bluuebunny/crossref_metadata_2025 huggingface dataset:
Diagnostic Ability of Dynamic Contrast-Enhanced Magnetic Resonance Imaging for Prostate Cancer and Clinically Significant Prostate Cancer in Equivocal Lesions: A Systematic Review and Meta-Analysis
Authors: Zeng Jing , Cheng Qingqing , Zhang Dong , Fan Meng , Shi Changzheng , Luo Liangping
Published: February 2021

Background

Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) now has been used to diagnose prostate cancer (PCa). Equivocal lesions are defined as PIRADS category 3 or a Likert scale of 1 to 5 category 3 lesions. Currently, there are no clear recommendations for the management of these lesions. This study aimed to estimate the diagnostic capacity of DCE-MRI for PCa and clinically significant prostate cancer (csPCa) in equivocal lesions.

Materials and methods

Two researchers searched PubMed, Embase and Web of Science to identify studies that met our subject. We searched for articles that mention the accuracy of the diagnosis of DCE-MRI for PCa or csPCa in equivocal lesions and used histopathological results as the reference standard. We used a tool (the Quality Assessment of Diagnostic Accuracy Studies-2 tool) to evaluate the quality of the studies that we screened out. Meta-regression was used to explore the reasons for heterogeneity in results.

Results

Ten articles were eventually included in our study. The sensitivity, specificity and 95% confidence intervals (CI) for DCE-MRI in diagnosing csPCa were 0.67 (95% CI, 0.56–0.76), 0.58 (95% CI, 0.46–0.68). The sensitivity and specificity and 95% CI for DCE-MRI in diagnosing PCa were 0.57 (95% CI, 0.46–0.68), 0.58 (95% CI, 0.45–0.70). The areas under the curve (AUC) of DCE-MRI were 0.67 (95% CI, 0.63–0.71) and 0.60 (95% CI, 0.55–0.64) while diagnosing csPCa and PCa. Through meta-regression, we found that study design, magnetic field strength, the definition of csPCa, and the scoring system were the sources of heterogeneity.

Conclusion

The results of our study indicate that the role of DCE-MRI in equivocal lesions may be limited.
Prostate-Specific Membrane Antigen Uptake and Survival in Metastatic Castration-Resistant Prostate Cancer
Authors: Vlachostergios Panagiotis J. , Niaz Muhammad Junaid , Sun Michael , Mosallaie Seyed Ali , Thomas Charlene , Christos Paul J. , Osborne Joseph R. , Molina Ana M. , Nanus David M. , Bander Neil H. , Tagawa Scott T.
Published: February 2021

Background

Prostate-specific membrane antigen (PSMA) imaging has been suggested as highly sensitive modality for detection of metastases in patients with biochemically recurrent or advanced prostate cancer (PCa). PSMA expression is associated with grade and stage and has a relationship with androgen receptor signaling. The aim of this study was to evaluate the prognostic utility of radiographic PSMA expression in men with metastatic castration-resistant prostate cancer (mCRPC).

Methods

Patients with mCRPC and available baseline PSMA imaging were studied. Images by planar/single-photon emission computed tomography (SPECT) or positron emission tomography (PET)/CT were reviewed. Planar/SPECT images were scored semi-quantitatively and PET/CT scored quantitatively with comparison of tumor uptake to liver uptake on a scale of 0–4 in order to determine an imaging score (IS). The IS (high: 2–4 versus low: 0–1), subsequent receipt of life-prolonging systemic therapies (taxane chemotherapy, potent androgen receptor pathway inhibitors, sipuleucel-T, and radium-223), and the CALGB prognostic risk stratification of patients were analyzed according to overall survival (OS) in univariate and multivariate Cox’s proportional hazards models.

Results

High PSMA expression (IS 2–4) was found in 179 (75.21%) patients, and 59 (24.79%) patients had low PSMA uptake. The median OS of the entire cohort was 16.8 (95%CI: 14.9–19.3) months. Patients with a high IS had a significantly shorter OS of 15.8 (95%CI 13.0–18.1) months compared to those with low expression [22.7 (95%CI: 17.7–30.7) months, p = 0.002]. After accounting for use of life-prolonging therapies (p<0.001) and CALGB prognostic groups (p = 0.001), high PSMA IS emerged as an independent prognostic factor for OS [HR(95%CI): 1.7 (1.2–2.2); p = 0.003].

Conclusion

Presence of high radiographic PSMA expression on SPECT or PET/CT may portend a poor prognosis in patients with mCRPC treated with standard systemic therapies. This provides implications for therapeutic targeting of PSMA-avid disease as a means to improve outcomes.
Sex Differences in Time to Treat and Outcomes for Gliomas
Authors: Stabellini Nickolas , Krebs Halle , Patil Nirav , Waite Kristin , Barnholtz-Sloan Jill S.
Published: February 2021

Background

Gliomas are the most common type of primary malignant brain tumor in adults, representing one third of all primary and central nervous system (CNS) tumors and 80% of malignant tumors diagnosed in the Western world. Epidemiological data indicate that the overall incidence and mortality of cancer is higher in males, while females have a better prognosis. The goal of this study is to determine whether there are sex differences in the time to treat and clinical outcomes in patients with glioma

Methods

Glioblastoma (GB) and Lower Grade Glioma (LGG) patients were defined per the Central Brain Tumor Registry of the United States (CBTRUS) from the National Cancer Database (NCDB) for diagnosis years 2004 to 2016. Associations between sex and time to treatment variables as well as associations between sex and multiple clinical outcomes were assessed using univariable and multivariable models.

Results

A total of 176,100 patients were used for analysis (124,502 GBM and 51,598 LGG). Males had a statistically significant association with >7 days to surgery (OR = 1.09, CI 1.05–1.13, p < 0.001) but this association was not observed in the multivariable model (OR = 1.05, CI 0.96–1.16, p = 0.25). After adjustment for key variables including time to treat variables, males with GB and LGG had a higher risk of death (HR = 1.11, CI 1.09–1.13, p < 0.001, HR = 1.09, CI 1.03–1.15, p < 0.001; respectfully). Sex differences in 90-day mortality for GBM were not found after adjustment (OR for males = 0.99, CI 0.91–1.08, p = 0.93). For LGG, both the univariable and multivariable logistic regression models showed no sex differences in 90-day mortality (OR for males = 1.03, CI 0.94–1.12, p = 0.45; multivariable OR for males = 0.81, CI 0.62–1.06, p = 0.13).

Conclusions

Based on NCDB data, there were no statistically significant differences in time to treatment between males and females, however males had a higher proportion of GB and LGG as well as a higher risk of death compared to females.
Case Report: De novo Variants of KMT2E Cause O'Donnell-Luria-Rodan Syndrome: Additional Cases and Literature Review
Authors: Li Yang , Fan Lijuan , Luo Rong , Yang Zuozhen , Yuan Meng , Zhang Jinxiu , Gan Jing
Published: February 2021

Introduction: O'Donnell-Luria-Rodan syndrome was recently identified as an autosomal dominant systemic disorder caused by variants in KMT2E. It is characterized by global developmental delay, some patients also exhibit autism, seizures, hypotonia, and/or feeding difficulties.

Methods: Whole-exome sequencing of family trios were performed for two independent children with unexplained recurrent seizures and developmental delay. Both cases were identified as having de novo variants in KMT2E. We also collected and summarized the clinical data and diagnosed them with O'Donnell-Luria-Rodan syndrome. Structural-prediction programs were used to draw the variants' locations.

Results: A 186 G>A synonymous variant [NM_182931.3:exon4: c.186G>A (p.Ala62=)] was found in one family, resulting in alternative splicing acid. A 5417 C>T transition variant [NM_182931.3:exon27: c.5417C>T (p.Pro1806Leu)] was found in another family, resulting in 1806 Pro-to-Leu substitution. Both variants were classified as likely pathogenic according to the ACMG (American College of Medical Genetics and Genomics) guidelines and verified by Sanger sequencing.

Conclusion: To date, three studies of O'Donnell-Luria-Rodan syndrome have been reported with heterogeneous clinical manifestations. As a newly recognized inherited systemic disorder, O'Donnell-Luria-Rodan syndrome needs to be paid more attention, especially in gene testing.
Potential Natural Products Against Respiratory Viruses: A Perspective to Develop Anti-COVID-19 Medicines
Authors: Omrani Marzieh , Keshavarz Mohsen , Nejad Ebrahimi Samad , Mehrabi Meysam , McGaw Lyndy J. , Ali Abdalla Muna , Mehrbod Parvaneh
Published: February 2021

The emergence of viral pneumonia caused by a novel coronavirus (CoV), known as the 2019 novel coronavirus (2019-nCoV), resulted in a contagious acute respiratory infectious disease in December 2019 in Wuhan, Hubei Province, China. Its alarmingly quick transmission to many countries across the world and a considerable percentage of morbidity and mortality made the World Health Organization recognize it as a pandemic on March 11, 2020. The perceived risk of infection has led many research groups to study COVID-19 from different aspects. In this literature review, the phylogenetics and taxonomy of COVID-19 coronavirus, epidemiology, and respiratory viruses similar to COVID-19 and their mode of action are documented in an approach to understand the behavior of the current virus. Moreover, we suggest targeting the receptors of SARS-CoV and SARS-CoV-2 such as ACE2 and other proteins including 3CLpro and PLpro for improving antiviral activity and immune response against COVID-19 disease. Additionally, since phytochemicals play an essential role in complementary therapies for viral infections, we summarized different bioactive natural products against the mentioned respiratory viruses with a focus on influenza A, SARS-CoV, MERS, and COVID-19.Based on current literature, 130 compounds have antiviral potential, and of these, 94 metabolites demonstrated bioactivity against coronaviruses. Interestingly, these are classified in different groups of natural products, including alkaloids, flavonoids, terpenoids, and others. Most of these compounds comprise flavonoid skeletons. Based on our survey, xanthoangelol E (88), isolated fromAngelica keiskei(Miq.) Koidz showed inhibitory activity against SARS-CoV PLpro with the best IC50value of 1.2 μM. Additionally, hispidulin (3), quercetin (6), rutin (8), saikosaponin D (36), glycyrrhizin (47), and hesperetin (55) had remarkable antiviral potential against different viral infections. Among these compounds, quercetin (6) exhibited antiviral activities against influenza A, SARS-CoV, and COVID-19 and this seems to be a highly promising compound. In addition, our report discusses the obstacles and future perspectives to highlight the importance of developing screening programs to investigate potential natural medicines against COVID-19.
The Widely Used Antihelmintic Drug Albendazole is a Potent Inducer of Loss of Heterozygosity
Authors: Will Castro Luiza S. E. P. , Pieters Wietske , Alemdehy Mir Farshid , Aslam Muhammad A. , Buoninfante Olimpia Alessandra , Raaijmakers Jonne A. , Pilzecker Bas , van den Berk Paul C. M. , te Riele Hein , Medema René H. , Pedrosa Rozangela C. , Jacobs Heinz
Published: February 2021

The antihelmintic drug ABZ and its metabolites belong to the chemical family of benzimidazoles (BZM) that act as potent tubulin polymerization inhibitors, suggesting a potential re-direction of BZMs for cancer therapy. Applying UV-Vis spectrometry we here demonstrate ABZ as a DNA intercalator. This insight led us to determine the primary mode of ABZ action in mammalian cells. As revealed by RNA sequencing, ABZ did neither grossly affect replication as analyzed by survival and replication stress signaling, nor the transcriptome. Actually, unbiased transcriptome analysis revealed a marked cell cycle signature in ABZ exposed cells. Indeed, short-term exposure to ABZ arrested mammalian cells in G2/M cell cycle stages associated with frequent gains and losses of chromatin. Cellular analyses revealed ABZ as a potent mammalian spindle poison for normal and malignant cells, explaining the serious chromosome segregation defects. Since chromosomal aberrations promote both cancer development and cell death, we determined if besides its general cytotoxicity, ABZ could predispose to tumor development. As measured by loss of heterozygosity (LOH) in vitro and in vivo ABZ was found as a potent inducer of LOH and accelerator of chromosomal missegregation.
Building Multi-Dimensional Induced Pluripotent Stem Cells-Based Model Platforms to Assess Cardiotoxicity in Cancer Therapies
Authors: Thomas Dilip , Shenoy Sushma , Sayed Nazish
Published: February 2021

Cardiovascular disease (CVD) complications have contributed significantly toward poor survival of cancer patients worldwide. These complications that result in myocardial and vascular damage lead to long-term multisystemic disorders. In some patient cohorts, the progression from acute to symptomatic CVD state may be accelerated due to exacerbation of underlying comorbidities such as obesity, diabetes and hypertension. In such situations, cardio-oncologists are often left with a clinical predicament in finding the optimal therapeutic balance to minimize cardiovascular risks and maximize the benefits in treating cancer. Hence, prognostically there is an urgent need for cost-effective, rapid, sensitive and patient-specific screening platform to allow risk-adapted decision making to prevent cancer therapy related cardiotoxicity. In recent years, momentous progress has been made toward the successful derivation of human cardiovascular cells from induced pluripotent stem cells (iPSCs). This technology has not only provided deeper mechanistic insights into basic cardiovascular biology but has also seamlessly integrated within the drug screening and discovery programs for early efficacy and safety evaluation. In this review, we discuss how iPSC-derived cardiovascular cells have been utilized for testing oncotherapeutics to pre-determine patient predisposition to cardiovascular toxicity. Lastly, we highlight the convergence of tissue engineering technologies and precision medicine that can enable patient-specific cardiotoxicity prognosis and treatment on a multi-organ level.
Fuyuan Xingnao Decoction Promotes Angiogenesis Through the Rab1/AT1R Pathway in Diabetes Mellitus Complicated With Cerebral Infarction
Authors: Deng Dong , Qu Yao , Sun Lihua , Jia Liyang , Bu Jianhong , Ye Miaoqing , Chen Zhenyi , Geng Yun , Zhou Shuang , Fang Bangjiang
Published: February 2021

Fuyuan Xingnao decoction (FYXN), a traditional Chinese formula comprised of seven herbs, has been utilized to treat diabetes mellitus complicated with cerebral infarction (DMCI) for years. Yet, its protective and regulatory mechanism is poorly understood. The aim of the study is to investigate the effects of FYXN on DMCI in vitro and in vivo, as well as its mechanism in angiogenesis. For in vivo experiments, FYXN was administered to DMCI rats with streptozotocin (STZ) injection-induced diabetes. Then middle cerebral artery occlusion (MCAO) was conducted and the cerebral cortex sections of the rats were obtained. The ultrastructure of cerebral microvessels and new vessel density of ischemic penumbra were evaluated by the transmission electron microscopy (TEM) assay and immunohistochemistry, respectively. Protein and mRNA expression levels of Rab1/AT1R in cortex were assayed by Western blotting and real-time fluorescence quantitative real-time polymerase chain reaction (RT-qPCR). In vitro, FYXN serum was produced in rats on the fourth day 2 h after the last FYXN administration. Green fluorescence was observed after transfection with lentivirus packaged Rab1-WT or siRNA for 24 h. The activity of brain microvascular endothelial cells (BMECs) treated with sera from these rats was tested by MTT assay and Transwell assays, respectively. The expression of AT1R on the cell membrane and endoplasmic reticulum of BMECs was evaluated by immunofluorescence staining. Protein expression levels of signaling molecules in the Rab1/AT1R pathways were also detected. Results showed that in vivo, FYXN treatment significantly intensified CD31 staining in the cortical areas and enhanced the mRNA and protein levels of AT1R, Ang II, Rab1a, Rab1b and VEGF expression in ischemic cerebral cortex tissues. In vitro, the expression levels of AT1R, Ang II, Rab1a, Rab1b and VEGF in the cerebral infarction model group were significantly higher than those in the control group, with further increases after administration of FYXN drug serum. FYXN promoted the proliferation and migration of BMECs by activating the Rab1/AT1R signaling pathway. In conclusion, FYXN exerts a protective effect against DMCI by promoting angiogenesis via the Rab1/AT1R pathway, which provides strong evidence for the therapeutic effect of FYXN on DMCI.
Associations Between Using Chinese Herbal Medicine and Long-Term Outcome Among Pre-dialysis Diabetic Nephropathy Patients: A Retrospective Population-Based Cohort Study
Authors: Guo Jenny Chun-Ling , Pan Heng-Chih , Yeh Bo-Yan , Lu Yen Chu , Chen Jiun-Liang , Yang Ching-Wei , Chen Yu-Chun , Lin Yi-Hsuan , Chen Hsing-Yu
Published: February 2021

Background: Chronic kidney disease (CKD) has become a worldwide burden due to the high co-morbidity and mortality. Diabetic nephropathy (DN) is one of the leading causes of CKD, and pre-dialysis is one of the most critical stages before the end-stage renal disease (ESRD). Although Chinese herbal medicine (CHM) use is not uncommon, the feasibility of using CHM among pre-dialysis DN patients remains unclear.

Materials and methods: We analyzed a population-based cohort, retrieved from Taiwan’s National Health Insurance Research Database, to study the long-term outcome of using CHM among incident pre-dialysis DN patients from January 1, 2004, to December 31, 2007. All patients were followed up to 5 years or the occurrence of mortality. The risks of all-cause mortality and ESRD were carried out using Kaplan-Meier and competing risk estimation, respectively. Further, we demonstrated the CHM prescriptions and core CHMs using the Chinese herbal medicine network (CMN) analysis.

Results: A total of 6,648 incident pre-dialysis DN patients were analyzed, including 877 CHM users and 5,771 CHM nonusers. With overlap weighing for balancing all accessible covariates between CHM users and nonusers, we found the use of CHM was associated with lower all-cause mortality (0.22 versus 0.56; log-rank test: p-value <0.001), and the risk of mortality was 0.42 (95% CI: 0.36–0.49; p-value <0.001) by adjusting all accessible covariates. Further, the use of CHM was associated with a lower risk of ESRD (cause-specific hazard ratio: 0.59, 95%CI: 0.55–0.63; p-value <0.001). Also, from the 5,901 CHM prescriptions, we found Ji-Sheng-Shen-Qi-Wan, Astragalus mongholicus Bunge or (Astragalus membranaceus (Fisch.) Bge.), Plantago asiatica L. (or Plantago depressa Willd.), Salvia miltiorrhiza Bunge, and Rheum palmatum L. (or Rheum tanguticum (Maxim. ex Regel) Balf., Rheum officinale Baill.) were used as core CHMs for different CHM indications. Use of core CHMs was associated with a lower risk of mortality than CHM users without using core CHMs.

Conclusions: The use of CHM seemed feasible among pre-dialysis DN patients; however, the beneficial effects still need to be validated by well-designed clinical trials.
Modeling and Simulation to Support Phase Ib/IIa Dose Selection for WBP216, A Long Half-Life Fully Human Monoclonal Antibody Against Interleukin-6
Authors: Tang Xiange , Zeng Xiaofeng , Guan Xiaoduo , Chen Rui , Hu Pei
Published: February 2021

WBP216 is an innovative IL-6 antibody, presenting high affinity to IL-6 and a long half-life (40–60 days). To optimize the dosage regimen for future clinical trials, pharmacokinetics (PK) and pharmacodynamics (PD) of WBP216 would be firstly characterized in Chinese rheumatoid arthritis (RA) patients. PK, CRP and DAS28 data of WBP216 were collected from 26 RA patients in a single ascending dose study. Non-linear mixed effects modeling was used for a population PK/PD analysis. A two-compartment model with a sequential zero-first order absorption and a first order elimination best described PK behavior of WBP216. Apparent systemic clearance was 0.015 L/h, central volume was 8.04 L. CRP as the fast-decreasing endpoint and DAS28 as the slow-reacting endpoint were both fitted well through an indirect response model. The baseline of ALT and free IL-6 were found associated with PK/PD parameters during covariates exploration. Simulation results confirmed that a loading dose regimen either of administration at weeks 0, 2, and 6 or doubling the maintenance dose level, followed by maintenance dosing of 75–150 mg every 8 weeks, was expected to provide a best risk/benefit ratio in future clinical studies. We hope this first PK/PD study of WBP216 in Chinese RA patients will help in the clinical development of WBP216 in future and provide a reference to the dosage optimization of similar antibodies with long half-life.

Clinical Trial Registration:CTR20170306
P2Y1 Receptor Agonist Attenuates Cardiac Fibroblasts Activation Triggered by TGF-β1
Authors: Tian Geer , Zhou Junteng , Quan Yue , Kong Qihang , Wu Wenchao , Liu Xiaojing
Published: February 2021

Cardiac fibroblasts (CFs) activation is a hallmark feature of cardiac fibrosis caused by cardiac remodeling. The purinergic signaling molecules have been proven to participate in the activation of CFs. In this study, we explored the expression pattern of P2Y receptor family in the cardiac fibrosis mice model induced by the transverse aortic constriction (TAC) operation and in the activation of CFs triggered by transforming growth factor β1 (TGF-β1) stimulation. We then investigated the role of P2Y1receptor (P2Y1R) in activated CFs. The results showed that among P2Y family members, only P2Y1R was downregulated in the heart tissues of TAC mice. Consistent with our in vivo results, the level of P2Y1R was decreased in the activated CFs, when CFs were treated with TGF-β1. Silencing P2Y1R expression with siP2Y1R accelerated the effects of TGF-β1 on CFs activation. Moreover, the P2Y1R selective antagonist BPTU increased the levels of mRNA and protein of profibrogenic markers, such as connective tissue growth factor (CTGF), periostin (POSTN). periostin (POSTN), and α-smooth muscle actin(α-SMA). Further, MRS2365, the agonist of P2Y1R, ameliorated the activation of CFs and activated the p38 MAPK and ERK signaling pathways. In conclusion , our findings revealed that upregulating of P2Y1R may attenuate the abnormal activation of CFs via the p38 MAPK and ERK signaling pathway.
Identification of Plasma hsa_circ_0005397 and Combined With Serum AFP, AFP-L3 as Potential Biomarkers for Hepatocellular Carcinoma
Authors: Liu Ruoyu , Li Yi , Wu Anqi , Kong Mingzhu , Ding Weijia , Hu Zeyang , Chen Lin , Cai Weihua , Wang Feng
Published: February 2021

Background: Mounting evidence has demonstrated that circular RNA (circRNA) plays crucial roles in the occurrence and development of hepatocellular carcinoma (HCC). However, the expression pattern and clinical application value of plasma circRNA in HCC are still largely unknown. Herein, we explored the role of plasma hsa_circ_0005397 in diagnosis and prognosis of HCC.

Methods: The expression level of plasma hsa_circ_0005397 was measured by quantitative real-time polymerase chain reaction (qRT-PCR). The identification and origin of plasma hsa_circ_0005397 were confirmed by RNase R assay, Sanger sequencing and HCC cell culture. In addition, its diagnostic value was assessed by receiver operating characteristic (ROC) curve and prognostic value was evaluated by dynamics monitoring and Kaplan–Meier curve analyses in HCC patients.

Results: The expression of plasma hsa_circ_0005397 was higher in patients with HCC than that in patients with benign liver diseases and healthy controls (both p < 0.05). Moreover, it was closely correlated with tumor size (p = 0.020) and TNM stage (p = 0.006) of HCC patients. The area under the ROC curve of plasma hsa_circ_0005397 was 0.737 and 95% confidence interval was 0.671–0.795. Furthermore, the combination of plasma hsa_cic_0005397, serum AFP and AFP-L3 could improve the diagnostic sensitivity of HCC. Additionally, dynamic monitoring plasma hsa_cic_0005397 might help us predict recurrence or metastasis in HCC patients after surgical resection. Besides, the increased plasma hsa_cic_0005397 was closely correlated with shorter overall survival of HCC patients (p = 0.007).

Conclusion: Plasma has_circ_0005397 represents a novel noninvasive biomarker for HCC. Moreover, the combination of plasma hsa_cic_0005397, serum AFP and AFP-L3 might improve the diagnostic value for HCC.
Qishen Yiqi Dripping Pill Protects Against Diabetic Nephropathy by Inhibiting the Wnt/β-Catenin and Transforming Growth Factor-β/Smad Signaling Pathways in Rats
Authors: Zhang Qian , Xiao Xinhua , Zheng Jia , Li Ming , Yu Miao , Ping Fan , Wang Tong , Wang Xiaojing
Published: February 2021

Diabetic nephropathy is a severe microvascular complication of diabetes. Qishen Yiqi dripping pill (QYDP) has been reported to be a renal protective drug. However, the mechanisms remain unclear. This study was performed to investigate the mechanisms. In this study, Sprague-Dawley rats were injected with streptozotocin to generate a diabetes model. Diabetic rats were administered 150 or 300 mg/kg/day QYDP. After 8 weeks of treatment, serum creatinine, serum blood urea nitrogen, and 24-h urinary albumin were measured. Kidney histological staining and immunostaining were analyzed. Then, the renal tissue was analyzed with a genome expression array. The results showed that QYDP treatment reduced serum creatinine, blood urea nitrogen, and 24-h urinary albumin and improved kidney histology and fibrosis. The gene array revealed that the expression of 189 genes was increased, and that of 127 genes was decreased in the high dosage QYDP group compared with the diabetic group. Pathway and gene ontology analyses showed that the differentially expressed genes were involved in the Wnt/β-catenin and transforming growth factor-β (TGF-β)/Smad2 signaling pathways. QYDP reduced the renal Wnt1, catenin β1, Tgfb1, and Smad2 gene expression and β-catenin, TGF-β, Smad2, collagen I, α-smooth muscle actin, and fibronectin protein expression in diabetic rats. Our results provide the first evidence that QYDP performs its renal-protective function by inhibiting the Wnt/β-catenin and TGF-β/Smad2 signaling pathways in diabetic rats.
The Fundamentals of Respiratory Physiology to Manage the COVID-19 Pandemic: An Overview
Authors: Allado Edem , Poussel Mathias , Valentin Simon , Kimmoun Antoine , Levy Bruno , Nguyen Duc Trung , Rumeau Cécile , Chenuel Bruno
Published: February 2021

The growing coronavirus disease (COVID-19) crisis has stressed worldwide healthcare systems probably as never before, requiring a tremendous increase of the capacity of intensive care units to handle the sharp rise of patients in critical situation. Since the dominant respiratory feature of COVID-19 is worsening arterial hypoxemia, eventually leading to acute respiratory distress syndrome (ARDS) promptly needing mechanical ventilation, a systematic recourse to intubation of every hypoxemic patient may be difficult to sustain in such peculiar context and may not be deemed appropriate for all patients. Then, it is essential that caregivers have a solid knowledge of physiological principles to properly interpret arterial oxygenation, to intubate at the satisfactory moment, to adequately manage mechanical ventilation, and, finally, to initiate ventilator weaning, as safely and as expeditiously as possible, in order to make it available for the next patient. Through the expected mechanisms of COVID-19-induced hypoxemia, as well as the notion of silent hypoxemia often evoked in COVID-19 lung injury and its potential parallelism with high altitude pulmonary edema, from the description of hemoglobin oxygen affinity in patients with severe COVID-19 to the interest of the prone positioning in order to treat severe ARDS patients, this review aims to help caregivers from any specialty to handle respiratory support following recent knowledge in the pathophysiology of respiratory SARS-CoV-2 infection.
COVID-19-Associated Neurological Manifestations: An Emerging Electroencephalographic Literature
Authors: Vellieux Geoffroy , Sonneville Romain , Vledouts Sérafima , Jaquet Pierre , Rouvel-Tallec Anny , d’Ortho Marie-Pia
Published: February 2021

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread worldwide since the end of year 2019 and is currently responsive for coronavirus infectious disease 2019 (COVID-19). The first reports considered COVID-19 as a respiratory tract disease responsible for pneumonia, but numerous studies rapidly emerged to warn the medical community of COVID-19-associated neurological manifestations, including encephalopathy at the acute phase and other postinfectious manifestations. Using standard visual analysis or spectral analysis, recent studies reported electroencephalographic (EEG) findings of COVID-19 patients with various neurological symptoms. Most EEG recordings were normal or revealed non-specific abnormalities, such as focal or generalized slowing, interictal epileptic figures, seizures, or status epilepticus. Interestingly, novel EEG abnormalities over frontal areas were also described at the acute phase. Underlying mechanisms leading to brain injury in COVID-19 are still unknown and matters of debate. These frontal EEG abnormalities could emphasize the hypothesis whereby SARS-CoV-2 enters the central nervous system (CNS) through olfactory structures and then spreads in CNS via frontal lobes. This hypothesis is reinforced by the presence of anosmia in a significant proportion of COVID-19 patients and by neuroimaging studies confirming orbitofrontal abnormalities. COVID-19 represents a new viral disease characterized by not only respiratory symptoms but also a systemic invasion associated with extra-respiratory signs. Neurological symptoms must be the focus of our attention, and functional brain evaluation with EEG is crucial, in combination with anatomical and functional brain imaging, to better understand its pathophysiology. Evolution of symptoms together with EEG patterns at the distance of the acute episode should also be scrutinized.
Magnetic Resonance-Compatible Arm-Crank Ergometry: A New Platform Linking Whole-Body Calorimetry to Upper-Extremity Biomechanics and Arm Muscle Metabolism
Authors: Vegter Riemer J. K. , van den Brink Sebastiaan , Mouton Leonora J. , Sibeijn-Kuiper Anita , van der Woude Lucas H. V. , Jeneson Jeroen A. L.
Published: February 2021

Introduction

Evaluation of the effect of human upper-body training regimens may benefit from knowledge of local energy expenditure in arm muscles. To that end, we developed a novel arm-crank ergometry platform for use in a clinical magnetic resonance (MR) scanner with31P spectroscopy capability to study arm muscle energetics. Complementary datasets on heart-rate, whole-body oxygen consumption, proximal arm-muscle electrical activity and power output, were obtained in a mock-up scanner. The utility of the platform was tested by a preliminary study over 4 weeks of skill practice on the efficiency of execution of a dynamic arm-cranking task in healthy subjects.

Results

The new platform successfully recorded the first everin vivo31P MR spectra from the human biceps brachii (BB) muscle during dynamic exercise in five healthy subjects. Changes in BB energy- and pH balance varied considerably between individuals. Surface electromyography and mechanical force recordings revealed that individuals employed different arm muscle recruitment strategies, using either predominantly elbow flexor muscles (pull strategy; two subjects), elbow extensor muscles (push strategy; one subject) or a combination of both (two subjects). The magnitude of observed changes in BB energy- and pH balance during ACT execution correlated closely with each strategy. Skill practice improved muscle coordination but did not alter individual strategies. Mechanical efficiency on group level seemed to increase as a result of practice, but the outcomes generated by the new platform showed the additional caution necessary for the interpretation that total energy cost was actually reduced at the same workload.

Conclusion

The presented platform integrates dynamicin vivo31P MRS recordings from proximal arm muscles with whole-body calorimetry, surface electromyography and biomechanical measurements. This new methodology enables evaluation of cyclic motor performance and outcomes of upper-body training regimens in healthy novices. It may be equally useful for investigations of exercise physiology in lower-limb impaired athletes and wheelchair users as well as frail patients including patients with debilitating muscle disease and the elderly.
Effects of Power-Oriented Resistance Training With Heavy vs. Light Loads on Muscle-Tendon Function in Older Adults: A Study Protocol for a Randomized Controlled Trial
Authors: Rodriguez-Lopez Carlos , Alcazar Julian , Losa-Reyna Jose , Martin-Espinosa Noelia Maria , Baltasar-Fernandez Ivan , Ara Ignacio , Csapo Robert , Alegre Luis M.
Published: February 2021

Background

Power-oriented resistance training (PRT) is one of the most effective exercise programs to counteract neuromuscular and physical function age-related declines. However, the optimal load that maximizes these outcomes or the load-specific adaptations induced on muscle power determinants remain to be better understood. Furthermore, to investigate whether these adaptations are potentially transferred to an untrained limb (i.e., cross-education phenomenon) could be especially relevant during limb-immobilization frequently observed in older people (e.g., after hip fracture).

Methods

At least 30 well-functioning older participants (>65 years) will participate in a within-person randomized controlled trial. After an 8-week control period, the effects of two 12-week PRT programs using light vs. heavy loads will be compared using an unilateral exercise model through three study arms (light-load PRT vs. non-exercise; heavy-load PRT vs. non-exercise; and light- vs. heavy- load PRT). Muscle-tendon function, muscle excitation and morphology and physical function will be evaluated to analyze the load-specific effects of PRT in older people. Additionally, the effects of PRT will be examined on a non-exercised contralateral limb.

Discussion

Tailored exercise programs are largely demanded given their potentially greater efficiency preventing age-related negative consequences, especially during limb-immobilization. This trial will provide evidence supporting the use of light- or heavy-load PRT on older adults depending on individual needs, improving decision making and exercise program efficacy.

Clinical Trial Registration

NCT03724461 registration data: October 30, 2018.
Visualizing and Quantifying Irregular Heart Rate Irregularities to Identify Atrial Fibrillation Events
Authors: Keidar Noam , Elul Yonatan , Schuster Assaf , Yaniv Yael
Published: February 2021

Background

Screening the general public for atrial fibrillation (AF) may enable early detection and timely intervention, which could potentially decrease the incidence of stroke. Existing screening methods require professional monitoring and involve high costs. AF is characterized by an irregular irregularity of the cardiac rhythm, which may be detectable using an index quantifying and visualizing this type of irregularity, motivating wide screening programs and promoting the research of AF patient subgroups and clinical impact of AF burden.

Methods

We calculated variability, normality and mean of the difference between consecutive RR interval series (denoted as modified entropy scale—MESC) to quantify irregular irregularities. Based on the variability and normality indices calculated for long 1-lead ECG records, we created a plot termed a regularogram (RGG), which provides a visual presentation of irregularly irregular rates and their burden in a given record. To inspect the potency of these indices, they were applied to train and test a machine learning classifier to identify AF episodes in gold-standard, publicly available databases (PhysioNet) that include recordings from both patients with AF and/or other rhythm disturbances, and from healthy volunteers. The classifier was trained and validated on one database and tested on three other databases.

Results

Irregular irregularities were identified using normality, variability and mean MESC indices. The RGG displayed visually distinct differences between patients with vs. without AF and between patients with different levels of AF burden. Training a simple, explainable machine learning tool integrating these three indices enabled AF detection with 99.9% accuracy, when trained on the same person, and 97.8%, when trained on patients from a different database. Comparison to other RR interval-based AF detection methods that utilize signal processing, classic machine learning and deep learning techniques, showed superiority of our suggested method.

Conclusion

Visualizing and quantifying irregular irregularities will be of value for both rapid visual inspection of long Holter recordings for the presence and the burden of AF, and for machine learning classification to identify AF episodes. A free online tool for calculating the indices, drawing RGGs and estimating AF burden, is available.
Histone Methyltransferase EZH2: A Potential Therapeutic Target for Kidney Diseases
Authors: Li Tingting , Yu Chao , Zhuang Shougang
Published: February 2021

Enhancer of zeste homolog 2 (EZH2) is a histone-lysine N-methyltransferase enzyme that catalyzes the addition of methyl groups to histone H3 at lysine 27, leading to gene silencing. Mutation or over-expression of EZH2 has been linked to many cancers including renal carcinoma. Recent studies have shown that EZH2 expression and activity are also increased in several animal models of kidney injury, such as acute kidney injury (AKI), renal fibrosis, diabetic nephropathy, lupus nephritis (LN), and renal transplantation rejection. The pharmacological and/or genetic inhibition of EZH2 can alleviate AKI, renal fibrosis, and LN, but potentiate podocyte injury in animal models, suggesting that the functional role of EZH2 varies with renal cell type and disease model. In this article, we summarize the role of EZH2 in the pathology of renal injury and relevant mechanisms and highlight EZH2 as a potential therapeutic target for kidney diseases.
New Insights Into Functions of IQ67-Domain Proteins
Authors: Guo Chunyue , Zhou Jun , Li Dengwen
Published: February 2021

IQ67-domain (IQD) proteins, first identified in Arabidopsis and rice, are plant-specific calmodulin-binding proteins containing highly conserved motifs. They play a critical role in plant defenses, organ development and shape, and drought tolerance. Driven by comprehensive genome identification and analysis efforts, IQDs have now been characterized in several species and have been shown to act as microtubule-associated proteins, participating in microtubule-related signaling pathways. However, the precise molecular mechanisms underpinning their biological functions remain incompletely understood. Here we review current knowledge on how IQD family members are thought to regulate plant growth and development by affecting microtubule dynamics or participating in microtubule-related signaling pathways in different plant species and propose some new insights.
How and When Does Outcrossing Occur in the Predominantly Selfing Species Medicago truncatula?
Authors: Jullien Margaux , Ronfort Joëlle , Gay Laurène
Published: February 2021

Empirical studies on natural populations ofMedicago truncatularevealed selfing rates higher than 80%, but never up to 100%. Similarly, several studies of predominantly selfing species show variability in the level of residual outcrossing between populations and also between temporal samples of the same population. However, these studies measure global selfing rates at the scale of the population and we do not know whether there is intra-population variation and how outcrossing events are distributed, between genotypes, plants, flowers, or seeds. Theoretical studies predict the maintenance of residual outcrossing in highly selfing species due to environmental (e.g., pollen biology) and/or genetic determinants and decompositions of the variation in outcrossing rate using experimental data can be very informative to test these hypotheses. Here, we focus on one natural population ofM. truncatulain order to describe precisely its mating system. In particular, we investigated the determinants of the selfing rate by testing for seasonal variations (environmental determinism) and variations between genotypes (genetic determinism). We measured selfing rates in maternal progenies from plants collected widely across a natural population. For each plant, we collected pods from flowers produced at the beginning and at the end of the flowering season to test for a seasonal variation in the outcrossing rate. For each collected offspring, we also estimated the likelihood that it was issued from a self-fertilization event and assessed the genetic component of variation of this mating system measure. We found a significant, albeit small, increase in outcrossing rate in progenies collected at the end [tm= 0.137 (SD= 0.025)] compared to those collected at the beginning [tm= 0.083 (0.016)] of the flowering season. A significant between genotypes variation in selfing rate was also detected, resulting in a heritability of 9% for the rate of residual outcrossing. Altogether, our work shows that despite a predominantly selfing reproductive mode,M. truncatuladisplays variation in residual outcrossing rate, and that this trait is likely under a complex determinism combining environmental and genetic factors. We discuss the evolutionary implications of our results for the population.
Polysaccharide Biosynthesis: Glycosyltransferases and Their Complexes
Authors: Zabotina Olga A. , Zhang Ning , Weerts Richard
Published: February 2021

Glycosyltransferases (GTs) are enzymes that catalyze reactions attaching an activated sugar to an acceptor substrate, which may be a polysaccharide, peptide, lipid, or small molecule. In the past decade, notable progress has been made in revealing and cloning genes encoding polysaccharide-synthesizing GTs. However, the vast majority of GTs remain structurally and functionally uncharacterized. The mechanism by which they are organized in the Golgi membrane, where they synthesize complex, highly branched polysaccharide structures with high efficiency and fidelity, is also mostly unknown. This review will focus on current knowledge about plant polysaccharide-synthesizing GTs, specifically focusing on protein-protein interactions and the formation of multiprotein complexes.
Complex-Type N-Glycans Influence the Root Hair Landscape of Arabidopsis Seedlings by Altering the Auxin Output
Authors: Frank Manuel , Kaulfürst-Soboll Heidi , Fischer Kerstin , von Schaewen Antje
Published: February 2021

Roots supply plants with nutrients and water, besides anchoring them in the soil. The primary root with its lateral roots constitutes the central skeleton of the root system. In particular, root hairs increase the root surface, which is critical for optimizing uptake efficiency. During root-cell growth and development, many proteins that are components of, e.g., the cell wall and plasma membrane are constitutively transported through the secretory system and become posttranslationally modified. Here, the best-studied posttranslational modification is protein N-glycosylation. While alterations in the attachment/modification of N-glycans within the ER lumen results in severe developmental defects, the impact of Golgi-localized complex N-glycan modification, particularly on root development, has not been studied in detail. We report that impairment of complex-type N-glycosylation results in a differential response to synthetic phytohormones with earlier and increased root-hair elongation. Application of either the cytokinin BAP, the auxin NAA, or the ethylene precursor ACC revealed an interaction of auxin with complex N-glycosylation during root-hair development. Especially in gntI mutant seedlings, the early block of complex N-glycan formation resulted in an increased auxin sensitivity. RNA-seq experiments suggest that gntI roots have permanently elevated nutrient-, hypoxia-, and defense-stress responses, which might be a consequence of the altered auxin responsiveness.
Ecophysiological Performance of Proteaceae Species From Southern South America Growing on Substrates Derived From Young Volcanic Materials
Authors: Delgado M. , Zúñiga-Feest A. , Reyes-Díaz M. , Barra P. J. , Ruiz S. , Bertin-Benavides A. , Valle S. , Pereira M. , Lambers H.
Published: February 2021

Southern South American Proteaceae thrive on young volcanic substrates, which are extremely low in plant-available phosphorus (P). Most Proteaceae exhibit a nutrient-acquisition strategy based on the release of carboxylates from specialized roots, named cluster roots (CR). Some Proteaceae colonize young volcanic substrates which has been related to CR functioning. However, physiological functioning of other Proteaceae on recent volcanic substrates is unknown. We conducted an experiment with seedlings of five Proteaceae (Gevuina avellana, Embothrium coccineum, Lomatia hirsuta, L. ferruginea, and L. dentata) grown in three volcanic materials. Two of them are substrates with very low nutrient concentrations, collected from the most recent deposits of the volcanoes Choshuenco and Calbuco (Chile). The other volcanic material corresponds to a developed soil that exhibits a high nutrient availability. We assessed morphological responses (i.e., height, biomass, and CR formation), seed and leaf macronutrient and micronutrient concentrations and carboxylates exuded by roots. The results show that G. avellana was less affected by nutrient availability of the volcanic substrate, probably because it had a greater nutrient content in its seeds and produced large CR exuding carboxylates that supported their initial growth. Embothrium coccineum exhibited greater total plant height and leaf P concentration than Lomatia species. In general, in all species leaf macronutrient concentrations were reduced on nutrient-poor volcanic substrates, while leaf micronutrient concentrations were highly variable depending on species and volcanic material. We conclude that Proteaceae from temperate rainforests differ in their capacity to grow and acquire nutrients from young and nutrient-poor volcanic substrates. The greater seed nutrient content, low nutrient requirements (only for G. avellana) and ability to mobilize nutrients help explain why G. avellana and E. coccineum are better colonizers of recent volcanic substrates than Lomatia species.