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Mucosal antigen-specific CD4 T-cell responses to intestinal pathogens remain incompletely understood. Here we examined the CD4 T-cell response after oral infection with an internalin A ‘murinized’ Listeria monocytogenes (Lm). Oral Lm infection induced a robust endogenous listeriolysin O (LLO)-specific CD4 T-cell response with distinct phenotypic and functional characteristics in the intestine. Circulating LLO-specific CD4 T cells transiently expressed the ‘gut-homing’ integrin α4β7 and accumulated in the intestinal lamina propria and epithelium where they were maintained independent of interleukin (IL)-15. The majority of intestinal LLO-specific CD4 T cells were CD27− Ly6C− and CD69+ CD103− while the lymphoid LLO-specific CD4 T cells were heterogeneous based on CD27 and Ly6C expression and predominately CD69−. LLO-specific effector CD4 T cells transitioned into a long-lived memory population that phenotypically resembled their parent effectors and displayed hallmarks of residency. In addition, intestinal effector and memory CD4 T cells showed a predominant polyfunctional Th1 profile producing IFNγ, TNFα, and IL-2 at high levels with minimal but detectable levels of IL-17A. Depletion of CD4 T cells in immunized mice led to elevated bacterial burden after challenge infection highlighting a critical role for memory CD4 T cells in controlling intestinal intracellular pathogens.

Plant roots contain both high- and low-affinity transport systems for uptake of K+ from the soil. In this study, we characterize a K+ transporter that functions in both high- and low-affinity uptake. Using yeast complementation analysis, we isolated a cDNA for a functional K+ transporter from Arabidopsis (referred to as AtKUP1 for Arabidopsis thaliana K+ uptake). When expressed in a yeast mutant, AtKUP1 dramatically increased K+ uptake capacity at both a low and high [K+] range. Kinetic analyses showed that AtKUP1-mediated K+ uptake displays a \"biphasic\" pattern similar to that observed in plant roots. The transition from the high-affinity phase (Km of 44 micromolars) to the low-affinity phase (Km of 11 mM) occurred at 100 to 200 micromolars external K+. Both low- and high-affinity K+ uptake via AtKUP1 were inhibited by 5 mM or higher concentrations of NaCl. In addition, AtKUP1-mediated K+ uptake was inhibited by K+ channel blockers, including tetraethylammonium, Cs+, and Ba2+. Consistent with a possible function in K+ uptake from the soil, the AtKUP1 gene is primarily expressed in roots. We conclude that the AtKUP1 gene product may function as a K+ transporter in Arabidopsis roots over a broad range of [K+] in the soil

Protein tyrosine kinases and phosphatases play a vital role in the regulation of cell growth and differentiation in animal systems. However, none of these enzymes has been characterized from higher plants. In this study, we isolated a cDNA encoding a putative protein tyrosine phosphatase (PTPase) from Arabidopsis (referred to as AtPTP1). The expression level of AtPTP1 is highly sensitive to environmental stresses. High-salt conditions increased AtPTP1 mRNA levels, whereas cold treatment rapidly eliminated the AtPTP1 transcript. The recombinant AtPTP1 protein specifically hydrolyzed phosphotyrosine, but not phosphoserine/threonine, in protein substrates. Site-directed mutagenesis defined two highly conserved amino acids, cysteine-265 and aspartate-234, as being essential for the phosphatase activity of the AtPTP1 protein, suggesting a common catalytic mechanism for PTPases from all eukaryotic systems. In summary, we have identified AtPTP1 as a tyrosine-specific protein phosphatase that may function in stress responses of higher plants

Three different glucagon-like peptide-1 (GLP-1) receptor agonists reduce cardiovascular outcomes in people with type 2 diabetes at high cardiovascular risk with high glycated haemoglobin A1c (HbA1c) concentrations. We assessed the effect of the GLP-1 receptor agonist dulaglutide on major adverse cardiovascular events when added to the existing antihyperglycaemic regimens of individuals with type 2 diabetes with and without previous cardiovascular disease and a wide range of glycaemic control. This multicentre, randomised, double-blind, placebo-controlled trial was done at 371 sites in 24 countries. Men and women aged at least 50 years with type 2 diabetes who had either a previous cardiovascular event or cardiovascular risk factors were randomly assigned (1:1) to either weekly subcutaneous injection of dulaglutide (1·5 mg) or placebo. Randomisation was done by a computer-generated random code with stratification by site. All investigators and participants were masked to treatment assignment. Participants were followed up at least every 6 months for incident cardiovascular and other serious clinical outcomes. The primary outcome was the first occurrence of the composite endpoint of non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes (including unknown causes), which was assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01394952. Between Aug 18, 2011, and Aug 14, 2013, 9901 participants (mean age 66·2 years [SD 6·5], median HbA1c 7·2% [IQR 6·6–8·1], 4589 [46·3%] women) were enrolled and randomly assigned to receive dulaglutide (n=4949) or placebo (n=4952). During a median follow-up of 5·4 years (IQR 5·1–5·9), the primary composite outcome occurred in 594 (12·0%) participants at an incidence rate of 2·4 per 100 person-years in the dulaglutide group and in 663 (13·4%) participants at an incidence rate of 2·7 per 100 person-years in the placebo group (hazard ratio [HR] 0·88, 95% CI 0·79–0·99; p=0·026). All-cause mortality did not differ between groups (536 [10·8%] in the dulaglutide group vs 592 [12·0%] in the placebo group; HR 0·90, 95% CI 0·80–1·01; p=0·067). 2347 (47·4%) participants assigned to dulaglutide reported a gastrointestinal adverse event during follow-up compared with 1687 (34·1%) participants assigned to placebo (p<0·0001). Dulaglutide could be considered for the management of glycaemic control in middle-aged and older people with type 2 diabetes with either previous cardiovascular disease or cardiovascular risk factors. Eli Lilly and Company.

The q 95 window for Type-I edge localized modes (ELMs) suppression using n  = 4 even parity resonant magnetic perturbations (RMPs) has been significantly expanded to the ranges [3.9, 4.1] and [4.2, 4.8] in EAST while maintaining good confinement, which is demonstrated to be reliable and repeatable over the last two years. This window is significantly wider than the previous one achieved using n  = 4 odd parity RMPs, which is around q 95 = 3.7 ± 0.1 . Here, n represents the toroidal mode number of the applied RMPs and q 95 is the safety factor at 95 % of the normalized poloidal magnetic flux. During ELM suppression, there is only a slight drop in the plasma stored energy and density ( ⩽ 10 % ). The comparison of changes in the pedestal profiles suggests that ELM suppression is achieved when the pedestal gradient is kept lower than a threshold. This wide q 95 window for ELM suppression is consistent with the prediction made by MARS-F modeling prior to the experiment, which located it at one of the resonant q 95 windows for plasma response. The Chirikov parameter taking into account plasma response near the pedestal top, which measures plasma edge stochasticity, significantly increases when q 95 exceeds 4, mainly due to the denser neighboring rational surfaces. The modeling of plasma response reveals a strong coupling between resonant and non-resonant components across the pedestal region, which is a characteristic of the kink-peeling like response observed during RMP-ELM suppression in previous studies on EAST. These promising results demonstrate the reliability of ELM suppression using the n  = 4 RMPs in EAST and expand the physical understanding on ELM suppression mechanism.

Two glucagon-like peptide-1 (GLP-1) receptor agonists reduced renal outcomes in people with type 2 diabetes at risk for cardiovascular disease. We assessed the long-term effect of the GLP-1 receptor agonist dulaglutide on renal outcomes in an exploratory analysis of the REWIND trial of the effect of dulaglutide on cardiovascular disease. REWIND was a multicentre, randomised, double-blind, placebo-controlled trial at 371 sites in 24 countries. Men and women aged at least 50 years with type 2 diabetes who had either a previous cardiovascular event or cardiovascular risk factors were randomly assigned (1:1) to either weekly subcutaneous injection of dulaglutide (1·5 mg) or placebo and followed up at least every 6 months for outcomes. Urinary albumin-to-creatinine ratios (UACRs) and estimated glomerular filtration rates (eGFRs) were estimated from urine and serum values measured in local laboratories every 12 months. The primary outcome (first occurrence of the composite endpoint of non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes), secondary outcomes (including a composite microvascular outcome), and safety outcomes of this trial have been reported elsewhere. In this exploratory analysis, we investigate the renal component of the composite microvascular outcome, defined as the first occurrence of new macroalbuminuria (UACR >33·9 mg/mmol), a sustained decline in eGFR of 30% or more from baseline, or chronic renal replacement therapy. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01394952. Between Aug 18, 2011, and Aug 14, 2013, 9901 participants were enrolled and randomly assigned to receive dulaglutide (n=4949) or placebo (n=4952). At baseline, 791 (7·9%) had macroalbuminuria and mean eGFR was 76·9 mL/min per 1·73 m2 (SD 22·7). During a median follow-up of 5·4 years (IQR 5·1–5·9) comprising 51 820 person-years, the renal outcome developed in 848 (17·1%) participants at an incidence rate of 3·5 per 100 person-years in the dulaglutide group and in 970 (19·6%) participants at an incidence rate of 4·1 per 100 person-years in the placebo group (hazard ratio [HR] 0·85, 95% CI 0·77–0·93; p=0·0004). The clearest effect was for new macroalbuminuria (HR 0·77, 95% CI 0·68–0·87; p<0·0001), with HRs of 0·89 (0·78–1·01; p=0·066) for sustained decline in eGFR of 30% or more and 0·75 (0·39–1·44; p=0·39) for chronic renal replacement therapy. Long-term use of dulaglutide was associated with reduced composite renal outcomes in people with type 2 diabetes. Eli Lilly and Company.

A Single Nucleotide Polymorphism in MGEA5 Encoding O-GlcNAc–selective N -Acetyl-β- d Glucosaminidase Is Associated With Type 2 Diabetes in Mexican Americans Donna M. Lehman 1 , Dong-Jing Fu 2 , Angela B. Freeman 2 , Kelly J. Hunt 1 , Robin J. Leach 3 4 , Teresa Johnson-Pais 4 , Jeanette Hamlington 1 , Thomas D. Dyer 5 , Rector Arya 1 , Hanna Abboud 1 , Harald H.H. Göring 6 , Ravindranath Duggirala 6 , John Blangero 6 , Robert J. Konrad 5 and Michael P. Stern 1 1 Department of Medicine, University of Texas Health Science Center, San Antonio, Texas 2 Lilly Research Laboratories, Indianapolis, Indiana 3 Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, Texas 4 Department of Pediatrics, University of Texas Health Science Center, San Antonio, Texas 5 Department of Genetics, Southwest Foundation for Biomedical Research, San Antonio, Texas 6 Department of Nephrology, University of Texas Health Science Center, San Antonio, Texas Address correspondence and reprint requests to Donna M. Lehman, Department of Medicine/Clinical Epidemiology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr., San Antonio, Texas 78229. E-mail: lehman{at}uthscsa.edu Abstract Excess O-glycosylation of proteins by O-linked β- N -acetylglucosamine (O-GlcNAc) may be involved in the pathogenesis of type 2 diabetes. The enzyme O-GlcNAc–selective N -acetyl-β- d glucosaminidase (O-GlcNAcase) encoded by MGEA5 on 10q24.1-q24.3 reverses this modification by catalyzing the removal of O-GlcNAc. We have previously reported the linkage of type 2 diabetes and age at diabetes onset to an overlapping region on chromosome 10q in the San Antonio Family Diabetes Study (SAFADS). In this study, we investigated menangioma-expressed antigen-5 (MGEA5) as a positional candidate gene. Twenty-four single nucleotide polymorphisms (SNPs), identified by sequencing 44 SAFADS subjects, were genotyped in 436 individuals from 27 families whose data were used in the original linkage report. Association tests indicated significant association of a novel SNP with the traits diabetes ( P = 0.0128, relative risk = 2.77) and age at diabetes onset ( P = 0.0017). The associated SNP is located in intron 10, which contains an alternate stop codon and may lead to decreased expression of the 130-kDa isoform, the isoform predicted to contain the O-GlcNAcase activity. We investigated whether this variant was responsible for the original linkage signal. The variance attributed to this SNP accounted for ∼25% of the logarithm of odds. These results suggest that this variant within the MGEA5 gene may increase diabetes risk in Mexican Americans. LD, linkage disequilibrium LOD, logarithm of odds MGEA5, menangioma-expressed antigen-5 O-GlcNAc, O-linked β-N-acetylglucosamine O-GlcNAcase, O-GlcNAc–selective N-acetyl-β-d glucosaminidase SAFADS, San Antonio Family Diabetes Study SNP, single nucleotide polymorphism Footnotes Additional information for this article can be found in an online appendix at http://diabetes.diabetesjournals.org . Accepted December 9, 2004. Received September 30, 2004. DIABETES

For aerosol retrieval from multi-angle polarimetric (MAP) measurements over the ocean it is important to accurately account for the contribution of the ocean-body to the top-of-atmosphere signal, especially for wavelengths <500 nm. Performing online radiative transfer calculations in the coupled atmosphere ocean system is too time consuming for operational retrieval algorithms. Therefore, mostly lookup-tables of the ocean body reflection matrix are used to represent the lower boundary in an atmospheric radiative transfer model. For hyperspectral measurements such as those from Spectro-Polarimeter for Planetary Exploration (SPEXone) on the NASA Plankton, Aerosol, Cloud and ocean Ecosystem (PACE) mission, also the use of look-up tables is unfeasible because they will become too big. In this paper, we propose a new method for aerosol retrieval over ocean from MAP measurements using a neural network (NN) to model the ocean body reflection matrix. We apply the NN approach to synthetic SPEXone measurements and also to real data collected by SPEX airborne during the Aerosol Characterization from Polarimeter and Lidar (ACEPOL) campaign. We conclude that the NN approach is well capable for aerosol retrievals over ocean, introducing no significant error on the retrieved aerosol properties

Background: The stability of Alzheimer’s disease (AD) biomarkers in plasma, measured by immunomagnetic reduction (IMR) after long-term storage at –80°C, has not been established before. Method: Ninety-nine human plasma samples from 53 normal controls (NCs), 5 patients with amnestic mild cognitive impairment (aMCI), and 41 AD patients were collected. Each plasma sample was aliquoted and stored as single-use aliquots at –80°C. The baseline measurements for Aβ 1–40 , Aβ 1–42 , and total Tau protein (T-Tau) concentrations for each sample were done within 3 months of blood draw by IMR. They are referred to as baseline concentrations. A separate aliquot from each sample was assayed with IMR to assess the stability of the measured analytes during storage at –80°C between 1.1 and 5.4 years. This is referred to as a repeated result. Results: IMR shows that plasma levels of Aβ 1–40 and Aβ 1–42 exhibit stability over 5-year storage at –80°C and that plasma levels of T-Tau are less stable (approximately 1.5 years). Conclusion: Although the measured concentrations of T-Tau in human plasma may alter during storage, the diagnostic utility of the results are only slightly affected when the product of Aβ 1–42 and T-Tau concentrations are used. The results show that the overall agreement between baseline and repeated measurements in the ability of discriminating NCs from aMCI/AD patients is higher than 80%.

Effects of tempering temperature on the microstructures and low temperature impact toughness of 42CrMo4-V steel were investigated. Microstructures of 42CrMo4-V steel after tempering at 570–720 °C for 3 h were experimentally investigated using scanning electron microscopy (SEM), electron back-scattered diffraction (EBSD), transmission electron microscopy (TEM) and X-ray diffraction (XRD). The results showed that the carbide precipitation sequence of 42CrMo4-V steel is M8C7 → M3C and the absorbed energies of 42CrMo4-V steel increase greatly from 21.7 J to 132.3 J with increasing tempering temperature from 570 °C to 720 °C. The changes of impact toughness with increasing tempering temperature were attributed to the softening of matrix, the evolution of carbide precipitates and grain structures.