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Mitochondrial transcription factor A (TFAM) controls the transcription of core proteins required for mitochondrial homeostasis. This study was undertaken to investigate changes in TFAM expression in systemic sclerosis (SSc), to analyze mitochondrial function, and to evaluate the consequences for fibroblast activation.TFAM expression was analyzed by immunofluorescence and Western blotting. The effects of TFAM knockout were investigated in cultured fibroblasts and in murine models of bleomycin-induced skin fibrosis, bleomycin-induced lung fibrosis, and skin fibrosis induced by overexpression of constitutively active transforming growth factor β type I receptor (TGFβRΙ).TFAM expression was down-regulated in fibroblasts in SSc skin and in cultured SSc fibroblasts. The down-regulation of TFAM was associated with decreased mitochondrial number and accumulation of damaged mitochondria with release of mitochondrial DNA (mtDNA), accumulation of deletions in mtDNA, metabolic alterations with impaired oxidative phosphorylation, and release of the mitokine GDF15. Normal fibroblasts subjected to long-term, but not acute, exposure to TGFβ mimicked SSc fibroblasts, with down-regulation of TFAM and accumulation of mitochondrial damage. Down-regulation of TFAM promoted fibroblast activation with up-regulation of fibrosis-relevant Gene Ontology terms in RNA-Seq, partially in a reactive oxygen species-dependent manner. Mice with fibroblast-specific knockout of Tfam were prone to fibrotic tissue remodeling, with fibrotic responses even to NaCl instillation and enhanced sensitivity to bleomycin injection and overexpression of constitutively active TGFβRI. TFAM knockout fostered Smad3 signaling to promote fibroblast activation.Alterations in the key mitochondrial transcription factor TFAM in response to prolonged activation of TGFβ and associated mitochondrial damage induce transcriptional programs that promote fibroblast-to-myofibroblast transition and drive tissue fibrosis.

ObjectivePathologically activated circulating immune cells, including monocytes, play major roles in systemic sclerosis (SSc). Their functional characterization can provide crucial information with direct clinical relevance. However, tools for the evaluation of pathologic immune cell activation and, in general, of clinical outcomes in SSc are scarce. Biophysical phenotyping (including characterization of cell mechanics and morphology) provides access to a novel, mostly unexplored layer of information regarding pathophysiologic immune cell activation. We hypothesized that the biophysical phenotyping of circulating immune cells, reflecting their pathologic activation, can be used as a clinical tool for the evaluation and risk stratification of patients with SSc.MethodsWe performed biophysical phenotyping of circulating immune cells by real-time fluorescence and deformability cytometry (RT-FDC) in 63 SSc patients, 59 rheumatoid arthritis (RA) patients, 28 antineutrophil cytoplasmic antibody–associated vasculitis (AAV) patients, and 22 age- and sex-matched healthy donors.ResultsWe identified a specific signature of biophysical properties of circulating immune cells in SSc patients that was mainly driven by monocytes. Since it is absent in RA and AAV, this signature reflects an SSc-specific monocyte activation rather than general inflammation. The biophysical properties of monocytes indicate current disease activity, the extent of skin or lung fibrosis, and the severity of manifestations of microvascular damage, as well as the risk of disease progression in SSc patients.ConclusionChanges in the biophysical properties of circulating immune cells reflect their pathologic activation in SSc patients and are associated with clinical outcomes. As a high-throughput approach that requires minimal preparations, RT-FDC–based biophysical phenotyping of monocytes can serve as a tool for the evaluation and risk stratification of patients with SSc.

Test-retest reliability — establishing that measurements remain consistent across multiple testing sessions — is critical to measuring, understanding, and predicting individual differences in infant language development. However, previous attempts to establish measurement reliability in infant speech perception tasks are limited, and reliability of frequently-used infant measures is largely unknown. The current study investigated the test-retest reliability of infants’ preference for infant-directed speech (hereafter, IDS) over adult-directed speech (hereafter, ADS) in a large sample (N=158) in the context of the ManyBabies1 collaborative research project (hereafter, MB1; Frank et al., 2017; ManyBabies Consortium, 2020). Labs of the original MB1 study were asked to bring in participating infants for a second appointment retesting infants on their IDS preference. This approach allows us to estimate test-retest reliability across three different methods used to investigate preferential listening in infancy: the head-turn preference procedure, central fixation, and eye-tracking. Overall, we find no consistent evidence of test-retest reliability in measures of infants’ speech preference (overall r = .09, 95% CI [-.06,.25]). While increasing the number of trials that infants needed to contribute for inclusion in the analysis revealed a numeric growth in test-retest reliability, it also considerably reduced the study’s effective sample size. Therefore, future research on infant development should take into account that not all experimental measures may be appropriate for assessing individual differences between infants.

Pathologically activated circulating immune cells, including monocytes, play major roles in systemic sclerosis (SSc). Their functional characterization can provide crucial information with direct clinical relevance. However, tools for evaluation of pathologic immune cell activation and, in general, of clinical outcomes in SSc are scarce. Biophysical phenotyping (including characterization of cell mechanics and morphology) provides access to a novel, mostly unexplored layer of information regarding physio-pathological immune cell activation. We hypothesized that the biophysical phenotyping of circulating immune cells, reflecting their pathologic activation, can be used as a clinical tool in SSc.We performed biophysical phenotyping of circulating immune cells by real-time fluorescence and deformability cytometry (RT-FDC) in 63 SSc patients, 59 rheumatoid arthritis (RA) patients, 28 ANCA-associated vasculitis (AAV) patients and 22 age- and sex-matched healthy donors.We identified a specific signature of biophysical properties of circulating immune cells in SSc mainly driven by monocytes. Since it is absent in RA and AAV, this signature reflects an SSc-specific monocyte activation rather than general inflammation. The biophysical properties of monocytes indicate current disease activity, the extent of skin or lung fibrosis and the severity of manifestations of microvascular damage, as well as the risk of disease progression in SSc.Changes in biophysical properties of circulating immune cells reflect their pathologic activation in SSc and are associated with clinical outcomes. As a high throughput approach that requires minimal preparations, RT-FDC-based biophysical phenotyping of monocytes can serve as a tool for evaluation and risk stratification of patients with SSc.

The chaperone protein calsperin is exclusively expressed in the testes and is essential for sperm migration from the uterus into the oviduct. During spermatogenesis, calsperin interacts with ADAM3, a spermatozoon membrane protein required for fertilization. In this study, we characterized a calsperin epitope by using two monoclonal antibodies and resin-bound calsperin peptides, which were tested for reactivity using a modified enzyme-linked immunosorbent assay. An epitope located at the C-terminal end of calsperin corresponding to amino acids

Summary Background Interstitial lung disease (ILD) is the most common cause of death in systemic sclerosis. To date, the progression of systemic sclerosis-associated ILD is judged by the accrual of lung damage on CT and pulmonary function tests. However, diagnostic tools to assess disease activity are not available. Here, we tested the hypothesis that quantification of fibroblast activation by PET-CT using a 68Ga-labelled selective inhibitor of prolyl endopeptidase FAP (68Ga-FAPI-04) would correlate with ILD activity and disease progression in patients with systemic sclerosis-associated ILD. Methods Between Sept 10, 2018, and April 8, 2020, 21 patients with systemic sclerosis-associated ILD confirmed by high-resolution CT (HRCT) within 12 months of inclusion and with onset of systemic sclerosis-associated ILD within 5 years or signs of progressive ILD and 21 controls without ILD were consecutively enrolled. All participants underwent 68Ga-FAPI-04 PET-CT imaging and standard-of-care procedures, including HRCT and pulmonary function tests at baseline. Patients with systemic sclerosis-associated ILD were followed for 6 months with HRCT and pulmonary function tests. We compared baseline 68Ga-FAPI-04 PET-CT uptake with standard diagnostic tools and predictors of ILD progression. The association of 68Ga-FAPI-04 uptake with changes in forced vital capacity was analysed using mixed-effects models. Follow-up 68Ga-FAPI-04 PET-CT scans were obtained in a subset of patients treated with nintedanib (follow-up between 6–10 months) to assess change over time. Findings 68Ga-FAPI-04 accumulated in fibrotic areas of the lungs in patients with systemic sclerosis-associated ILD compared with controls, with a median standardised uptake value (SUV) mean over the whole lung of 0·80 (IQR 0·60–2·10) in the systemic sclerosis-ILD group and 0·50 (0·40–0·50) in the control group (p Interpretation Our study presents the first in-human evidence that fibroblast activation correlates with fibrotic activity and disease progression in the lungs of patients with systemic sclerosis-associated ILD and that 68Ga-FAPI-04 PET-CT might improve risk assessment of systemic sclerosis-associated ILD. Funding German Research Foundation, Erlangen Anschubs-und Nachwuchsfinanzierung, Interdisziplinares Zentrum fur Klinische Forschung Erlangen, Bundesministerium fur Bildung und Forschung, Deutsche Stiftung Systemische Sklerose, Wilhelm-Sander-Foundation, Else-Kroner-Fresenius-Foundation, European Research Council, Ernst-Jung-Foundation, and Clinician Scientist Program Erlangen.

Early and effective discrimination (triage) of patients with inflammatory rheumatic diseases (IRD) and other diseases (non-IRD) is essential for successful treatment and preventing damage. The aim of this study was to investigate diagnostic delays and pre-diagnosis treatment in patients newly presenting to rheumatology outpatient clinics. A total of 600 patients newly presenting to one university hospital and two non-academic centers were included. Time from onset of symptoms to rheumatology consultation “total delay” as well as medical treatment before consultation were recorded. Median time from symptom onset to rheumatologist appointment (total delay) was 30 weeks. Median time to online search, first physician appointment request and first physician appointment was 2, 4 and 5 weeks, respectively. Total delay was significantly shorter for IRD patients compared to non-IRD patients, 26 vs 35 weeks (p = 0.007). Only 17.7% of all patients and 22.9% of IRD patients had a delay of less than 12 weeks. Total delay was significantly lower in patients seen in non-academic centers compared to the university center, 20 vs 50 weeks (p

Preregistration, the act of specifying a research plan in advance, is becoming a central step in the way science is conducted. Preregistration for infant researchers might be different than in other fields, due to the specific challenges having to do with testing infants. Infants are a hard-to-reach population, usually yielding small sample sizes, they have a low attention span which usually can limit the number of trials, and they can be excluded based on hard to predict complications (e.g., parental interference, fussiness). In addition, as effects themselves potentially change with age and population, it is hard to calculate an a priori effect size. At the same time, these very factors make preregistration in infant studies a valuable tool. A priori examination of the planned study, including the hypotheses, sample size, and resulting statistical power, increase the credibility of single studies and thus add value to the field. It might arguably also improve explicit decision-making to create better studies. We present an in-depth discussion of the issues uniquely relevant to infant researchers, and ways to contend with them in preregistration and study planning. We provide recommendations to researchers interested in following current best practices.

This article proposes the Hypository, a registration repository for sharing hypotheses resulting from unexpected findings, and hypotheses appearing to be so promising that researchers would like to publish them as soon as possible, whether they have the time and funding to study them or not. The goal of the Hypository is to enable researchers to get credit for their hypotheses when sharing them openly with the research community. The Hypository is expected to improve cumulative science by making sure that the hypothetico-deductive logic is not clouded by rogue intransparent exploratory approaches, while also enabling researchers to make the most of exploratory and/or unexpected findings.The Hypository contributes to solving the theory crisis by nudging researchers to better formalize their theories and hypotheses. It contributes to solving the replicability crisis by enabling researchers to find hypotheses waiting to be studied across labs, samples, and contexts. It contributes to new (or rediscovered) epistemological and methodological perspectives embracing both deductive and inductive steps of the research cycle while mitigating their respective limitations. We describe the possible usages, benefits and the possible features of this new registration platform for hypotheses, and provide a proof-of-concept shiny app and template illustrating the Hypository.

Meta-analyses provide researchers with an overview of the body of evidence in a topic, with quantified estimates of effect sizes and the role of moderators, and weighting studies according to their precision. We provide a guide for conducting a transparent and reproducible meta-analysis in the field of developmental psychology within the framework of the MetaLab platform, in 10 steps: (1) Choose a topic for your meta-analysis, (2) Formulate your research question and specify inclusion criteria, (3) Preregister and document all stages of your meta-analysis, (4) Conduct the literature search, (5) Collect and screen records, (6) Extract data from eligible studies, (7) Read the data into analysis software and compute effect sizes, (8) Visualize your data, (9) Create meta-analytic models to assess the strength of the effect and investigate possible moderators, (10) Write up and promote your meta-analysis. Meta-analyses can inform future studies, through power calculations, by identifying robust methods and exposing research gaps. By adding a new meta-analysis to MetaLab, datasets across multiple topics of developmental psychology can be synthesized, and the dataset can be maintained as a living, community-augmented meta-analysis to which researchers add new data, allowing for a cumulative approach to evidence synthesis.

When speaking to infants, adults often produce speech that differs systematically from that directed to other adults. In order to quantify the acoustic implementation of this speech style across a wide variety of languages and cultures, we extracted results from empirical studies on the acoustic features of infant-directed speech (IDS). We analyzed data from 87 unique studies (669 effect sizes) on the following five acoustic parameters that have been systematically examined in the literature: i) fundamental frequency (fo), ii) fo variability, iii) vowel space area, iv) articulation rate, and v) vowel duration. Moderator analyses were conducted in hierarchical Bayesian robust regression models in order to examine how these features change with infant age and differ across languages, experimental tasks and recording environments. The moderator analyses indicated that fo, articulation rate, and vowel duration became more similar to adult-directed speech (ADS) over time, whereas fo variability and vowel space area exhibited stability throughout development. These results point the way for future research to disentangle different accounts of the functions and learnability of IDS by conducting theory-driven comparisons among different languages and using computational models to formulate testable predictions.

Myeloproliferative Neoplasms (MPNs) constitute a group of rare blood cancers that are characterized by mutations in bone marrow stem cells leading to the overproduction of erythrocytes, leukocytes, and thrombocytes. Mutations in calreticulin (CRT) genes may initiate MPNs, causing a novel variable polybasic stretch terminating in a common C-terminal sequence in the frameshifted CRT (CRTfs) proteins. Peptide antibodies to the mutated C-terminal are important reagents for research in the molecular mechanisms of MPNs and for the development of new diagnostic assays and therapies. In this study, eight peptide antibodies targeting the C-terminal of CRTfs were produced and characterised by modified enzyme-linked immunosorbent assays using resin-bound peptides. The antibodies reacted to two epitopes: CREACLQGWTE for SSI-HYB 385-01, 385-02, 385-03, 385-04, 385-07, 385-08, and 385-09 and CLQGWT for SSI-HYB 385-06. For the majority of antibodies, the residues Cys1, Trp9, and Glu11 were essential for reactivity. SSI-HYB 385-06, with the highest affinity, recognised recombinant CRTfs produced in yeast and the MARIMO cell line expressing CRTfs when examined in Western immunoblotting. Moreover, SSI-HYB 385-06 occasionally reacted to CRTfs from MPN patients when analysed by flow cytometry. The characterized antibodies may be used to understand the role of CRTfs in the pathogenesis of MPNs and to design and develop new diagnostic assays and therapeutic targets.

Introduction: The impact of surgery on nutritional status, pancreatic function, and symptoms of patients affected by chronic pancreatitis (CP) has not been unequivocally determined. This study aimed to evaluate clinical follow-up after surgery for CP in an Italian-Austrian population. Materials and Methods: Patients operated for CP at two high-volume centers between 2000 and 2018 were analyzed. The following parameters were compared between the pre- and postoperative period: nutritional status, endocrine and exocrine pancreatic functions, and chronic pain. Results: Overall, 186 patients underwent surgery for CP. Among these, 68 (40%) answered a specific follow-up questionnaire. The body mass index showed a significant increase between pre- and postoperative assessments (21.1 vs. 22.5 p = 0.003). Furthermore, a 60% decrease in the prevalence of chronic pain (81 vs. 21%, p < 0.001) was observed. On the contrary, both exocrine and endocrine pancreatic functions pointed toward a worsening after surgery, with consistent higher rates of patients presenting with diabetes mellitus, as well as patients requiring insulin therapy and oral intake of pancreatic enzymes. The analysis of body composition performed on 40 (24%) patients with a complete imaging pack revealed no significant change in the nutritional status after surgery. Discussion/Conclusion: Despite the good results observed in terms of pain relief, the surgical approach led to a consistent worsening of the global pancreatic function. No significant influence of surgery on the nutritional status of patients was detected.

Yarkoni's analysis clearly articulates a number of concerns limiting the generalizability and explanatory power of psychological findings, many of which are compounded in infancy research. ManyBabies addresses these concerns via a radically collaborative, large-scale and open approach to research that is grounded in theory-building, committed to diversification, and focused on understanding sources of variation.

Older children with online schooling requirements, unsurprisingly, were reported to have increased screen time during the first COVID-19 lockdown in many countries. Here, we ask whether younger children with no similar online schooling requirements also had increased screen time during lockdown. We examined children’s screen time during the first COVID-19 lockdown in a large cohort (n = 2209) of 8-to-36-month-olds sampled from 15 labs across 12 countries. Caregivers reported that toddlers with no online schooling requirements were exposed to more screen time during lockdown than before lockdown. While this was exacerbated for countries with longer lockdowns, there was no evidence that the increase in screen time during lockdown was associated with socio-demographic variables, such as child age and socio-economic status (SES). However, screen time during lockdown was negatively associated with SES and positively associated with child age, caregiver screen time, and attitudes towards children’s screen time. The results highlight the impact of the COVID-19 lockdown on young children’s screen time.

Published on 06 Feb 2022 The COVID-19 pandemic, and the resulting closure of daycare centers worldwide, led to unprecedented changes in children’s learning environments. This period of increased time at home with caregivers, with limited access to external sources (e.g., daycares) provides a unique opportunity to examine the associations between the caregiver-child activities and children’s language development. The vocabularies of 1742 children aged 8-36 months across 13 countries and 12 languages were evaluated at the beginning and end of the first lockdown period in their respective countries (from March to September 2020). Children who had less passive screen exposure and whose caregivers read more to them showed larger gains in vocabulary development during lockdown, after controlling for SES and other caregiver-child activities. Children also gained more words than expected (based on normative data) during lockdown; either caregivers were more aware of their child’s development, or vocabulary development benefited from intense caregiver-child interaction during lockdown, or both. We discuss these results in the context of the extraordinary circumstances of the COVID-19 pandemic and highlight limitations of the study. Funding for Polish sample: grant from National Science Center NCN (Poland), no 2018/31/B/HS6/03916. NK was partly supported by the Research Council of Norway through its Centres of Excellence funding scheme [project number 223265].

Online testing holds great promise for infant scientists. It could increase participant diversity, improve reproducibility and collaborative possibilities, and reduce costs for researchers and participants. However, despite the rise of platforms and participant databases, little work has been done to overcome the challenges of making this approach available to researchers across the world. In this paper, we elaborate on the benefits of online infant testing from a global perspective and identify challenges for the international community that have been outside of the scope of previous literature. Furthermore, we introduce ManyBabies-AtHome, an international, multi-lab collaboration that is actively working to facilitate practical and technical aspects of online testing and address ethical concerns regarding data storage and protection, and cross-cultural variation. The ultimate goal of this collaboration is to improve the method of testing infants online and make it globally available.

The ability to learn and apply rules lies at the heart of cognition. In a seminal study, Marcus, Vijayan, Rao, and Vishton (1999) reported that seven-month-old infants learned abstract rules over syllable sequences and were able to generalize those rules to novel syllable sequences. Dozens of studies have since extended on that research using different rules, modalities, stimuli, participants (human adults and non-human animals) and experimental procedures. Yet questions remain about the robustness of Marcus et al.’s (1999) core findings, as the presence of significant learning effects has been mixed. In the current study, we aimed to address this issue by testing XX infants of a wide age range (5;0-12;0 months) in a multi-laboratory (XX laboratories) replication of the Marcus et al. (1999) study.

Contains fulltext : 240457.pdf (Publisher’s version ) (Open Access) Understanding the mechanisms that drive variation in children's language acquisition requires large, population-representative datasets of children’s word learning across development. Parent report measures such as the MacArthur-Bates Communicative Development Inventories (CDI) are commonly used to collect such data, but the traditional paper-based forms make the curation of large datasets logistically challenging. Many CDI datasets are thus gathered using convenience samples, often recruited from communities in proximity to major research institutions. Here, we introduce Web-CDI, a web-based tool which allows researchers to collect CDI data online. Web-CDI contains functionality to collect and manage longitudinal data, share links to test administrations, and download vocabulary scores. To date, over 3,500 valid Web-CDI administrations have been completed. General trends found in past norming studies of the CDI are present in data collected from Web-CDI: scores of children's productive vocabulary grow with age, female children show a slightly faster rate of vocabulary growth, and participants with higher levels of educational attainment report slightly higher vocabulary production scores than those with lower levels of education attainment. We also report results from an effort to oversample non-white, lower-education participants via online recruitment (N = 241). These data showed similar demographic trends to the full sample but this effort resulted in a high exclusion rate. We conclude by discussing implications and challenges for the collection of large, population-representative datasets. 44 p.

Purpose Many aspects of surgical therapy for chronic pancreatitis (CP), including the correct indication and timing, as well as the most appropriate operative techniques, are still a matter of debate in the surgical community and vary widely across different centers. The aim of the present study was to uncover and analyze these differences by comparing the experiences of two specialized surgical units in Italy and Austria. Methods All patients operated for CP between 2000 and 2018 at the two centers involved were included in this retrospective analysis. Data regarding the clinical history and the pre- and perioperative surgical course were analyzed and compared between the two institutions. Results Our analysis showed a progressive decrease in the annual rate of pancreatic surgical procedures performed for CP in Verona (no. = 91) over the last two decades (from 3% to less than 1%); by contrast, this percentage increased from 3 to 9% in Vienna (no. = 77) during the same time frame. Considerable differences were also detected with regard to the timing of surgery from the first diagnosis of CP — 4 years (IQR 5.5) in the Austrian series vs two (IQR 4.0) in the Italian series -, and of indications for surgery, with a 12% higher prevalence of groove pancreatitis among patients in the Verona cohort. Conclusion The comparison of the surgical attitude towards CP between two surgical centers proved that a consistent approach to this pathology still is lacking. The identification of common guidelines and labels of surgical eligibility is advisable in order to avoid interinstitutional treatment disparities.

Infant research is often underpowered, undermining the robustness and replicability of our findings. Improving the reliability of infant studies offers a solution for increasing statistical power independent of sample size. Here, we discuss two senses of the term reliability in the context of infant research: reliable (large) effects and reliable measures. We examine the circumstances under which effects are strongest and measures are most reliable, and use synthetic datasets to illustrate the relationship between effect size, measurement reliability, and statistical power. We then present six concrete solutions for more reliable infant research: (1) routinely estimating and reporting the effect size and measurement reliability of infant tasks, (2) selecting the best measurement tool, (3) developing better infant paradigms, (4) collecting more data points per infant, (5) excluding unreliable data from analysis, and (6) conducting more sophisticated data analyses. Deeper consideration of measurement in infant research will improve our ability to study infant development.

ObjectiveX-linked inhibitor of apoptosis protein (XIAP) is a multifunctional protein with important functions in apoptosis, cellular differentiation and cytoskeletal organisation and is emerging as potential target for the treatment of various cancers. The aim of the current study was to investigate the role of XIAP in the pathogenesis of systemic sclerosis (SSc).MethodsThe expression of XIAP in human skin samples of patients with SSc and chronic graft versus host disease (cGvHD) and healthy individuals was analysed by quantitative PCR, immunofluorescence (IF) and western blot. XIAP was inactivated by siRNA-mediated knockdown and pharmacological inhibition. The effects of XIAP inactivation were analysed in cultured fibroblasts and in the fibrosis models bleomycin-induced and topoisomerase-I-(topoI)-induced fibrosis and in Wnt10b-transgenic mice.ResultsThe expression of XIAP, but not of other inhibitor of apoptosis protein family members, was increased in fibroblasts in SSc and sclerodermatous cGvHD. Transforming growth factor beta (TGF-β) induced the expression of XIAP in a SMAD3-dependent manner. Inactivation of XIAP reduced WNT-induced fibroblast activation and collagen release. Inhibition of XIAP also ameliorated fibrosis induced by bleomycin, topoI and overexpression of Wnt10b in well-tolerated doses. The profibrotic effects of XIAP were mediated via WNT/β-catenin signalling. Inactivation of XIAP reduces binding of β-catenin to TCF to in a TLE-dependent manner to block WNT/β-catenin-dependent transcription.ConclusionsOur data characterise XIAP as a novel link between two core pathways of fibrosis. XIAP is overexpressed in SSc and cGvHD in a TGF-β/SMAD3-dependent manner and in turn amplifies the profibrotic effects of WNT/β-catenin signalling on fibroblasts via transducin-like enhancer of split 3. Targeted inactivation of XIAP inhibits the aberrant activation of fibroblasts in murine models of SSc.