bluuebunny/crossref_metadata_2025 huggingface dataset:
Rhizobium leguminosarum Glutathione Peroxidase Is Essential for Oxidative Stress Resistance and Efficient Nodulation
Authors: Hu Aiqi , Chen Xiaohong , Luo Sha , Zou Qian , Xie Jing , He Donglan , Li Xiaohua , Cheng Guojun
Published: February 2021

Glutathione (GSH) plays a key role in regulating the cellular Redox Homeostasis, and appears to be essential for initiation and development of root nodules. Glutathione peroxidase (Gpx) catalyzes the reduction of H2O2 and organic hydroperoxides by oxidation of GSH to oxidized GSH (GSSG), which in turn is reduced by glutathione reductase (GR). However, it has not been determined whether the Rhizobium leguminosarum Gpx or GR is required during symbiotic interactions with pea. To characterize the role of glutathione-dependent enzymes in the symbiotic process, single and double mutants were made in gpxA (encoding glutathione peroxidase) and gshR (encoding glutathione reductase) genes. All the mutations did not affect the rhizobial growth, but they increased the sensitivity of R. leguminosarum strains to H2O2. Mutant in GpxA had no effect on intracellular GSH levels, but can increase the expression of the catalase genes. The gshR mutant can induce the formation of normal nodules, while the gpxA single and double mutants exhibited a nodulation phenotype coupled to more than 50% reduction in the nitrogen fixation capacity, these defects in nodulation were characterized by the formation of ineffective nodules. In addition, the gpxA and gshR double mutant was severely impaired in rhizosphere colonization and competition. Quantitative proteomics using the TMT labeling method was applied to study the differential expression of proteins in bacteroids isolated from pea root nodules. A total of 27 differentially expressed proteins were identified in these root bacteroids including twenty down-regulated and seven up-regulated proteins. By sorting the down-regulated proteins, eight are transporter proteins, seven are dehydrogenase, deoxygenase, oxidase, and hydrolase. Moreover, three down-regulating proteins are directly involved in nodule process.
Bilateral MR-Guided Focused Ultrasound Pallidothalamic Tractotomy for Parkinson's Disease With 1-Year Follow-Up
Authors: Gallay Marc N. , Moser David , Magara Anouk E. , Haufler Fabio , Jeanmonod Daniel
Published: February 2021

Objective: Bilateral stereotactic neurosurgery for advanced Parkinson's disease (PD) has a long history beginning in the late 1940s. In view of improved lesioning accuracy and reduced bleeding risk and in spite of long-standing caveats about bilateral approaches, there is a need to investigate bilateral MR-guided focused ultrasound (MRgFUS) interventions. We hereby present the clinical results of bilateral pallidothalamic tractotomy (PTT), i.e., targeting of pallidal efferent fibers below the thalamus at the level of Forel's field H1, followed for 1 year after operation of the second side.

Methods: Ten patients suffering from chronic and therapy-resistant PD having received bilateral PTT were followed for 1 year after operation of the second side. The primary endpoints included the Unified Parkinson's Disease Rating Scale (UPDRS) scores in on- and off-medication states, dyskinesias, dystonia, sleep disturbances, pain, reduction in drug intake, and assessment by the patient of her/his global symptom relief as well as tremor control.

Results: The time frame between baseline UPDRS score and 1 year after the second side was 36 ± 15 months. The total UPDRS score off-medication at 1 year after the second PTT was reduced by 52% compared to that at baseline on-medication (p < 0.007). Percentage reductions of the mean scores comparing 1 year off- with baseline on-medication examinations were 91% for tremor (p = 0.006), 67% for distal rigidity (p = 0.006), and 54% for distal hypobradykinesia (p = 0.01). Gait and postural instability were globally unchanged to baseline (13% improvement of the mean, p = 0.67, and 5.3% mean reduction, p = 0.83). Speech difficulties, namely, hypophonia, tachyphemia, and initiation of speech, were increased by 58% (p = 0.06). Dyskinesias were suppressed in four over four, dystonia in four over five, and sleep disorders in three over four patients. There was 89% pain reduction. Mean L-Dopa intake was reduced from 690 ± 250 to 110 ± 190.

Conclusions: Our results suggest an efficiency of bilateral PTT in controlling tremor, distal rigidity, distal hypobradykinesia, dyskinesias, dystonia, and pain when compared to best medical treatment at baseline. Larger series are of course needed.
Vitamin D Receptor Polymorphism and Myasthenia Gravis in Chinese Han Population
Authors: Han Ji-Lan , Yue Yao-Xian , Gao Xiang , Xie Yan-Chen , Hao Hong-Jun , Li Hong-Yan , Yu Xiao-Long , Li Jie , Duan Rui-Sheng , Li Hai-Feng
Published: February 2021

Myasthenia gravis (MG) is an autoimmune disease in which antibodies bind to acetylcholine receptors (AChR) or other functional molecules in the postsynaptic membrane at the neuromuscular junction. Vitamin D (VD) has a number of pluripotent effects, which include immune-regulation and bone metabolism. The immunomodulatory actions of 1,25(OH)2D3 are mediated by its binding to a vitamin D receptor (VDR). In the study, we undertook a case-control study to explore the association between VDR gene polymorphism and the susceptibility and severity of MG patients. Four hundred and eighty MG patients and 487 healthy controls were included and gene polymorphisms of VDR were determined with improved multiplex ligation detection reaction technique and SNPscanTM technique. MG patients were classified into subgroups by essential clinical features and by a comprehensive classification. The frequencies of alleles and genotypes were compared between the MG group and the control group, between each MG subgroup and the control group, and between each pair of MG subgroups. There were no significant differences in frequencies of alleles and genotypes between MG patients and healthy controls, between MG subgroups and healthy controls, or between each pair of MG subgroups in the analysis of subgroups classified by essential clinical features (onset age, gender, thymoma, AChRAb positivity, onset involvement) and the maximal severity (modified Oosterhuis score). In the analysis of subgroups with a comprehensive classification, the frequencies of alleles and genotypes in rs731236 showed significant differences between adult non-thymoma AChRAb negative MG subgroup and the control group, as well as the adult non-thymoma AChRAb positive MG group. In the Chinese Han population, rs731236 was found to be possibly associated with adult non-thymoma AChRAb negative MG patients, although this needs further confirmation.
Glycinergic Transmission in the Presence and Absence of Functional GlyT2: Lessons From the Auditory Brainstem
Authors: Brill Sina E. , Maraslioglu Ayse , Kurz Catharina , Kramer Florian , Fuhr Martin F. , Singh Abhyudai , Friauf Eckhard
Published: February 2021

Synaptic transmission is controlled by re-uptake systems that reduce transmitter concentrations in the synaptic cleft and recycle the transmitter into presynaptic terminals. The re-uptake systems are thought to ensure cytosolic concentrations in the terminals that are sufficient for reloading empty synaptic vesicles (SVs). Genetic deletion of glycine transporter 2 (GlyT2) results in severely disrupted inhibitory neurotransmission and ultimately to death. Here we investigated the role of GlyT2 at inhibitory glycinergic synapses in the mammalian auditory brainstem. These synapses are tuned for resilience, reliability, and precision, even during sustained high-frequency stimulation when endocytosis and refilling of SVs probably contribute substantially to efficient replenishment of the readily releasable pool (RRP). Such robust synapses are formed between MNTB and LSO neurons (medial nucleus of the trapezoid body, lateral superior olive). By means of patch-clamp recordings, we assessed the synaptic performance in controls, in GlyT2 knockout mice (KOs), and upon acute pharmacological GlyT2 blockade. Via computational modeling, we calculated the reoccupation rate of empty release sites andRRPreplenishment kinetics during 60-s challenge and 60-s recovery periods. Control MNTB-LSO inputs maintained high fidelity neurotransmission at 50 Hz for 60 s and recovered very efficiently from synaptic depression. During 'marathon-experiments' (30,600 stimuli in 20 min),RRPreplenishment accumulated to 1,260-fold. In contrast, KO inputs featured severe impairments. For example, the input number was reduced to ~1 (vs. ~4 in controls), implying massive functional degeneration of the MNTB-LSO microcircuit and a role of GlyT2 during synapse maturation. Surprisingly, neurotransmission did not collapse completely in KOs as inputs still replenished their smallRRP80-fold upon 50 Hz | 60 s challenge. However, they totally failed to do so for extended periods. Upon acute pharmacological GlyT2 inactivation, synaptic performance remained robust, in stark contrast to KOs.RRPreplenishment was 865-fold in marathon-experiments, only ~1/3 lower than in controls. Collectively, our empirical and modeling results demonstrate that GlyT2 re-uptake activity is not the dominant factor in the SV recycling pathway that imparts indefatigability to MNTB-LSO synapses. We postulate that additional glycine sources, possibly the antiporter Asc-1, contribute toRRPreplenishment at these high-fidelity brainstem synapses.
Computational Model of Motion Sickness Describing the Effects of Learning Exogenous Motion Dynamics
Authors: Wada Takahiro
Published: February 2021

The existing computational models used to estimate motion sickness are incapable of describing the fact that the predictability of motion patterns affects motion sickness. Therefore, the present study proposes a computational model to describe the effect of the predictability of dynamics or the pattern of motion stimuli on motion sickness. In the proposed model, a submodel – in which a recursive Gaussian process regression is used to represent human features of online learning and future prediction of motion dynamics – is combined with a conventional model of motion sickness based on an observer theory. A simulation experiment was conducted in which the proposed model predicted motion sickness caused by a 900 s horizontal movement. The movement was composed of a 9 m repetitive back-and-forth movement pattern with a pause. Regarding the motion condition, the direction and timing of the motion were varied as follows: (a) Predictable motion (M_P): the direction of the motion and duration of the pause were set to 8 s; (b) Motion with unpredicted direction (M_dU): the pause duration was fixed as in (M_P), but the motion direction was randomly determined; (c) Motion with unpredicted timing (M_tU): the motion direction was fixed as in (M_P), but the pause duration was randomly selected from 4 to 12 s. The results obtained using the proposed model demonstrated that the predicted motion sickness incidence for (M_P) was smaller than those for (M_dU) and (M_tU) and no considerable difference was found between M_dU and M_tU. This tendency agrees with the sickness patterns observed in a previous experimental study in which the human participants were subject to motion conditions similar to those used in our simulations. Moreover, no significant differences were found in the predicted motion sickness incidences at different conditions when the conventional model was used.
Goals in Nutrition Science 2020-2025
Authors: Bassaganya-Riera Josep , Berry Elliot M. , Blaak Ellen E. , Burlingame Barbara , le Coutre Johannes , van Eden Willem , El-Sohemy Ahmed , German J. Bruce , Knorr Dietrich , Lacroix Christophe , Muscaritoli Maurizio , Nieman David C. , Rychlik Michael , Scholey Andrew , Serafini Mauro
Published: February 2021

Five years ago, with the editorial board of Frontiers in Nutrition, we took a leap of faith to outline the Goals for Nutrition Science – the way we see it (1). Now, in 2020, we can put ourselves to the test and take a look back. Without a doubt we got it right with several of the key directions. To name a few, Sustainable Development Goals (SDGs) for Food and Nutrition are part of the global public agenda, and the SDGs contribute to the structuring of international science and research. Nutritional Science has become a critical element in strengthening work on the SDGs, and the development of appropriate methodologies is built on the groundwork of acquiring and analyzing big datasets. Investigation of the Human Microbiome is providing novel insight on the interrelationship between nutrition, the immune system and disease. Finally, with an advanced definition of the gut-brain-axis we are getting a glimpse into the potential for Nutrition and Brain Health. Various milestones have been achieved, and any look into the future will have to consider the lessons learned from Covid-19 and the sobering awareness about the frailty of our food systems in ensuring global food security. With a view into the coming 5 years from 2020 to 2025, the editorial board has taken a slightly different approach as compared to the previous Goals article. A mind map has been created to outline the key topics in nutrition science. Not surprisingly, when looking ahead, the majority of scientific investigation required will be in the areas of health and sustainability.

Johannes le Coutre, Field Chief Editor, Frontiers in Nutrition.
The Cancer/Testis Antigen Gene VCX2 Is Rarely Expressed in Malignancies but Can Be Epigenetically Activated Using DNA Methyltransferase and Histone Deacetylase Inhibitors
Authors: Jakobsen Mie K. , Traynor Sofie , Stæhr Mette , Duijf Pascal G. , Nielsen Aaraby Y. , Terp Mikkel G. , Pedersen Christina B. , Guldberg Per , Ditzel Henrik J. , Gjerstorff Morten F.
Published: February 2021

Identification of novel tumor-specific targets is important for the future development of immunotherapeutic strategies using genetically engineered T cells or vaccines. In this study, we characterized the expression of VCX2, a member of the VCX/Y cancer/testis antigen family, in a large panel of normal tissues and tumors from multiple cancer types using immunohistochemical staining and RNA expression data. In normal tissues, VCX2 was detected in the germ cells of the testis at all stages of maturation but not in any somatic tissues. Among malignancies, VCX2 was only found in tumors of a small subset of melanoma patients and thus rarely expressed compared to other cancer/testis antigens such as GAGE and MAGE-A. The expression of VCX2 correlated with that of other VCX/Y genes. Importantly, we found that expression of VCX2 was inversely correlated with promoter methylation and could be activated by treatment with a DNA methyltransferase inhibitor in multiple breast cancer and melanoma cell lines and a breast cancer patient-derived xenograft. The effect could be further potentiated by combining the DNA methyltransferase inhibitor with a histone deacetylase inhibitor. Our results show that the expression of VCX2 can be epigenetically induced in cancer cells and therefore could be an attractive target for immunotherapy of cancer.
The Role of Interleukin-33 in Head and Neck Squamous Cell Carcinoma Is Determined by Its Cellular Sources in the Tumor Microenvironment
Authors: Peng Liang , Sun Wei , Chen Lin , Wen Wei-Ping
Published: February 2021

Objectives

To investigate the role of interleukin-33 (IL-33) in head and neck squamous cell carcinoma (HNSCC).

Materials and Methods

RNA-seq data of 520 cases of HNSCC were retrieved from The Cancer Genome Atlas. The tumor microenvironment was deconstructed by xCell using bulk RNA-seq data. The cohort was dichotomized by the median IL-33 expression level. Immune cell components and molecular markers were compared between the high and low IL-33 groups. The prognostic value of IL-33 was evaluated by the log-rank test. Differential gene expression analysis and KEGG pathway enrichment analysis were also conducted. The relationship between the IL-33 expression level and the abundance of its potential cellular sources was evaluated by Pearson’s partial correlation test. Subgroup analysis was conducted in laryngeal, oropharyngeal, and oral cavity squamous cell carcinoma (LSCC, OPSCC, and OCSCC).

Results

The role of IL-33 in HNSCC was heterogeneous among tumors at different sites. In LSCC, IL-33 may increase the extent of malignancy of tumor cells and act as a pro-tumor factor. In OCSCC, IL-33 may play a role in orchestrating the immune responses against tumor cells and act as an antitumor factor. The role of IL-33 in OPSCC was undetermined. IL-33 in LSCC was mainly derived from endothelial cells, while IL-33 in OCSCC was mainly derived from endothelial and epithelial cells.

Conclusion

According to the different sources of IL-33 in LSCC and OCSCC, we propose a hypothesis that stroma-derived IL-33 could favor tumor progression, while epithelial-derived IL-33 could favor antitumor immune responses in HNSCC.
RETRACTED: Emodin Interferes With AKT1-Mediated DNA Damage and Decreases Resistance of Breast Cancer Cells to Doxorubicin
Authors: Li Bo , Zhao Xin , Zhang Lei , Cheng Wen
Published: February 2021

Doxorubicin (DOX) is a cytotoxic drug used for the treatment of breast cancer (BC). However, the rapid emergence of resistance toward doxorubicin threatens its clinical application, thus the need for combination therapy. Here, we interrogate the role of Emodin, a chemical compound with tumor inhibitory properties, in the resistance of BC to Doxorubicin. We first evaluated the efficacy of Emodin in the treatment of BC cells. We then used γH2A to examine doxorubicin-induced DNA damage in BC cells, with or without Emodin. Data from CCK-8, flow cytometry, and tumor xenograft assays showed that Emodin suppresses the growth of BC cells. Further, we demonstrated that Emodin enhances γH2A levels in BC cells. Moreover, bioinformatics analysis and western blot assays indicated that Emodin down-regulates the AKT1 expression, and marginally decreases the levels of DNA damage proteins (XRCC1, PARP1, and RAD51) as well as increased p53 expression in BC cells. Taken together, our data demonstrates that Emodin affects cell proliferation, and DNA damage pathways in BC cells, thus increasing the sensitivity of BC cells to doxorubicin. Besides, we confirmed that Emodin confers sensitization of BC to doxorubicin through AKT1-mediated DNA.
Potential Clinical Significance of Overall Targeting Accuracy and Motion Management in the Treatment of Tumors That Move With Respiration: Lessons Learnt From a Quarter Century of Stereotactic Body Radiotherapy From Dose Response Models
Authors: Mahadevan Anand , Emami Bahman , Grimm Jimm , Kleinberg Lawrence R. , Redmond Kristin J. , Welsh James S. , Rostock Robert , Kemmerer Eric , Forster Kenneth M. , Stanford Jason , Shah Sunjay , Asbell Sucha O. , LaCouture Tamara A. , Scofield Carla , Butterwick Ian , Xue Jinyu , Muacevic Alexander , Adler John R.
Published: February 2021

Objective

To determine the long-term normal tissue complication probability with stereotactic body radiation therapy (SBRT) treatments for targets that move with respiration and its relation with the type of respiratory motion management (tracking vs. compression or gating).

Methods

A PubMed search was performed for identifying literature regarding dose, volume, fractionation, and toxicity (grade 3 or higher) for SBRT treatments for tumors which move with respiration. From the identified papers logistic or probit dose-response models were fitted to the data using the maximum-likelihood technique and confidence intervals were based on the profile-likelihood method in the dose-volume histogram (DVH) Evaluator.

Results

Pooled logistic and probit models for grade 3 or higher toxicity for aorta, chest wall, duodenum, and small bowel suggest a significant difference when live motion tracking was used for targeting tumors with move with respiration which was on the average 10 times lower, in the high dose range.

Conclusion

Live respiratory motion management appears to have a better toxicity outcome when treating targets which move with respiration with very steep peripheral dose gradients. This analysis is however limited by sparsity of rigorous data due to poor reporting in the literature.
Antitumor Effect and Immune Response of Nanosecond Pulsed Electric Fields in Pancreatic Cancer
Authors: Zhao Jing , Chen Shuochun , Zhu Lu , Zhang Liang , Liu Jingqi , Xu Danxia , Tian Guo , Jiang Tian’an
Published: February 2021

Nanosecond pulsed electric fields (nsPEFs) have emerged as a novel and effective strategy for the non-surgical and minimally invasive removal of tumors. However, the effects of nsPEFs treatment on the tumor immune microenvironment remain unknown. In this study, the changes in the morphology and function of pancreatic cancer cells after nsPEFs were assessed and the modifications in the immune profile in pancreatic cancer models were investigated. To this end, electrodes were inserted with different parameters applied to ablate the targeted tumor tissues. Tumor development was found to be inhibited, with decreased volumes post-nsPEFs treatment compared with control tumors (P < 0.05). Hematoxylin and eosin staining showed morphological changes in pancreatic cancer cells, Ki-67 staining confirmed the effects of nsPEFs on tumor growth, and caspase-3 staining indicated that nsPEFs caused apoptosis in the early stages after treatment. Three days after nsPEFs, positron emission tomography demonstrated little residual metabolic activity compared with the control group. Gene expression profiling identified significant changes in immune-related pathways. After treatment with nsPEFs, CD8+ T lymphocytes increased. We showed that nsPEFs led to a significant decrease in immune suppressive cells, including myeloid derived suppressor cells, T regulatory cells, and tumor-associated macrophages. In addition, the levels of TNF-α and IL-1β increased (P < 0.05), while the level of IL-6 was decreased (P < 0.05). NsPEFs alleviated the immunosuppressive components in pancreatic cancer stroma, including hyaluronic acid and fibroblast activation protein-α. Our data demonstrate that tumor growth can be effectively inhibited by nsPEFs in vivo. NsPEFs significantly altered the infiltration of immune cells and triggered immune response.
Targeting MYCN in Pediatric and Adult Cancers
Authors: Liu Zhihui , Chen Samuel S. , Clarke Saki , Veschi Veronica , Thiele Carol J.
Published: February 2021

The deregulation of theMYCfamily of oncogenes, includingc-MYC,MYCNandMYCLoccurs in many types of cancers, and is frequently associated with a poor prognosis. The majority of functional studies have focused onc-MYCdue to its broad expression profile in human cancers. The existence of highly conserved functional domains betweenMYCNandc-MYCsuggests thatMYCNparticipates in similar activities.MYCencodes a basic helix-loop-helix-leucine zipper (bHLH-LZ) transcription factor (TF) whose central oncogenic role in many human cancers makes it a highly desirable therapeutic target. Historically, as a TF, MYC has been regarded as “undruggable”. Thus, recent efforts focus on investigating methods to indirectly target MYC to achieve anti-tumor effects. This review will primarily summarize the recent progress in understanding the function ofMYCN. It will explore efforts at targetingMYCN, including strategies aimed at suppression ofMYCNtranscription, destabilization of MYCN protein, inhibition ofMYCNtranscriptional activity, repression of MYCN targets and utilization ofMYCNoverexpression dependent synthetic lethality.
A Position Statement on the Utility of Interval Imaging in Standard of Care Brain Tumour Management: Defining the Evidence Gap and Opportunities for Future Research
Authors: Booth Thomas C. , Thompson Gerard , Bulbeck Helen , Boele Florien , Buckley Craig , Cardoso Jorge , Dos Santos Canas Liane , Jenkinson David , Ashkan Keyoumars , Kreindler Jack , Huskens Nicky , Luis Aysha , McBain Catherine , Mills Samantha J. , Modat Marc , Morley Nick , Murphy Caroline , Ourselin Sebastian , Pennington Mark , Powell James , Summers David , Waldman Adam D. , Watts Colin , Williams Matthew , Grant Robin , Jenkinson Michael D.
Published: February 2021

Objectiv e

To summarise current evidence for the utility of interval imaging in monitoring disease in adult brain tumours, and to develop a position for future evidence gathering while incorporating the application of data science and health economics.

Methods

Experts in ‘interval imaging’ (imaging at pre-planned time-points to assess tumour status); data science; health economics, trial management of adult brain tumours, and patient representatives convened in London, UK. The current evidence on the use of interval imaging for monitoring brain tumours was reviewed. To improve the evidence that interval imaging has a role in disease management, we discussed specific themes of data science, health economics, statistical considerations, patient and carer perspectives, and multi-centre study design. Suggestions for future studies aimed at filling knowledge gaps were discussed.

Results

Meningioma and glioma were identified as priorities for interval imaging utility analysis. The “monitoring biomarkers” most commonly used in adult brain tumour patients were standard structural MRI features. Interval imaging was commonly scheduled to provide reported imaging prior to planned, regular clinic visits. There is limited evidence relating interval imaging in the absence of clinical deterioration to management change that alters morbidity, mortality, quality of life, or resource use. Progression-free survival is confounded as an outcome measure when using structural MRI in glioma. Uncertainty from imaging causes distress for some patients and their caregivers, while for others it provides an important indicator of disease activity. Any study design that changes imaging regimens should consider the potential for influencing current or planned therapeutic trials, ensure that opportunity costs are measured, and capture indirect benefits and added value.

Conclusion

Evidence for the value, and therefore utility, of regular interval imaging is currently lacking. Ongoing collaborative efforts will improve trial design and generate the evidence to optimise monitoring imaging biomarkers in standard of care brain tumour management.
Polyneuropathy in Acute Lymphoblastic Leukemia Long-Term Survivors: Clinical and Electrophysiological Characteristics With the Impact of Radiotherapy
Authors: Kroczka Slawomir , Stepien Konrad , Witek-Motyl Izabela , Klekawka Tomasz , Kapusta Eryk , Biedron Agnieszka , Skorek Pawel , Twardowska Hanna , Stasik Klaudia , Skoczen Szymon
Published: February 2021

Introduction:Acute lymphoblastic leukemia (ALL) is the most common childhood cancer with one of the highest survival rates. Long-term complications that occur after intensive oncological treatment often impair normal daily functioning. However, existing data on peripheral nervous system condition in ALL survivors remain conflicting.

Materials and Methods:The study group consisted of 215 ALL survivors. Patients were treated with New York (NY,n= 45), previous modified Berlin–Frankfurt–Münster (pBFM,n= 64), and BFM95 (n= 106) protocols. Time elapsed between the end of the treatment and the control examination varied from 0.3 to 20.9 years. The analyzed patients underwent a neurophysiological analysis with electroneurography (ENG) of motor (median and peroneal) and sensory (median and sural) nerves as well as electromyography (EMG) of tibialis anterior, vastus lateralis, and interosseous I muscles. To estimate the influence of radiotherapy on recorded neurophysiological responses, a joint analysis of NY, and pBFM groups was performed.

Results:Clinical symptoms of polyneuropathy were noted among 102 (47.4%) children during the ALL therapy and in 111 (51.6%) during follow-up. At the time of treatment, polyneuropathy was diagnosed in 57.8% participants from NY group, 35.9%—pBFM and 50.0%—BFM95 (p= 0.145). A significantly higher incidence of polyneuropathy was observed during a follow-up in the NY group (68.9%;p< 0.001 vs. pBFM,p= 0.002 vs. BFM95). The most frequent abnormality within all the protocols was demyelination (NY: 44.4%, pBFM: 59.4%, BFM95: 41.5%), in contrast to the least frequently registered isolated axonal changes. The negative influence of oncological treatment on neurophysiological parameters in ALL survivors was observed. Complex disorders of motor nerves, sensory nerves, and motor unit potentials were registered. Motor-sensory neuropathy was the most frequently found pathology in all analyzed protocols. The harmful effect of radiotherapy was also observed in EMG results.

Conclusions:Detailed neurophysiological analysis in long-term childhood ALL survivors has shown generalized abnormalities in registered parameters. To our knowledge, the current study is the largest and one of the most comprehensive ones among those examining disturbances in ENG and EMG in this group of patients. Moreover, we are the first ones to demonstrate the negative influence of radiotherapy on peripheral nerve conduction parameters.
Alternative Polyadenylation and Differential Regulation of Ucp1: Implications for Brown Adipose Tissue Thermogenesis Across Species
Authors: Lu Wen-Hsin , Chang Yao-Ming , Huang Yi-Shuian
Published: February 2021

Brown adipose tissue (BAT) is a thermogenic organ owing to its unique expression of uncoupling protein 1 (UCP1), which is a proton channel in the inner mitochondrial membrane used to dissipate the proton gradient and uncouple the electron transport chain to generate heat instead of adenosine triphosphate. The discovery of metabolically active BAT in human adults, especially in lean people after cold exposure, has provoked the “thermogenic anti-obesity” idea to battle weight gain. Because BAT can expend energy through UCP1-mediated thermogenesis, the molecular mechanisms regulating UCP1 expression have been extensively investigated at both transcriptional and posttranscriptional levels. Of note, the 3′-untranslated region (3′-UTR) of Ucp1 mRNA is differentially processed between mice and humans that quantitatively affects UCP1 synthesis and thermogenesis. Here, we summarize the regulatory mechanisms underlying UCP1 expression, report the number of poly(A) signals identified or predicted in Ucp1 genes across species, and discuss the potential and caution in targeting UCP1 for enhancing thermogenesis and metabolic fitness.
Factors Associated With Benefit of Treatment of Patent Ductus Arteriosus in Preterm Infants: A Systematic Review and Meta-Analysis
Authors: Jansen Esther J. S. , Hundscheid Tim , Onland Wes , Kooi Elisabeth M. W. , Andriessen Peter , de Boode Willem P.
Published: February 2021

Context:There is an ongoing debate on the optimal management of patent ductus arteriosus (PDA) in preterm infants. Identifying subgroup of infants who would benefit from pharmacological treatment might help.

Objective:To investigate the modulating effect of the differences in methodological quality, the rate of open-label treatment, and patient characteristics on relevant outcome measures in randomized controlled trials (RCTs).

Data Sources:Electronic database search between 1950 and May 2020.

Study Selection:RCTs that assessed pharmacological treatment compared to placebo/no treatment.

Data Extraction:Data is extracted following the PRISMA guidelines. Outcome measures were failure to ductal closure, surgical ligation, incidence of necrotizing enterocolitis, bronchopulmonary dysplasia, sepsis, periventricular leukomalacia, intraventricular hemorrhage (IVH) grade ≥3, retinopathy of prematurity and mortality.

Results:Forty-seven studies were eligible. The incidence of IVH grade ≥3 was lower in the treated infants compared to the placebo/no treatment (RR 0.77, 95% CI 0.64–0.94) and in the subgroups of infants with either a gestational age <28 weeks (RR 0.77, 95% CI 0.61–0.98), a birth weight <1,000 g (RR 0.77, 95% CI 0.61–0.97), or if untargeted treatment with indomethacin was started <24 h after birth (RR 0.70, 95% CI 0.54–0.90).

Limitations:Statistical heterogeneity caused by missing data and variable definitions of outcome parameters.

Conclusions:Although the quality of evidence is low, this meta-analysis suggests that pharmacological treatment of PDA reduces severe IVH in extremely preterm, extremely low birth weight infants or if treatment with indomethacin was started <24 h after birth. No other beneficial effects of pharmacological treatment were found.
Effect of Panax notoginseng Saponins on Focal Cerebral Ischemia-Reperfusion in Rat Models: A Meta-Analysis
Authors: Sun Tao , Wang Ping , Deng Ting , Tao Xingbao , Li Bin , Xu Ying
Published: February 2021

With the increase of the aging population, the high mortality and disability rates caused by ischemic stroke are some of the major problems facing the world, and they dramatically burden the society. Panax notoginseng (Burk) F. H. Chen, a traditional Chinese medicine, is commonly used for promoting blood circulation and removing blood stasis, and its main bioactive components are Panax notoginseng saponins (PNS). Therefore, we performed a meta-analysis on focal cerebral ischemia-reperfusion animal models established with middle cerebral artery occlusion (MCAO) surgery to evaluate the therapeutic effect of PNS. We systematically searched the reports of PNS in MCAO animal experiments in seven databases. We assessed the study quality using two literature quality evaluation criteria; evaluated the efficacy of PNS treatment based on the outcomes of the neurological deficit score (NDS), cerebral infarct volume (CIV), and biochemical indicators via a random/fixed-effects model; and performed a subgroup analysis utilizing ischemia duration, drug dosage, intervention time, and administration duration. We also compared the efficacy of PNS with positive control drugs or combination treatment. As a result, we selected 14 eligible studies from the 3,581 searched publications based on the predefined exclusion-inclusion criteria. PNS were significantly associated with reduced NDS, reduced CIV, and inhibited release of the inflammatory factors IL-1β and TNF-α in the focal MCAO rat models. The PNS combination therapy outperformed the PNS alone. In addition, ischemia time, drug dosage, intervention time, and administration duration in the rat models all had significant effects on the efficacy of PNS. Although more high-quality studies are needed to further determine the clinical efficacy and guiding parameters of PNS, our results also confirmed that PNS significantly relieves the focal cerebral ischemia-reperfusion in rat models. In the animal trials, it was suggested that an early intervention had significant efficacy with PNS alone or PNS combination treatment at a dosage lower than 25 mg/kg or 100–150 mg/kg for 4 days or longer. These findings further guide the therapeutic strategy for clinical cerebral ischemic stroke.
Deletion of Orphan G Protein-Coupled Receptor GPR37L1 in Mice Alters Cardiovascular Homeostasis in a Sex-Specific Manner
Authors: Mouat Margaret A. , Jackson Kristy L. , Coleman James L. J. , Paterson Madeleine R. , Graham Robert M. , Head Geoffrey A. , Smith Nicola J.
Published: February 2021

GPR37L1 is a family A orphan G protein-coupled receptor (GPCR) with a putative role in blood pressure regulation and cardioprotection. In mice, genetic ablation of Gpr37l1 causes sex-dependent effects; female mice lacking Gpr37l1 (GPR37L1−/−) have a modest but significant elevation in blood pressure, while male GPR37L1−/− mice are more susceptible to cardiovascular dysfunction following angiotensin II-induced hypertension. Given that this receptor is highly expressed in the brain, we hypothesize that the cardiovascular phenotype of GPR37L1−/− mice is due to changes in autonomic regulation of blood pressure and heart rate. To investigate this, radiotelemetry was employed to characterize baseline cardiovascular variables in GPR37L1−/− mice of both sexes compared to wildtype controls, followed by power spectral analysis to quantify short-term fluctuations in blood pressure and heart rate attributable to alterations in autonomic homeostatic mechanisms. Additionally, pharmacological ganglionic blockade was performed to determine vasomotor tone, and environmental stress tests were used to assess whether cardiovascular reactivity was altered in GPR37L1−/− mice. We observed that mean arterial pressure was significantly lower in female GPR37L1−/− mice compared to wildtype counterparts, but was unchanged in male GPR37L1−/− mice. GPR37L1−/− genotype had a statistically significant positive chronotropic effect on heart rate across both sexes when analyzed by two-way ANOVA. Power spectral analysis of these data revealed a reduction in power in the heart rate spectrum between 0.5 and 3 Hz in female GPR37L1−/− mice during the diurnal active period, which indicates that GPR37L1−/− mice may have impaired cardiac vagal drive. GPR37L1−/− mice of both sexes also exhibited attenuated depressor responses to ganglionic blockade with pentolinium, indicating that GPR37L1 is involved in maintaining sympathetic vasomotor tone. Interestingly, when these mice were subjected to aversive and appetitive behavioral stressors, the female GPR37L1−/− mice exhibited an attenuation of cardiovascular reactivity to aversive, but not appetitive, environmental stimuli. Together, these results suggest that loss of GPR37L1 affects autonomic maintenance of blood pressure, giving rise to sex-specific cardiovascular changes in GPR37L1−/− mice.
Fructose and Non-Alcoholic Steatohepatitis
Authors: Roeb Elke , Weiskirchen Ralf
Published: February 2021

Background: The excessive consumption of free sugars is mainly responsible for the high prevalence of obesity and metabolic syndrome in industrialized countries. More and more studies indicate that fructose is involved in the pathophysiology and also in the degree of disease of non-alcoholic fatty liver disease (NAFLD). In epidemiologic studies, energy-adjusted higher fructose consumption correlates with NAFLD in overweight adults. In addition to glucose, fructose, as an equivalent component of conventional household sugar, appears to have negative metabolic effects in particular due to its exclusive hepatic metabolism. Liver-related mortality is strictly associated with the degree of fibrosis, whereas the most common cause of death in patients suffering from NAFLD and non-alcoholic steatohepatitis (NASH) are still cardiovascular diseases. In this review article, we have summarized the current state of knowledge regarding a relationship between fructose consumption, liver fibrosis and life expectancy in NASH.

Method: Selective literature search in PubMed using the keywords ‘non-alcoholic fatty liver’, ‘fructose’, and ‘fibrosis’ was conducted.

Results: The rate of overweight and obesity is significantly higher in both, adult and pediatric NASH patients. The consumption of free sugars is currently three times the maximum recommended amount of 10% of the energy intake. The current literature shows weight gain, negative effects on fat and carbohydrate metabolism and NASH with hypercaloric intake of fructose.

Conclusions: Excessive fructose consumption is associated with negative health consequences. Whether this is due to an excess of energy or the particular metabolism of fructose remains open with the current study situation. The urgently needed reduction in sugar consumption could be achieved through a combination of binding nutritional policy measures including taxation of sugary soft drinks. Previous studies suggest that diet-related fructose intake exceeding the amount contained in vegetables and fruits lead to an increase of hepatic lipogenesis. Thus, further studies to clarify the protective contribution of low-fructose intake to positively influence NAFLD in industrial population are urgently required.
Inhibition of Small-Conductance Calcium-Activated Potassium Current (IK,Ca) Leads to Differential Atrial Electrophysiological Effects in a Horse Model of Persistent Atrial Fibrillation
Authors: Fenner Merle Friederike , Gatta Giulia , Sattler Stefan , Kuiper Marion , Hesselkilde Eva Melis , Adler Ditte M. T. , Smerup Morten , Schotten Ulrich , Sørensen Ulrik , Diness Jonas Goldin , Jespersen Thomas , Verheule Sander , Van Hunnik Arne , Buhl Rikke
Published: February 2021

Background

Small-conductance Ca2+-activated K+ (KCa2) channels have been proposed as a possible atrial-selective target to pharmacologically terminate atrial fibrillation (AF) and to maintain sinus rhythm. However, it has been hypothesized that the importance of the KCa2 current—and thereby the efficacy of small-conductance Ca2+-activated K+ current (IK,Ca) inhibition—might be negatively related to AF duration and the extent of AF-induced remodeling.

Experimental Approach and Methods

To address the hypothesis of the efficacy of IK,Ca inhibition being dependent on AF duration, the anti-arrhythmic properties of the IK,Ca inhibitor NS8593 (5 mg/kg) and its influence on atrial conduction were studied using epicardial high-density contact mapping in horses with persistent AF. Eleven Standardbred mares with tachypacing-induced persistent AF (42 ± 5 days of AF) were studied in an open-chest experiment. Unipolar AF electrograms were recorded and isochronal high-density maps analyzed to allow for the reconstruction of wave patterns and changes in electrophysiological parameters, such as atrial conduction velocity and AF cycle length. Atrial anti-arrhythmic properties and adverse effects of NS8593 on ventricular electrophysiology were evaluated by continuous surface ECG monitoring.

Results

IK,Ca inhibition by NS8593 administered intravenously had divergent effects on right and left AF complexity and propagation properties in this equine model of persistent AF. Despite global prolongation of AF cycle length, a slowing of conduction in the right atrium led to increased anisotropy and electrical dissociation, thus increasing AF complexity. In contrast, there was no significant change in AF complexity in the LA, and cardioversion of AF was not achieved.

Conclusions

Intra-atrial heterogeneity in response to IK,Ca inhibition by NS8593 was observed. The investigated dose of NS8593 increased the AF cycle length but was not sufficient to induce cardioversion. In terms of propagation properties during AF, IK,Ca inhibition by NS8593 led to divergent effects in the right and left atrium. This divergent behavior may have impeded the cardioversion success.
Evaluation of the Potential Use of a Collagen-Based Protein Hydrolysate as a Plant Multi-Stress Protectant
Authors: Ambrosini Stefano , Sega Davide , Santi Chiara , Zamboni Anita , Varanini Zeno , Pandolfini Tiziana
Published: February 2021

Protein hydrolysates (PHs) are a class of plant biostimulants used in the agricultural practice to improve crop performance. In this study, we have assessed the capacity of a commercial PH derived from bovine collagen to mitigate drought, hypoxic, and Fe deficiency stress in Zea mays. As for the drought and hypoxic stresses, hydroponically grown plants treated with the PH exhibited an increased growth and absorption area of the roots compared with those treated with inorganic nitrogen. In the case of Fe deficiency, plants supplied with the PH mixed with FeCl3 showed a faster recovery from deficiency compared to plants supplied with FeCl3 alone or with FeEDTA, resulting in higher SPAD values, a greater concentration of Fe in the leaves and modulation in the expression of genes related to Fe. Moreover, through the analysis of circular dichroism spectra, we assessed that the PH interacts with Fe in a dose-dependent manner. Various hypothesis about the mechanisms of action of the collagen-based PH as stress protectant particularly in Fe-deficiency, are discussed.
Apriori Algorithm for the Data Mining of Global Cyberspace Security Issues for Human Participatory Based on Association Rules
Authors: Li Zhi , Li Xuyu , Tang Runhua , Zhang Lin
Published: February 2021

This study explored the global cyberspace security issues, with the purpose of breaking the stereotype of people’s cognition of cyberspace problems, which reflects the relationship between interdependence and association. Based on the Apriori algorithm in association rules, a total of 181 strong rules were mined from 40 target websites and 56,096 web pages were associated with global cyberspace security. Moreover, this study analyzed support, confidence, promotion, leverage, and reliability to achieve comprehensive coverage of data. A total of 15,661 sites mentioned cyberspace security-related words from the total sample of 22,493 professional websites, accounting for 69.6%, while only 735 sites mentioned cyberspace security-related words from the total sample of 33,603 non-professional sites, accounting for 2%. Due to restrictions of language, the number of samples of target professional websites and non-target websites is limited. Meanwhile, the number of selections of strong rules is not satisfactory. Nowadays, the cores of global cyberspace security issues include internet sovereignty, cyberspace security, cyber attack, cyber crime, data leakage, and data protection.
How Family's Support of Perseverance in Creative Efforts Influences the Originality of Children's Drawing During the Period of COVID-19 Pandemic?
Authors: Shi Bowen , Xing Ziwei , Yang Mei , Tang Chaoying
Published: February 2021

This study points out that families' support of perseverance in creative efforts will increase children's originality of creative drawing through children's persistence in information searching. Data analysis based on 134 Chinese young children's creative drawings and survey supports the above hypothesis. Moreover, children's exposure to COVID-19 pandemic positively moderates the relationship between supporting perseverance and children's search persistence, such that high exposure to COVID-19 pandemic will increase the positive relationship between support of perseverance and search persistence. And children's prosocial motivation inhibits the influence of search persistence on originality. Contributions to the theory of children's creativity are discussed.
Does Workplace Bullying Produce Employee Voice and Physical Health Issues? Testing the Mediating Role of Emotional Exhaustion
Authors: Liang Huai-Liang
Published: February 2021

Workplace bullying is a reality in organizations. Employees’ experiences of workplace bullying can produce their voice that intends to challenge the status quo at work and can damage their physical health. This study examines the effects of workplace bullying on employee voice and physical health issues and considers individuals’ emotional reactions as a critical mechanism operating between workplace bullying and its consequences in workplace situations. Emotional exhaustion mediates the influence of workplace bullying on employee voice and damaged health. Data for 694 employees from a large Taiwanese retail organization revealed that workplace bullying relates to its outcomes at work. The findings of this study show that emotional exhaustion is a critical mechanism between workplace bullying and its consequences, i.e., employee voice and health issues. A time-lag study design is applied to reduce common method bias.
Do We Have a Match? Assessing the Role of Community in Coworking Spaces Based on a Person-Environment Fit Framework
Authors: Lashani Eileen , Zacher Hannes
Published: February 2021

As working arrangements become more flexible and many people work remotely, the risk of social isolation rises. Coworking spaces try to prevent this by offering not only a workplace, but also a community. Adopting a person-environment fit perspective, we examined how the congruence between workers' needs and supplies by coworking spaces relate to job satisfaction and intent to leave. We identified five needs (i.e., community, collaboration, amenities, location, and cost), of which community was expected to be the central need. An online questionnaire was distributed among coworkers in Germany and Austria, resulting in a sample of 181 coworkers. Results showed that needs-supplies fit regarding community was related to job satisfaction and intent to leave in coworking spaces. Findings for the other needs, however, did not show that congruence is associated with outcomes. Overall, the findings highlight the importance of community fit in coworking and offer insights for workers and entrepreneurs in this area.