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The epithelial Na+ channel (ENaC) located at the apical membrane in many epithelia is the rate-limiting step for Na+ reabsorption. Tight regulation of the plasma membrane population of ENaC is required, as hypertension or hypotension may result if too many or too few ENaCs are present. Endocytosed ENaC travels to the early endosome and is then either trafficked to the lysosome for degradation or recycled back to the plasma membrane. Recently, the retromer recycling complex, located at the early endosome, has been implicated in plasma membrane protein recycling pathways. We hypothesized that the retromer is required for recycling of ENaC. Stabilization of retromer function with the retromer stabilizing chaperone R55 increased ENaC current, whereas knockdown or overexpression of individual retromer and associated proteins altered ENaC current and cell surface population of ENaC. KIBRA was identified as an ENaC-binding protein allowing ENaC to link to sorting nexin 4 to alter ENaC trafficking. Knockdown of the retromer-associated cargo-binding sorting nexin 27 protein did not alter ENaC current, whereas CCDC22, a CCC-complex protein, coimmunoprecipitated with ENaC, and CCDC22 knockdown decreased ENaC current and population at the cell surface. Together, our results confirm that retromer and the CCC complex play a role in recycling of ENaC to the plasma membrane.

CARF (Collaborator of ARF) was discovered as an ARF-interacting protein that activated ARF-p53-p21(WAF1) signaling involved in cellular response to a variety of stresses, including oxidative, genotoxic, oncogenic, or telomere deprotection stresses, leading to senescence, growth arrest, or apoptosis. Of note, whereas suppression of CARF was lethal, its enrichment was associated with increased proliferation and malignant transformation of cells. These reports have predicted that CARF could serve as a multi-stress marker with a predictive value for cell fates. Here, we recruited various in vitro stress models and examined their effect on CARF expression using human normal fibroblasts. We demonstrate that CARF levels in stress and post-stress conditions could predict the fate of cells towards either death or enhanced proliferation and malignant transformation. We provide extensive molecular evidence that (i) CARF expression changes in response to stress, (ii) it modulates cell death or survival signaling and determines the fate of cells, and (iii) it may serve as a predictive measure of cellular response to stress and an important marker for biosafety. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s12192-020-01088-y) contains supplementary material, which is available to authorized users.

Renal Na+reabsorption, facilitated by the epithelial Na+channel (ENaC), is subject to multiple forms of control to ensure optimal body blood volume and pressure through altering both the ENaC population and activity at the cell surface. Here, the focus is on regulating the number of ENaCs present in the apical membrane domain through pathways of ENaC synthesis and targeting to the apical membrane as well as ENaC removal, recycling, and degradation. Finally, the mechanisms by which ENaC trafficking pathways are regulated are summarized.

Explore the feasibility, tolerability, and early efficacy of transcranial direct current stimulation (tDCS) as a therapeutic intervention for youth with cognitive persistent post-concussion symptoms (PPCS).tDCS improves performance on a dual task working memory (WM) paradigm in youth with cognitive PPCS.Twelve youth experiencing cognitive PPCS.A quasi-randomized pilot trial was used to explore the tolerability of, and performance differences on, a dual N-Back WM task paired with active or sham tDCS over 3 sessions.Accuracy and reaction time on WM task and self-report of tDCS tolerability.Trends toward increases in accuracy from Day 1 to 3 seen in both groups. Active tDCS group performed better than sham on Day 2 in N-Back level N2 (p = .019), and marginally better than the sham group on Day 3 in level N3 (p = .26). Participants reported tDCS as tolerable; compared to the active tDCS group, the sham group reported more "considerable" (p = .078) and "strong" symptoms (p = .097).tDCS is a promising tool for enhancing WM performance and is a feasible and tolerable adjunct to behavioral interventions in youth with cognitive PPCS. A clinical trial to demonstrate efficacy is warranted.

The accurate prediction of malignancy for a pelvic mass detected on ultrasound allows for appropriate referral to specialised care. IOTA simple rules are one of the best methods but are inconclusive in 25% of cases, where subjective assessment by an expert sonographer is recommended but may not always be available. In the present paper, we evaluate the methods for assessing the nature of a pelvic mass, including IOTA with subjective assessment by expert ultrasound, RMI and ROMA. In particular, we investigate whether ROMA can replace expert ultrasound when IOTA is inconclusive. This prospective study involves one cancer centre and three general units. Women scheduled for an operation for a pelvic mass underwent a pelvic ultrasound pre-operatively. The final histology was obtained from the operative sample. The sensitivity, specificity and accuracy for each method were compared with the McNemar test. Of the 690 women included in the study, 171 (25%) had an inconclusive IOTA. In this group, expert ultrasound was more sensitive in diagnosing a malignant mass compared to ROMA (81% vs. 63%, p = 0.009) with no significant difference in the specificity or accuracy. All assessment methods involving IOTA had similar accuracies and were more accurate than RMI or ROMA alone. In conclusion, when IOTA was inconclusive, assessment by expert ultrasound was more sensitive than ROMA, with similar specificity.

Objectives This study explored whether the excess cardiovascular (CV) disease (CVD) risk in RA could be ameliorated by suppression of inflammation using a treat-to-target (T2T) approach. We compared the CV event (CVE) incidence among ERA patients managed by a T2T strategy with a CV risk factor-matched non-RA population and a historical RA cohort (HRA). Methods This was an observational study using the city-wide hospital data and the ERA registry. ERA patients received T2T management while HRA patients received routine care. Each ERA/HRA patient was matched to three non-RA controls according to age, gender and CV risk factors. Patients on antiplatelet/anticoagulant agents, with pre-existing CVD, chronic kidney disease or other autoimmune diseases were excluded. All subjects were followed for up to 5 years. The primary end point was the first occurrence of a CVE. Results The incidence of CVE in the ERA cohort (n = 261) and ERA controls were similar with a hazard ratio of 0.53 (95% CI 0.15, 1.79). In contrast, the incidence of CVE in the HRA cohort (n = 268) was significantly higher than that of the HRA controls with a hazard ratio of 1.9 (95% CI 1.16, 3.13). The incidence of CVE in the ERA cohort was significantly lower than that of the HRA cohort and the difference became insignificant after adjusting for inflammation, the use of methotrexate and traditional CV risk factors. Conclusion ERA patients managed by a T2T strategy did not develop excess CVE compared with CV risk factor-matched controls over 5 years.

Deep hypothermic perfusionless circulatory arrest was the first practical neuroprotective technique used for open-heart surgery. It was refined at the Novosibirsk Medical Research Center in Siberia and was actively used from the mid-1950s until 2001.This review describes the development of this technique and its contribution to our understanding of the dynamic changes in human physiology during induced hypothermia for circulatory arrest without extracorporeal perfusion. Deep hypothermic perfusionless circulatory arrest was an important stepping stone in the development of modern approaches in neuroprotection and monitoring during cardiac surgery.

Copyright © 2021 The Author(s). Purpose This study translated the reaction to impairment and disability inventory (RIDI) to Chinese and validated it for use in Hong Kong. Methods We conducted an instrument validation of the Chinese RIDI, with a sample of 244 persons with CID. The research questionnaire collected demographic information, illness-related variables, the Chinese version of RIDI (C-RIDI), and measures of resilience and well-being. We examined the factor structure, internal consistency, convergent validity, and criterion-related validity of the C-RIDI. Results The C-RIDI has good content validity and no major changes to the translated items were needed for the use in Hong Kong. For factor structure, we replicated the results of Livneh et al. The C-RIDI has two second-order factors of adaptive and nonadaptive scales, which interact with the two denial subscales. Internal consistency of the subscales is satisfactory except for the three-item denial subscales. Correlations of the C-RIDI subscales with illness-related variables, resilience, and mental well-being are consistent with our hypotheses and provide support for the convergent and criterion-related validity of the scale. Conclusions The C-RIDI has satisfactory psychometric properties. The study results support its internal consistency, convergent validity, criterion-related validity, and factorial validity. IMPLICATIONS FOR REHABILITATION Emotional adjustment to chronic illness and disability is a key determinant of illness self-management, mental well-being, and quality of life. The study translated the reaction to impairment and disability inventory into Chinese and conducted a psychometric evaluation of the translated instrument. The Chinese RIDI had a similar second-order factor structure as in the validation studies of the English version, and result of this confirmatory factor analysis support the theory underlying the design of the RIDI. The Chinese RIDI had satisfactory convergent and criterion-related validity and internal consistency, and is ready for application in rehabilitation practice and research in the Chinese context. Faculty of Health and Social Sciences, The Hong Kong Polytechnic University (Project No. P0001302).

Introduction: Obesity is a public health crisis in the USA. This study aimed to estimate the prevalence of obesity and severe obesity in US children and adolescents and identify novel targetable risk factors associated with childhood obesity. Methods: From the US National Health and Nutrition Examination Survey from 1999 to 2018, 35,907 children aged 2–19 with body mass index (BMI) data were included. Obesity and severe obesity were defined as BMI ≥95th percentile and ≥120% of 95th percentile of US Centers for Disease Control and Prevention growth charts, respectively. Trends in the prevalence of obesity and subgroup analyses according to socioeconomic factors and language used in the interview were analyzed. Results: The prevalence of obesity and severe obesity increased from 14.7 [95% confidence interval: 12.9–17.0]% to 19.2 [17.2–21.0]% and 3.9 [2.9–5.0]% to 6.1 [4.8–8.0]% in 1999–2018, respectively (p = 0.001 and p = 0.014, respectively). In 2017–2018, the prevalence of obesity among children from Spanish-speaking households was 24.4 [22.4–27.0]%, higher than children from English-speaking households (p = 0.027). Conclusion: The prevalence of childhood obesity kept increasing in 1999–2018. The problem is worse in children from Spanish-speaking households. Novel and targeted public health intervention strategies are urgently warranted to effectively halt the rising epidemic of childhood obesity.

A robust association between dispositional envy and happiness was primarily concluded among young adults. As social contexts can vary across developmental stages, the effect of dispositional envy may be enhanced or diminished in different age groups. Thus, the present research attempted to quantify the differential associations between dispositional envy and happiness among adolescents and young adults (N = 586). Moreover, we examined another important question of why the association differed across the two age groups. Using mediated moderation analysis, we found a stronger association between dispositional envy and happiness among young adults than adolescents. We also revealed that self-esteem was a valid mechanism to unpack the differential associations across two age groups.

A bioorthogonal reaction between N,N -dialkylhydroxylamines and push-pull-activated halogenated alkynes is described. We explore the use of rehybridization effects in activating alkynes, and we show that electronic effects, when competing stereoelectronic and inductive factors are properly balanced, sufficiently activate a linear alkyne in the uncatalyzed conjugative retro-Cope elimination reaction while adequately protecting it against cellular nucleophiles. This design preserves the low steric profile of an alkyne and pairs it with a comparably unobtrusive hydroxylamine. The kinetics are on par with those of the fastest strain-promoted azide-alkyne cycloaddition reactions, the products regioselectively formed, the components sufficiently stable and easily installed, and the reaction suitable for cellular labeling.

Background: Economic evidence for vitiligo treatments is absent. Objectives: To determine the cost-effectiveness of (i) handheld narrowband ultraviolet B (NB-UVB) and (ii) a combination of topical corticosteroid (TCS) and NB-UVB compared with TCS alone for localized vitiligo. Methods: Cost-effectiveness analysis alongside a pragmatic, three-arm, placebo-controlled randomized controlled trial with 9 months’ treatment. In total 517 adults and children (aged ≥ 5 years) with active vitiligo affecting < 10% of skin were recruited from secondary care and the community and were randomized 1: 1: 1 to receive TCS, NB-UVB or both. Cost per successful treatment (measured on the Vitiligo Noticeability Scale) was estimated. Secondary cost–utility analyses measured quality-adjusted life-years using the EuroQol 5 Dimensions 5 Levels for those aged ≥ 11 years and the Child Health Utility 9D for those aged 5 to < 18 years. The trial was registered with number ISRCTN17160087 on 8 January 2015. Results: The mean ± SD cost per participant was £775 ± 83·7 for NB-UVB, £813 ± 111.4 for combination treatment and £600 ± 96·2 for TCS. In analyses adjusted for age and target patch location, the incremental difference in cost for combination treatment compared with TCS was £211 (95% confidence interval 188–235), corresponding to a risk difference of 10·9% (number needed to treat = 9). The incremental cost was £1932 per successful treatment. The incremental difference in cost for NB-UVB compared with TCS was £173 (95% confidence interval 151–196), with a risk difference of 5·2% (number needed to treat = 19). The incremental cost was £3336 per successful treatment. Conclusions: Combination treatment, compared with TCS alone, has a lower incremental cost per additional successful treatment than NB-UVB only. Combination treatment would be considered cost-effective if decision makers are willing to pay £1932 per additional treatment success.

Supplemental material, sj-docx-2-hpq-10.1177_1359105321990806 for Relationships between resilience and quality of life in parents of children with cancer by Y. H. Luo, W. H. C. Li, A. T. Cheung, L. L. K. Ho, W. Xia, X. L. He, J. P. Zhang and J. O. K. Chung in Journal of Health Psychology

Supplemental material, sj-docx-3-hpq-10.1177_1359105321990806 for Relationships between resilience and quality of life in parents of children with cancer by Y. H. Luo, W. H. C. Li, A. T. Cheung, L. L. K. Ho, W. Xia, X. L. He, J. P. Zhang and J. O. K. Chung in Journal of Health Psychology

Additional file 1 STROBE Statement, Checklist of items that should be included in reports of cross-sectional studies.

Background: In vivo characterization of mitral valve dynamics relies on image analysis algorithms that accurately reconstruct valve morphology and motion from clinical images. The goal of such algorithms is to provide patient-specific descriptions of both competent and regurgitant mitral valves, which can be used as input to biomechanical analyses and provide insights into the pathophysiology of diseases like ischemic mitral regurgitation (IMR). Objective: The goal is to generate accurate image-based representations of valve dynamics that visually and quantitatively capture normal and pathological valve function. Methods: We present a novel framework for 4D segmentation and geometric modeling of the mitral valve in real-time 3D echocardiography (rt-3DE), an imaging modality used for pre-operative surgical planning of mitral interventions. The framework integrates groupwise multi-atlas label fusion and template-based medial modeling with Kalman filtering to generate quantitatively descriptive and temporally consistent models of valve dynamics. Results: The algorithm is evaluated on rt-3DE data series from 28 patients: 14 with normal mitral valve morphology and 14 with severe IMR. In these 28 data series that total 613 individual 3DE images, each 3D mitral valve segmentation is validated against manual tracing, and temporal consistency between segmentations is demonstrated. Conclusions: Automated 4D image analysis allows for reliable non-invasive modeling of the mitral valve over the cardiac cycle for comparison of annular and leaflet dynamics in pathological and normal mitral valves. Future studies can apply this algorithm to cardiovascular mechanics applications, including patient-specific strain estimation, fluid dynamics simulation, inverse finite element analysis, and risk stratification for surgical treatment.

Supplemental material, sj-pdf-6-hpq-10.1177_1359105321990806 for Relationships between resilience and quality of life in parents of children with cancer by Y. H. Luo, W. H. C. Li, A. T. Cheung, L. L. K. Ho, W. Xia, X. L. He, J. P. Zhang and J. O. K. Chung in Journal of Health Psychology

Supplemental material, sj-doc-1-hpq-10.1177_1359105321990806 for Relationships between resilience and quality of life in parents of children with cancer by Y. H. Luo, W. H. C. Li, A. T. Cheung, L. L. K. Ho, W. Xia, X. L. He, J. P. Zhang and J. O. K. Chung in Journal of Health Psychology

The anesthetic and perioperative management of patients with acute aortic dissection is important for achieving successful outcomes. Because early mortality is contingent on the time to definitive treatment, open communication between the admitting, surgical, and anesthesia teams is necessary to safely expedite the management of patients with life-threatening complications such as aortic regurgitation, cardiac tamponade, or malperfusion who require emergency operation. The wide availability of intraoperative transesophageal echocardiography (TEE) has enabled aortic dissection to be diagnosed or confirmed in the operating room. TEE can also diagnose complications associated with acute aortic dissection, identify the location of the intimal tear, characterize the extent of the dissection or guide central cannulation for cardiopulmonary bypass. During operations on the thoracic aorta, the brain, spinal cord, and end-organs require protection during periods of ischemia. Postoperative intensive care is necessary for temporary mechanical ventilatory support and circulation management with vasoactive medications. In addition, lung injury, acute kidney injury, encephalopathy, bleeding, mesenteric ischemia, limb ischemia, and metabolic acidosis are common problems that require critical care after operations for acute aortic dissection.

Tumor hypoxia induces the large-scale adaptive reprogramming of cancer cells, promoting their transformation into highly invasive and metastatic species that lead to highly negative prognoses for cancer patients. We describe the synthesis and application of a hypoxia-responsive trigger derived from previously inaccessible enamine N-oxide structures. Hypoxia-dependent reduction of this motif by hemeproteins results in the concomitant activation of a caged molecule and a latent electrophile. We exploit the former in a hypoxia-activated prodrug application using a caged staurosporine molecule as a proof-of-principle. We demonstrate the latter in in vivo tumor labeling applications with enamine-N-oxide-modified near-infrared probes. Hypoxia-activated prodrug development has long been complicated by the heterogeneity of tumor hypoxia in patients. The dual drug release and imaging modalities of the highly versatile enamine N-oxide motif present an attractive opportunity for theranostic development that can address the need not only for new therapeutics but paired methods for patient stratification., We describe a hypoxia-sensitive chemical motif that can be incorporated into prodrugs and imaging agents with potential application to the treatment and diagnosis of tumors featuring poor oxygenation.

Aortic arch surgery requires obligatory alteration or cessation of blood flow to the brain and the rest of the body to accomplish the repair. The successful outcome of operations involving the aortic arch is largely dependent on effective strategies for neuroprotection. Neuroprotective strategies include deliberate hypothermia, neurocirculatory management, and surgical techniques. These strategies are often used together and no single approach has been proven to be superior. Considerations for neuroprotection include pathophysiology of brain injury, rewarming and protection of system organs, and intraoperative monitoring. Postoperative complications can include neurologic complications, bleeding, malperfusion, and renal injury.

Spinal cord ischemia, spinal cord infarction, and paraplegia remain an important complication of patients undergoing open surgical or endovascular repair of the thoracic and thoracoabdominal aorta. Improvements in surgical techniques such as endovascular repair, partial left heart bypass, reimplantation of segmental arteries, and staged repairs combined with anesthetic techniques that include arterial pressure augmentation, deliberate hypothermia, lumbar cerebrospinal fluid drainage, and intraoperative neurophysiologic monitoring has decreased the risk of intraoperative spinal cord ischemia. Despite improvements, patients remain at risk for delayed onset spinal cord ischemia. Serial neurologic assessment and precise circulatory management are necessary to prevent and detect delayed onset spinal cord ischemia. Immediate treatment of delayed onset spinal cord ischemia with arterial pressure augmentation and lumbar cerebrospinal fluid drainage is often effective for preventing paraplegia or decreasing the severity of the permanent neurologic injury in patients with reversible ischemic spinal cord syndrome.

Adult neurogenesis is modulated by many Gi-coupled receptors but the precise mechanism remains elusive. A key step for maintaining the population of neural stem cells in the adult is asymmetric cell division (ACD), a process which entails the formation of two evolutionarily conserved protein complexes that establish the cell polarity and spindle orientation. Since ACD is extremely difficult to monitor in stratified tissues such as the vertebrate brain, we employed human neural progenitor cell lines to examine the regulation of the polarity and spindle orientation complexes during neuronal differentiation. Several components of the spindle orientation complex, but not those of the polarity complex, were upregulated upon differentiation of ENStem-A and ReNcell VM neural progenitor cells. Increased expression of nuclear mitotic apparatus (NuMA), G&alpha, i subunit, and activators of G protein signaling (AGS3 and LGN) coincided with the appearance of a neuronal marker (&beta, III tubulin) and the concomitant loss of neural progenitor cell markers (nestin and Sox-2). Co-immunoprecipitation assays demonstrated that both G&alpha, i3 and NuMA were associated with AGS3 in differentiated ENStem-A cells. Interestingly, AGS3 appeared to preferentially interact with G&alpha, i3 in ENStem-A cells, and this specificity for G&alpha, i3 was recapitulated in co-immunoprecipitation experiments using HEK293 cells transiently overexpressing GST-tagged AGS3 and different G&alpha, i subunits. Moreover, the binding of G&alpha, i3 to AGS3 was suppressed by GTP&gamma, S and pertussis toxin. Disruption of AGS3/G&alpha, i3 interaction by pertussis toxin indicates that AGS3 may recognize the same site on the G&alpha, subunit as G protein-coupled receptors. Regulatory mechanisms controlling the formation of spindle orientation complex may provide novel means to manipulate ACD which in turn may have an impact on neurogenesis.

Stratified teaching is an effective method and means to implement teaching students per their aptitude. Domestic and foreign scholars have carried out many experimental and quasi-experimental studies to observe the impact of stratified teaching on students’ academic performance, but the results are quite different. So, can stratified teaching effectively help Chinese students improve their academic performance? How big is its impact? Which model is more suitable for Chinese students? To answer these questions, this article uses meta-analysis to quantitatively analyze 22 Chinese studies on the impact of Stratified teaching on student academic performance. We found that (i) stratified teaching has a positive effect on students’ academic performance, and the overall combined effect size is 0.53; (ii) among the seven subjects of mathematics, English, physics, chemistry, biology, geography, and information technology, stratified teaching has had a positive effect on their learning. Stratified teaching’s order of effect on different subjects was English > Physics > Geography > Information Technology > Mathematics > Biology > Chemistry; (iii) stratified teaching is suitable for students of different sizes of classrooms. However, the smaller the number of students in the classroom, the better the learning effect, and (iv) stratified teaching is more suitable for improving their learning in the mobile learning system.

Background: Evidence for the effectiveness of vitiligo treatments is limited. Objectives: To determine the effectiveness of (i) handheld narrowband UVB (NB-UVB) and (ii) a combination of potent topical corticosteroid (TCS) and NB-UVB, compared with TCS alone, for localized vitiligo. Methods: A pragmatic, three-arm, placebo-controlled randomized controlled trial (9-month treatment, 12-month follow-up). Adults and children, recruited from secondary care and the community, aged ≥ 5 years and with active vitiligo affecting

At which phase(s) does task demand affect object processing? Previous studies showed that task demand affects object representations in higher-level visual areas but not so much in earlier areas. There are, however, limitations in those studies concerning the relatively weak manipulation of task due to the use of familiar real-life objects, and/or the low temporal resolution in brain activation measures such as fMRI. In the current study, observers categorized images of artificial objects in one of two orthogonal dimensions, shape and texture. Electroencephalogram (EEG), a technique with higher temporal resolution, and multivariate pattern analysis (MVPA) were employed to reveal object processing across time under different task demands. Results showed that object processing along the task-relevant dimension was enhanced starting from a relatively late time (~230ms after image onset), within the time range of the event-related potential (ERP) components N170 and N250. The findings are consistent with the view that task exerts an effect on object processing at the later phases of processing in the ventral visual pathway.

Absolute pitch (AP) refers to labelling individual pitches in the absence of external reference. A widely endorsed theory regards AP as a privileged ability enjoyed by selected few with rare genetic makeup and musical training starting in early childhood. However, recent evidence showed that even adults can learn AP, and some can attain a performance level comparable to natural AP possessors. These training studies involved native tonal language speakers, whose acquisition of AP might be facilitated by tonal language exposure during early childhood. In this study, adults speaking non-tonal languages went through AP training that was 20-hr long, computerised and personalised. Performance on average improved, which was accompanied by enhanced working memory for tones, whereas relative pitch judgement and sensitivity to small pitch differences remained unchanged. Notably, two out of 13 learned to label all 12 pitches within an octave, with accuracy and response time comparable to natural AP possessors. Overall, the findings suggest that tonal language exposure is not a prerequisite for AP learning in adulthood. The understanding of the origin of AP would benefit from considering the role of lifelong learning instead of focusing only on early childhood experience.

The anti-inflammatory actions of interleukin-10 (IL10) are thought to be mediated primarily by the STAT3 transcription factor, but pro-inflammatory cytokines such as interleukin-6 (IL6) also act through STAT3. We now report that IL10, but not IL6 signaling, induces formation of a complex between STAT3 and the inositol polyphosphate-5-phosphatase SHIP1 in macrophages. Both SHIP1 and STAT3 translocate to the nucleus in macrophages. Remarkably, sesquiterpenes of the Pelorol family we previously described as allosteric activators of SHIP1 phosphatase activity, could induce SHIP1/STAT3 complex formation in cells, and mimic the anti-inflammatory action of IL10 in a mouse model of colitis. Using crystallography and docking studies we identified a drug-binding pocket in SHIP1. Our studies reveal new mechanisms of action for both STAT3 and SHIP1, and provide a rationale for use of allosteric SHIP1-activating compounds which mimic the beneficial anti-inflammatory actions of IL10.