bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy and safety of Chinese herbal medicine Wen Xin granules for the treatment of unstable angina pectoris with Yang deficiency and blood stasis syndrome: study protocol for a randomized controlled trial
Authors: Tian Pan-pan , Wu Qing-juan , Li Jun , Chen Heng-wen , Wu Ji , Deng Ya-wen , Xie Zi-cong , Zhao Wei , Tan Yu-qing 
Published: November 2021

Abstract
Introduction
Unstable angina pectoris (UAP) is the common type of coronary heart disease with the risk of developing into acute myocardial infarction (AMI). Currently, there are still numerous patients suffering from recurrent angina after revascularization or conventional medication due to the microvascular lesions, endothelial dysfunction, chronic inflammation, in-stent restenosis, and other factors. As an important part of China’s medical and health care system, traditional Chinese medicine (TCM) has rich clinical experience in the treatment of UAP. According to the theory of TCM, Yang deficiency and blood stasis syndrome is a common type of UAP. Wen Xin decoction, as a type of Chinese herbal medicine, has been used in the clinic for years and shown great efficacy in the treatment of UAP with Yang deficiency and blood stasis syndrome. This study aims to evaluate the efficacy and safety of Wen Xin granular in patients with UAP.

Methods and analysis
This is a double-blinded, randomized, placebo-controlled clinical trial. A total of 502 participants will be randomly allocated to the intervention group and the placebo group. Based on conventional medication, the intervention group will be treated with Wen Xin granular and the placebo group will be treated with Wen Xin granular placebo. The primary outcomes are major adverse cardiovascular events (MACE). Assessments will be performed 1 year after the treatment. The secondary outcomes include TCM symptom scale score, Seattle angina questionnaire, and thromboelastography. Assessments will be performed at baseline (before randomization) and 4 and 8 weeks after randomization.

Discussion
This trial will provide high-quality data on the benefits and risks of Wen Xin granular in patients with UAP.

Trial registration
ClinicalTrials.govNCT04661709. Registered on 30 November 2020
Multimodal cerebral imaging study on the effects of “Adjust Zang Dredge Meridian” electroacupuncture on cerebral central sensitization in PDPN patients: a study protocol for a sham-controlled, randomized trial
Authors: Li Mengyuan , Yao Lin , Huang Haipeng , Zhang Liying , Zheng Haizhu , Wang Guan , Zhong Zhen , Ma Shiqi , Yu Shuo , Wang Hongfeng 
Published: November 2021

Abstract
Background
Painful diabetic peripheral neuropathy (PDPN) has a great impact on an individual’s quality of life. The current researchers’ previous trial suggested that acupuncture was a promising adjunctive treatment for PDPN. However, the underlying mechanism of action of acupuncture treatment for PDPN is still unclear, especially its effects at the cerebral level. The aim of this trial will be to explore how acupuncture works in treating PDPN by using multimodal cerebral imaging.

Method and design
This will be a randomized controlled trial. A total of 150 participants will be recruited and assigned to one of three groups: the healthy group, the DM without PDPN group and the DM with PDPN group. Participants in the DM without PDPN and the DM with PDPN groups will each be further divided between an electroacupuncture group and a sham electroacupuncture group. Participants will receive six treatment sessions per week for 4 weeks. Multimodal cerebral imaging includes resting-state functional magnetic resonance imaging (rs-fMRI), diffusion tensor imaging (DTI) and magnetic resonance spectroscopy (MRS); this neurophysiological testing will be the primary outcome measure. Subjective pain scales and blood analysis will be a secondary outcome measure and will be used to assess the clinical efficacy of the intervention. Multimodal cerebral imaging will be used to detect cerebral activity changes in each treatment group. The clinical data and fMRI data will be analysed for all the groups. Multiple correlation regression analyses will be used to assess the association between changes in cerebral functional activity and the improvement of clinical outcomes after acupuncture treatment.

Discussion
This study is based on the results of the researchers’ previous study, and using combined clinical and cerebral function changes, it will help evaluate the effects of acupuncture on PDPN. The investigation of acupuncture’s central mechanism of action will further expand the understanding of acupuncture treatment of PDPN.

Trial registration
Chinese Clinical Trial Registry ChiCTR1900024109. Registered on 26 June 2019.
Visual attention and inhibitory control in children, teenagers and adults with autism without intellectual disability: results of oculomotor tasks from a 2-year longitudinal follow-up study (InFoR)
Authors: Amestoy Anouck , Guillaud Etienne , Bucchioni Giulia , Zalla Tiziana , Umbricht Daniel , Chatham Christopher , Murtagh Lorraine , Houenou Josselin , Delorme Richard , Moal Myriam Ly-Le , Leboyer Marion , Bouvard Manuel , Cazalets Jean-René 
Published: November 2021

Abstract
Background
Inhibitory control and attention processing atypicalities are implicated in various diseases, including autism spectrum disorders (ASD). These cognitive functions can be tested by using visually guided saccade-based paradigms in children, adolescents and adults to determine the time course of such disorders.

Methods
In this study, using Gap, Step, Overlap and Antisaccade tasks, we analyzed the oculomotor behavior of 82 children, teenagers and adults with high functioning ASD and their peer typically developing (TD) controls in a two-year follow-up study under the auspices of the InFoR-Autism project. Analysis of correlations between oculomotors task measurements and diagnostic assessment of attentional (ADHD-RS and ADHD comorbidity indices) and executive functioning (BRIEF scales) were conducted in order to evaluate their relationship with the oculomotor performance of participants with ASD.

Results
As indicated by the presence of a Gap and Overlap effects in all age groups, the oculomotor performances of ASD participants showed a preserved capability in overt attention switching. In contrast, the difference in performances of ASD participants in the Antisaccade task, compared to their TD peers, indicated an atypical development of inhibition and executive functions. From correlation analysis between our oculomotor data and ADHD comorbidity index, and scores of attention and executive function difficulties, our findings support the hypothesis that a specific dysfunction of inhibition skills occurs in ASD participants that is independent of the presence of ADHD comorbidity.

Limitations
These include the relatively small sample size of the ASD group over the study’s two-year period, the absence of an ADHD-only control group and the evaluation of a TD control group solely at the study’s inception.

Conclusions
Children and teenagers with ASD have greater difficulty in attention switching and inhibiting prepotent stimuli. Adults with ASD can overcome these difficulties, but, similar to teenagers and children with ASD, they make more erroneous and anticipatory saccades and display a greater trial-to-trial variability in all oculomotor tasks compared to their peers. Our results are indicative of a developmental delay in the maturation of executive and attentional functioning in ASD and of a specific impairment in inhibitory control.
TM9SF4 is a novel regulator in lineage commitment of bone marrow mesenchymal stem cells to either osteoblasts or adipocytes
Authors: Yu Libo , Xie Mingxu , Zhang Fengjie , Wan Chao , Yao Xiaoqiang 
Published: November 2021

Abstract
Background
Osteoporosis is a common bone disease in elderly population caused by imbalanced bone formation and bone resorption. Mesenchymal stem cells (MSCs) are responsible for maintaining this bone homeostasis. The phenotype of transmembrane 9 superfamily 4 (TM9SF4) knockout mice suggests a relationship between TM9SF4 proteins and bone homeostasis. But the effect of TM9SF4 in osteology has never been reported. In the present study, we investigated the function of TM9SF4 in MSC differentiation commitment, as well as its role in osteoporosis.

Methods
Primary bone marrow MSCs, isolated from TM9SF4 wildtype (TM9SF4+/+) and knockout (TM9SF4−/−) mice, were induced to differentiate into osteoblasts or adipocytes, respectively. The osteogenesis was examined by qRT-PCR detection of osteogenic markers, ALP staining and Alizarin Red S staining. The adipogenesis was tested by qRT-PCR quantification of adipogenic markers and Oil Red O staining. The cytoskeletal organization of MSCs was observed under confocal microscope. The osteoporotic model was induced by ovariectomy in TM9SF4+/+ and TM9SF4−/− mice, followed by Toluidine blue and H&E staining to assess lipid accumulation in trabecular bones, as well as micro-computed tomography scanning and immunohistochemistry staining for bone mass density assessment. The experiments on signaling pathways were conducted using qRT-PCR, Western blot and Alizarin Red S staining.

Results
We determined the role of TM9SF4 in MSC differentiation and found that TM9SF4−/− MSCs had higher potential to differentiate into osteoblasts and lower capability into adipocytes, without affecting osteoclastogenesis in vitro. In ovariectomy-induced osteoporotic model, TM9SF4−/− mice retained higher bone mass and less lipid accumulation in trabecular bones, indicating an important role of TM9SF4 in the regulation of osteoporosis. Mechanistically, TM9SF4-depleted cells showed elongated actin fibers, which may act through mTORC2/Akt/β-catenin pathway to promote their commitment into osteoblasts. Furthermore, TM9SF4-depleted cells showed higher activity of canonical Wnt pathway, suggesting the participation of Wnt/β-catenin during TM9SF4-regulated osteogenesis.

Conclusions
Our study demonstrates TM9SF4 as a novel regulator for MSC lineage commitment. Depletion of TM9SF4 preferentially drives MSCs into osteoblasts instead of adipocytes. Furthermore, TM9SF4−/− mice show delayed bone loss and reduced lipid accumulation during ovariectomy-induced osteoporosis. Our results indicate TM9SF4 as a promising target for the future clinical osteoporotic treatment.
Development of a human umbilical cord-derived mesenchymal stromal cell-based advanced therapy medicinal product to treat immune and/or inflammatory diseases
Authors: Mebarki Miryam , Iglicki Nathan , Marigny Céline , Abadie Camille , Nicolet Claire , Churlaud Guillaume , Maheux Camille , Boucher Hélène , Monsel Antoine , Menasché Philippe , Larghero Jérôme , Faivre Lionel , Cras Audrey 
Published: November 2021

Abstract
Background
Umbilical cord-derived mesenchymal stromal cells (UC-MSCs) revealed their key role in immune regulation, offering promising therapeutic perspectives for immune and inflammatory diseases. We aimed to develop a production process of an UC-MSC-based product and then to characterize UC-MSC properties and immunomodulatory activities in vitro, related to their clinical use and finally, to transfer this technology to a good manufacturing practice (GMP) compliant facility, to manufacture an advanced therapy medicinal product (ATMP).

Methods
Fifteen human umbilical cords (UCs) were collected to develop the production process. Three batches of UC-MSCs from a single donor were characterized at basal state and after in vitro pro-inflammatory stimulation by interferon-γ (IFNγ) and tumor necrosis factor-α (TNFα). Proliferation, immunophenotype, activation markers’ expression and the inhibition of T cell proliferation were assessed. Finally, this technology was transferred to a GMP-compliant facility to manufacture an UC-MSC-based ATMP, from a single donor, using the explant method followed by the establishment of master and work cell stocks.

Results
Twelve UCs were processed successfully allowing to isolate UC-MSCs with doubling time and population doubling remaining stable until passage 4. CD90, CD105, CD73, CD44, CD29, CD166 expression was positive; CD14, CD45, CD31, HLA-DR, CD40, CD80 and CD86 expression was negative, while CD146 and HLA-ABC expression was heterogeneous. Cell morphology, proliferation and immunophenotype were not modified by inflammatory treatment. Indoleamine 2,3-dioxygenase (IDO) expression was significantly induced by IFNγ and IFNγ + TNFα versus non-treated cells. Intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) expression was induced significantly after priming. T cell proliferation was significantly decreased in the presence of UC-MSCs in a dose-dependent manner. This inhibitory effect was improved by IFNγ or IFNγ + TNFα, at UC-MSCs:PBMC ratio 1:10 and 1:30, whereas only IFNγ allowed to decrease significantly T cell proliferation at ratio 1:100. The manufacturing process of the UC-MSC-based ATMP was qualified and authorized by the French regulatory agency for clinical use (NCT04333368).

Conclusion
This work allowed to develop an investigational UC-MSC-based ATMP authorized for clinical use. Our results showed that an inflammatory environment preserves the biological properties of UC-MSCs with an improvement of their immunomodulatory functions.
Hydrogel-hydroxyapatite-monomeric collagen type-I scaffold with low-frequency electromagnetic field treatment enhances osteochondral repair in rabbits
Authors: Yan Jiyuan , Liu Chaoxu , Tu Chang , Zhang Ruizhuo , Tang Xiangyu , Li Hao , Wang Huaixi , Ma Yongzhuang , Zhang Yingchi , Wu Hua , Sheng Gaohong 
Published: November 2021

Abstract
Background
Cartilage damage is a common medical issue in clinical practice. Complete cartilage repair remains a significant challenge owing to the inferior quality of regenerative tissue. Safe and non-invasive magnetic therapy combined with tissue engineering to repair cartilage may be a promising breakthrough.

Methods
In this study, a composite scaffold made of Hydroxyapatite-Collagen type-I (HAC) and PLGA-PEG-PLGA thermogel was produced to match the cartilage and subchondral layers in osteochondral defects, respectively. Bone marrow mesenchymal stem cells (BMSC) encapsulated in the thermogel were stimulated by an electromagnetic field (EMF). Effect of EMF on the proliferation and chondrogenic differentiation potential was evaluated in vitro. 4 mm femoral condyle defect was constructed in rabbits. The scaffolds loaded with BMSCs were implanted into the defects with or without EMF treatment. Effects of the combination treatment of the EMF and composite scaffold on rabbit osteochondral defect was detected in vivo.

Results
In vitro experiments showed that EMF could promote proliferation and chondrogenic differentiation of BMSCs partly by activating the PI3K/AKT/mTOR and Wnt1/LRP6/β-catenin signaling pathway. In vivo results further confirmed that the scaffold with EMF enhances the repair of osteochondral defects in rabbits, and, in particular, cartilage repair.

Conclusion
Hydrogel-Hydroxyapatite-Monomeric Collagen type-I scaffold with low-frequency EMF treatment has the potential to enhance osteochondral repair.
Biofunctionalised bacterial cellulose scaffold supports the patterning and expansion of human embryonic stem cell-derived dopaminergic progenitor cells
Authors: Robbins Miranda , Pisupati Venkat , Azzarelli Roberta , Nehme Samer I. , Barker Roger A. , Fruk Ljiljana , Schierle Gabriele S. Kaminski 
Published: November 2021

Abstract
Background
Stem cell-based therapies for neurodegenerative diseases like Parkinson’s disease are a promising approach in regenerative medicine and are now moving towards early stage clinical trials. However, a number of challenges remain including the ability to grow stem cells in vitro on a 3-dimensional scaffold, as well as their loss, by leakage or cell death, post-implantation. These issues could, however, be helped through the use of scaffolds that support the growth and differentiation of stem cells both in vitro and in vivo. The present study focuses on the use of bacterial cellulose as an in vitro scaffold to promote the growth of different stem cell-derived cell types. Bacterial cellulose was used because of its remarkable properties such as its wettability, ability to retain water and low stiffness, all of which is similar to that found in brain tissue.

Methods
We cultured human embryonic stem cell-derived progenitor cells on bacterial cellulose with growth factors that were covalently functionalised to the surface via silanisation. Epifluorescence microscopy and immunofluorescence were used to detect the differentiation of stem cells into dopaminergic ventral midbrain progenitor cells. We then quantified the proportion of cells that differentiated into progenitor cells and compared the effect of growing cells on biofunctionalised cellulose versus standard cellulose.

Results
We show that the covalent functionalisation of bacterial cellulose sheets with bioactive peptides improves the growth and differentiation of human pluripotent stem cells into dopaminergic neuronal progenitors.

Conclusions
This study suggests that the biocompatible material, bacterial cellulose, has potential applications in cell therapy approaches as a means to repair damage to the central nervous system, such as in Parkinson’s disease but also in tissue engineering.
Semi-automated workflow for molecular pair analysis and QSAR-assisted transformation space expansion
Authors: Yang Zi-Yi , Fu Li , Lu Ai-Ping , Liu Shao , Hou Ting-Jun , Cao Dong-Sheng 
Published: November 2021

AbstractIn the process of drug discovery, the optimization of lead compounds has always been a challenge faced by pharmaceutical chemists. Matched molecular pair analysis (MMPA), a promising tool to efficiently extract and summarize the relationship between structural transformation and property change, is suitable for local structural optimization tasks. Especially, the integration of MMPA with QSAR modeling can further strengthen the utility of MMPA in molecular optimization navigation. In this study, a new semi-automated procedure based on KNIME was developed to support MMPA on both large- and small-scale datasets, including molecular preparation, QSAR model construction, applicability domain evaluation, and MMP calculation and application. Two examples covering regression and classification tasks were provided to gain a better understanding of the importance of MMPA, which has also shown the reliability and utility of this MMPA-by-QSAR pipeline.
Deep scaffold hopping with multimodal transformer neural networks
Authors: Zheng Shuangjia , Lei Zengrong , Ai Haitao , Chen Hongming , Deng Daiguo , Yang Yuedong 
Published: November 2021

AbstractScaffold hopping is a central task of modern medicinal chemistry for rational drug design, which aims to design molecules of novel scaffolds sharing similar target biological activities toward known hit molecules. Traditionally, scaffolding hopping depends on searching databases of available compounds that can't exploit vast chemical space. In this study, we have re-formulated this task as asupervised molecule-to-molecule translationto generate hopped molecules novel in 2D structure but similar in 3D structure, as inspired by the fact that candidate compounds bind with their targets through 3D conformations. To efficiently train the model, we curated over 50 thousand pairs of molecules with increased bioactivity, similar 3D structure, but different 2D structure from public bioactivity database, which spanned 40 kinases commonly investigated by medicinal chemists. Moreover, we have designed a multimodal molecular transformer architecture by integrating molecular 3D conformer through a spatial graph neural network and protein sequence information through Transformer. The trained DeepHop model was shown able to generate around 70% molecules having improved bioactivity together with high 3D similarity but low 2D scaffold similarity to the template molecules. This ratio was 1.9 times higher than other state-of-the-art deep learning methods and rule- and virtual screening-based methods. Furthermore, we demonstrated that the model could generalize to new target proteins through fine-tuning with a small set of active compounds. Case studies have also shown the advantages and usefulness of DeepHop in practical scaffold hopping scenarios.
Radar signal recognition based on triplet convolutional neural network
Authors: Liu Lutao , Li Xinyu 
Published: November 2021

AbstractRecently, due to the wide application of low probability of intercept (LPI) radar, lots of recognition approaches about LPI radar signal modulations have been proposed. However, facing the increasingly complex electromagnetic environment, most existing methods have poor performance to identify different modulation types in low signal-to-noise ratio (SNR). This paper proposes an automatic recognition method for different LPI radar signal modulations. Firstly, time-domain signals are converted to time-frequency images (TFIs) by smooth pseudo-Wigner–Ville distribution. Then, these TFIs are fed into a designed triplet convolutional neural network (TCNN) to obtain high-dimensional feature vectors. In essence, TCNN is a CNN network that triplet loss is adopted to optimize parameters of the network in the training process. The participation of triplet loss can ensure that the distance between samples in different classes is greater than that between samples with the same label, improving the discriminability of TCNN. Eventually, a fully connected neural network is employed as the classifier to recognize different modulation types. Simulation shows that the overall recognition success rate can achieve 94% at − 10 dB, which proves the proposed method has a strong discriminating capability for the recognition of different LPI radar signal modulations, even under low SNR.
Generalized proportional fractional integral Hermite–Hadamard’s inequalities
Authors: Aljaaidi Tariq A. , Pachpatte Deepak B. , Abdeljawad Thabet , Abdo Mohammed S. , Almalahi Mohammed A. , Redhwan Saleh S. 
Published: November 2021

AbstractThe theory of fractional integral inequalities plays an intrinsic role in approximation theory also it has been a key in establishing the uniqueness of solutions for some fractional differential equations. Fractional calculus has been found to be the best for modeling physical and engineering processes. More precisely, the proportional fractional operators are one of the recent important notions of fractional calculus. Our aim in this research paper is developing some novel ways of fractional integral Hermite–Hadamard inequalities in the frame of a proportional fractional integral with respect to another strictly increasing continuous function. The considered fractional integral is applied to establish some new fractional integral Hermite–Hadamard-type inequalities. Moreover, we present some special cases throughout discussing this work.