RESUMO
BACKGROUND: Salt stress significantly reduces soybean yield. To improve salt tolerance in soybean, it is important to mine the genes associated with salt tolerance traits. RESULTS: Salt tolerance traits of 286 soybean accessions were measured four times between 2009 and 2015. The results were associated with 740,754 single nucleotide polymorphisms (SNPs) to identify quantitative trait nucleotides (QTNs) and QTN-by-environment interactions (QEIs) using three-variance-component multi-locus random-SNP-effect mixed linear model (3VmrMLM). As a result, eight salt tolerance genes (GmCHX1, GsPRX9, Gm5PTase8, GmWRKY, GmCHX20a, GmNHX1, GmSK1, and GmLEA2-1) near 179 significant and 79 suggested QTNs and two salt tolerance genes (GmWRKY49 and GmSK1) near 45 significant and 14 suggested QEIs were associated with salt tolerance index traits in previous studies. Six candidate genes and three gene-by-environment interactions (GEIs) were predicted to be associated with these index traits. Analysis of four salt tolerance related traits under control and salt treatments revealed six genes associated with salt tolerance (GmHDA13, GmPHO1, GmERF5, GmNAC06, GmbZIP132, and GmHsp90s) around 166 QEIs were verified in previous studies. Five candidate GEIs were confirmed to be associated with salt stress by at least one haplotype analysis. The elite molecular modules of seven candidate genes with selection signs were extracted from wild soybean, and these genes could be applied to soybean molecular breeding. Two of these genes, Glyma06g04840 and Glyma07g18150, were confirmed by qRT-PCR and are expected to be key players in responding to salt stress. CONCLUSIONS: Around the QTNs and QEIs identified in this study, 16 known genes, 6 candidate genes, and 8 candidate GEIs were found to be associated with soybean salt tolerance, of which Glyma07g18150 was further confirmed by qRT-PCR.
Assuntos
Interação Gene-Ambiente , Genes de Plantas , Glycine max , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Tolerância ao Sal , Glycine max/genética , Glycine max/fisiologia , Tolerância ao Sal/genética , Locos de Características Quantitativas/genética , FenótipoRESUMO
Small intestinal neuroendocrine tumors (SI-NETs) are serotonin-secreting well-differentiated neuroendocrine tumors of putative enterochromaffin (EC) cell origin. However, EC cell-derived tumorigenesis remains poorly understood. Here, we examined whether the gain of Myc and the loss of RB1 and Trp53 function in EC cells result in SI-NET using tryptophan hydroxylase 1 (TPH1) Cre-ERT2-driven RB1fl Trp53fl MycLSL (RPM) mice. TPH1-Cre-induced gain of Myc and loss of RB1 and Trp53 function resulted in endocrine or neuronal tumors in pancreas, lung, enteric neurons, and brain. Lineage tracing indicated that the cellular origin for these tumors was TPH1-expressing neuroendocrine, neuronal, or their precursor cells in these organs. However, despite that TPH1 is most highly expressed in EC cells of the small intestine, we observed no incidence of EC cell tumors. Instead, the tumor of epithelial cell origin in the intestine was exclusively nonendocrine adenocarcinoma, suggesting dedifferentiation of EC cells into intestinal stem cells (ISCs) as a cellular mechanism. Furthermore, ex vivo organoid studies indicated that loss of functions of Rb1 and Trp53 accelerated dedifferentiation of EC cells that were susceptible to apoptosis with expression of activated MycT58A, suggesting that the rare dedifferentiating cells escaping cell death went on to develop adenocarcinomas. Lineage tracing demonstrated that EC cells in the small intestine were short-lived compared with neuroendocrine or neuronal cells in other organs. In contrast, EC cell-derived ISCs were long-lasting and actively cycling and thus susceptible to transformation. These results suggest that tissue- and cell-specific properties of EC cells such as rapid cell turnover and homeostatic dedifferentiation, affect the fate and rate of tumorigenesis induced by genetic alterations and provide important insights into EC cell-derived tumorigenesis.NEW & NOTEWORTHY Small intestinal neuroendocrine tumors are of putative enterochromaffin (EC) cell origin and are the most common malignancy in the small intestine, followed by adenocarcinoma. However, the tumorigenesis of these tumor types remains poorly understood. The present lineage tracing studies showed that tissue- and cell-specific properties of EC cells such as rapid cell turnover and homeostatic dedifferentiation affect the fate and rate of tumorigenesis induced by genetic alterations toward a rare occurrence of adenocarcinoma.
Assuntos
Adenocarcinoma , Neoplasias Intestinais , Tumores Neuroendócrinos , Camundongos , Animais , Células Enterocromafins/metabolismo , Intestino Delgado/patologia , Carcinogênese/metabolismo , Transformação Celular Neoplásica/metabolismo , Neoplasias Intestinais/metabolismo , Tumores Neuroendócrinos/metabolismo , Adenocarcinoma/genéticaRESUMO
OBJECTIVE: To compare force degradation of elastomeric chains and NiTi coil springs in vivo and in vitro, and evaluate the effects of pre-stretched and reused elastomeric chains in the oral cavity during the time. METHODS: In the in vitro groups, 4-unit elastomeric chains and NiTi coil springs with an initial force of 200 g were placed in dry air and artificial saliva. The volunteers wore clear retainers which were used to hold the sample of 4-unit chains, pre-stretched 4-unit chains, and NiTi coil springs with the initial force of 200 g in the in vivo groups. After the first 4 weeks, 4-unit specimens were stretched to 200 g again for another 4 weeks in vivo. The force value and the percentage of force degradation were recorded at each measurement time interval in the in vivo and in vitro groups. RESULTS: The force degradation of elastomeric chains was greatest within the initial 4 hours, followed by a more stable phase after 1 week. The average force degradation of 4-unit elastomeric chains after 4 weeks was in vivo (64.8%) > artificial saliva (55.0%) > dry air (46.42%) (P < 0.05). The force degradation of NiTi coil springs in vivo (15.36%) or in artificial saliva (15.8%) was greater than in dry air (7.6%) (P < 0.05). NiTi coil springs presented a gentler force decay than elastomeric chains during the period (P < 0.05). In vivo, the force degradation of pre-stretched and reused elastomeric chains decreased less than the regular style(P < 0.05). CONCLUSION: The force degradation of the elastomeric chains and NiTi coil springs varied in different environments. NiTi coil springs presented a gentler force decay than elastomeric chains during the period. Orthodontists should consider the force degradation characteristics of orthodontic accessories in clinical practice.
Assuntos
Níquel , Titânio , Humanos , Saliva Artificial , Elasticidade , Aparelhos Ortodônticos , Teste de Materiais , Fios OrtodônticosRESUMO
AIM: Emerging studies have shown that immune response to biomaterial implants plays a central role in bone healing. Ipriflavone is clinically used for osteoporosis. However, the mechanism of ipriflavone in immune response to implants in early stages of osseointegration remains unclear. In this study, we aimed to investigate the potential role of ipriflavone in early bone healing process and uncover the underlying mechanism. MATERIALS AND METHODS: We carried out histological examination as well as analysis of proinflammatory cytokines and NLRP3 inflammasome activation in a tibial implantation mouse model with intra-peritoneal injection of ipriflavone. In addition, we explored the mechanism of ipriflavone in the regulation of NLRP3 inflammasome activation in macrophages. RESULTS: In vivo, ipriflavone ameliorated host inflammatory response related to NLRP3 inflammasome activation at implantation sites, characterized by reductions of inflammatory cell infiltration and proinflammatory cytokine interleukin-1ß levels. Ipriflavone treatment also showed beneficial effects on early osseointegration. Further investigations of the molecular mechanism showed that the suppression of NLRP3 inflammasome acts upstream of NLRP3 oligomerization through abrogating the production of reactive oxygen species. CONCLUSIONS: These results revealed an anti-inflammatory role of ipriflavone in NLRP3 inflammasome activation through improving mitochondrial function. This study provides a new strategy for the development of immune-regulated biomaterials and treatment options for NLRP3-related diseases.
Assuntos
Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Animais , Materiais Biocompatíveis , Citocinas , Imunidade , Interleucina-1beta , Isoflavonas , CamundongosRESUMO
In the genetic system that regulates complex traits, metabolites, gene expression levels, RNA editing levels and DNA methylation, a series of small and linked genes exist. To date, however, little is known about how to design an efficient framework for the detection of these kinds of genes. In this article, we propose a genome-wide composite interval mapping (GCIM) in F2. First, controlling polygenic background via selecting markers in the genome scanning of linkage analysis was replaced by estimating polygenic variance in a genome-wide association study. This can control large, middle and minor polygenic backgrounds in genome scanning. Then, additive and dominant effects for each putative quantitative trait locus (QTL) were separately scanned so that a negative logarithm P-value curve against genome position could be separately obtained for each kind of effect. In each curve, all the peaks were identified as potential QTLs. Thus, almost all the small-effect and linked QTLs are included in a multi-locus model. Finally, adaptive least absolute shrinkage and selection operator (adaptive lasso) was used to estimate all the effects in the multi-locus model, and all the nonzero effects were further identified by likelihood ratio test for true QTL identification. This method was used to reanalyze four rice traits. Among 25 known genes detected in this study, 16 small-effect genes were identified only by GCIM. To further demonstrate GCIM, a series of Monte Carlo simulation experiments was performed. As a result, GCIM is demonstrated to be more powerful than the widely used methods for the detection of closely linked and small-effect QTLs.
Assuntos
Modelos Genéticos , Locos de Características Quantitativas , Metilação de DNA , Ligação Genética , Humanos , Método de Monte CarloRESUMO
Small intestinal neuroendocrine tumors (SI-NET) are serotonin-secreting well-differentiated neuroendocrine tumors of putative enterochromaffin (EC) cell origin. Recent studies recognize a subset of EC cells that is label-retaining at the +4 position in the crypt and functions as a reserve intestinal stem cell. Importantly, this +4 reserve EC cell subset not only contributes to regeneration of the intestinal epithelium during injury and inflammation but also to basal crypt homeostasis at a constant rate. The latter function suggests that the +4 EC cell subset serves as an active reserve stem cell via a constant rate of dedifferentiation. Characterization of early tumor formation of SI-NET, observed as crypt-based EC cell clusters in many cases of familial SI-NETs, suggests that the +4 active reserve EC cell subset is the cell of origin. This newly discovered active reserve stem cell property of EC cells can account for unique biological mechanisms and processes associated with the genesis and development of SI-NETs. The recognition of this property of the +4 active reserve EC cell subset may provide novel opportunities to explore NETs in the gastrointestinal tract and other organs.
Assuntos
Células Enterocromafins/patologia , Neoplasias Intestinais/patologia , Intestino Delgado/patologia , Tumores Neuroendócrinos/patologia , Células-Tronco/patologia , Células-Tronco/fisiologia , Animais , Carcinogênese/patologia , Desdiferenciação Celular , Células Enterocromafins/fisiologia , Humanos , Camundongos , Tumores Neuroendócrinos/metabolismo , Serotonina/metabolismoRESUMO
BACKGROUND: Seed weight is a complex yield-related trait with a lot of quantitative trait loci (QTL) reported through linkage mapping studies. Integration of QTL from linkage mapping into breeding program is challenging due to numerous limitations, therefore, Genome-wide association study (GWAS) provides more precise location of QTL due to higher resolution and diverse genetic diversity in un-related individuals. RESULTS: The present study utilized 573 breeding lines population with 61,166 single nucleotide polymorphisms (SNPs) to identify quantitative trait nucleotides (QTNs) and candidate genes for seed weight in Chinese summer-sowing soybean. GWAS was conducted with two single-locus models (SLMs) and six multi-locus models (MLMs). Thirty-nine SNPs were detected by the two SLMs while 209 SNPs were detected by the six MLMs. In all, two hundred and thirty-one QTNs were found to be associated with seed weight in YHSBLP with various effects. Out of these, seventy SNPs were concurrently detected by both SLMs and MLMs on 8 chromosomes. Ninety-four QTNs co-localized with previously reported QTL/QTN by linkage/association mapping studies. A total of 36 candidate genes were predicted. Out of these candidate genes, four hub genes (Glyma06g44510, Glyma08g06420, Glyma12g33280 and Glyma19g28070) were identified by the integration of co-expression network. Among them, three were relatively expressed higher in the high HSW genotypes at R5 stage compared with low HSW genotypes except Glyma12g33280. Our results show that using more models especially MLMs are effective to find important QTNs, and the identified HSW QTNs/genes could be utilized in molecular breeding work for soybean seed weight and yield. CONCLUSION: Application of two single-locus plus six multi-locus models of GWAS identified 231 QTNs. Four hub genes (Glyma06g44510, Glyma08g06420, Glyma12g33280 & Glyma19g28070) detected via integration of co-expression network among the predicted candidate genes.
Assuntos
Genes de Plantas , Estudo de Associação Genômica Ampla , Glycine max/genética , Locos de Características Quantitativas , Sementes/fisiologia , Modelos Genéticos , Nucleotídeos/análise , Sementes/genéticaRESUMO
The mixed linear model has been widely used in genome-wide association studies (GWAS), but its application to multi-locus GWAS analysis has not been explored and assessed. Here, we implemented a fast multi-locus random-SNP-effect EMMA (FASTmrEMMA) model for GWAS. The model is built on random single nucleotide polymorphism (SNP) effects and a new algorithm. This algorithm whitens the covariance matrix of the polygenic matrix K and environmental noise, and specifies the number of nonzero eigenvalues as one. The model first chooses all putative quantitative trait nucleotides (QTNs) with ≤ 0.005 P-values and then includes them in a multi-locus model for true QTN detection. Owing to the multi-locus feature, the Bonferroni correction is replaced by a less stringent selection criterion. Results from analyses of both simulated and real data showed that FASTmrEMMA is more powerful in QTN detection and model fit, has less bias in QTN effect estimation and requires a less running time than existing single- and multi-locus methods, such as empirical Bayes, settlement of mixed linear model under progressively exclusive relationship (SUPER), efficient mixed model association (EMMA), compressed MLM (CMLM) and enriched CMLM (ECMLM). FASTmrEMMA provides an alternative for multi-locus GWAS.
Assuntos
Algoritmos , Proteínas de Arabidopsis/genética , Arabidopsis/genética , Estudo de Associação Genômica Ampla/métodos , Polimorfismo de Nucleotídeo Único , Teorema de Bayes , Simulação por Computador , Modelos Lineares , Modelos Genéticos , Herança Multifatorial , FenótipoRESUMO
INTRODUCTION: The objective of this study was to evaluate the characteristics of force degradation of latex elastics of 10 kinds of elastics over 48 hours, both in vivo and in vitro. METHODS: For the in vivo study, 10 different kinds of elastics were randomly chosen for investigation: 1/8-inch (2 oz); 1/8-inch (3.5 oz); 3/16-inch (2 oz); 3/16-inch (3.5 oz); 1/4-inch (2 oz); 1/4-inch (3.5 oz); 5/16-inch (2 oz); 5/16-inch (3.5 oz); 3/8-inch (2 oz); and 3/8-inch (3.5 oz). Ten volunteers (aged 22-24 years) were selected to wear personalized clear retainers, which were made to hold the elastics in the mouth and stretched to a specific length. Control samples of 1/4-inch (2 oz) and 1/4-inch (3.5 oz) latex elastics were stretched to the same length and held in dry air conditions (temperature = 25°C) and in artificial saliva (temperature = 37°C, pH = 6.7). Force value and percentage of force degradation were estimated 10 times over a 48-hour period in both the in vivo and in vitro groups. A 1-way ANOVA and t test were used to identify statistical significance (P <0.05). RESULTS: The force degradation of the latex elastic in vivo is greater than in vitro. In the in vivo groups, during the first hour, the extension rate of all elastics decreased sharply about 13.16%-18.79%, then the rate of force degradation declined. The degradation of initial force was about 29.35%-39.94% after 48 hours. The extension range of 2.0-oz elastics reduced less than that of the 3.5-oz elastics in vivo. At the same time, with the same initial force, elastics with larger inner diameters decreased more slowly than the smaller elastics (P <0.05). CONCLUSIONS: The force degradation of latex elastic in vivo is much greater than that in both air and artificial saliva. In vivo, the force value of the orthodontic latex elastics decreased sharply in the first hour. The larger the inner diameter and smaller the setting force value were, the slower the force decay.
Assuntos
Látex , Aparelhos Ortodônticos , Análise do Estresse Dentário , Elasticidade , Humanos , Teste de Materiais , Estresse Mecânico , Adulto JovemRESUMO
The normal intestinal epithelium is continuously regenerated at a rapid rate from actively cycling Lgr5-expressing intestinal stem cells (ISCs) that reside at the crypt base. Recent mathematical modeling based on several lineage-tracing studies in mice shows that the symmetric cell division-dominant neutral drift model fits well with the observed in vivo growth of ISC clones and suggests that symmetric divisions are central to ISC homeostasis. However, other studies suggest a critical role for asymmetric cell division in the maintenance of ISC homeostasis in vivo. Here, we show that the stochastic branching and Moran process models with both a symmetric and asymmetric division mode not only simulate the stochastic growth of the ISC clone in silico but also closely fit the in vivo stem cell dynamics observed in lineage-tracing studies. In addition, the proposed model with highest probability for asymmetric division is more consistent with in vivo observations reported here and by others. Our in vivo studies of mitotic spindle orientations and lineage-traced progeny pairs indicate that asymmetric cell division is a dominant mode used by ISCs under normal homeostasis. Therefore, we propose the asymmetric cell division-dominant neutral drift model for normal ISC homeostasis. NEW & NOTEWORTHY The prevailing mathematical model suggests that intestinal stem cells (ISCs) divide symmetrically. The present study provides evidence that asymmetric cell division is the major contributor to ISC maintenance and thus proposes an asymmetric cell division-dominant neutral drift model. Consistent with this model, in vivo studies of mitotic spindle orientation and lineage-traced progeny pairs indicate that asymmetric cell division is the dominant mode used by ISCs under normal homeostasis.
Assuntos
Divisão Celular Assimétrica/fisiologia , Homeostase/fisiologia , Intestinos/citologia , Células-Tronco/citologia , Animais , Diferenciação Celular/fisiologia , Linhagem da Célula/fisiologia , Células Cultivadas , Mucosa Intestinal/citologia , Camundongos , Regeneração/fisiologiaRESUMO
Marker segregation distortion is a natural phenomenon. Severely distorted markers are usually excluded in the construction of linkage maps. We investigated the effect of marker segregation distortion on linkage map construction and quantitative trait locus (QTL) mapping. A total of 519 recombinant inbred lines of soybean from orthogonal and reciprocal crosses between LSZZH and NN493-1 were genotyped by specific length amplified fragment markers and seed linoleic acid content was measured in three environments. As a result, twenty linkage groups were constructed with 11,846 markers, including 1513 (12.77%) significantly distorted markers, on 20 chromosomes, and the map length was 2475.86 cM with an average marker-interval of 0.21 cM. The inclusion of distorted markers in the analysis was shown to not only improve the grouping of the markers from the same chromosomes, and the consistency of linkage maps with genome, but also increase genome coverage by markers. Combining genotypic data from both orthogonal and reciprocal crosses decreased the proportion of distorted markers and then improved the quality of linkage maps. Validation of the linkage maps was confirmed by the high collinearity between positions of markers in the soybean reference genome and in linkage maps and by the high consistency of 24 QTL regions in this study compared with the previously reported QTLs and lipid metabolism related genes. Additionally, linkage maps that include distorted markers could add more information to the outputs from QTL mapping. These results provide important information for linkage mapping, gene cloning and marker-assisted selection in soybean.
Assuntos
Mapeamento Cromossômico , Ligação Genética , Genótipo , Glycine max/genética , Característica Quantitativa HerdávelRESUMO
OBJECTIVE: To investigate the effects of bio-crosslinker genipin pretreatment on type â collagen mineralization. METHODS: Type â collagen gels were prepared and pretreated with 0.5wt%genipin (experimental group) and deionized water (control group) for 2 h, respectively. The pretreated products were subjected to Fourier transform infrared spectroscopy (FT-IR). Reconstituted collagen fibrils were pretreated with genipin or deionized water for 2 h and were mineralized for 4 h. The collagen density and mineralization degree were examined with transmission electron microscopy (TEM) and analyzed with ImageJ software. Then scanning electron microscopy (SEM) and TEM were used to observe the mineralization of cross-linked demineralized dentin collagen. RESULTS: FT-IR spectrum showed that the genipin was crosslinked with collagen. TEM observation and ImageJ results showed that after 4 h mineralization, the mineralization effect of 0.5wt% genipin group was significantly better than that of the control group[(73.3±5.3)%vs.(7.4±3.5)%,P<0.01]. TEM and SEM observation showed that the mineralization rate of type â collagen and demineralized dentin pretreated with genipin were significantly faster than that of the control group. CONCLUSIONS: The study demonstrates that 0.5 wt% concentration of genipin can significantly promote the mineralization of type â collagen.
Assuntos
Colágeno Tipo I , Iridoides , Colágeno Tipo I/química , Colágeno Tipo I/ultraestrutura , Iridoides/química , Microscopia Eletrônica de Varredura , Microscopia Eletrônica de Transmissão , Espectroscopia de Infravermelho com Transformada de FourierRESUMO
Lgr5-expressing intestinal stem cells (ISCs) maintain continuous and rapid generation of the intestinal epithelium. Here, we present evidence that dedifferentiation of committed enteroendocrine cells (EECs) contributes to maintenance of the epithelium under both basal conditions and in response to injury. Lineage-tracing studies identified a subset of EECs that reside at +4 position for more than 2 wk, most of which were BrdU-label-retaining cells. Under basal conditions, cells derived from these EECs grow from the bottom of the crypt to generate intestinal epithelium according to neutral drift kinetics that is consistent with dedifferentiation of mature EECs to ISCs. The lineage tracing of EECs demonstrated reserve stem cell properties in response to radiation-induced injury with the generation of reparative EEC-derived epithelial patches. Finally, the enterochromaffin (EC) cell was the predominant EEC type participating in these stem cell dynamics. These results provide novel insights into the +4 reserve ISC hypothesis, stem cell dynamics of the intestinal epithelium, and in the development of EC-derived small intestinal tumors. NEW & NOTEWORTHY The current manuscript demonstrating that a subset of mature enteroendocrine cells (EECs), predominantly enterochromaffin cells, dedifferentiates to fully functional intestinal stem cells (ISCs) is novel, timely, and important. These cells dedifferentiate to ISCs not only in response to injury but also under basal homeostatic conditions. These novel findings provide a mechanism in which a specified cell can dedifferentiate and contribute to normal tissue plasticity as well as the development of EEC-derived intestinal tumors under pathologic conditions.
Assuntos
Células-Tronco Adultas/citologia , Diferenciação Celular , Proliferação de Células , Células Enteroendócrinas/citologia , Intestino Delgado/citologia , Células-Tronco Adultas/metabolismo , Animais , Células Cultivadas , Células Enteroendócrinas/metabolismo , Intestino Delgado/patologia , Camundongos , Camundongos Endogâmicos C57BL , Lesões Experimentais por Radiação/patologia , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismoRESUMO
BACKGROUND & AIMS: Small intestinal neuroendocrine tumors (SI-NETs) are serotonin-secreting well-differentiated neuroendocrine tumors believed to originate from enterochromaffin (EC) cells. Intestinal stem cell (ISC) are believed to contribute to the formation of SI-NETs, although little is known about tumor formation or development. We investigated the relationship between EC cells, ISCs, and SI-NETs. METHODS: We analyzed jejuno-ileal tissue specimens from 14 patients with familial SI-NETs enrolled in the Natural History of Familial Carcinoid Tumor study at the National Institutes of Health from January 2009 to December 2014. Frozen and paraffin-embedded tumor tissues of different stages and isolated crypts were analyzed by in situ hybridization and immunohistochemistry. Tumor clonality was assessed by analyses of mitochondrial DNA. RESULTS: We identified multifocal aberrant crypt-containing endocrine cell clusters (ACECs) that contain crypt EC cell microtumors in patients with familial SI-NETs. RNA in situ hybridization revealed expression of the EC cell and reserve stem cell genes TPH1, BMI1, HOPX, and LGR5(low), in the ACECs and more advanced extraepithelial tumor nests. This expression pattern resembled that of reserve EC cells that express reserve ISC genes; most reside at the +4 position in normal crypts. The presence of multifocal ACECs from separate tumors and in the macroscopic tumor-free mucosa indicated widespread, independent, multifocal tumorigenesis. Analyses of mitochondrial DNA confirmed the independent origin of the ACECs. CONCLUSIONS: Familial SI-NETs originate from a subset of EC cells (reserve EC cells that express reserve ISC genes) via multifocal and polyclonal processes. Increasing our understanding of the role of these reserve EC cells in the genesis of multifocal SI-NETs could improve diagnostic and therapeutic strategies for this otherwise intractable disease.
Assuntos
Carcinogênese/genética , Neoplasias do Íleo/genética , Neoplasias do Jejuno/genética , Família Multigênica/genética , Tumores Neuroendócrinos/genética , Células Enterocromafins/metabolismo , Proteínas de Homeodomínio/genética , Humanos , Hibridização In Situ , Intestino Delgado/citologia , Complexo Repressor Polycomb 1/genética , Receptores Acoplados a Proteínas G/genética , Células-Tronco/metabolismo , Triptofano Hidroxilase/genética , Proteínas Supressoras de Tumor/genéticaRESUMO
BACKGROUND & AIMS: Small intestinal carcinoids are rare and difficult to diagnose and patients often present with advanced incurable disease. Although the disease occurs sporadically, there have been reports of family clusters. Hereditary small intestinal carcinoid has not been recognized and genetic factors have not been identified. We performed a genetic analysis of families with small intestinal carcinoids to establish a hereditary basis and find genes that might cause this cancer. METHODS: We performed a prospective study of 33 families with at least 2 cases of small intestinal carcinoids. Affected members were characterized clinically and asymptomatic relatives were screened and underwent exploratory laparotomy for suspected tumors. Disease-associated mutations were sought using linkage analysis, whole-exome sequencing, and copy number analyses of germline and tumor DNA collected from members of a single large family. We assessed expression of mutant protein, protein activity, and regulation of apoptosis and senescence in lymphoblasts derived from the cases. RESULTS: Familial and sporadic carcinoids are clinically indistinguishable except for the multiple synchronous primary tumors observed in most familial cases. Nearly 34% of asymptomatic relatives older than age 50 were found to have occult tumors; the tumors were cleared surgically from 87% of these individuals (20 of 23). Linkage analysis and whole-exome sequencing identified a germline 4-bp deletion in the gene inositol polyphosphate multikinase (IPMK), which truncates the protein. This mutation was detected in all 11 individuals with small intestinal carcinoids and in 17 of 35 family members whose carcinoid status was unknown. Mutant IPMK had reduced kinase activity and nuclear localization, compared with the full-length protein. This reduced activation of p53 and increased cell survival. CONCLUSIONS: We found that small intestinal carcinoids can occur as an inherited autosomal-dominant disease. The familial form is characterized by multiple synchronous primary tumors, which might account for 22%-35% of cases previously considered sporadic. Relatives of patients with familial carcinoids should be screened to detect curable early stage disease. IPMK haploinsufficiency promotes carcinoid tumorigenesis.
Assuntos
Tumor Carcinoide/genética , Mutação em Linhagem Germinativa , Neoplasias Intestinais/genética , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Tumor Carcinoide/diagnóstico , Tumor Carcinoide/patologia , Família , Feminino , Humanos , Neoplasias Intestinais/diagnóstico , Neoplasias Intestinais/patologia , Laparotomia , Masculino , Pessoa de Meia-Idade , Linhagem , Estudos Prospectivos , Adulto JovemRESUMO
INTRODUCTION: In this study, we aimed to give insight into the article review process by investigating the characteristics and the fate of manuscripts submitted to the American Journal of Orthodontics and Dentofacial Orthopedics (AJO-DO). METHODS: The following information was obtained for original articles submitted to the AJO-DO in 2008: (1) for rejected articles: the reasons for rejection and the journal of subsequent publication when applicable; (2) for accepted articles: the number of revisions and the time elapsed to publication; and (3) for all articles: study topic, study design, area of origin, and statistically significant findings. Findings were reported using descriptive statistics, the chi-square test for equality of proportions, and multiple regression where appropriate. Post-hoc pair-wise tests were checked against the Bonferroni correction to account for multiple testing. RESULTS: Of the 440 original articles submitted to AJO-DO in 2008, 116 (26%) were accepted and published an average of 21 months (SD, 5 months) after acceptance. Rejected articles totaled 324 (74%), with 137 (42%) finding subsequent publication an average of 22 months (SD, 11 months) after rejection by the AJO-DO. The top 3 reasons for rejection by the AJO-DO were (1) poor study design (59% of rejected articles), (2) outdated or unoriginal topic (42%), and (3) inappropriate for the AJO-DO's audience (27%). Manuscripts rejected for poor study design had the least success for subsequent publication, whereas those rejected as inappropriate for the AJO-DO had the highest rate of publication elsewhere. Area of origin was significantly associated with acceptance by the AJO-DO, with articles from United States and Canada most likely to be accepted (P < 0.01). Articles from countries with the lowest publication rate in the AJO-DO had the highest publication rate elsewhere. The presence of statistically significant findings was shown to be significantly associated with acceptance by the AJO-DO (P = 0.013) but not with publication elsewhere (P = 0.77). CONCLUSIONS: Rejection by the AJO-DO does not preclude publication elsewhere, although articles rejected for poor study design were least likely to be eventually published. Many publishable articles are rejected by the AJO-DO as inappropriate for its readership, and these were the most likely to find publication elsewhere. Articles with the highest chance of acceptance by the AJO-DO were those from the United States and Canada and those reporting statistically significant results.
Assuntos
Bibliometria , Pesquisa em Odontologia , Ortodontia , Publicações Periódicas como Assunto , Editoração , Indexação e Redação de Resumos , Canadá , Políticas Editoriais , Humanos , Fator de Impacto de Revistas , Revisão da Pesquisa por Pares , Projetos de Pesquisa/normas , Estatística como Assunto , Fatores de Tempo , Estados UnidosRESUMO
Red crown rot (RCR) disease caused by Calonectria ilicicola negatively impacts soybean yield and quality. Unfortunately, the knowledge of the genetic architecture of RCR resistance in soybeans is limited. In this study, 299 diverse soybean accessions were used to explore their genetic diversity and resistance to RCR, and to mine for candidate genes via emergence rate (ER), survival rate (SR), and disease severity (DS) by a multi-locus random-SNP-effect mixed linear model of GWAS. All accessions had brown necrotic lesions on the primary root, with five genotypes identified as resistant. Nine single-nucleotide polymorphism (SNP) markers were detected to underlie RCR response (ER, SR, and DS). Two SNPs colocalized with at least two traits to form a haplotype block which possessed nine genes. Based on their annotation and the qRT-PCR, three genes, namely Glyma.08G074600, Glyma.08G074700, and Glyma.12G043600, are suggested to modulate soybean resistance to RCR. The findings from this study could serve as the foundation for breeding RCR-tolerant soybean varieties, and the candidate genes could be validated to deepen our understanding of soybean response to RCR.
RESUMO
The regulatory mechanisms involved in embryonic development are complex and yet remain unclear. SCP4 represents a novel nucleus-resident phosphatase identified in our previous study. The primary aim of this study was to elucidate the function of SCP4 in the progress of cartilage development and endochondral osteogenesis. SCP4-/- and SCP4Col2ER mice were constructed to assess differences in bone formation using whole skeleton staining. ABH/OG staining was used to compare chondrocyte differentiation and cartilage development. Relevant biological functions were analysed using RNA-sequencing and GO enrichment, further validated by immunohistochemical staining, Co-IP and Western Blot. Global SCP4 knockout led to abnormal embryonic development in SCP4-/- mice, along with delayed endochondral osteogenesis. In parallel, chondrocyte-specific removal of SCP4 yielded more severe embryonic deformities in SCP4Col2ER mice, including limb shortening, reduced chondrocyte number in the growth plate, disorganisation and cell enlargement. Moreover, RNA-sequencing analysis showed an association between SCP4 and chondrocyte apoptosis. Notably, Tunnel-positive cells were indeed increased in the growth plates of SCP4Col2ER mice. The deficiency of SCP4 up-regulated the expression levels of pro-apoptotic proteins both in vivo and in vitro. Additionally, phosphorylation of FoxO3a (pFoxO3a), a substrate of SCP4, was heightened in chondrocytes of SCP4Col2ER mice growth plate, and the direct interaction between SCP4 and pFoxO3a was further validated in chondrocytes. Our findings underscore the critical role of SCP4 in regulating cartilage development and endochondral osteogenesis during embryonic development partially via inhibition of chondrocytes apoptosis regulated by FoxO3a dephosphorylation.
RESUMO
The calcium-sensing receptor (CaR) is the major sensor and regulator of extracellular Ca(2+), whose activity is allosterically regulated by amino acids and pH. Recently, CaR has been identified in the stomach and intestinal tract, where it has been proposed to function in a non-Ca(2+) homeostatic capacity. Luminal nutrients, such as Ca(2+) and amino acids, have been recognized for decades as potent stimulants for gastrin and acid secretion, although the molecular basis for their recognition remains unknown. The expression of CaR on gastrin-secreting G cells in the stomach and their shared activation by Ca(2+), amino acids, and elevated pH suggest that CaR may function as the elusive physiologic sensor regulating gastrin and acid secretion. The genetic and pharmacologic studies presented here comparing CaR-null mice and wild-type littermates support this hypothesis. Gavage of Ca(2+), peptone, phenylalanine, Hepes buffer (pH 7.4), and CaR-specific calcimimetic, cinacalcet, stimulated gastrin and acid secretion, whereas the calcilytic, NPS 2143, inhibited secretion only in the wild-type mouse. Consistent with known growth and developmental functions of CaR, G-cell number was progressively reduced between 30 and 90 d of age by more than 65% in CaR-null mice. These studies of nutrient-regulated G-cell gastrin secretion and growth provide definitive evidence that CaR functions as a physiologically relevant multimodal sensor. Medicinals targeting diseases of Ca(2+) homeostasis should be reviewed for effects outside traditional Ca(2+)-regulating tissues in view of the broader distribution and function of CaR.