Current pharmaceutical research and development (R&D) is a high-risk investment which is usually faced with some unexpected even disastrous failures in different stages of drug discovery. One main ...reason for R&D failures is the efficacy and safety deficiencies which are related largely to absorption, distribution, metabolism and excretion (ADME) properties and various toxicities (T). Therefore, rapid ADMET evaluation is urgently needed to minimize failures in the drug discovery process. Here, we developed a web-based platform called ADMETlab for systematic ADMET evaluation of chemicals based on a comprehensively collected ADMET database consisting of 288,967 entries. Four function modules in the platform enable users to conveniently perform six types of drug-likeness analysis (five rules and one prediction model), 31 ADMET endpoints prediction (basic property: 3, absorption: 6, distribution: 3, metabolism: 10, elimination: 2, toxicity: 7), systematic evaluation and database/similarity searching. We believe that this web platform will hopefully facilitate the drug discovery process by enabling early drug-likeness evaluation, rapid ADMET virtual screening or filtering and prioritization of chemical structures. The ADMETlab web platform is designed based on the Django framework in Python, and is freely accessible at
http://admet.scbdd.com/
.
Few-layer black phosphorus (BP), as the most alluring graphene analogue owing to its similar structure as graphene and thickness dependent direct band-gap, has now triggered a new wave of research on ...two-dimensional (2D) materials based photonics and optoelectronics. However, a major obstacle of practical applications for few-layer BPs comes from their instabilities of laser-induced optical damage. Herein, we demonstrate that, few-layer BPs, which was fabricated through the liquid exfoliation approach, can be developed as a new and practical saturable absorber (SA) by depositing few-layer BPs with microfiber. The saturable absorption property of few-layer BPs had been verified through an open-aperture z-scan measurement at the telecommunication band. The microfiber-based BP device had been found to show a saturable average power of ~4.5 mW and a modulation depth of 10.9%, which is further confirmed through a balanced twin detection measurement. By integrating this optical SA device into an erbium-doped fiber laser, it was found that it can deliver the mode-locked pulse with duration down to 940 fs with central wavelength tunable from 1532 nm to 1570 nm. The prevention of BP from oxidation through the "lateral interaction scheme" owing to this microfiber-based few-layer BP SA device might partially mitigate the optical damage problem of BP. Our results not only demonstrate that black phosphorus might be another promising SA material for ultrafast photonics, but also provide a practical solution to solve the optical damage problem of black phosphorus by assembling with waveguide structures such as microfiber.
The Caco-2 cell monolayer model is a popular surrogate in predicting the in vitro human intestinal permeability of a drug due to its morphological and functional similarity with human enterocytes. A ...quantitative structure–property relationship (QSPR) study was carried out to predict Caco-2 cell permeability of a large data set consisting of 1272 compounds. Four different methods including multivariate linear regression (MLR), partial least-squares (PLS), support vector machine (SVM) regression and Boosting were employed to build prediction models with 30 molecular descriptors selected by nondominated sorting genetic algorithm-II (NSGA-II). The best Boosting model was obtained finally with R 2 = 0.97, RMSEF = 0.12, Q 2 = 0.83, RMSECV = 0.31 for the training set and R T 2 = 0.81, RMSET = 0.31 for the test set. A series of validation methods were used to assess the robustness and predictive ability of our model according to the OECD principles and then define its applicability domain. Compared with the reported QSAR/QSPR models about Caco-2 cell permeability, our model exhibits certain advantage in database size and prediction accuracy to some extent. Finally, we found that the polar volume, the hydrogen bond donor, the surface area and some other descriptors can influence the Caco-2 permeability to some extent. These results suggest that the proposed model is a good tool for predicting the permeability of drug candidates and to perform virtual screening in the early stage of drug development.
Background
With the increasing development of biotechnology and informatics technology, publicly available data in chemistry and biology are undergoing explosive growth. Such wealthy information in ...these data needs to be extracted and transformed to useful knowledge by various data mining methods. Considering the amazing rate at which data are accumulated in chemistry and biology fields, new tools that process and interpret large and complex interaction data are increasingly important. So far, there are no suitable toolkits that can effectively link the chemical and biological space in view of molecular representation. To further explore these complex data, an integrated toolkit for various molecular representation is urgently needed which could be easily integrated with data mining algorithms to start a full data analysis pipeline.
Results
Herein, the python library
PyBioMed
is presented, which comprises functionalities for online download for various molecular objects by providing different IDs, the pretreatment of molecular structures, the computation of various molecular descriptors for chemicals, proteins, DNAs and their interactions.
PyBioMed
is a feature-rich and highly customized python library used for the characterization of various complex chemical and biological molecules and interaction samples. The current version of
PyBioMed
could calculate 775 chemical descriptors and 19 kinds of chemical fingerprints, 9920 protein descriptors based on protein sequences, more than 6000 DNA descriptors from nucleotide sequences, and interaction descriptors from pairwise samples using three different combining strategies. Several examples and five real-life applications were provided to clearly guide the users how to use
PyBioMed
as an integral part of data analysis projects. By using
PyBioMed
, users are able to start a full pipelining from getting molecular data, pretreating molecules, molecular representation to constructing machine learning models conveniently.
Conclusion
PyBioMed
provides various user-friendly and highly customized APIs to calculate various features of biological molecules and complex interaction samples conveniently, which aims at building integrated analysis pipelines from data acquisition, data checking, and descriptor calculation to modeling.
PyBioMed
is freely available at
http://projects.scbdd.com/pybiomed.html
.
Drug–target interactions (DTIs) are central to current drug discovery processes and public health fields. Analyzing the DTI profiling of the drugs helps to infer drug indications, adverse drug ...reactions, drug–drug interactions, and drug mode of actions. Therefore, it is of high importance to reliably and fast predict DTI profiling of the drugs on a genome-scale level. Here, we develop the TargetNet server, which can make real-time DTI predictions based only on molecular structures, following the spirit of multi-target SAR methodology. Naïve Bayes models together with various molecular fingerprints were employed to construct prediction models. Ensemble learning from these fingerprints was also provided to improve the prediction ability. When the user submits a molecule, the server will predict the activity of the user’s molecule across 623 human proteins by the established high quality SAR model, thus generating a DTI profiling that can be used as a feature vector of chemicals for wide applications. The 623 SAR models related to 623 human proteins were strictly evaluated and validated by several model validation strategies, resulting in the AUC scores of 75–100 %. We applied the generated DTI profiling to successfully predict potential targets, toxicity classification, drug–drug interactions, and drug mode of action, which sufficiently demonstrated the wide application value of the potential DTI profiling. The TargetNet webserver is designed based on the Django framework in Python, and is freely accessible at
http://targetnet.scbdd.com
.
Aberrant increases in neuronal network excitability may contribute to cognitive deficits in Alzheimer's disease (AD). However, the mechanisms underlying hyperexcitability of neurons are not fully ...understood. Voltage‐gated sodium channels (VGSC or Nav), which are involved in the formation of excitable cell's action potential and can directly influence the excitability of neural networks, have been implicated in AD‐related abnormal neuronal hyperactivity and higher incidence of spontaneous non‐convulsive seizures. Here, we have shown that the reduction of VGSC α‐subunit Nav1.6 (by injecting adeno‐associated virus (AAV) with short hairpin RNA (shRNA) into the hippocampus) rescues cognitive impairments and attenuates synaptic deficits in APP/PS1 transgenic mice. Concurrently, amyloid plaques in the hippocampus and levels of soluble Aβ are significantly reduced. Interfering with Nav1.6 reduces the transcription level of β‐site APP‐cleaving enzyme 1 (BACE1), which is Aβ‐dependent. In the presence of Aβ oligomers, knockdown of Nav1.6 reduces intracellular calcium overload by suppressing reverse sodium–calcium exchange channel, consequently increasing inactive NFAT1 (the nuclear factor of activated T cells) levels and thus reducing BACE1 transcription. This mechanism leads to a reduction in the levels of Aβ in APP/PS1 transgenic mice, alleviates synaptic loss, improves learning and memory disorders in APP/PS1 mice after downregulating Nav1.6 in the hippocampus. Our study offers a new potential therapeutic strategy to counteract hippocampal hyperexcitability and subsequently rescue cognitive deficits in AD by selective blockade of Nav1.6 overexpression and/or hyperactivity.
In the presence of Aβ oligomers, knockdown of Nav1.6 reduces intracellular calcium overload by suppressing reverse sodium‐calcium exchange channel, consequently increasing inactive NFAT1 (the nuclear factor of activated T cells) levels and thus reducing BACE1 transcription. This mechanism leads to a reduction in the levels of Aβ in APP/PS1 transgenic mice, alleviates synaptic loss, and improves learning and memory disorders in APP/PS1 mice after down‐regulating Nav1.6 in the hippocampus.
Carbon fixation by chemoautotrophic microbes such as homoacetogens had a major impact on the transition from the inorganic to the organic world. Recent reports have shown the presence of genes for ...key enzymes associated with the Wood-Ljungdahl pathway (WLP) in the phylum Actinobacteria, which adds to the diversity of potential autotrophs. Here, we compiled 42 actinobacterial metagenome-assembled genomes (MAGs) from new and existing metagenomic datasets and propose three novel classes, Ca. Aquicultoria, Ca. Geothermincolia and Ca. Humimicrobiia. Most members of these classes contain genes coding for acetogenesis through the WLP, as well as a variety of hydrogenases (NiFe groups 1a and 3b-3d; FeFe group C; NiFe group 4-related hydrogenases). We show that the three classes acquired the hydrogenases independently, yet the carbon monoxide dehydrogenase/acetyl-CoA synthase complex (CODH/ACS) was apparently present in their last common ancestor and was inherited vertically. Furthermore, the Actinobacteria likely donated genes for CODH/ACS to multiple lineages within Nitrospirae, Deltaproteobacteria (Desulfobacterota), and Thermodesulfobacteria through multiple horizontal gene transfer events. Finally, we show the apparent growth of Ca. Geothermincolia and H
-dependent acetate production in hot spring enrichment cultures with or without the methanogenesis inhibitor 2-bromoethanesulfonate, which is consistent with the proposed homoacetogenic metabolism.
A series of CuO/CeO2 and inverse CeO2/CuO catalysts were prepared by an incipient wetness impregnation method and tested for CO oxidation. Crystallite sizes of CeO2 and CuO were evaluated by X-ray ...diffraction and N2O chemisorption, as well as transmission electron microscopy. It was found that a CuO(5)/CeO2-500 catalyst with a CuO crystallite size of 4.1 nm and a CeO2(5)/CuO-500 catalyst with a CeO2 crystallite size of 4.0 nm had identical activities, indicating that the reaction may occur at the interface of CuO−CeO2. According to the turnover frequency based on CuO sites located on the CuO−CeO2 interface, the activity on the larger CuO crystallite was much higher than that on the smaller one, indicating that CuO−CeO2 catalyst for CO oxidation is structure-sensitive. The enhanced activity was ascribed to a higher density of chemisorbed CO on the active sites for the larger CuO crystallite.
•The conventional methods and Next-generation sequencing to diagnose thalassemia have limitations.•Long-read SMRT sequencing has been demonstrated to be more effective and accurate than conventional ...methods, especially for rare and complicated thalassemia variants.•A 762 bp deletion and a 342 bp insertion in α-globin gene cluster were identified by SMRT sequencing and reported for the first time.•Subjects with other rare mutations including α Fusion mutation, α-triplicates, α-quadruplicates and conversion of HBA2 to HBA1 was precisely identified by SMRT sequencing.
Gap- polymerase chain reaction (PCR), reverse dot-blot assay (RDB), real-time PCR based multicolor melting curve analysis (MMCA assay), multiplex ligation-dependent probe amplification (MLPA) and Sanger sequencing are conventional methods to diagnose thalassemia but all of them have limitations. In this study, we applied single-molecule real-time (SMRT) sequencing following multiplex long-range PCR to uncover rare mutations in nine patients and their family members. The patients with different results between Gap-PCR and MMCA assay or with phenotype not matching genotype were included. Using SMRT sequencing, we first identified the carriers with αααanti3.7/HKαα, -α762bpα/αα (chr16:172,648–173,409), ααfusion/αQSα (in a trans configuration), two cases with novel gene rearrangements and another case with a novel 341 bp insertion in α-globin gene cluster, respectively. One carrier with --SEA/αααanti4.2, and two carriers with the coexistence of globin variant and an α-globin gene duplication were also found. Most importantly, we could determine two defects in α-globin gene cluster being a cis or trans configuration in a single test. Our results showed that SMRT has great advantages in detection of α-globin gene triplications, rare deletions and determination of a cis or trans configuration. SMRT is a comprehensive and one-step method for thalassemia screening and diagnosis, especially for detection of rare thalassemia mutations.
Purpose
To explore whether probiotic supplementation could attenuate serum trimethylamine-N-oxide (TMAO) level and impact the intestinal microbiome composition.
Design
Forty healthy males ...(20–25 years old) were randomized into the probiotic group (1.32 × 10
11
CFU live bacteria including strains of
Lactobacillus acidophilus
,
Lactobacillus rhamnosus
GG,
Bifidobacterium animalis,
and
Bifidobacterium longum
daily) or the control group for 4 weeks. All participants underwent a phosphatidylcholine challenge test (PCCT) before and after the intervention. Serum TMAO and its precursors (TMA, choline and betaine) were measured by UPLC-MS/MS. The faecal microbiome was analyzed by 16S rRNA sequencing.
Results
Serum TMAO and its precursors were markedly increased after the PCCT. No statistical differences were observed in the probiotic and the control group in area under the curve (AUC) (14.79 ± 0.97 μmol/L 8 h vs. 19.17 ± 2.55 μmol/L 8 h,
P
= 0.106) and the pre- to post-intervention AUC alterations (∆AUC) (− 6.33 ± 2.00 μmol/L 8 h vs. − 0.73 ± 3.04 μmol/L 8 h,
P
= 0.131) of TMAO; however, higher proportion of participants in probiotic group showed their TMAO decrease after the intervention (78.9% vs. 45.0%,
P
= 0.029). The abundance of
Faecalibacterium prausnitzii
(
P
= 0.043) and
Prevotella
(
P
= 0.001) in the probiotic group was significantly increased after the intervention but without obvious differences in
α
- and
β
-diversity.
Conclusions
The current probiotic supplementation resulted in detectable change of intestinal microbiome composition but failed to attenuate the serum TMAO elevation after PCCT.
Clinicaltrials.gov Identifier
NCT03292978.
Clinicaltrials.gov website
https://clinicaltrials.gov/ct2/show/NCT03292978
.
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