bluuebunny/crossref_metadata_2025 huggingface dataset:
The Relationship Between Cardio-Ankle Vascular Index and Left Atrial Phasic Function in Hypertensive Patients With Preserved Ejection Fraction
Authors: Tabata Tsuyoshi , Shimizu Kazuhiro , Morinaga Yukihiro , Tanji Naoaki , Yoshida Ruiko , Iwakawa Masahiro , Kiyokawa Hajime , Takada Nobuo
Published: September 2021

Background: To investigate the relationship between arterial stiffness, reflected by cardio-ankle vascular index (CAVI) value, and left atrial (LA) phasic function in hypertensive patients with preserved left ventricular ejection fraction (LVEF).

Methods: We retrospectively studied 165 consecutive patients (mean age, 66.5 ± 11.7 years) diagnosed with hypertension with preserved LVEF who had undergone CAVI measurement and echocardiography on the same day. The latter included speckle-tracking echocardiography to assess LA phasic function (reservoir, conduit, and pump strain) and left ventricular global longitudinal strain (LVGLS).

Results: The results of univariate analysis showed CAVI value to be correlated with LA reservoir strain and LA conduit strain (r = −0.387 and −0.448, respectively; both P < 0.0001). The results of multiple linear regression analysis showed CAVI value to be independently related to age (β = 0.241, P = 0.002) and LA conduit strain (β = −0.386, P = 0.021) but not LV mass index, LA volume index, or LV systolic function (including LVGLS).

Conclusion: In hypertensive patients with preserved LVEF, increased CAVI value appears to be independently associated with impaired LA phasic function (particularly LA conduit function) before LA and LV remodeling. CAVI determination to assess arterial stiffness may be useful in the early detection of interactions between cardiovascular abnormalities in hypertensive patients.
Succession of Fungal Communities at Different Developmental Stages of Cabernet Sauvignon Grapes From an Organic Vineyard in Xinjiang
Authors: Zhu Lihua , Li Tian , Xu Xiaoyu , Shi Xuewei , Wang Bin
Published: September 2021

Fungi present on grape surface considerably impact grape growth and quality. However, information of the fungal community structures and dynamics on the worldwide cash crop, the Cabernet Sauvignon grape, from the budding to ripening stages remains limited. Here, we investigated the succession of fungal communities on Cabernet Sauvignon grapes from an organic vineyard in Xinjiang, China at different developmental stages via high-throughput sequencing combined with multivariate data analysis. In total, 439 fungal amplicon sequence variants (ASVs) from six phyla were identified. The fungal communities differed over the budding to the berry stages. Moreover, Aspergillus, Malassezia, Metschnikowia, and Udeniomyces were predominant during the unripe stage, whereas Erysiphe, Cryptococcus, Vishniacozyma, and Cladosporium were dominant in the ripe stages. Notably, Vishniacozyma was the most abundant genus, conserved in all development stages. Moreover, network analysis resulted in 171 edges—96 negative and 75 positive. Moreover, fungal genera such as Vishniacozyma, Sporobolomyces, Aspergillus, Alternaria, Erysiphe, Toxicodendron, and Metschnikowia were present in the hubs serving as the main connecting nodes. Extensive mutualistic interactions potentially occur among the fungi on the grape surface. In conclusion, the current study expounded the characteristics of the Cabernet Sauvignon grape fungal community during the plant growth process, and the results provided essential insights into the potential impacts of fungal communities on grape growth and health.
Best Practices for Technical Reproducibility Assessment of Multiplex Immunofluorescence
Authors: Laberiano-Fernández Caddie , Hernández-Ruiz Sharia , Rojas Frank , Parra Edwin Roger
Published: September 2021

Multiplex immunofluorescence (mIF) tyramide signal amplification is a new and useful tool for the study of cancer that combines the staining of multiple markers in a single slide. Several technical requirements are important to performing high-quality staining and analysis and to obtaining high internal and external reproducibility of the results. This review manuscript aimed to describe the mIF panel workflow and discuss the challenges and solutions for ensuring that mIF panels have the highest reproducibility possible. Although this platform has shown high flexibility in cancer studies, it presents several challenges in pre-analytic, analytic, and post-analytic evaluation, as well as with external comparisons. Adequate antibody selection, antibody optimization and validation, panel design, staining optimization and validation, analysis strategies, and correct data generation are important for reproducibility and to minimize or identify possible issues during the mIF staining process that sometimes are not completely under our control, such as the tissue fixation process, storage, and cutting procedures.
Therapeutic Effects of an Inhibitor of Thioredoxin Reductase on Liver Fibrosis by Inhibiting the Transforming Growth Factor-β1/Smads Pathway
Authors: Jiao Wenxuan , Bai Man , Yin Hanwei , Liu Jiayi , Sun Jing , Su Xiaoxia , Zeng Huihui , Wen Jinhua
Published: September 2021

Liver fibrosis is an important stage in the progression of liver injury into cirrhosis or even liver cancer. Hepatic stellate cells (HSCs) are induced by transforming growth factor-β1 (TGF-β1) to produce α-smooth muscle actin (α-SMA) and collagens in liver fibrosis. Butaselen (BS), which was previously synthesized by our group, is an organic selenium compound that exerts antioxidant and tumor cell apoptosis–promoting effects by inhibiting the thioredoxin (Trx)/thioredoxin reductase (TrxR) system. The aim of this study was to investigate the potential effects of BS on liver fibrosis and explore the underlying molecular mechanisms of its action. Liver fibrosis models were established using male BALB/c mice through intraperitoneal injection of CCl4. BS was administered orally once daily at a dose of 36, 90, or 180 mg/kg. Silymarin (Si), which is a drug used for patients with nonalcoholic fatty liver disease and nonalcoholic steatohepatitis, was administered at a dose of 30 mg/kg per day as a control. The action mechanisms of BS against liver fibrosis progression were examined in HSCs. The study revealed that the activity and expression levels of TrxR were elevated in the mouse liver and serum after CCl4-induced liver fibrosis. Oral administration of BS relieved the pathological state of mice with liver fibrosis, showing significant therapeutic effects against liver fibrosis. Moreover, BS not only induced HSC apoptosis but also inhibited the production of α-SMA and collagens by HSCs by downregulating the TGF-β1 expression and blocking the TGF-β1/Smads pathway. The results of the study indicated that BS inhibited liver fibrosis by regulating the TGF-β1/Smads pathway.
Virulence Vs. Immunomodulation: Roles of the Paracoccin Chitinase and Carbohydrate-Binding Sites in Paracoccidioides brasiliensis Infection
Authors: Pitangui Nayla de Souza , Fernandes Fabrício Freitas , Gonçales Relber Aguiar , Roque-Barreira Maria Cristina
Published: September 2021

Paracoccin (PCN) is a bifunctional protein primarily present in the cell wall of Paracoccidioides brasiliensis, a human pathogenic dimorphic fungus. PCN has one chitinase region and four potential lectin sites and acts as both a fungal virulence factor and an immunomodulator of the host response. The PCN activity on fungal virulence, mediated by the chitinase site, was discovered by infecting mice with yeast overexpressing PCN (PCN-ov). PCN-ov are characterized by increased chitin hydrolysis, a narrow cell wall, and augmented resistance to phagocytes' fungicidal activity. Compared to wild-type (wt) yeast, infection with PCN-ov yeast causes a more severe disease, which is attributed to the increased PCN chitinase activity. In turn, immunomodulation of the host response was demonstrated by injecting, subcutaneously, recombinant PCN in mice infected with wt-P. brasiliensis. Through its carbohydrate binding site, the injected recombinant PCN interacts with Toll-like receptor 2 (TLR2) and Toll-like receptor 4 (TLR4) N-glycans on macrophages, triggers M1 polarization, and stimulates protective Th1 immunity against the fungus. The PCN-treatment of wt yeast-infected mice results in mild paracoccidioidomycosis. Therefore, PCN paradoxically influences the course of murine paracoccidioidomycosis. The disease is severe when caused by yeast that overexpress endogenous PCN, which exerts a robust local chitinase activity, followed by architectural changes of the cell wall and release of low size chito-oligomers. However, the disease is mild when exogenous PCN is injected, which recognizes N-glycans on systemic macrophages resulting in immunomodulation.
Extracellular Matrix Enzymes and Immune Cell Biology
Authors: McMahon Meagan , Ye Siying , Pedrina Jess , Dlugolenski Daniel , Stambas John
Published: September 2021

Remodelling of the extracellular matrix (ECM) by ECM metalloproteinases is increasingly being associated with regulation of immune cell function. ECM metalloproteinases, including Matrix Metalloproteinases (MMPs), A Disintegrin and Metalloproteinases (ADAMs) and ADAMs with Thombospondin-1 motifs (ADAMTS) play a vital role in pathogen defence and have been shown to influence migration of immune cells. This review provides a current summary of the role of ECM enzymes in immune cell migration and function and discusses opportunities and limitations for development of diagnostic and therapeutic strategies targeting metalloproteinase expression and activity in the context of infectious disease.
PROLIDASE: A Review from Discovery to its Role in Health and Disease
Authors: Eni-Aganga Ireti , Lanaghan Zeljka Miletic , Balasubramaniam Muthukumar , Dash Chandravanu , Pandhare Jui
Published: September 2021

Prolidase (peptidase D), encoded by the PEPD gene, is a ubiquitously expressed cytosolic metalloproteinase, the only enzyme capable of cleaving imidodipeptides containing C-terminal proline or hydroxyproline. Prolidase catalyzes the rate-limiting step during collagen recycling and is essential in protein metabolism, collagen turnover, and matrix remodeling. Prolidase, therefore plays a crucial role in several physiological processes such as wound healing, inflammation, angiogenesis, cell proliferation, and carcinogenesis. Accordingly, mutations leading to loss of prolidase catalytic activity result in prolidase deficiency a rare autosomal recessive metabolic disorder characterized by defective wound healing. In addition, alterations in prolidase enzyme activity have been documented in numerous pathological conditions, making prolidase a useful biochemical marker to measure disease severity. Furthermore, recent studies underscore the importance of a non-enzymatic role of prolidase in cell regulation and infectious disease. This review aims to provide comprehensive information on prolidase, from its discovery to its role in health and disease, while addressing the current knowledge gaps.
Proteomic Analysis of Cardiac Adaptation to Exercise by High Resolution Mass Spectrometry
Authors: Al-Menhali Afnan Saleh , Anderson Cali , Gourine Alexander V. , Abramov Andrey Y. , D’Souza Alicia , Jaganjac Morana
Published: September 2021

Regular exercise has many health benefits, among which is a significant reduction of cardiovascular risk. Although many beneficial effects of exercise are well described, the exact mechanisms by which exercise confers cardiovascular benefits are yet to be fully understood. In the current study, we have used high resolution mass spectrometry to determine the proteomic responses of the heart to exercise training in mice. The impact of exercise-induced oxidative stress on modifications of cardiomyocyte proteins with lipid peroxidation biomarker 4-hydroxynonenal (4-HNE) was examined as well. Fourteen male mice were randomized into the control (sedentary) group and the exercise group that was subjected to a swim exercise training program for 5 days a week for 5 months. Proteins were isolated from the left ventricular tissue, fractionated and digested for shotgun proteomics. Peptides were separated by nanoliquid chromatography and analyzed on an Orbitrap Fusion mass spectrometer using high-energy collision–induced dissociation and electron transfer dissociation fragmentation. We identified distinct ventricular protein signatures established in response to exercise training. Comparative proteomics identified 23 proteins that were upregulated and 37 proteins that were downregulated with exercise, in addition to 65 proteins that were identified only in ventricular tissue samples of exercised mice. Most of the proteins specific to exercised mice are involved in respiratory electron transport and/or implicated in glutathione conjugation. Additionally, 10 proteins were found to be modified with 4-HNE. This study provides new data on the effects of exercise on the cardiac proteome and contributes to our understanding of the molecular mechanisms underlying the beneficial effects of exercise on the heart.
Host Serine Proteases: A Potential Targeted Therapy for COVID-19 and Influenza
Authors: Rahbar Saadat Yalda , Hosseiniyan Khatibi Seyed Mahdi , Zununi Vahed Sepideh , Ardalan Mohammadreza
Published: September 2021

The ongoing pandemic illustrates limited therapeutic options for controlling SARS-CoV-2 infections, calling a need for additional therapeutic targets. The viral spike S glycoprotein binds to the human receptor angiotensin-converting enzyme 2 (ACE2) and then is activated by the host proteases. Based on the accessibility of the cellular proteases needed for SARS-S activation, SARS-CoV-2 entrance and activation can be mediated by endosomal (such as cathepsin L) and non-endosomal pathways. Evidence indicates that in the non-endosomal pathway, the viral S protein is cleaved by the furin enzyme in infected host cells. To help the virus enter efficiently, the S protein is further activated by the serine protease 2 (TMPRSS2), provided that the S has been cleaved by furin previously. In this review, important roles for host proteases within host cells will be outlined in SARS-CoV-2 infection and antiviral therapeutic strategies will be highlighted. Although there are at least five highly effective vaccines at this time, the appearance of the new viral mutations demands the development of therapeutic agents. Targeted inhibition of host proteases can be used as a therapeutic approach for viral infection.
Unraveling the Thermodynamics of Ultra-tight Binding of Intrinsically Disordered Proteins
Authors: Zavrtanik Uroš , Hadži San , Lah Jurij
Published: September 2021

Protein interactions mediated by the intrinsically disordered proteins (IDPs) are generally associated with lower affinities compared to those between globular proteins. Here, we characterize the association between the intrinsically disordered HigA2 antitoxin and its globular target HigB2 toxin from Vibrio cholerae using competition ITC experiments. We demonstrate that this interaction reaches one of the highest affinities reported for IDP-target systems (KD = 3 pM) and can be entirely attributed to a short, 20-residue-long interaction motif that folds into α-helix upon binding. We perform an experimentally based decomposition of the IDP-target association parameters into folding and binding contributions, which allows a direct comparison of the binding contribution with those from globular ultra-high affinity binders. We find that the HigA2-HigB2 interface is energy optimized to a similar extent as the interfaces of globular ultra-high affinity complexes, such as barnase-barstar. Evaluation of other ultra-high affinity IDP-target systems shows that a strategy based on entropy optimization can also achieve comparably high, picomolar affinities. Taken together, these examples show how IDP-target interactions achieve picomolar affinities either through enthalpy optimization (HigA2-HigB2), resembling the ultra-high affinity binding of globular proteins, or via bound-state fuzziness and entropy optimization (CcdA-CcdB, histone H1-prothymosin α).
Insights Into the Pathologic Roles and Regulation of Eukaryotic Elongation Factor-2 Kinase
Authors: Ballard Darby J. , Peng Hao-Yun , Das Jugal Kishore , Kumar Anil , Wang Liqing , Ren Yijie , Xiong Xiaofang , Ren Xingcong , Yang Jin-Ming , Song Jianxun
Published: September 2021

Eukaryotic Elongation Factor-2 Kinase (eEF2K) acts as a negative regulator of protein synthesis, translation, and cell growth. As a structurally unique member of the alpha-kinase family, eEF2K is essential to cell survival under stressful conditions, as it contributes to both cell viability and proliferation. Known as the modulator of the global rate of protein translation, eEF2K inhibits eEF2 (eukaryotic Elongation Factor 2) and decreases translation elongation when active. eEF2K is regulated by various mechanisms, including phosphorylation through residues and autophosphorylation. Specifically, this protein kinase is downregulated through the phosphorylation of multiple sites via mTOR signaling and upregulated via the AMPK pathway. eEF2K plays important roles in numerous biological systems, including neurology, cardiology, myology, and immunology. This review provides further insights into the current roles of eEF2K and its potential to be explored as a therapeutic target for drug development.
Altered Patterns of Amplitude of Low-Frequency Fluctuations and Fractional Amplitude of Low-Frequency Fluctuations Between Amnestic and Vascular Mild Cognitive Impairment: An ALE-Based Comparative Meta-Analysis
Authors: Zhang Xulian , Xue Chen , Cao Xuan , Yuan Qianqian , Qi Wenzhang , Xu Wenwen , Zhang Shaojun , Huang Qingling
Published: September 2021

Background: Changes in the amplitude of low-frequency fluctuations (ALFF) and the fractional amplitude of low-frequency fluctuations (fALFF) have provided stronger evidence for the pathophysiology of cognitive impairment. Whether the altered patterns of ALFF and fALFF differ in amnestic cognitive impairment (aMCI) and vascular mild cognitive impairment (vMCI) is largely unknown. The purpose of this study was to explore the ALFF/fALFF changes in the two diseases and to further explore whether they contribute to the diagnosis and differentiation of these diseases.

Methods: We searched PubMed, Ovid, and Web of Science databases for articles on studies using the ALFF/fALFF method in patients with aMCI and vMCI. Based on the activation likelihood estimation (ALE) method, connectivity modeling based on coordinate meta-analysis and functional meta-analysis was carried out.

Results: Compared with healthy controls (HCs), patients with aMCI showed increased ALFF/fALFF in the bilateral parahippocampal gyrus/hippocampus (PHG/HG), right amygdala, right cerebellum anterior lobe (CAL), left middle temporal gyrus (MTG), left cerebrum temporal lobe sub-gyral, left inferior temporal gyrus (ITG), and left cerebrum limbic lobe uncus. Meanwhile, decreased ALFF/fALFF values were also revealed in the bilateral precuneus (PCUN), bilateral cuneus (CUN), and bilateral posterior cingulate (PC) in patients with aMCI. Compared with HCs, patients with vMCI predominantly showed decreased ALFF/fALFF in the bilateral CUN, left PCUN, left PC, and right cingulate gyrus (CG).

Conclusions: The present findings suggest that ALFF and fALFF displayed remarkable altered patterns between aMCI and vMCI when compared with HCs. Thus, the findings of this study may serve as a reliable tool for distinguishing aMCI from vMCI, which may help understand the pathophysiological mechanisms of these diseases.
Comparison of Behavior-Related Features in the MMSE Sentence in Behavioral Variant Frontotemporal Dementia and Alzheimer’s Disease
Authors: Ruiz-Garcia Ramiro , Yu Soojung , Richardson Lauryn , Roberts Angela , Pasternak Stephen , Stewart Chloe , Finger Elizabeth
Published: September 2021

Background: Despite the ubiquity of cognitive assessments using the MMSE, there has been little investigation of currently unscored features of the MMSE sentence item relevant to behavior and language in patients with behavioral variant Frontotemporal Dementia (bvFTD) and Alzheimer’s disease (AD).

Objective: To describe and compare the unscored content and grammar elements of the MMSE sentence item in patients with bvFTD and AD.

Methods: Categorization of predefined content and grammar elements of the MMSE sentence was performed by two blinded raters in patients with bvFTD (n = 74) and AD (n = 84). Chi-square and ANCOVAs were conducted to identify differences between the diagnostic groups. A multinomial logistic regression analysis was conducted to determine whether these features aid in the prediction of diagnosis of bvFTD or AD.

Results: A higher proportion of patients with bvFTD wrote sentences addressed to the examiner (22.7% vs. 4.7%, X2 = 11.272, p = 0.001) and about interpersonal relationships (35.3% vs. 16.0%, X2 = 10.139, p = 0.017) in comparison to those with AD. The number of words written was lower in patients with AD and was positively correlated with lower total MMSE scores in AD but not in bvFTD (AD: r = 0.370, p < 0.001; FTD: r = 0.209, p = 0.07). Assessment of the MMSE sentence content and grammar variables did not add to the prediction bvFTD or AD diagnosis beyond the variance explained by age and total MoCA score.

Conclusions: Patients with bvFTD and AD showed differences in aspects of the content of the written MMSE sentence item, though these differences did not aid in the diagnosis prediction.
The Many Faces of Astrocytes in Alzheimer's Disease
Authors: Monterey Michael D. , Wei Haichao , Wu Xizi , Wu Jia Qian
Published: September 2021

Alzheimer's disease (AD) is a progressive neurodegenerative disease and is the most common cause of dementia in an aging population. The majority of research effort has focused on the role of neurons in neurodegeneration and current therapies have limited ability to slow disease progression. Recently more attention has been given to the role of astrocytes in the process of neurodegeneration. Specifically, reactive astrocytes have both advantageous and adverse effects during neurodegeneration. The ability to isolate and depict astrocyte phenotype has been challenging. However, with the recent development of single-cell sequencing technologies researchers are provided with the resource to delineate specific biomarkers associated with reactive astrocytes in AD. In this review, we will focus on the role of astrocytes in normal conditions and the pathological development of AD. We will further review recent developments in the understanding of astrocyte heterogeneity and associated biomarkers. A better understanding of astrocyte contributions and phenotypic changes in AD can ultimately lead to more effective therapeutic targets.
Altered Connectivity of the Frontoparietal Network During Attention Processing in Prolactinomas
Authors: Cao Chenglong , Wang Yu , Liu Jia , Chen Aobo , Lu Jinjiang , Xu Guozheng , Song Jian
Published: September 2021

Prolactinomas have been reported for the failure of cognitive functions. However, the electrophysiological mechanisms of attention processing in prolactinomas remain unclear. In a visual mission, we monitored the scalp electroencephalography (EEG) of the participants. Compared with the healthy controls (HCs), larger frontoparietal theta and alpha coherence were found in the patients, especially in the right-lateralized hemisphere, which indicated a deficit in attention processing. Moreover, the frontoparietal coherence was positively correlated with altered prolactin (PRL) levels, implying the significance of PRL for adaptive brain compensation in prolactinomas. Taken together, this research showed the variations in attention processing between the HCs and prolactinomas. The coherence between frontal and parietal regions may be one of the possible electrophysiological biomarkers for detecting deficient attention processing in prolactinomas.
Non-traditional Lipid Parameters as Potential Predictors of Asymptomatic Intracranial Arterial Stenosis
Authors: Guo Jiahuan , Wang Anxin , Wang Yu , Liu Xinmin , Zhang Xiaoli , Wu Shouling , Zhao Xingquan
Published: September 2021

Background: Intracranial arterial stenosis (ICAS) is a common cause of stroke. Identifying effective predictors of ICAS that could be easily obtained in clinical practice is important. The predictive values of serum individual lipid parameters have been well-established. In recent years, several non-traditional lipid parameters demonstrated greater predictive values for cardiovascular disease and ischemic stroke than traditional individual lipid parameters. However, their effects on asymptomatic ICAS (aICAS) are less clear. Therefore, we sought to observe the effects of non-traditional lipid parameters on aICAS.

Methods: We enrolled 5,314 participants from the Asymptomatic Polyvascular Abnormalities in Community study. Asymptomatic ICAS was detected by transcranial Doppler ultrasonography (TCD). Non-traditional lipid parameters, including non-high-density lipoprotein cholesterol (non-HDL-C), the triglycerides/high-density lipoprotein cholesterol ratio (TG/HDL-C), atherogenic coefficient (AC), atherogenic index of plasma, and Castelli's risk index (CRI) were measured. We used multivariable logistic analysis to assess the association of different lipid parameters with aICAS; a trend test and subgroup analyses were also performed.

Results: In total, 695 of 5,314 participants had aICAS in this study. For the comparison of the highest to the lowest tertile, the multivariable-adjusted odds ratios (ORs) (95% CIs) were 1.78 (1.39–2.27) (p trend < 0.001) for non-HDL-C, 1.48 (1.18–1.85) (p trend = 0.004) for the AC, 1.48 (1.18–1.85) (p trend = 0.004) for CRI-I, and 1.34 (1.09–1.66) (p trend = 0.032) for CRI-II. Subgroup analyses showed significant interactions between the AC, CRI-I, and diabetes.

Conclusions: This large community-based study showed that non-HDL-C, AC, CRI-I, and CRI-II were significantly associated with increased prevalence of aICAS.
Carotid Atheroinflammation Is Associated With Cerebral Small Vessel Disease Severity
Authors: Evans Nicholas R. , Tarkin Jason M. , Walsh Jessica , Chowdhury Mohammed M. , Patterson Andrew J. , Graves Martin J. , Rudd James H. F. , Warburton Elizabeth A.
Published: September 2021

Background: Atherosclerosis is a systemic inflammatory disease, with common inflammatory processes implicated in both atheroma vulnerability and blood-brain barrier disruption. This prospective multimodal imaging study aimed to measure directly the association between systemic atheroma inflammation (“atheroinflammation”) and downstream chronic cerebral small vessel disease severity.

Methods: Twenty-six individuals with ischemic stroke with ipsilateral carotid artery stenosis of >50% underwent 18fluoride-fluorodeoxyglucose-positron emission tomography within 2 weeks of stroke. Small vessel disease severity and white matter hyperintensity volume were assessed using 3-tesla magnetic resonance imaging also within 2 weeks of stroke.

Results: Fluorodeoxyglucose uptake was independently associated with more severe small vessel disease (odds ratio 6.18, 95% confidence interval 2.1–18.2, P < 0.01 for the non-culprit carotid artery) and larger white matter hyperintensity volumes (coefficient = 14.33 mL, P < 0.01 for the non-culprit carotid artery).

Conclusion: These proof-of-concept results have important implications for our understanding of the neurovascular interface and potential therapeutic exploitation in the management of systemic atherosclerosis, particularly non-stenotic disease previously considered asymptomatic, in order to reduce the burden of chronic cerebrovascular disease.
Dissociation of Connectivity for Syntactic Irregularity and Perceptual Ambiguity in Musical Chord Stimuli
Authors: Kim Chan Hee , Jin Seung-Hyun , Kim June Sic , Kim Youn , Yi Suk Won , Chung Chun Kee
Published: September 2021

Musical syntax has been studied mainly in terms of “syntactic irregularity” in harmonic/melodic sequences. However, “perceptual ambiguity” referring to the uncertainty of judgment/classification of presented stimuli can in addition be involved in our musical stimuli using three different chord sequences. The present study addresses how “syntactic irregularity” and “perceptual ambiguity” on musical syntax are dissociated, in terms of effective connectivity between the bilateral inferior frontal gyrus (IFGs) and superior temporal gyrus (STGs) by linearized time-delayed mutual information (LTDMI). Three conditions were of five-chord sequences with endings of dominant to tonic, dominant to submediant, and dominant to supertonic. The dominant to supertonic is most irregular, compared with the regular dominant to tonic. The dominant to submediant of the less irregular condition is the most ambiguous condition. In the LTDMI results, connectivity from the right to the left IFG (IFG-LTDMI) was enhanced for the most irregular condition, whereas that from the right to the left STG (STG-LTDMI) was enhanced for the most ambiguous condition (p= 0.024 in IFG-LTDMI,p< 0.001 in STG-LTDMI, false discovery rate (FDR) corrected). Correct rate was negatively correlated with STG-LTDMI, further reflecting perceptual ambiguity (p= 0.026). We found for the first time that syntactic irregularity and perceptual ambiguity coexist in chord stimulus testing musical syntax and that the two processes are dissociated in interhemispheric connectivities in the IFG and STG, respectively.
Forced Normalization Revisited: New Concepts About a Paradoxical Phenomenon
Authors: Bragatti José Augusto
Published: September 2021

The phenomenon of Forced Normalization (FN) was first described by Landolt in 1953, who described the disappearance of epileptiform discharges in the EEG of patients with epilepsy, concomitant with the development of psychotic symptoms. Later, Tellenbach coined the term “alternative psychosis” referring specifically to the alternation between clinical phenomena. Finally, in 1991, Wolf observed a degenerative process involved in the phenomenon, which he called “paradoxical normalization.” Initially, FN was explained through experimental models in animals and the demonstration of the kindling phenomenon, in its electrical and pharmacological subdivisions. At this stage of research on the epileptic phenomenon, repetitive electrical stimuli applied to susceptible regions of the brain (hippocampus and amygdala) were considered to explain the pathophysiological basis of temporal lobe epileptogenesis. Likewise, through pharmacological manipulation, especially of dopaminergic circuits, psychiatric comorbidities began to find their basic mechanisms. With the development of new imaging techniques (EEG/fMRI), studies in the area started to focus on the functional connectivity (FC) of different brain regions with specific neuronal networks, which govern emotions. Thus, a series of evidence was produced relating the occurrence of epileptic discharges in the limbic system and their consequent coactivation and deactivation of these resting-state networks. However, there are still many controversies regarding the basic mechanisms of network alterations related to emotional control, which will need to be studied with a more homogeneous methodology, in order to try to explain this interesting neuropsychiatric phenomenon with greater accuracy.
Revisiting the “Paradox of Stereotaxic Surgery”: Insights Into Basal Ganglia-Thalamic Interactions
Authors: Magnusson Jennifer L. , Leventhal Daniel K.
Published: September 2021

Basal ganglia dysfunction is implicated in movement disorders including Parkinson Disease, dystonia, and choreiform disorders. Contradicting standard “rate models” of basal ganglia-thalamic interactions, internal pallidotomy improves both hypo- and hyper-kinetic movement disorders. This “paradox of stereotaxic surgery” was recognized shortly after rate models were developed, and is underscored by the outcomes of deep brain stimulation (DBS) for movement disorders. Despite strong evidence that DBS activates local axons, the clinical effects of lesions and DBS are nearly identical. These observations argue against standard models in which GABAergic basal ganglia output gates thalamic activity, and raise the question of how lesions and stimulation can have similar effects. These paradoxes may be resolved by considering thalamocortical loops as primary drivers of motor output. Rather than suppressing or releasing cortex via motor thalamus, the basal ganglia may modulate the timing of thalamic perturbations to cortical activity. Motor cortex exhibits rotational dynamics during movement, allowing the same thalamocortical perturbation to affect motor output differently depending on its timing with respect to the rotational cycle. We review classic and recent studies of basal ganglia, thalamic, and cortical physiology to propose a revised model of basal ganglia-thalamocortical function with implications for basic physiology and neuromodulation.
Dietary Habits and Lifestyle During Coronavirus Pandemic Lockdown: Experience From Lebanon
Authors: Cheikh Ismail Leila , Hashim Mona , Mohamad Maysm N. , Hassan Hussein , Ajab Abir , Stojanovska Lily , Jarrar Amjad H. , Hasan Hayder , Abu Jamous Dima O. , Saleh Sheima T. , Al Daour Rameez , Osaili Tareq M. , Al Dhaheri Ayesha S.
Published: September 2021

This study aimed to examine the impact of quarantine on eating habits and lifestyle behaviors among the Lebanese adult population. A cross-sectional study was conducted using an online questionnaire designed on Google Forms between 3 June and 28 June 2020. The survey questions were adapted from the Short Food Frequency Questionnaire, the International Physical Activity Questionnaire Short Form, and the second version of the Copenhagen Psychosocial Questionnaire. A total of 2,507 adults completed the questionnaire. During the lockdown, 32.8% claimed weight gain, 44.7% did not eat fruits daily, 35.3% did not eat vegetables on daily basis, and 72.9% reported drinking less than eight cups of water per day. Moreover, there was a significant increase in the number of meals consumed per day, consumption of homemade meals, sedentary time, stress, and sleeping disturbances during the pandemic compared to before the pandemic (all p < 0.001). However, there was a significant decrease in physical activity engagement, sleep quality, and energy level during the lockdown compared to before the pandemic (all p < 0.001). The study highlights that the COVID-19 lockdown was associated with unfavorable changes in dietary habits and lifestyle behaviors in Lebanon. Sleep and mental health were also negatively impacted by the pandemic.
Effects of Molecular Distillation on the Chemical Components, Cleaning, and Antibacterial Abilities of Four Different Citrus Oils
Authors: Yang Feilong , Zhang Huijuan , Tian Guifang , Ren Wenbo , Li Juan , Xiao Hang , Zheng Jinkai
Published: September 2021

Essential oils (EOs) from citrus fruits are excellent aromatic resources that are used in food, cosmetics, perfume, and cleaning products. EOs extracted from four citrus varieties, sweet orange, grapefruit, mandarin, and lemon, were separated into two fractions by molecular distillation. The composition, physicochemical properties, cleaning ability, and antimicrobial activity of each EO were then systematically evaluated. The relationships between each of the aforementioned characteristics are also discussed. In keeping with the principle of “like dissolves like,” most citrus EOs show better cleaning ability than acetone and all tend to dissolve the fat-soluble pigment. The key components of citrus EOs are 1-Decanol, α-terpineol, geraniol, and linalool for the inhibition of Staphylococcus aureus, Escherichia coli, Candida albicans, and Vibrio parahaemolyticus, respectively. The findings of this study will be of significant importance for the effective utilization of citrus peel resources and in the development of future applications for citrus EOs.

Chemical Compounds Studied in This Article: (+)-α-Pinene (PubChem CID: 6654); β-Phellandrene (PubChem CID: 11142); 3-Carene (PubChem CID: 26049); β-Myrcene (PubChem CID: 31253); D-Limonene (PubChem CID: 440917); γ-Terpinene (PubChem CID: 7461); Octanal (PubChem CID: 454); Decanal (PubChem CID: 8175); Linalool (PubChem CID: 6549); 1-Octanol (PubChem CID: 957); β-Citral (PubChem CID: 643779); α-Terpineol (PubChem CID: 17100); Hedycaryol (PubChem CID: 5365392); α-Citral (PubChem CID: 638011); 1-Decanol (PubChem CID: 8174); Geraniol (PubChem CID: 637566).
Inhibition of MIR4435-2HG on Invasion, Migration, and EMT of Gastric Carcinoma Cells by Mediating MiR-138-5p/Sox4 Axis
Authors: Gao Li-Fei , Li Wei , Liu Ya-Gang , Zhang Cui , Gao Wei-Na , Wang Liang
Published: September 2021

Background

The previous investigations have identified that long non-coding RNA (lncRNAs) act as crucial regulators in gastric carcinoma. However, the function of lncRNA MIR4435-2HG in the modulation of gastric carcinoma remains elusive. Here, we aimed to explore the role of MIR4435-2HG in gastric carcinoma.

Method

The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) were applied to select the differently expressed lncRNAs in gastric carcinoma. The qRT-PCR was applied to analyze MIR4435-2HG expression in carcinoma tissues and cell lines. The effect of MIR4435-2HG on proliferation, invasion, migration, and apoptosis of gastric carcinoma cells was detected by Cell Counting Kit-8 (CCK-8) assays, transwell assays, and flow cytometry in vitro. A subcutaneous tumor model was constructed to examine the tumor growth of gastric carcinoma cells after knocking out MIR4435-2HG. RNA immunoprecipitation and luciferase reporting assays were applied to evaluate the interaction of MIR4435-2HG, miR-138-5p, and Sox4.

Results

The bioinformatics analysis based on TCGA and GEO databases indicated that MIR4435-2HG was obviously elevated in gastric carcinoma samples. The qRT-PCR analysis revealed that MIR4435-2HG was upregulated in clinical gastric carcinoma tissues and cells. The high expression of MIR4435-2HG is associated with the poor survival rate of patients. The knockout of MIR4435-2HG could repress the proliferation, invasion, migration, and epithelial–mesenchymal transition (EMT) and accelerate the apoptosis of gastric carcinoma cells. Moreover, the deletion of MIR4435-2HG was able to attenuate the tumor growth in vivo. Mechanically, we identified that MIR4435-2HG enhanced Sox4 expression by directly interacting with miR-138-5p as a competitive endogenous RNA (ceRNA) in gastric carcinoma cells, in which Sox4 was targeted by miR-138-5p.

Conclusion

MIR4435-2HG is elevated in gastric carcinoma cells and contributes to the growth, metastasis, and EMT of gastric carcinoma cells by targeting miR-138-5p/Sox4 axis. MIR4435-2HG may be applied as a potential therapeutic target in gastric carcinoma.
RNA Sequencing for Personalized Treatment of Metastatic Leiomyosarcoma: Case Report
Authors: Seryakov Alexander , Magomedova Zaynab , Suntsova Maria , Prokofieva Anastasia , Rabushko Elizaveta , Glusker Alexander , Makovskaia Lyudmila , Zolotovskaia Marianna , Buzdin Anton , Sorokin Maxim
Published: September 2021

Uterine leiomyosarcoma (UL) is a rare malignant tumor that develops from the uterine smooth muscle tissue. Due to the low frequency and lack of sufficient data from clinical trials there is currently no effective treatment that is routinely accepted for UL. Here we report a case of a 65-years-old female patient with metastatic UL, who progressed on ifosfamide and doxorubicin therapy and developed severe hypertensive crisis after administration of second line pazopanib, which lead to treatment termination. Rapid progression of the tumor stressed the need for the alternative treatment options. We performed RNA sequencing and whole exome sequencing profiling of the patient’s biopsy and applied Oncobox bioinformatic algorithm to prioritize targeted therapeutics. No clinically relevant mutations associated with drug efficiencies were found, but the Oncobox transcriptome analysis predicted regorafenib as the most effective targeted treatment option. Regorafenib administration resulted in a complete metabolic response which lasted for 10 months. In addition, RNA sequencing analysis revealed a novel cancer fusion transcript of YWHAE gene with fusion partner JAZF1. Several chimeric transcripts for YWHAE and JAZF1 genes were previously found in uterine neoplasms and some of them were associated with tumor prognosis. However, their combination was detected in this study for the first time. Taken together, these findings evidence that RNA sequencing may complement analysis of clinically relevant mutations and enhance management of oncological patients by suggesting putative treatment options.
A Retrospective Study of Brain Metastases From Solid Malignancies: The Effect of Immune Checkpoint Inhibitors
Authors: Du Wei , Sirbu Cristian , Lucas B. Daniel , Jubelirer Steven J. , Khalid Ahmed , Mei Lin
Published: September 2021

Introduction

Brain metastases (BM) are associated with dismal prognosis, and there is a dearth of effective systemic therapy. In this study, patients with BM from multiple solid tumors were identified from TriNetX databases, their clinicopathological features were evaluated, and the effects of immune checkpoint inhibitor (ICI) therapy were assessed.

Methods

Variables, including median overall survival (OS), Eastern Cooperative Oncology Group (ECOG) performance status, primary diagnosis, and date of diagnosis, were retrieved from TriNetX, a real-world database. Kaplan-Meier plots and log-rank tests were applied to assess significance of differences in survival. Hazard ratio (HR) and 95% confidence interval (CI) values were calculated. All patient data were deidentified.

Results

A total of 227,255 patients with BM were identified in the TriNetX database; median OS was 12.3 months from initial cancer diagnosis and 7.1 months from development of BM. OS of BM from nonsmall-cell lung cancer (NSCLC), triple-negative breast cancer (TNBC), melanoma, and renal cell carcinoma (RCC) were 8.7, 14.7, 17.8, and 15.6 months, respectively. After matching patient baseline characteristics, OS of cohorts with or without exposure to ICIs was evaluated. For all types of cancer, median OS durations for the ICI and no-ICI cohorts were 14.0 and 7.9 months, respectively (HR: 0.88; 95% CI: 0.85–0.91). More specifically, OS was remarkably prolonged in patients with NSCLC (14.4 vs. 8.2 months; HR: 0.86; 95% CI: 0.82–0.90), TNBC (23.9 vs. 11.6 months; HR: 0.87; 95% CI: 0.82–0.92), and melanoma (27.6 vs. 16.8 months; HR: 0.80; 95% CI: 0.73–0.88) if patients had exposure to ICIs. In contrast, there was no significant difference in OS of patients with RCC treated with and without ICIs (16.7 vs. 14.0 months; HR: 0.96; 95% CI: 0.86–1.10).

Conclusions

Overall, BM indicates poor patient outcome. Treatment with ICIs improves survival of patients with NSCLC, TNBC, and melanoma and BM; however, no significant improvement was observed in RCC. Investigations to identify prognostic features, oncogenomic profiles, and predictive biomarkers are warranted.
The Role of Neoantigens in Cancer Immunotherapy
Authors: Zhu Yueting , Liu Jiyan
Published: September 2021

Somatic mutation-derived neoantigens, expressed only on tumor cells, may elicit antitumor T-cell responses in cancer immunotherapies with minimal immune tolerance. Neoantigens can be identified by multiple bioinformatics technologies, mainly based on whole-exome sequencing. Personalized cancer vaccines and adoptive T cell therapies are two primary treatment modalities targeting neoantigens, and both of them have shown promising therapeutic effects. This review, summarizes the history of neoantigen-related tumor control, introduces recent neoantigen screening and identification methods, and discusses the role of neoantigen in cancer immunotherapies. Moreover, we propose the challenges of targeting neoantigens for cancer treatment.
Diagnostic Value of Delayed PET/MR in Liver Metastasis in Comparison With PET/CT
Authors: Zhou Nina , Meng Xiangxi , Zhang Yan , Yu Boqi , Yuan Jianmin , Yu Jiangyuan , Zhu Hua , Yang Zhi
Published: September 2021

Objectives

The aim of this study was to evaluate the value of a delayed positron emission tomography/magnetic resonance (PET/MR) scan relative to a single positron emission tomography/computed tomography (PET/CT) scan for liver metastasis detection.

Methods

In this study, 70 patients with solid malignancies and suspicious liver lesions undergoing 2-deoxy-2-[18F]fluoro-D-glucose [(18F)FDG] PET/CT and subsequent delayed liver PET/MR scans were analyzed. The histopathological analysis and/or imaging follow-up were performed as the standard of reference. Lesion maximum standardized uptake value (SUVmax), diameter, and tumor to nontumor ratio (T/N) were measured. Lesion detection sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated for both examinations.

Results

(1) The standard of reference revealed 208 liver lesions in 70 patients (metastasis in 56 patients with 196 lesions; benign in 14 patients with 12 lesions). Compared with PET/CT, PET/MR had higher accuracy (98.6% vs. 78.6%), sensitivity (98.2% vs. 76.8%), and specificity (100.0% vs. 85.7%) (2). The therapeutic strategies of 29 patients (41.4%) needed reconsideration after the additional PET/MR, including new metastases detected (13/70), new affected lobes identified (14/70), and false-positive corrected (2/70) (3). PET/MR detected significantly more metastases than PET/CT did, especially with small lesions. The SUVmax of the same lesion correlated well between the two acquisitions, while the delayed PET showed a higher T/N ratio.

Conclusions

In liver metastasis detection, the diagnostic value of the delayed PET/MR is validated to be superior to that of PET/CT, which may aid the clinical decision-making.
The Advance of Magnetic Resonance Elastography in Tumor Diagnosis
Authors: Yang Jin-Ying , Qiu Ben-Sheng
Published: September 2021

The change in tissue stiffness caused by pathological changes in the tissue’s structure could be detected earlier, prior to the manifestation of their clinical features. Magnetic resonance elastography (MRE) is a noninvasive imaging technique that uses low-frequency vibrations to quantitatively measure the elasticity or stiffness of tissues. In tumor tissue, stiffness is directly related to tumor development, invasion, metastasis, and chemoradiotherapy resistance. It also dictates the choice of surgical method. At present, MRE is widely used in assessing different human organs, such as the liver, brain, breast, prostate, uterus, gallbladder, and colon stiffness. In the field of oncology, MRE’s value lies in tumor diagnosis (especially early diagnosis), selection of treatment method, and prognosis evaluation. This article summarizes the principle of MRE and its research and application progress in tumor diagnosis and treatment.
Stress-Induced Polyploid Giant Cancer Cells: Unique Way of Formation and Non-Negligible Characteristics
Authors: Song Yanwei , Zhao Yucui , Deng Zheng , Zhao Ruyi , Huang Qian
Published: September 2021

Polyploidy is a conserved mechanism in cell development and stress responses. Multiple stresses of treatment, including radiation and chemotherapy drugs, can induce the polyploidization of tumor cells. Through endoreplication or cell fusion, diploid tumor cells convert into giant tumor cells with single large nuclei or multiple small nucleuses. Some of the stress-induced colossal cells, which were previously thought to be senescent and have no ability to proliferate, can escape the fate of death by a special way. They can remain alive at least before producing progeny cells through asymmetric cell division, a depolyploidization way named neosis. Those large and danger cells are recognized as polyploid giant cancer cells (PGCCs). Such cells are under suspicion of being highly related to tumor recurrence and metastasis after treatment and can bring new targets for cancer therapy. However, differences in formation mechanisms between PGCCs and well-accepted polyploid cancer cells are largely unknown. In this review, the methods used in different studies to induce polyploid cells are summarized, and several mechanisms of polyploidization are demonstrated. Besides, we discuss some characteristics related to the poor prognosis caused by PGCCs in order to provide readers with a more comprehensive understanding of these huge cells.