RESUMO
Notch has been implicated in human cancers and is a putative therapeutic target. However, the regulation of Notch activation in the nucleus remains largely uncharacterized. Therefore, characterizing the detailed mechanisms governing Notch degradation will identify attractive strategies for treating Notch-activated cancers. Here, we report that the long noncoding RNA (lncRNA) BREA2 drives breast cancer metastasis by stabilizing the Notch1 intracellular domain (NICD1). Moreover, we reveal WW domain containing E3 ubiquitin protein ligase 2 (WWP2) as an E3 ligase for NICD1 at K1821 and a suppressor of breast cancer metastasis. Mechanistically, BREA2 impairs WWP2-NICD1 complex formation and in turn stabilizes NICD1, leading to Notch signaling activation and lung metastasis. BREA2 loss sensitizes breast cancer cells to inhibition of Notch signaling and suppresses the growth of breast cancer patient-derived xenograft tumors, highlighting its therapeutic potential in breast cancer. Taken together, these results reveal the lncRNA BREA2 as a putative regulator of Notch signaling and an oncogenic player driving breast cancer metastasis.
Assuntos
Neoplasias da Mama , Neoplasias Pulmonares , RNA Longo não Codificante , Humanos , Feminino , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Ubiquitinação , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Neoplasias Pulmonares/genética , Neoplasias da Mama/genética , Receptor Notch1/genética , Receptor Notch1/metabolismoRESUMO
BACKGROUND: Yaks are a vital livestock in the Qinghai-Tibetan Plateau area for providing food products, maintaining sustainable ecosystems, and promoting cultural heritage. Because of uncontrolled mating, it is impossible to estimate inbreeding level of yak populations using the pedigree-based approaches. With the aims to accurately evaluate inbreeding level of two Chinese yak populations (Maiwa and Jiulong), we obtained genome-wide single nucleotide polymorphisms (SNPs) by DNA sequencing and calculated five SNP-by-SNP estimators ([Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text], and [Formula: see text]), as well as two segment-based estimators of runs of homozygosity (ROH, [Formula: see text]) and homozygous-by-descent (HBD, [Formula: see text]). Functional implications were analyzed for the positional candidate genes located within the related genomic regions. RESULTS: A total of 151,675 and 190,955 high-quality SNPs were obtained from 71 Maiwa and 30 Jiulong yaks, respectively. Jiulong had greater genetic diversity than Maiwa in terms of allele frequency and nucleotide diversity. The two populations could be genetically distinguished by principal component analysis, with the mean differentiation index (Fst) of 0.0054. The greater genomic inbreeding levels of Maiwa yaks were consistently supported by all five SNP-by-SNP estimators. Based on simple proportion of homozygous SNPs ([Formula: see text]), a lower inbreeding level was indicated by three successfully sequenced old leather samples that may represent historical Maiwa yaks about five generations ago. There were 3304 ROH detected among all samples, with mean and median length of 1.97 Mb and 1.0 Mb, respectively. A total of 94 HBD segments were found among all samples, whereas 92 of them belonged to the shortest class with the mean length of 10.9 Kb. Based on the estimates of [Formula: see text] and [Formula: see text], however, there was no difference in inbreeding level between Maiwa and Jiulong yaks. Within the genomic regions with the significant Fst or enriched by ROH, we found several candidate genes and pathways that have been reported to be related to diverse production traits in farm animals. CONCLUSIONS: We successfully evaluated the genomic inbreeding level of two Chinese yak populations. Although different estimators resulted in inconsistent conclusions on their genomic inbreeding levels, our results may be helpful to implement the genetic conservation and utilization programs for the two yak populations.
Assuntos
Genômica , Endogamia , Polimorfismo de Nucleotídeo Único , Animais , Bovinos/genética , Genômica/métodos , China , Frequência do Gene , Genética Populacional , Homozigoto , GenomaRESUMO
The nanoelectrosprayer is a key device in the hyphenation of nanoLC-ESI-MS, and its development plays a crucial role in pushing forward the mining depth of biological discovery and industrialization of omics science. In this work, a new type of nanoelectrospray emitter, a rod sprayer, was developed based on microfluidic manufacture. Due to its porous silica structure, the rod sprayer in effect worked as a multinozzle sprayer, which is composed of a bunch of micrometer sized spray channels. Without the need for sophisticated microfabrication equipment, a superclean environment, or a complicated assembling process, such sprayer rods can be facilely fabricated in a mass production style: 3,600 rods with excellent monodispersity have been fabricated in 1 h, and rod sprayers thus made have demonstrated excellent intraday, interday, and interbatch reproducibilities: RSD = 1.9, 4.9, and 6.1%, respectively. The rod sprayer can generate stable electrospray in a wide voltage range from 2.6 to 3.2 kV and flow rates from 50 to 1000 nL/min, covering typical flow rates of subnanoLC, nanoLC, to microLC, and work steadily even under complex matrix environments (e.g., Hank's balanced salt solution containing sodium, magnesium, and calcium ions) without clogging. Meanwhile, the rod sprayers exhibited 200-1800% ionization efficiency enhancement in comparison with commonly used tapered tip emitters, for small molecule drugs, peptides, and proteins, respectively, and provided a broadened linear dynamic range of 4 orders of magnitude. The excellent characteristics of the rod sprayer, together with its small size and mass production capacity, should provide a high quality, high durability, high consistency, and disposable use-supported nanoelectrospray solution for MS-based bioanalyses.
RESUMO
Whole-exome sequencing (WES) is frequently utilized in diagnosing reproductive genetic disorders to identify various genetic variants. Canonical ±1,2 splice sites are typically considered highly pathogenic, while variants at the 5' or 3' ends of exon boundaries are often considered synonymous or missense variants, with their potential impact on abnormal gene splicing frequently overlooked. In this study, we identified five variants located at the last two bases of the exons and two canonical splicing variants in five distinct families affected by reproductive genetic disorders through WES. Minigene analysis, RT-PCR and Quantitative Real-time PCR (RT-qPCR) confirmed that all seven variants induced aberrant splicing, with six variants altering gene transcriptional expression levels. These findings underscore the crucial role of splice variants, particularly non-canonical splice sites variants, in reproductive genetic disorders, with all identified variants classified as pathogenic.
RESUMO
Cytomegalovirus (CMV) reactivation post-allogeneic hematopoietic cell transplantation (post-alloHCT) increases morbidity and mortality. We sought to determine the frequency of CMV seroconversion in patients pre-alloHCT and to investigate the impact on posttransplant outcomes. We retrospectively investigated 752 adult patients who underwent alloHCT at our center from January 2015 to February 2020 before the adoption of letermovir prophylaxis. CMV serology was assessed at consult and pretransplant. The cohort was divided into four groups based on pretransplant CMV seroconversion: negative to positive (Group 1), positive to negative (Group 2), consistently negative (Group 3), and consistently positive (Group 4). Eighty-nine patients (12%) had seroconverted from negative to positive, 17 (2%) from positive to negative, 151 (20%) were consistently seronegative, and 495 (66%) were consistently seropositive pretransplant. For the four CMV serostatus groups, cumulative incidence of CMV reactivation at 6 months posttransplant was 4.5%, 47.1%, 6.6%, and 76.6% for Groups 1, 2, 3, and 4, respectively (p < .0001). No differences between groups were seen regarding Grade III-IV acute graft-versus-host disease (GVHD) (p = .91), moderate/severe chronic GVHD (p = .41), or graft failure (p = .28). On multivariable analysis, there was no impact of CMV serostatus group on overall survival (p = .67), cumulative incidence of relapse (p = .83) or non-relapse mortality. alloHCT patients who demonstrate CMV seroconversion pretransplant from negative to positive have a very low risk of CMV reactivation posttransplant. The observed seroconversion may be due to passive CMV immunity acquired through blood products. Quantitative CMV immunoglobulin G/immunoglobulin M pretransplant may help differentiate between true seroconversion and passively transmitted CMV immunoglobulin.
RESUMO
AIM: To investigate the efficacy and safety of glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 (SGLT2) inhibitors in liver transplant (LT) recipients with diabetes. METHODS: A single-centre, retrospective analysis of prospectively collected data from an LT recipient database (1990-2023) was conducted. We included adults with pre-existing diabetes and post-transplant diabetes, newly started on GLP-1RAs and/or SGLT2 inhibitors after LT. Metabolic and biochemical parameters and outcomes were collected for up to 12 months after starting medications and were compared to those in patients receiving dipeptidyl peptidase-4 (DPP-4) inhibitors. Statistical analysis included descriptive statistics and linear mixed models. RESULTS: We included participants on GLP-1RAs (n = 46), SGLT2 inhibitors (n = 87), combination therapy (n = 12), and a DPP-4 inhibitor comparator (n = 217). Both GLP-1RAs and combination therapy decreased mean glycated haemoglobin (HbA1c) levels, and combination therapy remained significant when adjusted for DPP-4 inhibitor treatment (-3.5%, 95% CI [-6.1, -0.95]; p = 0.0089) at 12 months. All three groups had significant decreases in mean weight and body mass index, but these remained significant in the GLP-1RA (-5.2 kg, 95% CI [-8.7, -1.7], p = 0.0039 and 1.99 kg/m2, 95% CI [-3.4, -0.6], p = 0.0048) and combination therapy groups (-5.4 kg, 95% CI [-10.5, -0.36], p = 0.04 and -3.4 kg/m2, 95% CI [-5.5, -1.3], p = 0.0015) when adjusted for DPP-4 inhibitor treatment at 12 months. Alanine aminotransferase levels decreased with GLP-1RA and combination therapy. There were two (1.4%) cases of graft rejection. CONCLUSION: We found that GLP-1RAs, SGLT2 inhibitors, and their combination, led to significant weight loss in LT recipients with diabetes. Combination therapy, in particular, lowered HbA1c and alanine aminotransferase levels compared to DPP-4 inhibitors. Further studies are needed to assess long-term safety and efficacy.
RESUMO
Nitrous acid (HONO) is an important source of hydroxyl radicals (OH) in the atmosphere. Precise determination of the absolute ultraviolet (UV) absorption cross section of gaseous HONO lays the basis for the accurate measurement of its concentration by optical methods and the estimation of HONO loss rate through photolysis. In this study, we performed a series of laboratory and field intercomparison experiments for HONO measurement between striping coil-liquid waveguide capillary cell (SC-LWCC) photometry and incoherent broadband cavity-enhanced absorption spectroscopy (IBBCEAS). Specified HONO concentrations prepared by an ultrapure standard HONO source were utilized for laboratory intercomparisons. Results show a consistent â¼22% negative bias in measurements of the IBBCEAS compared with a SC-LWCC photometer. It is confirmed that the discrepancies occurring between these techniques are associated with the overestimation of the absolute UV absorption cross sections through careful analysis of possible uncertainties. We quantified the absorption cross section of gaseous HONO (360-390 nm) utilizing a custom-built IBBCEAS instrument, and the results were found to be 22-34% lower than the previously published absorption cross sections widely used in HONO concentration retrieval and atmospheric chemical transport models (CTMs). This suggests that the HONO concentrations retrieved by optical methods based on absolute absorption cross sections may have been underestimated by over 20%. Plus, the daytime loss rate and unidentified sources of HONO may also have evidently been overestimated in pre-existing studies. In summary, our findings underscore the significance of revisiting the absolute absorption cross section of HONO and the re-evaluation of the previously reported HONO budgets.
Assuntos
Poluentes Atmosféricos , Ácido Nitroso , Ácido Nitroso/análise , Gases/análise , Poluentes Atmosféricos/análise , Análise Espectral , FotóliseRESUMO
INTRODUCTION AND OBJECTIVES: Recurrent cirrhosis complicates 10-30% of Liver transplants (LT) and can lead to consideration for re-transplantation. We evaluated the trajectories of relisted versus primary listed patients on the waitlist using a competing risk framework. MATERIALS AND METHODS: We retrospectively examined 1,912 patients listed for LT at our centre between from 2012 to 2020. Cox proportional hazard models were used to assess overall survival (OS) by listing type and competing risk analysis Fine-Gray models were used to assess cumulative incidence of transplant by listing type. RESULTS: 1,731 patients were included (104 relisted). 44.2% of relisted patients received exception points vs. 19.8% of primary listed patients (p<0.001). Patients relisted without exceptions, representing those with graft cirrhosis, had the worst OS (HR: 4.17, 95%CI 2.63 - 6.67, p=<0.0001) and lowest instantaneous rate of transplant (HR: 0.56, 95%CI 0.38 - 0.83, p=0.006) than primary listed with exception points. On multivariate analysis listing type, height, bilirubin and INR were associated with cumulative incidence of transplant, while listing type, bilirubin, INR, sodium, creatinine were associated with OS. Within relisted patients, there was a trend towards higher mortality (HR: 1.79, 95%CI 0.91 - 3.52, p=0.08) and low transplant incidence (HR: 0.51, 95%CI 0.22 - 1.15, p=0.07) for graft cirrhosis vs other relisting indications. CONCLUSIONS: Patients relisted for LT are carefully curated and comprise a minority of the waitlist population. Despite their younger age, they have worse liver/kidney function, poor waitlist survival, and decreased transplant incidence suggesting the need for early relisting, while considering standardized exception points.
Assuntos
Transplante de Fígado , Humanos , Transplante de Fígado/efeitos adversos , Estudos Retrospectivos , Cirrose Hepática/diagnóstico , Cirrose Hepática/epidemiologia , Cirrose Hepática/cirurgia , Modelos de Riscos Proporcionais , Listas de Espera , BilirrubinaRESUMO
The family Sisoridae is one of the largest and most diverse Asiatic catfish families, with most species occurring in the water systems of the Qinhai-Tibetan Plateau and East Himalayas. At present, the phylogenetic relationship of the Sisoridae is relatively chaotic. In this study, the mitochondrial genomes (mitogenomes) of three species Creteuchiloglanis kamengensis, Glaridoglanis andersonii, and Exostoma sp. were systematically investigated, the phylogenetic relationships of the family were reconstructed and to determine the phylogenetic position of Exostoma sp. within Sisoridae. The lengths of the mitogenomes' sequences of C. kamengensis, G. andersonii, and Exostoma sp. were 16,589 bp, 16,531 bp, and 16,529 bp, respectively. They all contained one identical control region (D-loop), two ribosomal RNAs (rRNAs), 13 protein-coding genes (PCGs) and 22 transfer RNA (tRNA) genes. We applied two approaches, Bayesian Inference (BI) and Maximum Likelihood (ML), to construct phylogenetic trees. Our findings revealed that the topological structure of both ML and BI trees exhibited significant congruence. Specifically, the phylogenetic tree strongly supports the monophyly of Sisorinae and Glyptosternoids and provides new molecular biological data to support the reconstruction of phylogenetic relationships with Sisoridae. This study is of great scientific value for phylogenetic and genetic variation studies of the Sisoridae.
RESUMO
Breeding more resilient animals will benefit the dairy cattle industry in the long term, especially as global climate changes become more severe. Previous studies have reported genetic parameters for various milk yield-based resilience indicators, but the underlying genomic background of these traits remain unknown. In this study, we conducted GWAS of 62,029 SNPs with 4 milk yield-based resilience indicators, including the weighted occurrence frequency (wfPert) and accumulated milk losses (dPert) of milk yield perturbations, and log-transformed variance (LnVar) and lag-1 autocorrelation (rauto) of daily yield residuals. These variables were previously derived from 5.6 million daily milk yield records from 21,350 lactations (parities 1-3) of 11,787 North American Holstein cows. The average daily milk yield (ADMY) throughout lactation was also included to compare the shared genetic background of resilience indicators with milk yield. The differential genetic background of these indicators was first revealed by the significant genomic regions identified and significantly enriched biological pathways of positional candidate genes, which confirmed the genetic difference among resilience indicators. Interestingly, the functional analyses of candidate genes suggested that the regulation of intestinal homeostasis is most likely affecting resilience derived based on variability in milk yield. Based on Mendelian randomization analyses of multiple instrumental SNPs, we further found an unfavorable causal association of ADMY with LnVar. In conclusion, the resilience indicators evaluated are genetically different traits, and there are causal associations of milk yield with some of the resilience indicators evaluated. In addition to providing biological insights into the molecular regulation mechanisms of resilience derived based on variability in milk yield, this study also indicates the need for developing selection indexes combining multiple indicator traits and taking into account their genetic relationship for breeding more resilient dairy cattle.
Assuntos
Leite , Resiliência Psicológica , Feminino , Bovinos/genética , Animais , Leite/metabolismo , Estudo de Associação Genômica Ampla/veterinária , Análise da Randomização Mendeliana/veterinária , Lactação/genética , Fenótipo , Genômica , América do NorteRESUMO
Identifying genome-enabled methods that provide more accurate genomic prediction is crucial when evaluating complex traits such as dairy cow behavior. In this study, we aimed to compare the predictive performance of traditional genomic prediction methods and deep learning algorithms for genomic prediction of milking refusals (MREF) and milking failures (MFAIL) in North American Holstein cows measured by automatic milking systems (milking robots). A total of 1,993,509 daily records from 4,511 genotyped Holstein cows were collected by 36 milking robot stations. After quality control, 57,600 SNPs were available for the analyses. Four genomic prediction methods were considered: Bayesian least absolute shrinkage and selection operator (LASSO), multiple layer perceptron (MLP), convolutional neural network (CNN), and GBLUP. We implemented the first 3 methods using the Keras and TensorFlow libraries in Python (v.3.9) but the GBLUP method was implemented using the BLUPF90+ family programs. The accuracy of genomic prediction (mean square error) for MREF and MFAIL was 0.34 (0.08) and 0.27 (0.08) based on LASSO, 0.36 (0.09) and 0.32 (0.09) for MLP, 0.37 (0.08) and 0.30 (0.09) for CNN, and 0.35 (0.09) and 0.31(0.09) based on GBLUP, respectively. Additionally, we observed a lower reranking of top selected individuals based on the MLP versus CNN methods compared with the other approaches for both MREF and MFAIL. Although the deep learning methods showed slightly higher accuracies than GBLUP, the results may not be sufficient to justify their use over traditional methods due to their higher computational demand and the difficulty of performing genomic prediction for nongenotyped individuals using deep learning procedures. Overall, this study provides insights into the potential feasibility of using deep learning methods to enhance genomic prediction accuracy for behavioral traits in livestock. Further research is needed to determine their practical applicability to large dairy cattle breeding programs.
Assuntos
Genômica , Aprendizado de Máquina , Animais , Bovinos/genética , Feminino , Indústria de Laticínios/métodos , Genótipo , Lactação/genética , Leite , Algoritmos , Fenótipo , Comportamento AnimalRESUMO
Udder conformation is directly related to milk yield, cow health, workability, and welfare. Automatic milking systems (AMS, also known as milking robots) have become popular worldwide, and the number of dairy farms adopting these systems has increased considerably over the past years. In each milking visit, AMS record the location of the 4 teats as Cartesian coordinates in an xyz plan, which can then be used to derive udder conformation traits. Because AMS generate a large amount of data for individual cows per milking visit, they can contribute to an accurate assessment of important traits such as udder conformation without the addition of human classifier errors (in subjective scoring systems). Therefore, the primary objectives of this study were to estimate genomic-based genetic parameters for udder conformation traits derived from AMS records in North American Holstein cattle and to assess the genetic correlation between the derived traits for evaluating the feasibility of multitrait genomic selection for breeding cows that are more suitable for milking in AMS. The Cartesian teat coordinates measured during each milking visit were collected by 36 milking robots in 4,480 Holstein cows from 2017 to 2021, resulting in 5,317,488 records. A total of 4,118 of these Holstein cows were also genotyped for 57,600 SNPs. Five udder conformation traits were derived: udder balance (UB, mm), udder depth (UD, mm), front teat distance (FTD, mm), rear teat distance (RTD, mm), and distance front-rear (DFR, mm). In addition, 2 traits directly related to cow productivity in the system were added to the study: daily milk yield (DY) and milk electroconductivity (EC; as an indicator of mastitis). Variance components and genetic parameters for UB, UD, FTD, RTD, DFR, DY, and EC were estimated based on repeatability animal models. The estimates of heritability (± SE) for UB, UD, FTD, RTD, DFR, DY, and EC were 0.41 ± 0.02, 0.79 ± 0.01, 0.53 ± 0.02, 0.40 ± 0.02, 0.65 ± 0.02, 0.20 ± 0.02, and 0.46 ± 0.02, respectively. The repeatability estimates (± SE) for UB, UD, FTD, RTD, and DFR were 0.82 ± 0.01, 0.93 ± 0.01, 0.87 ± 0.01, 0.83 ± 0.01, and 0.88 ± 0.01, respectively. The strongest genetic correlations were observed between FTD and RTD (0.54 ± 0.03), UD and DFR (-0.47 ± 0.03), DFR and FTD (0.32 ± 0.03), and UD and FTD (-0.31 ± 0.03). These results suggest that udder conformation traits derived from Cartesian coordinates from AMS are moderately to highly heritable. Furthermore, the moderate genetic correlations between these traits should be considered when developing selection subindexes. The most relevant genetic correlations between traits related to cow milk productivity and udder conformation traits were between UD and EC (-0.25 ± 0.03) and between DFR and DY (0.30 ± 0.04), in which both genetic correlations are favorable. These findings will contribute to the design of genomic selection schemes for improving udder conformation in North American Holstein cattle, especially in precision dairy farms.
Assuntos
Indústria de Laticínios , Lactação , Glândulas Mamárias Animais , Leite , Animais , Bovinos/genética , Feminino , Lactação/genética , Glândulas Mamárias Animais/anatomia & histologia , Genótipo , Fenótipo , CruzamentoRESUMO
PURPOSE: To compare the diagnostic performance of a thick-slab reconstruction obtained from an ultra-low-dose CT (termed thoracic tomogram) with standard-of-care low-dose CT (SOC-CT) for rapid interpretation and detection of pneumonia in hemato-oncology patients. METHODS: Hemato-oncology patients with a working diagnosis of pneumonia underwent an SOC-CT followed by an ultra-low-dose CT, from which the thoracic tomogram (TT) was reconstructed. Three radiologists evaluated the TT and SOC-CT in the following categories: (I) infectious/inflammatory opacities, (II) small airways infectious/inflammatory changes, (III) atelectasis, (IV) pleural effusions, and (V) interstitial abnormalities. The TT interpretation time and radiation dose were recorded. Sensitivity, specificity, diagnostic accuracy, ROC, and AUC were calculated with the corresponding power analyses. The agreement between TT and SOC-CT was calculated by Correlation Coefficient for Repeated Measures (CCRM), and the Shrout-Fleiss intra-class correlations test was used to calculate interrater agreement. RESULTS: Forty-seven patients (mean age 58.7 ± 14.9 years; 29 male) were prospectively enrolled. Sensitivity, specificity, accuracy, AUC, and Power for categories I/II/III/IV/V were: 94.9/99/97.9/0.971/100, 78/91.2/86.5/0.906/100, 88.6/100/97.2/0.941/100, 100/99.2/99.3/0.995/100, and 47.6/100/92.2/0.746/87.3. CCRM between TT and SOC-CT for the same categories were .97/.81/.92/.96/.62 with an interobserver agreement of .93/.88/.82/.96/.61. Mean interpretation time was 18.6 ± 5.4 seconds. The average effective radiation dose of TT was similar to a frontal and lateral chest X-ray (0.27 ± 0.08 vs 1.46 ± 0.64 mSv for SOC-CT; P < .01). CONCLUSION: Thoracic tomograms provide comparable diagnostic information to SOC-CT for the detection of pneumonia in immunocompromised patients at one-fifth of the radiation dose with high interobserver agreement.
Assuntos
Pneumonia , Doses de Radiação , Radiografia Torácica , Tomografia Computadorizada por Raios X , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Pneumonia/diagnóstico por imagem , Tomografia Computadorizada por Raios X/métodos , Radiografia Torácica/métodos , Sensibilidade e Especificidade , Neoplasias Hematológicas/diagnóstico por imagem , Neoplasias Hematológicas/complicações , Idoso , Adulto , Reprodutibilidade dos Testes , Estudos Prospectivos , Pulmão/diagnóstico por imagemRESUMO
Designing materials capable of adapting their mechanical properties in response to external stimuli is the key to preventing failure and extending their service life. However, existing mechanically adaptive polymers are hindered by limitations such as inadequate load-bearing capacity, difficulty in achieving reversible changes, high cost, and a lack of multiple responsiveness. Herein, we address these challenges using dynamic coordination bonds. A new type of mechanically adaptive material with both rate- and temperature-responsiveness was developed. Owing to the stimuli-responsiveness of the coordination equilibria, the prepared polymers, PBMBD-Fe and PBMBD-Co, exhibit mechanically adaptive properties, including temperature-sensitive strength modulation and rate-dependent impact hardening. Benefitting from the dynamic nature of the coordination bonds, the polymers exhibited impressive energy dissipation, damping capacity (loss factors of 1.15 and 2.09 at 1.0â Hz), self-healing, and 3D printing abilities, offering durable and customizable impact resistance and protective performance. The development of impact-resistant materials with comprehensive properties has potential applications in the sustainable and intelligent protection fields.
RESUMO
Interleukin-36α (IL-36α) is essential for various inflammatory conditions, such as psoriasis and rheumatoid arthritis, whereas its role in tumor immunity is unclear. In this study, it was demonstrated that IL-36α could activate the NF-κB and MAPK signaling pathways in macrophages, leading to the expression of IL-1ß, IL-6, TNF-α, CXCL1, CXCL2, CXCL3, CXCL5 and iNOS. Importantly, IL-36α has significant antitumor effects, altering the tumor microenvironment and promoting the infiltration of MHC IIhigh macrophages and CD8+ T cells while decreasing the levels of monocyte myeloid-derived suppressor cells, CD4+ T cells and regulatory T cells. This ultimately results in the inhibition of tumor growth and migration. Furthermore, IL-36α synergized with the PD-L1 antibody increased the immune cells infiltration and enhanced the anti-tumor effect of the PD-L1 antibody on melanoma. Collectively, this study reveals a new role for IL-36α in promoting anti-tumor immune responses in macrophages and suggests its potential for cancer immunotherapy.
Assuntos
Antígeno B7-H1 , Melanoma , Humanos , Antígeno B7-H1/metabolismo , Linfócitos T CD8-Positivos , Interleucinas/metabolismo , Macrófagos , Melanoma/metabolismo , Microambiente TumoralRESUMO
BACKGROUND: Liver injury plays a major role in the development of sepsis. Liver damage after sepsis is an independent risk factor for multiple organ failure and death. Cancer susceptibility candidate 9 (CASC9) exerts a protective effect on sepsis-induced acute lung injury (ALI). However, the role and underlying mechanism haven't been fully evaluated. METHODS: Animal and cell models of sepsis were established in vivo and in vitro experiments. The histological and apoptosis analyses of liver tissues were tested by hematoxylin-eosin (HE) staining and terminal dUTP nick end labeling (TUNEL) assay, respectively. Serum levels of inflammatory cytokines were detected via using an enzyme-linked immunosorbent assay (ELISA). The expressions of CASC9, suppressor of cytokine signaling (SOCS)-1, Bcl-2, Bax, Bad, and caspase3 were measured by reverse-transcription quantitative polymerase chain reaction (RT-qPCR) and western blotting. Cell counting kit-8 (CCK-8) and flow cytometry were applied to examine cell viability and apoptosis, respectively. RNA immunoprecipitation (RIP) and RNA-pull down assay were used to verify the binding relationships among CASC9, SOCS-1 and FUS. RESULTS: CASC9 and SOCS-1 were lowly expressed in animal and cell models of sepsis liver injury. CASC9 or SOCS-1 overexpression could inhibit cell apoptosis upon lipopolysaccharide (LPS) induction. Meanwhile, the serum levels of tumor necrosis factor-α (TNF-α), interleukin (IL)-1ß, IL-6 and IL-8 were reduced by CASC9 or SOCS-1 overexpression in LPS-induced LO2 cells. Mechanistically, CASC9 interacted with fused in sarcoma (FUS) to stabilize the mRNA of SOCS-1. SOCS-1 silencing antagonized the effects of CASC9 on improving sepsis liver injury. CONCLUSION: CASC9 overexpression ameliorated the sepsis-induced liver injury, and the probable underlying mechanism may be that CASC9 stabilized the SOCS-1 mRNA by interacting with FUS.
Assuntos
Doença Hepática Crônica Induzida por Substâncias e Drogas , MicroRNAs , RNA Longo não Codificante , Sepse , Animais , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Lipopolissacarídeos/farmacologia , Proteínas Supressoras da Sinalização de Citocina/metabolismo , Sepse/complicações , Sepse/patologia , RNA Mensageiro , Apoptose , MicroRNAs/genéticaRESUMO
In this Letter, we propose a novel strategy for significantly enhancing the heat transfer in convection turbulence. By introducing a boundary deformation of the standing-wave type, flow modulation can be realized when the amplitude is comparable or larger than the boundary-layer thickness. For a fixed moderate frequency, the entire fluid layer follows the boundary motion at small wave numbers, while only the near-wall regions are affected by the boundary deformation at large wave numbers. The heat-flux enhancement happens for the latter. For a fixed wave number and gradually increasing frequency, the vortical flows inside the wave valleys exhibit nonlinear transition and alter the distribution of boundary heat flux, and the global heat flux increases significantly at large enough frequencies. The current findings suggest that oscillating deformations of boundary can efficiently break the boundary layers, which serves as the bottleneck of global heat transfer, and open a new venue for modulating the convection turbulence.
RESUMO
The outcomes of allogeneic hematopoietic cell transplantation (HCT) in older patients are not well defined. We retrospectively analyzed the outcomes of 332 patients, with the median age of 65 years (range, 60-76), between 2014 and 2019. We categorized them to 3 age groups (G): G1, 60-65 years (n = 175); G2, > 65-70 years (n = 127); and G3, > 70 years (n = 30). The median length of hospitalization during the initial HCT period was 30 days, with a significant difference when stratified by age (p = 0.049). Overall, 183 (58.7%) patients were re-hospitalized within the first 6 months post HCT, and 60 (21.6%) in the second 6-month period. The 2-year OS was 56% in G1, 53% in G2, and 34% in G3 (p = 0.05). The 2-year event-free survival (EFS) was 54% for G1, 49% for G2, and 31% for G3 (p = 0.04). Non-relapse mortality (NRM) at 2 years was 25% in G1, 36% in G2, and 52% in G3 (p = 0.008). In multivariable analysis, patients aged 60-65 years had significantly better EFS (p = 0.04) and had a trend toward lower NRM (p = 0.05) than those aged > 70 years. Re-admission in the first 6 months post HCT had a significant impact on OS, EFS, and NRM. HCT-specific comorbidity index > 3 had significantly affected NRM. Finally, age had a significant influence on length of hospitalization during HCT. In conclusion, patients aged > 70 years have an inferior EFS and higher NRM. This likely related to higher rate of re-admissions due to infectious complications (84%).
Assuntos
Transplante de Células-Tronco Hematopoéticas , Humanos , Idoso , Pessoa de Meia-Idade , Estudos Retrospectivos , Transplante Homólogo , Análise de Sobrevida , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Condicionamento Pré-Transplante , HospitalizaçãoRESUMO
Multifunctional all-in-one biomaterial combining the therapeutic and regeneration functionalities for successive tumor therapy and tissue regeneration is in high demand in interdisciplinary research. In this study, a three-dimensional (3D) aerogel-based composite scaffold with a dual-network structure generated through self-assembly and photo-cross-linking with combined properties of photothermally triggered controlled anticancer drug release and photothermal cancer cell ablation was successfully fabricated. The fabrication of composites consists of self-assembly of a silk fibroin methacrylate (SF-MA) biopolymer incorporated with hydrothermally driven bismuth sulfide (Bi2S3) methacrylate nanobelts, followed by a photo-cross-linking-assisted 3D-printing process. The developed scaffolds presented hierarchically organized porosity and excellent photothermal conversion thanks to the strong near-infrared (NIR) photon absorption of incorporated Bi2S3 nanobelts inside the scaffold matrix. The heat generated in the scaffold mediated by laser irradiation has not only triggered controlled and prolonged release of the anticancer drug but also significantly ablated the bone cancer cells adhered on the scaffold. In addition, the developed 3D composite scaffolds have demonstrated excellent biodegradability for organic and inorganic network constituents at different media, enabling them as potential implants to be replaced by de novo tissue. In combination of chemotherapy and photothermal therapy, the multifunctional 3D-printed composite aerogel scaffold is expected to be an excellent implantable material in bone tissue engineering (BTE) for successive cancer therapy and tissue regeneration.
Assuntos
Antineoplásicos , Neoplasias Ósseas , Fibroínas , Humanos , Alicerces Teciduais/química , Fibroínas/química , Terapia Fototérmica , Engenharia Tecidual/métodos , Antineoplásicos/farmacologia , Impressão TridimensionalRESUMO
PURPOSE: Simvastatin is a prodrug of the potent 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor. The main purpose of the current study is to assess the accurate function of simvastatin on osteoporosis of extremity bones in aging rats. MATERIALS AND METHODS: Fifty 15-month-old SD rats were divided into five groups (four simvastatin groups and one control group). The rats in four simvastatin groups were fed with different doses of simvastatin (5, 10, 20, and 40 mg/kg/d, respectively) for 3 months, whereas the rats in control group were fed the equal physiological saline. Calcium (Ca), phosphorus (P), and the lipid spectrum in serum were measured. Biochemical markers of bone metabolism, osteocalcin (OC), and tartrate-resistant acid phosphatase (Trap-5b), were analyzed using ELISA. The content of adipocytes in bone marrow was analyzed by histological staining. Finally, the bone quality of the femur and tibia were evaluated using dual-energy X-ray absorptiometry (DEXA), peri-quantity CT (pQCT), and the 3-point bending biomechanical test. RESULTS: Simvastatin reduced serum triglycerides (TG), and 10 mg/kg/d of simvastatin significantly reduced the content of adipocytes in bone marrow compared to the control group. However, statistically significant differences between the simvastatin groups and the control group were not found in the CA, P, OC, Trap-5b, or the evaluation indexes of bone quality from DEXA, pQCT, and biomechanical tests. CONCLUSION: Simvastatin could not prevent osteoporosis of the extremity bones in aging rats.