RESUMO
Growing resistance toward ribosome-targeting macrolide antibiotics has limited their clinical utility and urged the search for superior compounds. Macrolones are synthetic macrolide derivatives with a quinolone side chain, structurally similar to DNA topoisomerase-targeting fluoroquinolones. While macrolones show enhanced activity, their modes of action have remained unknown. Here, we present the first structures of ribosome-bound macrolones, showing that the macrolide part occupies the macrolide-binding site in the ribosomal exit tunnel, whereas the quinolone moiety establishes new interactions with the tunnel. Macrolones efficiently inhibit both the ribosome and DNA topoisomerase in vitro. However, in the cell, they target either the ribosome or DNA gyrase or concurrently both of them. In contrast to macrolide or fluoroquinolone antibiotics alone, dual-targeting macrolones are less prone to select resistant bacteria carrying target-site mutations or to activate inducible macrolide resistance genes. Furthermore, because some macrolones engage Erm-modified ribosomes, they retain activity even against strains with constitutive erm resistance genes.
RESUMO
BACKGROUND: Fish scales are typical products of biomineralization and play an important role in the adaptation of fish to their environment. The Gymnocypris przewalskii scales are highly specialized, with scales embedded in only specific parts of the dermis, such as the areas around the anal fin and branchiostegite, making G. przewalskii an ideal material for biomineralization research. In this study, we aimed to unveil genes and pathways controlling scale formation through an integrated analysis of both transcriptome and proteome, of which G. przewalskii tissues of the dorsal skin (no scales) and the rump side skin (with scales) were sequenced. The sequencing results were further combined with cellular experiments to clarify the relationship between genes and signaling pathways. RESULTS: The results indicated the following: (1) a total of 4,904 differentially expressed genes were screened out, including 3,294 upregulated genes and 1,610 downregulated genes (with a filtering threshold of |log2Fold-Change|> 1 and p-adjust < 0.05). The identified differentially expressed genes contained family members such as FGF, EDAR, Wnt10, and bmp. (2) A total of 535 differentially expressed proteins (DEPs) were filtered out from the proteome, with 204 DEPs downregulated and 331 DEPs upregulated (with a filtering threshold of |Fold-Change|> 1.5 and p < 0.05). (3) Integrated analyses of transcriptome and proteome revealed that emefp1, col1a1, col6a2, col16a1, krt8, and krt18 were important genes contributing to scale development and that PI3K-AKT was the most important signaling pathway involved. (4) With the use of the constructed G. przewalskii fibroblast cell line, emefp1, col1a1, col6a2, col16a1, krt8, and krt18 were confirmed to be positively regulated by the PI3K-AKT signaling pathway. CONCLUSION: This study provides experimental evidence for PI3K-AKT controlled scale development in G. przewalskii and would benefit further study on stress adaptation, scale biomineralization, and the development of skin appendages.
Assuntos
Cyprinidae , Transcriptoma , Animais , Proteoma/genética , Fosfatidilinositol 3-Quinases/genética , Proteômica , Proteínas Proto-Oncogênicas c-akt/genética , Perfilação da Expressão Gênica/métodos , Cyprinidae/genéticaRESUMO
Salinity adaptation is an important issue in aquaculture. Understanding the immediate-early response to salinity stress helps in comprehending this process. In vitro experiments using cell lines can explain cell-independent reactions without the involvement of hormones in vivo. In this study, salinity stress experiments were conducted using cell line derived from the gills of Gymnocypris przewalskii (GPG cell line) to isolate immediate-early response-related genes and miRNAs using transcriptomics, followed by bioinformatics analysis. The results showed that intracellular free Ca2+ appeared to be a key factor in cell sensing and initiating downstream cell signaling in response to external salinity. Additionally, cell apoptosis was the most common feature of salinity stress, with multiple signaling pathways involved in salinity-induced cell apoptosis. Furthermore, MiRNAs played a crucial role in the rapid response to salinity stress by selectively inhibiting the expression of specific genes. Additionally, for the first time in the G. przewalskii genome, Tf2 and TY3 families of transposons were found to have responsive roles to the external salinity stress. This study contributes to a better understanding of osmotic sensing in G. przewalskii and provides theoretical assistance for improving salinity adaptation in aquaculture fish species.
Assuntos
Brânquias , MicroRNAs , RNA Mensageiro , Estresse Salino , Animais , MicroRNAs/genética , MicroRNAs/metabolismo , Brânquias/metabolismo , Linhagem Celular , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Perfilação da Expressão Gênica , Apoptose , Transcriptoma , Cyprinidae/genética , Cyprinidae/metabolismo , SalinidadeRESUMO
Asperosaponin VI (ASA VI) is a bioactive triterpenoid saponin extracted from Diptychus roots, of Diptyl, and has previously shown protective functions in rheumatoid arthritis and sepsis. This study investigates the effects and molecular mechanisms of ASA VI on skeletal muscle regeneration in a cardiotoxin (CTX)-induced skeletal muscle injury mouse model. Mice were subjected to CTX-induced injury in the tibialis anterior and C2C12 myotubes were treated with CTX. Muscle fiber histology was analyzed at 7 and 14 days postinjury. Apoptosis and autophagy-related protein expression were evaluated t s by Western blot, and muscle regeneration markers were quantified by quantitative polymerase chain reaction. Docking studies, cell viability assessments, and glycogen synthase kinase-3ß (GSK-3ß) activation analyses were performed to elucidate the mechanism. ASA VI was observed to improve muscle interstitial fibrosis, remodeling, and performance in CTX-treated mice, thereby increased skeletal muscle size, weight, and locomotion. Furthermore, ASA VI modulated the expression of apoptosis and autophagy-related proteins through GSK-3ß inhibition and activated the transcription of regeneration genes. Our results suggest that ASA VI mitigates skeletal muscle injury by modulating apoptosis and autophagy via GSK-3ß signaling and promotes regeneration, thus presenting a probable therapeutic agent for skeletal muscle injury.
Assuntos
Músculo Esquelético , Saponinas , Camundongos , Animais , Glicogênio Sintase Quinase 3 beta/genética , Glicogênio Sintase Quinase 3 beta/metabolismo , Músculo Esquelético/metabolismo , Apoptose , Saponinas/farmacologiaRESUMO
Colitis-associated colorectal cancer (CAC) frequently develops in patients with inflammatory bowel disease (IBD) who have been exposed to a prolonged state of chronic inflammation. The investigation of pharmacological agents and their mechanisms to prevent precancerous lesions and inhibit their progression remains a significant focus and challenge in CAC research. Previous studies have demonstrated that vitexin effectively mitigates CAC, however, its precise mechanism of action warrants further exploration. This study reveals that the absence of the Vitamin D receptor (VDR) accelerates the progression from chronic colitis to colorectal cancer. Our findings indicate that vitexin can specifically target the VDR protein, facilitating its translocation into the cell nucleus to exert transcriptional activity. Additionally, through a co-culture model of macrophages and cancer cells, we observed that vitexin promotes the polarization of macrophages towards the M1 phenotype, a process that is dependent on VDR. Furthermore, ChIP-seq analysis revealed that vitexin regulates the transcriptional activation of phenazine biosynthesis-like domain protein (PBLD) via VDR. ChIP assays and dual luciferase reporter assays were employed to identify the functional PBLD regulatory region, confirming that the VDR/PBLD pathway is critical for vitexin-mediated regulation of macrophage polarization. Finally, in a mouse model with myeloid VDR gene knockout, we found that the protective effects of vitexin were abolished in mid-stage CAC. In summary, our study establishes that vitexin targets VDR and modulates macrophage polarization through the VDR/PBLD pathway, thereby alleviating the transition from chronic colitis to colorectal cancer.
Assuntos
Apigenina , Neoplasias Colorretais , Macrófagos , Receptores de Calcitriol , Apigenina/farmacologia , Receptores de Calcitriol/metabolismo , Receptores de Calcitriol/agonistas , Receptores de Calcitriol/genética , Animais , Camundongos , Humanos , Neoplasias Colorretais/patologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/tratamento farmacológico , Macrófagos/metabolismo , Macrófagos/efeitos dos fármacos , Modelos Animais de Doenças , Colite/tratamento farmacológico , Colite/patologia , Colite/metabolismo , Colite/induzido quimicamente , Progressão da Doença , Células RAW 264.7 , Camundongos Endogâmicos C57BLRESUMO
Current immune checkpoint inhibiters (ICIs) have contrasting clinical results in poorly immunogenic cancers such as microsatellite-stable colorectal cancer (MSS-CRC). Therefore, understanding and developing the combinational therapeutics for ICI-unresponsive cancers is critical. Here, we demonstrated that the novel topoisomerase I inhibitor TLC388 can reshape the tumor immune landscape, corroborating their antitumor effects combined with radiotherapy as well as immunotherapy. We found that TLC388 significantly triggered cytosolic single-stranded DNA (ssDNA) accumulation for STING activation, leading to type I interferons (IFN-Is) production for increased cancer immunogenicity to enhance antitumor immunity. TLC388-treated tumors were infiltrated by a vast number of dendritic cells, immune cells, and costimulatory molecules, contributing to the favorable antitumor immune response within the tumor microenvironment. The infiltration of cytotoxic T and NK cells were more profoundly existed within tumors in combination with radiotherapy and ICIs, leading to superior therapeutic efficacy in poorly immunogenic MSS-CRC. Taken together, these results showed that the novel topoisomerase I inhibitor TLC388 increased cancer immunogenicity by ssDNA/STING-mediated IFN-I production, enhancing antitumor immunity for better therapeutic efficacy in combination with radiotherapy and ICIs for poorly immunogenic cancer.
Assuntos
Camptotecina/análogos & derivados , Neoplasias Colorretais , Inibidores da Topoisomerase I , Humanos , Inibidores da Topoisomerase I/farmacologia , Inibidores da Topoisomerase I/uso terapêutico , Neoplasias Colorretais/terapia , Citosol , Microambiente TumoralRESUMO
Twisted bilayer graphene (tBLG) with C vacancies would greatly improve the density of states (DOS) around the Fermi level (EF) and quantum capacitance; however, the single-band tight-binding model only considering pz orbitals cannot accurately capture the low-energy physics of tBLG with C vacancies. In this work, a three-band tight-binding model containing three p orbitals of C atoms is proposed to explore the modulation mechanism of C vacancies on the DOS and quantum capacitance of tBLG. We first obtain the hopping integral parameters of the three-band tight-binding model, and then explore the electronic structures and the quantum capacitance of tBLG at a twisting angle of θ = 1.47° under different C vacancy concentrations. The impurity states contributed by C atoms with dangling bonds located around the EF and the interlayer hopping interaction could induce band splitting of the impurity states. Therefore, compared with the quantum capacitance of pristine tBLG (â¼18.82 µF cm-2) at zero bias, the quantum capacitance is improved to â¼172.76 µF cm-2 at zero bias, and the working window with relatively large quantum capacitance in the low-voltage range is broadened in tBLG with C vacancies due to the enhanced DOS around the EF. Moreover, the quantum capacitance of tBLG is further increased at zero bias with an increase of the C vacancy concentration induced by more impurity states. These findings not only provide a suitable multi-band tight-binding model to describe tBLG with C vacancies but also offer theoretical insight for designing electrode candidates for low-power consumption devices with improved quantum capacitance.
RESUMO
BACKGROUND: Cardiac masses can encompass a variety of conditions, such as tumors, thrombi, vegetations, calcific lesions, and other rare diseases. Treatment and management of these types of cardiac masses differ considerably. Thus, accurately distinguishing among thrombi, benign tumors, and malignant tumors in the heart is of great importance. Contrast echocardiography (CE) has emerged as a promising technology. Although published guidelines suggest that CE can enhance image quality and assist in differentiating between benign and malignant lesions, most studies on CE diagnosis of cardiac masses are limited to case reports or retrospective/small-sample-sized prospective cohorts. This study aims to evaluate the diagnostic accuracy of CE in patients with suspected cardiac masses and address the insufficient evidence for differential diagnosis using CE. METHODS: Between April 2018 and July 2022, a prospective multicenter study was conducted, which included 145 consecutive patients suspected to have cardiac masses based on transthoracic echocardiography. All patients underwent CE examinations. The echocardiographic diagnosis relied on qualitative factors such as echogenicity, boundary, morphology of the base, mass perfusion, pericardial effusion, and motility as well as quantitative factors such as the area of the masses and the peak intensity ratio of the masses to adjacent myocardium (A1/A2). RESULTS: The final confirmed diagnoses were as follows: 2 patients had no cardiac mass, 4 patients had pseudomass, 43 patients had thrombus, 66 patients had benign tumors, and 30 patients had malignant tumors. The receiver operating characteristic (ROC) analysis indicated that an optimal A1/A2 cutoff value of 0.499 distinguished a cardiac tumor from a thrombus, with AUC, sensitivity, specificity, PPV, and NPV of 0.977, 97.9%, 90.7%, 95.9%, and 95.1%, respectively. The optimal A1/A2 cutoff value of 1.583 distinguished a cardiac tumor from a thrombus, with AUC, sensitivity, specificity, PPV, and NPV of 0.950, 93.3%, 93.9%, 87.5%, and 96.9%, respectively. CONCLUSIONS: Combined with qualitative and quantitative analyses, CE has the potential to accurately differentiate among different types of cardiac masses.
Assuntos
Neoplasias Cardíacas , Trombose , Humanos , Estudos Retrospectivos , Estudos Prospectivos , Meios de Contraste , Ecocardiografia/métodos , Neoplasias Cardíacas/diagnóstico por imagem , Diagnóstico Diferencial , Sensibilidade e EspecificidadeRESUMO
Ketolides (3-keto) such as TE-802 and acylides (3-O-acyl) like TEA0929 are ineffective against constitutively resistant pathogens harboring erythromycin ribosomal methylation (erm) genes. Following our previous work on alkylides (3-O-alkyl), we explored the structure-activity relationships of hybrids combining (R/S) 3-descladinosyl erythromycin with 6/7-quinolone motifs, featuring extended ether-linked spacers, with a focus on their efficacy against pathogens bearing constitutive erm gene resistance. Optimized compounds 17a and 31f not only reinstated efficacy against inducibly resistant pathogens but also demonstrated significantly augmented activities against constitutively resistant strains of Streptococcus pneumoniae and Streptococcus pyogenes, which are typically refractory to existing C-3 modified macrolides. Notably, hybrid 31f (coded ZN-51) represented a pioneering class of agents distinguished by its dual modes of action, with ribosomes as the primary target and topoisomerases as the secondary target. As a novel chemotype of macrolide-quinolone hybrids, alkylide 31f is a valuable addition to our armamentarium against macrolide-resistant bacteria.
Assuntos
Antibacterianos , Macrolídeos , Testes de Sensibilidade Microbiana , Quinolonas , Streptococcus pneumoniae , Relação Estrutura-Atividade , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/síntese química , Quinolonas/química , Quinolonas/farmacologia , Quinolonas/síntese química , Macrolídeos/química , Macrolídeos/farmacologia , Streptococcus pneumoniae/efeitos dos fármacos , Estrutura Molecular , Desenho de Fármacos , Streptococcus pyogenes/efeitos dos fármacos , Streptococcus pyogenes/enzimologia , Relação Dose-Resposta a Droga , Éteres/química , Éteres/farmacologia , Éteres/síntese químicaRESUMO
ATP citrate lyase (ACLY), a strategic metabolic enzyme that catalyzes the glycolytic to lipidic metabolism, has gained increasing attention as an attractive therapeutic target for hyperlipidemia, cancers and other human diseases. Despite of continual research efforts, targeting ACLY has been very challenging. In this field, most reported ACLY inhibitors are "substrate-like" analogues, which occupied with the same active pockets. Besides, some ACLY inhibitors have been disclosed through biochemical screening or high throughput virtual screening. In this review, we briefly summarized the cancer-related functions and the recent advance of ACLY inhibitors with a particular focus on the SAR studies and their modes of action. We hope to provide a timely and updated overview of ACLY and the discovery of new ACLY inhibitors.
Assuntos
ATP Citrato (pro-S)-Liase , Neoplasias , Humanos , ATP Citrato (pro-S)-Liase/metabolismo , Neoplasias/metabolismo , Metabolismo dos LipídeosRESUMO
Tumor immunotherapy characterized by its high specificity and minimal side effects has achieved revolutionary progress in the field of cancer treatment. However, the complex mechanisms of tumor immune microenvironment (TIME) and the individual variability of patients' immune system still present significant challenges to its clinical application. Immunocyte membrane-coated nanocarrier systems, as an innovative biomimetic drug delivery platform, exhibit remarkable advantages in tumor immunotherapy due to their high targeting capability, good biocompatibility and low immunogenicity. In this review we summarize the latest research advances in biomimetic delivery systems based on immune cells for tumor immunotherapy. We outline the existing methods of tumor immunotherapy including immune checkpoint therapy, adoptive cell transfer therapy and cancer vaccines etc. with a focus on the application of various immunocyte membranes in tumor immunotherapy and their prospects and challenges in drug delivery and immune modulation. We look forward to further exploring the application of biomimetic delivery systems based on immunocyte membrane-coated nanoparticles, aiming to provide a new framework for the clinical treatment of tumor immunity.
RESUMO
The ongoing evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), resulting in the emergence of new variants that are resistant to existing vaccines and therapeutic antibodies, has raised the need for novel strategies to combat the persistent global COVID-19 epidemic. In this study, a monoclonal anti-human angiotensin-converting enzyme 2 (hACE2) antibody, ch2H2, was isolated and humanized to block the viral receptor-binding domain (RBD) binding to hACE2, the major entry receptor of SARS-CoV-2. This antibody targets the RBD-binding site on the N terminus of hACE2 and has a high binding affinity to outcompete the RBD. In vitro, ch2H2 antibody showed potent inhibitory activity against multiple SARS-CoV-2 variants, including the most antigenically drifted and immune-evading variant Omicron. In vivo, adeno-associated virus (AAV)-mediated delivery enabled a sustained expression of monoclonal antibody (mAb) ch2H2, generating a high concentration of antibodies in mice. A single administration of AAV-delivered mAb ch2H2 significantly reduced viral RNA load and infectious virions and mitigated pulmonary pathological changes in mice challenged with SARS-CoV-2 Omicron BA.5 subvariant. Collectively, the results suggest that AAV-delivered hACE2-blocking antibody provides a promising approach for developing broad-spectrum antivirals against SARS-CoV-2 and potentially other hACE2-dependent pathogens that may emerge in the future.
Assuntos
Anticorpos Monoclonais , Anticorpos Amplamente Neutralizantes , COVID-19 , Animais , Humanos , Camundongos , Enzima de Conversão de Angiotensina 2/genética , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Anticorpos Antivirais , COVID-19/terapia , Dependovirus/genética , RNA Viral , SARS-CoV-2/genética , Anticorpos Amplamente Neutralizantes/farmacologia , Anticorpos Amplamente Neutralizantes/uso terapêuticoRESUMO
Tubulointerstitial fibrosis (TIF) plays a crucial role in the progression of diabetic kidney disease (DKD). However, the underlying molecular mechanisms remain obscure. The present study aimed to examine whether transmembrane member 16A (TMEM16A), a Ca2+-activated chloride channel, contributes to the development of TIF in DKD. Interestingly, we found that TMEM16A expression was significantly up-regulated in tubule of murine model of DKD, which was associated with development of TIF. In vivo inhibition of TMEM16A channel activity with specific inhibitors Ani9 effectively protects against TIF. Then, we found that TMEM16A activation induces tubular mitochondrial dysfunction in in vivo and in vitro models, with the evidence of the TMEM16A inhibition with specific inhibitor. Mechanically, TMEM16A mediated tubular mitochondrial dysfunction through inhibiting PGC-1α, whereas overexpression of PGC-1α could rescue the changes. In addition, TMEM16A-induced fibrogenesis was dependent on increased intracellular Cl-, and reducing intracellular Cl- significantly blunted high glucose-induced PGC-1α and profibrotic factors expression. Taken together, our studies demonstrated that tubular TMEM16A promotes TIF by suppressing PGC-1α-mediated mitochondrial homeostasis in DKD. Blockade of TMEM16A may serve as a novel therapeutic approach to ameliorate TIF.
Assuntos
Diabetes Mellitus , Nefropatias Diabéticas , Animais , Camundongos , Nefropatias Diabéticas/genética , Homeostase , Mitocôndrias , FibroseRESUMO
BACKGROUND: The purpose of this study was to evaluate the safety and efficacy of preoperative concurrent chemoradiotherapy (preCRT) for locally advanced rectal cancer in older people who were classified as "fit" by comprehensive geriatric assessment (CGA). METHODS: A single-arm, multicenter, phase II trial was designed. Patients were eligible for this study if they were aged 70 years or above and met the standards of "fit" (SIOG1) as evaluated by CGA and of the locally advanced risk category. The primary endpoint was 2-year disease-free survival (DFS). Patients were scheduled to receive preCRT (50 Gy) with raltitrexed (3 mg/m2 on days 1 and 22). RESULTS: One hundred and nine patients were evaluated by CGA, of whom eighty-six, eleven and twelve were classified into the fit, intermediate and frail category. Sixty-eight fit patients with a median age of 74 years were enrolled. Sixty-four patients (94.1%) finished radiotherapy without dose reduction. Fifty-four (79.3%) patients finished the prescribed raltitrexed therapy as planned. Serious toxicity (grade 3 or above) was observed in twenty-four patients (35.3%), and fourteen patients (20.6%) experienced non-hematological side effects. Within a median follow-up time of 36.0 months (range: 5.9-63.1 months), the 2-year overall survival (OS), cancer-specific survival (CSS) and disease-free survival (DFS) rates were 89.6% (95% CI: 82.3-96.9), 92.4% (95% CI: 85.9-98.9) and 75.6% (95% CI: 65.2-86.0), respectively. Forty-eight patients (70.6%) underwent surgery (R0 resection 95.8%, R1 resection 4.2%), the corresponding R0 resection rate among the patients with positive mesorectal fascia status was 76.6% (36/47). CONCLUSION: This phase II trial suggests that preCRT is efficient with tolerable toxicities in older rectal cancer patients who were evaluated as fit based on CGA. TRIAL REGISTRATION: The registration number on ClinicalTrials.gov was NCT02992886 (14/12/2016).
Assuntos
Quimiorradioterapia , Avaliação Geriátrica , Neoplasias Retais , Humanos , Idoso , Masculino , Feminino , Neoplasias Retais/terapia , Idoso de 80 Anos ou mais , Avaliação Geriátrica/métodos , Quimiorradioterapia/métodos , Intervalo Livre de Doença , Cuidados Pré-Operatórios/métodos , Tiofenos/administração & dosagem , Tiofenos/uso terapêutico , Equipe de Assistência ao Paciente , Quinazolinas/administração & dosagem , Quinazolinas/uso terapêuticoRESUMO
OBJECTIVE: The aim of this study was to systematically investigate the ultrasonographic features of nodular hidradenoma (NH). METHODS: A retrospective analysis was used to systematically summarize the ultrasonographic data of 27 patients diagnosed with NH by surgical pathology, including 13 eccrine nodular hidradenomas (ENH) and 14 apocrine nodular hidradenomas (ANH). RESULTS: All instances of NH presented as solitary, well-defined lesions that infiltrated the dermis and subcutaneous fat layer, characterized by a heterogeneous hypoechoic internal solid component on ultrasound imaging. Color Doppler ultrasound revealed blood flow signals of Grade 2 or higher within 74% (20/27) of the lesions. Solid + cystic (cystic >50%) NH (14/27, 51.4%) were typically large and predominantly had an oval shape (11/14, 78.5%). Their distinctive sonographic features included the presence of inner septa within the cystic area (8/14, 57.1%), "snow falling" sign (7/14, 50%), or "fluid-fluid level" sign (7/14, 50%). Solid + cystic (cystic ≤50%) NH exhibited a lobulated morphology in all instances (5/5, 100%). No inner septa, "snow falling" sign or "fluid-fluid level" sign was observed within the cystic regions. The solid NH (8/27, 29.7%) morphology predominantly featured lobulation (6 out of 8, 75%). Ultrasound analysis revealed distinct differences between ENH and ANH. ENH were more lobulated, while ANH were predominantly oval. ANH were mainly solid + cystic (cystic >50%), whereas ENH were mostly solid. Inner septa, "snow falling" sign, and "fluid-fluid level" sign frequencies were similar in both groups, correlating more with cystic-solid composition than pathological subtype. CONCLUSIONS: Ultrasonographic features of lobulated morphology and the presence of inner septa, "snow falling" sign or "fluid-fluid level" sign in the cystic region provide strong support for the diagnosis of NH.
RESUMO
Spatial evolutionary games provide a valuable framework for elucidating the emergence and maintenance of cooperative behaviors. However, most previous studies assume that individuals are profiteers and neglect to consider the effects of memory. To bridge this gap, in this paper, we propose a memory-based spatial evolutionary game with dynamic interaction between learners and profiteers. Specifically, there are two different categories of individuals in the network, including profiteers and learners with different strategy updating rules. Notably, there is a dynamic interaction between profiteers and learners, i.e., each individual has the transition probability between profiteers and learners, which is portrayed by a Markov process. Besides, the payoff of each individual is not only determined by a single round of the game but also depends on the memory mechanism of the individual. Extensive numerical simulations validate the theoretical analysis and uncover that dynamic interactions between profiteers and learners foster cooperation, memory mechanisms facilitate the emergence of cooperative behaviors among profiteers, and increasing the learning rate of learners promotes a rise in the number of cooperators. In addition, the robustness of the model is verified through simulations across various network sizes. Overall, this work contributes to a deeper understanding of the mechanisms driving the formation and evolution of cooperation.
RESUMO
This paper proposes a full-automatic high-efficiency Mueller matrix microscopic imaging (MMMI) system based on the tissue microarray (TMA) for cancer inspection for the first time. By performing a polar decomposition on the sample's Mueller matrix (MM) obtained by a transmissive MMMI system we established, the linear phase retardance equivalent waveplate fast-axis azimuth and the linear phase retardance are obtained for distinguishing the cancerous tissues from the normal ones based on the differences in their polarization characteristics, where three analyses methods including statistical analysis, the gray-level co-occurrence matrix analysis (GLCM) and the Tamura image processing method (TIPM) are used. Previous MMMI medical diagnostics typically utilized discrete slices for inspection under a high-magnification objective (20×-50×) with a small field of view, while we use the TMA under a low-magnification objective (5×) with a large field of view. Experimental results indicate that MMMI based on TMA can effectively analyze the pathological variations in biological tissues, inspect cancerous cervical tissues, and thus contribute to the diagnosis of postoperative cancer biopsies. Such an inspection method, using a large number of samples within a TMA, is beneficial for obtaining consistent findings and good reproducibility.
Assuntos
Processamento de Imagem Assistida por Computador , Análise Serial de Tecidos , Humanos , Análise Serial de Tecidos/métodos , Processamento de Imagem Assistida por Computador/métodos , Microscopia/métodos , Feminino , Reprodutibilidade dos Testes , Algoritmos , Neoplasias/patologia , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/diagnósticoRESUMO
Spacecraft pose estimation using computer vision has garnered increasing attention in research areas such as automation system theory, control theory, sensors and instruments, robot technology, and automation software. Confronted with the extreme environment of space, existing spacecraft pose estimation methods are predominantly multi-stage networks with complex operations. In this study, we propose an approach for spacecraft homography pose estimation with a single-stage deep convolutional neural network for the first time. We formulated a homomorphic geometric constraint equation for spacecraft with planar features. Additionally, we employed a single-stage 2D keypoint regression network to obtain homography 2D keypoint coordinates for spacecraft. After decomposition to obtain the rough spacecraft pose based on the homography matrix constructed according to the geometric constraint equation, a loss function based on pixel errors was employed to refine the spacecraft pose. We conducted extensive experiments using widely used spacecraft pose estimation datasets and compared our method with state-of-the-art techniques in the field to demonstrate its effectiveness.
RESUMO
Soybean phytophthora blight is a severe menace to global agriculture, causing annual losses surpassing USD 1 billion. Present crop loss mitigation strategies primarily rely on chemical pesticides and disease-resistant breeding, frequently surpassed by the pathogens' quick adaptive evolution. In this urgent scenario, our research delves into innovative antimicrobial peptides characterized by low drug resistance and environmental friendliness. Inhibiting chitin synthase gene activity in Phytophthora sojae impairs vital functions such as growth and sporulation, presenting an effective method to reduce its pathogenic impact. In our study, we screened 16 previously tested peptides to evaluate their antimicrobial effects against Phytophthora using structure-guided drug design, which involves molecular docking, saturation mutagenesis, molecular dynamics, and toxicity prediction. The in silico analysis identified AMP_04 with potential inhibitory activity against Phytophthora sojae's chitin synthase. Through three rounds of saturation mutagenesis, we pin-pointed the most effective triple mutant, TP (D10K, G11I, S14L). Molecular dynamic simulations revealed TP's stability in the chitin synthase-TP complex and its transmembrane mechanism, employing an all-atom force field. Our findings demonstrate the efficacy of TP in occupying the substrate-binding pocket and translocation catalytic channel. Effective inhibition of the chitin synthase enzyme can be achieved. Specifically, the triple mutant demonstrates enhanced antimicrobial potency and decreased toxicity relative to the wild-type AMP_04, utilizing a mechanism akin to the barrel-stave model during membrane translocation. Collectively, our study provides a new strategy that could be used as a potent antimicrobial agent in combatting soybean blight, contributing to sustainable agricultural practices.
Assuntos
Anti-Infecciosos , Phytophthora , Glycine max/genética , Phytophthora/fisiologia , Quitina Sintase/genética , Peptídeos Antimicrobianos , Simulação de Acoplamento Molecular , Resistência à Doença , Melhoramento Vegetal , Doenças das Plantas/prevenção & controle , Doenças das Plantas/genéticaRESUMO
We previously discovered WS-6 as a new antidepressant in correlation to its function of stimulating neurogenesis. Herein, several different scaffolds (stilbene, 1,3-diphenyl 1-propene, 1,3-diphenyl 2-propene, 1,2-diphenyl acrylo-1-nitrile, 1,2-diphenyl acrylo-2-nitrile, 1,3-diphenyl trimethylamine), further varied through substitutions of twelve amide substituents plus the addition of a methylene unit and an inverted amide, were examined to elucidate the SARs for promoting adult rat neurogenesis. Most of the compounds could stimulate proliferation of progenitors, but just a few chemicals possessing a specific structural profile, exemplified by diphenyl acrylonitrile 29b, 32a, and 32b, showed better activity than the clinical drug NSI-189 in promoting newborn cells differentiation into mature neurons. The most potent diphenyl acrylonitrile 32b had an excellent brain AUC to plasma AUC ratio (B/P = 1.6), suggesting its potential for further development as a new lead.