bluuebunny/crossref_metadata_2025 huggingface dataset:
Epigenetic histone acetylation modulating prenatal Poly I:C induced neuroinflammation in the prefrontal cortex of rats: a study in a maternal immune activation model
Authors: Su Yueqing , Lian Jiamei , Chen Shiyan , Zhang Wenchang , Deng Chao
Published: November 2022

Introduction: Neuroinflammation in the central nervous system, particularly the prefrontal cortex (PFC), plays a role in the pathogenesis of schizophrenia, which has been found to be associated with maternal immune activation (MIA). Recent evidence suggests that epigenetic regulation involves in the MIA-induced neurodevelopmental disturbance. However, it is not well-understood how epigenetic modulation is involved in the neuroinflammation and pathogenesis of schizophrenia.

Methods: This study explored the modulation of histone acetylation in both neuroinflammation and neurotransmission using an MIA rat model induced by prenatal polyriboinosinic-polyribocytidylic acid (Poly I:C) exposure, specifically examining those genes that were previously observed to be impacted by the exposure, including a subunit of nuclear factor kappa-B (Rela), Nod-Like-Receptor family Pyrin domain containing 3 (Nlrp3), NMDA receptor subunit 2A (Grin2a), 5-HT2A (Htr2a), and GABAA subunit β3 (Gabrb3).

Results: Our results revealed global changes of histone acetylation on H3 (H3ace) and H4 (H4ace) in the PFC of offspring rats with prenatal Poly I:C exposure. In addition, it revealed enhancement of both H3ace and H4ace binding on the promoter region of Rela, as well as positive correlations between Rela and genes encoding histone acetyltransferases (HATs) including CREB-binding protein (CBP) and E1A-associated protein p300 (EP300). Although there was no change in H3ace or H4ace enrichment on the promoter region of Nlrp3, a significant enhancement of histone deacetylase 6 (HDAC6) binding on the promoter region of Nlrp3 and a positive correlation between Nlrp3 and Hdac6 were also observed. However, prenatal Poly I:C treatment did not lead to any specific changes of H3ace and H4ace on the promoter region of the target genes encoding neurotransmitter receptors in this study.

Discussion: These findings demonstrated that epigenetic modulation contributes to NF-κB/NLRP3 mediated neuroinflammation induced by prenatal Poly I:C exposure via enhancement of histone acetylation of H3ace and H4ace on Rela and HDAC6-mediated NLRP3 transcriptional activation. This may further lead to deficits in neurotransmissions and schizophrenia-like behaviors observed in offspring.
Constructing brain functional network by Adversarial Temporal-Spatial Aligned Transformer for early AD analysis
Authors: Zuo Qiankun , Lu Libin , Wang Lin , Zuo Jiahui , Ouyang Tao
Published: November 2022

Introduction

The brain functional network can describe the spontaneous activity of nerve cells and reveal the subtle abnormal changes associated with brain disease. It has been widely used for analyzing early Alzheimer's disease (AD) and exploring pathological mechanisms. However, the current methods of constructing functional connectivity networks from functional magnetic resonance imaging (fMRI) heavily depend on the software toolboxes, which may lead to errors in connection strength estimation and bad performance in disease analysis because of many subjective settings.

Methods

To solve this problem, in this paper, a novel Adversarial Temporal-Spatial Aligned Transformer (ATAT) model is proposed to automatically map 4D fMRI into functional connectivity network for early AD analysis. By incorporating the volume and location of anatomical brain regions, the region-guided feature learning network can roughly focus on local features for each brain region. Also, the spatial-temporal aligned transformer network is developed to adaptively adjust boundary features of adjacent regions and capture global functional connectivity patterns of distant regions. Furthermore, a multi-channel temporal discriminator is devised to distinguish the joint distributions of the multi-region time series from the generator and the real sample.

Results

Experimental results on the Alzheimer's Disease Neuroimaging Initiative (ADNI) proved the effectiveness and superior performance of the proposed model in early AD prediction and progression analysis.

Discussion

To verify the reliability of the proposed model, the detected important ROIs are compared with clinical studies and show partial consistency. Furthermore, the most significant altered connectivity reflects the main characteristics associated with AD.

Conclusion

Generally, the proposed ATAT provides a new perspective in constructing functional connectivity networks and is able to evaluate the disease-related changing characteristics at different stages for neuroscience exploration and clinical disease analysis.
A cerebellum inspired spiking neural network as a multi-model for pattern classification and robotic trajectory prediction
Authors: Vijayan Asha , Diwakar Shyam
Published: November 2022

Spiking neural networks were introduced to understand spatiotemporal information processing in neurons and have found their application in pattern encoding, data discrimination, and classification. Bioinspired network architectures are considered for event-driven tasks, and scientists have looked at different theories based on the architecture and functioning. Motor tasks, for example, have networks inspired by cerebellar architecture where the granular layer recodes sparse representations of the mossy fiber (MF) inputs and has more roles in motor learning. Using abstractions from cerebellar connections and learning rules of deep learning network (DLN), patterns were discriminated within datasets, and the same algorithm was used for trajectory optimization. In the current work, a cerebellum-inspired spiking neural network with dynamics of cerebellar neurons and learning mechanisms attributed to the granular layer, Purkinje cell (PC) layer, and cerebellar nuclei interconnected by excitatory and inhibitory synapses was implemented. The model’s pattern discrimination capability was tested for two tasks on standard machine learning (ML) datasets and on following a trajectory of a low-cost sensor-free robotic articulator. Tuned for supervised learning, the pattern classification capability of the cerebellum-inspired network algorithm has produced more generalized models than data-specific precision models on smaller training datasets. The model showed an accuracy of 72%, which was comparable to standard ML algorithms, such as MLP (78%), Dl4jMlpClassifier (64%), RBFNetwork (71.4%), and libSVM-linear (85.7%). The cerebellar model increased the network’s capability and decreased storage, augmenting faster computations. Additionally, the network model could also implicitly reconstruct the trajectory of a 6-degree of freedom (DOF) robotic arm with a low error rate by reconstructing the kinematic parameters. The variability between the actual and predicted trajectory points was noted to be ± 3 cm (while moving to a position in a cuboid space of 25 × 30 × 40 cm). Although a few known learning rules were implemented among known types of plasticity in the cerebellum, the network model showed a generalized processing capability for a range of signals, modulating the data through the interconnected neural populations. In addition to potential use on sensor-free or feed-forward based controllers for robotic arms and as a generalized pattern classification algorithm, this model adds implications to motor learning theory.
Propensity score matching comparing short-term nerve electrical stimulation to pulsed radiofrequency for herpes zoster-associated pain: A retrospective study
Authors: Liu Liu , Zhang Wen-jing , Xu Shu-xiang , Guo Wen-shuai , Yan Ran-ran , Jiang Xiao-han , Li Shi-yao , Sun Tao
Published: November 2022

Background

Zoster-associated pain (ZAP) is notoriously difficult to treat. Pulsed radiofrequency (PRF) and short-term nerve electrical stimulation (st-NES) have been proven effective treatments for ZAP. However, it is still unclear which technique provides improved analgesia in ZAP. This study is based on a large-scale, long-term follow-up to evaluate the efficacy and safety between st-NES and PRF.

Materials and methods

All eligible ZAP patients treated with st-NES or PRF in our department were enrolled. Cohorts were divided into the st-NES group and the PRF group. A 1:1 ratio propensity score matching (PSM) was used to balance the baseline characteristics. The PS-matched cohort was adopted to investigate the efficacy and safety of the two treatments. The ordinal regression analysis was performed to determine the variables affecting the treatment effect of ZAP.

Results

A total of 226 patients were included after PSM. The numerical rating scale (NRS) scores in st-NES and PRF groups considerably reduced compared to baseline levels after treatment. The NRS scores in the st-NES group were obviously lower than those in the PRF group at discharge, 1, 3, 6, 12, and 24 months. During the follow-up period, the NRS reduction rate remained higher in the st-NES group than in the PRF group (P < 0.01). The dosage of medication, Pittsburgh Sleep Quality Index (PSQI) score, and the number of patients with aggravated pain after discharge in the st-NES group were significantly less than in the PRF group after treatment.

Conclusion

Short-term nerve electrical stimulation has been shown to be more advantageous than PRF for pain relief and quality of life improvement for ZAP patients.
Comprehensive comparison of industrial cannabinoid extraction techniques: Evaluation of the most relevant patents and studies at pilot scale
Authors: López-Olmos Cristina , García-Valverde María Teresa , Hidalgo Jesús , Ferrerio-Vera Carlos , Sánchez de Medina Verónica
Published: November 2022

Cannabinoids are gaining attention in many sectors, including the pharmaceutical, nutraceutical, and cosmetic sectors. To date, several conventional and alternative techniques have been applied for Cannabis sativa L (C. sativa L.) extraction at the industrial scale. The conventional methods are liquid solvent extraction, including polar and non-polar solvents such as ethanol, hexane, petroleum ether, and other solvent extraction. Pressurized gas extraction is another conventional method and comprises gaseous hydrocarbon extraction such as n-butane and n-propane, supercritical or subcritical carbon dioxide extraction, and extraction using a refrigerant gas such as 1,1,1,2-tetrafluoroethane (HFC 134a). Alternative extraction methods include microwave-assisted extraction (MAE), ultrasound-assisted extraction (UAE), hydrodynamic cavitation, and pulsed electric fields (PEF). This review thoroughly analyzes and compares the main extraction techniques and technologies at the industrial scale found in the patent literature. In addition, several aspects of the pretreatment of cannabis plant material and its influence on extraction are also discussed.
Diagnostic performance of radiomics in predicting axillary lymph node metastasis in breast cancer: A systematic review and meta-analysis
Authors: Gong Xiuru , Guo Yaxin , Zhu Tingting , Peng Xiaolin , Xing Dongwei , Zhang Minguang
Published: November 2022

Background

This study aimed to perform a meta‐analysis to evaluate the diagnostic performance of radiomics in predicting axillary lymph node metastasis (ALNM) and sentinel lymph node metastasis (SLNM) in breast cancer.

Materials and methods

Multiple electronic databases were systematically searched to identify relevant studies published before April 29, 2022: PubMed, Embase, Web of Science, Cochrane Library, China National Knowledge Infrastructure, and Wanfang Data. The quality of the included studies was assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 tool. The overall diagnostic odds ratio (DOR), sensitivity, specificity, and area under the curve (AUC) were calculated to evaluate the diagnostic performance of radiomic features for lymph node metastasis (LNM) in patients with breast cancer. Spearman’s correlation coefficient was determined to assess the threshold effect, and meta-regression and subgroup analyses were performed to explore the possible causes of heterogeneity.

Results

A total of 30 studies with 5611 patients were included in the meta-analysis. Pooled estimates suggesting overall diagnostic accuracy of radiomics in detecting LNM were determined: DOR, 23 (95% CI, 16-33); sensitivity, 0.86 (95% CI, 0.82-0.88); specificity, 0.79 (95% CI, 0.73-0.84); and AUC, 0.90 (95% CI, 0.87-0.92). The meta-analysis showed significant heterogeneity between sensitivity and specificity across the included studies, with no evidence for a threshold effect. Meta-regression and subgroup analyses showed that combined clinical factors, modeling method, region, and imaging modality (magnetic resonance imaging [MRI], ultrasound, computed tomography [CT], and X-ray mammography [MMG]) contributed to the heterogeneity in the sensitivity analysis (P < 0.05). Furthermore, modeling methods, MRI, and MMG contributed to the heterogeneity in the specificity analysis (P < 0.05).

Conclusion

Our results show that radiomics has good diagnostic performance in predicting ALNM and SLNM in breast cancer. Thus, we propose this approach as a clinical method for the preoperative identification of LNM.
Proton therapy for isolated local regional recurrence of breast cancer after mastectomy alone
Authors: Laughlin Brady S. , Bhangoo Ronik S. , Niska Joshua R. , Thorpe Cameron S. , Girardo Marlene E. , Anderson Justin D. , Kosiorek Heidi E. , McGee Lisa A. , Hartsell William F. , Chang John H. , Rossi Carl J. , Tsai Henry K. , Choi Isabelle J. , Vargas Carlos E.
Published: November 2022

Purpose/Objectives

To assess adverse events (AEs) and disease-specific outcomes after proton therapy for isolated local-regional recurrence (LRR) of breast cancer after mastectomy without prior radiotherapy (RT).

Materials/Methods

Patients were identified from a multi-institutional prospective registry and included if diagnosed with invasive breast cancer, initially underwent mastectomy without adjuvant RT, experienced an LRR, and subsequently underwent salvage treatment, including proton therapy. Follow-up and cancer outcomes were measured from the date of RT completion.

Results

Nineteen patients were included. Seventeen patients were treated with proton therapy to the chest wall and comprehensive regional lymphatics (17/19, 90%). Maximum grade AE was grade 2 in 13 (69%) patients and grade 3 in 4 (21%) patients. All patients with grade 3 AE received > 60 GyE (p=0.04, Spearman correlation coefficient=0.5). At the last follow-up, 90% of patients were alive with no LRR or distant recurrence.

Conclusions

For breast cancer patients with isolated LRR after initial mastectomy without adjuvant RT, proton therapy is well-tolerated in the salvage setting with excellent loco-regional control. All grade 3 AEs occurred in patients receiving > 60 GyE.
Visualizing knowledge evolution trends and research hotspots of artificial intelligence in colorectal cancer: A bibliometric analysis
Authors: Liu Guangwei , Zhao Jun , Tian Guangye , Li Shuai , Lu Yun
Published: November 2022

Background

In recent years, the rapid development of artificial intelligence (AI) technology has created a new diagnostic and therapeutic opportunity for colorectal cancer (CRC). Numerous academic and clinical studies have demonstrated that high-level auxiliary diagnosis and treatment systems based on AI technology can significantly improve the readability of medical data, objectively provide a reliable and comprehensive reference for physicians, reduce the experience gap between physicians, and aid physicians in making more accurate diagnosis decisions. In this study, we used bibliometric techniques to visually analyze the literature about AI in the CRC field and summarize the current situation and research hotspots in this field.

Methods

The relevant literature on AI in the field of CRC research was obtained from the Web of Science Core Collection (WoSCC) database. The software CiteSpace was utilized to analyze the number of papers, countries, institutions, authors, journals, cited literature, and keywords of the included literature and generate a visual knowledge map. The present study aims to evaluate the origin, current hotspots, and research trends of AI in CRC using bibliometric analysis.

Results

As of March 2022, 64 nations/regions, 230 institutions, 245 journals, and 300 authors had published 562 AI-related articles in the field of CRC. Since 2016, each year has seen an exponential increase. China and the United States were the largest contributors, with the largest number of beneficial research institutions and the closest collaboration relationship. The World Journal of Gastroenterology is this field’s most widely published journal. Diagnosis and treatment research, gene and immunology research, intestinal polyp research, tumor grading research, gastrointestinal endoscopy research, and prognosis research comprised the six topics derived from high-frequency keyword cluster analysis.

Conclusion

In recent years, field research has been a popular topic of discussion. The results of our bibliometric analysis allow us to comprehend better the current situation and trend of this research field, and the quantitative data indicators can serve as a guide for the research and application of global scholars.
Development and validation of an ultrasound-based radiomics nomogram for predicting the luminal from non-luminal type in patients with breast carcinoma
Authors: Wu Jiangfeng , Ge Lifang , Jin Yun , Wang Yunlai , Hu Liyan , Xu Dong , Wang Zhengping
Published: November 2022

Introduction

The molecular subtype plays a significant role in breast carcinoma (BC), which is the main indicator to guide treatment and is closely associated with prognosis. The aim of this study was to investigate the feasibility and efficacy of an ultrasound-based radiomics nomogram in preoperatively discriminating the luminal from non-luminal type in patients with BC.

Methods

A total of 264 BC patients who underwent routine ultrasound examination were enrolled in this study, of which 184 patients belonged to the training set and 80 patients to the test set. Breast tumors were delineated manually on the ultrasound images and then radiomics features were extracted. In the training set, the T test and least absolute shrinkage and selection operator (LASSO) were used for selecting features, and the radiomics score (Rad-score) for each patient was calculated. Based on the clinical risk features, Rad-score, and combined clinical risk features and Rad-score, three models were established, respectively. The performances of the models were validated with receiver operator characteristic (ROC) curve and decision curve analysis.

Results

In all, 788 radiomics features per case were obtained from the ultrasound images. Through radiomics feature selection, 11 features were selected to constitute the Rad-score. The area under the ROC curve (AUC) of the Rad-score for predicting the luminal type was 0.828 in the training set and 0.786 in the test set. The nomogram comprising the Rad-score and US-reported tumor size showed AUCs of the training and test sets were 0.832 and 0.767, respectively, which were significantly higher than the AUCs of the clinical model in the training and test sets (0.691 and 0.526, respectively). However, there was no significant difference in predictive performance between the Rad-score and nomogram.

Conclusion

Both the Rad-score and nomogram can be applied as useful, noninvasive tools for preoperatively discriminating the luminal from non-luminal type in patients with BC. Furthermore, this study might provide a novel technique to evaluate molecular subtypes of BC.
Genome-wide DNA methylation study identifies significant epigenomic changes associated with internalized stigma in adults with non-specific chronic low back pain
Authors: Aroke Edwin N. , Hobson Joanna M. , Ptacek Travis , Jackson Pamela , Goodin Burel R.
Published: November 2022

Non-specific chronic low back pain (cLBP) represents a common musculoskeletal condition with no identifiable cause. It cannot be diagnosed with conventional neuroimaging techniques such as computerized tomography (CT). The diagnostic uncertainty that characterizes non-specific cLBP can lead to stigmatizing responses from others that can become internalized Among individuals with non-specific cLBP, internalized stigma is associated with greater pain intensity and disability. Yet, no study has examined the biological mechanism linking high internalized stigma to worse outcomes in individuals with non-specific cLBP. We aimed to identify differentially methylated loci (DML), enrichment pathways, and associated network interactions among individuals with non-specific cLBP experiencing low vs. high internalized stigma. We examined DNA methylation in whole blood samples from 48 adults, ages 19–85, using reduced representation bisulfite sequencing (RRBS). After controlling for age, sex, race, and multiple testing, differentially methylated loci (DML) differed in adults with low vs. high internalized stigma by at least 10% and q < 0.01 in 3,665 CpG sites: 2,280 hypomethylated and 1,385 hypermethylated. Gene ontology (GO) analyses of the annotated genes from these sites revealed significant enrichment of 274 biological processes, 29 cellular components, and 24 molecular functions (adjusted p < 0.05). The top enriched molecular functions regulate protein binding and DNA binding of transcription factor activity. Pathway analyses indicated that many functional genomic pathways, including Hippo Signaling, Melanogenesis, and Pathways in Cancer, were enriched with differentially methylated genes. Also, there was a significant interaction between relevance pathways such as P53, mTOR, PI3K-Akt, and Wnt signaling pathways. These pathways have previously been associated with neuroinflammation, neurodegeneration, and stress-related conditions. Thus, findings point to possible stress-induced DNAm changes as the link between high levels of internalized stigma and worse outcomes in adults with non-specific cLBP.
Immunotherapy and targeted therapy for lung cancer: Current status and future perspectives
Authors: Zulfiqar Bilal , Farooq Asim , Kanwal Shahzina , Asghar Kashif
Published: November 2022

Lung cancer has the highest incidence of morbidity and mortality throughout the globe. A large number of patients are diagnosed with lung cancer at the later stages of the disease. This eliminates surgery as an option and places complete dependence on radiotherapy or chemotherapy, and/or a combination of both, to halt disease progression by targeting the tumor cells. Unfortunately, these therapies have rarely proved to be effective, and this necessitates the search for alternative preventive approaches to reduce the mortality rate of lung cancer. One of the effective therapies against lung cancer comprises targeting the tumor microenvironment. Like any other cancer cells, lung cancer cells tend to use multiple pathways to maintain their survival and suppress different immune responses from the host’s body. This review comprehensively covers the role and the mechanisms that involve the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) in lung adenocarcinoma and methods of treating it by altering the tumor microenvironment. It focuses on the insight and understanding of the lung cancer tumor microenvironment and chemokines, cytokines, and activating molecules that take part in angiogenesis and metastasis. The review paper accounts for the novel and current immunotherapy and targeted therapy available for lung cancer in clinical trials and in the research phases in depth. Special attention is being paid to mark out single or multiple genes that are required for malignancy and survival while developing targeted therapies for lung cancer treatment.
From tryptamine to the discovery of efficient multi-target directed ligands against cholinesterase-associated neurodegenerative disorders
Authors: Wu Junbo , Zhang Honghua , Wang Yuying , Yin Gaofeng , Li Qien , Zhuo Linsheng , Chen Hongjin , Wang Zhen
Published: November 2022

A novel class of benzyl-free and benzyl-substituted carbamylated tryptamine derivatives (CDTs) was designed and synthesized to serve as effective building blocks for the development of novel multi-target directed ligands (MTDLs) for the treatment of neurological disorders linked to cholinesterase (ChE) activity. The majority of them endowed butyrylcholinesterase (BuChE) with more substantial inhibition potency than acetylcholinesterase (AChE), according to the full study of ChE inhibition. Particularly, hybrids with dibenzyl groups (2b-2f, 2j, 2o, and 2q) showed weak or no neuronal toxicity and hepatotoxicity and single-digit nanomolar inhibitory effects against BuChE. Through molecular docking and kinetic analyses, the potential mechanism of action on BuChE was first investigated. In vitro H2O2-induced HT-22 cells assay demonstrated the favorable neuroprotective potency of 2g, 2h, 2j, 2m, 2o, and 2p. Besides, 2g, 2h, 2j, 2m, 2o, and 2p endowed good antioxidant activities and COX-2 inhibitory effects. This study suggested that this series of hybrids can be applied to treat various ChE-associated neurodegenerative disorders such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), as well as promising building blocks for further structure modification to develop efficient MTDLs.
Pharmacokinetics of fluorobenzyl polyethylene glycol conjugated tetraiodothyroacetic acid (NP751), a novel anticancer thyrointegrin αvβ3 antagonist
Authors: Fujioka Kazutoshi , Hay Bruce A. , Godugu Kavitha , Mousa Shaker A.
Published: November 2022

We have recently reported on the development of fb-PMT (NP751), a conjugate of the thyroid hormone metabolite tetraiodothyroacetic acid (tetrac) and monodisperse polyethylene glycol 36. It exhibited high affinity for thyrointegrin αvβ3 receptor and potent anti-angiogenic and anticancer activity in vivo. The objective of the current study is to determine the pharmacokinetics (PK) of fb-PMT in experimental animals, such as mice, rats, and monkeys. NP751 was quantified using a propylene diamine-modified tetraiodothyroacetic acid (DAT) as an internal standard. The limit of quantification (LOQ) for fb-PMT was 1.5 ng/μL and the recovery efficiency was 93.9% with the developed method. The peak plasma concentration (Cmax) and the area under the curve (AUC) results at different doses in mice, rats and monkeys suggest that pharmacokinetics of NP751 is dose-dependent within the dose ranges administered. Results indicate that NP751 has comparable PK parameters that provides enough exposure as a molecularly tumor targeted molecule in multiple species and is a promising anticancer therapeutic.
Demyelinating diseases of the central nervous system registry for patients with traditional Chinese medicine: Rationale and design of a prospective, multicenter, observational study
Authors: Liu Jia , Zhang Chi , Xie Yao , Zhou Li , Guo Li , Li Bin , Jia Zhen , Zhang Jingze , Sugimoto Kazuo , Gao Ying
Published: November 2022

Background: Traditional Chinese medicine (TCM), a main form of complementary and alternative medicine provides a potential possibility for demyelinating disease of the central nervous system (DDC) management and has been applied in considerable amounts of patients with this disorder. Nevertheless, powerful real-world evidences regarding the epidemiological and clinical characteristics, safety, and outcomes of TCM in DDC are lacking. The primary objective of the Demyelinating Diseases of the Central Nervous System Registry for Patients with Traditional Chinese Medicine (DATE-TCM) is to create an organized multicenter data collection structure to define integrative characteristics of DDC patients treated with TCM in an endeavor to fill these knowledge gaps to better inform clinical care and health policy.

Method: This study provides a prospective and voluntary registry by using a web-based system. Baseline data will be recorded and subsequently regular follow-up visits will be implemented every 3–6 months for a total of 5 years. The primary outcome is Annualized Aggregate Relapse Rate at 5-year follow-up.

Results: DATE-TCM is currently designed to capture the multidimensional (epidemiologic, demographic, clinical, etc.) features of DDC patients receiving TCM treatment, the type and long-term safety and efficacy of TCM intervenes in the DDC populations, as well as the interaction of TCM treatments and disease modifying therapies in the management of DDC, aiming to include 2000 eligible adult DDC patients with TCM intervenes from 35 participating centers, covering 77.4% of provincial administrative regions of mainland China.

Conclusion: DATE-TCM is the first, largest, most geographically extensive, and standard registry-based observational study that systematically document the real-world data regarding the TCM application in the DDC populations, which will be extraordinarily important for clarifying the comprehensive characteristics and outcomes of TCM in DDC, further shed light on standardizing and optimizing the TCM measures for DDC management and establishing evidence-based clinical practice guidelines for TCM application in DDC.
Evaluation of therapeutic strategies targeting BCAA catabolism using a systems pharmacology model
Authors: Voronova Veronika , Sokolov Victor , Morias Yannick , Boezelman Malin Jonsson , Wågberg Maria , Henricsson Marcus , Hansson Karl , Goltsov Alexey , Peskov Kirill , Sundqvist Monika
Published: November 2022

Background: Abnormal branched-chained amino acids (BCAA) accumulation in cardiomyocytes is associated with cardiac remodeling in heart failure. Administration of branched-chain α-keto acid dehydrogenase (BCKD) kinase inhibitor BT2 has been shown to reduce cardiac BCAA levels and demonstrated positive effects on cardiac function in a preclinical setting. The current study is focused on evaluating the impact of BT2 on the systemic and cardiac levels of BCAA and their metabolites as well as activities of BCAA catabolic enzymes using a quantitative systems pharmacology model.

Methods: The model is composed of an ordinary differential equation system characterizing BCAA consumption with food, disposal in the proteins, reversible branched-chain-amino-acid aminotransferase (BCAT)-mediated transamination to branched-chain keto-acids (BCKA), followed by BCKD-mediated oxidation. Activity of BCKD is regulated by the balance of BCKDK and protein phosphatase 2Cm (PP2Cm) activities, affected by BT2 treatment. Cardiac BCAA levels are assumed to directly affect left ventricular ejection fraction (LVEF). Biochemical characteristics of the enzymes are taken from the public domains, while plasma and cardiac BCAA and BCKA levels in BT2 treated mice are used to inform the model parameters.

Results: The model provides adequate reproduction of the experimental data and predicts synchronous BCAA responses in the systemic and cardiac space, dictated by rapid BCAA equilibration between the tissues. The model-based simulations indicate maximum possible effect of BT2 treatment on BCAA reduction to be 40% corresponding to 12% increase in LVEF. Model sensitivity analysis demonstrates strong impact of BCKDK and PP2Cm activities as well as total BCKD and co-substrate levels (glutamate, ketoglutarate and ATP) on BCAA and BCKA levels.

Conclusion: Model based simulations confirms using of plasma measurements as a marker of cardiac BCAA changes under BCKDK inhibition. The proposed model can be used for optimization of preclinical study design for novel compounds targeting BCAA catabolism.
The effect of a pressure ventilatory support on quadriceps endurance is maintained after exercise training in severe COPD patients. A longitudinal randomized, cross over study
Authors: Labeix Pierre , Court Fortune Isabelle , Muti Daniela , Berger Mathieu , Chomette-Ballereau Stéphanie , Barthelemy Jean Claude , Féasson Léonard , Costes Frédéric
Published: November 2022

Purpose: In severe chronic obstructive pulmonary disease (COPD) patients, the application of an inspiratory pressure support (IPS) during exercise increases exercise tolerance and the benefit of exercise training during pulmonary rehabilitation (PR). Moreover, it improves quadriceps endurance after a session of cycling exercise suggesting a reduced muscle fatigue. We looked for the persistence of this effect after PR and sought an association between the improved quadriceps endurance with IPS and the training load during PR.

Patients and methods: We studied 20 patients with severe COPD (6 in stage 3and 14 in stage 4 of GOLD) before and after PR. As part of a PR program, patients completed 16 cycling sessions over 6 weeks with the addition of IPS during exercise. As a surrogate of muscular fatigue, quadriceps endurance was measured at 70% of maximal strength in a control condition, after a constant work rate exercise test (CWR) with IPS (TlimQ IPS) or with a sham ventilation (TlimQsham), in a random order. These tests were repeated similarly at the end of PR.

Results: PR was associated with a significant increase in maximal power output, cycling endurance, quadriceps strength and endurance. Session training load (power output x duration of the session) increased by 142% during the course of the program. Before PR, CWR duration increases with IPS compared to sham ventilation (Δtime = +244s, p = 0.001). Compared to control condition, post-exercise TlimQ reduction was lower with IPS at isotime than at the end of CWR or than with sham ventilation (−9 ± 21%, −18 ± 16% and −23 ± 18%, respectively, p = 0.09, p < 0.0001 and p < 0.0001). After PR, the post-exercise decrease of TlimQ was reduced after IPS compared to sham (−9 ± 18% vs. −21 ± 17%, respectively, p = 0.004). No relationship was found between the prevention of quadriceps fatigue and the training load.

Conclusion: In severe COPD patients, the beneficial effect of a ventilator support on quadriceps endurance persisted after PR with IPS. However, it was not related to the increase in training load, and could not predict the training response to non-invasive ventilation during exercise.
Molecular insights into the axon guidance molecules Sidestep and Beaten path
Authors: Heymann Caroline , Paul Christine , Huang Na , Kinold Jaqueline C. , Dietrich Ann-Christin , Aberle Hermann
Published: November 2022

The transmembrane protein Sidestep (Side) functions as a substrate-bound attractant for motor axons in Drosophila. Outgrowing motor axons recognize Side via Beaten path Ia (Beat) and migrate along Side-expressing tissues. Here, we report a structure-function analysis of these guidance molecules using a variety of mutant lines and transgenic constructs. Investigation of Side mutants shows that the exchange of a single amino acid (L241H) in the second immunoglobulin domain disturbs Side function and subcellular localization. Overexpression of Side and Beat deletion constructs in S2 cells and muscles demonstrate that the first Ig domains of both proteins are necessary for their interaction. Furthermore, subcellular distributions of several Beat constructs identify functional domains and suggest a potential posttranslational processing step in ER compartments. In fact, fusing full-length Beat at both the N- and C-terminus with GFP and mCherry, respectively, shows that the N-terminal domain is transported to the plasma membrane and exposed on the cell surface, while the C-terminal domain accumulated in the nucleus. Taken together, these results give insights into the interaction of Side and Beat and imply that Beat might be subject to proteolytic cleavage during maturation.
Running economy and lower extremity stiffness in endurance runners: A systematic review and meta-analysis
Authors: Liu Bowen , Wu Jinlong , Shi Qiuqiong , Hao Fengwei , Xiao Wen , Yu Jingxuan , Yu Fengyu , Ren Zhanbing
Published: November 2022

Background: Lower extremity stiffness simulates the response of the lower extremity to landing in running. However, its relationship with running economy (RE) remains unclear. This study aims to explore the relationship between lower extremity stiffness and RE.

Methods: This study utilized articles from the Web of Science, PubMed, and Scopus discussing the relationships between RE and indicators of lower extremity stiffness, namely vertical stiffness, leg stiffness, and joint stiffness. Methodological quality was assessed using the Joanna Australian Centre for Evidence-Based Care (JBI). Pearson correlation coefficients were utilized to summarize effect sizes, and meta-regression analysis was used to assess the extent of this association between speed and participant level.

Result: In total, thirteen studies involving 272 runners met the inclusion criteria and were included in this review. The quality of the thirteen studies ranged from moderate to high. The meta-analysis results showed a negative correlation between vertical stiffness (r = −0.520, 95% CI, −0.635 to −0.384, p < 0.001) and leg stiffness (r = −0.568, 95% CI, −0.723 to −0.357, p < 0.001) and RE. Additional, there was a small negative correlation between knee stiffness and RE (r = −0.290, 95% CI, −0.508 to −0.037, p = 0.025). Meta-regression results showed that the extent to which leg stiffness was negatively correlated with RE was influenced by speed (coefficient = −0.409, p = 0.020, r2 = 0.79) and participant maximal oxygen uptake (coefficient = −0.068, p = 0.010, r2 = 0.92).

Conclusion: The results of this study suggest that vertical, leg and knee stiffness were negatively correlated with RE. In addition, maximum oxygen uptake and speed will determine whether the runner can take full advantage of leg stiffness to minimize energy expenditure.
Characterization of the antagonistic potential of the glyphosate-tolerant Pseudomonas resinovorans SZMC 25872 strain against the plant pathogenic bacterium Agrobacterium tumefaciens
Authors: Zhumakayev Anuar R. , Varga Mónika , Vörös Mónika , Kocsubé Sándor , Ramteke Pramod W. , Szekeres András , Vágvölgyi Csaba , Hatvani Lóránt , Marik Tamás
Published: November 2022

The utilization of microorganisms with biocontrol activity against fungal and bacterial pathogens of plants is recognized as a promising, effective, and environment-friendly strategy to protect agricultural crops. We report the glyphosate-tolerant Pseudomonas resinovorans SZMC 25872 isolate as a novel strain with antagonistic potential towards the plant pathogenic bacterium Agrobacterium tumefaciens. In our studies, the growth of the P. resinovorans SZMC 25872 and A. tumefaciens SZMC 14557 isolates in the presence of 74 different carbon sources, and the effect of 11 carbon sources utilized by both strains on the biocontrol efficacy was examined. Seven variations of media with different carbon sources were selected for the assays to observe the biocontrol potential of the P. resinovorans strain. Also, 50% concentrations of the cell-free culture filtrates (CCF) obtained from medium amended with L-alanine or succinic acid as sole carbon source were found to be effective for the growth suppression of A. tumefaciens by 83.03 and 56.80%, respectively. The effect of 7 media on siderophore amount and the activity of extracellular trypsin- and chymotrypsin-like proteases, as well as esterases were also evaluated. Significant positive correlation was found between the siderophore amount and the percentage of inhibition, and the inhibitory effect of the CCFs obtained from medium amended with succinic acid was eliminated in the presence of an additional iron source, suggesting that siderophores produced by P. resinovorans play an important role in its antagonistic potential. The metabolic profile analysis of the P. resinovorans SZMC 25872 strain, performed by high performance liquid chromatography - high resolution mass spectrometry (HPLC-HRMS), has identified several previously not reported metabolites that might play role in the antagonistic effect against A. tumefaciens. Based on our findings we suggest that the possible inhibition modes of A. tumefaciens SZMC 14557 by P. resinovorans SZMC 25872 include siderophore-mediated suppression, extracellular enzyme activities and novel bioactive metabolites.
Fhb1 disease resistance QTL does not exacerbate wheat grain protein loss at elevated CO2
Authors: Hay William T. , Anderson James A. , Garvin David F. , McCormick Susan P. , Vaughan Martha M.
Published: November 2022

Fusarium head blight, a devastating cereal crop disease, can cause significant yield losses and contaminate grain with hazardous fungal toxins. Concerningly, recent evidence indicates that substantial grain protein content loss is likely to occur in wheat that is moderately resistant to head blight when it is grown at elevated CO2. Although wheat breeders in North America utilize a number of resistance sources and genes to reduce pathogen damage, the Fhb1 gene is widely deployed. To determine whether Fhb1 is associated with the protein content loss at elevated CO2, twelve near-isogenic spring wheat lines from either a susceptible or moderately susceptible genetic background, and with, or without the Fhb1 QTL, were grown at ambient and elevated CO2 conditions. The near-isogenic lines were evaluated for differences in physiology, productivity, and grain protein content. Our results showed that the Fhb1 QTL did not have any significant effect on plant growth, development, yield, or grain protein content at ambient or elevated CO2. Therefore, other factors in the moderately susceptible wheat genetic background are likely responsible for the more severe grain protein loss at elevated CO2.
Sex-specific photosynthetic capacity and Na+ homeostasis in Populus euphratica exposed to NaCl stress and AMF inoculation
Authors: Wu Na , Li Zhen , Wu Fei , Zhen Lina
Published: November 2022

Soil salinity and associated land degradation are major ecological problems. Excess Na+ ions in soil impede the plant photosynthetic process and Na+ homeostasis status. Arbuscular mycorrhizal fungi (AMF) can alleviate salt stress in host plants. Although a number of studies have demonstrated that Na+ accumulation is decreased by mycorrhizae, the molecular mechanisms involved have received little attention from researchers. Populus euphratica is a typical natural woody tree with excellent salt tolerance. Due to its symbiosis forming capability with AMF, we explored the influence of Funneliformis mosseae on the growth, photosynthesis, and expression of three genes involved in Na+ homeostasis within dioecious P. euphratica under salt stress. The results indicated that salt stress significantly increases Na+ contents and inhibits growth status and photosynthetic capacity, especially in females. However, AMF had positive effects on the growth status, photosynthetic capacity and Na+ homeostasis, especially in males. The expression levels of NHX1 in shoots and HKT1 and SOS1 in roots, all of which are involved in Na+ homeostasis, were upregulated by F. mosseae under salt stress. For males, the beneficial effect of AMF centered on extruding, sequestering and long-distance transporting of Na+ ions . For females, the beneficial effect of AMF centered on extruding excessive Na+.
Novel trifluoromethylpyridine piperazine derivatives as potential plant activators
Authors: Zhang Wei , Guo Shengxin , Wang Ya , Tu Hong , Yu Lijiao , Zhao Zhichao , Wang Zhenchao , Wu Jian
Published: November 2022

Plant virus diseases seriously affect crop yield, especially tobacco mosaic virus (TMV) and cucumber mosaic virus (CMV). The development of plant immune activators has been an important direction in the innovation of new pesticides. Therefore, we designed and synthesized a series of trifluoromethyl pyridine piperazine derivatives (A1-A27), and explored the action mechanism of active compound. The antiviral activity test showed that compounds A1, A2, A3, A9, A10, A16, A17 and A21 possessed higher activities than commercialized ningnanmycin. Particularly, the in vivo antiviral activity indicated that compound A16 showed the most potent protective activity toward TMV (EC50 = 18.4 μg/mL) and CMV (EC50 = 347.8 μg/mL), compared to ningnanmycin (50.2 μg /mL for TMV, 359.6 μg/mL for CMV). The activities of defense enzyme, label -free proteomic and qRT-PCR analysis showed that compound A16 could enhance the defensive enzyme activities of superoxide dismutase (SOD),polyphenol oxidase (PPO) and phenylalanine ammonialyase (PAL), and activate the phenylpropanoid biosynthesis pathway to strenthen the antiviral activities of tobacco. This study provides reliable support for the development of new antiviral pesticides and potential antiviral mechanism.
Physiological basis and differentially expressed genes in the salt tolerance mechanism of Thalassia hemprichii
Authors: Shen Jie , Wu Zhongjie , Yin Lei , Chen Shiquan , Cai Zefu , Geng Xiaoxiao , Wang Daoru
Published: November 2022

Seagrass plays a vital role in the stability of marine ecology. The human development of marine resources has greatly affected the survival of seagrass. Seawater salinity is one of the important factors affecting its survival. Seagrass can survive in high saline environments for a long time and has evolved a variety of effective tolerance mechanisms. However, little is known about the molecular mechanisms underlying salinity tolerance by seagrass. Thalassia hemprichii is a seagrass species with a global distribution. It is also an ecologically important plant species in coastal waters. Nevertheless, the continuous environmental deterioration has gradually reduced the ecological niche of seagrasses. In this study, experiments were conducted to examine the effects of salinity changes on T. hemprichii. The result showed that the optimal salinity for T. hemprichii is 25 to 35 PSU. Although it can survive under high and low salinity, high mortality rates are common in such environments. Further analyses revealed that high salinity induces growth and developmental retardation in T. hemprichii and further causes yellowing. The parenchyma cells in T. hemprichii also collapse, the structure changes, soluble sugar accumulates rapidly, soluble proteins accumulate rapidly, the malondialdehyde (MDA) content reduces, and lipid peroxidation reduces in plant membranes. The molecular mechanisms of salt tolerance differ significantly between marine and terrestrial plants. We found 319 differentially expressed genes (DEGs). These genes regulate transport and metabolism, promoting environmental adaptation. The expression of these genes changed rapidly upon exposure of T. hemprichii to salinity stress for three hours. This is the first report on the physiological and biochemical changes and gene expression regulation of T. hemprichii under different salinity conditions. The findings of this study well deepen our understanding of T. hemprichii adaptations to changes in the shoal living environment.