17 research outputs found
Interleukin-23 regulates interleukin-17 expression in wounds, and its inhibition accelerates diabetic wound healing through the alteration of macrophage polarization
No full textInflammation is a critical phase in the healing of skin wounds. Excessive inflammation and inflammatory macrophages are known to cause impaired wound closure and outcome. This prompted us to test the role of IL-23 in IL-17 expression and in modulating wound inflammation and macrophage polarization. Full-thickness wounds (4 × 6 mm) were created on the dorsal surface of multiple genetically modified mouse models. Obese diabetic mouse wounds were treated with anti-IL-17A, anti-IL-23, or isotype-matched antibodies. We found IL-23- but not IL-12-deficient mice displayed significantly reduced IL-17 expression in wounds. This was rescued by delivery of recombinant IL-23. IL-23- and IL-17-deficient mice showed a significant increase in noninflammatory macrophages. Obese diabetic mice treated with anti-IL-17A and anti-IL-23p19 blocking antibodies had significantly improved wound reepithelialization. Similarly, IL-17-/- obese mice had accelerated wound closure, resulting in reduced iNOS expression and inflammatory macrophages while maintaining prohealing CD206 and lymphatic vessel endothelial hyaluronic acid receptor 1 (LYVE1)-expressing macrophages. This study highlights the importance of the IL-17 pathway in wound closure offering new possibilities of therapeutic intervention in chronic wounds.-Lee, J., Rodero, M. P., Patel, J., Moi, D., Mazzieri, R., Khosrotehrani, K. Interleukin-23 regulates interleukin-17 expression in wounds, and its inhibition accelerates diabetic wound healing through the alteration of macrophage polarization
Control of Both Myeloid Cell Infiltration and Angiogenesis by CCR1 Promotes Liver Cancer Metastasis Development in Mice
No full textAbstractExpression of the CC chemokine receptor 1 (CCR1) by tumor cells has been associated with protumoral activity; however, its role in nontumoral cells during tumor development remains elusive. Here, we investigated the role of CCR1 deletion on stromal and hematopoietic cells in a liver metastasis tumor model. Metastasis development was strongly impaired in CCR1-deficient mice compared to control mice and was associated with reduced liver monocyte infiltration. To decipher the role of myeloid cells, sublethally irradiated mice were reconstituted with CCR1-deficient bone marrow (BM) and showed better survival rates than the control reconstituted mice. These results point toward the involvement of CCR1 myeloid cell infiltration in the promotion of tumor burden. In addition, survival rates were extended in CCR1-deficient mice receiving either control or CCR1-deficient BM, indicating that host CCR1 expression on nonhematopoietic cells also supports tumor growth. Finally, we found defective tumor-induced neoangiogenesis (in vitro and in vivo) in CCR1-deficient mice. Overall, our results indicate that CCR1 expression by both hematopoietic and nonhematopoietic cells favors tumor aggressiveness. We propose CCR1 as a potential therapeutical target for liver metastasis therapy
Expanding the clinical spectrum of Fowler syndrome: Three siblings with survival into adulthood and systematic review of the literature
No full textProliferative vasculopathy and hydranencephaly-hydrocephaly syndrome (PVHH, OMIM 225790), also known as Fowler syndrome, is a rare autosomal recessive disorder of brain angiogenesis. PVHH has long been considered to be prenatally lethal. We evaluated the phenotypes of the first three siblings with survival into adulthood, performed a systematic review of the Fowler syndrome literature and delineated genotype-phenotype correlations using a scoring system to rate the severity of the disease. Thirty articles were included, describing 69 individual patients. To date, including our clinical reports, 72 patients have been described with Fowler syndrome. Only 6/72 (8%) survived beyond birth. Although our three patients carry the same mutations (c.327T>A-p.Asn109Lys and c.887C>T-p.Ser296Leu) in FLVCR2, only two of them presented with the same cerebral features, ventriculomegaly and cerebral calcifications, as affected fetuses. The third sibling has a surprisingly milder clinical and radiological phenotype, suggesting intrafamilial variability. Although no clear phenotype-genotype correlation exists, some variants appear to be associated with a less severe phenotype compatible with life. As such, it is important to consider Fowler syndrome in patients with gross ventriculomegaly, cortical malformations and/or cerebral calcifications on brain imaging.sponsorship: Internal fund of the University of Leuven, Grant/Award Number: PDM/17/195; MSDAvenir fund, Grant/Award Number: DEVO-DECODE Project; National Research Agency (France) `Investments for the Future', Grant/Award Number: ANR-10-IAHU-01 (University of Leuven|PDM/17/195, MSDAvenir fund, National Research Agency (France) `Investments for the Future'|ANR-10-IAHU-01)status: Publishe
Mutations in SNORD118 cause the cerebral microangiopathy leukoencephalopathy with calcifications and cysts
No full textAlthough ribosomes are ubiquitous and essential for life, recent data indicate that monogenic causes of ribosomal dysfunction can confer a remarkable degree of specificity in terms of human disease phenotype. Box C/D small nucleolar RNAs (snoRNAs) are evolutionarily conserved non-protein-coding RNAs involved in ribosome biogenesis. Here we show that biallelic mutations in the gene SNORD118, encoding the box C/D snoRNA U8, cause the cerebral microangiopathy leukoencephalopathy with calcifications and cysts (LCC), presenting at any age from early childhood to late adulthood. These mutations affect U8 expression, processing and protein binding and thus implicate U8 as essential in cerebral vascular homeostasis.</p
OPOS: object-parallel optimization software
No full textThis dissertation describes OPOS, a C++ software library and framework for developing massively parallel continuous optimization software. We show that classical iterative optimization algorithms such as gradient projection and augmented Lagrangian methods can be parallelized to run efficiently on distributed memory machines using OPOS.
In Chapter 1 we provide some background on general optimization software and algorithms, as well as parallel software for LASSO and stochastic programming problems.
Chapter 2 introduces OPOS’s software development methodology. We start out by describing a set of optimization-domain-specific C++ classes and routines that embody the building blocks of OPOS. The main goal of these classes and routines is to allow the user to code efficient, reusable, maintainable, and readily parallelizable optimization algorithms. OPOS enables the optimization software developer to build optimization algorithm classes that are independent of the problem structure as well as the program’s
desired execution.
Details of a spectral projected gradient algorithm by Birgin and Martı́nez and its implementation, OPSPG, are discussed in Chapter 3. Initially, we review the optimization algorithm and OPSPG’s code. Next we describe an application to the LASSO problem, and a novel data distribution technique which achieves an even load balance. Followed by implementation details of objective function and gradient evaluations given our data distribution. We close the chapter by presenting computational results.
Chapter 4 introduces the basic theory behind augmented Lagrangian algorithms and a specific version called ALGENCAN, which was developed by Birgin and Martı́nez. Then we discuss the building blocks of our object-parallel augmented Lagrangian software OPAL, which is based on ALGENCAN. OPAL is applied to solve linear stochastic programming problems. We describe a scenario-based data distribution technique using PySP, a python-based modeling software for stochastic programs. This is followed by implementation details of objective function, constraint and gradient evaluations given our data distribution. At the end of the chapter, we demonstrate our computational results.
Chapter 5 summarizes findings of our work and discusses future research opportunities for both LASSO and stochastic programming problems.Ph.D.Includes bibliographical referencesby György Mátyásfalv
Muscle Spatial Transcriptomic Reveals Heterogeneous Profiles in Juvenile Dermatomyositis and Persistence of Abnormal Signature After Remission
No full textThis study aimed to investigate the spatial heterogeneity of molecular signature in the muscle of juvenile dermatomyositis (JDM) patients before and after treatment. Unsupervised reference-free deconvolution of spatial transcriptomics and standardized morphometry were performed in two JDM muscle biopsies with different clinical severity at disease onset and compared to healthy muscle. Identified signatures were scored in two additional JDM muscle biopsies from the same patient before and after remission. Disappearance of the normal muscle signature mostly corresponding to mitochondrial biology was observed in JDM. Three pathological transcriptomic signatures were isolated, related to “myofibrillar stress”, “muscle remodeling” and “interferon signaling” signatures. The “myofibrillar stress signature” was prominent in the most severe biopsy while the “muscle remodeling” signature was mostly present in the biopsy from the patient with good outcome. These signatures unveiled genes not previously associated with JDM including ANKRD1 and FSLT1 for “myofibrillar stress” and “muscle remodeling” signatures, respectively. Post-treatment analysis of muscle after two years remission showed a persistence of pathological signatures. This pilot study of JDM muscle identified spatially distributed pathological signatures that persist after remission. This work paves the way for a better understanding of the pathophysiology in affected muscle and the identification of biomarkers that predict relapse
Effect of breast feeding on intelligence in children: prospective study, sibling pairs analysis, and meta-analysis
No full textObjective To assess the importance of maternal intelligence, and the effect of controlling for it and other important confounders, in the link between breast feeding and children's intelligence.
Design Examination of the effect of breast feeding on cognitive ability and the impact of a range of potential confounders, in particular maternal IQ, within a national database. Additional analyses compared pairs of siblings from the sample who were and were not breast fed. The results are considered in the context of other studies that have also controlled for parental intelligence via meta-analysis.
Setting 1979 US national longitudinal survey of youth.
Subjects Data on 5475 children, the offspring of 3161 mothers in the longitudinal survey.
Main outcome measure IQ in children measured by Peabody individual achievement test.
Results The mother's IQ was more highly predictive of breastfeeding status than were her race, education, age, poverty status, smoking, the home environment, or the child's birth weight or birth order. One standard deviation advantage in maternal IQ more than doubled the odds of breast feeding. Before adjustment, breast feeding was associated with an increase of around 4 points in mental ability. Adjustment for maternal intelligence accounted for most of this effect. When fully adjusted for a range of relevant confounders, the effect was small (0.52) and non-significant (95% confidence interval -0.19 to 1.23). The results of the sibling comparisons and meta-analysis corroborated these findings.
Conclusions Breast feeding has little or no effect on intelligence in children. While breast feeding has many advantages for the child and mother, enhancement of the child's intelligence is unlikely to be among them
