Spin-polarized spatially indirect excitons in a topological insulator.

The exciton, a bound state of an electron and a hole, is a fundamental quasiparticle induced by coherent light-matter interactions in semiconductors. When the electrons and holes are in distinct spatial locations, spatially indirect excitons are formed with a much longer lifetime and a higher condensation temperature. One of the ultimate frontiers in this field is to create long-lived excitonic topological quasiparticles by driving exciton states with topological properties, to simultaneously leverage both topological effects and correlation1,2. Here we reveal the existence of a transient excitonic topological surface state (TSS) in a topological insulator, Bi2Te3. By using time-, spin- and angle-resolved photoemission spectroscopy, we directly follow the formation of a long-lived exciton state as revealed by an intensity buildup below the bulk-TSS mixing point and an anomalous band renormalization of the continuously connected TSS in the momentum space. Such a state inherits the spin-polarization of the TSS and is spatially indirect along the z axis, as it couples photoinduced surface electrons and bulk holes in the same momentum range, which ultimately leads to an excitonic state of the TSS. These results establish Bi2Te3 as a possible candidate for the excitonic condensation of TSSs3 and, in general, opens up a new paradigm for exploring the momentum space emergence of other spatially indirect excitons, such as moiré and quantum well excitons4-6, and for the study of non-equilibrium many-body topological physics.

The BMP inhibitor Coco reactivates breast cancer cells at lung metastatic sites.

The mechanistic underpinnings of metastatic dormancy and reactivation are poorly understood. A gain-of-function cDNA screen reveals that Coco, a secreted antagonist of TGF-ß ligands, induces dormant breast cancer cells to undergo reactivation in the lung. Mechanistic studies indicate that Coco exerts this effect by blocking lung-derived BMP ligands. Whereas Coco enhances the manifestation of traits associated with cancer stem cells, BMP signaling suppresses it. Coco induces a discrete gene expression signature, which is strongly associated with metastatic relapse to the lung, but not to the bone or brain in patients. Experiments in mouse models suggest that these latter organs contain niches devoid of bioactive BMP. These findings reveal that metastasis-initiating cells need to overcome organ-specific antimetastatic signals in order to undergo reactivation.

ChemMORT: an automatic ADMET optimization platform using deep learning and multi-objective particle swarm optimization.

Drug discovery and development constitute a laborious and costly undertaking. The success of a drug hinges not only good efficacy but also acceptable absorption, distribution, metabolism, elimination, and toxicity (ADMET) properties. Overall, up to 50% of drug development failures have been contributed from undesirable ADMET profiles. As a multiple parameter objective, the optimization of the ADMET properties is extremely challenging owing to the vast chemical space and limited human expert knowledge. In this study, a freely available platform called Chemical Molecular Optimization, Representation and Translation (ChemMORT) is developed for the optimization of multiple ADMET endpoints without the loss of potency (https://cadd.nscc-tj.cn/deploy/chemmort/). ChemMORT contains three modules: Simplified Molecular Input Line Entry System (SMILES) Encoder, Descriptor Decoder and Molecular Optimizer. The SMILES Encoder can generate the molecular representation with a 512-dimensional vector, and the Descriptor Decoder is able to translate the above representation to the corresponding molecular structure with high accuracy. Based on reversible molecular representation and particle swarm optimization strategy, the Molecular Optimizer can be used to effectively optimize undesirable ADMET properties without the loss of bioactivity, which essentially accomplishes the design of inverse QSAR. The constrained multi-objective optimization of the poly (ADP-ribose) polymerase-1 inhibitor is provided as the case to explore the utility of ChemMORT.

Induction-concurrent chemoradiotherapy with or without sintilimab in patients with locoregionally advanced nasopharyngeal carcinoma in China (CONTINUUM): a multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial.

BACKGROUND: Anti-PD-1 therapy and chemotherapy is a recommended first-line treatment for recurrent or metastatic nasopharyngeal carcinoma, but the role of PD-1 blockade remains unknown in patients with locoregionally advanced nasopharyngeal carcinoma. We assessed the addition of sintilimab, a PD-1 inhibitor, to standard chemoradiotherapy in this patient population. METHODS: This multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial was conducted at nine hospitals in China. Adults aged 18-65 years with newly diagnosed high-risk non-metastatic stage III-IVa locoregionally advanced nasopharyngeal carcinoma (excluding T3-4N0 and T3N1) were eligible. Patients were randomly assigned (1:1) using blocks of four to receive gemcitabine and cisplatin induction chemotherapy followed by concurrent cisplatin radiotherapy (standard therapy group) or standard therapy with 200 mg sintilimab intravenously once every 3 weeks for 12 cycles (comprising three induction, three concurrent, and six adjuvant cycles to radiotherapy; sintilimab group). The primary endpoint was event-free survival from randomisation to disease recurrence (locoregional or distant) or death from any cause in the intention-to-treat population. Secondary endpoints included adverse events. This trial is registered with ClinicalTrials.gov (NCT03700476) and is now completed; follow-up is ongoing. FINDINGS: Between Dec 21, 2018, and March 31, 2020, 425 patients were enrolled and randomly assigned to the sintilimab (n=210) or standard therapy groups (n=215). At median follow-up of 41·9 months (IQR 38·0-44·8; 389 alive at primary data cutoff [Feb 28, 2023] and 366 [94%] had at least 36 months of follow-up), event-free survival was higher in the sintilimab group compared with the standard therapy group (36-month rates 86% [95% CI 81-90] vs 76% [70-81]; stratified hazard ratio 0·59 [0·38-0·92]; p=0·019). Grade 3-4 adverse events occurred in 155 (74%) in the sintilimab group versus 140 (65%) in the standard therapy group, with the most common being stomatitis (68 [33%] vs 64 [30%]), leukopenia (54 [26%] vs 48 [22%]), and neutropenia (50 [24%] vs 46 [21%]). Two (1%) patients died in the sintilimab group (both considered to be immune-related) and one (<1%) in the standard therapy group. Grade 3-4 immune-related adverse events occurred in 20 (10%) patients in the sintilimab group. INTERPRETATION: Addition of sintilimab to chemoradiotherapy improved event-free survival, albeit with higher but manageable adverse events. Longer follow-up is necessary to determine whether this regimen can be considered as the standard of care for patients with high-risk locoregionally advanced nasopharyngeal carcinoma. FUNDING: National Natural Science Foundation of China, Key-Area Research and Development Program of Guangdong Province, Natural Science Foundation of Guangdong Province, Overseas Expertise Introduction Project for Discipline Innovation, Guangzhou Municipal Health Commission, and Cancer Innovative Research Program of Sun Yat-sen University Cancer Center. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Reducing false positive rate of docking-based virtual screening by active learning.

Machine learning-based scoring functions (MLSFs) have become a very favorable alternative to classical scoring functions because of their potential superior screening performance. However, the information of negative data used to construct MLSFs was rarely reported in the literature, and meanwhile the putative inactive molecules recorded in existing databases usually have obvious bias from active molecules. Here we proposed an easy-to-use method named AMLSF that combines active learning using negative molecular selection strategies with MLSF, which can iteratively improve the quality of inactive sets and thus reduce the false positive rate of virtual screening. We chose energy auxiliary terms learning as the MLSF and validated our method on eight targets in the diverse subset of DUD-E. For each target, we screened the IterBioScreen database by AMLSF and compared the screening results with those of the four control models. The results illustrate that the number of active molecules in the top 1000 molecules identified by AMLSF was significantly higher than those identified by the control models. In addition, the free energy calculation results for the top 10 molecules screened out by the AMLSF, null model and control models based on DUD-E also proved that more active molecules can be identified, and the false positive rate can be reduced by AMLSF.

Serum IgA as a Prognostic Beacon: Anticipating Systemic Therapy Efficacy in Metastatic Clear Cell Renal Cell Carcinoma.

OBJECTIVE: Immunotherapy-tyrosine kinase inhibitor (IO-TKI) therapy has revolutionized the treatment landscape for metastatic clear cell renal cell carcinoma (mccRCC); however, the absence of effective biomarkers poses a challenge in predicting the efficacy of these regimens. This study aims to explore the predictive and prognostic value of serum immunoglobulin A (IgA) in mccRCC patients undergoing IO-TKI therapy. METHODS: Ninety-six mccRCC patients treated with IO-TKI therapy from 2019 to 2023 were enrolled and serum IgA levels were assessed at the pretreatment baseline and after 3 months of treatment. RESULTS: Notably, baseline levels of IgA showed no correlation with the objective response rate. However, patients achieving complete or partial responses exhibited a remarkable decrease in IgA levels, while those with stable or progressive disease displayed an increase in IgA levels after 3 months of treatment. Furthermore, the dynamic alteration in IgA levels after 3 months of treatment demonstrated predictive value for both progression-free survival (PFS) and overall survival (OS). The time-dependent receiver operating characteristic curves exhibited outstanding performance in predicting PFS (AUC 0.793) and OS (AUC 0.738). CONCLUSION: Taken together, this study demonstrates that dynamic alteration of serum IgA after 3 months of treatment was significantly correlated with prognosis and therapeutic efficacy in mccRCC patients.

Impact of third-order dispersion on the dynamics of dissipative solitons in an ultrafast fiber laser.

Dissipative solitons (DSs), due to the complex interplay among dispersion, nonlinear, gain and loss, illustrate abundant nonlinear dynamics behaviors. Especially, dispersion plays an important role in the research of DS dynamics in ultrafast fiber lasers. Previous studies have mainly focused on the effect of even-order dispersion, i.e., group velocity dispersion (GVD) and fourth-order dispersion. In fact, odd-order dispersions, such as third-order dispersion (TOD), also significantly influences the dynamics of DSs. However, due to the lack of dispersion engineering tools, few experimental researches in this domain have been reported. In this work, by employing a pulse shaper in ultrafast fiber laser, an in-depth exploration of the DS dynamics influenced by TOD was conducted. With the increase of TOD value, the stable single DS undergoes a splitting into two solitons and then enters explosion state, and ultimately evolves into a chaotic state. The laser operation state is correlated to dispersion profile, which could be controlled by TOD. Here, the positive dispersion at long-wavelength side will be gradually shifted to negative dispersion by increasing the TOD, where soliton effect will drive the transitions. These findings offer valuable insights into the nonlinear dynamics of ultrafast lasers and may also foster applications involving higher-order dispersion.

Periodically tunable multimode soliton pulsation in a spatiotemporal mode-locked fiber laser.

Multimode fiber lasers have become a new platform for investigating nonlinear phenomena since the report on spatiotemporal mode-locking. In this work, the multimode soliton pulsation with a tunable period is achieved in a spatiotemporal mode-locked fiber laser. It demonstrates that the pulsation period drops while increasing the pump power. Moreover, it is found that different transverse modes have the same pulsation period, asynchronous pulsation evolution and different dynamical characteristics through the spatial sampling technique and the dispersive Fourier transform technique. To further verify the experimental results, we numerically investigate the influences of the gain and the loss on the pulsation properties. It is found that within a certain parameter range, the pulsation period drops and rises linearly with the increase of the gain and the loss, respectively. The obtained results contribute to understanding the formation and regulating of soliton pulsations in fiber lasers.

Dosimetric comparison of advanced radiation techniques for scalp-sparing in low-grade gliomas.

BACKGROUND: Alopecia causes significant distress for patients and negatively impacts quality of life for low-grade glioma (LGG) patients. We aimed to compare and evaluate variations in dose distribution for scalp-sparing in LGG patients with proton therapy and photon therapy, namely intensity-modulated proton therapy (IMPT), intensity-modulated radiotherapy (IMRT), volumetric modulated arc therapy (VMAT), and helical tomotherapy (HT). METHODS: This retrospective study utilized a dataset comprising imaging data from 22 patients with LGG who underwent postoperative radiotherapy. Treatment plans were generated for each patient with scalp-optimized (SO) approaches and scalp-non-optimized (SNO) approaches using proton techniques and photons techniques; all plans adhered to the same dose constraint of delivering a total radiation dose of 54.04 Gy to the target volume. All treatment plans were subsequently analyzed. RESULTS: All the plans generated in this study met the dose constraints for the target volume and OARs. The SO plans resulted in reduced maximum scalp dose (Dmax), mean scalp dose (Dmean), and volume of the scalp receiving 30 Gy (V30) and 40 Gy (V40) compared with SNO plans in all radiation techniques. Among all radiation techniques, the IMPT plans exhibited superior performance compared to other plans for dose homogeneity as for SO plans. Also, IMPT showed lower values for Dmean and Dmax than all photon radiation techniques. CONCLUSION: Our study provides evidence that the SO approach is a feasible technique for reducing scalp radiation dose. However, it is imperative to conduct prospective trials to assess the benefits associated with this approach.

Sub-50†fs, 0.5†W average power Nd-doped fiber amplifier at 920†nm.

We develop an all polarization-maintaining (PM) 920 nm Nd-doped fiber amplifier delivering a train of pulses with ∼0.53 W average power and sub-50 fs duration. The sub-50 fs pulse benefits from the pre-chirping management method that allows for over 60 nm broadening spectrum without pulse breaking in the amplification stage. By virtue of the short pulse duration, the pulse peak power can reach to ∼0.31 MW in spite of the moderate average power. These results represent a key step in developing high-peak-power pulse Nd-doped fiber laser systems at 920 nm, which will find important applications in fields such as biomedical imaging, ultrafast optical spectroscopy, and excitation of quantum-dot single photon sources.

Spatiotemporal dual-periodic soliton pulsation in a multimode fiber laser.

Spatiotemporal mode-locked (STML) fiber lasers have become a new platform for investigating nonlinear phenomena. In this work, spatiotemporal dual-periodic soliton pulsation (SDSP) is firstly observed in an STML fiber laser. It is found that in the SDSP, the long-period pulsations (LPPs) of different transverse modes are synchronous, while the short-period pulsations (SPPs) exhibit asynchronous modulations. The numerical simulation confirms the experimental results and further reveals that the proportion of transverse mode components can manipulate the periods of the LPP and SPP but does not affect the synchronous and asynchronous pulsations of different transverse modes. The obtained results bring the study of spatiotemporal dissipative soliton pulsation into the multi-period modulation stage, which helps to understand the complex spatiotemporal dynamics in STML fiber lasers and discover new dynamics in high-dimensional nonlinear systems.

Cancer cost-related subjective financial distress among breast cancer: a scoping review.

PURPOSE: This article provided a comprehensive scoping review, synthesizing existing literature on the financial distress faced by breast cancer patients. It examined the factors contributing to financial distress, the impact on patients, coping mechanisms employed, and potential alleviation methods. The goal was to organize existing evidence and highlight possible directions for future research. METHODS: We followed the scoping review framework proposed by the Joanna Briggs Institute (JBI) to synthesize and report evidence. We searched electronic databases, including PubMed, Web of Science, Embase, and Cochrane Library, for relevant literature. We included English articles that met the following criteria: (a) the research topic was financial distress or financial toxicity, (b) the research subjects were adult breast cancer patients, and (c) the article type was quantitative, qualitative, or mixed-methods research. We then extracted and integrated relevant information for reporting. RESULTS: After removing duplicates, 5459 articles were retrieved, and 43 articles were included based on the inclusion and exclusion criteria. The articles addressed four main themes related to financial distress: factors associated with financial distress, impact on breast cancer patients, coping mechanisms, and potential methods for alleviation. The impact of financial distress on patients was observed in six dimensions: financial expenses, financial resources, social-psychological reactions, support seeking, coping care, and coping lifestyle. While some studies reported potential methods for alleviation, few discussed the feasibility of these solutions. CONCLUSIONS: Breast cancer patients experience significant financial distress with multidimensional impacts. Comprehensive consideration of possible confounding factors is essential when measuring financial distress. Future research should focus on exploring and validating methods to alleviate or resolve this issue.

Pedigree Analysis of Nonclassical Cholesteryl Ester Storage Disease with Dominant Inheritance in a LIPA I378T Heterozygous Carrier.

BACKGROUND: Cholesterol ester storage disorder (CESD; OMIM: 278,000) was formerly assumed to be an autosomal recessive allelic genetic condition connected to diminished lysosomal acid lipase (LAL) activity due to LIPA gene abnormalities. CESD is characterized by abnormal liver function and lipid metabolism, and in severe cases, liver failure can occur leading to death. In this study, one Chinese nonclassical CESD pedigree with dominant inheritance was phenotyped and analyzed for the corresponding gene alterations. METHODS: Seven males and eight females from nonclassical CESD pedigree were recruited. Clinical features and LAL activities were documented. Whole genome Next-generation sequencing (NGS) was used to screen candidate genes and mutations, Sanger sequencing confirmed predicted mutations, and qPCR detected LIPA mRNA expression. RESULTS: Eight individuals of the pedigree were speculatively thought to have CESD. LAL activity was discovered to be lowered in four living members of the pedigree, but undetectable in the other four deceased members who died of probable hepatic failure. Three of the four living relatives had abnormal lipid metabolism and all four had liver dysfunctions. By liver biopsy, the proband exhibited diffuse vesicular fatty changes in noticeably enlarged hepatocytes and Kupffer cell hyperplasia. Surprisingly, only a newly discovered heterozygous mutation, c.1133T>C (p. Ile378Thr) on LIPA, was found by gene sequencing in the proband. All living family members who carried the p.I378T variant displayed reduced LAL activity. CONCLUSIONS: Phenotypic analyses indicate that this may be an autosomal dominant nonclassical CESD pedigree with a LIPA gene mutation.

Correlation between serum trimethylamine-N-oxide and body fat distribution in middle-aged and older adults: a prospective cohort study.

BACKGROUND: Trimethylamine-N-oxide (TMAO) is linked with obesity, while limited evidence on its relationship with body fat distribution. Herein, we investigated the associations between serum TMAO and longitudinal change of fat distribution in this prospective cohort study. METHODS: Data of 1964 participants (40-75y old) from Guangzhou Nutrition and Health Study (GNHS) during 2008-2014 was analyzed. Serum TMAO concentration was quantified by HPLC-MS/MS at baseline. The body composition was assessed by dual-energy X-ray absorptiometry at each 3-y follow-up. Fat distribution parameters were fat-to-lean mass ratio (FLR) and trunk-to-leg fat ratio (TLR). Fat distribution changes were derived from the coefficient of linear regression between their parameters and follow-up duration. RESULTS: After an average of 6.2-y follow-up, analysis of covariance (ANCOVA) and linear regression displayed women with higher serum TMAO level had greater increments in trunk FLR (mean ± SD: 1.47 ± 4.39, P-trend = 0.006) and TLR (mean ± SD: 0.06 ± 0.24, P-trend = 0.011). Meanwhile, for women in the highest TMAO tertile, linear mixed-effects model (LMEM) analysis demonstrated the annual estimated increments (95% CI) were 0.03 (95% CI: 0.003 - 0.06, P = 0.032) in trunk FLR and 1.28 (95% CI: -0.17 - 2.73, P = 0.083) in TLR, respectively. In men, there were no similar significant observations. Sensitivity analysis yielded consistent results. CONCLUSION: Serum TMAO displayed a more profound correlation with increment of FLR and TLR in middle-aged and older community-dwelling women in current study. More and further studies are still warranted in the future. TRIAL REGISTRATION: NCT03179657.

Clinical and laboratory characteristics of salivary gland ultrasonography-positive patients with primary Sjögren's syndrome.

OBJECTIVE: This study aimed to investigate the clinical and laboratory characteristics of salivary gland ultrasonography (SGUS)-positive patients with primary Sjögren's syndrome (pSS) compared to SGUS-negative patients and to analyse the diagnostic value of SGUS and labial salivary gland biopsy (LSGB) grading in pSS. METHODS: A retrospective analysis of patients admitted to the Affiliated Hospital of Yangzhou University between May 2019 and November 2023 was conducted. According to the OMERACT scoring system, patients with pSS were divided into an SGUS-negative group (score <2) and an SGUS-positive group (score ≥2). The patient's age, gender, clinical symptoms, laboratory parameters and diagnostic examinations were compared and analysed, and Spearman correlation analysis was used to analyse the correlation between SGUS, LSGB and influencing factors. RESULTS: There was no significant difference in dry mouth, dry eyes, tooth loss, fever, joint pain, fatigue, interstitial lung disease or renal tubular acidosis between the two groups, although there were more patients with salivary gland enlargement in the SGUS-positive group (p < 0.05). In terms of high levels of immunoglobulin G (IgG), high levels of rheumatoid factor (RF), anti-nuclear antibody ≥1:320, anti-Sjögren's syndrome A-52KD and anti-Sjögren's syndrome B, the number of cases in the SGUS-positive group was greater than that in the SGUS-negative group (p < 0.05). LSGB samples were graded per the Chisholm-Mason system with significant differences between multiple groups. SGUS score negatively correlated with age and positively correlated with LSGB grade. CONCLUSION: This study showed that the SGUS score positively correlated with LSGB grade in pSS patients and negatively correlated with patient age. Thus, SGUS and LSGB are consistent in the diagnosis of pSS to reflect the degree of salivary gland involvement, and patients who are SGUS positive have high RF and IgG levels, a variety of autoantibodies positive and a tendency toward salivary gland enlargement.

Ferviditalea candida gen. nov., sp. nov., a novel member of the family Paenibacillaceae isolated from a geothermal area.

OBJECTIVE: The family Paenibacillaceae is linked to the order Caryophanales. Paenibacillaceae members residing in compost or soil play crucial roles in nutrient recycling and breaking down complex organic materials. However, our understanding of Paenibacillaceae remains limited. METHODS: Strain SYSU GA230002T was conclusively identified using a polyphasic taxonomic approach frequently utilized in bacterial systematics. Standard microbiological techniques were employed to characterize the morphology and biochemistry of strain SYSU GA230002T. RESULTS: An anaerobic and gram--negative bacterium, designated SYSU GA230002T, was isolated from geothermally heated soil of Tengchong, Yunnan Province, south-west China. Phylogenetic analyses based on 16S rRNA gene sequences and genomes showed that strain SYSU GA230002T belongs to the family Paenibacillaceae. 16S rRNA gene sequence similarity (<94.0 %), ANI (<71.95 %) and AAI values (<58.67 %) between strain SYSU GA230002T with other members of the family were lower than the threshold values recommended for distinguishing novel species. Growth was observed at 30-45 °C (optimum, 37 °C), pH 7.0-8.0 (optimum, pH 7.5) and in 0-3.0 % (w/v) NaCl concentrations (optimum, 0 %). The major fatty acids detected were anteiso-C15:0, iso-C16:0 and iso-C17:0. The polar lipids included diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol, one unidentified phospholipid, one unidentified aminolipid and two unidentified glycolipids. The respiratory quinone was MK-7. The DNA G + C content of strain SYSU GA230002T was 49.87 %. CONCLUSION: Based on the results of morphological, physiological properties, and chemotaxonomic characteristics, this strain is proposed to represent a new species of a new genus Ferviditalea candida gen. nov., sp. nov. The type strain of the type species is SYSU GA230002T (=KCTC 25726T = GDMCC 1.4160T).

A new classification for emergency critically ill patients and analysis of their adverse events during intrahospital transport: A cluster analysis.

BACKGROUND: Critical patients may experience various adverse events during transportation within hospitals. Therefore, quickly evaluating and classifying patients before transporting them from the emergency department and focusing on managing high-risk patients are critical. At present, no unified classification method exists; all the current approaches are subjective. AIMS: To ensure transportation safety, we conducted a cluster analysis of critically ill patients transferred from the emergency department to the intensive care unit. STUDY DESIGN: Single-centre cohort study. This study was conducted at a comprehensive first-class teaching hospital in Beijing. Convenience sampling and continuous enrolment were employed. We collected data from 1 January 2019, to 31 December 2021. All patients were transferred from the emergency department to the intensive care unit, and cluster analysis was conducted using five variables. RESULTS: A total of 584 patients were grouped into three clusters. Cluster 1 (high systolic blood pressure group) included 208 (35.6%) patients. Cluster 2 (high heart rate and low blood oxygen group) included 55 (9.4%) patients. Cluster 3 (normal group) included the remaining 321 (55%) patients. The oxygen saturation levels of all the patients were lower after transport, and the proportion of adverse events (61.8%) was the highest in Cluster 2 (p < .05). CONCLUSIONS: This study utilized data on five important vital signs from a cluster analysis to explore possible patient classifications and provide a reference for ensuring transportation safety. RELEVANCE TO CLINICAL PRACTICE: Before transferring patients, we should classify them and implement targeted care. Changes in blood oxygen levels in all patients should be considered, with a focus on the occurrence of adverse events during transportation among patients with high heart rates and low blood oxygen levels.

Improving structure-based virtual screening performance via learning from scoring function components.

Scoring functions (SFs) based on complex machine learning (ML) algorithms have gradually emerged as a promising alternative to overcome the weaknesses of classical SFs. However, extensive efforts have been devoted to the development of SFs based on new protein-ligand interaction representations and advanced alternative ML algorithms instead of the energy components obtained by the decomposition of existing SFs. Here, we propose a new method named energy auxiliary terms learning (EATL), in which the scoring components are extracted and used as the input for the development of three levels of ML SFs including EATL SFs, docking-EATL SFs and comprehensive SFs with ascending VS performance. The EATL approach not only outperforms classical SFs for the absolute performance (ROC) and initial enrichment (BEDROC) but also yields comparable performance compared with other advanced ML-based methods on the diverse subset of Directory of Useful Decoys: Enhanced (DUD-E). The test on the relatively unbiased actives as decoys (AD) dataset also proved the effectiveness of EATL. Furthermore, the idea of learning from SF components to yield improved screening power can also be extended to other docking programs and SFs available.

BioMedR: an R/CRAN package for integrated data analysis pipeline in biomedical study.

BACKGROUND: With the increasing development of biotechnology and information technology, publicly available data in chemistry and biology are undergoing explosive growth. Such wealthy information in these resources needs to be extracted and then transformed to useful knowledge by various data mining methods. However, a main computational challenge is how to effectively represent or encode molecular objects under investigation such as chemicals, proteins, DNAs and even complicated interactions when data mining methods are employed. To further explore these complicated data, an integrated toolkit to represent different types of molecular objects and support various data mining algorithms is urgently needed. RESULTS: We developed a freely available R/CRAN package, called BioMedR, for molecular representations of chemicals, proteins, DNAs and pairwise samples of their interactions. The current version of BioMedR could calculate 293 molecular descriptors and 13 kinds of molecular fingerprints for small molecules, 9920 protein descriptors based on protein sequences and six types of generalized scale-based descriptors for proteochemometric modeling, more than 6000 DNA descriptors from nucleotide sequences and six types of interaction descriptors using three different combining strategies. Moreover, this package realized five similarity calculation methods and four powerful clustering algorithms as well as several useful auxiliary tools, which aims at building an integrated analysis pipeline for data acquisition, data checking, descriptor calculation and data modeling. CONCLUSION: BioMedR provides a comprehensive and uniform R package to link up different representations of molecular objects with each other and will benefit cheminformatics/bioinformatics and other biomedical users. It is available at: https://CRAN.R-project.org/package=BioMedR and https://github.com/wind22zhu/BioMedR/.

Scopy: an integrated negative design python library for desirable HTS/VS database design.

BACKGROUND: High-throughput screening (HTS) and virtual screening (VS) have been widely used to identify potential hits from large chemical libraries. However, the frequent occurrence of 'noisy compounds' in the screened libraries, such as compounds with poor drug-likeness, poor selectivity or potential toxicity, has greatly weakened the enrichment capability of HTS and VS campaigns. Therefore, the development of comprehensive and credible tools to detect noisy compounds from chemical libraries is urgently needed in early stages of drug discovery. RESULTS: In this study, we developed a freely available integrated python library for negative design, called Scopy, which supports the functions of data preparation, calculation of descriptors, scaffolds and screening filters, and data visualization. The current version of Scopy can calculate 39 basic molecular properties, 3 comprehensive molecular evaluation scores, 2 types of molecular scaffolds, 6 types of substructure descriptors and 2 types of fingerprints. A number of important screening rules are also provided by Scopy, including 15 drug-likeness rules (13 drug-likeness rules and 2 building block rules), 8 frequent hitter rules (four assay interference substructure filters and four promiscuous compound substructure filters), and 11 toxicophore filters (five human-related toxicity substructure filters, three environment-related toxicity substructure filters and three comprehensive toxicity substructure filters). Moreover, this library supports four different visualization functions to help users to gain a better understanding of the screened data, including basic feature radar chart, feature-feature-related scatter diagram, functional group marker gram and cloud gram. CONCLUSION: Scopy provides a comprehensive Python package to filter out compounds with undesirable properties or substructures, which will benefit the design of high-quality chemical libraries for drug design and discovery. It is freely available at https://github.com/kotori-y/Scopy.