Online Statistical Inference for Stochastic Optimization via Kiefer-Wolfowitz Methods

This paper investigates the problem of online statistical inference of model parameters in stochastic optimization problems via the Kiefer-Wolfowitz algorithm with random search directions. We first present the asymptotic distribution for the Polyak-Ruppert-averaging type Kiefer-Wolfowitz (AKW) estimators, whose asymptotic covariance matrices depend on the function-value query complexity and the distribution of search directions. The distributional result reflects the trade-off between statistical efficiency and function query complexity. We further analyze the choices of random search directions to minimize the asymptotic covariance matrix, and conclude that the optimal search direction depends on the optimality criteria with respect to different summary statistics of the Fisher information matrix. Based on the asymptotic distribution result, we conduct online statistical inference by providing two construction procedures of valid confidence intervals. We provide numerical experiments verifying our theoretical results with the practical effectiveness of the procedures

Many-Objective Optimization Using Adaptive Differential Evolution with a New Ranking Method

Pareto dominance is an important concept and is usually used in multiobjective evolutionary algorithms (MOEAs) to determine the nondominated solutions. However, for many-objective problems, using Pareto dominance to rank the solutions even in the early generation, most obtained solutions are often the nondominated solutions, which results in a little selection pressure of MOEAs toward the optimal solutions. In this paper, a new ranking method is proposed for many-objective optimization problems to verify a relatively smaller number of representative nondominated solutions with a uniform and wide distribution and improve the selection pressure of MOEAs. After that, a many-objective differential evolution with the new ranking method (MODER) for handling many-objective optimization problems is designed. At last, the experiments are conducted and the proposed algorithm is compared with several well-known algorithms. The experimental results show that the proposed algorithm can guide the search to converge to the true PF and maintain the diversity of solutions for many-objective problems

Simultaneous Single-Position Oblique Lateral Interbody Fusion Combined With Unilateral Percutaneous Pedicle Screw Fixation for Single-Level Lumbar Tuberculosis: A 3-Year Retrospective Comparative Study

Objective To illustrate a simultaneous single-position oblique lateral interbody fusion (SP-OLIF) combined with unilateral percutaneous pedicle screw fixation in treating single-level lumbar tuberculosis, compared with posterior-only approach in clinical and radiographic evaluations. Methods Consecutive patients who had undergone surgeries for single-level lumbar tuberculosis from January 2018 to December 2020 were retrospectively reviewed. The patients included were divided into SP-OLIF and posterior-only groups according to surgical methods applied, with follow-up for at least 36 months. Outcomes included estimated blood loss, operative time, and complications for safety evaluation; visual analogue scale (VAS), Oswestry Disability Index (ODI) for efficacy evaluation; erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) for evaluating tuberculosis activity; x-ray and computed tomography scan were used for radiographic evaluation. Results A total of 136 patients had been enrolled in the study (60 for SP-OLIF and 76 for Posterior-only). The median operative time, blood loss, and hospital stay in SP-OLIF group were significantly less, with a lower complication rate. Meanwhile, the SP-OLIF group showed substantially lower VAS in 1 and 7 days and decreased ODI in the first month postoperatively, without significant difference afterward. Similarly, the median CRP and ESR in SP-OLIF group were significantly lower in 3 and 7 days postoperatively. All indicators had reduced to normal after 3 months. No recurrence had been reported throughout the whole follow-up. Conclusion SP-OLIF was an efficient minimally invasive protocol for single-level lumbar tuberculosis, facilitating earlier clinical improvement, with decreased blood loss, operative time and hospital stay compared with posterior-only approach

BinauralGrad: A Two-Stage Conditional Diffusion Probabilistic Model for Binaural Audio Synthesis

Binaural audio plays a significant role in constructing immersive augmented and virtual realities. As it is expensive to record binaural audio from the real world, synthesizing them from mono audio has attracted increasing attention. This synthesis process involves not only the basic physical warping of the mono audio, but also room reverberations and head/ear related filtrations, which, however, are difficult to accurately simulate in traditional digital signal processing. In this paper, we formulate the synthesis process from a different perspective by decomposing the binaural audio into a common part that shared by the left and right channels as well as a specific part that differs in each channel. Accordingly, we propose BinauralGrad, a novel two-stage framework equipped with diffusion models to synthesize them respectively. Specifically, in the first stage, the common information of the binaural audio is generated with a single-channel diffusion model conditioned on the mono audio, based on which the binaural audio is generated by a two-channel diffusion model in the second stage. Combining this novel perspective of two-stage synthesis with advanced generative models (i.e., the diffusion models),the proposed BinauralGrad is able to generate accurate and high-fidelity binaural audio samples. Experiment results show that on a benchmark dataset, BinauralGrad outperforms the existing baselines by a large margin in terms of both object and subject evaluation metrics (Wave L2: 0.128 vs. 0.157, MOS: 3.80 vs. 3.61). The generated audio samples (https://speechresearch.github.io/binauralgrad) and code (https://github.com/microsoft/NeuralSpeech/tree/master/BinauralGrad) are available online.Comment: NeurIPS 2022 camera versio

Anticonvulsant activities of α-asaronol ((E)-3'-hydroxyasarone), an active constituent derived from α-asarone.

BACKGROUND: Epilepsy is one of chronic neurological disorders that affects 0.5-1.0% of the world's population during their lifetime. There is a still significant need to develop novel anticonvulsant drugs that possess superior efficacy, broad spectrum of activities and good safety profile. METHODS: α-Asaronol and two current antiseizure drugs (α-asarone and carbamazepine (CBZ)) were assessed by in vivo anticonvulsant screening with the three most employed standard animal seizure models, including maximal electroshock seizure (MES), subcutaneous injection-pentylenetetrazole (PTZ)-induced seizures and 3-mercaptopropionic acid (3-MP)-induced seizures in mice. Considering drug safety evaluation, acute neurotoxicity was assessed with minimal motor impairment screening determined in the rotarod test, and acute toxicity was also detected in mice. RESULTS: In our results, α-asaronol displayed a broad spectrum of anticonvulsant activity (ACA) and showed better protective indexes (PI = 11.11 in MES, PI = 8.68 in PTZ) and lower acute toxicity (LD50 = 2940 mg/kg) than its metabolic parent compound (α-asarone). Additionally, α-asaronol displayed a prominent anticonvulsant profile with ED50 values of 62.02 mg/kg in the MES and 79.45 mg/kg in the sc-PTZ screen as compared with stiripentol of ED50 of 240 mg/kg and 115 mg/kg in the relevant test, respectively. CONCLUSION: The results of the present study revealed α-asaronol can be developed as a novel molecular in the search for safer and efficient anticonvulsants having neuroprotective effects as well as low toxicity. Meanwhile, the results also suggested that α-asaronol has great potential to develop into another new aromatic allylic alcohols type anticonvulsant drug for add-on therapy of Dravet's syndrome

Autologous Skin Fibroblast-Based PLGA Nanoparticles for Treating Multiorgan Fibrosis

Fibrotic diseases remain a substantial health burden with few therapeutic approaches. A hallmark of fibrosis is the aberrant activation and accumulation of myofibroblasts, which is caused by excessive profibrotic cytokines. Conventional anticytokine therapies fail to undergo clinical trials, as simply blocking a single or several antifibrotic cytokines cannot abrogate the profibrotic microenvironment. Here, biomimetic nanoparticles based on autologous skin fibroblasts are customized as decoys to neutralize multiple fibroblast-targeted cytokines. By fusing the skin fibroblast membrane onto poly(lactic-co-glycolic) acid cores, these nanoparticles, termed fibroblast membrane-camouflaged nanoparticles (FNPs), are shown to effectively scavenge various profibrotic cytokines, including transforming growth factor-beta, interleukin (IL)-11, IL-13, and IL-17, thereby modulating the profibrotic microenvironment. FNPs are sequentially prepared into multiple formulations for different administration routines. As a proof-of-concept, in three independent animal models with various organ fibrosis (lung fibrosis, liver fibrosis, and heart fibrosis), FNPs effectively reduce the accumulation of myofibroblasts, and the formation of fibrotic tissue, concomitantly restoring organ function and indicating that FNPs are a potential broad-spectrum therapy for fibrosis management.Peer reviewe

Transcriptome profile analysis in spinal cord injury rats with transplantation of menstrual blood-derived stem cells

IntroductionMenstrual blood-derived stem cells (MenSCs) are vital in treating many degenerative and traumatic disorders. However, the underlying molecular mechanisms remain obscure in MenSCs-treating spinal cord injury (SCI) rats.MethodsMenSCs were adopted into the injured sites of rat spinal cords at day 7 post surgery and the tissues were harvested for total RNA sequencing analysis at day 21 after surgery to investigate the expression patterns of RNAs. The differentially expressed genes (DEGs) were analyzed with volcano and heatmap plot. DEGs were sequentially analyzed by weighted gene co-expression network, functional enrichment, and competitive endogenous RNAs (ceRNA) network analysis. Next, expression of selected miRNAs, lncRNAs, circRNAs and mRNAs were validated by quantitative real-time polymerase chain reaction (qRT-PCR). Bioinformatics packages and extra databases were enrolled to scoop the genes functions and their interaction relationships.ResultsA total of 89 lncRNAs, 65 circRNAs, 120 miRNAs and 422 mRNAs were significantly upregulated and 65 lncRNAs, 72 circRNAs, 74 miRNAs, and 190 mRNAs were significantly downregulated in the MenSCs treated rats compared to SCI ones. Current investigation revealed that MenSCs treatment improve the recovery of the injured rats and the most significantly involved pathways in SCI regeneration were cell adhesion molecules, nature killer cell mediated cytotoxicity, primary immunodeficiency, chemokine signaling pathway, T cell receptor signaling pathway and B cell receptor signaling pathway. Moreover, the lncRNA-miRNA-mRNA and circRNA-miRNA-mRNA ceRNA network of SCI was constructed. Finally, the protein-protein interaction (PPI) network was constructed using the top 100 DE mRNAs. The constructed PPI network included 47 nodes and 70 edges.DiscussionIn summary, the above results revealed the expression profile and potential functions of differentially expressed (DE) RNAs in the injured spinal cords of rats in the MenSCs-treated and SCI groups, and this study may provide new clues to understand the mechanisms of MenSCs in treating SCI

Promoting Cardiac Repair through Simple Engineering of Nanoparticles with Exclusive Targeting Capability toward Myocardial Reperfusion Injury by Thermal Resistant Microfluidic Platform

Nanoparticle (NP)-based intravenous administration represents the most convenient cardiac targeting delivery routine, yet, there are still therapeutic issues due to the lack of targeting efficiency and specificity. Active targeting methods using functionalization of ligands onto the NPs' surface may be limited by trivial modification procedures and reduced targeting yield in vivo. Here, a microfluidics assisted single step, green synthesis method is introduced for producing targeting ligands free heart homing NPs in a tailored manner. The generated beta-glucan-based NPs exhibit precise and efficient targeting capability toward Dectin-1(+) monocytes/macrophages, which are confirmed as main pathogenesis mediators for cardiac ischemic/reperfusion (I/R) injury, with a sequentially enhanced cardiac NP accumulation, and this targeting strategy is exclusively suitable for cardiac I/R but not for other cardiovascular diseases, as confirmed both in murine and human model. Comparing to FDA-approved nano-micelles formulation, beta-glucan NPs loaded with NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome inhibitor (CY-09) exhibit better efficiency in ameliorating myocardial injury and heart failure induced by surgically induced I/R. These findings indicate a simple production of targeting-ligand free NPs, and demonstrate their potential therapeutic applications for preclinical I/R-induced cardiac injury amelioration.Peer reviewe