An uncertainty-based interpretable deep learning framework for predicting breast cancer outcome.

BACKGROUND: Predicting outcome of breast cancer is important for selecting appropriate treatments and prolonging the survival periods of patients. Recently, different deep learning-based methods have been carefully designed for cancer outcome prediction. However, the application of these methods is still challenged by interpretability. In this study, we proposed a novel multitask deep neural network called UISNet to predict the outcome of breast cancer. The UISNet is able to interpret the importance of features for the prediction model via an uncertainty-based integrated gradients algorithm. UISNet improved the prediction by introducing prior biological pathway knowledge and utilizing patient heterogeneity information. RESULTS: The model was tested in seven public datasets of breast cancer, and showed better performance (average C-index = 0.691) than the state-of-the-art methods (average C-index = 0.650, ranged from 0.619 to 0.677). Importantly, the UISNet identified 20 genes as associated with breast cancer, among which 11 have been proven to be associated with breast cancer by previous studies, and others are novel findings of this study. CONCLUSIONS: Our proposed method is accurate and robust in predicting breast cancer outcomes, and it is an effective way to identify breast cancer-associated genes. The method codes are available at: https://github.com/chh171/UISNet .

Improvement of electrocatalytic water oxidation activity of novel copper complex by modulating the axial coordination of phosphate on metal center.

The structure of organic ligand scaffolds of copper complexes critically affects their electrocatalytic properties toward water oxidation, which is widely regarded as the bottleneck of overall water splitting. Herein, two novel mononuclear Cu complexes, [Cu(dmabpy)](ClO4)2 (1, dmabpy = 6,6'-bis(dimethylaminomethyl)-2,2'-bipyridine) and [Cu(mabpy)](ClO4)2 (2, mabpy = 6,6'-bis(methylaminomethyl)-2,2'-bipyridine), with four-coordinated distorted planar quadrilateral geometry were synthesized and explored as efficient catalysts for electrochemical oxygen evolution in phosphate buffer solution. Interestingly, complex 1 with a tertiary amine group catalyzes water oxidation with lower onset overpotential and better catalytic performance, while complex 2 containing a secondary amine fragment displays much lower catalytic activity under identical conditions. The water oxidation catalytic mechanism of the two complexes is proposed based on the electrochemical test results. Experimental methods indicate that phosphate coordinated on the Cu center of the two complexes inhibits their reaction with substrate water molecules, resulting in lower activity toward water oxidation. Electrochemical tests reveal that the structure of the coordinated nitrogen atom improves the catalytic performance of the Cu complexes by modulating the coordination of phosphate on the Cu center, indicating that a minor alteration of the coordinating nitrogen atom of the ligand has a detrimental effect on the catalytic performance of electrochemical WOCs based on transition metal complexes.

Identification of a novel diagnosis model based on 5 hub genes for chronic thromboembolic pulmonary hypertension.

BACKGROUND: As a type of precapillary pulmonary hypertension, chronic thromboembolic pulmonary hypertension (CTEPH) results from incomplete pulmonary embolism resolution. In this study, we aimed to determine biomarker genes for predicting the prognosis of CTEPH. METHOD: RNAseq of CTEPH was collected from the public database, namely Gene Expression Omnibus (GEO), including GSE84538 and GSE188938, which combined a dataset (GSE). Differentially expressed genes (DEG) or miRNA (DEM) were identified by limma package. Functional enrichment analysis was performed by the WebGestaltR package. Then, the miRNA-mRNA network was presented by Cytoscape, and the protein-protein interactions (PPI) network was constructed by STRING. MCODE was mined by mature MCODE algorithm. Immune infiltration analysis was conducted by ESTIMATER and ssGSEA analysis. A diagnosis model was established by SVM algorithm. RESULT: In the GSE dataset, CTEPH samples had a lower GOBP_RESPONSE_TO_OXIDATIVE_STRESS score. A total of 628 DEGs and 31 DEMs were identified between CTEPH and normal samples. Afterward, DEGs were intersected with genes, which correlated with the GOBP_RESPONSE_TO_OXIDATIVE_STRESS score. A 26 DEMs-152 DEGs network was constructed, and a PPI network was established based on 152 DEGs to find 149 target genes. From the above 149 target genes, 3 modules were extracted to obtain 15 core targets. Finally, 5 hub genes were obtained by the intersection of 15 core targets and genes in MCODE2. A total of 5 hub genes were positively correlated with most immune cell scores as well as GOBP_RESPONSE_TO_OXIDATIVE_STRESS. It was found that a diagnosis model based on 5 hub genes had a well diagnostic ability for CTEPH. CONCLUSION: We identified 5 hub genes associated with oxidative stress. It can be concluded that they may be beneficial in diagnosing CTEPH.

Bioinformatics analysis based on DNA methylation data identified in lung adenocarcinoma subgroups with different immune characteristics and clinical outcomes.

Background: DNA methylation can be used to predict clinical outcomes and improve the classification of tumors. The present study aimed to develop a new lung adenocarcinoma (LUAD) classification system according to the immune cell gene-related methylation sites and to reveal the survival outcomes, clinical characteristics, immune cell infiltration, stem cell characteristics, and genomic variations of each molecular subgroup. Methods: The DNA methylation sites of LUAD samples collected from The Cancer Genome Atlas (TCGA) database were analyzed, and the prognosis-related differential methylation sites (DMS) were screened. Consistent clustering of the samples was conducted using ConsensusClusterPlus, and the classification results were verified by principal component analysis (PCA). The survival and clinical results, immune cell infiltration, stemness, DNA mutation, and copy number variation (CNV) of each molecular subgroup were analyzed. Results: A total of 40 DMS were obtained by difference and univariate COX analyses, and the TCGA LUAD samples were divided into three subgroups: cluster 1 (C1), cluster 2 (C2), and cluster 3 (C3). Among these subgroups, the overall survival (OS) of C3 was significantly higher than that of C1 and C2. Compared with C1 and C3, C2 had the lowest innate immune cell and adaptive immune cell infiltration scores; the lowest stromal score, immune score, and iconic immune checkpoint expression; and the highest expression of messenger RNA (mRNA) expression-based stemness indices (mRNAsi), DNA methylation-based stemness index (mDNAsi), and tumor mutational burden (TMB). Conclusions: In this study, we proposed a LUAD typing system based on DMS, which was closely related to the survival, clinical features, immune characteristics, and genomic variations of LUAD, and may contribute to the development of personalized therapy for new specific subtypes.

Systematically analyzed molecular characteristics of lung adenocarcinoma using metabolism-related genes classification.

High heterogeneity of lung adenocarcinoma (LUAD) is a major clinical challenge. This study aims to characterize the molecular features of LUAD through classification based on metabolism-related genes. A total of 500 LUAD samples from The Cancer Genome Atlas (TCGA) and 612 from Gene Expression Omnibus (GEO) were integrated with 2,753 metabolism-related genes to determine the molecular classification. Systematic bioinformatics analysis was used to conduct correlation analysis between metabolism-related classification and molecular characteristics of LUAD. LUAD patients were divided into three molecular clusters (C1-C3). Survival analysis revealed that C1 and C2 showed good and poor prognoses, respectively. Associational analysis of classification and molecular characteristics revealed that C1 was associated with low pathological stage, metabolic pathways, high metabolic process, active immune process and checkpoint, sensitive drug response, as well as a low genetic mutation. Nevertheless, C2 was associated with high pathological stage, carcinogenic pathways, low metabolic process, inactive immune signatures, resistant drug response, and frequent genetic mutation. Eventually, a classifier with 60 metabolic genes was constructed, confirming the robustness of molecular classification on LUAD. Our findings promote the understanding of LUAD molecular characteristics, and the research data may be used for providing information be helpful for clinical diagnosis and treatment.

Structural plasticity of omicron BA.5 and BA.2.75 for enhanced ACE-dependent entry into cells.

The current study investigated the binding variations among the wilt type, Omicron sub-variants BA.2.75 and BA.5, using protein-protein docking, protein structural graphs (P SG), and molecular simulation methods. HADDOCK predicted docking scores and dissociation constant (KD) revealed tighter binding of these sub-variants in contrast to the WT. Further investigation revealed variations in the hub residues, protein sub-networks, and GlobalMetapath in these variants as compared to the WT. A very unusual dynamic for BA.2.75 and BA.5 was observed, and secondary structure transition can also be witnessed in the loops (44-505). The results show that the flexibility of these three loops is increased by the mutations as an allosteric effect and thus enhances the chances of bonding with the nearby residues to connect and form a stable connection. Furthermore, the additional hydrogen bonding contacts steer the robust binding of these variants in contrast to the wild type. The total binding free energy for the wild type was calculated to be -61.38 kcal/mol, while for BA.2.75 and BA.5 variants the T BE was calculated to be -70.42 kcal/mol and 69.78 kcal/mol, respectively. We observed that the binding of BA.2.75 is steered by the electrostatic interactions while the BA.5 additional contacts are due to the vdW (Van der Waal) energy. From these findings, it can be observed the Spike (S) protein is undergoing structural adjustments to bind efficiently to the hACE2 (human angiotensin-converting enzyme 2) receptor and, in turn, increase entry to the host cells. The current study will aid the development of structure-based drugs against these variants.Communicated by Ramaswamy H. Sarma.

Modulating the electrocatalytic activity of mononuclear nickel complexes toward water oxidation by tertiary amine group.

Water oxidation is the bottleneck of water splitting, which is a promising strategy for hydrogen production. Therefore, it is significant to develop efficient water oxidation catalysts. Herein, electrochemical water oxidation catalyzed by three nickel complexes, namely [Ni(bptn)(H2O)](ClO4)2 (1), [Ni(mbptn)(CH3CN)](ClO4)2 (2), and [Ni(tmbptn)(H2O)](ClO4)2 (3) (bptn = 1,9-bis(2-pyridyl)-2,5,8-triazanonane, mbptn = 5-methyl-1,9-bis(2-pyridyl)-2,5,8-triazanonane, and tmbptn = 1,9-bis(2-pyridyl)-2,5,8-triazanonane), is studied under near-neutral condition (pH 9.0). Meanwhile, the homogeneous catalytic behaviors of the three mononuclear nickel complexes were investigated and confirmed by scanning electron microscopy, energy dispersive spectrometry, X-ray photoelectron spectroscopy and electrochemical method. Complex 1 stabilized by a pentadentate ligand with three N-H fragments homogeneously catalyzes water oxidation to oxygen with the lowest onset overpotential. Complex 2 stabilized by a similar ligand with two N-H groups and one N-CH3 group exhibits relatively higher onset overpotential but higher catalytic current and turnover frequency. However, complex 3 with three N-CH3 coordination environment shows the highest onset overpotential and the highest catalytic current at higher potential. Comparison of catalytic behaviors and ligand structure of the three complexes reveals that the methyl group on the polypyridine amine ligand affects the water oxidation activity of the complexes obviously. The electronic effect of N-CH3 coordination environment leads to higher redox potential of the metal center and potential demand for water oxidation, while it leads to higher reaction activity of high-valent intermediates, which account for higher catalytic current and efficiency of water oxidation. This work reveals that electrocatalytic water oxidation performance of nickel complexes can be finely modulated by constructing suitable N-CH3 coordination.

Ultra-Large-Scale Screening of Natural Compounds and Free Energy Calculations Revealed Potential Inhibitors for the Receptor-Binding Domain (RBD) of SARS-CoV-2.

The emergence of immune-evading variants of SARS-CoV-2 further aggravated the ongoing pandemic. Despite the deployments of various vaccines, the acquired mutations are capable of escaping both natural and vaccine-induced immune responses. Therefore, further investigation is needed to design a decisive pharmacological treatment that could efficiently block the entry of this virus into cells. Hence, the current study used structure-based methods to target the RBD of the recombinant variant (Deltacron) of SARS-CoV-2, which was used as a model variant. From the virtual drug screenings of various databases, a total of four hits were identified as potential lead molecules. Key residues were blocked by these molecules with favorable structural dynamic features. The binding free energies further validated the potentials of these molecules. The TBE for MNP was calculated to be -32.86 ± 0.10 kcal/mol, for SANC00222 the TBE was -23.41 ± 0.15 kcal/mol, for Liriodenine the TBE was -34.29 ± 0.07 kcal/mol, while for Carviolin the TBE was calculated to be -27.67 ± 0.12 kcal/mol. Moreover, each complex demonstrated distinct internal motion and a free energy profile, indicating a different strategy for the interaction with and inhibition of the RBD. In conclusion, the current study demands further in vivo and in vitro validation for the possible usage of these compounds as potential drugs against SARS-CoV-2 and its variants.

Heterometallic Dual-Liganded AE-Ln-CPs Luminescent Probes for Efficient Sensing of Fe(III) Ions.

Iron ion is widely present in the environment and in biological systems, and are indispensable trace elements in living organisms, so development of an efficient and simple sensor for sensing Fe(III) ions has attracted much attention. Here, six heterometallic AE-Ln coordination polymers (CPs) [Ln2 (pda)4(Hnda)2Ca2(H2O)2]·MeOH (Ln = Eu (1), Tb (2); H2pda = 2,6-pyridinedicarboxylic acid, H2nda = 2,3-naphthalenedicarboxylic acid), [Ln (pda)2 (nda)AE2(HCOO)(H2O)] (AE = Sr, Ln = Eu (3), Tb (4); AE = Ba, Ln = Eu (5), Tb (6)) with two-dimensional (2D) layer structures were synthesized by hydrothermal method. All of them were characterized by elemental analysis, XRD, IR, TG, as well as single crystal X-ray diffraction. They all show infinite 2D network structure, where complexes 1 and 2 are triclinic with space group of P 1 ¯ , while 3-6 belong to the monoclinic system, space group P21/n . The solid-state fluorescence lifetimes of complexes 1, 3 and 5 are τobs1 = 1930.94, 2049.48 and 2,413.04 µs, respectively, and the quantum yields Ф total are 63.01, 60.61, 87.39%, respectively, which are higher than those of complexes 2, 4 and 6. Complexes 1-6 all exhibited efficient fluorescence quenching response to Fe3+ ions in water, and were not interfered by the following metal ions: Cu2+, Cd2+, Mg2+, Ni2+, Co2+, Ca2+, Ba2+, Sr2+, Li+, Na+, K+, Al3+, Fe2+, Pb2+, Cr3+, Mn2+ and Zn2+. The quenching coefficient K SV for complexes 1-6 is 1.41 × 105 M-1, 7.10 × 104 M-1, 1.70 × 105 M-1, 1.57 × 105 M-1, 9.37 × 104 M-1, 1.27 × 105 M-1, respectively. The fluorescence quenching mechanism of these complexes towards Fe3+ ions was also investigated. It is possible that the weak interaction formed between the complexes and the Fe3+ ions reduce the energy transfer from the ligand to the Ln3+ ion, producing the emission burst effect. This suggests that complexes 1-6 can be candidate for efficient luminescent sensor of Fe3+.

Exosomal circSHKBP1 participates in non-small cell lung cancer progression through PKM2-mediated glycolysis.

Non-small cell lung cancer (NSCLC) has a high morbidity and mortality, and it is imperative to explore the latent pathogenesis mechanism of NSCLC progression to find potential prognostic biomarkers and therapeutic targets. The present study aimed to explore the biological function of circSHKBP1 in NSCLC. circSHKBP1 was found to be upregulated in NSCLC tissues and cell lines and was enriched in exosomes derived from NSCLC cells. Exosomal circSHKBP1 enhanced the proliferation, migration, invasion, and stemness of NSCLC cells. miRNA-1294 was identified as a target for circSHKBP1, and circSHKBP1 upregulated PKM2 expression by sponging miR-1294. Exosomal circSHKBP1 regulated glycolysis through PKM2 in a HIF-1α-dependent manner in NSCLC cells and promoted M2 polarization and macrophage recruitment. Moreover, exosomal circSHKBP1 promoted NSCLC cell growth, metastasis, and M2 infiltration in vivo. Thus, exosomal circSHKBP1 participated in the progression of NSCLC via the miR-1294/PKM2 axis. circSHKBP1 may be potential biomarker for the diagnosis and treatment of NSCLC.

Development of label-free fluorescent biosensor for the detection of kanamycin based on aptamer capped metal-organic framework.

The abuse of antibiotics has caused serious threat to human health, so it is of great significance to develop a simple and sensitive method for the detection of trace residues of antibiotics in the environment and food. Herein, a novel label-free fluorescent biosensing platform based on the fluorescence change of aptamers-capped zeolitic imidazolate framework-8 (ZIF-8) @ 2,2',2″,2‴-((ethene-1,1,2,2-tetrayltetrakis (benzene-4,1-diyl)) tetrakis (oxy)) tetraacetic acid (TPE) through ATP-assisted competitive coordination reaction was designed for such an end. ZIF-8@TPE/Aptamer (Apt) emits strong fluorescence at 425 nm in HEPES buffer due to the aggregation induced luminescence properties of TPE molecules in confined state. Once kanamycin was added, the conformation of aptamer capped on the surface of ZIF-8@TPE changes because of the specific recognition of kanamycin with aptamer, leading to the collapse of ZIF-8 and release of TPE, accompanied with a dramatic decrease of fluorescence intensity. Under the optimal conditions, a good correlation was obtained between the fluorescence intensity of ZIF-8@TPE/Apt and the concentration of kanamycin ranging from 10 to 103 ng/mL with a detection limit of 7.3 ng/mL. The satisfactory analytical performance of the assay for kanamycin detection suggests good prospect for its application in food safety analysis.

FeO x Derived from an Iron-Containing Polyoxometalate Boosting the Photocatalytic Water Oxidation Activity of Ti3+-Doped TiO2.

The development of efficient and stable catalyst systems using low-cost, abundant, and nontoxic materials is the primary demand for photocatalytic water oxidation. Distinguishing the true active species in a heterogeneous catalytic system is important for construction of efficient catalytic systems. Herein, hydrothermally synthesized Ti3+ self-doped TiO2, labeled as Ti3+/TiO2, was first used as a light absorber in a powder visible light-driven photocatalytic water oxidation reaction. When an iron-containing polyoxometalate Na27[Fe11(H2O)14(OH)2(W3O10)2(α-SbW9O33)6] (Fe11) was used as a cocatalyst, an amorphous layer of active species was wrapped outside the initial Ti3+/TiO2 nanorod and the in situ formed composite was labeled as F/Ti3+/TiO2. When the composite F/Ti3+/TiO2 was tested as a photocatalytic water oxidation catalyst, dramatically improved oxygen evolution performance was achieved. The composite F/Ti3+/TiO2 showed an oxygen evolution rate of 410 µmol/g/h, which was about 11-fold higher than that of prism Ti3+/TiO2. After 24 h of illumination, an O2 yield of 36.4% was achieved. The contrast experiments, high-resolution transmission electron microscopy, and X-ray photoelectron spectroscopy characterization demonstrated that FeO x is the true cocatalyst that enhanced the oxygen evolution activity of TiO2. A recycling experiment proved that the composite F/Ti3+/TiO2 has favorable stability in the oxygen production process.

Enhanced photocatalytic activity of BiVO4 coupled with iron-based complexes for water oxidation under visible light irradiation.

[Fe2(TPA)2(µ-O)Cl2]2+ (TPA = tris(2-pyridylmethyl)amine) was investigated as a pre-catalyst, and greatly enhanced the photocatalytic water oxidation activity of BiVO4. An extremely high oxygen yield of 99.1% and apparent quantum yield of 44.3% were obtained in the BiVO4-NaIO3 photocatalytic water oxidation system.

Amorphous Ni-Fe double hydroxide hollow nanocubes enriched with oxygen vacancies as efficient electrocatalytic water oxidation catalysts.

In this study, we present an ingenious design of Fe-modulated nickel hydroxide hollow nanocubes with a systematically engineered structure. The Ni0.75Fe0.25(OH)x sample exhibits good O2 evolution activity, which should be attributed to electronic modulation and abundant oxygen vacancies. Based on Pourbaix slope analysis, a two proton-one electron transfer is discovered in the amorphous Ni0.75Fe0.25(OH)x catalyst. Ni0.75Fe0.25(OH)x exhibits an enhanced performance for the electrocatalytic OER with a low overpotential of 310 mV at a current density of 10 mA cm-2.

An octanuclear Cu(ii) cluster with a bio-inspired Cu4O4 cubic fragment for efficient photocatalytic water oxidation.

An octanuclear Cu(ii) cluster [Cu8(dpk·OH)8(OAc)4](ClO4)4 (dpk·OH = the monoanion of the hydrated, gem-diol form of di-2-pyridyl ketone) that contains two Cu4O4 cubic fragments similar to the Mn4CaO5 cluster in photosystem II (PSII) was found to be an efficient catalyst for photocatalytic water oxidation. In the [Ru(bpy)3]2+/Na2S2O8 system, it afforded an optimal oxygen yield, turnover number (TON) and turnover frequency (TOF) of 35.6%, 178 and 3.6 s-1, respectively, which are the highest values amongst all of the Cu-based photocatalytic water oxidation catalysts (WOCs).

Catalysts Based on Earth-Abundant Metals for Visible Light-Driven Water Oxidation Reaction.

Exploration of water oxidation catalyst (WOC) with excellent performance is the key for the overall water splitting reaction, which is a feasible strategy to convert solar energy to chemical energy. Although some compounds composed of noble metals, mainly Ru and Ir, have been reported to catalyze water oxidation with high efficiency, catalysts based on low-cost and earth-abundant transition metals are essential for realizing economical and large-scale light-driven water splitting. Various WOCs containing earth-abundant metals (mainly Mn, Fe, Co, Ni, Cu) have been utilized for visible light-driven water oxidation in recent years. In this Personal Account, we summarize our recent developments in WOCs based on earth-abundant transition metals including polyoxometalates (POMs), metal oxides or bimetal oxides, and metal complexes containing multidentate ligand scaffolds for visible light-driven water oxidation reaction.

Homogeneous electrocatalytic water oxidation at neutral pH by a robust trinuclear copper(ii)-substituted polyoxometalate.

[(α-SbW9O33)2Cu3(H2O)3]12- (1) was tested as the first copper-containing polyoxometalate catalyst for O2 production via electrocatalytic water oxidation at a neutral pH. Multiple lines of experimental evidence confirm that catalytic water oxidation by 1 takes place in the absence of any heterogeneous species generated in situ. The catalytic capabilities of 1 and equal amounts of CuCl2 are completely different for electrocatalytic water oxidation behavior.

Efficient light-driven water oxidation catalyzed by a mononuclear cobalt(III) complex.

A mononuclear Co complex, [Co(III)(DPK·OH)2]Cl (DPK = di(2-pyridyl)ketone), was synthesized and reported as a stable catalyst in visible light-driven water oxidation. The optimum turnover number (TON) of complex 1 is 1610, which, to the best of our knowledge, is the largest TON among metal-organic complexes for photocatalytic water oxidation.

MnO2 spontaneously coated on carbon nanotubes for enhanced water oxidation.

δ-MnO2/o-MWCNTs were synthesized by coating MnO2 spontaneously on oxidized multi-walled carbon nanotubes via simple immersion of the o-MWCNTs into KMnO4 solution. This catalyst comprising the outer region of catalytic MnO2 and the inner region of highly conductive o-MWCNTs enhanced photocatalytic water oxidation activity.

[Root canal therapy of resinified teeth with surgical operating microscope and ultrasonic instruments].

PURPOSE: To evaluate the role of surgical operating microscope and ultrasonic instruments in endodontic treatment of patients who underwent previous resinifying therapy. METHODS: 63 premolars and molars that had been treated with resinifying therapy before were selected for root canal therapy. The coronal portion of resinified root canals were negotiated with ultrasonic instruments under surgical operating microscope, and the apical portion was managed with small size hand files and 15% EDTA. The root canals of all cases were shaped by Nickel-Titanium rotary instruments Hero 642, and obturated with lateral condensation technique. The negotiation of root canal system, instrument fracture, alterations of canal morphology, and operation time were recorded. The efficiency of preparation and obturation was analyzed by radiographs before and after treatment. RESULTS: The root canals of 54 teeth were negotiated, enlarged and obturated, with a success rate of 85.7%. No complications were found, such as vertical fracture, ledge, perforation and instrument separation. Good result of treatment was achieved in the 54 cases. CONCLUSIONS: The use of surgical operating microscope and ultrasonic instruments is proved to be effective in negotiation of coronal portion of the resinified root canals. Nevertheless, the use of ultrasonic instruments in apical or curved portion of root canals is not encouraged.