Inhibition of the NLRP3 inflammasome is a promising strategy for the development of new treatments for inflammatory diseases. MCC950 is a potent and specific small-molecule inhibitor of the NLRP3 ...pathway, but its molecular target is not defined. Here, we show that MCC950 directly interacts with the Walker B motif within the NLRP3 NACHT domain, thereby blocking ATP hydrolysis and inhibiting NLRP3 activation and inflammasome formation.
The gateway for invasion by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into human host cells is via the angiotensin-converting enzyme 2 (ACE2) transmembrane receptor ...expressed in multiple immune and nonimmune cell types. SARS-CoV-2, that causes coronavirus disease 2019 (COVID-19; CoV-19) has the unusual capacity to attack many different types of human host cells simultaneously via novel clathrin- and caveolae-independent endocytic pathways, becoming injurious to diverse cells, tissues and organ systems and exploiting any immune weakness in the host. The elicitation of this multipronged attack explains in part the severity and extensive variety of signs and symptoms observed in CoV-19 patients. To further our understanding of the mechanism and pathways of SARS-CoV-2 infection and susceptibility of specific cell- and tissue-types and organ systems to SARS-CoV-2 attack in this communication we analyzed ACE2 expression in 85 human tissues including 21 different brain regions, 7 fetal tissues and 8 controls. Besides strong ACE2 expression in respiratory, digestive, renal-excretory and reproductive cells, high ACE2 expression was also found in the amygdala, cerebral cortex and brainstem. The highest ACE2 expression level was found in the pons and medulla oblongata in the human brainstem, containing the medullary respiratory centers of the brain, and may in part explain the susceptibility of many CoV-19 patients to severe respiratory distress.
High surface area porous n-type WO3 electrodes were prepared electrochemically and used as a photoanode in a water-splitting photoelectrochemical cell. Various electrolytes containing different ...anions (acetate, chloride, phosphate, perchlorate, and sulfate) and cations (Li+, Na+, and K+) were prepared at pH 1, 3, and 5 to investigate how these anions and cations affect the efficiency of the photo-oxidation reaction of water on the WO3 surface. To quantitatively compare their effects on O2 evolution, photocurrent to oxygen conversion efficiency was obtained for each electrolyte by simultaneously measuring photocurrent and O2 produced in a sealed divided cell. The type of competing reactions present in each electrolyte and their effects on water oxidation to O2 or to hydrogen peroxide, which is known to accumulate on the WO3 surface and cause photocorrosion, were investigated. The results reported in this study will be useful in formulating optimum electrolyte compositions to enhance desired photo-oxidation reactions for various photoelectrochemical cells.
The intent of this paper is to address the obesity epidemic, which is a term used to describe the sudden and rapid increase in obesity rates that began in the 1980s and continues unabated today. ...Since 1980, the entire population, regardless of starting weight, is gradually gaining weight. This has led to escalating obesity rates and to obesity being considered one of the most serious public health challenges facing the world. At one level, the obesity epidemic is a classic gene-environment interaction where the human genotype is susceptible to environmental influences that affect energy intake and energy expenditure. It is also a problem of energy balance. Understanding the etiology of obesity requires the study of how behavioral and environmental factors have interacted to produce positive energy balance and weight gain. Reversing the epidemic of obesity will require modifying some combination of these factors to help the population achieve energy balance at a healthy body weight. While body weight is strongly influenced by biological and behavioral factors, changes in the environment promoting positive energy balance have been most responsible for the obesity epidemic. Our best strategy for reversing the obesity epidemic is to focus on preventing positive energy balance in the population through small changes in diet and physical activity that take advantage of our biological systems for regulating energy balance. Simultaneously, we must address the environment to make it easier to make better food and physical activity choices. This is a very long-term strategy for first stopping and then reversing the escalating obesity rates, but one that can, over time, return obesity rates to pre-1980s levels.
Electrochemical synthesis methods were developed to produce CuBi2O4, a promising p-type oxide for use in solar water splitting, as high surface area electrodes with uniform coverage. These methods ...involved electrodepositing nanoporous Cu/Bi films with a Cu:Bi ratio of 1:2 from dimethyl sulfoxide or ethylene glycol solutions, and thermally oxidizing them to CuBi2O4 at 450 °C in air. Ag-doped CuBi2O4 electrodes were also prepared by adding a trace amount of Ag+ in the plating medium and codepositing Ag with the Cu/Bi films. In the Ag-doped CuBi2O4, Ag+ ions substitutionally replaced Bi3+ ions and increased the hole concentration in CuBi2O4. As a result, photocurrent enhancements for both O2 reduction and water reduction were achieved. Furthermore, while undoped CuBi2O4 electrodes suffered from anodic photocorrosion during O2 reduction due to poor hole transport, Ag-doped CuBiO4 effectively suppressed anodic photocorrosion. The flat-band potentials of CuBi2O4 and Ag-doped CuBi2O4 electrodes prepared in this study were found to be more positive than 1.3 V vs RHE in a 0.1 M NaOH solution (pH 12.8), which make these photocathodes highly attractive for use in solar hydrogen production. The optimized CuBi2O4/Ag-doped CuBi2O4 photocathode showed a photocurrent onset for water reduction at 1.1 V vs RHE, achieving a photovoltage higher than 1 V for water reduction. The thermodynamic feasibility of photoexcited electrons in the conduction band of CuBi2O4 to reduce water was also confirmed by detection of H2 during photocurrent generation. This study provides new understanding for constructing improved CuBi2O4 photocathodes by systematically investigating photocorrosion as well as photoelectrochemical properties of high-quality CuBi2O4 and Ag-doped CuBi2O4 photoelectrodes for photoreduction of both O2 and water.
Target identification is a high-priority, albeit challenging, aspect of drug discovery. Diazirine-based photoaffinity probes (PAPs) can facilitate the process by covalently capturing transient ...molecular interactions. This can help identify target proteins and map the ligand’s interactome. Diazirine probes have even been incorporated by cellular machinery into proteins. Embarking on the synthesis of customized PAPs, containing either an aliphatic or trifluoromethyl phenyl diazirine, can be a considerable endeavor, particularly for medicinal chemists and chemical biologists new to the field. This review takes a synthetic focus, aiming to summarize available routes, propose new avenues, and illuminate recent advances in diazirine synthesis. Select examples of diazirine photoaffinity labeling applications have been included throughout to provide instructive definition of the advantages and limitations of the technology while simultaneously highlighting how these reagents can be applied in a practical sense.
Creek Internationalism in an Age of Revolution, 1763-1818
examines how Creek communities and their leaders remained viable
geopolitical actors in the trans-Appalachian West well after the
American ...Revolution. The Creeks pursued aggressive and far-reaching
diplomacy between 1763 and 1818 to assert their territorial and
political sovereignty while thwarting American efforts to establish
control over the region. The United States and the Creeks fought to
secure recognition from the powers of Europe that would guarantee
political and territorial sovereignty: the Creeks fought to
maintain their connections to the Atlantic world and preserve their
central role in the geopolitics of the trans-Appalachian West,
while the American colonies sought first to establish themselves as
an independent nation, then to expand borders to secure diplomatic
and commercial rights. Creeks continued to forge useful ties with
agents of European empires despite American attempts to
circumscribe Creek contact with the outside world. The Creeks'
solicitation of trade and diplomatic channels with British and
Spanish colonists in the West Indies, Canada, and various Gulf
Coast outposts served key functions for defenders of local
autonomy. Native peoples fought to preserve the geopolitical order
that dominated the colonial era, making the trans-Appalachian West
a kaleidoscope of sovereign peoples where negotiation prevailed. As
a result, the United States lacked the ability to impose its will
on its Indigenous neighbors, much like the European empires that
had preceded them. Hill provides a significant revisionist history
of Creek diplomacy and power that fills gaps within the broader
study of the Atlantic world and early American history to show how
Indigenous power thwarted European empires in North America.
The continued rise in obesity rates in most countries suggests that current programs and initiatives designed to combat obesity have not been successful in reversing the obesity epidemic. Obesity ...rates are increasing because of a gradual weight gain in most populations. There has been little long-term success in treating established obesity through lifestyle change, perhaps because of the large permanent changes in diet and physical activity required to keep weight off. An alternative strategy to address the obesity epidemic involves not focusing on weight loss but promoting small changes in diet and physical activity to initially prevent further weight gain. With the use of this strategy, obesity rates could first be stabilized in most populations and then, over time, decrease gradually. Supporting data show that small reductions in conscious energy intake and increases in physical activity can reduce excessive weight gain. The opportunity exists to use the small-changes approach to bring different stakeholders together to create a national initiative to address the global epidemic of obesity. The Joint Task Force of the American Society for Nutrition, Institute of Food Technologists, and International Food Information Council believe that a small-changes framework, aimed at helping people make conscious small changes in lifestyle behaviors, in combination with efforts by the private sector to gradually “ratchet down” some of the environmental factors that have contributed to excessive energy intake and the declining rates of physical activity, can be successful in reducing obesity rates. Such an initiative would benefit from the support of educational and social marketing campaigns developed with governmental input and support.
Energy Balance and Obesity HILL, James O; WYATT, Holly R; PETERS, John C
Circulation,
07/2012, Letnik:
126, Številka:
1
Journal Article
Recenzirano
Odprti dostop
This paper describes the interplay among energy intake, energy expenditure and body energy stores and illustrates how an understanding of energy balance can help develop strategies to reduce obesity. ...First, reducing obesity will require modifying both energy intake and energy expenditure and not simply focusing on either alone. Food restriction alone will not be effective in reducing obesity if human physiology is biased toward achieving energy balance at a high energy flux (i.e. at a high level of energy intake and expenditure). In previous environments a high energy flux was achieved with a high level of physical activity but in today's sedentary environment it is increasingly achieved through weight gain. Matching energy intake to a high level of energy expenditure will likely be more a more feasible strategy for most people to maintain a healthy weight than restricting food intake to meet a low level of energy expenditure. Second, from an energy balance point of view we are likely to be more successful in preventing excessive weight gain than in treating obesity. This is because the energy balance system shows much stronger opposition to weight loss than to weight gain. While large behavior changes are needed to produce and maintain reductions in body weight, small behavior changes may be sufficient to prevent excessive weight gain. In conclusion, the concept of energy balance combined with an understanding of how the body achieves balance may be a useful framework in helping develop strategies to reduce obesity rates.
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