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BACKGROUND: Hepatocarcinogenesis is a multifactorial process that arises from a integration of genetic and epigenetic anomalies leading to abnormal gene expression and function. It is difficult to characterize HCC with a single biomarker. Our study aimed at detecting the expression of a panel of 8 methylated genes (SOCS1, APC, Gadd45b, CDKN1B, P15, PAX6, STAT1 and MSH2) as regulatory factors among Egyptian patients with HCC. METHODS: This study was conducted on HCC tissue samples of 30 Egyptian patients in comparison with their non-cancerous adjacent cirrhotic tissue as a control. Tissue samples were obtained from patients who have undergone living donor liver transplantation (LDLT) or liver resection at El Sahel Teaching Hospital (Cairo, Egypt). A special Custom designed PCR Arrays was used to analyze the expression profiles of chosen methylated genes associated with HCC. RESULTS: Expression of SOCS1, APC, Gadd45b, CDKN1B, P15, PAX6, STAT1 and MSH2 were lower in the HCC tissue compared to the cirrhotic tissue (pvalue = 0.015, 0.081, 0.004, 0.027, 0.211, 0.015, 0.025 and 0.0001 respectively). 5 genes (SOCS1, APC, GAdd45b, CDKN1B, and MSH2) showed the ability to be used as diagnostic biomarkers for HCC with high sensitivity and specificity values at cut off values: 1.05, 1.17, 0.995, 0.546, and 0.125 respectively. As for the other 3 genes (P15, PAX6, STAT1), PAX6 gene has the highest sensitivity at a cut off value of 0.3364. A significant negative correlation was shown between alpha fetoprotein (AFP) and 5 of the studied genes (SOCS1, APC, Gadd45b, STAT1, and MSH2). CONCLUSIONS: Expression of the selected hypermethylated genes (SOCS1, APC, Gadd45b, CDKN1B, P15, PAX6, STAT1 and MSH2) in HCC tissue samples was lower than adjacent tissue. Their role should be further studied to solve the mystery that surrounds the pathogenesis of HCC.
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Prosthodontics is a dental subspecialty that includes the preparation of dental prosthetics for missing or damaged teeth. It increasingly uses computer-assisted technologies for planning and preparing dental prosthetics. This study aims to present the findings from a systematic review of publications on artificial intelligence (AI) in prosthodontics to identify current trends and future opportunities. The review question was "What are the applications of AI in prosthodontics and how good is their performance in prosthodontics?" Electronic searching in the Web of Science, ScienceDirect, PubMed, and Cochrane Library was conducted. The search was limited to full text from January 2012 to January 2024. Quadas-2 was used for assessing quality and potential risk of bias for the selected studies. A total of 1925 studies were identified in the initial search. After removing the duplicates and applying exclusion criteria, a total of 30 studies were selected for this review. Results of the Quadas-2 assessment of included studies found that a total of 18.3% of studies were identified as low risk of bias studies, whereas 52.6% and 28.9% of included studies were identified as studies with high and unclear risk of bias, respectively. Although they are still developing, AI models have already shown promise in the areas of dental charting, tooth shade selection, automated restoration design, mapping the preparation finishing line, manufacturing casting optimization, predicting facial changes in patients wearing removable prostheses, and designing removable partial dentures.
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Inteligência Artificial , Prostodontia , Inteligência Artificial/tendências , Humanos , Prostodontia/métodos , Prostodontia/tendências , Prótese DentáriaRESUMO
Paneth cells (PCs), a subset of intestinal epithelial cells (IECs) found at the base of small intestinal crypts, play an essential role in maintaining intestinal homeostasis. Altered PCs function is associated with diverse intestinal pathologies, including ileal Crohn's disease (CD). CD patients with ileal involvement have been previously demonstrated to display impairment in PCs and decreased levels of anti-microbial peptides. Although the immunosuppressive drug Azathioprine (AZA) is widely used in CD therapy, the impact of AZA on IEC differentiation remains largely elusive. In the present study, we hypothesized that the orally administered drug AZA also exerts its effect through modulation of the intestinal epithelium and specifically via modulation of PC function. AZA-treated CD patients exhibited an ileal upregulation of AMPs on both mRNA and protein levels compared to non-AZA treated patients. Upon in vitro AZA stimulation, intestinal epithelial cell line MODE-K exhibited heightened expression levels of PC marker in concert with diminished cell proliferation but boosted mitochondrial OXPHOS activity. Moreover, differentiation of IECs, including PCs differentiation, was boosted in AZA-treated murine small intestinal organoids and was associated with decreased D-glucose consumption and decreased growth rates. Of note, AZA treatment strongly decreased Lgr5 mRNA expression as well as Ki67 positive cells. Further, AZA restored dysregulated PCs associated with mitochondrial dysfunction. AZA-dependent inhibition of IEC proliferation is accompanied by boosted mitochondria function and IEC differentiation into PC.
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Azatioprina , Diferenciação Celular , Doença de Crohn , Mucosa Intestinal , Celulas de Paneth , Doença de Crohn/tratamento farmacológico , Doença de Crohn/patologia , Doença de Crohn/metabolismo , Azatioprina/farmacologia , Celulas de Paneth/metabolismo , Celulas de Paneth/efeitos dos fármacos , Celulas de Paneth/patologia , Humanos , Diferenciação Celular/efeitos dos fármacos , Animais , Camundongos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Feminino , Masculino , Íleo/efeitos dos fármacos , Íleo/metabolismo , Íleo/patologia , Adulto , Organoides/efeitos dos fármacos , Organoides/metabolismo , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Proliferação de Células/efeitos dos fármacos , Pessoa de Meia-Idade , Linhagem Celular , Índice de Gravidade de DoençaRESUMO
We previously demonstrated that mice carrying natural mtDNA variants of the FVB/NJ strain (m.7778â¯G>T in the mt-Atp8 gene in mitochondrial complex V), namely C57BL/6â¯J-mtFVB/NJ (B6-mtFVB), exhibited (i) partial protection from experimental skin inflammatory diseases in an anti-murine type VII collagen antibody-induced skin inflammation model and psoriasiform dermatitis model; (ii) significantly altered metabolites, including short-chain fatty acids, according to targeted metabolomics of liver, skin and lymph node samples; and (iii) a differential composition of the gut microbiota according to bacterial 16â¯S rRNA gene sequencing of stool samples compared to wild-type C57BL/6â¯J (B6) mice. To further dissect these disease-contributing factors, we induced an experimental antibody-induced skin inflammatory disease in gnotobiotic mice. We performed shotgun metagenomic sequencing of caecum contents and untargeted metabolomics of liver, CD4+ T cell, and caecum content samples from conventional B6-mtFVB and B6 mice. We identified D-glucosamine as a candidate mediator that ameliorated disease severity in experimental antibody-induced skin inflammation by modulating immune cell function in T cells, neutrophils and macrophages. Because mice carrying mtDNA variants of the FVB/NJ strain show differential disease susceptibility to a wide range of experimental diseases, including diet-induced atherosclerosis in low-density lipoprotein receptor knockout mice and collagen antibody-induced arthritis in DBA/1â¯J mice, this experimental approach is valuable for identifying novel therapeutic options for skin inflammatory conditions and other chronic inflammatory diseases to which mice carrying specific mtDNA variants show differential susceptibility.
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DNA Mitocondrial , Camundongos Endogâmicos C57BL , Animais , DNA Mitocondrial/genética , Microbioma Gastrointestinal , Camundongos , Pele/metabolismo , Pele/microbiologia , Pele/patologia , Dermatite/imunologia , Dermatite/microbiologia , Dermatite/genética , Dermatite/tratamento farmacológico , Dermatite/metabolismo , Inflamação/genética , Inflamação/imunologia , Modelos Animais de Doenças , Masculino , Vida Livre de Germes , Psoríase/tratamento farmacológico , Psoríase/imunologia , Psoríase/genética , Ceco/microbiologia , Doença Crônica , FemininoRESUMO
BACKGROUND: Obesity is a complex metabolic disorder that is associated with several diseases. Recently, precision nutrition (PN) has emerged as a tailored approach to provide individualised dietary recommendations. AIM: This review discusses the major intrinsic and extrinsic components considered when applying PN during the management of obesity and common associated chronic conditions. RESULTS: The review identified three main PN components: gene-nutrient interactions, intestinal microbiota, and lifestyle factors. Genetic makeup significantly contributes to inter-individual variations in dietary behaviours, with advanced genome sequencing and population genetics aiding in detecting gene variants associated with obesity. Additionally, PN-based host-microbiota evaluation emerges as an advanced therapeutic tool, impacting disease control and prevention. The gut microbiome's composition regulates diverse responses to nutritional recommendations. Several studies highlight PN's effectiveness in improving diet quality and enhancing adherence to physical activity among obese patients. PN is a key strategy for addressing obesity-related risk factors, encompassing dietary patterns, body weight, fat, blood lipids, glucose levels, and insulin resistance. CONCLUSION: PN stands out as a feasible tool for effectively managing obesity, considering its ability to integrate genetic and lifestyle factors. The application of PN-based approaches not only improves current obesity conditions but also holds promise for preventing obesity and its associated complications in the long term.
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Microbioma Gastrointestinal , Manejo da Obesidade , Humanos , Obesidade/epidemiologia , Estilo de Vida , NutrientesRESUMO
Mitochondrial genomes co-evolve with the nuclear genome over evolutionary timescales and are shaped by selection in the female germline. Here we investigate how mismatching between nuclear and mitochondrial ancestry impacts the somatic evolution of the mitochondrial genome in different tissues throughout ageing. We used ultrasensitive duplex sequencing to profile ~2.5 million mitochondrial genomes across five mitochondrial haplotypes and three tissues in young and aged mice, cataloguing ~1.2 million mitochondrial somatic and ultralow-frequency inherited mutations, of which 81,097 are unique. We identify haplotype-specific mutational patterns and several mutational hotspots, including at the light strand origin of replication, which consistently exhibits the highest mutation frequency. We show that rodents exhibit a distinct mitochondrial somatic mutational spectrum compared with primates with a surfeit of reactive oxygen species-associated G > T/C > A mutations, and that somatic mutations in protein-coding genes exhibit signatures of negative selection. Lastly, we identify an extensive enrichment in somatic reversion mutations that 're-align' mito-nuclear ancestry within an organism's lifespan. Together, our findings demonstrate that mitochondrial genomes are a dynamically evolving subcellular population shaped by somatic mutation and selection throughout organismal lifetimes.
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Envelhecimento , Genoma Mitocondrial , Haplótipos , Mutação , Seleção Genética , Animais , Envelhecimento/genética , Camundongos , DNA Mitocondrial/genética , Núcleo Celular/genética , Feminino , Mitocôndrias/genética , Camundongos Endogâmicos C57BL , MasculinoRESUMO
The link between gut and lung starts as early as during organogenesis. Even though they are anatomically distinct, essential bidirectional crosstalk via complex mechanisms supports GLA. Emerging studies have demonstrated the association of gut and lung diseases via multifaceted mechanisms. Advancements in omics and metagenomics technologies revealed a potential link between gut and lung microbiota, adding further complexity to GLA. Despite substantial studies on GLA in various disease models, mechanisms beyond microbial dysbiosis regulating the interplay between gut and lung tissues during disease conditions are not thoroughly reviewed. This review outlines disease specific GLA mechanisms, emphasizing research gaps with a focus on gut-to-lung direction based on current GLA literature. Moreover, the review discusses potential gut microbiota and their products like metabolites, immune modulators, and non-bacterial contributions as a basis for developing treatment strategies for lung diseases. Advanced experimental methods, modern diagnostic tools, and technological advancements are also highlighted as crucial areas for improvement in developing novel therapeutic approaches for GLA-related diseases. In conclusion, this review underscores the importance of exploring additional mechanisms within the GLA to gain a deeper understanding that could aid in preventing and treating a wide spectrum of lung diseases.
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Breast cancer is one of the leading causes of death in females, mainly because of metastasis. Oncometabolites, produced via metabolic reprogramming, can influence metastatic signaling cascades. Accordingly, and based on our previous results, we propose that metabolites from highly metastatic breast cancer cells behave differently from less-metastatic cells and may play a significant role in metastasis. For instance, we aim to identify these metabolites and their role in breast cancer metastasis. Less metastatic cells (MCF-7) were treated with metabolites secreted from highly metastatic cells (MDA-MB-231) and the gene expression of three epithelial-to-mesenchymal transition (EMT) markers including E-cadherin, N-cadherin and vimentin were examined. Some metabolites secreted from MDA-MB-231 cells significantly induced EMT activity. Specifically, hypoxanthine demonstrated a significant EMT effect and increased the migration and invasion effects of MCF-7 cells through a hypoxia-associated mechanism. Hypoxanthine exhibited pro-angiogenic effects via increasing the VEGF and PDGF gene expression and affected lipid metabolism by increasing the gene expression of PCSK-9. Notably, knockdown of purine nucleoside phosphorylase, a gene encoding for an important enzyme in the biosynthesis of hypoxanthine, and inhibition of hypoxanthine uptake caused a significant decrease in hypoxanthine-associated EMT effects. Collectively for the first time, hypoxanthine was identified as a novel metastasis-associated metabolite in breast cancer cells and represents a promising target for diagnosis and therapy.
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Neoplasias da Mama , Feminino , Humanos , Neoplasias da Mama/patologia , Espectroscopia de Prótons por Ressonância Magnética , Células MCF-7 , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal/genética , Movimento Celular , Hipoxantinas/farmacologiaRESUMO
Asthma is an allergic airway inflammatory disease characterized by type 2 immune responses. Growing evidence suggests an association between allergic airways and intestinal diseases. However, the primary site of disease origin and initial mechanisms involved in the development of allergic airway inflammation (AAI) is not yet understood. Therefore, the initial contributing organs and mechanisms involved in the development of AAI are investigated using a mouse model of asthma. This study, without a local allergen challenge into the lungs, demonstrates a significant increase in intestinal inflammation with signature type-2 mediators including IL-4, IL-13, STAT6, eosinophils, and Th2 cells. In addition, gut leakage and mRNA expressions of gut leakage markers significantly increase in the intestine. Moreover, reduced mRNA expressions of tight junction proteins are observed in gut and interestingly, in lung tissues. Furthermore, in lung tissues, an increased pulmonary barrier permeability and IL-4 and IL-13 levels associated with significant increase of lipopolysaccharide-binding protein (LBP-gut leakage marker) and eosinophils are observed. However, with local allergen challenges into the lungs, these mechanisms are further enhanced in both gut and lungs. In conclusion, the primary gut originated inflammatory responses translocates into the lungs to orchestrate AAI in a mouse model of asthma.
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Asma , Hipersensibilidade , Humanos , Interleucina-13/genética , Interleucina-4/genética , Inflamação , Alérgenos , RNA Mensageiro/genéticaRESUMO
Bullous pemphigoid (BP) is an autoimmune blistering disease that primarily affects the elderly. An altered skin microbiota in BP was recently revealed. Accumulating evidence points toward a link between the gut microbiota and skin diseases; however, the gut microbiota composition of BP patients remains largely underexplored, with only one pilot study to date, with a very limited sample size and no functional profiling of gut microbiota. To thoroughly investigate the composition and function of the gut microbiota in BP patients, and explore possible links between skin conditions and gut microbiota, we here investigated the gut microbiota of 66 patients (81.8% firstly diagnosed) suffering from BP and 66 age-, sex-, and study center-matched controls (CL) with non-inflammatory skin diseases (132 total participants), using 16S rRNA gene and shotgun sequencing data. Decreased alpha-diversity and an overall altered gut microbial community is observed in BP patients. Similar trends are observed in subclassifications of BP patients, including first diagnoses and relapsed cases. Furthermore, we observe a set of BP disease-associated gut microbial features, including reduced Faecalibacterium prausnitzii and greater abundance of pathways related to gamma-aminobutyric acid (GABA) metabolism in BP patients. Interestingly, F. prausnitzii is a well-known microbiomarker of inflammatory diseases, which has been reported to be reduced in the gut microbiome of atopic dermatitis and psoriasis patients. Moreover, GABA plays multiple roles in maintaining skin health, including the inhibition of itching by acting as a neurotransmitter, attenuating skin lesions by balancing Th1 and Th2 levels, and maintaining skin elasticity by increasing the expression of type I collagen. These findings thus suggest that gut microbiota alterations present in BP may play a role in the disease, and certain key microbes and functions may contribute to the link between gut dysbiosis and BP disease activity. Further studies to investigate the underlying mechanisms of the gut-skin interaction are thus clearly warranted, which could aid in the development of potential therapeutic interventions.
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Microbioma Gastrointestinal , Penfigoide Bolhoso , Humanos , Idoso , Microbioma Gastrointestinal/fisiologia , RNA Ribossômico 16S/genética , Suscetibilidade a Doenças , Projetos Piloto , Ácido gama-AminobutíricoRESUMO
Type 2 Diabetes Mellitus has reached epidemic levels globally, and several studies have confirmed a link between gut microbial dysbiosis and aberrant glucose homeostasis among people with diabetes. While the assumption is that abnormal metabolomic signatures would often accompany microbial dysbiosis, the connection remains largely unknown. In this study, we investigated how diet changed the gut bacteriome, mycobiome and metabolome in people with and without type 2 Diabetes.1 Differential abundance testing determined that the metabolites Propionate, U8, and 2-Hydroxybutyrate were significantly lower, and 3-Hydroxyphenyl acetate was higher in the high fiber diet compared to low fiber diet in the healthy control group. Next, using multi-omics factor analysis (MOFA2), we attempted to uncover sources of variability that drive each of the different groups (bacterial, fungal, and metabolite) on all samples combined (control and DM II). Performing variance decomposition, ten latent factors were identified, and then each latent factor was tested for significant correlations with age, BMI, diet, and gender. Latent Factor1 was the most significantly correlated. Remarkably, the model revealed that the mycobiome explained most of the variance in the DM II group (12.5%) whereas bacteria explained most of the variance in the control group (64.2% vs. 10.4% in the DM II group). The latent Factor1 was significantly correlated with dietary intake (q < 0.01). Further analyses of the impact of bacterial and fungal genera on Factor1 determined that the nine bacterial genera (Phocaeicola, Ligilactobacillus, Mesosutterella, Acidaminococcus, Dorea A, CAG-317, Caecibacter, Prevotella and Gemmiger) and one fungal genus (Malassezia furfur) were found to have high factor weights (absolute weight > 0.6). Alternatively, a linear regression model was fitted per disease group for each genus to visualize the relationship between the factor values and feature abundances, showing Xylose with positive weights and Propionate, U8, and 2-Hydroxybutyrate with negative weights. This data provides new information on the microbially derived changes that influence metabolic phenotypes in response to different diets and disease conditions in humans.
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Diabetes Mellitus Tipo 2 , Microbioma Gastrointestinal , Humanos , Diabetes Mellitus Tipo 2/metabolismo , Microbioma Gastrointestinal/genética , Disbiose/microbiologia , Propionatos , Multiômica , Metabolômica , Bactérias/genética , Ingestão de Alimentos , HidroxibutiratosRESUMO
BACKGROUND: Like its human counterpart, canine atopic dermatitis (cAD) is a chronic relapsing condition; thus, most cAD-affected dogs will require lifelong treatment to maintain an acceptable quality of life. A potential intervention is modulation of the composition of gut microbiota, and in fact, probiotic treatment has been proposed and tried in human atopic dermatitis (AD) patients. Since dogs are currently receiving intensive medical care, this will be the same option for dogs, while evidence of gut dysbiosis in cAD is still missing, although skin microbial profiling in cAD has been conducted in several studies. Therefore, we conducted a comprehensive analysis of both gut and skin microbiota in cAD in one specific cAD-predisposed breed, Shiba Inu. Additionally, we evaluated the impact of commonly used medical management on cAD (Janus kinase; JAK inhibitor, oclacitinib) on the gut and skin microbiota. Furthermore, we genotyped the Shiba Inu dogs according to the mitochondrial DNA haplogroup and assessed its association with the composition of the gut microbiota. RESULTS: Staphylococcus was the most predominant bacterial genus observed in the skin; Escherichia/Shigella and Clostridium sensu stricto were highly abundant in the gut of cAD-affected dogs. In the gut microbiota, Fusobacteria and Megamonas were highly abundant in healthy dogs but significantly reduced in cAD-affected dogs. The abundance of these bacterial taxa was positively correlated with the effect of the treatment and state of the disease. Oclacitinib treatment on cAD-affected dogs shifted the composition of microbiota towards that in healthy dogs, and the latter brought it much closer to healthy microbiota, particularly in the gut. Additionally, even within the same dog breed, the mtDNA haplogroup varied, and there was an association between the mtDNA haplogroup and microbial composition in the gut and skin. CONCLUSIONS: Dysbiosis of both the skin and the gut was observed in cAD in Shiba Inu dogs. Our findings provide a basis for the potential treatment of cAD by manipulating the gut microbiota as well as the skin microbiota. Video Abstract.
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Dermatite Atópica , Microbiota , Cães , Humanos , Animais , Dermatite Atópica/veterinária , Dermatite Atópica/microbiologia , Disbiose , Qualidade de Vida , Bactérias , DNA MitocondrialRESUMO
Inflammatory bowel disease (IBD) is a prototypic complex disease in the gastrointestinal tract that has been increasing in incidence and prevalence in recent decades. Although the precise pathophysiology of IBD remains to be elucidated, a large body of evidence suggests the critical roles of mitochondria and intestinal microbiota in the pathogenesis of IBD. In addition to their contributions to the disease, both mitochondria and gut microbes may interact with each other and modulate disease-causing cell activities. Therefore, we hypothesize that dissecting this unique interaction may help to identify novel pathways involved in IBD, which will further contribute to discovering new therapeutic approaches to the disease. As poorly treated IBD significantly affects the quality of life of patients and is associated with risks and complications, successful treatment is crucial. In this review, we stratify previously reported experimental and clinical observations of the role of mitochondria and intestinal microbiota in IBD. Additionally, we review the intercommunication between mitochondria, and the intestinal microbiome in patients with IBD is reviewed along with the potential mediators for these interactions. We specifically focus on their roles in cellular metabolism in intestinal epithelial cells and immune cells. To this end, we propose a potential therapeutic intervention strategy for IBD.
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Doenças Inflamatórias Intestinais , Microbiota , Humanos , Qualidade de Vida , Doenças Inflamatórias Intestinais/metabolismo , Mitocôndrias/metabolismoRESUMO
Psoriasis is a chronic inflammatory skin condition. Repeated epicutaneous application of Aldara® (imiquimod) cream results in psoriasiform dermatitis in mice. The Aldara®-induced psoriasiform dermatitis (AIPD) mouse model has been used to examine the pathogenesis of psoriasis. Here, we used a forward genetics approach in which we compared AIPD that developed in 13 different inbred mouse strains to identify genes and pathways that modulated disease severity. Among our primary results, we found that the severity of AIPD differed substantially between different strains of inbred mice and that these variations were associated with polymorphisms in Itga11. The Itga11 gene encodes the integrin α11 subunit that heterodimerizes with the integrin ß1 subunit to form integrin α11ß1. Less information is available about the function of ITGA11 in skin inflammation; however, a role in the regulation of cutaneous wound healing, specifically the development of dermal fibrosis, has been described. Experiments performed with Itga11 gene-deleted (Itga11-/- ) mice revealed that the integrin α11 subunit contributes substantially to the clinical phenotype as well as the histopathological and molecular findings associated with skin inflammation characteristic of AIPD. Although the skin transcriptomes of Itga11-/- and WT mice do not differ from one another under physiological conditions, distinct transcriptomes emerge in these strains in response to the induction of AIPD. Most of the differentially expressed genes contributed to extracellular matrix organization, immune system, and metabolism of lipids pathways. Consistent with these findings, we detected a reduced number of fibroblasts and inflammatory cells, including macrophages, T cells, and tissue-resident memory T cells in skin samples from Itga11-/- mice in response to AIPD induction. Collectively, our results reveal that Itga11 plays a critical role in promoting skin inflammation in AIPD and thus might be targeted for the development of novel therapeutics for psoriasiform skin conditions. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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Dermatite , Cadeias alfa de Integrinas , Psoríase , Animais , Camundongos , Dermatite/genética , Dermatite/patologia , Modelos Animais de Doenças , Imiquimode/efeitos adversos , Inflamação/patologia , Cadeias alfa de Integrinas/genética , Cadeias alfa de Integrinas/metabolismo , Psoríase/induzido quimicamente , Psoríase/genética , Pele/patologiaRESUMO
A novel reactor methodology was developed for chemical looping ammonia synthesis processes using microwave plasma for pre-activation of the stable dinitrogen molecule before reaching the catalyst surface. Microwave plasma-enhanced reactions benefit from higher production of activated species, modularity, quick startup, and lower voltage input than competing plasma-catalysis technologies. Simple, economical, and environmentally benign metallic iron catalysts were used in a cyclical atmospheric pressure synthesis of ammonia. Rates of up to 420.9 µmol min-1 g-1 were observed under mild nitriding conditions. Reaction studies showed that both surface-mediated and bulk-mediated reaction domains were found to exist depending on the time under plasma treatment. The associated density functional theory (DFT) calculations indicated that a higher temperature promoted more nitrogen species in the bulk of iron catalysts but the equilibrium limited the nitrogen converion to ammonia, and vice versa. Generation of vibrationally active N2 and, N2+ ions is associated with lower bulk nitridation temperatures and increased nitrogen contents versus thermal-only systems. Additionally, the kinetics of other transition metal chemical looping ammonia synthesis catalysts (Mn and CoMo) were evaluated by high-resolution time-on-stream kinetic analysis and optical plasma characterization. This study sheds new light on phenomena arising in transient nitrogen storage, kinetics, effect of plasma treatment, apparent activation energies, and rate-limiting reaction steps.
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[This corrects the article DOI: 10.3389/fpsyt.2022.902433.].
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Proteolysis targeting chimeras (PROTACs) are heterobifunctional small molecules that uses the proteasome ubiquitin system to target proteins of interest and promote their degradation with remarkable selectivity. Importantly, unlike conventional small molecule inhibitors, PROTACs have proven highly effective in targeting undruggable proteins and those bearing mutations. Because of these considerations, PROTACs have increasingly become an emerging technology for the development of novel targeted anticancer therapeutics. Interestingly, many PROTACs have demonstrated a great potency and specificity in degrading several oncogenic drivers. Many of these, following extensive preclinical evaluation, have reached advanced stages of clinical testing in various cancers including hematologic malignancies. In this review, we provide a comprehensive summary of the recent advances in the development of PROTACs as therapeutic strategies in diverse hematological malignancies. A particular attention has been given to clinically relevant PROTACs and those targeting oncogenic mutants that drive resistance to therapies. We also discus limitations, and various considerations to optimize the design for effective PROTACs.
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Mitochondrial genomes co-evolve with the nuclear genome over evolutionary timescales and are shaped by selection in the female germline. Here, we investigate how mismatching between nuclear and mitochondrial ancestry impacts the somatic evolution of the mt-genome in different tissues throughout aging. We used ultra-sensitive Duplex Sequencing to profile ~2.5 million mt-genomes across five mitochondrial haplotypes and three tissues in young and aged mice, cataloging ~1.2 million mitochondrial somatic and ultra low frequency inherited mutations, of which 81,097 are unique. We identify haplotype-specific mutational patterns and several mutational hotspots, including at the Light Strand Origin of Replication, which consistently exhibits the highest mutation frequency. We show that rodents exhibit a distinct mitochondrial somatic mutational spectrum compared to primates with a surfeit of reactive oxygen species-associated G>T/C>A mutations, and that somatic mutations in protein coding genes exhibit signatures of negative selection. Lastly, we identify an extensive enrichment in somatic reversion mutations that "re-align" mito-nuclear ancestry within an organism's lifespan. Together, our findings demonstrate that mitochondrial genomes are a dynamically evolving subcellular population shaped by somatic mutation and selection throughout organismal lifetimes.
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INTRODUCTION: Mitochondria are maternally inherited cell organelles with their own genome, and perform various functions in eukaryotic cells such as energy production and cellular homeostasis. Due to their inheritance and manifold biological roles in health and disease, mitochondrial genetics serves a dual purpose of tracing the history as well as disease susceptibility of human populations across the globe. This work requires a comprehensive catalogue of commonly observed genetic variations in the mitochondrial DNAs for all regions throughout the world. So far, however, certain regions, such as North and East Africa have been understudied. OBJECTIVES: To address this shortcoming, we have created the most comprehensive quality-controlled North and East African mitochondrial data set to date and use it for characterizing mitochondrial genetic variation in this region. METHODS: We compiled 11 published cohorts with novel data for mitochondrial genomes from 159 Sudanese individuals. We combined these 641 mitochondrial sequences with sequences from the 1000 Genomes (n = 2504) and the Human Genome Diversity Project (n = 828) and used the tool haplocheck for extensive quality control and detection of in-sample contamination, as well as Nanopore long read sequencing for haplogroup validation of 18 samples. RESULTS: Using a subset of high-coverage mitochondrial sequences, we predict 15 potentially novel haplogroups in North and East African subjects and observe likely phylogenetic deviations from the established PhyloTree reference for haplogroups L0a1 and L2a1. CONCLUSION: Our findings demonstrate common hitherto unexplored variants in mitochondrial genomes of North and East Africa that lead to novel phylogenetic relationships between haplogroups present in these regions. These observations call for further in-depth population genetic studies in that region to enable the prospective use of mitochondrial genetic variation for precision medicine.
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DNA Mitocondrial , População da África Oriental , População do Norte da África , Humanos , DNA Mitocondrial/genética , População da África Oriental/genética , Variação Genética/genética , Haplótipos , Filogenia , Medicina de Precisão , Análise de Sequência de DNA , População do Norte da África/genéticaRESUMO
INTRODUCTION: Bullous pemphigoid (BP) is the most common autoimmune blistering disease. It predominately afflicts the elderly and is significantly associated with increased mortality. The observation of age-dependent changes in the skin microbiota as well as its involvement in other inflammatory skin disorders suggests that skin microbiota may play a role in the emergence of BP blistering. We hypothesize that changes in microbial diversity associated with BP might occur before the emergence of disease lesions, and thus could represent an early indicator of blistering risk. OBJECTIVES: The present study aims to investigate potential relationships between skin microbiota and BP and elaborate on important changes in microbial diversity associated with blistering in BP. METHODS: The study consisted of an extensive sampling effort of the skin microbiota in patients with BP and age- and sex-matched controls to analyze whether intra-individual, body site, and/or geographical variation correlate with changes in skin microbial composition in BP and/or blistering status. RESULTS: We find significant differences in the skin microbiota of patients with BP compared to that of controls, and moreover that disease status rather than skin biogeography (body site) governs skin microbiota composition in patients with BP. Our data reveal a discernible transition between normal skin and the skin surrounding BP lesions, which is characterized by a loss of protective microbiota and an increase in sequences matching Staphylococcus aureus, a known inflammation-promoting species. Notably, Staphylococcus aureus is ubiquitously associated with BP disease status, regardless of the presence of blisters. CONCLUSION: The present study suggests Staphylococcus aureus may be a key taxon associated with BP disease status. Importantly, we however find contrasting patterns in the relative abundances of Staphylococcus hominis and Staphylococcus aureus reliably discriminate between patients with BP and matched controls. This may serve as valuable information for assessing blistering risk and treatment outcomes in a clinical setting.