bluuebunny/crossref_metadata_2025 huggingface dataset:
Genomic and Transcriptomic Investigation of the Physiological Response of the Methylotroph Bacillus methanolicus to 5-Aminovalerate
Authors: Haupka Carsten , Brito Luciana F. , Busche Tobias , Wibberg Daniel , Wendisch Volker F.
Published: April 2021

The methylotrophic thermophile Bacillus methanolicus can utilize the non-food substrate methanol as its sole carbon and energy source. Metabolism of L-lysine, in particular its biosynthesis, has been studied to some detail, and methanol-based L-lysine production has been achieved. However, little is known about L-lysine degradation, which may proceed via 5-aminovalerate (5AVA), a non-proteinogenic ω-amino acid with applications in bioplastics. The physiological role of 5AVA and related compounds in the native methylotroph was unknown. Here, we showed that B. methanolicus exhibits low tolerance to 5AVA, but not to related short-chain (C4–C6) amino acids, diamines, and dicarboxylic acids. In order to gain insight into the physiological response of B. methanolicus to 5AVA, transcriptomic analyses by differential RNA-Seq in the presence and absence of 5AVA were performed. Besides genes of the general stress response, RNA levels of genes of histidine biosynthesis, and iron acquisition were increased in the presence of 5AVA, while an Rrf2 family transcriptional regulator gene showed reduced RNA levels. In order to test if mutations can overcome growth inhibition by 5AVA, adaptive laboratory evolution (ALE) was performed and two mutants—AVA6 and AVA10—with higher tolerance to 5AVA were selected. Genome sequencing revealed mutations in genes related to iron homeostasis, including the gene for an iron siderophore-binding protein. Overexpression of this mutant gene in the wild-type (WT) strain MGA3 improved 5AVA tolerance significantly at high Fe2+ supplementation. The combined ALE, omics, and genetics approach helped elucidate the physiological response of thermophilic B. methanolicus to 5AVA and will guide future strain development for 5AVA production from methanol.
Homogeneous Cytochrome 579 Is an Octamer That Reacts Too Slowly With Soluble Iron to Be the Initial Iron Oxidase in the Respiratory Chain of Leptospirillum ferriphilum
Authors: Blake Robert C. , Shively John E. , Timkovich Russell , White Richard Allen
Published: May 2021

The exact role that cytochrome 579 plays in the aerobic iron respiratory chain of Leptospirillum ferriphilum is unclear. This paper presents genomic, structural, and kinetic data on the cytochrome 579 purified from cell-free extracts of L. ferriphilum cultured on soluble iron. Electrospray mass spectrometry of electrophoretically homogeneous cytochrome 579 yielded two principal peaks at 16,015 and 16,141 Daltons. N-terminal amino acid sequencing of the purified protein yielded data that were used to determine the following: there are seven homologs of cytochrome 579; each homolog possesses the CXXCH heme-binding motif found in c-type cytochromes; each of the seven sequenced strains of L. ferriphilum expresses only two of the seven homologs of the cytochrome; and each homolog contains an N-terminal signal peptide that directs the mature protein to an extra-cytoplasmic location. Static light scattering and macroion mobility measurements on native cytochrome 579 yielded masses of 125 and 135 kDaltons, respectively. The reduced alkaline pyridine hemochromogen spectrum of the purified cytochrome had an alpha absorbance maximum at 567 nm, a property not exhibited by any known heme group. The iron-dependent reduction and oxidation of the octameric cytochrome exhibited positively cooperative kinetic behavior with apparent Hill coefficients of 5.0 and 3.7, respectively, when the purified protein was mixed with mM concentrations of soluble iron. Consequently, the extrapolated rates of reduction at sub-mM iron concentrations were far too slow for cytochrome 579 to be the initial iron oxidase in the aerobic respiratory chain of L. ferriphilum. Rather, these observations support the hypothesis that the acid-stable cytochrome 579 is a periplasmic conduit of electrons from initial iron oxidation in the outer membrane of this Gram-negative bacterium to a terminal oxidase in the plasma membrane.
The Second-Generation XPO1 Inhibitor Eltanexor Inhibits Human Cytomegalovirus (HCMV) Replication and Promotes Type I Interferon Response
Authors: Liao Yueyan , Ke Xiangyu , Deng Tianyi , Qin Qingsong
Published: May 2021

Human cytomegalovirus (HCMV) is a ubiquitous opportunistic pathogen and can be life-threatening for immunocompromised individuals. There is currently no available vaccine for the prevention of HCMV- associated diseases and most of the available antiviral drugs that target viral DNA synthesis become ineffective in treating HCMV mutants that arise after long-term use in immunocompromised patients. Here, we examined the effects of Eltanexor, a second-generation selective inhibitor of nuclear export (SINE), on HCMV replication. Eltanexor effectively inhibits HCMV replication in human foreskin fibroblasts in a dose-dependent manner. Eltanexor does not significantly inhibit viral entry and nuclear import of viral genomic DNA, but rather suppress the transcript and protein levels of viral immediate-early (IE), early (E) and late (L) genes, and abolishes the production of infectious virions. We further found Eltanexor treatment promotes proteasome-mediated degradation of XPO1, which contributes to the nuclear retention of interferon regulatory factor 3 (IRF-3), resulting in increased expression of type I interferon as well as interferon stimulating genes ISG15 and ISG54. This study reveals a novel antiviral mechanism of Eltanexor which suggests it has potential to inhibit a broad spectrum of viral pathogens.
USP18 Mediates Interferon Resistance of Dengue Virus Infection
Authors: Ye Haiyan , Duan Xiaoqiong , Yao Min , Kang Lan , Li Yujia , Li Shilin , Li Bin , Chen Limin
Published: April 2021

Previous studies demonstrated that dengue virus (DENV) infection developed resistance to type-I interferons (IFNα/β). The underlying mechanism remains unclear. USP18 is a negative regulator of IFNα/β signaling, and its expression level is significantly increased following DENV infection in cell lines and patients’ blood. Our previous study revealed that increased USP18 expression contributed to the IFN-α resistance of Hepatitis C Virus (HCV). However, the role of USP18 in DENV replication and resistance to IFN-α is elusive. In this current study, we aimed to explore the role of USP18 in DENV-2 replication and resistance to IFN-α. The level of USP18 was up-regulated by plasmid transfection and down-regulated by siRNA transfection in Hela cells. USP18, IFN-α, IFN-β expression, and DENV-2 replication were monitored by qRT-PCR and Western blot. The activation of the Jak/STAT signaling pathway was assessed at three levels: p-STAT1/p-STAT2 (Western blot), interferon-stimulated response element (ISRE) activity (Dual-luciferase assay), and interferon-stimulated genes (ISGs) expression (qRT-PCR). Our data showed that DENV-2 infection increased USP18 expression in Hela cells. USP18 overexpression promoted DENV-2 replication, while USP18 silence inhibited DENV-2 replication. Silence of USP18 potentiated the anti-DENV-2 activity of IFN-α through activation of the IFN-α-mediated Jak/STAT signaling pathway as shown by increased expression of p-STAT1/p-STAT2, enhanced ISRE activity, and elevated expression of some ISGs. Our data indicated that USP18 induced by DENV-2 infection is a critical host factor utilized by DENV-2 to confer antagonism on IFN-α.
Universal Architectural Concepts Underlying Protein Folding Patterns
Authors: Konagurthu Arun S. , Subramanian Ramanan , Allison Lloyd , Abramson David , Stuckey Peter J. , Garcia de la Banda Maria , Lesk Arthur M.
Published: April 2021

What is the architectural “basis set” of the observed universe of protein structures? Using information-theoretic inference, we answer this question with a dictionary of 1,493 substructures—calledconcepts—typically at a subdomain level, based on an unbiased subset of known protein structures. Eachconceptrepresents a topologically conserved assembly of helices and strands that make contact. Any protein structure can be dissected into instances of concepts from this dictionary. We dissected the Protein Data Bank and completely inventoried all the concept instances. This yields many insights, including correlations between concepts and catalytic activities or binding sites, useful for rational drug design; local amino-acid sequence–structure correlations, useful forab initiostructure prediction methods; and information supporting the recognition and exploration of evolutionary relationships, useful for structural studies. An interactive site,Proçodic, athttp://lcb.infotech.monash.edu.au/prosodic(click), provides access to and navigation of the entire dictionary of concepts and their usages, and all associated information. This report is part of a continuing programme with the goal of elucidating fundamental principles of protein architecture, in the spirit of the work of Cyrus Chothia.
Critical Involvement of TFIIB in Viral Pathogenesis
Authors: O’Brien Michael J. , Ansari Athar
Published: April 2021

Viral infections and the harm they cause to their host are a perpetual threat to living organisms. Pathogenesis and subsequent spread of infection requires replication of the viral genome and expression of structural and non-structural proteins of the virus. Generally, viruses use transcription and translation machinery of the host cell to achieve this objective. The viral genome encodes transcriptional regulators that alter the expression of viral and host genes by manipulating initiation and termination steps of transcription. The regulation of the initiation step is often through interactions of viral factors with gene specific factors as well as general transcription factors (GTFs). Among the GTFs, TFIIB (Transcription Factor IIB) is a frequent target during viral pathogenesis. TFIIB is utilized by a plethora of viruses including human immunodeficiency virus, herpes simplex virus, vaccinia virus, Thogoto virus, hepatitis virus, Epstein-Barr virus and gammaherpesviruses to alter gene expression. A number of viral transcriptional regulators exhibit a direct interaction with host TFIIB in order to accomplish expression of their genes and to repress host transcription. Some viruses have evolved proteins with a three-dimensional structure very similar to TFIIB, demonstrating the importance of TFIIB for viral persistence. Upon viral infection, host transcription is selectively altered with viral transcription benefitting. The nature of viral utilization of TFIIB for expression of its own genes, along with selective repression of host antiviral genes and downregulation of general host transcription, makes TFIIB a potential candidate for antiviral therapies.
Collective Dynamics of Neural Networks With Sleep-Related Biological Drives in Drosophila
Authors: Qiu Shuihan , Sun Kaijia , Di Zengru
Published: May 2021

The collective electrophysiological dynamics of the brain as a result of sleep-related biological drives in Drosophila are investigated in this paper. Based on the Huber-Braun thermoreceptor model, the conductance-based neurons model is extended to a coupled neural network to analyze the local field potential (LFP). The LFP is calculated by using two different metrics: the mean value and the distance-dependent LFP. The distribution of neurons around the electrodes is assumed to have a circular or grid distribution on a two-dimensional plane. Regardless of which method is used, qualitatively similar results are obtained that are roughly consistent with the experimental data. During wake, the LFP has an irregular or a regular spike. However, the LFP becomes regular bursting during sleep. To further analyze the results, wavelet analysis and raster plots are used to examine how the LFP frequencies changed. The synchronization of neurons under different network structures is also studied. The results demonstrate that there are obvious oscillations at approximately 8 Hz during sleep that are absent during wake. Different time series of the LFP can be obtained under different network structures and the density of the network will also affect the magnitude of the potential. As the number of coupled neurons increases, the neural network becomes easier to synchronize, but the sleep and wake time described by the LFP spectrogram do not change. Moreover, the parameters that affect the durations of sleep and wake are analyzed.
Neural Mechanisms of Reward-by-Cueing Interactions: ERP Evidence
Authors: Li Xian , Zhang Meichen , Wu Lulu , Zhang Qin , Wei Ping
Published: May 2021

Inhibition of return (IOR) refers to the phenomenon that a person is slower to respond to targets at a previously cued location. The present study aimed to explore whether target-reward association is subject to IOR, using event-related potentials (ERPs) to explore the underlying neural mechanism. Each participant performed a localization task and a color discrimination task in an exogenous cueing paradigm, with the targets presented in colors (green/red) previously associated with high- or low-reward probability. The results of both tasks revealed that the N1, Nd, and P3 components exhibited differential amplitudes between cued and uncued trials (i.e., IOR) under low reward, with the N1 and Nd amplitudes being enhanced for uncued trials compared to cued trials, and the P3 amplitude being enhanced for cued trials vs. uncued trials. Under high reward, however, no difference was found between the amplitudes on cued and uncued trials for any of the components. These findings demonstrate that targets that were previously associated with high reward can be resistant to IOR and the current results enrich the evidence for interactions between reward-association and attentional orientation in the cueing paradigm.
Tremor-Suppression Orthoses for the Upper Limb: Current Developments and Future Challenges
Authors: Nguyen Hoai Son , Luu Trieu Phat
Published: April 2021

Introduction: Pathological tremor is the most common motor disorder in adults and characterized by involuntary, rhythmic muscular contraction leading to shaking movements in one or more parts of the body. Functional Electrical Stimulation (FES) and biomechanical loading using wearable orthoses have emerged as effective and non-invasive methods for tremor suppression. A variety of upper-limb orthoses for tremor suppression have been introduced; however, a systematic review of the mechanical design, algorithms for tremor extraction, and the experimental design is still missing.

Methods: To address this gap, we applied a standard systematic review methodology to conduct a literature search in the PubMed and PMC databases. Inclusion criteria and full-text access eligibility were used to filter the studies from the search results. Subsequently, we extracted relevant information, such as suppression mechanism, system weights, degrees of freedom (DOF), algorithms for tremor estimation, experimental settings, and the efficacy.

Results: The results show that the majority of tremor-suppression orthoses are active with 47% prevalence. Active orthoses are also the heaviest with an average weight of 561 ± 467 g, followed by semi-active 486 ± 395 g, and passive orthoses 191 ± 137 g. Most of the orthoses only support one DOF (54.5%). Two-DOF and three-DOF orthoses account for 33 and 18%, respectively. The average efficacy of tremor suppression using wearable orthoses is 83 ± 13%. Active orthoses are the most efficient with an average efficacy of 83 ± 8%, following by the semi-active 77 ± 19%, and passive orthoses 75 ± 12%. Among different experimental setups, bench testing shows the highest efficacy at 95 ± 5%, this value dropped to 86 ± 8% when evaluating with tremor-affected subjects. The majority of the orthoses (92%) measured voluntary and/or tremorous motions using biomechanical sensors (e.g., IMU, force sensor). Only one system was found to utilize EMG for tremor extraction.

Conclusions: Our review showed an improvement in efficacy of using robotic orthoses in tremor suppression. However, significant challenges for the translations of these systems into clinical or home use remain unsolved. Future challenges include improving the wearability of the orthoses (e.g., lightweight, aesthetic, and soft structure), and user control interfaces (i.e., neural machine interface). We also suggest addressing non-technical challenges (e.g., regulatory compliance, insurance reimbursement) to make the technology more accessible.
Contrasting Electroencephalography-Derived Entropy and Neural Oscillations With Highly Skilled Meditators
Authors: Young Jacob H. , Arterberry Martha E. , Martin Joshua P.
Published: April 2021

Meditation is an umbrella term for a number of mental training practices designed to improve the monitoring and regulation of attention and emotion. Some forms of meditation are now being used for clinical intervention. To accompany the increased clinical interest in meditation, research investigating the neural basis of these practices is needed. A central hypothesis of contemplative neuroscience is that meditative states, which are unique on a phenomenological level, differ on a neurophysiological level. To identify the electrophysiological correlates of meditation practice, the electrical brain activity of highly skilled meditators engaging in one of six meditation styles (shamatha, vipassana, zazen, dzogchen, tonglen, and visualization) was recorded. A mind-wandering task served as a control. Lempel–Ziv complexity showed differences in nonlinear brain dynamics (entropy) during meditation compared with mind wandering, suggesting that meditation, regardless of practice, affects neural complexity. In contrast, there were no differences in power spectra at six different frequency bands, likely due to the fact that participants engaged in different meditation practices. Finally, exploratory analyses suggest neurological differences among meditation practices. These findings highlight the importance of studying the electroencephalography (EEG) correlates of different meditative practices.
Dissociating Sensorimotor Recovery and Compensation During Exoskeleton Training Following Stroke
Authors: Nibras Nadir , Liu Chang , Mottet Denis , Wang Chunji , Reinkensmeyer David , Remy-Neris Olivier , Laffont Isabelle , Schweighofer Nicolas
Published: April 2021

The quality of arm movements typically improves in the sub-acute phase of stroke affecting the upper extremity. Here, we used whole arm kinematic analysis during reaching movements to distinguish whether these improvements are due to true recovery or to compensation. Fifty-three participants with post-acute stroke performed ∼80 reaching movement tests during 4 weeks of training with the ArmeoSpring exoskeleton. All participants showed improvements in end-effector performance, as measured by movement smoothness. Four ArmeoSpring angles, shoulder horizontal (SH) rotation, shoulder elevation (SE), elbow rotation, and forearm rotation, were recorded and analyzed. We first characterized healthy joint coordination patterns by performing a sparse principal component analysis on these four joint velocities recorded during reaching tests performed by young control participants. We found that two dominant joint correlations [SH with elbow rotation and SE with forearm rotation] explained over 95% of variance of joint velocity data. We identified two clusters of stroke participants by comparing the evolution of these two correlations in all tests. In the “Recoverer” cluster (N = 19), both joint correlations converged toward the respective correlations for control participants. Thus, Recoverers relearned how to generate smooth end-effector movements while developing joint movement patterns similar to those of control participants. In the “Compensator” cluster (N = 34), at least one of the two joint correlations diverged from the corresponding correlation of control participants. Compensators relearned how to generate smooth end-effector movements by discovering various new compensatory movement patterns dissimilar to those of control participants. New compensatory patterns included atypical decoupling of the SE and forearm joints, and atypical coupling of the SH rotation and elbow joints. There was no difference in clinical impairment level between the two groups either at the onset or at the end of training as assessed with the Upper Extremity Fugl-Meyer scale. However, at the start of training, the Recoverers showed significantly faster improvements in end-effector movement smoothness than the Compensators. Our analysis can be used to inform neurorehabilitation clinicians on how to provide movement feedback during practice and suggest avenues for refining exoskeleton robot therapy to reduce compensatory patterns.
A Close Examination of the Use of Systolic Time Intervals in the Calculation of Impedance Derived Cardiac Autonomic Balance and Regulation
Authors: Wiley Cameron R. , Pourmand Vida , Thayer Julian F. , Williams DeWayne P.
Published: April 2021

Traditionally, impedance derived measures of cardiac autonomic balance (CAB) and regulation (CAR) are calculated using indices of heart rate variability (HRV) that primarily reflect parasympathetic nervous system activity (e.g., high-frequency HRV | HF-HRV) and pre-ejection period (PEP; a systolic time interval and measure of sympathetic activity). However, HF-HRV and PEP are considered measures of chronotropic and inotropic cardiac influence, respectively. Left ventricular ejection time (LVET) is a systolic time interval that reflects sympathetic chronotropic influence, and therefore may be a more appropriate measure for calculating CAB and CAR compared to PEP. Thus, the current study evaluates both PEP and LVET in the calculation of CAB and CAR. Data from 158 healthy participants (mean age = 19.09 years old, SD = 1.84 years) were available for analyses. CAB and CAR values were calculated using both HF-HRV and the root mean square of successive differences, in addition to both PEP and LVET, in accordance with previously established guidelines. Analyses showed that correlations were significantly weaker between CAB and CAR calculated using LVET for both HF (z = 5.12, p < 0.001) and RMSSD (z = 5.26, p < 0.001) than with PEP. These data suggest that LVET, compared to PEP, provides better “autonomic space” as evidenced by a lack of correlation between CAB and CAR computed using LVET. We stress that future research consider calculating CAB and CAR using chronotropic measures for both parasympathetic and sympathetic activity, as doing so may yield more accurate and independent measures of cardiac autonomic activity compared to a mixture of inotropic (i.e., PEP) and chronotropic (i.e., HF-HRV) measures.
The Clinical Effect of Repetitive Transcranial Magnetic Stimulation on the Disturbance of Consciousness in Patients in a Vegetative State
Authors: Zhang Xiao-Hua , Han Ping , Zeng Yuan-Yuan , Wang Yu-Long , Lv Hui-Lan
Published: April 2021

Objective

To explore the effect of combining repetitive transcranial magnetic stimulation (rTMS) and conventional rehabilitation on the recovery of consciousness in patients in a persistent vegetative state (PVS).

Methods

A total of 48 patients in a PVS were randomly divided into a treatment and control group. Patients in the treatment group were treated with rTMS to stimulate the dorsolateral prefrontal cortex, and patients in the control group were treated with false stimulation. All patients were evaluated using scales and neuroelectrophysiological assessment before treatment, after 30 days of treatment, and following 60 days of treatment.

Results

Based on the Coma Recovery Scale-Revised (CRS-R) and electroencephalogram (EEG) grading indexes, the treatment group was significantly higher than those of the control group after 30 and 60 days of treatment. The average difference in the three measurements between the two groups before treatment, at 30 days, and 60 days was 0.04, 1.54, and 2.09 for CRS-R and 0.08, −0.83, and −0.62 for EEG indexes, respectively. The latency periods of each wave of the brainstem auditory evoked potentials (BAEPs) in the treatment group were shorter than those in the control group after 30 and 60 days of treatment. In both groups, the BAEP scores after 30 days of treatment were significantly higher than the scores before treatment, and the scores after 60 days of treatment were higher than the scores after 30 days.

Conclusion

In patients in a PVS, rTMS assists in the recovery of consciousness function.
Increased Resting-State Interhemispheric Functional Connectivity of Posterior Superior Temporal Gyrus and Posterior Cingulate Cortex in Congenital Amusia
Authors: Jin Zhishuai , Huyang Sizhu , Jiang Lichen , Yan Yajun , Xu Ming , Wang Jinyu , Li Qixiong , Wu Daxing
Published: April 2021

Interhemispheric connectivity of the two cerebral hemispheres is crucial for a broad repertoire of cognitive functions including music and language. Congenital amusia has been reported as a neurodevelopment disorder characterized by impaired music perception and production. However, little is known about the characteristics of the interhemispheric functional connectivity (FC) in amusia. In the present study, we used a newly developed voxel-mirrored homotopic connectivity (VMHC) method to investigate the interhemispheric FC of the whole brain in amusia at resting-state. Thirty amusics and 29 matched participants underwent a resting-state functional magnetic resonance imaging (fMRI) scanning. An automated VMHC approach was used to analyze the fMRI data. Compared to the control group, amusics showed increased VMHC within the posterior part of the default mode network (DMN) mainly in the posterior superior temporal gyrus (pSTG) and posterior cingulate cortex (PCC). Correlation analyses revealed negative correlations between the VMHC value in pSTG/PCC and the music perception ability among amusics. Further ROC analyses showed that the VMHC value of pSTG/PCC showed a good sensibility/specificity to differentiate the amusics from the controls. These findings provide a new perspective for understanding the neural basis of congenital amusia and imply the immature state of DMN may be a credible neural marker of amusia.
Novel Insight Into the Role of Immune Dysregulation in Amyotrophic Lateral Sclerosis Based on Bioinformatic Analysis
Authors: Xie Yongzhi , Luo Ximei , He Haiqing , Tang Min
Published: April 2021

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the progressive degeneration of motor neurons. The causative pathogenic mechanisms in ALS remain unclear, limiting the development of treatment strategies. Neuroinflammation and immune dysregulation were involved in the disease onset and progression of several neurodegenerative disorders, including ALS. In this study, we carried out a bioinformatic analysis using publicly available datasets from Gene Expression Omnibus (GEO) to investigate the role of immune cells and genes alterations in ALS. Single-sample gene set enrichment analysis revealed that the infiltration of multiple types of immune cells, including macrophages, type-1/17 T helper cells, and activated CD4 + /CD8 + T cells, was higher in ALS patients than in controls. Weighted gene correlation network analysis identified immune genes associated with ALS. The Gene Ontology analysis revealed that receptor and cytokine activities were the most highly enriched terms. Pathway analysis showed that these genes were enriched not only in immune-related pathways, such as cytokine-cytokine receptor interaction, but also in PI3K-AKT and MAPK signaling pathways. Nineteen immune-related genes (C3AR1,CCR1,CCR5,CD86,CYBB,FCGR2B,FCGR3A,HCK,ITGB2,PTPRC,TLR1,TLR2,TLR7,TLR8,TYROBP,VCAM1,CD14,CTSS, andFCER1G) were identified as hub genes based on least absolute shrinkage and selection operator analysis. This gene signature could differentiate ALS patients from non-neurological controls (p< 0.001) and predict disease occurrence (AUC = 0.829 in training set; AUC = 0.862 in test set). In conclusion, our study provides potential biomarkers of ALS for disease diagnosis and therapeutic monitoring.
Auricular Vagus Neuromodulation—A Systematic Review on Quality of Evidence and Clinical Effects
Authors: Verma Nishant , Mudge Jonah D. , Kasole Maïsha , Chen Rex C. , Blanz Stephan L. , Trevathan James K. , Lovett Eric G. , Williams Justin C. , Ludwig Kip A.
Published: April 2021

Background: The auricular branch of the vagus nerve runs superficially, which makes it a favorable target for non-invasive stimulation techniques to modulate vagal activity. For this reason, there have been many early-stage clinical trials on a diverse range of conditions. These trials often report conflicting results for the same indication.

Methods: Using the Cochrane Risk of Bias tool we conducted a systematic review of auricular vagus nerve stimulation (aVNS) randomized controlled trials (RCTs) to identify the factors that led to these conflicting results. The majority of aVNS studies were assessed as having “some” or “high” risk of bias, which makes it difficult to interpret their results in a broader context.

Results: There is evidence of a modest decrease in heart rate during higher stimulation dosages, sometimes at above the level of sensory discomfort. Findings on heart rate variability conflict between studies and are hindered by trial design, including inappropriate washout periods, and multiple methods used to quantify heart rate variability. There is early-stage evidence to suggest aVNS may reduce circulating levels and endotoxin-induced levels of inflammatory markers. Studies on epilepsy reached primary endpoints similar to previous RCTs testing implantable vagus nerve stimulation therapy. Preliminary evidence shows that aVNS ameliorated pathological pain but not evoked pain.

Discussion: Based on results of the Cochrane analysis we list common improvements for the reporting of results, which can be implemented immediately to improve the quality of evidence. In the long term, existing data from aVNS studies and salient lessons from drug development highlight the need for direct measures of local neural target engagement. Direct measures of neural activity around the electrode will provide data for the optimization of electrode design, placement, and stimulation waveform parameters to improve on-target engagement and minimize off-target activation. Furthermore, direct measures of target engagement, along with consistent evaluation of blinding success, must be used to improve the design of controls—a major source of concern identified in the Cochrane analysis. The need for direct measures of neural target engagement and consistent evaluation of blinding success is applicable to the development of other paresthesia-inducing neuromodulation therapies and their control designs.
How Native Background Affects Human Performance in Real-World Visual Object Detection: An Event-Related Potential Study
Authors: Wang Yue , Yan Jianpu , Yin Zhongliang , Ren Shenghan , Dong Minghao , Zheng Changli , Zhang Wei , Liang Jimin
Published: April 2021

Visual processing refers to the process of perceiving, analyzing, synthesizing, manipulating, transforming, and thinking of visual objects. It is modulated by both stimulus-driven and goal-directed factors and manifested in neural activities that extend from visual cortex to high-level cognitive areas. Extensive body of studies have investigated the neural mechanisms of visual object processing using synthetic or curated visual stimuli. However, synthetic or curated images generally do not accurately reflect the semantic links between objects and their backgrounds, and previous studies have not provided answers to the question of how the native background affects visual target detection. The current study bridged this gap by constructing a stimulus set of natural scenes with two levels of complexity and modulating participants' attention to actively or passively attend to the background contents. Behaviorally, the decision time was elongated when the background was complex or when the participants' attention was distracted from the detection task, and the object detection accuracy was decreased when the background was complex. The results of event-related potentials (ERP) analysis explicated the effects of scene complexity and attentional state on the brain responses in occipital and centro-parietal areas, which were suggested to be associated with varied attentional cueing and sensory evidence accumulation effects in different experimental conditions. Our results implied that efficient visual processing of real-world objects may involve a competition process between context and distractors that co-exist in the native background, and extensive attentional cues and fine-grained but semantically irrelevant scene information were perhaps detrimental to real-world object detection.
Association of Disinhibited Eating and Trait of Impulsivity With Insula and Amygdala Responses to Palatable Liquid Consumption
Authors: Nakamura Yuko , Koike Shinsuke
Published: May 2021

Eating behavior is not only influenced by the current energy balance, but also by the behavioral characteristics of eating. One of the recognized eating behavior constructs is ‘disinhibited eating,’ which refers to the tendency to overeat in response to negative emotional states or the presence of highly palatable foods. Food-related disinhibition is involved in binge eating, weight gain, and obesity and is also associated with the trait of impulsivity, which in turn, is linked to weight gain or maladaptive eating. However, the relationships among food-related disinhibition, the trait of impulsivity, and the neural substrates of eating behaviors in adolescence remain unclear. Therefore, we designed a functional magnetic resonance imaging (fMRI) study to examine the associations between brain responses to palatable liquid consumption and disinhibited eating behavior or impulsivity in healthy adolescents. Thirty-four adolescents (mean age ± standard deviation = 17.12 ± 1.91 years, age range = 14–19 years, boys = 15, girls = 19) participated in this study. Disinhibited eating was assessed with the disinhibition subscale of the Three-Factor Eating Questionnaire, while impulsivity was assessed using the Barratt impulsiveness scale. Participants received two fMRI sessions−a palatable liquid consumption fMRI and a resting-state fMRI. The fMRI experiment showed that increased disinhibited eating was positively associated with a greater insular response to palatable liquid consumption, while increased impulsivity was positively correlated with a greater amygdala response. The resting-state fMRI experiment showed that increased disinhibited eating was positively correlated with strengthened intrinsic functional connectivity between the insula and the amygdala, adjusting for sex (estimates of the beta coefficients = 0.146, standard error = 0.068, p = 0.040). Given that the amygdala and insular cortex are structurally and functionally connected and involved in trait impulsivity and ingestive behavior, our findings suggest that increased disinhibited eating would be associated with impulsivity via strengthened intrinsic functional connectivity between the insula and amygdala and linked to maladaptive eating.
Comparison of Antioxidant and Antibacterial Activities of Camellia Oil From Hainan With Camellia Oil From Guangxi, Olive Oil, and Peanut Oil
Authors: Wang Lanying , Ahmad Shakil , Wang Xi , Li Hua , Luo Yanping
Published: May 2021

Background/Aim: Camellia oil from Hainan (SY) is a unique vegetable oil in Hainan, China, due to the geographical environment and oil extraction only through simple physical treatments. To compare SY with camellia oil from Guangxi (SC), olive oil (GL), and peanut oil (HS), this study analyzed the antioxidant and antibacterial activity of four vegetable oils.

Methods: Using Gallic acid, BHT as the control, Saccharomyces cerevisiae as the model organism, the antioxidant activities of vegetable oils were measured in vitro and in vivo, and the antibacterial activity was measured with the minimum inhibitory concentration (MIC) method.

Results: The major contents of SY, SC, and HS were oleic Acid; the major content of GL was squalene. The highest total flavonoids content of SY was 39.50 ± 0.41 mg RE/g DW; and the highest total phenolic content of SC was 47.05 ± 0.72 mg GAE/g DW. SY exhibited the strongest scavenging activity of hydroxyl radical (HO·) and superoxide anions (O2-·), the IC50 value were 2.06 mg/mL, 0.62 mg/mL, respectively; and SC showed the strongest DPPH· and ABTS· scavenging activity and the reducing abilities. SY showed excellent effect on survival rate, protection rate, flavonoids uptake of S. cerevisiae cells, decreased MDA content and ROS level, inhibited CAT, POD, and GR enzyme activity. The absorption of SC total phenols was the highest by cells. The activity showed GL had a broad-spectrum antibacterial activity.

Conclusion: Thus, SY shows potential antioxidant activity and provides an important reference value for people to choose edible vegetable oils.
Efficacy and Safety of Pyrotinib Versus T-DM1 in HER2+ Metastatic Breast Cancer Patients Pre-Treated With Trastuzumab and a Taxane: A Bayesian Network Meta-Analysis
Authors: Liao Hao , Huang Wenfa , Liu Yaxin , Pei Wendi , Li Huiping
Published: May 2021

Purpose

To compare the efficacy and safety between pyrotinib (Pyr) and trastuzumab emtansine (T-DM1) in pre-treated human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (MBC) patients.

Methods

A comprehensive literature search of the PubMed, EMBASE, and Web of Science was performed in August 2020. Randomized clinical trials comparing the efficacy and safety between different anti-HER2 regimens in patients pre-treated with trastuzumab (Tra) and a taxane in metastatic settings (≤second-line treatment) were included. A fixed effects network meta-analysis based on the Bayesian inferential framework was conducted for progression-free survival (PFS), overall survival (OS), overall response rate (ORR), and grade ≥3 adverse events (AEs). Values of surface under cumulative ranking probability curve (SUCRA) were calculated to offer a ranking of all regimens.

Results

Twelve studies with 4,353 subjects were identified. Nine regimens were included into the network: T-DM1, lapatinib-capecitabine (Lap-Cap), Tra-Cap, Cap, neratinib (Ner), pertuzumab (Per)-Tra-Cap, Pyr-Cap, atezolizumab (Ate)-T-DM1, and Ner-Cap. For PFS, Pyr-Cap was more favorable than T-DM1 (hazard ratio, 95% confidence interval: 0.77, 0.70–0.86), Lap-Cap (0.64, 0.59–0.69), Tra-Cap (0.63, 0.56–0.70), Cap (0.50, 0.45–0.56), Ner (0.59, 0.51–0.69), Per-Tra-Cap (0.68, 0.59–0.79), and Ner-Cap (0.72, 0.64–0.81). For OS, Pyr-Cap showed further improvement than Lap-Cap (hazard ratio, 95% confidence interval: 0.71, 0.52–0.99), Cap (0.68, 0.49–0.96), and Ner (0.65, 0.45–0.94). For ORR, Pyr-Cap was significantly superior than Cap (odds ratio, 95% confidence interval: 7.87, 1.22–56.51). No significant difference was observed in grade ≥3 AEs among all the regimens. Pyr-Cap ranked in the highest in PFS, OS, ORR, and grade ≥3 AEs (SUCRA = 99.4, 89.7, 86.4, and 89.3%).

Conclusions

These results indicate that Pyr may be more effective than T-DM1 in HER2+ MBC patients pre-treated with Tra and a taxane. However, it may be associated with more grade ≥3 AEs.
An Exploration of the Tumor Microenvironment Identified a Novel Five-Gene Model for Predicting Outcomes in Bladder Cancer
Authors: Li Xinjie , Feng Jiahao , Sun Yazhou , Li Xin
Published: May 2021

Bladder cancer (BC) is one of the top ten most common cancer types globally, accounting for approximately 7% of all male malignancies. In the last few decades, cancer research has focused on identifying oncogenes and tumor suppressors. Recent studies have revealed that the interplay between tumor cells and the tumor microenvironment (TME) plays an important role in the initiation and development of cancer. However, the current knowledge regarding its effect on BC is scarce. This study aims to explore how the TME influences the development of BC. We focused on immune and stromal components, which represent the major components of TME. We found that the proportion of immune and stromal components within the TME was associated with the prognosis of BC. Furthermore, based on the scores of immune and stromal components, 811 TME-related differentially expressed genes were identified. Three subclasses with distinct biological features were divided based on these TME-genes. Finally, five prognostic genes were identified and used to develop a prognostic prediction model for BC patients based on TME-related genes. Additionally, we validated the prognostic value of the five-gene model using three independent cohorts. By further analyzing features based on the five-gene signature, higher CD8+ T cells, higher tumor mutational burden, and higher chemosensitivity were found in the low-risk group, which presented a better prognosis. In conclusion, our exploration comprehensively analyzed the TME and identified TME-related prognostic genes for BC, providing new insights into potential therapeutic targets.
KRAS-Mutant Non-Small Cell Lung Cancer: An Emerging Promisingly Treatable Subgroup
Authors: Xie Mingying , Xu Xiaoling , Fan Yun
Published: May 2021

Lung cancer, the leading cause of cancer-related deaths worldwide, can be classified into small cell lung cancer and non-small cell lung cancer (NSCLC). NSCLC is the most common histological type, accounting for 85% of all lung cancers. Kirsten rat sarcoma viral oncogene (KRAS) mutations, common in NSCLC, are associated with poor prognosis, likely due to poor responses to most systemic therapies and lack of targeted drugs. The latest published clinical trial data on new small-molecule KRAS G12C inhibitors, AMG510 and MRTX849, indicate that these molecules may potentially help treat KRAS-mutant NSCLC. Simultaneously, within the immuno-therapeutic process, immune efficacy has been observed in those patients who have KRAS mutations. In this article, the pathogenesis, treatment status, progress of immunotherapy, and targeted therapy of KRAS-mutant NSCLC are reviewed.
Necrotizing Enterocolitis and Intestinal Microbiota: The Timing of Disease and Combined Effects of Multiple Species
Authors: Fu Xin , Li Siwen , Jiang Yanfang , Hu Xintong , Wu Hui
Published: May 2021

Background:The purpose of this study was to investigate the relationship between intestinal microbiota and necrotizing enterocolitis (NEC).

Methods:16S rRNA gene sequencing was used to compare the microbial composition of feces. The first sample was collected within 48 h after birth, then once per week until the NEC diagnosis, and finally 1–2 weeks after treatment or 28 days after birth.

Results:The alpha diversity of the microbiota in the NEC group was higher than that in the control group. Beta diversity analysis showed that the control group had a higher similarity at the onset of NEC, while the NEC group was distributed in subgroups. Linear discriminant analysis effect size and taxonomic composition analyses indicated that the abundance of Bacteroides and Actinobacteria in NEC infants at birth was much higher than that in the control group, and this trend continued until NEC occurred. At this time, Rhizobiales, Dysgonomonas, Ochrobactrum, Ralstonia, Pelomonas, Acinetobacter, etc., were also more abundant in NEC infants. The upregulated different metabolic pathways in the NEC group were mainly concentrated on degradation/utilization/assimilation, biosynthesis, and generation of precursor metabolites and energy.

Conclusions:

1. The microbial community differs according to the time of NEC diagnosis (bounded by 20 days).

2. No single microorganism is related to NEC, and the combined effect of multiple species is of great significance in the occurrence of NEC. Premature infants are easily affected by bacteria living in the environment, and compared with ordinary premature infants, NEC infants have a higher abundance of waterborne bacteria. Therefore, attention should be paid to the contamination of water sources and various ventilator pipelines for premature infants hospitalized in the neonatal intensive care unit.

3. An in-depth study of the mode of microbial colonization in premature infants combined with the different functions of various metabolic pathways involved in different microorganisms may be able to identify the cause of NEC.
Health Insurance and Out-Of-Pocket Expenditure on Health and Medicine: Heterogeneities along Income
Authors: Al-Hanawi Mohammed Khaled , Mwale Martin Limbikani , Qattan Ameerah M. N.
Published: April 2021

Background: Achieving universal health coverage is an important objective enshrined in the 2015 global Sustainable Development Goals. However, the rising cost of healthcare remains an obstacle to the attainment of the universal health coverage. Health insurance is considered an option to reduce out-of-pocket (OOP) expenditure on health and medicine. Nevertheless, the relationship between insurance and the OOP along welfare distributions is not well understood. This study investigates the heterogeneous association between health insurance and OOP expenditure on health and medicine, along income, using data from the Kingdom of Saudi Arabia.

Methods: This study used data of 8655 individuals drawn from the Saudi Family Health Survey conducted in 2018. The study adopts Tobit models to account for possible corner solution due to individuals with zero expenditure on health. We minimize the confounding effects of non-random selection into the insurance program by estimating the Tobit equations on a sample weighted by inverse propensity scores of insurance participation. In addition, we test whether the health insurance differently relates to OOP on health and medicine amongst people with access to free medical care as opposed to those without this privilege. The study estimates separate models for OOP expenditure on health and on medicines.

Results: Health insurance reduces OOP expenditure on health by 2.0% and OOP expenditure on medicine by 2.4% amongst the general population while increasing the OOP expenditure on health by 0.2% and OOP expenditure on medicine by 0.2%, once income of the insured rises. The relationship between the insurance and OOP expenditure is robust only amongst the citizens, a sub-sample that also has access to free public healthcare. Specifically, the insurance reduces OOP expenditure on health by 3.6% and OOP on medicine by 5.2% and increases OOP expenditure on health by 0.4% and OOP expenditure on medicine by 0.5% once income of the insured increases amongst Saudi citizens. In addition, targeting medicines can lead to greater changes in OOP. The relationship between insurance and OOP is stronger for medicine relative to that observed on health expenditure.

Conclusion: Our findings suggest that insurance induces different effects along the income spectrum. Hence, policy needs to be aware of the possible welfare distribution impacts of upscaling or downscaling the coverage of insurance amongst the populations, while pursuing universal healthcare coverage.