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1.
Front Immunol ; 13: 918404, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35935963

RESUMO

Background: Observational and in-vivo research suggested a bidirectional relationship between depression and periodontitis. We estimated the genetic correlation and examined directionality of causation. Methods: The study used summary statistics from published genome wide association studies, with sample sizes ranging from 45,563 to 797,563 individuals of European ancestry. We performed linkage disequilibrium score regression (LDSC) to estimate global correlation and used Heritability Estimation from Summary Statistics (ρ-HESS) to further examine local genetic correlation. Latent Heritable Confounder Mendelian randomization (LHC-MR), Causal Analysis using Summary Effect estimates (CAUSE), and conventional MR approaches assessed bidirectional causation. Results: LDSC observed only weak genetic correlation (rg = 0.06, P-Value = 0.619) between depression and periodontitis. Analysis of local genetic correlation using ρ-HESS did not reveal loci of significant local genetic covariance. LHC-MR, CAUSE and conventional MR models provided no support for bidirectional causation between depression and periodontitis, with odds ratios ranging from 1.00 to 1.06 in either direction. Conclusions: Results do not support shared heritability or a causal connection between depression and periodontitis.


Assuntos
Análise da Randomização Mendeliana , Periodontite , Depressão/genética , Estudo de Associação Genômica Ampla , Humanos , Desequilíbrio de Ligação , Análise da Randomização Mendeliana/métodos , Periodontite/genética
2.
Int J Mol Sci ; 23(13)2022 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-35806269

RESUMO

Periodontitis is a multifactorial disease. The aim of this explorative study was to investigate the role of Interleukin-(IL)-1, IL-4, GATA-3 and Cyclooxygenase-(COX)-2 polymorphisms after non-surgical periodontal therapy with adjunctive systemic antibiotics (amoxicillin/metronidazole) and subsequent maintenance in a Caucasian population. Analyses were performed using blood samples from periodontitis patients of a multi-center trial (ClinicalTrials.gov NCT00707369=ABPARO-study). Polymorphisms were analyzed using quantitative real-time PCR. Clinical attachment levels (CAL), percentage of sites showing further attachment loss (PSAL) ≥1.3 mm, bleeding on probing (BOP) and plaque score were assessed. Exploratory statistical analysis was performed. A total of 209 samples were genotyped. Patients carrying heterozygous genotypes and single-nucleotide-polymorphisms (SNP) on the GATA-3-IVS4 +1468 gene locus showed less CAL loss than patients carrying wild type. Heterozygous genotypes and SNPs on the IL-1A-889, IL-1B +3954, IL-4-34, IL-4-590, GATA-3-IVS4 +1468 and COX-2-1195 gene loci did not influence CAL. In multivariate analysis, CAL was lower in patients carrying GATA-3 heterozygous genotypes and SNPs than those carrying wild-types. For the first time, effects of different genotypes were analyzed in periodontitis progression after periodontal therapy and during supportive treatment using systemic antibiotics demonstrating a slight association of GATA-3 gene locus with CAL. This result suggests that GATA-3 genotypes are a contributory but non-essential risk factor for periodontal disease progression.


Assuntos
Ciclo-Oxigenase 2 , Fator de Transcrição GATA3 , Interleucina-1 , Interleucina-4 , Periodontite , Antibacterianos , Ciclo-Oxigenase 2/genética , Fator de Transcrição GATA3/genética , Humanos , Interleucina-1/genética , Interleucina-4/genética , Periodontite/genética , Polimorfismo de Nucleotídeo Único
3.
Front Genet ; 13: 820772, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35656328

RESUMO

Sex-determining regions have been identified in the Nile tilapia on linkage groups (LG) 1, 20 and 23, depending on the domesticated strains used. Sex determining studies on wild populations of this species are scarce. Previous work on two wild populations, from Lake Volta (Ghana) and from Lake Koka (Ethiopia), found the sex-determining region on LG23. These populations have a Y-specific tandem duplication containing two copies of the Anti-Müllerian Hormone amh gene (named amhY and amhΔY). Here, we performed a whole-genome short-reads analysis using male and female pools on a third wild population from Lake Hora (Ethiopia). We found no association of sex with LG23, and no duplication of the amh gene. Furthermore, we found no evidence of sex linkage on LG1 or on any other LGs. Long read whole genome sequencing of a male from each population confirmed the absence of a duplicated region on LG23 in the Lake Hora male. In contrast, long reads established the structure of the Y haplotype in Koka and Kpandu males and the order of the genes in the duplicated region. Phylogenies constructed on the nuclear and mitochondrial genomes, showed a closer relationship between the two Ethiopian populations compared to the Ghanaian population, implying an absence of the LG23Y sex-determination region in Lake Hora males. Our study supports the hypothesis that the amh region is not the sex-determining region in Hora males. The absence of the Y amh duplication in the Lake Hora population reflects a rapid change in sex determination within Nile tilapia populations. The genetic basis of sex determination in the Lake Hora population remains unknown.

4.
J Prosthet Dent ; 2022 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-35753826

RESUMO

STATEMENT OF PROBLEM: Dental restorations and removable dental prostheses have been considered as risk factors for potentially malignant disorders of the oral mucosa. It remains unclear whether amalgam, composite resins, and prosthesis materials can induce potentially malignant disorders. PURPOSE: The purpose of this clinical study was to determine the relationship between the presence of amalgam and composite resin restorations, crowns and fixed partial dentures, and removable prostheses in potentially malignant disorders. MATERIAL AND METHODS: The data of 6041 participants in the population-based Studies of Health in Pomerania (SHIP) were accessed. Potentially malignant disorders had been clinically diagnosed by calibrated dentists and documented with photographs. Dental treatment was subdivided into restored and replaced teeth. Dental restorations were subclassified as buccal composite resin or amalgam restorations. Prosthetic treatment was subclassified into removable partial or complete prostheses and definitive restorations with crowns and fixed partial dentures. RESULTS: In the maxilla, participants with removable prostheses had a higher incidence of potentially malignant disorders than participants not undergoing treatment with removable prostheses (OR 2.12; 95% CI: 1.08-4.18), but not in the mandible (OR 1.30; 95% CI: 0.67-2.53). The surfaces with composite resin restorations were associated with a slightly higher risk of mucosal lesions than those without the restorations (OR 1.04; 95% CI: 1.01-1.07). No significant association was found between amalgam restorations and mucosal lesions. CONCLUSIONS: Participants with removable prostheses have a higher risk of potentially malignant disorders. Composite resin restorations are associated with a higher risk of mucosal lesions, whereas no significant association was found between amalgam restorations and mucosal lesions.

5.
BMC Oral Health ; 22(1): 157, 2022 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-35524324

RESUMO

BACKGROUND: Peri-implantitis therapy is a major problem in implantology. Because of challenging rough implant surface and implant geometry, microorganisms can hide and survive in implant microstructures and impede debridement. We developed a new water jet (WJ) device and a new cold atmospheric pressure plasma (CAP) device to overcome these problems and investigated aspects of efficacy in vitro and safety with the aim to create the prerequisites for a clinical pilot study with these medical devices. METHODS: We compared the efficiency of a single treatment with a WJ or curette and cotton swab (CC) without or with adjunctive use of CAP (WJ + CAP, CC + CAP) to remove biofilm in vitro from rough titanium discs. Treatment efficacy was evaluated by measuring turbidity up to 72 h for bacterial re-growth or spreading of osteoblast-like cells (MG-63) after 5 days with scanning electron microscopy. With respect to application safety, the WJ and CAP instruments were examined according to basic regulations for medical devices. RESULTS: After 96 h of incubation all WJ and CC treated disks were turbid but 67% of WJ + CAP and 46% CC + CAP treated specimens were still clear. The increase in turbidity after WJ treatment was delayed by about 20 h compared to CC treatment. In combination with CAP the cell coverage significantly increased to 82% (WJ + CAP) or 72% (CC + CAP), compared to single treatment 11% (WJ) or 10% (CC). CONCLUSION: The newly developed water jet device effectively removes biofilm from rough titanium surfaces in vitro and, in combination with the new CAP device, biologically acceptable surfaces allow osteoblasts to grow. WJ in combination with CAP leads to cleaner surfaces than the usage of curette and cotton swabs with or without subsequent plasma treatment. Our next step will be a clinical pilot study with these new devices to assess the clinical healing process.


Assuntos
Implantes Dentários , Gases em Plasma , Biofilmes , Implantes Dentários/microbiologia , Humanos , Microscopia Eletrônica de Varredura , Projetos Piloto , Gases em Plasma/química , Propriedades de Superfície , Titânio/química , Água
6.
Genes (Basel) ; 13(5)2022 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-35627189

RESUMO

African cichlid fishes harbor an extraordinary diversity of sex-chromosome systems. Within just one lineage, the tribe Haplochromini, at least 6 unique sex-chromosome systems have been identified. Here we focus on characterizing sex chromosomes in cichlids from the Lake Victoria basin. In Haplochromis chilotes, we identified a new ZW system associated with the white blotch color pattern, which shows substantial sequence differentiation over most of LG16, and is likely to be present in related species. In Haplochromis sauvagei, we found a coding polymorphism in amh that may be responsible for an XY system on LG23. In Pundamilia nyererei, we identified a feminizing effect of B chromosomes together with XY- and ZW-patterned differentiation on LG23. In Haplochromis latifasciatus, we identified a duplication of amh that may be present in other species of the Lake Victoria superflock. We further characterized the LG5-14 XY system in Astatotilapia burtoni and identified the oldest stratum on LG14. This species also showed ZW differentiation on LG2. Finally, we characterized an XY system on LG7 in Astatoreochromis alluaudi. This report brings the number of distinct sex-chromosome systems in haplochromine cichlids to at least 13, and highlights the dynamic evolution of sex determination and sex chromosomes in this young lineage.


Assuntos
Ciclídeos , Animais , Ciclídeos/genética , Lagos , Polimorfismo Genético , Cromossomos Sexuais/genética , Análise para Determinação do Sexo
7.
J Clin Periodontol ; 49(8): 749-757, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35634709

RESUMO

AIM: According to retrospective clinical studies, periodontal treatment retains teeth. However, evidence on the effectivity of periodontal treatment stemming from the general population is lacking. MATERIALS AND METHODS: We analysed data of periodontally treated patients from routine data of a major German national health insurance (BARMER-MV; sub-sample of the Federal State of Mecklenburg-Vorpommern) and from a clinical cohort (Greifswald Approach to Individualized Medicine, GANI_MED), as well as periodontally untreated and treated participants of the Study of Health in Pomerania (SHIP-TREND) with either ≥2 or ≥4 teeth with pocket depths ≥4 mm. Yearly tooth loss (YTL) estimates and incidence rates were evaluated. RESULTS: For moderately to severely affected groups, YTL and incidence rates were higher in BARMER-MV patients (0.35 and 0.18, respectively) than in untreated SHIP-TREND controls (0.19 and 0.08, respectively). In line, treated SHIP-TREND participants exhibited higher YTL rates than untreated SHIP-TREND controls (0.26 vs. 0.19). For severely affected groups, results with respect to tooth loss were inconclusive regarding the beneficial effects of periodontal treatment conducted either in the university (GANI_MED data) or in the general practice. CONCLUSION: Until 2021, periodontal treatment performed in German general dental practices within the national health insurance system was probably not efficient in retaining more teeth in the short- to mid-term. Since reimbursement schemes were changed in 2021 and now cover periodontal treatment to a much larger extent, the future will show whether these new reimbursement codes will improve the quality of periodontal treatment and whether they will lead to more long-term tooth retainment.


Assuntos
Perda de Dente , Estudos de Coortes , Assistência Odontológica/efeitos adversos , Humanos , Sistema de Registros , Estudos Retrospectivos , Perda de Dente/epidemiologia , Perda de Dente/etiologia
8.
J Clin Periodontol ; 49(7): 642-653, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35569026

RESUMO

AIM: This study aimed to identify the factors influencing the changes in the number of teeth present and the number of healthy or filled surfaces between two time points. MATERIALS AND METHODS: Repeated cross-sectional data from population-based studies, namely the German Oral Health Studies (DMS-III vs. DMS-V), the Studies of Health in Pomerania (SHIP-START-0 vs. SHIP-TREND-0), and the Jönköping study (2003 vs. 2013), were analysed. Oaxaca decomposition models were constructed for the outcomes (number of teeth, number of healthy surfaces, and number of filled surfaces). RESULTS: The number of teeth increased between examinations (DMS: +2.26 [adults], +4.92 [seniors], SHIP: +1.67, Jönköping: +0.96). Improvements in education and dental awareness brought a positive change in all outcomes. An increase in powered toothbrushing and inter-dental cleaning had a great impact in DMS (adults: +0.25 tooth, +0.78 healthy surface, +0.38 filled surface; seniors: +1.19 teeth, 5.79 healthy surfaces, +0.48 filled surface). Inter-dental cleaning decreased by 4% between SHIP-START-0 and SHIP-TREND-0, which negatively affected the outcomes. CONCLUSIONS: From this study, it can be concluded that education may be the most important factor having a direct and indirect effect on the outcomes. However, for better oral health, powered toothbrushing and inter-dental cleaning should not be neglected.


Assuntos
Cárie Dentária , Perda de Dente , Adulto , Estudos Transversais , Humanos , Saúde Bucal , Perda de Dente/epidemiologia , Escovação Dentária
9.
J Clin Periodontol ; 49(7): 633-641, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35569034

RESUMO

AIM: To examine the associations between bone turnover markers and periodontitis in two cross-sectional population-based studies. MATERIALS AND METHODS: We used data from two independent adult samples (N = 4993), collected within the Study of Health in Pomerania project, to analyse cross-sectional associations of N-procollagen type 1 amino-terminal propeptide (P1NP), C-terminal cross-linking telopeptide, osteocalcin, bone-specific alkaline phosphatase (BAP), fibroblast growth factor 23, wingless-type mouse mammary tumour virus integration site family member 5a (WNT5A), and sclerostin values with periodontitis. Confounder-adjusted gamma and fractional response regression models were applied. RESULTS: Positive associations were found for P1NP with mean pocket probing depth (PPD; e ß = 1.008 ; 95% confidence interval [CI]: 1.001-1.015), mean clinical attachment loss (mean CAL; e ß = 1.027 ; 95% CI: 1.011-1.044), and proportion of sites with bleeding on probing (%BOP; e ß = 1.055 ; 95% CI: 1.005-1.109). Similar associations were seen for BAP with %BOP ( e ß = 1.121 ; 95% CI: 1.042-1.205), proportion of sites with PPD ≥4 mm (%PPD4) ( e ß = 1.080 ; 95% CI: 1.005-1.161), and sclerostin with %BOP ( e ß = 1.308 ; 95% CI: 1.005-1.704). WNT5A was inversely associated with mean PPD ( e ß = 0.956 ; 95% CI: 0.920-0.993) and %PPD4 ( e ß = 0.794 ; 95% CI: 0.642-0.982). CONCLUSIONS: This study revealed scattered associations of P1NP, BAP, WNT5A, and sclerostin with periodontitis, but the results are contradictory in the overall context. Associations reported in previous studies could not be confirmed.


Assuntos
Remodelação Óssea , Periodontite , Fosfatase Alcalina , Animais , Biomarcadores , Remodelação Óssea/fisiologia , Colágeno Tipo I , Estudos Transversais , Camundongos
10.
Mol Ther ; 30(8): 2680-2692, 2022 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-35490295

RESUMO

Junctional epidermolysis bullosa (JEB) is a debilitating hereditary skin disorder caused by mutations in genes encoding laminin-332, type XVII collagen (C17), and integrin-α6ß4, which maintain stability between the dermis and epidermis. We designed patient-specific Cas9-nuclease- and -nickase-based targeting strategies for reframing a common homozygous deletion in exon 52 of COL17A1 associated with a lack of full-length C17 expression. Subsequent characterization of protein restoration, indel composition, and divergence of DNA and mRNA outcomes after treatment revealed auspicious efficiency, safety, and precision profiles for paired nicking-based COL17A1 editing. Almost 46% of treated primary JEB keratinocytes expressed reframed C17. Reframed COL17A1 transcripts predominantly featured 25- and 37-nt deletions, accounting for >42% of all edits and encoding C17 protein variants that localized accurately to the cell membrane. Furthermore, corrected cells showed accurate shedding of the extracellular 120-kDa C17 domain and improved adhesion capabilities to laminin-332 compared with untreated JEB cells. Three-dimensional (3D) skin equivalents demonstrated accurate and continuous deposition of C17 within the basal membrane zone between epidermis and dermis. Our findings constitute, for the first time, gene-editing-based correction of a COL17A1 mutation and demonstrate the superiority of proximal paired nicking strategies based on Cas9 D10A nickase over wild-type Cas9-based strategies for gene reframing in a clinical context.


Assuntos
Autoantígenos , Epidermólise Bolhosa Juncional , Epidermólise Bolhosa , Colágenos não Fibrilares , Autoantígenos/genética , Desoxirribonuclease I/genética , Epidermólise Bolhosa/metabolismo , Epidermólise Bolhosa Juncional/genética , Epidermólise Bolhosa Juncional/terapia , Homozigoto , Humanos , Laminina/genética , Mutação , Colágenos não Fibrilares/genética , Deleção de Sequência
11.
Nat Protoc ; 17(6): 1486-1517, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35478248

RESUMO

Chromosome conformation capture (Hi-C) techniques map the 3D organization of entire genomes. How sister chromatids fold in replicated chromosomes, however, cannot be determined with conventional Hi-C because of the identical DNA sequences of sister chromatids. Here, we present a protocol for sister chromatid-sensitive Hi-C (scsHi-C) that enables the distinction of DNA contacts within individual sister chromatids (cis sister contacts) from those between sister chromatids (trans sister contacts), thereby allowing investigation of the organization of replicated genomes. scsHi-C is based on live-cell labeling of nascent DNA by the synthetic nucleoside 4-thio-thymidine (4sT), which incorporates into a distinct DNA strand on each sister chromatid because of semi-conservative DNA replication. After purification of genomic DNA and in situ Hi-C library preparation, 4sT is chemically converted into 5-methyl-cytosine in the presence of OsO4/NH4Cl to introduce T-to-C signature point mutations on 4sT-labeled DNA. The Hi-C library is then sequenced, and ligated fragments are assigned to sister chromatids on the basis of strand orientation and the presence of signature mutations. The ensemble of scsHi-C contacts thereby represents genome-wide contact probabilities within and across sister chromatids. scsHi-C can be completed in 2 weeks, has been successfully applied in HeLa cells and can potentially be established for any cell type that allows proper cell cycle synchronization and incorporation of sufficient amounts of 4sT. The genome-wide maps of replicated chromosomes detected by scsHi-C enable investigation of the molecular mechanisms shaping sister chromatid topologies and the relevance of sister chromatid conformation in crucial processes like DNA repair, mitotic chromosome formation and potentially other biological processes.


Assuntos
Cromátides , Replicação do DNA , Cromátides/genética , Reparo do DNA , Células HeLa , Humanos
12.
J Hered ; 113(4): 398-413, 2022 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-35385582

RESUMO

Premelanosome protein (pmel) is a key gene for melanogenesis. Mutations in this gene are responsible for white plumage in chicken, but its role in pigmentation of fish remains to be demonstrated. In this study, we found that most fishes have 2 pmel genes arising from the teleost-specific whole-genome duplication. Both pmela and pmelb were expressed at high levels in the eyes and skin of Nile tilapia. We mutated both genes in tilapia using CRISPR/Cas9. Homozygous mutation of pmela resulted in yellowish body color with weak vertical bars and a hypopigmented retinal pigment epithelium (RPE) due to significantly reduced number and size of melanophores. In contrast, we observed an increased number and size of xanthophores in mutants compared to wild-type fish. Homozygous mutation of pmelb resulted in a similar, but milder phenotype than pmela-/- mutants. Double mutation of pmela and pmelb resulted in loss of additional melanophores compared to the pmela-/- mutants, and also an increase in the number and size of xanthophores, producing a golden body color. The RPE pigmentation of pmela-/-;pmelb-/- was similar to pmela-/- mutants, with much less pigmentation than pmelb-/- mutants and wild-type fish. Taken together, our results indicate that, although both pmel genes are important for the formation of body color in tilapia, pmela plays a more important role than pmelb. To our knowledge, this is the first report on mutation of pmelb or both pmela;pmelb in fish. Studies on these mutants suggest new strategies for breeding golden tilapia, and also provide a new model for studies of pmel function in vertebrates.


Assuntos
Tilápia , Animais , Melanóforos/metabolismo , Mutação , Fenótipo , Pigmentação/genética , Tilápia/genética
13.
J Clin Periodontol ; 49(7): 654-661, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35451161

RESUMO

AIM: This study aimed to leverage human genetic data to investigate whether cannabis use causally affects periodontitis. MATERIALS AND METHODS: Data were obtained from summary statistics of genome-wide association studies of lifetime cannabis use (N = 184,765), cannabis use disorder (17,068 cases; 357,219 controls), and periodontitis (17,353 cases; 28,210 controls). We performed two-sample Mendelian randomization (MR) analysis using 6 genetic variants as instrumental variables for lifetime cannabis use and 11 variants as instruments for cannabis use disorder to estimate associations with periodontitis. RESULTS: There was no evidence for an association between genetic liability for lifetime cannabis use or cannabis use disorder with periodontitis. The estimates from the primary analyses were supported in multivariable MR analysis, which considered potential pleiotropic pathways and in weak instrument analyses. CONCLUSIONS: This study provides little evidence to support a detrimental effect of genetic liability for cannabis use on periodontal health.


Assuntos
Cannabis , Abuso de Maconha , Periodontite , Cannabis/genética , Estudo de Associação Genômica Ampla , Humanos , Análise da Randomização Mendeliana , Periodontite/genética , Polimorfismo de Nucleotídeo Único
14.
Expert Opin Biol Ther ; : 1-14, 2022 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-35235467

RESUMO

INTRODUCTION: The genodermatosis epidermolysis bullosa (EB) is a monogenetic disease, characterized by severe blister formation on the skin and mucous membranes upon minimal mechanical trauma. Causes for the disease are mutations in genes encoding proteins that are essential for skin integrity. In EB, one of these proteins is either functionally impaired or completely absent. Therefore, the development and improvement of DNA and RNA-based therapeutic approaches for this severe blistering skin disease is mandatory to achieve a treatment option for the patients. AREAS COVERED: Currently, there are several forms of DNA/RNA therapies potentially feasible for EB. Whereas some of them are still at the preclinical stage, others are clinically advanced and have already been applied to patients. In particular, this is the case for a cDNA replacement approach successfully applied for a small number of patients with junctional EB. EXPERT OPINION: The heterogeneity of EB justifies the development of therapeutic options with distinct modes of action at a DNA or RNA level. In addition, splicing-modulating therapies, based on RNA trans-splicing or short antisense oligonucleotides, especially designer nucleases, have steadily improved in efficiency and safety and thus likely represent the most promising gene therapy tool in the near future.

17.
EMBO J ; 41(12): e109049, 2022 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-35319107

RESUMO

Cellular metabolism must adapt to changing demands to enable homeostasis. During immune responses or cancer metastasis, cells leading migration into challenging environments require an energy boost, but what controls this capacity is unclear. Here, we study a previously uncharacterized nuclear protein, Atossa (encoded by CG9005), which supports macrophage invasion into the germband of Drosophila by controlling cellular metabolism. First, nuclear Atossa increases mRNA levels of Porthos, a DEAD-box protein, and of two metabolic enzymes, lysine-α-ketoglutarate reductase (LKR/SDH) and NADPH glyoxylate reductase (GR/HPR), thus enhancing mitochondrial bioenergetics. Then Porthos supports ribosome assembly and thereby raises the translational efficiency of a subset of mRNAs, including those affecting mitochondrial functions, the electron transport chain, and metabolism. Mitochondrial respiration measurements, metabolomics, and live imaging indicate that Atossa and Porthos power up OxPhos and energy production to promote the forging of a path into tissues by leading macrophages. Since many crucial physiological responses require increases in mitochondrial energy output, this previously undescribed genetic program may modulate a wide range of cellular behaviors.


Assuntos
Drosophila , Sacaropina Desidrogenases , Animais , Drosophila/metabolismo , Metabolismo Energético , Macrófagos/metabolismo , Mitocôndrias/metabolismo , RNA Mensageiro/metabolismo , Sacaropina Desidrogenases/genética , Sacaropina Desidrogenases/metabolismo
18.
Proc Biol Sci ; 289(1971): 20212645, 2022 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-35291838

RESUMO

Teleosts are important models to study sex chromosomes and sex-determining (SD) genes because they present a variety of sex determination systems. Here, we used Nanopore and Hi-C technologies to generate a high-contiguity chromosome-level genome assembly of a YY southern catfish (Silurus meridionalis). The assembly is 750.0 Mb long, with contig N50 of 15.96 Mb and scaffold N50 of 27.22 Mb. We also sequenced and assembled an XY male genome with a size of 727.2 Mb and contig N50 of 13.69 Mb. We identified a candidate SD gene through comparisons to our previous assembly of an XX individual. By resequencing male and female pools, we characterized a 2.38 Mb sex-determining region (SDR) on Chr24. Analysis of read coverage and comparison of the X and Y chromosome sequences showed a Y specific insertion (approx. 500 kb) in the SDR which contained a male-specific duplicate of amhr2 (named amhr2y). amhr2y and amhr2 shared high-nucleotide identity (81.0%) in the coding region but extremely low identity in the promotor and intron regions. The exclusive expression in the male gonadal primordium and loss-of-function inducing male to female sex reversal confirmed the role of amhr2y in male sex determination. Our study provides a new example of amhr2 as the SD gene in fish and sheds light on the convergent evolution of the duplication of AMH/AMHR2 pathway members underlying the evolution of sex determination in different fish lineages.


Assuntos
Peixes-Gato , Animais , Peixes-Gato/genética , Mapeamento Cromossômico , Feminino , Genoma , Masculino , Filogenia , Cromossomos Sexuais , Processos de Determinação Sexual , Cromossomo X , Cromossomo Y/genética
19.
Mol Cell ; 82(5): 920-932.e7, 2022 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-35245456

RESUMO

IDO1 oxidizes tryptophan (TRP) to generate kynurenine (KYN), the substrate for 1-carbon and NAD metabolism, and is implicated in pro-cancer pathophysiology and infection biology. However, the mechanistic relationships between IDO1 in amino acid depletion versus product generation have remained a longstanding mystery. We found an unrecognized link between IDO1 and cell survival mediated by KYN that serves as the source for molecules that inhibit ferroptotic cell death. We show that this effect requires KYN export from IDO1-expressing cells, which is then available for non-IDO1-expressing cells via SLC7A11, the central transporter involved in ferroptosis suppression. Whether inside the "producer" IDO1+ cell or the "receiver" cell, KYN is converted into downstream metabolites, suppressing ferroptosis by ROS scavenging and activating an NRF2-dependent, AHR-independent cell-protective pathway, including SLC7A11, propagating anti-ferroptotic signaling. IDO1, therefore, controls a multi-pronged protection pathway from ferroptotic cell death, underscoring the need to re-evaluate the use of IDO1 inhibitors in cancer treatment.


Assuntos
Sistema y+ de Transporte de Aminoácidos , Ferroptose , Cinurenina , Neoplasias , Sistema y+ de Transporte de Aminoácidos/genética , Sistema y+ de Transporte de Aminoácidos/metabolismo , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Cinurenina/metabolismo , Cinurenina/farmacologia , Neoplasias/metabolismo , Transdução de Sinais , Triptofano/metabolismo
20.
Int J Mol Sci ; 23(1)2022 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-35008999

RESUMO

Conventional anti-cancer therapies based on chemo- and/or radiotherapy represent highly effective means to kill cancer cells but lack tumor specificity and, therefore, result in a wide range of iatrogenic effects. A promising approach to overcome this obstacle is spliceosome-mediated RNA trans-splicing (SMaRT), which can be leveraged to target tumor cells while leaving normal cells unharmed. Notably, a previously established RNA trans-splicing molecule (RTM44) showed efficacy and specificity in exchanging the coding sequence of a cancer target gene (Ct-SLCO1B3) with the suicide gene HSV1-thymidine kinase in a colorectal cancer model, thereby rendering tumor cells sensitive to the prodrug ganciclovir (GCV). In the present work, we expand the application of this approach, using the same RTM44 in aggressive skin cancer arising in the rare genetic skin disease recessive dystrophic epidermolysis bullosa (RDEB). Stable expression of RTM44, but not a splicing-deficient control (NC), in RDEB-SCC cells resulted in expression of the expected fusion product at the mRNA and protein level. Importantly, systemic GCV treatment of mice bearing RTM44-expressing cancer cells resulted in a significant reduction in tumor volume and weight compared with controls. Thus, our results demonstrate the applicability of RTM44-mediated targeting of the cancer gene Ct-SLCO1B3 in a different malignancy.


Assuntos
Epidermólise Bolhosa Distrófica/complicações , Epidermólise Bolhosa/complicações , Terapia Genética/métodos , Splicing de RNA , Neoplasias Cutâneas/etiologia , Neoplasias Cutâneas/terapia , Trans-Splicing , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Gerenciamento Clínico , Modelos Animais de Doenças , Suscetibilidade a Doenças , Epidermólise Bolhosa/genética , Epidermólise Bolhosa Distrófica/genética , Ganciclovir/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Loci Gênicos , Terapia Genética/efeitos adversos , Humanos , Camundongos , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
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