Explore the vast range of titles available.

Inflammasomes are multiprotein complexes that orchestrate proinflammatory cytokine secretion and cell death. Proteases such as anthrax lethal factor can activate an inflammasome known as NLRP1B, but the mechanism for this activation has been unclear. Chui et al. used genome-wide knockout screens to show that proteolysis of NLRP1B by lethal factor induces proteasomal degradation of the amino-terminal domains of NLRP1B and eventual cell death. Sandstrom et al. found that degradation of the amino-terminal domains of NLRP1B resulted in the release of a carboxyl-terminal fragment that activates caspase-1. This process, called “functional degradation,” allows the immune system to detect pathogen-associated activities, much as it recognizes pathogen-associated antigens. Science , this issue p. 82 , p. eaau1330 Pathogen-associated proteasomal degradation is detected by innate immune sensor NLRP1B. Inflammasomes are multiprotein platforms that initiate innate immunity by recruitment and activation of caspase-1. The NLRP1B inflammasome is activated upon direct cleavage by the anthrax lethal toxin protease. However, the mechanism by which cleavage results in NLRP1B activation is unknown. In this study, we find that cleavage results in proteasome-mediated degradation of the amino-terminal domains of NLRP1B, liberating a carboxyl-terminal fragment that is a potent caspase-1 activator. Proteasome-mediated degradation of NLRP1B is both necessary and sufficient for NLRP1B activation. Consistent with our functional degradation model, we identify IpaH7.8, a Shigella flexneri ubiquitin ligase secreted effector, as an enzyme that induces NLRP1B degradation and activation. Our results provide a unified mechanism for NLRP1B activation by diverse pathogen-encoded enzymatic activities.

Ion-beam-induced luminescence (IBIL) measurements were performed in Cr-doped β -Ga 2 O 3 using both protons and helium ions, showing a strong enhancement of the Cr 3+ luminescence upon ion irradiation. Theoretical modelling of the IBIL intensity curves as a function of the fluence allowed estimating the effective cross-sections associated with the defect-induced IBIL enhancement and quenching processes. The results suggest that sensitizing the Cr 3+ luminescence is more efficient for H + than for He + irradiation. Thermoluminescence (TL) studies were performed in the pristine sample, with no TL signal being observed in the spectral region corresponding to the Cr 3+ emission. In agreement with the IBIL study, upon ion irradiation (with either protons or helium ions), this TL emission is activated. Moreover, it can be quenched by annealing at 923 K for 10 s, thus revealing the role played by the defects induced by the irradiation. These results show that the irradiation-induced defects play a major role in the activation of the Cr 3+ luminescence, a fact that can be exploited for radiation sensing and dosimetry.

Motor neurons (MNs) die in amyotrophic lateral sclerosis (ALS), a clinically heterogeneous neurodegenerative disease of unknown etiology. In human or rodent studies, MN loss is preceded by increased excitability. As increased neuronal excitability correlates with structural changes in dendritic arbors and spines, we have examined longitudinal changes in dendritic structure in vulnerable neuron populations in a mouse model of familial ALS. We used a modified Golgi-Cox staining method to determine the progressive changes in dendritic structure of hippocampal CA1 pyramidal neurons, striatal medium spiny neurons, and resistant (trochlear, IV) or susceptible (hypoglossal, XII; lumbar) MNs from brainstem and spinal cord of mice over-expressing the human SOD1 (SOD1) mutation, in comparison to wild-type (WT) mice, at four postnatal (P) ages of 8-15, 28-35, 65-75, and 120 days. In SOD1 mice, dendritic changes occur at pre-symptomatic ages in both XII and spinal cord lumbar MNs. Spine loss without dendritic changes was present in striatal neurons from disease onset. Spine density increases were present at all ages studied in SOD1 XII MNs. Spine density increased in neonatal lumbar MNs, before decreasing to control levels by P28-35 and was decreased by P120. SOD1 XII MNs and lumbar MNs, but not trochlear MNs showed vacuolization from the same time-points. Trochlear MN dendrites were unchanged. Dendritic structure and spine alterations correlate with the neuro-motor phenotype in ALS and with cognitive and extra-motor symptoms seen in patients. Prominent early changes in dendritic arbors and spines occur in susceptible cranial and spinal cord MNs, but are absent in MNs resistant to loss in ALS.

High-temperature confocal scanning laser microscopy (HT-CSLM) is a potent methodology for investigating various phenomena in the field of metallurgy. Initially applied to the observation of solid phase transformations and solidification, this method has gained traction in the field of non-metallic inclusion in steels in recent years. An overview of the experimental capabilities of HT-CSLM and the most important results of recent investigations regarding the topics of clean steel production are provided. It includes the formation of intragranular acicular ferrite (IAF) from the surface of non-metallic inclusions during the continuous cooling and heat treatment, which can be especially beneficial in the toughness of heat-affected zones of welded pieces. Furthermore, the investigation of agglomeration mechanisms of non-metallic inclusions (NMIs) in liquid steel is discussed to improve the insight into attraction forces between particles and clogging phenomena during continuous casting. Also, the dissolution of NMIs in various steelmaking slags can be observed by HT-CSLM to compare dissolution rates and mechanisms of NMI, where significant influences of temperature and chemical composition of the slag were shown. Last but not least, the experimental work regarding the interface between steel and slag is discussed, where novel techniques are currently being developed. A comprehensive summary of experimental techniques using HT-CSLM equipment to investigate different interactions of NMIs with steel and slag phases is compiled.

Holonomic quantum computing offers a promising paradigm for quantum computation due to its error resistance and the ability to perform universal quantum computations. Here, we propose a scheme for the rapid implementation of a holonomic swap gate in neutral atomic systems, based on the selective Rydberg pumping mechanism. By employing time-dependent soft control, we effectively mitigate the impact of off-resonant terms even at higher driving intensities compared to time-independent driving. This approach accelerates the synthesis of logic gates and passively reduces the decoherence effects. Furthermore, by introducing an additional atom and applying the appropriate driving field, our scheme can be directly extended to implement a three-qubit controlled-swap gate. This advancement makes it a valuable tool for quantum state preparation, quantum switches, and a variational quantum algorithm in neutral atom systems.

This paper aims to analyze and identify the purchase behavior and preferences of 976 Chinese wine consumers, especially to explore the differences in consumers’ demographics, purchase behaviors, recognition about wine, based on a price segmentation of High, Moderate, and Low Spenders. For this study, price segmentation was defined as the price typically paid for a bottle (750ml) of wine for daily drinking at home. Signi?cant differences among the three segments were discovered based on income, educational background, job category, purchasing places, favorite brands and recognition about importance of wine attributes. Little previous research on market segmentation by price has been conducted about Chinese wine market. This study provides a new thought into market segmentation and may assist with relative study.

The modern diet has become highly sweetened, resulting in unprecedented levels of sugar consumption, particularly among adolescents. While chronic long-term sugar intake is known to contribute to the development of metabolic disorders including obesity and type II diabetes, little is known regarding the direct consequences of long-term, binge-like sugar consumption on the brain. Because sugar can cause the release of dopamine in the nucleus accumbens (NAc) similarly to drugs of abuse, we investigated changes in the morphology of neurons in this brain region following short- (4 weeks) and long-term (12 weeks) binge-like sucrose consumption using an intermittent two-bottle choice paradigm. We used Golgi-Cox staining to impregnate medium spiny neurons (MSNs) from the NAc core and shell of short- and long-term sucrose consuming rats and compared these to age-matched water controls. We show that prolonged binge-like sucrose consumption significantly decreased the total dendritic length of NAc shell MSNs compared to age-matched control rats. We also found that the restructuring of these neurons resulted primarily from reduced distal dendritic complexity. Conversely, we observed increased spine densities at the distal branch orders of NAc shell MSNs from long-term sucrose consuming rats. Combined, these results highlight the neuronal effects of prolonged binge-like intake of sucrose on NAc shell MSN morphology.

Insulin resistance, a hallmark of type 2 diabetes, is associated with oxidative stress. However, the role of reactive oxygen species or specific antioxidant enzymes in its development has not been tested under physiological conditions. The objective of our study was to investigate the impact of overexpression of glutathione peroxidase 1 (GPX1), an intracellular selenoprotein that reduces hydrogen peroxide ( H2O2) in vivo, on glucose metabolism and insulin function. The GPX1-overexpressing (OE) and WT male mice (n = 80) were fed a selenium-adequate diet (0.4 mg/kg) from 8 to 24 weeks of age. Compared with the WT, the OE mice developed (P < 0.05) hyperglycemia (117 vs. 149 mg/dl), hyperinsulinemia (419 vs. 1,350 pg/ml), and elevated plasma leptin (5 vs. 16 ng/ml) at 24 weeks of age. Meanwhile, these mice were heavier (37 vs. 27 g, P < 0.001) and fatter (37% vs. 17% fat, P < 0.01) than the WT mice. At 30-60 min after an insulin challenge, the OE mice had 25% less (P < 0.05) of a decrease in blood glucose than the WT mice. Their insulin resistance was associated with a 30-70% reduction (P < 0.05) in the insulin-stimulated phosphorylations of insulin receptor (β-subunit) in liver and Akt ( Ser473and Thr308) in liver and soleus muscle. Here we report the development of insulin resistance in mammals with elevated expression of an antioxidant enzyme and suggest that increased GPX1 activity may interfere with insulin function by overquenching intracellular reactive oxygen species required for insulin sensitizing.

Purpose Elderly melanoma patients are known to have lower survival rates than younger patients with melanoma. Paradoxically, a few recent studies have shown a lower frequency of sentinel lymph node (SLN) positivity in older individuals. This is the first analysis of a large national sample to examine the relationship between SLN metastasis and melanoma death across all age groups. Methods The U.S. Surveillance Epidemiology and End Results (SEER) Databases were queried to examine SLN biopsy and mortality outcomes in 158,813 melanoma cases reported from 2003 to 2011, the most current data available in SEER. Results In bivariate analyses of the 47,577 cases with coded tumor depths and nodal surgery, increasing age varied directly with melanoma death and inversely with SLN positivity, for tumor depths >1 mm ( P  < 0.001). In multivariate regression analyses, 60–79 year-olds were more likely to die of melanoma compared with 20–39 year-olds [odds ratio (OR) 1.83, 95 % confidence interval (CI) 1.64–2.05], but they were less likely to be SLN-positive (OR 0.62, 95 % CI 0.57–0.68). The inverse association between melanoma mortality and SLN positivity was most pronounced at the extremes of age. Discussion The finding that increasing age is associated with a higher incidence of melanoma death but a lower incidence of SLN metastasis highlights the need for further study into age-related differences in melanoma biology, immunological surveillance, and host response. It also questions whether the 5- and 10-year survival rates associated with the current melanoma staging system should be stratified by age to predict outcomes more accurately for melanoma patients.

Fourier transform infrared (FTIR) imaging and microspectroscopy have been extensively applied in the identification and investigation of both healthy and diseased tissues. FTIR imaging can be used to determine the biodistribution of several molecules of interest (carbohydrates, lipids, proteins) for tissue analysis, without the need for prior staining of these tissues. Molecular structure data, such as protein secondary structure and collagen triple helix exhibits, can also be obtained from the same analysis. Thus, several histopathological lesions, for example myocardial infarction, can be identified from FTIR-analyzed tissue images, the latter which can allow for more accurate discrimination between healthy tissues and pathological lesions. Accordingly, we propose FTIR imaging as a new tool integrating both molecular and histopathological assessment to investigate the degree of pathological changes in tissues. In this study, myocardial infarction is presented as an illustrative example of the wide potential of FTIR imaging for biomedical applications.