RESUMEN
The asymmetrical distribution of auxin supports high intensity blue light (HBL)-mediated phototropism. Flavonoids, secondary metabolites induced by blue light and TRANSPARENT TESTA GLABRA1 (TTG1), alter auxin transport. However, the role of TTG1 in HBL-induced phototropism in Arabidopsis (Arabidopsis thaliana) remains unclear. We found that TTG1 regulates HBL-mediated phototropism. HBL-induced degradation of CRYPTOCHROME 1 (CRY1) was repressed in ttg1-1, and depletion of CRY1 rescued the phototropic defects of the ttg1-1 mutant. Moreover, overexpression of CRY1 in a cry1 mutant background led to phototropic defects in response to HBL. These results indicated that CRY1 is involved in the regulation of TTG1-mediated phototropism in response to HBL. Further investigation showed that TTG1 physically interacts with CRY1 via its N-terminus and that the added TTG1 promotes the dimerization of CRY1. The interaction between TTG1 and CRY1 may promote HBL-mediated degradation of CRY1. TTG1 also physically interacted with blue light inhibitor of cryptochrome 1 (BIC1) and Light-Response Bric-a-Brack/Tramtrack/Broad 2 (LRB2), and these interactions either inhibited or promoted their interaction with CRY1. Exogenous gibberellins (GA) and auxins, two key plant hormones that crosstalk with CRY1, may confer the recovery of phototropic defects in the ttg1-1 mutant and CRY1-overexpressing plants. Our results revealed that TTG1 participates in the regulation of HBL-induced phototropism by modulating CRY1 levels, which are coordinated with GA or IAA signaling.
RESUMEN
CD25, also known as the interleukin-2 receptor α chain (IL-2Rα), is highly expressed on regulatory T cells (Tregs), but relatively lower on effector T cells (Teffs). This makes it a potential target for Treg depletion, which can be used in tumor immunotherapy. However, marketed anti-CD25 antibodies (Basiliximab and Daclizumab) were originally developed as immunosuppressive drugs to prevent graft rejection, because these antibodies can block IL-2 binding to CD25 on Teffs, which in turn destroys the function of Teffs. Recent studies have shown that non-IL-2-blocking anti-CD25 antibodies have displayed exciting antitumor effects. Here, we screened out a non-IL-2-blocking anti-CD25 monoclonal antibody (mAb) 7B7 by hybridoma technology, and confirmed its antitumor activity via depleting Tregs in a CD25 humanized mouse model. Subsequently, we verified that the humanized 7B7, named as h7B7-15S, has comparable activities to 7B7, and that its Treg depletion is further increased when combined with anti-CTLA-4, leading to enhanced remodeling of the tumor immune microenvironment. Moreover, our findings reveal that the Fab form of h7B7-15S has the ability to deplete Tregs, independent of the Fc region. Taken together, our studies expand the application of anti-CD25 in tumor immunotherapy and provide insight into the underlying mechanism.
Asunto(s)
Anticuerpos Monoclonales , Neoplasias , Ratones , Animales , Subunidad alfa del Receptor de Interleucina-2/metabolismo , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéutico , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Inmunosupresores , Linfocitos T Reguladores , Microambiente TumoralRESUMEN
BACKGROUND: Leukemia inhibitory factor (LIF) is a multifunctional member of the IL-6 cytokine family that activates downstream signaling pathways by binding to the heterodimer consisting of LIFR and gp130 on the cell surface. Previous research has shown that LIF is highly expressed in various tumor tissues (e.g. pancreatic cancer, breast cancer, prostate cancer, and colorectal cancer) and promotes cancer cell proliferation, migration, invasion, and differentiation. Moreover, the overexpression of LIF correlates with poor clinicopathological characteristics. Therefore, we hypothesized that LIF could be a promising target for the treatment of cancer. In this work, we developed the antagonist antibody 1G11 against LIF and investigated its anti-tumor mechanism and its therapeutic efficacy in mouse models. RESULTS: A series of single-chain variable fragments (scFvs) targeting LIF were screened from a naive human scFv phage library. These scFvs were reconstructed in complete IgG form and produced by the mammalian transient expression system. Among the antibodies, 1G11 exhibited the excellent binding activity to human, cynomolgus monkey and mouse LIF. Functional analysis demonstrated 1G11 could block LIF binding to LIFR and inhibit the intracellular STAT3 phosphorylation signal. Interestingly, 1G11 did not block LIF binding to gp130, another LIF receptor that is involved in forming the receptor complex together with LIFR. In vivo, intraperitoneal administration of 1G11 inhibited tumor growth in CT26 and MC38 models of colorectal cancer. IHC analysis demonstrated that p-STAT3 and Ki67 were decreased in tumor tissue, while c-caspase 3 was increased. Furthermore, 1G11 treatment improves CD3+, CD4 + and CD8 + T cell infiltration in tumor tissue. CONCLUSIONS: We developed antagonist antibodies targeting LIF/LIFR signaling pathway from a naive human scFv phage library. Antagonist anti-LIF antibody exerts antitumor effects by specifically reducing p-STAT3. Further studies revealed that anti-LIF antibody 1G11 increased immune cell infiltration in tumor tissues.
Asunto(s)
Factor Inhibidor de Leucemia , Anticuerpos de Cadena Única , Animales , Humanos , Anticuerpos de Cadena Única/inmunología , Anticuerpos de Cadena Única/farmacología , Ratones , Factor Inhibidor de Leucemia/inmunología , Factor Inhibidor de Leucemia/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Factor de Transcripción STAT3/metabolismo , Factor de Transcripción STAT3/inmunología , Receptor gp130 de Citocinas/inmunología , Receptor gp130 de Citocinas/metabolismo , Receptor gp130 de Citocinas/antagonistas & inhibidores , Biblioteca de Péptidos , Transducción de Señal , Femenino , Macaca fascicularis , Ratones Endogámicos BALB C , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Insect-induced plant volatile organic compounds (VOCs) may function as either direct defence molecules to deter insects or indirect defence signals to attract the natural enemies of the invading insects. Tea (Camellia sinensis L.), an important leaf-based beverage crop, is mainly infested by Ectropis obliqua which causes the most serious damage. Here, we report a mechanistic investigation of tea plant-derived VOCs in an indirect defence mechanism against E. obliqua. Parasitoid wasp Parapanteles hyposidrae, a natural enemy of E. obliqua, showed strong electrophysiological response and selection behaviour towards S-linalool and ß-ocimene, two monoterpenes with elevated emission from E. obliqua-damaged tea plants. Larvae frass of E. obliqua, which also released S-linalool and ß-ocimene, was found to attract both mated female or male Pa. hyposidrae according to gas chromatography-electroantennogram detection and Y-tube olfactometer assays. In a field setting, both S-linalool and ß-ocimene were effective in recruiting both female and male Pa. hyposidrae wasps. To understand the molecular mechanism of monoterpenes-mediated indirect defence in tea plants, two novel monoterpene synthase genes, CsLIS and CsOCS-SCZ, involved in the biosynthesis of S-linalool or ß-ocimene, respectively, were identified and biochemically characterised. When the expression of these two genes in tea plants was inhibited by antisense oligodeoxynucleotide, both volatile emission and attraction of wasps were reduced. Furthermore, gene expression analysis suggested that the expression of CsLIS and CsOCS-SCZ is regulated by the jasmonic acid signalling pathway in the tea plant.
Asunto(s)
Monoterpenos Acíclicos , Alquenos , Camellia sinensis , Mariposas Nocturnas , Avispas , Animales , Monoterpenos , Camellia sinensis/genética , Señales (Psicología) , Mariposas Nocturnas/fisiología , Insectos , TéRESUMEN
Achieving high-efficiency tunable emission in a single phosphor remains a significant challenge. Herein, we report a series of Sb3+-doped all-inorganic double perovskites, Sb3+:Cs2NaScCl6, with efficient excitation-dependent emission. In 0.5%Sb3+:Cs2NaScCl6, strong blue emission with a high photoluminescence quantum yield (PLQY) of 85% is obtained under 265 nm light irradiation, which turns into bright neutral white light with a PLQY of 56% when excited at 303 nm. Spectroscopic and computational investigations were performed to reveal the mechanism of this excitation-dependent emission. Sb3+ doping induces two different excitation channels: the internal transition of Sb3+: 5s2 â 5s5p and the electron transfer transition of Sb3+: 5s â Sc3+ 3d. The former one generates excited Sb3+ ions, which can undergo efficient energy transfer to populate the host self-trapped exciton (STE) state, yielding enhanced blue emission. The latter one leads to the formation of a new STE state with the hole localized on Sb3+ and the electron delocalized on the nearest Sc3+, which accounts for the newly exhibited low-energy emission. The difference in the excitation pathways of the two emitting STE states results in the highly efficient excitation-dependent emission, making the doped systems promising anticounterfeiting materials.
RESUMEN
Monoacylglycerol lipase (MAGL) is a key enzyme responsible for the metabolism of the endocannabinoid 2-arachidonoylglycerol (2-AG), and has attracted great interest due to its involvement in various physiological and pathological processes, such as cancer progression. In the past, a number of covalent irreversible inhibitors have been reported for MAGL, however, experimental evidence highlighted some drawbacks associated with the use of these irreversible agents. Therefore, efforts were mainly focused on the development of reversible MAGL inhibitor in recent years. Here, we designed and synthesized a series of naphthyl amide derivatives (12-39) as another type of reversible MAGL inhibitors, exemplified by ± 34, which displayed good MAGL inhibition with a pIC50 of 7.1, and the potency and selectivity against endogenous MAGL were further demonstrated by competitive ABPP. Moreover, the compound showed appreciable antiproliferative activities against several cancer cells, including H460, HT29, CT-26, Huh7 and HCCLM-3. The investigations culminated in the discovery of the naphthyl amide derivative ± 34, and it may represent as a new scaffold for MAGL inhibitor development, particularly for the reversible ones.
Asunto(s)
Amidas , Antineoplásicos , Proliferación Celular , Diseño de Fármacos , Inhibidores Enzimáticos , Monoacilglicerol Lipasas , Monoacilglicerol Lipasas/antagonistas & inhibidores , Monoacilglicerol Lipasas/metabolismo , Humanos , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Amidas/química , Amidas/farmacología , Amidas/síntesis química , Relación Estructura-Actividad , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Estructura Molecular , Ensayos de Selección de Medicamentos Antitumorales , Naftalenos/farmacología , Naftalenos/síntesis química , Naftalenos/química , Relación Dosis-Respuesta a Droga , Simulación del Acoplamiento MolecularRESUMEN
The role of Dy-S coordination in a single-molecule magnet (SMM) is investigated via an ab initio study in a group of mononuclear structures. The SMM performance of this group is well interpreted via a concise criterion consisting of long quantum tunneling of magnetization (QTM) time τQTM and high effective barrier for magnetic reversal Ueff. The best SMMs in the selected group, i.e., 1Dy (CCDC refcode: PUKFAF) and 2Dy (CCDC refcode: NIKSEJ), are just those holding the longest τQTM and the highest Ueff simultaneously. Further analysis based on the crystal field model and ab initio magneto-structural exploration indicates that the influence of Dy-S coordination on the SMM performance of 1Dy is weaker than that of axial Dy-O coordination. Thus, Dy-S coordination is more likely to play an auxiliary role rather than a dominant one. However, if placed at the suitable equatorial position, Dy-S coordination could provide important support for good SMM performance. Consequently, starting from 1Dy, we built two new structures where Dy-S coordination only exists at the equatorial position and two axial positions are occupied by strong Dy-O/Dy-F coordination. Compared to 1Dy and 2Dy, these new ones are predicted to have significantly longer τQTM and higher Ueff, as well as a nearly doubled blocking temperature TB. Thus, they are probable candidates of SMM having clearly improved performance.
RESUMEN
KEY MESSAGE: CmMYB308 was identified as a key regulator in chrysanthemum flower color variation from purple to pink by conducting transcriptome and metabolome analysis. CmMYB308 can inhibit anthocyanin biosynthesis by suppressing the expression of CmPAL, CmC4H, and Cm4CL. Flower color variation is a widespread natural occurrence that plays a significant role in floral breeding. We discovered a variation in the flower of the chrysanthemum cultivar 'Dante Purple' (abbreviated as 'DP'), where the flower color shifted from purple to pink. We successfully propagated these pink flowers through tissue culture and designated them as DPM. By conducting transcriptome and metabolome analysis, we identified a reduction in the expression of critical genes involved in anthocyanin biosynthesis-CmPAL, CmC4H, and Cm4CL-in the DPM. This downregulation led to an accumulation of phenylalanine and cinnamic acid within the general phenylpropanoid pathway (GPP), which prevented their conversion into cyanidin and cyanidin 3-glucoside. As a result, the flowers turned pink. Additional transformation and biochemical experiments confirmed that the upregulation of CmMYB308 gene expression in the DPM directly suppressed CmPAL-1 and CmC4H genes, which indirectly affected Cm4CL-3 expression and ultimately inhibited anthocyanin biosynthesis in the DPM. This study offers a preliminary insight into the molecular mechanism underlying chrysanthemum flower color mutation, paving the way for genetic improvements in chrysanthemum flower color breeding.
Asunto(s)
Antocianinas , Chrysanthemum , Flores , Regulación de la Expresión Génica de las Plantas , Pigmentación , Proteínas de Plantas , Chrysanthemum/genética , Chrysanthemum/metabolismo , Flores/genética , Flores/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Antocianinas/metabolismo , Pigmentación/genética , Transcriptoma/genética , Metabolómica/métodos , Metaboloma/genética , Perfilación de la Expresión Génica , Color , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
BACKGROUND: Oxidative stress is closely related to gut health. Exposures to oxidative stress in one's diet and lifestyle can be evaluated by the oxidative balance score (OBS). However, the relationship between OBS and intestinal habits is unknown. This study aimed to investigate the relationships between OBS and intestinal habits (chronic diarrhea and chronic constipation) and the underlying mechanisms involved. METHODS: Using data from the National Health and Nutrition Examination Survey (NHANES) database from 2005 to 2010, we included a total of 8065 participants. Twenty dietary and lifestyle factors were selected for the OBS calculates. Chronic constipation and chronic diarrhea were defined using the Bristol stool form scale (BSFS) types 1 and 2 and the BSFS 6 and 7, respectively. Multivariate logistic regression, subgroup analysis, and restricted cubic splines (RCS) analysis were used to evaluate the relationship between OBS and defecation habits. Finally, we used mediation analysis to explore the indirect effects of oxidative stress and inflammatory markers on these associations. RESULTS: After adjusting for all the covariates, multivariate logistic regression analysis revealed that OBS was negatively correlated with diarrhea (OR = 0.57; 95%CI = 0.39-0.83; P = 0.008)and positively correlated with constipation (OR = 1.75; 95%CI = 1.19-2.25; P = 0.008). The RCS showed a nonlinear relationship between OBS and diarrhea (P for nonlinearity = 0.02) and a linear relationship between OBS and constipation (P for nonlinearity = 0.19). Mediation analysis showed that the C-reactive protein (CRP) concentration and white blood cell (WBC) count mediated the correlation between OBS and diarrhea by 6.28% and 6.53%, respectively (P < 0.05). CONCLUSIONS: OBS is closely related to changes in patients' defecation habits. Oxidative stress and inflammation may play a role in the relationship between the two. This result emphasizes the importance of the public adjusting their lifestyle and dietary habits according to their own situation. However, further prospective studies are needed to analyze the relationship between oxidative stress and changes in defecation habits.
Asunto(s)
Estreñimiento , Diarrea , Encuestas Nutricionales , Estrés Oxidativo , Humanos , Estreñimiento/epidemiología , Estrés Oxidativo/fisiología , Femenino , Diarrea/epidemiología , Masculino , Persona de Mediana Edad , Adulto , Enfermedad Crónica , Estilo de Vida , Anciano , Estudios TransversalesRESUMEN
BACKGROUND: Although sorafenib has been consistently used as a first-line treatment for advanced hepatocellular carcinoma (HCC), most patients will develop resistance, and the mechanism of resistance to sorafenib needs further study. METHODS: Using KAS-seq technology, we obtained the ssDNA profiles within the whole genome range of SMMC-7721 cells treated with sorafenib for differential analysis. We then intersected the differential genes obtained from the analysis of hepatocellular carcinoma patients in GSE109211 who were ineffective and effective with sorafenib treatment, constructed a PPI network, and obtained hub genes. We then analyzed the relationship between the expression of these genes and the prognosis of hepatocellular carcinoma patients. RESULTS: In this study, we identified 7 hub ERGs (ACTB, CFL1, ACTG1, ACTN1, WDR1, TAGLN2, HSPA8) related to drug resistance, and these genes are associated with the cytoskeleton. CONCLUSIONS: The cytoskeleton is associated with sorafenib resistance in hepatocellular carcinoma. Using KAS-seq to analyze the early changes in tumor cells treated with drugs is feasible for studying the drug resistance of tumors, which provides reference significance for future research.
Asunto(s)
Antineoplásicos , Carcinoma Hepatocelular , Resistencia a Antineoplásicos , Neoplasias Hepáticas , Sorafenib , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Humanos , Sorafenib/farmacología , Sorafenib/uso terapéutico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Resistencia a Antineoplásicos/genética , Pronóstico , Antineoplásicos/uso terapéutico , Antineoplásicos/farmacología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Citoesqueleto/efectos de los fármacos , Citoesqueleto/patología , Citoesqueleto/metabolismo , Biomarcadores de Tumor/genética , Células Tumorales Cultivadas , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Perfilación de la Expresión GénicaRESUMEN
OBJECTIVE: To investigate the content of rare earth elements(REs)in blood and hair of residents in a RE mining area in Northwest Hubei, and evaluate the impact of REs on the health status of local residents. METHODS: A total of 191 residents from the core area of RE mining areas and 186 residents from non RE mining areas, aged 20-69, were selected. The content of REs in the blood and hair of the survey subjects was measured using inductively coupled plasma mass spectrometry, and compared with existing literature values. At the same time, blood tests and questionnaire surveys will be conducted on the health status of residents to examine whether human RE enrichment can lead to endemic diseases. RESULTS: The average total content of REs in the blood of residents in the mining area was 60.22 ng/mL, which was 3.35 times that of the control area; The average total content of REs in hair was 1197.91 ng/g, which was 6.32 times higher than the control area. As age increasing, the abundance of REs in the blood and hair of both men and women in mining areas increased. The proportion of Yttrium and Scandium in the blood and hair were much higher than that in the soil. Compared to hair, Yttrium and Scandium were more easily enriched in the blood. There was no significant difference in the probability of fatty liver, hepatitis B, hypoglycemia, hypotension, hypertension and heart disease and the average life span between residents in RE mining areas and those in the control area. CONCLUSION: The high daily average dietary intake of REs in residents leads to a relatively large accumulation of REs in human blood and hair, but no significant and substantial human health damage has been found at present.
Asunto(s)
Hipertensión , Metales de Tierras Raras , Masculino , Humanos , Femenino , Escandio/análisis , Metales de Tierras Raras/análisis , Cabello/química , Itrio/análisis , China , Monitoreo del AmbienteRESUMEN
Gibberellin (GA) is an important plant hormone that is involved in various physiological processes during plant development. Sweet cherries planted in southern China have always encountered difficulty in bearing fruit. In recent years, gibberellin has successfully solved this problem, but there has also been an increase in malformed fruits. This study mainly explores the mechanism of malformed fruit formation in sweet cherries. By analyzing the synthesis pathway of gibberellin using metabolomics and transcriptomics, the relationship between gibberellin and the formation mechanism of deformed fruit was preliminarily determined. The results showed that the content of GA3 in malformed fruits was significantly higher than in normal fruits. The differentially expressed genes in the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway were mainly enriched in pathways such as "plant hormone signal transduction", "diterpenoid biosynthesis", and "carotenoid biosynthesis". Using Quantitative Real-Time Reverse Transcription PCR (qRT-PCR) analysis, the gibberellin hydrolase gene GA2ox and gibberellin synthase genes GA20ox and GA3ox were found to be significantly up-regulated. Therefore, we speculate that the formation of malformed fruits in sweet cherries may be related to the accumulation of GA3. This lays the foundation for further research on the mechanism of malformed sweet cherry fruits.
Asunto(s)
Prunus avium , Prunus avium/genética , Transcriptoma , Frutas/genética , Reguladores del Crecimiento de las Plantas , Giberelinas , Metaboloma , ChinaRESUMEN
Projector video compensation aims to cancel the geometric and photometric distortions caused by non-ideal projection surfaces and environments when projecting videos. Most existing projector compensation methods start by projecting and capturing a set of sampling images, followed by an offline compensation model training step. Thus, abundant user effort is required before the users can watch the video. Moreover, the sampling images have little prior knowledge of the video content and may lead to suboptimal results. To address these issues, this paper builds a video compensation system that can online adapt the compensation parameters. Our approach consists of five threads and can perform compensation, projection, capturing, and short-term and long-term model updates in parallel. Due to the parallel mechanism, rather than projecting and capturing hundreds of sampling images and training the model offline, we can directly use the projected and captured video frames for model updates on the fly. To quickly apply to the new environment, we introduce a deep learning-based compensation model that integrates a fixed transformer-based method and a novel CNN-based network. Moreover, for fast convergence and to reduce error accumulation during fine-tuning, we present a strategy that cooperates with short-term and long-term memory model updates. Experiments show that it significantly outperforms state-of-the-art baselines.
RESUMEN
Bispecific antibodyâdrug conjugates (BsADCs) represent an innovative therapeutic category amalgamating the merits of antibodyâdrug conjugates (ADCs) and bispecific antibodies (BsAbs). Positioned as the next-generation ADC approach, BsADCs hold promise for ameliorating extant clinical challenges associated with ADCs, particularly pertaining to issues such as poor internalization, off-target toxicity, and drug resistance. Presently, ten BsADCs are undergoing clinical trials, and initial findings underscore the imperative for ongoing refinement. This review initially delves into specific design considerations for BsADCs, encompassing target selection, antibody formats, and the linker-payload complex. Subsequent sections delineate the extant progress and challenges encountered by BsADCs, illustrated through pertinent case studies. The amalgamation of BsAbs with ADCs offers a prospective solution to prevailing clinical limitations of ADCs. Nevertheless, the symbiotic interplay among BsAb, linker, and payload necessitates further optimizations and coordination beyond a simplistic "1 + 1" to effectively surmount the extant challenges facing the BsADC domain.
RESUMEN
Traditional clinical diagnoses relying on symptoms may overlook latent factors that illuminate mechanisms and potentially guide treatment. The Operationalized Psychodynamic Diagnosis (OPD) system may compensate for symptom-based diagnosis by measuring psychodynamic profiles underlying mental disorders through conflicts and structure axes. However, OPD has not been widely adopted in China, and it remains unclear whether OPD can be used as an effective approach to distinguish between depression and anxiety. The current study aims to adopt the OPD system to investigate the psychodynamic profiles of major depressive disorder (MDD) and generalized anxiety disorder (GAD) in China, targeting patients with "pure" symptoms without comorbidity. We recruited 42 MDD patients, 32 GAD patients, and 31 healthy controls (HC), and assessed their self-report depression and anxiety symptoms, along with their underlying psychodynamic profiles through OPD interviews. Overall, both MDD and GAD patients showed more prominent conflict issues and lower levels of structure than HC. The MDD and GAD groups yielded different conflict profiles and conflict processing modes when processing their second conflicts. Importantly, the multi-dimensional psychodynamic profiles achieved machine learning classification of clinical groups with an accuracy of 0.84, supporting successful distinction of MDD and GAD patients. In conclusion, the OPD demonstrated sensitivity in revealing distinct psychodynamic profiles underlying "pure" depression and anxiety clinical populations in China. This work calls for future incorporation of OPD as a tool to investigate psychodynamic formulations underlying mental disorders, compensating for traditional symptom-based diagnostic approaches to guide precise individualized interventions.
RESUMEN
Biodiversity plays a pivotal role in sustaining ecosystem processes, encompassing diverse biological species, genetic types and the intricacies of ecosystem composition. However, the precise definition of biodiversity at the individual level remains a challenging endeavour. Hill numbers, derived from Rényi's entropy, have emerged as a popular measure of diversity, with a recent unified framework extending their application across various levels, from genetics to ecosystems. In this study, we employ a computational approach to exploring the diversity of mitochondrial heteroplasmy using real-world data. By adopting Hill numbers with q = 2, we demonstrate the feasibility of quantifying mitochondrial heteroplasmy diversity within and between individuals and populations. Furthermore, we investigate the alpha diversity of mitochondrial heteroplasmy among different species, revealing heterogeneity at multiple levels, including mitogenome components and protein-coding genes (PCGs). Our analysis explores large-scale mitochondrial heteroplasmy data in humans, examining the relationship between alpha diversity at the mitogenome components and PCGs level. Notably, we do not find a significant correlation between these two levels. Additionally, we observe significant correlations in alpha diversity between mothers and children in blood samples, exceeding the reported R2 value for allele frequency correlations. Moreover, our investigation of beta diversity and local overlay similarity demonstrates that heteroplasmy variant distributions in different tissues of children more closely resemble those of their mothers. Through systematic quantification and analysis of mitochondrial heteroplasmy diversity, this study enhances our understanding of heterogeneity at multiple levels, from individuals to populations, providing new insights into this fundamental dimension of biodiversity.
Asunto(s)
Ecosistema , Heteroplasmia , Niño , Humanos , Mitocondrias/genética , Biodiversidad , ADN Mitocondrial/genéticaRESUMEN
Source-free domain adaptation has developed rapidly in recent years, where the well-trained source model is adapted to the target domain instead of the source data, offering the potential for privacy concerns and intellectual property protection. However, a number of feature alignment techniques in prior domain adaptation methods are not feasible in this challenging problem setting. Thereby, we resort to probing inherent domain-invariant feature learning and propose a curriculum-style self-training approach for source-free domain adaptive semantic segmentation. In particular, we introduce a curriculum-style entropy minimization method to explore the implicit knowledge from the source model, which fits the trained source model to the target data using certain information from easy-to-hard predictions. We then train the segmentation network by the proposed complementary curriculum-style self-training, which utilizes the negative and positive pseudo labels following the curriculum-learning manner. Although negative pseudo-labels with high uncertainty cannot be identified with the correct labels, they can definitely indicate absent classes. Moreover, we employ an information propagation scheme to further reduce the intra-domain discrepancy within the target domain, which could act as a standard post-processing method for the domain adaptation field. Furthermore, we extend the proposed method to a more challenging black-box source model scenario where only the source model's predictions are available. Extensive experiments validate that our method yields state-of-the-art performance on source-free semantic segmentation tasks for both synthetic-to-real and adverse conditions datasets. The code and corresponding trained models are released at https://github.com/yxiwang/ATP.
RESUMEN
In vivo real-time detection of hypochlorous acid (HClO) in biological systems plays a crucial role in diagnosing immune-related diseases. Experimentally, a benzo-bodipy probe based on the photo-induced electron transfer (PeT) sensing mechanism has been developed for live fluorescence imaging. However, there have been no theoretical studies conducted to substantiate the precision of the sensing mechanism. This paper employs density functional theory (DFT) and time-dependent density functional theory (TDDFT) methods to investigate the fluorescence detection mechanism of benzo-bodipy derivatives (BBy-T and BBy-TO), proposing a detection approach based on dark nπ* state quenching. The study reveals that the fluorescence quenching mechanism of BBy-T is primarily regulated by a thiomorpholine moiety, involving a dark nπ* state transition non-radiatively. Furthermore, this paper explains the fluorescence enhancement observed in BBy-TO. Theoretical investigations demonstrate, based on frontier molecular orbitals (FMOs) and hole-electron analysis, that the fluorescence enhancement for BBy-TO is not governed by the previously proposed intramolecular charge transfer (ICT) mechanism in experiments but rather follows a locally excited (LE) ππ* pattern. This work offers new insights for the design of novel fluorescence probes based on bodipy and benzo derivatives, expanding the understanding of their fluorescence properties.
RESUMEN
The targeted protein degradation (TPD) technology employing proteolysis-targeting chimeras (PROTACs) has been widely applied in drug chemistry and chemical biology for the treatment of cancer and other diseases. PROTACs have demonstrated significant advantages in targeting undruggable targets and overcoming drug resistance. However, despite the efficient degradation of targeted proteins achieved by PROTACs, they still face challenges related to selectivity between normal and cancer cells, as well as issues with poor membrane permeability due to their substantial molecular weight. Additionally, the noteworthy toxicity resulting from off-target effects also needs to be addressed. To solve these issues, Degrader-Antibody Conjugates (DACs) have been developed, leveraging the targeting and internalization capabilities of antibodies. In this review, we elucidates the characteristics and distinctions between DACs, and traditional Antibody-drug conjugates (ADCs). Meanwhile, we emphasizes the significance of DACs in facilitating the delivery of PROTACs and delves into the impact of various components on DAC activity. These components include antibody targets, drug-antibody ratio (DAR), linker types, PROTACs targets, PROTACs connections, and E3 ligase ligands. The review also explores the suitability of different targets (antibody targets or PROTACs targets) for DACs, providing insights to guide the design of PROTACs better suited for antibody conjugation.
Asunto(s)
Inmunoconjugados , Inmunoconjugados/farmacología , Anticuerpos , Permeabilidad de la Membrana Celular , Química Farmacéutica , Peso Molecular , Proteolisis , Ubiquitina-Proteína LigasasRESUMEN
Discoidin domain receptor 1 (DDR1) is a collagen-activated receptor tyrosine kinase (RTK) and plays pivotal roles in regulating cellular functions such as proliferation, differentiation, invasion, migration, and matrix remodeling. DDR1 is involved in the occurrence and progression of many human diseases, including cancer, fibrosis, and inflammation. Therefore, DDR1 represents a highly promising therapeutic target. Although no selective small-molecule inhibitors have reached clinical trials to date, many molecules have shown therapeutic effects in preclinical studies. For example, BK40143 has demonstrated significant promise in the therapy of neurodegenerative diseases. In this context, our perspective aims to provide an in-depth exploration of DDR1, encompassing its structure characteristics, biological functions, and disease relevance. Furthermore, we emphasize the importance of understanding the structure-activity relationship of DDR1 inhibitors and highlight the unique advantages of dual-target or multitarget inhibitors. We anticipate offering valuable insights into the development of more efficacious DDR1-targeted drugs.