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The sequence of monomers within a polymer chain plays a pivotal role in determining the physicochemical properties of the polymer. In the copolymerization of two or more monomers, the arrangement of monomers within the resulting polymer is primarily dictated by the intrinsic reactivity of the monomers. Precisely controlling the monomer sequence in copolymerization, particularly through the manipulation of catalysts, is a subject of intense interest and poses significant challenges. In this study, we report the catalyst-controlled copolymerization of epoxides, N-tosyl aziridine (TAz), and cyclic anhydrides. To achieve this, a binary catalyst system comprising a Lewis acid, triethylborane, and Brønsted base, t-BuP1, was utilized. This system was utilized to regulate the selectivity between two catalytic reactions: ring-opening alternating copolymerization (ROAC) of epoxides/cyclic anhydrides and ROAC of TAz/cyclic anhydrides. Changing the catalyst ratio made it possible to continuously modulate the resulting poly(ester-amide ester) from ABA-type real block copolymers to gradient, random-like, reversed gradient, and reversed BAB-type block-like copolymers. A range of epoxides and anhydrides was investigated, demonstrating the versatility of this polymerization system. Additionally, density functional theory calculations were conducted to enhance our mechanistic understanding of the process. This synthetic method not only provides a versatile means for producing copolymers with comparable chemical compositions but also facilitates the exploration of the intricate relationship between monomer sequences and the resultant polymer properties, offering valuable insights for advancements in polymer science.
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Phase-change materials such as Ge-Sb-Te (GST) exhibiting amorphous and crystalline phases can be used for phase-change random-access memory (PCRAM). GST-based PCRAM has been applied as a storage-class memory; however, its relatively low ON/OFF ratio and the large Joule heating energy required for the RESET process (amorphization) significantly limit the storage density. This study proposes a phase-change nitride, CrN, with a much wider programming window (ON/OFF ratio more than 105) and lower RESET energy (one order of magnitude reduction from GST). High-resolution transmission electron microscopy revealed a phase-change from the low-resistance cubic CrN phase into the highly resistive hexagonal CrN2 phase induced by the Soret-effect. The proposed phase-change nitride could greatly expand the scope of conventional phase-change chalcogenides and offer a strategy for the next-generation of PCRAM, enabling a large ON/OFF ratio (â¼105), low switching energy (â¼100 pJ), and fast operation (â¼30 ns).
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Recent advances have made modeling human small intestines in vitro possible, but it remains a challenge to recapitulate fully their structural and functional characteristics. We suspected interstitial flow within the intestine, powered by circulating blood plasma during embryonic organogenesis, to be a vital factor. We aimed to construct an in vivo-like multilayered small intestinal tissue by incorporating interstitial flow into the system and, in turn, developed the micro-small intestine system by differentiating definitive endoderm and mesoderm cells from human pluripotent stem cells simultaneously on a microfluidic device capable of replicating interstitial flow. This approach enhanced cell maturation and led to the development of a three-dimensional small intestine-like tissue with villi-like epithelium and an aligned mesenchymal layer. Our micro-small intestine system not only overcomes the limitations of conventional intestine models but also offers a unique opportunity to gain insights into the detailed mechanisms underlying intestinal tissue development.
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Spermatogonial stem cells (SSCs) undergo self-renewal division to sustain spermatogenesis. Although it is possible to derive SSC cultures in most mouse strains, SSCs from a 129 background never proliferate under the same culture conditions, suggesting they have distinct self-renewal requirements. Here, we established long-term culture conditions for SSCs from mice of the 129 background (129 mice). An analysis of 129 testes showed significant reduction of GDNF and CXCL12, whereas FGF2, INHBA and INHBB were higher than in testes of C57BL/6 mice. An analysis of undifferentiated spermatogonia in 129 mice showed higher expression of Chrna4, which encodes an acetylcholine (Ach) receptor component. By supplementing medium with INHBA and Ach, SSC cultures were derived from 129 mice. Following lentivirus transduction for marking donor cells, transplanted cells re-initiated spermatogenesis in infertile mouse testes and produced transgenic offspring. These results suggest that the requirements of SSC self-renewal in mice are diverse, which has important implications for understanding self-renewal mechanisms in various animal species.
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Ratones Endogámicos C57BL , Espermatogénesis , Espermatogonias , Testículo , Animales , Masculino , Ratones , Espermatogonias/citología , Espermatogonias/metabolismo , Espermatogénesis/genética , Espermatogénesis/fisiología , Testículo/metabolismo , Testículo/citología , Autorrenovación de las Células , Células Madre Germinales Adultas/metabolismo , Células Madre Germinales Adultas/citología , Células Cultivadas , Receptores Nicotínicos/metabolismo , Receptores Nicotínicos/genética , Ratones Endogámicos , Diferenciación Celular , Proliferación Celular , Células Madre/citología , Células Madre/metabolismo , Ratones TransgénicosRESUMEN
Epigenetic reprogramming resets parental epigenetic memories and differentiates primordial germ cells (PGCs) into mitotic pro-spermatogonia or oogonia. This process ensures sexually dimorphic germ cell development for totipotency1. In vitro reconstitution of epigenetic reprogramming in humans remains a fundamental challenge. Here we establish a strategy for inducing epigenetic reprogramming and differentiation of pluripotent stem-cell-derived human PGC-like cells (hPGCLCs) into mitotic pro-spermatogonia or oogonia, coupled with their extensive amplification (about >1010-fold). Bone morphogenetic protein (BMP) signalling is a key driver of these processes. BMP-driven hPGCLC differentiation involves attenuation of the MAPK (ERK) pathway and both de novo and maintenance DNA methyltransferase activities, which probably promote replication-coupled, passive DNA demethylation. hPGCLCs deficient in TET1, an active DNA demethylase abundant in human germ cells2,3, differentiate into extraembryonic cells, including amnion, with de-repression of key genes that bear bivalent promoters. These cells fail to fully activate genes vital for spermatogenesis and oogenesis, and their promoters remain methylated. Our study provides a framework for epigenetic reprogramming in humans and an important advance in human biology. Through the generation of abundant mitotic pro-spermatogonia and oogonia-like cells, our results also represent a milestone for human in vitro gametogenesis research and its potential translation into reproductive medicine.
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Reprogramación Celular , Epigénesis Genética , Células Germinativas , Técnicas In Vitro , Femenino , Humanos , Masculino , Amnios/citología , Proteínas Morfogenéticas Óseas/metabolismo , Reprogramación Celular/genética , Metilación de ADN/genética , Células Germinativas/metabolismo , Células Germinativas/citología , Sistema de Señalización de MAP Quinasas , Mitosis/genética , Oxigenasas de Función Mixta/deficiencia , Oogénesis/genética , Oogonios/citología , Oogonios/metabolismo , Células Madre Pluripotentes/citología , Células Madre Pluripotentes/metabolismo , Regiones Promotoras Genéticas/genética , Espermatogénesis/genética , Espermatogonias/citología , Espermatogonias/metabolismo , Regulación del Desarrollo de la Expresión GénicaRESUMEN
Heterogeneity among both primed and naive pluripotent stem cell lines remains a major unresolved problem. Here we show that expressing the maternal-specific linker histone H1FOO fused to a destabilizing domain (H1FOO-DD), together with OCT4, SOX2, KLF4, and LMYC, in human somatic cells improves the quality of reprogramming to both primed and naive pluripotency. H1FOO-DD expression was associated with altered chromatin accessibility around pluripotency genes and with suppression of the innate immune response. Notably, H1FOO-DD generates naive induced pluripotent stem cells with lower variation in transcriptome and methylome among clones and a more uniform and superior differentiation potency. Furthermore, we elucidated that upregulation of FKBP1A, driven by these five factors, plays a key role in H1FOO-DD-mediated reprogramming.
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Reprogramación Celular , Histonas , Células Madre Pluripotentes Inducidas , Factor 4 Similar a Kruppel , Reprogramación Celular/genética , Humanos , Células Madre Pluripotentes Inducidas/citología , Células Madre Pluripotentes Inducidas/metabolismo , Histonas/metabolismo , Diferenciación Celular/genética , Factores de Transcripción de Tipo Kruppel/metabolismo , Factores de Transcripción de Tipo Kruppel/genética , Factores de Transcripción SOXB1/metabolismo , Factores de Transcripción SOXB1/genética , Cromatina/metabolismo , Células Madre Pluripotentes/metabolismo , Células Madre Pluripotentes/citología , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , TranscriptomaRESUMEN
Accumulating evidence suggests that endothelial cells can be useful therapeutic targets. One of the potential targets is an endothelial cell-specific protein, Roundabout4 (ROBO4). ROBO4 has been shown to ameliorate multiple diseases in mice, including infectious diseases and sepsis. However, its mechanisms are not fully understood. In this study, using RNA-seq analysis, we found that ROBO4 downregulates prostaglandin-endoperoxide synthase 2 (PTGS2), which encodes cyclooxygenase-2. Mechanistic analysis reveals that ROBO4 interacts with IQ motif-containing GTPase-activating protein 1 (IQGAP1) and TNF receptor-associated factor 7 (TRAF7), a ubiquitin E3 ligase. In this complex, ROBO4 enhances IQGAP1 ubiquitination through TRAF7, inhibits prolonged RAC1 activation, and decreases PTGS2 expression in inflammatory endothelial cells. In addition, Robo4-deficiency in mice exacerbates PTGS2-associated inflammatory diseases, including arthritis, edema, and pain. Thus, we reveal the molecular mechanism by which ROBO4 suppresses the inflammatory response and vascular hyperpermeability, highlighting its potential as a promising therapeutic target for inflammatory diseases.
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Ciclooxigenasa 2 , Inflamación , Receptores de Superficie Celular , Ciclooxigenasa 2/metabolismo , Ciclooxigenasa 2/genética , Animales , Ratones , Inflamación/metabolismo , Inflamación/genética , Humanos , Receptores de Superficie Celular/metabolismo , Receptores de Superficie Celular/genética , Ratones Noqueados , Ratones Endogámicos C57BL , Masculino , Células Endoteliales/metabolismo , Proteínas RoundaboutRESUMEN
Although the mRNA SARS-CoV-2 vaccine has improved the mortality rate in the general population, its efficacy against rapidly mutating virus strains, especially in kidney transplant recipients, remains unclear. We examined the anti-SARS-CoV-2 spike protein IgG antibody and neutralizing antibody titers and cellular immunity against B.1.1, BA.1, and BA.5 antigens in 73 uninfected kidney recipients and 16 uninfected healthy controls who received three doses of an mRNA SARS-CoV-2 vaccine. The IgG antibody titers were significantly lower in recipients than in healthy controls. Similarly, neutralizing antibody titers against three viral variants were significantly lower in recipients. When the virus was mutated, the neutralizing antibody titers decreased significantly in both groups. In cellular immunity analysis, the number of spike-specific CD8 + non-naïve T cells against three variants significantly decreased in recipients. Conversely, the frequency of spike-specific Th2 CD4 + T-cells in recipients was higher than that in healthy controls. Nineteen recipients and six healthy controls also received a bivalent omicron-containing booster vaccine, leading to increase IgG and neutralizing antibody titers in both groups. After that, eleven recipients and five healthy controls received XBB.1.5 monovalent vaccines, increasing the neutralizing antibody titers against not only XBB.1.5, but also EG.5.1 and BA.2.86 antigens in kidney recipients. Although kidney recipients did not gain sufficient immunity against Omicron BA.5 with the third dose of vaccine, humoral response against mutant SARS-CoV-2 lineages significantly increased after bivalent Omicron-containing booster vaccine and the XBB.1.5 monovalent vaccine. Therefore, it is important for kidney recipients to continue to administer updated vaccines.
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Anticuerpos Neutralizantes , Anticuerpos Antivirales , Vacunas contra la COVID-19 , COVID-19 , Inmunoglobulina G , Trasplante de Riñón , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus , Humanos , Anticuerpos Neutralizantes/inmunología , Anticuerpos Neutralizantes/sangre , Trasplante de Riñón/efectos adversos , SARS-CoV-2/inmunología , SARS-CoV-2/genética , Femenino , Masculino , Persona de Mediana Edad , Anticuerpos Antivirales/inmunología , Anticuerpos Antivirales/sangre , COVID-19/inmunología , COVID-19/prevención & control , COVID-19/virología , Adulto , Vacunas contra la COVID-19/inmunología , Vacunas contra la COVID-19/administración & dosificación , Glicoproteína de la Espiga del Coronavirus/inmunología , Glicoproteína de la Espiga del Coronavirus/genética , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Inmunidad Celular , Vacunación/métodos , Receptores de Trasplantes , Anciano , Inmunización SecundariaRESUMEN
Human-induced pluripotent stem cells (hiPSCs) have great therapeutic potential. The cell source differentiated from hiPSCs requires xeno-free and robust methods for lineage-specific differentiation. Here, a system is described for differentiating hiPSCs on new generation laminin fragments (NGLFs), a recombinant form of a laminin E8 fragment conjugated to the heparan sulfate chains (HS) attachment domain of perlecan. Using NGLFs, hiPSCs are highly promoted to direct differentiation into a paraxial mesoderm state with high-efficiency muscle lineage generation. HS conjugation to the C-terminus of Laminin E8 fragments brings fibroblast growth factors (FGFs) bound to the HS close to the cell surface of hiPSCs, thereby facilitating stronger FGF signaling pathways stimulation and initiating HOX gene expression, which triggers the paraxial mesoderm differentiation of hiPSCs. This highly efficient differentiation system can provide a roadmap for paraxial mesoderm development and an infinite source of myocytes and muscle stem cells for disease modeling and regenerative medicine.
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Diferenciación Celular , Heparitina Sulfato , Células Madre Pluripotentes Inducidas , Laminina , Mesodermo , Diferenciación Celular/fisiología , Mesodermo/citología , Mesodermo/metabolismo , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Células Madre Pluripotentes Inducidas/citología , Laminina/metabolismo , Heparitina Sulfato/metabolismo , Desarrollo de Músculos/fisiología , Desarrollo de Músculos/genética , Células CultivadasRESUMEN
BACKGROUND: Perioperative management methods that reduce surgery-associated invasiveness and improve the quality of postoperative recovery are being promoted as enhanced recovery after surgery programs in various areas. Early enteral nutrition and mobilization are essential elements for enhanced recovery after surgery; however, their safety and feasibility are unclear in head and neck surgery with free tissue transfer reconstruction. This study aimed to clarify these uncertainties. METHODS: This is a retrospective before-after study. From 2018 to 2022, 187 and 173 patients received conventional management on or before April 2020 and early management on or after May 2020, respectively. The conventional management and early management groups received enteral nutrition and mobilization on postoperative days 2 and 1, respectively. The primary outcome for safety assessment was the incidence of complications. The secondary outcome was the compliance rate of conventional management or early management for feasibility assessment and the length of hospital stay. RESULTS: The clinical tumour-node-metastasis stage and American Society of Anesthesiologists physical status showed significant differences between the groups. In multivariable analysis, the early management group demonstrated a significantly lower incidence of treatment-required complication classified Clavien-Dindo Grade 2 and above (odds ratio = 0.57; 95% confidence interval = 0.31-0.92) and lower wound infection (odds ratio = 0.53; 95% confidence interval = 0.31-0.92). The early management group had lower compliance rate than the conventional management group; however, no statistically significant difference was observed (79.8% vs. 85.0%, P = 0.21). CONCLUSION: Early management is safe and feasible following head and neck surgery with free tissue transfer reconstruction. It could reduce the complication rate and is considered a useful postoperative management method.
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Nutrición Enteral , Colgajos Tisulares Libres , Neoplasias de Cabeza y Cuello , Procedimientos de Cirugía Plástica , Humanos , Nutrición Enteral/métodos , Masculino , Femenino , Neoplasias de Cabeza y Cuello/cirugía , Estudios Retrospectivos , Persona de Mediana Edad , Procedimientos de Cirugía Plástica/métodos , Anciano , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/epidemiología , Ambulación Precoz , Tiempo de Internación/estadística & datos numéricos , Recuperación Mejorada Después de la Cirugía , AdultoRESUMEN
The emergence of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) variants necessitated a rapid evaluation system for their pathogenesis. Lung epithelial cells are their entry points; however, in addition to their limited source, the culture of human alveolar epithelial cells is especially complicated. Induced pluripotent stem cells (iPSCs) are an alternative source of human primary stem cells. Here, we report a model for distinguishing SARS-CoV-2 variants at high resolution, using separately induced iPSC-derived alveolar and airway cells in micro-patterned culture plates. The position-specific signals induced the apical-out alveolar type 2 and multiciliated airway cells at the periphery and center of the colonies, respectively. The infection studies in each lineage enabled profiling of the pathogenesis of SARS-CoV-2 variants: infection efficiency, tropism to alveolar and airway lineages, and their responses. These results indicate that this culture system is suitable for predicting the pathogenesis of emergent SARS-CoV-2 variants.
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COVID-19 , Células Madre Pluripotentes Inducidas , Humanos , SARS-CoV-2/fisiología , PulmónRESUMEN
CD8+ T cells affect the outcomes of pancreatic ductal adenocarcinoma (PDAC). Using tissue samples at pre-treatment to monitor the immune response is challenging, while blood samples are beneficial in overcoming this limitation. In this study, we measured peripheral antigen-specific CD8+ T cell responses against four different tumor-associated antigens (TAAs) in PDAC using flow cytometry and investigated their relationships with clinical features. We analyzed the optimal timing within the treatment course for effective immune checkpoint inhibition in vitro. We demonstrated that the frequency of TAA-specific IFNγ+4-1BB+ CD8+ T cells was correlated with a fold reduction in CA19-9 before and after neoadjuvant therapy. Moreover, patients with TAA-specific IFNγ+4-1BB+ CD8+ T cells after surgery exhibited a significantly improved disease-free survival. Anti-PD-1 treatment in vitro increased the frequency of TAA-specific IFNγ+4-1BB+ CD8+ T cells before neoadjuvant therapy in patients, suggesting the importance of the timing of anti-PD-1 inhibition during the treatment regimen. Our results indicate that peripheral immunophenotyping, combined with highly sensitive identification of TAA-specific responses in vitro as well as detailed CD8+ T cell subset profiling via ex vivo analysis, may serve as peripheral biomarkers to predict treatment outcomes and therapeutic efficacy of immunotherapy plus neoadjuvant chemotherapy.
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Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Linfocitos T CD8-positivos , Neoplasias Pancreáticas/terapia , Resultado del Tratamiento , Carcinoma Ductal Pancreático/terapia , BiomarcadoresRESUMEN
To gain insight into how immunity develops against SARS-CoV-2 from 2020 to 2022, we analyzed the immune response of a small group of university staff and students who were either infected or vaccinated. We investigated the levels of receptor-binding domain (RBD)-specific and nucleocapsid (N)-specific IgG and IgA antibodies in serum and saliva samples taken early (around 10 days after infection or vaccination) and later (around 1 month later), as well as N-specific T-cell responses. One patient who had been infected in 2020 developed serum RBD and N-specific IgG antibodies, but declined eight months later, then mRNA vaccination in 2021 produced a higher level of anti-RBD IgG than natural infection. In the vaccination of naïve individuals, vaccines induced anti-RBD IgG, but it declined after six months. A third vaccination boosted the IgG level again, albeit to a lower level than after the second. In 2022, when the Omicron variant became dominant, familial transmission occurred among vaccinated people. In infected individuals, the levels of serum anti-RBD IgG antibodies increased later, while anti-N IgG peaked earlier. The N-specific activated T cells expressing IFN γ or CD107a were detected only early. Although SARS-CoV-2-specific salivary IgA was undetectable, two individuals showed a temporary peak in RBD- and N-specific IgA antibodies in their saliva on the second day after infection. Our study, despite having a small sample size, revealed that SARS-CoV-2 infection triggers the expected immune responses against acute viral infections. Moreover, our findings suggest that the temporary mucosal immune responses induced early during infection may provide better protection than the currently available intramuscular vaccines.
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Antígenos de Grupos Sanguíneos , COVID-19 , Vacunas , Humanos , SARS-CoV-2 , Pandemias , COVID-19/prevención & control , Vacunación , Inmunoglobulina G , Inmunidad Mucosa , Inmunoglobulina A , Anticuerpos AntiviralesRESUMEN
The human immune system comprises a diverse array of cells involved in innate and adaptive immunity, and these immune cells coordinate immune responses against pathogens through intricate interactions. Multicolor flow cytometry is a powerful technique for qualitatively and quantitatively measuring the characteristics of immune cells, offering advantages, such as high-dimensional analysis, elucidation of cellular heterogeneity, understanding of pathogenesis, development of therapeutic strategies, and platform flexibility. Here, we demonstrate a new immunophenotyping panel that allows simultaneous evaluation of the characteristics of T and B cells. This panel enables tracking of changes in the immune status due to aging, environmental factors, pathogen infections, and vaccine administration. Additionally, it includes co-stimulatory molecules for assessing the activation state of immune cells and inhibitory checkpoint molecules for evaluating exhaustion status, thereby providing valuable insights into the features of human immune responses. These analyses contribute to understanding the pathophysiology of diseases and developing therapeutic strategies while offering crucial information for assessing the correlation of symptoms with infections and evaluating the efficacy of vaccines.
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Inmunidad Adaptativa , Linfocitos B , Humanos , Inmunofenotipificación , Citometría de Flujo/métodosRESUMEN
We recently achieved the first-in-human transfusion of induced pluripotent stem cell-derived platelets (iPSC-PLTs) as an alternative to standard transfusions, which are dependent on donors and therefore variable in supply. However, heterogeneity characterized by thrombopoiesis-biased or immune-biased megakaryocytes (MKs) continues to pose a bottleneck against the standardization of iPSC-PLT manufacturing. To address this problem, here we employ microRNA (miRNA) switch biotechnology to distinguish subpopulations of imMKCLs, the MK cell lines producing iPSC-PLTs. Upon miRNA switch-based screening, we find imMKCLs with lower let-7 activity exhibit an immune-skewed transcriptional signature. Notably, the low activity of let-7a-5p results in the upregulation of RAS like proto-oncogene B (RALB) expression, which is crucial for the lineage determination of immune-biased imMKCL subpopulations and leads to the activation of interferon-dependent signaling. The dysregulation of immune properties/subpopulations, along with the secretion of inflammatory cytokines, contributes to a decline in the quality of the whole imMKCL population.
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Células Madre Pluripotentes Inducidas , MicroARNs , Humanos , Megacariocitos , Células Madre Pluripotentes Inducidas/metabolismo , Plaquetas/metabolismo , Trombopoyesis/genética , MicroARNs/genética , MicroARNs/metabolismoRESUMEN
Continuing emergence of variants of concern resulting in reduced SARS-CoV-2 vaccine efficacy necessitates additional prevention strategies. The structure of VLPCOV-01, a lipid nanoparticle-encapsulated, self-amplifying RNA COVID-19 vaccine with a comparable immune response to BNT162b2, was revised by incorporating a modified base, 5-methylcytosine, to reduce reactogenicity, and an updated receptor-binding domain derived from the Brazil (gamma) variant. Interim analyses of a phase 1 dose-escalation booster vaccination study with the resulting construct, VLPCOV-02, in healthy, previously vaccinated Japanese individuals (N = 96) are reported (jRCT2051230005). A dose-related increase in solicited local and systemic adverse events was observed, which were generally rated mild or moderate. The most commonly occurring events were tenderness, pain, fatigue, and myalgia. Serum SARS-CoV-2 immunoglobulin titers increased during the 4 weeks post-immunization. VLPCOV-02 demonstrated a favorable safety profile compared with VLPCOV-01, with reduced adverse events and fewer fever events at an equivalent dose. These findings support further study of VLPCOV-02.
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BACKGROUND: Instrumentation failure (IF) is a major complication associated with growth-sparing surgery for pediatric spinal deformities; however, studies focusing on IF following each surgical procedure are lacking. We aimed to evaluate the incidence, timing, and rates of unplanned return to the operating room (UPROR) associated with IF following each surgical procedure in growth-sparing surgeries using traditional growing rods (TGRs) and vertical expandable prosthetic titanium ribs (VEPTRs). METHODS: We reviewed 1,139 surgical procedures documented in a Japanese multicenter database from 2015 to 2017. Of these, 544 TGR and 455 VEPTR procedures were included for evaluation on a per-surgery basis. IF was defined as the occurrence of an implant-related complication requiring revision surgery. RESULTS: The surgery-based incidences of IF requiring revision surgery in the TGR and VEPTR groups were 4.3% and 4.0%, respectively, with no significant intergroup difference. Remarkably, there was a negative correlation between IF incidence per surgical procedure and the number of lengthening surgeries in both groups. In addition, rod breakage in the TGR group and anchor-related complications in the VEPTR group tended to occur relatively early in the treatment course. The surgery-based rates of UPROR due to IF in the TGR and VEPTR groups were 2.0% and 1.5%, respectively, showing no statistically significant difference. CONCLUSIONS: We found that IF, such as anchor related-complications and rod breakage, occurs more frequently earlier in the course of lengthening surgeries. This finding may help in patient counseling and highlights the importance of close postoperative follow-up to detect IF and improve outcomes.
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Escoliosis , Niño , Humanos , Escoliosis/cirugía , Escoliosis/diagnóstico , Titanio , Prótesis e Implantes/efectos adversos , Costillas/cirugía , Costillas/anomalías , Reoperación , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/cirugía , Columna Vertebral/diagnóstico por imagen , Columna Vertebral/cirugía , Columna Vertebral/anomalías , Estudios Retrospectivos , Resultado del Tratamiento , Estudios Multicéntricos como AsuntoRESUMEN
Heterotopic ossification (HO) is a non-physiological bone formation where soft tissue progenitor cells differentiate into chondrogenic cells. In fibrodysplasia ossificans progressiva (FOP), a rare genetic disease characterized by progressive and systemic HO, the Activin A/mutated ACVR1/mTORC1 cascade induces HO in progenitors in muscle tissues. The relevant biological processes aberrantly regulated by activated mTORC1 remain unclear, however. RNA-sequencing analyses revealed the enrichment of genes involved in oxidative phosphorylation (OXPHOS) during Activin A-induced chondrogenesis of mesenchymal stem cells derived from FOP patient-specific induced pluripotent stem cells. Functional analyses showed a metabolic transition from glycolysis to OXPHOS during chondrogenesis, along with increased mitochondrial biogenesis. mTORC1 inhibition by rapamycin suppressed OXPHOS, whereas OXPHOS inhibitor IACS-010759 inhibited cartilage matrix formation in vitro, indicating that OXPHOS is principally involved in mTORC1-induced chondrogenesis. Furthermore, IACS-010759 inhibited the muscle injury-induced enrichment of fibro/adipogenic progenitor genes and HO in transgenic mice carrying the mutated human ACVR1. These data indicated that OXPHOS is a critical downstream mediator of mTORC1 signaling in chondrogenesis and therefore is a potential FOP therapeutic target.
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Miositis Osificante , Osificación Heterotópica , Ratones , Animales , Humanos , Miositis Osificante/genética , Miositis Osificante/metabolismo , Fosforilación Oxidativa , Osificación Heterotópica/genética , Osificación Heterotópica/metabolismo , Transducción de Señal/genética , Ratones Transgénicos , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismoRESUMEN
BACKGROUND: Liver transplant recipients (LTRs) are at a high risk of severe COVID-19 owing to immunosuppression and comorbidities. LTRs are less responsive to mRNA vaccines than healthy donors (HDs) or other immunosuppressed patients. However, the disruption mechanism in humoral and cellular immune memory responses is unclear. METHODS: We longitudinally collected peripheral blood mononuclear cells and plasma samples from HDs (n = 44) and LTRs (n = 54) who received BNT162b2 or mRNA-1273 vaccines. We measured the levels of anti-receptor-binding domain (RBD) antibodies and spike-specific CD4+ and CD8+ T-cell responses. RESULTS: Here, we show that the induction of anti-RBD IgG was weaker in LTRs than in HDs. The use of multiple immunosuppressive drugs is associated with lower antibody titers than only calcineurin inhibitor, and limits the induction of CD4+ T-cell responses. However, spike-specific CD4+ T-cell and antibody responses improved with a third vaccination. Furthermore, mRNA vaccine-induced spike-specific CD8+ T cells are quantitatively, but not qualitatively, limited to LTRs. Both CD4+ and CD8+ T cells react to omicron sublineages, regardless of the presence in HDs or LTRs. However, there is no boosting effect of spike-specific memory CD8+ T-cell responses after a third vaccination in HDs or LTRs. CONCLUSIONS: The third mRNA vaccination improves both humoral responses and spike-specific CD4+ T-cell responses in LTRs but provides no booster effect for spike-specific memory CD8+ T-cell responses. A third mRNA vaccination could be helpful in LTRs to prevent severe COVID-19, although further investigation is required to elicit CD8+ T-cell responses in LTRs and HDs.
People with a liver transplant don't have as strong an immune response to COVID-19 vaccines as healthy people. This study investigates how these individuals produce protective proteins, called antibodies, and CD4 and CD8 T cell immune responses. CD4 T cells are responsible for commanding the immune response and CD8 T cells for remembering and fighting the virus in future. We found that liver transplant recipients have a weaker ability to produce antibodies after vaccination, which is even more noticeable in those taking drugs to prevent transplant rejection. While a third vaccine dose improves their ability to produce antibodies, and to have a CD4 T cell response, it doesn't boost the CD8 T cell response. In summary, an extra vaccine dose can strengthen the immune response in liver transplant recipients but doesn't improve some aspects of their immune memory.