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Probabilistic machine learning utilizes controllable sources of randomness to encode uncertainty and enable statistical modeling. Harnessing the pure randomness of quantum vacuum noise, which stems from fluctuating electromagnetic fields, has shown promise for high speed and energy-efficient stochastic photonic elements. Nevertheless, photonic computing hardware which can control these stochastic elements to program probabilistic machine learning algorithms has been limited. Here, we implement a photonic probabilistic computer consisting of a controllable stochastic photonic element - a photonic probabilistic neuron (PPN). Our PPN is implemented in a bistable optical parametric oscillator (OPO) with vacuum-level injected bias fields. We then program a measurement-and-feedback loop for time-multiplexed PPNs with electronic processors (FPGA or GPU) to solve certain probabilistic machine learning tasks. We showcase probabilistic inference and image generation of MNIST-handwritten digits, which are representative examples of discriminative and generative models. In both implementations, quantum vacuum noise is used as a random seed to encode classification uncertainty or probabilistic generation of samples. In addition, we propose a path towards an all-optical probabilistic computing platform, with an estimated sampling rate of ~1 Gbps and energy consumption of ~5 fJ/MAC. Our work paves the way for scalable, ultrafast, and energy-efficient probabilistic machine learning hardware.
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BACKGROUND: Fatigue stands out as a prevalent and debilitating symptom in both Multiple Sclerosis (MS) and the aging population. Traditional methods for measuring perceived fatigue may not adequately account for individual activity differences, leading to varied prevalence rates. Perceived fatigability anchors fatigue to specific activities with predetermined intensity and duration, thereby mitigating self-pacing bias. Despite its potential, perceived fatigability is poorly understood in older adults, particularly those with neurological conditions, including MS. This study thus aimed to (1) investigate whether, among older adults, MS was associated with worse perceived physical and mental fatigability; (2) evaluate whether, among older adults with MS (OAMS), greater patient-reported disease-related disability was associated with worse perceived physical and mental fatigability. METHODS: Participants were 96 older adults with a physician-confirmed diagnosis of MS (mean age: 64.6 ± 4.2) and 110 healthy controls (mean age: 68.2 ± 7.2), all confirmed to be dementia-free through established case conference procedures. Physical and mental fatigability were measured using the Pittsburgh Fatigability Scale, a 10-item questionnaire (score range: 0 to 50) designed to assess fatigue levels that individuals expect to feel after engaging in a range of typical activities for older adults. MS disease-related disability was assessed with the Patient Determined Disease Steps scale, which ranges from 0 (normal) to 8 (bedridden), with scores ≥ 2 indicating worse MS-related disability after a median split. Separate linear regression models were performed to investigate associations between group status (MS vs. Control) as the predictor and perceived physical and mental fatigability scores as the outcome variables. Within the MS group, additional linear regression models were performed to explore the relationship between disease-related disability and fatigability levels. All models adjusted for age, sex, race, education, global health, general cognitive function, and depressive symptoms levels. RESULTS: The fully adjusted models yielded the following key findings: OAMS reported significantly higher levels of perceived physical fatigability (M = 25.11 ± 9.67) compared to controls (M = 17.95 ± 8.35) (p = 0.003). Similarly, the perceived mental fatigability in OAMS (M = 16.82 ± 11.79) was significantly greater than that in controls (M = 9.15 ± 7.12) (p = 0.003). Within the MS group, individuals with greater disease-related disability reported significantly greater levels of both physical (M = 30.13 ± 7.71 vs. 18.67 ± 8.00, p < 0.001) and mental fatigability (M = 20.31 ± 12.18 vs. 12.33 ± 9.69, p = 0.009) compared to those with lower MS-related disability. Of note, the significance of these findings persisted in models that adjusted for depressive symptoms. CONCLUSION: Our study provides compelling evidence that OAMS exhibit significantly higher perceived physical and mental fatigability compared to healthy controls. Additionally, worse MS-related disability correlates with worse physical and mental fatigability. These results persist after adjusting for confounders including depressive symptoms. Our findings underscore the necessity of holistic management strategies that cater to both physical and psychological aspects of MS, laying a foundation for future studies to uncover the pathophysiological mechanisms of fatigability in older adults with and without MS.
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Fadiga , Fadiga Mental , Esclerose Múltipla , Humanos , Feminino , Masculino , Esclerose Múltipla/fisiopatologia , Esclerose Múltipla/complicações , Idoso , Pessoa de Meia-Idade , Fadiga/fisiopatologia , Fadiga/etiologia , Fadiga Mental/fisiopatologia , Fadiga Mental/etiologia , Envelhecimento/fisiologiaRESUMO
Skin diseases have become serious issues to human health and affect one-third of the world's population according to the World Health Organisation (WHO). These consist of internal (endogenous) and external (exogenous) factors referring to genetics, hormones, and the body's immune system, as well as environmental situations, UV radiation, or environmental pollution respectively. Generally, Western Medicines (WMs) are usually treated with topical creams or strong medications for skin diseases that help superficially, and often do not treat the root cause. The relief may be instant and strong, sometimes these medicines have adverse reactions that are too strong to be able and sustained over a long period, especially steroid drug type. Chinese Medicinal Herbs (CMHs) are natural resources and relatively mild in the treatment of both manifestation and the root cause of disease. Nowadays, CMHs are attractive to many scientists, especially in studying their formulations for the treatment of skin diseases. METHODS: The methodology of this review was searched in nine electronic databases including WanFang Data, PubMed, Science Direct, Scopus, Web of Science, Springer Link, SciFinder, and China National Knowledge Infrastructure (CNKI), without regard to language constraints. All eligible studies are analysed and summarised. RESULTS: Based on the literature findings, some extracts or active metabolites divided from CMHs, including Curcumin, Resveratrol, Liquorice, Dandelions, Cortex Moutan, and Calendula officinalis L., are effective for the treatment and prevention of skin diseases because of a wide range of pharmacological activities, e.g. anti-bacterial, anti-microbial, anti-virus, and anti-inflammation to enhance the body's immune system. It is also responsible for skin whitening to prevent pigmentation and premature ageing through several mechanisms, such as regulation or inhibition of nuclear factor kappa B (IκB/NF-κB) signalling pathways. CONCLUSION: This is possible to develop CMHs, such as Curcumin, Resveratrol, Liquorice, Dandelions, Cortex Moutan and Calendula officinalis L. The ratio of multiple CMH formulations and safety assessments on human skin diseases required studying to achieve better pharmacological activities. Nano formulations are the future investigation for CMHs to combat skin diseases.
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Recent mounting evidence suggests that shortening of telomere length (TL) is associated with impaired bone health; yet, a genetic causal relationship between TL and osteonecrosis remains uncertain. This study aimed to investigate the potential causal relationship between TL and osteonecrosis using bidirectional two-sample Mendelian randomization (MR). Genome-wide association study summary statistics for TL were sourced from the IEU Open genome-wide association study project, while osteonecrosis data were obtained from the FinnGen Biobank database. A range of MR methodologies-including inverse variance weighting, MR-Egger, weighted median, simple mode, and weighted mode-were utilized for analysis, along with the MR-Egger intercept method for horizontal pleiotropy assessment, and Cochran Q and leave-one-out methods for heterogeneity testing. The forward MR analysis indicated a significant causal relationship between TL and osteonecrosis, suggesting that genetically predicted shorter TL is associated with an elevated risk of developing osteonecrosis (ORâ =â 0.611, 95% confidence interval 0.394-0.948, Pâ =â .028). The reverse MR analysis revealed no significant influence of osteonecrosis on TL (ORâ =â 0.999, 95% confidence interval 0.994-1.005, Pâ =â .802). Analyses for heterogeneity and horizontal pleiotropy yielded robust results. Our study demonstrates that individuals with shorter TL have an increased risk of developing osteonecrosis, whereas osteonecrosis has no effect on TL.
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Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Osteonecrose , Humanos , Osteonecrose/genética , Encurtamento do Telômero/genética , Telômero/genética , Predisposição Genética para DoençaRESUMO
Background: Teriparatide is approved for osteoporosis. Post-marketing surveillance is critical given its widespread use. Objective: To investigate adverse events (AEs) associated with teriparatide using the FAERS database, compare association strengths for key AEs, and explore potential applications to provide clinical reference. Methods: FAERS data from 2004 to 2023 were analyzed. Reports where teriparatide was the primary suspect drug were included. Adverse events were mapped to System Organ Classes and Preferred Terms. Disproportionality analysis using ROR, PRR, BCPNN and EBGM algorithms was conducted to detect safety signals. Results: Out of 107,123 reports with teriparatide as the primary suspect, key AEs identified included pain in extremity (PRR: 4.54), muscle spasms (PRR: 5.11), fractures (PRR range: 17.67-552.95), and increased calcium levels (PRR: 50.73). Teriparatide exhibited a stronger association with increased calcium levels (PRR: 50.73) compared to fractures (PRR range: 17.67-552.95). Notably, only 10.86% of AE reports were submitted by physicians and another 10% by other health professionals. Subset analyses showed a higher consistency of reported AEs from health professionals compared to the general dataset. Off-label uses were noted in conditions such as arthritis (0.57%) and cancer (0.12%). For osteoporosis, main AEs were pain (18.2%), fractures (12.4%), muscle spasms (7.7%), and nausea (6.5%), while glucocorticoid-induced osteoporosis AEs included fractures (24.1%), pain (13.2%), decreased bone density (9.8%), and nausea (5.1%). Conclusion: Our findings provide real-world safety data on teriparatide, revealing key AEs and their association strengths. The low proportion of reports by healthcare professionals suggests the need for cautious interpretation. Continuous vigilance and further research are imperative to guide teriparatide's clinical use.
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Chronic prostatitis is a process of kidney deficiency and blood stasis mixed with various pathological factors involving the essence chamber, which is manifested as kidney deficiency and blood stasis. Based on the concept of the "brain-heart-kidney-essence chamber" axis of medication, Xiongji Formula is applied to the treatment of chronic prostatitis, due to its "simultaneous holistic and local action" and effects of tonifying the kidney yang and assisting the systemic yang, acting on the brain, heart and kidney as a whole, and meanwhile activating blood circulation, eliminating blood stasis and restoring the function of the essence chamber. This paper discusses the etiology and pathogenesis of chronic prostatitis with kidney deficiency and blood stasis in Chinese medicine, expounds the significance of "brain-heart-kidney-essence chamber" axis of medication, and explores the specific value and clinical application of Xiongji Formula.
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Medicamentos de Ervas Chinesas , Prostatite , Masculino , Prostatite/tratamento farmacológico , Humanos , Medicamentos de Ervas Chinesas/uso terapêutico , Doença Crônica , Medicina Tradicional Chinesa/métodos , Rim , Encéfalo , Coração/fisiopatologiaRESUMO
This study aims to analyze the risk factors associated with delayed postoperative bleeding (DPPB) following colorectal polyp surgery, develop a dynamic nomogram and evaluate the model efficacy, provide a reference for clinicians to identify the patients at high risk of DPPB. Retrospective study was done on patients who underwent endoscopic colorectal polypectomy at the First Hospital of Lanzhou University from January 2020 to March 2023. Differences between the group with and without DPPB were compared, and independent risk factors for DPPB occurrence were identified through univariate analysis and combination LASSO and logistic regression. A dynamic nomogram was constructed based on multiple logistic regression to predict DPPB following colorectal polyp surgery. Model evaluation included receiver operating characteristic (ROC), Calibration curve, Decision curve analysis (DCA). DPPB occurred in 38 of the 1544 patients included. multivariate analysis showed that direct oral anticoagulants (DOACs), polyp location in the right hemi colon, polyp diameter, drink, and prophylactic hemoclips were the independent risk factors for DPPB and dynamic nomogram were established. Model validation indicated area under the ROC curve values of 0.936, 0.796, and 0.865 for the training set, validation set, and full set, respectively. The calibration curve demonstrated a strong alignment between the predictions of the column-line diagram model and actual observations. The decision curve analysis (DCA) displayed a significant net clinical benefit across the threshold probability range of 0-100%. The dynamic nomogram aids clinicians in identifying high-risk patients, enabling personalized diagnosis and treatment.
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Pólipos do Colo , Nomogramas , Hemorragia Pós-Operatória , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Hemorragia Pós-Operatória/etiologia , Hemorragia Pós-Operatória/diagnóstico , Hemorragia Pós-Operatória/epidemiologia , Estudos Retrospectivos , Fatores de Risco , Pólipos do Colo/cirurgia , Idoso , Curva ROC , AdultoRESUMO
Iturin A (IA) encapsulated in chitosan (CS) microcapsules (IA/CS) underwent thorough physicochemical characterization using thermogravimetric analysis (TGA), Fourier-transform infrared (FTIR) spectroscopy, and scanning electron microscopy (SEM). SEM confirmed the smooth, spherical morphology of the IA/CS microcapsules, while FTIR revealed complex intermolecular interactions between IA and CS. TGA demonstrated thermal stability within the 0-100 °C range, while particle size analysis revealed an average diameter of 553.4 nm. To evaluate IA/CS efficacy in post-harvest grape preservation, grapes were treated with sterile water (CK), 10 g/L CS, 0.1 g/L IA/CS, and 0.1 g/L chitosan empty microcapsules (CKM), then stored at 25 °C for 16 days. IA/CS significantly reduced decay and respiration intensity by 52.3 % and 23.8 %, respectively, compared to CK. IA/CS treatment also inhibited abscission rate, weight loss, firmness reduction, total soluble solids consumption, titratable acidity consumption, polyphenol oxidase, and peroxidase activities on par with CS treatment (p > 0.05), but performed better than CK (reductions of 26.9 %, 41.2 %, 25.8 %, 27.2 %, 24.2 %, 19.4 %, and 17.4 %, respectively) and CKM (p < 0.05). Sensory evaluation confirmed that IA/CS effectively suppressed decay, slowed post-harvest metabolic activity, and maintained grape quality. Therefore, IA/CS microcapsules offer a promising method for extending grape shelf life and preserving quality.
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Cápsulas , Quitosana , Conservação de Alimentos , Vitis , Quitosana/química , Vitis/química , Conservação de Alimentos/métodos , Tamanho da Partícula , Frutas/química , Espectroscopia de Infravermelho com Transformada de FourierRESUMO
BACKGROUND: Osteoporosis (OP), characterized by low bone mass and increased fracture risk, is a prevalent skeletal disorder. Teriparatide (TP) and abaloparatide (ABL) are anabolic agents that may reduce fracture incidence, but their impact on musculoskeletal and connective tissue disorders (MCTD) risk is uncertain. RESEARCH DESIGN AND METHODS: A retrospective, observational disproportionality analysis was conducted utilizing FAERS data from Q1 2004 to Q3 2023, where TP or ABL was identified as the primary suspect drug. Multiple data mining algorithms, including reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and multi-item gamma Poisson shrinker (MGPS), were employed to detect MCTD safety signals. RESULTS: A total of 366,747 TP-related and 422,377 ABL-related cases were identified, predominantly among female patients aged ≥45 years. The top specific AEs involved musculoskeletal, connective tissue, and administration site disorders. Comparative analysis revealed a higher frequency of AEs related to the nervous, cardiovascular, and gastrointestinal systems for ABL compared to TP. Both drugs exhibited strong signals for arthralgia, limb pain, back pain, muscle spasms, bone pain, muscle pain, and muscle weakness. CONCLUSION: The analysis suggests a potential MCTD risk with TP and ABL treatment in OP patients, highlighting the need for AE monitoring and management in clinical practice. This contributes to a better understanding of the safety profiles of these anabolic medications.
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BACKGROUND: To evaluate the incidence of metabolic syndrome (MetS) in patients with unilateral and bilateral staghorn calculi (SC) and evaluate the impact on the outcome of percutaneous nephrolithotomy (PCNL). METHODS: The clinical data of patients who underwent PCNL for the treatment of SC between 2019 and 2022 were retrospectively reviewed. SC was divided into unilateral and bilateral. The incidence of MetS was compared between the patients with unilateral SC and the patients with bilateral SC, and the impact on the outcome of PCNL was assessed. RESULTS: A total of 1778 patients underwent PCNL between 2019 and 2022. After screening computed tomography, 379 patients were confirmed to have SC, finally, leaving 310 patients with follow-up and complete data to be included in the study. Eighty-four had bilateral SC and 226 had unilateral SC. The patients with bilateral SC had a significantly higher body mass index and higher rates of complete staghorn stones and metabolic syndrome. Higher body mass index, hypertension, diabetes mellitus, hyperlipidaemia, and MetS were present in 62.58%, 44.84%, 21.94%, 60.65% and 27.42% of all patients, respectively. The number of MetS components remained significantly associated with bilateral SC. Specifically, when the number of MetS components increases from 0 to 3-4, the likelihood of developing bilateral staghorn calculi increases by 21.967 times. Eighty-five patients with MetS( +) had a higher rate of overall complications (number (N)(%), 29 (34.12) vs.33 (14.46), P < 0.001) and a comparable stone-free rate to 225 MetS(-) patients. Multivariable analysis confirmed that hyperlipidaemia (P = 0.044, odds ratio [OR] = 1.991, 95% confidence interval [CI] 1.020-3.888) and MetS (P = 0.005, OR = 2.427, 95% CI 1.316-4.477) were independent risk factors for overall complications. CONCLUSIONS: MetS is correlated with the formation of bilateral SC and is the main predictor for complications of PCNL especially for low-grade complications (I-II).
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Síndrome Metabólica , Nefrolitotomia Percutânea , Cálculos Coraliformes , Humanos , Síndrome Metabólica/complicações , Síndrome Metabólica/epidemiologia , Masculino , Nefrolitotomia Percutânea/efeitos adversos , Feminino , Pessoa de Meia-Idade , Estudos Retrospectivos , Incidência , Cálculos Coraliformes/cirurgia , Adulto , Resultado do Tratamento , Idoso , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologiaRESUMO
Introduction: Emerging evidence suggests that the gut microbiota is closely associated with bone homeostasis. However, little is known about the relationships among the bone mineral density (BMD) index, bone turnover markers, and the gut microbiota and its metabolites in postmenopausal women. Methods: In this study, to understand gut microbiota signatures and serum metabolite changes in postmenopausal women with reduced BMD, postmenopausal individuals with normal or reduced BMD were recruited and divided into normal and OS groups. Feces and serum samples were collected for 16S rRNA gene sequencing, liquid chromatography coupled with mass spectrometry (LC-MS)-based metabolomics and integrated analysis. Results: The results demonstrated that bacterial richness and diversity were greater in the OS group than in the normal group. Additionally, distinguishing bacteria were found among the two groups and were closely associated with the BMD index and bone turnover markers. Metabolomic analysis revealed that the expression of serum metabolites, such as etiocholanolone, testosterone sulfate, and indole-3-pyruvic acid, and the corresponding signaling pathways, especially those involved in tryptophan metabolism, fatty acid degradation and steroid hormone biosynthesis, also changed significantly. Correlation analysis revealed positive associations between normal group-enriched Bacteroides abundance and normal group-enriched etiocholanolone and testosterone sulfate abundances; in particular, Bacteroides correlated positively with BMD. Importantly, the tryptophan-indole metabolism pathway was uniquely metabolized by the gut bacteria-derived tnaA gene, the predicted abundance of which was significantly greater in the normal group than in the control group, and the abundance of Bacteroides was strongly correlated with the tnaA gene. Discussion: Our results indicated a clear difference in the gut microbiota and serum metabolites of postmenopausal women. Specifically altered bacteria and derived metabolites were closely associated with the BMD index and bone turnover markers, indicating the potential of the gut microbiota and serum metabolites as modifiable factors and therapeutic targets for preventing osteoporosis.
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Bactérias , Densidade Óssea , Fezes , Microbioma Gastrointestinal , Metabolômica , Pós-Menopausa , RNA Ribossômico 16S , Humanos , Feminino , Pós-Menopausa/sangue , Fezes/microbiologia , Pessoa de Meia-Idade , RNA Ribossômico 16S/genética , Bactérias/classificação , Bactérias/genética , Bactérias/metabolismo , Idoso , Metaboloma , Biomarcadores/sangue , Cromatografia Líquida , Espectrometria de Massas , Osteoporose Pós-Menopausa/sangue , Osteoporose Pós-Menopausa/microbiologia , Remodelação ÓsseaRESUMO
BACKGROUND: Currently, industrial fermentation of Botrytis cinerea is a significant source of abscisic acid (ABA). The crucial role of ABA in plants and its wide range of applications in agricultural production have resulted in the constant discovery of new derivatives and analogues. While modifying the ABA synthesis pathway of existing strains to produce ABA derivatives is a viable option, it is hindered by the limited synthesis capacity of these strains, which hinders further development and application. RESULTS: In this study, we knocked out the bcaba4 gene of B. cinerea TB-31 to obtain the 1',4'-trans-ABA-diol producing strain ZX2. We then studied the fermentation broth of the batch-fed fermentation of the ZX2 strain using metabolomic analysis. The results showed significant accumulation of 3-hydroxy-3-methylglutaric acid, mevalonic acid, and mevalonolactone during the fermentation process, indicating potential rate-limiting steps in the 1',4'-trans-ABA-diol synthesis pathway. This may be hindering the flow of the synthetic pathway. Additionally, analysis of the transcript levels of terpene synthesis pathway genes in this strain revealed a correlation between the bchmgr, bcerg12, and bcaba1-3 genes and 1',4'-trans-ABA-diol synthesis. To further increase the yield of 1',4'-trans-ABA-diol, we constructed a pCBg418 plasmid suitable for the Agrobacterium tumefaciens-mediated transformation (ATMT) system and transformed it to obtain a single-gene overexpression strain. We found that overexpression of bchmgr, bcerg12, bcaba1, bcaba2, and bcaba3 genes increased the yield of 1',4'-trans-ABA-diol. The highest yielding ZX2 A3 strain was eventually screened, which produced a 1',4'-trans-ABA-diol concentration of 7.96 mg/g DCW (54.4 mg/L) in 144 h of shake flask fermentation. This represents a 2.1-fold increase compared to the ZX2 strain. CONCLUSIONS: We utilized metabolic engineering techniques to alter the ABA-synthesizing strain B. cinerea, resulting in the creation of the mutant strain ZX2, which has the ability to produce 1',4'-trans-ABA-diol. By overexpressing the crucial genes involved in the 1',4'-trans-ABA-diol synthesis pathway in ZX2, we observed a substantial increase in the production of 1',4'-trans-ABA-diol.
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Ácido Abscísico , Botrytis , Fermentação , Engenharia Metabólica , Botrytis/metabolismo , Botrytis/genética , Ácido Abscísico/metabolismo , Engenharia Metabólica/métodos , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismoRESUMO
In our search for neuroprotective agents, six previously undescribed highly oxidized guaiane sesquiterpenes, linderaggrols A-F (1-6), together with three known sesquiterpenes, were isolated from the roots of Lindera aggregata (Sims) Kosterm. Their structures including absolute configurations were established by a combination of NMR spectroscopic techniques and single crystal X-ray diffraction experiments. Compounds 1-6 represented the first instances of guaiane 12(8),15(6)-dilactones. Additionally, compound 6 possessed a rare 1,8-O-bridge. Neuroprotective effects against erastin-induced ferroptosis on HT-22 cells showed that some compounds demonstrated neuroprotective effects at 20.0 µM.
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Lindera , Fármacos Neuroprotetores , Raízes de Plantas , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/isolamento & purificação , Raízes de Plantas/química , Lindera/química , Estrutura Molecular , Oxirredução , Sesquiterpenos de Guaiano/química , Sesquiterpenos de Guaiano/farmacologia , Sesquiterpenos de Guaiano/isolamento & purificação , Camundongos , Lactonas/farmacologia , Lactonas/química , Lactonas/isolamento & purificação , Animais , Sobrevivência Celular/efeitos dos fármacos , Linhagem Celular , Relação Estrutura-Atividade , Relação Dose-Resposta a Droga , Modelos MolecularesRESUMO
Abscisic acid (ABA) is a conserved and important "sesquiterpene signaling molecule" widely distributed in different organisms with unique biological functions. ABA coordinates reciprocity and competition between microorganisms and their hosts. In addition, ABA also regulates immune and stress responses in plants and animals. Therefore, ABA has a wide range of applications in agriculture, medicine and related fields. The plant pathogenic ascomycete B. cinerea has been extensively studied as a model strain for ABA production. Nevertheless, there is a relative dearth of research regarding the regulatory mechanism governing ABA biosynthesis in B. cinerea. Here, we discovered that H3K9 methyltransferase BcDIM5 is physically associated with the H3K14 deacetylase BcHda1. Deletion of Bcdim5 and Bchda1 in the high ABA-producing B. cinerea TB-31 led to severe impairment of ABA synthesis. The combined analysis of RNA-seq and ChIP-seq has revealed that the absence of BcDIM5 and BcHda1 has resulted in significant global deficiencies in the normal distribution and level of H3K9me3 modification. In addition, we found that the cause of the decreased ABA production in the ΔBcdim5 and ΔBchda1 mutants was due to cluster gene repression caused by the emergence of hyper-H3K9me3 in the ABA gene cluster. We concluded that the ABA gene cluster is co-regulated by BcDIM5 and BcHda1, which are essential for the normal distribution of the B. cinerea TB-31 ABA gene cluster H3K9me3. This work expands our understanding of the complex regulatory network of ABA biosynthesis and provides a theoretical basis for genetic improvement of high-yielding ABA strains.
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Parkinson's disease (PD) patients exhibit deficits in primary sensorimotor and higher-order executive functions. The gradient reflects the functional spectrum in sensorimotor-associated areas of the brain. We aimed to determine whether the gradient is disrupted in PD patients and how this disruption is associated with treatment outcome. Seventy-six patients (mean age, 59.2 ± 12.4 years [standard deviation], 44 women) and 34 controls participants (mean age, 58.1 ± 10.0 years [standard deviation], 19 women) were evaluated. We explored functional and structural gradients in PD patients and control participants. Patients were followed during 2 weeks of multidisciplinary intensive rehabilitation therapy (MIRT). The Unified Parkinson's Disease Rating Scale Part III (UPDRS-III) was administered to patients before and after treatment. We investigated PD-related alterations in the principal functional and structural gradients. We further used a support vector machine (SVM) and correlation analysis to assess the classification ability and treatment outcomes related to PD gradient alterations, respectively. The gradients showed significant differences between patients and control participants, mainly in somatosensory and visual networks involved in primary function, and higher-level association networks (dorsal attentional network (DAN) and default mode network (DMN)) related to motor control and execution. On the basis of the combined functional and structural gradient features of these networks, the SVM achieved an accuracy of 91.2% in discriminating patients from control participants. Treatment reduced the gradient difference. The altered gradient exhibited a significant correlation with motor improvement and was mainly distributed across the visual network, DAN and DMN. This study revealed damage to gradients in the brain characterized by sensorimotor and executive control deficits in PD patients. The application of gradient features to neurological disorders could lead to the development of potential diagnostic and treatment markers for PD.
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Doença de Parkinson , Córtex Sensório-Motor , Humanos , Feminino , Pessoa de Meia-Idade , Idoso , Imageamento por Ressonância Magnética , Função Executiva , Mapeamento EncefálicoRESUMO
Achieving the complete mineralization of persistent pollutants in wastewater is still a big challenge. Here, we propose an efficient photo-self-Fenton reaction for the degradation of different pollutants using the high-density (Ag: 22â wt %) of atomically dispersed AgCo dual sites embedded in graphic carbon nitride (AgCo-CN). Comprehensive experimental measurements and density functional theory (DFT) calculations demonstrate that the Ag and Co dual sites in AgCo-CN play a critical role in accelerating the photoinduced charge separation and forming the self-Fenton redox centers, respectively. The bimetallic AgCo-CN exhibited excellent photocatalytic performance toward the phenol even under extreme conditions due to an efficient degradation pathway and in situ generation of the hydrogen peroxide producing the main active oxygen species (â OH and 1 O2 ) and showed long-term activity in a self-design photo-Filter reactor for the purification of the phenol. Our discoveries pave the way for the design of efficient single-atoms photocatalysts-based photo-self-Fenton reaction for recalcitrant pollutant treatment.
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Owing to the avascular and aneural nature of cartilage tissue and the complex, multilayered structure of osteochondral units, the repair of osteochondral defects poses significant challenges. Traditional monophasic scaffolds have difficulty meeting the repair requirements of both cartilage and bone tissues, whereas multiphasic scaffolds face the issue of interfacial integration. In this study, a triphasic methylpropenylated gelatin (GELMA) hydrogel scaffold was employed to repair osteochondral defects, in which three layers of hydrogel were covalently bonded through a sequential curing process. The upper layer of the scaffold was covalently bonded with chondroitin sulfate, promoting chondrogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). The middle and lower layers of the hydrogel introduced a gradient content of hydroxyapatite, forming a scaffold with gradient mechanical strength and effectively enhancing its angiogenic and osteogenic induction capabilities. Finally, the triphasic integrated scaffold cartilage and bone repair performance was evaluated using a rabbit knee joint defect model. The results demonstrated that the scaffold facilitated accelerated regeneration of osteochondral defects, thus providing a novel strategy for the treatment of osteochondral defects.
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Engenharia Tecidual , Alicerces Teciduais , Animais , Coelhos , Alicerces Teciduais/química , Engenharia Tecidual/métodos , Cartilagem , Osso e Ossos , Hidrogéis/químicaRESUMO
OBJECTIVE: Osteonecrosis of the femoral head (ONFH) is a common orthopedic disease with a high disability rate. The clinical effect of BuShenHuoXue decoction (BSHX) for ONFH is satisfactory. We aimed to elucidate the potential angiogenic mechanisms of BSHX in a rat femoral osteonecrosis model and bone marrow mesenchymal stem cells (BMSCs). METHODS: With in vivo experiments, we established the steroid-induced osteonecrosis of the femoral head (SONFH) model using Sprague-Dawley (SD) rats (8-week-old). The rats were randomly divided into five group of 12 rats each and given the corresponding interventions: control, model (gavaged with 0.9% saline), BSHX low-, medium- and high-dose groups (0.132 3, 0.264 6, and 0.529 2 g/mL BSHX solution by gavage). After 12 weeks, haematoxylin and eosin (H&E) staining was preformed to evaluate rat osteonecrosis. the expression of angiogenic factors (CD31, VEGFA, KDR, VWF) in rat femoral head was detected by immunohistochemistry, qPCR and western blotting. In cell experiment, BMSCs were isolated and cultured in the femoral bone marrow cavity of 4-week-old SD rats. BMSCs were randomly divided into eight groups and intervened with different doses of BSHX-containing serum and glucocorticoids: control group (CG); BSHX low-, medium-, and high-dose groups (CG + 0.661 5, 1.323, and 2.646 g/kg BSHX gavage rat serum); dexamethasone (Dex) group; and Dex + BSHX low-, medium-, and high-dose groups (Dex + 0.661 5, 1.323, and 2.646 g/kg BSHX gavaged rat serum), the effects of BSHX-containing serum on the angiogenic capacity of BMSCs were examined by qPCR and Western blotting. A co-culture system of rat aortic endothelial cells (RAOECs) and BMSCs was then established. Migration and angiogenesis of RAOECs were observed using angiogenesis and transwell assay. Identification of potential targets of BSHX against ONFH was obtained using network pharmacology. RESULTS: BSHX upregulated the expression of CD31, VEGFA, KDR, and VWF in rat femoral head samples and BMSCs (p < 0.05, vs. control group or model group). Different concentrations of BSHX-containing serum significantly ameliorated the inhibition of CD31, VEGFA, KDR and VWF expression by high concentrations of Dex. BSHX-containing serum-induced BMSCs promoted the migration and angiogenesis of RAOECs, reversed to some extent the adverse effect of Dex on microangiogenesis in RAOECs, and increased the number of microangiogenic vessels. Furthermore, we identified VEGFA, COL1A1, COL3A1, and SPP1 as important targets of BSHX against ONFH. CONCLUSION: BSHX upregulated the expression of angiogenic factors in the femoral head tissue of ONFH model rats and promoted the angiogenic capacity of rat RAOECs and BMSCs. This study provides an important basis for the use of BSHX for ONFH prevention and treatment.
Assuntos
Necrose da Cabeça do Fêmur , Osteonecrose , Ratos , Animais , Cabeça do Fêmur , Necrose da Cabeça do Fêmur/induzido quimicamente , Necrose da Cabeça do Fêmur/tratamento farmacológico , Necrose da Cabeça do Fêmur/metabolismo , Células Endoteliais/metabolismo , Farmacologia em Rede , Fator de von Willebrand/efeitos adversos , Ratos Sprague-Dawley , OsteogêneseRESUMO
Autophagy is a conserved lysosomal degradation process that has recently been found to be associated with stress-related psychological diseases. However, previous studies have yielded inconsistent results regarding the effects of various stress patterns on autophagy in different brain regions. This discrepancy may arise from differences in autophagy flux across nuclei, the type of stress experienced, and the timing of autophagy assessment after stress exposure. In this study, we assessed autophagy flux in the rat hippocampus (HPC), medial prefrontal cortex (mPFC), and basal lateral amygdala (BLA) by quantifying protein levels of p-ULK1, LC3-I, LC3-II, and p62 via Western blot analysis at 15 min, 30 min, and 60 min following various stress paradigms: restraint stress, foot shock, single corticosterone injection, and chronic corticosterone treatment. We found that: (1) hippocampal autophagy decreased within 1 h of restraint stress, foot shock, and corticosterone injection, except for a transient increase at 30 min after restraint stress; (2) autophagy increased 1 h after restraint stress and corticosterone injection but decreased 1 h after foot shock in mPFC; (3) In BLA, autophagy increased 1 h after foot shock and corticosterone injection but decreased 1 h after restraint stress; (4) Chronic corticosterone increased autophagy in mPFC and BLA but had no effects in HPC. These findings suggest that stress regulates autophagy in a brain region- and stressor-specific manner within 1 h after stress exposure, which may contribute to the development of stress-related psychological disorders.