PediaTrac V.3.0 protocol: a prospective, longitudinal study of the development and validation of a web-based tool to measure and track infant and toddler development from birth through 18 months.

INTRODUCTION: The need for an efficient, low-cost, comprehensive measure to track infant/toddler development and treatment outcomes is critical, given the importance of early detection and monitoring. This manuscript describes the protocol for the development and testing of a novel measure, PediaTrac, that collects longitudinal, prospective, multidomain data from parents/caregivers to characterise infant/toddler developmental trajectories in term and preterm infants. PediaTrac, a web-based measure, has the potential to become the standard method for monitoring development and detecting risk in infancy and toddlerhood. METHODS AND ANALYSES: Using a multisite, prospective design, primarcaregivers will complete PediaTrac V.3.0, a survey tool that queries core domains of early development, including feeding/eating/elimination, sleep, sensorimotor, social/sensory information processing, social/communication/cognition and early relational health. Information also will be obtained about demographic, medical and environmental factors and embedded response bias indices are being developed as part of the measure. Using an approach that systematically measures infant/toddler developmental domains during a schedule that corresponds to well-child visits (newborn, 2, 4, 6, 9, 12, 15, 18 months), we will assess 360 caregiver/term infant dyads and 240 caregiver/preterm infant dyads (gestational age <37 weeks). Parameter estimates of our items and latent traits (eg, sensorimotor) will be estimated by theta using item response theory-graded response modelling. Participants also will complete legacy (ie, established) measures of development and caregiver health and functioning, used to provide evidence for construct (discriminant) validity. Predictive validity will be evaluated by examining relationships between the PediaTrac domains and the legacy measures in the total sample and in a subsample of 100 participants who will undergo a neurodevelopmental assessment at 24 months of age. ETHICS AND DISSEMINATION: This investigation has single Institutional Review Board (IRB) multisite approval from the University of Michigan (IRB HUM00151584). The results will be presented at prominent conferences and published in peer-reviewed scientific journals.

How different aspects of motor dysfunction influence day-to-day function in huntington's disease.

PURPOSE: This study examined the relationships between different aspects of motor dysfunction (chorea, dystonia, rigidity, incoordination, oculomotor dysfunction, dysarthria, and gait difficulties) and functional status in persons with Huntington's disease. METHODS: A total of 527 persons with Huntington's disease completed the Unified Huntington's Disease Rating Scale motor, total functional capacity, and functional assessments. RESULTS: Confirmatory factor analysis indicated that a 4-factor model provided a better model fit than the existing 5-factor model. Exploratory factor analysis identified the following 4 factors from the motor scale: dystonia, chorea, rigidity, and a general motor factor. Regression indicated that dystonia (ß = -0.47 and -0.79) and rigidity (ß = -0.28 and -0.59) had strong associations with function, whereas chorea had modest correlations (ß = -0.16 and -0.15). CONCLUSIONS: Dystonia and rigidity have stronger relationships with functional status than chorea in persons with Huntington's disease. The findings underscore the need for further research regarding the effects of dystonia and rigidity on functioning. © 2019 International Parkinson and Movement Disorder Society.

Glaucoma-Associated Visual Task Performance and Vision-Related Quality of Life in South India.

Objective/Purpose: Performance-based measures may provide an objective assessment of how glaucoma affects daily functioning. We sought to validate a clinically-applicable performance-based measure of visual ability for patients with glaucoma in south India and to describe its relationship to clinical and patient-reported outcomes. Design: Cross-sectional validation study. Subjects/Participants/Controls: 145 participants with glaucoma were recruited at Aravind Eye Hospital. Methods/Intervention/Testing: We modified the compressed assessment of activities related to vision (CAARV), a performance-based measure validated in the U.S., to be culturally relevant in south India. Participants underwent a series of tests, including the Indian CAARV (I-CAARV), Indian Visual Functioning Questionnaire (IND-VFQ), Spaeth/Richman Contrast Sensitivity (SPARCS) test, standard automated perimetry, and visual acuity (VA). Factor analysis and Rasch modeling were used to validate the I-CAARV. Correlations between the I-CAARV and other outcomes were evaluated. Main Outcome Measure: Psychometric properties of the I-CAARV for individuals with glaucoma in south India. Results: The study included 142 participants (51.7% female, mean age 56.4 years). Average presenting visual acuity and visual field mean deviation (MD) in the better-seeing eye were 0.26 logMAR and -6.57 dB, respectively. The four tasks of the I-CAARV were found to measure a single underlying construct. Rasch analysis of the I-CAARV revealed that the outcome measure had moderate reliability, good construct and content validity, and fair measurement precision. Tasks were well-targeted to the study sample. Rasch-calibrated scores on the I-CAARV were significantly correlated with Rasch-calibrated IND-VFQ scores (r=-0.54) and with visual field MD, presenting VA, best-corrected VA, and SPARCS contrast sensitivity in both the better-seeing eye (r=0.60, -0.51, -0.53, 0.76, respectively) and worse-seeing eye (r=0.48, -0.61, -0.46, 0.69, respectively). Conclusions: The I-CAARV is a valid performance-based measure of vision-dependent functioning in glaucoma in south India. This study also found that I-CAARV task performance was strongly correlated with contrast sensitivity and suggests that performance-based and patient-reported outcomes are related but distinct measures of the impact of glaucoma on functioning and vision-related quality of life. Future studies are needed to determine the sensitivity of the I-CAARV to detect changes due to disease progression that are relevant to functioning and vision-related quality of life.

Self-report of pain in young people and adults with spastic cerebral palsy: interrater reliability of the revised Face, Legs, Activity, Cry, and Consolability (r-FLACC) scale ratings.

AIM: People with cerebral palsy (CP) are often unable to express pain owing to cognitive or speech impairments. Reports that rely on observation can be inaccurate, because behaviours such as grimacing, common in people with spastic CP, resemble pain expressions. We examined preliminary validity and reliability of the revised Face, Legs, Activity, Cry, and Consolability (r-FLACC) scale in people with spastic CP. METHOD: Forty-eight young people and adults (35 females, 13 males; mean [SD] age 29y 2mo [13y]) were video-recorded during a standard examination, rating their pain (0-10) afterwards. Two raters completed the r-FLACC using the video recordings. Interrater reliability was assessed with an unconditional cross-classified random-effects model and item response theory approach; Pearson correlations measured agreement between raters and participants. RESULTS: Mean (SD) participant (n=48) pain scores were 2.48 (2.5) and mean (SD) r-FLACC scores were 1.46 (1.68). There was moderate agreement between raters (intraclass coefficient 0.41 and 0.57 respectively) but low agreement between participants and raters (r=0.26). There were no significant effects for raters (lay observers, nurses, physicians, and inexperienced raters). INTERPRETATION: Results provide mixed support for the interrater reliability of the r-FLACC in people with spastic CP. WHAT THIS PAPER ADDS: The revised Face, Legs, Activity, Cry, and Consolability (r-FLACC) scale can be reliably used by experts and lay raters for people with spastic cerebral palsy (CP). Support is mixed for interrater reliability of the r-FLACC scale used with people with spastic CP.

The reliability of end of day and ecological momentary assessments of pain and pain interference in individuals with spinal cord injury.

PURPOSE: This study investigated the most efficient means of measuring pain intensity and pain interference comparing ecological momentary assessment (EMA) to end of day (EOD) data, with the highest level of measurement reliability as examined in individuals with spinal cord injury. METHODS: EMA (five times throughout the day) and EOD ratings of pain and pain interference were collected over a 7-day period. Multilevel models were used to examine the reliability for both EOD and EMA assessments in order to determine the amount of variability in these assessments over the course of a week or the day, and a multilevel version of the Spearman-Brown Prophecy formula was used to estimate values for reliability. RESULTS: Findings indicate the minimum of number of EOD and EMA assessments needed to achieve different levels of reliability ("adequate" > 0.70, "good" > 0.80 and excellent > 0.90). In addition, the time of day (either morning, midday or evening) did not impact the estimated reliability for the EMA assessments. CONCLUSIONS: These findings can help researchers and clinician balance the cost/benefit tradeoffs of these different types of assessments by providing specific cutoffs for the numbers of each type of assessment that are needed to achieve excellent reliability.

Development and validation of PediaTrac™: A web-based tool to track developing infants.

OBJECTIVE: PediaTrac™, a 363-item web-based tool to track infant development, administered in modules of ∼40-items per sampling period, newborn (NB), 2--, 4--, 6--, 9-- and 12--months was validated. Caregivers answered demographic, medical, and environmental questions, and questions covering the sensorimotor, feeding/eating, sleep, speech/language, cognition, social-emotional, and attachment domains. METHODS: Expert Panel Reviews and Cognitive Interviews (CI) were conducted to validate the item bank. Classical Test Theory (CTT) and Item Response Theory (IRT) methods were employed to examine the dimensionality and psychometric properties of PediaTrac with pooled longitudinal and cross-sectional cohorts (N = 132). RESULTS: Intraclass correlation coefficients (ICC) for the Expert Panel Review revealed moderate agreement at 6 -months and good reliability at other sampling periods. ICC estimates for CI revealed moderate reliability regarding clarity of the items at NB and 4 months, good reliability at 2--, 9-- and 12--months and excellent reliability at 6 -months. CTT revealed good coefficient alpha estimates (α ≥ 0.77 for five of the six ages) for the Social-Emotional/Communication, Attachment (α ≥ 0.89 for all ages), and Sensorimotor (α ≥ 0.75 at 6-months) domains, revealing the need for better targeting of sensorimotor items. IRT modeling revealed good reliability (r = 0.85-0.95) for three distinct domains (Feeding/Eating, Social-Emotional/Communication and Attachment) and four subdomains (Feeding Breast/Formula, Feeding Solid Food, Social-Emotional Information Processing, Communication/Cognition). Convergent and discriminant construct validity were demonstrated between our IRT-modeled domains and constructs derived from existing developmental, behavioral and caregiver measures. Our Attachment domain was significantly correlated with existing measures at the NB and 2-month periods, while the Social-Emotional/Communication domain was highly correlated with similar constructs at the 6-, 9- and 12-month periods. CONCLUSION: PediaTrac has potential for producing novel and effective estimates of infant development via the Sensorimotor, Feeding/Eating, Social-Emotional/Communication and Attachment domains.

Development of a rapid point-of-care patient reported outcome measure for cataract surgery in India.

BACKGROUND: For patient undergoing cataract surgery in India, existing patient-reported outcome (PRO) measures are either not culturally relevant, have not been adequately validated, or are too long to be used in a busy clinical setting. We sought to develop and validate a brief and culturally relevant point-of-care PRO measure to address this need. METHODS: Twelve items from the Indian Visual Functioning Questionnaire (IND-VFQ) were selected based on preliminary data. Patients 18 years and older were prospectively recruited at Aravind Eye Care System in Madurai, India. Clinical and sociodemographic data were collected and the 12-item short-form IND-VFQ (SF-IND-VFQ) was administered pre- and post-operatively to 225 patients; Factor analysis and Rasch modeling was performed to assess its psychometric properties. RESULTS: One item that did not fit a unidimensional scale and had poor fit with the Rasch model was eliminated from the questionnaire. The remaining 11 items represented a single construct (no residual correlations> 0.1) and were largely unaffected by differential item functioning. Five items had disordered thresholds resolved by collapsing the response scale from four to three categories. The survey had adequate reliability (0.80) and good construct (infit range, 0.77-1.29; outfit range, 0.56-1.30) and content (item separation index, 5.87 logits) validity. Measurement precision was fair (person separation index, 1.97). There was evidence that items were not optimally targeted to patients' visual ability (preoperatively, - 1.92 logits; overall, - 3.41 logits), though the survey measured a very large effect (Cohen's d 1.80). In a subset of patients, the average time to complete the questionnaire was 2 min 6.3 s. CONCLUSIONS: The SF-IND-VFQ is a valid, reliable, sensitive, and rapidly administered point-of-care PRO measure to assess changes in visual functioning in patients undergoing cataract surgery in India.

Patient-reported outcome measures in Huntington disease: Quality of life in neurological disorders (Neuro-QoL) social functioning measures.

Social functioning is an essential but poorly understood component of health-related quality of life (HRQOL) for people with Huntington disease (HD). We report on the psychometric properties of 2 Neuro-QoL patient-reported outcome measures to assess social functioning in HD. Persons with prodromal (n = 198) or manifest HD (n = 195 early and n = 117 late) completed Neuro-QoL Ability to Participate in Social Roles and Activities, and Satisfaction with Social Roles and Activities. Items from 2 generic HRQOL patient-reported outcome measures were used to create a social functioning composite score; items from the Unified Huntington's Disease Rating Scale and Problem Behaviors Assessment Scale were used to create a clinician-rated composite score of social function. Internal consistencies for the scores on the Neuro-QoL measures were excellent (> .88). Computer adaptive test administration had some advantages over computer-administered static Short Forms. Validity was supported by significant associations between the scores on the Neuro-QoL measures and other self- and clinician-reports of social function. Individuals with prodromal HD had better social functioning than the manifest HD groups; individuals with late-HD had less satisfaction and ability to participate in social roles and activities than the other 2 groups. Neuro-QoL provides brief, reliable scores of social functioning that measure ability to participate in, and satisfaction with, social roles and activities in persons with prodromal and manifest HD. In addition, test score interpretations of these measures support their validity in people with prodromal and manifest HD. These measurement tools add breadth to treatment outcome measures in HD and can increase understanding of the social implications of living with HD. (PsycINFO Database Record

Patient-reported outcomes in Huntington's disease: Quality of life in neurological disorders (Neuro-QoL) and Huntington's disease health-related quality of life (HDQLIFE) physical function measures.

BACKGROUND: There is a need for patient-reported outcome measures that capture the impact that motor impairments have on health-related quality of life in individuals with Huntington's disease. OBJECTIVES: The objectives of this study were to establish the reliability and validity of new physical functioning patient-reported outcome measures in Huntington's disease. METHODS: A total of 510 individuals with Huntington's disease completed 2 Quality of Life in Neurological Disorders (Lower Extremity Function and Upper Extremity Function) and 3 Huntington's Disease Health-Related Quality of Life (Chorea, Speech Difficulties, and Swallowing Difficulties) measures. Clinician-rated and generic self-report measures were also administered. RESULTS: Reliabilities for the new patient reported physical functioning measures were excellent (all Cronbach's α > .92). Convergent, discriminant validity and known group validity was supported. CONCLUSIONS: The results provide psychometric support for new patient-reported physical functioning measures and the fact that these measures can be used as clinically meaningful endpoints in Huntington's disease research and clinical practice. © 2017 International Parkinson and Movement Disorder Society.

The PROMIS FatigueFM Profile: a self-report measure of fatigue for use in fibromyalgia.

PURPOSE: Fibromyalgia (FM) is characterized by myriad symptoms and problems. Fatigue is one of the most common, distressing, and disabling symptoms in FM. The purpose of this study was to use fatigue item banks that were developed as part of the Patient-Reported Outcomes Measurement Information System (PROMIS) to devise a self-report measure of fatigue for use in individuals with FM. METHODS: A sample of 532 adults with FM (age range = 18-77, 96.1 % female) completed the PROMIS fatigue item bank. Factor analyses and item response theory analyses were used to identify dimensionality and optimally performing items. These data were used in combination with clinical input to select items for a fatigue self-report measure for use in FM. RESULTS: Factor analyses revealed four distinct factors in the PROMIS fatigue item bank; items for each univariate subscale were identified by selecting four items with high item information values. A 16-item measure, the PROMIS FatigueFM Profile, consisting of four 4-item short forms reflecting fatigue experience ("intensity") and fatigue impact in three subdomains-social, cognitive, and motivation-was created. The new PROMIS FatigueFM Profile short forms showed excellent internal reliability, low ceiling and floor effects, and equivalent or higher test information compared to the standard 4- and 7-item PROMIS fatigue short forms. CONCLUSIONS: The newly developed PROMIS FatigueFM Profile, a 16-item measure consisting of four 4-item short forms of self-reported fatigue severity, shows early evidence of good psychometric characteristics, provides the ability to use short forms that assess distinct aspects of fatigue experience and fatigue impact, and demonstrates equivalent or higher levels of test information compared to standard PROMIS fatigue short forms with similar number of items. The PROMIS FatigueFM Profile indicated fatigue experience and impact levels approximately 1.5 standard deviations above the normative sample mean across all short forms. Future work to evaluate the validity and reliability of this new measure in individuals with FM is needed.

Development and initial validation of a brief self-report measure of cognitive dysfunction in fibromyalgia.

UNLABELLED: Pain is often the focus of research and clinical care in fibromyalgia (FM); however, cognitive dysfunction is also a common, distressing, and disabling symptom in FM. Current efforts to address this problem are limited by the lack of a comprehensive, valid measure of subjective cognitive dysfunction in FM that is easily interpretable, accessible, and brief. The purpose of this study was to leverage cognitive functioning item banks that were developed as part of the Patient Reported Outcomes Measurement Information System (PROMIS) to devise a 10-item short form measure of cognitive functioning for use in FM. In study 1, a nationwide (U.S.) sample of 1,035 adults with FM (age range = 18-82, 95.2% female) completed 2 cognitive item pools. Factor analyses and item response theory analyses were used to identify dimensionality and optimally performing items. A recommended 10-item measure, called the Multidimensional Inventory of Subjective Cognitive Impairment (MISCI) was created. In study 2, 232 adults with FM completed the MISCI and a legacy measure of cognitive functioning that is used in FM clinical trials, the Multiple Ability Self-Report Questionnaire (MASQ). The MISCI showed excellent internal reliability, low ceiling/floor effects, and good convergent validity with the MASQ (r = -.82). PERSPECTIVE: This paper presents the MISCI, a 10-item measure of cognitive dysfunction in FM, developed through classical test theory and item response theory. This brief but comprehensive measure shows evidence of excellent construct validity through large correlations with a lengthy legacy measure of cognitive functioning.

DNA as patentable subject matter and a narrow framework for addressing the perceived problems caused by gene patents.

Concerns about the alleged harmful effects of gene patents--including hindered research and innovation and impeded patient access to high-quality genetic diagnostic tests--have resulted in overreactions from the public and throughout the legal profession. These overreactions are exemplified by Association for Molecular Pathology v. U.S. Patent and Trademark Office, a 2010 case in the Southern District of New York that held that isolated DNA is unpatentable subject matter under 35 U.S.C. § 101. The problem with these responses is that they fail to adequately consider the role that gene patents and patents on similar biomolecules play in facilitating investment in the costly and risky developmental processes required to transform the underlying inventions into marketable products. Accordingly, a more precisely refined solution is advisable. This Note proposes a narrowly tailored set of solutions to address the concerns about gene patents without destroying the incentives for companies to create and commercialize inventions derived from these and similar patents.

Trefoil factor 1 acts to suppress senescence induced by oncogene activation during the cellular transformation process.

Senescence is a cellular stress response characterized by persistent cell growth arrest under various stress conditions, including oncogene activation or tumor suppressor loss, which functions as a critical barrier that must be overcome to allow the progression from a precancerous or preinvasive lesion to a malignant tumor. Trefoil factor 1 (TFF1) is a secreted protein involved in maintaining the gastrointestinal epithelium by serving a tumor-suppressive role; however, TFF1 is overexpressed in several types of cancers. Here we report that TFF1 acts as a promoter of tumorigenesis in the context of prostate and pancreatic cancers by suppressing oncogene-induced senescence (OIS). Expression of TFF1 allows human prostate epithelial cells to escape OIS caused by the activated Ras oncogene or by reduced expression of the tumor suppressor PTEN, in part by the involvement of the EGF receptor-mediated pathway and inhibition of the expression of the cell cycle regulator p21. Without intrinsic promitogenic activity TFF1 may act in both autocrine and paracrine manners to enable cells to undergo the initial transformation and expansion against the restrictive microenvironment during early stage tumorigenesis. Taken together, our findings identify TFF1 as a soluble factor designed to act mainly to antagonize the OIS process to accelerate tumorigenesis.

Advances in the assessment of fibromyalgia.

Fibromyalgia (FM) has historically been considered a chronic pain condition. Recent clinical studies, however, reveal that while pain may be the cardinal symptom of FM, there are many other symptoms and consequences of having FM that have an impact on the lives of individuals with this condition. As such, an area of intense clinical research has focused upon improving approaches to assessment for FM. This article provides an overview of how the art of assessing FM has evolved over time, current methods of assessment, the value of patients' perspectives in assessment, and emerging advancements representing the future of for FM.

NDRG4 is required for cell cycle progression and survival in glioblastoma cells.

NDRG4 is a largely unstudied member of the predominantly tumor suppressive N-Myc downstream-regulated gene (NDRG) family. Unlike its family members NDRG1-3, which are ubiquitously expressed, NDRG4 is expressed almost exclusively in the heart and brain. Given this tissue-specific expression pattern and the established tumor suppressive roles of the NDRG family in regulating cellular proliferation, we investigated the cellular and biochemical functions of NDRG4 in the context of astrocytes and glioblastoma multiforme (GBM) cells. We show that, in contrast to NDRG2, NDRG4 expression is elevated in GBM and NDRG4 is required for the viability of primary astrocytes, established GBM cell lines, and both CD133(+) (cancer stem cell (CSC)-enriched) and CD133(-) primary GBM xenograft cells. While NDRG4 overexpression has no effect on cell viability, NDRG4 knockdown causes G(1) cell cycle arrest followed by apoptosis. The initial G(1) arrest is associated with a decrease in cyclin D1 expression and an increase in p27(Kip1) expression, and the subsequent apoptosis is associated with a decrease in the expression of XIAP and survivin. As a result of these effects on cell cycle progression and survival, NDRG4 knockdown decreases the tumorigenic capacity of established GBM cell lines and GBM CSC-enriched cells that have been implanted intracranially into immunocompromised mice. Collectively, these data indicate that NDRG4 is required for cell cycle progression and survival, thereby diverging in function from its tumor suppressive family member NDRG2 in astrocytes and GBM cells.

Arabidopsis photorespiratory serine hydroxymethyltransferase activity requires the mitochondrial accumulation of ferredoxin-dependent glutamate synthase.

The dual affinity of ribulose-1,5-bisphosphate carboxylase/oxygenase for O(2) and CO(2) results in the net loss of fixed carbon and energy in a process termed photorespiration. The photorespiratory cycle is complex and occurs in three organelles, chloroplasts, peroxisomes, and mitochondria, which necessitates multiple steps to transport metabolic intermediates. Genetic analysis has identified a number of mutants exhibiting photorespiratory chlorosis at ambient CO(2), including several with defects in mitochondrial serine hydroxymethyltransferase (SHMT) activity. One class of mutants deficient in SHMT1 activity affects SHM1, which encodes the mitochondrial SHMT required for photorespiration. In this work, we describe a second class of SHMT1-deficient mutants defective in a distinct gene, GLU1, which encodes Ferredoxin-dependent Glutamate Synthase (Fd-GOGAT). Fd-GOGAT is a chloroplastic enzyme responsible for the reassimilation of photorespiratory ammonia as well as for primary nitrogen assimilation. We show that Fd-GOGAT is dual targeted to the mitochondria and the chloroplasts. In the mitochondria, Fd-GOGAT interacts physically with SHMT1, and this interaction is necessary for photorespiratory SHMT activity. The requirement of protein-protein interactions and complex formation for photorespiratory SHMT activity demonstrates more complicated regulation of this crucial high flux pathway than anticipated.

TGFbeta-stimulated Smad1/5 phosphorylation requires the ALK5 L45 loop and mediates the pro-migratory TGFbeta switch.

During the course of breast cancer progression, normally dormant tumour-promoting effects of transforming growth factor beta (TGFbeta), including migration, invasion, and metastasis are unmasked. In an effort to identify mechanisms that regulate the pro-migratory TGFbeta 'switch' in mammary epithelial cells in vitro, we found that TGFbeta stimulates the phosphorylation of Smad1 and Smad5, which are typically associated with bone morphogenetic protein signalling. Mechanistically, this phosphorylation event requires the kinase activity and, unexpectedly, the L45 loop motif of the type I TGFbeta receptor, ALK5, as evidenced by studies using short hairpin RNA-resistant ALK5 mutants in ALK5-depleted cells and in vitro kinase assays. Functionally, Smad1/5 co-depletion studies demonstrate that this phosphorylation event is essential to the initiation and promotion of TGFbeta-stimulated migration. Moreover, this phosphorylation event is preferentially detected in permissive environments such as those created by tumorigenic cells or oncogene activation. Taken together, our data provide evidence that TGFbeta-stimulated Smad1/5 phosphorylation, which occurs through a non-canonical mechanism that challenges the notion of selective Smad phosphorylation by ALK5, mediates the pro-migratory TGFbeta switch in mammary epithelial cells.

A phosphatase controls the fate of receptor-regulated Smads.

In this issue of Cell, Lin et al. (2006) answer one of the long-standing questions in the TGFbeta field by identifying a phosphatase, PPM1A, that directly dephosphorylates Smad2 and Smad3 to limit their activation.

TGF-beta regulates the mechanical properties and composition of bone matrix.

The characteristic toughness and strength of bone result from the nature of bone matrix, the mineralized extracellular matrix produced by osteoblasts. The mechanical properties and composition of bone matrix, along with bone mass and architecture, are critical determinants of a bone's ability to resist fracture. Several regulators of bone mass and architecture have been identified, but factors that regulate the mechanical properties and composition of bone matrix are largely unknown. We used a combination of high-resolution approaches, including atomic-force microscopy, x-ray tomography, and Raman microspectroscopy, to assess the properties of bone matrix independently of bone mass and architecture. Properties were evaluated in genetically modified mice with differing levels of TGF-beta signaling. Bone matrix properties correlated with the level of TGF-beta signaling. Smad3+/- mice had increased bone mass and matrix properties, suggesting that the osteopenic Smad3-/- phenotype may be, in part, secondary to systemic effects of Smad3 deletion. Thus, a reduction in TGF-beta signaling, through its effector Smad3, enhanced the mechanical properties and mineral concentration of the bone matrix, as well as the bone mass, enabling the bone to better resist fracture. Our results provide evidence that bone matrix properties are controlled by growth factor signaling.

TLR agonists regulate PDGF-B production and cell proliferation through TGF-beta/type I IFN crosstalk.

Transforming growth factor-beta (TGF-beta) and type I interferon (IFN) autocrine/paracrine loops are recognized as key mediators of signaling cascades that control a variety of cellular functions. Here, we describe a novel mechanism by which Toll-like receptor (TLR) agonists utilize these two autocrine/paracrine loops to differentially regulate the induction of PDGF-B, a growth factor implicated in a number of diseases ranging from tumor metastasis to glomerulonephritis. We demonstrate that CpG-specific induction of PDGF-B requires activation of Smads through TGFbeta1 autocrine/paracrine signaling. In contrast, polyinosinic:polycytidylic acid strongly represses CpG's as well as its own intrinsic ability to induce PDGF-B mRNA through type I IFN-mediated induction of Smad7, a negative regulator of Smad3/4. Furthermore, we have shown that this crosstalk mechanism translates into similar regulation of mesangial cell proliferation. Thus, our results demonstrate the importance of crosstalk between TGF-beta and type I IFNs in determining the specificity of TLR-mediated gene induction.