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Cerebral small vessel disease (CSVD) is the most common cause of vascular cognitive impairment (CI). However, the cognitive performance of individuals with CSVD varies considerably. Early identification of neuroimaging changes related to CI caused by CSVD is important for the prediction and management of CI. The present study aimed to explore the early alterations in cortical thickness and regional homogeneity (ReHo) related to CI in people with CSVD. A total of 106 participants with CSVD with CI, 77 participants with CSVD without CI, and 121 control participants underwent neuropsychological tests and multimodal magnetic resonance imaging scans. Cortical thickness was analyzed using FreeSurfer software, and ReHo patterns were explored using the DPARSF toolbox in brain regions that exhibited alterations in cortical thickness. The CSVD with CI group exhibited decreased cortical thickness but normal ReHo in the right anterior cingulate gyrus (ACG), right cuneus, bilateral insula, and right middle temporal gyrus compared with that in the other two groups. Specifically, both cortical thickness and ReHo in the right ACG were significantly associated with memory performance in CSVD patients with CI. In addition, impaired visuospatial function occurred earlier than the decline of global function in CSVD patients and was related to cortical thinning in the right middle temporal gyrus. In conclusion, decreased cortical thickness but normal ReHo in the right ACG, right cuneus, bilateral insula, and right middle temporal gyrus are characteristic alterations related to the development of CI in CSVD patients. These findings may contribute to the early prediction of CI in CSVD patients.

BackgroundThere is high variability in the clinical outcomes of patients with acute ischemic stroke (AIS) after mechanical thrombectomy (MT).Methods217 consecutive patients with anterior circulation large vessel occlusion who underwent MT between August 2018 and January 2022 were analysed. The primary outcome was functional independence defined as a modified Rankin Scale score of 0–2 at 3 months. In the derivation cohort (August 2018 to December 2020), 7 ensemble ML models were trained on 70% of patients and tested on the remaining 30%. The model’s performance was further validated on the temporal validation cohort (January 2021 to January 2022). The SHapley Additive exPlanations (SHAP) framework was applied to interpret the prediction model.ResultsDerivation analyses generated a 9-item score (PFCML-MT) comprising age, National Institutes of Health Stroke Scale score, collateral status, and postoperative laboratory indices (albumin-to-globulin ratio, estimated glomerular filtration rate, blood neutrophil count, C-reactive protein, albumin and serum glucose levels). The area under the curve was 0.87 for the test set and 0.84 for the temporal validation cohort. SHAP analysis further determined the thresholds for the top continuous features. This model has been translated into an online calculator that is freely available to the public (https://zhelvyao-123-60-sial5s.streamlitapp.com).ConclusionsUsing ML and readily available features, we developed an ML model that can potentially be used in clinical practice to generate real-time, accurate predictions of the outcome of patients with AIS treated with MT.

Default-mode network (DMN) may be the earliest affected network and is associated with cognitive decline in Alzheimer's disease (AD). Repetitive transcranial magnetic stimulation (rTMS) may help to modulate DMN plasticity. Still, stimulation effects substantially vary across studies and individuals. Global left frontal cortex (gLFC) connectivity, a substitute for reserve capacity, may contribute to the heterogeneous physiological effects of neuro-navigated rTMS. This study investigated the effects of left angular gyrus-navigated rTMS on DMN connectivity in different reserve capacity participants. gLFC connectivity, was computed through resting-state fMRI correlations. Thirty-one prodromal AD patients were divided into low connection group (LCG) and high connection group (HCG) by the median of gLFC connectivity. Distinct reserve capacity impacts on DMN in response to rTMS were identified in these two groups. Then, brain-behavior relationships were examined. gLFC connectivity within a certain range is directly proportional to cognitive reserve ability (i.e., LCG), and the effectiveness of functional connectivity beyond this range decreases (i.e, HCG). Moreover, LCG exhibited increased DMN connectivity and significantly positive memory improvements, while HCG showed a contrary connectivity decline and maintained or slightly improved their cognitive function after neuro-navigated rTMS treatment. The prodromal AD patients with the distinct reserve capacity may benefit differently from left angular gyrus-navigated rTMS, which may lead to increasing attention in defining personalized medicine approach of AD.

A key to the content diversity on user-generated content platforms is what subjects users choose to contribute on. This research investigates how two factors can shape contributors’ subject choice decisions, namely, the amount of existing content and content contributed by online friends, or “friend content.” Our experimental findings show that both the amount of existing content and friend content can shape a contributor’s subject choice decisions: ceteris paribus, contributors prefer subjects with less existing content and ones with friend content when the amount of existing content is the same. In addition, contributors’ preference for subjects with friend content weakens as the amount of existing content on other subjects decreases. Our findings hold important implications for research and practice in user-generated content platforms and beyond.

Dental pulp stem cells (DPSCs) and stem cells from the apical papilla (SCAPs) are oral mesenchymal stem cells capable of self-renewal and have a potential for multilineage differentiation. Increasing evidence shows that microRNAs (miRNAs) play important roles in stem cell biology. Here, we focused on exploring miR-146a-5p and its relationship to the undifferentiated status of STRO-1+ SCAPs and STRO-1+ DPSCs, as well as its role during STRO-1+ DPSC differentiation and proliferation. Our data indicated that baseline miR-146a-5p expression is significantly lower in STRO-1+ SCAPs than in STRO-1+ DPSCs and increased in the latter during osteogenic induction. Moreover, we identified miR-146a-5p as a key miRNA that promotes osteo/odontogenic differentiation of STRO-1+ DPSCs and attenuates cell proliferation. Additionally, it was observed that STRO-1+ DPSC mineralization results in the downregulation of notch receptor 1 (NOTCH1) and hes family bHLH transcription factor 1 (HES1). Interference with neurogenic locus notch homolog protein 1 (Notch 1) signaling was verified to enhance differentiation and suppress STRO-1+ DPSC proliferation. It was further observed that miR-146a-5p directly targets the 3'-untranslated region (3'-UTR) of NOTCH1 and inhibits expression of both NOTCH1 and HES1mRNAs and Notch 1 and transcription factor HES-1 (HES-1) proteins in STRO-1+ DPSCs. We conclude that miR-146a-5p exerts its regulatory effect on STRO-1+ DPSC differentiation and proliferation partially by suppressing Notch signaling.

Cutting simulation technology is widely used to predict the micro-scale and instantaneous information in cutting and can be used to reduce the manufacturing costs in industry. Material constitutive models characterize the deformation behaviors involved in cutting and are the key factors affecting the simulation accuracy. In this work, different plastic constitutive models, JC model, JCM model and KHL models were used to simulate the segmented chip formation in Ti-6Al-4V alloy orthogonal cutting. Meanwhile, the JC damage initiation as well as energy-density based damage evolution criteria were applied in cutting simulation. A VUMAT subroutine was developed to characterize the stable plastic and damage constitutive model. The simulated chip morphology using different constitutive models was compared with the experimental results. The plastic models and the ductile failure model can characterize the flow softening behavior during segmented chip formation. The influence of plastic model on the principle cutting force and the segmented chip morphology at different cutting conditions was discussed.

Ductile damage behavior of Ti-6Al-4V alloy was characterized by the evolution of flow curves and deformed specimens in compression tests at high strain rates and various temperatures. Cracks along the shear bands of deformed specimens were observed at lower temperatures (20 °C and 100 °C) and high strain rates (2500–10,000 s−1). The failure initial strains (FIS) during crack generation were calculated according to the measured flow stresses at the transition from stable plastic to damage evolution stage. Special emphasis is placed on the influence of strain rate and temperature on the ductile failure initiation. The failure initiation parameters of Johnson-Cook (JC) damage model were obtained by genetic algorithm (GA) optimization using a combined experimental–numerical approach. That is, the ductile damage parameters were optimized according to the measured FIS and the simulated stress triaxiality, equivalent strains, stresses and temperatures, using compression simulation without damage model. At lower temperatures (T

Understanding relative statures of channels for disseminating knowledge is of practical interest to both generators and consumers of knowledge flows. For generators, stature can influence attractiveness of alternative dissemination routes and deliberations of those who assess generator performance. For knowledge consumers, channel stature may influence knowledge content to which they are exposed. This study introduces a novel approach to conceptualizing and measuring stature of knowledge-dissemination channels: the power-impact PI technique. It is a flexible technique having 3 complementary variants, giving holistic insights about channel stature by accounting for both attraction of knowledge generators to a distribution channel and degree to which knowledge consumers choose to use a channel's knowledge content. Each PI variant is expressed in terms of multiple parameters, permitting customization of stature evaluation to suit its user's preferences. In the spirit of analytics, each PI variant is driven by objective evidence of actual behaviors. The PI technique is based on 2 building blocks: a power that channels have for attracting results of generators' knowledge work, and b impact that channel contents' exhibit on prospective recipients. Feasibility and functionality of the PI-technique design are demonstrated by applying it to solve a problem of journal stature evaluation for the information-systems discipline.

In this work, the orthogonal cutting experiments on Ti-6Al-4V alloy were conducted at different cutting speeds(10—160 m/min)and feed rates(20—160 μm/rev). The tool-chip contact length was measured by the track of tool rake face; meanwhile, the chip morphology caused by the localized and overall chip deformation was characterized by the degree of segmentation and the chip compression ratio, respectively. These parameters were analyzed and calculated according to the segmented chip morphology. In addition, three modified models considering the overall chip deformation and the localized deformation of adiabatic shear band were proposed, and the constants of the models were calculated by the genetic algorithm optimization. Considering the overall and localized chip deformation, the value and variation trend of the tool-contact length predicted by these three models agreed well with the experimental results.

Introduction. Pulp regeneration, as a treatment for pulp necrosis, has significant advantages over root canal therapy for the preservation of living pulp. To date, research on pulp regeneration has mainly focused on the transplantation of pulp stem cells into the root canal, but there is still a lack of research on the migration of pulp cells into the root canal via cell homing. Stem cells from the apical tooth papilla (SCAP) are recognized as multidirectional stem cells, but these cells are difficult to obtain. MicroRNAs are small noncoding RNAs that play crucial roles in regulating normal and pathologic functions. We hypothesized that some types of microRNAs might improve the migration and proliferation function of dental pulp stem cells (DPSCs), which are easily obtained in clinical practice, and as a result, DPSCs might replace SCAP and provide valuable information for regenerative endodontics. Methods. Magnetic activated cell sorting of DPSCs and SCAP was performed. Next-generation sequencing was performed to examine DPSCs and SCAP miRNAs expression and to identify the most significant differentially expressed miRNA. CCK-8 and transwell assays were used to determine the impact of this miRNA on DPSCs proliferation and migration. Results. The most significant differentially expressed miRNA between DPSCs and SCAP was miR-224-5p. Downregulating miR-224-5p promoted DPSCs proliferation and migration; the opposite results were observed when miR-224-5p was upregulated. Conclusion. MiR-224-5p promotes proliferation and migration in DPSCs, a finding that is of great significance for further exploring the role of dental pulp stem cells in regenerative endodontics.

Dental pulp stem cells (DPSCs) and stem cells from the apical papilla (SCAPs) are oral mesenchymal stem cells capable of self-renewal and have a potential for multilineage differentiation. Increasing evidence shows that microRNAs (miRNAs) play important roles in stem cell biology. Here, we focused on exploring miR-146a-5p and its relationship to the undifferentiated status of STRO-1

A key to the content diversity on user-generated content platforms is what subjects users choose to contribute on. This research investigates how two factors can shape contributors’ subject choice decisions, namely, the amount of existing content and content contributed by online friends, or “friend content.” Our experimental findings show that both the amount of existing content and friend content can shape a contributor’s subject choice decisions: ceteris paribus, contributors prefer subjects with less existing content and ones with friend content when the amount of existing content is the same. In addition, contributors’ preference for subjects with friend content weakens as the amount of existing content on other subjects decreases. Our findings hold important implications for research and practice in user-generated content platforms and beyond.

A constitutive model is critical for the prediction accuracy of a metal cutting simulation. The highest strain rate involved in the cutting process can be in the range of 104–106 s–1. Flow stresses at high strain rates are close to that of cutting are difficult to test via experiments. Split Hopkinson compression bar (SHPB) technology is used to study the deformation behavior of Ti-6Al-4V alloy at strain rates of 10–4–104s–1. The Johnson Cook (JC) model was applied to characterize the flow stresses of the SHPB tests at various conditions. The parameters of the JC model are optimized by using a genetic algorithm technology. The JC plastic model and the energy density-based ductile failure criteria are adopted in the proposed SHPB finite element simulation model. The simulated flow stresses and the failure characteristics, such as the cracks along the adiabatic shear bands agree well with the experimental results. Afterwards, the SHPB simulation is used to simulate higher strain rate(approximately 3×104 s–1) conditions by minimizing the size of the specimen. The JC model parameters covering higher strain rate conditions which are close to the deformation condition in cutting were calculated based on the flow stresses obtained by using the SHPB tests (10–4–104 s–1) and simulation (up to 3×104 s–1). The cutting simulation using the constitutive parameters is validated by the measured forces and chip morphology. The constitutive model and parameters for high strain rate conditions that are identical to those of cutting were obtained based on the SHPB tests and simulation.

The compression mechanical behaviors of 7050-T7451 alloy over a wide range of strain rates were studied. The quasi-static and dynamic uniaxial compression tests were presented over a wide range of strain rates (0.0001 s −1 , 0.01 s −1 , 2500 s −1 , 4000 s −1 , 7500 s −1 and 10,000 s −1 ) and temperatures (20 °C, 100 °C, 200 °C and 270 °C). The work hardening behavior changes from work hardening to flow softening with the increase of plastic strain at dynamic conditions. In addition, the dynamic recrystallization (DRX), grain refining and phase transition were observed from the microstructures of the cross-section of the compressed specimens. The microstructure evolution at dynamic condition leads to a smaller work hardening rate than that at most of the quasi-static conditions, indicating a coupling effect of the work hardening and strain rate for 7050-T7451 alloy. Besides, the calculated average thermal softening rate decreases with the increase of logarithmic strain rate, which indicates a coupled effect of thermal softening and strain rate. Based on the calculated work hardening and thermal softening behaviors, a modified Johnson Cook (JC) model was developed to incorporate the coupled effects into the items of work hardening and thermal softening. Most of the average absolute relative errors ( AARE ) between the predicted and measured flow stresses were less than 5%. In addition, the prediction accuracy of the proposed constitutive model was further evaluated by a loading condition jump test.

Oral squamous cell carcinoma (OSCC) is a major malignant cancer of the head and neck. Long non-coding RNAs (lncRNAs) have emerged as critical regulators during the development and progression of cancers. This study aimed to identify a lncRNA-related signature with prognostic value for evaluating survival outcomes and to explore the underlying molecular mechanisms of OSCC. Associations between overall survival (OS), disease-free survival (DFS) and candidate lncRNAs were evaluated by Kaplan–Meier survival analysis and univariate and multivariate Cox proportional hazards regression analyses. The robustness of the prognostic significance was shown via the Gene Expression Omnibus (GEO) database. A total of 2,493 lncRNAs were differentially expressed between OSCC and control samples (fold change >2, p p AC012456.4 especially contributed to poor DFS (p = 0.00828) and OS (p = 0.00987). Furthermore, decreased expression of AC012456.4 was identified as an independent prognostic risk factor through multivariate Cox proportional hazards regression analyses (DFS: p = 0.004, hazard ratio (HR) = 0.600, 95% confidence interval(CI) [0.423–0.851]; OS: p = 0.002, HR = 0.672, 95% CI [0.523–0.863). Gene Set Enrichment Analysis (GSEA) indicated that lncRNA AC012456.4 were significantly enriched in critical biological functions and pathways and was correlated with tumorigenesis, such as regulation of cell activation, and the JAK-STAT and MAPK signal pathway. Overall, these findings were the first to evidence that AC012456.4 may be an important novel molecular target with great clinical value as a diagnostic, therapeutic and prognostic biomarker for OSCC patients.

Motivated by the importance of having reliable online rating systems, we examine the ebb and flow of online ratings with a focus on whether aberrations in online ratings cast a long shadow in subsequent ratings. Our study consists of two complementary pieces: first, we reveal the dynamics following rating aberrations using an econometric analysis of Yelp ratings for 8,943 restaurants in the state of Washington, over a period of 26 months; then, we follow up with two randomized online experiments of joke ratings to corroborate the field evidence and establish the causal nature of our findings. Overall, we find that aberrations in online ratings do not appear to cast a long shadow on future ratings: in the observational study, we find correction percentages of 102.8 % and 103.2% for positive and negative aberrations respectively; in the experiments, the corresponding numbers are 63% and 74% respectively. By and large, these findings suggest that online rating systems are fairly resilient to aberrations. Furthermore, we also find that the correction strength for positive aberrations is on par with those for negative ones, and larger aberrations are followed by stronger corrections. Our findings contribute to the nascent literature on the reliability of online ratings and hold important implications for consumers and online rating platforms.

Small molecules capable of selective covalent protein modification are of significant interest for the development of biological probes and therapeutics. We recently reported that 2-methyl-4-bromopyridine is a quiescent affinity label for the nitric oxide controlling enzyme dimethylarginine dimethylaminohydrolase (DDAH) (Johnson, C. M.; Linsky, T. W.; Yoon, D. W.; Person, M. D.; Fast, W. J. Am. Chem. Soc. 2011, 133, 1553-1562). Discovery of this novel protein modifier raised the possibility that the 4-halopyridine motif may be suitable for wider application. Therefore, the inactivation mechanism of the related compound 2-hydroxymethyl-4-chloropyridine is probed here in more detail. Solution studies support an inactivation mechanism in which the active site Asp66 residue stabilizes the pyridinium form of the inactivator, which has enhanced reactivity toward the active site Cys, resulting in covalent bond formation, loss of the halide, and irreversible inactivation. A 2.18 Å resolution X-ray crystal structure of the inactivated complex elucidates the orientation of the inactivator and its covalent attachment to the active site Cys, but the structural model does not show an interaction between the inactivator and Asp66. Molecular modeling is used to investigate inactivator binding, reaction, and also a final pyridinium deprotonation step that accounts for the apparent differences between the solution-based and structural studies with respect to the role of Asp66. This work integrates multiple approaches to elucidate the inactivation mechanism of a novel 4-halopyridine "warhead," emphasizing the strategy of using pyridinium formation as a "switch" to enhance reactivity when bound to the target protein.

Protein arginine deiminase 4 (PAD4) catalyzes the citrullination of the peptidylarginine via two successive stages: deimination and hydrolysis. Herein, by employing state-of-the-art Born-Oppenheimer ab initio QM/MM molecular dynamics simulations with the umbrella sampling method, we characterized the catalytic mechanism of the hydrolysis reaction: first, the nucleophilic attack of a water molecule to the C(zeta) of the thiouronium intermediate yields a stable tetrahedral intermediate, and then the S-C(zeta) bond breaks to generate the final product, citrulline. Throughout the hydrolysis reaction, His471 and Asp473 play pivotal catalytic roles by first enhancing the nucleophilic ability of the active water through forming shorter and low-barrier hydrogen bonds and then by serving as proton-accepting groups to deprotonate the water molecule, which is consistent with experimental findings. At the transition state, the spontaneous proton transfer among the reactive water, His471 and Asp473 have been observed. The determined overall free energy barrier for this hydrolysis stage is 16.5 kcal x mol(-1), which is lower than the barrier of 20.9 kcal x mol(-1) for the deimination stage determined previously with the same computational approach [J. Phys. Chem. B 2009, 113, 12750-12758]. Thus, the rate-determining step of the PAD4-catalyzed citrullination is the first step of the deimination. Our current work further demonstrates the strength and applicability of the ab initio QM/MM MD approach in simulating enzyme reactions.

The newly discovered SpvC effector protein from Salmonella typhimurium interferes with the host immune response by dephosphorylating mitogen-activated protein kinases (MAPKs) with a beta-elimination mechanism. To understand this unique phosphothreonine lyase catalysis, the dynamics of the enzyme-substrate complex of the SpvC effector is investigated with a 3.2 ns molecular dynamics simulation, which reveals that the phosphorylated peptide substrate is tightly held in the active site by a hydrogen bond network and the lysine general base is positioned for the abstraction of the alpha hydrogen. The catalysis is further modeled with density functional theory (DFT) in a truncated active-site model at the B3LYP/6-31+G(d,p) level of theory. The DFT calculations indicate the reaction proceeds via a single transition state, featuring a concerted proton abstraction from the alpha-carbon by Lys136 and beta-elimination of the phosphate leaving group. Key kinetic isotopic effects are predicted based on the truncated active-site model.

The protein arginine deiminase 4 (PAD4) catalyzes the citrullination of the peptidylarginine and plays a critical role in rheumatoid arthritis (RA) and gene regulation. Understanding its catalytic mechanism is not only of fundamental importance but also of significant medical interest for the rational design of new inhibitors. By employing on-the-fly Born-Oppenheimer ab initio QM/MM molecular dynamics simulations, we have demonstrated that it is unlikely for the active site cysteine and histidine to exist as a thiolate-imidazolium ion pair in the PAD4 Michaelis reactant complex. Instead, a substrate-assisted proton transfer mechanism for the deimination reaction step has been characterized: both Cys645 and His471 in the PAD4 active site are neutral prior to the reaction; the deprotonation of Cys645 by the substrate arginine occurs in concert with the nucleophilic addition of the Cys thiolate to Czeta of the substrate, and leads to a covalent tetrahedral intermediate; then, the Czeta-Neta1 bond cleaves and the resulted ammonia is displaced by a solvent water molecule. The initial deprotonation and nucleophilic attack step is found to be rate-determining. The computed free energy barrier with B3LYP(6-31G*) QM/MM MD simulations and umbrella sampling is 20.9 kcal.mol(-1), consistent with the experimental kinetic data. During the deimination, His471 plays an important role in stabilizing the transition state through the formation of the hydrogen bond with the guanidinium group. Our current studies further demonstrated the viability and strength of the ab initio QM/MM molecular dynamics approach in simulating enzyme reactions.

The newly discovered bacterial phosphothreonine lyases perform a post-translational modification of host cell signaling proteins employing a novel catalytic mechanism that irreversibly removes the phosphate group from a phosphorylated threonine via β-elimination. This “eliminylation” reaction is shown by ab initio QM/MM studies to proceed via the E1cB-like pathway, in which the carbanion intermediate is stabilized by an enzyme oxyanion hole provided by Lys104 and Tyr158 of SpvC.

Phosphorylation reactions catalyzed by kinases and phosphatases play an indispensible role in cellular signaling, and their malfunctioning is implicated in many diseases. A better understanding of the catalytic mechanism will help design novel and effective mechanism-based inhibitors of these enzymes. In this work, ab initio quantum mechanical/molecular mechanical studies are reported for the phosphoryl transfer reaction catalyzed by a cyclin-dependent kinase, CDK2. Our results suggest that an active-site Asp residue, rather than ATP as previously proposed, serves as the general base to activate the Ser nucleophile. The corresponding transition state features a dissociative, metaphosphate-like structure, stabilized by the Mg(2+) ion and several hydrogen bonds. The calculated free-energy barrier is consistent with experimental values. Implications of our results in this and other protein kinases are discussed.

The first step of the hydrolytic deimination of L-arginine catalyzed by arginine deiminase is examined using ab initio quantum mechanical/molecular mechanical molecular dynamics simulations. Two possible protonation states of the nucleophilic Cys406 residue were investigated, and the corresponding activation free energies were obtained via umbrella sampling. Our calculations indicated a reaction free-energy barrier of 21.3 kcal/mol for the neutral cysteine, which is in reasonably good agreement with the experimental k(cat) value of 6.3 s(-1), i.e., a barrier of 16.7 kcal/mol. On the other hand, the deprotonated Cys nucleophile yields a free-energy barrier of 6.7 kcal/mol, much lower than the experimental result. The reaction free-energy barriers along with other data suggest that the Cys nucleophile is dominated by its protonated state in the Michaelis complex, and the reaction barrier corresponds largely to its deprotonation.