Hunger is controlled by specialized neural circuits that translate homeostatic needs into motivated behaviors. These circuits are under chronic control by circulating signals of nutritional state, ...but their rapid dynamics on the timescale of behavior remain unknown. Here, we report optical recording of the natural activity of two key cell types that control food intake, AgRP and POMC neurons, in awake behaving mice. We find unexpectedly that the sensory detection of food is sufficient to rapidly reverse the activation state of these neurons induced by energy deficit. This rapid regulation is cell-type specific, modulated by food palatability and nutritional state, and occurs before any food is consumed. These data reveal that AgRP and POMC neurons receive real-time information about the availability of food in the external world, suggesting a primary role for these neurons in controlling appetitive behaviors such as foraging that promote the discovery of food.
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•Sensory detection of food rapidly inhibits AgRP and activates POMC neurons•Rapid sensory feedback occurs before any food is consumed•The magnitude of neuronal response depends on food palatability and nutritional state•AgRP/POMC neurons may play a primary role in driving food discovery
Simply presenting food to a hungry mouse resets the activity of its AgRP and POMC neurons from a pattern associated with energy deficit to one associated with satiety, even if no food is consumed. The extent of the neuronal activity changes depends on the accessibility and palatability of the food.
In this paper, we summarize how internationalization research has evolved over time, where it stands today, and how it might evolve going forward. Specifically, we examine internationalization ...research from earlier times to the present day. We contrast the incremental internationalization characteristic of older multinational enterprises with the early, rapid internationalization of born global firms. The paper summarizes the evolution of research on early internationalization and born global firms, and provides evidence to suggest why this area now has attained legitimacy in scholarly research. We then examine important theoretical issues in born global research and suggest avenues for future research.
As long as a square non-negative matrix A has total support then it can be balanced, that is, we can find a diagonal scaling of A that has row and column sums equal to one. A number of algorithms ...have been proposed to achieve the balancing, the most well known of these being Sinkhorn-Knopp. In this paper, we derive new algorithms based on inner-outer iteration schemes. We show that Sinkhorn-Knopp belongs to this family, but other members can converge much more quickly. In particular, we show that while stationary iterative methods offer little or no improvement in many cases, a scheme using a preconditioned conjugate gradient method as the inner iteration converges at much lower cost (in terms of matrix-vector products) for a broad range of matrices; and succeeds in cases where the Sinkhorn-Knopp algorithm fails.
The mammalian brain is composed of thousands of interacting neural cell types. Systematic approaches to establish the molecular identity of functional populations of neurons would advance our ...understanding of neural mechanisms controlling behavior. Here, we show that ribosomal protein S6, a structural component of the ribosome, becomes phosphorylated in neurons activated by a wide range of stimuli. We show that these phosphorylated ribosomes can be captured from mouse brain homogenates, thereby enriching directly for the mRNAs expressed in discrete subpopulations of activated cells. We use this approach to identify neurons in the hypothalamus regulated by changes in salt balance or food availability. We show that galanin neurons are activated by fasting and that prodynorphin neurons restrain food intake during scheduled feeding. These studies identify elements of the neural circuit that controls food intake and illustrate how the activity-dependent capture of cell-type-specific transcripts can elucidate the functional organization of a complex tissue.
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► Ribosomal protein S6 becomes phosphorylated in activated neurons ► Immunoprecipitation of pS6 ribosomes enriches for mRNA from activated cells ► Enriched mRNAs reveal molecular identity of neurons activated by nutritional signals ► Dynorphin signaling restrains bouts of intense feeding
Phosphorylation of ribosomal protein S6 correlates with neural activity. The immunoprecipitation of phosphorylated S6 thus enriches for mRNAs that are expressed specifically in activated cells and allows for the identification of neuronal subpopulations that respond to particular stimuli.
Targeting the cancer kinome through polypharmacology Knight, Zachary A; Shokat, Kevan M; Lin, Henry
Nature reviews. Cancer,
201002, 2010-02-00, 2010-2-00, 20100201, Letnik:
10, Številka:
2
Journal Article, Book Review
Recenzirano
Odprti dostop
Kinase inhibitors are the largest class of new cancer drugs. However, it is already apparent that most tumours can escape from the inhibition of any single kinase. If it is necessary to inhibit ...multiple kinases, how do we choose which ones? In this Opinion article, we discuss some of the strategies that are currently being used to identify new therapeutic combinations of kinase targets.
Airway epithelial barrier dysfunction is frequently observed in asthma and may have important implications. The physical barrier function of the airway epithelium is tightly interwoven with its ...immunomodulatory actions, while abnormal epithelial repair responses may contribute to remodelling of the airway wall. We propose that abnormalities in the airway epithelial barrier play a crucial role in the sensitization to allergens and pathogenesis of asthma. Many of the identified susceptibility genes for asthma are expressed in the airway epithelium, supporting the notion that events at the airway epithelial surface are critical for the development of the disease. However, the exact mechanisms by which the expression of epithelial susceptibility genes translates into a functionally altered response to environmental risk factors of asthma are still unknown. Interactions between genetic factors and epigenetic regulatory mechanisms may be crucial for asthma susceptibility. Understanding these mechanisms may lead to identification of novel targets for asthma intervention by targeting the airway epithelium. Moreover, exciting new insights have come from recent studies using single‐cell RNA sequencing (scRNA‐Seq) to study the airway epithelium in asthma. This review focuses on the role of airway epithelial barrier function in the susceptibility to develop asthma and novel insights in the modulation of epithelial cell dysfunction in asthma.
Communication between the gut and brain is critical for homeostasis, but how this communication is represented in the dynamics of feeding circuits is unknown. Here we describe nutritional regulation ...of key neurons that control hunger in vivo. We show that intragastric nutrient infusion rapidly and durably inhibits hunger-promoting AgRP neurons in awake, behaving mice. This inhibition is proportional to the number of calories infused but surprisingly independent of macronutrient identity or nutritional state. We show that three gastrointestinal signals—serotonin, CCK, and PYY—are necessary or sufficient for these effects. In contrast, the hormone leptin has no acute effect on dynamics of these circuits or their sensory regulation but instead induces a slow modulation that develops over hours and is required for inhibition of feeding. These findings reveal how layers of visceral signals operating on distinct timescales converge on hypothalamic feeding circuits to generate a central representation of energy balance.
•Intragastric nutrients rapidly and durably inhibit hunger-promoting AgRP neurons•AgRP neuron inhibition by nutrients depends on total calories, not nutrient identity•A hormone screen identifies CCK, PYY, and 5HT as post-prandial AgRP neuron regulators•Leptin induces slow modulation of AgRP and POMC neurons on a timescale of hours
Beutler et al. reveal how nutritional signals regulate the hypothalamic hunger circuit. They show that intragastric nutrients inhibit AgRP neurons rapidly in a way dependent solely on calorie content, whereas the satiety hormone leptin only acts on timescale of hours.
Betaine supplementation in the context of human nutrition, athletic performance, and clinical therapy demonstrate that the osmolyte and methyl donor, betaine, is cytoprotective and beneficial to ...human health. These studies also demonstrate that betaine supplementation in healthy humans is straight-forward with no reported adverse effects. Here, we explore betaine uptake in the central nervous system (CNS) and contribute to evidence that betaine may be uniquely protective to the brain. We specifically describe the therapeutic potential of betaine and explore the potential implications of betaine on inhibition mediated by GABA and glycine neurotransmission. The influence of betaine on neurophysiology complement betaine’s role as an osmolyte and metabolite and is consistent with clinical evidence of betaine-mediated improvements to cognitive function (reported in elderly populations) and its anti-convulsant properties. Betaine’s therapeutic potential in neurological disorders including epilepsy and neurodegenerative diseases combined with benefits of betaine supplementation on athletic performance support the unique application of betaine as a prophylaxis to concussion. As an example, we identify young athletes (15–24 years old), especially females, for prophylactic betaine supplementation to promote brain health and resilience in a cohort at high risk for concussion and for developing Alzheimer’s disease.
We investigate born-global firms as early adopters of internationalization - that is, companies that expand into foreign markets and exhibit international business prowess and superior performance, ...from or near their founding. Our explication highlights the critical role of innovative culture, as well as knowledge and capabilities, in this unique breed of international, entrepreneurial firm. Case studies are analyzed to better understand the early internationalization phenomenon and reveal key orientations and strategies that engender international success among these innovative firms. Case findings are then validated in a survey-based study. Despite the scarce resources typical of young firms, our findings reveal that born-global firms leverage a distinctive mix of orientations and strategies that allow them to succeed in diverse international markets. Findings have important implications for the internationalization of contemporary firms.
Thirst motivates animals to drink in order to maintain fluid balance. Thirst has conventionally been viewed as a homeostatic response to changes in blood volume or tonicity. However, most drinking ...behaviour is regulated too rapidly to be controlled by blood composition directly, and instead seems to anticipate homeostatic imbalances before they arise. How this is achieved remains unknown. Here we reveal an unexpected role for the subfornical organ (SFO) in the anticipatory regulation of thirst in mice. By monitoring deep-brain calcium dynamics, we show that thirst-promoting SFO neurons respond to inputs from the oral cavity during eating and drinking and then integrate these inputs with information about the composition of the blood. This integration allows SFO neurons to predict how ongoing food and water consumption will alter fluid balance in the future and then to adjust behaviour pre-emptively. Complementary optogenetic manipulations show that this anticipatory modulation is necessary for drinking in several contexts. These findings provide a neural mechanism to explain longstanding behavioural observations, including the prevalence of drinking during meals, the rapid satiation of thirst, and the fact that oral cooling is thirst-quenching.
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