The multicellular nature of metazoans means that all cellular processes need to be tuned by adhesive interactions between cells and their local microenvironment. The spatial organization of cells ...within tissues requires sophisticated networks of extracellular signals to control their survival and proliferation, movements and positioning, and differentiated function. These cellular characteristics are mediated by multiple inputs from adhesion systems in combination with soluble and developmental signals. In the present review we explore how one class of adhesion receptor, the integrins, co-operate with other types of receptor to control diverse aspects of cell fate. In particular we discuss: (i) how beta3 and beta1 integrins work together with growth factors to control angiogenesis; (ii) how alpha6beta4 integrin co-operates with receptor tyrosine kinases in normal epithelial function and cancer; (iii) the interplay between beta1 integrins and EGF (epidermal growth factor) receptor; (iv) signal integration connecting integrins and cytokine receptors for interleukins, prolactin and interferons; and (v) how integrins and syndecans co-operate in cell migration.
The nature of nutrition Simpson, Stephen J; Simpson, Stephen J; Raubenheimer, David
2012., 20120722, 2012, 2012-07-22
eBook
Nutrition has long been considered more the domain of medicine and agriculture than of the biological sciences, yet it touches and shapes all aspects of the natural world. The need for nutrients ...determines whether wild animals thrive, how populations evolve and decline, and how ecological communities are structured.The Nature of Nutritionis the first book to address nutrition's enormously complex role in biology, both at the level of individual organisms and in their broader ecological interactions.
Stephen Simpson and David Raubenheimer provide a comprehensive theoretical approach to the analysis of nutrition--the Geometric Framework. They show how it can help us to understand the links between nutrition and the biology of individual animals, including the physiological mechanisms that determine the nutritional interactions of the animal with its environment, and the consequences of these interactions in terms of health, immune responses, and lifespan. Simpson and Raubenheimer explain how these effects translate into the collective behavior of groups and societies, and in turn influence food webs and the structure of ecosystems. Then they demonstrate how the Geometric Framework can be used to tackle issues in applied nutrition, such as the problem of optimizing diets for livestock and endangered species, and how it can also help to address the epidemic of human obesity and metabolic disease
Drawing on a wealth of examples from slime molds to humans,The Nature of Nutritionhas important applications in ecology, evolution, and physiology, and offers promising solutions for human health, conservation, and agriculture.
The highly specific relationships between parallel fiber (PF) and climbing fiber (CF) receptive fields in Purkinje cells and interneurons suggest that normal PF receptive fields are established by ...CF-specific plasticity. To test this idea, we used PF stimulation that was either paired or unpaired with CF activity. Conspicuously, unpaired PF stimulation that induced long-lasting, very large increases in the receptive field sizes of Purkinje cells induced long-lasting decreases in receptive field sizes of their afferent interneurons. In contrast, PF stimulation paired with CF activity that induced long-lasting decreases in the receptive fields of Purkinje cells induced long-lasting, large increases in the receptive fields of interneurons. These properties, and the fact the mossy fiber receptive fields were unchanged, suggest that the receptive field changes were due to bidirectional PF synaptic plasticity in Purkinje cells and interneurons.
Microglial cells are the resident macrophages in the central nervous system. These cells of mesodermal/mesenchymal origin migrate into all regions of the central nervous system, disseminate through ...the brain parenchyma, and acquire a specific ramified morphological phenotype termed "resting microglia." Recent studies indicate that even in the normal brain, microglia have highly motile processes by which they scan their territorial domains. By a large number of signaling pathways they can communicate with macroglial cells and neurons and with cells of the immune system. Likewise, microglial cells express receptors classically described for brain-specific communication such as neurotransmitter receptors and those first discovered as immune cell-specific such as for cytokines. Microglial cells are considered the most susceptible sensors of brain pathology. Upon any detection of signs for brain lesions or nervous system dysfunction, microglial cells undergo a complex, multistage activation process that converts them into the "activated microglial cell." This cell form has the capacity to release a large number of substances that can act detrimental or beneficial for the surrounding cells. Activated microglial cells can migrate to the site of injury, proliferate, and phagocytose cells and cellular compartments.
Pluripotency can be induced in somatic cells by overexpressing transcription factors, including POU class 5 homeobox 1 (OCT3/4), sex determining region Y-box 2 (SOX2), Krüppel-like factor 4 (KLF4), ...and myelocytomatosis oncogene (c-MYC). However, some induced pluripotent stem cells (iPSCs) exhibit defective differentiation and inappropriate maintenance of pluripotency features. Here we show that dynamic regulation of human endogenous retroviruses (HERVs) is important in the reprogramming process toward iPSCs, and in re-establishment of differentiation potential. During reprogramming, OCT3/4, SOX2, and KLF4 transiently hyperactivated LTR7s—the long-terminal repeats of HERV type-H (HERV-H)—to levels much higher than in embryonic stem cells by direct occupation of LTR7 sites genome-wide. Knocking down LTR7s or long intergenic non-protein coding RNA, regulator of reprogramming (lincRNA-RoR), a HERV-H–driven long noncoding RNA, early in reprogramming markedly reduced the efficiency of iPSC generation. KLF4 and LTR7 expression decreased to levels comparable with embryonic stem cells once reprogramming was complete, but failure to resuppress KLF4 and LTR7s resulted in defective differentiation. We also observed defective differentiation and LTR7 activation when iPSCs had forced expression of KLF4. However, when aberrantly expressed KLF4 or LTR7s were suppressed in defective iPSCs, normal differentiation was restored. Thus, a major mechanism by which OCT3/4, SOX2, and KLF4 promote human iPSC generation and reestablish potential for differentiation is by dynamically regulating HERV-H LTR7s.
The role of the gut microbiota in NAFLD Leung, Christopher; Rivera, Leni; Furness, John B ...
Nature reviews. Gastroenterology & hepatology,
07/2016, Volume:
13, Issue:
7
Journal Article
Peer reviewed
NAFLD is now the most common cause of liver disease in Western countries. This Review explores the links between NAFLD, the metabolic syndrome, dysbiosis, poor diet and gut health. Animal studies in ...which the gut microbiota are manipulated, and observational studies in patients with NAFLD, have provided considerable evidence that dysbiosis contributes to the pathogenesis of NAFLD. Dysbiosis increases gut permeability to bacterial products and increases hepatic exposure to injurious substances that increase hepatic inflammation and fibrosis. Dysbiosis, combined with poor diet, also changes luminal metabolism of food substrates, such as increased production of certain short-chain fatty acids and alcohol, and depletion of choline. Changes to the microbiome can also cause dysmotility, gut inflammation and other immunological changes in the gut that might contribute to liver injury. Evidence also suggests that certain food components and lifestyle factors, which are known to influence the severity of NAFLD, do so at least in part by changing the gut microbiota. Improved methods of analysis of the gut microbiome, and greater understanding of interactions between dysbiosis, diet, environmental factors and their effects on the gut-liver axis should improve the treatment of this common liver disease and its associated disorders.
Central neural circuits orchestrate a homeostatic repertoire to maintain body temperature during environmental temperature challenges and to alter body temperature during the inflammatory response. ...This review summarizes the functional organization of the neural pathways through which cutaneous thermal receptors alter thermoregulatory effectors: the cutaneous circulation for heat loss, the brown adipose tissue, skeletal muscle and heart for thermogenesis and species-dependent mechanisms (sweating, panting and saliva spreading) for evaporative heat loss. These effectors are regulated by parallel but distinct, effector-specific neural pathways that share a common peripheral thermal sensory input. The thermal afferent circuits include cutaneous thermal receptors, spinal dorsal horn neurons and lateral parabrachial nucleus neurons projecting to the preoptic area to influence warm-sensitive, inhibitory output neurons which control thermogenesis-promoting neurons in the dorsomedial hypothalamus that project to premotor neurons in the rostral ventromedial medulla, including the raphe pallidus, that descend to provide the excitation necessary to drive thermogenic thermal effectors. A distinct population of warm-sensitive preoptic neurons controls heat loss through an inhibitory input to raphe pallidus neurons controlling cutaneous vasoconstriction.
dynamic blood–brain barrier Keaney, James; Campbell, Matthew
The FEBS journal,
November 2015, Volume:
282, Issue:
21
Journal Article
Peer reviewed
Open access
With the endothelium as its central unit, the blood–brain barrier (BBB) is a complex multicellular structure separating the central nervous system (CNS) from the systemic circulation. Disruption of ...the BBB has now been implicated in a multitude of acute and chronic CNS disorders indicating the potentially devastating effects of BBB breakdown on brain function. However, the healthy BBB is not an impermeable wall, but rather a communication ‘centre’, responding to and passing signals between the CNS and blood. New studies are identifying BBB‐specific transport pathways that tightly regulate the entry and exit of molecules to and from the brain. They are revealing a highly plastic barrier in which dynamic changes in BBB components like paracellular tight junction complexes can contribute to BBB maintenance. Here, we provide a succinct overview of the current state‐of‐play in BBB research and summarize novel findings into BBB regulation in homeostatic regulation of the brain.
To test the hypothesis that hypoxia centrally affects performance independently of afferent feedback and peripheral fatigue, we conducted two experiments under complete vascular occlusion of the ...exercising muscle under different systemic O(2) environmental conditions. In experiment 1, 12 subjects performed repeated submaximal isometric contractions of the elbow flexor to exhaustion (RCTE) with inspired O(2) fraction fixed at 9% (severe hypoxia, SevHyp), 14% (moderate hypoxia, ModHyp), 21% (normoxia, Norm), or 30% (hyperoxia, Hyper). The number of contractions (performance), muscle (biceps brachii), and prefrontal near-infrared spectroscopy (NIRS) parameters and high-frequency paired-pulse (PS100) evoked responses to electrical muscle stimulation were monitored. In experiment 2, 10 subjects performed another RCTE in SevHyp and Norm conditions in which the number of contractions, biceps brachii electromyography responses to electrical nerve stimulation (M wave), and transcranial magnetic stimulation responses (motor-evoked potentials, MEP, and cortical silent period, CSP) were recorded. Performance during RCTE was significantly reduced by 10-15% in SevHyp (arterial O(2) saturation, SpO(2) = ∼75%) compared with ModHyp (SpO(2) = ∼90%) or Norm/Hyper (SpO(2) > 97%). Performance reduction in SevHyp occurred despite similar 1) metabolic (muscle NIRS parameters) and functional (changes in PS100 and M wave) muscle states and 2) MEP and CSP responses, suggesting comparable corticospinal excitability and spinal and cortical inhibition between SevHyp and Norm. It is concluded that, in SevHyp, performance and central drive can be altered independently of afferent feedback and peripheral fatigue. It is concluded that submaximal performance in SevHyp is partly reduced by a mechanism related directly to brain oxygenation.
Gamma oscillations appear to be dependent on inhibitory neurotransmission from parvalbumin (PV)-containing gamma-amino butyric acid neurons. Thus, the abnormalities in PV neurons found in ...schizophrenia may underlie the deficits of gamma-band synchrony in the illness. Because gamma-band synchrony is thought to be crucial for cognition, cognitive deficits in schizophrenia may reflect PV neuron dysfunction in cortical neural circuits. Interestingly, it has been suggested that PV alterations in schizophrenia are the consequence of a hypofunction of signaling through N-methyl-D-aspartate (NMDA) receptors (NMDARs). Here, we review recent findings that address the question of how NMDAR hypofunction might produce deficits of PV neuron-mediated inhibition in schizophrenia. We conclude that while dysregulation of NMDARs may play an important role in the pathophysiology of schizophrenia, additional research is required to determine the particular cell type(s) that mediate dysfunctional NMDAR signaling in the illness.
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