Development of a Scalable Fabrication Concept for Sustainable, Programmable Shape‐Morphing Metamaterials

Programmable materials are a novel development, in which specialized production processes are used to introduce a framework of information capabilities into the inner structure of materials. Since the design and fabrication of programmable materials are still challenging, this aims to introduce a design and fabrication concept to pave the way toward industrial application. Herein, complex shape morphing has been implemented in the sense that the shape changes in response to external conditions, following a predefined program. First, the feasibility of a fabrication concept for uniform metamaterials with auxetic behavior is presented. A material with a predetermined nonuniform inner structure that deforms to a symmetrical shape has been developed and fabricated according to this concept. More complex behavior can be implemented by facilitating optimization methods to find inner structures according to a target shape. Lastly, an optimized and producible design for asymmetrical shape morphing is described to demonstrate the applicability of the approach

LPIN1 gene mutations: a major cause of severe rhabdomyolysis in early childhood.

International audienceAutosomal recessive LPIN1 mutations have been recently described as a novel cause of rhabdomyolysis in a few families. The purpose of the study was to evaluate the prevalence of LPIN1 mutations in patients exhibiting severe episodes of rhabdomyolysis in infancy. After exclusion of primary fatty acid oxidation disorders, LPIN1 coding sequence was determined in genomic DNA and cDNA. Among the 29 patients studied, 17 (59%) carried recessive nonsense or frameshift mutations, or a large scale intragenic deletion. In these 17 patients, episodes of rhabdomyolysis occurred at a mean age of 21 months. Secondary defect of mitochondrial fatty oxidation or respiratory chain was found in skeletal muscle of two patients. The intragenic deletion, c.2295-866_2410-30del, was identified in 8/17 patients (47%), all Caucasians, and occurred on the background of a common haplotype, suggesting a founder effect. This deleted human LPIN1 form was unable to complement ∆pah1 yeast for growth on glycerol, in contrast to normal LPIN1. Since more than 50% of our series harboured LPIN1 mutations, LPIN1 should be regarded as a major cause of severe myoglobinuria in early childhood. The high frequency of the intragenic LPIN1 deletion should provide a valuable criterion for fast diagnosis, prior to muscle biopsy

Multi-ancestry genome-wide association study of 21,000 cases and 95,000 controls identifies new risk loci for atopic dermatitis

Genetic association studies have identified 21 loci associated with atopic dermatitis risk predominantly in populations of European ancestry. To identify further susceptibility loci for this common, complex skin disease, we performed a meta-analysis of >15 million genetic variants in 21,399 cases and 95,464 controls from populations of European, African, Japanese and Latino ancestry, followed by replication in 32,059 cases and 228,628 controls from 18 studies. We identified ten new risk loci, bringing the total number of known atopic dermatitis risk loci to 31 (with new secondary signals at four of these loci). Notably, the new loci include candidate genes with roles in the regulation of innate host defenses and T cell function, underscoring the important contribution of (auto)immune mechanisms to atopic dermatitis pathogenesis

European and multi-ancestry genome-wide association meta-analysis of atopic dermatitis highlights importance of systemic immune regulation

Atopic dermatitis (AD) is a common inflammatory skin condition and prior genome-wide association studies (GWAS) have identified 71 associated loci. In the current study we conducted the largest AD GWAS to date (discovery N = 1,086,394, replication N = 3,604,027), combining previously reported cohorts with additional available data. We identified 81 loci (29 novel) in the European-only analysis (which all replicated in a separate European analysis) and 10 additional loci in the multi-ancestry analysis (3 novel). Eight variants from the multi-ancestry analysis replicated in at least one of the populations tested (European, Latino or African), while two may be specific to individuals of Japanese ancestry. AD loci showed enrichment for DNAse I hypersensitivity and eQTL associations in blood. At each locus we prioritised candidate genes by integrating multi-omic data. The implicated genes are predominantly in immune pathways of relevance to atopic inflammation and some offer drug repurposing opportunities.</p

Redefining the MED13L syndrome

Congenital cardiac and neurodevelopmental deficits have been recently linked to the mediator complex subunit 13-like protein MED13L, a subunit of the CDK8-associated mediator complex that functions in transcriptional regulation through DNA-binding transcription factors and RNA polymerase II. Heterozygous MED13L variants cause transposition of the great arteries and intellectual disability (ID). Here, we report eight patients with predominantly novel MED13L variants who lack such complex congenital heart malformations. Rather, they depict a syndromic form of ID characterized by facial dysmorphism, ID, speech impairment, motor developmental delay with muscular hypotonia and behavioral difficulties. We thereby define a novel syndrome and significantly broaden the clinical spectrum associated with MED13L variants. A prominent feature of the MED13L neurocognitive presentation is profound language impairment, often in combination with articulatory deficits

Aspectos biológicos e implicações clínicas na dor lombar crônica: uma revisão narrativa

Introduction: Chronic low back pain has a high prevalence and social burden, but its pathophysiology is uncertain, and treatment is unsatisfactory.Objective: To perform a narrative review of the literature on chronic nonspecific low back pain, possible phenomena, biological mechanisms and clinical implications.Materials and Methods: Articles published between 2014 and 2020, in English, with keywords “chronic low back pain” and “central sensitization” in the LILACS and MEDLINE databases were included.Results: Chronic low back pain may present changes in brain neuroplasticity due to central sensitization and nociplastic pain. The brain-derived neurotrophic factor is related to the hyperexcitability of central neurons, facilitating nociception and central sensitization. Biological pathways involve the degradation of glutamate receptors, coupled to protein G, by glial hyperactivity and opiordergic and dopaminergic cortico-limbic circuits. This processing dysfunction, perception amplification and pain modulation are the characteristics of nociplastic pain. In addition to clinical evaluation to exclude red flags, blood dosages of pro and anti-infl ammatory cytokines; quantitative sensory tests, and instruments such as the Central Sensitization Inventory seem relevant to clinical practice.Conclusion: Changes by central sensitization may be associated with chronic low back pain, requiring further investigation since the evidence on this topic is still incipient.Introdução: A dor lombar crônica possui alta prevalência e carga social, mas sua fisiopatologia é incerta e o tratamento insatisfatório.Objetivo: Realizar revisão narrativa da literatura sobre dor lombar crônica inespecífica, possíveis fenômenos, mecanismos biológicos e implicações clínicas.Materiais e Métodos: Artigos publicados entre 2014 e 2020, em inglês, com palavras-chave “chronic low back pain” e “central sensitization” nas bases de dados LILACS e MEDLINE foram incluídos.Resultados: A dor lombar crônica pode apresentar alterações da neuroplasticidade cerebral por sensibilização central e dor nociplástica. O fator neurotrófico derivado do cérebro é relacionado com a hiperexcitabilidade de neurônios centrais, facilitação da nocicepção e sensibilização central. As vias biológicas envolvem a degradação dos receptores glutamato, acoplados à proteína G, por hiperatividade glial e circuitos córtico-límbicos opiordérgicos e dopaminérgicos. Essa disfunção do processamento, amplificação da percepção e modulação da dor são as características da dor nociplástica. Além da avaliação clínica para excluir red flags, dosagens sanguíneas de citocinas pró e anti-inflamatórias; testes sensoriais quantitativos; e instrumentos como Inventário de Sensibilização Central parecem relevantes para a prática clínica.Conclusão: Alterações por sensibilização central podem estar associadas à dor lombar crônica, sendo necessárias maiores investigações já que as evidências sobre este tópico ainda são incipientes

Familial Glucocorticoid Deficiency Type 1 due to a Novel Compound Heterozygous MC2R Mutation

Objective: Description of the clinical, biochemical and genetic features of a Polish patient with familial glucocorticoid deficiency. Methods: Detailed clinical investigation, hormonal analysis and sequencing of the coding region of the melanocortin 2 receptor (MC2R) gene in this patient. Results: We report on a 3-month-old boy with familial glucocorticoid deficiency who presented at the age of 3 months with skin hyperpigmentation, muscle weakness, mild jaundice and constipation. Hormonal analyses revealed high ACTH and TSH serum concentrations, low serum cortisol concentration along with normal blood electrolytes. On hydrocortisone supplementation, the disease symptoms disappeared and the child recovered completely. His physical and mental development progresses normally. Genetic analysis disclosed a novel compound heterozygous MC2R mutation p.Leu46fs and p.Val49Met. Conclusion: The heterozygous p.Leu46fs mutation adds to the small number of MC2R nonsense mutations and is the first frameshift mutation within the first transmembrane domain of the receptor. According to molecular modeling the Val49Met mutation results in a structural change of the first transmembrane domain and in a potential novel interaction of the transmembrane domains I and VII.Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich

Long-Term Outcomes, Genetics, and Pituitary Morphology in Patients with Isolated Growth Hormone Deficiency and Multiple Pituitary Hormone Deficiencies: A Single-Centre Experience of Four Decades of Growth Hormone Replacement

Background: Growth hormone (GH) has been used to treat children with GH deficiency (GHD) since 1966. Aims: Using a combined retrospective and cross-sectional approach, we explored the long-term outcomes of patients with GHD, analysed factors influencing therapeutic response, determined persistence into adulthood, investigated pituitary morphology, and screened for mutations in causative genes. Methods: The files of 96 GH-deficient children were reviewed. In a subset of 50 patients, re-assessment in adulthood was performed, including GHRH-arginine testing, pituitary magnetic resonance imaging (MRI), and mutational screening for the growth hormone-1 gene (GH1) and the GHRH receptor gene (GHRHR) in isolated GHD (IGHD), and HESX1 , PROP1 , POU1F1 , LHX3 , LHX4 , and GLI2 in multiple pituitary hormone deficiency (MPHD) patients. Results: GH was started at a height SDS of –3.2 ± 1.4 in IGHD patients and of –4.1 ± 2.1 in MPHD patients. Relative height gain was 0.3 SDS/year, absolute gain 1.6 SDS, and 1.2/2.6 SDS in IGHD/MPHD, respectively. Mid-parental target height was reached in 77%. Initial height SDS, bone age retardation and duration of GH replacement were correlated with height SDS gain. GHD persisted into adulthood in 19 and 89% of subjects with IGHD and MPHD, respectively. In 1/42 IGHD patients a GH1 mutation was detected; PROP1 mutations were found in 3/7 MPHD subjects. Anterior pituitary hypoplasia, combined with posterior pituitary ectopy and pituitary stalk invisibility on MRI, was an exclusive finding in MPHD patients. Conclusions: GH replacement successfully corrects the growth deficit in children with GHD. While the genetic aetiology remains undefined in most cases of IGHD, PROP1 mutations constitute a major cause for MPHD. Persistence of GHD into adulthood is related to abnormal pituitary morphology

Anne Frank and After

Between 1940 and 1945, 110,000 of the 140,000 Dutch Jews were deported to the death camps in Eastern Europe. 80% never returned. In Anne Frank and After the authors focus on two main questions: how exactly did this happen, and how has Dutch literature come to terms with this appalling event? In the book's final chapter they analyze the relationship between history and the literature of the Holocaust. Does literature add to what we know or does it actually distort historical evidence? Based on the work of leading historians of the period, the book examines literary works from Gerard Durlacher, Anne Frank, W.F. Hermans, Harry Mulisch, Gerard Reve and many others