In cancer, the programmed death-1 (PD-1) pathway suppresses T cell stimulation and mediates immune escape. Upon stimulation, PD-1 becomes phosphorylated at its immune receptor tyrosine-based ...inhibitory motif (ITIM) and immune receptor tyrosine-based switch motif (ITSM), which then bind the Src homology 2 (SH2) domains of SH2-containing phosphatase 2 (SHP2), initiating T cell inactivation. The SHP2-PD-1 complex structure and the exact functions of the two SH2 domains and phosphorylated motifs remain unknown. Here, we explain the structural basis and provide functional evidence for the mechanism of PD-1-mediated SHP2 activation. We demonstrate that full activation is obtained only upon phosphorylation of both ITIM and ITSM: ITSM binds C-SH2 with strong affinity, recruiting SHP2 to PD-1, while ITIM binds N-SH2, displacing it from the catalytic pocket and activating SHP2. This binding event requires the formation of a new inter-domain interface, offering opportunities for the development of novel immunotherapeutic approaches.
Objective: To examine the potential therapeutic effect of methotrexate 20 mg given weekly as subcutaneous injections to 20 patients with ankylosing spondylitis refractory to non-steriodal ...antirheumatic drugs. Patients and methods: 20 patients with ankylosing spondylitis, a mean Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score of 5.6 (range 4–9.3) and predominantly axial manifestations were treated with weekly 15 mg methotrexate subcutaneously for 4 weeks, which was then increased to 20 mg subcutaneously for the next 12 weeks. Clinical outcome assessments included, among others, BASDAI score physical function, spinal mobility, patients’ and physicians’ global assessment (visual analogue scale), peripheral joint assessment, quality of life (Short Form 36) and C reactive protein. The primary end point of the study was a 20% improvement on the ASsessments in Ankylosing Spondylitis (ASAS 20) scale. Results: Using an intention-to-treat analysis, ASAS 20 was achieved in only 25% of patients. An ASAS 40 response was achieved in 10% of patients, and no patient reached an ASAS 70 response or the ASAS criteria for partial remission. For the mean BASDAI score, no change was observed between baseline and week 16 (baseline 5.6 v week 16, 5.6). No improvement was observed in any of the clinical parameters or C reactive protein, except a small but non-significant decrease in the number of swollen joints. Conclusions: In this open study, methotrexate did not show any benefit for axial manifestations in patients with active ankylosing spondylitis beyond the expected placebo response.
Aims
To investigate the effects of empagliflozin on measured glomerular filtration rate (mGFR), estimated plasma volume (PV) and estimated extracellular volume (ECV) in a cohort of patients with type ...2 diabetes (T2D) and high risk of cardiovascular events.
Materials and Methods
In this prespecified substudy of the randomized, placebo‐controlled SIMPLE trial, patients with T2D at high risk of cardiovascular events were allocated to either empagliflozin 25 mg or placebo once daily for 13 weeks. The prespecified outcome was between‐group change in mGFR, measured by the 51Cr‐EDTA method after 13 weeks; changes in estimated PV and estimated ECV were included.
Results
From April 4, 2017 to May 11, 2020, 91 participants were randomized. Of these, 45 patients from the empagliflozin group and 45 patients from the placebo group were included in the intention‐to‐treat analysis. Treatment with empagliflozin reduced mGFR by −7.9 mL/min (95% confidence interval CI −11.1 to −4.7; P < 0.001), estimated ECV by −192.5 mL (95% CI −318.0 to −66.9; P = 0.003) and estimated PV by −128.9 mL (95% CI −218.0 to 39.8; P = 0.005) at Week 13.
Conclusions
Treatment with empagliflozin for 13 weeks reduced mGFR, estimated ECV and estimated PV in patients with T2D and high risk of cardiovascular events.
ABSTRACT
Blazars research is one of the hot topics of contemporary extragalactic astrophysics. That is because these sources are the most abundant type of extragalactic γ-ray sources and are ...suspected to play a central role in multimessenger astrophysics. We have used Swift$\_$xrtproc, a tool to carry out an accurate spectral and photometric analysis of the Swift-XRT data of all blazars observed by Swift at least 50 times between December 2004 and the end of 2020. We present a database of X-ray spectra, best-fit parameter values, count rates and flux estimations in several energy bands of over 31 000 X-ray observations and single snapshots of 65 blazars. The results of the X-ray analysis have been combined with other multifrequency archival data to assemble the broad-band Spectral Energy Distributions (SEDs) and the long-term light curves of all sources in the sample. Our study shows that large X-ray luminosity variability on different time-scales is present in all objects. Spectral changes are also frequently observed with a ‘harder-when-brighter’ or ‘softer-when-brighter’ behaviour depending on the SED type of the blazars. The peak energy of the synchrotron component (νpeak) in the SED of HBL blazars, estimated from the log-parabolic shape of their X-ray spectra, also exhibits very large changes in the same source, spanning a range of over two orders of magnitude in Mrk421 and Mrk501, the objects with the best data sets in our sample.
Objective
Ectopic accumulation of cardiac adipose tissue volume (CAT) has been associated with cardiac remodelling and cardiac dysfunction in type 2 diabetes and may be a future therapeutic target. ...In this substudy from the SIMPLE‐trial, we investigated short‐term empagliflozin therapy's effects on CAT in patients with type 2 diabetes.
Research design and Methods
Between 4 April 2017 and 11 May 2020, we randomized 90 patients with type 2 diabetes and established or high risk of cardiovascular disease to 25 mg empagliflozin or placebo for 13 weeks. The substudy focused on change in CAT evaluated by images acquired during 82Rubidium‐positron emissions tomography/computed tomography. The analysis included 78 patients who had at least one scan. Furthermore, we report on the relation to the concurrent effects on left ventricular mass, end‐diastolic volume and end‐systolic volume, body composition and glucometabolic status.
Results
Mean ± SD baseline CAT was 258.5 ± 117.9 ml. Empagliflozin reduced CAT after 13 weeks by 12.41 ml 95% CI (−23.83 to −0.99), p = .034 as compared with placebo. Similarly, left ventricular mass −5.16 g, 95% CI (−8.80 to −1.52), p = .006, end‐diastolic volume and end‐systolic volume decreased with empagliflozin. In addition, significant improvements were observed in body composition, with reduced total fat mass, and in measures of glucose and lipid metabolism. However, no correlation was observed between changes in CAT and changes in cardiac parameters and change in CAT appeared mediated primarily by concurrent change in weight.
Conclusions
Empagliflozin provides an early reduction of CAT; however, no association was observed with concurrent changes in cardiac volumetrics.
Punishment and reputation in spatial public goods games Brandt, H.; Hauert, C.; Sigmund, K.
Proceedings - Royal Society. Biological sciences/Proceedings - Royal Society. Biological Sciences,
05/2003, Letnik:
270, Številka:
1519
Journal Article
Recenzirano
Odprti dostop
The puzzle of the emergence of cooperation between unrelated individuals is shared across diverse fields of behavioural sciences and economics. In this article we combine the public goods game ...originating in economics with evolutionary approaches traditionally used in biology. Instead of pairwise encounters, we consider the more complex case of groups of three interacting individuals. We show that territoriality is capable of promoting cooperative behaviour, as in the case of the Prisoner's Dilemma. Moreover, by adding punishment opportunities, the readiness to cooperate is greatly enhanced and asocial strategies can be largely suppressed. Finally, as soon as players carry a reputation for being willing or unwilling to punish, highly cooperative and fair outcomes are achieved. This group-beneficial result is obtained, intriguingly, by making individuals more likely to exploit their co-players if they can get away with it. Thus, less-cooperative individuals make more-cooperative societies.
Early heart failure prevention is central in patients with type 2 diabetes, and mineralocorticoid receptor antagonists (MRAs) have shown to improve prognosis. We investigated the effect of high-dose ...MRA, eplerenone, on cardiac function and structure in patients with type 2 diabetes and established or increased risk of cardiovascular disease but without heart failure.
In the current randomized, placebo-controlled clinical trial, 140 patients with high-risk type 2 diabetes were randomized to high-dose eplerenone (100-200 mg daily) or placebo as add-on to standard care for 26 weeks. Left ventricular systolic and diastolic function, indexed left ventricular mass (LVMi), and global longitudinal strain (GLS) were assessed using echocardiography at baseline and after 26 weeks of treatment.
Of the included patients, 138 (99%) had an echocardiography performed at least once. Baseline early diastolic in-flow velocity (E-wave) indexed by mitral annulus velocity (e') was mean (SD) 11.1 (0.5), with 31% of patients reaching above 12. No effect of treatment on diastolic function was observed measured by E/e' (0.0, 95%CI -1.2 to 1.2, P = 0.992) or E/A (-0.1, 95%CI -0.2 to 0.0, P = 0.191). Mean left ventricular ejection fraction (LVEF) at baseline was 59.0% (8.0). No improvement in systolic function was observed when comparing groups after 26 weeks (LVEF: 0.9, 95%CI -1.1 to 2.8, P = 0.382; GLS: -0.4%, 95%CI -1.5 to 0.6, P = 0.422), nor in LVMi (-3.8 g/m
95%CI -10.2 to 2.7, P = 0.246).
In the present echo sub-study, no change in left ventricular function was observed following high-dose MRA therapy in patients with type 2 diabetes when evaluated by conventional echocardiography.
Date of registration 25/08/2015 (EudraCT number: 2015-002,519-14).
The aim of this study was to investigate activity and rumination time (RT) measured by collar-mounted acceleration and microphone-based technology (HR-Tag monitoring system, SCR Engineers Ltd., ...Netanya, Israel) of dairy cows over the peri-estrus period. The data base consisted of 453 estrous cycles and cows, respectively. To ensure true estrus, only cows with AI leading to conception were included in the study. The reference period was defined as the mean of 3 d prior and 3 d post the day of estrus. With large intra- and inter-individual variation, activity and RT were significantly influenced by cows’ estrus. On the day of estrus, activity behavior was on average increased by 38.7%, whereas data of daily RT were on average reduced by 19.6% (83min/d). The percentage of estrual cows with increased activity was 76.5%. In contrast, 86.2% of all cows showed decreased RT during estrus. Circadian rhythms of activity and RT were bimodal. Cows displaying estrus showed highest activity and lowest RT during the nocturnal and early morning hours between 0200 and 0800h and 0400 and 1000h on the day of estrus. Clear estrus-related deviations from base level were measured much earlier for RT than for activity. Activity behavior tended to be more pronounced in primiparous cows and high-yielding cows (>40kg/d) on the day of estrus compared with multiparous herd mates and cows with lower milk production (≤40kg/d). Rumination time was associated positively with parity and negatively with cows’ milk production on the day of estrus. During the reference period, RT was 384min/d and 443min/d for primiparous and multiparous (>3 lactations) cows and 445min/d and 407min/d for low- and high-yielding cows. Comprehensive knowledge of characteristics indicating estrus is important for improving estrus detection. Further research is recommended to investigate the potential benefit of combining data of activity and RT for practical application in daily herd management.
•Low reproductive performance of cows is still a major problem in dairy farms.•Worldwide, there are severe problems in detection of cows’ estrus.•Estrus can be detected automatically by different traits.•We investigated activity and rumination time of cows in the peri-estrous period.•Increased activity behavior as well as decreased rumination time are found to be indicators of estrus.
A total of 3,050 German Angus (Aberdeen Angus x German dual-purpose breeds), Charolais, Hereford, Limousin, and German Simmental calves were used to examine temperament traits of beef cattle using 2 ...different test procedures. The chute test and the flight-speed test have been validated in terms of routine on-farm applicability. Behavior tests were performed in 2006 and 2007 on 24 commercial beef cattle farms located in the northern and eastern part of Germany. A single, trained observer assigned subjective scores to characterize the behavior of each animal during restraint in the head gate (calm, restless shifting, squirming, vigorous movement, violent struggling) and when leaving the chute (walk, trot, run, jumping out of the chute). Breed was a significant source of variation in chute scores and flight-speed scores (P < 0.001). Charolais and Limousin cattle had the greatest scores in both traits, whereas Herefords had the least (P < 0.001) chute scores. German Angus and Hereford calves had the least (P < 0.001) flight-speeds, indicating that these breeds have a more favorable temperament. Temperament scores differed significantly between male and female calves (P < 0.01), with females scoring better for both traits. Average daily BW gains of the calves were significantly influenced by effects of breed (P < 0.001) and sex (P < 0.001) of the calves. Heritabilities were estimated for chute- and flight-speed scores of beef cattle. They were least for chute score and flight-speed score of Limousin cattle with values of 0.11. In contrast, greatest heritabilities were 0.33 for chute score and 0.36 for flight-speed score of Hereford cattle. Genetic correlations were estimated among both temperament traits, with values between 0.57 and 0.98. Chute scores and visual flight-speed scores were negatively correlated with daily BW gain of the calves in most breeds. The results presented in this paper indicate that on-farm evaluation of beef cattle temperament is possible, either using the chute test or the flight-speed test. Genetic selection seems to be promising to improve temperament traits of beef cattle without decreasing production traits like ADG of the calves.
•Adolescent HPV vaccination in five Southern and Midwestern states remains low.•HPV vaccination hesitancy was associated with a lower likelihood of HPV vaccination initiation.•Having received other ...adolescent vaccines was associated with a higher odds of HPV vaccination.•Gaps remain in HPV vaccination uptake among younger adolescents and male children.
In the United States (US), half of new human papillomavirus (HPV) infections occur among young people aged 15–24 years. Despite the effectiveness of HPV vaccination in protecting against HPV-associated cancers, its coverage among adolescents remains suboptimal. This study examined the association of sociodemographic characteristics and HPV vaccination hesitancy with HPV vaccination coverage in five US states with disproportionately low adolescent coverage rates compared to the national average.
Responses to an online Qualtrics survey from 926 parents of children aged 9–17 years in Arkansas, Mississippi, Missouri, Tennessee, and Southern Illinois in July 2021 were analyzed using multivariate logistic regression to estimate the association of sociodemographic characteristics and HPV vaccination hesitancy with HPV vaccination coverage.
Of the parents, 78 % were female, 76 % were non-Hispanic White, 61.9 % lived in rural areas, 22 % were classified as HPV vaccine hesitant, and 42 % had vaccinated their oldest child between the ages of 9–17 years against HPV. Children of vaccine hesitant parents were less likely to have received any doses of the HPV vaccine than children of non-vaccine hesitant parents (AOR: 0.17, 95 % CI:0.11–0.27). Male children were less likely to have initiated the HPV vaccine series than female children (AOR: 0.70, 95 % CI:0.50–0.97). Older children (13–17 vs 9–12 years), receiving the meningococcal conjugate or most recent seasonal influenza vaccine were all associated with higher likelihoods of receiving any doses of the HPV vaccine (AOR: 6.01, 95 % CI:3.98–9.08; AOR: 2.24, 95 % CI:1.27–3.95; AOR: 2.41, 95 % CI:1.73–3.36, respectively).
Adolescent HPV vaccination coverage remains low in our targeted states. Children’s age, sex, and parental vaccine hesitancy were significantly associated with likelihood of HPV vaccination. These findings offer the opportunity for targeted interventions among parents in regions with low vaccine uptake and underscore the importance of developing and implementing strategies to address parental HPV vaccination hesitancy to improve uptake in the US.
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