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Assisted reproductive technologies (ARTs), including in vitro maturation and fertilization (IVF), are increasingly used in human and animal reproduction. Whether these technologies directly affect the rate of de novo mutation (DNM), and to what extent, has been a matter of debate. Here we take advantage of domestic cattle, characterized by complex pedigrees that are ideally suited to detect DNMs and by the systematic use of ART, to study the rate of de novo structural variation (dnSV) in this species and how it is impacted by IVF. By exploiting features of associated de novo point mutations (dnPMs) and dnSVs in clustered DNMs, we provide strong evidence that (1) IVF increases the rate of dnSV approximately fivefold, and (2) the corresponding mutations occur during the very early stages of embryonic development (one- and two-cell stage), yet primarily affect the paternal genome.
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Desarrollo Embrionario , Familia , Embarazo , Femenino , Animales , Bovinos , Humanos , Mutación , Linaje , Genoma HumanoRESUMEN
Clinical mastitis (CM) is an inflammatory disease occurring in the mammary glands of lactating cows. CM is under genetic control, and a prominent CM resistance QTL located on chromosome 6 was reported in various dairy cattle breeds. Nevertheless, the biological mechanism underpinning this QTL has been lacking. Herein, we mapped, fine-mapped, and discovered the putative causal variant underlying this CM resistance QTL in the Dutch dairy cattle population. We identified a ~12 kb multi-allelic copy number variant (CNV), that is in perfect linkage disequilibrium with a lead SNP, as a promising candidate variant. By implementing a fine-mapping and through expression QTL mapping, we showed that the group-specific component gene (GC), a gene encoding a vitamin D binding protein, is an excellent candidate causal gene for the QTL. The multiplicated alleles are associated with increased GC expression and low CM resistance. Ample evidence from functional genomics data supports the presence of an enhancer within this CNV, which would exert cis-regulatory effect on GC. We observed that strong positive selection swept the region near the CNV, and haplotypes associated with the multiplicated allele were strongly selected for. Moreover, the multiplicated allele showed pleiotropic effects for increased milk yield and reduced fertility, hinting that a shared underlying biology for these effects may revolve around the vitamin D pathway. These findings together suggest a putative causal variant of a CM resistance QTL, where a cis-regulatory element located within a CNV can alter gene expression and affect multiple economically important traits.
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Elementos de Facilitación Genéticos , Mastitis Bovina/genética , Proteína de Unión a Vitamina D/genética , Animales , Bovinos , Variaciones en el Número de Copia de ADN , Femenino , Predisposición Genética a la Enfermedad , Haplotipos , Desequilibrio de Ligamiento , Polimorfismo de Nucleótido Simple , Sitios de Carácter Cuantitativo , Secuenciación Completa del GenomaRESUMEN
BACKGROUND: Structural variants (SVs) are chromosomal segments that differ between genomes, such as deletions, duplications, insertions, inversions and translocations. The genomics revolution enabled the discovery of sub-microscopic SVs via array and whole-genome sequencing (WGS) data, paving the way to unravel the functional impact of SVs. Recent human expression QTL mapping studies demonstrated that SVs play a disproportionally large role in altering gene expression, underlining the importance of including SVs in genetic analyses. Therefore, this study aimed to generate and explore a high-quality bovine SV catalogue exploiting a unique cattle family cohort data (total 266 samples, forming 127 trios). RESULTS: We curated 13,731 SVs segregating in the population, consisting of 12,201 deletions, 1,509 duplications, and 21 multi-allelic CNVs (> 50-bp). Of these, we validated a subset of copy number variants (CNVs) utilising a direct genotyping approach in an independent cohort, indicating that at least 62% of the CNVs are true variants, segregating in the population. Among gene-disrupting SVs, we prioritised two likely high impact duplications, encompassing ORM1 and POPDC3 genes, respectively. Liver expression QTL mapping results revealed that these duplications are likely causing altered gene expression, confirming the functional importance of SVs. Although most of the accurately genotyped CNVs are tagged by single nucleotide polymorphisms (SNPs) ascertained in WGS data, most CNVs were not captured by individual SNPs obtained from a 50K genotyping array. CONCLUSION: We generated a high-quality SV catalogue exploiting unique whole genome sequenced bovine family cohort data. Two high impact duplications upregulating the ORM1 and POPDC3 are putative candidates for postpartum feed intake and hoof health traits, thus warranting further investigation. Generally, CNVs were in low LD with SNPs on the 50K array. Hence, it remains crucial to incorporate CNVs via means other than tagging SNPs, such as investigation of tagging haplotypes, direct imputation of CNVs, or direct genotyping as done in the current study. The SV catalogue and the custom genotyping array generated in the current study will serve as valuable resources accelerating utilisation of full spectrum of genetic variants in bovine genomes.
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Genoma , Genómica , Femenino , Humanos , Bovinos , Animales , Genómica/métodos , Genotipo , Variaciones en el Número de Copia de ADN , Haplotipos , Polimorfismo de Nucleótido Simple , Proteínas Musculares/genética , Moléculas de Adhesión Celular/genéticaRESUMEN
BACKGROUND: Copy Number Variations (CNVs) are gain or loss of DNA segments that are known to play a role in shaping a wide range of phenotypes. In this study, we used two dairy cattle populations, Holstein Friesian and Jersey, to discover CNVs using the Illumina BovineHD Genotyping BeadChip aligned to the ARS-UCD1.2 assembly. The discovered CNVs were investigated for their functional impact and their population genetics features. RESULTS: We discovered 14,272 autosomal CNVs, which were aggregated into 1755 CNV regions (CNVR) from 451 animals. These CNVRs together cover 2.8% of the bovine autosomes. The assessment of the functional impact of CNVRs showed that rare CNVRs (MAF < 0.01) are more likely to overlap with genes, than common CNVRs (MAF ≥ 0.05). The Population differentiation index (Fst) based on CNVRs revealed multiple highly diverged CNVRs between the two breeds. Some of these CNVRs overlapped with candidate genes such as MGAM and ADAMTS17 genes, which are related to starch digestion and body size, respectively. Lastly, linkage disequilibrium (LD) between CNVRs and BovineHD BeadChip SNPs was generally low, close to 0, although common deletions (MAF ≥ 0.05) showed slightly higher LD (r2 = ~ 0.1 at 10 kb distance) than the rest. Nevertheless, this LD is still lower than SNP-SNP LD (r2 = ~ 0.5 at 10 kb distance). CONCLUSIONS: Our analyses showed that CNVRs detected using BovineHD BeadChip arrays are likely to be functional. This finding indicates that CNVs can potentially disrupt the function of genes and thus might alter phenotypes. Also, the population differentiation index revealed two candidate genes, MGAM and ADAMTS17, which hint at adaptive evolution between the two populations. Lastly, low CNVR-SNP LD implies that genetic variation from CNVs might not be fully captured in routine animal genetic evaluation, which relies solely on SNP markers.
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Variaciones en el Número de Copia de ADN , Genética de Población , Animales , Cruzamiento , Bovinos , Genoma , Desequilibrio de Ligamiento , Sitios de Carácter CuantitativoRESUMEN
Transforming growth factor ß1 (TGFß1) is a major mediator in the modulation of osteoblast differentiation. However, the underlying molecular mechanism is still not fully understood. Here, we show that TGFß1 has a dual stage-dependent role in osteoblast differentiation; TGFß1 induced matrix maturation but inhibited matrix mineralization. We discovered the underlying mechanism of the TGFß1 inhibitory role in mineralization using human osteoprogenitors. In particular, the matrix mineralization-related genes of osteoblasts such as osteocalcin (OCN), Dickkopf 1 (DKK1), and CCAAT/enhancer-binding protein beta (C/EBPß) were dramatically suppressed by TGFß1 treatment. The suppressive effects of TGFß1 were reversed with anti-TGFß1 treatment. Mechanically, TGFß1 decreased protein levels of C/EBPß without changing mRNA levels and reduced both mRNA and protein levels of DKK1. The degradation of the C/EBPß protein by TGFß1 was dependent on the ubiquitin-proteasome pathway. TGFß1 degraded the C/EBPß protein by inducing the expression of the E3 ubiquitin ligase Smad ubiquitin regulatory factor 1 (SMURF1) at the transcript level, thereby reducing the C/EBPß-DKK1 regulatory mechanism. Collectively, our findings suggest that TGFß1 suppressed the matrix mineralization of osteoblast differentiation by regulating the SMURF1-C/EBPß-DKK1 axis.
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Proteína beta Potenciadora de Unión a CCAAT/metabolismo , Calcificación Fisiológica/efectos de los fármacos , Diferenciación Celular , Matriz Extracelular/efectos de los fármacos , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Osteoblastos/citología , Factor de Crecimiento Transformador beta1/farmacología , Ubiquitina-Proteína Ligasas/metabolismo , Anciano , Proteína beta Potenciadora de Unión a CCAAT/genética , Matriz Extracelular/metabolismo , Regulación de la Expresión Génica , Humanos , Péptidos y Proteínas de Señalización Intercelular/genética , Osteoblastos/efectos de los fármacos , Osteoblastos/metabolismo , Osteogénesis , Ubiquitina-Proteína Ligasas/genéticaRESUMEN
Arsenic trioxide (ATO) is a therapeutic agent for acute promyelocytic leukemia (APL) which induces PML-RARA protein degradation via enhanced UBE2I-mediated sumoylation. PCGF2, a Polycomb group protein, has been suggested as an anti-SUMO E3 protein by inhibiting the sumoylation of UBE2I substrates, HSF2 and RANGAP1, via direct interaction. Thus, we hypothesized that PCGF2 might play a role in ATO-induced PML-RARA degradation by interacting with UBE2I. PCGF2 protein was down-regulated upon ATO treatment in human APL cell line, NB4. Knockdown of PCGF2 in NB4 cells, in the absence of ATO treatment, was sufficient to induce sumoylation-, ubiquitylation- and PML nuclear body-mediated degradation of PML-RARA protein. Moreover, overexpression of PCGF2 protected ATO-mediated degradation of ectopic and endogenous PML-RARA in 293T and NB4 cells, respectively. In 293T cells, UBE2I-mediated PML-RARA degradation was reduced upon PCGF2 co-expression. In addition, UBE2I-mediated sumoylation of PML-RARA was reduced upon PCGF2 co-expression and PCGF2-UBE2I interaction was confirmed by co-immunoprecipitation. Likewise, endogenous PCGF2-UBE2I interaction was detected by co-immunoprecipitation and immunofluorescence assays in NB4 cells. Intriguingly, upon ATO-treatment, such interaction was disrupted and UBE2I was co-immunoprecipitated or co-localized with its SUMO substrate, PML-RARA. Taken together, our results suggested a novel role of PCGF2 in ATO-mediated degradation of PML-RARA that PCGF2 might act as a negative regulator of UBE2I via direct interaction.
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Antineoplásicos/farmacología , Arsenicales/farmacología , Leucemia Promielocítica Aguda/tratamiento farmacológico , Proteínas de Fusión Oncogénica/metabolismo , Óxidos/farmacología , Complejo Represivo Polycomb 1/metabolismo , Enzimas Ubiquitina-Conjugadoras/metabolismo , Trióxido de Arsénico , Línea Celular Tumoral , Técnica del Anticuerpo Fluorescente , Regulación Enzimológica de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Células HEK293 , Humanos , Inmunoprecipitación , Leucemia Promielocítica Aguda/enzimología , Leucemia Promielocítica Aguda/genética , Leucemia Promielocítica Aguda/patología , Proteínas de Fusión Oncogénica/genética , Complejo Represivo Polycomb 1/genética , Unión Proteica , Proteolisis , Interferencia de ARN , Transducción de Señal/efectos de los fármacos , Sumoilación , Factores de Tiempo , Transfección , Enzimas Ubiquitina-Conjugadoras/genética , UbiquitinaciónRESUMEN
The main aim of this study are to explore the role of bone-derived cells (BdCs) in ankylosing spondylitis (AS) and determine the underlying molecular mechanisms of IL-23 production. Primary BdCs were isolated from diced bone of facet joints obtained during surgery from seven AS patients and seven disease control (Ct) patients. Osteoblastic activity of BdCs was assessed by measuring their alkaline phosphatase activity and by alizarin red staining. Osteoblast and endoplasmic reticulum (ER) stress-related genes were assessed by quantitative PCR, immunoblotting, immunofluorescence, and immunohistochemistry. In addition, expression of IL-23 in response to BIX (selective BIP inducer X)-induced ER stress was evaluated by qPCR and ELISA. Protein interaction and binding to IL-23 promoter were confirmed by Immunoprecipitation and Chromatin immunoprecipitation, respectively. Transcript levels of genes involved in osteoblast function, as well as of the ER stress marker were higher in the AS group than the Ct group, and elevated RUNX2, BiP and IL-23 expression were observed in the BdCs, serum, and bone biopsies from the AS group. BIX-induced ER stress stimulated osteoblastic activity and IL-23 secretion by upregulating RUNX2 expression. Furthermore, in AS BdCs, RUNX2 interacted with C/EBPß to bind to IL-23 promoter and RUNX2 knockdown suppressed IL-23 secretion. These finding may provide a molecular mechanism involved in sustained ER stress in AS BdCs stimulates the activation of RUNX2 and C/EBPß genes, leading to IL-23 production.
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Huesos/inmunología , Citocinas/inmunología , Estrés del Retículo Endoplásmico/inmunología , Interleucina-23/inmunología , Osteoblastos/inmunología , Espondilitis Anquilosante/inmunología , Adulto , Huesos/patología , Células Cultivadas , Femenino , Humanos , Masculino , Persona de Mediana Edad , Osteoblastos/patología , Espondilitis Anquilosante/patologíaRESUMEN
Many studies have reported that perceived shape is systematically distorted, but Lind et al. (Inf Vis 2:51-57, 2003) and Todd and Norman (Percept Psychophys 65:31-47, 2003) both found that distortions varied with tasks and observers. We now investigated the hypothesis that perception of 3D metric (or Euclidean) shape is ambiguous rather than systematically distorted by testing whether variations in context would systematically alter apparent distortions. The task was to adjust the aspect ratio of an ellipse on a computer screen to match the cross-section of a target elliptical cylinder object viewed in either frontoparallel elliptical cross-section (2D) or elliptical cross-section in depth (3D). Three different groups were tested using two tasks and two different ranges of aspect ratio: Group 1) 2D(Small) â 3D(Large), Group 2) 2D(Large) â 3D(Small), Group 3a) 2D(Small) â 3D(Small), and Group 3b) 2D(Large) â 3D(Large). Observers performed the 2D task accurately. This provided the context. The results showed the expected order of slopes when judged aspect ratios were regressed on actual aspect ratios: Group 1 (SL) < Group 3 (SS and LL) < Group 2 (LS). The ambiguity of perceived 3D aspect ratios allowed the range of aspect ratios experienced in the 2D task to affect the 3D judgments systematically. Nevertheless, when the 2D and 3D ranges of aspect ratios were the same (LL and SS) and the 2D were judged accurately, this did not yield accurate 3D judgments. The results supported the hypothesis that perceived 3D metric shape is merely ambiguous rather than systematically distorted.
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Percepción de Profundidad/fisiología , Percepción de Forma/fisiología , Adulto , Femenino , Humanos , Juicio , Masculino , Reconocimiento Visual de Modelos/fisiología , Estimulación Luminosa , PsicofísicaRESUMEN
Background: An understanding of the economic life activities of persons with disabilities (PWD) is important. Their ability to perform tasks and an increase in their income are more likely to yield an improvement in their Self-Rated Health (SRH) and happiness. However, there is still a lack of understanding of the specific associations among PWD in South Korea. Thus, this study conducted a longitudinal analysis of the association between job satisfaction and SRH, happiness among the Korean PWD. Methods: After excluding missing values, data on 1,637 participants at baseline (1st wave) were analyzed using the chi-square test, t-test, Analysis of Variance (ANOVA) and generalized estimating equation (GEE) model for data from 1st to 3rd Panel Survey of Employment for the Disabled (PSED). All analyses were conducted using the SAS statistical software package, version 9.4. Results: Compared to very high job satisfaction group, low job satisfaction group was more likely to experience negative SRH [odds ratio (OR): 3.497, value of p: <0.0001] and experience low happiness (B: -0.291, value of p: <0.0001). Furthermore, in terms of the overall satisfaction with current job among the PWD, compared to the 'very satisfied' group, 'very unsatisfied' group had higher negative SRH (OR: 5.158, value of p: 0.003) and lower happiness (B: -0.327, value of p: <0.0001). Conclusion: This study suggests that increasing job satisfaction of PWD possibly leads to decreased negative SRH and to increased happiness, resulting in better SRH and happiness. Furthermore, it suggests the establishment of systemic, policy-oriented measures to enhance the employment opportunities for disabled individuals in Korea and create an inclusive working environment that aligns with their respective job responsibilities.
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Personas con Discapacidad , Satisfacción en el Trabajo , Humanos , Felicidad , Empleo , República de CoreaRESUMEN
The purpose of this study was to gather opinions from experts via the Delphi method to inform the future development of a virtual reality based English language communication program for university level students in Korea. The participants, who consisted of a panel of experts and professors who majored in English language and multimedia education, completed three Delphi surveys based on Context, Input, Process, and Product evaluation, which is referred to as CIPP. In the first Delphi survey, the participants answered multiple choice questions and open-ended questions related to four areas relevant to the development of a virtual reality based program. Based on their answers, a second Delphi survey was designed to determine the participants' level of agreement with the appropriateness of the questions related to the four areas. In the third Delphi survey, participants were shown the results (mean, standard deviation, median, interquartile range, consensus chart, and convergence degree) and were asked to confirm or modify their answers based on the other participants' answers. According to the analysis of the Delphi survey results, need for the development of a virtual reality based English language communication program was suggested, and recommendations were made regarding the content and application of the program.
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Lenguaje , Realidad Virtual , Comunicación , Consenso , Técnica Delphi , Humanos , Encuestas y CuestionariosRESUMEN
We measured the ability to discriminate 3D shapes across changes in viewpoint and illumination based on rich monocular 3D information and tested whether the addition of stereo information improves shape constancy. Stimuli were images of smoothly curved, random 3D objects. Objects were presented in three viewing conditions that provided different 3D information: shading-only, stereo-only, and combined shading and stereo. Observers performed shape discrimination judgments for sequentially presented objects that differed in orientation by rotation of 0°-60° in depth. We found that rotation in depth markedly impaired discrimination performance in all viewing conditions, as evidenced by reduced sensitivity (d') and increased bias toward judging same shapes as different. We also observed a consistent benefit from stereo, both in conditions with and without change in viewpoint. Results were similar for objects with purely Lambertian reflectance and shiny objects with a large specular component. Our results demonstrate that shape perception for random 3D objects is highly viewpoint-dependent and that stereo improves shape discrimination even when rich monocular shape cues are available.
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Sensibilidad de Contraste/fisiología , Señales (Psicología) , Percepción de Profundidad/fisiología , Percepción de Forma/fisiología , Reconocimiento Visual de Modelos/fisiología , Adulto , Femenino , Humanos , Imagenología Tridimensional/métodos , Iluminación/métodos , Masculino , Orientación/fisiología , Estimulación Luminosa/métodos , Visión Monocular/fisiología , Adulto JovenRESUMEN
Because damage to hyaline cartilage is irreversible, relieving progressive cartilage destruction is an important therapeutic approach for inflammatory arthritis. In the present study, human hyaline chondrocytes were isolated from total knee replacements of 15 patients with osteoarthritis (OA) and three with rheumatoid arthritis (RA). Synovial fluid of OA (n=25) and RA (n=34) were collected to measure tumor necrosis factor α (TNFα) using ELISA. Consistent with previous studies, the synovial fluid exhibited high TNFα levels and hyaline cartilage was severely destroyed in patients with RA. TNFα-treated chondrocytes were used as model for inflammatory arthritis. TNFα did not influence proliferation or extracellular matrix expression in chondrocytes, but induced matrix metalloproteinase (MMP)1, 3 and 13 expression levels in chondrocytes, which was accompanied by activation of nuclear factor-κB signaling. During chondrogenic differentiation, TNFα attenuated mRNA expression levels of anabolic factors (collagen type 2 and aggrecan) and enhanced mRNA expression of catabolic factors (MMP1, MMP3 and MMP13) in chondrocytes. Moreover, anti-TNFα agents (Golimumab) inhibited the TNFα-induced metabolic shift in chondrocytes and chondrogenic differentiation. The present study revealed a mechanism by which TNFα may induce metabolic shift in chondrocytes, leading to progressive chondrocyte destruction.
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Objective: This study aimed to determine the serum Dickkopf 1 (DKK1) levels in ankylosing spondylitis (AS) patients and decipher the mechanism of tumor necrosis factor (TNF)-mediated DKK1 regulation in human AS enthesis cells. Methods: The sera were obtained from 103 patients with AS and 30 healthy controls (HCs) The enthesis of facet joints were obtained from 4 AS patients and 5 controls The serum levels of DKK1 were measured using ELISA and compared between AS and HCs The impact of TNF on DKK1 expression in human primary spinal enthesis cells was evaluated using various molecular biology techniques and bone formation indicators. Results: AS patients showed higher serum DKK1 levels than HCs after adjusting for age (9174 [6153â¼1,3100] pg/mL vs 8262 [6703â¼9278] pg/mL, p=0043) TNF treatment promoted bone formation and DKK1 expression in both control enthesis cells and those of AS This enhanced bone formation by TNF was pronounced in AS-enthesis than those of controls Mechanically, TNF induced NF-kB activation upregulates the DKK1 transcript level While, NF-kB inhibitor led to downregulate DKK1 expression in the enthesis Besides, DKK1 overexpression promoted bone formation in enthesis. Conclusion: TNF induced DKK1 expression in the enthesis through NF-kB activation TNF-induced DKK1 expression may play a bone formation in the radiologic progression of ankylosing spondylitis.
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Muscle tissue is often removed during hamstring tendon graft preparation for anterior cruciate ligament (ACL) reconstruction. The purpose of the study was to test whether preservation of muscle remnants on a tendon graft is beneficial to the graft healing process following ACL reconstruction. Co-culturing of tendon-derived cells (TDCs) and muscle-derived cells (MDCs) was performed at various ratios, and their potential for cell viability and multilineage differentiation was compared to a single TDC cell group. Ligamentous and chondrogenic differentiation was most enhanced when a small population of MDCs was co-cultured with TDCs (6:2 co-culture group). Cell viability and osteogenic differentiation were proportionally enhanced with increasing MDC population size. MDCs co-cultured with TDCs possess both the ability to enhance cell viability and differentiate into other cell lineages.
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Diferenciación Celular , Tendones Isquiotibiales/trasplante , Células Musculares/citología , Preservación Biológica , Adolescente , Adulto , Becaplermina/farmacología , Calcificación Fisiológica/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Condrocitos/efectos de los fármacos , Condrocitos/metabolismo , Condrogénesis/efectos de los fármacos , Técnicas de Cocultivo , Colágeno/biosíntesis , Matriz Extracelular/genética , Matriz Extracelular/metabolismo , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Ligamentos/citología , Masculino , Células Musculares/efectos de los fármacos , Osteogénesis/efectos de los fármacos , Adulto JovenRESUMEN
Excessive tumor necrosis factor-α (TNF-α) is associated with the pathogenesis of rheumatoid arthritis (RA). Approximately 90% of patients with RA, who have inadequate response to methotrexate, follow anti-TNF-α therapy as the first-line immuno-treatment. However, ineffective long-term anti-TNF-α antibody cycling for 40% of non-responders to anti-TNF-α antibodies is costly and associated with various side effects, which needs alternative mechanism of action therapies. In the present study, a novel strategy to down-regulate TNF-α level was developed by using an alternative method of suppressing TNF-α converting enzyme (TACE), a transmembrane enzyme involved in cleaving and releasing bioactive soluble TNF-α. TACE suppression can be an effective remedy to block the production of soluble TNF-α, leading to an increased sensitivity to anti-TNF-α non-responders. A disease site-targeted RNA interference system was developed by forming non-viral complex between shRNA against TACE (shTACE) and bone resorption site-specific peptide carrier composed of aspartate repeating and arginine repeating sequences. The shTACE/peptide carrier complex alleviated arthritic symptoms in collagen induced arthritis (CIA) models by demonstrating enhanced anti-inflammatory and anti-osteoclastogenic effects. Similar results were obtained with human primary synovial cells and osteoclast precursor isolated from tissues and synovial fluids of RA patients. Taken together, the shTACE/targeting peptide complex provides a strong potential as an alternative anti-TNF-α therapeutic for RA treatment.
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Artritis Experimental , Artritis Reumatoide , Proteína ADAM17 , Animales , Artritis Reumatoide/tratamiento farmacológico , Humanos , Interferencia de ARN , Inhibidores del Factor de Necrosis Tumoral , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Lee et al. (Percept Psychophys 70:1032-1046, 2008a) investigated whether visual perception of metric shape could be calibrated when used to guide feedforward reaches-to-grasp. It could not. Seated participants viewed target objects (elliptical cylinders) in normal lighting using stereo vision and free head movements that allowed small (approximately 10 degrees) perspective changes. The authors concluded that poor perception of metric shape was the reason reaches-to-grasp should be visually guided online. However, Bingham and Lind (Percept Psychophys 70:524-540, 2008) showed that large perspective changes (> or =45 degrees) yield good perception of metric shape. So, now we repeated the Lee et al.'s study with the addition of information from large perspective changes. The results were accurate feedforward reaches-to-grasp reflecting accurate perception of both metric shape and metric size. Large perspective changes occur when one locomotes into a workspace in which reaches-to-grasp are subsequently performed. Does the resulting perception of metric shape persist after the large perspective changes have ceased? Experiments 2 and 3 tested reaches-to-grasp with delays (Exp. 2, 5-s delay; Exp. 3, approximately 16-s delay) and multiple objects to be grasped after a single viewing. Perception of metric shape and metric size persisted yielding accurate reaches-to-grasp. We advocate the study of nested actions using a dynamic approach to perception/action.
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Percepción de Forma/fisiología , Fuerza de la Mano , Percepción del Tamaño/fisiología , Percepción Visual/fisiología , Adolescente , Adulto , Femenino , Humanos , Juicio , Masculino , Adulto JovenRESUMEN
Histological and cytological observations of the human anterior cruciate ligament (ACL) had been described, but the differentiation potency based on their location is still unknown. To determine and compare proliferation and differentiation potential of cells derived from distal and middle thirds of the ACL remnant, ACL remnant was initially marked at the distal third (within 10 mm from the tibial insertion) and middle third (between 10-20 mm from the tibial insertion) and then dissected. Both the middle and distal third regions of ACL remnant were analyzed using CD34+ cell counting. Cell proliferation rate did not differ in both middle and distal third regions of ACL remnant, but they showed different characteristics in cell differentiation depending on their location. The distal third region of the ACL remnant had a tendency for chondrogenic differentiation with higher expression of CD34+ cells. On the other hand, the middle third region of ACL remnant had a strong tendency for osteogenic and ligamentous differentiation. Characteristics of the ACL remnant tissues should be considered when performing remnant-preserving or harvesting ACL remnants for tissue engineering.
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Ligamento Cruzado Anterior/citología , Diferenciación Celular , Adolescente , Adulto , Lesiones del Ligamento Cruzado Anterior/cirugía , Antígenos CD34/metabolismo , Proliferación Celular , Condrogénesis , Femenino , Citometría de Flujo , Humanos , Masculino , Osteogénesis , Células Madre/citología , Adulto JovenRESUMEN
Receptor activator of nuclear factor kappa B ligand (RANKL) expression in osteoblasts is regulated by 1,25-dihydroxyvitamin D3 (1,25D3). CCAAT/enhancer-binding protein beta (C/EBPß) has been proposed to function as a transcription factor and upregulate RANKL expression, but it is still uncertain how C/EBPß is involved in 1,25D3-induced RANKL expression of osteoblasts. 1,25D3 stimulation increased the expression of RANKL and C/EPBß genes in osteoblasts and enhanced phosphorylation and stability of these proteins. Moreover, induction of RANKL expression by 1,25D3 in osteoblasts was downregulated upon knockdown of C/EBPß. In contrast, C/EBPß overexpression directly upregulated RANKL promoter activity and exhibited a synergistic effect on 1,25D3-induced RANKL expression. In particular, 1,25D3 treatment of osteoblasts increased C/EBPß protein binding to the RANKL promoter. In conclusion, C/EBPß is required for induction of RANKL by 1,25D3. [BMB Reports 2019; 52(6): 391-396].
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Proteína beta Potenciadora de Unión a CCAAT/metabolismo , Calcitriol/farmacología , Osteoblastos/efectos de los fármacos , Osteoblastos/metabolismo , Ligando RANK/metabolismo , Sitios de Unión , Diferenciación Celular/efectos de los fármacos , Línea Celular , Núcleo Celular/metabolismo , Humanos , FN-kappa B/metabolismo , Osteoblastos/citología , Fosforilación/efectos de los fármacos , Regiones Promotoras Genéticas , Unión Proteica , Estabilidad Proteica , Ligando RANK/biosíntesis , Ligando RANK/genética , ARN Mensajero/metabolismoRESUMEN
Wild boar (Sus scrofa) drastically colonized mainland Eurasia and North Africa, most likely from East Asia during the Plio-Pleistocene (2-1Mya). In recent studies, based on genome-wide information, it was hypothesized that wild boar did not replace the species it encountered, but instead exchanged genetic materials with them through admixture. The highly endangered pygmy hog (Porcula salvania) is the only suid species in mainland Eurasia known to have outlived this expansion, and therefore provides a unique opportunity to test this hybridization hypothesis. Analyses of pygmy hog genomes indicate that despite large phylogenetic divergence (~2 My), wild boar and pygmy hog did indeed interbreed as the former expanded across Eurasia. In addition, we also assess the taxonomic placement of the donor of another introgression, pertaining to a now-extinct species with a deep phylogenetic placement in the Suidae tree. Altogether, our analyses indicate that the rapid spread of wild boar was facilitated by inter-specific/inter-generic admixtures.
Asunto(s)
Genómica/métodos , Sus scrofa/clasificación , Sus scrofa/genética , África del Norte , Animales , ADN Mitocondrial/genética , Filogenia , Análisis de Secuencia de ADN , PorcinosRESUMEN
BACKGROUND: IL-17A has recently emerged as a potential target that regulates the extensive inflammation and abnormal bone formation observed in ankylosing spondylitis (AS). Blocking IL-17A is expected to inhibit bony ankylosis. Here, we investigated the effects of anti IL-17A agents in AS. METHODS: TNFα, IL-17A, and IL-12/23 p40 levels in serum and synovial fluid from patients with ankylosing spondylitis (AS), rheumatoid arthritis (RA), osteoarthritis (OA), or healthy controls (HC) were measured by ELISA. Bone tissue samples were obtained at surgery from the facet joints of ten patients with AS and ten control (Ct) patients with noninflammatory spinal disease. The functional relevance of IL-17A, biological blockades, Janus kinase 2 (JAK2), and non-receptor tyrosine kinase was assessed in vitro with primary bone-derived cells (BdCs) and serum from patients with AS. RESULTS: Basal levels of IL-17A and IL-12/23 p40 in body fluids were elevated in patients with AS. JAK2 was also highly expressed in bone tissue and primary BdCs from patients with AS. Furthermore, addition of exogenous IL-17A to primary Ct-BdCs promoted the osteogenic stimulus-induced increase in ALP activity and mineralization. Intriguingly, blocking IL-17A with serum from patients with AS attenuated ALP activity and mineralization in both Ct and AS-BdCs by inhibiting JAK2 phosphorylation and downregulating osteoblast-involved genes. Moreover, JAK2 inhibitors effectively reduced JAK2-driven ALP activity and JAK2-mediated events. CONCLUSIONS: Our findings indicate that IL-17A regulates osteoblast activity and differentiation via JAK2/STAT3 signaling. They shed light on AS pathogenesis and suggest new rational therapies for clinical AS ankylosis.