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1.
JMIR Med Inform ; 2021 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-33818393

RESUMO

BACKGROUND: The 2019 coronavirus (COVID-19) has led to unprecedented strain on healthcare facilities across the United States. Accurately identifying patients at an increased risk of deterioration may help hospitals manage their resources while improving the quality of patient care. Here we present the results of an analytical model, PICTURE (Predicting Intensive Care Transfers and Other UnfoReseen Events), to identify patients at a high risk for imminent intensive care unit (ICU) transfer, respiratory failure, or death with the intention to improve prediction of deterioration due to COVID-19. OBJECTIVE: To validate the PICTURE model's ability to predict unexpected deterioration in general ward and COVID-19 patients, and to compare its performance with the Epic Deterioration Index (EDI), an existing model which has recently been assessed for use in COVID-19 patients. METHODS: The PICTURE model was trained and validated on a cohort of hospitalized non-COVID-19 patients using electronic health record data from 2014-2018. It was then applied to two hold-out test sets: non-COVID-19 patients from 2019 and patients testing positive for COVID-19 in 2020. PICTURE results were aligned to EDI and NEWS scores for head-to-head comparison via Area Under the Receiver Operator Curve (AUROC) and Area Under the Precision Recall Curve (AUPRC). We compared the models' ability to predict an adverse event (defined as ICU transfer, mechanical ventilation use, or death). Shapley values were used to provide explanations for PICTURE predictions. RESULTS: In non-COVID-19 general ward patients, PICTURE achieved an AUROC (95% CI) of 0.819 (0.805 - 0.834) per observation, compared to the EDI's 0.763 (0.746 - 0.781) (n = 21,740, P < 0.001). In patients testing positive for COVID-19, PICTURE again outperformed the EDI with an AUROC (95% CI) of 0.849 (0.820 - 0.878) compared to the EDI's 0.803 (0.772 - 0.838) (n = 607, P < 0.001). The most important variables influencing PICTURE predictions in the COVID-19 cohort were a rapid respiratory rate, a high level of oxygen support, low oxygen saturation, and impaired mental status (Glasgow coma score). CONCLUSIONS: The PICTURE model is more accurate in predicting adverse patient outcomes for both general ward patients and COVID-19 positive patients in our cohorts compared to the EDI. The ability to consistently anticipate these events may be especially valuable when considering potential incipient waves of COVID-19 infections. The generalizability of the model will require testing in other health care systems for validation.

3.
Eur J Med Chem ; 218: 113383, 2021 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-33799069

RESUMO

Histone deacetylase 6 (HDAC6) has become a promising therapeutic target for central nervous system diseases due to its more complex protein structure and biological functions. However, low brain penetration of reported HDAC6 inhibitors limits its clinical application in neurological disorders. Therefore, the benzazepine, a brain-penetrant rigid fragment, was utilized to design a series of selective HDAC6 inhibitors to improve brain bioavailability. Various synthetic strategies were applied to assemble the tetrahydro-benzazepine ring, and 22 compounds were synthesized. Among them, compound 5 showed low nanomolar potency and strong isozyme selectivity for the inhibition of HDAC6 (IC50 = 1.8 nM, 141-fold selectivity over HDAC1) with efficient binding patterns like coordination with the zinc ion and π-π stacking effect. Western blot results showed it could efficiently transport into SH-SY5Y cells and selectively enhance the acetylation level of α-tubulin with a moderate effect on Histone H3. Notably, pharmacokinetic studies demonstrated that compound 5 (brain/plasma ratio of 2.30) had an excellent ability to penetrate the blood-brain barrier of C57 mice. In male rats with transient middle cerebral artery occlusion (MCAO), compound 5 significantly reduced the cerebral infarction from 21.22% to 11.47% and alleviated neurobehavioral deficits in post-ischemic treatment, which provided a strong rationale for pursuing HDAC6-based therapies for ischemic stroke.

4.
BMC Cancer ; 21(1): 382, 2021 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-33836678

RESUMO

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a leading causes of cancer mortality worldwide. Currently, laparoscopic pancreatic resection (LPR) is extensively applied to treat benign and low-grade diseases related to the pancreas. The viability and safety of LPR for PDAC needs to be understood better. Laparoscopic distal pancreatectomy (LDP) and pancreaticoduodenectomy (LPD) are the two main surgical approaches for PDAC. We performed separate propensity score matching (PSM) analyses to assess the surgical and oncological outcomes of LPR for PDAC by comparing LDP with open distal pancreatectomy (ODP) as well as LPD with open pancreaticoduodenectomy (OPD). METHODS: We assessed the data of patients who underwent distal pancreatectomy (DP) and pancreaticoduodenectomy (PD) for PDAC between January 2004 and February 2020 at our hospital. A one-to-one PSM was applied to prevent selection bias by accounting for factors such as age, sex, body mass index, and tumour size. The DP group included 86 LDP patients and 86 ODP patients, whereas the PD group included 101 LPD patients and 101 OPD patients. Baseline characteristics, intraoperative effects, postoperative recovery, and survival outcomes were compared. RESULTS: Compared to ODP, LDP was associated with shorter operative time, lesser blood loss, and similar overall morbidity. Of the 101 patients who underwent LPD, 10 patients (9.9%) required conversion to laparotomy. The short-term surgical advantage of LPD is not as apparent as that of LDP due to conversions. Compared with OPD, LPD was associated with longer operative time, lesser blood loss, and similar overall morbidity. For oncological and survival outcomes, there were no significant differences in tumour size, R0 resection rate, and tumour stage in both the DP and PD subgroups. However, laparoscopic procedures appear to have an advantage over open surgery in terms of retrieved lymph nodes (DP subgroup: 14.4 ± 5.2 vs. 11.7 ± 5.1, p = 0.03; PD subgroup 21.9 ± 6.6 vs. 18.9 ± 5.4, p = 0.07). These two groups did not show a significant difference in the pattern of recurrence and overall survival rate. CONCLUSIONS: Laparoscopic DP and PD are feasible and oncologically safe procedures for PDAC, with similar postoperative outcomes and long-term survival among patients who underwent open surgery.

5.
Med Phys ; 2021 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-33837541

RESUMO

PURPOSE: In circular-scanning-based photoacoustic tomography (PAT), the effect of finite transducer aperture has not been effectively resolved. The goal of this paper is to propose a practical reconstruction method that accounts for the finite transducer aperture to improve the lateral resolution. METHODS: We for the first time propose to calculate the spatial temporal response (STR) of the employed finite-sized transducer in a forward model, and then compensate the time delay and the directional sensitivity of the transducer in the framework of the back-projection method. Both simulation and phantom experiments were carried out to evaluate the lateral resolution improvement with the proposed method. The performance of this new method for imaging complicated targets was also assessed by calculating the mean image gradient. RESULTS: Simulation results showed that with this new method the lateral resolution for off-center targets can be as good as that for the center targets. Phantom experimental results showed that this new method can improve the lateral resolution more than 2 times for a point target about 5 mm far from the rotation center. Phantom experimental results also showed that many blurred fine structures of a piece of leaf veins at the off-center regions were well restored with the new method, and the mean image gradient improved about 1.3 times. CONCLUSION: The proposed new method can effectively account for the effect of finite transducer aperture for circular-scanning-based PAT in homogenous acoustic media. This new method also features for its robustness and computational efficiency, so that it is a worthy replacement to the conventional back-projection algorithm in circular-scanning-based PAT. This new method can be of great importance to the design of circular-scanning or spherical-scanning-based PAT systems.

6.
Sheng Wu Gong Cheng Xue Bao ; 37(3): 1004-1016, 2021 Mar 25.
Artigo em Chinês | MEDLINE | ID: mdl-33783164

RESUMO

Currently, biomanufacturing technology and industry are receiving worldwide attention. However, there are still great challenges on bioprocess optimization and scale-up, including: lacing the process detection methods, which makes it difficult to meet the requirement of monitoring of key indicators and parameters; poor understanding of cell metabolism, which arouses problems to rationally achieve process optimization and regulation; the reactor environment is very different across the scales, resulting in low efficiency of stepwise scale-up. Considering the above key issues that need to be resolved, here we summarize the key technological innovations of the whole chain of fermentation process, i.e., real-time detection-dynamic regulation-rational scale-up, through case analysis. In the future, bioprocess design will be guided by a full lifecycle in-silico model integrating cellular physiology (spatiotemporal multiscale metabolic models) and fluid dynamics (CFD models). This will promote computer-aided design and development, accelerate the realization of large-scale intelligent production and serve to open a new era of green biomanufacturing.


Assuntos
Reatores Biológicos , Hidrodinâmica , Simulação por Computador , Fermentação
7.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 37(3): 219-224, 2021 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-33766229

RESUMO

Objective To investigate the inhibitory effect of astragaloside II (AS-II) on the proliferation of pulmonary artery smooth muscle cells (PASMCs) induced by hypoxia and its relevant mechanism. Methods Rat primary PASMCs were divided into normoxia group, hypoxia group, hypoxia combined with 20, 40, 80 µmol/L AS-II treated groups, hypoxia combined with nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) inhibitor VAS2870 treated group, and then cultured either in normoxic (210 mL/L O2) or hypoxic (20 mL/L O2) condition for 24 hours. The proliferation of PASMCs was detected by CCK-8 assay. The level of intracellular reactive oxygen species (ROS) was detected by DCFH-DA staining. Protein kinase B (AKT), phospho-AKT (p-AKT), mammalian target of rapamycin (mTOR), phospho-mTOR (p-mTOR), proliferating cell nuclear antigen (PCNA), NOX1 and NOX4 protein expression were assessed by Western blotting. Results In the hypoxia group, the proliferation of PASMCs, level of intracellular ROS, protein expression of PCNA, p-AKT, p-mTOR, NOX1 and NOX4 increased significantly compared with those in the normoxia group. However, AS-II treatment inhibited hypoxia-induced PASMCs proliferation, decreased the level of intracellular ROS, and suppressed protein expression of PCNA, p-AKT, p-mTOR, NOX1 and NOX4. Moreover, VAS2870 treatment lead to similar changes. Conclusion AS-II can inhibit the proliferation of PASMCs induced by hypoxia, which may be associated with the blocking of NOX/ROS/AKT/mTOR signaling pathway.


Assuntos
Proteínas Proto-Oncogênicas c-akt , Artéria Pulmonar , Animais , Hipóxia Celular , Proliferação de Células , Células Cultivadas , Hipóxia , Miócitos de Músculo Liso/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Artéria Pulmonar/metabolismo , Ratos , Espécies Reativas de Oxigênio , Saponinas , Transdução de Sinais , Serina-Treonina Quinases TOR
8.
J Nanobiotechnology ; 19(1): 90, 2021 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-33781296

RESUMO

BACKGROUND: Despite tremendous progress has been achieved in tumor theranostic over the past decade, accurate identification and complete eradication of tumor cells remain a great challenge owing to the limitation of single imaging modality and therapeutic strategy. RESULTS: Herein, we successfully design and construct BiVO4/Fe3O4@polydopamine (PDA) superparticles (SPs) for computed tomography (CT)/photoacoustic (PA)/magnetic resonance (MR) multimodal imaging and radiotherapy (RT)/photothermal therapy (PTT) synergistic therapy toward oral epithelial carcinoma. On the one hand, BiVO4 NPs endow BiVO4/Fe3O4@PDA SPs with impressive X-ray absorption capability due to the high X-ray attenuation coefficient of Bi, which is beneficial for their utilization as radiosensitizers for CT imaging and RT. On the other hand, Fe3O4 NPs impart BiVO4/Fe3O4@PDA SPs with the superparamagnetic property as a T2-weighted contrast agent for MR imaging. Importantly, the aggregation of Fe3O4 NPs in SPs and the presence of PDA shell greatly improve the photothermal conversion capability of SPs, making BiVO4/Fe3O4@PDA SPs as an ideal photothermal transducer for PA imaging and PTT. By integrating advantages of various imaging modalities (CT/PA/MR) and therapeutic strategies (RT/PTT), our BiVO4/Fe3O4@PDA SPs exhibit the sensitive multimodal imaging feature and superior synergistic therapeutic efficacy on tumors. CONCLUSIONS: Since there are many kinds of building blocks with unique properties appropriating for self-assembly, our work may largely enrich the library of nanomateirals for tumor diagnosis and treatment.

9.
J Med Chem ; 64(7): 3493-3507, 2021 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-33764774

RESUMO

A series of tools for targeted protein degradation are inspiring scientists to develop new drugs with advantages over traditional small-molecule drugs. Among these tools, proteolysis-targeting chimeras (PROTACs) are most representative of the technology based on proteasomes. However, the proteasome has little degradation effect on certain macromolecular proteins or aggregates, extracellular proteins, and organelles, which limits the application of PROTACs. Additionally, lysosomes play an important role in protein degradation. Therefore, lysosome-induced protein degradation drugs can directly regulate protein levels in vivo, achieve the goal of treating diseases, and provide new strategies for drug discovery. Lysosome-based degradation technology has the potential for clinical translation. In this review, strategies targeting lysosomal pathways and lysosome-based degradation techniques are summarized. In addition, lysosome-based degrading drugs are described, and the advantages and challenges are listed. Our efforts will certainly promote the design, discovery, and clinical application of drugs associated with this technology.

10.
Air Qual Atmos Health ; : 1-13, 2021 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-33758631

RESUMO

Hospitalisation risks for chronic obstructive pulmonary disease (COPD) have been attributed to ambient air pollution worldwide. However, a rise in COPD hospitalisations may indicate a considerable increase in fatality rate in public health. The current study focuses on the association between consecutive ambient air pollution (CAAP) and COPD hospitalisation to offer predictable early guidance towards estimates of COPD hospital admissions in the event of consecutive exposure to air pollution. Big data analytics were collected from 3-year time series recordings (from 2015 to 2017) of both air data and COPD hospitalisation data in the Chengdu region in China. Based on the combined effects of CAAP and unit increase in air pollutant concentrations, a quasi-Poisson regression model was established, which revealed the association between CAAP and estimated COPD admissions. The results show the dynamics and outbreaks in the variations in COPD admissions in response to CAAP. Cross-validation and mean squared error (MSE) are applied to validate the goodness of fit. In both short-term and long-term air pollution exposures, Z test outcomes show that the COPD hospitalisation risk is greater for men than for women; similarly, the occurrence of COPD hospital admissions in the group of elderly people (> 65 years old) is significantly larger than that in lower age groups. The time lag between the air quality and COPD hospitalisation is also investigated, and a peak of COPD hospitalisation risk is found to lag 2 days for air quality index (AQI) and PM10, and 1 day for PM2.5. The big data-based predictive paradigm would be a measure for the early detection of a public health event in post-COVID-19. The study findings can also provide guidance for COPD admissions in the event of consecutive exposure to air pollution in the Chengdu region.

11.
J Neural Eng ; 2021 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-33690185

RESUMO

Objective.Noise-assisted Multivariate Empirical Mode Decomposition (NA-MEMD) based Causal Decomposition depicts a cause and effect relationship that is not based on the term of prediction, but rather on the phase dependence of time series. Here, we present the NA-MEMD based Causal Decomposition approach according to the covariation and power views traced to Hume and Kant: a priori cause-effect interaction is first acquired, and the presence of a candidate cause and of the effect is then computed from the sensory input somehow.Approach.Based on the definition of NA-MEMD based Causal Decomposition, we show such causal relation is a phase relation where the candidate causes are not merely followed by effects, but rather produce effects.Main results.The predominant methods used in neuroscience (Granger causality, EMD-based Causal Decomposition) are validated, showing the applicability of NA-MEMD based Causal Decomposition, particular to brain physiological processes in bivariate and multiscale time series.Significance.We point to the potential use in the causality inference analysis in a complex dynamic process.

12.
Artigo em Inglês | MEDLINE | ID: mdl-33684043

RESUMO

Hashing is a popular search algorithm for its compact binary representation and efficient Hamming distance calculation. Benefited from the advance of deep learning, deep hashing methods have achieved promising performance. However, those methods usually learn with expensive labeled data but fail to utilize unlabeled data. Furthermore, the traditional pairwise loss used by those methods cannot explicitly force similar/dissimilar pairs to small/large distances. Both weaknesses limit existing methods' performance. To solve the first problem, we propose a novel semi-supervised deep hashing model named adversarial binary mutual learning (ABML). Specifically, our ABML consists of a generative model GH and a discriminative model DH, where DH learns labeled data in a supervised way and GH learns unlabeled data by synthesizing real images. We adopt an adversarial learning (AL) strategy to transfer the knowledge of unlabeled data to DH by making GH and DH mutually learn from each other. To solve the second problem, we propose a novel Weibull cross-entropy loss (WCE) by using the Weibull distribution, which can distinguish tiny differences of distances and explicitly force similar/dissimilar distances as small/large as possible. Thus, the learned features are more discriminative. Finally, by incorporating ABML with WCE loss, our model can acquire more semantic and discriminative features. Extensive experiments on four common data sets (CIFAR-10, large database of handwritten digits (MNIST), ImageNet-10, and NUS-WIDE) and a large-scale data set ImageNet demonstrate that our approach successfully overcomes the two difficulties above and significantly outperforms state-of-the-art hashing methods.

13.
J Med Chem ; 64(5): 2382-2418, 2021 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-33650861

RESUMO

Triple negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, but an effective targeted therapy has not been well-established so far. Considering the lack of effective targets, where do we go next in the current TNBC drug development? A promising intervention for TNBC might lie in de novo small-molecule drugs that precisely target different molecular characteristics of TNBC. However, an ideal single-target drug discovery still faces a huge challenge. Alternatively, other new emerging strategies, such as dual-target drug, drug repurposing, and combination strategies, may provide new insight into the improvement of TNBC therapeutics. In this review, we focus on summarizing the current situation of a series of candidate small-molecule drugs in TNBC therapy, including single-target drugs, dual-target drugs, as well as drug repurposing and combination strategies that will together shed new light on the future directions targeting TNBC vulnerabilities with small-molecule drugs for future therapeutic purposes.

14.
Mol Plant Pathol ; 22(5): 564-579, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33675291

RESUMO

Most plant intracellular immune receptors belong to nucleotide-binding, leucine-rich repeat (NLR) proteins. The recognition between NLRs and their corresponding pathogen effectors often triggers a hypersensitive response (HR) at the pathogen infection sites. The nicotinate N-methyltransferase (NANMT) is responsible for the conversion of nicotinate to trigonelline in plants. However, the role of NANMT in plant defence response is unknown. In this study, we demonstrated that the maize ZmNANMT, but not its close homolog ZmCOMT, an enzyme in the lignin biosynthesis pathway, suppresses the HR mediated by the autoactive NLR protein Rp1-D21 and its N-terminal coiled-coil signalling domain (CCD21 ). ZmNANMT, but not ZmCOMT, interacts with CCD21 , and they form a complex with HCT1806 and CCoAOMT2, two key enzymes in lignin biosynthesis, which can also suppress the autoactive HR mediated by Rp1-D21. ZmNANMT is mainly localized in the cytoplasm and nucleus, and either localization is important for suppressing the HR phenotype. These results lay the foundation for further elucidating the molecular mechanism of NANMTs in plant disease resistance.

15.
Sports Med ; 2021 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-33761127

RESUMO

Sport is historically designated by the binary categorization of male and female that conflicts with modern society. Sport's governing bodies should consider reviewing rules determining the eligibility of athletes in the female category as there may be lasting advantages of previously high testosterone concentrations for transwomen athletes and currently high testosterone concentrations in differences in sex development (DSD) athletes. The use of serum testosterone concentrations to regulate the inclusion of such athletes into the elite female category is currently the objective biomarker that is supported by most available scientific literature, but it has limitations due to the lack of sports performance data before, during or after testosterone suppression. Innovative research studies are needed to identify other biomarkers of testosterone sensitivity/responsiveness, including molecular tools to determine the functional status of androgen receptors. The scientific community also needs to conduct longitudinal studies with specific control groups to generate the biological and sports performance data for individual sports to inform the fair inclusion or exclusion of these athletes. Eligibility of each athlete to a sport-specific policy needs to be based on peer-reviewed scientific evidence made available to policymakers from all scientific communities. However, even the most evidence-based regulations are unlikely to eliminate all differences in performance between cisgender women with and without DSD and transwomen athletes. Any remaining advantage held by transwomen or DSD women could be considered as part of the athlete's unique makeup.

16.
Int J Surg ; 87: 105896, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33588125

RESUMO

BACKGROUND: Though hepatic resection (HR) is the standard local therapy for patients with colorectal cancer liver metastases (CRLMs), currently, radiofrequency ablation (RFA) may play an alternative role for elderly and vulnerable patients with various organ dysfunctions. This study aims to compare the prognosis of RFA and HR in treatment of CRLMs. METHODS: A systematic search of PubMed, Embase, Cochrane Library and Web of Science up to October 1, 2020 was conducted for relevant studies that compared the prognosis of RFA with HR in the treatment of CRLMs. The primary outcomes were 30-day mortality, long-term recurrence, overall survival (OS) and disease-free survival (DFS). The secondary outcomes were various factors of OS, recurrence-free survival (RFS), survival, recurrence and complication. RESULTS: A total of 22 studies including 4385 CRLM patients were identified. There was no significant difference between RFA and HR in 30-day mortality, with a pooled OR of 0.88 (95% CI 0.34-2.29; P = 0.80). CRLM patients undergoing RFA experienced significantly higher incidences of marginal and intrahepatic recurrence than HR, with pooled ORs of 7.09 (95% CI 4.56-11.2; 1251 pts) and 2.02 (95% CI 1.24-3.28; 1038 pts). In addition, RFA showed lower 1-, 3- and 5-yr OS rate than HR with pooled ORs of 0.39, 0.40 and 0.60 respectively. A lower 5-yr DFS rate was also found in RFA than HR group, with a pooled OR of 0.74 (95% CI 0.56-0.97; P = 0.03; 1231 pts). Multivariable analysis showed that tumor size, multiple tumors, age, primary node positive and metachronous metastasis were independent factors of OS, and multiple tumors was also an independent factor of RFS. CONCLUSIONS: Though the 30-day mortality of RFA was equal to HR, RFA showed a higher recurrence rate and poor long-term survival outcomes for CRLM patients. Tumor size, multiple tumors, age, primary node positive and metachronous metastasis were independent factors of survival. However, the results were limited because of the inequality baseline characteristics between the comparative groups. Randomized or propensity score matching studies should be performed to clarify the effectiveness of RFA and to determine target populations that benefit most from RFA in the future.

17.
ACS Sens ; 6(3): 1103-1110, 2021 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-33576603

RESUMO

The urgent requirement of monitoring air pollution worldwide evokes intensive research interest in developing chemiresistive gas sensing techniques. To overcome the limits in sensitivity and selectivity of room temperature (RT) chemiresistive sensing materials, a new strategy using single-atom catalysts (SACs) via surface coordination is proposed. As a proof-of-concept, single Pd atoms on TiO2 (Pd1-TiO2) possess high efficiency in generating adsorbed O2- as well as high activity and selectivity in catalyzing CO oxidation at RT. As a result, Pd1-TiO2 shows record high sensitivity among the reported RT sensing materials, which is even comparable to those of the best materials working at high temperature. It also provides an approximately 1 order of magnitude lower limit of detection than the best CO sensing materials. Moreover, Pd1-TiO2 presents high selectivity toward 12 kinds of interference gases. This work not only paves a way to design high-performance RT gas sensing materials but also extends the application of SACs.

18.
Molecules ; 26(4)2021 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-33579052

RESUMO

Microtubules composed of α/ß tubulin heterodimers are an essential part of the cytoskeleton of eukaryotic cells and are widely regarded as targets for cancer chemotherapy. IC261, which is discovered as an ATP-competitive inhibitor of serine/threonine-specific casein kinase 1 (CK1), has shown its inhibitory activity on microtubule polymerization in recent studies. However, the structural information of the interaction between tubulin and IC261 is still unclear. Here, we provided a high-resolution (2.85 Å) crystal structure of tubulin and IC261 complex, revealed the intermolecular interaction between tubulin and IC261, and analyzed the structure-activity relationship (SAR). Subsequently, the structure of tubulin-IC261 complex was compared with tubulin-colchicine complex to further elucidate the novelty of IC261. Furthermore, eight optimal candidate compounds of new IC261-based microtubule inhibitors were obtained through molecular docking studies. In conclusion, the co-crystal structure of tubulin-IC261 complex paves a way for the design and development of microtubule inhibitor drugs.

19.
Mol Plant Pathol ; 22(4): 465-479, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33641256

RESUMO

Common rust, caused by Puccinia sorghi, is a widespread and destructive disease of maize. The Rp1-D gene confers resistance to the P. sorghi IN2 isolate, mediating a hypersensitive cell death response (HR). To identify differentially expressed genes (DEGs) and metabolites associated with the compatible (susceptible) interaction and with Rp1-D-mediated resistance in maize, we performed transcriptomics and targeted metabolome analyses of P. sorghi IN2-infected leaves from the near-isogenic lines H95 and H95:Rp1-D, which differed for the presence of Rp1-D. We observed up-regulation of genes involved in the defence response and secondary metabolism, including the phenylpropanoid, flavonoid, and terpenoid pathways. Metabolome analyses confirmed that intermediates from several transcriptionally up-regulated pathways accumulated during the defence response. We identified a common response in H95:Rp1-D and H95 with an additional H95:Rp1-D-specific resistance response observed at early time points at both transcriptional and metabolic levels. To better understand the mechanisms underlying Rp1-D-mediated resistance, we inferred gene regulatory networks occurring in response to P. sorghi infection. A number of transcription factors including WRKY53, BHLH124, NKD1, BZIP84, and MYB100 were identified as potentially important signalling hubs in the resistance-specific response. Overall, this study provides a novel and multifaceted understanding of the maize susceptible and resistance-specific responses to P. sorghi.

20.
Sci Total Environ ; 770: 144833, 2021 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-33508670

RESUMO

Long-term afforestation has important implications on soil properties and quality in semi-arid areas. A large-scale afforestation project has been carried out in the Loess Plateau in the last 20 years. This work aims to study the afforestation (Robinia pseudoacacia, Caragana korshinskii and natural grassland recover 10, 20, 30, and 40 years after) impacts on soil properties and quality. The results showed that coverage and root biomass (RB) was the highest 30 years after the restoration in Robinia pseudoacacia and Caragana korshinskii treatments, while the highest 40 years post-restoration in natural grasslands. Sand content and BD showed the highest values 10 years post afforestation in all study areas. Clay, Silt, mean weight diameter (MWD), and geometric mean diameter (GMD) in Robinia pseudoacacia, Caragana korshinskii had the highest values 30 years after the afforestation, while in natural grasslands, this was observed 40 years after. In Robinia pseudoacacia, Caragana korshinskii treatments, soil moisture content (SMC) reached the highest levels 30 years post afforestation at 20-40 and 40-60 cm. Regarding natural grasslands, SMC had the highest values 40 years post-afforestation. Sand content and BD increased with soil depth, while the opposite was identified in RB, clay, silt, MWD, GMD and SMC. In Robinia pseudoacacia and Caragana korshinskii treatments, soil organic matter, total nitrogen, available nitrogen, total phosphorous, and available phosphorus had the highest levels 40 years post-restoration at 0-20 cm, while at 20-40 and 40-60 cm, the highest concentrations were identified 30 years after. In all the treatments, the soil quality index (SQI) was the highest 40 years post-restoration. The values of SQI were always higher in natural grasslands than in Robinia pseudoacacia and Caragana korshinskii treatments. Overall, natural recovery (natural grasslands) is more efficient than afforestation (Robinia pseudoacacia and Caragana korshinskii treatments) in soil quality.


Assuntos
Caragana , Robinia , China , Pradaria , Solo
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