible avenue of biofilm protection.     

'Generic' physical mechanisms of morphogenesis and pattern formation

The role of 'generic' physical mechanisms in morphogenesis and pattern formation of tissues is considered. Generic mechanisms are defined as those physical processes that are broadly applicable to living and non-living systems, such as adhesion, surface tension and gravitational effects, viscosity, phase separation, convection and reaction-diffusion coupling. They are contrasted with 'genetic' mechanisms, a term reserved for highly evolved, machine-like, biomolecular processes. Generic mechanisms acting upon living tissues are capable of giving rise to morphogenetic rearrangements of cytoplasmic, tissue and extracellular matrix components, sometimes leading to 'microfingers', and to chemical waves or stripes. We suggest that many morphogenetic and patterning effects are the inevitable outcome of recognized physical properties of tissues, and that generic physical mechanisms that act on these properties are complementary to, and interdependent with genetic mechanisms. We also suggest that major morphological reorganizations in phylogenetic lineages may arise by the action of generic physical mechanisms on developing embryos. Subsequent evolution of genetic mechanisms could stabilize and refine developmental outcomes originally guided by generic effects.     

General theory of competitive coexistence in spatially-varying environments

A general model of competitive and apparent competitive interactions in a spatially-variable environment is developed and analyzed to extend findings on coexistence in a temporally-variable environment to the spatial case and to elucidate new principles. In particular, coexistence mechanisms are divided into variation-dependent and variation-independent mechanisms with variation-dependent mechanisms including spatial generalizations of relative nonlinearity and the storage effect. Although directly analogous to the corresponding temporal mechanisms, these spatial mechanisms involve different life history traits which suggest that the spatial storage effect should arise more commonly than the temporal storage effect and spatial relative nonlinearity should arise less commonly than temporal relative nonlinearity. Additional mechanisms occur in the spatial case due to spatial covariance between the finite rate of increase of a local population and its local abundance, which has no clear temporal analogue. A limited analysis of these additional mechanisms shows that they have similar properties to the storage effect and relative nonlinearity and potentially may be considered as enlargements of the earlier mechanisms. The rate of increase of a species perturbed to low density is used to quantify coexistence. A general quadratic approximation, which is exact in some important cases, divides this rate of increase into contributions from the various mechanisms above and admits no other mechanisms, suggesting that opportunities for coexistence in a spatially-variable environment are fully characterized by these mechanisms within this general model. Three spatially-implicit models are analyzed as illustrations of the general findings and of techniques using small variance approximations. The contributions to coexistence of the various mechanisms are expressed in terms of simple interpretable formulae. These spatially-implicit models include a model of an annual plant community, a spatial multispecies version of the lottery model, and a multispecies model of an insect community competing for spatially-patchy and ephemeral food.     

In vivo mechanisms of cutaneous vasodilation and vasoconstriction in humans during thermoregulatory challenges.

This review focuses on the neural and local mechanisms that have been demonstrated to effect cutaneous vasodilation and vasoconstriction in response to heat and cold stress in vivo in humans. First, our present understanding of the mechanisms by which sympathetic cholinergic nerves mediate cutaneous active vasodilation during reflex responses to whole body heating is discussed. These mechanisms include roles for cotransmission as well as nitric oxide (NO). Next, the mechanisms by which sympathetic noradrenergic nerves mediate cutaneous active vasoconstriction during whole body cooling are reviewed, including cotransmission by neuropeptide Y (NPY) acting through NPY Y1 receptors. Subsequently, current concepts for the mechanisms that effect local cutaneous vascular responses to direct skin warming are examined. These mechanisms include the roles of temperature-sensitive afferent neurons as well as NO in causing vasodilation during local heating of skin. This section is followed by a review of the mechanisms that cause local cutaneous vasoconstriction in response to direct cooling of the skin, including the dependence of these responses on intact sensory and sympathetic, noradrenergic innervation as well as roles for nonneural mechanisms. Finally, unresolved issues that warrant further research on mechanisms that control cutaneous vascular responses to heating and cooling are discussed.     

Integrated tolerance mechanisms: constitutive and adaptive plant responses to elevated metal concentrations in the environment

Isolation and study of metal tolerant and hypersensitive strains of higher plant (and yeast) species has greatly increased our knowledge of the individual pathways that are involved in tolerance. Plants have both constitutive (present in most phenotypes) and adaptive (present only in tolerant phenotypes) mechanisms for coping with elevated metal concentrations. Where studies on the mechanisms of tolerance fall down is in their failure to integrate tolerance mechanisms within cell or whole-plant function by not relating adaptive mechanisms to constitutive mechanisms. This failure often distorts the relative importance of a proposed tolerance mechanism, and indeed has confused the search for adaptive mechanisms. The fundamental goal of both constitutive and adaptive mechanisms is to limit the perturbation of cell homeostasis after exposure to metals so that normal or near-normal physiological function may take place. Consideration of the response to metals at a cellular rather than a biochemical level will lead to a greater understanding of mechanisms to withstand elevated levels of metals in both contaminated and uncontaminated environments. Recent advances in the study of Al, As, Cd, and Cu tolerance and hypersensitivity are reported with respect to the cellular response to toxic metals. The role of genetics in unravelling tolerance mechanisms is also considered.     

Mechanisms of statin-induced new-onset diabetes

Statins, with their lipid-lowering properties, are a first-line therapy for the prevention of cardiovascular diseases. Recent evidence, however, suggests that statins can increase the risk of new-onset diabetes (NOD). The molecular mechanisms of statin-induced NOD are not precisely known, although some pathophysiologic mechanisms have been suggested. Specific to the beta cell, these mechanisms include alterations in insulin secretion, changes in ion channels, modulation of signaling pathways, and inflammation/oxidative stress. Outwith the beta cell, other suggested mechanisms involve adipocytes, including alterations in adipocyte differentiation and modulation of leptin and adiponectin, and genetic and epigenetic mechanisms, including alterations in microRNA. The evidence supporting these and other mechanisms will be discussed. Greater understanding of the underlying mechanisms linking the onset of diabetes to statin therapy is essential and clinically relevant, as it may enable novel preventative or therapeutic approaches to be instituted and guide the production of a new generation of statins lacking this side effect.     

Some mechanisms of Helicobacter pylori persistence

The mechanisms of the pathogenesis of Helicobacter pylori infection, ensuring the prolonged survival of these bacteria in the aggressive medium (gastric mucosa), are considered. A new approach to the systematization of the mechanisms of H. pylori persistence is proposed: the mechanisms ensuring the stability of H. pylori in the presence of aggressive physical and chemical factors, the mechanisms ensuring antagonistic effects in biocenosis and the mechanisms ensuring resistance to the protective factors of the host. Data on the persistence potential of H. pylori in accordance with the proposed classification are presented.     

Perception and transduction of abscisic acid signals: keys to the function of the versatile plant hormone ABA

During the past decade, much progress has been made toward understanding the mechanisms underlying plant hormone activity, from perception to nuclear events. However, the signaling mechanisms for abscisic acid (ABA) have remained largely obscure. Recent breakthroughs identifying FCA, which is an RNA-binding protein, the Mg-chelatase H subunit, and a G protein-coupled receptor as receptors for ABA provide a major leap forward in understanding the initial steps of ABA signaling mechanisms. Recent studies have also revealed the molecular mechanisms of second messenger production, protein modifications such as phosphorylation, and regulatory mechanisms of gene expression in the ABA response. Therefore, the connections between these events are also beginning to be determined. Here, we review recent progress and discuss the overall scheme of the ABA response mechanisms.     

The role of hormones of hypothalamic-pituitary-adrenocortical system in regulation of pain sensitivity

The review focuses on the role of hypothalamic-pituitary-adrenocortical system (HPAS) in regulation of pain sensitivity and discusses the mechanisms involved in this process. Analgesic effects of exogenous hormones of HPAS (corticotropin-releasing hormone (CRH), ACTH, glucocorticoids) have been shown in rats. It is mediated by both opioid and non-opioid mechanisms. Endogenous glucocorticoids produce development of analgesia mediated by non-opioid mechanisms. Analgesic effect of ACTH is mediated by both non-glucocorticoids mechanisms associated with endogenous glucocorticoids and opioid mechanisms. In contrast to ACTH, analgesic effect of CRH is mediated only by non-opioid mechanisms associated or dissociated with endogenous glucocorticoids. The neurons of midbrain periaqueductal gray matter may be involved in the analgesia induced by glucocorticoids.     

Oscillations in a Simple Neuromechanical System: Underlying Mechanisms

A half-center neural oscillator was coupled to a simple mechanical system to study the closed-loop interactions between a central pattern generator and its effector muscles. After a review of the open-loop mechanisms that were previously introduced by Skinner et al. (1994), we extend their geometric approach and introduce four additional closed-loop mechanisms by the inclusion of an antagonistic muscle pair acting on a mass and connected to the half-center neural oscillator ipsilaterally. Two of the closed-loop mechanisms, mechanical release mechanisms, have close resemblance to open-loop release mechanisms whereas the latter two, afferent mechanisms, have a strong dependence on the mechanical properties of the system. The results also show that stable oscillations can emerge in the presence of sensory feedback even if the neural system is not oscillatory. Finally, the feasibility of the closed-loop mechanisms was shown by weakening the idealized assumptions of the synaptic and the feedback connections as well as the rapidity of the oscillations.     

Tenth Enzyme Mechanisms Conference

The tenth biennial conference on enzyme mechanisms was organized by T. Fink (chairman), R. Abeles, W. Cleland, B. Metcalf, and N. Oppenheimer. It was held at the Asilomar Conference center in Pacific Grove, California. Session topics included: 1, Bioorganic mechanisms; 2, structural mechanisms; 3, mechanisms through mutagenesis; 4, mechanism-based inhibition; 5, mechanisms—general; and 6, bioinorganic mechanisms. In addition to the lectures, two poster sessions were held which included topics from several areas of mechanistic enzymology. A brief summary of the lectures and a few references are presented below. As in the past, the authors and titles of the posters will also be listed.     

Bacterial avoidance of phagocytosis

Phagocytosis constitutes the primary line of host innate and adaptive defence against incoming microbial pathogens, providing an efficient means for their removal and destruction. However, several virulent bacteria that do not function as intracellular pathogens have evolved mechanisms to avoid and prevent phagocytosis that constitute an essential part of their pathogenic capacity. Some of these mechanisms include preventing recognition by phagocytic receptors or blocking uptake by professional phagocytes. Recently, the molecular mechanisms of such antiphagocytic properties have been elucidated for some pathogens. Such mechanisms illustrate the diversity of mechanisms bacterial pathogens use to avoid phagocytic uptake.     

Seed dispersal systems in the New Zealand flora

Knowledge of the dispersal mechanisms used by plants is important in phylogenetic, ecological, biogeographical, and conservation studies. Here we attempt to assign dispersal mechanisms to the entire flora-2595 plant species of the New Zealand Botanical Region. Anemochory is the most frequent dispersal mechanism, utilised by 79% of species. The next most frequent mechanisms are endozoochory (33%), hydrochory (28%), epizoochory (26%), and ballistic (8%). Polychory is common, particularly in monocotyledonous and dicotyledonous families and hydrochorous, epizoochorous, and ballistically dispersed species. Epizoochory is more common in New Zealand than in other regions, and species using this dispersal mechanism are over-represented among threatened species. Frugivory is less common than previously reported, and is under-represented among threatened species. Some mechanisms are poorly known, and entanglement and capsulivory are dispersal mechanisms apparently unique to New Zealand. Dispersal mechanisms reflective of New Zealand's distinctive assemblages of large flightless birds and reptiles are not apparent. A pattern of reduction in dispersal-related structures is evident in some genera. The mechanisms utilised by some species are ambiguous. Thus there remains a need for further investigation of the dispersal mechanisms utilised by plants in New Zealand.