Stochastic neuro-fuzzy system implemented in memristor crossbar arrays.

Neuro-symbolic artificial intelligence has garnered considerable attention amid increasing industry demands for high-performance neural networks that are interpretable and adaptable to previously unknown problem domains with minimal reconfiguration. However, implementing neuro-symbolic hardware is challenging due to the complexity in symbolic knowledge representation and calculation. We experimentally demonstrated a memristor-based neuro-fuzzy hardware based on TiN/TaOx/HfOx/TiN chips that is superior to its silicon-based counterpart in terms of throughput and energy efficiency by using array topological structure for knowledge representation and physical laws for computing. Intrinsic memristor variability is fully exploited to increase robustness in knowledge representation. A hybrid in situ training strategy is proposed for error minimizing in training. The hardware adapts easier to a previously unknown environment, achieving ~6.6 times faster convergence and ~6 times lower error than deep learning. The hardware energy efficiency is over two orders of magnitude greater than field-programmable gate arrays. This research greatly extends the capability of memristor-based neuromorphic computing systems in artificial intelligence.

A composite semiparametric homogeneity test for the distributions of multigroup interval-bounded longitudinal data.

Motivated by comparing the distribution of longitudinal quality of life (QoL) data among different treatment groups from a cancer clinical trial, we propose a semiparametric test statistic for the homogeneity of the distributions of multigroup longitudinal measurements, which are bounded in a closed interval with excess observations taking the boundary values. Our procedure is based on a three-component mixed density ratio model and a composite empirical likelihood for the longitudinal data taking values inside the interval. A nonparametric bootstrap method is applied to calculate the p-value of the proposed test. Simulation studies are conducted to evaluate the proposed procedure, which show that the proposed test is effective in controlling type I errors and more powerful than the procedure which ignores the values on the boundaries. It is also robust to the model mispecification than the parametric test. The proposed procedure is also applied to compare the distributions of the scores of Physical Function subscale and Global Heath Status between the patients randomized to two treatment groups in a cancer clinical trial.

Preorganized Internal Electric Field Promotes a Double-Displacement Mechanism for the Adenine Excision Reaction by Adenine DNA Glycosylase.

Adenine DNA glycosylase (MutY) is a monofunctional glycosylase, removing adenines (A) misinserted opposite 8-oxo-7,8-dihydroguanine (OG), a common product of oxidative damage to DNA. Through multiscale calculations, we decipher a detailed adenine excision mechanism of MutY that is consistent with all available experimental data, involving an initial protonation step and two nucleophilic displacement steps. During the first displacement step, N-glycosidic bond cleavage is accompanied by the attack of the carboxylate group of residue Asp144 at the anomeric carbon (C1'), forming a covalent glycosyl-enzyme intermediate to stabilize the fleeting oxocarbenium ion. After departure of the excised base, water nucleophiles can be recruited to displace Asp144, completing the catalytic cycle with retention of stereochemistry at the C1' position. The two displacement reactions are found to mostly involve the movement of the oxocarbenium ion, occurring with large charge reorganization and thus sensitive to the internal electric field (IEF) exerted by the polar protein environment. Intriguingly, we find that the negatively charged carboxylate group is a good nucleophile for the oxocarbenium ion, yet an unactivated water molecule is not, and that the electric field catalysis strategy is used by the enzyme to enable its unique double-displacement reaction mechanism. A strong IEF, pointing toward 5' direction of the substrate sugar ring, greatly facilitates the second displacement reaction at the expense of elevating the barrier of the first one, thereby allowing both reactions to occur. These findings not only increase our understanding of the strategies used by DNA glycosylases to repair DNA lesions, but also have important implications for how internal/external electric field can be applied to modulate chemical reactions.

Detection of Interaction Effects in a Nonparametric Concurrent Regression Model.

Many methods have been developed to study nonparametric function-on-function regression models. Nevertheless, there is a lack of model selection approach to the regression function as a functional function with functional covariate inputs. To study interaction effects among these functional covariates, in this article, we first construct a tensor product space of reproducing kernel Hilbert spaces and build an analysis of variance (ANOVA) decomposition of the tensor product space. We then use a model selection method with the L1 criterion to estimate the functional function with functional covariate inputs and detect interaction effects among the functional covariates. The proposed method is evaluated using simulations and stroke rehabilitation data.

A threshold longitudinal Tobit quantile regression model for identification of treatment-sensitive subgroups based on interval-bounded longitudinal measurements and a continuous covariate.

Identification of a subgroup of patients who may be sensitive to a specific treatment is an important problem in precision medicine. This article considers the case where the treatment effect is assessed by longitudinal measurements, such as quality of life scores assessed over the duration of a clinical trial, and the subset is determined by a continuous baseline covariate, such as age and expression level of a biomarker. Recently, a linear mixed threshold regression model has been proposed but it assumes the longitudinal measurements are normally distributed. In many applications, longitudinal measurements, such as quality of life data obtained from answers to questions on a Likert scale, may be restricted in a fixed interval because of the floor and ceiling effects and, therefore, may be skewed. In this article, a threshold longitudinal Tobit quantile regression model is proposed and a computational approach based on alternating direction method of multipliers algorithm is developed for the estimation of parameters in the model. In addition, a random weighting method is employed to estimate the variances of the parameter estimators. The proposed procedures are evaluated through simulation studies and applications to the data from clinical trials.

Reply to Correspondence on "Structural Insight into the Catalytic Mechanism of the Endoperoxide Synthase FtmOx1''.

The high-resolution X-ray crystal structure of the ternary complex FtmOx1 ⋅ 2OG ⋅ fumitremorgin B and the catalytic mechanism were recently reported by us (DOI 10.1002/anie.202112063). In their Correspondence, Zhang, Costello, Liu et al. criticize our work in several aspects. Herein, we address these questions one by one. These structural clarifications and new computational results further support the CarC-like mechanistic model.

Unveiling orientation dependence of anisotropic plasticity in polycrystalline copper by nanoindentation.

The mechanical properties of crystalline materials are influenced by their deformation behavior, which is associated with their microstructural characteristics. Specifically, crystallographic orientation greatly affects the microscale plastic deformation of individual grains. In this study, experiments and finite element simulations of Berkovich nanoindentations are conducted to investigate the impact of crystallographic orientation in polycrystalline copper. A crystal plasticity constitutive model is developed for copper materials, which accurately captures their indentation mechanical response. The results showed that the indentation behavior of polycrystalline copper exhibits a high degree of anisotropy due to significant variation in slip systems for different crystallographic orientations. This results in different mechanical responses of individual grains and distinct material pileup morphologies on the indented surface. Additionally, the study revealed that crystallographic orientation plays a critical role in determining the indentation size effect. These findings have important implications for the design of materials where plasticity is a crucial factor.

Clinical value of anterior segment optical coherence tomography­assisted Wuerzburg bleb classification system for bleb assessment following trabeculectomy.

The Wuerzburg bleb classification system (WBCS) is an established tool for evaluating filtering blebs, while anterior segment optical coherence tomography (ASOCT) provides detailed information on inner bleb structure. The present study aimed to investigate the clinical value of ASOCT-assisted WBCS following trabeculectomy (TRAB). The present prospective, observational study included eyes that underwent TRAB. Bleb assessments using the WBCS were based on the image acquired by ASOCT. The WBCS scores were assessed at postoperative week 2 and postoperative month (POM) 1, 2, 3, 6 and 12. The surgical outcomes at 1 year were determined as success or failure. Spearman's analysis explored the correlation of WBCS scores with intraocular pressure (IOP) and surgical outcome. A total of 32 eyes from 32 patients were included in the present study. The WBCS total score significantly correlated with IOP at POM 1, 2, 3, 6 and 12 (P<0.05). For single parameters, microcysts demonstrated a good correlation with IOP at POM 1, 2, 3, 6 and 12 (P<0.05). The WBCS total score correlated well with surgical outcome at POM 2, 3, 6 and 12 (P≤0.005). Microcysts, vascularity and encapsulation significantly correlated with surgical outcomes (P<0.05). The results of the present study suggest that ASOCT-assisted WBCS is a simple and effective measurement system for blebs after TRAB in clinical practice, which correlates well with IOP and surgical outcomes. Blebs with a higher WBCS total score and microcysts score in the early postoperative period, such as at POM 2 and 3, are less likely to have surgical failure in the long term.

A combination of TEXTCNN model and Bayesian classifier for microblog sentiment analysis.

More and more individuals are paying attention to the research on the emotional information found in micro-blog comments. TEXTCNN is growing rapidly in the short text space. However, because the training model of TEXTCNN model itself is not very extensible and interpretable, it is difficult to quantify and evaluate the relative importance of features and themselves. At the same time, word embedding can't solve the problem of polysemy at one time. This research suggests a microblog sentiment analysis method based on TEXTCNN and Bayes that addresses this flaw. First, the word embedding vector is obtained by word2vec tool, and based on the word vector, the ELMo word vector integrating contextual features and different semantic features is generated by ELMo model. Second, the local features of ELMo word vector are extracted from multiple angles by using the convolution layer and pooling layer of TEXTCNN model. Finally, the training task of emotion data classification is completed by combining Bayes classifier. On the Stanford Sentiment Classification Corpus data set SST (Stanford Sentiment Classification Corpus Data bank), the experimental findings demonstrate that the model in this paper is compared with TEXTCNN, LSTM, and LSTM-TEXTCNN models. The Accuracy, Precision, Recall, and F1-score of the experimental results of this research have all greatly increased. Their values are respectively 0.9813, 0.9821, 0.9804 and 0.9812, which are superior to other comparison models and can be effectively used for emotional accurate analysis and identification of events in microblog emotion analysis.

How the Conformational Movement of the Substrate Drives the Regioselective C-N Bond Formation in P450 TleB: Insights from Molecular Dynamics Simulations and Quantum Mechanical/Molecular Mechanical Calculations.

P450 TleB catalyzes the oxidative cyclization of the dipeptide N-methylvalyl-tryptophanol into indolactam V through selective intramolecular C-H bond amination at the indole C4 position. Understanding its catalytic mechanism is instrumental for the engineering or design of P450-catalyzed C-H amination reactions. Using multiscale computational methods, we show that the reaction proceeds through a diradical pathway, involving a hydrogen atom transfer (HAT) from N1-H to Cpd I, a conformational transformation of the substrate radical species, and a second HAT from N13-H to Cpd II. Intriguingly, the conformational transformation is found to be the key to enabling efficient and selective C-N coupling between N13 and C4 in the subsequent diradical coupling reaction. The underlined conformational transformation is triggered by the first HAT, which proceeds with an energy-demanding indole ring flip and is followed by the facile approach of the N13-H group to Cpd II. Detailed analysis shows that the internal electric field (IEF) from the protein environment plays key roles in the transformation process, which not only provides the driving force but also stabilizes the flipped conformation of the indole radical. Our simulations provide a clear picture of how the P450 enzyme can smartly modulate the selective C-N coupling reaction. The present findings are in line with all available experimental data, highlighting the crucial role of substrate dynamics in controlling this highly valuable reaction.

Novel Cuproptosis-Related Gene Signature for Precise Identification of High-Risk Populations in Low-Grade Gliomas.

Background: Patients with low-grade glioma (LGG) have wildly varying average lifespans. However, no effective way exists for identifying LGG patients at high risk. Cuproptosis is a recently described form of cell death associated with the abnormal aggregation of lipid acylated proteins. Few investigations have been conducted on cuproptosis-associated genes and LGG thus far. The purpose of this research is to establish a predictive model for cuproptosis-related genes in order to recognise LGG populations at high risk. Methods: We analyzed 926 LGGs from 2 public datasets, all of which were RNA sequencing datasets. On the basis of immune scores, the LGG population was split into different risk categories with X-tile. LASSO and Cox regressions were employed to filter cuproptosis-associated genes and construct prediction models. The accuracy of the predictive models was measured by using TCGA internal validation set and the CGGA external validation set. In addition, LGG immune cell infiltration was viewed using CIBERSORT and ssGSEA algorithms and correlation analysis was done with cuproptosis-related genes. Finally, immune escape capacity in LGG low- and high-risk groups was evaluated using the TIDE method. Results: The prediction model constructed by four cuproptosis-related genes was used to identify high-risk populations in LGG. It performed well in training and all validation sets (AUC values: 0.915, 0.894, and 0.774). Meanwhile, we found that FDX1 and ATP7A in the four cuproptosis-related genes were positively correlated with immune response, while GCSH and ATP7B were opposite. In addition, the high immune score group had a lower TIDE score, indicating that their immune escape capacity was weak. Conclusion: High-risk individuals in LGG can be reliably identified by the model based on cuproptosis-related genes. Furthermore, cuproptosis is closely related to tumor immune microenvironment, which gives a novel approach to treating LGG.

Coordination Switch Drives Selective C-S Bond Formation by the Non-Heme Sulfoxide Synthases.

The non-heme iron ergothioneine synthase (EgtB) is a sulfoxide synthase that catalyzes oxidative C-S bond formation in the synthesis of ergothioneine, which plays roles against oxidative stress in cells. Despite extensive experimental and computational studies of the catalytic mechanisms of EgtB, the root causes for the selective C-S bond formation remain elusive. Using quantum mechanics/molecular mechanics (QM/MM) calculations, we show herein that a coordination switch of the sulfoxide intermediate is involved in the catalysis of the non-heme iron EgtB. This coordination switch from the S to the O atom is driven by the S/π electrostatic interactions, which efficiently promotes the observed stereoselective C-S bond formation while bypassing cysteine dioxygenation. The present mechanism is in agreement with all available experimental data, including regioselectivity, stereoselectivity and KIE results. This match underscores the critical role of coordination switching in the catalysis of non-heme enzymes.

RTPN method for cooperative interception of maneuvering target by gun-launched UAV.

According to the actual situation of gun-launched UAV intercepting "Low-slow-small" target and the specific maneuverability of gun-launched UAV, an enhanced real proportion guidance law (RTPN) guidance interception method is designed. The traditional RTPN method does not consider the saturation overload limit and the capture region of arbitrary maneuvering target. In addition, aiming at the measurement error and the dynamic response delay of the gun-launched UAV during the interception, the EKF data fusion track prediction algorithm is proposed. Simulation results show that the proposed method can effectively solve the problem.

Structural Insight into the Catalytic Mechanism of the Endoperoxide Synthase FtmOx1.

The 2-oxoglutarate (2OG)-dependent non-heme enzyme FtmOx1 catalyzes the endoperoxide biosynthesis of verruculogen. Although several mechanistic studies have been carried out, the catalytic mechanism of FtmOx1 is not well determined owing to the lack of a reliable complex structure of FtmOx1 with fumitremorgin B. Herein we provide the X-ray crystal structure of the ternary complex FtmOx1⋅2OG⋅fumitremorgin B at a resolution of 1.22 Å. Our structures show that the binding of fumitremorgin B induces significant compression of the active pocket and that Y68 is in close proximity to C26 of the substrate. Further MD simulation and QM/MM calculations support a CarC-like mechanism, in which Y68 acts as the H atom donor for quenching the C26-centered substrate radical. Our results are consistent with all available experimental data and highlight the importance of accurate complex structures in the mechanistic study of enzymatic catalysis.

Estimation and model selection for nonparametric function-on-function regression.

Regression models with a functional response and functional covariate have received significant attention recently. While various nonparametric and semiparametric models have been developed, there is an urgent need for model selection and diagnostic methods. In this article, we develop a unified framework for estimation and model selection in nonparametric function-on-function regression. We propose a general nonparametric functional regression model with the model space constructed through smoothing spline analysis of variance (SS ANOVA). The proposed model reduces to some of the existing models when selected components in the SS ANOVA decomposition are eliminated. We propose new estimation procedures under either L 1 or L 2 penalty and show that the combination of the SS ANOVA decomposition and L 1 penalty provides powerful tools for model selection and diagnostics. We establish consistency and convergence rates for estimates of the regression function and each component in its decomposition under both the L 1 and L 2 penalties. Simulation studies and real examples show that the proposed methods perform well. Technical details and additional simulation results are available in online supplementary materials.

Tumor microenvironment-triggered in situ cancer vaccines inducing dual immunogenic cell death for elevated antitumor and antimetastatic therapy.

Cancer vaccines are made from tumor-specific antigens, which are then injected back into the body to activate immune responses for cancer immunotherapy. Despite the high specificity and therapeutic efficiency, the vaccine has huge challenges such as complex preparation process, expensiveness and limited durational effects. Herein, a strategy to develop in situ cancer vaccines by enhancing the immunomodulatory effects for immunogenic cell death (ICD) is presented. First, amorphous iron oxide-packaged oxaliplatin (AIOoxp) nanoprodrugs with a high drug loading efficiency of 12.9% were prepared. By utilizing tumor microenvironment (TME) as an endogenous stimulus, this inorganic nanoprodrug can effectively realize TME-responsive combined treatments of chemotherapy and chemodynamic therapy (CDT), and thus achieve dual and precise ICD induction. Further, in vivo immunopotentiation performances further prove that this enhanced ICD effect is able to efficiently promote the maturity of dendritic cells (DCs), T cell activation and correlative cytokine secretion. Furthermore, the obtained nanoprodrugs not only reduce systemic toxicities of Oxp and achieve T1/T2 magnetic resonance imaging (MRI), but also dramatically inhibit tumor growth and lung metastasis. We believe that the design of in situ cancer vaccines by enhancing the ICD effects will inspire future studies on cancer vaccines.

Conformational Motion of Ferredoxin Enables Efficient Electron Transfer to Heme in the Full-Length P450TT.

Cytochrome P450 monooxygenases (P450s) are versatile biocatalysts used in natural products biosynthesis, xenobiotic metabolisms, and biotechnologies. In P450s, the electrons required for O2 activation are supplied by NAD(P)H through stepwise electron transfers (ETs) mediated by redox partners. While much is known about the machinery of the catalytic cycle of P450s, the mechanisms of long-range ET are largely unknown. Very recently, the first crystal structure of full-length P450TT was solved. This enables us to decipher the interdomain ET mechanism between the [2Fe-2S]-containing ferredoxin and the heme, by use of molecular dynamics simulations. In contrast to the "distal" conformation characterized in the crystal structure where the [2Fe-2S] cluster is ∼28 Šaway from heme-Fe, our simulations demonstrated a "proximal" conformation of [2Fe-2S] that is ∼17 Š[and 13.7 Šedge-to-edge] away from heme-Fe, which may enable the interdomain ET. Key residues involved in ET pathways and interdomain complexation were identified, some of which have already been verified by recent mutation studies. The conformational transit of ferredoxin between "distal" and "proximal" was found to be controlled mostly by the long-range electrostatic interactions between the ferredoxin domain and the other two domains. Furthermore, our simulations show that the full-length P450TT utilizes a flexible ET pathway that resembles either P450Scc or P450cam. Thus, this study provides a uniform picture of the ET process between reductase domains and heme domain.

The molecular mechanism of P450-catalyzed amination of the pyrrolidine derivative of lidocaine: insights from multiscale simulations.

Nitrogen heterocycles are key and prevalent motifs in drugs. Evolved variants of cytochrome P450BM3 (CYP102A1) from Bacillus megaterium employ high-valent oxo-iron(iv) species to catalyze the synthesis of imidazolidine-4-ones via an intramolecular C-H amination. Herein, we use multi-scale simulations, including classical molecular dynamics (MD) simulations, quantum mechanical/molecular mechanical (QM/MM) calculations and QM calculations, to reveal the molecular mechanism of the intramolecular C-H amination of the pyrrolidine derivative of lidocaine bearing cyclic amino moieties catalyzed by the variant RP/FV/EV of P450BM3, which bears five mutations compared to wild type. Our calculations show that overall catalysis includes both the enzymatic transformation in P450 and non-enzymatic transformation in water solution. The enzymatic transformation involves the exclusive hydroxylation of the C-H bond of the pyrrolidine derivative of lidocaine, leading to the hydroxylated intermediate, during which the substrate radical would be bypassed. The following dehydration and C-N coupling reactions are found to be much favored in aqueous situation compared to that in the non-polar protein environment. The present findings expand our understanding of the P450-catalyzed C(sp3)-H amination reaction.

How Oxygen Binding Enhances Long-Range Electron Transfer: Lessons From Reduction of Lytic Polysaccharide Monooxygenases by Cellobiose Dehydrogenase.

Long-range electron transfer (ET) in metalloenzymes is a general and fundamental process governing O2 activation and reduction. Lytic polysaccharide monooxygenases (LPMOs) are key enzymes for the oxidative cleavage of insoluble polysaccharides, but their reduction mechanism by cellobiose dehydrogenase (CDH), one of the most commonly used enzymatic electron donors, via long-range ET is still an enigma. Using multiscale simulations, we reveal that interprotein ET between CDH and LPMO is mediated by the heme propionates of CDH and solvent waters. We also show that oxygen binding to the copper center of LPMO is coupled with the long-range interprotein ET. This process, which is spin-regulated and enhanced by the presence of O2 , directly leads to LPMO-CuII -O2- , bypassing the formation of the generally assumed LPMO-CuI species. The uncovered ET mechanism rationalizes experimental observations and might have far-reaching implications for LPMO catalysis as well as the O2 - or CO-binding-enhanced long-range ET processes in other metalloenzymes.

Redox responsive paclitaxel dimer for programmed drug release and selectively killing cancer cells.

Redox stimulus responsive drug delivery systems have been widely investigated and proved to be promising prospects for efficient cancer therapy due to the abnormal high level of reactive oxygen species and glutathione in tumor microenvironment. Herein, three paclitaxel dimers (named as PTX2-R, R = S, Se and Te) bridged with alkyl sulfide, selenide or telluride are synthesized. These dimers can self-assemble into stable uniform nanoparticles (named as PTX2-R NPs, R = S, Se and Te) with impressively high drug loading. As expected, sulfur/selenium/tellurium bonds exhibit different redox responsiveness, thereby affecting the drug release and cytotoxicity. Of note, tellurium bridged paclitaxel dimer shows ultra-sensitivity to hydrogen peroxide, which rapidly cleaves into two paclitaxel under the subsequent dithiothreitol stimulation. Our findings provide deep insight into the redox sensitivity of chalcogenide elements and offer the rational design strategies to biologically redox condition for programmed drug release.