bluuebunny/crossref_metadata_2025 huggingface dataset:
Review of Post-embedding Immunogold Methods for the Study of Neuronal Structures
Authors: Petralia Ronald S. , Wang Ya-Xian
Published: October 2021

The post-embedding immunogold (PI) technique for immunolabeling of neuronal tissues utilizing standard thin-section transmission electron microscopy (TEM) continues to be a prime method for understanding the functional localization of key proteins in neuronal function. Its main advantages over other immunolabeling methods for thin-section TEM are (1) fairly accurate and quantifiable localization of proteins in cells; (2) double-labeling of sections using two gold particle sizes; and (3) the ability to perform multiple labeling for different proteins by using adjacent sections. Here we first review in detail a common method for PI of neuronal tissues. This method has two major parts. First, we describe the freeze-substitution embedding method: cryoprotected tissue is frozen in liquid propane via plunge-freezing, and is placed in a freeze-substitution instrument in which the tissue is embedded in Lowicryl at low temperatures. We highlight important aspects of freeze-substitution embedding. Then we outline how thin sections of embedded tissue on grids are labeled with a primary antibody and a secondary gold particle-conjugated antibody, and the particular problems encountered in TEM of PI-labeled sections. In the Discussion, we compare our method both to earlier PI methods and to more recent PI methods used by other laboratories. We also compare TEM immunolabeling using PI vs. various pre-embedding immunolabeling methods, especially relating to neuronal tissue.
Up-Regulation of CD146 in Schwann Cells Following Peripheral Nerve Injury Modulates Schwann Cell Function in Regeneration
Authors: Shen Yinying , Zhu Jun , Liu Qianyan , Ding Shiyan , Dun Xinpeng , He Jianghong
Published: October 2021

CD146 is cell adhesion molecule and is implicated in a variety of physiological and pathological processes. However, the involvement of CD146 in peripheral nerve regeneration has not been studied yet. Here, we examine the spatial and temporal expression pattern of CD146 in injured mouse sciatic nerve via high-throughput data analysis, RT-PCR and immunostaining. By microarray data analysis and RT-PCR validation, we show that CD146 mRNA is significantly up-regulated in the nerve bridge and in the distal nerve stump following mouse sciatic nerve transection injury. By single cell sequencing data analysis and immunostaining, we demonstrate that CD146 is up-regulated in Schwann cells and cells associated with blood vessels following mouse peripheral nerve injury. Bioinformatic analysis revealed that CD146 not only has a key role in promoting of blood vessel regeneration but also regulates cell migration. The biological function of CD146 in Schwann cells was further investigated by knockdown of CD146 in rat primary Schwann cells. Functional assessments showed that knockdown of CD146 decreases viability and proliferation of Schwann cells but increases Schwann cell migration. Collectively, our findings imply that CD146 could be a key cell adhesion molecule that is up-regulated in injured peripheral nerves to regulate peripheral nerve regeneration.
Respiratory Muscle Function Tests and Diaphragm Ultrasound Predict Nocturnal Hypoventilation in Slowly Progressive Myopathies
Authors: Spiesshoefer Jens , Lutter Riccarda , Kabitz Hans-Joachim , Henke Carolin , Herkenrath Simon , Randerath Winfried , Young Peter , Dreher Michael , Görlich Dennis , Boentert Matthias
Published: October 2021

Introduction: In slowly progressive myopathies, diaphragm weakness early manifests through sleep-related hypoventilation as reflected by nocturnal hypercapnia. This study investigated whether daytime tests of respiratory muscle function and diaphragm ultrasound predict hypercapnia during sleep.

Methods: Twenty-seven patients with genetic myopathies (myotonic dystrophy type 1 and 2, late-onset Pompe disease, facioscapulohumeral dystrophy; 48 ± 11 years) underwent overnight transcutaneous capnometry, spirometry, measurement of mouth occlusion pressures, and diaphragm ultrasound.

Results: Sixteen out of 27 patients showed nocturnal hypercapnia (peak ptcCO2 ≥ 50 mmHg for ≥ 30 min or increase in ptcCO2 by 10 mmHg or more from the baseline value). In these patients, forced vital capacity (FVC; % predicted) and maximum inspiratory pressure (MIP; % of lower limit or normal or LLN) were significantly reduced compared to normocapnic individuals. Nocturnal hypercapnia was predicted by reduction in FVC of <60% [sensitivity, 1.0; area under the curve (AUC), 0.82] and MIP (%LLN) <120% (sensitivity, 0.83; AUC, 0.84), the latter reflecting that in patients with neuromuscular disease, pretest likelihood of abnormality is per se higher than in healthy subjects. Diaphragm excursion velocity during a sniff maneuver excluded nocturnal hypercapnia with high sensitivity (0.90) using a cutoff of 8.0 cm/s.

Conclusion: In slowly progressive myopathies, nocturnal hypercapnia is predicted by FVC <60% or MIP <120% (LLN). As a novelty, nocturnal hypercapnia can be excluded with acceptable sensitivity by diaphragm excursion velocity >8.0 cm/s on diaphragm ultrasound.
Challenging the Boundaries of the Physical Self: Distal Cues Impact Body Ownership
Authors: Grechuta Klaudia , De La Torre Costa Javier , Ballester Belén Rubio , Verschure Paul
Published: October 2021

The unique ability to identify one’s own body and experience it as one’s own is fundamental in goal-oriented behavior and survival. However, the mechanisms underlying the so-called body ownership are yet not fully understood. Evidence based on Rubber Hand Illusion (RHI) paradigms has demonstrated that body ownership is a product of reception and integration of self and externally generated multisensory information, feedforward and feedback processing of sensorimotor signals, and prior knowledge about the body. Crucially, however, these designs commonly involve the processing of proximal modalities while the contribution of distal sensory signals to the experience of ownership remains elusive. Here we propose that, like any robust percept, body ownership depends on the integration and prediction across all sensory modalities, including distal sensory signals pertaining to the environment. To test our hypothesis, we created an embodied goal-oriented Virtual Air Hockey Task, in which participants were to hit a virtual puck into a goal. In two conditions, we manipulated the congruency of distal multisensory cues (auditory and visual) while preserving proximal and action-driven signals entirely predictable. Compared to a fully congruent condition, our results revealed a significant decrease on three dimensions of ownership evaluation when distal signals were incongruent, including the subjective report as well as physiological and kinematic responses to an unexpected threat. Together, these findings support the notion that the way we represent our body is contingent upon all the sensory stimuli, including distal and action-independent signals. The present data extend the current framework of body ownership and may also find applications in rehabilitation scenarios.
Structural Differences Across Multiple Visual Cortical Regions in the Absence of Cone Function in Congenital Achromatopsia
Authors: Lowndes Rebecca , Molz Barbara , Warriner Lucy , Herbik Anne , de Best Pieter B. , Raz Noa , Gouws Andre , Ahmadi Khazar , McLean Rebecca J. , Gottlob Irene , Kohl Susanne , Choritz Lars , Maguire John , Kanowski Martin , Käsmann-Kellner Barbara , Wieland Ilse , Banin Eyal , Levin Netta , Hoffmann Michael B. , Morland Antony B. , Baseler Heidi A.
Published: October 2021

Most individuals with congenital achromatopsia (ACHM) carry mutations that affect the retinal phototransduction pathway of cone photoreceptors, fundamental to both high acuity vision and colour perception. As the central fovea is occupied solely by cones, achromats have an absence of retinal input to the visual cortex and a small central area of blindness. Additionally, those with complete ACHM have no colour perception, and colour processing regions of the ventral cortex also lack typical chromatic signals from the cones. This study examined the cortical morphology (grey matter volume, cortical thickness, and cortical surface area) of multiple visual cortical regions in ACHM (n = 15) compared to normally sighted controls (n = 42) to determine the cortical changes that are associated with the retinal characteristics of ACHM. Surface-based morphometry was applied to T1-weighted MRI in atlas-defined early, ventral and dorsal visual regions of interest. Reduced grey matter volume in V1, V2, V3, and V4 was found in ACHM compared to controls, driven by a reduction in cortical surface area as there was no significant reduction in cortical thickness. Cortical surface area (but not thickness) was reduced in a wide range of areas (V1, V2, V3, TO1, V4, and LO1). Reduction in early visual areas with large foveal representations (V1, V2, and V3) suggests that the lack of foveal input to the visual cortex was a major driving factor in morphological changes in ACHM. However, the significant reduction in ventral area V4 coupled with the lack of difference in dorsal areas V3a and V3b suggest that deprivation of chromatic signals to visual cortex in ACHM may also contribute to changes in cortical morphology. This research shows that the congenital lack of cone input to the visual cortex can lead to widespread structural changes across multiple visual areas.
White Matter Integrity and Nicotine Dependence: Evaluating Vertical and Horizontal Pleiotropy
Authors: Ye Zhenyao , Mo Chen , Liu Song , Hatch Kathryn S. , Gao Si , Ma Yizhou , Hong L. Elliot , Thompson Paul M. , Jahanshad Neda , Acheson Ashley , Garavan Hugh , Shen Li , Nichols Thomas E. , Kochunov Peter , Chen Shuo , Ma Tianzhou
Published: October 2021

Tobacco smoking is an addictive behavior that supports nicotine dependence and is an independent risk factor for cancer and other illnesses. Its neurogenetic mechanisms are not fully understood but may act through alterations in the cerebral white matter (WM). We hypothesized that the vertical pleiotropic pathways, where genetic variants influence a trait that in turn influences another trait, link genetic factors, integrity of cerebral WM, and nicotine addiction. We tested this hypothesis using individual genetic factors, WM integrity measured by fractional anisotropy (FA), and nicotine dependence-related smoking phenotypes, including smoking status (SS) and cigarettes per day (CPDs), in a large epidemiological sample collected by the UK Biobank. We performed a genome-wide association study (GWAS) to identify previously reported loci associated with smoking behavior. Smoking was found to be associated with reduced WM integrity in multiple brain regions. We then evaluated two competing vertical pathways: Genes → WM integrity → Smoking versus Genes → Smoking → WM integrity and a horizontal pleiotropy pathway where genetic factors independently affect both smoking and WM integrity. The causal pathway analysis identified 272 pleiotropic single-nucleotide polymorphisms (SNPs) whose effects on SS were mediated by FA, as well as 22 pleiotropic SNPs whose effects on FA were mediated by CPD. These SNPs were mainly located in important susceptibility genes for smoking-induced diseases NCAM1 and IREB2. Our findings revealed the role of cerebral WM in the maintenance of the complex addiction and provided potential genetic targets for future research in examining how changes in WM integrity contribute to the nicotine effects on the brain.
Restoring Sensorimotor Function Through Neuromodulation After Spinal Cord Injury: Progress and Remaining Challenges
Authors: Zhang Hui , Liu Yaping , Zhou Kai , Wei Wei , Liu Yaobo
Published: October 2021

Spinal cord injury (SCI) is a major disability that results in motor and sensory impairment and extensive complications for the affected individuals which not only affect the quality of life of the patients but also result in a heavy burden for their families and the health care system. Although there are few clinically effective treatments for SCI, research over the past few decades has resulted in several novel treatment strategies which are related to neuromodulation. Neuromodulation—the use of neuromodulators, electrical stimulation or optogenetics to modulate neuronal activity—can substantially promote the recovery of sensorimotor function after SCI. Recent studies have shown that neuromodulation, in combination with other technologies, can allow paralyzed patients to carry out intentional, controlled movement, and promote sensory recovery. Although such treatments hold promise for completely overcoming SCI, the mechanisms by which neuromodulation has this effect have been difficult to determine. Here we review recent progress relative to electrical neuromodulation and optogenetics neuromodulation. We also examine potential mechanisms by which these methods may restore sensorimotor function. We then highlight the strengths of these approaches and remaining challenges with respect to its application.
GRIN2A Variants Associated With Idiopathic Generalized Epilepsies
Authors: Liu Xiao-Rong , Xu Xing-Xing , Lin Si-Mei , Fan Cui-Ying , Ye Ting-Ting , Tang Bin , Shi Yi-Wu , Su Tao , Li Bing-Mei , Yi Yong-Hong , Luo Jian-Hong , Liao Wei-Ping
Published: October 2021

Objective: The objective of this study is to explore the role of GRIN2A gene in idiopathic generalized epilepsies and the potential underlying mechanism for phenotypic variation.

Methods: Whole-exome sequencing was performed in a cohort of 88 patients with idiopathic generalized epilepsies. Electro-physiological alterations of the recombinant N-methyl-D-aspartate receptors (NMDARs) containing GluN2A mutants were examined using two-electrode voltage-clamp recordings. The alterations of protein expression were detected by immunofluorescence staining and biotinylation. Previous studies reported that epilepsy related GRIN2A missense mutations were reviewed. The correlation among phenotypes, functional alterations, and molecular locations was analyzed.

Results: Three novel heterozygous missense GRIN2A mutations (c.1770A > C/p.K590N, c.2636A > G/p.K879R, and c.3199C > T/p.R1067W) were identified in three unrelated cases. Electrophysiological analysis demonstrated R1067W significantly increased the current density of GluN1/GluN2A NMDARs. Immunofluorescence staining indicated GluN2A mutants had abundant distribution in the membrane and cytoplasm. Western blotting showed the ratios of surface and total expression of the three GluN2A-mutants were significantly increased comparing to the wild type. Further analysis on the reported missense mutations demonstrated that mutations with severe gain-of-function were associated with epileptic encephalopathy, while mutations with mild gain of function were associated with mild phenotypes, suggesting a quantitative correlation between gain-of-function and phenotypic severity. The mutations located around transmembrane domains were more frequently associated with severe phenotypes and absence seizure-related mutations were mostly located in carboxyl-terminal domain, suggesting molecular sub-regional effects.

Significance: This study revealed GRIN2A gene was potentially a candidate pathogenic gene of idiopathic generalized epilepsies. The functional quantitative correlation and the molecular sub-regional implication of mutations helped in explaining the relatively mild clinical phenotypes and incomplete penetrance associated with GRIN2A variants.
Pericardial Injection of Kainic Acid Induces a Chronic Epileptic State in Larval Zebrafish
Authors: Heylen Lise , Pham Duc-Hung , De Meulemeester Ann-Sofie , Samarut Éric , Skiba Adrianna , Copmans Daniëlle , Kazwiny Youcef , Vanden Berghe Pieter , de Witte Peter A. M. , Siekierska Aleksandra
Published: October 2021

Epilepsy is a common disorder of the brain characterized by spontaneous recurrent seizures, which develop gradually during a process called epileptogenesis. The mechanistic processes underlying the changes of brain tissue and networks toward increased seizure susceptibility are not fully understood. In rodents, injection of kainic acid (KA) ultimately leads to the development of spontaneous epileptic seizures, reflecting similar neuropathological characteristics as seen in patients with temporal lobe epilepsy (TLE). Although this model has significantly contributed to increased knowledge of epileptogenesis, it is technically demanding, costly to operate and hence not suitable for high-throughput screening of anti-epileptic drugs (AEDs). Zebrafish, a vertebrate with complementary advantages to rodents, is an established animal model for epilepsy research. Here, we generated a novel KA-induced epilepsy model in zebrafish larvae that we functionally and pharmacologically validated. KA was administered by pericardial injection at an early zebrafish larval stage. The epileptic phenotype induced was examined by quantification of seizure-like behavior using automated video recording, and of epileptiform brain activity measured via local field potential (LFP) recordings. We also assessed GFP-labeled GABAergic and RFP-labeled glutamatergic neurons in double transgenic KA-injected zebrafish larvae, and examined the GABA and glutamate levels in the larval heads by liquid chromatography with tandem mass spectrometry detection (LC-MS/MS). Finally, KA-injected larvae were exposed to five commonly used AEDs by immersion for pharmacological characterization of the model. Shortly after injection, KA induced a massive damage and inflammation in the zebrafish brain and seizure-like locomotor behavior. An abnormal reorganization of brain circuits was observed, a decrease in both GABAergic and glutamatergic neuronal population and their associated neurotransmitters. Importantly, these changes were accompanied by spontaneous and continuous epileptiform brain discharges starting after a short latency period, as seen in KA rodent models and reminiscent of human pathology. Three out of five AEDs tested rescued LFP abnormalities but did not affect the seizure-like behavior. Taken together, for the first time we describe a chemically-induced larval zebrafish epilepsy model offering unique insights into studying epileptogenic processes in vivo and suitable for high-throughput AED screening purposes and rapid genetic investigations.
Widely Targeted Metabolomics Analysis to Reveal Transformation Mechanism of Cistanche Deserticola Active Compounds During Steaming and Drying Processes
Authors: Ai Ziping , Zhang Yue , Li Xingyi , Sun Wenling , Liu Yanhong
Published: October 2021

Cistanche deserticola is one of the most precious plants, traditionally as Chinese medicine, and has recently been used in pharmaceutical and healthy food industries. Steaming and drying are two important steps in the processing of Cistanche deserticola. Unfortunately, a comprehensive understanding of the chemical composition changes of Cistanche deserticola during thermal processing is limited. In this study, ultra-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS)-based widely targeted metabolomics analysis was used to investigate the transformation mechanism of Cistanche deserticola active compounds during steaming and drying processes. A total of 776 metabolites were identified in Cistanche deserticola during thermal processing, among which, 77 metabolites were differentially regulated (p < 0.05) wherein 39 were upregulated (UR) and 38 were downregulated (DR). Forty-seven (17 UR, 30 DR) and 30 (22 UR, 8 DR) differential metabolites were identified during steaming and drying, respectively. The most variation of the chemicals was observed during the process of steaming. Metabolic pathway analysis indicated that phenylpropanoid, flavonoid biosynthesis, and alanine metabolism were observed during steaming, while glycine, serine, and threonine metabolism, thiamine metabolism, and unsaturated fatty acid biosynthesis were observed during drying. The possible mechanisms of the chemical alterations during thermal processing were also provided by the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Furthermore, the blackening of the appearance of Cistanche deserticola mainly occurred in the steaming stage rather than the drying stage, which is associated with the metabolism of the amino acids. All results indicated that the formation of active compounds during the processing of Cistanche deserticola mainly occurred in the steaming stage.
CircFAM114A2 Promotes Cisplatin Sensitivity via miR-222-3p/P27 and miR-146a-5p/P21 Cascades in Urothelial Carcinoma
Authors: Lv Jiancheng , Zhou Zijian , Wang Jingzi , Yang Xiao , Yu Hao , Han Jie , Feng Dexiang , Yuan Baorui , Wu Qikai , Li Pengchao , Lu Qiang , Yang Haiwei
Published: October 2021

Introduction

Circular RNAs (circRNAs) are non-coding RNAs that have the structure of a covalently closed loop. Increasing data have proven that circRNAs can influence the progression and chemotherapy sensitivity of tumors. Therefore, the underlying function and mechanisms of more circRNAs in progression and chemotherapy resistance are important.

Methods

We conducted RNA sequencing on five pairs of urothelial carcinoma samples and screened for circRNAs. CircFAM114A2 was found to be low expressed in urothelial carcinoma. The functions of circFAM114A2 in urothelial carcinoma were explored by cell cycle assay, IC50 determination assay, cell proliferation assay, apoptosis assay, and tumorigenesis assay.

Results

We discovered that the levels of circFAM114A2 were decreased in urothelial carcinoma cell lines and tissues. According to follow-up data, urothelial carcinoma patients with higher circFAM114A2 expression had better survival. Importantly, the levels of circFAM114A2 were associated with the histological grade of urothelial carcinoma. CircFAM114A2 could inhibit cell proliferation and block more urothelial carcinoma cells in the G1 phase and then increase the sensitivity of urothelial carcinoma to cisplatin chemotherapy. Mechanistically, circFAM114A2 directly sponged miR-222-3p/miR-146a-5p and subsequently influenced the expressions of the downstream target genes P27/P21, which, in turn, inhibited the progression of urothelial carcinoma and increased the sensitivity of cancer cells to cisplatin chemotherapy.

Conclusion

CircFAM114A2 could inhibit progression and promote cisplatin sensitivity in urothelial carcinoma through novel circFAM114A2/miR-222-3p/P27 and circFAM114A2/miR-146a-5p/P21 pathways. CircFAM1142 has therefore great potential as a prognostic biomarker and therapeutic target for urothelial carcinoma.
Redefining Hepatocellular Carcinoma Staging Systems Based on the Bile Duct Invasion Status: A Multicenter Study
Authors: Huang Qizhen , Chen Yufeng , Lin Kongying , Sun Chuandong , Zheng Shuguo , Chen Jinhong , Wang Yifan , Zhou Yanming , Zhou Weiping , Liu Jingfeng , Zeng Yongyi
Published: October 2021

Background and Aims

The prognostic value of bile duct invasion (BDI) remains controversial. We aimed to investigate the prognostic value of BDI and the stage of BDI in different staging systems.

Methods

Patients with hepatocellular carcinoma (HCC) from nine hepatobiliary medical centers who underwent R0 resection were included. Overall survival (OS) was assessed using the Kaplan–Meier method and tested using the log-rank test. The prognostic effect of BDI was analyzed using univariate and multivariate Cox proportional hazard regression analyses. The predictive performance of these models was evaluated using the concordance index and time-dependent receiver operating characteristic curve (tdAUC).

Results

Of 1021 patients with HCC, 177 had BDI. OS was worse in the HCC with BDI group than in the HCC without BDI group (p<0.001); multivariate analysis identified BDI as an independent risk factor for OS. After adjustment for interference of confounding factors using the Cox proportional hazard regression model, HCC with BDI and without macrovascular invasion was classified as Barcelona Clinic Liver Cancer (BCLC) B, eighth edition American Joint Committee on Cancer (AJCC) IIIA, and China Liver Cancer (CNLC) IIb, respectively, whereas HCC with BDI and macrovascular was classified as BCLC C, AJCC IIIB, and CNLC IIIA, respectively. C-indexes and tdAUCs of the adjusted staging systems were superior to those of the corresponding current staging systems.

Conclusion

We constructed adjusted staging systems with the BDI status, improved their predictive performance and facilitate clinical use.
Balancing the Risk-Benefit Ratio of Immune Checkpoint Inhibitor and Anti-VEGF Combination Therapy in Renal Cell Carcinoma: A Systematic Review and Meta-Analysis
Authors: Tao Li , Zhang Huiyun , An Guangyu , Lan Haoning , Xu Yaoqi , Ge Yang , Yao Jiannan
Published: October 2021

Background

Although immune checkpoint inhibitors (ICIs) combined with vascular endothelial growth factor receptor (VEGFR)-targeted therapy and sunitinib monotherapy have been widely applied to metastatic renal cell carcinoma (mRCC), effectiveness and safety data are still lacking. To optimize clinical decision-making, we conducted a systematic review and meta-analysis of published randomized clinical trials to characterize the efficacy and the risk of adverse events (AEs) in patients treated with ICIs plus anti-VEGF therapy.

Materials and Methods

We used PubMed, EMBASE, and the Cochrane Library to retrieve randomized controlled trials (RCTs) published before March 27, 2021. The efficacy outcomes were progression-free survival (PFS), overall survival (OS), and objective response rate (ORR). The pooled risk ratio (RR) and 95% confidence intervals (CI) of AEs were calculated in the safety analysis.

Results

Six RCTs involving 4,227 patients were identified after a systematic search. For OS, ICI and anti-VEGF combination therapy decreased mortality approximately 30% in the intention-to-treat population (ITT) (hazard ratio (HR) = 0.70, 95% CI: 0.57–0.87), but there was no statistical difference in patients evaluated as “favorable” by the International Metastatic Renal-Cell Carcinoma Database Consortium (IMDC) criteria compared with monotherapy (HR = 0.90, 95% CI: 0.55–1.46, p = 0.66). In terms of PFS, the progression risk for all participants declined 35% (HR = 0.65, 95% CI: 0.50–0.83) and patients evaluated as “poor” by IMDC benefited further (HR = 0.46, 95% CI: 0.36–0.58). No evident divergence was found in age and sex subgroups. The RRs of all-grade hypertension, arthralgia, rash, proteinuria, high-grade (grades 3–5) arthralgia, and proteinuria developed after combination therapy were increased compared with sunitinib. The risk of high-grade hypertension and rash showed no statistical difference. However, the risk of hand-foot skin reaction (HFSR), stomatitis, and dysgeusia decreased in combination therapy groups.

Conclusions

Compared with sunitinib, OS, PFS, and ORR were significantly improved in patients receiving ICI and anti-VEGF combination therapy at the expense of increased specific AEs. More attention should be paid to individualized application of these combination therapies to achieve the best benefit-risk ratio in the clinic.

Systematic Review Registration

[https://inplasy.com/] INPLASY: 202130104.
Multiparametric Prostate MRI in Biopsy-Naïve Men: A Prospective Evaluation of Performance and Biopsy Strategies
Authors: Krüger-Stokke Brage , Bertilsson Helena , Langørgen Sverre , Sjøbakk Torill Anita Eidhammer , Bathen Tone Frost , Selnæs Kirsten Margrete
Published: October 2021

Objectives

This study aims to prospectively estimate the diagnostic performance of multiparametric prostate MRI (mpMRI) and compare the detection rates of prostate cancer using cognitive targeted transrectal ultrasound (TRUS) guided biopsies, targeted MR-guided in-bore biopsies (MRGB), or both methods combined in biopsy-naïve men.

Methods

The biopsy-naïve men referred for mpMRI (including T2-weighted, diffusion-weighted and dynamic contrast enhanced MRI) due to prostate cancer suspicion (elevated prostate-specific antigen or abnormal digital rectal examination) were eligible for inclusion. The images were scored according to Prostate Imaging Reporting and Data System (PI-RADS) v2, and men with PI-RADS 1–2 lesions were referred for routine systematic TRUS, while those with PI-RADS 3–5 lesions were randomized to MRGB or cognitive targeted TRUS. Men randomized to MRGB were referred to a secondary TRUS 2 weeks after MRGB. Gleason grade group ≥2 was defined as clinically significant prostate cancer. The performance of mpMRI was estimated using prostate cancer detected by any biopsy method as the reference test.

Results

A total of 210 men were included. There was no suspicion of prostate cancer after mpMRI (PI-RADS 1–2) in 48% of the men. Among these, significant and insignificant prostate cancer was diagnosed in five and 11 men, respectively. Thirty-five men who scored as PI-RADS 1–2 did not undergo biopsy and were therefore excluded from the calculation of diagnostic accuracy. The overall sensitivity, specificity, negative predictive value, and positive predictive value of mpMRI for the detection of significant prostate cancer were 0.94, 0.63, 0.92, and 0.67, respectively. In patients with PI-RADS 3–5 lesions, the detection rates for significant prostate cancer were not significantly different between cognitive targeted TRUS (68.4%), MRGB (57.7%), and the combination of the two biopsy methods (64.4%). The median numbers of biopsy cores taken per patient undergoing systematic TRUS, cognitive targeted TRUS, and MRGB were 14 [8-16], 12 [6-17], and 2 [1-4] respectively.

Conclusions

mpMRI, in a cohort of biopsy-naïve men, has high negative predictive value, and our results support that it is safe to avoid biopsy after negative mpMRI. Furthermore, MRGB provides a similar diagnosis to the cognitive targeted TRUS but with fewer biopsies.
Bidirectional Interaction Between Cancer Cells and Platelets Provides Potential Strategies for Cancer Therapies
Authors: Yu Liuting , Guo Yao , Chang Zhiguang , Zhang Dengyang , Zhang Shiqiang , Pei Hanzhong , Pang Jun , Zhao Zhizhuang Joe , Chen Yun
Published: October 2021

Platelets are essential components in the tumor microenvironment. For decades, clinical data have demonstrated that cancer patients have a high risk of thrombosis that is associated with adverse prognosis and decreased survival, indicating the involvement of platelets in cancer progression. Increasing evidence confirms that cancer cells are able to induce production and activation of platelets. Once activated, platelets serve as allies of cancer cells in tumor growth and metastasis. They can protect circulating tumor cells (CTCs) against the immune system and detachment-induced apoptosis while facilitating angiogenesis and tumor cell adhesion and invasion. Therefore, antiplatelet agents and platelet-based therapies should be developed for cancer treatment. Here, we discuss the mechanisms underlying the bidirectional cancer-platelet crosstalk and platelet-based therapeutic approaches.
Hederagenin Protects PC12 Cells Against Corticosterone-Induced Injury by the Activation of the PI3K/AKT Pathway
Authors: Lin Ruohong , Liu Linlin , Silva Marta , Fang Jiankang , Zhou Zhiwei , Wang Haitao , Xu Jiangping , Li Tiejun , Zheng Wenhua
Published: October 2021

Depression is a prevalent psychiatric disorder and a leading cause of disability worldwide. Despite a variety of available treatments currently being used in the clinic, a substantial proportion of patients is unresponsive to these treatments, urging the development of more effective therapeutic approaches. Hederagenin (Hed), a triterpenoid saponin extracted from Fructus Akebiae, has several biological activities including anti-apoptosis, anti-hyperlipidemic and anti-inflammatory properties. Over the years, its potential therapeutic effect in depression has also been proposed, but the information is limited and the mechanisms underlying its antidepressant-like effects are unclear. The present study explored the neuroprotective effects and the potential molecular mechanisms of Hederagenin action in corticosterone (CORT)-injured PC12 cells. Obtained results show that Hederagenin protected PC12 cells against CORT-induced damage in a concentration dependent manner. In adittion, Hederagenin prevented the decline of mitochondrial membrane potential, reduced the production of intracellular reactive oxygen species (ROS) and decreased the apoptosis induced by CORT. The protective effect of Hederagenin was reversed by a specific phosphatidylinositol-3-kinase (PI3K) inhibitor LY294002 and AKT (also known as protein kinase B) inhibitor MK2206, suggesting that the effect of Hederagenin is mediated by the PI3K/AKT pathway. In line with this, western blot analysis results showed that Hederagenin stimulated the phosphorylation of AKT and its downstream target Forkhead box class O 3a (FoxO3a) and Glycogen synthase kinase-3-beta (GSK3β) in a concentration dependent manner. Taken together, these results indicate that the neuroprotective effect of Hederagenin is likely to occur via stimulation of the PI3K/AKT pathway.
Mitochondrial Contributions in the Genesis of Delayed Afterdepolarizations in Ventricular Myocytes
Authors: Pandey Vikas , Xie Lai-Hua , Qu Zhilin , Song Zhen
Published: October 2021

Mitochondria fulfill the cell’s energy demand and affect the intracellular calcium (Ca2+) dynamics via direct Ca2+ exchange, the redox effect of reactive oxygen species (ROS) on Ca2+ handling proteins, and other signaling pathways. Recent experimental evidence indicates that mitochondrial depolarization promotes arrhythmogenic delayed afterdepolarizations (DADs) in cardiac myocytes. However, the nonlinear interactions among the Ca2+ signaling pathways, ROS, and oxidized Ca2+/calmodulin-dependent protein kinase II (CaMKII) pathways make it difficult to reveal the mechanisms. Here, we use a recently developed spatiotemporal ventricular myocyte computer model, which consists of a 3-dimensional network of Ca2+ release units (CRUs) intertwined with mitochondria and integrates mitochondrial Ca2+ signaling and other complex signaling pathways, to study the mitochondrial regulation of DADs. With a systematic investigation of the synergistic or competing factors that affect the occurrence of Ca2+ waves and DADs during mitochondrial depolarization, we find that the direct redox effect of ROS on ryanodine receptors (RyRs) plays a critical role in promoting Ca2+ waves and DADs under the acute effect of mitochondrial depolarization. Furthermore, the upregulation of mitochondrial Ca2+ uniporter can promote DADs through Ca2+-dependent opening of mitochondrial permeability transition pores (mPTPs). Also, due to much slower dynamics than Ca2+ cycling and ROS, oxidized CaMKII activation and the cytosolic ATP do not appear to significantly impact the genesis of DADs during the acute phase of mitochondrial depolarization. However, under chronic conditions, ATP depletion suppresses and enhanced CaMKII activation promotes Ca2+ waves and DADs.
Leaf Water Storage and Robustness to Intermittent Drought: A Spatially Explicit Capacitive Model for Leaf Hydraulics
Authors: Luo Yongtian , Ho Che-Ling , Helliker Brent R. , Katifori Eleni
Published: October 2021

Leaf hydraulic networks play an important role not only in fluid transport but also in maintaining whole-plant water status through transient environmental changes in soil-based water supply or air humidity. Both water potential and hydraulic resistance vary spatially throughout the leaf transport network, consisting of xylem, stomata and water-storage cells, and portions of the leaf areas far from the leaf base can be disproportionately disadvantaged under water stress. Besides the suppression of transpiration and reduction of water loss caused by stomatal closure, the leaf capacitance of water storage, which can also vary locally, is thought to be crucial for the maintenance of leaf water status. In order to study the fluid dynamics in these networks, we develop a spatially explicit, capacitive model which is able to capture the local spatiotemporal changes of water potential and flow rate in monocotyledonous and dicotyledonous leaves. In electrical-circuit analogs described by Ohm's law, we implement linear capacitors imitating water storage, and we present both analytical calculations of a uniform one-dimensional model and numerical simulation methods for general spatially explicit network models, and their relation to conventional lumped-element models. Calculation and simulation results are shown for the uniform model, which mimics key properties of a monocotyledonous grass leaf. We illustrate water status of a well-watered leaf, and the lowering of water potential and transpiration rate caused by excised water source or reduced air humidity. We show that the time scales of these changes under water stress are hugely affected by leaf capacitance and resistances to capacitors, in addition to stomatal resistance. Through this modeling of a grass leaf, we confirm the presence of uneven water distribution over leaf area, and also discuss the importance of considering the spatial variation of leaf hydraulic traits in plant biology.
Ethephon-Mediated Bloom Delay in Peach Is Associated With Alterations in Reactive Oxygen Species, Antioxidants, and Carbohydrate Metabolism During Dormancy
Authors: Islam Md Tabibul , Liu Jianyang , Sherif Sherif M.
Published: October 2021

Ethephon (ET) is an ethylene-based plant growth regulator (PGR) that has demonstrated greater efficacy in delaying bloom in deciduous fruit species. However, the underlying mechanisms by which ET modulates dormancy and flowering time remain obscure. This study aimed to delineate the ET-mediated modulations of reactive oxygen species (ROS), antioxidants, and carbohydrate metabolism in relation to chilling and heat requirements of “Redhaven” peach trees during dormancy. Peach trees were treated with ethephon (500ppm) in the fall (at 50% leaf fall), and floral buds were collected at regular intervals of chilling hours (CH) and growing degree hours (GDH). In the control trees, hydrogen peroxide (H2O2) levels peaked at the endodormancy release and declined thereafter; a pattern that has been ascertained in other deciduous fruit trees. However, H2O2levels were higher and sustained for a more extended period than control in the ET-treated trees. ET also increased the activity of ROS generating (e.g., NADPH-oxidase; superoxide dismutase) and scavenging (e.g., catalase, CAT; glutathione peroxidase) enzymes during endodormancy. However, CAT activity dropped significantly just before the bud burst in the ET-treated trees. In addition, ET affected the accumulation profiles of starch and soluble sugars (hexose and sucrose); significantly reducing the sucrose and glucose levels and increasing starch levels during endodormancy. However, our study concluded that variations in ROS levels and antioxidation pathways, rather than carbohydrate metabolism, could explain the differences in bloom time between ET-treated and -untreated trees. The present study also revealed several important bud dormancy controlling factors that are subject to modulation by ethephon. These factors can serve as potential targets for developing PGRs to manipulate bloom dates in stone fruits to avoid the ever-increasing threat of spring frosts.
Do Self-Compassion Factors Affect Value-Based Behavior Promotion for Adolescents? The Context of Behavioral Activation
Authors: Takagaki Koki , Yokoyama Satoshi , Kambara Kohei
Published: October 2021

Behavioral activation has been shown to engender improvement of depressive symptoms. Behavioral activation specifically addresses behavioral patterns that maintain depressive symptoms and increases activation of rewarding behaviors based on a person’s own values. Nevertheless, behaving according to those values can be difficult. Consequently, discussing reduction in barriers to activation of value-based behaviors is important. Self-compassion might promote value-based behavior when a person confronts some obstacle. We evaluated differences in self-compassion and behavioral characteristics at high and low levels of value-based behaviors. Furthermore, we examined relations of self-compassion to value-based behaviors while considering activation, avoidance, and positive reinforcement in the context of behavioral activation. All 800 university student participants (415 women, 385 men; mean age=20.47years; age range 18–24years) in this study completed assessments. Descriptive statistics, MANOVA, and stepwise regression analysis relations elucidated their value-based behavior, self-compassion, and behavioral characteristics. Results suggest that participants who behaved according to values had high levels of self-kindness, common humanity, and mindfulness. Results of stepwise regression analyses suggest as a new finding that positive components of self-compassion (self-kindness, common humanity, and mindfulness) are related to value-based behaviors even when behavioral factors are considered in the context of behavioral activation.
Comparison of Japanese and Scottish Mother–Infant Intersubjectivity: Resonance of Timing, Anticipation, and Empathy During Feeding
Authors: Negayama Koichi , Delafield-Butt Jonathan T. , Momose Keiko , Ishijima Konomi , Kawahara Noriko
Published: October 2021

Feeding involves communication between mothers and infants and requires precise synchrony in a special triadic relationship with the food. It is deeply related to their intersubjectivity. This study compared the development of mother–infant intersubjectivity through interactional synchrony in feeding between 11 Japanese and 10 Scottish mother–infant dyads, observed at 6 and 9 months by video. Japanese mothers were more deliberate in feeding at an earlier age, whereas Scottish mothers were significantly more coercive than Japanese mothers at an earlier age. Japanese mothers brought the spoon to infants with a pause to adjust the timing of insertion to match their infants’ readiness, whereas this pause was not observed in Scottish mothers. Isomorphic mouth opening between mothers and infants was observed. This empathic maternal display is an important element of intersubjectivity in infant feeding that differed between Scottish and Japanese mothers. Scottish mothers’ mouth opening always followed their infants’ mouth opening, but about half of Japanese mothers preceded their infants. Further, the mouths of Scottish infants and mothers opened almost at the same time as spoon insertion. In contrast, Japanese mothers’ mouth opening did not co-occur with the insertion but was close to spoon arrival, a subtle but important difference that allows for greater infant autonomy. The time structure of Scottish mother-infant interactions was simpler and more predictable at 9 months than in Japan, where the structure was more variable, likely due to a stronger regulation by Scottish mothers. In conclusion, Scottish mother-infant intersubjectivity is characterized as more maternally reactive and mother-centered, whereas Japanese mother-infant intersubjectivity is characterized as more maternally empathetic and infant-centered. Cultural differences in intersubjectivity during feeding between Japan and Scotland are further discussed in relation to triadic relationships and parenting styles.
Importance of Maternal Persistence in Young Children's Persistence
Authors: Imafuku Masahiro , Saito Atsuko , Hosokawa Kenchi , Okanoya Kazuo , Hosoda Chihiro
Published: October 2021

Persistence of a distant goal is an important personality trait that determines academic and social success. Recent studies have shown that individual differences in persistence involve both genetic and environmental factors; however, these studies have not examined the role of maternal factors on a young children's persistence. The present study examined whether mothers' persistence is associated with persistence in children aged 3–6 years. In addition, the associations between mothers' persistence/parenting style and children's self-control/social development (prosocial behaviors and difficulties) were examined. Our results showed that maternal persistence is essential for the child's persistence. Children's self-control and social development were also associated with the mothers' persistence and parenting style. Our findings suggest that a young child's persistence may develop under the influence of a familiar adult (i.e., mother) and characterizes their social development, highlighting the importance of persistence in parenting.
Electrophysiological Prints of Grit
Authors: Aguerre Nuria V. , Gómez-Ariza Carlos J. , Ibáñez-Molina Antonio J. , Bajo M. Teresa
Published: October 2021

While scientific interest in understanding the grit trait has grown exponentially in recent years, one important gap in the grit literature relates to its biological and neural substrate. In the present study, we adopted a hypotheses-driven approach in a large sample of young adults (N = 120) with diverse educational backgrounds and work experiences in order to investigate the electrophysiological correlates of grit both during rest and while performing a learning task. Additionally, we selected a measure of impulsiveness to better understand the neural similarities and differences between grit and related self-control constructs. Based on previous work that implicated the prefrontal cortex in grit, we hypothesized that high grit participants would have lower frontal theta/beta ratio (a broadly used index that reflects prefrontally-mediated top–down processes, which might indicate better control over subcortical information). Furthermore, we expected the perseverance of effort facet of grit to be linked to higher complexity during task engagement because previous research has shown complexity indexes (entropy and fractal dimension) to be linked to effort while performing cognitive tasks. Our results revealed that although there were no differences at rest as a function of grit, the participants with high grit and high consistency of interest scores exhibited lower frontal theta/beta ratios during the learning task. This pattern suggests that individual differences in grit might be more evident when top-down control processes are at work. Furthermore, there was a positive association between perseverance of effort and entropy at task, which might indicate more effort and engagement in the task. Finally, no association was found between the neural indexes (frontal theta/beta ratio, entropy, or fractal dimension) and impulsiveness, neither impulsiveness mediated between grit and brain measures. Finally, when controlling for impulsiveness and demographic variables (gender, age, education, and work experience) the effects at the facet level remained statistically significant. While there is still a long way to fully understand the neural mechanisms of grit, the present work constitutes a step toward unveiling the electrophysiological prints of grit.