bluuebunny/crossref_metadata_2025 huggingface dataset:
Gabaergic Interneurons in Early Brain Development: Conducting and Orchestrated by Cortical Network Activity
Authors: Warm Davide , Schroer Jonas , Sinning Anne
Published: January 2022

Throughout early phases of brain development, the two main neural signaling mechanisms—excitation and inhibition—are dynamically sculpted in the neocortex to establish primary functions. Despite its relatively late formation and persistent developmental changes, the GABAergic system promotes the ordered shaping of neuronal circuits at the structural and functional levels. Within this frame, interneurons participate first in spontaneous and later in sensory-evoked activity patterns that precede cortical functions of the mature brain. Upon their subcortical generation, interneurons in the embryonic brain must first orderly migrate to and settle in respective target layers before they can actively engage in cortical network activity. During this process, changes at the molecular and synaptic level of interneurons allow not only their coordinated formation but also the pruning of connections as well as excitatory and inhibitory synapses. At the postsynaptic site, the shift of GABAergic signaling from an excitatory towards an inhibitory response is required to enable synchronization within cortical networks. Concomitantly, the progressive specification of different interneuron subtypes endows the neocortex with distinct local cortical circuits and region-specific modulation of neuronal firing. Finally, the apoptotic process further refines neuronal populations by constantly maintaining a controlled ratio of inhibitory and excitatory neurons. Interestingly, many of these fundamental and complex processes are influenced—if not directly controlled—by electrical activity. Interneurons on the subcellular, cellular, and network level are affected by high frequency patterns, such as spindle burst and gamma oscillations in rodents and delta brushes in humans. Conversely, the maturation of interneuron structure and function on each of these scales feeds back and contributes to the generation of cortical activity patterns that are essential for the proper peri- and postnatal development. Overall, a more precise description of the conducting role of interneurons in terms of how they contribute to specific activity patterns—as well as how specific activity patterns impinge on their maturation as orchestra members—will lead to a better understanding of the physiological and pathophysiological development and function of the nervous system.
(M)Unc13s in Active Zone Diversity: A Drosophila Perspective
Authors: Piao Chengji , Sigrist Stephan J.
Published: January 2022

The so-called active zones at pre-synaptic terminals are the ultimate filtering devices, which couple between action potential frequency and shape, and the information transferred to the post-synaptic neurons, finally tuning behaviors. Within active zones, the release of the synaptic vesicle operates from specialized “release sites.” The (M)Unc13 class of proteins is meant to define release sites topologically and biochemically, and diversity between Unc13-type release factor isoforms is suspected to steer diversity at active zones. The two major Unc13-type isoforms, namely, Unc13A and Unc13B, have recently been described from the molecular to the behavioral level, exploiting Drosophila being uniquely suited to causally link between these levels. The exact nanoscale distribution of voltage-gated Ca2+ channels relative to release sites (“coupling”) at pre-synaptic active zones fundamentally steers the release of the synaptic vesicle. Unc13A and B were found to be either tightly or loosely coupled across Drosophila synapses. In this review, we reported recent findings on diverse aspects of Drosophila Unc13A and B, importantly, their nano-topological distribution at active zones and their roles in release site generation, active zone assembly, and pre-synaptic homeostatic plasticity. We compared their stoichiometric composition at different synapse types, reviewing the correlation between nanoscale distribution of these two isoforms and release physiology and, finally, discuss how isoform-specific release components might drive the functional heterogeneity of synapses and encode discrete behavior.
COVID-19 Risk Appears to Vary Across Different Alcoholic Beverages
Authors: Dai Xi-jian , Tan Liang , Ren Lina , Shao Yuan , Tao Weiqun , Wang Yongjun
Published: January 2022

Objectives: To evaluate the associations of status, amount, and frequency of alcohol consumption across different alcoholic beverages with coronavirus disease 2019 (COVID-19) risk and associated mortality.

Methods: This study included 473,957 subjects, 16,559 of whom tested positive for COVID-19. Multivariate logistic regression analyses were used to evaluate the associations of alcohol consumption with COVID-19 risk and associated mortality. The non-linearity association between the amount of alcohol consumption and COVID-19 risk was evaluated by a generalized additive model.

Results: Subjects who consumed alcohol double above the guidelines had a higher risk of COVID-19 (1.12 [1.00, 1.25]). Consumption of red wine above or double above the guidelines played protective effects against the COVID-19. Consumption of beer and cider increased the COVID-19 risk, regardless of the frequency and amount of alcohol intake. Low-frequency of consumption of fortified wine (1–2 glasses/week) within guidelines had a protective effect against the COVID-19. High frequency of consumption of spirits (≥5 glasses/week) within guidelines increased the COVID-19 risk, whereas the high frequency of consumption of white wine and champagne above the guidelines decreased the COVID-19 risk. The generalized additive model showed an increased risk of COVID-19 with a greater number of alcohol consumption. Alcohol drinker status, frequency, amount, and subtypes of alcoholic beverages were not associated with COVID-19 associated mortality.

Conclusions: The COVID-19 risk appears to vary across different alcoholic beverage subtypes, frequency, and amount. Red wine, white wine, and champagne have chances to reduce the risk of COVID-19. Consumption of beer and cider and spirits and heavy drinking are not recommended during the epidemics. Public health guidance should focus on reducing the risk of COVID-19 by advocating healthy lifestyle habits and preferential policies among consumers of beer and cider and spirits.
OncoVee™-MiniPDX-Guided Anticancer Treatment for Gastric Cancer Patients With Synchronous Liver Metastases: A Retrospective Cohort Analysis
Authors: Ge Yutong , Zhang Xin , Liang Wei , Tang Cuiju , Gu Dongying , Shi Junfeng , Wei Xiaowei
Published: January 2022

Background

It is estimated that 35% of gastric cancer patients appear with synchronous distant metastases—the vast majority of patients presenting with metastatic hepatic disease. How to choose the most appropriate drugs or regimens is crucial to improve the prognosis of patients. We conducted this retrospective cohort analysis to evaluate the efficacy of OncoVee™-MiniPDX-guided treatment for these patients.

Methods

Gastric cancer patients with liver metastases (GCLM) were enrolled. Patients were divided into MiniPDX and control group according to their wishes. In the observation group, the OncoVee™-MiniPDX model was conducted to screen the most sensitive drug or regimens to determine the clinical administration. Meanwhile, patients were treated with regular medications in the control group according to the guidelines without the MiniPDX model. The primary endpoint was overall survival (OS), and the secondary outcomes included objective response rate (ORR), disease control rate (DCR), and progression-free survival (PFS).

Results

A total of 68 patients with GCLM were included, with the observation and control groups of 21 and 47 patients, respectively. The baseline characteristics of patients were balanced between these two groups. MiniPDX drug sensitivity tests were associated with the increased use of targeted drugs when compared with the control group (33.3 vs. 0%, p=0.032). Median OS was estimated to be 9.4 (95% CI, 7.9–11.2) months and 7.9 (95% CI, 7.2–8.7) months in the observation and control group, respectively. Both univariate (control group vs. MiniPDX group: HR=2.586, 95% CI= 1.362–4.908, p=0.004) and multivariate regression analyses (Control group vs. MiniPDX group: adjusted HR (aHR)=4.288, 95% CI= 1.452–12.671, p=0.008) showed the superiority of the observation group on OS. Similarly, MiniPDX-based regiments significantly improve the PFS of these cases (median PFS 6.7 months vs. 4.2 months, aHR=2.773, 95% CI=1.532–3.983, p=0.029). ORR and DCR were also improved in MiniPDX group comparing with control group (ORR, 57.14 vs. 25.53%, p=0.029; DCR: 85.71 vs. 68.08%, p=0.035).

Conclusion

OncoVee™-MiniPDX model, which was used to select drugs to guide antitumor treatment, was promising to prolong survival and improve the response rate of patients with GCLM. Further well-designed studies are needed to confirm the clinical benefits of MiniPDX.
Therapeutic Effect of CAOLD Chemotherapy Regimen on Patients With Relapsed/Refractory Angioimmunoblastic T-Cell Lymphoma: A Case Study
Authors: Liu Yu , Li Pingping , Qian Liren
Published: January 2022

Angioimmunoblastic T-cell lymphoma (AITL) is a kind of peripheral T-cell lymphomas (PTCLs) with a highly invasive feature. At present, patients are often treated with CHOP or CHOP-like regimens which is of poor prognosis whilst having high recurrence rate. Once the patient fails to achieve remission or relapse after the first-line treatment, many salvage chemotherapy regimens are always ineffective, and the long-term survival will be difficult to achieve for them. In this circumstance, more effective therapy methods are needed. In this study, two patients with relapsed/refractory AITL were treated with the CAOLD regimen [cyclophosphamide 400 mg/m2 qd d1, cytarabine 30 mg/m2 qd d1–d4, vindesine 2 mg/m2 qd d1, pegaspargase (PEG-ASP) 2,500 IU/m2 qd d2, dexamethasone 7.5 mg/m2 qd d1–d5], and long-term remission was achieved after chemotherapy. One is still alive after achieving complete remission (CR) after two cycles of chemotherapy, who has been followed up for 82 months. Besides, another patient achieved partial remission (PR) after the first course of chemotherapy. Then, CR was obtained after four courses of consolidation chemotherapy. The patient has been followed up for 63 months and is still alive. Both of them achieved long-time survival. These two successful cases demonstrated that the CAOLD regimen can be a better choice for relapsed/refractory AITL and offers hope of breakthrough in this medical field.
Dihydroartemisinin-Transferrin Adducts Enhance TRAIL-Induced Apoptosis in Triple-Negative Breast Cancer in a P53-Independent and ROS-Dependent Manner
Authors: Zhou Xinyu , Soto-Gamez Abel , Nijdam Fleur , Setroikromo Rita , Quax Wim J.
Published: January 2022

Triple-negative breast cancer (TNBC) is a highly aggressive breast cancer subtype independent of estrogen receptor, progesterone receptor, or human epidermal growth factor receptor 2. It has a poor prognosis and high recurrence. Due to its limited treatment options in the clinic, novel therapies are urgently needed. Single treatment with the death receptor ligand TRAIL was shown to be poorly effective. Recently, we have shown that artemisinin derivatives enhance TRAIL-induced apoptosis in colon cancer cells. Here, we utilized transferrin (TF) to enhance the effectiveness of dihydroartemisinin (DHA) in inducing cell death in TNBC cell lines (MDA-MB-231, MDA-MB-436, MDA-MB-468 and BT549). We found that the combination of DHA-TF and the death receptor 5-specific TRAIL variant DHER leads to an increase in DR5 expression in all four TNBC cell lines, while higher cytotoxicity was observed in MDA-MB-231, and MDA-MB-436. All the data point to the finding that DHA-TF stimulates cell death in TNBC cells, while the combination of DHA-TF with TRAIL variants will trigger more cell death in TRAIL-sensitive cells. Overall, DHA-TF in combination with TRAIL variants represents a potential novel combination therapy for triple-negative breast cancer.
Mediator Complex Subunit 19 Promotes the Development of Hepatocellular Carcinoma by Regulating the AKT/mTOR Signaling Pathway
Authors: Zhang Yuting , Qin Peifang , Xu Xingfeng , Li Mao , Huang Haitao , Yan Jianguo , Zhou Yali
Published: January 2022

Background

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors, the pathogenesis of which remains unclear. Mediator complex subunit 19 (MED19), a subunit of the Mediator complex, is a multi-protein co-activator necessary for DNA transcription factors to induce RNA polymerase II transcription. In the current study, we aimed to study the role of MED19 in HCC and elucidate its mechanism.

Methods

MED19 expression in HCC tissues was determined. The relationship between MED19 and the clinical prognosis was explored. The influence of MED19 on HCC cell viability, migration, invasion, and apoptosis was studied. The expression of AKT/mTOR pathway genes and proteins was detected by qRT-PCR and western blot. The correlation between MED19 and immune infiltration was investigated.

Results

MED19 was upregulated in HCC tissues compared with tumor-adjacent tissues, and was associated with a poor prognosis. Furthermore, high MED19 expression was correlated with race, gender, etc. Knockdown of MED19 inhibited cell proliferation, migration, invasion, and promoted apoptosis. Knockdown of MED19 decreased p-AKT and p-mTOR protein expression. Additionally, the downstream effectors of the AKT/mTOR pathway, p70S6K1 and 4EBP1, were affected by MED19. Notably, MED19 expression was positively correlated with the infiltration levels of B cells, CD4+ T cells, CD8+ T cells, macrophages, etc.

Conclusion

MED19 is significantly upregulated in HCC tissues and cells. MED19 may promote the progression of HCC in vitro and may be related to immune infiltration. Together, our data show that MED19 could be considered as a new possible biomarker as well as a novel therapeutic target for HCC.
The Elephant in The Room: AML Relapse Post Allogeneic Hematopoietic Cell Transplantation
Authors: Abou Dalle Iman , Atoui Ali , Bazarbachi Ali
Published: January 2022

Relapsed acute myeloid leukemia (AML) following allogeneic hematopoietic cell transplantation (allo-HCT) is an unfavorable event associated with a poor prognosis, particularly for patients with early relapses. It usually arises from resistant leukemic blasts that escaped both preparative chemotherapy regimen and the graft-versus-leukemia (GVL) effect. Independent from the choice of salvage treatment, only minority of patients can achieve durable remissions. In recent years, better understanding of the disease relapse biology post allo-HCT allowed the application of newer strategies that could induce higher rates of remission, and potential longer survival. Those strategies aim at optimizing drugs that have a direct anti-leukemia activity by targeting different oncogenic mutations, metabolism pathways or surface antigens, and concurrently enhancing the immune microenvironment to promote GVL effect. This review discusses the current treatment landscape of AML relapse post allo-HCT.
Imaging Evaluation of Thymoma and Thymic Carcinoma
Authors: Strange Chad D. , Ahuja Jitesh , Shroff Girish S. , Truong Mylene T. , Marom Edith M.
Published: January 2022

Imaging is integral in the management of patients with thymoma and thymic carcinoma. At initial diagnosis and staging, imaging provides the clinical extent of local invasion as well as distant metastases to stratify patients for therapy and to determine prognosis. Following various modalities of therapy, imaging serves to assess treatment response and detect recurrent disease. While imaging findings overlap, a variety of CT, MRI, and PET/CT characteristics can help differentiate thymoma and thymic carcinoma, with new CT and MRI techniques currently under evaluation showing potential.
Metabolomic Profiling and Immunomodulatory Activity of a Polyherbal Combination in Cyclophosphamide-Induced Immunosuppressed Mice
Authors: Zahiruddin Sultan , Parveen Abida , Khan Washim , Ibrahim Mohammad , Want Muzamil Y. , Parveen Rabea , Ahmad Sayeed
Published: January 2022

The study was aimed to develop a characterized polyherbal combination as an immunomodulator containing Phyllanthus emblica L., Piper nigrum L., Withania somnifera (L.) Dunal, and Tinospora cordifolia (Willd.) Miers. Through response surface methodology (RSM), the ratio of aqueous extracts of four plant materials was optimized and comprised 49.76% of P. emblica, 1.35% of P. nigrum, 5.41% of W. somnifera, and 43.43% of T. cordifolia for optimum immunomodulatory activity. The optimized combination showed antioxidant potential and contains more than 180 metabolites, out of which gallic acid, quercetin, ellagic acid, caffeic acid, kaempferitrin, and p-coumaric acid are some common and significant metabolites found in plant extracts and in polyherbal combination. Treatment with the polyherbal combination of different doses in cyclophosphamide-induced immunosuppressed mice significantly (p < 0.01) enhanced the subsets of immune cells such as natural killer (NK) cells (60%), B cells (18%), CD4 cells (14%), and CD8 cells (7%). The characterized polyherbal combination exhibited potent immunomodulatory activity, which can be further explored clinically for its therapeutic applicability.
Ginsenoside Rb1 Attenuates Triptolide-Induced Cytotoxicity in HL-7702 Cells via the Activation of Keap1/Nrf2/ARE Pathway
Authors: Peng Hulinyue , You Longtai , Yang Chunjing , Wang Kaixin , Liu Manting , Yin Dongge , Xu Yuchen , Dong Xiaoxv , Yin Xingbin , Ni Jian
Published: January 2022

Triptolide (TP) is the major bioactive compound extracted from Tripterygium wilfordii Hook F. It exerts anti-inflammatory, antirheumatic, antineoplastic, and neuroprotective effects. However, the severe hepatotoxicity induced by TP limits its clinical application. Ginsenoside Rb1 has been reported to possess potential hepatoprotective effects, but its mechanism has not been fully investigated. This study was aimed at investigating the effect of ginsenoside Rb1 against TP-induced cytotoxicity in HL-7702 cells, as well as the underlying mechanism. The results revealed that ginsenoside Rb1 effectively reversed TP-induced cytotoxicity in HL-7702 cells. Apoptosis induced by TP was suppressed by ginsenoside Rb1 via inhibition of death receptor-mediated apoptotic pathway and mitochondrial-dependent apoptotic pathway. Pretreatment with ginsenoside Rb1 significantly reduced Bax/Bcl-2 ratio and down-regulated the expression of Fas, cleaved poly ADP-ribose polymerase (PARP), cleaved caspase-3, and -9. Furthermore, ginsenoside Rb1 reversed TP-induced cell cycle arrest in HL-7702 cells at S and G2/M phase, via upregulation of the expressions of cyclin-dependent kinase 2 (CDK2), cyclin E, cyclin A, and downregulation of the expressions of p53, p21, and p-p53. Ginsenoside Rb1 increased glutathione (GSH) and superoxide dismutase (SOD) levels, but decreased the reactive oxygen species (ROS) and malondialdehyde (MDA) levels. Pretreatment with ginsenoside Rb1 enhanced the expression levels of nuclear factor-erythroid 2-related factor 2 (Nrf2), total Nrf2, NAD(P)H: quinone oxidoreductases-1 (NQO-1), heme oxygenase-1 (HO-1), and Kelch-like ECH-associated protein 1 (Keap1)/Nrf2 complex. Therefore, ginsenoside Rb1 effectively alleviates TP-induced cytotoxicity in HL-7702 cells through activation of the Keap1/Nrf2/ARE antioxidant pathway.
Dangshen Erling Decoction Ameliorates Myocardial Hypertrophy via Inhibiting Myocardial Inflammation
Authors: Zhong Yigang , Chen Liuying , Li Miaofu , Chen Lian , Qian Yufeng , Chen Chaofeng , Wang Yi , Xu Yizhou
Published: January 2022

Myocardial hypertrophy plays an essential role in the structural remodeling of the heart and the progression to heart failure (HF). There is an urgent need to understand the mechanisms underlying cardiac hypertrophy and to develop treatments for early intervention. Dangshen Erling decoction (DSELD) is a clinically used formula in Chinese medicine for treating coronary heart disease in patients with HF. However, the mechanism by which DSELD produces its cardioprotective effects remains largely unknown. This study explored the effects of DSELD on myocardial hypotrophy both in vitro and in vivo. In vitro studies indicated that DSELD significantly (p < 0.05) reduced the cross-sectional area of the myocardium and reduced elevated lactate dehydrogenase (LDH), tumor necrosis factor (TNF)-α, and interleukin (IL)-6 levels in the induced H9C2 cell model to study inflammation. In vivo experiments revealed that DSELD restores cardiac function and significantly reduces myocardial fibrosis in isoproterenol (ISO)-induced HF mouse model (p < 0.05). In addition, DSELD downregulated the expression of several inflammatory cytokines, such as granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte CSF (G-CSF), IL-1α, IL-1β, IL-3, IL-5, IL-7, IL-12, IL-13, and TNF-α in HF (p < 0.05). Further analysis of the cardiac tissue demonstrated that DSELD produces its anti-inflammatory effects via the Toll-like receptor (TLR)4 signaling pathway. The expression of TLR4 downstream proteins such as matrix metalloproteinase-9 (MMP9) and myeloid differentiation factor-88 (MyD88) was among the regulated targets. In conclusion, these observations suggest that DSELD exerts antihypertrophic effects by alleviating the inflammatory injury via the TLR4 signaling pathway in HF and thus holds promising therapeutic potentials.
Application of Population Pharmacokinetic Analysis to Characterize CYP2C19 Mediated Metabolic Mechanism of Voriconazole and Support Dose Optimization
Authors: Li SiChan , Wu SanLan , Gong WeiJing , Cao Peng , Chen Xin , Liu Wanyu , Xiang Liping , Wang Yang , Huang JianGeng
Published: January 2022

Purpose: The aims of this study were to establish a joint population pharmacokinetic model for voriconazole and its N-oxide metabolite in immunocompromised patients, to determine the extent to which the CYP2C19 genetic polymorphisms influenced the pharmacokinetic parameters, and to evaluate and optimize the dosing regimens using a simulating approach.

Methods: A population pharmacokinetic analysis was conducted using the Phoenix NLME software based on 427 plasma concentrations from 78 patients receiving multiple oral doses of voriconazole (200 mg twice daily). The final model was assessed by goodness of fit plots, non-parametric bootstrap method, and visual predictive check. Monte Carlo simulations were carried out to evaluate and optimize the dosing regimens.

Results: A one-compartment model with first-order absorption and mixed linear and concentration-dependent-nonlinear elimination fitted well to concentration-time profile of voriconazole, while one-compartment model with first-order elimination well described the disposition of voriconazole N-oxide. Covariate analysis indicated that voriconazole pharmacokinetics was substantially influenced by the CYP2C19 genetic variations. Simulations showed that the recommended maintenance dose regimen would lead to subtherapeutic levels in patients with different CYP2C19 genotypes, and elevated daily doses of voriconazole might be required to attain the therapeutic range.

Conclusions: The joint population pharmacokinetic model successfully characterized the pharmacokinetics of voriconazole and its N-oxide metabolite in immunocompromised patients. The proposed maintenance dose regimens could provide a rationale for dosage individualization to improve clinical outcomes and minimize drug-related toxicities.
Mapping Thematic Trends and Analysing Hotspots Concerning the Use of Stem Cells for Cartilage Regeneration: A Bibliometric Analysis From 2010 to 2020
Authors: Xia Demeng , Wu Jianghong , Zhou Feng , Wang Sheng , Zhang Zhentao , Zhou Panyu , Xu Shuogui
Published: January 2022

Background: Defects of articular cartilage represent a common condition that usually progresses to osteoarthritis with pain and dysfunction of the joint. Current treatment strategies have yielded limited success in these patients. Stem cells are emerging as a promising option for cartilage regeneration. We aim to summarize the developmental history of stem cells for cartilage regeneration and to analyse the relevant trends and hotspots.

Methods: We screened all relevant literature on stem cells for cartilage regeneration from Web of Science during 2010–2020 and analysed the research trends in this field by VOSviewer and CiteSpace. We also summarized previous clinical trials.

Results: We screened 1,011 publications. China contributed the largest number of publications (317, 31.36%) and citations (81,376, 48.61%). The United States achieved the highest H-index (39). Shanghai Jiao Tong University had the largest number of publications (34) among all full-time institutions. The Journal of Biomaterials and Stem Cell Research and Therapy published the largest number of studies on stem cells for cartilage regeneration (35). SEKIYA I and YANG F published the majority of articles in this field (14), while TOH WS was cited most frequently (740). Regarding clinical research on stem cells for cartilage regeneration, the keyword “double-blind” emerged in recent years, with an average year of 2018.75. In tissue engineering, the keyword “3D printing” appeared latest, with an average year of 2019.625. In biological studies, the key word “extracellular vesicles” appeared latest, with an average year of 2018.9091. The current research trend indicates that basic research is gradually transforming to tissue engineering. Clinical trials have confirmed the safety and feasibility of stem cells for cartilage regeneration.

Conclusion: Multiple scientific methods were employed to reveal productivity, collaborations, and research hotspots related to the use of stem cells for cartilage regeneration. 3D printing, extracellular vesicles, and double-blind clinical trials are research hotspots and are likely to be promising in the near future. Further studies are needed for to improve our understanding of this field, and clinical trials with larger sample sizes and longer follow-up periods are needed for clinical transformation.
Vagus Nerve Stimulation Attenuates Acute Skeletal Muscle Injury Induced by Hepatic Ischemia/Reperfusion Injury in Rats
Authors: Xin Ying , Zhang Yifeng , Deng Simin , Hu Xinqun
Published: January 2022

Vagus nerve stimulation (VNS) has a protective effect on distal organ injury after ischemia/reperfusion (I/R) injury. We aimed to investigate the protective efficacy of VNS on hepatic I/R injury-induced acute skeletal muscle injury and explore its underlying mechanisms. To test this hypothesis, male Sprague-Dawley rats were randomly divided into three groups: sham group (sham operation, n = 6); I/R group (hepatic I/R with sham VNS, n = 6); and VNS group (hepatic I/R with VNS, n = 6). A hepatic I/R injury model was prepared by inducing hepatic ischemia for 1 h (70%) followed by hepatic reperfusion for 6 h. VNS was performed during the entire hepatic I/R process. Tissue and blood samples were collected at the end of the experiment for biochemical assays, molecular biological preparations, and histological examination. Our results showed that throughout the hepatic I/R process, VNS significantly reduced inflammation, oxidative stress, and apoptosis, while significantly increasing the protein levels of silent information regulator 1 (SIRT1) and decreasing the levels of acetylated forkhead box O1 and Ac-p53, in the skeletal muscle. These data suggest that VNS can alleviate hepatic I/R injury-induced acute skeletal muscle injury by suppressing inflammation, oxidative stress, and apoptosis, potentially via the SIRT1 pathway.
Real-World Effects of Chinese Herbal Medicine for Idiopathic Membranous Nephropathy (REACH-MN): Protocol of a Registry-Based Cohort Study
Authors: Yang Lihong , Chen Xueyin , Li Chuang , Xu Peng , Mao Wei , Liang Xing , Zuo Qi , Ma Weizhong , Guo Xinfeng , Bao Kun
Published: January 2022

Introduction: Some encouraging findings of Chinese herbal medicine (CHM) in management of idiopathic membranous nephropathy (IMN) obtained in the setting of clinical trials are hard to validate in the daily clinical practice due to a complicated treatment scenario of CHM in practice. The primary objective of this registry is to provide a description of treatment patterns used in management of IMN and assess clinical remission in daily practice in a Chinese population sample with IMN.

Methods and analysis: This is a prospective, multicenter cohort which will comprise 2000 adults with IMN regardless of urinary protein levels that will be recruited from 11 nephrology centers across China. The participants will be followed for up to at least 2 years. Primary outcome is composite remission (either complete remission or partial remission) 24 months after enrolment. The secondary outcomes are complete remission, partial remission, time to remission, no response, relapse, proteinuria, annual change of glomerular filtration rate, antibodies against PLA2R, and composite endpoint of 40% reduction of glomerular filtration rate, doubling of serum creatinine, end-stage renal disease, and death. Propensity score analysis will be used for matching and adjustment.

Ethics and dissemination: This study has been approved by the Ethics Committee of Guangdong Provincial Hospital of Chinese Medicine (BF2020-094-01). Results of the study will be published in both national and international peer-reviewed journals, and presented at scientific conferences. Investigators will inform the participants as well as other IMN patients of the findings via health education.

Study registration: ChiCTR2000033680 (prospectively registered).
Ginsenoside Rb2 Alleviated Atherosclerosis by Inhibiting M1 Macrophages Polarization Induced by MicroRNA-216a
Authors: Wang Shuting , Yang Shujun , Chen Yu , Chen Yutong , Li Rongxia , Han Shuang , Kamili Adalaiti , Wu Yiyi , Zhang Weili
Published: January 2022

Introduction: Atherosclerosis is a chronic disease characterized by the inflammatory process and lipid depositions. We previously reported that microRNA-216a (miR-216a) can accelerate the progression of atherosclerosis by promoting the polarization of M1 pro-inflammatory phenotype. Ginsenoside Rb2 (Rb2), the major pharmacologically active compound extracted from ginseng, has a high affinity to miR-216a. In this study, we aimed to investigate whether Rb2 can counteract the effect of miR-216a in macrophages to ameliorate atherosclerosis.

Methods: The apolipoprotein E deficiency (ApoE−/−) mice model was chronically infected with miR-216a adenovirus via the tail vein and then intraperitoneally injected with Rb2. The plaque lesion area and stability of thoracic aorta were examined. The human myeloid leukemia mononuclear cells (THP-1) or human peripheral blood mononuclear cells (PBMCs) were cultured in vitro, transfected with miR-216a mimics, and treated with Rb2 to explore the mechanisms of Rb2 on the polarization of M1 macrophages, inflammatory process, and lipid accumulation.

Results: In the atherosclerotic ApoE−/− mice model, miR-216a greatly increased en face aortic lesion area of the thoracic aorta, lipid accumulation, and M1 macrophages infiltration in plaques, whereas these effects of miR-216a on atherosclerosis burden were significantly alleviated by Rb2 treatment. In the in vitro THP-1 model, the flow cytometry experiment showed that Rb2 treatment inhibited miR-216a–mediated polarization of M1 macrophages characterized by the surface marker CD86 expression but had no effects on M2 polarization characterized by the surface marker CD206 expression. Mechanistically, Rb2 suppressed the miR-216a–mediated inflammatory response through the Smad3/nuclear factor kappa B inhibitor alpha pathway. Moreover, Rb2 reduced the lipid uptake and promoted cholesterol efflux by counteracting the effects of miR-216a in the THP-1–derived foam cells and in the PBMC-derived foam cells under the oxidized low-density lipoproteins.

Conclusion: Our findings indicated that Rb2 might be a potential therapeutic molecule for atherosclerosis by attenuating the atherosclerosis plaque lesion, lipid accumulation, and M1 macrophages polarization by targeting miR-216a. Given that accumulation of foam cells in the intima takes place chronically, the role of Rb2 in atherosclerosis progression needs further investigation.
Production of Bovine Colostrum for Human Consumption to Improve Health
Authors: Kaplan Merve , Arslan Ayşenur , Duman Hatice , Karyelioğlu Melda , Baydemir Barış , Günar Bilgetekin Burak , Alkan Merve , Bayraktar Ayşe , Tosun Halil İbrahim , Ertürk Melih , Eskici Günay , Duar Rebbeca M. , Henrick Bethany M. , Frese Steven A. , Karav Sercan
Published: January 2022

Colostrum contains all essential nutrients for the neonate during the first days of life, with impacts that continue far beyond these first days. Bovine colostrum has been used for human consumption due to the high concentrations of bioactive proteins, vitamins, minerals, growth factors, as well as free and conjugated oligosaccharides. Processes involved in the preparation of bovine colostrum for human consumption play a pivotal role in preserving and maintaining the activity of the bioactive molecules. As bovine colostrum is a multifunctional food that offers a myriad of benefits for human health, assessing the main processes used in preparing it with both advantages and disadvantages is a crucial point to discuss. We discuss major processes effects for colostrum production on the nutritional value, some advanced technologies to preserve processed bovine colostrum and the end-product forms consumed by humans whether as dairy products or dietary supplements.
Sex Hormone–Dependent Lipid Mediator Formation in Male and Female Mice During Peritonitis
Authors: Troisi Fabiana , Pace Simona , Jordan Paul M. , Meyer Katharina P. L. , Bilancia Rossella , Ialenti Armando , Borrelli Francesca , Rossi Antonietta , Sautebin Lidia , Serhan Charles N. , Werz Oliver
Published: January 2022

Introduction: Sex differences in inflammation are obvious and contribute to divergences in the incidence and severity of inflammation-related diseases that frequently preponderate in women. Lipid mediators (LMs), mainly produced by lipoxygenase (LOX) and cyclooxygenase (COX) pathways from polyunsaturated fatty acids (PUFAs), regulate all stages of inflammation. Experimental and clinical studies revealed sex divergences for selected LM pathways without covering the entire LM spectrum, and only few studies have addressed the respective role of sex hormones. Here, we performed the comprehensive LM profile analysis with inflammatory peritoneal exudates and plasma from male and female mice in zymosan-induced peritonitis to identify the potential sex differences in LM biosynthesis during the inflammatory response. We also addressed the impact of sex hormones by employing gonadectomy.

Methods: Adult male and female CD1 mice received intraperitoneal injection of zymosan to induce peritonitis, a well-established experimental model of acute, self-resolving inflammation. Mice were gonadectomized 5 weeks prior to peritonitis induction. Peritoneal exudates and plasma were taken at 4 (peak of inflammation) and 24 h (onset of resolution) post zymosan and subjected to UPLC–MS-MS–based LM signature profiling; exudates were analyzed for LM biosynthetic proteins by Western blot; and plasma was analyzed for cytokines by ELISA.

Results: Pro-inflammatory COX and 5-LOX products predominated in the peritoneum of males at 4 and 24 h post-zymosan, respectively, with slightly higher 12/15-LOX products in males after 24 h. Amounts of COX-2, 5-LOX/FLAP, and 15-LOX-1 were similar in exudates of males and females. In plasma of males, only moderate elevation of these LMs was apparent. At 4 h post-zymosan, gonadectomy strongly elevated 12/15-LOX products in the exudates of males, while in females, free PUFA and LOX products were rather impaired. In plasma, gonadectomy impaired most LMs in both sexes at 4 h with rather up-regulatory effects at 24 h. Finally, elevated 15-LOX-1 protein was evident in exudates of males at 24 h which was impaired by orchiectomy without the striking impact of gonadectomy on other enzymes in both sexes.

Conclusions: Our results reveal obvious sex differences and roles of sex hormones in LM biosynthetic networks in acute self-resolving inflammation in mice, with several preponderances in males that appear under the control of androgens.
A Dynamic Statistical Subseasonal Forecast Model for OLR Over Tropical Pacific Region
Authors: Wang Kuo , Fan Gao-Feng , Feng Guo-Lin
Published: January 2022

How to improve the subseasonal forecast skills of dynamic models has always been an important issue in atmospheric science and service. This study proposes a new dynamical-statistical forecast method and a stable components dynamic statistical forecast (STsDSF) for subseasonal outgoing long-wave radiation (OLR) over the tropical Pacific region in January-February from 2004 to 2008. Compared with 11 advanced multi-model ensemble (MME) daily forecasts, the STsDSF model was able to capture the change characteristics of OLR better when the lead time was beyond 30 days in 2005 and 2006. The average pattern correlation coefficients (PCC) of STsDSF are 0.24 and 0.16 in 2005 and 2006, while MME is 0.10 and 0.05, respectively. In addition, the average value of PCC of the STsDSF model in five years is higher than MME in 7–11 pentads. Although both the STsDSF model and MME show a similar temporal correlation coefficient (TCC) pattern over the tropical Pacific region, the STsDSF model error grows more slowly than the MME error during 8–12 pentads in January 2005. This phenomenon demonstrates that STsDSF can reduce dynamical model error in some situations. According to the comparison of subseasonal forecasts between STsDSF and MME in five years, STsDSF model skill depends strictly on the predictability of the dynamical model. The STsDSF model shows some advantages when the dynamical model could not forecast well above a certain level. In this study, the STsDSF model can be used as an effective reference for subseasonal forecast and could feasibly be used in real-time forecast business in the future.
Numerical Study on Water Sealing Effect of Freeze-Sealing Pipe-Roof Method Applied in Underwater Shallow-Buried Tunnel
Authors: Hong Zequn , Zhang Jun , Han Lei , Wu Yuanhao
Published: January 2022

The freezing-sealing pipe-roof method is a new presupporting technique, which fully combines the advantages of pipe-roof method and artificial ground-freezing method, and can adapt to the construction needs of underground projects in complex and sensitive strata. After the Gongbei Tunnel of Hong Kong–Zhuhai–Macao Bridge, this method will be applied for the first time in an underwater shallow-buried railroad tunnel, and there are still many urgent problems to be solved. In this article, based on the field situation and the preliminary design scheme, a convective heat transfer model under complex boundary conditions was first established. Then, the development of frozen wall thickness during the active freezing period was solved by numerical simulation for three different pipe filling modes, and the cloud map of temperature distribution in the whole section is analyzed. After that, the moving state of river water was characterized by different heat transfer coefficients, and the weakening effect of flow velocity on the top freezing wall was studied. Finally, six critical water sealing paths were selected, and the temperature differences of the frozen curtain were calculated. The results show that the mode with interval concrete filling can form a reliable frozen curtain within the scheduled time, whereas the nonfilling mode cannot achieve the water sealing requirement. River water has a large effect on the temperature at the boundary of jacking pipe and almost no effect on the center of the jacked pipe. It takes approximately 15 days from the frozen soil covering the pipe wall to reach the designed thickness, and the freezing effect of empty pipe lags approximately 28 days compared with that of solid pipe, which requires targeted enhancement measures in field projects.
Investigation on the Formation of Laser Transverse Pattern Possessing Optical Lattices
Authors: Wang Xin , Zhang Zilong , Gao Yuan , Zhao Suyi , Jie Yuchen , Zhao Changming
Published: January 2022

Optical lattices (OLs) with diverse transverse patterns and optical vortex lattices (OVLs) with special phase singularities have played important roles in the fields of atomic cooling, particle manipulation, quantum entanglement, and optical communication. As a matter of consensus until now, the OL patterns are generated by coherently superimposing multiple transverse modes with a fixed phase difference through the transverse mode locking (TML) effect. There are phase singularities in the dark area of this kind of OL pattern, so it is also called OVL pattern. However, in our research, it is found that some high-order complex symmetric OL patterns can hardly be analyzed by TML model. Instead, the analysis method of incoherent superposition of mode intensity could be applied. The OL pattern obtained by this method can be regarded as in non-TML state. Therefore, in this article, we mainly study the distinct characteristics and properties of OL patterns in TML and non-TML states. Through intensity comparison, interferometry, and beat frequency spectrum, we can effectively distinguish OL pattern in TML and non-TML states, which is of significance to explore the formation of laser transverse pattern possessing OL.
Self-Focusing Property of Partially Coherent Beam With Non-Uniform Correlation Structure in Non-Linear Media
Authors: Lu Lu , Wang Zhiqiang , Yu Jiayi , Qiao Chunhong , Lin Rong , Cai Yangjian
Published: January 2022

Coherence in a light beam has the potential to serve as a degree of freedom for manipulating the beam. In this work, the self-focusing property of a partially coherent beam with a non-uniform correlation structure propagating in a non-linear medium is investigated. The analysis of the evolution of beam width reveals that the coherence structure plays a vital role in the self-focusing formation. A threshold condition for the coherence radius is proposed for the first time, and the relation of self-focusing length and initial coherence radius is studied numerically and analytically. It is shown that a feasible approach for manipulating the self-focusing length by adjusting the initial coherence radius is achieved.
Seizure Prediction With HIVE-CODAs: The Hierarchical Vote Collective of Domain Adaptation Methods
Authors: Peng Peizhen
Published: January 2022

Epileptic seizure prediction is one of the most used therapeutic adjuvant strategies for drug-resistant epilepsy. Conventional methods are usually trained and tested on the same patient due to the interindividual variability. However, the challenging problem of the domain shift between different subjects remains unsolved, resulting in low prevalence of clinical application. In this study, a generic model based on the domain adaptation (DA) technique is proposed to alleviate such problems. Ensemble learning is employed by developing a hierarchical vote collective of seven DA modules over multi-modality data, such that the predictive performance is improved by training multiple models. Moreover, to increase the feasibility of its implementation, this study mimics the data distribution of clinical sampling and tests the model under this simulated realistic condition. Based on the performance of seven subnetworks, the applicability of each DA algorithm for seizure prediction is evaluated, which is the first study that provides the assessment. Experimental results on both intracranial and scalp EEG databases demonstrate that this method can reduce the domain gap effectively compared with previous studies.
Interleukin-33/ Suppression of Tumorigenicity 2 in Renal Fibrosis: Emerging Roles in Prognosis and Treatment
Authors: Tan Xiao-Yang , Jing Hao-Yue , Ma Yue-Rong
Published: January 2022

Chronic kidney disease (CKD) is a major public health problem that affects more than 10% of the population worldwide and has a high mortality rate. Therefore, it is necessary to identify novel treatment strategies for CKD. Incidentally, renal fibrosis plays a central role in the progression of CKD to end-stage renal disease (ESRD). The activation of inflammatory pathways leads to the development of renal fibrosis. In fact, interleukin-33 (IL-33), a newly discovered member of the interleukin 1 (IL-1) cytokine family, is a crucial regulator of the inflammatory process. It exerts pro-inflammatory and pro-fibrotic effects via the suppression of tumorigenicity 2 (ST2) receptor, which, in turn, activates other inflammatory pathways. Although the role of this pathway in cardiac, pulmonary, and hepatic fibrotic diseases has been extensively studied, its precise role in renal fibrosis has not yet been completely elucidated. Recent studies have shown that a sustained activation of IL-33/ST2 pathway promotes the development of renal fibrosis. However, with prolonged research in this field, it is expected that the IL-33/ST2 pathway will be used as a diagnostic and prognostic tool for renal diseases. In addition, the IL-33/ST2 pathway seems to be a new target for the future treatment of CKD. Here, we review the mechanisms and potential applications of the IL-33/ST2 pathway in renal fibrosis; such that it can help clinicians and researchers to explore effective treatment options and develop novel medicines for CKD patients.