Human Intestinal Dendritic Cells Can Overcome Retinoic Acid Signaling to Generate Proinflammatory CD4 T Cells with Both Gut and Skin Homing Properties.

Retinoic acid, produced by intestinal dendritic cells (DCs), promotes T cell trafficking to the intestinal mucosa by upregulating α4ß7 integrin and inhibiting the generation of cutaneous leukocyte Ag (CLA) required for skin entry. In the present study, we report that activation of human naive CD4 T cells in an APC-free system generates cells expressing α4ß7 alone; in contrast, activation by intestinal DCs that produce retinoic acid and induce high levels of α4ß7 also results in CLA expression, generating CLA+α4ß7+ "dual tropic" cells, with both gut and skin trafficking potential, that also express high levels of α4ß1 integrin. DC generation of CLA+α4ß7+ T cells is associated with upregulation of FUT7, a fucosyltransferase involved in CLA generation; requires cell contact; and is enhanced by IL-12/IL-23. The blood CD4+ T cell population contains CLA+α4ß7+ cells, which are significantly enriched for cells capable of IFN-γ, IL-17, and TNF-α production compared with conventional CLA-α4ß7+ cells. Dual tropic lymphocytes are increased in intestinal tissue from patients with Crohn's disease, and single-cell RNA-sequencing analysis identifies a transcriptionally distinct cluster of FUT7-expressing cells present only in inflamed tissue; expression of genes associated with cell proliferation suggests that these cells are undergoing local activation. The expression of multiple trafficking molecules by CLA+α4ß7+ T cells can enable their recruitment by alternative pathways to both skin and gut; they may contribute to both intestinal and cutaneous manifestations of inflammatory bowel disease.

Single cell sequencing data identify distinct B cell and fibroblast populations in stricturing Crohn's disease.

Single cell RNA sequencing of human full thickness Crohn's disease (CD) small bowel resection specimens was used to identify potential therapeutic targets for stricturing (S) CD. Using an unbiased approach, 16 cell lineages were assigned within 14,539 sequenced cells from patient-matched SCD and non-stricturing (NSCD) preparations. SCD and NSCD contained identical cell types. Amongst immune cells, B cells and plasma cells were selectively increased in SCD samples. B cell subsets suggested formation of tertiary lymphoid tissue in SCD and compared with NSCD there was an increase in IgG, and a decrease in IgA plasma cells, consistent with their potential role in CD fibrosis. Two Lumican-positive fibroblast subtypes were identified and subclassified based on expression of selectively enriched genes as fibroblast clusters (C) 12 and C9. Cells within these clusters expressed the profibrotic genes Decorin (C12) and JUN (C9). C9 cells expressed ACTA2; ECM genes COL4A1, COL4A2, COL15A1, COL6A3, COL18A1 and ADAMDEC1; LAMB1 and GREM1. GO and KEGG Biological terms showed extracellular matrix and stricture organization associated with C12 and C9, and regulation of WNT pathway genes with C9. Trajectory and differential gene analysis of C12 and C9 identified four sub-clusters. Intra sub-cluster gene analysis detected 13 co-regulated gene modules that aligned along predicted pseudotime trajectories. CXCL14 and ADAMDEC1 were key markers in module 1. Our findings support further investigation of fibroblast heterogeneity and interactions with local and circulating immune cells at earlier time points in fibrosis progression. Breaking these interactions by targeting one or other population may improve therapeutic management for SCD.

The Biomechanics Research and Innovation Challenge: Development, Implementation, Uptake, and Reflections on the Inaugural Program.

Biomechanics as a discipline is ideally placed to increase awareness and participation of girls and women in science, technology, engineering, and mathematics. A nationwide Biomechanics and Research Innovation Challenge (BRInC) centered on mentoring and role modeling was developed to engage high school girls (mentees) and early-mid-career women (mentors) in the field of biomechanics through the completion of a 100-day research and/or innovation project. This manuscript describes the development, implementation, and uptake of the inaugural BRInC program and synthesizes the research and innovation projects undertaken, providing a framework for adoption of this program within the global biomechanics community. Eighty-seven high school girls in years 9 and 10 (age range: 14-16 y) were mentored in teams (n = 17) by women in biomechanics (n = 24). Using a design thinking approach, teams generated solutions to biomechanics-based problem(s)/research question(s). Eight key reflections on program strengths, as well as areas for improvement and planned changes for future iterations of the BRInC program, are outlined. These key reflections highlight the innovation, impact, and scalability of the program; the importance of a program framework and effective communication tools; and implementation of strategies to sustain the program as well as the importance of diversity and building a sense of community.

Small-molecule Wnt inhibitors are a potential novel therapy for intestinal fibrosis in Crohns disease.

Intestinal fibrosis and stricture formation is an aggressive complication of Crohns disease (CD), linked to increased morbidity and costs. The present study investigates the contribution of Wingless-Int-1 (Wnt) signalling to intestinal fibrogenesis, considers potential cross-talk between Wnt and transforming growth factor ß1 (TGFß) signalling pathways, and assesses the therapeutic potential of small-molecule Wnt inhibitors. ß-catenin expression was explored by immunohistochemistry (IHC) in formalin-fixed paraffin embedded (FFPE) tissue from patient-matched nonstrictured (NSCD) and strictured (SCD) intestine (n=6 pairs). Functional interactions between Wnt activation, TGFß signalling, and type I collagen (Collagen-I) expression were explored in CCD-18Co cells and primary CD myofibroblast cultures established from surgical resection specimens (n=16) using small-molecule Wnt inhibitors and molecular techniques, including siRNA-mediated gene knockdown, immunofluorescence (IF), Wnt gene expression arrays, and western blotting. Fibrotic SCD tissue was marked by an increase in ß-catenin-positive cells. In vitro, activation of Wnt-ß-catenin signalling increased Collagen-I expression in CCD-18Co cells. Conversely, ICG-001, an inhibitor of ß-catenin signalling, reduced Collagen-I expression in cell lines and primary CD myofibroblasts. TGFß increased ß-catenin protein levels but did not activate canonical Wnt signalling. Rather, TGFß up-regulated WNT5B, a noncanonical Wnt ligand, and the Wnt receptor FZD8, which contributed directly to the up-regulation of Collagen-I through a ß-catenin-independent mechanism. Treatment of CCD-18Co fibroblasts and patient-derived myofibroblasts with the FZD8 inhibitor 3235-0367 reduced extracellular matrix (ECM) expression. Our data highlight small-molecule Wnt inhibitors of both canonical and noncanonical Wnt signalling, as potential antifibrotic drugs to treat SCD intestinal fibrosis. They also highlight the importance of the cross-talk between Wnt and TGFß signalling pathways in CD intestinal fibrosis.

Hif-1α-Induced Expression of Il-1ß Protects against Mycobacterial Infection in Zebrafish.

Drug-resistant mycobacteria are a rising problem worldwide. There is an urgent need to understand the immune response to tuberculosis to identify host targets that, if targeted therapeutically, could be used to tackle these currently untreatable infections. In this study we use an Il-1ß fluorescent transgenic line to show that there is an early innate immune proinflammatory response to well-established zebrafish models of inflammation and Mycobacterium marinum infection. We demonstrate that host-derived hypoxia signaling, mediated by the Hif-1α transcription factor, can prime macrophages with increased levels of Il-1ß in the absence of infection, upregulating neutrophil antimicrobial NO production, leading to greater protection against infection. Our data link Hif-1α to proinflammatory macrophage Il-1ß transcription in vivo during early mycobacterial infection and importantly highlight a host protective mechanism, via antimicrobial NO, that decreases disease outcomes and that could be targeted therapeutically to stimulate the innate immune response to better deal with infections.

Increased yield and CO2 sequestration potential with the C4 cereal Sorghum bicolor cultivated in basaltic rock dust-amended agricultural soil.

Land-based enhanced rock weathering (ERW) is a biogeochemical carbon dioxide removal (CDR) strategy aiming to accelerate natural geological processes of carbon sequestration through application of crushed silicate rocks, such as basalt, to croplands and forested landscapes. However, the efficacy of the approach when undertaken with basalt, and its potential co-benefits for agriculture, require experimental and field evaluation. Here we report that amending a UK clay-loam agricultural soil with a high loading (10 kg/m2 ) of relatively coarse-grained crushed basalt significantly increased the yield (21 ± 9.4%, SE) of the important C4 cereal Sorghum bicolor under controlled environmental conditions, without accumulation of potentially toxic trace elements in the seeds. Yield increases resulted from the basalt treatment after 120 days without P- and K-fertilizer addition. Shoot silicon concentrations also increased significantly (26 ± 5.4%, SE), with potential benefits for crop resistance to biotic and abiotic stress. Elemental budgets indicate substantial release of base cations important for inorganic carbon removal and their accumulation mainly in the soil exchangeable pools. Geochemical reactive transport modelling, constrained by elemental budgets, indicated CO2 sequestration rates of 2-4 t CO2 /ha, 1-5 years after a single application of basaltic rock dust, including via newly formed soil carbonate minerals whose long-term fate requires assessment through field trials. This represents an approximately fourfold increase in carbon capture compared to control plant-soil systems without basalt. Our results build support for ERW deployment as a CDR technique compatible with spreading basalt powder on acidic loamy soils common across millions of hectares of western European and North American agriculture.

Remodelling of microRNAs in colorectal cancer by hypoxia alters metabolism profiles and 5-fluorouracil resistance.

Solid tumours have oxygen gradients and areas of near and almost total anoxia. Hypoxia reduces sensitivity to 5-fluorouracil (5-FU)-chemotherapy for colorectal cancer (CRC). MicroRNAs (miRNAs) are hypoxia sensors and were altered consistently in six CRC cell lines (colon cancer: DLD-1, HCT116 and HT29; rectal cancer: HT55, SW837 and VACO4S) maintained in hypoxia (1 and 0.2% oxygen) compared with normoxia (20.9%). CRC cell lines also showed altered amino acid metabolism in hypoxia and hypoxia-responsive miRNAs were predicted to target genes in four metabolism pathways: beta-alanine; valine, leucine, iso-leucine; aminoacyl-tRNA; and alanine, aspartate, glutamate. MiR-210 was increased in hypoxic areas of CRC tissues and hypoxia-responsive miR-21 and miR-30d, but not miR-210, were significantly increased in 5-FU resistant CRCs. Treatment with miR-21 and miR-30d antagonists sensitized hypoxic CRC cells to 5-FU. Our data highlight the complexity and tumour heterogeneity caused by hypoxia. MiR-210 as a hypoxic biomarker, and the targeting of miR-21 and miR-30d and/or the amino acid metabolism pathways may offer translational opportunities.

The Effects of Personalized Versus Generic Scaling of Body Segment Masses on Joint Torques During Stationary Wheelchair Racing.

The anthropometries of elite wheelchair racing athletes differ from the generic, able-bodied anthropometries commonly used in computational biomechanical simulations. The impact of using able-bodied parameters on the accuracy of simulations involving wheelchair racing is currently unknown. In this study, athlete-specific mass segment inertial parameters of the head and neck, torso, upper arm, forearm, hand, thigh, shank, and feet for five elite wheelchair athletes were calculated using dual-energy X-ray absorptiometry (DXA) scans. These were compared against commonly used anthropometrics parameters of data presented in the literature. A computational biomechanical simulation of wheelchair propulsion using the upper extremity dynamic model in opensim assessed the sensitivity of athlete-specific mass parameters using Kruskal-Wallis analysis and Spearman correlations. Substantial between-athlete body mass distribution variances (thigh mass between 7.8% and 22.4% total body mass) and between-limb asymmetries (<62.4% segment mass; 3.1 kg) were observed. Compared to nonathletic able-bodied anthropometric data, wheelchair racing athletes demonstrated greater mass in the upper extremities (up to 3.8% total body mass) and less in the lower extremities (up to 9.8% total body mass). Computational simulations were sensitive to individual body mass distribution, with joint torques increasing by up to 31.5% when the scaling of segment masses (measured or generic) differed by up to 2.3% total body mass. These data suggest that nonathletic, able-bodied mass segment inertial parameters are inappropriate for analyzing elite wheelchair racing motion.

Estimating the Maximum Isometric Force Generating Capacity of Wheelchair Racing Athletes for Simulation Purposes.

For the wheelchair racing population, it is uncertain whether musculoskeletal models using the maximum isometric force generating capacity of non-athletic, able-bodied individuals, are appropriate, as few anthropometric parameters for wheelchair athletes are reported in the literature. In this study, a sensitivity analysis was performed in OpenSim, whereby the maximum isometric force generating capacity of muscles was adjusted in 25% increments to literature defined values between scaling factors of 0.25x to 4.0x for two elite athletes, at three speeds representative of race conditions. Convergence of the solution was used to assess the results. Artificially weakening a model presented unrealistic values, and artificially strengthening a model excessively (4.0x) demonstrated physiologically invalid muscle force values. The ideal scaling factors were 1.5x and 1.75x for each of the athletes, respectively, as was assessed through convergence of the solution. This was similar to the relative difference in limb masses between dual energy X-Ray absorptiometry (DXA) data and anthropometric data in the literature (1.49x and 1.70x), suggesting that DXA may be used to estimate the required scaling factors. The reliability of simulations for elite wheelchair racing athletes can be improved by appropriately increasing the maximum isometric force generating capacity of muscles.

Epithelial down-regulation of the miR-200 family in fibrostenosing Crohn's disease is associated with features of epithelial to mesenchymal transition.

Intestinal mesenchymal cells deposit extracellular matrix in fibrotic Crohn's disease (CD). The contribution of epithelial to mesenchymal transition (EMT) to the mesenchymal cell pool in CD fibrosis remains obscure. The miR-200 family regulates fibrosis-related EMT in organs other than the gut. E-cadherin, cytokeratin-18 and vimentin expression was assessed using immunohistochemistry on paired strictured (SCD) and non-strictured (NSCD) ileal CD resections and correlated with fibrosis grade. MiR-200 expression was measured in paired SCD and NSCD tissue compartments using laser capture microdissection and RT-qPCR. Serum miR-200 expression was also measured in healthy controls and CD patients with stricturing and non-stricturing phenotypes. Extra-epithelial cytokeratin-18 staining and vimentin-positive epithelial staining were significantly greater in SCD samples (P = 0.04 and P = 0.03, respectively). Cytokeratin-18 staining correlated positively with subserosal fibrosis (P < 0.001). Four miR-200 family members were down-regulated in fresh SCD samples (miR-141, P = 0.002; miR-200a, P = 0.002; miR-200c, P = 0.001; miR-429; P = 0.004); miR-200 down-regulation in SCD tissue was localised to the epithelium (P = 0.001-0.015). The miR-200 target ZEB1 was up-regulated in SCD samples (P = 0.035). No difference in serum expression between patient groups was observed. Together, these observations suggest the presence of EMT in CD strictures and implicate the miR-200 family as regulators. Functional studies to prove this relationship are now warranted.

Verbal-spatial IQ discrepancies impact brain activation associated with the resolution of cognitive conflict in children and adolescents.

Verbal-spatial discrepancies are common in healthy individuals and in those with neurodevelopmental disorders associated with cognitive control deficits including: Autism Spectrum Disorder, Non-Verbal Learning Disability, Fragile X, 22q11 deletion, and Turner Syndrome. Previous data from healthy individuals suggest that the magnitude of the difference between verbal IQ (VIQ) and performance IQ (PIQ) scores (the VIQ>PIQ discrepancy) is associated with reduced thickness in frontal and parietal cortices (inferior frontal, anterior cingulate, inferior parietal lobule, and supramarginal gyrus) that support cognitive control. Unknown is whether the VIQ>PIQ discrepancy is associated with functional deficits in these areas in healthy or ill children and adolescents. We assessed the effects of the VIQ>PIQ discrepancy on fMRI BOLD response during the resolution of cognitive conflict in 55 healthy children and adolescents during performance of a Simon Spatial Incompatibility task. As the magnitude of the VIQ>PIQ discrepancy increased, activation of fronto-striatal, limbic, and temporal regions decreased during conflict resolution (p < .05, corrected). In exploratory analyses, the VIQ>PIQ discrepancy was associated with reduced functional connectivity from right inferior frontal gyrus to right thalamus and increased functional connectivity to right supramarginal gyrus (ps < .03, uncorrected). The VIQ>PIQ discrepancy may be an important aspect of an individual's cognitive profile and likely contributes to, or is associated with, deficient cognitive control processes characteristic of many childhood disorders.

MicroRNA-542 Promotes Mitochondrial Dysfunction and SMAD Activity and Is Elevated in Intensive Care Unit-acquired Weakness.

RATIONALE: Loss of skeletal muscle mass and function is a common consequence of critical illness and a range of chronic diseases, but the mechanisms by which this occurs are unclear. OBJECTIVES: To identify microRNAs (miRNAs) that were increased in the quadriceps of patients with muscle wasting and to determine the molecular pathways by which they contributed to muscle dysfunction. METHODS: miRNA-542-3p/5p (miR-542-3p/5p) were quantified in the quadriceps of patients with chronic obstructive pulmonary disease and intensive care unit-acquired weakness (ICUAW). The effect of miR-542-3p/5p was determined on mitochondrial function and transforming growth factor-ß signaling in vitro and in vivo. MEASUREMENTS AND MAIN RESULTS: miR-542-3p/5p were elevated in patients with chronic obstructive pulmonary disease but more markedly in patients with ICUAW. In vitro, miR-542-3p suppressed the expression of the mitochondrial ribosomal protein MRPS10 and reduced 12S ribosomal RNA (rRNA) expression, suggesting mitochondrial ribosomal stress. miR-542-5p increased nuclear phospho-SMAD2/3 and suppressed expression of SMAD7, SMURF1, and PPP2CA, proteins that inhibit or reduce SMAD2/3 phosphorylation, suggesting that miR-542-5p increased transforming growth factor-ß signaling. In mice, miR-542 overexpression caused muscle wasting, and reduced mitochondrial function, 12S rRNA expression, and SMAD7 expression, consistent with the effects of the miRNAs in vitro. Similarly, in patients with ICUAW, the expression of 12S rRNA and of the inhibitors of SMAD2/3 phosphorylation were reduced, indicative of mitochondrial ribosomal stress and increased transforming growth factor-ß signaling. In patients undergoing aortic surgery, preoperative levels of miR-542-3p/5p were positively correlated with muscle loss after surgery. CONCLUSIONS: Elevated miR-542-3p/5p may cause muscle atrophy in intensive care unit patients through the promotion of mitochondrial dysfunction and activation of SMAD2/3 phosphorylation.

Non-goal-directed recall of specific events in apes after long delays.

We examined if apes spontaneously remember one-time, distinctive events across long delays when probed by discriminant cues. Apes witnessed an experimenter hide a cache of food, which they could then retrieve. They retrieved one of two food types; one more distinctive than the other. Two, 10 or 50 weeks later, the apes returned to the same enclosure and found a piece of the previously hidden food on the ground. An experimenter who had not hidden the food was also present. Apes immediately searched the location where the food was previously hidden (no food was here), showing recall of the event. One week later, apes returned to the same enclosure, with the same food on the ground, but now the experimenter that had hidden the food was present. Again, apes immediately searched the hiding location. Apes that had not witnessed the hiding event did not search. There was no significant effect of food type, and retention declined from exposure to the two-week delay, then levelled, consistent with the forgetting curve in humans (Ebbinghaus, H. 1964 Memory: a contribution to experimental psychology (transl. H.A. Ruger & C.E. Bussenvis). New York, NY: Dover. (Original work published 1885.)). This is the first study to show apes can recall a one-time, non-goal-directed event longer than two weeks ago and that apes' recall declines in accordance with a standard retention function.

Using laser capture microdissection to study fiber specific signaling in locomotor muscle in COPD: A pilot study.

INTRODUCTION: Quadriceps dysfunction is important in chronic obstructive pulmonary disease (COPD), with an associated increased proportion of type II fibers. Investigation of protein synthesis and degradation has yielded conflicting results, possibly due to study of whole biopsy samples, whereas signaling may be fiber-specific. Our objective was to develop a method for fiber-specific gene expression analysis. METHODS: 12 COPD and 6 healthy subjects underwent quadriceps biopsy. Cryosections were immunostained for type II fibers, which were separated using laser capture microdissection (LCM). Whole muscle and different fiber populations were subject to quantitative polymerase chain reaction. RESULTS: Levels of muscle-RING-finger-protein-1 and Atrogin-1 were lower in type II fibers of COPD versus healthy subjects (P = 0.02 and P = 0.03, respectively), but differences were not apparent in whole muscle or type I fibers. CONCLUSIONS: We describe a novel method for studying fiber-specific gene expression in optimum cutting temperature compound-embedded muscle specimens. LCM offers a more sensitive way to identify molecular changes in COPD muscle. Muscle Nerve 55: 902-912, 2017.

Distinctiveness enhances long-term event memory in non-human primates, irrespective of reinforcement.

Non-human primates are capable of recalling events that occurred as long as 3 years ago, and are able to distinguish between similar events; akin to human memory. In humans, distinctiveness enhances memory for events, however, it is unknown whether the same occurs in non-human primates. As such, we tested three great ape species on their ability to remember an event that varied in distinctiveness. Across three experiments, apes witnessed a baiting event in which one of three identical containers was baited with food. After a delay of 2 weeks, we tested their memory for the location of the baited container. Apes failed to recall the baited container when the event was undistinctive (Experiment 1), but were successful when it was distinctive (Experiment 2), although performance was equally good in a less-distinctive condition. A third experiment (Experiment 3) confirmed that distinctiveness, independent of reinforcement, was a consistent predictor of performance. These findings suggest that distinctiveness may enhance memory for events in non-human primates in the same way as in humans, and provides further evidence of basic similarities between the ways apes and humans remember past events.

Hypoxia-inducible factor 2α regulates key neutrophil functions in humans, mice, and zebrafish.

Neutrophil lifespan and function are regulated by hypoxia via components of the hypoxia inducible factor (HIF)/von Hippel Lindau/hydroxylase pathway, including specific roles for HIF-1α and prolyl hydroxylase-3. HIF-2α has both distinct and overlapping biological roles with HIF-1α and has not previously been studied in the context of neutrophil biology. We investigated the role of HIF-2α in regulating key neutrophil functions. Human and murine peripheral blood neutrophils expressed HIF-2α, with expression up-regulated by acute and chronic inflammatory stimuli and in disease-associated inflammatory neutrophil. HIF2A gain-of-function mutations resulted in a reduction in neutrophil apoptosis both ex vivo, through the study of patient cells, and in vivo in a zebrafish tail injury model. In contrast, HIF-2α-deficient murine inflammatory neutrophils displayed increased sensitivity to nitrosative stress induced apoptosis ex vivo and increased neutrophil apoptosis in vivo, resulting in a reduction in neutrophilic inflammation and reduced tissue injury. Expression of HIF-2α was temporally dissociated from HIF-1α in vivo and predominated in the resolution phase of inflammation. These data support a critical and selective role for HIF-2α in persistence of neutrophilic inflammation and provide a platform to dissect the therapeutic utility of targeting HIF-2α in chronic inflammatory diseases.

MiR-181a: a potential biomarker of acute muscle wasting following elective high-risk cardiothoracic surgery.

INTRODUCTION: Acute muscle wasting in the critically ill is common and associated with significant morbidity and mortality. Although some aetiological factors are recognised and muscle wasting can be detected early with ultrasound, it not possible currently to predict in advance of muscle loss those who will develop muscle wasting. The ability to stratify the risk of muscle wasting associated with critical illness prior to it becoming clinically apparent would provide the opportunity to predict prognosis more accurately and to intervene at an early stage. MicroRNAs are small non-coding RNAs that modulate post-transcriptional regulation of translation, some are tissue specific and can be detected and quantified in plasma. We hypothesised that certain plasma microRNAs could be biomarkers of ICU acquired muscle weakness. METHODS: Plasma levels of selected microRNAs were measured in pre- and post-operative samples from a previously reported prospective observational study of 42 patients undergoing elective high-risk cardiothoracic surgery, 55% of whom developed muscle wasting. RESULTS: The rise in miR-181a was significantly higher on the second post-operative day in those who developed muscle wasting at 1 week compared to those who did not (p = 0.03). A rise in miR-181a of greater than 1.7 times baseline had 91% specificity and 56% sensitivity for subsequent muscle wasting. Other microRNAs did not show significant differences between the groups. CONCLUSION: Plasma miR-181a deserves further investigation as a potential biomarker of muscle wasting. Additionally, since mir-181a is involved in both regulation of inflammation and muscle regeneration and differentiation; our observation therefore also suggests directions for future research.

The Potential Role of Topically Applied Heparan Sulfate in the Treatment of Photodamage.

Heparan sulfate is an essential glycosaminoglycan that plays important roles in development, homeostasis, and disease. As a group, the glycosaminoglycans provide mechanical strength to skin, as they can absorb water and occupy the space between elastin fibers and collagen. Heparan sulfate is also a key participant in cell proliferation, cell migration, collagen fiber formation, basement membrane regeneration, granulation tissue formation, and cell adhesion associated with wound healing. A variety of dermatological disorders are associated with changes in glycosaminoglycans or their associated proteoglycans. A new topical formulation of low molecular weight heparan sulfate glycosaminoglycan has been shown to penetrate the epidermis, basement membrane, and dermis within 24 hours of application. In an 8-week study, 15 patients using this new formulation showed improvement in skin hydration, skin firmness, skin elasticity, skin barrier function, and global fine lines and wrinkles. Incorporating low molecular weight heparan sulfate into topically applied formulations may represent a new approach to improving the appearance of photodamaged skin.

In Crohn's disease fibrosis-reduced expression of the miR-29 family enhances collagen expression in intestinal fibroblasts.

Intestinal fibrosis with stricture formation is a complication of CD (Crohn's disease) that may mandate surgical resection. Accurate biomarkers that reflect the relative contribution of fibrosis to an individual stricture are an unmet need in managing patients with CD. The miRNA-29 (miR-29) family has been implicated in cardiac, hepatic and pulmonary fibrosis. In the present study, we investigated the expression of miR-29a, miR-29b and miR-29c in mucosa overlying a stricture in CD patients (SCD) paired with mucosa from non-strictured areas (NSCD). There was significant down-regulation of the miR-29 family in mucosa overlying SCD compared with mucosa overlying NSCD. miR-29b showed the largest fold-decrease and was selected for functional analysis. Overexpression of miR-29b in CD fibroblasts led to a down-regulation of collagen I and III transcripts and collagen III protein, but did not alter MMP (matrix metalloproteinase)-3, MMP-12 and TIMP (tissue inhibitor of metalloproteinase)-1 production. TGF (transforming growth factor)-ß1 up-regulated collagen I and III transcripts and collagen III protein as a consequence of the down-regulation of miR-29b, and TGF-ß1-induced collagen expression was reversed by exogenous overexpression of miR-29b. Furthermore, serum levels of miR-29 were lower in patients with stricturing disease compared with those without. These findings implicate the miR-29 family in the pathogenesis of intestinal fibrosis in CD and provide impetus for the further evaluation of the miR-29 family as biomarkers.