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BACKGROUND: The escalating prevalence of fertility problems in the aging population necessitates a comprehensive exploration of contributing factors, extending beyond environmental concerns, work-related stress, and unhealthy lifestyles. Among these, the rising incidence of testicular disorders emerges as a pivotal determinant of fertility issues. Current treatment challenges are underscored by the limitations of high-dose and frequent drug administration, coupled with substantial side effects and irreversible trauma inflicted by surgical interventions on testicular tissue. MATERIAL AND METHODS: The formidable barrier posed by the blood-testis barrier compounds the complexities of treating testicular diseases, presenting a significant therapeutic obstacle. The advent of nanocarriers, with their distinctive attributes, holds promise in overcoming this impediment. These nanocarriers exhibit exceptional biocompatibility, and membrane penetration capabilities, and can strategically target the blood-testis barrier through surface ligand modification, thereby augmenting drug bioavailability and enhancing therapeutic efficacy. RESULTS AND DISCUSSION: This review concentrates on the transformative potential of nanocarriers in the delivery of therapeutic agents to testicular tissue. By summarizing key applications, we illuminate the strides made in utilizing nanocarriers as a novel avenue to effectively treat testicular diseases. CONCLUSIONS: Nanocarriers are critical in delivering therapeutic agents to testicular tissue.
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AIMS: This study aimed to assess the knowledge, attitudes and practices (KAP) towards cervical cancer screening among ethnic minorities in Inner Mongolia, China. METHODS: A cross-sectional study was conducted in Inner Mongolia between May and September, 2023, and recruiting participants undergoing dual-cancer screening. Demographic characteristics and KAP status were assessed using a self-administered questionnaire. RESULTS: A total of 533 valid questionnaires were collected, with 53.66% aged 40 years or younger. Mean scores for knowledge, attitude, and practice were 13.58 ± 5.41, 41.06 ± 4.53, and 13.35 ± 1.53, respectively. Positive associations were found between knowledge and attitude (r = 0.348, p < 0.001), knowledge and practice (r = 0.288, p < 0.001), and attitude and practice (r = 0.817, p < 0.001). Structural equation modelling confirmed direct positive associations between knowledge and attitude (path coefficient = 0.307, p < 0.001) and attitude and practice (path coefficient = 0.270, p < 0.001). Additionally, knowledge demonstrated an indirectly positive association with practice (path coefficient = 0.083, p = 0.007). CONCLUSION: Ethnic minorities in Inner Mongolia exhibit insufficient knowledge, positive attitudes, and proactive practices toward cervical cancer screening. Implementing targeted educational initiatives is crucial to enhance their KAP.
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To establish a predictive model of bone metastasis in patients with non-small cell lung cancer (NSCLC) using peripheral blood CX3CL and CCL28, and to verify its application value. We retrospectively gathered clinical data from 210 patients with NSCLC treated at our institution between April 2021 and December 2023. These patients were stratified into two groups based on the presence of bone metastases: a bone metastasis group (n = 49) and a non-bone metastasis group (n = 161). A logistic regression model was developed to predict bone metastasis and to evaluate the model's predictive performance. Multivariate logistic regression analysis identified age (OR = 6.689, P < 0.001), carcinoembryonic antigen (CEA, OR = 5.699, P < 0.001), CX3CL1 (OR = 5.418, P < 0.001), and CCL28 (OR = 7.692, P < 0.001) as independent predictors of bone metastasis in NSCLC patients. The receiver operating characteristic (ROC) curve analysis yielded an area under the curve (AUC) of 0.794 for both the modeling and validation cohorts. Decision curve analysis (DCA) indicated a superior net benefit of the model. Calibration curves confirmed close concordance between predicted and observed probabilities of bone metastasis. The Hosmer-Lemeshow test yielded a chi-square statistic of 4.743 with a P-value of 0.178, suggesting a good fit. The predictive model utilizing serum levels of CX3CL1 and CCL28 demonstrates robust predictive accuracy and efficacy for bone metastasis in patients with NSCLC.
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BACKGROUND: HOIP is the catalytic subunit of the E3 ligase complex (linear ubiquitin chain assembly complex), which is able to generate linear ubiquitin chains. However, the role of rare HOIP functionally deficient variants remains unclear. The pathogenic mechanism and the relationship with immune deficiency phenotypes remain to be clarified. METHODS: Based on a next-generation sequencing panel of 270 genes, we identified a HOIP deletion variant that causes common variable immunodeficiency disease. Bioinformatics analysis and cell-based experiments were performed to study the molecular mechanism by which the variant causes immunodeficiency diseases. FINDINGS: A homozygous loss-of-function variant in HOIP was identified. The variant causes a frameshift and generates a premature termination codon in messenger RNA, resulting in a C-terminal truncated HOIP mutant, that is, the loss of the linear ubiquitin chain-specific catalytic domain. The truncated HOIP mutant has impaired E3 ligase function in linear ubiquitination, leading to the suppression of canonical NF-κB signalling and increased TNF-induced multiple forms of cell death. INTERPRETATION: The loss-of-function HOIP variant accounts for the immune deficiencies. The canonical NF-κB pathway and cell death are involved in the pathogenesis of the disease. FUNDING: This study was funded by the National Natural Science Foundation of China (No. 82270444 and 81501851). RESEARCH IN CONTEXT: Evidence before this study LUBAC is the only known linear ubiquitin chain assembly complex for which HOIP is an essential catalytic subunit. Three HOIP variants have now been identified in two immunodeficient patients and functionally characterised. However, there have been no reports on the pathogenicity of only catalytic domain deletion variants in humans, or the pathogenic mechanisms of catalytic domain deletion variants. Added value of this study We report the first case of an autosomal recessive homozygous deletion variant that results in deletion of the HOIP catalytic structural domain. We demonstrate that this variant is a loss-of-function variant using a heterologous expression system. The variant has impaired E3 ligase function. It can still bind to other subunits of LUBAC, but it fails to generate linear ubiquitin chains. We also explored the underlying mechanisms by which this variant leads to immunodeficiency. The variant attenuates the canonical NF-κB and MAPK signalling cascades and increases the sensitivity of TNFα-induced diverse cell death and activation of mitochondrial apoptosis pathways. These findings provide support for the treatment and drug development of patients with inborn errors of immunity in HOIP and related signalling pathways. Implications of all the available evidence First, this study expands the HOIP pathogenic variant database and phenotypic spectrum. Furthermore, studies on the biological functions of pathogenic variants in relation to the NF-κB signalling pathway and cell death provided new understanding into the genetic basis and pathogenesis of HOIP-deficient immune disease, indicating the necessity of HOIP and related signalling pathway variants as diagnostic targets in patients with similar genetic deficiency phenotypes..
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Brain-inspired Spiking Neural Networks (SNNs) have attracted much attention due to their event-based computing and energy-efficient features. However, the spiking all-or-none nature has prevented direct training of SNNs for various applications. The surrogate gradient (SG) algorithm has recently enabled spiking neural networks to shine in neuromorphic hardware. However, introducing surrogate gradients has caused SNNs to lose their original sparsity, thus leading to the potential performance loss. In this paper, we first analyze the current problem of direct training using SGs and then propose Masked Surrogate Gradients (MSGs) to balance the effectiveness of training and the sparseness of the gradient, thereby improving the generalization ability of SNNs. Moreover, we introduce a temporally weighted output (TWO) method to decode the network output, reinforcing the importance of correct timesteps. Extensive experiments on diverse network structures and datasets show that training with MSG and TWO surpasses the SOTA technique.
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Background: Investigating the effects of monetary incentives on dishonest behavior provides valuable insights into human integrity and ethical decision-making processes. This study is conducted through the lens of self-concept maintenance theory. Aim: The aim of this study is to examine the influence of different types of rewards (score-based vs. monetary) and their magnitude on dishonest behavior within a gender judgment task. Method: Using a quantitative experimental design, this study involved 116 participants who were randomly assigned to conditions that differed in reward type (score or money) and magnitude (10 yuan vs. 50 yuan). Dishonest behavior was assessed using a gender judgment task with mechanisms to simulate conditions conducive to planned cheating. Results: Results revealed significant differences in dishonesty rates between score and money conditions, with a higher proportion of dishonest participants observed in the score condition compared to the money condition. The timing of initial cheating was earlier in the score condition compared to the money condition. No significant differences were found in the proportion of dishonest participants, the cheating rate, or the timing of initial cheating across reward levels within either condition. The rate of cheating increased over time, suggesting a temporal dynamic in unethical decision making. Conclusion: The study demonstrates that the nature of rewards significantly influences the likelihood of dishonest behavior, with intangible score-based rewards facilitating rationalizations for dishonesty more readily than tangible financial incentives. These findings enrich the understanding of moral psychology by highlighting the complex interplay between reward types, ethical rationalization, and the dynamics of dishonest behavior.
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The aim of this study is to explore the mechanism of IL-17A infection in the development of bacterial mastitis in dairy cows. In this study, RT-qPCR and ELISA were used to measure the promoting effect of IL-17A on the generation of pro-inflammatory cytokines (TNF-α, IL-1ß, and IL-6) and chemokine (IL-8). In addition, Western blot (WB) was applied to measure the influences of IL-17A on the inflammation-related ERK and p38 proteins in the MAPK pathways. The results show that under the stimulation of LPS on cow mammary epithelial cells (CMECs), cytokines IL-1ß, IL-6, IL-8, TNF-α, and IL-17A will exhibit significantly increased expression levels (p < 0.05). With inhibited endogenous expression of IL-17A, cytokines IL-1ß, IL-6, IL-8, and TNF-α will present reduced genetic expression (p < 0.01), with reduced phosphorylation levels of ERK and p38 proteins in the MAPK signaling pathways (p < 0.001). Upon the exogenous addition of the IL-17A cytokine, the genetic expression of cytokines IL-1ß, IL-6, IL-8, and TNF-α will increase (p < 0.05), with increased phosphorylation levels of the ERK and p38 proteins in the MAPK signaling pathways (p < 0.001). These results indicate that under the stimulation of CMECs with LPS, IL-17A can be expressed together with relevant inflammatory cytokines. Meanwhile, the inflammatory responses of mammary epithelial cells are directly proportional to the expression levels of IL-17A inhibited alone or exogenously added. In summary, this study shows that IL-17A could be used as an important indicator for assessing the bacterial infections of mammary glands, indicating that IL-17A could be regarded as one potential therapeutic target for mastitis.
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Integration of solar cells and electrochromic windows offers crucial contributions to green buildings. Solar-charging zinc anode-based electrochromic devices (ZECDs) present opportunities for addressing the solar intermittency issue. However, the limited energy storage capacity of ZECDs results in wasted harnessing of solar energy as well as overcharging. Herein, spectral-selective dual-band ZECDs that continuously transport solar energy to indoor appliances by remotely controlling the repeated bleached-tinted cycles during the daytime, are reported. Hexagonal phase cesium-doped tungsten bronze (h-Cs0.32WO3, CWO) nanocrystals are adopted for dual-band ZECDs due to their independent control ability of near-infrared (NIR) and visible (VIS) light transmittance (∆T = 73.0%, 700 nm; ∆T = 83.7%, 1200 nm) and excellent cycling stability (0.8% optical contrast decay at 1200 nm after 10 000 cycles). The prototype device (i.e., CWO//Zn//CWO) delivers extraordinary thermal insulation capability, displaying a 10 °C difference between "bright" and "dark" modes. Furthermore, an Internet of Things (IoT) controller to control the NIR and VIS lights of the CWO//Zn//CWO window wirelessly with a smartphone, empowering the continuous discharging of the solar-charged window during the daytime remotely, is developed. Such windows represent an intriguing potential technology whose future impact on green buildings may be substantial.
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Circular RNAs (circRNAs) are stable RNAs present in cell-free RNA, which may comprise cellular debris and pathogen genomes. Here, we investigate the phenomenon and mechanism of cellular uptake and intracellular fate of exogenous circRNAs. Human myeloid cells and B cells selectively internalize extracellular circRNAs. Macrophage uptake of circRNA is rapid, energy dependent, and saturable. CircRNA uptake can lead to translation of encoded sequences and antigen presentation. The route of internalization influences immune activation after circRNA uptake, with distinct gene expression programs depending on the route of RNA delivery. Genome-scale CRISPR screens and chemical inhibitor studies nominate macrophage scavenger receptor MSR1, Toll-like receptors, and mTOR signaling as key regulators of receptor-mediated phagocytosis of circRNAs, a dominant pathway to internalize circRNAs in parallel to macropinocytosis. These results suggest that cell-free circRNA serves as an "eat me" signal and danger-associated molecular pattern, indicating orderly pathways of recognition and disposal.
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Macrófagos , Fagocitose , RNA Circular , Transdução de Sinais , RNA Circular/genética , RNA Circular/metabolismo , Humanos , Macrófagos/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Serina-Treonina Quinases TOR/genética , Animais , Receptores Toll-Like/metabolismo , Receptores Toll-Like/genética , Linfócitos B/metabolismo , Linfócitos B/imunologia , Receptores Depuradores Classe A/metabolismo , Receptores Depuradores Classe A/genética , Apresentação de Antígeno , Pinocitose , CamundongosRESUMO
Background: Previous studies have reported that the occurrence and development of osteonecrosis is closely associated with immune-inflammatory responses. Mendelian randomization was performed to further assess the causal correlation between 41 inflammatory cytokines and osteonecrosis. Methods: Two-sample Mendelian randomization utilized genetic variants for osteonecrosis from a large genome-wide association study (GWAS) with 606 cases and 209,575 controls of European ancestry. Another analysis included drug-induced osteonecrosis with 101 cases and 218,691 controls of European ancestry. Inflammatory cytokines were sourced from a GWAS abstract involving 8,293 healthy participants. The causal relationship between exposure and outcome was primarily explored using an inverse variance weighting approach. Multiple sensitivity analyses, including MR-Egger, weighted median, simple model, weighted model, and MR-PRESSO, were concurrently applied to bolster the final results. Results: The results showed that bFGF, IL-2 and IL2-RA were clinically causally associated with the risk of osteonecrosis (OR=1.942, 95% CI=1.13-3.35, p=0.017; OR=0.688, 95% CI=0.50-0.94, p=0.021; OR=1.386, 95% CI=1.04-1.85, p = 0.026). there was a causal relationship between SCF and drug-related osteonecrosis (OR=3.356, 95% CI=1.09-10.30, p=0.034). Conclusion: This pioneering Mendelian randomization study is the first to explore the causal link between osteonecrosis and 41 inflammatory cytokines. It conclusively establishes a causal association between osteonecrosis and bFGF, IL-2, and IL-2RA. These findings offer valuable insights into osteonecrosis pathogenesis, paving the way for effective clinical management. The study suggests bFGF, IL-2, and IL-2RA as potential therapeutic targets for osteonecrosis treatment.
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Citocinas , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Osteonecrose , Humanos , Osteonecrose/genética , Citocinas/genética , Polimorfismo de Nucleotídeo Único , Interleucina-2/genética , Fator 2 de Crescimento de Fibroblastos/genética , Inflamação/genéticaRESUMO
OBJECTIVE: To analyse the related influencing factors of adolescent major depressive disorder (MDD) with suicidal and self-injurious behaviour (SSIB). METHODS: A total of 299 adolescents with MDD who were admitted to the psychiatric department of the hospital between February 2022 and July 2023 were selected using the convenience sampling method. The participants were divided into the SSIB group (n = 110) and the non-SSIB group (n = 189) according to whether SSIB was present, and related indicators were collected and compared. RESULTS: The patients' ages at the time of their first SSIB ranged from 10 to 18 years old, with a mean age of 13.30 ± 1.74 years. The most commonly injured parts were the lower arm and wrist (42.13%), and the most common injury was cutting, accounting for 40.00% of the total patients. The most common type of self-injury differed by sex (X2 = 17.798, P = 0.006); for men, hitting was the most common, and for women, cutting was the most common. In 51.41% of the patients, the period between the initial thought and the actual committing of the SSIB was less than 5 minutes. The scores of the Eysenck Personality Questionnaire, the Barratt Impulsivity Scale, the Buss-Perry Aggression Questionnaire, the Symptom Checklist-90 (all P < 0.001), and the health-risk behaviour scale (67.47 ± 12.59 vs. 41.58 ± 11.36, t = 9.587, P < 0.001) were significantly increased in the SSIB group compared with the non-SSIB group. In addition, the total score of quality of life (QOL) (11.36 ± 4.32 vs. 16.43 ± 5.64, t = 5.496, P < 0.001) was decreased in the SSIB group compared with the non-SSIB group. CONCLUSION: The SSIB of adolescent patients with MDD is related to various factors, including impulsiveness, aggressiveness, personality traits, QOL, and mental health level.
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Fusarium head blight (FHB), caused by Fusarium graminearum species complexes (FGSG), is an epidemic disease in wheat and poses a serious threat to wheat production and security worldwide. Profilins are a class of actin-binding proteins that participate in actin depolymerization. However, the roles of profilins in plant fungal pathogens remain largely unexplored. Here, we identified FgPfn, a homolog to profilins in F. graminearum, and the deletion of FgPfn resulted in severe defects in mycelial growth, conidia production, and pathogenicity, accompanied by marked disruptions in toxisomes formation and deoxynivalenol (DON) transport, while sexual development was aborted. Additionally, FgPfn interacted with Fgα1 and Fgß2, the significant components of microtubules. The organization of microtubules in the ΔFgPfn was strongly inhibited under the treatment of 0.4 µg/mL carbendazim, a well-known group of tubulin interferers, resulting in increased sensitivity to carbendazim. Moreover, FgPfn interacted with both myosin-5 (FgMyo5) and actin (FgAct), the targets of the fungicide phenamacril, and these interactions were reduced after phenamacril treatment. The deletion of FgPfn disrupted the normal organization of FgMyo5 and FgAct cytoskeleton, weakened the interaction between FgMyo5 and FgAct, and resulting in increased sensitivity to phenamacril. The core region of the interaction between FgPfn and FgAct was investigated, revealing that the integrity of both proteins was necessary for their interaction. Furthermore, mutations in R72, R77, R86, G91, I101, A112, G113, and D124 caused the non-interaction between FgPfn and FgAct. The R86K, I101E, and D124E mutants in FgPfn resulted in severe defects in actin organization, development, and pathogenicity. Taken together, this study revealed the role of FgPfn-dependent cytoskeleton in development, DON production and transport, fungicides sensitivity in F. graminearum.
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Actinas , Proteínas Fúngicas , Fungicidas Industriais , Fusarium , Microtúbulos , Doenças das Plantas , Triticum , Microtúbulos/metabolismo , Fusarium/metabolismo , Fusarium/patogenicidade , Fusarium/genética , Fusarium/efeitos dos fármacos , Fusarium/crescimento & desenvolvimento , Actinas/metabolismo , Doenças das Plantas/microbiologia , Proteínas Fúngicas/metabolismo , Proteínas Fúngicas/genética , Triticum/microbiologia , Fungicidas Industriais/farmacologia , Esporos Fúngicos/metabolismo , Esporos Fúngicos/crescimento & desenvolvimento , ReproduçãoRESUMO
With rapid economic growth, the issue of water pollution has become increasingly prominent, and there is a consensus that river basin management systems and cross-regional management coordination mechanisms need improving. In this study, 171 transboundary sections of the Yangtze River Basin were matched with the data of 57 cities to construct panel data from 2015 to 2021. Based on the four-dimensional framework of environment-determination-process-resources, the dynamic qualitative comparative analysis (QCA) method is used to identify the key influencing factors and action paths of water pollution collaborative governance effects. The results show that a single antecedent condition is not necessary to achieve efficient collaborative governance effects, and only the "number of collaborative governance" and "scale of collaboration" conditions played important roles. There are five paths that can achieve efficient collaborative governance effects: economy-oriented, ecology-oriented, technology-oriented, government-oriented, and all-oriented. Additionally, heterogeneous results show that the impact of the regional governance intention on efficient collaborative governance effect is limited in the middle and upstream sections of the Yangtze River Basin, while the downstream sections are more dependent on the basic condition of the basin. The results can help promote effective cross-regional collaboration in the Yangtze River Basin, provide scientific basis for regions to formulate targeted governance measures, and provide models for governance in other regions.
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Rios , Poluição da Água , China , Poluição da Água/prevenção & controle , Conservação dos Recursos NaturaisRESUMO
Background: The rapid spread of bacteria with plasmid-mediated resistance to antibiotics poses a serious threat to public health. The search for potential compounds that can increase the antibacterial activity of existing antibiotics is a promising strategy for addressing this issue. Methods: Synergistic activity of the FDA-approved agent oxethazine combined with colistin was investigated in vitro using checkerboard assays and time-kill curves. The synergistic mechanisms of their combination of oxethazine and colistin was explored by fluorescent dye, scanning electron microscopy (SEM) and LC-MS/MS. The synergistic efficacy was evaluated in vivo by the Galleria mellonella and mouse sepsis models. Results: In this study, we found that oxethazine could effectively enhance the antibacterial activity of colistin against both mcr-positive and -negative pathogens, and mechanistic assays revealed that oxethazine could improve the ability of colistin to destruct bacterial outer membrane and cytoplasmic membrane permeability. In addition, their combination triggered the accumulation of reactive oxygen species causing additional damage to the membrane structure resulting in cell death. Furthermore, oxethazine significantly enhanced the therapeutic efficacy of colistin in two animal models. Conclusion: These results suggested that oxethazine, as a promising antibiotic adjuvant, can effectively enhance colistin activity, providing a potential strategy for treating multidrug-resistant bacteria.
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Antibacterianos , Compostos Azabicíclicos , Aztreonam , Ceftazidima , Combinação de Medicamentos , Escherichia coli , Testes de Sensibilidade Microbiana , beta-Lactamases , Compostos Azabicíclicos/farmacologia , Ceftazidima/farmacologia , Escherichia coli/efeitos dos fármacos , Escherichia coli/genética , beta-Lactamases/genética , Aztreonam/farmacologia , Antibacterianos/farmacologia , Humanos , Infecções por Escherichia coli/microbiologia , Infecções por Escherichia coli/tratamento farmacológico , Farmacorresistência Bacteriana Múltipla/genéticaRESUMO
BACKGROUND: Cervical cancer survivors can experience vaginal length shortening, vaginal stenosis, vaginal elasticity deterioration, sexual frequency reduction and sexual dysfunction. This prospective, uncontrolled, monocentric clinical interventional study aimed to evaluate the effect of vaginal dilation therapy on vaginal condition and sexual function of cervical cancer survivors who had not received timely vaginal dilation. METHODS: A total of 139 patients completed the study. They received 6 months of vaginal dilation therapy. We evaluated their vaginal elasticity, vaginal diameter, vaginal length and sexual function before and after vaginal dilation therapy. Their vaginal conditions were evaluated by customised vaginal moulds, and the sexual function was assessed by female sexual function index. The SPSS 25 software was used to analyse all the data. RESULTS: Age, vaginal diameter and sexual intercourse frequency before diagnosis were significantly associated with female sexual dysfunction of the patients after cancer treatment. Vaginal dilation therapy improved vaginal stenosis, vaginal length and sexual function in all the patients; however, the vaginal elasticity and incidence of sexual dysfunction did not improve significantly. Sexual intercourse frequency before diagnosis, vaginal elasticity, time interval from last treatment and treatment modalities were significantly associated with the change in female sexual function index score before and after vaginal dilation therapy. Patients with a time interval from the last treatment less than 24 months or those who had moderate or good vaginal elasticity, benefitted more from vaginal dilatation therapy. CONCLUSIONS: Cervical cancer survivors who had not received timely vaginal dilation still benefitted from vaginal dilation therapy, irrespective of the treatment methods they received. Moreover, vaginal dilation therapy should be performed as early as possible after cervical cancer treatment.
Cervical cancer survivors can experience vaginal condition deterioration and sexual dysfunction after treatment. Vaginal dilation can help improve vaginal stenosis, vaginal length and sexual function of these patients. However, some medical institutions in China do not provide timely vaginal dilation for this population. This study aimed to explore whether vaginal dilation was still effective for cervical cancer survivors who had not received timely vaginal dilation. The results showed that these patients still benefitted from vaginal dilation, irrespective of the treatment methods they received. Patients with a time interval from the last treatment less than 24 months or those who had moderate or good vaginal elasticity, benefitted more from vaginal dilation. The findings of the study is an indication to developing countries that more attention should be given to sexual issue of cervical cancer survivors in clinical practice, and vaginal dilation therapy should be performed promptly after treatment.
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Sobreviventes de Câncer , Neoplasias do Colo do Útero , Humanos , Feminino , Neoplasias do Colo do Útero/terapia , Vagina , Constrição Patológica/etiologia , Constrição Patológica/terapia , Dilatação/efeitos adversos , Estudos Prospectivos , ElasticidadeRESUMO
Nucleoside diphosphate kinase (NDK) plays an important role in many cellular processes in all organisms. In this study, we functionally characterized a nucleoside diphosphate kinase (FgNdk1) in Fusarium graminearum, a causal agent of Fusarium head blight (FHB). FgNdk1 was involved in the generation of energy in the electron-transfer chain by interacting with succinate dehydrogenase (FgSdhA, FgSdhC1, and FgSdhC2). Deletion of FgNdk1 not only resulted in abnormal mitochondrial morphology, decreased ATP content, defective fungal development, and impairment in the formation of the toxisome but also led to the suppressed expression level of DON biosynthesis enzymes, decreased DON biosynthesis, and declined pathogenicity as well. Furthermore, deletion of FgNdk1 caused increasing transcriptional levels of FgSdhC1 and FgdhC2, in the presence of pydiflumetofen, related to the decreased sensitivity to SDHI fungicides. Overall, this study identified a new regulatory mechanism of FgNdk1 in the pathogenicity and SDHI fungicide sensitivity of Fusarium graminearum.
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Fungicidas Industriais , Fusarium , Núcleosídeo-Difosfato Quinase , Succinato Desidrogenase/genética , Succinato Desidrogenase/metabolismo , Fusarium/genética , Fusarium/metabolismo , Fungicidas Industriais/farmacologia , Fungicidas Industriais/metabolismo , Virulência , Doenças das Plantas/microbiologia , Mitocôndrias/metabolismo , Núcleosídeo-Difosfato Quinase/metabolismoRESUMO
The emergence of plasmid-mediated colistin resistance threatens the efficacy of colistin as a last-resort antibiotic used to treat infection caused by Gram-negative bacteria (GNB). Given the shortage of new antibiotics, the discovery of adjuvants to existing antibiotics is a promising strategy to combat infections caused by multidrug-resistant (MDR) GNB. This study was designed to investigate the potential synergistic antibacterial activity of bavachin, a bioactive compound extracted from the Psoralea Fructus, combined with colistin against MDR GNB. Herein, the synergistic efficacy in vitro and the therapeutic efficacy of colistin combined with bavachin in vivo were evaluated. The synergistic mechanism was detected by fluorescent probe and the transcript levels of mcr-1. Bavachin combined with colistin showed an excellent synergistic activity against GNB, as the FICI ≤ 0.5. In contrast to colistin alone, combination therapy dramatically increased the survival rate of Galleria mellonella and mice in vivo. Moreover, the combination of bavachin and colistin significantly reduced the amount of bacterial biofilm formation, improved the membrane disruption of colistin and inhibited mcr-1 transcription. These findings show that bavachin is a potential adjuvant of colistin, which may provide a new strategy to combat colistin-resistant bacteria infection with lower doses of colistin.
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Antibacterianos , Colistina , Animais , Camundongos , Colistina/farmacologia , Antibacterianos/farmacologia , Flavonoides/farmacologia , Bactérias Gram-Negativas , Farmacorresistência Bacteriana Múltipla , Testes de Sensibilidade MicrobianaRESUMO
Studies suggest that the brain's high efficiency and low energy consumption may be closely related to its small-world topology and critical dynamics. However, existing efforts on the performance-oriented structural evolution of spiking neural networks (SNNs) are time-consuming and ignore the core structural properties of the brain. Here, we introduce a multi-objective Evolutionary Liquid State Machine (ELSM), which blends the small-world coefficient and criticality to evolve models and guide the emergence of brain-inspired, efficient structures. Experiments reveal ELSM's consistent and comparable performance, achieving 97.23% on NMNIST and outperforming LSM models on MNIST and Fashion-MNIST with 98.12% and 88.81% accuracies, respectively. Further analysis shows its versatility and spontaneous evolution of topologies such as hub nodes, short paths, long-tailed degree distributions, and numerous communities. This study evolves recurrent spiking neural networks into brain-inspired energy-efficient structures, showcasing versatility in multiple tasks and potential for adaptive general artificial intelligence.
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Sarcomas (SARC) are a highly heterogeneous cancer type that is prone to recurrence and metastasis. Numerous studies have confirmed that Siglecs are involved in immune signaling and play a key role in regulating immune responses in inflammatory diseases and various cancers. However, studies that systematically explore the therapeutic and prognostic value of Siglecs in SARC patients are very limited. The online databases GEPIA, UALCAN, TIMER, The Kaplan-Meier Plotter, GeneMANIA, cBioPortal, and STING were used in this study. IHC staining was performed on the collected patient tissues, and clinical data were statistically analyzed. The transcript levels of most Siglec family members showed a high expression pattern in SARC. Compared with normal tissues, Siglec-5, Siglec-10, and Siglec-12 were abnormally highly expressed in tumor tissues. Importantly, Siglec-15 was significantly associated with poor prognosis. Functional enrichment analysis showed that the Siglec family was mainly enriched in hematopoietic cell lineages. The genes associated with molecular mutations in the Siglec family were mainly TP53 and MUC16, among which Siglec-2 and Siglec-15 were significantly associated with the survival of patients. The expression levels of all Siglec family members were significantly correlated with various types of immune cells (B cells, CD8 + T cells, CD4 + T cells, macrophages, neutrophils and dendritic cells). Furthermore, a significant correlation was found between the somatic copy number changes of all Siglec molecules and the abundance of immune infiltrates. Our study paints a promising vision for the development of immunotherapy drugs and the construction of prognostic stratification models by investigating the therapeutic and prognostic potential of the Siglec family for SARC.