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The British Journal of Dermatology Jun 2024Extracellular matrices play a critical role in tissue structure and function and aberrant remodelling of these matrices is a hallmark of many age-related diseases. In...
BACKGROUND
Extracellular matrices play a critical role in tissue structure and function and aberrant remodelling of these matrices is a hallmark of many age-related diseases. In skin, loss of dermal collagens and disorganization of elastic fibre components are key features of photoageing. Although the application of some small matrix-derived peptides to aged skin has been shown to beneficially affect in vitro cell behaviour and, in vivo, molecular architecture and clinical appearance, the discovery of new peptides has lacked a guiding hypothesis.
OBJECTIVES
To identify, using protease cleavage site prediction, novel putative matrikines with beneficial activities for skin composition and structure.
METHODS
Here, we present an in silico (peptide cleavage prediction) to in vitro (proteomic and transcriptomic activity testing in cultured human dermal fibroblasts) to in vivo (short-term patch test and longer-term split-face clinical study) discovery pipeline, which enables the identification and characterization of peptides with differential activities.
RESULTS
Using this pipeline we showed that cultured fibroblasts were responsive to all applied peptides, but their associated bioactivity was sequence-dependent. Based on bioactivity, toxicity and protein source, we further characterized a combination of two novel peptides, GPKG (glycine-proline-lysine-glycine) and LSVD (leucine-serine-valine-aspartate), that acted in vitro to enhance the transcription of matrix -organization and cell proliferation genes and in vivo (in a short-term patch test) to promote processes associated with epithelial and dermal maintenance and remodelling. Prolonged use of a formulation containing these peptides in a split-face clinical study led to significantly improved measures of crow's feet and firmness in a mixed population.
CONCLUSIONS
This approach to peptide discovery and testing can identify new synthetic matrikines, providing insights into biological mechanisms of tissue homeostasis and repair and new pathways to clinical intervention.
Topics: Humans; Fibroblasts; Skin Aging; Rejuvenation; Oligopeptides; Skin; Cells, Cultured; Female; Middle Aged; Cell Proliferation; Extracellular Matrix; Male; Extracellular Matrix Proteins; Adult; Aged; Proteomics
PubMed: 38375775
DOI: 10.1093/bjd/ljae061 -
Circulation. Genomic and Precision... Apr 2024Less than 40% of patients with dilated cardiomyopathy (DCM) have a pathogenic/likely pathogenic genetic variant identified. has been linked to congenital heart defects;...
BACKGROUND
Less than 40% of patients with dilated cardiomyopathy (DCM) have a pathogenic/likely pathogenic genetic variant identified. has been linked to congenital heart defects; although an association with left ventricular noncompaction (LVNC) and DCM has been proposed, it is still considered a gene with limited evidence for these phenotypes. This study sought to investigate the association between the truncating variant () and DCM/LVNC.
METHODS
was sequenced by next-generation sequencing in 7463 unrelated probands with a diagnosis of DCM or LVNC, 22 773 probands of an internal comparison group (hypertrophic cardiomyopathy, channelopathies, or aortic diseases), and 124 098 external controls (individuals from the gnomAD database). Enrichment of in DCM/LVNC was calculated, cosegregation was determined in selected families, and clinical characteristics and outcomes were analyzed in carriers.
RESULTS
was enriched in DCM/LVNC (24/7463; 0.32%) compared with internal (1/22 773; 0.004%) and external comparison groups (4/124 098; 0.003%), with odds ratios of 73.23 (95% CI, 9.90-541.45; <0.0001) and 99.76 (95% CI, 34.60-287.62; <0.0001), respectively. was cosegregated with DCM/LVNC phenotype in 21 families for a combined logarythm of the odds score of 4.53 (strong linkage). Among 57 individuals with (49.1% men; mean age, 35.9±20.8 years), 41 (71.9%) exhibited DCM/LVNC, of whom 14 (34.1%) had also congenital heart defects. After a median follow-up of 6.9 (95% CI, 25-75:3.6-14.5) years, 9.7% of patients with DCM/LVNC had end-stage heart failure events and 4.8% experienced malignant ventricular arrhythmias.
CONCLUSIONS
is associated with DCM/LVNC; congenital heart defect is also present in around one-third of cases. -associated DCM/LVNC is characterized by a nonaggressive phenotype, with a low incidence of major cardiovascular events. should be considered a definitive gene for DCM and LVNC and routinely included in genetic testing panels for these phenotypes.
Topics: Male; Humans; Adolescent; Young Adult; Adult; Middle Aged; Female; Cardiomyopathy, Dilated; Heart Defects, Congenital; Arrhythmias, Cardiac; Phenotype; T-Box Domain Proteins
PubMed: 38353104
DOI: 10.1161/CIRCGEN.123.004404 -
Movement Disorders : Official Journal... Feb 2024Congenital mirror movements (CMM) is a rare neurodevelopmental disorder characterized by involuntary movements from one side of the body that mirror voluntary movements...
BACKGROUND
Congenital mirror movements (CMM) is a rare neurodevelopmental disorder characterized by involuntary movements from one side of the body that mirror voluntary movements on the opposite side. To date, five genes have been associated with CMM, namely DCC, RAD51, NTN1, ARHGEF7, and DNAL4.
OBJECTIVE
The aim of this study is to characterize the genetic landscape of CMM in a large group of 80 affected individuals.
METHODS
We screened 80 individuals with CMM from 43 families for pathogenic variants in CMM genes. In large CMM families, we tested for presence of pathogenic variants in multiple affected and unaffected individuals. In addition, we evaluated the impact of three missense DCC variants on binding between DCC and Netrin-1 in vitro.
RESULTS
Causal pathogenic/likely pathogenic variants were found in 35% of probands overall, and 70% with familial CMM. The most common causal gene was DCC, responsible for 28% of CMM probands and 80% of solved cases. RAD51, NTN1, and ARHGEF7 were rare causes of CMM, responsible for 2% each. Penetrance of CMM in DCC pathogenic variant carriers was 68% and higher in males than females (74% vs. 54%). The three tested missense variants (p.Ile164Thr; p.Asn176Ser; and p.Arg1343His) bind Netrin-1 similarly to wild type DCC.
CONCLUSIONS
A genetic etiology can be identified in one third of CMM individuals, with DCC being the most common gene involved. Two thirds of CMM individuals were unsolved, highlighting that CMM is genetically heterogeneous and other CMM genes are yet to be discovered. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Topics: Male; Female; Humans; Netrin-1; DCC Receptor; Movement Disorders; Dyskinesias; Mutation, Missense; Rho Guanine Nucleotide Exchange Factors
PubMed: 38314870
DOI: 10.1002/mds.29669 -
Pathology, Research and Practice Feb 2024Solitary fibrous tumors (SFTs) are known for their heterogeneous morphology, characterized by a variety of cell shapes and different growth patterns. They can also arise...
Solitary fibrous tumors (SFTs) are known for their heterogeneous morphology, characterized by a variety of cell shapes and different growth patterns. They can also arise in various anatomical locations, most commonly in extremities and deep soft tissues. Despite this diversity in morphology and location, all SFTs share a common molecular signature involving the NAB2::STAT6 gene fusion. Due to their unpredictable clinical behavior, establishing prognostic factors is crucial. This study aims to evaluate an orbital risk stratification system (RSS) proposed by Huang et al. for use in extraorbital SFTs using a database of 97 cases. The Huang model takes into consideration tumor size, mitotic figures, Ki-67 index, and dominant constituent cell (DCC) as key variables. Survival analysis confirmed the model's predictive value, with higher-risk scores being associated with poorer outcomes. However, in contrast to the orbital SFTs studied by Huang et al., our study did not find a correlation between tumor size and recurrence in extraorbital cases. While the Huang model performs slightly better than other RSS, it falls short on achieving statistical significance in distinguishing recurrence risk groups in extraorbital locations. In conclusion, this study validates the Huang RSS for use in extraorbital SFTs and underscores the importance of considering DCC, mitotic count, and Ki-67 together. However, we found that including tumor size in this model did not improve prognostic significance in extraorbital SFTs. Despite the benefits of this additional RSS, vigilant monitoring remains essential, even in cases classified as low-risk due to the inherent unpredictability of SFT clinical outcomes.
Topics: Humans; Orbital Neoplasms; Prognosis; Ki-67 Antigen; Severe Fever with Thrombocytopenia Syndrome; Repressor Proteins; Solitary Fibrous Tumors; Hemangiopericytoma; STAT6 Transcription Factor; Risk Assessment; Biomarkers, Tumor
PubMed: 38301364
DOI: 10.1016/j.prp.2024.155143 -
Molecular Biology Reports Feb 2024The 9p deletion syndrome, which was defined in a detailed way in the previous studies, was characterized by various clinical features such as psychomotor retardation,...
The 9p deletion syndrome, which was defined in a detailed way in the previous studies, was characterized by various clinical features such as psychomotor retardation, dysmorphic features and genital anomalies. In contrast to 9p deletion syndrome, 20p duplication was rarely reported in the literature with only a few case reports. Regarding the combination of 9p deletion syndrome and 20p duplication, we found that it was reported in only four patients. In the current study, we aimed to investigate a rare chromosomal rearrangement, partial monosomy 9p and trisomy 20p which was observed in two patients with mirror hand movements. The mirror hand movements was influenced by the combination of genetic and environmental factors. While some cases have been associated with mutations in the DCC, NTN1, RAD51, and DNAL4, there were many cases where the genetic basis of mirror hand movements remained unexplained. There was no alteration detected in genes that were previously known as a cause of mirror hand movement in our patients. This new finding could potentially be attributed to the dosage effect of genes within the 9p deletion or 20p duplication regions or to the genes disrupted within the breakpoint region. Future research focusing on the genes within this genomic locus may hold the potential to uncover novel etiologic reasons for mirror hand movements.
Topics: Humans; Chromosome Aberrations; Genomics; Mutation; Trisomy
PubMed: 38300327
DOI: 10.1007/s11033-023-09192-9 -
Scientific Reports Jan 2024Among the most prevalent neurodevelopmental disorders, Autism Spectrum Disorder (ASD) is highly diverse showing a broad phenotypic spectrum. ASD also couples with a...
Among the most prevalent neurodevelopmental disorders, Autism Spectrum Disorder (ASD) is highly diverse showing a broad phenotypic spectrum. ASD also couples with a broad range of mutations, both de novo and inherited. In this study, we used a proprietary SNP genotyping chip to analyze the genomic DNA of 250 Vietnamese children diagnosed with ASD. Our Single Nucleotide Polymorphism (SNP) genotyping chip directly targets more than 800 thousand SNPs in the genome. Our primary focus was to identify pathogenic/likely pathogenic mutations that are potentially linked to more severe symptoms of autism. We identified and validated 23 pathogenic/likely pathogenic mutations in this initial study. The data shows that these mutations were detected in several cases spanning multiple biological pathways. Among the confirmed SNPs, mutations were identified in genes previously known to be strongly associated with ASD such as SLCO1B1, ACADSB, TCF4, HCP5, MOCOS, SRD5A2, MCCC2, DCC, and PRKN while several other mutations are known to associate with autistic traits or other neurodevelopmental disorders. Some mutations were found in multiple patients and some patients carried multiple pathogenic/likely pathogenic mutations. These findings contribute to the identification of potential targets for therapeutic solutions in what is considered a genetically heterogeneous neurodevelopmental disorder.
Topics: Child; Humans; Autism Spectrum Disorder; Polymorphism, Single Nucleotide; Genotype; Vietnam; Genetic Predisposition to Disease; Mutation; Liver-Specific Organic Anion Transporter 1; Sulfurtransferases; Membrane Proteins; 3-Oxo-5-alpha-Steroid 4-Dehydrogenase
PubMed: 38287090
DOI: 10.1038/s41598-024-52777-y -
Translational Pediatrics Dec 2023Gene editing of the porcine genome has enabled the production of pigs that do not express the three known carbohydrate antigens that are associated with hyperacute... (Review)
Review
Gene editing of the porcine genome has enabled the production of pigs that do not express the three known carbohydrate antigens that are associated with hyperacute rejection of a pig organ xenotransplant. In addition, it is now possible to insert a variety of human transgenes to protect against the human immune response, e.g., to protect from complement and coagulation activation. As a result, cardiac xenotransplantation of the gene-edited porcine heart is progressing towards clinical application. Many hope that it will definitively address the disparity between organ supply and demand. The role of cardiac xenotransplantation in pediatric care remains controversial but we believe there is an infant patient population with complex congenital heart disease (CHD) (not optimally managed by conventional surgical approaches) that is ideally suited to initial clinical application of this new technology. The most efficacious start would be to initiate clinical use as a short-term bridge to allotransplantation, particularly in infants with single ventricle pathology and significant risk factors for first stage Norwood palliation. Infants with end-stage heart failure after first stage palliation would represent a second target population. Infants experience unacceptably high mortality and morbidity when placed on mechanical circulatory support as a bridge to allotransplant. Effectively bridging these vulnerable populations could promote acceptance of cardiac xenotransplantation, allowing indications and use to expand, e.g., by (I) bridging patients with failed second and third stage single ventricle disease, or (II) with complex biventricular CHD, or (III) those with a restrictive or dilated cardiomyopathy. Finally, there is a reasonable expectation that the immunologic privilege of infants will allow porcine heart xenotransplantation to be destination therapy for some patients. In summary, heart allotransplantation in infants offers superior outcomes when compared to three-stage single ventricle palliation, but there is a continual shortage of deceased human donor organs. We should pursue research towards the application of xenotransplantation in patients with single ventricle pathology, in whom the results of staged palliation are likely to be suboptimal. There are many remaining issues to be resolved before cardiac xenotransplantation enters regular pediatric clinical use, but experience in this field is progressing rapidly.
PubMed: 38197100
DOI: 10.21037/tp-22-664 -
Doklady. Biochemistry and Biophysics Dec 2023The proteins MSL1, MSL2, MSL3, MLE, and MOF and noncoding RNAs roX1 and roX2 form the Drosophila dosage compensation complex (DCC), which specifically binds to the X...
The proteins MSL1, MSL2, MSL3, MLE, and MOF and noncoding RNAs roX1 and roX2 form the Drosophila dosage compensation complex (DCC), which specifically binds to the X chromosome of males. It is known that noncoding RNA roX are primary component of the DCC in the process of assembly and spreading of the complex among the X chromosome of males. However, the role of this RNA in maintaining the structure of the already assembled complex remains unclear. In this work, we have shown that the full-assembled dosage compensation complex dissociates rather weakly when treated with RNases: the MLE helicase is effectively released from the complex, and the remaining protein components (MSL1, MSL2, and MSL3) undergo partial disassembly and continue to be part of subcomplexes. The results confirm the importance of the noncoding roX2 RNA not only in the processes of initiation of DCC assembly but also at the stage of maintaining the structure of the already assembled complex.
Topics: Animals; Male; Drosophila; Drosophila melanogaster; Drosophila Proteins; RNA, Long Noncoding; Transcription Factors; X Chromosome
PubMed: 38189885
DOI: 10.1134/S160767292370062X -
Scientific Reports Jan 2024Lewis lung carcinoma (LLC), as a widely used preclinical cancer model, has still not been genetically and genomically characterized. Here, we performed a whole-exome...
Lewis lung carcinoma (LLC), as a widely used preclinical cancer model, has still not been genetically and genomically characterized. Here, we performed a whole-exome sequencing analysis on the LLC cell line to elucidate its molecular characteristics and etiologies. Our data showed that LLC originated from a male mouse belonging to C57BL/6L (a transitional strain between C57BL/6J and C57BL/6N) and contains substantial somatic SNV and InDel mutations (> 20,000). Extensive regional mutation clusters are present in its genome, which were caused mainly by the mutational processes underlying the SBS1, SBS5, SBS15, SBS17a, and SBS21 signatures during frequent structural rearrangements. Thirty three deleterious mutations are present in 30 cancer genes including Kras, Nras, Trp53, Dcc, and Cacna1d. Cdkn2a and Cdkn2b are biallelically deleted from the genome. Five pathways (RTK/RAS, p53, cell cycle, TGFB, and Hippo) are oncogenically deregulated or affected. The major mutational processes in LLC include chromosomal instability, exposure to metabolic mutagens, spontaneous 5-methylcytosine deamination, defective DNA mismatch repair, and reactive oxygen species. Our data also suggest that LLC is a lung cancer similar to human lung adenocarcinoma. This study lays a molecular basis for the more targeted application of LLC in preclinical research.
Topics: Male; Humans; Mice; Animals; Adenocarcinoma; Carcinoma, Lewis Lung; Exome Sequencing; Mice, Inbred C57BL; Mutation; Lung Neoplasms; Proto-Oncogene Proteins p21(ras)
PubMed: 38167599
DOI: 10.1038/s41598-023-50703-2 -
Circulation Research Jan 2024Single-nucleotide polymorphisms linked with the rs1474868 T allele ( [mitofusin-2] T/T) in the human mitochondrial fusion protein gene are associated with reduced...
BACKGROUND
Single-nucleotide polymorphisms linked with the rs1474868 T allele ( [mitofusin-2] T/T) in the human mitochondrial fusion protein gene are associated with reduced platelet RNA expression and platelet counts. This study investigates the impact of MFN2 on megakaryocyte and platelet biology.
METHODS
Mice with megakaryocyte/platelet deletion of ( [ conditional knockout]) were generated using Pf4-Cre crossed with floxed mice. Human megakaryocytes were generated from cord blood and platelets isolated from healthy subjects genotyped for rs1474868. Ex vivo approaches assessed mitochondrial morphology, function, and platelet activation responses. In vivo measurements included endogenous/transfused platelet life span, tail bleed time, transient middle cerebral artery occlusion, and pulmonary vascular permeability/hemorrhage following lipopolysaccharide-induced acute lung injury.
RESULTS
Mitochondria was more fragmented in megakaryocytes derived from mice and from human cord blood with T/T genotype compared with control megakaryocytes. Human resting platelets of T/T genotype had reduced MFN2 protein, diminished mitochondrial membrane potential, and an increased rate of phosphatidylserine exposure during ex vivo culture. Platelet counts and platelet life span were reduced in mice accompanied by an increased rate of phosphatidylserine exposure in resting platelets, especially aged platelets, during ex vivo culture. also decreased platelet mitochondrial membrane potential (basal) and activated mitochondrial oxygen consumption rate, reactive oxygen species generation, calcium flux, platelet-neutrophil aggregate formation, and phosphatidylserine exposure following dual agonist activation. Ultimately, mice showed prolonged tail bleed times, decreased ischemic stroke infarct size after cerebral ischemia-reperfusion, and exacerbated pulmonary inflammatory hemorrhage following lipopolysaccharide-induced acute lung injury. Analysis of SNPs in the iSPAAR study (Identification of SNPs Predisposing to Altered ALI Risk) identified a significant association between and 28-day mortality in patients with acute respiratory distress syndrome.
CONCLUSIONS
Mfn2 preserves mitochondrial phenotypes in megakaryocytes and platelets and influences platelet life span, function, and outcomes of stroke and lung injury.
Topics: Aged; Animals; Humans; Mice; Acute Lung Injury; Blood Platelets; Hemorrhage; Lipopolysaccharides; Mitochondria; Phosphatidylserines
PubMed: 38156445
DOI: 10.1161/CIRCRESAHA.123.322914