The homozygous M712T mutation of UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase results in reduced enzyme activities but not in altered overall cellular sialylation in hereditary inclusion body myopathy

AbstractHereditary inclusion body myopathy (HIBM) is a neuromuscular disorder, caused by mutations in UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase, the key enzyme of sialic acid biosynthesis. In Middle Eastern patients a single homozygous mutation occurs, converting methionine-712 to threonine. Recombinant expression of the mutated enzyme revealed slightly reduced N-acetylmannosamine kinase activity, in agreement with the localization of the mutation within the kinase domain. B lymphoblastoid cell lines derived from patients expressing the mutated enzyme also display reduced UDP-N-acetylglucosamine 2-epimerase activity. Nevertheless, no reduced cellular sialylation was found in those cells by colorimetric assays and lectin analysis, indicating that HIBM is not directly caused by an altered overall expression of sialic acids

Regulation of DMD pathology by an ankyrin-encoded miRNA

<p>Abstract</p> <p>Background</p> <p>Duchenne muscular dystrophy (DMD) is an X-linked myopathy resulting from the production of a nonfunctional dystrophin protein. MicroRNA (miRNA) are small 21- to 24-nucleotide RNA that can regulate both individual genes and entire cell signaling pathways. Previously, we identified several mRNA, both muscle-enriched and inflammation-induced, that are dysregulated in the skeletal muscles of DMD patients. One particularly muscle-enriched miRNA, miR-486, is significantly downregulated in dystrophin-deficient mouse and human skeletal muscles. miR-486 is embedded within the <it>ANKYRIN1(ANK1) </it>gene locus, which is transcribed as either a long (erythroid-enriched) or a short (heart muscle- and skeletal muscle-enriched) isoform, depending on the cell and tissue types.</p> <p>Results</p> <p>Inhibition of miR-486 in normal muscle myoblasts results in inhibited migration and failure to repair a wound in primary myoblast cell cultures. Conversely, overexpression of miR-486 in primary myoblast cell cultures results in increased proliferation with no changes in cellular apoptosis. Using bioinformatics and miRNA reporter assays, we have identified platelet-derived growth factor receptor β, along with several other downstream targets of the phosphatase and tensin homolog deleted on chromosome 10/AKT (PTEN/AKT) pathway, as being modulated by miR-486. The generation of muscle-specific transgenic mice that overexpress miR-486 revealed that miR-486 alters the cell cycle kinetics of regenerated myofibers <it>in vivo</it>, as these mice had impaired muscle regeneration.</p> <p>Conclusions</p> <p>These studies demonstrate a link for miR-486 as a regulator of the PTEN/AKT pathway in dystrophin-deficient muscle and an important factor in the regulation of DMD muscle pathology.</p

Middle ground approach to paradox: Within- and between-culture examination of the creative benefits of paradoxical frames

The authors contributed equally to this work.</p

Confirmation that a specific haplotype of the dopamine transporter gene is associated with Combined-Type ADHD

Objective: The primary purpose of this study was to confirm the association of a specific haplotype of the dopamine transporter gene and attention deficit hyperactivity disorder (ADHD), which could be one source of the heterogeneity seen across published studies. Method: The authors previously reported the association of ADHD with a subgroup of chromosomes containing specific alleles of two variable-number tandem repeat polymorphisms within the 3' untranslated region and intron 8 of the dopamine transporter gene. They now report on this association in a sample of ADHD combined-type probands. Results: The original observations were confirmed, with an overall odds ratio of 1.4 across samples. Conclusions: These data challenge results of meta-analyses suggesting that dopamine transporter variation does not have an effect on the risk for ADHD, and they indicate that further investigation of functional variation in the gene is required. <br/

Complementary and conventional medicine: a concept map

BACKGROUND: Despite the substantive literature from survey research that has accumulated on complementary and alternative medicine (CAM) in the United States and elsewhere, very little research has been done to assess conceptual domains that CAM and conventional providers would emphasize in CAM survey studies. The objective of this study is to describe and interpret the results of concept mapping with conventional and CAM practitioners from a variety of backgrounds on the topic of CAM. METHODS: Concept mapping, including free sorts, ratings, and multidimensional scaling was used to organize conceptual domains relevant to CAM into a visual "cluster map." The panel consisted of CAM providers, conventional providers, and university faculty, and was convened to help formulate conceptual domains to guide the development of a CAM survey for use with United States military veterans. RESULTS: Eight conceptual clusters were identified: 1) Self-assessment, Self-care, and Quality of Life; 2) Health Status, Health Behaviors; 3) Self-assessment of Health; 4) Practical/Economic/ Environmental Concerns; 5) Needs Assessment; 6) CAM vs. Conventional Medicine; 7) Knowledge of CAM; and 8) Experience with CAM. The clusters suggest panelists saw interactions between CAM and conventional medicine as a critical component of the current medical landscape. CONCLUSIONS: Concept mapping provided insight into how CAM and conventional providers view the domain of health care, and was shown to be a useful tool in the formulation of CAM-related conceptual domains

Nanomateriales compuestos de polímeros biodegradables

Películas de materiales compuestos basados en el polímero diodegradable policaprolactona y 5% en peso de organoarcillas fueron preparadas por mezcla de fundentes. Las organoarcillas se obtuvieron por modificación de bentonita patagónica mediante intercambio catiónico con distintas proporciones de bromuro de hexadeciltrimetilamonio (HD) y octadeciltrimetilamonio (OD). Las respuestas SAXS y WAXS de todas las películas muestran expansión de las organoarcillas indicando ingreso del polímero en las galerías. Las medidas dieléctricas mostraron un incremento en la constante dieléctrica y en la pérdida dieléctrica a baja frecuencia.Facultad de Ingenierí

Nanomateriales compuestos de polímeros biodegradables

Películas de materiales compuestos basados en el polímero diodegradable policaprolactona y 5% en peso de organoarcillas fueron preparadas por mezcla de fundentes. Las organoarcillas se obtuvieron por modificación de bentonita patagónica mediante intercambio catiónico con distintas proporciones de bromuro de hexadeciltrimetilamonio (HD) y octadeciltrimetilamonio (OD). Las respuestas SAXS y WAXS de todas las películas muestran expansión de las organoarcillas indicando ingreso del polímero en las galerías. Las medidas dieléctricas mostraron un incremento en la constante dieléctrica y en la pérdida dieléctrica a baja frecuencia.Facultad de Ingenierí

Nanomateriales compuestos de polímeros biodegradables

Películas de materiales compuestos basados en el polímero diodegradable policaprolactona y 5% en peso de organoarcillas fueron preparadas por mezcla de fundentes. Las organoarcillas se obtuvieron por modificación de bentonita patagónica mediante intercambio catiónico con distintas proporciones de bromuro de hexadeciltrimetilamonio (HD) y octadeciltrimetilamonio (OD). Las respuestas SAXS y WAXS de todas las películas muestran expansión de las organoarcillas indicando ingreso del polímero en las galerías. Las medidas dieléctricas mostraron un incremento en la constante dieléctrica y en la pérdida dieléctrica a baja frecuencia.Facultad de Ingenierí

A de novo paradigm for male infertility

Funding Information: (DFG, CRU326) to C.F. and F.T. This project was also supported in part by funding from the Australian National Health and Medical Research Council (APP1120356) to M.K.O.B., by grants from the National Institutes of Health of the United States of America (R01HD078641 to D.F.C. and K.I.A., P50HD096723 to D.F.C.) and from the Biotechnology and Biological Sciences Research Council (BB/S008039/1) to D.J.E. Funding Information: We are grateful for the participation of all patients and their parents in this study. We thank Laurens van de Wiel (Radboudumc), Sebastian Judd-Mole (Monash University), Arron Scott and Bryan Hepworth (Newcastle University) for technical support, and Margot J Wyrwoll (University of Münster) for help with handling MERGE samples and data. This project was funded by The Netherlands Organization for Scientific Research (918-15-667) to J.A.V. as well as an Investigator Award in Science from the Wellcome Trust (209451) to J.A.V. a grant from the Catherine van Tussenbroek Foundation to M.S.O. a grant from MERCK to R.S. a UUKi Rutherford Fund Fellowship awarded to B.J.H. and the German Research Foundation Clinical Research Unit “Male Germ Cells” Publisher Copyright: © 2022, The Author(s).De novo mutations are known to play a prominent role in sporadic disorders with reduced fitness. We hypothesize that de novo mutations play an important role in severe male infertility and explain a portion of the genetic causes of this understudied disorder. To test this hypothesis, we utilize trio-based exome sequencing in a cohort of 185 infertile males and their unaffected parents. Following a systematic analysis, 29 of 145 rare (MAF < 0.1%) protein-altering de novo mutations are classified as possibly causative of the male infertility phenotype. We observed a significant enrichment of loss-of-function de novo mutations in loss-of-function-intolerant genes (p-value = 1.00 × 10−5) in infertile men compared to controls. Additionally, we detected a significant increase in predicted pathogenic de novo missense mutations affecting missense-intolerant genes (p-value = 5.01 × 10−4) in contrast to predicted benign de novo mutations. One gene we identify, RBM5, is an essential regulator of male germ cell pre-mRNA splicing and has been previously implicated in male infertility in mice. In a follow-up study, 6 rare pathogenic missense mutations affecting this gene are observed in a cohort of 2,506 infertile patients, whilst we find no such mutations in a cohort of 5,784 fertile men (p-value = 0.03). Our results provide evidence for the role of de novo mutations in severe male infertility and point to new candidate genes affecting fertility.publishersversionpublishe

A de novo paradigm for male infertility

Genetics of Male Infertility Initiative (GEMINI) consortium: Donald F. Conrad, Liina Nagirnaja, Kenneth I. Aston, Douglas T. Carrell, James M. Hotaling, Timothy G. Jenkins, Rob McLachlan, Moira K. O’Bryan, Peter N. Schlegel, Michael L. Eisenberg, Jay I. Sandlow, Emily S. Jungheim, Kenan R. Omurtag, Alexandra M. Lopes, Susana Seixas, Filipa Carvalho, Susana Fernandes, Alberto Barros, João Gonçalves, Iris Caetano, Graça Pinto, Sónia Correia, Maris Laan, Margus Punab, Ewa Rajpert-De Meyts, Niels Jørgensen, Kristian Almstrup, Csilla G. Krausz & Keith A. Jarvi.De novo mutations are known to play a prominent role in sporadic disorders with reduced fitness. We hypothesize that de novo mutations play an important role in severe male infertility and explain a portion of the genetic causes of this understudied disorder. To test this hypothesis, we utilize trio-based exome sequencing in a cohort of 185 infertile males and their unaffected parents. Following a systematic analysis, 29 of 145 rare (MAF < 0.1%) protein-altering de novo mutations are classified as possibly causative of the male infertility phenotype. We observed a significant enrichment of loss-of-function de novo mutations in loss-of-function-intolerant genes (p-value = 1.00 × 10−5) in infertile men compared to controls. Additionally, we detected a significant increase in predicted pathogenic de novo missense mutations affecting missense-intolerant genes (p-value = 5.01 × 10−4) in contrast to predicted benign de novo mutations. One gene we identify, RBM5, is an essential regulator of male germ cell pre-mRNA splicing and has been previously implicated in male infertility in mice. In a follow-up study, 6 rare pathogenic missense mutations affecting this gene are observed in a cohort of 2,506 infertile patients, whilst we find no such mutations in a cohort of 5,784 fertile men (p-value = 0.03). Our results provide evidence for the role of de novo mutations in severe male infertility and point to new candidate genes affecting fertility.This project was funded by The Netherlands Organization for Scientific Research (918-15-667) to J.A.V. as well as an Investigator Award in Science from the Wellcome Trust (209451) to J.A.V. a grant from the Catherine van Tussenbroek Foundation to M.S.O. a grant from MERCK to R.S. a UUKi Rutherford Fund Fellowship awarded to B.J.H. and the German Research Foundation Clinical Research Unit “Male Germ Cells” (DFG, CRU326) to C.F. and F.T. This project was also supported in part by funding from the Australian National Health and Medical Research Council (APP1120356) to M.K.O.B., by grants from the National Institutes of Health of the United States of America (R01HD078641 to D.F.C. and K.I.A., P50HD096723 to D.F.C.) and from the Biotechnology and Biological Sciences Research Council (BB/S008039/1) to D.J.E.info:eu-repo/semantics/publishedVersio