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1.
Sci Total Environ ; : 155886, 2022 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-35569652

RESUMO

An accurate estimation of thaw depth is critical to understanding permafrost changes due to climate warming on the Qinghai-Tibetan Plateau (QTP). However, previous studies mainly focused on the interannual changes of active layer thickness (ALT) across the QTP, and little is known about the changes in the seasonal thaw depth. Machine learning (ML) is a critical tool to accurately estimate the ALT of permafrost, but a direct comparison of ML with deep learning (DL) in ALT projection regarding the model performance is still lacking. Here, ML, namely random forest (RF), and DL algorithms like convolutional neural networks (CNN) and long short-term memory (LSTM) neural networks were compared to estimate the interannual changes of ALT and seasonal thaw depth on the QTP. Meteorological series, in-situ collected ALT observations, and geospatial information were used as predictors. The results show that both ML and DL methods are capable of estimating ALT and seasonal thaw depth in permafrost areas. The CNN and LSTM models developed using longer lagging times exhibit better performance in thaw depth prediction while the RF models are either mediocre or sometimes even worse as the lagging time increases. The results show that the ALT from 2003 to 2011 on the QTP exhibits an increasing trend, especially in the northern region. In addition, 68.8%, 88.7%, 52.5%, and 47.5% of the permafrost regions on the QTP have deepened seasonal thaw depth in spring, summer, autumn, and winter, respectively. The correlation between air temperature and permafrost thaw depth ranges from 0.65 to 1 with the time lag ranging from 1 to 32 days. This study shows that ML and DL can be effectively used in retrieving ALT and seasonal thaw depth of permafrost, and could present an efficient way to figure out the interannual and seasonal variations of permafrost conditions under climate warming.

2.
Opt Lett ; 47(10): 2406-2409, 2022 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-35561362

RESUMO

In this Letter, we report a four-wavelength quadrature phase demodulation technique for extrinsic Fabry-Perot interferometric (EFPI) sensors and dynamic signals. Four interferometric signals are obtained from four different laser wavelengths. A wavelength interval of four wavelengths is chosen according to the free spectrum range (FSR) of EFPI sensors to generate two groups of anti-phase signals and two groups of orthogonal signals. The linear fitting (LF) method is applied to two groups of anti-phase signals to eliminate the dc component and ac amplitude to obtain two normalized orthogonal signals. The differential cross multiplication (DCM) method is then used to demodulate the phase signal from these two normalized orthogonal signals. The proposed LF and DCM (LF-DCM) based four-wavelength quadrature phase demodulation overcomes the drawback of the traditional ellipse fitting (EF) and DCM (EF-DCM) based dual-wavelength demodulation method that it is not suitable for weak signal demodulation since the ellipse degenerates into a straight line, which makes the EF algorithm invalid. Moreover, it also avoids the assumption that the dc component and ac amplitude of interferometric signals are identical, which is widely used in three-wavelength demodulation. An EFPI acoustic sensor is tested to prove the four-wavelength quadrature phase demodulation and experimental results show that the proposed phase demodulation method shows advantages of large dynamic range and wide frequency band. Linearity is as high as 0.9999 and a high signal-to-noise ratio (SNR) is observed from 1 Hz to 100 kHz.

3.
Spine J ; 2022 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-35508287

RESUMO

BACKGROUND: C2 pedicle screw placement in patients with basilar invagination (BI) is fraught with risks because of high incidence of anatomical variations and high-riding vertebral artery (HRVA). However, no study can be found in the literature that attempted to identify the ideal entry point and trajectory through the C2 pedicle in BI patients with HRVA. PURPOSE: To investigate the parameters of ideal entry point and trajectory for C2 pedicle screw placement in BI patients with HRVA and compare them with those in BI patients without HRVA and patients without BI as control. These parameters would serve as a guide to pedicle screw placement. STUDY DESIGN: A retrospective comparative study PATIENT SAMPLE: A total of 396 patients (198 consecutive BI patients and 198 matched patients without BI as control) and 792 unilateral pedicles from April 2017 to October 2021 at two medical centers were included. OUTCOME MEASURES: The insertion parameters of mediolateral angle, surface distance, cephalad angle, and vertical distance from the superior border of the lamina were the primary outcome measures for the reference of C2 pedicle screw placement. Furthermore, factors that affect the primary insertion parameters were assessed via multiple linear regression analyses. METHOD: According to the diagnosis of BI and HRVA, the unilateral pedicles were assigned into HRVA of BI, non-HRVA of BI, HRVA of control, and non-HRVA of control groups. Subgroup analyses based on Goel types A and B were also performed. Moreover, vertebral artery (VA) anomalies that might result in potentially serious complications were identified and systematically compared. RESULTS: The measurements of insertion parameters in BI patients with HRVA indicated a mean mediolateral angle of 27.42°, a mean cephalad angle of 43.02°, a mean surface distance of 9.74 mm, and a mean vertical distance from the superior border of the lamina of 3.85 mm. Compared with that in BI patients without HRVA, the measurements suggested that the entry point in BI patients with HRVA should be shifted upward by 0.38 mm and the trajectory should be angled cephalad by 6.05° and medially by 4.78°. In the control group, changes in the insertion parameters between HRVA and non-HRVA showed a similar trend with the BI group. Multiple linear regression showed that mediolateral angle was significantly associated with the male gender (B = -0.930, P = 0.017) and the diagnoses of HRVA (B = 6.964, P < 0.001), Goel type A (B = -1.656, P = 0.003), and Goel type B (B = 0.981, P = 0.030). Moreover, cephalad angle was significantly associated with the length of lateral mass (B = -0.319, P = 0.001) and the diagnoses of HRVA (B = 3.254, P < 0.001) and Goel type A (B = 6.924, P < 0.001). The VA anomalies were significantly higher in the BI group than in the control group. CONCLUSION: The insertion parameters of the ideal entry point and trajectory for C2 screw placement in BI patients with HRVA were remarkably different from those of non-HRVA of BI, HRVA of control, and non-HRVA of control cohorts. Preoperative 3D computed tomography (CT) and CT angiography are highly recommended in such patients to improve intraoperative safety and reduce postoperative complications.

4.
PLoS One ; 17(5): e0267887, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35536828

RESUMO

BACKGROUND AND AIM: Head and neck cancer patients are vulnerable to various psychological complications due to the effects of both cancer itself and cancer treatment on patients' appearance and physical well-being. Nevertheless, few data have been obtained on effective psychosocial interventions that could protect this group of cancer patients' psychological well-being. Therefore, this three-armed, parallel-group, double-blind, randomized control trial (RCT) aims to evaluate and compare the effects of acceptance and commitment therapy (ACT) and mindfulness-based stress reduction (MBSR) on positive psychology (such as posttraumatic growth [PTG], hope, and optimism), quality of life (QoL), and psychological complications (depression, anxiety, and experiential avoidance) among newly diagnosed head and neck cancer patients. METHODS AND ANALYSIS: This RCT will target newly diagnosed head and neck cancer patients who have been treated only with surgery or who have not yet received any treatment. In total, 120 patients who meet all of the study's inclusion criteria and none of its exclusion criteria will be randomly assigned into three groups-an ACT group, an MBSR group, and a treatment-as-usual control group-at a 1:1:1 allocation ratio. Participants in the two intervention groups (the ACT and MBSR groups) will undergo an eight-week group intervention program. During this program, each intervention will comprise eight modules based on ACT and MBSR, respectively. Outcome assessments will be performed across a three-point timeline, including before the intervention (t0), immediately after the psychosocial intervention at eight weeks (t1), and six months after the intervention (t2). The primary outcome that will be assessed during this RCT is PTG. Meanwhile, the secondary outcomes that will be evaluated in this study are such as QoL, hope, optimism, depression, anxiety, and experiential avoidance. TRIAL REGISTRATION NUMBER: NCT04800419 (ClinicalTrials.gov). Registered on March 16, 2021.

5.
Ear Nose Throat J ; : 1455613221096622, 2022 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-35491876

RESUMO

Objective: Cochlear nerve deficiency (CND) accounts for 10-19% of hearing loss in children; this study investigated the imaging and audiological features of 25 CND children. Methods: A total of 563 children with an unpassed automatic auditory brainstem response were diagnosed with hearing loss in our department between December 2018 and December 2021, of which, the imaging and audiological features of 25 children (25/563, 4.4%) diagnosed with a CND were reviewed. Results: Twenty-one (21/25, 84.0%) CND children had unilateral deafness, and 4 cases of bilateral deafness. All deaf ears were diagnosed as severe hearing loss due to an auditory brainstem response. CM waves were recorded in 8 cases and DPOAE in 3 cases, suggesting the audiological characteristics of auditory neuropathy spectrum disorders (ANSD). MRI results indicated 23 cases had small cochlear nerves and 2 cases had absent cochlear nerves. No genetic mutations were identified in the 25 CND children. Conclusions: Most CND children had unilateral hearing loss; therefore, high-resolution MRI imaging of the internal auditory canal should be performed to detect the auditory nerve in children with severe hearing loss. Some CND children had characteristics of ANSD.

6.
Ann Otol Rhinol Laryngol ; : 34894221092201, 2022 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-35499129

RESUMO

OBJECTIVE: The aim of this meta-analysis was to critically assess the effect of cochlear implantation on auditory and speech performance outcomes of children with auditory neuropathy spectrum disorder (ANSD). MATERIAL AND METHODS: A systematic literature search was conducted on PubMed, EMbase, and Web of Science. The outcomes included speech recognition score, Categories of Auditory Performance (CAP), Speech Intelligibility Rating (SIR) score, and open-set speech perception. Results were expressed as standardized mean difference (SMD) or risk ratio (RR) with a 95% confidence interval (95% CI). RESULTS: A total of 15 studies was included in this meta-analysis. Pooled data showed that, there were no significant differences between ANSD and sensorineural hearing loss (SNHL) groups in terms of speech recognition score (SMD = 0.01, 95% CI: -0.45, 0.47; P = .959),CAP (SMD = 0.71, 95% CI: -0.13, 1.54; P = .098), SIR score (SMD = -0.09, 95% CI: -0.49, 0.32; P = .667), and open-set speech perception (RR = 0.85, 95% CI: 0.69, 1.05; P = .142). Sensitivity analysis by removing individual studies one at a time showed that the overall estimate and level of heterogeneity did not change substantially. CONCLUSION: The current evidence suggested that children with ANSD who underwent cochlear implants achieved comparable effects in auditory and speech performance as children with non-ANSD SNHL.

7.
Pediatr Nephrol ; 2022 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-35507146

RESUMO

BACKGROUND: We compared plasma metabolites of amino acid oxidation and the tricarboxylic acid (TCA) cycle in youth with and without type 1 diabetes mellitus (T1DM) and related the metabolites to glomerular filtration rate (GFR), renal plasma flow (RPF), and albuminuria. Metabolites associated with impaired kidney function may warrant future study as potential biomarkers or even future interventions to improve kidney bioenergetics. METHODS: Metabolomic profiling of fasting plasma samples using a targeted panel of 644 metabolites and an untargeted panel of 19,777 metabolites was performed in 50 youth with T1DM ≤ 10 years and 20 controls. GFR and RPF were ascertained by iohexol and p-aminohippurate clearance, and albuminuria calculated as urine albumin to creatinine ratio. Sparse partial least squares discriminant analysis and moderated t tests were used to identify metabolites associated with GFR and RPF. RESULTS: Adolescents with and without T1DM were similar in age (16.1 ± 3.0 vs. 16.1 ± 2.9 years) and BMI (23.4 ± 5.1 vs. 22.7 ± 3.7 kg/m2), but those with T1DM had higher GFR (189 ± 40 vs. 136 ± 22 ml/min) and RPF (820 ± 125 vs. 615 ± 65 ml/min). Metabolites of amino acid oxidation and the TCA cycle were significantly lower in adolescents with T1DM vs. controls, and the measured metabolites were able to discriminate diabetes status with an AUC of 0.82 (95% CI: 0.71, 0.93) and error rate of 0.21. Lower glycine (r:-0.33, q = 0.01), histidine (r:-0.45, q < 0.001), methionine (r: -0.29, q = 0.02), phenylalanine (r: -0.29, q = 0.01), serine (r: -0.42, q < 0.001), threonine (r: -0.28, q = 0.02), citrate (r: -0.35, q = 0.003), fumarate (r: -0.24, q = 0.04), and malate (r: -0.29, q = 0.02) correlated with higher GFR. Lower glycine (r: -0.28, q = 0.04), phenylalanine (r:-0.3, q = 0.03), fumarate (r: -0.29, q = 0.04), and malate (r: -0.5, q < 0.001) correlated with higher RPF. Lower histidine (r: -0.28, q = 0.02) was correlated with higher mean ACR. CONCLUSIONS: In conclusion, adolescents with relatively short T1DM duration exhibited lower plasma levels of carboxylic acids that associated with hyperfiltration and hyperperfusion. TRIAL REGISTRATION: ClinicalTrials.gov NCT03618420 and NCT03584217 A higher resolution version of the Graphical abstract is available as Supplementary information.

8.
Innovation (N Y) ; 3(3): 100239, 2022 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-35509869

RESUMO

Lack of effective targeted therapy in metastatic esophageal squamous cell carcinoma (ESCC) underscores the urgent need for identifying new treatment approaches for this challenging disease. We sought to assess the addition of cetuximab to paclitaxel-cisplatin chemotherapy for first-line treatment in patients with metastatic ESCC. In this randomized, multicenter, open-label, phase II clinical trial, patients were randomized to receive paclitaxel-cisplatin (TP) (paclitaxel [175 mg/m2 intravenously (i.v.) on day 1 of every 3-week cycle] and cisplatin [75 mg/m2 i.v. on day 1 of every 3-week cycle]) and TP plus cetuximab (CTP) (cetuximab, 400 mg/m2 i.v. on day 1 of week 1, followed by 250 mg/m2 weekly), respectively. Targeted next-generation sequencing (NGS) was performed on 89 tumor samples for biomarker exploration. The primary endpoint was progression-free survival (PFS) in the intention-to-treat population. With a median follow-up of 22.6 months, median PFS was 5.7 months (95% confidence interval [CI]: 4.8-7.0) in patients administered CTP versus 4.2 months (95% CI: 3.0-5.3) in the TP group (hazard ratio [HR] = 0.61; 95% CI: 0.40-0.93; p = 0.02). Median overall survival was 11.5 months (95% CI: 7.9-13.1) in the CTP group and 10.5 months (95% CI: 9.0-13.2) in the TP arm (HR = 0.98; 95% CI: 0.67-1.44; p = 0.91). The most common reported greater than or equal to grade 3 adverse events were neutropenia (35.2% versus 22.4%) and leukopenia (25.4% versus 13.2%). In patients with epidermal growth factor receptor (EGFR) amplification tumors (15.7%), PFS was improved with CTP compared with TP treatment (HR = 0.11; 95% CI: 0.01-0.98; p = 0.018). First-line CTP significantly improves PFS, with a manageable safety profile in patients with metastatic ESCC.

9.
Zool Res ; 43(3): 469-480, 2022 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-35514224

RESUMO

Effective conservation of threatened biota relies on accurate assessments and scientific guidance. As an unfortunate example, Chinese giant salamanders ( Andrias, CGS) remain critically endangered in nature. Misguided conservation efforts, e.g., commercial propagation and releasing of millions of likely non-indigenous or interspecific hybrids, have further compromised conservation initiatives. Limited information on wild populations of CGS poses a significant conservation challenge. Following 18-month long field monitoring, we now report the discovery of a wild population of CGS in a closed nature reserve in Jiangxi Province, China. Genomic assessments reveal its genetic distinctiveness and do not detect genetic admixture with other species. Based on morphological and molecular evidences, we describe this CGS as a new species Andrias jiangxiensis sp. nov. This is the only known species of CGS today with a genetically pure, reproducing, in situ population. This discovery emphasizes the important role that closed nature reserves play in protecting species, and the necessity of integrating long-term field monitoring and genetic assessments. It sets a new pathway for discovering and conserving endangered species, especially for those biotas that are similarly being extirpated by anthropogenic translocations and overexploitation.


Assuntos
Conservação dos Recursos Naturais , Espécies em Perigo de Extinção , Animais , China , Urodelos/genética
10.
Cell Transplant ; 31: 9636897221094244, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35506155

RESUMO

Use of chimeric antigen receptors (CARs), as an immune cell therapy, has generated excellent clinical outcomes against hematologic tumors in recent years. Among them, the CAR-NK (natural killer) therapy has shown better efficacy, and less toxicity, than chimeric antigen receptor T-cell (CAR-T) therapy. In our phase II clinical trials, administering chimeric costimulatory converting receptor (CCCR)-NK92 cells on advanced non-small cell lung cancer patients proved efficacious in cell and animal experiments. However, we observed occurrence of cytokine release syndrome (CRS), a rare and unexpected side effect, never reported before during CAR-NK therapy. Here, we provide a detailed report of the patient's case, emphasize on the need to pay attention to CRS in NK cell therapy, and suggest improvements that will minimize potential toxicity.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Receptores de Antígenos Quiméricos , Animais , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Síndrome da Liberação de Citocina , Humanos , Células Matadoras Naturais , Neoplasias Pulmonares/tratamento farmacológico , Receptores de Antígenos Quiméricos/uso terapêutico
11.
RSC Adv ; 12(6): 3423-3430, 2022 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-35425351

RESUMO

Compounds with human ether-à-go-go related gene (hERG) blockade activity may cause severe cardiotoxicity. Assessing the hERG liability in the early stages of the drug discovery process is important, and the in silico methods for predicting hERG channel blockers are actively pursued. In the present study, the directed message passing neural network (D-MPNN) was applied to construct classification models for identifying hERG blockers based on diverse datasets. Several descriptors and fingerprints were tested along with the D-MPNN model. Among all these combinations, D-MPNN with the moe206 descriptors generated from MOE (D-MPNN + moe206) showed significantly improved performances. The AUC-ROC values of the D-MPNN + moe206 model reached 0.956 ± 0.005 under random split and 0.922 ± 0.015 under scaffold split on Cai's hERG dataset, respectively. Moreover, the comparisons between our models and several recently reported machine learning models were made based on various datasets. Our results indicated that the D-MPNN + moe206 model is among the best classification models. Overall, the excellent performance of the DMPNN + moe206 model achieved in this study highlights its potential application in the discovery of novel and effective hERG blockers.

12.
J Clin Med ; 11(7)2022 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-35407587

RESUMO

Given the central role of interstitial fibrosis in disease progression in chronic kidney disease (CKD), a role for diffusion-weighted MRI has been pursued. We evaluated the feasibility and preliminary efficacy of using radiomic features to phenotype apparent diffusion coefficient (ADC) maps and hence to the clinical classification(s) of the participants. The study involved 40 individuals (10 healthy and 30 with CKD (eGFR < 60 mL/min/1.73 m2)). Machine learning methods, such as hierarchical clustering and logistic regression, were used. Clustering resulted in the identification of two clusters, one including all individuals with CKD (n = 17), while the second one included all the healthy volunteers (n = 10) and the remaining individuals with CKD (n = 13), resulting in 100% specificity. Logistic regression identified five radiomic features to classify participants as with CKD vs. healthy volunteers, with a sensitivity and specificity of 93% and 70%, respectively, and an AUC of 0.95. Similarly, four radiomic features were able to classify participants as rapid vs. non-rapid CKD progressors among the 30 individuals with CKD, with a sensitivity and specificity of 71% and 43%, respectively, and an AUC of 0.75. These promising preliminary data should support future studies with larger numbers of participants with varied disease severity and etiologies to improve performance.

13.
Artigo em Inglês | MEDLINE | ID: mdl-35409961

RESUMO

A majority of subsidence lakes were reclaimed as fish ponds, but the widespread use of antibiotics has caused the pollution of antibiotic resistance genes (ARGs). This paper uses zeolite as a filter material to construct a horizontal submersible wastewater treatment device and explores its effect on the removal of conventional pollutants and sulfonamide ARGs in wastewater. The results showed that the removal of total nitrogen and ammonia nitrogen by the zeolite filter media were 59.0% and 63.8%, respectively, which were higher than the removal of total phosphorus and COD. The absolute abundances of sul1 and sul2 in wastewater were 2.81 × 104 copies·L-1 and 2.42 × 103 copies·L-1. On average, 60.62% of sul1 and 75.84% of sul2 can be removed, and more than 90% of sul1 and sul2 can be removed. Experiments showed that the residence time of wastewater in the treatment device had a significant impact on removal. The microbial community structure of aquaculture wastewater was quite different before and after wastewater treatment. The abundance changes of Saccharimonadales and Mycobacterium affect the removal of sulfonamide ARGs.


Assuntos
Águas Residuárias , Zeolitas , Animais , Antibacterianos , Pesqueiros , Genes Bacterianos , Nitrogênio , Sulfonamidas , Águas Residuárias/microbiologia
14.
New Phytol ; 2022 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-35451076

RESUMO

Alternative splicing (AS) and alternative polyadenylation (APA) contribute significantly to the regulation of gene expression in higher eukaryotes. Their biological impact in filamentous fungi, however, is largely unknown. Here we combine PacBio Isoform-Sequencing and strand-specific RNA-sequencing of multiple tissues and mutant characterization to reveal the landscape and regulation of AS and APA in Fusarium graminearum. We generated a transcript annotation comprising 51 617 isoforms from 17 189 genes. In total, 4997 and 11 133 genes are alternatively spliced and polyadenylated, respectively. Majority of the AS events alter coding sequences. Unexpectedly, the AS transcripts containing premature-termination codons are not sensitive to nonsense-mediated messenger RNA decay. Unlike in yeasts and animals, distal APA sites have strong signals, but proximal APA isoforms are highly expressed in F. graminearum. The 3'-end processing factors FgRNA15, FgHRP1, and FgFIP1 play roles in promoting proximal APA site usage and intron splicing. A genome-wide increase in intron inclusion and distal APA site usage and downregulation of the spliceosomal and 3'-end processing factors were observed in older and quiescent tissues, indicating intron inclusion and 3'-untranslated region lengthening as novel mechanisms in regulating aging and dormancy in fungi. This study provides new insights into the complexity and regulation of AS and APA in filamentous fungi.

15.
Cancer Lett ; 538: 215693, 2022 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-35472437

RESUMO

Owing to the lack of early diagnosis, pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal tumours. Because acinar-to-ductal metaplasia (ADM) is a critical process to pancreatic regeneration and PDAC initiation, we applied GSE65146, a dataset composed of transcripts at different time points in wild-type and KrasG12D mutant mice upon pancreatitis induction, to obtain regeneration- and tumour initiation-related genes. By overlapping with genes differentially expressed in human PDAC, we defined the initiation- and progression-related genes, and the most prognostic gene, SULF2, was selected for further verification. By using multiple PDAC genetically engineered murine models (GEMMs), we further verified that the expression of SULF2 was increased at the ADM and PDAC stages. Functionally, SULF2 was able to promote the dedifferentiation of acinar cells as well as the metastatic ability of PDAC. Additionally, our study revealed that SULF2 could enhance TGFß-SMAD signalling via GDF15. More importantly, serum SULF2 was elevated in patients with PDAC, and in combination with CA19-9, it provided a better method for PDAC diagnosis. Herein, our study screened out key genes for the initiation and progression of PDAC, providing potential indicators for the diagnosis of the disease.

16.
ACS Med Chem Lett ; 13(4): 734-741, 2022 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-35450359

RESUMO

Mutant isocitrate dehydrogenase 1 (IDH1) has been identified as an attractive oncology target for which >70% of grade II and III gliomas and ∼10% of acute myeloid leukemia (AML) harbor somatic IDH1 mutations. These mutations confer a neomorphic gain of function, leading to the production of the oncometabolite (R)-2-hydroxyglutarate (2-HG). We identified and developed a potent, selective, and orally bioavailable brain-penetrant tricyclic diazepine scaffold that inhibits mutant IDH1. During the course of in vitro metabolism studies, GSH-adduct metabolites were observed. The hypothesis for GSH-adduct formation was driven by the electron-rich nature of the tricyclic core. Herein, we describe our efforts to reduce the electron-rich nature of the core. Ultimately, a strategy focused on core modifications to block metabolic hot spots coupled with substitution pattern changes (C8 N → C linked) led to the identification of new tricyclic analogues with minimal GSH-adduct formation across species while maintaining an overall balanced profile.

17.
Langmuir ; 38(15): 4774-4784, 2022 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-35380846

RESUMO

Water-soluble amphiphilic polymers are vital chemicals in the oil and gas industry to retard crystal growth of hydrocarbon hydrate via surface adsorption and suppress nucleation of a pristine hydrate nucleus, thereby preventing formation of hydrate blockages in flow lines during oil and natural gas production. Apart from a few theoretical modeling studies, an experimental method to study the polymer/water interface in the crystal growth is critically needed. Here, water motions in the hydration shells of an exemplary kinetic inhibitor, poly(N-vinylcaprolactam), during hydrate formation from the tetrahydrofuran/water system are revealed via nuclear magnetic resonance relaxometry. Unequivocal experiments show that the pivotal interfacial water in the tightly bound state gradually freezes at rates depending on the polymer molecular weight (MW). This is supported by nonfreezable water analysis, which is correlated to the inhibition time. The polymers tune the kinetics of the hydration process via interaction with and perturbation of the water molecules. The free water component in the polymer solution crystallizes at a very slow rate when in partially restricted mobility, whereas the bound water component increases in the reaction, with the polymer/water interface serving as the reaction sites. The appropriate MW (including average MW and polydispersity values) of the inhibitive polymers can give rise to maximal retardation of the hydrate crystal growth. This work will help control other multiphase crystallization kinetic processes through the design of inhibitors or promoters functioning in the interface.


Assuntos
Polímeros , Água , Caprolactama/análogos & derivados , Cinética , Espectroscopia de Ressonância Magnética , Água/química
18.
Foods ; 11(8)2022 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-35454676

RESUMO

Chlorpyrifos (CPF) and 2,4-dichlorophenoxyacetic acid (2,4-D) are insecticides and herbicides which has been widely used on farms. However, CPF and 2,4-D residues on corps can bring high risks to human health. Accurate detection of pesticide residues is important for controlling health risks caused by CPF and 2,4-D. Therefore, we developed a fast, sensitive, economical, and lossless surface-enhanced Raman spectroscopy (SERS)-based method for pesticide detection. It can rapidly and simultaneously determine the CPF and 2,4-D mixed pesticide residues on an apple surface at a minimum of 0.001 mg L-1 concentration, which is far below the pesticide residue standard in China and the EU. The limits of detection reach down to 1.28 × 10-9 mol L-1 for CPF and 2.47 × 10-10 mol L-1 for 2,4-D. The limits of quantification are 4.27 × 10-9 mol L-1 and 8.23 × 10-10 mol L-1 for CPF and 2,4-D. This method has a great potential for the accurate detection of pesticide residues, and may be applied to other fields of agricultural products and food industry.

19.
Front Aging Neurosci ; 14: 879006, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35431889

RESUMO

Background: The vigilance fluctuation and decrement of sustained attention have large detrimental consequences to most tasks in daily life, especially among the elderly. Non-invasive brain stimulations (e.g., transcranial direct current stimulation, tDCS) have been widely applied to improve sustained attention, however, with mixed results. Objective: An infraslow frequency oscillatory tDCS approach was designed to improve sustained attention. Methods: The infraslow frequency oscillatory tDCS (O-tDCS) over the left dorsolateral prefrontal cortex at 0.05 Hz was designed and compared with conventional tDCS (C-tDCS) to test whether this new protocol improves sustained attention more effectively. The sustained attention was evaluated by reaction time and accuracy. Results: Compared with the C-tDCS and sham, the O-tDCS significantly enhanced sustained attention by increasing response accuracy, reducing response time, and its variability. These effects were predicted by the evoked oscillation of response time at the stimulation frequency. Conclusion: Similar to previous studies, the modulation effect of C-tDCS on sustained attention is weak and unstable. In contrast, the O-tDCS effectively and systematically enhances sustained attention by optimizing vigilance fluctuation. The modulation effect of O-tDCS is probably driven by neural oscillations at the infraslow frequency range.

20.
Front Cardiovasc Med ; 9: 851214, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35433881

RESUMO

Background: This study aimed to investigate the impact of the COVID-19 pandemic on ST-segment elevation myocardial infarction (STEMI) care in China. Methods: We conducted a multicenter, retrospective cohort study in Hunan province (adjacent to the epidemic center), China. Consecutive patients presenting with STEMI within 12 h of symptom onset and receiving primary percutaneous coronary intervention, pharmaco-invasive strategy and only thrombolytic treatment, were enrolled from January 23, 2020 to April 8, 2020 (COVID-19 era group). The same data were also collected for the equivalent period of 2019 (pre-COVID-19 era group). Results: A total of 610 patients with STEMI (COVID-19 era group n = 286, pre-COVID-19 era group n = 324) were included. There was a decline in the number of STEMI admissions by 10.5% and STEMI-related PCI procedures by 12.7% in 2020 compared with the equivalent period of 2019. The key time intervals including time from symptom onset to first medical contact, symptom onset to door, door-to-balloon, symptom onset to balloon and symptom onset to thrombolysis showed no significant difference between these two groups. There were no significant differences for in-hospital death and major adverse cardiovascular events between these two groups. Conclusion: During the COVID-19 pandemic outbreak in China, we observed a decline in the number of STEMI admissions and STEMI-related PCI procedures. However, the key quality indicators of STEMI care were not significantly affected. Restructuring health services during the COVID-19 pandemic has not significantly adversely influenced the in-hospital outcomes.

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