Abstract
Protein-ligand blind docking is a powerful method for exploring the binding sites of receptors and the corresponding binding poses of ligands. It has seen wide applications in pharmaceutical ...and biological researches. Previously, we proposed a blind docking server, CB-Dock, which has been under heavy use (over 200 submissions per day) by researchers worldwide since 2019. Here, we substantially improved the docking method by combining CB-Dock with our template-based docking engine to enhance the accuracy in binding site identification and binding pose prediction. In the benchmark tests, it yielded the success rate of ∼85% for binding pose prediction (RMSD < 2.0 Å), which outperformed original CB-Dock and most popular blind docking tools. This updated docking server, named CB-Dock2, reconfigured the input and output web interfaces, together with a highly automatic docking pipeline, making it a particularly efficient and easy-to-use tool for the bioinformatics and cheminformatics communities. The web server is freely available at https://cadd.labshare.cn/cb-dock2/.
Graphical Abstract
Graphical Abstract
CB-Dock2 integrates the structure-based and template-based blind docking algorithms.
As the number of elucidated protein structures is rapidly increasing, the growing data call for methods to efficiently exploit the structural information for biological and pharmaceutical purposes. ...Given the three-dimensional (3D) structure of a protein and a ligand, predicting their binding sites and affinity are a key task for computer-aided drug discovery. To address this task, a variety of docking tools have been developed. Most of them focus on docking in the preset binding sites given by users. To automatically predict binding modes without information about binding sites, we developed a user-friendly blind docking web server, named CB-Dock, which predicts binding sites of a given protein and calculates the centers and sizes with a novel curvature-based cavity detection approach, and performs docking with a popular docking program, Autodock Vina. This method was carefully optimized and achieved ~70% success rate for the top-ranking poses whose root mean square deviation (RMSD) were within 2 Å from the X-ray pose, which outperformed the state-of-the-art blind docking tools in our benchmark tests. CB-Dock offers an interactive 3D visualization of results, and is freely available at http://cao.labshare.cn/cb-dock/.
Abstract
Protein–ligand docking is an essential method in computer-aided drug design and structural bioinformatics. It can be used to identify active compounds and reveal molecular mechanisms of ...biological processes. A successful docking usually requires thorough conformation sampling and scoring, which are computationally expensive and difficult. Recent studies demonstrated that it can be beneficial to docking with the guidance of existing similar co-crystal structures. In this work, we developed a protein–ligand docking method, named FitDock, which fits initial conformation to the given template using a hierarchical multi-feature alignment approach, subsequently explores the possible conformations and finally outputs refined docking poses. In our comprehensive benchmark tests, FitDock showed 40%–60% improvement in terms of docking success rate and an order of magnitude faster over popular docking methods, if template structures exist (> 0.5 ligand similarity). FitDock has been implemented in a user-friendly program, which could serve as a convenient tool for drug design and molecular mechanism exploration. It is now freely available for academic users at http://cao.labshare.cn/fitdock/.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Crop residue retention (RR) is a recommended practice in China and globally. However, comprehensive assessment of changes and mechanisms affecting crop production and soil processes with RR and thus ...identifying systems of sustainable residues management are not widely studied. A national meta‐analysis was conducted to assess changes in 24 indicators (related to soil quality, soil nutrients, crop yield, and environmental impacts) along with their relationships under RR through 4,910 comparisons from 278 publications across China's croplands. Positively, RR significantly increased crop yield (7.8%), soil organic carbon (SOC) pool (12.3% to 36.8%), soil nutrient reserves (1.9% to 15.2%), soil temperature (6.7%), and water contents (5.9%) and improved soil structure when compared with residue removal (P < .05). Negatively, RR may increase soil acidification and significantly increase emissions of greenhouse gases (by 31.7%, 130.9%, and 12.2% for CO2, CH4, and N2O). Nonetheless, the negative effects can be alleviated, and the positive effects can be strengthened by adopting RR in conjunction with appropriate crops, specific farming practices, and avoiding more than 10 years of consecutive use. The results indicated that a higher decomposition of native and newly added organic matters, induced by RR and attendant changes in soil physical properties, could enhance the dynamics of SOC, microbial biomass, soil nutrients, and the final increase in crop yield and greenhouse gases emissions. Thus, the sustainability of RR‐based system could be enhanced by a careful choice and adoption of integrated farming practices. Proper RR management strategies could offer a climate‐smart solution to ensure food security and sustain soil productivity.
The remarkable progress in cancer immunotherapy in recent years has led to the heat of great development for therapeutic antibodies. Antibody numbering, which standardizes a residue index at each ...position of an antibody variable domain, is an important step in immunoinformatic analysis. It provides an equivalent index for the comparison of sequences or structures, which is particularly valuable for antibody modeling and engineering. However, due to the extremely high diversity of antibody sequences, antibody‐numbering tools cannot work in all cases. This article introduces a new antibody‐numbering tool named AbRSA, which integrates heuristic knowledge of region‐specific features into sequence mapping to enhance the robustness. The benchmarks demonstrate that, AbRSA exhibits robust performance in numbering sequences with diverse lengths and patterns compared with the state‐of‐the‐art tools. AbRSA offers a user‐friendly interface for antibody numbering, complementarity‐determining region delimitation, and 3D structure rendering. It is freely available at http://cao.labshare.cn/AbRSA.
Circulating tumor DNA (ctDNA) provides a potential non‐invasive biomarker for cancer diagnosis and prognosis, but whether it could reflect tumor heterogeneity and monitor therapeutic responses in ...hepatocellular carcinoma (HCC) is unclear. Focusing on 574 cancer genes known to harbor actionable mutations, we identified the mutation repertoire of HCC tissues, and monitored the corresponding ctDNA features in blood samples to evaluate its clinical significance. Analysis of 3 HCC patients' mutation profiles revealed that ctDNA could overcome tumor heterogeneity and provide information of tumor burden and prognosis. Further analysis was conducted on the 4th HCC case with multiple lesion samples and sequential plasma samples. We identified 160 subclonal SNVs in tumor tissues as well as matched peritumor tissues with PBMC as control. 96.9% of this patient's tissue mutations could be also detected in plasma samples. These subclonal SNVs were grouped into 9 clusters according to their trends of cellular prevalence shift in tumor tissues. Two clusters constituted of tumor stem somatic mutations showed circulating levels relating with cancer progression. Analysis of tumor somatic mutations revealed that circulating level of such tumor stem somatic mutations could reflect tumor burden and even predict prognosis earlier than traditional strategies. Furthermore, HCK (p.V174M), identified as a recurrent/metastatic related mutation site, could promote migration and invasion of HCC cells. Taken together, study of mutation profiles in biopsy and plasma samples in HCC patients showed that ctDNA could overcome tumor heterogeneity and real‐time track the therapeutic responses in the longitudinal monitoring.
What's new?
Hepatocellular carcinoma (HCC) is a heterogenous disease, with significant variability in morphology, molecular alterations, and progression. Accurately evaluating the prognosis of this complicated disease is challenging but could potentially overcome through the use of circulating tumor DNA (ctDNA), according to the present study. Analysis of mutation profiles in HCC patients showed that more than 98% of subclonal mutations are captured in ctDNA. The majority of changes in circulating levels of subclonal mutations were correlated to tumor burden. By providing real‐time information on tumor lesions, the screening of somatic ctDNA alterations could facilitate tumor burden tracking and enable earlier prognostic determination.
The nuclear import receptor karyopherin β1 (KPNB1) is involved in the nuclear import of most proteins and in the regulation of multiple mitotic events. Upregulation of KPNB1 has been observed in ...cancers including glioblastoma. Depletion of KPNB1 induces mitotic arrest and apoptosis in cancer cells, but the underlying mechanism is not clearly elucidated. Here, we found that downregulation and functional inhibition of KPNB1 in glioblastoma cells induced growth arrest and apoptosis without apparent mitotic arrest. KPNB1 inhibition upregulated Puma and Noxa and freed Mcl-1-sequestered Bax and Bak, leading to mitochondrial outer membrane permeabilization (MOMP) and apoptosis. Moreover, combination of Bcl-xL inhibitors and KPNB1 inhibition enhanced apoptosis in glioblastoma cells. KPNB1 inhibition promoted cytosolic retention of its cargo and impaired cellular proteostasis, resulting in elevated polyubiquitination, formation of aggresome-like-induced structure (ALIS), and unfolded protein response (UPR). Ubiquitination elevation and UPR activation in KPNB1-deficient cells were reversed by KPNB1 overexpression or inhibitors of protein synthesis but aggravated by inhibitors of autophagy-lysosome or proteasome, indicating that rebalance of cytosolic/nuclear protein distribution and alleviation of protein overload favor proteostasis and cell survival. Chronic activation of eIF2α/ATF4 cascade of UPR was responsible for the upregulation of Puma and Noxa, apoptosis and ABT-263 sensitivity. Taken together, our findings demonstrate that KPNB1 is required for proteostasis maintenance and its inhibition induces apoptosis in glioblastoma cells through UPR-mediated deregulation of Bcl-2 family members.
Initial 3-year results from our clinical trial in locoregionally advanced nasopharyngeal carcinoma (NPC) patients showed that induction chemotherapy (IC) with cisplatin and fluorouracil resulted in ...improved disease-free survival (DFS) with a marginally significant effect on distant metastasis-free survival (DMFS), but the effect of IC on locoregional relapse-free survival and overall survival (OS) did not differ significantly. Here, we present 5-year follow-up results.
Our trial was a randomised, open-label phase III trial comparing IC followed by concurrent chemoradiotherapy (CCRT) versus CCRT alone in patients with stage III-IVB (except T3N0-1) NPC. The IC followed by CCRT group received cisplatin (80 mg/m2 d1) and fluorouracil (800 mg/m2 d1-5) every 3 weeks for two cycles before CCRT. Both groups were treated with 80 mg/m2 cisplatin every 3 weeks concurrently with radiotherapy. The primary end-points were DFS and DMFS. We did efficacy analyses in the 476 randomised patients (intention-to-treat population).
After a median follow-up of 82.6 months, the 5-year DFS rate was 73.4% (95% confidence interval CI 67.7–79.1) in the IC followed by CCRT group and 63.1% (95% CI 56.8–69.4) in the CCRT alone group (p = 0.007). The 5-year DMFS rate was also significantly higher in the IC followed by CCRT group (82.8%, 95% CI 77.9–87.7) than in the CCRT alone group (73.1%, 95% CI 67.2–79.0, p = 0.014). Our updated analysis revealed an OS benefit of IC: the 5-year OS rate was 80.8% in the IC followed by CCRT group versus 76.8% in the CCRT alone group (p = 0.040). The proportion of patients with eye damage was significantly higher in the CCRT alone group than the IC followed by CCRT group (16.4% 39/238 versus 9.7% 23/238, p = 0.029).
IC followed by CCRT provides long-term DFS, DMFS and OS benefits compared with CCRT alone in locoregionally advanced NPC and, therefore, can be recommended for these patients.
•IC followed by CCRT improved not only DMFS and DFS, but also OS at 5 years in patients with locoregionally advanced NPC.•The addition of cisplatin and fluorouracil induction chemotherapy did not significantly increase late toxicities.•IC followed by CCRT can be recommended for patients with locoregionally advanced NPC.
Considerable researches implicate that the circadian clock regulates the responsive rhythms of organs and sets the orderly aging process of cells indirectly. It influences an array of diverse ...biological process including intestinal flora, peripheral inflammatory responses, and redox homeostasis. People with sleep disoders and other kinds of circadian disruptions are prone to have vascular aging earlier. Meanwhile, those people are always faced with chronic vascular inflammation. It has not been elucidated that the specific mechanism of the interaction between the circadian system and early vascular aging. To explore the biphasic relationship between vascular aging and the circadian system, we summarize what is linking circadian clock with early vascular aging through four major prospect: inflammatory process, oxidative stress response, intestinal flora, and cellular senescence. Meanwhile, we discuss the hypothesis that the deterioration of circadian rhythms may exacerbate the process of early vascular aging, leading to the cardiovascular diseases. It will help us to provide new ideas for understanding the process of vascular aging and exploring the possible ways to design personalized chronotherapies.
•Circadian clock disturbance leads to the dyshomeostasis, accelerating aging process.•Early vascular aging is intrinsically driven which indicates the early onset of arterial stiffness.•Aiming at circadian clocks will be a new target to prevent EVA.
This paper surveys the formation acquisition and maintenance of multi-agent systems, while the communication graph is obtained without human designations. Given that all agents move along ...unpredictable paths during formation acquisition, the systems adopt the leader-follower model. For better expression of the graph construction, a relational tree is introduced to describe the follower-leader pairs. Then, a distributed method is proposed for suboptimal relational tree configuration. By utilizing particle swarm optimization (PSO), the search for follower-leader pairs is converted to permutation optimization. Based on principal component analysis (PCA), the entire group is divided into several small groups, and the optimization can be implemented in each group, thus releasing the computation burden. To acquire the formation defined by the suboptimal relational tree, a second nonlinear controller subject to the loss of GPS information is established. The controller takes the reference in the local velocity frame as inputs, and proportional and differential components are introduced to provide a soft control. In addition, adaptive parameters are designed for robust control. By tuning the parameters autonomously, self-organized systems can work well in various scenarios even without manual adjustment of parameters. Mathematical and numerical analyses are conducted to prove the feasibility of the proposed strategy.
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