bluuebunny/crossref_metadata_2025 huggingface dataset:
Rap1 Activity Is Essential for Focal Adhesion and Slit Diaphragm Integrity
Authors: Maywald Mee-Ling , Picciotto Cara , Lepa Carolin , Bertgen Luisa , Yousaf Farwah Sanam , Ricker Andrea , Klingauf Jürgen , Krahn Michael P. , Pavenstädt Hermann , George Britta
Published: March 2022

Glomerular podocytes build, with their intercellular junctions, part of the kidney filter. The podocyte cell adhesion protein, nephrin, is essential for developing and maintaining slit diaphragms as functional loss in humans results in heavy proteinuria. Nephrin expression and function are also altered in many adult-onset glomerulopathies. Nephrin signals from the slit diaphragm to the actin cytoskeleton and integrin β1 at focal adhesions by recruiting Crk family proteins, which can interact with the Rap guanine nucleotide exchange factor 1 C3G. As Rap1 activity affects focal adhesion formation, we hypothesize that nephrin signals via Rap1 to integrin β. To address this issue, we combined Drosophila in vivo and mammalian cell culture experiments. We find that Rap1 is necessary for correct targeting of integrin β to focal adhesions in Drosophila nephrocytes, which also form slit diaphragm-like structures. In the fly, the Rap1 activity is important for signaling of the nephrin ortholog to integrin β, as well as for nephrin-dependent slit diaphragm integrity. We show by genetic interaction experiments that Rap1 functions downstream of nephrin signaling to integrin β and downstream of nephrin signaling necessary for slit diaphragm integrity. Similarly, in human podocyte culture, nephrin activation results in increased activation of Rap1. Thus, Rap1 is necessary for downstream signal transduction of nephrin to integrin β.
Therapeutic Potential of Stem Cell-Derived Extracellular Vesicles on Atherosclerosis-Induced Vascular Dysfunction and Its Key Molecular Players
Authors: Comariţa Ioana Karla , Vîlcu Alexandra , Constantin Alina , Procopciuc Anastasia , Safciuc Florentina , Alexandru Nicoleta , Dragan Emanuel , Nemecz Miruna , Filippi Alexandru , Chiţoiu Leona , Gherghiceanu Mihaela , Georgescu Adriana
Published: March 2022

Atherosclerosis is a progressive, chronic inflammatory disease of the large arteries caused by the constant accumulation of cholesterol, followed by endothelial dysfunction and vascular inflammation. We hypothesized that delivery of extracellular vesicles (EVs), recognized for their potential as therapeutic targets and tools, could restore vascular function in atherosclerosis. We explored by comparison the potential beneficial effects of EVs from subcutaneous adipose tissue stem cells (EVs (ADSCs)) or bone marrow mesenchymal stem cells (EVs (MSCs)) on the consequences of atherogenic diet on vascular health. Also, the influences of siRNA-targeting Smad2/3 (Smad2/3siRNA) on endothelial dysfunction and its key molecular players were analyzed. For this study, an animal model of atherosclerosis (HH) was transplanted with EVs (ADSCs) or EVs (MSCs) transfected or not with Smad2/3siRNA. For controls, healthy or HH animals were used. The results indicated that by comparison with the HH group, the treatment with EVs(ADSCs) or EVs(MSCs) alone or in combination with Smad2/3siRNA of HH animals induced a significant decrease in the main plasma parameters and a noticeable improvement in the structure and function of the thoracic aorta and carotid artery along with a decrease in the selected molecular and cellular targets mediating their changes in atherosclerosis: 1) a decrease in expression of structural and inflammatory markers COL1A1, α-SMA, Cx43, VCAM-1, and MMP-2; 2) a slight infiltration of total/M1 macrophages and T-cells; 3) a reduced level of cytosolic ROS production; 4) a significant diminution in plasma concentrations of TGF-β1 and Ang II proteins; 5) significant structural and functional improvements (thinning of the arterial wall, increase of the inner diameter, enhanced distensibility, diminished VTI and Vel, and augmented contractile and relaxation responses); 6) a reduced protein expression profile of Smad2/3, ATF-2, and NF-kBp50/p65 and a significant decrease in the expression levels of miR-21, miR-29a, miR-192, miR-200b, miR-210, and miR-146a. We can conclude that 1) stem cell-derived EV therapies, especially the EVs (ADSCs) led to regression of structural and functional changes in the vascular wall and of key orchestrator expression in the atherosclerosis-induced endothelial dysfunction; 2) transfection of EVs with Smad2/3siRNA amplified the ability of EVs(ADSCs) or EVs(MSCs) to regress the inflammation-mediated atherosclerotic process.
mtTB: A Web-Based R/Shiny App for Pulmonary Tuberculosis Screening
Authors: Ling Zhougui , Huang Shuangping , Wen Zhongwei , Tang Zhenming , Huang Ying , Wei Ni , Liu Mei , Wu Jinyan
Published: March 2022

Pulmonary tuberculosis caused by Mycobacterium tuberculosis remains a global issue. However, the diagnosis of active pulmonary tuberculosis (TB) remains a challenge in the clinic. Small non-coding RNAs are potential diagnostic biomarkers for pulmonary tuberculosis. However, the current normalization methods are not stable and usually fail to reliably detect differentially expressed sncRNAs. To identify reliable biomarkers for pulmonary tuberculosis screening, we utilized the ratio-based method on the newly discovered mitochondria-derived small RNAs in human peripheral blood mononuclear cells. The prediction model of seven mtRNA biomarkers noteworthily enables the discrimination between pulmonary tuberculosis patients and controls in discovery (AUC = 0.906, 23 patients) and independent validation cohort (AUC = 0.968, 20 patients). Moreover, we present mtTB (https://tuberculosis.shinyapps.io/mtTB/), a novel R Graphical User Interface (GUI) that provides reliable biomarkers for the feasibility of blood-based screening, and produce a more accurate tool for pulmonary tuberculosis diagnosis in real clinical practice.
Valosin Containing Protein as a Specific Biomarker for Predicting the Development of Acute Coronary Syndrome and Its Complication
Authors: Xu Chenchao , Yu Bokang , Zhao Xin , Lin Xinyi , Tang Xinru , Liu Zheng , Gao Pan , Ge Junbo , Wang Shouyu , Li Liliang
Published: March 2022

Background

Acute coronary syndrome (ACS) consists of a range of acute myocardial ischemia-related manifestations. The adverse events of ACS are usually associated with ventricular dysfunction (VD), which could finally develop to heart failure. Currently, there is no satisfactory indicator that could specifically predict the development of ACS and its prognosis. Valosin-containing protein (VCP) has recently been proposed to protect against cardiac diseases. Hence, we aimed to assess whether VCP in serum can serve as a valuable biomarker for predicting ACS and its complication.

Methods

Human serum samples from 291 participants were collected and classified into four groups based on their clinical diagnosis, namely healthy control (n = 64), ACS (n = 40), chronic coronary syndrome (CCS, n = 99), and nonischemic heart disease (non-IHD, n = 88). Clinical characteristics of these participants were recorded and their serum VCP levels were detected by enzyme-linked immunosorbent assay (ELISA). Association of serum VCP with the development of ACS and its complication VD was statistically studied. Subsequently, GWAS and eQTL analyses were performed to explore the association between VCP polymorphism and monocyte count. A stability test was also performed to investigate whether VCP is a stable biomarker.

Results

Serum VCP levels were significantly higher in the ACS group compared with the rest groups. Besides, the VCP levels of patients with ACS with VD were significantly lower compared to those without VD. Multivariate logistic regression analysis revealed that VCP was associated with both the risk of ACS (P = 0.042, OR = 1.222) and the risk of developing VD in patients with ACS (P = 0.035, OR = 0.513) independently. The GWAS analysis also identified an association between VCP polymorphism (rs684562) and monocyte count, whereas the influence of rs684562 on VCP mRNA expression level was further verified by eQTL analysis. Moreover, a high stability of serum VCP content was observed under different preservation circumstances.

Conclusion

Valosin-containing protein could act as a stable biomarker in predicting the development of ACS and its complication VD.
Seasonal Variation: A Non-negligible Factor Associated With Blood Pressure in Patients Undergoing Hemodialysis
Authors: Wu Zhibin , Lan Shan , Chen Chengqiang , Zhang Xiuan , Zhang Yazhen , Chen Shanying
Published: March 2022

Objective

To investigate a seasonal variation in blood pressure (BP) for patients undergoing hemodialysis (HD).

Methods

In this retrospective study, we exported all BP measurements from the information system to investigate a seasonal variation of BP. We also investigated a seasonal variation in BP for patients of different gender types, of different age groups, with diabetic nephropathy (DN), and with non-DN having HD. Multiple linear regression models were used to explore the associations between BP and climatic parameters.

Results

In 2019, a total of 367 patients had received HD therapy in the Longwen HD unit. We included nearly 40,000 pre-dialysis BP measurements. The result of our study demonstrated a clear seasonal variation in pre-dialysis BP in general patients with HD, in male and female patients, and patients with DN and non-DN. December seemed to be a peak in the values of pre-dialysis systolic BP (SBP) and diastolic BP (DBP). The nadir values of pre-dialysis SBP and DBP were observed in June and July, respectively. A difference between peak and nadir values of BP is 3.81/2.20 mmHg in patients undergoing HD. Maximal seasonal variation in BP is 9.03/5.08 mmHg for patients with DN. A significant association of SBP and DBP with climatic parameters was found in this study. Pre-dialysis BP was inversely correlated with outdoor temperature, daytime length, and relative humidity.

Conclusion

A clear seasonal variation in BP is observed for patients with HD. Pre-dialysis SBP and DBP are inversely associated with outdoor temperature, daytime length, and relative humidity. The magnitude of a seasonal variation in BP increases in patients with DN.
Initial Invasive or Conservative Strategy in Heart Failure With Preserved Ejection Fraction and Coronary Artery Disease
Authors: Gu Jun , Pan Jian-an , Zhang Jun-feng , Wang Chang-qian
Published: March 2022

Background

In patients with both heart failure with preserved ejection fraction (HFpEF) and coronary artery disease (CAD), whether adopting an initial invasive strategy benefits better in clinical outcomes compared with those who received an initial conservative strategy remains inconclusive.

Methods

With data from the heart failure (HF) cohort study, we analyzed patients who had HFpEF and CAD amenable to the invasive intervention using propensity score matching of 1:1 ratio to compare the initial invasive strategy and the initial conservative strategy of medical therapy alone. The primary outcome was the composite endpoints of all-cause mortality or cardiovascular hospitalization, and the secondary outcome was all-cause mortality or cardiovascular hospitalization.

Results

Of 1,718 patients, 706 were treated with the invasive strategy and 1,012 with the conservative strategy initially. Propensity score matching was used to assemble a matched cohort of 1,320 patients receiving the invasive intervention (660 patients) or the medical therapy alone (660 patients). With a follow-up of 5 years, 378 (57.3%) in the invasive-strategy group and 403 (61.1%) in the conservative-strategy group reached the primary endpoint, and there was no significant difference in the rate of the primary endpoint (P = 0.162). The initial invasive strategy only improved the secondary outcome of cardiovascular hospitalization (P = 0.035). Also, the multivariable Cox regression model revealed that antiplatelet therapy, angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker (ACEI/ARB), or statin prescription was associated with a decreased risk of the primary outcome.

Conclusion

In this well-profiled, propensity-matched cohort of patients with HFpEF and CAD, the addition of invasive intervention to medical therapy did not improve the long-term composite of all-cause mortality or cardiovascular hospitalization.
Evolving Antithrombotic Treatment Patterns for Patients With Nonvalvular Atrial Fibrillation and Acute Coronary Syndrome or Underwent Percutaneous Coronary Intervention in China: A Cross-Sectional Study
Authors: Suo Ni , Yang Yan-min , Wang Juan , Zhang Han , Shao Xing-hui , Wu Shuang , Zhu Jun
Published: March 2022

Objective

Antithrombotic therapy in patients with nonvalvular atrial fibrillation (NVAF) concomitant with the acute coronary syndrome (ACS) or underwent percutaneous coronary intervention (PCI) is challenging and has evolved in recent years. However, real-world data on this issue about antithrombotic regimens at discharge and its evolving trend were relatively scarce, especially in China.

Methods

A total of 2,182 patients with NVAF and ACS/PCI were enrolled from 2017 to 2019. A total of 1,979 patients were finally analyzed and divided in three sequential cohorts: cohort 1 (2017), n = 674; cohort 2 (2018), n = 793; and cohort 3 (2019), n = 512. Baseline characteristics and antithrombotic therapy at discharge were analyzed by cohort.

Results

In our cross-sectional study, the majority of patients (59.6%) received dual antiplatelet therapy (DAPT). Over the 3 years, DAPT prescription reduced from nearly 70% to <50% (P trend < 0.001), while triple therapy (TT)/double therapy (DT) increased from 27.2 to 50.0% (P trend < 0.001). This trend was also seen in different subgroups stratified by CHA2DS2-VASc score, HAS-BLED score, coronary artery disease type, or management type, and was validated after multivariate adjustment. Persistent atrial fibrillation and history of congestive heart failure, hypertension, diabetes mellitus, and stroke/transient ischemic attack/systemic embolism were the independent predictors of TT/DT use, while ACS, PCI, or advanced chronic kidney disease was related with more DAPT prescription.

Conclusion

There is a shift of antithrombotic regime at discharge for patients with NVAF with recent ACS/PCI with reducing DAPT prescription and increasing TT/DT prescription. While the appropriate antithrombotic regimen for patients with NVAF having ACS/PCI is still underused in China.
Implementation of Mobile Psychological Testing on Smart Devices: Evaluation of a ResearchKit-Based Design Approach for the Implicit Association Test
Authors: Jungnickel Tobias , von Jan Ute , Albrecht Urs-Vito
Published: March 2022

Objective

To determine whether a framework-based approach for mobile apps is appropriate for the implementation of psychological testing, and equivalent to established methods.

Methods

Apple's ResearchKit was used for implementing native implicit association test methods (IAT), and an exemplary app was developed to examine users' implicit attitudes toward overweight or thin individuals. For comparison, a web-based IAT app, based on code provided by Project Implicit, was used. Adult volunteers were asked to test both versions on an iPad with touch as well as keyboard input (altogether four tests per participant, random order). Latency values were recorded and used to calculate parameters relevant to the implicit setting. Measurements were analyzed with respect to app type and input method, as well as test order (ANOVA and χ2tests).

Results

Fifty-one datasets were acquired (female,n= 21; male,n= 30, average age 35 ± 4.66 years). Test order and combination of app type and input method influenced the latency values significantly (bothP<0.001). This was not mirrored for the D scores or average number of errors vs. app type combined with input method (D scores:P= 0.66; number of errors:P= 0.733) or test order (D scores:P= 0.096; number of errors:P= 0.85).Post-hocpower analysis of the linear ANOVA showed 0.8 byf2=0.25, with α = 0.05 and 4 predictors.

Conclusions

The results suggest that a native mobile implementation of the IAT may be comparable to established implementations. The validity of the acquired measurements seems to depend on the properties of the chosen test rather than the specifics of the chosen platform or input method.
Fate of Carbonates in the Earth’s Mantle (10-136 GPa)
Authors: Gao Jing , Wu Xiang , Yuan Xueyin , Su Wen
Published: March 2022

Earth carbon cycle shapes the evolution of our planet and our habitats. As a key region of carbon cycle, subduction zone acts as a sole channel transporting supracrustal carbonate rocks down to the mantle, balancing carbon budget between the Earth’s surface and the interior, and regulating CO2 concentration of the atmosphere. How carbonates evolve at depth is thus, a most fundamental issue in understanding carbon flux and carbon sequestration mechanism in the Earth. This study reviews prominent progresses made in the field of crystal chemistry of carbonates along subduction geotherms. It clearly finds that, in addition to common carbonates in the Earth’s crust, several new polymorphs of carbonates have been discovered to be stable under high-pressure and high-temperature conditions. This opens possibilities for oxidized carbon species in the deep Earth. However, metamorphic decarbonatation and reduction reactions restrict subducting carbonates to the top-mid region of the lower mantle. Specifically, subsolidus decarbonatation in the form of carbonates reacting with silicates has been proposed as an efficient process releasing CO2 from slabs to the mantle. Besides, carbonate reduction in the metal-saturated mantle likely results in generation of super-deep diamonds and a considerable degree of carbon isotope fractionation. Review of these novel findings leads us to consider three issues in the further studies, including 1) searching for new chemical forms of carbon in the mantle, 2) determining the reduction efficiency of carbonates to diamonds and the accompanying carbon isotope fractionation and 3) concerning carbon cycle in subduction of continental crust.
Whole Genome Transcriptomic Analysis of Ovary Granulosa Cells Revealed an Anti-Apoptosis Regulatory Gene DLGAP5 in Polycystic Ovary Syndrome
Authors: Deng Yan , Li Hu , Song Yi , Cen Juan , Zhang Yuying , Sui Yi , Cui Dexuan , Li Tin Chiu , Xu Yan , Wang Chi Chiu , Chung Pui Wah Jacqueline , Tang Tao
Published: March 2022

The mechanisms underlining pathogenesis of polycystic ovary syndrome (PCOS) remain largely unknown. Dysfunction of ovarian granulosa cells plays an important role. The present study performed the lncRNA and mRNA profiling by whole genome transcriptomic sequencing of ovary granulosa cells from women with PCOS and investigated the potential role of differentially expressed gens (DEGs) in the pathomechanism of PCOS. In total, 1,936 DEGs (30 upregulated and 1,906 downregulated mRNAs and lncRNAs) were identified in the ovary granulosa cells between control and PCOS group. Functional enrichment analysis showed that DEGs were mainly associated with cytokine–cytokine receptor interaction, neuroactive ligand–receptor interaction, and olfactory transduction. qRT-PCR validated the upregulation of DLGAP5 mRNA in ovary from PCOS group when compared to control group. Immunostaining and TUNEL assays showed that DLGAP5 protein level was increased while apoptosis was decreased in follicles of ovary in PCOS group. In vitro functional assays showed that DLGPA5 knockdown repressed viability and proliferation, but enhanced apoptosis and disrupted cell cycle in granulosa cells; while DLGAP5 overexpression had the opposite effects in granulosa cells. In conclusion, the study showed differentially expressed lncRNA and mRNA profile in the granulosa cells in ovaries of PCOS. Functional results demonstrated that DLGAP5 is a dysregulated candidate gene in the pathogenesis of PCOS, especially granulosa cell apoptosis and proliferation.
Case Report: Primary Aldosteronism Due to Bilateral Aldosterone-Producing Micronodules With HISTALDO Classical and Contralateral Non-Classical Pathology
Authors: Chen Yi-Ju , Peng Kang-Yung , Chueh Jeff S. , Liao Hung-Wei , Hsieh Tsung-Yi , Wu Vin-Cent , Wang Shuo-Meng
Published: March 2022

Background

Non-classical multiple aldosterone-producing micronodules/nodules (mAPM/mAPN) could be the pathogenesis of primary aldosteronism (PA). The co-existence of mAPM with adenomas harboring somatic mutations has not previously been reported.

Methods

We presented a PA patient with bilateral mAPM and concomitant autonomous cortisol secretion (ACS).

Results

A 46-year-old Taiwanese woman presented with hypertension, hypokalemia, and bilateral adrenal adenomas. A 1 mg low-dose dexamethasone suppression test showed elevated morning serum cortisol. An adrenal vein sampling (AVS) suggested a left-sided lateralization of hyperaldosteronism. A right partial adrenalectomy and a left total adrenalectomy were performed. The patient showed biochemical and hypertension remission after the operation. This patient had bilateral mAPM with concomitant ACS, a right histopathologically classical PA adenoma, and a left non-classical PA adenoma. The right adrenal adenoma showed CYP11B1-negative and CYP11B2-positive staining and harbored the KCNJ5-L168R mutation. The left adrenal adenoma showed CYP11B1-positive and CYP11B2-negative staining and harbored the PRKACA-L206R mutation.

Conclusion

In a PA patient with concomitant ACS, bilateral APM could coexist with both histopathologically classical and non-classical PA adenomas, each with different somatic mutations. The presence of ACS could lead to the misinterpretation of AVS results.
Optimal Follow-Up Duration for Assessment of Birth Defects After In Vitro Fertilization–Embryo Transfer: A Multicenter 5-Year Cohort Study in China
Authors: Liu Chun-Lin , Li Ping , Cai Gui-Feng , Morse Abraham , Liu Jun , Chen Zhi-Heng , Zhang Xiu , Sun Ling
Published: March 2022

Objective

To investigate the impact of a 5-year follow-up on the incidence of identified birth defects in children conceived using assisted reproductive technologies (ART).

Methods

A 5-year cohort study was performed in three ART centers from January 2013 to October 2018. 1,543 women with 1,985 infants who delivered successfully or underwent termination of pregnancy due to malformations were recruited in this study. Follow-up was conducted by phone interview, 7 days, 1 year, 3 years, and 5 years after birth. Collected data included whether one or more birth defects were diagnosed, the category of birth defects, and when the malformation was diagnosed. Cumulative incidence of birth defects and the loss to follow-up rate of each follow-up was compared.

Results

According to the diagnostic criterion of birth defects, 111 cases of one or more birth defects were recorded, with a total of 117 birth defects after the 5-year follow-up. 0.2% (4/1,985) of birth defects were diagnosed before delivery; 2.7% (54/1,985) at 7 days; 5.0% (100/1,985) after 1 year; 5.5% (109/1,985) after 3 years; and 5.6% (111/1,985) after 5 years. 3.4% (4/117) of defects were diagnosed prenatally, 45.3% (53/117) of defects diagnosed within the first 7 days after delivery, 40.2% (47/117) diagnosed during 7 days to 1 year, and 9.4% (11/117) of defects diagnosed in 1–3 years after birth. The remaining 1.7% (2/117) of defects were diagnosed between the ages of 3 and 5 years. Among the 1,543 patients, 99.9% patients (1,542/1,543) responded to the telephone interview at 7 days after delivery; the response rate was 89.0% (1,373/1,543) at 1 year, 81% (1,250/1,543) at 3 years, and 64.5% (995/1,543) after 5 years.

Conclusion

We suggest that in ART, 1-year follow-up should be the minimum requirement and 3-year follow up the optimal length of follow-up that balances resource requirements with ascertainment completeness.
Composition of the Gut Microbiota in Attention Deficit Hyperactivity Disorder: A Systematic Review and Meta-Analysis
Authors: Wang Ning , Gao Xuping , Zhang Zifeng , Yang Li
Published: March 2022

Background

The latest research accumulates information to explore the correlation between gut microbiota and neurodevelopmental disorders, which may lead to new approaches to treat diseases such as attention deficit/hyperactivity disorder (ADHD). However, the conclusions of previous studies are not completely consistent. The objective of the systematic review and meta-analysis was to identify evidence on the dysbiosis of gut microbiota in ADHD and find potential distinctive traits compared to healthy controls.

Methods

Electronic databases, including PubMed, Embase, Web of Science, Cochrane Library, and PsycINFO, were searched up to August 24, 2021, using predetermined terms. Meta-analysis was performed to estimate the comparison of microbiota profiles (alpha and beta diversity) and the relative abundance of gut microbiota in ADHD patients and healthy controls.

Results

A total of eight studies were included in the meta-analysis, containing 316 ADHD patients and 359 healthy controls. There was a higher Shannon index in ADHD patients than in healthy controls (SMD = 0.97; 95% CI, 0.13 to 1.82; P = 0.02; I2 = 96%), but the significance vanished after sensitivity analysis because of high heterogeneity. No significant differences in other alpha diversity indexes were found. Regarding the relative abundance of gut microbiota, the genus Blautia was significantly elevated in ADHD patients compared with controls (SMD = 0.34; 95% CI, 0.06 to 0.63; P = 0.02; I2 = 0%).

Conclusions

Patients with ADHD had gut microbiome alterations compared to healthy controls. Though more studies with strict methodology are warranted due to the high heterogeneity, further studies to translate the findings of gut microbiota dysbiosis to clinical application in ADHD patients are needed and may guide targeted therapies.

Systematic Review Registration

[https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=273993], identifier PROSPERO (CRD42021273993).
Targeting Oncoproteins for Degradation by Small Molecule-Based Proteolysis-Targeting Chimeras (PROTACs) in Sex Hormone-Dependent Cancers
Authors: Liu Li , Shi Lihong , Wang Zhaodi , Zeng Jun , Wang Yue , Xiao Hongtao , Zhu Yongxia
Published: March 2022

Sex hormone-dependent cancers, including breast, ovary, and prostate cancer, contribute to the high number of cancer-related deaths worldwide. Steroid hormones promote tumor occurrence, development, and metastasis by acting on receptors, such as estrogen receptors (ERs), androgen receptors (ARs), and estrogen-related receptors (ERRs). Therefore, endocrine therapy targeting ERs, ARs, and ERRs represents the potential and pivotal therapeutic strategy in sex hormone-dependent cancers. Proteolysis-targeting chimeras (PROTACs) are a novel strategy that can harness the potential of the endogenous ubiquitin-proteasome system (UPS) to target and degrade specific proteins, rather than simply inhibiting the activity of target proteins. Small molecule PROTACs degrade a variety of proteins in cells, mice, and humans and are an emerging approach for novel drug development. PROTACs targeting ARs, ERs, ERRs, and other proteins in sex hormone-dependent cancers have been reported and may overcome the problem of resistance to existing endocrine therapy and receptor antagonist treatments. This review briefly introduces the PROTAC strategy and summarizes the progress on the development of small molecule PROTACs targeting oncoproteins in sex hormone-dependent cancers, focusing on breast and prostate cancers.
A Case Series of Ketoacidosis After Coronavirus Disease 2019 Vaccination in Patients With Type 1 Diabetes
Authors: Yakou Fumiyoshi , Saburi Masuo , Hirose Ai , Akaoka Hiroaki , Hirota Yusuke , Kobayashi Takaaki , Awane Naoko , Asahi Nobuteru , Amagawa Toshihiro , Ozawa Sachihiko , Ohno Atsushi , Matsushita Takaya
Published: March 2022

Introduction

We report a case series of severe ketoacidosis after COVID-19 vaccination in a type 1 diabetes patients treated with insulin and an SGLT-2 inhibitor.

Case Report

We present two cases of type 1 diabetes mellitus. One patient was treated with insulin therapy and an SGLT-2 inhibitor, and the other patient was treated with insulin therapy alone. Both patients became ill after coronavirus disease-2019 vaccination, making it difficult to continue their diet or insulin injections. On admission, they developed severe diabetic ketoacidosis. This is the first report of ketoacidosis after coronavirus disease-2019 vaccination.

Conclusion

The vaccine should be carefully administered to type 1 diabetes patients receiving intensive insulin therapy and a sodium-glucose transporter due to the high risk ketoacidosis. It is important to instruct patients to drink sufficient fluids and to continue insulin injections when they become sick.
RETRACTED: Recent Trends, Challenges, and Future Aspects of P2P Energy Trading Platforms in Electrical-Based Networks Considering Blockchain Technology: A Roadmap Toward Environmental Sustainability
Authors: Javed Haseeb , Irfan Muhammad , Shehzad Moazzam , Abdul Muqeet Hafiz , Akhter Jumshed , Dagar Vishal , Guerrero Josep M.
Published: March 2022

Peer-to-peer (P2P) energy trading platform is an upcoming energy generation and effective energy managing strategy that rewards proactive customers (acting as prosumers) in which individuals trade energy for products and services. On the other hand, P2P trading is expected to give multiple benefits to the grid in minimizing the peak load demand, energy consumption costs, and eliminating network losses. However, installing P2P energy trading on a broader level in electrical-based networks presents a number of modeling problems in physical and virtual network layers. As a result, this article presents a thorough examination of P2P studies of energy trade literature. An overview is given with the essential characteristics of P2P energy trading and comparatively analyzed with multiple advantages for the utility grid and individual prosumers. The study then addresses the physical and virtual levels that systematically categorize the available research. Furthermore, the technological techniques have been gone through multiple problems that need to overcome for P2P energy trading in electrical networks. Finally, the article concludes with suggestions for further research.
Combing Effects of Economic Development and Globalization Towards Energy Efficiency and Environmental Degradation: Fresh Analysis From Energy Efficient Resources
Authors: Tang Jinquan
Published: March 2022

How much environmental pollution can be reduced by the efficient use of financial, natural, and energy resources in the current globalization. Thus, this study provides empirical evidence in support of the theoretical argument by investigating the impact of financial development, environmental assets, globalization, coal, natural gas, and sustainable carbon emissions in 32 developed countries from 1990 to 2018. Ecological degradation (estimated by carbon dioxide emissions) experienced a structural shift that was considerably more pronounced in 2000–2011 than in 1991–1998. A broad variety of econometric methodologies (such as the Chow test, Cross-country regression, and the Generalized Method of Moments (GMM)) were applied. As a consequence, environmental deterioration is strongly linked to economic development and urbanization, according to the findings. These nations’ ecological footprints are favorably influenced by financial development, environmental assets, and non-renewable energy, whereas globalization and sustainable sources have a negative impact. Environmental degradation may be slowed by combining globalization’s impact on financial growth with the conservation of natural resources such as renewable energy sources. In order to improve their economic and ecological resource frameworks, these nations will need to increase their use of solar and other renewable energy.
Prediction of the 3D Distribution of NOx in a Furnace via CFD Data Based on ELM
Authors: Lv Manli , Zhao Jianping , Cao Shengxian , Shen Tao
Published: March 2022

A novel method for the prediction of three-dimensional (3D) spatial distribution of NOx in a furnace is proposed and evaluated. Computational fluid dynamics (CFD) simulations are conducted to generate the data sets of 3D NOx spatial distribution. The data sets are partitioned based on NOx generation mechanisms to improve the model accuracy. Combining the Pearson coefficient and mutual information (PMI), the model input variables are optimized by feature selection. The prediction model of 3D NOx spatial distribution in the furnace is established based on extreme learning machine (ELM). The experiments are conducted considering a 350 MW coal-fired boiler with a change in the burner tilt angles under a rated load. The experimental results show that the data-driven method based on PMI-ELM can realize the rapid prediction of the 3D spatial distribution of NOx in the furnace with 12.84% mean absolute percentage error.
Data-Driven Traction Substations’ Health Condition Monitoring via Power Quality Analysis
Authors: Xie Jingyi
Published: March 2022

Electrified railway traction substations are an important part of the transportation system, the health of its operation condition indirectly affects the national economy. Generally, traction substations’ conditions are studied from their power quality, while the nonlinearity of loads and effects from the outside environment are factors mainly affecting the accuracy of condition monitoring. In order to recognize the status of traction substations intelligently and govern them with fast measurements, this paper proposed a data-driven approach for recognizing types of power quality problems, and developed a system with intelligent governance strategies. The proposed approach contains two parts. Firstly, a double discrete Fourier transform (DDFT) algorithm was developed to extract valid feature vectors from power data. Then, a well-known data-driven method, support vector machine (SVM), was applied to build classifiers. Finally, based on classification results, a strategy library for power quality problems was built. Industrial data of a real traction substation in Wuhan, China, was tested for the experiment. Compared with traditional methods, the proposed approach is validated to be useful in improving the classification performance of power quality problems, and fast and effective for governance in traction substations.
Farm Typology for Targeting Extension Interventions Among Smallholders in Tribal Villages in Jharkhand State of India
Authors: Sinha Aditya , Basu Debabrata , Priyadarshi Prashant , Ghosh Amitava , Sohane Ravindra Kumar
Published: March 2022

The highly heterogeneous and complex farm holdings operated by the smallholders in developing countries are often deprived of optimum production and profitability. The farming systems in the state of Jharkhand, India, are heterogeneous due to biophysical (e.g., climatic conditions, fertilizer status, elevation, etc.) and socio-economic (investment potential, production goals, income preferences) factors. The extension interventions to reach the smallholders often face the one-size-fits-all approach making farming less attractive with diminished potential. There is a need to understand the diversity of the farms to classify them into different homogenous groups after studying the nature and characteristics of the farm and operators on the farms. In the current study, twenty-one different variables related to socio-economic,biophysical and geospatial features of the farms from 394 farm households were used for the analysis using Principal Component Analysis to identify six principal components explaining 73.07% of the total variability in the dataset. The first six factors were further analyzed using Euclidean Distance as distance measure and Ward’s technique as agglomerative clustering to form four clusters that were found to represent the farm households in the three villages. The four farm types identified were, Type 1. Large farm household with a diversification of crops and intensification of labour (22%), Type 2. Small farm households with major income from livestock (9%), Type 3. Small farm households with diversified cropping system and income from other sources (17%), and Type 4. Small farm households with monocropping dominated by senior farmers with an additional source of income (51%). The validation of the clusters was undertaken through qualitative methods such as focused group discussions and participatory workshops. The findings back up previous research that showed a positive association between farmer categorization and mathematical classification. The study offers a verifiable scientific methodology that could help scale agricultural technologies by forming a specific cluster of farmers based on their characteristics. The technologies applied to various farm types would be helpful to the extension system to target the interventions among the precise members of the identified farm types. Thus, the study suggests the farming system typology based on socio-economic, biophysical and geospatial factors for targeted farming systems interventions among smallholders.
The Issue Isn’t Which Model of Consumer Interference Is Right, but Which One Is Least Wrong
Authors: Ginzburg Lev R. , Damuth John
Published: March 2022

Empirical observations and an analogy with the history of ballistics illuminate the ongoing debate about the default choice for types of functional responses, based on consumer interference. The two ideal views of consumer interference are: (1) There is no direct mutual interference among consumers (“prey-dependence”), and (2) Consumers show strong mutual interference, the functional response depending on the number of prey per consumer (“ratio-dependence”). Each of these minimal-information concepts are what we refer to as “root” models, of limited accuracy in themselves, but they are the base upon which we erect complex models for specific, real-world cases. We argue that the ratio dependent view coincides more naturally with the way we model the dynamics of any population, and taken alone it is the model more consistent with empirical observations. Both root models often will give the “wrong answer” when applied directly to real world cases. Nevertheless, one root model may be “less wrong” than the other. This is not unlike developments 400 years ago in physics, when two root models competed in ballistics. Galileo’s demonstration that the default trajectory of a projectile is a parabola eventually replaced what had been the dominant root model since Aristotle. Both ballistic root models are inaccurate in the presence of air friction, but the parabolic model is, overall, less wrong. We argue that the ratio-dependent model, like the parabolic trajectory, is the “less wrong” and it is therefore a natural view from which to start thinking about consumer-resource interaction and developing more elaborate models.
A Novel Prognostic Model for Identifying the Risk of Hepatocellular Carcinoma Based on Angiogenesis Factors
Authors: Gao Yuan , Liu Jia , Zhao Dexi , Diao Guanghao
Published: March 2022

Hepatocellular carcinoma (HCC) is the most common primary liver cancer with poor prognosis. An optimized stratification of HCC patients to discriminate clinical benefit regarding different degrees of malignancy is urgently needed because of no effective and reliable prognostic biomarkers currently. HCC is typically characterized by rich vascular. The dysregulated vascular endothelial growth factor was proved a pivotal regulator of the development of HCC. Therefore, we investigated the capability of angiogenic factors (AFs) in stratifying patients and constructed a prognostic risk model. A total of 6 prognostic correlated AFs (GRM8, SPC25, FSD1L, SLC386A, FAM72A and SLC39A10) were screened via LASSO Cox regression, which provided the basis for developing a novel prognostic risk model. Based on the risk model, HCC patients were subdivided into high-risk and low-risk groups. Kaplan-Meier curve indicated that patients in the high-risk group have a lower survival rate compared with those in the low-risk group. The prognostic model showed good predictive efficacy, with AUCs reaching 0.802 at 1 year, 0.694 at 2 years, and 0.672 at 3 years. Univariate and multivariate cox regression analysis demonstrated that the risk score had significant prognostic value and was an independent prognostic factor for HCC. Moreover, this model also showed a good diagnostic positive rate in the ICGC-LIRI-JP and GSE144269. Finally, we demonstrated the efficacy of the AF-risk model in HCC patients following sorafenib adjuvant chemotherapy. And revealed the underlying molecular features involving tumor stemness, immune regulation, and genomic alterations associated with the risk score. Based on a large population, we established a novel prognostic model based on 6 AFs to help identify HCC patients with a greater risk of death. The model may provide a reference for better clinical management of HCC patients in the era of cancer precision medicine.
A Combined Transcriptomic and Proteomic Approach to Reveal the Effect of Mogroside V on OVA-Induced Pulmonary Inflammation in Mice
Authors: Dou Tong , Wang Juan , Liu Yisa , Jia Jiangang , Zhou Luwei , Liu Guoxiang , Li Xiaojuan , Han Mengjie , Lin Jiaxun , Huang Fengxiang , Chen Xu
Published: March 2022

Mogroside V is a bioactive ingredient extracted from the natural food Siraitia grosvenorii which possesses functions that stimulate lung humidification and cough relief activities, but its underlying mechanisms were rarely studied. To estimate its potential protective effect on ovalbumin (OVA)-induced pulmonary inflammation and understand its system-wide mechanism, integrated omics was applied in this study. Mogroside V effectively reduced the levels of IgE, TNF-α, and IL-5 in OVA-induced mice. The results of RNA-seq and data-independent acquisition proteomics approach revealed that 944 genes and 341 proteins were differentially expressed in the normal control group (NC) and ovalbumin-induced control group (OC) and 449 genes and 259 proteins were differentially expressed between the OC and the group treated with 50 mg/kg mogroside V (MV). After a combined analysis of the transcriptome and the proteome, 93 major pathways were screened, and we discovered that mogroside V exerts an anti-inflammation effect in the lung via NF-κB and JAK-STAT, both of which are among the signaling pathways mentioned above. In addition, we found that the key regulatory molecules (Igha, Ighg1, NF-κB, Jak1, and Stat1) in the two pathways were activated in inflammation and inhibited by mogroside V. Thus, mogroside V may be the main bioactivity component in S. grosvenorii that exerts lung humidification and cough relief effects.
Taking Lessons from CAR-T Cells and Going Beyond: Tailoring Design and Signaling for CAR-NK Cells in Cancer Therapy
Authors: Ruppel Katharina Eva , Fricke Stephan , Köhl Ulrike , Schmiedel Dominik
Published: March 2022

Cancer immunotherapies utilize the capabilities of the immune system to efficiently target malignant cells. In recent years, chimeric antigen receptor (CAR) equipped T cells showed promising results against B cell lymphomas. Autologous CAR-T cells require patient-specific manufacturing and thus extensive production facilities, resulting in high priced therapies. Along with potentially severe side effects, these are the major drawbacks of CAR-T cells therapies. Natural Killer (NK) cells pose an alternative for CAR equipped immune cells. Since NK cells can be safely transferred from healthy donors to cancer patients, they present a suitable platform for an allogeneic “off-the-shelf” immunotherapy. However, administration of activated NK cells in cancer therapy has until now shown poor anti-cancer responses, especially in solid tumors. Genetic modifications such as CARs promise to enhance recognition of tumor cells, thereby increasing anti-tumor effects and improving clinical efficacy. Although the cell biology of T and NK cells deviates in many aspects, the development of CAR-NK cells frequently follows within the footsteps of CAR-T cells, meaning that T cell technologies are simply adopted to NK cells. In this review, we underline the unique properties of NK cells and their potential in CAR therapies. First, we summarize the characteristics of NK cell biology with a focus on signaling, a fine-tuned interaction of activating and inhibitory receptors. We then discuss why tailored NK cell-specific CAR designs promise superior efficacy compared to designs developed for T cells. We summarize current findings and developments in the CAR-NK landscape: different CAR formats and modifications to optimize signaling, to target a broader pool of antigens or to increase in vivo persistence. Finally, we address challenges beyond NK cell engineering, including expansion and manufacturing, that need to be addressed to pave the way for CAR-NK therapies from the bench to the clinics.
A Randomized Open-Labeled Trial of Methotrexate as a Steroid-Sparing Agent for Patients With Generalized Myasthenia Gravis
Authors: Di Li , Shen Faxiu , Wen Xinmei , Lu Yan , Zhu Wenjia , Wang Min , Da Yuwei
Published: March 2022

Background and Purpose

Two clinical trials assessing the steroid-sparing effect of methotrexate (MTX) yielded conflicting results. Our objective was to investigate whether MTX would show a steroid-sparing effect in the treatment of generalized myasthenia gravis (MG) patients who fitted Myasthenia Gravis Foundation of America (MGFA) Class II and Class III.

Methods

We performed an 18-month prospective, randomized, open-labeled trial of prednisone combined with MTX 10 mg orally every week versus prednisone alone in 40 recently diagnosed MG patients of MGFA Class II and Class III between July 2014 and July 2018. The primary endpoint was the prednisone area under the dose–time curve (AUDTC) from months 3 to 18. Secondary endpoints included changes of the Quantitative Myasthenia Gravis Score (QMG), the Myasthenia Gravis Activity of Daily Living Score (MG-ADL), initial time of prednisone reduction, the median prednisone daily dose in each month, adverse events, and treatment failures in each group.

Results

Forty participants were included; among those, 5 individuals withdrew. A total of 35 participants completed 18 months of follow-up (18 in prednisone+MTX, 17 in prednisone group). Combined use of MTX reduced the month 3–18 prednisone AUDTC (prednisone+MTX 5,663.44 ± 1,678.08 mg, prednisone 6,683.94 ± 678.08 mg, p = 0.03, 95% confidence interval -1916.01 to -124.98). The initial times of prednisone reduction were 4.34 ± 1.44 months in the prednisone+MTX group and 5.56 ± 2.05 months in the prednisone group (p = 0.04, 95% CI -2.41 to -0.03). The median daily prednisone dose was significantly lower in the prednisone+MTX group at month 6 and months 9–18. No significant differences were found in QMG and MG-ADL scores between the two groups. No serious drug-related adverse events were observed in both groups.

Conclusions

This study provides evidence that MTX has the steroid-sparing ability in generalized MG patients of MGFA Class II and Class III.

Clinical Trial Registration

http://www.chictr.org.cn/showproj.aspx?proj=10563 identifier ChiCTR-IPR-15006081.