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1.
J Alzheimers Dis ; 98(3): 1133-1143, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38578896

RESUMO

Background: Patients with transient ischemic attack (TIA) or ischemic stroke demonstrate an increased risk of cognitive dysfunction. Accumulating evidence indicates that ischemic cerebrovascular disease (ICVD) may interact with the amyloid/tau/neurodegeneration (AT[N]) biomarkers to promote dementia. However, the precise pathological mechanisms remain to be fully characterized. Objective: To elucidate the interrelationships among ICVD, ATN biomarkers in cerebrospinal fluid (CSF), and cognition. Methods: A total of 2524 participants were recruited from the CABLE study. ICVD referred to TIA/ischemic stroke. Cognitive performance was assessed by China Modified Mini-Mental State Examination (CM-MMSE) and Montreal Cognitive Assessment-b (MoCA-b). Multivariate linear regression analyses were performed to evaluate the associations of ICVD with CSF ATN biomarkers and cognition. Causal mediation analyses were used to identify whether the association was mediated by ATN biomarkers. Results: ICVD was associated with higher total-tau (t-tau) (p = 2.828×10-2) and poorer cognition (CM-MMSE: p = 1.539×10-5, MoCA-b: p = 4.552×10-6). Additionally, no discernible correlation surfaced between ICVD and amyloid-ß (Aß) 42 (p = 6.910×10-1) or phosphorylated tau (p-tau) (p = 4.324×10-1). The influence of ICVD on cognitive function was partially mediated by CSF t-tau (CM-MMSE: proportion: 2.74%, MoCA-b: proportion: 2.51%). Subgroup analyses revealed the influences of t-tau were especially evident in male (CM-MMSE: proportion: 5.45%, MoCA-b: proportion: 5.38%) and mid-life group (CM-MMSE: proportion: 9.83%, MoCA-b: proportion: 5.31%). Conclusions: These results delineated t-tau as a potential mediator for the influence of ICVD on cognition. Targeting brain ischemia and alleviating neuronal injury induced by ischemia may be a promising approach for preventing cognitive decline.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Ataque Isquêmico Transitório , AVC Isquêmico , Humanos , Masculino , Proteínas tau/líquido cefalorraquidiano , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Doença de Alzheimer/psicologia
2.
Materials (Basel) ; 17(7)2024 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-38612094

RESUMO

The accurate online detection of laser welding penetration depth has been a critical problem to which the industry has paid the most attention. Aiming at the laser welding process of TC4 titanium alloy, a multi-sensor monitoring system that obtained the keyhole/molten pool images and laser-induced plasma spectrum was built. The influences of laser power on the keyhole/molten pool morphologies and plasma thermo-mechanical characteristics were investigated. The results showed that there were significant correlations among the variations of the keyhole-molten pool, plasma spectrum, and penetration depth. The image features and spectral features were extracted by image processing and dimension-reduction methods, respectively. Moreover, several penetration depth prediction models based on single-sensor features and multi-sensor features were established. The mean square error of the neural network model built by multi-sensor features was 0.0162, which was smaller than that of the model built by single-sensor features. The established high-precision model provided a theoretical basis for real-time feedback control of the penetration depth in the laser welding process.

3.
Opt Express ; 32(6): 8778-8790, 2024 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-38571127

RESUMO

Recent advancements in ptychography have demonstrated the potential of coded ptychography (CP) for high-resolution optical imaging in a lensless configuration. However, CP suffers imaging throughput limitations due to scanning inefficiencies. To address this, we propose what we believe is a novel 'fly-scan' scanning strategy utilizing two eccentric rotating mass (ERM) vibration motors for high-throughput coded ptychographic microscopy. The intrinsic continuity of the 'fly-scan' technique effectively eliminates the scanning overhead typically encountered during data acquisition. Additionally, its randomized scanning trajectory considerably reduces periodic artifacts in image reconstruction. We also developed what we believe to be a novel rolling-shutter distortion correction algorithm to fix the rolling-shutter effects. We built up a low-cost, DIY-made prototype platform and validated our approach with various samples including a resolution target, a quantitative phase target, a thick potato sample and biospecimens. The reported platform may offer a cost-effective and turnkey solution for high-throughput bio-imaging.

4.
PLoS One ; 19(4): e0301096, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38564612

RESUMO

This retrospective study aimed to determine the short-term efficacy and safety of brolucizumab treatment for recalcitrant neovascular age-related macular degeneration (nAMD) in a real-world setting in Taiwan. Recalcitrant nAMD patients who were treated with brolucizumab from November 2021 to August 2022 at Taipei Veterans General Hospital were included. Patients were followed for 3 months after switching to brolucizumab. The primary outcomes were changes in mean best-corrected visual acuity (BCVA) and central retinal thickness (CRT) from baseline to the third month. The secondary outcomes included the incidence of intraocular inflammation (IOI), proportion of patients with subretinal and intraretinal fluid (SRF and IRF), and change in pigment epithelial detachment (PED) height from baseline to the third month. The significance level was considered as p < .05 in all tests. A total of 38 patients (40 eyes) with a mean (±SD) age of 76.3 (±10.84) years were included. The baseline BCVA was 0.92±0.64 logMAR, and the CRT and PED height were 329.0±171.18 and 189.8±114.94 um, respectively. The patients had a significant reduction in CRT and resolution of IRF and SRF from baseline to the third month. There were numerical improvements in mean BCVA and PED height, but they were not significant. The percentages of achieving at least 0.1, 0.2, and 0.3 logMAR (equivalent to 5, 10, 15 ETDRS letters) visual gain were 50%, 37.5%, and 30%, respectively, during the first 3 months of follow-up. No IOI occurred in these patients. This study demonstrated that brolucizumab had good short-term structural and functional efficacy in recalcitrant nAMD patients.


Assuntos
Anticorpos Monoclonais Humanizados , Degeneração Macular , Descolamento Retiniano , Degeneração Macular Exsudativa , Humanos , Idoso , Idoso de 80 Anos ou mais , Resultado do Tratamento , Seguimentos , Estudos Retrospectivos , Receptores de Fatores de Crescimento do Endotélio Vascular/uso terapêutico , Tomografia de Coerência Óptica , Acuidade Visual , Injeções Intravítreas , Descolamento Retiniano/etiologia , Transtornos da Visão/complicações , Degeneração Macular/tratamento farmacológico , Degeneração Macular/epidemiologia , Degeneração Macular/complicações , China , Inibidores da Angiogênese/uso terapêutico , Degeneração Macular Exsudativa/tratamento farmacológico , Degeneração Macular Exsudativa/complicações
5.
Nat Commun ; 15(1): 2606, 2024 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-38521807

RESUMO

The diffusion model is used to calculate both the time-averaged flow of particles in stochastic media and the propagation of waves averaged over ensembles of disordered static configurations. For classical waves exciting static disordered samples, such as a layer of paint or a tissue sample, the flux transmitted through the sample may be dramatically enhanced or suppressed relative to predictions of diffusion theory when the sample is excited by a waveform corresponding to a transmission eigenchannel. Even so, it is widely assumed that the velocity of waves is irretrievably randomized in scattering media. Here we demonstrate in microwave measurements and numerical simulations that the statistics of velocity of different transmission eigenchannels are distinct and remains so on all length scales and are identical on the incident and output surfaces. The interplay between eigenchannel velocities and transmission eigenvalues determines the energy density within the medium, the diffusion coefficient, and the dynamics of propagation. The diffusion coefficient and all scattering parameters, including the scattering mean free path, oscillate with the width of the sample as the number and shape of the propagating channels in the medium change.

6.
J Alzheimers Dis ; 98(2): 629-642, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38427482

RESUMO

Background: Frailty is a vulnerability state increasing the risk of many adverse health outcomes, but little is known about the effects of frailty on neuropsychiatric health. Objective: To explore the associations between frailty and the risk of neuropsychiatric symptoms (NPSs) in Alzheimer's disease (AD), especially in its different clinical stages. Methods: We included 2,155 individuals assessed using modified frailty index-11 (mFI-11), Neuropsychiatric Inventory (NPI) and Neuropsychiatric Inventory Questionnaire (NPI-Q) in the Alzheimer's Disease Neuroimaging Initiative (ADNI). The relationships between frailty and NPSs were explored with logistic regression models and Cox proportional hazard regression models. Causal mediation analyses were conducted to explore the mediation factors between frailty and NPSs. Results: Among mild cognitive impairment (MCI) participants, frailty was cross-sectionally associated with an increased risk of apathy, and longitudinally associated with increased risk of depression and apathy. Among AD participants, frailty was cross-sectionally associated with increased risk of depression and anxiety, and longitudinally associated with an increased risk of apathy. Among participants with cognitive progression, frailty was associated with increased risk of depression and apathy. In MCI participants, the influence of frailty on NPSs was partially mediated by hippocampus volume, whole brain volume, and monocytes, with mediating proportions ranging from 8.40% to 9.29%. Conclusions: Frailty was associated with NPSs such as depression, anxiety, and apathy among MCI, AD, and cognitive progression participants. Atrophy of the hippocampus and whole brain, as well as peripheral immunity may be involved in the potential mechanisms underlying the above associations.


Assuntos
Doença de Alzheimer , Apatia , Disfunção Cognitiva , Fragilidade , Humanos , Doença de Alzheimer/complicações , Doença de Alzheimer/diagnóstico por imagem , Estudos Longitudinais , Fragilidade/complicações , Disfunção Cognitiva/psicologia , Testes Neuropsicológicos
7.
Cell Mol Biol (Noisy-le-grand) ; 70(2): 104-112, 2024 Feb 29.
Artigo em Inglês | MEDLINE | ID: mdl-38430034

RESUMO

Acute lung injury (ALI) is a serious lung disease. The apoptosis and inflammation of pulmonary microvascular endothelial cells (PMVECs) are the primary reasons for ALI. This study aimed to explore the treatment effect and regulatory mechanism of bone mesenchymal stem cell-derived exosomes (BMSC-expos) on ALI. PMVECs were stimulated by Lipopolysaccharide (LPS) to imitate ALI environment. Cell viability was determined by CCK-8 assay. Cell apoptosis was evaluated by TUNEL and flow cytometry. ELISA was utilized for testing the contents of TNF-α, IL-1ß, IL-6, and IL-17. Western blot was applied for testing the levels of autophagy-related proteins LC3, p62, and Beclin-1. RNA interaction was determined by luciferase reporter assay. The ALI rat model was established by intratracheal injection of LPS. Evans blue staining was utilized for detecting pulmonary vascular permeability. Our results showed that LPS stimulation notably reduced cell viability, increased cell apoptosis rate, and enhanced the contents of inflammatory factors in PMVECs. However, BMSC-exo treatment significantly abolished the promoting effects of LPS on cell injury. In addition, we discovered that BMSC-exo treatment notably activated autophagy in LPS-induced PMVECs. Furthermore, BMSC-expos upregulated miR-26a-3p expression and downregulated PTEN in PMVECs. MiR-26a-3p was directly bound to PTEN. MiR-26a-3p overexpression reduced cell apoptosis, and inflammation and promoted autophagy by silencing PTEN. Animal experiments proved that miR-26a-3p overexpression effectively improved LPS-induced lung injury in rats. The results proved that BMSC-expos promotes autophagy to attenuate LPS-induced apoptosis and inflammation in pulmonary microvascular endothelial cells via miR-26a-3p/PTEN axis.


Assuntos
Lesão Pulmonar Aguda , Células-Tronco Mesenquimais , MicroRNAs , Ratos , Animais , Lipopolissacarídeos/toxicidade , Células Endoteliais/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Inflamação/genética , Inflamação/metabolismo , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/genética , Lesão Pulmonar Aguda/terapia , Apoptose/genética , Células-Tronco Mesenquimais/metabolismo , Autofagia/genética
8.
Eye (Lond) ; 2024 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-38548946

RESUMO

OBJECTIVES: To unveil the candidate susceptibility genes in chloroquine/hydroxychloroquine (CQ/HCQ) retinopathy using whole exome sequencing (WES) and genome-wide association study (GWAS). METHODS: Patients with a diagnosis of CQ/HCQ retinopathy based on the comprehensive demographic and ocular examination were included. The peripheral blood was extracted for WES and GWAS analyses. The Chinese Han Southern database from 1000 genomes was used as control group to compare the affected percentage. Multivariate logistic regression analysis adjusted for age, HCQ dose, duration and renal disease were used to analyze the correlation between genetic variants and visual outcome. A poor vision outcome was defined as visual acuity <6/12. An abnormal anatomical outcome was defined as disruption of ellipsoid zone in the fovea. RESULTS: Twenty-nine patients with an average age of 60.9 ± 13.4 years, treatment duration of 12.1 ± 6.2 years, daily dose of 8.5 ± 4.1 mg/kg, and the cumulative dose of 1637.5 ± 772.5 g, were genotyped. Several candidate genes associated with CQ/HCQ retinopathy were found, including RP1L1, RPGR and RPE65, with a difference of affected percentage over 50% in mutation between the case and control groups. New foci in CCDC66: rs56616026 (OR = 63.43, p = 1.63 × 10-8) and rs56616023 (OR = 104.7, p = 5.02 × 10-10) were identified significantly associated with HCQ retinopathy. Multivariate analysis revealed increased genetic variants were significantly associated with poor functional (OR = 1.600, p = 0.004) and structural outcome (OR = 1.318, p = 0.043). CONCLUSIONS: Several candidate susceptibility genes including RP1L1, RPGR, RPE65 and CCDC66 were identified to be associated with CQ/HCQ retinopathy. In addition to disease susceptibility, patients with increased genetic variants are more vulnerable to poor visual outcomes.

9.
Adv Mater ; : e2310032, 2024 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-38316396

RESUMO

Conjugated polymers (CPs) have promising applications in biomedical fields, such as disease monitoring, real-time imaging diagnosis, and disease treatment. As a promising luminescent material with tunable emission, high brightness and excellent stability, CPs are widely used as fluorescent probes in biological detection and imaging. Rational molecular design and structural optimization have broadened absorption/emission range of CPs, which are more conductive for disease diagnosis and precision therapy. This review provides a comprehensive overview of recent advances in the application of CPs, aiming to elucidate their structural and functional relationships. The fluorescence properties of CPs and the mechanism of detection signal amplification are first discussed, followed by an elucidation of their emerging applications in biological detection. Subsequently, CPs-based imaging systems and therapeutic strategies are illustrated systematically. Finally, recent advancements in utilizing CPs as electroactive materials for bioelectronic devices are also investigated. Moreover, the challenges and outlooks of CPs for precision medicine are discussed. Through this systematic review, it is hoped to highlight the frontier progress of CPs and promote new breakthroughs in fundamental research and clinical transformation.

10.
Environ Sci Pollut Res Int ; 31(11): 17005-17017, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38329670

RESUMO

The formulation of long-term step-by-step emission reduction plan is an important step for effective scientific emission reduction. This paper takes Shanghai as the research object, constructs PSO-LSTM model on the basis of STIRPAT model, and further constructs three dynamic policy scenarios combined with China's actual situation and makes short-, medium-, and long-term multivariate predictions for them. The study finds that only the improvement of energy consumption structure has a promotion effect on carbon emission reduction, and urbanization, industrial structure, technology level, population, and economic level all have an increasing effect, and secondly, the carbon emission reduction path of Shanghai basically achieves the core objective of steady decrease under the three scenarios. Secondly, under the three scenarios, Shanghai's carbon emission reduction path basically achieves the core objective of steady decline, but the decline in the GU scenario is more significant. It is recommended that Shanghai further adjusts its industrial structure, optimizes its energy consumption structure, promotes technological innovation and progress, and promotes the development of the circular economy model.


Assuntos
Desenvolvimento Econômico , Urbanização , Cidades , China , Carbono/análise , Dióxido de Carbono/análise
11.
Science ; 383(6682): eadj9198, 2024 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-38300992

RESUMO

Mapping single-neuron projections is essential for understanding brain-wide connectivity and diverse functions of the hippocampus (HIP). Here, we reconstructed 10,100 single-neuron projectomes of mouse HIP and classified 43 projectome subtypes with distinct projection patterns. The number of projection targets and axon-tip distribution depended on the soma location along HIP longitudinal and transverse axes. Many projectome subtypes were enriched in specific HIP subdomains defined by spatial transcriptomic profiles. Furthermore, we delineated comprehensive wiring diagrams for HIP neurons projecting exclusively within the HIP formation (HPF) and for those projecting to both intra- and extra-HPF targets. Bihemispheric projecting neurons generally projected to one pair of homologous targets with ipsilateral preference. These organization principles of single-neuron projectomes provide a structural basis for understanding the function of HIP neurons.


Assuntos
Axônios , Mapeamento Encefálico , Hipocampo , Neurônios , Animais , Camundongos , Axônios/fisiologia , Axônios/ultraestrutura , Hipocampo/ultraestrutura , Neurônios/classificação , Neurônios/ultraestrutura , Análise de Célula Única/métodos , Rede Nervosa , Masculino , Camundongos Endogâmicos C57BL
12.
Int J Mol Sci ; 25(4)2024 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-38396714

RESUMO

The NAC family of transcription factors (TFs) regulate plant development and abiotic stress. However, the specific function and response mechanism of NAC TFs that increase drought resistance in Picea wilsonii remain largely unknown. In this study, we functionally characterized a member of the PwNAC family known as PwNAC31. PwNAC31 is a nuclear-localized protein with transcriptional activation activity and contains an NAC domain that shows extensive homology with ANAC072 in Arabidopsis. The expression level of PwNAC31 is significantly upregulated under drought and ABA treatments. The heterologous expression of PwNAC31 in atnac072 Arabidopsis mutants enhances the seed vigor and germination rates and restores the hypersensitive phenotype of atnac072 under drought stress, accompanied by the up-regulated expression of drought-responsive genes such as DREB2A (DEHYDRATION-RESPONSIVE ELEMENT BINDING PROTEIN 2A) and ERD1 (EARLY RESPONSIVE TO DEHYDRATION STRESS 1). Yeast two-hybrid and bimolecular fluorescence complementation assays confirmed that PwNAC31 interacts with DREB2A and ABF3 (ABSCISIC ACID-RESPONSIVE ELEMENT-BINDING FACTOR 3). Yeast one-hybrid and dual-luciferase assays showed that PwNAC31, together with its interaction protein DREB2A, directly regulated the expression of ERD1 by binding to the DRE element of the ERD1 promoter. Collectively, our study provides evidence that PwNAC31 activates ERD1 by interacting with DREB2A to enhance drought tolerance in transgenic Arabidopsis.


Assuntos
Proteínas de Arabidopsis , Arabidopsis , Resistência à Seca , Picea , Ácido Abscísico/farmacologia , Ácido Abscísico/metabolismo , Arabidopsis/metabolismo , Proteínas de Arabidopsis/metabolismo , Desidratação/genética , Resistência à Seca/genética , Secas , Regulação da Expressão Gênica de Plantas , Picea/genética , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Plantas Geneticamente Modificadas/metabolismo , Saccharomyces cerevisiae/metabolismo , Estresse Fisiológico/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Adenosina Trifosfatases/genética , Adenosina Trifosfatases/metabolismo
13.
Nat Commun ; 15(1): 1891, 2024 Feb 29.
Artigo em Inglês | MEDLINE | ID: mdl-38424084

RESUMO

Plasma membrane lysis is an effective anticancer strategy, which mostly relying on soluble molecular membranolytic agents. However, nanomaterial-based membranolytic agents has been largely unexplored. Herein, we introduce a mesoporous membranolytic nanoperforators (MLNPs) via a nano- and molecular-scale multi-patterning strategy, featuring a spiky surface topography (nanoscale patterning) and molecular-level periodicity in the spikes with a benzene-bridged organosilica composition (molecular-scale patterning), which cooperatively endow an intrinsic membranolytic activity. Computational modelling reveals a nanospike-mediated multivalent perforation behaviour, i.e., multiple spikes induce nonlinearly enlarged membrane pores compared to a single spike, and that benzene groups aligned parallelly to a phospholipid molecule show considerably higher binding energy than other alignments, underpinning the importance of molecular ordering in phospholipid extraction for membranolysis. Finally, the antitumour activity of MLNPs is demonstrated in female Balb/c mouse models. This work demonstrates assembly of organosilica based bioactive nanostructures, enabling new understandings on nano-/molecular patterns co-governed nano-bio interaction.


Assuntos
Benzeno , Nanoestruturas , Feminino , Animais , Camundongos , Benzeno/química , Nanoestruturas/química , Fosfolipídeos
14.
Bioorg Chem ; 145: 107188, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38377815

RESUMO

Despite the advances of multistep enzymatic cascade reactions, their incorporation with abiotic reactions in living organisms remains challenging in synthetic biology. Herein, we combined microbial metabolic pathways and Pd-catalyzed processes for in-situ generation of bioactive conjugated oligomers. Our biocompatible one-pot coupling reaction utilized the fermentation process of engineered E. coli that converted glucose to styrene, which participated in the Pd-catalyzed Heck reaction for in-situ synthesis of conjugated oligomers. This process serves a great interest in understanding resistance evolution by utilizing the inhibitory activity of the synthesized conjugated oligomers. The approach allows for the in-situ combination of biological metabolism and CC coupling reactions, opening up new possibilities for the biosynthesis of unnatural molecules and enabling the in-situ regulation of the bioactivity of the obtained products.


Assuntos
Escherichia coli , Paládio , Escherichia coli/metabolismo , Catálise , Fermentação
15.
JACS Au ; 4(1): 3-19, 2024 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-38274265

RESUMO

Solar-driven biosynthesis and bioconversion are essential for achieving sustainable resources and renewable energy. These processes harness solar energy to produce biomass, chemicals, and fuels. While they offer promising avenues, some challenges and limitations should be investigated and addressed for their improvement and widespread adoption. These include the low utilization of light energy, the inadequate selectivity of products, and the limited utilization of inorganic carbon/nitrogen sources. Organic semiconducting polymers offer a promising solution to these challenges by collaborating with natural microorganisms and developing artificial photosynthetic biohybrid systems. In this Perspective, we highlight the latest advancements in the use of appropriate organic semiconducting polymers to construct artificial photosynthetic biohybrid systems. We focus on how these systems can enhance the natural photosynthetic efficiency of photosynthetic organisms, create artificial photosynthesis capability of nonphotosynthetic organisms, and customize the value-added chemicals of photosynthetic synthesis. By examining the structure-activity relationships and emphasizing the mechanism of electron transfer based on organic semiconducting polymers in artificial photosynthetic biohybrid systems, we aim to shed light on the potential of this novel strategy for artificial photosynthetic biohybrid systems. Notably, these coupling strategies between organic semiconducting polymers and organisms during artificial photosynthetic biohybrid systems will pave the way for a more sustainable future with solar fuels and chemicals.

16.
NPJ Parkinsons Dis ; 10(1): 23, 2024 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-38233432

RESUMO

Inconsistent findings exist regarding the potential association between polluted air and Parkinson's disease (PD), with unclear insights into the role of inherited sensitivity. This study sought to explore the potential link between various air pollutants and PD risk, investigating whether genetic susceptibility modulates these associations. The population-based study involved 312,009 initially PD-free participants with complete genotyping data. Annual mean concentrations of PM2.5, PM10, NO2, and NOx were estimated, and a polygenic risk score (PRS) was computed to assess individual genetic risks for PD. Cox proportional risk models were employed to calculate hazard ratios (HR) and 95% confidence intervals (CI) for the associations between ambient air pollutants, genetic risk, and incident PD. Over a median 12.07-year follow-up, 2356 PD cases (0.76%) were observed. Compared to the lowest quartile of air pollution, the highest quartiles of NO2 and PM10 pollution showed HRs and 95% CIs of 1.247 (1.089-1.427) and 1.201 (1.052-1.373) for PD incidence, respectively. Each 10 µg/m3 increase in NO2 and PM10 yielded elevated HRs and 95% CIs for PD of 1.089 (1.026-1.155) and 1.363 (1.043-1.782), respectively. Individuals with significant genetic and PM10 exposure risks had the highest PD development risk (HR: 2.748, 95% CI: 2.145-3.520). Similarly, those with substantial genetic and NO2 exposure risks were over twice as likely to develop PD compared to minimal-risk counterparts (HR: 2.414, 95% CI: 1.912-3.048). Findings suggest that exposure to air contaminants heightens PD risk, particularly in individuals genetically predisposed to high susceptibility.

17.
Toxicology ; 502: 153731, 2024 02.
Artigo em Inglês | MEDLINE | ID: mdl-38253231

RESUMO

Lanthanum (La) and cerium (Ce), rare earth elements with physical properties similar to calcium (Ca), are generally considered non-toxic when used appropriately. However, their ions possess anti-tumor capabilities. This investigation explores the potential applications and mechanisms of LaCl3 or CeCl3 treatment in triple-negative breast cancer (TNBC) cell lines. TNBC, characterized by the absence of estrogen receptor (ERα), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2) expression, is prone to early metastasis and resistant to hormone therapy. Our results demonstrate that La/Ce treatment reduces cell growth, and when combined with cisplatin, it synergistically inhibits cell growth and the PI3K/AKT pathway. La and Ce induce oxidative stress by disrupting mitochondrial function, leading to protein oxidation. Additionally, they interfere with protein homeostasis and induce nucleolar stress. Furthermore, disturbance in F-actin web formation impairs cell migration. This study delves into the mechanism by which calcium-like elements La and Ce inhibit breast cancer cell growth, shedding light on their interference in mitochondrial function, protein homeostasis, and cytoskeleton assembly.


Assuntos
Elementos da Série dos Lantanídeos , Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Cálcio , Cisplatino , Lantânio/toxicidade , Linhagem Celular Tumoral
18.
Nat Microbiol ; 9(2): 561-575, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38233648

RESUMO

Many drugs can perturb the gut microbiome, potentially leading to negative health consequences. However, mechanisms of most microorganism-drug responses have not been elucidated at the genetic level. Using high-throughput bacterial transcriptomics, we systematically characterized the gene expression profiles of prevalent human gut bacteria exposed to the most frequently prescribed orally administered pharmaceuticals. Across >400 drug-microorganism pairs, significant and reproducible transcriptional responses were observed, including pathways involved in multidrug resistance, metabolite transport, tartrate metabolism and riboflavin biosynthesis. Importantly, we discovered that statin-mediated upregulation of the AcrAB-TolC efflux pump in Bacteroidales species enhances microbial sensitivity to vitamin A and secondary bile acids. Moreover, gut bacteria carrying acrAB-tolC genes are depleted in patients taking simvastatin, suggesting that drug-efflux interactions generate collateral toxicity that depletes pump-containing microorganisms from patient microbiomes. This study provides a resource to further understand the drivers of drug-mediated microbiota shifts for better informed clinical interventions.


Assuntos
Proteínas de Bactérias , Microbioma Gastrointestinal , Humanos , Proteínas de Bactérias/metabolismo , Bactérias/genética , Perfilação da Expressão Gênica , Antibacterianos
19.
Commun Biol ; 7(1): 91, 2024 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-38216635

RESUMO

Bone metastasis is of common occurrence in renal cell carcinoma with poor prognosis, but no optimal treatment approach has been established for bone metastatic renal cell carcinoma. To explore the potential therapeutic targets for bone metastatic renal cell carcinoma, we profile single cell transcriptomes of 6 primary renal cell carcinoma and 9 bone metastatic renal cell carcinoma. We also include scRNA-seq data of early-stage renal cell carcinoma, late-stage renal cell carcinoma, normal kidneys and healthy bone marrow samples in the study to better understand the bone metastasis niche. The molecular properties and dynamic changes of major cell lineages in bone metastatic environment of renal cell carcinoma are characterized. Bone metastatic renal cell carcinoma is associated with multifaceted immune deficiency together with cancer-associated fibroblasts, specifically appearance of macrophages exhibiting malignant and pro-angiogenic features. We also reveal the dominance of immune inhibitory T cells in the bone metastatic renal cell carcinoma which can be partially restored by the treatment. Trajectory analysis showes that myeloid-derived suppressor cells are progenitors of macrophages in the bone metastatic renal cell carcinoma while monocytes are their progenitors in primary tumors and healthy bone marrows. Additionally, the infiltration of immune inhibitory CD47+ T cells is observed in bone metastatic tumors, which may be a result of reduced phagocytosis by SIRPA-expressing macrophages in the bone microenvironment. Together, our results provide a systematic view of various cell types in bone metastatic renal cell carcinoma and suggest avenues for therapeutic solutions.


Assuntos
Neoplasias Ósseas , Carcinoma de Células Renais , Neoplasias Renais , Humanos , Carcinoma de Células Renais/genética , Neoplasias Renais/genética , Neoplasias Ósseas/genética , Macrófagos/metabolismo , Microambiente Tumoral
20.
Biotechnol Bioeng ; 121(1): 355-365, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-37807718

RESUMO

Foreign proteins are produced by introducing synthetic constructs into host bacteria for biotechnology applications. This process can cause resource competition between synthetic circuits and host cells, placing a metabolic burden on the host cells which may result in load stress and detrimental physiological changes. Consequently, the host bacteria can experience slow growth, and the synthetic system may suffer from suboptimal function. To help in the detection of bacterial load stress, we developed machine-learning strategies to select a minimal number of genes that could serve as biomarkers for the design of load stress reporters. We identified pairs of biomarkers that showed discriminative capacity to detect the load stress states induced in 41 engineered Escherichia coli strains.


Assuntos
Biotecnologia , Escherichia coli , Escherichia coli/metabolismo , Bactérias
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