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1.
Plant J ; 117(4): 1250-1263, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37991990

RESUMO

High-temperature stress results in protein misfolding/unfolding and subsequently promotes the accumulation of cytotoxic protein aggregates that can compromise cell survival. Heat shock proteins (HSPs) function as molecular chaperones that coordinate the refolding and degradation of aggregated proteins to mitigate the detrimental effects of high temperatures. However, the relationship between HSPs and protein aggregates in apples under high temperatures remains unclear. Here, we show that an apple (Malus domestica) chloroplast-localized, heat-sensitive elongation factor Tu (MdEF-Tu), positively regulates apple thermotolerance when it is overexpressed. Transgenic apple plants exhibited higher photosynthetic capacity and better integrity of chloroplasts during heat stress. Under high temperatures, MdEF-Tu formed insoluble aggregates accompanied by ubiquitination modifications. Furthermore, we identified a chaperone heat shock protein (MdHsp70), as an interacting protein of MdEF-Tu. Moreover, we observed obviously elevated MdHsp70 levels in 35S: MdEF-Tu apple plants that prevented the accumulation of ubiquitinated MdEF-Tu aggregates, which positively contributes to the thermotolerance of the transgenic plants. Overall, our results provide new insights into the molecular chaperone function of MdHsp70, which mediates the homeostasis of thermosensitive proteins under high temperatures.


Assuntos
Malus , Termotolerância , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Fator Tu de Elongação de Peptídeos/genética , Fator Tu de Elongação de Peptídeos/metabolismo , Malus/genética , Malus/metabolismo , Agregados Proteicos , Chaperonas Moleculares/metabolismo , Plantas Geneticamente Modificadas/metabolismo
2.
Plant Physiol ; 195(1): 502-517, 2024 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-38243831

RESUMO

Apple Valsa canker, caused by the ascomycete fungus Valsa mali, employs virulence effectors to disturb host immunity and poses a substantial threat to the apple industry. However, our understanding of how V. mali effectors regulate host defense responses remains limited. Here, we identified the V. mali effector Vm_04797, which was upregulated during the early infection stage. Vm_04797, a secreted protein, suppressed Inverted formin 1 (INF1)-triggered cell death in Nicotiana benthamiana and performed virulence functions inside plant cells. Vm_04797 deletion mutants showed substantially reduced virulence toward apple. The adaptor protein MdAP-2ß positively regulated apple Valsa canker resistance and was targeted and degraded by Vm_04797 via the ubiquitination pathway. The in vitro analysis suggested that Vm_04797 possesses E3 ubiquitin ligase activity. Further analysis revealed that MdAP-2ß is involved in autophagy by interacting with Malus domestica autophagy protein 16 MdATG16 and promoting its accumulation. By degrading MdAP-2ß, Vm_04797 inhibited autophagic flux, thereby disrupting the defense response mediated by autophagy. Our findings provide insights into the molecular mechanisms employed by the effectors of E3 ubiquitin ligase activity in ascomycete fungi to regulate host immunity.


Assuntos
Ascomicetos , Autofagia , Proteínas Fúngicas , Malus , Nicotiana , Doenças das Plantas , Proteínas de Plantas , Doenças das Plantas/microbiologia , Malus/microbiologia , Malus/metabolismo , Malus/genética , Ascomicetos/patogenicidade , Ascomicetos/fisiologia , Proteínas de Plantas/metabolismo , Proteínas de Plantas/genética , Proteínas Fúngicas/metabolismo , Proteínas Fúngicas/genética , Nicotiana/microbiologia , Nicotiana/genética , Nicotiana/metabolismo , Interações Hospedeiro-Patógeno , Virulência , Imunidade Vegetal/genética , Ubiquitinação , Resistência à Doença/genética
3.
Hum Genomics ; 18(1): 41, 2024 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-38654324

RESUMO

BACKGROUND: Congenital anomalies of the kidney and urinary tract (CAKUT) are prevalent birth defects. Although pathogenic CAKUT genes are known, they are insufficient to reveal the causes for all patients. Our previous studies indicated GEN1 as a pathogenic gene of CAKUT in mice, and this study further investigated the correlation between GEN1 and human CAKUT. METHODS: In this study, DNA from 910 individuals with CAKUT was collected; 26 GEN1 rare variants were identified, and two GEN1 (missense) variants in a non-CAKUT group were found. Mainly due to the stability results of the predicted mutant on the website, in vitro, 10 variants (eight CAKUT, two non-CAKUT) were selected to verify mutant protein stability. In addition, mainly based on the division of the mutation site located in the functional region of the GEN1 protein, 8 variants (six CAKUT, two non-CAKUT) were selected to verify enzymatic hydrolysis, and the splice variant GEN1 (c.1071 + 3(IVS10) A > G) was selected to verify shear ability. Based on the results of in vitro experiments and higher frequency, three sites with the most significant functional change were selected to build mouse models. RESULTS: Protein stability changed in six variants in the CAKUT group. Based on electrophoretic mobility shift assay of eight variants (six CAKUT, two non-CAKUT), the enzymatic hydrolysis and DNA-binding abilities of mutant proteins were impaired in the CAKUT group. The most serious functional damage was observed in the Gen1 variant that produced a truncated protein. A mini-gene splicing assay showed that the variant GEN1 (c.1071 + 3(IVS10) A > G) in the CAKUT group significantly affected splicing function. An abnormal exon10 was detected in the mini-gene splicing assay. Point-mutant mouse strains were constructed (Gen1: c.1068 + 3 A > G, p.R400X, and p.T105R) based on the variant frequency in the CAKUT group and functional impairment in vitro study and CAKUT phenotypes were replicated in each. CONCLUSION: Overall, our findings indicated GEN1 as a risk factor for human CAKUT.


Assuntos
Anormalidades Urogenitais , Refluxo Vesicoureteral , Animais , Feminino , Humanos , Masculino , Camundongos , Predisposição Genética para Doença , Rim/anormalidades , Rim/patologia , Rim/metabolismo , Mutação/genética , Estabilidade Proteica , Fatores de Risco , Sistema Urinário/anormalidades , Sistema Urinário/patologia , Anormalidades Urogenitais/genética , Anormalidades Urogenitais/patologia , Refluxo Vesicoureteral/genética , Refluxo Vesicoureteral/patologia
4.
Chemphyschem ; : e202300966, 2024 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-38787917

RESUMO

The ongoing advancements in lithium-ion battery technology are pivotal in propelling the performance of modern electronic devices and electric vehicles. Amongst various components, the cathode material significantly influences the battery performance, such as the specific capacity, capacity retention and the rate performance. Ternary cathode materials, composed of nickel, manganese, and cobalt (NCM), offer a balanced combination of these traits. Recent developments focus on elemental doping, which involves substituting a fraction of NCM constituent ions with alternative cations such as aluminum, titanium, or magnesium. This strategic substitution aims to enhance structural stability, increase capacity retention, and improve resistance to thermal runaway. Doped ternary materials have shown promising results, with improvements in cycle life and operational safety. However, the quest for optimal doping elements and concentrations persists to maximize performance while minimizing cost and environmental impact, ensuring the progression towards high-energy-density, durable, and safe battery technologies.

5.
Sheng Wu Yi Xue Gong Cheng Xue Za Zhi ; 40(3): 499-507, 2023 Jun 25.
Artigo em Zh | MEDLINE | ID: mdl-37380389

RESUMO

The increasing prevalence of the aging population, and inadequate and uneven distribution of medical resources, have led to a growing demand for telemedicine services. Gait disturbance is a primary symptom of neurological disorders such as Parkinson's disease (PD). This study proposed a novel approach for the quantitative assessment and analysis of gait disturbance from two-dimensional (2D) videos captured using smartphones. The approach used a convolutional pose machine to extract human body joints and a gait phase segmentation algorithm based on node motion characteristics to identify the gait phase. Moreover, it extracted features of the upper and lower limbs. A height ratio-based spatial feature extraction method was proposed that effectively captures spatial information. The proposed method underwent validation via error analysis, correction compensation, and accuracy verification using the motion capture system. Specifically, the proposed method achieved an extracted step length error of less than 3 cm. The proposed method underwent clinical validation, recruiting 64 patients with Parkinson's disease and 46 healthy controls of the same age group. Various gait indicators were statistically analyzed using three classic classification methods, with the random forest method achieving a classification accuracy of 91%. This method provides an objective, convenient, and intelligent solution for telemedicine focused on movement disorders in neurological diseases.


Assuntos
Doença de Parkinson , Humanos , Idoso , Doença de Parkinson/diagnóstico , Envelhecimento , Algoritmos , Marcha , Extremidade Inferior
6.
Artigo em Inglês | MEDLINE | ID: mdl-36549658

RESUMO

BACKGROUND: Congenital anomalies of the kidney and urinary tracts (CAKUT) are the leading cause of kidney failure in children with phenotypic and genotypic heterogeneity. Our objective was to describe the genetic spectrum and identify the risk factors for kidney failure in children with CAKUT. METHODS: Clinical and genetic data were derived from a multicenter network (Chinese Children Genetic Kidney Disease Database, CCGKDD) and the Chigene database. A total of 925 children with CAKUT who underwent genetic testing from 2014 to 2020 across China were studied. Data for a total of 584 children wereobtained from the CCGKDD, including longitudinal data regarding kidney function. The risk factors for kidney failure were determined by the Kaplan-Meier method and Cox proportional hazards models. RESULTS: A genetic diagnosis was established in 96 out of 925 (10.3%) children, including 72 (8%) with monogenic variants, 20 (2%) with copy number variants (CNVs), and 4 (0.4%)with major chromosomal anomalies. Patients with skeletal abnormalities were more likely to have large CNVs or abnormal karyotypes than monogenic variants. Eighty-two patients from the CCGKDD progressed to kidney failure at a median age of 13.0 (95% confidence interval, 12.4-13.6) years, and twenty-four were genetically diagnosed with variants of PAX2, TNXB, EYA1, HNF1B and GATA3 or the 48, XXYY karyotype. The multivariate analysis indicated that solitary kidney, posterior urethral valves, bilateral hypodysplasia, the presence of certain variants and premature birth were independent prognostic factors. CONCLUSIONS: The genetic spectrum of CAKUT varies among different subphenotypes. The identified factors indicate areas that require special attention.

7.
Pestic Biochem Physiol ; 183: 105077, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35430069

RESUMO

There are various types of compounds studied and applied for plant disease management, and some of them are environment friendly and suitable in organic production. An example is indole-3-carboxaldehyde (A1) and indole-3-carboxylic acid (A2) derived from Purpureocillium lilacinum H1463, which have shown a strong activity in the control of tobacco mosaic virus (TMV). In this study, the effects of these compounds were studied on suppressing TMV and corresponding mechanism. Both A1 and A2 exhibited strong anti-TMV activities in vitro and in vivo. They fractured TMV virions and forced the fractured particles agglomerated. A1 and A2 also induced immune responses or resistance of tobacco to TMV infection, including expressing hypersensitive reaction (HR), increasing defense-related enzymes and overexpressing pathogenesis-related (PR) proteins. The upregulation of salicylic acid (SA) biosynthesis genes PAL, ICS, and PBS3 confirmed that SA served as a defense-related signal molecule. Therefore, indole derivatives have a potential for activating defense of tobacco against TMV and other pathogens and can be used for disease control.


Assuntos
Vírus do Mosaico do Tabaco , Hypocreales , Indóis , Doenças das Plantas , Proteínas de Plantas/metabolismo , Ácido Salicílico/metabolismo , Ácido Salicílico/farmacologia , Nicotiana
8.
Molecules ; 27(5)2022 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-35268633

RESUMO

The Valsa canker caused by Valsa mali seriously harmed the production of East Asian apples and caused very significant economic losses. Considering the chemical residues and the improvement of people's awareness of environmental protection, there is a need for screening new green pesticides for the control of Valsa canker. Therefore, we conducted systematic evaluations on the antifungal activity of wood tar. In this research, the effective concentration (EC50) of six strains of V. mali to wood tar was determined, and the EC50 ranged from 69.54 to 92.81 µg/mL. After treatment with wood tar, the hyphae of V. mali broke, swelled, and deformed; the permeability of the cell membrane increased; and the activity of pectinase reduced. Moreover, the expression levels of five genes related to pectinase also decreased significantly. In addition, the activities of phenylalanine ammonia lyase (PAL) and peroxidase (POD) of apple leaves treated with wood tar also increased. On detached apple branches, wood tar also showed therapeutic and protective activities. In the 2016-2019 field experiments, wood tar also showed good efficacy against Valsa canker and promoted the formation of callus. (In the experiments from 2016 to 2019, it can be seen that the control effect of 50% wood tar and 100% wood tar in the field is above 75% and promoted the formation of callus.) This study is the first to report the bidirectional efficacy of wood tar against Valsa mali and for trunk wound healing. The above results evidenced that wood tar has great potential to be developed as a natural alternative to commercial fungicides for the management of apple Valsa canker.


Assuntos
Ascomicetos , Fungicidas Industriais , Malus , Ascomicetos/genética , Fungicidas Industriais/farmacologia , Humanos , Malus/genética , Doenças das Plantas/microbiologia , Doenças das Plantas/prevenção & controle , Madeira
9.
J Clean Prod ; 370: 133362, 2022 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-36238656

RESUMO

The present study explores the possibility of replacing blast furnace slag (BFS) with coal fly ash (FA) to produce alkali-activated material (AAM) concrete with hybrid precursors. With an increased FA replacement ratio, the reaction kinetics, fresh and hardened properties of AAM mixtures have been investigated. The retardation effect on the reaction kinetics with an increased FA content has been observed, which not only extended the induction period along with the heat flow evolution but also reduced the cumulative heat release up to 24 h. Spherical FA particles can provide a ball-bearing effect to improve the workability of the hybrid AAM mixtures, while FA also slows down the deterioration of fresh properties since they are less reactive compared to BFS particles. Regarding the strength development, FA results in the reduction at all curing ages in the mixtures with a low silicate modulus (Ms0.25). Similarly, reduction in 1-day compressive strength has been detected in high silicate modulus mixtures (Ms0.5) with FA replacement, while the mixture with 10% FA exhibits the highest compressive strength among Ms0.5 concretes at later curing ages. Bigger capillary pores have been detected in AAM mixtures with an increase in FA content. However, AAM with 10% FA shows the lowest porosity in Ms0.5 mixtures, which is in agreement with the compressive strength results.

10.
Sheng Wu Yi Xue Gong Cheng Xue Za Zhi ; 39(6): 1181-1188, 2022 Dec 25.
Artigo em Zh | MEDLINE | ID: mdl-36575088

RESUMO

Intelligent medical image segmentation methods have been rapidly developed and applied, while a significant challenge is domain shift. That is, the segmentation performance degrades due to distribution differences between the source domain and the target domain. This paper proposed an unsupervised end-to-end domain adaptation medical image segmentation method based on the generative adversarial network (GAN). A network training and adjustment model was designed, including segmentation and discriminant networks. In the segmentation network, the residual module was used as the basic module to increase feature reusability and reduce model optimization difficulty. Further, it learned cross-domain features at the image feature level with the help of the discriminant network and a combination of segmentation loss with adversarial loss. The discriminant network took the convolutional neural network and used the labels from the source domain, to distinguish whether the segmentation result of the generated network is from the source domain or the target domain. The whole training process was unsupervised. The proposed method was tested with experiments on a public dataset of knee magnetic resonance (MR) images and the clinical dataset from our cooperative hospital. With our method, the mean Dice similarity coefficient (DSC) of segmentation results increased by 2.52% and 6.10% to the classical feature level and image level domain adaptive method. The proposed method effectively improves the domain adaptive ability of the segmentation method, significantly improves the segmentation accuracy of the tibia and femur, and can better solve the domain transfer problem in MR image segmentation.


Assuntos
Processamento de Imagem Assistida por Computador , Redes Neurais de Computação , Humanos , Processamento de Imagem Assistida por Computador/métodos , Imageamento por Ressonância Magnética , Joelho , Articulação do Joelho
11.
Pestic Biochem Physiol ; 171: 104697, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33357538

RESUMO

Glycoprotein (GP)-1 is a glycoprotein elicitor with antiviral activity found in Streptomyces kanasensis zx01. GP-1 can induce programmed cell death (PCD) in vitro; however, the underlying mechanism is unclear. In the present study, we demonstrated that GP-1 induced PCD in tobacco suspension cells, which was modulated by hydrogen peroxide (H2O2). GP-1 participated in and modulated biologically relevant signaling in plant cells. GP-1 induced tobacco cell death in a dose- and time-dependent manner; affected the expression of BRI1-associated receptor kinase 1 (BAK1) and the accumulation of salicylic acid (SA), which are related to PCD; and enzymatic activities and mitochondrial functions. In conclusion, GP-1-induced PCD in tobacco may be mediated by H2O2 which alters BAK1 and SA levels, as well as mitochondrial and gene function. This cell signal cascade played an important role in the process of GP-1 induced plant disease resistance.


Assuntos
Peróxido de Hidrogênio , Nicotiana , Apoptose , Glicoproteínas , Streptomyces
12.
Pestic Biochem Physiol ; 171: 104719, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33357541

RESUMO

GP-1, a novel glycoprotein from Streptomyces sp. ZX01 has a plant immunity-inducing effect. GP-1-treated plants exhibited enhanced systemic resistance with a significant reduction in TMV lesions on tobacco leaves, but its antiviral mechanism remains unclear. In this study, early plant defense-related responses, such as Ca2+ influx, callose apposition, oxidative burst, hypersensitive response, programmed cell death, increase in nitric oxide (NO), and stomatal closure, were investigated under GP-1 treatment, and the mechanism of how GP-1 induces viral resistance in Nicotiana benthamiana was studied. Results showed that GP-1 induced [Ca2+]cyt rapidly in tobacco leaves and suspended cells, followed by reactive oxygen species (ROS) and NO elevation. Transcriptome analysis showed significant differences in expression levels between the GP-1-treated N. benthamiana and the control and showed significantly upregulated and enriched pathways including defense and immune reaction. Similar to typical pathogen-associated molecular patterns, GP-1 induced callose deposition and stomatal closure to form defense barriers against pathogen invasion. The expression of defense-related genes further confirmed the above conclusions. By analyzing transcriptome in N. benthamiana and the contents of salicylic acid (SA) and jasmonic acid (JA), GP-1 enhanced viral resistance of tobacco by improving the SA and JA contents, strengthening plant secondary metabolites activities, promoting systemic accumulation of pathogenesis-related proteins in TMV- inoculated tobacco there by producing antiviral activity.


Assuntos
Doenças das Plantas , Streptomyces , Regulação da Expressão Gênica de Plantas , Glicoproteínas , Folhas de Planta/metabolismo , Proteínas de Plantas/genética , Ácido Salicílico , Streptomyces/metabolismo , Nicotiana/metabolismo
13.
Biochem Biophys Res Commun ; 523(2): 315-321, 2020 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-31864712

RESUMO

Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disease for which specific biomarkers and pathological mechanisms have yet to be identified. Methylphenidate (MPH) is commonly used to treat ADHD, but its therapeutic mechanisms and its impact on brain metabolites remain unclear. Metabolomics can help to discover biomarkers and identify pathophysiological mechanisms. We adopted an untargeted metabolomics approach based on gas chromatography-mass spectrometry to investigate the potential biomarkers and pathogenesis of ADHD. Ten Wistar-Kyoto (WKY) rats were chosen as healthy controls (vehicle, i.g.). Twenty young spontaneously hypertensive rats (SHR) were randomly allocated to the SHR group (vehicle, i.g.) and MPH group (2 mg/kg/day, i.g.). We identified 103 metabolites from the prefrontal cortex (PFC). Orthogonal partial least square-discriminate analysis showed the differential expression of these metabolites between the groups. Multivariate and univariate statistical analyses isolated 12 metabolites that differed significantly between the WKY and SHR groups: 3-hydroxymethylglutaric acid, 3-phosphoglyceric acid, adenosine monophosphate, cholesterol, lanosterol, and o-phosphoethanolamine; 3-hydroxymethylglutaric acid and cholesterol were reversed with MPH treatment. Pathway and enrichment analyses revealed that the altered metabolites belonged to the cholesterol metabolism pathways. ELISA and western blotting showed that the activity of 3-hydroxy-3-methyl-glutaryl-CoA reductase and the expression of sterol regulatory element-binding protein-2 and ATP-binding cassette transporter A1 were reduced in the PFC of the SHR; the latter two proteins were upregulated by MPH. In conclusion, metabolomics analysis identified potential biomarkers that influence cholesterol metabolism and may be implicated in the development of ADHD-like behavior. MPH can regulate cholesterol metabolism in the PFC of ADHD models. This study uncovered potential biomarkers and pathways involved in ADHD, providing new insight into its pathogenesis.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/metabolismo , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Colesterol/metabolismo , Córtex Pré-Frontal/metabolismo , Animais , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Comportamento Animal/efeitos dos fármacos , Biomarcadores/metabolismo , Estimulantes do Sistema Nervoso Central/uso terapêutico , Modelos Animais de Doenças , Masculino , Redes e Vias Metabólicas , Metabolômica , Metilfenidato/uso terapêutico , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY
14.
Sol Energy Mater Sol Cells ; 198: 53-62, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-32116413

RESUMO

This work introduces a new software package "Sesame" for the numerical computation of classical semiconductor equations. It supports 1 and 2-dimensional systems and provides tools to easily implement extended defects such as grain boundaries or sample surfaces. Sesame is designed to facilitate fast exploration of the system parameter space and to visualize local charge transport properties. Sesame has been benchmarked against other software packages, and results for single crystal and polycrystalline CdS-CdTe heterojunctions are presented. Sesame is distributed as a Python package or as a standalone GUI application, and is available at https://pages.nist.gov/sesame/.

16.
Am J Pathol ; 186(6): 1635-48, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27109613

RESUMO

Fukutin-related protein-muscular dystrophy is characterized by defects in glycosylation of α-dystroglycan with variable clinical phenotypes, most commonly as limb-girdle muscular dystrophy 2I. There is no effective therapy available. Glucocorticoid steroids have become the standard treatment for Duchenne and other muscular dystrophies with serious adverse effects, including excessive weight gain, immune suppression, and bone loss. Bisphosphonates have been used to treat Duchenne muscular dystrophy for prevention of osteoporosis. Herein, we evaluated prednisolone and alendronate for their therapeutic potential in the FKRPP448L-mutant mouse representing moderate limb-girdle muscular dystrophy 2I. Mice were treated with prednisolone, alendronate, and both in combination for up to 6 months. Prednisolone improved muscle pathology with significant reduction in muscle degeneration, but had no effect on serum creatine kinase levels and muscle strength. Alendronate treatment did not ameliorate muscle degeneration, but demonstrated a limited enhancement on muscle function test. Combined treatment of prednisolone and alendronate provided best improvement in muscle pathology with normalized fiber size distribution and significantly reduced serum creatine kinase levels, but had limited effect on muscle force generation. The use of alendronate significantly mitigated the bone loss. Prednisolone alone and in combination with alendronate enhance functionally glycosylated α-dystroglycan. These results, for the first time, demonstrate the efficacy and feasibility of this alliance treatment of the two drugs for fukutin-related protein-muscular dystrophy.


Assuntos
Corticosteroides/farmacologia , Alendronato/farmacologia , Conservadores da Densidade Óssea/farmacologia , Músculo Esquelético/efeitos dos fármacos , Distrofia Muscular Animal/patologia , Prednisona/farmacologia , Animais , Western Blotting , Densidade Óssea/efeitos dos fármacos , Distroglicanas/metabolismo , Glicosilação/efeitos dos fármacos , Camundongos , Camundongos Mutantes , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Distrofia Muscular do Cíngulo dos Membros/metabolismo , Distrofia Muscular do Cíngulo dos Membros/patologia , Distrofia Muscular Animal/metabolismo , Fenótipo
17.
BMC Musculoskelet Disord ; 16: 270, 2015 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-26424660

RESUMO

BACKGROUND: It is believed that phosphocitrate (PC) exerts its disease-modifying effects on osteoarthritis (OA) by inhibiting the formation of crystals. However, recent findings suggest that PC exerts its disease-modifying effect, at least in part, through a crystal-independent action. This study sought to examine the disease-modifying effects of PC and its analogue PC-ß-ethyl ester (PC-E) on partial meniscectomy-induced OA and the structure-activity relationship. METHODS: Calcification- and proliferation-inhibitory activities were examined in OA fibroblast-like synoviocytes (FLSs) culture. Disease-modifying effects were examined using Hartley guinea pigs undergoing partial meniscectomy. Cartilage degeneration was examined with Indian ink, safranin-O, and picrosirius red. Levels of matrix metalloproteinase-13 (MMP-13), ADAM metallopeptidase with thrombospondin type 1 motif 5 (ADAMTS5), chemokine (C-C motif) ligand 5 (CCL5), and cyclooxygenase-2 (Cox-2) were examined with immunostaining. The effects of PC-E and PC on gene expressions in OA FLSs were examined with microarray. Results are expressed as mean ± standard deviation and analyzed using Student's t test or Wilcoxon rank sum test. RESULTS: PC-E was slightly less powerful than PC as a calcification inhibitor but as powerful as PC in the inhibition of OA FLSs proliferation. PC significantly inhibited cartilage degeneration in the partial meniscectomied right knee. PC-E was less powerful than PC as a disease-modifying drug, especially in the inhibition of cartilage degeneration in the non-operated left knee. PC significantly reduced the levels of ADAMTS5, MMP-13 and CCL5, whereas PC-E reduced the levels of ADAMTS5 and CCL5. Microarray analyses revealed that PC-E failed to downregulate the expression of many PC-downregulated genes classified in angiogenesis and inflammatory response. CONCLUSIONS: PC is a disease-modifying drug for posttraumatic OA therapy. PC exerts its disease-modifying effect through two independent actions: inhibiting pathological calcification and modulating the expression of many genes implicated in OA. The ß-carboxyl group of PC plays an important role in the inhibition of cartilage degeneration, little role in the inhibition of FLSs proliferation, and a moderate role in the inhibition of FLSs-mediated calcification.


Assuntos
Antirreumáticos/farmacologia , Cartilagem Articular/efeitos dos fármacos , Citratos/farmacologia , Meniscos Tibiais/cirurgia , Osteoartrite/tratamento farmacológico , Membrana Sinovial/efeitos dos fármacos , Proteínas ADAM/genética , Proteínas ADAM/metabolismo , Animais , Antirreumáticos/química , Calcinose/prevenção & controle , Cartilagem Articular/metabolismo , Cartilagem Articular/patologia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Quimiocina CCL5/genética , Quimiocina CCL5/metabolismo , Citratos/química , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Regulação da Expressão Gênica , Cobaias , Masculino , Metaloproteinase 13 da Matriz/genética , Metaloproteinase 13 da Matriz/metabolismo , Estrutura Molecular , Osteoartrite/etiologia , Osteoartrite/genética , Osteoartrite/metabolismo , Osteoartrite/patologia , Relação Estrutura-Atividade , Membrana Sinovial/metabolismo , Membrana Sinovial/patologia
18.
ScientificWorldJournal ; 2014: 194706, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24883357

RESUMO

Particle swarm optimization (PSO) has attracted many researchers interested in dealing with various optimization problems, owing to its easy implementation, few tuned parameters, and acceptable performance. However, the algorithm is easy to trap in the local optima because of rapid losing of the population diversity. Therefore, improving the performance of PSO and decreasing the dependence on parameters are two important research hot points. In this paper, we present a human behavior-based PSO, which is called HPSO. There are two remarkable differences between PSO and HPSO. First, the global worst particle was introduced into the velocity equation of PSO, which is endowed with random weight which obeys the standard normal distribution; this strategy is conducive to trade off exploration and exploitation ability of PSO. Second, we eliminate the two acceleration coefficients c 1 and c 2 in the standard PSO (SPSO) to reduce the parameters sensitivity of solved problems. Experimental results on 28 benchmark functions, which consist of unimodal, multimodal, rotated, and shifted high-dimensional functions, demonstrate the high performance of the proposed algorithm in terms of convergence accuracy and speed with lower computation cost.


Assuntos
Algoritmos , Inteligência Artificial , Comportamento , Benchmarking , Eficiência Organizacional , Humanos , Modelos Teóricos , Estatística como Assunto/métodos
19.
Front Pharmacol ; 15: 1352113, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38562463

RESUMO

Background and aim: Vancomycin, a glycopeptide antimicrobial drug. PPK has problems such as difficulty in accurately reflecting inter-individual differences, and the PPK model may not be accurate enough to predict individual pharmacokinetic parameters. Therefore, the aim of this study is to investigate whether the application of machine learning combined with the PPK method can improve the prediction of vancomycin CL in adult Chinese patients. Methods: In the first step, a vancomycin CL prediction model for Chinese adult patients is given by PPK and Hamilton Monte Carlo sampling is used to obtain the reference CL of 1,000 patients; the second step is to obtain the final prediction model by machine learning using an appropriate model for the predictive factor and the reference CL; and the third step is to randomly select, in the simulated data, a total of 250 patients for prediction effect evaluation. Results: XGBoost model is selected as final machine learning model. More than four-fifths of the subjects' predictive values regarding vancomycin CL are improved by machine learning combined with PPK. Machine learning combined with PPK models is more stable in performance than the PPK method alone for predicting models. Conclusion: The first combination of PPK and machine learning for predictive modeling of vancomycin clearance in adult patients. It provides a reference for clinical pharmacists or clinicians to optimize the initial dosage given to ensure the effectiveness and safety of drug therapy for each patient.

20.
Heliyon ; 10(11): e31363, 2024 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-38882366

RESUMO

The frequent occurrence of extreme heat events has notably affected human's living environment, and a considerable number of studies have reported that green space is an efficient measure by investigating the correlation between green space and land surface temperature (LST). However, spatiotemporal effects of green space on LST still remain unclear. In this study, green space patterns (e.g., core, islet, perforation, edge, loop, bridge, and branch) were identified through morphological spatial pattern analysis (MSPA). Moreover, the effects of green space pattern on LST in three periods were investigated through three kinds of models. As indicated by the results: (1) the geographically and temporally weighted regression model exhibited the optimal performance compared with other two models. (2) in general, the core, the edge, the bridge, and the branch significantly contributed to cooling, and the islet hindered cooling. However, the perforation and the loop exerted significant dual nature effects with the similar quantity of the negative and positive coefficients, showing relatively complex impact mechanism. (3) the intensity of the effect of the respective MSPA class varied across the study area. The core had the most substantial effect, which distributed in the south and middle corners. (4) the result suggested that a neighborhood scale in China, which was 960 m in this study, served as a basic unit in green space management. The spatiotemporal non-stationarity of the effects of green space morphological patterns on LST provided important insights into urban thermal environment improvement through urban green space planning and design.

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