bluuebunny/crossref_metadata_2025 huggingface dataset:
Differential Expression Profiles and Functional Prediction of Circular RNAs in Pediatric Dilated Cardiomyopathy
Authors: Sun Wei , Han Bo , Cai Dongxiao , Wang Jing , Jiang Diandong , Jia Hailin
Published: December 2020

Circular RNAs (circRNAs) have emerged as essential regulators and biomarkers in various diseases. To assess the different expression levels of circRNAs in pediatric dilated cardiomyopathy (PDCM) and explore their biological and mechanistic significance, we used RNA microarrays to identify differentially expressed circRNAs between three children diagnosed with PDCM and three healthy age-matched volunteers. The biological function of circRNAs was assessed with a circRNA–microRNA (miRNA)–mRNA interaction network constructed from Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes. Differentially expressed circRNAs were validated by quantitative real-time polymerase chain reaction (qRT-PCR) in 25 children with PDCM and 25 healthy volunteers. We identified 257 up-regulated (fold change ≤ 0.5, P < 0.05) and 899 down-regulated (fold change ≥2, P < 0.05) circRNAs in PDCM patients when compared to healthy volunteers. The qRT-PCR experiments confirmed has_circ_0067735 down-regulation (0.45-fold, P < 0.001), has_circ_0070186 up-regulation (2.82-fold, P < 0.001), and has_circ_0069972 down-regulation (0.50-fold, P < 0.05). A functional analysis of these differentially expressed circRNAs suggests that they are associated with hypertrophy, remodeling, fibrosis, and autoimmunity. CircRNAs have been implicated in PDCM through largely unknown mechanisms. Here we report differentially expressed circRNAs in PDCM patients that may illuminate the mechanistic roles in the etiology of PDCM that could serve as non-invasive diagnostic biomarkers.
Prediction Correction Topic Evolution Research for Metabolic Pathways of the Gut Microbiota
Authors: Ning Li , Lifang Peng , Huixin He
Published: December 2020

The gut microbiota is composed of a large number of different bacteria, that play a key role in the construction of a metabolic signaling network. Deepening the link between metabolic pathways of the gut microbiota and human health, it seems increasingly essential to evolutionarily define the principal technologies applied in the field and their future trends. We use a topic analysis tool, Latent Dirichlet Allocation, to extract themes as a probabilistic distribution of latent topics from literature dataset. We also use the Prophet neural network prediction tool to predict future trend of this area of study. A total of 1,271 abstracts (from 2006 to 2020) were retrieved from MEDLINE with the query on “gut microbiota” and “metabolic pathway.” Our study found 10 topics covering current research types: dietary health, inflammation and liver cancer, fatty and diabetes, microbiota community, hepatic metabolism, metabolomics-based approach and SFCAs, allergic and immune disorders, gut dysbiosis, obesity, brain reaction, and cardiovascular disease. The analysis indicates that, with the rapid development of gut microbiota research, the metabolomics-based approach and SCFAs (topic 6) and dietary health (topic 1) have more studies being reported in the last 15 years. We also conclude from the data that, three other topics could be heavily focused in the future: metabolomics-based approach and SCFAs (topic 6), obesity (topic 8) and brain reaction and cardiovascular disease (topic 10), to unravel microbial affecting human health.
Deletion of BST2 Cytoplasmic and Transmembrane N-Terminal Domains Results in SARS-CoV, SARS-CoV-2, and Influenza Virus Production Suppression in a Vero Cell Line
Authors: Dolskiy Alexander A. , Bodnev Sergei A. , Nazarenko Anastasia A. , Smirnova Anastasia M. , Pyankova Olga G. , Matveeva Anna K. , Grishchenko Irina V. , Tregubchak Tatiana V. , Pyankov Oleg V. , Ryzhikov Alexander B. , Gavrilova Elena V. , Maksyutov Rinat A. , Yudkin Dmitry V.
Published: December 2020

SARS-CoV-2, which emerged in Wuhan (China), has become a great worldwide problem in 2020 and has led to more than 1,000,000 deaths worldwide. Many laboratories are searching for ways to fight this pandemic. We studied the action of the cellular antiviral protein tetherin, which is encoded by the BST2 gene. We deleted the transmembrane domain-encoding part of the gene in the Vero cell line. The transmembrane domain is a target for virus-antagonizing proteins. We showed a decrease in SARS-CoV-2 in cells with deleted transmembrane BST2 domains compared to the initial Vero cell line. Similar results were obtained for SARS-CoV and avian influenza virus. This finding may help the development of antiviral therapies competitively targeting the transmembrane domain of tetherin with viral-antagonizing proteins.
Age-Dependent Activation and Neuronal Differentiation of Lgr5+ Basal Cells in Injured Olfactory Epithelium via Notch Signaling Pathway
Authors: Li Xuewen , Tong Meimei , Wang Li , Qin Yumei , Yu Hongmeng , Yu Yiqun
Published: December 2020

Aging is an important factor affecting function of smell, leading to the degeneration of mature olfactory sensory neurons and inducing the occurrence of smell loss. The mammalian olfactory epithelium (OE) can regenerate when subjected to chemical assaults. However, this capacity is not limitless. Inactivation of globose basal cells and failure to generate sensory neurons are the main obstacles to prevent the OE regeneration. Here, we found the significant attenuation in mature sensory neuronal generation and apparent transcriptional alternation in the OE from aged mice compared with young ones. The recruitment of leucine-rich repeat-containing G-protein coupled receptor 5 (Lgr5)-positive cells in injured OE was weakened in aged mice, and more Lgr5+ cells remained quiescence in aged OE postinjury. Lineage-traced progenies from Lgr5+ cells were significantly fewer in the OE with aging. Moreover, Notch activation enhanced the neuronal regeneration in aged OE, making the regenerative capacity of aged OE comparable with that of young animals after injury. The growth and morphology of three-dimensional (3D)-cultured organoids from the OE of young and aged mice varied and was modulated by small molecules regulating the Notch signaling pathway. Thus, we concluded that activation of Lgr5+ cells in injured OE was age dependent and Notch activation could enhance the capacity of neuronal generation from Lgr5+ cells in aged OE after injury.
Use of Surface EMG in Clinical Rehabilitation of Individuals With SCI: Barriers and Future Considerations
Authors: Pilkar Rakesh , Momeni Kamyar , Ramanujam Arvind , Ravi Manikandan , Garbarini Erica , Forrest Gail F.
Published: December 2020

Surface electromyography (sEMG) is a widely used technology in rehabilitation research and provides quantifiable information on the myoelectric output of a muscle. In this perspective, we discuss the barriers which have restricted the wide-spread use of sEMG in clinical rehabilitation of individuals with spinal cord injury (SCI). One of the major obstacles is integrating the time-consuming aspects of sEMG in the already demanding schedule of physical therapists, occupational therapists, and other clinicians. From the clinicians' perspective, the lack of confidence to use sEMG technology is also apparent due to their limited exposure to the sEMG technology and possibly limited mathematical foundation through educational and professional curricula. Several technical challenges include the limited technology-transfer of ever-evolving knowledge from sEMG research into the off-the-shelf EMG systems, lack of demand from the clinicians for systems with advanced features, lack of user-friendly intuitive interfaces, and the need for a multidisciplinary approach for accurate handling and interpretation of data. We also discuss the challenges in the application and interpretation of sEMG that are specific to SCI, which are characterized by non-standardized approaches in recording and interpretation of EMGs due to the physiological and structural state of the spinal cord. Addressing the current barriers will require a collaborative, interdisciplinary, and unified approach. The most relevant steps could include enhancing user-experience for students pursuing clinical education through revised curricula through sEMG-based case studies/projects, hands-on involvement in the research, and formation of a common platform for clinicians and technicians for self-education and knowledge share.
Quality of Life in Newly Diagnosed Patients With Parkin-Related Parkinson's Disease
Authors: Zhou Xin-Yue , Liu Feng-Tao , Chen Chen , Luo Su-Shan , Zhao Jue , Tang Yi-Lin , Shen Bo , Yu Wen-Bo , Zuo Chuan-Tao , Wu Jian-Jun , Ding Zheng-Tong , Wang Jian , Sun Yi-Min
Published: December 2020

Introduction: Mutations in the Parkin gene are the most common cause of autosomal recessive early-onset Parkinson's disease (PD). However, little is known about the quality of life (QoL) in Parkin-related PD. Here, we investigated the patterns of QoL in newly diagnosed Parkin-related PD patients.

Methods: Newly diagnosed PD patients (diagnosis made within 12 months) who had an age of onset (AOO) below 40 and underwent a PD-related genetic testing, were recruited (n = 148). Among them, 24 patients carried bi-allelic variants in Parkin (PD-Parkin) and 24 patients did not have any known causative PD mutations, or risk variants (GU-EOPD). The clinical materials, relevant factors and determinants of QoL were analyzed.

Results: PD-Parkin patients had a younger AOO (p = 0.003) and longer disease duration (p = 0.005). After adjustment for AOO and disease duration, more dystonia (p = 0.034), and worse scores of non-motor symptoms including Beck depression inventory (BDI, p = 0.035), Epworth sleepiness scale (ESS, p = 0.044), and subdomains of depression/anxiety (p = 0.015) and sleep disorders (p = 0.005) in Non-motor symptoms questionnaire, were found in PD-Parkin comparing with GU-EOPD. PD-Parkin patients had poorer QoL (adjusted p = 0.045), especially in the mobility (adjusted p = 0.025), emotional well-being (adjusted p = 0.015) and bodily discomfort dimensions (adjusted p = 0.016). BDI scores (p = 0.005) and ESS scores (p = 0.047) were significant determinants of QoL in PD-Parkin.

Conclusion: Newly diagnosed PD-Parkin patients showed worse QoL. More depression and excessive daytime sleepiness predicted worse QoL. For clinicians, management of depression and excessive daytime sleepiness is suggested to better improve QoL in patients with Parkin mutations.
Who Should Rather Undergo Transesophageal Echocardiography to Determine Stroke Etiology: Young or Elderly Stroke Patients?
Authors: Strecker Christoph , Günther Felix , Harloff Andreas
Published: December 2020

Introduction: The indication of transesophageal echocardiography (TEE) in acute stroke is unclear. Thus, we systematically studied the impact of TEE on determining stroke etiology and secondary prevention in patients of different age-groups with cryptogenic stroke.

Methods: Four hundred and eighty five consecutive patients with acute retinal or cerebral ischemia were prospectively included and underwent routine stroke workup including TEE. Stroke etiology was identified according to the TOAST classification and patients were divided in those with determined and cryptogenic stroke etiology without TEE results. Then, the frequency of high- and potential-risk sources in TEE was evaluated in <55, 55–74, and ≥75 year-old patients with cryptogenic stroke etiology.

Results: Without TEE, stroke etiology was cryptogenic in 329(67.8%) patients and TEE determined possible etiology in 158(48.4%) of them. In patients aged <55, 55–74, ≥75, TEE detected aortic arch plaques ≥4 mm thickness in 2(1.2%), 37(23.0%), and 33(40.2%) and plaques with superimposed thrombi in 0(0.0%), 5(3.1%), and 7(8.5%); left atrial appendage peak emptying flow velocity ≤30cm/s in 0(0.0%), 1(0.6%), and 2(2.4%), spontaneous echo contrast in 0(0.0%), 1(0.6%), and 6(7.3%), endocarditis in 0(0.0%), 0(0.0%), and 1(1.2%) and patent foramen ovale (PFO) plus atrial septum aneurysm (ASA) in 18(20.9%), 32(19.9%), and 14(17.1%), respectively. TEE changed secondary prevention in 16.4% of these patients following guidelines of 2010/11 and still 9.4% when applying the guidelines of 2020.

Conclusions: TEE was highly valuable for determining stroke etiology and influenced individual secondary prevention based on available treatment guidelines and expert opinion in most cases. In young patients the impact of TEE was limited to the detection of septal anomalies. By contrast, in older patients TEE detected high numbers of complex aortic atheroma and potential indicators of paroxysmal atrial fibrillation.
Poor Bone Quality in Patients With Amyotrophic Lateral Sclerosis
Authors: Caplliure-Llopis Jordi , Escrivá Dolores , Benlloch María , de la Rubia Ortí José Enrique , Estrela José María , Barrios Carlos
Published: December 2020

Objective: Musculoskeletal functional deterioration in Amyotrophic lateral sclerosis (ALS) is associated with an increase in bone fractures. The purpose of this study was to evaluate the influence of sex, ALS type, on bone quality in patients with ALS compared to healthy controls. The impact on bone health of the clinical status and some metabolic parameters was also analyzed in ALS patients.

Methods: A series of 33 voluntary patients with ALS, and 66 healthy individuals matched in sex and age underwent assessment of bone mass quality using quantitative ultrasound (QUS) of the calcaneus. Ultrasonic broadband attenuation (BUA), the speed of sound (SOS), stiffness index and T-score were measured. Bone mineral density (BMD) was estimated using standard equations. Apart from fat and muscle mass percentage determinations, clinical baseline measures in ALS patients included ALSFRS-R score, Barthel index for activities of daily living, pulmonary function measured using FVC, and muscular strength assessed by a modified MRC grading scale. Laboratory tests included serum calcium, 25-HO-cholecalciferol (Vitamin D), alkaline phosphatase (ALP), T4 and TSH.

Results: All bone parameters evaluated were statistically significant lower in ALS patients than in healthy controls. ALS females showed significantly lower bone parameters than healthy females. According to the estimated BMD, there were 25 ALS patients (75.8%) and 36 (54.5%) healthy individuals showing an osteoporotic profile (BMD <0.700 g/cm2). Only 16.7% of the ALS females had T-scores indicative of healthy bones. There was no correlation between any of the clinical parameters analyzed and the bone QUS measurements. Vitamin D and TSH levels positively correlated with all the bone parameters.

Conclusions: This study confirms that ALS patients, particularly females, exhibited deteriorated bone health as compared to healthy individuals. These structural bone changes were independent of ALS subtype and clinical status. Bone health in ALS patients seems to be related to certain metabolic parameters such as Vitamin D and TSH levels.
Impact of Cryotherapy on Sensory, Motor, and Autonomic Neuropathy in Breast Cancer Patients Receiving Paclitaxel: A Randomized, Controlled Trial
Authors: Ng Ding Quan , Tan Chia Jie , Soh Boon Chua , Tan Mabel May Leng , Loh Soon Yue , Tan Yam Eng , Ong Hui Hui , Teng Peggy Pei Chee , Chan Jack Junjie , Chay Wen Yee , Lee Joycelyn , Lai Gillianne , Beh Sok Yuen , Tan Tira Jing Ying , Yap Yoon Sim , Lee Guek Eng , Wong Mabel , Dent Rebecca , Lo Yew Long , Chan Alexandre , Loh Kiley Wei-Jen
Published: December 2020

Introduction: We conducted a randomized controlled trial evaluating the efficacy and tolerability of cryotherapy in preventing chemotherapy-induced peripheral neuropathy (CIPN) in patients with early breast cancer receiving neo/adjuvant weekly paclitaxel.

Methods: Patients were recruited from the National Cancer Centre Singapore and randomized (1:1) to receive either cryotherapy or usual care. Cryotherapy was applied as frozen gloves and socks on all extremities from 15 min before paclitaxel until 15 min post-infusion every cycle. Efficacy was measured by patient-reported outcomes (Patient Neurotoxicity Questionnaire [PNQ] and EORTC QLQ-CIPN20) and electrophysiological assessments. The primary endpoint was PNQ severity at 2 weeks after 12 cycles of weekly paclitaxel.

Results: A total of 46 patients were recruited, of which 8 dropped out before paclitaxel treatment, leaving 38 evaluable. There was no significant difference in PNQ severity between cryotherapy and usual care at 2 weeks after paclitaxel treatment (sensory: p = 0.721; motor: p = 1.000). A benefit was observed at 3 months post-paclitaxel based on PNQ (sensory: 14.3 vs. 41.2%, p = 0.078; motor: 0 vs. 29.4%, p = 0.012) and CIPN20 (sensory: β = −3.6, 95%CI = −10.5–3.4, p = 0.308; motor: β = −7.3, 95%CI = −14.6–0, p = 0.051). Additionally, cryotherapy subjects have lower CIPN20 autonomic score (β = −5.84, 95%CI = −11.15 to −0.524, p = 0.031) and higher sympathetic skin response hand amplitudes (β = 0.544, 95%CI = 0.108–0.98, p = 0.014), suggesting possible autonomic benefits from cryotherapy. Temporary interruption with cryotherapy occurred in 80.9% of the subjects due to cold intolerance.

Conclusions: There is insufficient evidence that cryotherapy prevents sensory neuropathy which may be due to the high rates of cryotherapy interruption in this study. The autonomic benefits of cryotherapy should be further investigated with appropriate outcome measures.

Clinical Trial Registration:ClinicalTrials.gov: NCT03429972.
Astrocytic GABA Accumulation in Experimental Temporal Lobe Epilepsy
Authors: Müller Julia , Timmermann Aline , Henning Lukas , Müller Hendrik , Steinhäuser Christian , Bedner Peter
Published: December 2020

An imbalance of excitation and inhibition has been associated with the pathophysiology of epilepsy. Loss of GABAergic interneurons and/or synaptic inhibition has been shown in various epilepsy models and in human epilepsy. Despite this loss, several studies reported preserved or increased tonic GABAA receptor-mediated currents in epilepsy, raising the question of the source of the inhibitory transmitter. We used the unilateral intracortical kainate mouse model of temporal lobe epilepsy (TLE) with hippocampal sclerosis (HS) to answer this question. In our model we observed profound loss of interneurons in the sclerotic hippocampal CA1 region and dentate gyrus already 5 days after epilepsy induction. Consistent with the literature, the absence of interneurons caused no reduction of tonic inhibition of CA1 pyramidal neurons. In dentate granule cells the inhibitory currents were even increased in epileptic tissue. Intriguingly, immunostaining of brain sections from epileptic mice with antibodies against GABA revealed strong and progressive accumulation of the neurotransmitter in reactive astrocytes. Pharmacological inhibition of the astrocytic GABA transporter GAT3 did not affect tonic inhibition in the sclerotic hippocampus, suggesting that this transporter is not responsible for astrocytic GABA accumulation or release. Immunostaining further indicated that both decarboxylation of glutamate and putrescine degradation accounted for the increased GABA levels in reactive astrocytes. Together, our data provide evidence that the preserved tonic inhibitory currents in the epileptic brain are mediated by GABA overproduction and release from astrocytes. A deeper understanding of the underlying mechanisms may lead to new strategies for antiepileptic drug therapy.
Severity of Peri-ictal Respiratory Dysfunction With Epilepsy Duration and Patient Age at Epilepsy Onset
Authors: Kanth Kiran , Park Katherine , Seyal Masud
Published: December 2020

Respiratory dysfunction preceding death is fundamental in sudden unexpected death in epilepsy (SUDEP) pathophysiology. Hypoxia occurs with one-third of seizures. In temporal lobe epilepsy, there is volume loss in brainstem regions involved in autonomic control and increasing neuropathological changes with duration of epilepsy suggesting increasingly impaired regulation of ventilation. In animal models, recurrent hypoxic episodes induce long-term facilitation (LTF) of ventilatory function, however, LTF is less robust in older animals. LTF of ventilation may, to some degree, ameliorate the deleterious effects of progressive brainstem atrophy. We investigated the possibility that the duration of epilepsy, or age at epilepsy onset, may impact the severity of seizure-associated respiratory dysfunction. Patients with focal epilepsy undergoing video-EEG telemetry in the epilepsy monitoring unit (EMU) were studied. We found a significant relationship between age at epilepsy onset and duration of peri-ictal oxygen desaturation for focal seizures not progressing to bilateral tonic-clonic seizures, with longer duration of peri-ictal oxygen desaturation in patients with epilepsy onset at an older age but no significant relationships between duration of epilepsy or age at EMU admission and ventilatory dysfunction. Our findings suggest an intriguing possibility that LTF of ventilation may be protective when epilepsy starts at a younger age.
The Extracellular Matrix-Derived Biomarkers for Diagnosis, Prognosis, and Personalized Therapy of Malignant Tumors
Authors: Petersen Elena V. , Chudakova Daria A. , Skorova Ekaterina Yu. , Anikin Vladimir , Reshetov Igor V. , Mynbaev Ospan A.
Published: December 2020

The tumor biomarkers already have proven clinical value and have become an integral part in cancer management and modern translational oncology. The tumor tissue microenvironment (TME), which includes extracellular matrix (ECM), signaling molecules, immune and stromal cells, and adjacent non-tumorous tissue, contributes to cancer pathogenesis. Thus, TME-derived biomarkers have many clinical applications. This review is predominately based on the most recent publications (manuscripts published in a last 5 years, or seminal publications published earlier) and fills a gap in the current literature on the cancer biomarkers derived from the TME, with particular attention given to the ECM and products of its processing and degradation, ECM-associated extracellular vesicles (EVs), biomechanical characteristics of ECM, and ECM-derived biomarkers predicting response to the immunotherapy. We discuss the clinical utility of the TME-incorporating three-dimensional in vitro and ex vivo cell culture models for personalized therapy. We conclude that ECM is a critical driver of malignancies and ECM-derived biomarkers should be included in diagnostics and prognostics panels of markers in the clinic.
Development of a Novel Autophagy-Related Prognostic Signature and Nomogram for Hepatocellular Carcinoma
Authors: Fang Qiongxuan , Chen Hongsong
Published: December 2020

Background

Hepatocellular carcinoma (HCC) is the seventh most common malignancy and the second most common cause of cancer-related deaths. Autophagy plays a crucial role in the development and progression of HCC.

Methods

Univariate and Lasso Cox regression analyses were performed to determine a gene model that was optimal for overall survival (OS) prediction. Patients in the GSE14520 and GSE54236 datasets of the Cancer Genome Atlas (TCGA) were divided into the high-risk and low-risk groups according to established ATG models. Univariate and multivariate Cox regression analyses were used to identify risk factors for OS for the purpose of constructing nomograms. Calibration and receiver operating characteristic (ROC) curves were used to evaluate model performance. Real-time PCR was used to validate the effects of the presence or absence of an autophagy inhibitor on gene expression in HepG2 and Huh7 cell lines.

Results

OS in the high-risk group was significantly shorter than that in the low-risk group. Gene set enrichment analysis (GSEA) indicated that the association between the low-risk group and autophagy- as well as immune-related pathways was significant. ULK2, PPP3CC, and NAFTC1 may play vital roles in preventing HCC progression. Furthermore, tumor environment analysisviaESTIMATION indicated that the low-risk group was associated with high immune and stromal scores. Based on EPIC prediction, CD8+ T and B cell fractions in the TCGA and GSE54236 datasets were significantly higher in the low-risk group than those in the high-risk group. Finally, based on the results of univariate and multivariate analyses three variables were selected for nomogram development. The calibration plots showed good agreement between nomogram prediction and actual observations. Inhibition of autophagy resulted in the overexpression of genes constituting the gene model in HepG2 and Huh7 cells.

Conclusions

The current study determined the role played by autophagy-related genes (ATGs) in the progression of HCC and constructed a novel nomogram that predicts OS in HCC patients, through a combined analysis of TCGA and gene expression omnibus (GEO) databases.
Choosing PD-1 Inhibitors in Oncology Setting, Left or Right?—Lessons From Value Assessment With ASCO-VF and ESMO-MCBS
Authors: Jiang Qian , Feng Mei , Li Youping , Lang Jinyi , Wei Hua , Yu Ting
Published: December 2020

Background: Influx of innovative therapies and dramatic rise in prices have been prompting value-driven decision-making. Both the American Society of Clinical Oncology (ASCO) and the European Society for Medical Oncology (ESMO) have independently proposed value assessment frameworks.

Objectives: To comprehensively examine the value of nivolumab and pembrolizumab by two value assessment frameworks with a cohort of published randomized controlled trials and offer insight into the association between these two frameworks.

Methods: Trials were identified with a cutoff date of Nov 30th, 2019. Receiver operating characteristic curves were generated to establish the predictive value of ASCO-VF score to meet ESMO-MCBS grade and discriminate the agreement of these two value assessment tools. Spearman correlation was used to assess the association between monthly cost and ASCO-VF score/ESMO-MCBS grade.

Results: 19 randomized controlled trials were eligible. seven (36.8%) trials were of treatment included nivolumab while 12 (63.2%) pembrolizumab. 8 (42.1%) of the trials were of treatments for non-small-cell lung cancer, 5 (26.3%) for melanoma, 2 (10.5%) were for head and neck squamous cell carcinoma, 2 (10.5%) for gastric or gastro-oesophageal junction cancer and 1 (5.3%) for urothelial cancer and renal-cell carcinoma respectively. ASCO scores ranged from 7 to 94.7 with median 40.90. 11 (57.9%) trials met the ESMO criteria for meaningful value achieved. Of 14 trials not meeting the ASCO cutoff score, only 8 did not meet the meaningful ESMO criteria. Agreement between these two frameworks thresholds was only fair (κ = 0.412, P＜0.05). A negative correlation was noted between increment monthly cost and value assessment results.

Conclusion: There is only fair correlation between ASCO and ESMO value assessment frameworks. Not all treatment with nivolumab and pembrolizumab meet valuable thresholds.
Identification of an Identical de Novo SCAMP5 Missense Variant in Four Unrelated Patients With Seizures and Severe Neurodevelopmental Delay
Authors: Jiao Xianru , Morleo Manuela , Nigro Vincenzo , Torella Annalaura , D’Arrigo Stefano , Ciaccio Claudia , Pantaleoni Chiara , Gong Pan , Grand Katheryn , Sanchez-Lara Pedro A. , Krier Joel , Fieg Elizabeth , Stergachis Andrew , Wang Xiaodong , Yang Zhixian
Published: December 2020

Objective: To establish and broaden the phenotypic spectrum of secretory carrier membrane protein (SCAMP5) associated with epilepsy and neurodevelopmental delay.

Methods: A Chinese patient was identified at the First Hospital of Peking University, and the three unrelated patients were recruited from two different countries (Italy and United States) through GeneMatcher. SCAMP5 pathogenic variants were identified by whole exome sequencing; clinical data of the patients were retrospectively collected and analyzed.

Result: The onset age of seizures was ranged from 6 to 15 months. Patients had different types of seizures, including focal seizures, generalized tonic-clonic seizures and tonic seizure. One patient showed typical autism spectrum disorder (ASD) symptoms. Electroencephalogram (EEG) findings presented as focal or multifocal discharges, sometimes spreading to generalization. Brain magnetic resonance imaging (MRI) abnormalities were present in each patient. Severe intellectual disability and language and motor developmental disorders were found in our patients, with all patients having poor language development and were nonverbal at last follow-up. All but one of the patients could walk independently in childhood, but the ability to walk independently in one patient had deteriorated with age. All patients had abnormal neurological exam findings, mostly signs of extrapyramidal system involvement. Dysmorphic features were found in 2/4 patients, mainly in the face and trunk. All four unrelated patients were found to have the same heterozygous pathogenic SCAMP5 de novo variant (p. Gly180Trp).

Conclusion: Epilepsy, severe developmental delay, abnormal neurological exam findings, with or without ASD or variably dysmorphic features and were common in patients with SCAMP5 variant. The onset time and type of seizure varied greatly. The EEG and brain MRI findings were not consistent, but diverse and nonspecific. The motor ability of patients with heterozygous SCAMP5 variant might have a regressive course; language development was more severely affected.
Effect of Transcriptional Regulatory Factor FoxO3a on Central Nervous System Oxygen Toxicity
Authors: Zhang Yanan , You Benming , Chen Yuliang , Yang Junlin , Xie Chengwei , Huang Guoyang , Li Runping , Hu Ping
Published: December 2020

Central nervous system (CNS) oxygen toxicity (CNS-OT) is a toxic reaction that appears after the inhalation of gas at an excessive oxygen partial pressure during underwater operation or hyperbaric oxygen (HBO) treatment. The mechanism of CNS-OT has not been clearly characterized. Though it has been attributed to the excessive oxidative stress induced by HBO, evidences against this hypothesis have been reported. Here we find that Forkhead box protein O3 (FoxO3a) is important for CNS-OT protection. FoxO3a knock-out (KO) mice had a shorter latency to develop convulsions and greater number of seizures within a certain period of time. The acute lung injury (ALI) induced by CNS-OT was also more severe in FoxO3a KO mice. Further analysis reveals a significant decrease in the activity of catalase (CAT), an antioxidant enzyme and a significant increase in the content of malondialdehyde (MDA), an oxidative product, in brain tissues of FoxO3a KO mice. Short-time HBO exposure could increase FoxO3a expression level and trigger its nuclear translocation. The level of nuclear localized FoxO3a peaked at 8 h after exposure. Our results demonstrate that the activity of FoxO3a is highly sensitive to HBO exposure and FoxO3a plays important roles in protecting CNS-OT. Further mechanic analysis reveals that FoxO3a protects CNS-OT via activating antioxidative signaling pathway.
Micro-Rheological Changes of Red Blood Cells in the Presence of an Arterio-Venous Fistula or a Loop-Shaped Venous Graft in the Rat
Authors: Szabo Balazs , Tanczos Bence , Varga Adam , Barath Barbara , Ghanem Souleiman , Rezsabek Zsofia , Al-Smadi Mohammad Walid , Nemeth Norbert
Published: December 2020

Introduction: In case of kidney failure, hemodialysis is the primary kidney replacement technique. Several vascular access methods used for the therapy, one of which is the arterio-venous fistula (AVF). In the AVF, the blood flow is altered, which can elevate the mechanical stress on the red blood cells (RBCs). This can affect the RBC hemorheological properties, and it can further cause systemic changes. To lower the turbulence and shear stress, we performed a loop-shaped arterio-arterial venous interposition graft (loop-shaped graft) to compare its effect to the conventional AVF.

Materials and Methods: Thirty male Wistar were used (permission registration Nr.: 25/2016/UDCAW). The animals were randomly divided into sham-operated, AVF, and loop groups (n = 10/each). The superficial inferior epigastric vein (SIEV) was used to create the AVF and the loop-shaped graft. Blood samples were taken before/after the surgery and at the 1st, 3rd, and 5th postoperative weeks. We measured hemorhelogical, hematological, and blood gas parameters. The microcirculation of the hind limbs was also monitored using Laser Doppler fluxmetry.

Results: Hematocrit, RBC count, and hemoglobin decreased by the 1st postoperative week. The erythrocyte aggregation values significantly increased in the fistula group by the 5th week (6.43 ± 2.31 vs. 13.60; p < 0.0001; vs. before operation). At the postoperative 1st week in the loop group, the values showed a significant decrease in RBC deformability. During the maturation period, dominantly at the 5th week, all values were normalized. The operated hind limb’s skin microcirculation significantly increased in the sham and loop group by the 1st week (39 ± 10.57 vs. 73.93 ± 1.97 BFU, p < 0.01). This increase wasn’t observed in the fistula group probably due to a steal-effect.

Conclusion: Unlike in the loop group, in the presence of the fistula, several rheological parameters have changed. The loop-shaped graft had only minimal impact on micro-rheological parameters.
The Role of DNA in the Extracellular Environment: A Focus on NETs, RETs and Biofilms
Authors: Monticolo Francesco , Palomba Emanuela , Termolino Pasquale , Chiaiese Pasquale , de Alteriis Elisabetta , Mazzoleni Stefano , Chiusano Maria Luisa
Published: December 2020

The capacity to actively release genetic material into the extracellular environment has been reported for bacteria, archaea, fungi, and in general, for microbial communities, but it is also described in the context of multicellular organisms, animals and plants. This material is often present in matrices that locate outside the cells. Extracellular matrices have important roles in defense response and disease in microbes, animal and plants cells, appearing as barrier against pathogen invasion or for their recognition. Specifically, neutrophils extracellular traps (NETs) in animals and root extracellular traps (RETs) in plants, are recognized to be important players in immunity. A growing amount of evidence revealed that the extracellular DNA, in these contexts, plays an active role in the defense action. Moreover, the protective role of extracellular DNA against antimicrobials and mechanical stress also appears to be confirmed in bacterial biofilms. In parallel, recent efforts highlighted different roles of self (homologous) and non-self (heterologous) extracellular DNA, paving the way to discussions on its role as a “Damage-associated molecular pattern” (DAMP). We here provide an evolutionary overview on extracellular DNA in extracellular matrices like RETs, NETs, and microbial biofilms, discussing on its roles and inferring on possible novel functionalities.
Somaclonal Variation in Chrysanthemum × morifolium Protoplast Regenerants
Authors: Eeckhaut Tom , Van Houtven Wouter , Bruznican Silvia , Leus Leen , Van Huylenbroeck Johan
Published: December 2020

Chrysanthemum × morifolium protoplasts were isolated and regenerated to assess possible protoclonal variation in the regenerants. After a preliminary screening of the potential of different regeneration systems for protoplast regeneration, we produced a series of cut chrysanthemum ‘Arjuna’ leaf protoplast regenerants through liquid culture. Regenerants (54) were vegetatively propagated and grown under a commercial production system in 2 different seasons. All screened regenerants were significantly affected with regard to either flower number, flower size, flower weight, leaf weight, stalk weight, or plant size. A significant plant size reduction in 43/52 and 48/49 regenerants for both seasons was the most recorded effect. Also a reduction in flowering induction time up to 10 days, altered flower types and colors were observed. Differences between growing seasons were notable. Possible molecular backgrounds including genome size variation and commercial applications in breeding of chrysanthemum are discussed.
Interspecific Hybrids Between Pelargonium × hortorum and Species From P. Section Ciconium Reveal Biparental Plastid Inheritance and Multi-Locus Cyto-Nuclear Incompatibility
Authors: Breman Floris C. , Snijder Ronald C. , Korver Joost W. , Pelzer Sieme , Sancho-Such Mireia , Schranz M. Eric , Bakker Freek T.
Published: December 2020

The genetics underlying Cyto-Nuclear Incompatibility (CNI) was studied in Pelargonium interspecific hybrids. We created hybrids of 12 closely related crop wild relatives (CWR) with the ornamental P. × hortorum. Ten of the resulting 12 (F1) interspecific hybrids segregate for chlorosis suggesting biparental plastid inheritance. The segregation ratios of the interspecific F2 populations show nuclear interactions of one, two, or three nuclear genes regulating plastid function dependent on the parents. We further validated that biparental inheritance of plastids is common in section Ciconium, using diagnostic PCR primers. Our results pave the way for using the diverse species from section Ciconium, each with its own set of characteristics, as novel sources of desired breeding traits for P. × hortorum cultivars.
Psychology Meets Archaeology: Psychoarchaeoacoustics for Understanding Ancient Minds and Their Relationship to the Sacred
Authors: Valenzuela Jose , Díaz-Andreu Margarita , Escera Carles
Published: December 2020

How important is the influence of spatial acoustics on our mental processes related to sound perception and cognition? There is a large body of research in fields encompassing architecture, musicology, and psychology that analyzes human response, both subjective and objective, to different soundscapes. But what if we want to understand how acoustic environments influenced the human experience of sound in sacred ritual practices in premodern societies? Archaeoacoustics is the research field that investigates sound in the past. One of its branches delves into how sound was used in specific landscapes and at sites with rock art, and why past societies endowed a special significance to places with specific acoustical properties. Taking advantage of the advances made in sound recording and reproduction technologies, researchers are now exploring how ancient social and sacred ceremonies and practices related to the acoustic properties of their sound environment. Here, we advocate for the emergence of a new and innovative discipline, experimental psychoarchaeoacoustics. We also review underlying methodological approaches and discuss the limitations, challenges, and future directions for this new field.
Spanish Women Making Risky Decisions in the Social Domain: The Mediating Role of Femininity and Fear of Negative Evaluation
Authors: Villanueva-Moya Laura , Expósito Francisca
Published: December 2020

Authors have empirically evidenced that cultural stereotypes influence gender-typed behavior. With the present work, we have added to this literature by demonstrating that gender roles can explain sex differences in risk-taking, a stereotypically masculine domain. Our aim was to replicate previous findings and to analyze what variables affect women making risky decisions in the social domain. A sample composed of 417 Spanish participants (281 women and 136 men), between 17 and 30 years old (M = 22.34, SD = 3.01), answered a set of self-report measures referring to femininity, fear of negative evaluation, and social risk-taking. According to the main results, sex indirectly linked to risk-taking in the social domain, through femininity and fear of negative evaluation. Specifically, women (vs. men) self-reported higher feminine traits, which were associated with increased fear of negative evaluation, which in turn was associated with less risky decisions in the social domain. Thus, we have showed the relationship between gender roles and women’s behaviors in a stereotypically masculine domain (risk-taking). Our findings highlight the necessity of considering a gender-based perspective in the field of risk-taking, showing that not all women make more risky decisions in the social domain.
SEM-Based Methods to Form Confidence Intervals for Indirect Effect: Still Applicable Given Nonnormality, Under Certain Conditions
Authors: Pesigan Ivan Jacob Agaloos , Cheung Shu Fai
Published: December 2020

A SEM-based approach using likelihood-based confidence interval (LBCI) has been proposed to form confidence intervals for unstandardized and standardized indirect effect in mediation models. However, when used with the maximum likelihood estimation, this approach requires that the variables are multivariate normally distributed. This can affect the LBCIs of unstandardized and standardized effect differently. In the present study, the robustness of this approach when the predictor is not normally distributed but the error terms are conditionally normal, which does not violate the distributional assumption of ordinary least squares (OLS) estimation, is compared to four other approaches: nonparametric bootstrapping, two variants of LBCI, LBCI assuming the predictor is fixed (LBCI-Fixed-X) and LBCI based on ADF estimation (LBCI-ADF), and Monte Carlo. A simulation study was conducted using a simple mediation model and a serial mediation model, manipulating the distribution of the predictor. The Monte Carlo method performed worst among the methods. LBCI and LBCI-Fixed-X had suboptimal performance when the distributions had high kurtosis and the population indirect effects were medium to large. In some conditions, the problem was severe even when the sample size was large. LBCI-ADF and nonparametric bootstrapping had coverage probabilities close to the nominal value in nearly all conditions, although the coverage probabilities were still suboptimal for the serial mediation model when the sample size was small with respect to the model. Implications of these findings in the context of this special case of nonnormal data were discussed.
Large-Scale Assessment of Health-Related Physical Fitness in French Older Adults: Feasibility and Validity
Authors: Mack-Inocentio Damien , Menai Mehdi , Doré Eric , Doreau Bastien , Gaillard Camille , Finaud Julien , Pereira Bruno , Duché Pascale
Published: December 2020

Objectives: This study aims to assess the validity, internal consistency, implementation, and feasibility of a sequence of tests, the Vitality Test Battery, designed to measure physical fitness, at a large scale in French older adults.

Methods: A total of 528 volunteers (age ≥60 years) took the battery of 10 tests: 6-min walk, trunk strength, hand grip strength, medicine ball throwing, 30-s chair stand, flexibility, balance, plate tapping, ruler drop, and dual task.

Results: Internal consistency was high, with the Cronbach alpha coefficients at around 0.77, explaining 64% of the variance. The test–retest correlations (0.3–0.6) between the items were acceptable and displayed an internal consistency property. Although five components explained 65% of the variance, all the items were kept because their eigenvalues were near to 0.9. External consistency was validated by a significant decrease in fitness scores (p < 0.001) with age and body mass index.

Discussion: The Vitality Test Battery is a safe, valid tool for assessing physical fitness in persons aged over 60 years.
The Eternal Robot: Anchoring Effects in Humans' Mental Models of Robots and Their Self
Authors: Ullrich Daniel , Butz Andreas , Diefenbach Sarah
Published: December 2020

Current robot designs often reflect an anthropomorphic approach, apparently aiming to convince users through an ideal system, being most similar or even on par with humans. The present paper challenges human-likeness as a design goal and questions whether simulating human appearance and performance adequately fits into how humans think about robots in a conceptual sense, i.e., human's mental models of robots and their self. Independent of the technical possibilities and limitations, our paper explores robots' attributed potential to become human-like by means of a thought experiment. Four hundred eighty-one participants were confronted with fictional transitions from human-to-robot and robot-to-human, consisting of 20 subsequent steps. In each step, one part or area of the human (e.g., brain, legs) was replaced with robotic parts providing equal functionalities and vice versa. After each step, the participants rated the remaining humanness and remaining self of the depicted entity on a scale from 0 to 100%. It showed that the starting category (e.g., human, robot) serves as an anchor for all former judgments and can hardly be overcome. Even if all body parts had been exchanged, a former robot was not perceived as totally human-like and a former human not as totally robot-like. Moreover, humanness appeared as a more sensible and easier denied attribute than robotness, i.e., after the objectively same transition and exchange of the same parts, the former human was attributed less humanness and self left compared to the former robot's robotness and self left. The participants' qualitative statements about why the robot has not become human-like, often concerned the (unnatural) process of production, or simply argued that no matter how many parts are exchanged, the individual keeps its original entity. Based on such findings, we suggest that instead of designing most human-like robots in order to reach acceptance, it might be more promising to understand robots as an own “species” and underline their specific characteristics and benefits. Limitations of the present study and implications for future HRI research and practice are discussed.
Is Vestibular Meniere's Disease Associated With Endolymphatic Hydrops?
Authors: Morita Yuka , Takahashi Kuniyuki , Ohshima Shinsuke , Yagi Chihiro , Kitazawa Meiko , Yamagishi Tatsuya , Izumi Shuji , Horii Arata
Published: December 2020

Background: Vestibular Meniere's disease (American Academy of Ophthalmology and Otolaryngology, 1972) also known as possible Meniere's disease (American Academy of Otolaryngology Head and Neck Surgery, 1995) or vestibular type of atypical Meniere's disease (V-AMD) (Japan Society for Equilibrium Research, 2017) is characterized by an episodic vertigo without hearing loss. Though named as Meniere's disease (MD), this entity may not be caused solely by endolymphatic hydrops (EH).

Objective: To estimate the role of EH in vestibular Meniere's disease in comparison with definite Meniere's disease.

Methods: Thirty patients with unilateral definite MD and 16 patients with vestibular Meniere's disease were included. Those who met the criteria for definite or probable vestibular migraine were excluded. All patients underwent vestibular assessments including inner ear MRI 4 h after intravenous gadolinium injection, bithermal caloric testing, directional preponderance of vestibulo-ocular reflex in rotatory chair test, cervical- and ocular-vestibular evoked myogenic potential, stepping test, dizziness handicap inventory (DHI), and hospital anxiety and depression scale (HADS). All above tests and frequency/duration of vertigo spells were compared between vestibular Meniere's disease and MD.

Results: Even in unilateral MD, cochlear and vestibular endolymphatic hydrops (c-, v-EH) were demonstrated not only in the affected side but also in the healthy side in more than half of patients. Positive rate of v-EH in vestibular Meniere's disease (68.8%) was as high as that of MD (80%). In vestibular Meniere's disease, the number of bilateral EH was higher in the vestibule (56.3%) than that in the cochlea (25.0%). There were no differences in vestibular tests and DHI between vestibular Meniere's disease and MD; however, the frequency of vertigo spells was lower in vestibular Meniere's disease (p = 0.001). The total HADS score in the MD group was significantly higher than that in the vestibular Meniere's disease group.

Conclusions: MD is a systemic disease with bilateral involvement of inner ears. V-EH is a major pathophysiology of vestibular Meniere's disease, which would precede c-EH in the development of vestibular Meniere's disease, a milder subtype of MD. MRI is useful for differentiating MD from other vertigo attacks caused by different pathologies in bringing EH into evidence.