bluuebunny/crossref_metadata_2025 huggingface dataset:
Case Report: Migraine-Induced Dystonia of the Lower Extremities
Authors: Jiang Ting , Xie Yinyin , Maimaiti Buajieerguli , Cheng Yu , Li Zhaoran , Meng Hongmei
Published: May 2022

Migraine is a highly prevalent neurological disorder characterized by recurrent, unilateral, or bilateral throbbing severe headaches. Currently, there are extremely rare cases of migraine-induced dystonia. A 52-year-old woman was admitted for intractable migraine for about 5 days and walking difficulties for 1 day. The symptom of an inability to walk appeared on the fourth day of the headache attack lasting for 1 day and resolved on its own as the headache subsided. The same symptoms appeared once 6 years ago. Neurological examination, brain Magnetic resonance imaging (MRI), laboratory tests of blood and cerebrospinal fluid (CSF) were normal. The contrast transcranial Doppler echocardiography (cTCD) revealed a latent and massive right-to-left shunt (RLS) after the release of the Valsalva maneuver. The patient was diagnosed with migraine-induced dystonia of the lower limbs. Oral ibuprofen and flunarizine and avoidance of increased chest pressure maneuvers were used for treatment and prevention. During the 6-month follow-up, the patient was free of headaches and walking difficulties. Our study reported a rare case of migraine-induced dystonia of the lower extremities.
Disparities Influencing Functional Outcomes Between Rural and Urban Patients With Acute Stroke
Authors: Llanos-Leyton Natalia , Pardo Carlos , Pinilla-Monsalve Gabriel D. , Arango Akemi , Valderrama Jaime , Pugliese Isabella , Amaya Pablo
Published: May 2022

Introduction

There is scarce information in Latin America about factors related to stroke patient outcomes in rural areas compared to urban ones.

Objective

To evaluate functional outcomes of stroke code patients from rural and urban areas and their relationship with socioeconomic disparity.

Methods

Prospective cohort study included patients of urban, semi-urban, and rural origin with stroke code from a high complexity hospital in southwestern Colombia between 2018 and 2019. Demographic, clinical data modified Rankin at discharge, and 3-month follow-up were analyzed. The poverty index, barriers to health access and availability of ambulances by the municipality was assessed at an ecological level.

Results

Five hundred and fifty five stroke patients were registered, 21.2% from rural areas, 432 (77.98%) had an ischemic stroke. There were no significant differences in sociodemographic factors and medical background. Urban patients had lower reperfusion therapies rates (23.25%). Favorable mRS at discharge (<3) was higher in urban areas (63.03%) and mortality was superior in rural patients (13.56%). The ambulance rate in semi-urban and rural areas was as low as 0.03 per 100.000 inhabitants, the poverty index was 11.9% in urban areas vs. 23.3% in semi urban and rural areas.

Conclusions

Rural patients treated in our center were more likely to present with severe strokes and unfavorable mRS at hospital discharge and 3-month follow-up compared to urban, despite having similar risk factors. There is an inverse relationship, which is not related to the poverty rate or the percentage of people with barriers to access to health. There is a need for further studies that assess barriers inherent in rural patients and establish a regional stroke network.
The Effects of a 3-Week Heartbeat Perception Training on Interoceptive Abilities
Authors: Schillings Christine , Karanassios Georgios , Schulte Niklas , Schultchen Dana , Pollatos Olga
Published: May 2022

Recent studies showed promising short-term effects of heartbeat perception training on interoceptive abilities. Research on the effects of heartbeat perception training on interoceptive abilities over time is sparse. Therefore, the aim of this study was to examine the short-term effects and the effects of a 3-week heartbeat perception training over time on interoceptive abilities, namely, cardiac interoceptive accuracy (IAc) and interoceptive sensibility (IS). A total of 40 healthy participants were randomized to the intervention group (n = 20) or the control group (n = 20). The intervention group conducted three cardiac biofeedback sessions (one per week) at the laboratory, whereas the control group watched a documentary instead. Interoceptive abilities were assessed via the heartbeat perception task (IAc) and confidence ratings (IS) at baseline, after each laboratory session, and 1 week after the last session (post-measurement). IAc was significantly increased in the intervention group compared to the control group after the first training session (short-term effect). There were no significant improvements in IS due to the first session, and neither on IAc nor IS over time. Descriptive trends of improved interoceptive abilities over time were found in both groups. Single session of heartbeat perception training seems to be a promising approach to improve IAc. Future research should further investigate the long-term effects of diverse heartbeat perception training varying in frequency and intensity of the training sessions in diverse samples aiming to improve interoceptive abilities.
Diprotin A TFA Exerts Neurovascular Protection in Ischemic Cerebral Stroke
Authors: Zhou Ming-Yue , Zhang Ya-Jie , Ding Hong-Mei , Wu Wei-Feng , Cai Wei-Wei , Wang Yan-Qiang , Geng De-Qin
Published: May 2022

Background

It has been established that the dipeptidyl peptidase-4 (DPP-4) inhibitor Diprotin A TFA can reduce vascular endothelial (VE)-cadherin disruption by inhibiting the increase in cleaved β-catenin in response to hypoxia, thereby protecting the vascular barrier of human umbilical vein endothelial cells. In this study, we sought to investigate the possible effect of Diprotin A TFA on the VE barrier after cerebral ischemic stroke in mice.

Methods

C57BL/6J mice were divided into five groups, namely, (1) sham, (2) stroke, (3) stroke + dimethyl sulfoxide (DMSO), (4) stroke + Diprotin A TFA, and (5) stroke + Diprotin A TFA + XAV-939. First, the cerebral ischemia model was established by photothrombotic ischemia, followed by intraperitoneal injection with Diprotin A TFA and XAV-939 at doses of 70 μg/kg and 40 mg/kg 30 min once in the morning and once in the evening for 3 days. Immunofluorescence staining and Western blot methods were used to analyze the expression of vascular and blood-brain barrier (BBB)-associated molecular markers in the peri-infarct area.

Results

Compared with the vehicle control group, we found that mice injected with Diprotin A TFA exhibited reduced cerebral infarction volume, increased vascular area and length around the brain injury, increased pericyte and basement membrane coverage, upregulated expression of BBB tight junction proteins, and improved their BBB permeability, whereas the group injected with both drug and inhibitor exhibited significantly aggravated vascular injury and BBB permeability.

Conclusion

Diprotin A TFA can reduce VE-cadherin disruption by inhibiting ischemia-hypoxia-induced β-catenin cleavage to protect blood vessels.
Navigated Intraoperative 3D Ultrasound in Glioblastoma Surgery: Analysis of Imaging Features and Impact on Extent of Resection
Authors: Saß Benjamin , Zivkovic Darko , Pojskic Mirza , Nimsky Christopher , Bopp Miriam H. A.
Published: May 2022

Background

Neuronavigation is routinely used in glioblastoma surgery, but its accuracy decreases during the operative procedure due to brain shift, which can be addressed utilizing intraoperative imaging. Intraoperative ultrasound (iUS) is widely available, offers excellent live imaging, and can be fully integrated into modern navigational systems. Here, we analyze the imaging features of navigated i3D US and its impact on the extent of resection (EOR) in glioblastoma surgery.

Methods

Datasets of 31 glioblastoma resection procedures were evaluated. Patient registration was established using intraoperative computed tomography (iCT). Pre-operative MRI (pre-MRI) and pre-resectional ultrasound (pre-US) datasets were compared regarding segmented tumor volume, spatial overlap (Dice coefficient), the Euclidean distance of the geometric center of gravity (CoG), and the Hausdorff distance. Post-resectional ultrasound (post-US) and post-operative MRI (post-MRI) tumor volumes were analyzed and categorized into subtotal resection (STR) or gross total resection (GTR) cases.

Results

The mean patient age was 59.3 ± 11.9 years. There was no significant difference in pre-resectional segmented tumor volumes (pre-MRI: 24.2 ± 22.3 cm3; pre-US: 24.0 ± 21.8 cm3). The Dice coefficient was 0.71 ± 0.21, the Euclidean distance of the CoG was 3.9 ± 3.0 mm, and the Hausdorff distance was 12.2 ± 6.9 mm. A total of 18 cases were categorized as GTR, 10 cases were concordantly classified as STR on MRI and ultrasound, and 3 cases had to be excluded from post-resectional analysis. In four cases, i3D US triggered further resection.

Conclusion

Navigated i3D US is reliably adjunct in a multimodal navigational setup for glioblastoma resection. Tumor segmentations revealed similar results in i3D US and MRI, demonstrating the capability of i3D US to delineate tumor boundaries. Additionally, i3D US has a positive influence on the EOR, allows live imaging, and depicts brain shift.
Hsian-Tsao (Mesona chinensis Benth.) Extract Improves the Thermal Tolerance of Drosophila melanogaster
Authors: Huang Yan , Cai Pumo , Su Xinxin , Zheng Mingjing , Chi Wenwen , Lin Shaoling , Huang Zhiwei , Qin Si , Zeng Shaoxiao
Published: May 2022

Global warming has prompted scientific communities to consider how to alleviate thermal stress in humans and animals. The present study assessed the supplementation of hsian-tsao extract (HTE) on thermal stress in Drosophila melanogaster and preliminarily explicated its possible physiological and molecular mechanisms. Our results indicated that the lethal time for 50% of female flies fed on HTE was significantly longer than that of male flies at the same heat stress temperature. Under thermal stress, the survival time of females was remarkably increased in the HTE addition groups compared to the non-addition group. Thermal hardening by acute exposure to 36°C for 30 min (9:00 to 9:30 a.m.) every day could significantly prolong the longevity of females. Without thermal hardening, HTE increased the antioxidant capacity of females under heat stress, accompanied by an increment of catalase (CAT) activity, and the inhibition for hydroxyl radicals (OH⋅) and superoxide anions (⋅O2–). Superoxide dismutase (SOD) activity and the inhibition for ⋅O2– was significantly affected by thermal hardening in the non-HTE addition groups, and significant differences were shown in CAT and SOD activities, and the inhibition for ⋅O2– among groups with thermal hardening. After heat exposure, heat shock protein 70 (Hsp70) was only up-regulated in the group with high levels of added HTE compared with the group without and this was similar in the thermal hardening group. It was concluded that the heat stress-relieving ability of HTE might be partly due to the enhancement of enzymatic activities of SOD and CAT, and the inhibition for OH⋅ and ⋅O2–. However, the expression levels of Hsp70 were not well related to thermal tolerance or heat survival.
Antioxidant and Anti-inflammatory Extracts From Sea Cucumbers and Tunicates Induce a Pro-osteogenic Effect in Zebrafish Larvae
Authors: Carletti Alessio , Cardoso Carlos , Lobo-Arteaga Jorge , Sales Sabrina , Juliao Diana , Ferreira Inês , Chainho Paula , Dionísio Maria Ana , Gaudêncio Maria J. , Afonso Cláudia , Lourenço Helena , Cancela M. Leonor , Bandarra Narcisa M. , Gavaia Paulo J.
Published: May 2022

Bone metabolic disorders such as osteoporosis are characterized by the loss of mineral from the bone tissue leading to its structural weakening and increased susceptibility to fractures. A growing body of evidence suggests that inflammation and oxidative stress play an important role in the pathophysiological processes involved in the rise of these conditions. As the currently available therapeutic strategies are often characterized by toxic effects associated with their long-term use, natural antioxidants and anti-inflammatory compounds such as polyphenols promise to be a valuable alternative for the prevention and treatment of these disorders. In this scope, the marine environment is becoming an important source of bioactive compounds with potential pharmacological applications. Here, we explored the bioactive potential of three species of holothurians (Echinodermata) and four species of tunicates (Chordata) as sources of antioxidant and anti-inflammatory compounds with a particular focus on polyphenolic substances. Hydroethanolic and aqueous extracts were obtained from animals’ biomass and screened for their content of polyphenols and their antioxidant and anti-inflammatory properties. Hydroethanolic fractions of three species of tunicates displayed high polyphenolic content associated with strong antioxidant potential and anti-inflammatory activity. Extracts were thereafter tested for their capacity to promote bone formation and mineralization by applying an assay that uses the developing operculum of zebrafish (Danio rerio) to assess the osteogenic activity of compounds. The same three hydroethanolic fractions from tunicates were characterized by a strong in vivo osteogenic activity, which positively correlated with their anti-inflammatory potential as measured by COX-2 inhibition. This study highlights the therapeutic potential of polyphenol-rich hydroethanolic extracts obtained from three species of tunicates as a substrate for the development of novel drugs for the treatment of bone disorders correlated to oxidative stress and inflammatory processes.
Absorption and Resonance Rayleigh Scattering Spectra of Ag(I) and Erythrosin System and Their Analytical Application in Food Safety
Authors: Wang Jian , Liu Shaopu , Shen Wei
Published: May 2022

In pH 4.4∼4.6 weakly acidic media, erythrosine (Ery) can react with Ag(I) to form hydrophobic ion-association complex, which can further aggregate to form nanoparticles with an average particle size of about 45 nm under the action of water phase extrusion and van der Waals force. As a result, it could lead to a decrease of absorbance, a significant enhancement of resonance Rayleigh scattering (RRS) and the appearance of a new emission spectrum. Based on these Phenomena, two new methods (spectrophotometry and RRS) were established for the determination of trace Ag(I). The detection limits for Ag(I) by spectrophotometry and RRS are 9.74 and 0.12 ng/ml, respectively. In this paper, we have investigated the formation of nanoparticles, the optimum reaction conditions, the influence factors, explored the reason for enhancement of the scattering intensity and the effect of coexisting substance. This research shows that RRS method not only has good selectivity and high sensitivity, but also is simple and rapid. Analyzing of actual samples and standard samples, the determination result of this method is consistent with that of standard methods (Flame atomic absorption spectroscopy). Thus the method had potential feasibility to analysis for Ag(I) in the environmental water samples, pharmaceutical, and food industries.
Transfer of IGF2BP3 Through Ara-C-Induced Apoptotic Bodies Promotes Survival of Recipient Cells
Authors: Gou Junjie , Li Hongjiao , Bi Jingjing , Pang Xingchen , Li Xiang , Wang Yi
Published: May 2022

Cytosine arabinoside (Ara-C) has been the standard therapeutic agent for myelodysplastic syndromes (MDS) and adult acute myeloid leukemia (AML) patients for decades. Considerable progress has been made in development of new treatments for MDS/AML patients, but drug resistance remains a major clinical problem. Apoptotic bodies (ABs), produced by late apoptotic cells, can enclose bioactive components that affect cell-cell interactions and disease progression. We isolated and identified drug-induced ABs from Ara-C-tolerance cells. Treatment of sensitive cells with Ara-C-induced ABs resulted in Ara-C-resistant phenotype. We further investigated components and functions of Ara-C-induced ABs. Proteomics analysis in combination with mass spectrometry revealed that Ara-C-induced ABs carried numerous RNA-binding proteins, notably including insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3). Delivery of AB-encapsulated IGF2BP3 promoted survival of recipient cells by activating PI3K-AKT and p42-44 MAPK pathways. High IGF2BP3 level in ABs from MDS/AML patient plasma was correlated with poor overall survival. Our findings demonstrate that AB-derived IGF2BP3 plays an essential role in acquired Ara-C resistance in MDS/AML patients, and is a potential therapeutic target for suppression of Ara-C resistance.
ST08 Altered NF-κB Pathway in Breast Cancer Cells In Vitro as Revealed by miRNA-mRNA Analysis and Enhanced the Effect of Cisplatin on Tumour Reduction in EAC Mouse Model
Authors: Nirgude Snehal , Desai Sagar , Mahadeva Raghunandan , Ravindran Febina , Choudhary Bibha
Published: May 2022

ST08 is a novel curcumin derivative that exhibited apoptotic and anti-migratory activity in MDA-MB-231, triple-negative breast cancer cells reported earlier. In this study, we further explored the anticancer properties of ST08. ST08 reduced tumor burden in vivo and induced apoptosis through the mitochondrial pathway both in vitro and in vivo. ST08 potentiated the effect of cisplatin in vitro and in vivo in mouse EAC breast cancer models with minimal toxicity. ST08 induced alterations in the gene expression were studied by parallel analysis of miRNA and mRNA. 74 differentially expressed miRNA regulated 114 mRNA in triple-negative (MDA-MB-231) cancer cells. Pathway related to the ECM was altered in mesenchymal MDA-MB-231 cells. We constructed a unique miRNA-mRNA interaction network, and one of the pathways regulated by miRNA was NF-κB. Targets of NF-κB like MMP1, PTX3, and MMP2 were downregulated in MDA-MB-231 in response to ST08 treatment. PMA induced cell proliferation was abrogated by ST08 treatment, and no additional cell cytotoxicity was observed when used in combination with IKK-16 indicating ST08 regulation of NF-κB pathway in MDA-MB-231 cells.
ROBO1 p.E280* Loses the Inhibitory Effects on the Proliferation and Angiogenesis of Wild-Type ROBO1 in Cholangiocarcinoma by Interrupting SLIT2 Signal
Authors: Zhou Tao , Zhang Yaodong , Chen Yananlan , Shan Jijun , Wang Jifei , Wang Yirui , Chang Jiang , Jiang Wangjie , Chen Ruixiang , Wang Ziyi , Shi Xiaoli , Yu Yue , Li Changxian , Li Xiangcheng
Published: May 2022

Background

Cholangiocarcinoma (CCA) remains one of the most lethal malignancies with an increasing incidence globally. Through whole-exome sequencing of 67 CCA tissues, we identified new mutated genes in CCA, including MACF1, METTL14, ROBO1, and so on. The study was designed to explore the effects and mechanism of ROBO1 wild type (ROBO1WT) and ROBO1E280* mutation on the progression of CCA.

Methods

Whole-exome sequencing was performed to identify novel mutations in CCAs. In vitro and in vivo experiments were used to examine the function and mechanism of ROBO1WT and ROBO1E280* in cholangiocarcinoma. A tissue microarray including 190 CCA patients and subsequent analyses were performed to indicate the clinical significance of ROBO1.

Results

Through whole-exome sequencing, we identified a novel CCA-related mutation, ROBO1E280*. ROBO1 was downregulated in CCA tissues, and the downregulation of ROBO1 was significantly correlated with poor prognosis. ROBO1WT suppressed the proliferation and angiogenesis of CCA in vitro and in vivo, while ROBO1E280* lost the inhibitory effects. Mechanically, ROBO1E280* translocated from the cytomembrane to the cytoplasm and interrupted the interaction between SLIT2 and ROBO1. We identified OLFML3 as a potential target of ROBO1 by conducting RNA-Seq assays. OLFML3 expression was downregulated by ROBO1WT and recovered by ROBO1E280*. Functionally, the silence of OLFML3 inhibited CCA proliferation and angiogenesis and was sufficient to repress the loss-of-function role of ROBO1E280*.

Conclusions

These results suggest that ROBO1 may act as a tumor suppressor and potential prognostic marker for CCA. ROBO1E280* mutation is a loss-of-function mutation, and it might serve as a candidate therapeutic target for CCA patients.
Statin Use and the Risk of Prostate Cancer Biochemical Recurrence Following Definitive Therapy: A Systematic Review and Meta-Analysis of Cohort Studies
Authors: Sun Jian-Xuan , Liu Chen-Qian , Zhong Xing-Yu , Xu Jin-Zhou , An Ye , Xu Meng-Yao , Hu Jia , Zhang Zong-Biao , Xia Qi-Dong , Wang Shao-Gang
Published: May 2022

Background

Numerous studies have reported the role of statins on biochemical recurrence (BCR) among patients with prostate cancer (PCa) after definite treatment. However, the conclusions of these studies are contradictory. We aimed to determine the effect of statins on BCR of PCa using a systematic review and meta-analysis.

Methods

We searched PubMed (Medline) and other databases for cohort studies evaluating the effect of statins on the BCR of patients with PCa between January 1, 2000, and December 31, 2021. The random effects (RE) model and quality effects (QE) model were used to calculate the pooled hazard ratio (pHR) and pooled risk ratio (pRR) and their 95% confidence interval (95% CI).

Results

A total of 33 cohort studies were finally selected and included in this systematic review and meta-analysis. Statin use was significantly associated with a 14% reduction in the HR of BCR (pHR: 0.86, 95% CI: 0.78 to 0.95, I2 = 64%, random effects model, 31 studies) and a 26% reduction in the RR of BCR (pRR: 0.74, 95% CI: 0.57 to 0.94, 24,591 patients, I2 = 88%, random effects model, 15 studies) among patients with PCa. The subgroup analyses showed that statins could result in 22% reduction in the HR of BCR (pHR: 0.78, 95% CI: 0.61 to 0.98, I2 = 57%, random effects model) among patients accepting radiotherapy (RT).

Conclusions

Our study suggests that statins have a unique role in the reduction of BCR in patients with PCa after definite treatment, especially RT. In the future, more clinical trials and in vitro and animal experiments are needed to further verify the effects of statins in PCa and the potential mechanisms.
Cell Based Treatment of Autoimmune Diseases in Children
Authors: Jones Olcay Y. , McCurdy Deborah
Published: May 2022

Mesenchymal stem cells have recently been recoined as medicinal signaling cells (MSC) for their ability to promote tissue homeostasis through immune modulation, angiogenesis and tropism. During the last 20 years, there has been a plethora of publications using MSC in adults and to lesser extent neonates on a variety of illnesses. In parts of the world, autologous and allogeneic MSCs have been purified and used to treat a range of autoimmune conditions, including graft versus host disease, Crohn’s disease, multiple sclerosis, refractory systemic lupus erythematosus and systemic sclerosis. Generally, these reports are not part of stringent clinical trials but are of note for good outcomes with minimal side effects. This review is to summarize the current state of the art in MSC therapy, with a brief discussion of cell preparation and safety, insights into mechanisms of action, and a review of published reports of MSC treatment of autoimmune diseases, toward the potential application of MSC in treatment of children with severe autoimmune diseases using multicenter clinical trials and treatment algorithms.
Cost-Effectiveness of Tislelizumab Versus Docetaxel for Previously Treated Advanced Non-Small-Cell Lung Cancer in China
Authors: Gong Jinhong , Su Dan , Shang Jingjing , Xu Shan , Tang Lidan , Sun Zhiqiang , Liu Guangjun
Published: May 2022

Background: Tislelizumab, a new high-affinity programmed cell death protein-1 (PD-1) inhibitor, significantly prolonged the overall survival in pretreated non-small-cell lung cancer (NSCLC). This study aimed to assess the cost-effectiveness of tislelizumab versus docetaxel for this population in China.

Methods: A three-state partitioned survival model was developed to simulate advanced NSCLC. Efficacy and safety data were based on a global phase 3 clinical trial (RATIONALE 303). Utilities were mainly extracted from previously published resources. Costs were calculated from the Chinese healthcare system’s perspective, and only direct medical costs were covered. The main outcomes included total costs, life years (LYs), quality-adjusted life years (QALYs), and incremental cost effectiveness ratio (ICER). One-way and probabilistic sensitivity analyses were carried to test the uncertainty of the modeling results. In addition, several scenarios including tislelizumab price before negotiation, different docetaxel price calculation, 50-year time horizon, and alternative utility values were assessed.

Results: The model predicted an average gain of 0.62 LYs and 0.51 QALY for tislelizumab vs. docetaxel, at the additional cost of $9,219. The resulting ICER was $15,033.92/LY and $18,122.04/QALY, both below the cost-effective threshold (CET) of three times gross domestic product (GDP) per capita in China. Sensitivity analyses showed that the results are robust over a plausible range for majority of inputs. Utility of progression-free survival (PFS), followed by the price of tislelizumab, had the greatest impact on the ICER. The probability of being cost-effective for tislelizumab was 96.79% at the CET we set.

Conclusion: Tislelizumab improves survival, increases QALYs, and can be considered a cost-effective option at current price compared with docetaxel for pretreated advanced NSCLC in China.
Iguratimod Attenuates Macrophage Polarization and Antibody-Mediated Rejection After Renal Transplant by Regulating KLF4
Authors: Hang Zhou , Wei Jintao , Zheng Ming , Gui Zeping , Chen Hao , Sun Li , Fei Shuang , Han Zhijian , Tao Jun , Wang Zijie , Tan Ruoyun , Gu Min
Published: May 2022

Background: This study aimed to explore the effect and mechanism of iguratimod (IGT) on M1 macrophage polarization and antibody-mediated rejection (ABMR) after renal transplant.

Methods: Bioinformatics analysis was performed using three public databases derived from the GEO database. Sprague–Dawley (SD) rats were pre-sensitized with donors of Wistar rats in skin transplantation and a rat renal transplant ABMR model was established from the donors to skin pre-sensitized recipients. Subsequently, IGT was treated on the ABMR model. Routine staining and immunofluorescence (IF) staining were performed to observe the pathological changes in each group and flow cytometry was performed to detect the changes of DSA titers in peripheral blood. In addition, bone-marrow-derived macrophage (BMDM) was extracted and interfered with IGT to explore the effect of IGT in vivo. PCR, IF staining, and Western blot were used to detect the expression of related genes and proteins.

Results: Bioinformatics analysis revealed that several immune cells were significantly infiltrated in the ABMR allograft, while M1 macrophage was noticed with the most significance. Results of IF staining and PCR proved the findings of the bioinformatics analysis. Based on this, IGT was observed to significantly attenuate the degree of peritubular capillary vasculitis and arteriolitis in the rat renal transplant ABMR model, whereas it decreases the expression of C4d and reduces the titer of DSA. Results in vitro suggested that M1 macrophage-related transcripts and proteins were significantly reduced by the treatment of IGT in a dose- and time-dependent manner. Furthermore, IGT intervention could remarkably decrease the expression of KLF4.

Conclusion: Polarization of M1 macrophages may aggravate ABMR after renal transplant by promoting DSA-mediated endothelial cell injury, and IGT may attenuate the pathogenesis of ABMR by targeting KLF4.
Drugsniffer: An Open Source Workflow for Virtually Screening Billions of Molecules for Binding Affinity to Protein Targets
Authors: Venkatraman Vishwesh , Colligan Thomas H. , Lesica George T. , Olson Daniel R. , Gaiser Jeremiah , Copeland Conner J. , Wheeler Travis J. , Roy Amitava
Published: May 2022

The SARS-CoV2 pandemic has highlighted the importance of efficient and effective methods for identification of therapeutic drugs, and in particular has laid bare the need for methods that allow exploration of the full diversity of synthesizable small molecules. While classical high-throughput screening methods may consider up to millions of molecules, virtual screening methods hold the promise of enabling appraisal of billions of candidate molecules, thus expanding the search space while concurrently reducing costs and speeding discovery. Here, we describe a new screening pipeline, called drugsniffer, that is capable of rapidly exploring drug candidates from a library of billions of molecules, and is designed to support distributed computation on cluster and cloud resources. As an example of performance, our pipeline required ∼40,000 total compute hours to screen for potential drugs targeting three SARS-CoV2 proteins among a library of ∼3.7 billion candidate molecules.
Biomechanical Regulatory Factors and Therapeutic Targets in Keloid Fibrosis
Authors: Feng Fan , Liu Mingying , Pan Lianhong , Wu Jiaqin , Wang Chunli , Yang Li , Liu Wanqian , Xu Wei , Lei Mingxing
Published: May 2022

Keloids are fibroproliferative skin disorder caused by abnormal healing of injured or irritated skin and are characterized by excessive extracellular matrix (ECM) synthesis and deposition, which results in excessive collagen disorders and calcinosis, increasing the remodeling and stiffness of keloid matrix. The pathogenesis of keloid is very complex, and may include changes in cell function, genetics, inflammation, and other factors. In this review, we aim to discuss the role of biomechanical factors in keloid formation. Mechanical stimulation can lead to excessive proliferation of wound fibroblasts, deposition of ECM, secretion of more pro-fibrosis factors, and continuous increase of keloid matrix stiffness. Matrix mechanics resulting from increased matrix stiffness further activates the fibrotic phenotype of keloid fibroblasts, thus forming a loop that continuously invades the surrounding normal tissue. In this process, mechanical force is one of the initial factors of keloid formation, and matrix mechanics leads to further keloid development. Next, we summarized the mechanotransduction pathways involved in the formation of keloids, such as TGF-β/Smad signaling pathway, integrin signaling pathway, YAP/TAZ signaling pathway, and calcium ion pathway. Finally, some potential biomechanics-based therapeutic concepts and strategies are described in detail. Taken together, these findings underscore the importance of biomechanical factors in the formation and progression of keloids and highlight their regulatory value. These findings may help facilitate the development of pharmacological interventions that can ultimately prevent and reduce keloid formation and progression.
The Solution Comparison of Time-Fractional Non-Linear Dynamical Systems by Using Different Techniques
Authors: Khan Hassan , Kumam Poom , Khan Qasim , Khan Shahbaz , Hajira  , Arshad Muhammad , Sitthithakerngkiet Kanokwan
Published: May 2022

This comparative study of fractional nonlinear fractional Burger’s equations and their systems has been done using two efficient analytical techniques. The generalized schemes of the proposed techniques for the suggested problems are obtained in a very sophisticated manner. The numerical examples of Burger’s equations and their systems have been solved using Laplace residual power series method and Elzaki transform decomposition method. The obtained results are compared through graphs and tables. The error tables have been constructed to show the associated accuracy of each method. The procedures of both techniques are simple and attractive and, therefore, can be extended to solve other important fractional order problems.
Performance-Related Physiological and Haematological Changes During Pregnancy and Postpartum in a Well-Trained Cyclist Performing Endurance Training
Authors: Almquist Nicki Winfield , Sandbakk Øyvind , Solli Guro Strøm
Published: May 2022

Purpose: To describe the performance-related physiological and haematological changes in a well-trained cyclist (peak oxygen uptake, VO2peak: 54.9 ml min−1·kg−1) performing endurance training during pregnancy and postpartum.

Methods: Training data was systemized by training form (endurance and resistance), intensity (low- (LIT), moderate-, and high-intensity training), and modality (cycling, running, hiking, XC-skiing, strength training and other). Power output at 4 mmol L−1 [BLa−] (L4), maximal aerobic power (Wmax), and VO2peak as well as haemoglobin mass, blood volume, plasma volume and red blood cell volume (RBCV) were measured at different time points during pregnancy and 12 weeks postpartum.

Results: L4 and Wmax increased by 3% while absolute VO2peak was unaltered from gestational wk 2 to 14, despite 12 and 14% increases in RBCV and BV. After delivery, BV was reduced by 7% but RBCV was maintained 5% above start-pregnancy levels, while VO2peak almost returned to (-1%), and Wmax increased by 5% above start-pregnancy levels 12 weeks postpartum.

Conclusion: This case-study illustrates a disassociation between increases in haematological values and VO2peak during pregnancy. Furthermore, a quick resumption of LIT and a gradually increasing intensity of training in the 12 weeks following delivery ensured a return to start-pregnancy levels of VO2peak and corresponding improvements in Wmax. Although general recommendations cannot be given on the basis of these data, this study provides a framework for investigating pregnant endurance athletes and contributes to the generation of new hypotheses in this field.
Dyssynchronous Left Ventricular Activation is Insufficient for the Breakdown of Wringing Rotation
Authors: Gerach Tobias , Appel Stephanie , Wilczek Jacek , Golba Krzysztof S. , Jadczyk Tomasz , Loewe Axel
Published: May 2022

Cardiac resynchronization therapy is a valuable tool to restore left ventricular function in patients experiencing dyssynchronous ventricular activation. However, the non-responder rate is still as high as 40%. Recent studies suggest that left ventricular torsion or specifically the lack thereof might be a good predictor for the response of cardiac resynchronization therapy. Since left ventricular torsion is governed by the muscle fiber orientation and the heterogeneous electromechanical activation of the myocardium, understanding the relation between these components and the ability to measure them is vital. To analyze if locally altered electromechanical activation in heart failure patients affects left ventricular torsion, we conducted a simulation study on 27 personalized left ventricular models. Electroanatomical maps and late gadolinium enhanced magnetic resonance imaging data informed our in-silico model cohort. The angle of rotation was evaluated in every material point of the model and averaged values were used to classify the rotation as clockwise or counterclockwise in each segment and sector of the left ventricle. 88% of the patient models (n = 24) were classified as a wringing rotation and 12% (n = 3) as a rigid-body-type rotation. Comparison to classification based on in vivo rotational NOGA XP maps showed no correlation. Thus, isolated changes of the electromechanical activation sequence in the left ventricle are not sufficient to reproduce the rotation pattern changes observed in vivo and suggest that further patho-mechanisms are involved.
Metabonomic Characteristics of Myocardial Diastolic Dysfunction in Type 2 Diabetic Cardiomyopathy Patients
Authors: Hao Mingyu , Deng Jianxin , Huang Xiaohong , Li Haiyan , Ou Huiting , Cai Xiangsheng , She Jiajie , Liu Xueting , Chen Ling , Chen Shujuan , Liu Wenlan , Yan Dewen
Published: May 2022

Diabetic cardiomyopathy (DCM) is one of the most essential cardiovascular complications in diabetic patients associated with glucose and lipid metabolism disorder, fibrosis, oxidative stress, and inflammation in cardiomyocytes. Despite increasing research on the molecular pathogenesis of DCM, it is still unclear whether metabolic pathways and alterations are probably involved in the development of DCM. This study aims to characterize the metabolites of DCM and to identify the relationship between metabolites and their biological processes or biological states through untargeted metabolic profiling. UPLC-MS/MS was applied to profile plasma metabolites from 78 patients with diabetes (39 diabetes with DCM and 39 diabetes without DCM as controls). A total of 2,806 biochemical were detected. Compared to those of DM patients, 78 differential metabolites in the positive-ion mode were identified in DCM patients, including 33 up-regulated and 45 down-regulated metabolites; however, there were only six differential metabolites identified in the negative mode including four up-regulated and two down-regulated metabolites. Alterations of several serum metabolites, including lipids and lipid-like molecules, organic acids and derivatives, organic oxygen compounds, benzenoids, phenylpropanoids and polyketides, and organoheterocyclic compounds, were associated with the development of DCM. KEGG enrichment analysis showed that there were three signaling pathways (metabolic pathways, porphyrin, chlorophyll metabolism, and lysine degradation) that were changed in both negative- and positive-ion modes. Our results demonstrated that differential metabolites and lipids have specific effects on DCM. These results expanded our understanding of the metabolic characteristics of DCM and may provide a clue in the future investigation of reducing the incidence of DCM. Furthermore, the metabolites identified here may provide clues for clinical management and the development of effective drugs.
Therapeutic Potential of Electromyostimulation (EMS) in Critically Ill Patients—A Systematic Review
Authors: Balke Maryam , Teschler Marc , Schäfer Hendrik , Pape Pantea , Mooren Frank C. , Schmitz Boris
Published: May 2022

Ample evidence exists that intensive care unit (ICU) treatment and invasive ventilation induce a transient or permanent decline in muscle mass and function. The functional deficit is often called ICU-acquired weakness with critical illness polyneuropathy (CIP) and/or myopathy (CIM) being the major underlying causes. Histopathological studies in ICU patients indicate loss of myosin filaments, muscle fiber necrosis, atrophy of both muscle fiber types as well as axonal degeneration. Besides medical prevention of risk factors such as sepsis, hyperglycemia and pneumonia, treatment is limited to early passive and active mobilization and one third of CIP/CIM patients discharged from ICU never regain their pre-hospitalization constitution. Electromyostimulation [EMS, also termed neuromuscular electrical stimulation (NMES)] is known to improve strength and function of healthy and already atrophied muscle, and may increase muscle blood flow and induce angiogenesis as well as beneficial systemic vascular adaptations. This systematic review aimed to investigate evidence from randomized controlled trails (RCTs) on the efficacy of EMS to improve the condition of critically ill patients treated on ICU. A systematic search of the literature was conducted using PubMed (Medline), CENTRAL (including Embase and CINAHL), and Google Scholar. Out of 1,917 identified records, 26 articles (1,312 patients) fulfilled the eligibility criteria of investigating at least one functional measure including muscle function, functional independence, or weaning outcomes using a RCT design in critically ill ICU patients. A qualitative approach was used, and results were structured by 1) stimulated muscles/muscle area (quadriceps muscle only; two to four leg muscle groups; legs and arms; chest and abdomen) and 2) treatment duration (≤10 days, >10 days). Stimulation parameters (impulse frequency, pulse width, intensity, duty cycle) were also collected and the net EMS treatment time was calculated. A high grade of heterogeneity between studies was detected with major cofactors being the analyzed patient group and selected outcome variable. The overall efficacy of EMS was inconclusive and neither treatment duration, stimulation site or net EMS treatment time had clear effects on study outcomes. Based on our findings, we provide practical recommendations and suggestions for future studies investigating the therapeutic efficacy of EMS in critically ill patients.

Systematic Review Registration: [https://www.crd.york.ac.uk/prospero/], identifier [CRD42021262287].
Experimental Preeclampsia Causes Long-Lasting Hippocampal Vascular Dysfunction and Memory Impairment
Authors: Johnson Abbie C. , Tremble Sarah M. , Cipolla Marilyn J.
Published: May 2022

Preeclampsia (PE) is a hypertensive disorder of pregnancy that is associated with memory impairment, cognitive decline and brain atrophy later in life in women at ages as young as early-to-mid 40 s. PE increases the risk of vascular dementia three-fold, however, long-lasting effects of PE on the vasculature of vulnerable brain regions involved in memory and cognition, such as the hippocampus, remain unknown. Here, we used a rat model of experimental PE (ePE) induced by maintaining rats on a 2% cholesterol diet beginning on day 7 of gestation to investigate hippocampal function later in life. Hippocampal-dependent memory and hippocampal arteriole (HA) function were determined in Sprague Dawley rats 5 months after either a healthy pregnancy or ePE (n = 8/group). Rats that had ePE were hypertensive and had impaired vasoreactivity of HAs to mediators involved in matching neuronal activity with local blood flow (i.e., neurovascular coupling). ePE rats also had impaired long-term memory, but not spatial memory. Thus, this model of ePE mimics some of the long-lasting cardiovascular and cognitive consequences that occur in women who previously had PE. These findings suggest endothelial and vascular smooth muscle dysfunction of HAs were present months after PE that could impair hippocampal neurovascular coupling. This represents a novel vascular mechanism by which PE causes early-onset dementia.
Piezo1 Affects Temporomandibular Joint Osteoarthritis by Influencing pSmad3
Authors: Wu Chuan-Bin , Ma Tie , Ma Lin , Wang Qiang , Zhou Qing
Published: May 2022

Objective: The aim of this research was to study the expression of Piezo1 in a rat temporomandibular joint osteoarthritis animal model and to explore its mechanism for inducing inflammatory changes.

Methods: A total of 24male SD rats aged approximately 8 weeks were randomly divided into three groups: the blank control group, complete Freund’s adjuvant group (CFA), and CFA + inhibitor (GsMTx4) group. After 3 weeks, the condylar heads of the rats were evaluated by micro-CT, HE, immunohistochemistry, safranin O staining, and other experimental techniques. Protein was extracted from the subchondral bone, and the changes in Piezo1, Smad3, and pSmad3 levels in each group were detected by Western blotting. p < 0.05 was considered to indicate statistical significance.

Results: The degree of damage to the cartilage and subchondral bone in the Piezo1 inhibitor group was smaller than that in the CFA group. The expression level of Piezo1 in the CFA group was higher than that in the other groups, and the difference was statistically significant. The expression of pSmad3 in the CFA group was also higher than that in the other groups (p < 0.05).

Conclusion: Piezo1 is expressed in the condylar cartilage and subchondral bone of rats, and the degree of condylar destruction can be improved by influencing the pSmad3 expression.
MdJa2 Participates in the Brassinosteroid Signaling Pathway to Regulate the Synthesis of Anthocyanin and Proanthocyanidin in Red-Fleshed Apple
Authors: Su Mengyu , Wang Shuo , Liu Wenjun , Yang Ming , Zhang Zongying , Wang Nan , Chen Xuesen
Published: May 2022

Anthocyanin and proanthocyanidin play important roles in plant secondary metabolism. Although previous studies identified many transcription factors involved in anthocyanin and proanthocyanidin synthesis, the effects of MADS-box transcription factors are unclear in apple. Brassinosteroids (BRs) are steroid hormones that affect plant flavonoid biosynthesis, but the underlying regulatory mechanism is not yet well established. In this study, we identified a MADS-box transcription factor, MdJa2, which contained a highly conserved MADS-box domain and belonged to the STMADS11 subfamily. Additionally, MdJa2 was responsive to BR signal, and the overexpression of MdJa2 inhibited the synthesis of anthocyanin and proanthocyanidin. The silencing of MdJa2 in “Orin” calli promoted anthocyanin and proanthocyanidin accumulations. Moreover, MdJa2 interacted with MdBZR1. MdJa2 was revealed to independently regulate anthocyanin and proanthocyanidin synthesis pathways. The MdJa2–MdBZR1 complex enhanced the binding of MdJa2 to the promoters of downstream target genes. Our research provides new insights into how MADS-box transcription factors in the BR signaling pathway control the accumulations of anthocyanin and proanthocyanidin in red-fleshed apple.
Melatonin-Mediated Abiotic Stress Tolerance in Plants
Authors: Zeng Wen , Mostafa Salma , Lu Zhaogeng , Jin Biao
Published: May 2022

Melatonin is a multi-functional molecule that is ubiquitous in all living organisms. Melatonin performs essential roles in plant stress tolerance; its application can reduce the harmful effects of abiotic stresses. Plant melatonin biosynthesis, which usually occurs within chloroplasts, and its related metabolic pathways have been extensively characterized. Melatonin regulates plant stress responses by directly inhibiting the accumulation of reactive oxygen and nitrogen species, and by indirectly affecting stress response pathways. In this review, we summarize recent research concerning melatonin biosynthesis, metabolism, and antioxidation; we focus on melatonin-mediated tolerance to abiotic stresses including drought, waterlogging, salt, heat, cold, heavy metal toxicity, light and others. We also examine exogenous melatonin treatment in plants under abiotic stress. Finally, we discuss future perspectives in melatonin research and its applications in plants.
Triticale Improvement: Mining of Genes Related to Yellow Rust Resistance in Triticale Based on Transcriptome Sequencing
Authors: Zhao Fangyuan , Niu Kuiju , Tian Xinhui , Du Wenhua
Published: May 2022

Yellow (stripe) rust caused by Puccinia striiformis f. sp. tritici (Pst) is a major destructive fungal disease of small grain cereals, leading to large yield losses. The breeding of resistant varieties is an effective, sustainable way to control yellow rust. Elucidation of resistance mechanisms against yellow rust and identification of candidate genes associated with rust resistance are thus crucial. In this study, seedlings of two Triticosecale Wittmack cultivars, highly resistant Gannong No. 2 and susceptible Shida No. 1, were inoculated with Pst race CYR34. Transcriptome sequencing (RNA-seq) was then used to investigate their transcriptional responses against pathogen infection before and after the appearance of symptoms—10 and 20 days after inoculation, respectively. According to the RNA-seq data, the number of upregulated and downregulated differentially expressed genes (DEGs) in the resistant cultivar was greater than in the susceptible cultivar. A total of 2,560 DEGs commonly expressed in the two cultivars on two sampling dates were subjected to pathway analysis, which revealed that most DEGs were closely associated with defense and metabolic activities. Transcription factor enrichment analysis indicated that the expressions of NAC, WRKY, and FAR1 families were also significantly changed. Further in-depth analysis of resistance genes revealed that almost all serine/threonine-protein kinases were upregulated in the resistant cultivar. Other genes related to disease resistance, such as those encoding disease-resistance- and pathogenesis-related proteins were differentially regulated in the two cultivars. Our findings can serve as a resource for gene discovery and facilitate elucidation of the complex defense mechanisms involved in triticale resistance to Pst.