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1.
J Enzyme Inhib Med Chem ; 38(1): 84-99, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36342274

RESUMO

Understanding selectivity-dependent molecular mechanism of inhibitors towards CDK2 over CDK6 is prominent for improving drug design towards the CDK family. Multiple short molecular dynamics (MD) simulations combined with MM-GBSA approach are adopted to investigate molecular mechanism on binding selectivity of inhibitors X64, X3A, and 4 AU to CDK2 and CDK6. The RMSF analysis and calculations of molecular surface areas indicate that local structural and global flexibility of CDK6 are stronger than that of CDK2. Based on dynamics cross-correlation maps (DCCMs), motion modes of CDK2 and CDK6 produce difference due to associations of X64, X3A, and 4 AU. The calculated binding free energies (BFEs) demonstrate that the compensation between binding enthalpy and entropy of X64, X34, and 4 AU is a key force driving selectivity of inhibitors towards CDK2 over CDK6. This work provides valuable information for designing highly selective inhibitors towards CDK2 and CDK6 and further promotes identification of efficient anticancer drugs in the future.


Assuntos
Simulação de Dinâmica Molecular , Entropia , Ligação Proteica , Quinase 2 Dependente de Ciclina/metabolismo , Termodinâmica
2.
Injury ; 2022 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-36414499

RESUMO

OBJECTIVE: To compare the effect of internal fixation vs. external fixation after debridement in stage I of the Masquelet technique for Cierny-Mader (C-M) type Ⅳ chronic post-traumatic tibial osteomyelitis. METHODS: This retrospective observational study included patients with tibial osteomyelitis who underwent staged treatment with the Masquelet technique between January 2016 and June 2020 at the 920 Hospital of Joint Logistic Support Force of the PLA. The patients were grouped according to the fixation they received after stage I. Infection recurrence, time to radiological bone healing and full weight-bearing, self-rating anxiety scale (SAS) score, Hospital for Special Surgery (HSS) Knee Score, and American Orthopedic Foot and Ankle Society (AOFAS) Ankle-Hindfoot Score were compared. RESULTS: Sixty-three patients were included (50 males and 13 females). There were 40 and 23 patients with internal and external fixation, respectively. There were no significant differences between the two groups regarding the preoperative and intraoperative data (all P>0.05). After stage I operation, the infection control rates were 85.0% and 82.6% in the internal and external fixation groups (P=0.803), and these rates were 92.5% and 95.7% after stage II (P=0.621). There were no differences in the SAS scores (P=0.278), time to radiological union (P=0.795), time to full weight-bearing (P=0.725), AOFAS scores (P=0.302), HSS scores (P=0.085), and complication rates (P=0.593). There were 27 times complications in 19 patients, with an incidence of 42.9%, without significant differences between groups. CONCLUSION: There were no differences between the two fixation methods after debridement in stage I of the Masquelet technique for C-M type Ⅳ chronic post-traumatic tibia osteomyelitis.

3.
Psychiatry Res Neuroimaging ; 327: 111557, 2022 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-36327866

RESUMO

This study was the first to explore whether abnormal spontaneous neuronal activities exist in patients in the long-term remission stage of major depressive disorder (MDD). We recruited 34 MDD patients (PTs) and 30 sex- and age-matched healthy controls (HCs). Resting-state functional magnetic resonance imaging (rs-fMRI) was employed to scan all subjects' brain regions, and independent two-sample t-test was used for regional homogeneity (ReHo) and functional connectivity (FC) analysis. Compared with the HCs, the ReHo of PTs increased in the right superior frontal gyrus and left middle frontal gyrus, and decreased in the right anterior and collateral cingulate gyrus, right middle frontal gyrus, right inferior parietal lobule. The cingulate gyrus as a mask showed that FC of the cingulate gyrus with the bilateral lingual gyrus and the right middle temporal gyrus decreased, and FC with the left supper frontal gyrus increased. The correlation analysis revealed no significant correlation between the abnormal ReHo and HAMD-24 scores in PTs. The ReHo of inferior parietal lobule and the duration of remission were positively correlated. We concluded that the spontaneous neuronal activities might be disrupted in MDD patients in the long-term remission stage. Our findings provided new reasons for MDD relapse.

4.
JMIR Ment Health ; 9(11): e41482, 2022 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-36331539

RESUMO

BACKGROUND: Mobile health (mHealth) technologies have been used extensively in psychosis research. In contrast, their integration into real-world clinical care has been limited despite the broad availability of smartphone-based apps targeting mental health care. Most apps developed for treatment of individuals with psychosis have focused primarily on encouraging self-management skills of patients via practicing cognitive behavioral techniques learned during face-to-face clinical sessions (eg, challenging dysfunctional thoughts and relaxation exercises), reminders to engage in health-promoting activities (eg, exercising, sleeping, and socializing), or symptom monitoring. In contrast, few apps have sought to enhance the clinical encounter itself to improve shared decision-making (SDM) and therapeutic relationships with clinicians, which have been linked to positive clinical outcomes. OBJECTIVE: This qualitative study sought clinicians' input to develop First Episode Digital Monitoring (FREEDoM), an app-based mHealth intervention. FREEDoM was designed to improve the quality, quantity, and timeliness of clinical and functional data available to clinicians treating patients experiencing first-episode psychosis (FEP) to enhance their therapeutic relationship and increase SDM. METHODS: Following the app's initial development, semistructured qualitative interviews were conducted with 11 FEP treatment providers at 3 coordinated specialty care clinics to elicit input on the app's design, the data report for clinicians, and planned usage procedures. We then generated a summary template and conducted matrix analysis to systematically categorize suggested adaptations to the evidence-based intervention using dimensions of the Framework for Reporting Adaptations and Modifications-Enhanced (FRAME) and documented the rationale for adopting or rejecting suggestions. RESULTS: The clinicians provided 31 suggestions (18 adopted and 13 rejected). Suggestions to add or refine the content were most common (eg, adding questions in the app). Adaptations to context were most often related to plans for implementing the intervention, how the reported data were displayed to clinicians, and with whom the reports were shared. Reasons for suggestions primarily included factors related to health narratives and priorities of the patients (eg, focus on the functional impact of symptoms vs their severity), providers' clinical judgment (eg, need for clinically relevant information), and organizations' mission and culture. Reasons for rejecting suggestions included requests for data and procedures beyond the intervention's scope, concerns regarding dilution of the intervention's core components, and concerns about increasing patient burden while using the app. CONCLUSIONS: FREEDoM focuses on a novel target for the deployment of mHealth technologies in the treatment of FEP patients-the enhancement of SDM and improvement of therapeutic relationships. This study illustrates the use of the FRAME, along with methods and tools for rapid qualitative analysis, to systematically track adaptations to the app as part of its development process. Such adaptations may contribute to enhanced acceptance of the intervention by clinicians and a higher likelihood of integration into clinical care. TRIAL REGISTRATION: ClinicalTrials.gov NCT04248517; https://tinyurl.com/tjuyxvv6.

5.
iScience ; 25(11): 105329, 2022 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-36325060

RESUMO

Glioblastoma (GBM) is identified to share common signal pathways between glioma and immune cells. Here, we find that T cell immunoglobulin domain and mucin domain protein 3 (TIM-3) is one of the most common co-inhibitory immune checkpoints in GBM shared by tumor and non-tumor cells. Glioma cell-intrinsic TIM-3 is involved in not only regulating malignant behaviors of glioma cells but also inducing macrophage migration and transition to anti-inflammatory/pro-tumorigenic phenotype by a TIM-3/interleukin 6 (IL6) signal. In mechanism, as one of the major regulators of IL6, TIM-3 regulates its expression through activating NF-κB. Blocking this feedback loop by Tocilizumab, an IL6R inhibitor, inhibited the above effects and repressed the tumorigenicity of GBM in vivo. Our work identifies glioma cell-intrinsic functions of TIM-3/IL6 signal mediating the crosstalk feedback loop between glioma cells and tumor-associated macrophages (TAMs). Blocking this feedback loop may provide a novel therapeutic strategy for GBM.

6.
Cancer ; 2022 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-36370049

RESUMO

BACKGROUND: NOTCH mutations (NOTCHmut ) are recognized as major oncogenic drivers associated with controversial clinical impact on T-cell acute lymphoblastic leukemia (T-ALL), whereas their clinical value on acute myeloid leukemia (AML) is poorly defined. METHODS: A study involving 878 consecutive newly diagnosed patients with AML was undertaken in an institution with available clinical data to unravel the impact of NOTCHmut on prognosis. RESULTS: In the study, NOTCHmut were discovered in 3.6% (32/878) of included patients with AML and composed substitution-missense, frameshift mutation, substitution-nonsense, and insertion-in frame. These mutations were more commonly associated with low platelet (29 vs 42 × 109 /L, p = .024) count and coexisted with BCOR/BCORL1 (15.6% vs 3.2%, p = .001), DNMT3A (28.1% vs 12.5%, p = .021), and MPL (9.4% vs 0.8%, p = .004) mutations compared with NOTCH wild-type (NOTCHwt ). No significant difference was observed in treatment responses between NOTCHmut and NOTCHwt . The presence of NOTCHmut was associated with worse overall survival ([OS], 1 year-OS: 68.0% vs 84.2%; 3 year-OS: 48.3% vs 59.6%; p = .059) and relapse-free survival ([RFS], 1 year-RFS: 78.3% vs 85.4%; 3 year-RFS: 54.5% vs 76.9%; p = .018), especially within the European Leukemia Net 2017 intermediate-risk group. Furthermore, allogeneic hematopoietic stem cell transplantation might abrogate the dismal impact of NOTCHmut on RFS. In multivariate analysis, NOTCHmut were found to be an independent factor negatively influencing RFS (hazard ratio, 2.153; 95% CI, 1.166-3.975; p = .014). CONCLUSION: This study suggests that NOTCHmut may serve as an indicator for poor prognosis of AML. PLAIN LANGUAGE SUMMARY: Although NOTCH mutations (NOTCHmut ) are well studied in T-cell acute lymphoblastic leukemia (T-ALL), less is known about their incidence and prognostic implications in acute myeloid leukemia (AML). A total of 878 newly diagnosed patients with AML was retrospectively analyzed; it was found that the frequency of NOTCHmut was relatively low but was associated with an adverse prognosis.

7.
J Agric Food Chem ; 70(42): 13796-13807, 2022 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-36239255

RESUMO

Data-dependent acquisition (DDA) is widely utilized for metabolite identification in natural product research and food science, which, however, can suffer from low coverage. A potential solution to improve DDA coverage is to include the precursor ions list (PIL). Here, we aimed to construct a PIL-containing DDA strategy based on an in-house library of ginsenosides (VLG) and identify ginsenosides simultaneously from seven Panax herbal extracts. VLG, combined with mass defect filtering, could efficiently screen the ginsenoside precursors and elaborate the separate PIL involved in DDA for each ginseng extract. Consequently, we could characterize 500 ginsenosides, including 176 ones with unknown masses. Using the Panax ginseng extract, the superiority of this strategy was embodied in targeting more known ginsenoside masses and newly acquiring the MS2 spectra of 13 components. Conclusively, knowledge-based large-scale molecular prediction and PIL-DDA can represent a powerful targeted/untargeted strategy beneficial to novel natural compound discovery.


Assuntos
Produtos Biológicos , Ginsenosídeos , Panax , Panax/metabolismo , Ginsenosídeos/metabolismo , Cromatografia Líquida de Alta Pressão , Bibliotecas Digitais , Íons/metabolismo , Produtos Biológicos/metabolismo , Extratos Vegetais/metabolismo
8.
Oncol Rep ; 48(6)2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36300249

RESUMO

In a previous study by the authors, the longevity assurance homolog 2 (LASS2) gene was determined to inhibit activity of vacuolar H+­ATPase (V­ATPase) by combining with the C subunit (ATP6L) of V­ATPase. However, the influence of LASS2 overexpression and silencing on apoptosis of human lung cancer cells 95D or 95C remains unclear. Thus, the effect of LASS2 on apoptosis and its potential mechanisms were investigated in 95D and 95C cells. Using the lentiviral transfection method, lentiviral vectors of LASS2 overexpression and silencing were transfected into 95D and 95C cells, respectively. The apoptotic ability of tumor cells was observed by flow cytometry. The expression levels of LASS2, Bcl­2, Bax, cytochrome c, caspase­9, and caspase­3 were detected by western blotting. CCK­8 assay was used to detect the growth ability of tumor cells in vitro. Flow cytometric analysis revealed that LASS2 overexpression could promote the early apoptosis of lung cancer cells 95D. CCK­8 assay demonstrated that LASS2 overexpression inhibited the proliferation of 95D cells. Additionally, LASS2 overexpression decreased the expression of Bcl­2, induced the release of cytochrome c from mitochondria, and promoted the activation of caspase­9 and caspase­3. There was a significant difference in the expression of Bcl­2, cytochrome c, caspase­9 and caspase­3 in the LASS2­overexpression group compared with the normal and negative control groups. Alternatively, the aforementioned experiments in lung cancer cells 95C following LASS2 silencing produced the opposite effects. LASS2 may induce early apoptosis of lung cancer cells by influencing the caspase­dependent mitochondrial pathway.


Assuntos
Neoplasias Pulmonares , ATPases Vacuolares Próton-Translocadoras , Humanos , Esfingosina N-Aciltransferase/genética , Esfingosina N-Aciltransferase/metabolismo , Caspases/metabolismo , Caspase 3/genética , Caspase 3/metabolismo , Caspase 9/metabolismo , Citocromos c/genética , Citocromos c/metabolismo , Sincalida , Proteína X Associada a bcl-2/metabolismo , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Apoptose/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , ATPases Vacuolares Próton-Translocadoras/metabolismo , Linhagem Celular Tumoral
9.
Exp Hematol Oncol ; 11(1): 74, 2022 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-36258263

RESUMO

Acute myeloid leukemia (AML) is a complex, heterogeneous malignant hematologic disease. Although multiple prognostic-related genes gave been explored in previous studies, there are still many genes whose prognostic value remains unclear. In this study, a total of 1532 AML patients from three GEO databases were included, five genes with potential prognostic value (DLC1, NF1B, DENND5B, TANC2 and ELAVL4) were screened by weighted gene co-expression network analysis (WGCNA), least absolute shrinkage and selection operator (LASSO) and support vector machine recursive feature elimination (SVM-RFE). Based on this, we conducted survival analysis of the above five genes through the TCGA database and found that low level of DLC1 was detrimental to the long-term prognosis of AML patients. We also performed external validation in 48 AML patients from our medical center to analyze the impact of DLC1 level on prognosis. In conclusion, DLC1 may be a potential marker affecting the prognosis of AML, and its deficiency is associated with poor prognosis.

10.
PLoS One ; 17(10): e0276176, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36251670

RESUMO

Chenopodium album L. is a troublesome annual species in various cropping systems, and a sound knowledge of the ecological response of C. album germination to environmental factors would suggest suitable management strategies for inhibiting its spread. Preliminary laboratory-based research was conducted to investigate germination and emergence requirements of C. album under various environmental conditions (e.g., photoperiods, constant temperature, salinity, moisture, soil pH, burial depth, and oat crop residue). Results showed C. album seeds were found to be photoblastic, with only 13% germination in darkness. The maximum germination (94%) of C. album occurred at an optimal temperature of 25°C, and the depressive effect of other temperatures on germination was more severe at lower rather than higher temperatures. Seed germination was suitably tolerant of salinity and osmotic potential, with germination observed at 200 mM NaCl (37.0%) and -0.8 MPa (20%), respectively. Germination was relatively uniform (88-92%) at pH levels ranging from 4 to 10. The maximum germination of C. album was observed on the soil surface, with no or rare emergence of seeds at a burial depth of 2 cm or under 7000 kg ha-1 oat straw cover, respectively. Information provided by this study will help to develop more sustainable and effective integrated weed management strategies for the control of C. album, including (i) a shallow-tillage procedures to bury weed seeds in conventional-tillage systems and (ii) oat residue retention or coverage on the soil surface in no-tillage systems.


Assuntos
Chenopodium album , Germinação , Sementes/fisiologia , Cloreto de Sódio/farmacologia , Solo/química , Temperatura , Controle de Plantas Daninhas/métodos
11.
World Neurosurg ; 2022 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-36228930

RESUMO

OBJECTIVE: To evaluate the prognostic value of the buffer coefficient, calculated as the ratio of the buffer volume (volume of intracranial cerebrospinal fluid) at the peak of brain edema to the baseline brain volume, and some other parameters in patients with massive cerebral infarction (MCI). METHODS: The cohort comprised 161 patients with MCI who were divided into good and poor prognosis groups according to modified Rankin Scale score at 90 days after onset. Differences in clinical and imaging parameters between these groups were analyzed by univariate analysis, and multifactorial binary logistic regression analysis was used to further identify influencing factors that were significantly different. Receiver operating characteristic curve was used to evaluate the diagnostic performance between the buffer volume and the buffer coefficient. RESULTS: The findings showed that a history of atrial fibrillation, intravenous tissue-type plasminogen activator administration, successful reperfusion, successful craniectomy, low-density lesion volume, brain volume, buffer volume, and buffer coefficient were significantly different between the poor and good prognosis groups (P < 0.05 for all comparisons). Multifactorial binary logistic regression analyses revealed that patients who had large low-density lesion volume and patients who had not achieved successful reperfusion or received intravenous tissue-type plasminogen activator were likely to have a poor prognosis (P < 0.05). The buffer coefficient was identified as an independent predictive factor for MCI (P < 0.001). The area under the receiver operating characteristic curve for the buffer coefficient was 0.862. When the cutoff value was 9.3%, sensitivity of predicting poor prognosis of patients with MCI was 94.7%. CONCLUSIONS: The buffer coefficient has potential benefits as a prognostic indicator for MCI that can be used to detect even subtle changes in brain edema.

12.
Parasit Vectors ; 15(1): 393, 2022 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-36303229

RESUMO

BACKGROUND: Women in early pregnancy infected by Toxoplasma gondii may have severe adverse pregnancy outcomes, such as spontaneous abortion and fetal malformation. The inhibitory molecule T cell immunoglobulin and mucin domain 3 (Tim-3) is highly expressed on decidual dendritic cells (dDCs) and plays an important role in maintaining immune tolerance. However, whether T. gondii infection can cause dDC dysfunction by influencing the expression of Tim-3 and further participate in adverse pregnancy outcomes is still unclear. METHODS: An abnormal pregnancy model in Tim-3-deficient mice and primary human dDCs treated with Tim-3 neutralizing antibodies were used to examine the effect of Tim-3 expression on dDC dysfunction after T. gondii infection. RESULTS: Following T. gondii infection, the expression of Tim-3 on dDCs was downregulated, those of the pro-inflammatory functional molecules CD80, CD86, MHC-II, tumor necrosis factor-α (TNF-α), and interleukin-12 (IL-12) were increased, while those of the tolerant molecules indoleamine 2,3-dioxygenase (IDO) and interleukin-10 (IL-10) were significantly reduced. Tim-3 downregulation by T. gondii infection was closely associated with an increase in proinflammatory molecules and a decrease in tolerant molecules, which further resulted in dDC dysfunction. Moreover, the changes in Tim-3 induced by T. gondii infection further reduced the secretion of the cytokine IL-10 via the SRC-signal transducer and activator of transcription 3 (STAT3) pathway, which ultimately contributed to abnormal pregnancy outcomes. CONCLUSIONS: Toxoplasma gondii infection can significantly downregulate the expression of Tim-3 and cause the aberrant expression of functional molecules in dDCs. This leads to dDC dysfunction, which can ultimately contribute to abnormal pregnancy outcomes. Further, the expression of the anti-inflammatory molecule IL-10 was significantly decreased by Tim-3 downregulation, which was mediated by the SRC-STAT3 signaling pathway in dDCs after T. gondii infection.


Assuntos
Células Dendríticas , Receptor Celular 2 do Vírus da Hepatite A , Toxoplasmose , Animais , Feminino , Humanos , Camundongos , Gravidez , Células Dendríticas/parasitologia , Células Dendríticas/patologia , Regulação para Baixo , Receptor Celular 2 do Vírus da Hepatite A/genética , Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Interleucina-10/genética , Interleucina-10/metabolismo , Toxoplasma , Toxoplasmose/imunologia
13.
Artigo em Inglês | MEDLINE | ID: mdl-36300811

RESUMO

The aim of this study was to investigate the effect of a high-fat meal on the single-dose pharmacokinetics (PK) and tolerability of HMPL-689 in Chinese healthy volunteers. In this study, 34 eligible male volunteers received a single 30-mg dose of HMPL-689 capsules following an overnight fast or a high-fat breakfast prior to dosing. Blood samples were collected at the designated time points for pharmacokinetic analysis. Safety and tolerability were assessed throughout the study. Total 32 healthy male volunteers were completed in the study. The GMRs of AUC0-t , AUC0-∞ , and Cmax and their 90% CIs were 1.12 (1.09, 1.15), 1.12 (1.09, 1.15), and 0.64 (0.58, 0.70), respectively, in healthy male subjects after oral administration of HMPL-689 following intake of a high-fat diet versus under fasting state. The 90% CI of Cmax GMR fell outside the acceptable equivalent range (0.8-1.25). In addition, the median Tmax of HMPL-689 was 1.0 and 4.0 h under the fasting and the fed conditions. The study indicated that intake of a high-fat diet had an impact on the in vivo PK profile of HMPL-689 in healthy Chinese male subjects, which could obviously reduce the oral absorption rate of HMPL-689 and had little effect on the extent of oral absorption (AUC).

14.
Front Psychiatry ; 13: 941566, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36159932

RESUMO

Background: A large number of clinical RCTs have verified that Jin's three-needle therapy (JTNT) has a great contribution to promoting the function of paralyzed limbs and relieving anxiety disorders for patients with post-stroke anxiety (PSA). However, there is still a lack of sham needle control, and its placebo effect cannot be ruled out. This study firstly verifies the real effectiveness of JTNT. Besides, the changes in serum indexes on the hypothalamic-pituitary-adrenal axis (HPA axis) are observed dynamically by the Enzyme-Linked ImmunoSorbent Assay (ELISA). The activation of different brain regions by JTNT is recorded using resting functional magnetic resonance imaging (rs-fMRI). Therefore, we can provide more practical and powerful evidence-based medical evidence for clinical decisions. Method: This is a 16 week parallel, single-blind, random, controlled trial, including baseline, 4 weeks of treatment, and 12 weeks of follow-up. A total of 114 participants will be randomly divided into three groups in the proportion of 1:1:1. Participants will receive Jin's three-needle therapy in the active acupuncture group and accept sham needle treatment in the sham acupuncture group. In the waitlist control group, patients will not receive any acupuncture treatment. Outcomes cover three types of indicators, including scale indicators, serum indicators, and imaging indicators. The primary outcome is the change in the performance of anxiety symptoms, which is estimated by the 14-item Hamilton Anxiety Rating Scale (HAMA-14) and the 7-item Generalized Anxiety Disorder scale (GAD-7). Secondary outcomes are physical recovery and daily quality of life, which are evaluated by the National Institute of Health stroke scale (NIHSS) and the Modified Barthel Index Score (MBI Scale). Therefore, the assessment of the scale is carried out at baseline, 2nd, 4th, 8, 12, and 16 weeks. Adrenocorticotropin and cortisol will be quantitatively detected by ELISA at baseline and 4 weeks after treatment. In addition, regional homogeneity analysis (ReHo) will be used to record the activity of brain regions at baseline and 4 weeks after intervention. Discussion: The study aims to provide high-quality clinical evidence on the effectiveness and safety of JTNT for patients with PSA. In addition, this trial explores a possible mechanism of JTNT for patients with PSA. Clinical trial registration: Chinese Clinical Trial Registry, identifier [ChiCTR2200058992].

15.
Brain Sci ; 12(9)2022 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-36138978

RESUMO

Animal models play a central role in all areas of biomedical research. The similarities in anatomical structure and physiological characteristics shared by non-human primates (NHPs) and humans make NHPs ideal models with which to study human disorders, such as cerebral palsy (CP). However, the methodologies for systematically evaluating NHP models of CP have rarely been assessed, despite the long history of using NHP models to understand CP. Such models should be evaluated using multidisciplinary approaches prior to being used to research the diagnosis and treatment of CP. In this study, we evaluated rhesus macaque CP models established by partial resection of the motor cortex and intrathecal injection of bilirubin. Abnormal posture, motor dysfunction, gross and fine motor behavior, and muscular tension were evaluated, and changes in the cerebral cortex and basal ganglia were observed using 9.4 T magnetic resonance imaging. The results clearly demonstrated the utility of the established evaluation methodology for assessing CP models. This model evaluation methodology may guide researchers through the model building process.

16.
Molecules ; 27(17)2022 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-36080314

RESUMO

The leaves of Panax species (e.g., Panax ginseng-PGL, P. quinquefolius-PQL, and P. notoginseng-PNL) can serve as a source for healthcare products. Comprehensive characterization and unveiling of the metabolomic difference among PGL, PQL, and PNL are critical to ensure their correct use. For this purpose, enhanced profiling and chemometrics were integrated to probe into the ginsenoside markers for PGL/PQL/PNL by ultra-high performance liquid chromatography/ion mobility-quadrupole time-of-flight mass spectrometry (UHPLC/IM-QTOF-MS). A hybrid scan approach (HDMSE-HDDDA) was established achieving the dimension-enhanced metabolic profiling, with 342 saponins identified or tentatively characterized from PGL/PQL/PNL. Multivariate statistical analysis (33 batches of leaf samples) could unveil 42 marker saponins, and the characteristic ginsenosides diagnostic for differentiating among PGL/PQL/PNL were primarily established. Compared with the single DDA or DIA, the HDMSE-HDDDA hybrid scan approach could balance between the metabolome coverage and spectral reliability, leading to high-definition MS spectra and the additional collision-cross section (CCS) useful to differentiate isomers.


Assuntos
Ginsenosídeos , Panax notoginseng , Panax , Saponinas , Biomarcadores/metabolismo , Quimiometria , Cromatografia Líquida de Alta Pressão/métodos , Ginsenosídeos/análise , Espectrometria de Massas/métodos , Panax/química , Folhas de Planta/química , Reprodutibilidade dos Testes , Saponinas/análise
17.
Accid Anal Prev ; 177: 106821, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36055150

RESUMO

Understanding crash causation to the extent needed for applying countermeasures has always been a focus as well as a difficulty in the field of traffic safety. Previous research has been limited by insufficient crash data and analysis methods more suitable to single crashes. The use of crashes and near crashes (CNCs) and naturalistic driving studies can help solve the data problem, and use of pre-crash scenarios can identify the high-prevalence causes across multiple crashes of a given scenario. This study therefore proposes a two-stage crash causation analysis method based on pre-crash scenarios and a crash causation derivation framework that systematically categorizes and analyzes contributing factors. From the Shanghai Naturalistic Driving Study (SH-NDS), 536 CNCs were extracted, and were grouped into 23 different pre-crash scenarios based on the National Highway Traffic Safety Administration (NHTSA) pre-crash scenario typology. In-depth investigations were conducted, and CNCs sharing the same scenario were analyzed using the proposed framework, which identifies causation patterns based on the interaction of the framework's road user, vehicle, roadway infrastructure, and roadway environment subsystems. Through statistical analysis, the causation patterns and their contributing factors were compared for three common pre-crash scenarios of highest incidence: rear-end, lane change, and vehicle-pedalcyclist. Braking error in low-speed car following, following too closely, and non-driving-related distraction were important causes of rear-end scenarios. In lane change scenarios, the main causation patterns included illegal use of turn signals and dangerous lane changes as critical factors. Pedalcyclist scenarios were particularly impacted by visual obstructions, inadequate lanes for non-motorized vehicles, and pedalcyclists violating traffic regulations. Based on the identified causation patterns and their contributing factors, countermeasures for the three common scenarios are suggested, which provide support for safety improvement projects and the development of advanced driver assistance systems.


Assuntos
Acidentes de Trânsito , Condução de Veículo , Causalidade , China , Humanos
18.
Accid Anal Prev ; 177: 106799, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36081222

RESUMO

The Responsibility-Sensitive Safety (RSS) model was proposed by Mobileye as a mathematical model that defines the real-time safety distance that the automated vehicle (AV) needs to maintain from surrounding vehicles. However, RSS strategy tends to be overly conservative. This research made modifications to the RSS safe distance to reduce its conservativeness without affecting safety, and evaluated the modified (RSS_X) and original RSS (RSS_O) in freeway car-following scenarios extracted from the Shanghai Naturalistic Driving Study (SH-NDS). The modifications were replacing the maximum acceleration with the positive previous time-step acceleration and adding standstill gap. In this study, 6,146 car-following scenarios were extracted and divided into two groups, normal scenarios (5,923) and safety-critical events (SCEs, near crashes) (223), to evaluate the efficiency and safety performance of RSS. The RSS_O and RSS_X were then embedded into the intelligent driver model (IDM) and model predictive control (MPC), but because the RSS modifications caused a few acceleration stability problems, the IDM and MPC were also modified to accommodate the RSS_X. The efficiency performance results showed that the modified models (IDM + RSS_X, MPC + RSS_X) performed better than the originals (IDM + RSS_O, MPC + RSS_O) in that they had higher average speeds, more comfortable acceleration pattern, and smaller longitudinal clearance between vehicles, which leads to less conservativeness. To evaluate safety, human drivers were compared with the original and modified models. RSS reduced the severity of at least 80 % of the human driver SCEs. MPC + RSS_X increased the mean minimum time to collision (TTC) for the majority of SCEs from 1.65 s to 4.08 s, and IDM + RSS_X increased the mean minimum TTC for the majority of SCEs from 1.53 s to 3.44 s.


Assuntos
Acidentes de Trânsito , Condução de Veículo , Aceleração , Acidentes de Trânsito/prevenção & controle , Automóveis , China , Humanos
19.
Accid Anal Prev ; 178: 106834, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36150234

RESUMO

In public road tests of autonomous vehicles in California, rear-end crashes have been the most common type of crash. Collision avoidance systems, such as autonomous emergency braking (AEB), have provided an effective way for autonomous vehicles to avoid collisions with the lead vehicle, but to avert false alarms, AEB tends to apply late and hard brake only if a collision becomes unavoidable. Automatic preventive braking (APB) is a new collision avoidance method used in Mobileye's Responsibility-Sensitive Safety (RSS) model that aims to reduce crashes with a milder brake and decreased impact on traffic flow, but APB's safety performance is inferior to that of AEB. This study therefore proposes three safety improvement strategies for APB, the addition of response time, safety buffer, and minimum following distance; and combines them in different ways into four improved APB systems, IP1-IP4. Simulating car-following safety-critical events (SCEs) extracted from the Shanghai Naturalistic Driving Study in MATLAB's Simulink, the safety performance, conservativeness, and driving comfort of the four systems were evaluated and compared with the original APB system, two AEB systems, and human drivers. The results show that 1) IP4, the system that integrated all three strategies, outperformed the baseline APB and IP1-IP3 and prevented all SCEs from becoming crashes; 2) IP4 was slightly more conservative than AEB, but less conservative than RSS; 3) APB's jerk-bounded braking profile improved driving comfort; and 4) higher deceleration was found in the two AEB systems (both 8.1 m/s2) than in IP4 (6.7 m/s2), but they failed to prevent all crashes. Our proposed APB system, IP4, can provide safe, efficient, and comfortable braking for AVs in car-following SCEs, and has the potential to be practically applied in vehicle collision avoidance systems.


Assuntos
Condução de Veículo , Desaceleração , Humanos , Acidentes de Trânsito/prevenção & controle , Equipamentos de Proteção , Automóveis , China
20.
Parasit Vectors ; 15(1): 337, 2022 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-36153598

RESUMO

BACKGROUND: Infections are a major threat to human reproductive health because they can induce pregnancy failure, including recurrent abortion, stillbirth, and preterm birth. Toxoplasma gondii (T. gondii) infection can result in adverse pregnancy outcomes by affecting certain immune molecules and cytokines. However, the detailed mechanisms behind T. gondii-induced pregnancy failure are poorly understood. METHODS: Toxoplasma gondii-infected wild-type (WT) pregnant mice and 2B4 knockout (2B4-/-) pregnant mice were established for in vivo study. Human decidual natural killer (dNK) cells were cultured for in vitro study. Abnormal pregnancy outcomes were observed, and the expression of 2B4, functional molecules (CD69, CD107a, tumor necrosis factor alpha [TNF-α], interferon gamma [IFN-γ]), and signaling molecules (SHP-2, Fyn, p-ERK, p-P38) in dNK cells were detected by flow cytometry, Western blot, reverse transcriptase polymerase chain reaction (RT-PCR), and/or immunofluorescence. The direct interactions (2B4 interacts with SHP-2 and Fyn; SHP-2 interacts with p-P38 and 2B4; Fyn interacts with p-ERK and 2B4) were verified by co-immunoprecipitation (co-IP) in NK-92 cells. RESULTS: Here, results showed that 2B4 was significantly downregulated after T. gondii infection. Subsequently, infected 2B4-/- pregnant mice displayed worse pregnancy outcomes compared with infected WT pregnant mice. Also, increased TNF-α and IFN-γ expression and elevated dNK cell cytotoxicity were found in 2B4-/- pregnant mice during T. gondii infection. In contrast, reduced TNF-α and IFN-γ expression and decreased human dNK cell activity were found following 2B4 activation during T. gondii infection. Interestingly, results showed that 2B4 binds to adaptor SHP-2 or Fyn, which then triggers different signaling pathways to regulate TNF-α and IFN-γ expression in dNK cells during T. gondii infection. Further, SHP-2 binds 2B4 and p-P38 directly after 2B4 activation, which generates an inhibitory signal for TNF-α and IFN-γ in NK-92 cells. In addition, Fyn can bind to 2B4 and p-ERK after activation of 2B4, thereby inhibiting TNF-α and IFN-γ expression in NK-92 cells following T. gondii infection. CONCLUSIONS: These data suggest that 2B4 may be a novel danger-signaling molecule that is implicated in pregnancy failure during T. gondii infection. Unraveling the mechanism by which 2B4 regulates dNK cell activity will provide novel insights to aid our understanding of T. gondii-induced adverse pregnancy outcomes.


Assuntos
Nascimento Prematuro , Família de Moléculas de Sinalização da Ativação Linfocitária , Toxoplasma , Toxoplasmose , Animais , Citocinas/metabolismo , Feminino , Humanos , Interferon gama , Células Matadoras Naturais/metabolismo , Camundongos , Gravidez , Resultado da Gravidez , Nascimento Prematuro/metabolismo , Família de Moléculas de Sinalização da Ativação Linfocitária/genética , Fator de Necrose Tumoral alfa/metabolismo
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