The splitting of dinitrogen (N₂) and reduction to ammonia (NH₃) is a kinetically complex and energetically challenging multistep reaction. In the Haber-Bosch process, N₂ reduction is accomplished at ...high temperature and pressure, whereas N₂ fixation by the enzyme nitrogenase occurs under ambient conditions using chemical energy from adenosine 5'-triphosphate (ATP) hydrolysis. We show that cadmium sulfide (CdS) nanocrystals can be used to photosensitize the nitrogenase molybdenum-iron (MoFe) protein, where light harvesting replaces ATP hydrolysis to drive the enzymatic reduction of N₂ into NH₃. The turnover rate was 75 per minute, 63% of the ATP-coupled reaction rate for the nitrogenase complex under optimal conditions. Inhibitors of nitrogenase (i.e., acetylene, carbon monoxide, and dihydrogen) suppressed N₂ reduction. The CdS:MoFe protein biohybrids provide a photochemical model for achieving light-driven N₂ reduction to NH₃.
The tumor suppressor p53 has established functions in cancer. Specifically, it has been shown to cause cell-cycle arrest and apoptosis in response to DNA damage. It is also one of the most commonly ...mutated or silenced genes in cancer and for this reason has been extensively studied. Recently, the role of p53 has been shown to go beyond its effects on cell cycle and apoptosis, with effects on metabolism emerging as a key contributor to cancer growth in situations where p53 is lost. Beyond this, the role of p53 in the tumor microenvironment is poorly understood. The publication by Wang and colleagues demonstrates for the first time that p53 is a key negative regulator of aromatase and, hence, estrogen production in the breast tumor microenvironment. It goes further by demonstrating that an important regulator of aromatase, the obesity-associated and tumor-derived factor prostaglandin E2, inhibits p53 in the breast adipose stroma. This review presents these findings in the context of established and emerging roles of p53 and discusses possible implications for the treatment of breast cancer.
The excitable behaviour of neurons is determined by the activity of their endogenous membrane ion channels. Since muscarinic receptors are not themselves ion channels, the acute effects of muscarinic ...receptor stimulation on neuronal function are governed by the effects of the receptors on these endogenous neuronal ion channels. This review considers some principles and factors determining the interaction between subtypes and classes of muscarinic receptors with neuronal ion channels, and summarizes the effects of muscarinic receptor stimulation on a number of different channels, the mechanisms of receptor – channel transduction and their direct consequences for neuronal activity. Ion channels considered include potassium channels (voltage-gated, inward rectifier and calcium activated), voltage-gated calcium channels, cation channels and chloride channels.
This article is part of the Special Issue entitled ‘Neuropharmacology on Muscarinic Receptors’.
•Activation of muscarinic receptors (MRs) modifies neuronal signalling by altering the activity of membrane ion channels.•The principles governing MR-channel interaction are illustrated with reference to regulation of Kv7 and Kirchannels.•Effects of stimulating Gq-coupled MRs on various K+Cl−, cation and Ca2+ channel are discussed.•Gi/Go-coupled MRs activate Kir potassium channels, inhibit CaV calcium channels and inhibit transmitter release.•The topographical relation between MRs and channels and possible macromolecular channel-receptor complexes are discussed.
Cyclic polymers are an intriguing class of macromolecules. Because of the constraints of the cyclic topology and the absence of chain ends, the properties of these molecules differ from those of ...linear polymers in ways that remain poorly understood. Cyclic polymers present formidable synthetic challenges because the entropic penalty of coupling the chain ends grows exponentially with increasing molecular weight. In this Account, we describe recent progress in the application of zwitterionic ring-opening polymerization (ZROP) as a strategy for the synthesis of high molecular weight, cyclic polymers. Zwitterionic ring-opening polymerization involves the addition of neutral organic nucleophiles to strained heterocyclic monomers; under appropriate conditions, cyclization of the resultant macrozwitterions generates cyclic macromolecules. We discuss the mechanistic and kinetic features of these zwitterionic ring-opening reactions and the conditions that influence the efficiency of the initiation, propagation, and cyclization to generate high molecular weight cyclic polymers. N-Heterocyclic carbenes (NHC) are potent nucleophiles and relatively poor leaving groups, two features that are important for the generation of high molecular weight polymers. Investigations of the nature of the monomer and nucleophile have helped researchers understand the factors that govern the reactivity of these systems and their impact on the molecular weight and molecular weight distributions of the resulting cyclic polymers. We focus primarily on ZROP mediated by N-heterocyclic carbene nucleophiles but also discuss zwitterionic polymerizations with amidine, pyridine, and imidazole nucleophiles. The ZROP of N-carboxyanhydrides with N-hetereocyclic carbenes generates a family of functionalized cyclic polypeptoids. We can synthesize gradient lactone copolymers by exploiting differences in relative reactivity present in ZROP that differ from those of traditional metal-mediated polymerizations. These new synthetic methods have allowed us to investigate the influence of topology on the crystallization behavior, stereocomplexation, and solution properties of cyclic macromolecules.
Osteosarcoma (OS) is the most frequent pediatric malignant bone tumor that has a high propensity for metastases. Through osteoblast-specific alteration of p53 status, we developed a genetically ...engineered mouse model of localized and metastatic OS to gain an understanding into the molecular pathogenesis of OS. Microarray analysis of both localized tumors and metastatic tumors identified the downregulation of the naked cuticle homolog 2 (NKD2) gene, a negative regulator of Wnt signaling. Overexpression of NKD2 in metastatic human and mouse OS cells significantly decreases cell proliferation, migration and invasion ability in vitro and drastically diminishes OS tumor growth and metastasis in vivo, whereas downregulation enhances migratory and invasive potential. Evaluation of NKD2-overexpressing tumors revealed upregulation of tumor-suppressor genes and downregulation of molecules involved in blood vessel formation and cell migration. Furthermore, assessment of primary human OS revealed downregulation of NKD2 in metastatic and recurrent OS. Finally, we provide biological evidence that use of small-molecule inhibitors targeting the Wnt pathway can have therapeutic efficacy in decreasing metastatic properties in OS. Our studies provide compelling evidence that downregulation of NKD2 expression and alterations in associated regulated pathways have a significant role in driving OS tumor growth and metastasis.
This study aimed to identify country-level predictors of COVID-19 mortality, after controlling for diverse potential factors, and utilizing current worldwide mortality data. COVID-19 deaths, as well ...as geographic, demographic, socioeconomic, healthcare, population health, and pandemic-related variables, were obtained for 152 countries. Continuous variables were examined with Spearman's correlation, categorical variables with ANOVA or Welch's Heteroscedastic F Test, and country-level independent predictors of COVID-19 mortality identified by weighted generalized additive models. This study identified independent mortality predictors in six limited models, comprising groups of related variables. However, in the full model, only WHO region, percent of population ≥ 65 years, Corruption Perception Index, hospital beds/100,000 population, and COVID-19 cases/100,000 population were predictive of mortality, with model accounting for 80.7% of variance. These findings suggest areas for focused intervention in the event of similar future public health emergencies, including prioritization of the elderly, optimizing healthcare capacity, and improving deficient health sector-related governance.
Dietary protein and its metabolites, amino acids, are essential nutrients for humans and animals. Accumulated research has revealed that the gut microbiota mediate the crosstalk between protein ...metabolism and host immune response. Gut microbes are involved in the digestion, absorption, metabolism and transformation process of dietary protein in the gastrointestinal tract. Amino acids can be metabolized into numerous microbial metabolites, and these metabolites participate in various physiological functions related to host health and diseases. The components of dietary protein impact the gut microbiota composition and microbial metabolites. The source, concentration, and amino acid balance of dietary protein are primary factors which contribute to the composition, structure and function of gut microbes. A suitable ratio between protein and carbohydrate or even a low protein diet is recommended over a diet with protein in excess of requirements. Greater levels and undigested protein lead to an increase of pathogenic microorganism with associated higher risk of metabolic diseases. Herein, the crosstalk between dietary protein and gut microbiota composition and function is summarized, which will help to reveal the potential mechanism of gut microbes on the gastrointestinal tract health.
We examine recent evidence on the consequences of selfishness and otherishness for psychological well-being, physical health, and relationships. In the first sections, we consider recent evidence ...regarding the costs and benefits of giving time, money, and support to others and the costs and benefits of taking or receiving those things from others. Then, because the behaviors of giving and taking can be motivated either by selfish or otherish concerns, we next consider the costs and benefits of the motivation underlying giving and taking. We also examine why and for whom selfishness and otherishness have consequences for psychological well-being, physical health, and relationships. We focus on mechanisms identified in research, including intrapsychic mechanisms such as positive and negative affect, self-esteem and self-efficacy, a sense of meaning and purpose in life, and a sense of connectedness to or isolation from others, as well as interpersonal processes such as reciprocation of support and responsiveness.
Neural KCNQ (Kv7) channels Brown, David A; Passmore, Gayle M
British journal of pharmacology,
April 2009, Letnik:
156, Številka:
8
Journal Article
Recenzirano
Odprti dostop
KCNQ genes encode five Kv7 K+ channel subunits (Kv7.1–Kv7.5). Four of these (Kv7.2–Kv7.5) are expressed in the nervous system. Kv7.2 and Kv7.3 are the principal molecular components of the slow ...voltage‐gated M‐channel, which widely regulates neuronal excitability, although other subunits may contribute to M‐like currents in some locations. M‐channels are closed by receptors coupled to Gq such as M1 and M3 muscarinic receptors; this increases neuronal excitability and underlies some forms of cholinergic excitation. Muscarinic closure results from activation of phospholipase C and consequent hydrolysis and depletion of membrane phosphatidylinositol‐4,5‐bisphosphate, which is required for channel opening. Some effects of M‐channel closure, determined from transmitter action, selective blocking drugs (linopirdine and XE991) and KCNQ2 gene disruption or manipulation, are as follows: (i) in sympathetic neurons: facilitation of repetitive discharges and conversion from phasic to tonic firing; (ii) in sensory nociceptive systems: facilitation of A‐delta peripheral sensory fibre responses to noxious heat; and (iii) in hippocampal pyramidal neurons: facilitation of repetitive discharges, enhanced after‐depolarization and burst‐firing, and induction of spontaneous firing through a reduction of action potential threshold at the axon initial segment. Several drugs including flupirtine and retigabine enhance neural Kv7/M‐channel activity, principally through a hyperpolarizing shift in their voltage gating. In consequence they reduce neural excitability and can inhibit nociceptive stimulation and transmission. Flupirtine is in use as a central analgesic; retigabine is under clinical trial as a broad‐spectrum anticonvulsant and is an effective analgesic in animal models of chronic inflammatory and neuropathic pain.
We study the three dimensional arrangement of young stars in the solar neighbourhood using the second release of the Gaia mission (Gaia DR2) and we provide a new, original view of the spatial ...configuration of the star-forming regions within 500 pc of the Sun. By smoothing the star distribution through a Gaussian filter, we construct three dimensional (3D) density maps for early-type stars (upper-main sequence, UMS) and pre-main sequence (PMS) sources. The PMS and the UMS samples are selected through a combination of photometric and astrometric criteria. A side product of the analysis is a 3D, G-band extinction map, which we use to correct our colour-magnitude diagram for extinction and reddening. Both density maps show three prominent structures, Scorpius-Centaurus, Orion, and Vela. The PMS map shows a plethora of lower-mass star-forming regions, such as Taurus, Perseus, Cepheus, Cassiopeia, and Lacerta, which are less visible in the UMS map due to the lack of large numbers of bright, early-type stars. We report the finding of a candidate new open cluster towards l, b ∼ 218.5° , − 2°, which could be related to the Orion star-forming complex. We estimate ages for the PMS sample and we study the distribution of PMS stars as a function of their age. We find that younger stars cluster in dense, compact clumps, and are surrounded by older sources, whose distribution is instead more diffuse. The youngest groups that we find are mainly located in Scorpius-Centaurus, Orion, Vela, and Taurus. Cepheus, Cassiopeia, and Lacerta are instead more evolved and less numerous. Finally, we find that the 3D density maps show no evidence for the existence of the ring-like structure which is usually referred to as the Gould Belt.
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