Evolutionary Multiobjective Molecule Optimization in an Implicit Chemical Space.

Optimization techniques play a pivotal role in advancing drug development, serving as the foundation of numerous generative methods tailored to efficiently design optimized molecules derived from existing lead compounds. However, existing methods often encounter difficulties in generating diverse, novel, and high-property molecules that simultaneously optimize multiple drug properties. To overcome this bottleneck, we propose a multiobjective molecule optimization framework (MOMO). MOMO employs a specially designed Pareto-based multiproperty evaluation strategy at the molecular sequence level to guide the evolutionary search in an implicit chemical space. A comparative analysis of MOMO with five state-of-the-art methods across two benchmark multiproperty molecule optimization tasks reveals that MOMO markedly outperforms them in terms of diversity, novelty, and optimized properties. The practical applicability of MOMO in drug discovery has also been validated on four challenging tasks in the real-world discovery problem. These results suggest that MOMO can provide a useful tool to facilitate molecule optimization problems with multiple properties.

Adaptive Fuzzy Integral Sliding Mode Cooperative Control Based on Time-Delay Estimation for Free-Floating Close-Chain Manipulators.

Space manipulators are expected to perform more challenging missions in on-orbit service (OOS) systems, but there are some unique characteristics that are not found on ground-based robots, such as dynamic coupling between space bases and manipulators, limited fuel supply, and working with unfixed bases. This paper focuses on trajectory-tracking control and internal force control for free-floating close-chain manipulators. First, the kinematics and dynamics of free-floating close-chain manipulators are given using the momentum conservation and spatial operator algebra (SOA) methodologies, respectively. Furthermore, an adaptive fuzzy integral sliding mode controller (AFISMC) based on time delay estimation (TDE) was designed for trajectory-tracking control, and a proportional-integral (PI) control strategy was adopted for internal force control. The global asymptotic stability of the proposed controller was proven by using the Lyapunov methodology. Three cases were conducted to verify the efficiency of the controller by using numerical simulations on two six-link manipulators with a free-floating base. The controller presents the desired tracking capability.

AMPFLDAP: Adaptive Message Passing and Feature Fusion on Heterogeneous Network for LncRNA-Disease Associations Prediction.

Exploration of the intricate connections between long noncoding RNA (lncRNA) and diseases, referred to as lncRNA-disease associations (LDAs), plays a pivotal and indispensable role in unraveling the underlying molecular mechanisms of diseases and devising practical treatment approaches. It is imperative to employ computational methods for predicting lncRNA-disease associations to circumvent the need for superfluous experimental endeavors. Graph-based learning models have gained substantial popularity in predicting these associations, primarily because of their capacity to leverage node attributes and relationships within the network. Nevertheless, there remains much room for enhancing the performance of these techniques by incorporating and harmonizing the node attributes more effectively. In this context, we introduce a novel model, i.e., Adaptive Message Passing and Feature Fusion (AMPFLDAP), for forecasting lncRNA-disease associations within a heterogeneous network. Firstly, we constructed a heterogeneous network involving lncRNA, microRNA (miRNA), and diseases based on established associations and employing Gaussian interaction profile kernel similarity as a measure. Then, an adaptive topological message passing mechanism is suggested to address the information aggregation for heterogeneous networks. The topological features of nodes in the heterogeneous network were extracted based on the adaptive topological message passing mechanism. Moreover, an attention mechanism is applied to integrate both topological and semantic information to achieve the multimodal features of biomolecules, which are further used to predict potential LDAs. The experimental results demonstrated that the performance of the proposed AMPFLDAP is superior to seven state-of-the-art methods. Furthermore, to validate its efficacy in practical scenarios, we conducted detailed case studies involving three distinct diseases, which conclusively demonstrated AMPFLDAP's effectiveness in the prediction of LDAs.

A domain-label-guided translation model for molecular optimization.

Molecular optimization, which aims to improve molecular properties by modifying complex molecular structures, is a crucial and challenging task in drug discovery. In recent years, translation models provide a promising way to transform low-property molecules to high-property molecules, which enables molecular optimization to achieve remarkable progress. However, most existing models require matched molecular pairs, which are prone to be limited by the datasets. Although some models do not require matched molecular pairs, their performance is usually sacrificed due to the lack of useful supervising information. To address this issue, a domain-label-guided translation model is proposed in this paper, namely DLTM. In the model, the domain label information of molecules is exploited as a control condition to obtain different embedding representations, enabling the model to generate diverse molecules. Besides, the model adopts a classifier network to identify the property categories of transformed molecules, guiding the model to generate molecules with desired properties. The performance of DLTM is verified on two optimization tasks, namely the quantitative estimation of drug-likeness and penalized logP. Experimental results show that the proposed DLTM is superior to the compared baseline models.

Genomic insights into the evolution of flavonoid biosynthesis and O-methyltransferase and glucosyltransferase in Chrysanthemum indicum.

Flavonoids are a class of secondary metabolites widely distributed in plants. Regiospecific modification by methylation and glycosylation determines flavonoid diversity. A rare flavone glycoside, diosmin (luteolin-4'-methoxyl-7-O-glucosyl-rhamnoside), occurs in Chrysanthemum indicum. How Chrysanthemum plants evolve new biosynthetic capacities remains elusive. Here, we assemble a 3.11-Gb high-quality C. indicum genome with a contig N50 value of 4.39 Mb and annotate 50,606 protein-coding genes. One (CiCOMT10) of the tandemly repeated O-methyltransferase genes undergoes neofunctionalization, preferentially transferring the methyl group to the 4'-hydroxyl group of luteolin with ortho-substituents to form diosmetin. In addition, CiUGT11 (UGT88B3) specifically glucosylates 7-OH group of diosmetin. Next, we construct a one-pot cascade biocatalyst system by combining CiCOMT10, CiUGT11, and our previously identified rhamnosyltransferase, effectively producing diosmin with over 80% conversion from luteolin. This study clarifies the role of transferases in flavonoid diversity and provides important gene elements essential for producing rare flavone.

Interval Type-2 Fuzzy PID Controller Using Disassembled Gradational Optimization.

This paper presents an interval type-2 fuzzy proportional-integral-derivative (IT2F-PID) controller that is designed using a new disassembled gradational optimization (D-GO) method. A PID controller is first optimized using the D-GO method and then connected to a type-1 fuzzy logic system (T1-FLS). The parameters of the T1-FLS are optimized, and the T1-FLS is blurred into the interval type-2 fuzzy logic system (IT2-FLS). Finally, the IT2F-PID controller is formed. The proposed method is compared with the concurrent and general optimization methods. The simulation results show that the D-GO method reduces the optimization time by over 90% compared with the general method, and decreases the integral-of-time-absolute-error (ITAE) by 30%. Beyond that, compared with the concurrent optimization method, the D-GO method reduces time by over 25%, and the ITAE value by about 95%. In the normal case, model uncertainty, target uncertainty, and external disturbance, the control ability of the IT2F-PID controller designed using the D-GO method is verified via simulations using a nonlinear forced closed-loop system. The results show that the overshoot is reduced by 80% and the fluctuation is reduced by 67% compared with a traditional PID controller and an IT2F-PID controller built using the general method.

Design and analysis of the power-trigonometric function-shaped flexure hinges.

In this paper, a generalized flexure hinge model, that is, power-trigonometric function-shaped flexure hinges (PTFHs), is proposed. The power function and trigonometric function in the curve function are changed, which obtains different notch types of flexure hinges to meet the needs of flexure hinges in different scenarios. For the flexure hinge model, the notch curve equation of the hinge is presented first, and the influence of the degree of power function, degree of trigonometric function, and other parameters on the structure of the curve is analyzed. Then, the compliance and rotation precision equations of the flexure hinge are derived based on Castigliano's second theorem. Both equations are verified using the finite element method and achieve errors of less than 8.5%. Then, based on the flexure hinge equation, the influence of the size parameters on the compliance and rotation precision of the hinge is analyzed, and a new comparison method is proposed. Parameter ß is defined to analyze the influence of five parameters on ß. Through the comparison of PTFHs and three commonly used flexure hinges, the results prove that the proposed PTFHs have better comprehensive performance. Then, the flexure hinge is statically analyzed. Finally, a test system for flexure hinges is established to verify the performance of the model.

Bidirectional Jump Point Search Path-Planning Algorithm Based on Electricity-Guided Navigation Behavior of Electric Eels and Map Preprocessing.

The electric eel has an organ made up of hundreds of electrocytes, which is called the electric organ. This organ is used to sense and detect weak electric field signals. By sensing electric field signals, the electric eel can identify changes in their surroundings, detect potential prey or other electric eels, and use it for navigation and orientation. Path-finding algorithms are currently facing optimality challenges such as the shortest path, shortest time, and minimum memory overhead. In order to improve the search performance of a traditional A* algorithm, this paper proposes a bidirectional jump point search algorithm (BJPS+) based on the electricity-guided navigation behavior of electric eels and map preprocessing. Firstly, a heuristic strategy based on the electrically induced navigation behavior of electric eels is proposed to speed up the node search. Secondly, an improved jump point search strategy is proposed to reduce the complexity of jump point screening. Then, a new map preprocessing strategy is proposed to construct the relationship between map nodes. Finally, path planning is performed based on the processed map information. In addition, a rewiring strategy is proposed to reduce the number of path inflection points and path length. The simulation results show that the proposed BJPS+ algorithm can generate optimal paths quickly and with less search time when the map is known.

Genome-wide identification and functional characterization of borneol dehydrogenases in Wurfbainia villosa.

MAIN CONCLUSION: Genome-wide screening of short-chain dehydrogenases/reductases (SDR) family reveals functional diversification of borneol dehydrogenase (BDH) in Wurfbainia villosa. Wurfbainia villosa is an important medicinal plant, the fruits of which accumulate abundant terpenoids, especially bornane-type including borneol and camphor. The borneol dehydrogenase (BDH) responsible for the conversion of borneol to camphor in W. villosa remains unknown. BDH is one member of short-chain dehydrogenases/reductases (SDR) family. Here, a total of 115 classical WvSDR genes were identified through genome-wide screening. These WvSDRs were unevenly distributed on different chromosomes. Seven candidate WvBDHs based on phylogenetic analysis and expression levels were selected for cloning. Of them, four BDHs can catalyze different configurations of borneol and other monoterpene alcohol substrates to generate the corresponding oxidized products. WvBDH1 and WvBDH2, preferred (+)-borneol to (-)-borneol, producing the predominant ( +)-camphor. WvBDH3 yielded approximate equivalent amount of (+)-camphor and (-)-camphor, in contrast, WvBDH4 generated exclusively (+)-camphor. The metabolic profiles of the seeds showed that the borneol and camphor present were in the dextrorotatory configuration. Enzyme kinetics and expression pattern in different tissues suggested WvBDH2 might be involved in the biosynthesis of camphor in W. villosa. All results will increase the understanding of functional diversity of BDHs.

Tandem duplication and sub-functionalization of clerodane diterpene synthase originate the blooming of clerodane diterpenoids in Scutellaria barbata.

Scutellaria barbata is a traditional Chinese herb medicine and a major source of bioactive clerodane diterpenoids. However, barely clerodanes have been isolated from the closely related S. baicalensis. Here we assembled a chromosome-level genome of S. barbata and identified three class II clerodane diterpene synthases (SbarKPS1, SbarKPS2 and SbaiKPS1) from these two organisms. Using in vitro and in vivo assays, SbarKPS1 was characterized as a monofunctional (-)-kolavenyl diphosphate synthases ((-)-KPS), while SbarKPS2 and SbaiKPS1 produced major neo-cleroda-4(18),13E-dienyl diphosphate with small amount of (-)-KPP. SbarKPS1 and SbarKPS2 shared a high protein sequence identity and formed a tandem gene pair, indicating tandem duplication and sub-functionalization probably led to the evolution of monofunctional (-)-KPS in S. barbata. Additionally, SbarKPS1 and SbarKPS2 were primarily expressed in the leaves and flowers of S. barbata, which was consistent with the distribution of major clerodane diterpenoids scutebarbatine A and B. In contrast, SbaiKPS1 was barely expressed in any tissue of S. baicalensis. We further explored the downstream class I diTPS by functional characterizing of SbarKSL3 and SbarKSL4. Unfortunately, no dephosphorylated product was detected in the coupled assays with SbarKSL3/KSL4 and four class II diTPSs (SbarKPS1, SbarKPS2, SbarCPS2 and SbarCPS4) when a phosphatase inhibitor cocktail was included. Co-expression of SbarKSL3/KSL4 with class II diTPSs in yeast cells did not increase the yield of the corresponding dephosphorylated products, either. Together, these findings elucidated the involvement of two class II diTPSs in clerodane biosynthesis in S. barbata, while the class I diTPS is likely not responsible for the subsequent dephosphorylation step.

Biologically Inspired Complete Coverage Path Planning Algorithm Based on Q-Learning.

Complete coverage path planning requires that the mobile robot traverse all reachable positions in the environmental map. Aiming at the problems of local optimal path and high path coverage ratio in the complete coverage path planning of the traditional biologically inspired neural network algorithm, a complete coverage path planning algorithm based on Q-learning is proposed. The global environment information is introduced by the reinforcement learning method in the proposed algorithm. In addition, the Q-learning method is used for path planning at the positions where the accessible path points are changed, which optimizes the path planning strategy of the original algorithm near these obstacles. Simulation results show that the algorithm can automatically generate an orderly path in the environmental map, and achieve 100% coverage with a lower path repetition ratio.

Rhamnosyltransferases involved in the biosynthesis of flavone rutinosides in Chrysanthemum species.

Linarin (acacetin-7-O-rutinoside), isorhoifolin (apigenin-7-O-rutinoside), and diosmin (diosmetin-7-O-rutinoside) are chemically and structurally similar flavone rutinoside (FR) compounds found in Chrysanthemum L. (Anthemideae, Asteraceae) plants. However, their biosynthetic pathways remain largely unknown. In this study, we cloned and compared FRs and genes encoding rhamnosyltransferases (RhaTs) among eight accessions of Chrysanthemum polyploids. We also biochemically characterized RhaTs of Chrysanthemum plants and Citrus (Citrus sinensis and Citrus maxima). RhaTs from these two genera are substrate-promiscuous enzymes catalyzing the rhamnosylation of flavones, flavanones, and flavonols. Substrate specificity analysis revealed that Chrysanthemum 1,6RhaTs preferred flavone glucosides (e.g. acacetin-7-O-glucoside), whereas Cs1,6RhaT preferred flavanone glucosides. The nonsynonymous substitutions of RhaTs found in some cytotypes of diploids resulted in the loss of catalytic function. Phylogenetic analysis and specialized pathways responsible for the biosynthesis of major flavonoids in Chrysanthemum and Citrus revealed that rhamnosylation activity might share a common evolutionary origin. Overexpression of RhaT in hairy roots resulted in 13-, 2-, and 5-fold increases in linarin, isorhoifolin, and diosmin contents, respectively, indicating that RhaT is mainly involved in the biosynthesis of linarin. Our findings not only suggest that the substrate promiscuity of RhaTs contributes to the diversity of FRs in Chrysanthemum species but also shed light on the evolution of flavone and flavanone rutinosides in distant taxa.

Determination of quality markers for quality control of Zanthoxylum nitidum using ultra-performance liquid chromatography coupled with near infrared spectroscopy.

With the increasing demand for quality control in the traditional Chinese medicine industry, there is a need for the development of quality markers and a quick, non-destructive technique for the discrimination of related species. In our previous study, ultra-performance liquid chromatography (UPLC) was used for the simultaneous determination of five compounds, including three alkaloids (nitidine chloride, chelerythrine, and magnoflorine), one flavonoid (aurantiamarin), and one lignan (sesamin). In this study, the simultaneous quantification of the above-mentioned compounds could be used to discriminate the powders of roots from those of stems. To further test the reliability of the five compounds, seventy-two batches of wild and seventy-five batches of cultivated Zanthoxylum nitidum samples collected from Guangdong, Guangxi, and Fujian provinces in China were analyzed by UPLC and near-infrared spectroscopy (NIRS). In general, the quantitative results of UPLC were consistent with those of NIRS, and cultivated Z. nitidum has similar major bioactive compounds as the wild one, as supported by principal component analysis. Consequently, these five major bioactive compounds are suggested as potential quality markers. In addition, the NIRS method with discriminant analysis successfully differentiated Z. nitidum from three related species (Z. avicennae, Z. scandens and Toddalia asiatica) of the Rutaceae family. In summary, this study provides a method for the rapid identification of Z. nitidum and discrimination of root and stem powders, and suggests five compounds as quality markers for the evaluation of Z. nitidum.

Genome-Wide Identification of BAHD Superfamily and Functional Characterization of Bornyl Acetyltransferases Involved in the Bornyl Acetate Biosynthesis in Wurfbainia villosa.

Bornyl acetate (BA) is known as a natural aromatic monoterpene ester with a wide range of pharmacological and biological activities. Borneol acetyltransferase (BAT), catalyzing borneol and acetyl-CoA to synthesize BA, is alcohol acetyltransferase, which belongs to the BAHD super acyltransferase family, however, BAT, responsible for the biosynthesis of BA, has not yet been characterized. The seeds of Wurfbainia villosa (homotypic synonym: Amomum villosum) are rich in BA. Here we identified 64 members of the BAHD gene family from the genome of W. villosa using both PF02458 (transferase) and PF07247 (AATase) as Hidden Markov Model (HMM) to screen the BAHD genes. A total of sixty-four WvBAHDs are distributed on 14 chromosomes and nine unanchored contigs, clustering into six clades; three WvBAHDs with PF07247 have formed a separated and novel clade: clade VI. Twelve candidate genes belonging to clade I-a, I-b, and VI were selected to clone and characterize in vitro, among which eight genes have been identified to encode BATs acetylating at least one type of borneol to synthesize BA. All eight WvBATs can utilize (-)-borneol as substrates, but only five WvBATs can catalyze (+)-borneol, which is the endogenous borneol substrate in the seeds of W. villosa; WvBAT3 and WvBAT4 present the better catalytic efficiency on (+)-borneol than the others. The temporal and spatial expression patterns of WvBATs indicate that WvBAT3 and WvBAT4 are seed-specific expression genes, and their expression levels are correlated with the accumulation of BA, suggesting WvBAT3 and WvBAT4 might be the two key BATs for BA synthesis in the seeds of W. villosa. This is the first report on BAT responsible for the last biosynthetic step of BA, which will contribute to further studies on BA biosynthesis and metabolism engineering of BA in other plants or heterologous hosts.

Evidence for quasar fast outflows being accelerated at the scale of tens of parsecs.

Quasar outflows may play a crucial role in regulating the host galaxy, although the spatial scale of quasar outflows remain a major enigma, with their acceleration mechanism poorly understood. The kinematic information of outflow is the key to understanding its origin and acceleration mechanism. Here, we report the galactocentric distances of different outflow components for both a sample and an individual quasar. We find that the outflow distance increases with velocity, with a typical value from several parsecs to more than one hundred parsecs, providing direct evidence for an acceleration happening at a scale of the order of 10 parsecs. These outflows carry ∼1% of the total quasar energy, while their kinematics are consistent with a dust-driven model with a launching radius comparable to the scale of a dusty torus, indicating that the coupling between dust and quasar radiation may produce powerful feedback that is crucial to galaxy evolution.

Identification and functional characterization of three iridoid synthases in Gardenia jasminoides.

MAIN CONCLUSION: The discovery of three iridoid synthases (GjISY, GjISY2 and GjISY4) from Gardenia jasminoides and their functional characterization increase the understanding of iridoid scaffold/iridoid glycoside biosynthesis in iridoid-producing plants. Iridoids are a class of noncanonical monoterpenes that are found naturally in the plant kingdom mostly as glycosides. Over 40 iridoid glycosides (e.g., geniposide, gardenoside and shanzhiside) have been isolated from Gardenia jasminoides. They have multiple pharmacological properties and health-promoting effects. However, their biosynthetic pathway is poorly understood, and the iridoid synthase (ISY) responsible for the cyclization of the core scaffold remains unclear. In this study, three homologs of ISYs from G. jasminoides (GjISY, GjISY2 and GjISY4) were identified on the basis of transcriptomic data and functionally characterized. The genomic structure and intron-exon arrangement revealed that all three ISYs contained an intron. Biochemical assays indicated that all three recombinant enzymes reduced 8-oxogeranial to nepetalactol and its open forms (iridodials) as the products of the classical CrISY (Catharanthus roseus). In addition, all three enzymes reduced progesterone to 5-ß-prognane-3,20-dione. However, only GjISY2 and GjISY4 reduced 2-cyclohexen-1-one to cyclohexanone. Overall, the GjISY2 expression levels in the flowers and fruits were similar to the GjISY and GjISY4 expression levels. By contrast, the GjISY2 expression levels in the upper and lower leaves were substantially higher than the GjISY and GjISY4 expression levels. Among the three, GjISY2 exhibited the highest catalytic efficiency for 8-oxogeranial. GjISY2 might be the major contributor to iridoid biosynthesis in G. jasminoides. Collectively, our results advance the understanding of iridoid scaffold/iridoid glycoside biosynthesis in G. jasminoides and provide a potential target for metabolic engineering and breeding.

A New Method Based on Matrix Completion and Non-Negative Matrix Factorization for Predicting Disease-Associated miRNAs.

Numerous studies have shown that microRNAs are associated with the occurrence and development of human diseases. Thus, studying disease-associated miRNAs is significantly valuable to the prevention, diagnosis and treatment of diseases. In this paper, we proposed a novel method based on matrix completion and non-negative matrix factorization (MCNMF)for predicting disease-associated miRNAs. Due to the information inadequacy on miRNA similarities and disease similarities, we calculated the latter via two models, and introduced the Gaussian interaction profile kernel similarity. In addition, the matrix completion (MC)was employed to further replenish the miRNA and disease similarities to improve the prediction performance. And to reduce the sparsity of miRNA-disease association matrix, the method of weighted K nearest neighbor (WKNKN)was used, which is a pre-processing step. We also utilized non-negative matrix factorization (NMF)using dual L2,1-norm, graph Laplacian regularization, and Tikhonov regularization to effectively avoid the overfitting during the prediction. Finally, several experiments and a case study were implemented to evaluate the effectiveness and performance of the proposed MCNMF model. The results indicated that our method could reliably and effectively predict disease-associated miRNAs.

Extra Trees Method for Predicting LncRNA-Disease Association Based On Multi-Layer Graph Embedding Aggregation.

Lots of experimental studies have revealed the significant associations between lncRNAs and diseases. Identifying accurate associations will provide a new perspective for disease therapy. Calculation-based methods have been developed to solve these problems, but these methods have some limitations. In this paper, we proposed an accurate method, named MLGCNET, to discover potential lncRNA-disease associations. Firstly, we reconstructed similarity networks for both lncRNAs and diseases using top k similar information, and constructed a lncRNA-disease heterogeneous network (LDN). Then, we applied Multi-Layer Graph Convolutional Network on LDN to obtain latent feature representations of nodes. Finally, the Extra Trees was used to calculate the probability of association between disease and lncRNA. The results of extensive 5-fold cross-validation experiments show that MLGCNET has superior prediction performance compared to the state-of-the-art methods. Case studies confirm the performance of our model on specific diseases. All the experiment results prove the effectiveness and practicality of MLGCNET in predicting potential lncRNA-disease associations.

Effects of a short eight Tai Chi-forms for the pre-frail elderly people in senior living communities.

PURPOSE: To investigate effects of a short 8-form Tai Chi exercise on physical function, fear of falling, and depression in pre-frail elderly people living in senior communities. METHODS: This 8-week randomized controlled trial was conducted in senior living communities with qualified pre-frail elderly subjects in a Tai Chi group (TCG, n= 32) and a control group (CG, n = 33). The TCG received TC intervention: three times/week, 60 min each; while the CG did usual care only. Assessments of the 30-s chair rise test (CRT), 4.5-m walking speed (WS), fear of falling (FOF), and Geriatric Depression Scale (GDS), were all applied at baseline, end of 4th week, and end of 8th week. RESULTS: Between-group comparison at the 4th week showed significantly better outcomes in CRT (TCG: 14.56 ± 1.87; CG: 11.48 ± 2.83; P< .001) and WS (TCG: 4.28 ± 0.69; CG: 5.11 ± 1.16; P = .001) in the TCG than those in the CG, but not in FOF (TCG: 0.56 ± 0.56; CG: 0.79 ± 0.89; P = .228) and GDS (TCG: 7.91 ± 5.54; CG: 9.58 ± 6.85; P = .285). However, at the 8th week, significant differences (P< .001) were found in all four assessments: (1) CRT: TCG vs CG: 17.28 ± 2.00 vs 11.36± 2.94; (2) WS: TCG vs CG: 3.94 ± 0.59 vs 5.17 ± 1.22; (3) FOF: TCG vs CG: 0.16 ± 0.37 vs 1.00 ± 0.90; and (4) GDS: TCG vs CG: 3.84 ± 3.60 vs 9.97 ± 6.80, and the intervention effect of 8 weeks was better than at 4 weeks. For within-group comparison of the TCG, significant improvements were identified in CRT (P< .001), WS (P = .008), and FOF (P = .002); but not in GDS, P = .121 at the 4th week, and also in CRT (P< .001), WS (P< .001), FOF (P< .001), and GDS (P< .001) at the 8th week. On the other hand, there were no significant differences in the CG for pre- and post-comparison (CRT: P = .891; WS: P = .984; FOF: P = .636; GDS: P = .822). CONCLUSION: This short-form TC exercise could improve physical function (the lower limbs' strength and gait speed), fear of falling, and depression.

Protective multi­target effects of DL­3­n­butylphthalide combined with 3­methyl­1­phenyl­2­pyrazolin­5­one in mice with ischemic stroke.

DL­3­n­butylphthalide (NBP) and 3­methyl­1- phenyl­2­pyrazolin­5­one (edaravone) are acknowledged neuroprotective agents that protect against ischemic stroke. However, the underlying mechanisms of a combination therapy with NBP and edaravone have not yet been fully clarified. The aim of the present study was to explore whether the co­administration of NBP and edaravone had multi­target protective effects on the neurovascular unit (NVU) of mice affected by ischemic stroke. Male C57BL/6 mice were randomly divided into the following three groups: i) Sham operation control, ii) middle cerebral artery occlusion (MCAO) and reperfusion, iii) and MCAO/reperfusion with the co­administration of NBP (40 mg/kg) and edaravone (6 mg/kg) delivered via intraperitoneal injection at 0 and 4 h after reperfusion (NBP + edaravone). After ischemia and reperfusion, infarct volumes and neurological deficits were evaluated. The immunoreactivity of the NVU, comprising neurons, endothelial cells and astrocytes, was determined using immunofluorescence staining of neuronal nuclei (NeuN), platelet and endothelial cell adhesion molecule 1 (CD31) and glial fibrillary acidic protein (GFAP). Western blotting was used to detect the expression levels of apoptosis­related proteins. The infarct volume, neurological function scores and cell damage were increased in the MCAO group compared with the sham operation group. Furthermore, the MCAO mice had reduced NeuN and CD31 expression and increased GFAP expression compared with the sham group. By contrast, the NBP + edaravone group exhibited reduced cell damage and consequently lower infarct volume and neurological deficit scores compared with the MCAO group. The NBP + edaravone group exhibited increased NeuN and CD31 expression and decreased GFAP expression compared with the MCAO group. Furthermore, the expression levels of Bax and cleaved caspase­3 in the NBP + edaravone group were decreased significantly compared with the MCAO group, while the expression levels of Bcl­2 and mitochondrial cytochrome c were increased. In conclusion, the results of the present study demonstrated that NBP and edaravone effectively prevented ischemic stroke damage with multi­target protective effects. In addition, NBP + edaravone may be a promising combination therapy for ischemic stroke.