RESUMO
Tuberculosis (TB) in humans is characterized by formation of immune-rich granulomas in infected tissues, the architecture and composition of which are thought to affect disease outcome. However, our understanding of the spatial relationships that control human granulomas is limited. Here, we used multiplexed ion beam imaging by time of flight (MIBI-TOF) to image 37 proteins in tissues from patients with active TB. We constructed a comprehensive atlas that maps 19 cell subsets across 8 spatial microenvironments. This atlas shows an IFN-γ-depleted microenvironment enriched for TGF-ß, regulatory T cells and IDO1+ PD-L1+ myeloid cells. In a further transcriptomic meta-analysis of peripheral blood from patients with TB, immunoregulatory trends mirror those identified by granuloma imaging. Notably, PD-L1 expression is associated with progression to active TB and treatment response. These data indicate that in TB granulomas, there are local spatially coordinated immunoregulatory programs with systemic manifestations that define active TB.
Assuntos
Granuloma/imunologia , Tuberculose/imunologia , Antígeno B7-H1/imunologia , Células Cultivadas , Citocinas/imunologia , Perfilação da Expressão Gênica/métodos , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/imunologia , Pulmão/imunologia , Mycobacterium tuberculosis/imunologia , Células Mieloides/imunologiaRESUMO
Stem-cell differentiation to desired lineages requires navigating alternating developmental paths that often lead to unwanted cell types. Hence, comprehensive developmental roadmaps are crucial to channel stem-cell differentiation toward desired fates. To this end, here, we map bifurcating lineage choices leading from pluripotency to 12 human mesodermal lineages, including bone, muscle, and heart. We defined the extrinsic signals controlling each binary lineage decision, enabling us to logically block differentiation toward unwanted fates and rapidly steer pluripotent stem cells toward 80%-99% pure human mesodermal lineages at most branchpoints. This strategy enabled the generation of human bone and heart progenitors that could engraft in respective in vivo models. Mapping stepwise chromatin and single-cell gene expression changes in mesoderm development uncovered somite segmentation, a previously unobservable human embryonic event transiently marked by HOPX expression. Collectively, this roadmap enables navigation of mesodermal development to produce transplantable human tissue progenitors and uncover developmental processes. VIDEO ABSTRACT.
Assuntos
Mesoderma/citologia , Transdução de Sinais , Proteínas Morfogenéticas Ósseas/metabolismo , Osso e Ossos/citologia , Osso e Ossos/metabolismo , Coração/crescimento & desenvolvimento , Proteínas de Homeodomínio/metabolismo , Humanos , Mesoderma/metabolismo , Miócitos Cardíacos/metabolismo , Células-Tronco Pluripotentes/metabolismo , Linha Primitiva/citologia , Linha Primitiva/metabolismo , Análise de Célula Única , Somitos/metabolismo , Células-Tronco , Proteínas Supressoras de Tumor/metabolismo , Proteínas Wnt/antagonistas & inibidores , Proteínas Wnt/metabolismoRESUMO
Altered metabolism is a hallmark of both cell division and cancer. Chronic lymphocytic leukemia (CLL) cells circulate between peripheral blood (PB) and lymph nodes (LNs), where they receive proliferative and prosurvival signals from surrounding cells. However, insight into the metabolism of LN CLL and how this may relate to therapeutic response is lacking. To obtain insight into CLL LN metabolism, we applied a 2-tiered strategy. First, we sampled PB from 8 patients at baseline and after 3-month ibrutinib (IBR) treatment, which forces egress of CLL cells from LNs. Second, we applied in vitro B-cell receptor (BCR) or CD40 stimulation to mimic the LN microenvironment and performed metabolomic and transcriptomic analyses. The combined analyses indicated prominent changes in purine, glucose, and glutamate metabolism occurring in the LNs. CD40 signaling mostly regulated amino acid metabolism, tricarboxylic acid cycle (TCA), and energy production. BCR signaling preferably engaged glucose and glycerol metabolism and several biosynthesis routes. Pathway analyses demonstrated opposite effects of in vitro stimulation vs IBR treatment. In agreement, the metabolic regulator MYC and its target genes were induced after BCR/CD40 stimulation and suppressed by IBR. Next, 13C fluxomics performed on CD40/BCR-stimulated cells confirmed a strong contribution of glutamine as fuel for the TCA cycle, whereas glucose was mainly converted into lactate and ribose-5-phosphate. Finally, inhibition of glutamine import with V9302 attenuated CD40/BCR-induced resistance to venetoclax. Together, these data provide insight into crucial metabolic changes driven by the CLL LN microenvironment. The prominent use of amino acids as fuel for the TCA cycle suggests new therapeutic vulnerabilities.
Assuntos
Leucemia Linfocítica Crônica de Células B , Antígenos CD40 , Glucose/metabolismo , Glutamina/metabolismo , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Linfonodos/patologia , Receptores de Antígenos de Linfócitos B/metabolismo , Microambiente TumoralRESUMO
CD40 signaling upregulates BCL-XL and MCL-1 expression in the chronic lymphocytic leukemia (CLL) lymph node microenvironment, affording resistance to the BCL-2 inhibitor, venetoclax. Venetoclax resistance in the therapeutic setting and after long-term laboratory selection has been linked to metabolic alterations, but the underlying mechanism(s) are unknown. We aimed here to discover how CD40 stimulation as a model for tumor microenvironment-mediated metabolic changes, affects venetoclax sensitivity/resistance. CD40 stimulation increased oxidative phosphorylation and glycolysis, but only inhibition of oxidative phosphorylation countered venetoclax resistance. Furthermore, blocking mitochondrial import of pyruvate, glutamine or fatty acids affected CLL metabolism, but did not prevent CD40-mediated resistance to venetoclax. In contrast, inhibition of the electron transport chain (ETC) at complex I, III or V attenuated CLL activation and ATP production, and downregulated MCL-1 and BCL-XL, correlating with reduced CD40 surface expression. Moreover, ETC inhibition equaled mTOR1/2 but not mTOR1 inhibition alone for venetoclax resistance, and all three pathways were linked to control of general protein translation. In line with this, ETC plus mTOR inhibition synergistically counteracted venetoclax resistance. These findings link oxidative CLL metabolism to CD40 expression and cellular signaling, and may hold clinical potential.
Assuntos
Leucemia Linfocítica Crônica de Células B , Humanos , Leucemia Linfocítica Crônica de Células B/patologia , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Transporte de Elétrons , Resistencia a Medicamentos Antineoplásicos , Serina-Treonina Quinases TOR/metabolismo , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Antígenos CD40/metabolismo , Apoptose , Microambiente TumoralRESUMO
Temperature-dependent plastic deformation behaviors of single crystals of quaternary and ternary equiatomic medium-entropy alloys (MEAs) belonging to the Cr-Mn-Fe-Co-Ni system were investigated in compression at temperatures in the range 9 K to 1373 K. Their critical resolved shear stresses (CRSSs) increase with decreasing temperature below room temperature. There is also a dulling of the temperature dependence of CRSS below 77 K due to dislocation inertial effects that we attribute to a decrease in the phonon drag coefficient. These behaviors were compared with those of previously investigated single crystals of the equiatomic Cr-Co-Ni and Cr-Fe-Co-Ni MEAs, and the equiatomic Cr-Mn-Fe-Co-Ni high-entropy alloy (HEA). The temperature dependence of CRSS and the apparent activation volumes below room temperature can be well described by conventional thermal activation theories of face-centered cubic (FCC) alloys. Above 673 K, there is a small increase in CRSS, which we believe is due to elastic interactions between solutes and mobile dislocations, the so-called Portevin-Le Chatelier (PL) effect. The CRSS at 0 K was obtained by extrapolation of fitted CRSS vs. temperature curves and compared with predictions from solid solution strengthening models of HEA and MEAs.
The novelty of our work entitled 'Analysis of the temperature-dependent plastic deformation of single crystals of quinary, quaternary and ternary equiatomic high- and medium-entropy alloys of the Cr-Mn-Fe-Co-Ni system' can be summarized as follows: The temperature dependences of CRSS were experimentally deduced from bulk single crystals of the six MEAs for the first time, so that fair comparison among the FCC HEA/MEAs is made.
RESUMO
As an effective approach for materials synthesis, bipolar electrochemistry has been earning a renewed interest nowadays thanks to its unique features compared to conventional electrochemistry. Indeed, the wireless mode of electrode reactions and the generation of a gradient potential distribution above the bipolar electrode are among the most appealing qualities of bipolar electrochemistry. In particular, the gradient potential distribution is a highly attractive characteristic for the fabrication of surfaces with gradients in their chemical properties or molecular functionalities. Herein, we report the high-throughput electrosynthesis of gradient polypyrrole films by means of a new electrochemical cell design named the single-electrode electrochemical system (SEES). SEESs are made by attaching an inert plastic board with holes onto an indium tin oxide electrode, constructing multiple microelectrochemical cells on the same electrode. This type of arrangement enables parallel electrochemical reactions to be carried out simultaneously and controlled in a contactless manner by a single electrode. Several experimental conditions for polypyrrole film growth were extensively investigated. Furthermore, the gradient property of the polymer films was evaluated by thickness determination, surface morphology analysis, and contact angle measurements. The use of SEES has been demonstrated as a convenient and cost-effective strategy for high-throughput electrosynthesis and electroanalytical applications and has opened up a new door for gradient film preparation via a rapid condition screening process.
RESUMO
Recently, alternating current (AC)-bipolar electropolymerization of 3,4-ethylenedioxythiophene (EDOT) has been reported to produce poly(3,4-ethylenedioxythiophene) (PEDOT) fibers from the terminals of bipolar electrodes in acetonitrile solution (MeCN) containing low concentrations of supporting salts in a template-free manner. Here, we extend such methodology in ionic liquid (IL) media. Three kinds of ILs, diethylmethyl(2-methoxyethyl)ammonium tetrafluoroborate ([DEME][BF4]), 1-ethyl-3-methylimidazolium tetrafluoroborate ([EMIM][BF4]), and diethylmethyl(2-methoxyethyl)ammonium bis(trifluoromethylsulfonyl)imide ([DEME][TFSI]), with different electric field transmission efficiencies and diffusion coefficients were employed as solvents for the AC-bipolar electropolymerization of EDOT. A variety of PEDOT morphologies were obtained in these three ILs, showing a relationship with the physicochemical properties of the ILs. We successfully confirmed the growth of PEDOT fibers in ILs and systematically discussed the factors that influenced their growth.
RESUMO
This study included 46 patients with class II malocclusion ranging in age from 19 to 39 years old treated with bilateral sagittal split ramous osteotomy (BSSRO). Left and right temporomandibular joints (TMJs) of each subject were evaluated independently with cone-beam computed tomography (CBCT) before operation (T1), 1 week after operation (T2), and 1 year after operation (T3) and assessed the effects of orthognathic surgery (OGS) on the temporomandibular joint disease (TMD) symptoms. Temporomandibular joint morphology evaluation included condylar volume, condylar area, cortical bone thickness, depth of the mandibular fossa, fossa thickness, joint nodule angle, joint space, and condyle-fossa relationship, which were calculated by using the Mimics software and 3-matic software. Data were statistically analyzed with SPSS software (P <0.05 means statistically significant). In our study, bilateral TMJs have no difference in T3. Bilateral sagittal split ramous osteotomy had no significant effect on the articular fossa. The condyle volume and surface area decreased from T1 to T3, but the cortical thickness of the bone did not change significantly. More anterior condyle positions in T1 and more posterior in T3.21 patients had at least 1 sign or symptom of TMD in T1 and 27 patients in T3. Four patients who were asymptomatic in T1 developed pain after surgery, 10 developed noises, 12 showed limited mouth opening, and 8 had abnormal opening patterns. It is concluded that more condylar posterior position after BSSRO and the reduction of condyle may be related to the enlargement of anterior space. The number of patients with joint symptoms increased postoperative, and the impact of BSSRO on TMD may be negative.
Assuntos
Má Oclusão Classe II de Angle , Transtornos da Articulação Temporomandibular , Humanos , Adulto Jovem , Adulto , Côndilo Mandibular , Osteotomia Sagital do Ramo Mandibular/métodos , Articulação Temporomandibular/diagnóstico por imagem , Má Oclusão Classe II de Angle/diagnóstico por imagem , Má Oclusão Classe II de Angle/cirurgia , Transtornos da Articulação Temporomandibular/diagnóstico por imagem , Transtornos da Articulação Temporomandibular/cirurgia , Tomografia Computadorizada de Feixe CônicoRESUMO
ABSTRACT: Anterior maxillary osteotomy is a traditional operation in the treatment of maxillary protrusion. Varies fields about operation have been changed or improved in those years to avoid different kinds of complications. In our study, the authors would present 1 kind of improved anterior maxillary osteotomy surgical method. The study was conducted at the Department of Oral and Maxillofacial Surgery, Guanghua School of Stomatology, Hospital of Stomatology, Guangzhou, Guangdong province. Patients are divided into improved group and general group. Patients after surgery were claimed to have regular return visits. Occlusion, tooth vitalities, postoperative complications would be well evaluated. The operative time, blood losses, complications showed no different at maxillary operation. Our procedure could give much better and direct sight of anterior maxillary bone, and the simplified osteotomy lines could help maxilla move, reduce the times spent on hard tissue cut off or grind. The modified procedure can meet clinical command, improve dentofacial deformities, and gives convenience to surgeon.
Assuntos
Maxila , Osteotomia Maxilar , Humanos , Maxila/anormalidades , Maxila/cirurgia , Osteotomia/métodos , Complicações Pós-OperatóriasRESUMO
BACKGROUND: To evaluate the clinical effectiveness of a novel CellDetect staining technique, compared with fluorescent in situ hybridization (FISH), and urine cytology, in the diagnosis of urothelial carcinoma (UC). METHODS: A total of 264 patients with suspicious UC were enrolled in this study. All tissue specimens were collected by biopsy or surgery. Urine specimen was obtained for examinations prior to the surgical procedure. CellDetect staining was carried out with CellDetect kit, and FISH was performed with UroVysion detection kit, according to the manufacturer's instructions. For urine cytology, all specimens were centrifuged using the cytospin method, and the slides were stained by standard Papanicolaou stain. RESULTS: In this study, there were 128 cases of UC and 136 cases of non-UC, with no significant difference in gender and age between the two groups. Results for sensitivity of CellDetect, FISH, and urine cytology were 82.8%, 83.6%, and 39.8%, respectively. The specificity of the three techniques were 88.2%, 90.4%, and 86.0%, respectively. The sensitivity of CellDetect and FISH are significantly superior compared to the conventional urine cytology; however, there was no significant difference in specificity among three staining techniques. In addition, the sensitivity of CellDetect in lower urinary tract UC, upper urinary tract UC, non-muscle-invasive bladder cancer (NMIBC), and muscle-invasive bladder cancer (MIBC) were 83.3%, 81.8%, 83.5%, and 72.0%, respectively. The screening ability of CellDetect has no correlation with tumor location and the tumor stage. The sensitivity of CellDetect in low-grade UC and high-grade UC were 51.6 and 92.8%. Thus, screening ability of CellDetect in high-grade UC is significantly superior compared to that in low-grade UC. CONCLUSIONS: CellDetect and FISH show equal value in diagnosing UC, both are superior to conventional urine cytology. Compared to FISH, CellDetect is cost effective, easy to operate, with extensive clinical application value to monitor recurrence of UC, and to screen indetectable UC.
RESUMO
Literature documents an age-related reduction of bladder sensory function. Transient receptor potential vanilloid (TRPV)1 or TRPV4 channels have been implicated in bladder mechanotransduction. To investigate contributions of TRPV1 or TRPV4 to the age-related reduction of bladder sensory function, bladder responses to capsaicin (CAP; TRPV1 agonist) and GSK-1016790A (GSK; TRPV4 agonist) in retired breeder (RB; 12-15 mo) and young adult (2-3 mo) female rats were compared using multiple methods. Metabolic cage and continuous infusion cystometry [cystometrogram (CMG)] recordings revealed that RB rats exhibit larger bladder capacity and lower voiding frequency. RB rats also have a greater intravesical pressure threshold for micturition; however, the voiding contraction strength was equivalent to that in young rats. CAP (1 µM) or GSK (20 nM) administered intravesically evoked smaller changes in all CMG parameters in RB rats. In vitro, CAP (1 µM) or GSK (20 nM) evoked smaller enhancement of bladder strip contractions, while the muscarinic receptor agonist carbachol (at 100, 300, and 1,000 nM) elicited greater amplitude contractions in RB rats. Patch-clamp recording revealed smaller CAP (100 nM) induced inward currents in bladder primary sensory neurons, and Ca2+ imaging revealed smaller GSK (20 nM) evoked increases in intracellular Ca2+ concentration in urothelial cells in RB rats. These results suggest that RB rats have a decreased bladder sensory function commonly observed in elderly women, and could be used as an animal model to study the underling mechanisms. Reduced functional expression of TRPV1 in bladder afferents or reduced functional expression of urothelial TRPV4 may be associated with the diminished sensory function.
Assuntos
Capsaicina/farmacologia , Leucina/análogos & derivados , Neurônios Aferentes/efeitos dos fármacos , Sulfonamidas/farmacologia , Canais de Cátion TRPV/agonistas , Bexiga Urinária/efeitos dos fármacos , Micção/efeitos dos fármacos , Urodinâmica/efeitos dos fármacos , Urotélio/efeitos dos fármacos , Administração Intravesical , Fatores Etários , Envelhecimento , Animais , Sinalização do Cálcio/efeitos dos fármacos , Capsaicina/administração & dosagem , Feminino , Leucina/administração & dosagem , Leucina/farmacologia , Mecanotransdução Celular/efeitos dos fármacos , Potenciais da Membrana/efeitos dos fármacos , Contração Muscular/efeitos dos fármacos , Neurônios Aferentes/metabolismo , Ratos Sprague-Dawley , Sulfonamidas/administração & dosagem , Canais de Cátion TRPV/metabolismo , Bexiga Urinária/inervação , Bexiga Urinária/metabolismo , Urotélio/metabolismoRESUMO
Background: The clinical prognosis assessment of renal cell carcinoma (RCC) still relies on nuclear grading and nuclear score by naked eye with microscope, which has defects long time, low efficiency, and uneven evaluation level criteria. There are few machine learning (ML) studies investigating the prognosis in the RCC literature which could also quantify the risk of postoperative recurrence of RCC patients and guide cancer patients to conduct individualized postoperative clinical management. This study evaluated the suitability of ML algorithms for survival prediction in patients with RCC. Methods: A total of 192,912 RCC patients from the Surveillance, Epidemiology, and End Results (SEER) were obtained from 2004 to 2015. Six ML algorithms including support vector machine (SVM), Bayesian method, decision tree, random forest, neural network, and Extreme Gradient Boosting (XGBoost) were applied to predict overall survival (OS) of RCC. Results: Patients from the SEER with a median age of 62 years and the pathological types were clear cell RCC (47.6%), papillary RCC (9.5%), chromophobe RCC (4.0%) and others (4.1%) were collected. In the deleting patients with missing data, the highest accurate model was XGBoost [area under the curve (AUC) 67.0%]. In the deleting patients with missing data and survival time <5 years, the accuracy of random forest, neural network and XGBoost were high, with AUC of 80.8%, 81.5% and 81.8%, respectively. In the only deleting the missing tumor diameter and filling the missing dataset with missForest, the highest accurate model was random forest (AUC: 71.9%). In this study, the overall accuracy of the SVM model was not high, apart from in the population of patients with deleting the missing tumor diameter and survival time <5 years, and filling the missing data with missForest. Random forest, neural network and XGBoost had high accuracy, with AUC of 84.1%, 84.7% and 84.8%, respectively. Conclusions: ML algorithms could be used to predict the prognosis of RCC. It could quantify the recurrence possibility of patients and help more individualized postoperative clinical management. Given the limitations and complexity of datasets, ML may be used as an auxiliary tool to analyze and process larger datasets and complex data.
RESUMO
OBJECTIVE: To investigate clinicopathological characteristics, surgical treatments, and oncological outcomes of patients with localized primary unifocal urothelial carcinoma involving the ureterovesical junction (UC-UVJ). PATIENTS AND METHODS: Localized primary unifocal UC-UVJ cases in patients admitted to our hospital from March 2013 to August 2021 were reviewed. Clinicopathological parameters, perioperative data, and oncological outcomes were compared between patients grouped by tumor location and surgical treatment. RESULTS: A total of 130 patients with localized primary unifocal UC-UVJ were enrolled in this study. These included 72 cases of bladder cancer (BC) involving the ureteral orifice, and 58 cases of upper urinary tract urothelial carcinoma (UTUC) involving the intramural ureter. The proportion of male patients, hydronephrosis, flank pain/abdominal pain, and tumor size differed significantly between the BC and UTUC groups (all P < 0.05). During the median follow-up period of 32.9 months, 49 cases (37.7%) recurred and 29 (22.3%) died from urothelial carcinoma (UC), though no statistical difference in recurrence (P = 0.436) or cancer-specific mortality (P = 0.653) was observed between the BC and UTUC groups. Cox proportional hazards regression analysis identified age, tumor grade, and lymphovascular invasion (LVI) as independent predictors of cancer-specific survival (CSS), and sex, T stage, tumor grade, and LVI as independent predictors of recurrence-free survival (RFS). CONCLUSION: Owing to positional properties, patients with localized primary unifocal UC-UVJ exhibited significant heterogeneity, leading to varied treatment strategies. No statistically significant differences in CSS or RFS were observed between the BC and UTUC groups. Furthermore, age, sex, T stage, tumor grade, and LVI should be carefully considered in clinical practice because of their associations with CSS and RFS.
Assuntos
Carcinoma de Células de Transição , Ureter , Neoplasias Ureterais , Neoplasias da Bexiga Urinária , Humanos , Masculino , Ureter/cirurgia , Ureter/patologia , Carcinoma de Células de Transição/patologia , Neoplasias da Bexiga Urinária/cirurgia , Neoplasias da Bexiga Urinária/patologia , Nefrectomia , Neoplasias Ureterais/patologia , Estudos Retrospectivos , PrognósticoRESUMO
Photothermal superhydrophobic surfaces are one of the most promising anti-/deicing materials, yet they are limited by the low energy density and intermittent nature of solar energy. Here, a coupling solution based on microencapsulated phase change materials (MPCMs) that integrates photothermal effect and phase change thermal storage is proposed. Dual-shell octahedral MPCMs with Cu2 O as the first layer and 3D Cu2-x S as the second layer for the first time is designed. By morphology and phase manipulation of the Cu2-x S shell, the local surface plasmonic heating modulation of MPCMs is realized, and the MPCM reveals full-spectrum high absorption with a photothermal conversion efficiency up to 96.1%. The phase change temperature and enthalpy remain in good consistency after 200 cycles. Multifunctional photothermal phase-change superhydrophobic composite coatings are fabricated by combining the hydrolyzed and polycondensation products of octadecyl trichlorosilane and the dual-shell MPCM. The multifunctional coatings exhibit excellent anti-/deicing performance under low temperature and high humidity conditions. This work not only provides a new approach for the design of high-performance MPCMs but also opens up an avenue for the anti-icing application of photothermal phase-change superhydrophobic composite coatings.
RESUMO
The design and development of high-performance and long-life Pt-free catalysts for the oxygen reduction reaction (ORR) is of great important with respect to metal-air batteries and fuel cells. Herein, a new low-cost covalent organic frameworks (COFs)-derived CoNC single-atoms catalyst (SAC) is fabricated and compared with the engineered nanoparticle (NP) counterpart for ORR activity. The ORR performance of the SAC catalyst (CoSA@NC) surpasses the NP counterpart (CoNP-NC) under the same operation condition. CoSA@NC also achieves improved long-term durability and better methanol tolerance compared with the Pt/C. The zinc-air battery assembled by the CoSA@NC cathode delivers a higher power density and energy density than that of commercial Pt/C catalyst. Molecular dynamics (MD) is performed to explain the spontaneous evolution from clusters to single-atom metal configuration and density functional theory (DFT) calculations find that CoSA@NC possesses lower d-band center, resulting in weaker interaction between the surface and the O-containing intermediates. Consequently, the reductive desorption of OH*, the rate-determine step, is further accelerated.
RESUMO
The tumor suppressor p53 has been described to control various aspects of metabolic reprogramming in solid tumors, but in B cell malignancies that role is as yet unknown. We generated pairs of p53 functional and knockout (KO) clones from distinct B cell malignancies (acute lymphoblastic leukemia, chronic lymphocytic leukemia, diffuse large B cell lymphoma, and multiple myeloma). Metabolomics and isotope tracing showed that p53 loss did not drive a common metabolic signature. Instead, cell lines segregated according to cell of origin. Next, we focused on glutamine as a crucial energy source in the B cell tumor microenvironment. In both TP53 wild-type and KO cells, glutamine deprivation induced cell death through the integrated stress response, via CHOP/ATF4. Lastly, combining BH3 mimetic drugs with glutamine starvation emerged as a possibility to target resistant clones. In conclusion, our analyses do not support a common metabolic signature of p53 deficiency in B cell malignancies and suggest therapeutic options for exploration based on glutamine dependency.
RESUMO
In this study, polysaccharides (RRTPs) were extracted from Rosa roxburghii Tratt pomace by hot water or ultrasound (US)-assisted extraction. The structural properties and potential prebiotic functions of RRTPs were investigated. Structural characterization was conducted through HPAEC, HPGPC, GC-MS, FT-IR and SEM. Chemical composition analysis revealed that RRTPs extracted by hot water (RRTP-HW) or US with shorter (RRTP-US-S) or longer duration (RRTP-US-L) all consisted of galacturonic acid, galactose, glucose, arabinose, rhamnose and glucuronic acid in various molar ratio. US extraction caused notable reduction in molecular weight of RRTPs but no significant changes in primary structures. Fecal fermentation showed RRTPs could reshape microbial composition toward a healthier balance, leading to a higher production of beneficial metabolites including total short-chain fatty acids, curcumin, noopept, spermidine, 3-feruloylquinic acid and citrulline. More beneficial shifts in bacterial population were observed in RRTP-HW group, while RRTP-US-S had stronger ability to stimulate bacterial short-chain fatty acids production. Additionally, metabolic profiles with the intervention of RRTP-HW, RRTP-US-S or RRTP-US-L were significantly different from each other. The results suggested RRTPs had potential prebiotic effects which could be modified by power US via molecular weight degradation.
Assuntos
Polissacarídeos , Prebióticos , Rosa , Rosa/química , Polissacarídeos/química , Polissacarídeos/isolamento & purificação , Peso Molecular , Ondas Ultrassônicas , Fermentação , Fracionamento Químico/métodosRESUMO
Human aging is marked by the emergence of a tapestry of clonal expansions in dividing tissues, particularly evident in blood as clonal hematopoiesis (CH). CH, linked to cancer risk and aging-related phenotypes, often stems from somatic mutations in a set of established genes. However, the majority of clones lack known drivers. Here we infer gene-level positive selection in whole blood exomes from 200,618 individuals in UK Biobank. We identify 17 additional genes, ZBTB33, ZNF318, ZNF234, SPRED2, SH2B3, SRCAP, SIK3, SRSF1, CHEK2, CCDC115, CCL22, BAX, YLPM1, MYD88, MTA2, MAGEC3 and IGLL5, under positive selection at a population level, and validate this selection pattern in 10,837 whole genomes from single-cell-derived hematopoietic colonies. Clones with mutations in these genes grow in frequency and size with age, comparable to classical CH drivers. They correlate with heightened risk of infection, death and hematological malignancy, highlighting the significance of these additional genes in the aging process.
Assuntos
Hematopoiese Clonal , Mutação , Humanos , Hematopoiese Clonal/genética , Envelhecimento/genética , Idoso , Seleção Genética , Masculino , Pessoa de Meia-Idade , Adulto , Feminino , Exoma/genéticaRESUMO
Refractory high-entropy alloys (RHEAs) are of interest for ultrahigh-temperature applications. To overcome their drawbacks - low-temperature brittleness and poor creep strength at high temperatures - improved fundamental understanding is needed. Using experiments, theory, and modeling, we investigated prototypical body-centered cubic (BCC) RHEAs, TiZrHfNbTa and VNbMoTaW. The former is compressible to 77 K, whereas the latter is not below 298 K. Hexagonal close-packed (HCP) elements in TiZrHfNbTa lower its dislocation core energy, increase lattice distortion, and lower its shear modulus relative to VNbMoTaW whose elements are all BCC. Screw dislocations dominate TiZrHfNbTa plasticity, but equal numbers of edges and screws exist in VNbTaMoW. Dislocation cores are compact in VNbTaMoW and extended in TiZrHfNbTa, and different macroscopic slip planes are activated in the two RHEAs, which we attribute to the concentration of HCP elements. Our findings demonstrate how ductility and strength can be controlled through the ratio of HCP to BCC elements in RHEAs.