bluuebunny/crossref_metadata_2025 huggingface dataset:
Blast in Context: The Neuropsychological and Neurocognitive Effects of Long-Term Occupational Exposure to Repeated Low-Level Explosives on Canadian Armed Forces' Breaching Instructors and Range Staff
Authors: Vartanian Oshin , Tenn Catherine , Rhind Shawn G. , Nakashima Ann , Di Battista Alex P. , Sergio Lauren E. , Gorbet Diana J. , Fraser Douglas D. , Colantonio Angela , King Kristen , Lam Quan , Saunders Doug , Jetly Rakesh
Published: December 2020

Currently, there is strong interest within the military to better understand the effects of long-term occupational exposure to repeated low-level blast on health and performance. To gain traction on the chronic sequelae of blast, we focused on breaching—a tactical technique for gaining entry into closed/blocked spaces by placing explosives and maintaining a calculated safe distance from the detonation. Using a cross-sectional design, we compared the neuropsychological and neurocognitive profiles of breaching instructors and range staff to sex- and age-matched Canadian Armed Forces (CAF) controls. Univariate tests demonstrated that breaching was associated with greater post-concussive symptoms (Rivermead Post Concussion Symptoms Questionnaire) and lower levels of energy (RAND SF-36). In addition, breaching instructors and range staff were slower on a test that requires moving and thinking simultaneously (i.e., cognitive-motor integration). Next, using a multivariate approach, we explored the impact of other possible sources of injury, including concussion and prior war-zone deployment on the same outcomes. Concussion history was associated with higher post-concussive scores and musculoskeletal problems, whereas deployment was associated with higher post-concussive scores, but lower energy and greater PTSD symptomatology (using PCL-5). Our results indicate that although breaching, concussion, and deployment were similarly correlated with greater post-concussive symptoms, concussion history appears to be uniquely associated with altered musculoskeletal function, whereas deployment history appears to be uniquely associated with lower energy and risk of PTSD. We argue that the broader injury context must, therefore, be considered when studying the impact of repetitive low-level explosives on health and performance in military members.
The Enterprise2 Stent for Endovascular Treatment of Intracranial Aneurysms: Short-Term Results From a Single Center Experience
Authors: Chen Linhui , Zheng Chaobo , Wu Jiong , Gong Jie , Gao Yuhai , Wan Shu
Published: December 2020

Background: Self-expanding devices, such as the Enterprise VRD (EP-VRD) have widely used for stent-assisted coiling treatment in wided-necked aneuryms while some thromboembolic complications were reported due to its incomplete stent apposition (ISA). We report our experiences on the novel Enterprise2 (EP-VRD2) stent in vivo in the treatment of intracranial and cranial cervical junction aneurysms.

Methods: Twenty-five consecutive patients with intracranial or cranial cervical junction aneurysms were treated with EP-VRD2 stents retrospectively collected in our institution. We use the ‘jailing' technique in all cases and deployed the stent by using pushing over the outer curve technique. The 3- or 6-monthS follow-up was done regularly by DSA.

Results: Twenty-five EP-VRD2 stents were implanted to treat 21 aneurysms at the siphon segment of internal carotid artery (ICA), one at the petrous segment, two at the cervical segment, one at the verteral artery with five accompanied with stenosis. Two patients had kinking during the procedure and were solved by microwire or microcatheter massaging. Four patients with a larger arc angle and a smaller radius of the parent vessel was detected ISA. No patient underwent the ischemic event after the operation. Twenty-three of 25 patients were evaluated after 3- or 6-months by DSA, 22 showed complete occlusion (RROC1), one slight re-stenosis in the follow-up within those five patients with stenosis. A length of 23 mm seemed associated with ISA (p < 0.01).

Conclusion: The EP-VRD2 performed well in our small patient series; however, ISA could still occur with a sharp angle of the parent vessel.
Case Report: Four Cases of Panayiotopoulos Syndrome Evolving to Juvenile Myoclonic Epilepsy
Authors: Enoki Hideo , Itamura Shinji , Baba Shimpei , Okanishi Tohru , Fujimoto Ayataka
Published: December 2020

Panayiotopoulos syndrome (PS) is a self-limited focal epilepsy appearing in childhood. Seizures in PS are self-limiting and do not usually continue into adulthood. Juvenile myoclonic epilepsy (JME) is the most common type of idiopathic generalized epilepsy, developing around puberty and continuing throughout adulthood. We describe four cases of PS in childhood in which JME developed in adolescence. Age at onset ranged from 4 to 8 years for PS, and 11 to 14 years for JME. JME developed after PS subsided, with the interval between last PS seizure and first JME seizure ranging from 1 to 10 years. No link between the two conditions has previously been described. Since PS is considered to show good prognosis and to be self-limiting, long-term observation has been considered unnecessary. No definitive factors were found to predict future evolution to JME in our series, so longer-term follow-up may be warranted for all PS patients.
Effect of the Epley Maneuver and Brandt-Daroff Exercise on Benign Paroxysmal Positional Vertigo Involving the Posterior Semicircular Canal Cupulolithiasis: A Randomized Clinical Trial
Authors: Choi Seo-Young , Cho Jae Wook , Choi Jae-Hwan , Oh Eun Hye , Choi Kwang-Dong
Published: December 2020

Objective: To investigate the therapeutic efficacies of the Epley maneuver and Brandt-Daroff (BD) exercise in patients with benign paroxysmal positional vertigo involving the posterior semicircular canal cupulolithiasis (PC-BPPV-cu).

Methods: We conducted a randomized clinical trial to evaluate the therapeutic effect of the Epley maneuver and BD exercise in patients with PC-BPPV-cu. Patients were randomly assigned to undergo the Epley maneuver (n = 29) or BD exercise (n = 33). The primary outcome was an immediate resolution of positional nystagmus within 1 h after a single treatment of each maneuver on the visit day. Secondary outcomes included the resolution of positional nystagmus at 1 week, the change of maximal slow phase velocity (mSPV) of positional nystagmus, and dizziness handicap inventory (DHI) immediately and at 1 week.

Results: Immediate resolution occurred in none of 29 patients in the Epley maneuver group and only 1 of 33 patients in the BD exercise group. The Epley maneuver and BD exercise had an equivalent effect at 1 week in treating PC-BPPV-cu in terms of resolving positional nystagmus (48 vs. 36%, p = 0.436) and the decrease of mSPV and DHI.

Conclusion: Neither the Epley maneuver nor BD exercise has an immediate therapeutic effect in treating PC-BPPV-cu. Clear classification of PC-BPPV should be required at the time of different pathology and different treatment response.
Effect of Gender on Development of Hippocampal Subregions From Childhood to Adulthood
Authors: Mu Shu Hua , Yuan Bin Ke , Tan Li Hai
Published: December 2020

The hippocampus is known to be comprised of several subfields, but the developmental trajectories of these subfields are under debate. In this study, we analyzed magnetic resonance imaging (MRI) data from a cross-sectional sample (198 healthy Chinese) using an automated segmentation tool to delineate the development of the hippocampal subregions from 6 to 26 years of age. We also examined whether gender and hemispheric differences influence the development of these subregions. For the whole hippocampus, the trajectory of development was observed to be an inverse-u. A significant increase in volume with age was found for most of the subregions, except for the L/R-parasubiculum, L/R-fimbria, and L-HATA. Gender-related differences were also found in the development of most subregions, especially for the hippocampal tail, CA1, molecular layer HP, GC-DG, CA3, and CA4, which showed a consistent increase in females and an early increase followed by a decrease in males. A comparison of the average volumes showed that the right whole hippocampus was significantly larger, along with the R-presubiculum, R-hippocampal-fissure, L/R-CA1, and L/R-molecular layer HP in males in comparison to females. Additionally, the average volume of the right hemisphere was shown to be significantly larger for the hippocampal tail, CA1, molecular layer HP, GC-DG, CA3, and CA4. However, for the presubiculum, parasubiculum, and fimbria, the left side was shown to be larger. In conclusion, the hippocampal subregions appear to develop in various ways from childhood to adulthood, with both gender and hemispheric differences affecting their development.
Amplitude of fNIRS Resting-State Global Signal Is Related to EEG Vigilance Measures: A Simultaneous fNIRS and EEG Study
Authors: Chen Yuxuan , Tang Julia , Chen Yafen , Farrand Jesse , Craft Melissa A. , Carlson Barbara W. , Yuan Han
Published: December 2020

Recently, functional near-infrared spectroscopy (fNIRS) has been utilized to image the hemodynamic activities and connectivity in the human brain. With the advantage of economic efficiency, portability, and fewer physical constraints, fNIRS enables studying of the human brain at versatile environment and various body positions, including at bed side and during exercise, which complements the use of functional magnetic resonance imaging (fMRI). However, like fMRI, fNIRS imaging can be influenced by the presence of a strong global component. Yet, the nature of the global signal in fNIRS has not been established. In this study, we investigated the relationship between fNIRS global signal and electroencephalogram (EEG) vigilance using simultaneous recordings in resting healthy subjects in high-density and whole-head montage. In Experiment 1, data were acquired at supine, sitting, and standing positions. Results found that the factor of body positions significantly affected the amplitude of the resting-state fNIRS global signal, prominently in the frequency range of 0.05–0.1 Hz but not in the very low frequency range of less than 0.05 Hz. As a control, the task-induced fNIRS or EEG responses to auditory stimuli did not differ across body positions. However, EEG vigilance plays a modulatory role in the fNIRS signals in the frequency range of less than 0.05 Hz: resting-state sessions of low EEG vigilance measures are associated with high amplitudes of fNIRS global signals. Moreover, in Experiment 2, we further examined the epoch-to-epoch fluctuations in concurrent fNIRS and EEG data acquired from a separate group of subjects and found a negative temporal correlation between EEG vigilance measures and fNIRS global signal amplitudes. Our study for the first time revealed that vigilance as a neurophysiological factor modulates the resting-state dynamics of fNIRS, which have important implications for understanding and processing the noises in fNIRS signals.
Prodromal Alzheimer’s Disease: Constitutive Upregulation of Neuroglobin Prevents the Initiation of Alzheimer’s Pathology
Authors: de Vidania Silvia , Palomares-Perez Irene , Frank-García Ana , Saito Takashi , Saido Takaomi C. , Draffin Jonathan , Szaruga María , Chávez-Gutierrez Lucía , Calero Miguel , Medina Miguel , Guix Francesc X. , Dotti Carlos G.
Published: December 2020

In humans, a considerable number of the autopsy samples of cognitively normal individuals aged between 57 and 102 years have revealed the presence of amyloid plaques, one of the typical signs of AD, indicating that many of us use mechanisms that defend ourselves from the toxic consequences of Aß. The human APP NL/F (hAPP NL/F) knockin mouse appears as the ideal mouse model to identify these mechanisms, since they have high Aß42 levels at an early age and moderate signs of disease when old. Here we show that in these mice, the brain levels of the hemoprotein Neuroglobin (Ngb) increase with age, in parallel with the increase in Aß42. In vitro, in wild type neurons, exogenous Aß increases the expression of Ngb and Ngb over-expression prevents Aß toxicity. In vivo, in old hAPP NL/F mice, Ngb knockdown leads to dendritic tree simplification, an early sign of Alzheimer’s disease. These results could indicate that Alzheimer’s symptoms may start developing at the time when defense mechanisms start wearing out. In agreement, analysis of plasma Ngb levels in aged individuals revealed decreased levels in those whose cognitive abilities worsened during a 5-year longitudinal follow-up period.
Reduced Information Transmission of Medial Prefrontal Cortex to Basolateral Amygdala Inhibits Exploratory Behavior in Depressed Rats
Authors: Qi Chengxi , Wang Zihe , Bai Wenwen , Liu Tiaotiao , Zheng Xuyuan
Published: December 2020

Depression is a mental and neurological disease that reduces the desire for exploration. Dysregulation of the information transmission between medial prefrontal cortex (mPFC) and basolateral amygdala (BLA) is associated with depression. However, which direction of information transmission (mPFC-BLA or BLA-mPFC) related to the decline of exploratory interests in depression is unclear. Therefore, it is important to determine what specific changes occur in mPFC and BLA information transmission in depressed rats during exploratory behavior. In the present study, local field potentials (LFPs) were recorded via multi-electrodes implanted in the mPFC and BLA for the control and depression groups of rats when they were exploring in an open field. The theta band was determined to be the characteristic band of exploratory behavior. The direct transfer function (DTF) was used to calculate the mPFC and BLA bidirectional information flow (IF) to measure information transmission. Compared with the control group, the theta IF of mPFC-BLA in the depression group was significantly reduced, and there was no significant difference in theta IF of BLA-mPFC between the two groups. Our results indicated that the reduction of mPFC-BLA information transmission can inhibit the exploratory behavior of depressed rats.
New Insights Into Drug Discovery Targeting Tau Protein
Authors: Soeda Yoshiyuki , Takashima Akihiko
Published: December 2020

Microtubule-associated protein tau is characterized by the fact that it is an intrinsically disordered protein due to its lack of a stable conformation and high flexibility. Intracellular inclusions of fibrillar forms of tau with a β-sheet structure accumulate in the brain of patients with Alzheimer's disease and other tauopathies. Accordingly, detachment of tau from microtubules and transition of tau from a disordered state to an abnormally aggregated state are essential events preceding the onset of tau-related diseases. Many reports have shown that this transition is caused by post-translational modifications, including hyperphosphorylation and acetylation. The misfolded tau is self-assembled and forms a tau oligomer before the appearance of tau inclusions. Animal and pathological studies using human samples have demonstrated that tau oligomer formation contributes to neuronal loss. During the progression of tauopathies, tau seeds are released from cells and incorporated into other cells, leading to the propagation of pathological tau aggregation. Accumulating evidence suggests several potential approaches for blocking tau-mediated toxicity: (1) direct inhibition of pathological tau aggregation and (2) inhibition of tau post-translational modifications that occur prior to pathological tau aggregation, (3) inhibition of tau propagation and (4) stabilization of microtubules. In addition to traditional low-molecular-weight compounds, newer drug discovery approaches such as the development of medium-molecular-weight drugs (peptide- or oligonucleotide-based drugs) and high-molecular-weight drugs (antibody-based drugs) provide alternative pathways to preventing the formation of abnormal tau. Of particular interest are recent studies suggesting that tau droplet formation by liquid-liquid phase separation may be the initial step in aberrant tau aggregation, as well results that implicate roles for tau in dendritic and nuclear functions. Here, we review the mechanisms through which drugs can target tau and consider recent clinical trials for the treatment of tauopathies. In addition, we discuss the utility of these newer strategies and propose future directions for research on tau-targeted therapeutics.
Development and Validation of Nomograms Based on Gamma-Glutamyl Transpeptidase to Platelet Ratio for Hepatocellular Carcinoma Patients Reveal Novel Prognostic Value and the Ratio Is Negatively Correlated With P38MAPK Expression
Authors: Luo Dingan , Li Haoran , Hu Jie , Zhang Mao , Zhang Shun , Wu Liqun , Han Bing
Published: December 2020

Background

Early prediction of recurrence and death risks is significant to the treatment of hepatocellular carcinoma (HCC) patients. We aimed to develop and validate prognosis nomogram models based on the gamma-glutamyl transpeptidase (GGT)-to-platelet (PLT) ratio (GPR) for HCC and to explore the relationship between the GPR and inflammation-related signaling pathways.

Methods

All data were obtained from 2000 to 2012 in the Affiliated Hospital of Qingdao University. In the training cohort, factors included in the nomograms were determined by univariate and multivariate analyses. In the training and validation cohorts, the concordance index (C-index) and calibration curves were used to assess predictive accuracy, and receiver operating characteristic curves were used to assess discriminative ability. Clinical utility was evaluated using decision curve analysis. Moreover, improvement of the predictive accuracy of the nomograms was evaluated by calculating the decision curve analysis, the integrated discrimination improvement, and the net reclassification improvement. Finally, the relationship between the GPR and inflammation-related signaling pathways was evaluated using the independent-samples t-test.

Results

A larger tumor size and higher GPR were common independent risk factors for both disease-free survival (DFS) and overall survival (OS) in HCC (P < 0.05). Good agreement between our nomogram models’ predictions and actual observations was detected by the C-index and calibration curves. Our nomogram models showed significantly better performance in predicting the HCC prognosis compared to other models (P < 0.05). Online webserver and scoring system tables were built based on the proposed nomogram for convenient clinical use. Notably, including the GPR greatly improved the predictive ability of our nomogram models (P < 0.05). In the validation cohort, p38 mitogen-activated protein kinase (P38MAPK) expression was significantly negatively correlated with the GPR (P < 0.01) and GGT (P = 0.039), but was not correlated with PLT levels (P = 0.063). And we found that P38MAPK can regulate the expression of GGT by quantitative real-time PCR and Western blotting experiments.

Conclusions

The dynamic nomogram based on the GPR provides accurate and effective prognostic predictions for HCC, and P38MAPK-GGT may be a suitable therapeutic target to improve the prognosis of HCC patients.
Diagnostic Value of Telomerase Activity in Patients With Bladder Cancer: A Meta-Analysis of Diagnostic Test
Authors: Peng Lei , Li Jinze , Meng Chunyang , Li Jinming , Tang Dandan , Guan Fangxue , Xu Peng , Wei Tangqiang , Li Yunxiang
Published: December 2020

Background

This study aimed to evaluate the diagnostic value of telomerase activity (TA) for bladder cancer (BC) by meta-analysis.

Methods

We conducted a systematic search of studies published on PubMed, Embase, and Web of Science up to June 1, 2019. We used Stata 15 and Review Manager 5.3 for calculations and statistical analysis.

Results

To evaluate the diagnostic value of TA for BC, we performed a meta-analysis on 22 studies, with a total of 2,867 individuals, including sensitivity, specificity, positive and negative likelihood ratio (PLR, NLR), diagnostic odds ratio (DOR), and 95% confidence intervals (CIs). The pooled parameters were calculated from all studies, and we found a sensitivity of 0.79 (95% CI: 0.72–0.84), a specificity of 0.91 (95% CI: 0.87–0.94), a PLR of 8.91 (95% CI: 5.91–13.43), an NLR of 0.24 (95% CI: 0.15–0.37), a DOR of 37.90 (95% CI: 23.32–61.59), and an AUC of 0.92 (95% CI: 0.90–0.94). We also conducted a subgroup analysis based on the different stages and grades of BC. Results from the subgroup analysis showed that there was no significant difference in TA in either high and low stages of BC, but that low-grade tumors had a lower TA than high-grade tumours.

Conclusions

TA can be used as a potential biomarker for the diagnosis of bladder cancer with its high specificity. Rigorous and high-quality prospective studies are required to verify our conclusion.
Screening for Genetic Mutations for the Early Diagnosis of Common Variable Immunodeficiency in Children With Refractory Immune Thrombocytopenia: A Retrospective Data Analysis From a Tertiary Children's Center
Authors: Ma Jingyao , Fu Lingling , Gu Hao , Chen Zhenping , Zhang Jialu , Zhao Shasha , Zhu Xiaojing , Liu Huiqing , Wu Runhui
Published: December 2020

Aim: This study aimed to identify common variable immunodeficiency (CVID) by high-throughput next-generation sequencing (NGS) in children with refractory immune thrombocytopenia (RITP) to facilitate early diagnosis.

Methods: CVID-related genetic mutations were explored in patients with RITP during 2016–2019. They were tested consecutively through NGS by the ITP team of the tertiary children hospital in China. An evaluation system was devised based on the phenotype, genetic rule, and serum immunoglobulins (Igs) of all patients with RITP. The patients were divided into highly suspicious, suspicious, and negative groups using the evaluation system.

Results: Among 176 patients with RITP, 16 (9.1%) harbored CVID-related genetic mutations: 8 (4.5%) were highly suspicious of CVIDs. Five had mutations in tumor necrosis factor receptor superfamily 13B (TNFRSF13B), one in lipopolysaccharide responsive beige-like anchor protein (LRBA), one in nuclear factor kappa-B2 (NF-κB2), and one in caspase recruitment domain11 (CARD11). Others were classified into the suspicious group because the clinical phenotype and pedigree were suggestive, yet insufficient, for diagnosis. Repeated infection existed in all patients. Two had an allergic disease. Positive autoimmune serologies were noted in 62.5%. Five had a definite positive family history. The median serum immunoglobulin (Ig)A, IgG, and IgM levels were 0.3875, 6.14, and 0.522 g/L, respectively. Nearly 85.7% of patients had insufficient serum IgA levels, while 37.5% had low IgG and IgM levels.

Conclusions: High-throughput NGS and a thorough review of the medical history are beneficial for the early diagnosis of patients without any significant clinical characteristics, distinguishing them from those with primary pediatric ITP. The cases suspicious of CVID need further investigation and follow-up to avoid deterioration.
Gene-Based Association Analysis Suggests Association of HTR2A With Antidepressant Treatment Response in Depressed Patients
Authors: Kao Chung-Feng , Kuo Po-Hsiu , Yu Younger W.-Y. , Yang Albert C. , Lin Eugene , Liu Yu-Li , Tsai Shih-Jen
Published: December 2020

The serotonin [5-hydroxytryptamine (5-HT)] system has been implicated in the pathogenesis of major depressive disorder (MDD). Among the 5-HT receptor subtypes, 5-HT2 is one of the major pharmacological therapeutic targets for MDD. There have been inconsistent findings in previous pharmacogenetic studies investigating the antidepressant therapeutic response using one or several 5-HT2A (HTR2A) genetic polymorphisms. By using gene-based association analysis, we hope to identify genetic variants of HTR2A which are related to MDD susceptibility and its antidepressant therapeutic response. 288 HTR2A single nucleotide polymorphisms in MDD susceptibility have been investigated through a case–control (455 MDD patients and 2, 998 healthy controls) study, as well as in antidepressant efficacy (n = 455) in our current research. The 21-item Hamilton Rating Scale for Depression was used to evaluate measures of antidepressant therapeutic efficacy. From two MDD groups in the antidepressant therapeutic response, by using gene-based analyses, we have identified 14 polymorphisms as suggestive markers for therapeutic response (13 for remission and 1 for response) in both meta- and mega-analyses. All of these HTR2A reported polymorphisms did not reach statistical significance in the case–control association study. This current investigation supported the link between HTR2A variants and antidepressant therapeutic response in MDD but not with MDD susceptibility.
Acute Digital Ischemia After Arterial Injection of Crushed Zolpidem Tablets: Role of Microcrystalline Cellulose? A Case Report
Authors: Détriché Grégoire , Goudot Guillaume , Khider Lina , Galloula Alexandre , Guillet Matthieu , Lillo-Le Louët Agnès , Messas Emmanuel , Mirault Tristan
Published: December 2020

Literature is scarce on acute ischemia after intra-arterial injection of crushed tablets and no effective medical treatment against the progression of lesions is reported. The only factor able to modify the outcome is the delay between injection and management by a specialized vascular team. Moreover the risk of necrosis seems higher after benzodiazepine intra-arterial injection than with other drugs. We tried to find out mechanistic explanations. We report on the case of a 31-year-old drug addict woman who self-injected into her left brachial artery crushed tablets of zolpidem. She developed an acute ischemia of the left hand, with necrosis of the intermediate and distal phalanges of fingers II, III, and IV. Angiogram of the left upper arm confirmed the distal arterial occlusions with no run-off after the palmar arch in the necrotic fingers. Once she was admitted into our vascular unit, intravenous vasodilator therapy by iloprost, heparin and local protective care were rapidly introduced. After delineation between living and necrotic tissues, she required distal amputations of the affected fingers. The clinical severity of arterial injections of benzodiazepine tablets is linked to the association of several pathophysiological mechanisms. Rather than related benzodiazepine pharmacologic effects with tissue ischemia, by the inhibition of phosphodiesterase, a vasodilator intermediate, or through the peripheral benzodiazepine-type receptor, the predominant mechanism is more likely in relation with microcrystalline cellulose, one component of zolpidem tablets, known as potential embolic agents. They are insoluble and resistant to degradation in water. These properties are probably prominent in the case we described here. Through this case report we want to drag attention of physicians in charge of a patient with acute ischemia after crushed tablet accidental intra-arterial injection, not only to look at the drug injected but also the other components of the tablet and especially to microcrystalline cellulose.
Synthetic Lethal Activity of Benzophenanthridine Alkaloids From Zanthoxylum coco Against BRCA1-Deficient Cancer Cells
Authors: García Iris A. , Pansa Maria Florencia , Pacciaroni Adriana Del Valle , García Manuela E. , Gonzalez Maria Laura , Oberti Juan Carlos , Bocco José Luís , Carpinella Maria Cecilia , Barboza Gloria E. , Nicotra Viviana E. , Soria Gastón
Published: December 2020

Several plants from South America show strong antitumoral properties based on anti-proliferative and/or pro-apoptotic activities. In this work we aimed to identify selective cytotoxic compounds that target BRCA1-deficient cancer cells by Synthetic Lethality (SL) induction. Using a high-throughput screening technology developed in our laboratory, we analyzed a collection of extracts from 46 native plant species from Argentina using a wide dose-response scheme. A highly selective SL-induction capacity was found in an alkaloidal extract from Zanthoxylum coco (Fam. Rutaceae). Bio-guided fractionation coupled to HPLC led to the identification of active benzophenanthridine alkaloids. The most potent SL activity was found with the compound oxynitidine, which showed a remarkably low relative abundance in the active fractions. Further validation experiments were performed using the commercially available and closely related analog nitidine, which showed SL-induction activity against various BRCA1-deficient cell lines with different genetic backgrounds, even in the nanomolar range. Exploration of the underlying mechanism of action using BRCA1-KO cells revealed AKT and topoisomerases as the potential targets responsible of nitidine-triggered SL-induction. Taken together, our findings expose an unforeseen therapeutic activity of alkaloids from Zanthoxylum-spp. that position them as novel lead molecules for drug discovery.
Non-Alcoholic Steatohepatitis: A Review of Its Mechanism, Models and Medical Treatments
Authors: Peng Cheng , Stewart Alastair G. , Woodman Owen L. , Ritchie Rebecca H. , Qin Cheng Xue
Published: December 2020

Non-alcoholic steatohepatitis (NASH) develops from non-alcoholic fatty liver disease (NAFLD). Currently, around 25% of the population is estimated to have NAFLD, and 25% of NAFLD patients are estimated to have NASH. NASH is typically characterized by liver steatosis inflammation, and fibrosis driven by metabolic disruptions such as obesity, diabetes, and dyslipidemia. NASH patients with significant fibrosis have increased risk of developing cirrhosis and liver failure. Currently, NASH is the second leading cause for liver transplant in the United States. More importantly, the risk of developing hepatocellular carcinoma from NASH has also been highlighted in recent studies. Patients may have NAFLD for years before progressing into NASH. Although the pathogenesis of NASH is not completely understood, the current “multiple-hits” hypothesis suggests that in addition to fat accumulation, elevated oxidative and ER stress may also drive liver inflammation and fibrosis. The development of clinically relevant animal models and pharmacological treatments for NASH have been hampered by the limited understanding of the disease mechanism and a lack of sensitive, non-invasive diagnostic tools. Currently, most pre-clinical animal models are divided into three main groups which includes: genetic models, diet-induced, and toxin + diet-induced animal models. Although dietary models mimic the natural course of NASH in humans, the models often only induce mild liver injury. Many genetic and toxin + diet-induced models rapidly induce the development of metabolic disruption and serious liver injury, but not without their own shortcomings. This review provides an overview of the “multiple-hits” hypothesis and an evaluation of the currently existing animal models of NASH. This review also provides an update on the available interventions for managing NASH as well as pharmacological agents that are currently undergoing clinical trials for the treatment of NASH.
Peregrine Solitons of the Higher-Order, Inhomogeneous, Coupled, Discrete, and Nonlocal Nonlinear Schrödinger Equations
Authors: Uthayakumar T. , Al Sakkaf L. , Al Khawaja U.
Published: December 2020

This study reviews the Peregrine solitons appearing under the framework of a class of nonlinear Schrödinger equations describing the diverse nonlinear systems. The historical perspectives include the various analytical techniques developed for constructing the Peregrine soliton solutions, followed by the derivation of the general breather solution of the fundamental nonlinear Schrödinger equation through Darboux transformation. Subsequently, we collect all forms of nonlinear Schrödinger equations, involving systematically the effects of higher-order nonlinearity, inhomogeneity, external potentials, coupling, discontinuity, nonlocality, higher dimensionality, and nonlinear saturation in which Peregrine soliton solutions have been reported.
Cardiac Pacemaker Dysfunction Arising From Different Studies of Ion Channel Remodeling in the Aging Rat Heart
Authors: Alghamdi Aaazh M. , Boyett Mark R. , Hancox Jules C. , Zhang Henggui
Published: December 2020

The function of the sinoatrial node (SAN), the pacemaker of the heart, declines with age, resulting in increased incidence of sinoatrial node dysfunction (SND) in older adults. The present study assesses potential ionic mechanisms underlying age associated SND. Two group studies have identified complex and various changes in some of membrane ion channels in aged rat SAN, the first group (Aging Study-1) indicates a considerable changes of gene expression with up-regulation of mRNA in ion channels of Cav1.2, Cav1.3 and KvLQT1, Kv4.2, and the Ca2+handling proteins of SERCA2a, and down-regulation of Cav3.1, NCX, and HCN1 and the Ca2+-clock proteins of RYR2. The second group (Aging Study-2) suggests a different pattern of changes, including down regulation of Cav1.2, Cav1.3 and HCN4, and RYR2, and an increase of NCX and SERCA densities and proteins. Although both data sets shared a similar finding for some specific ion channels, such as down regulation of HCN4, NCX, and RYR2, there are contradictory changes for some other membrane ion channels, such as either up-regulation or down-regulation of Cav1.2, NCX and SERCA2a in aged rat SAN. The present study aims to test a hypothesis that age-related SND may arise from different ionic and molecular remodeling patterns. To test this hypothesis, a mathematical model of the electrical action potential of rat SAN myocytes was modified to simulate the functional impact of age-induced changes on membrane ion channels and intracellular Ca2+handling as observed in Aging Study-1 and Aging Study-2. The role and relative importance of each individually remodeled ion channels and Ca2+-handling in the two datasets were evaluated. It was shown that the age-induced changes in ion channels and Ca2+-handling, based on either Aging Study-1 or Aging Study-2, produced similar bradycardic effects as manifested by a marked reduction in the heart rate (HR) that matched experimental observations. Further analysis showed that although the SND arose from an integrated action of all remodeling of ion channels and Ca2+-handling in both studies, it was the change toICaLthat played the most important influence.
New Insights Into Implications of CTRP3 in Obesity, Metabolic Dysfunction, and Cardiovascular Diseases: Potential of Therapeutic Interventions
Authors: Guo Bei , Zhuang Tongtian , Xu Feng , Lin Xiao , Li Fuxingzi , Shan Su-Kang , Wu Feng , Zhong Jia-Yu , Wang Yi , Zheng Ming-Hui , Xu Qiu-Shuang , Ehsan Ullah Muhammad Hasnain , Yuan Ling-Qing
Published: December 2020

Adipose tissue, as the largest endocrine organ, secretes many biologically active molecules circulating in the bloodstream, collectively termed adipocytokines, which not only regulate the metabolism but also play a role in pathophysiological processes. C1q tumor necrosis factor (TNF)-related protein 3 (CTRP3) is a member of C1q tumor necrosis factor-related proteins (CTRPs), which is a paralog of adiponectin. CTRP3 has a wide range of effects on glucose/lipid metabolism, inflammation, and contributes to cardiovascular protection. In this review, we comprehensively discussed the latest research on CTRP3 in obesity, diabetes, metabolic syndrome, and cardiovascular diseases.
Multicomponent Analysis of Sleep Using Electrocortical, Respiratory, Autonomic and Hemodynamic Signals Reveals Distinct Features of Stable and Unstable NREM and REM Sleep
Authors: Wood Christopher , Bianchi Matt Travis , Yun Chang-Ho , Shin Chol , Thomas Robert Joseph
Published: December 2020

A new concept of non-rapid eye movement (NREM) and rapid eye movement (REM) sleep is proposed, that of multi-component integrative states that define stable and unstable sleep, respectively, NREMS, NREMUS REMS, and REMUS. Three complementary data sets are used: obstructive sleep apnea (20), healthy subjects (11), and high loop gain sleep apnea (50). We use polysomnography (PSG) with beat-to-beat blood pressure monitoring, and electrocardiogram (ECG)-derived cardiopulmonary coupling (CPC) analysis to demonstrate a bimodal, rather than graded, characteristic of NREM sleep. Stable NREM (NREMS) is characterized by high probability of occurrence of the <1 Hz slow oscillation, high delta power, stable breathing, blood pressure dipping, strong sinus arrhythmia and vagal dominance, and high frequency CPC. Conversely, unstable NREM (NREMUS) has the opposite features: a fragmented and discontinuous <1 Hz slow oscillation, non-dipping of blood pressure, unstable respiration, cyclic variation in heart rate, and low frequency CPC. The dimension of NREM stability raises the possibility of a comprehensive integrated multicomponent network model of NREM sleep which captures sleep onset (e.g., ventrolateral preoptic area-based sleep switch) processes, synaptic homeostatic delta power kinetics, and the interaction of global and local sleep processes as reflected in the spatiotemporal evolution of cortical “UP” and “DOWN” states, while incorporating the complex dynamics of autonomic-respiratory-hemodynamic systems during sleep. Bimodality of REM sleep is harder to discern in health. However, individuals with combined obstructive and central sleep apnea allows ready recognition of REMS and REMUS (stable and unstable REM sleep, respectively), especially when there is a discordance of respiratory patterns in relation to conventional stage of sleep.
Sympathetic Effect of Auricular Transcutaneous Vagus Nerve Stimulation on Healthy Subjects: A Crossover Controlled Clinical Trial Comparing Vagally Mediated and Active Control Stimulation Using Microneurography
Authors: Gauthey Anaïs , Morra Sofia , van de Borne Philippe , Deriaz Denis , Maes Nathalie , le Polain de Waroux Jean-Benoît
Published: December 2020

Introduction: Auricular low-level transcutaneous vagus nerve stimulation (aLL-tVNS) has emerged as a promising technology for cardiac arrhythmia management but is still experimental. In this physiological study, we hypothesized that aLL-tVNS modulated the autonomic nervous balance through a reduction of sympathetic tone and an increase in heart rate variability (HRV). We investigated the muscle sympathetic nerve activity (MSNA) recorded by microneurography during vagally mediated aLL-tVNS and active control on healthy volunteers. Methods: In this crossover, double-blind controlled study, healthy men (N = 28; 27 ± 4 years old) were assigned to aLL-tVNS applied to cymba and lobe (active control) of the right ear. Each participant was randomly allocated to the three sequences (5 Hz, 20 Hz, and active control-5 Hz) during one session. MSNA signal was recorded at rest, during voluntarily apnea and aLL-tVNS. Sympathetic activity was expressed as: 1) number of bursts per minute (burst frequency, BF) and 2) MSNA activity calculated as BF x mean burst amplitude and expressed as changes from baseline (%). RR intervals, HRV parameters and sympathetic activity were analyzed during 5 min-baseline, 10 min-stimulation, and 10 min-recovery periods. Mixed regression models were performed to evaluate cymba-(5—20 Hz) effects on the parameters with stimulation. Results: During apnea and compared to baseline, BF and MSNA activity increased (p = 0.002, p = 0.001, respectively). No stimulation effect on RR intervals and HRV parameters were showed excepted a slightly increase of the LF/HF ratio with stimulation in the cymba-5Hz sequence (coef. ± SE: 0.76 ± 0.32%; p = 0.02). During stimulation, reductions from baseline in BF (Coef. ± SE: −4.8 ± 1.1, p < 0.001) was observed but was not statistically different from that one in the active control. Reduction of MSNA activity was not significantly different between sequences. Conclusion: Acute right cymba aLL-tVNS did not induce any overall effects neither on heart rate, HRV nor MSNA variables on healthy subjects when compared to active control. Interestingly, these findings questioned the role of active controls in medical device clinical trials that implied subjective endpoints.
3D Muscle Deformation Mapping at Submaximal Isometric Contractions: Applications to Aging Muscle
Authors: Malis Vadim , Sinha Usha , Sinha Shantanu
Published: December 2020

3D strain or strain rate tensor mapping comprehensively captures regional muscle deformation. While compressive strain along the muscle fiber is a potential measure of the force generated, radial strains in the fiber cross-section may provide information on the material properties of the extracellular matrix. Additionally, shear strain may potentially inform on the shearing of the extracellular matrix; the latter has been hypothesized as the mechanism of lateral transmission of force. Here, we implement a novel fast MR method for velocity mapping to acquire multi-slice images at different % maximum voluntary contraction (MVC) for 3D strain mapping to explore deformation in the plantar-flexors under isometric contraction in a cohort of young and senior subjects. 3D strain rate and strain tensors were computed and eigenvalues and two invariants (maximum shear and volumetric strain) were extracted. Strain and strain rate indices (contractile and in-plane strain/strain rate, shear strain/strain rate) changed significantly with %MVC (30 and 60% MVC) and contractile and shear strain with age in the medial gastrocnemius. In the soleus, significant differences with age in contractile and shear strain were seen. Univariate regression revealed weak but significant correlation ofin-planeandshear strainandshear strain rateindices to %MVC and correlation ofcontractileandshear strainindices to force. The ability to map strain tensor components provides unique insights into muscle physiology: with contractile strain providing an index of the force generated by the muscle fibers while the shear strain could potentially be a marker of lateral transmission of force.
Potential Roles of Exercise-Induced Plasma Metabolites Linking Exercise to Health Benefits
Authors: Yang Yong Ryoul , Kwon Ki-Sun
Published: December 2020

Regular exercise has a myriad of health benefits. An increase in circulating exercise factors following exercise is a critical physiological response. Numerous studies have shown that exercise factors released from tissues during physical activity may contribute to health benefitsviaautocrine, paracrine, and endocrine mechanisms. Myokines, classified as proteins secreted from skeletal muscle, are representative exercise factors. The roles of myokines have been demonstrated in a variety of exercise-related functions linked to health benefits. In addition to myokines, metabolites are also exercise factors. Exercise changes the levels of various metabolitesviametabolic reactions. Several studies have identified exercise-induced metabolites that positively influence organ functions. Here, we provide an overview of selected metabolites secreted into the circulation upon exercise.
Regulatory Roles of PINK1-Parkin and AMPK in Ubiquitin-Dependent Skeletal Muscle Mitophagy
Authors: Seabright Alex P. , Lai Yu-Chiang
Published: December 2020

The selective removal of damaged mitochondria, also known as mitophagy, is an important mechanism that regulates mitochondrial quality control. Evidence suggests that mitophagy is adversely affected in aged skeletal muscle, and this is thought to contribute toward the age-related decline of muscle health. While our knowledge of the molecular mechanisms that regulate mitophagy are derived mostly from work in non-muscle cells, whether these mechanisms are conferred in muscle under physiological conditions has not been thoroughly investigated. Recent findings from our laboratory and those of others have made several novel contributions to this field. Herein, we consolidate current literature, including our recent work, while evaluating how ubiquitin-dependent mitophagy is regulated both in muscle and non-muscle cells through the steps of mitochondrial fission, ubiquitylation, and autophagosomal engulfment. During ubiquitin-dependent mitophagy in non-muscle cells, mitochondrial depolarization activates PINK1-Parkin signaling to elicit mitochondrial ubiquitylation. TANK-binding kinase 1 (TBK1) then activates autophagy receptors, which in turn, tether ubiquitylated mitochondria to autophagosomes prior to lysosomal degradation. In skeletal muscle, evidence supporting the involvement of PINK1-Parkin signaling in mitophagy is lacking. Instead, 5′-AMP-activated protein kinase (AMPK) is emerging as a critical regulator. Mechanistically, AMPK activation promotes mitochondrial fission before enhancing autophagosomal engulfment of damaged mitochondria possibly via TBK1. While TBK1 may be a point of convergence between PINK1-Parkin and AMPK signaling in muscle, the critical question that remains is: whether mitochondrial ubiquitylation is required for mitophagy. In future, improving understanding of molecular processes that regulate mitophagy in muscle will help to develop novel strategies to promote healthy aging.
An Endophytic Trichoderma Strain Promotes Growth of Its Hosts and Defends Against Pathogen Attack
Authors: Tseng Yu-Heng , Rouina Hamid , Groten Karin , Rajani Pijakala , Furch Alexandra C. U. , Reichelt Michael , Baldwin Ian T. , Nataraja Karaba N. , Uma Shaanker Ramanan , Oelmüller Ralf
Published: December 2020

Plants host numerous endophytic microbes which promote plant performance, in particular under stress. A new endophytic fungus was isolated from the leaves of a deciduous wood tree Leucas aspera. Morphological inspection and multilocus phylogeny identified the fungus as a new Trichoderma strain. If applied to Arabidopsis thaliana and Nicotiana attenuata, it mainly colonizes their roots and strongly promotes initial growth of the plants on soil. The fungus grows on high NaCl or mannitol concentrations, and shows predatory capability on the pathogenic fungus Alternaria brassicicola. Colonized Arabidopsis plants tolerate higher salt stress and show lower A. brassicicola spread in roots and shoots, while arbuscular mycorrhiza formation in N. attenuata is not affected by the Trichoderma strain. These beneficial features of the novel Trichoderma strain are important prerequisites for agricultural applications.
Metabolomics Reveal Induction of ROS Production and Glycosylation Events in Wheat Upon Exposure to the Green Leaf Volatile Z-3-Hexenyl Acetate
Authors: Ameye Maarten , Van Meulebroek Lieven , Meuninck Bianca , Vanhaecke Lynn , Smagghe Guy , Haesaert Geert , Audenaert Kris
Published: December 2020

The activation and priming of plant defense upon perception of green leaf volatiles (GLVs) have often been reported. However, information as to which metabolic pathways in plants are affected by GLVs remains elusive. We report the production of reactive oxygen species in the tip of young wheat leaves followed by activation of antioxidant-related enzyme activity. In this study, we aimed to uncover metabolic signatures upon exposure to the GLV Z-3-hexenyl acetate (Z-3-HAC). By using an untargeted metabolomics approach, we observed changes in the phenylpropanoid pathways which yield metabolites that are involved in many anti-oxidative processes. Furthermore, exposure to GLV, followed by infection withFusarium graminearum(Fg), induced significantly greater changes in the phenylpropanoid pathway compared to a sole Z-3-HAC treatment. Fragmentation of a selection of metabolites, which are significantly more upregulated in the Z-3-HAC + Fg treatment, showed D-glucose to be present as a substructure. This suggests that Z-3-HAC induces early glycosylation processes in plants. Additionally, we identified the presence of hexenyl diglycosides, which indicates that aerial Z-3-HAC is metabolized in the leaves by glycosyltransferases. Together these data indicate that GLV Z-3-HAC is taken up by leaves and incites oxidative stress. This subsequently results in the modulation of the phenylpropanoid pathway and an induction of glycosylation processes.