The E3 ligase ARIH2 has an unusual structure and mechanism of elongating ubiquitin chains. To understand its physiological role, we generated gene-targeted mice deficient in ARIH2. ARIH2 deficiency ...resulted in the embryonic death of C57BL/6 mice. On a mixed genetic background, the lethality was attenuated, with some mice surviving beyond weaning and then succumbing to an aggressive multiorgan inflammatory response. We found that in dendritic cells (DCs), ARIH2 caused degradation of the inhibitor IκBβ in the nucleus, which abrogated its ability to sequester, protect and transcriptionally coactivate the transcription factor subunit p65 in the nucleus. Loss of ARIH2 caused dysregulated activation of the transcription factor NF-κB in DCs, which led to lethal activation of the immune system in ARIH2-sufficent mice reconstituted with ARIH2-deficient hematopoietic stem cells. Our data have therapeutic implications for targeting ARIH2 function.
Abstract This paper develops efficient preconditioned iterative solvers for incompressible flow problems discretised by an enriched Taylor–Hood mixed approximation, in which the usual pressure space ...is augmented by a piecewise constant pressure to ensure local mass conservation. This enrichment process causes over-specification of the pressure when the pressure space is defined by the union of standard Taylor–Hood basis functions and piecewise constant pressure basis functions, which complicates the design and implementation of efficient solvers for the resulting linear systems. We first describe the impact of this choice of pressure space specification on the matrices involved. Next, we show how to recover effective solvers for Stokes problems, with preconditioners based on the singular pressure mass matrix, and for Oseen systems arising from linearised Navier–Stokes equations, by using a two-stage pressure convection–diffusion strategy. The codes used to generate the numerical results are available online.
New Findings
What is the central question of this study?
The aim of this study was to determine the influence of menstrual phase on flow‐mediated dilatation in response to sustained, exercise‐induced ...increases in shear stress.
What is the main finding and its importance?
We showed, for the first time, that in healthy, premenopausal women the flow‐mediated dilatation stimulated by exercise‐induced increases in shear stress did not fluctuate across two phases of the menstrual cycle, despite significant fluctuations in oestrogen. This suggests that endothelial function is not consistently augmented in the high‐oestrogen phase.
Flow‐mediated dilatation (FMD) in response to a sustained shear‐stress stimulus (e.g. via handgrip exercise; HGEX) is emerging as a useful tool for assessing endothelial function; however, the impact of menstrual phase on HGEX‐FMD is unknown. The purpose of this study was to determine whether HGEX‐FMD fluctuates with cyclical changes in oestrogen concentrations over two discrete phases (low and high oestrogen) of the menstrual cycle. Brachial artery (BA) diameter and blood velocity were assessed with two‐dimesional and Doppler ultrasound, respectively. Shear stress was estimated using shear rate (SR = BA blood velocity/BA diameter). Participants (12 healthy, regularly cycling women, 21 ± 2 years of age) completed two experimental visits: (i) low oestrogen (early follicular, EF); and (ii) high oestrogen (late follicular, LF). Reactive hyperaemia‐stimulated FMD (RH‐FMD) and HGEX‐FMD (6 min of handgrip exercise) were assessed during each visit. Results are mean values ± SD. Oestrogen increased from the EF to LF phase (EF, 33 ± 9 pg ml−1; LF, 161 ± 113 pg ml−1, P = 0.003). However, neither the SR stimuli (HGEX, P = 0.501; RH, P = 0.173) nor the FMD responses differed between phases (EF versus LF: HGEX‐FMD, 4.8 ± 2.8 versus 4.6 ± 2.2%, P = 0.601; RH‐FMD, 7.9 ± 4.3 versus 6.4 ± 3.1%, P = 0.071). These results extend existing RH‐FMD findings indicating that not all women experience fluctuations in FMD with the menstrual cycle. Further research is needed to investigate the mechanisms that underlie variability in the impact of menstrual phase on FMD.
Villus height to crypt depth ratio (Vh:Cd) and intraepithelial lymphocytes (IEL) are key measures of histology of the small intestine in celiac disease. Although the field of celiac disease has ...advanced, there remains no broadly accepted measure of mucosal injury. We assessed whether a composite Vh:Cd and IEL scale (VCIEL) can improve accuracy and statistical precision for assessing histology, compared with individual measures.
The formulation of the VCIEL composite histologic scale was based on combining the Vh:Cd and IEL measurements for individual patients with equal weighting, by converting each scale to a fraction of their standard deviation and summing the results. The VCIEL formula was applied to several clinical trials and the results for Vh:Cd and IEL were compared with those for VCIEL with regards to clinical significance (effect size) and statistical significance.
For the ALV003-1021 trial, we observed an effect size and P value (analysis of covariance) of 1.37 and 0.038 for ΔVh:Cd, 1.17 and 0.005 for ΔIEL, and 1.86 and 0.004 for ΔVCIEL. For the similar gluten-challenge IMGX003-NCCIH-1721 trial, the corresponding results were 0.76 and 0.057 for ΔVh:Cd, 0.98 and 0.018 for ΔIEL, and 1.14 and 0.007 for ΔVCIEL. Similar improvements with the use of VCIEL over individual Vh:Cd and IEL measures were observed for other studies, including a nontherapeutic gluten challenge study.
The composite VCIEL scale combining Vh:Cd and IEL values seems to improve accuracy and statistical precision compared with either component alone.
Background Recent clinical practice guidelines have highlighted the importance of advance care planning (ACP) for improving end-of-life care for people with chronic kidney disease (CKD). Study Design ...We conducted a systematic integrative review of the literature to inform future ACP practice and research in CKD, searching electronic databases in April 2013. Synthesis used narrative methods. Setting & Population We focused on adults with a primary diagnosis of CKD in any setting. Selection Criteria for Studies We included studies of any design, quantitative or qualitative. Interventions ACP was defined as any formal means taken to ensure that health professionals and family members are aware of patients’ wishes for care in the event they become too unwell to speak for themselves. Outcomes Measures of all kinds were considered of interest. Results 55 articles met criteria reporting on 51 discrete samples. All patient samples included people with CKD stage 5; 2 also included patients with stage 4. Seven interventions were tested; all were narrowly focused and none was evaluated by comparing wishes for end-of-life care with care received. One intervention demonstrated effects on patient and family outcomes in the form of improved well-being and anxiety following sessions with a peer mentor. Insights from qualitative studies that have not been used to inform interventions include the importance of instilling patient confidence that their advance directives will be enacted and discussing decisions about (dis)continuing dialysis therapy separately from “aggressive” life-sustaining treatments (eg, ventilation). Limitations Although quantitative and qualitative findings were integrated according to best practice, methods for this are in their infancy. Conclusions Research on ACP in patients with CKD is limited, especially intervention studies. Interventions in CKD should attend to barriers and facilitators at the levels of patient, caregiver, health professional, and system. Intervention studies should measure impact on compliance with patient wishes for end-of-life care.
This paper is concerned with the implementation of efficient solution algorithms for elliptic problems with constraints. We establish theory which shows that including a simple scaling within ...well-established block diagonal preconditioners for Stokes problems can result in significantly faster convergence when applying the preconditioned MINRES method. The codes used in the numerical studies are available online.
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