bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical and Immune Responses of Peripheral Chemical Sympathectomy in Enterovirus 71 Infection
Authors: Liao Yu-Ting , Tsai Huey-Pin , Wang Shih-Min , Chen Shun-Hua
Published: September 2021

The activation of the sympathetic nervous system, release of norepinephrine (NE), and adrenergic receptor signaling participate in and regulate the complicated enterovirus 71 (EV71) brainstem encephalitis (BE). The neurotoxin 6-hydroxydopamine (6-OHDA) selectively ablates sympathetic nerves and markedly depletes NE in innervated organs. Changes in the plasma levels of NE, severity score, cytokine profiles, and percentages of immunophenotype expression in 7-day-old Bltw : CD1 (ICR) mice infected with EV71, with or without 6-OHDA treatment, were compared. The survival rate (76.9%) of EV71-infected and 6-OHDA (30 μg/g)-treated mice was increased significantly. The clinical scores were decreased markedly on days 8-12 in MP4-infected and 6-OHDA-treated mice compared to those without treatment. The results showed that the plasma levels of NE, epinephrine, and dopamine were decreased on days 4–8 after 6-OHDA treatment and at most on day 8. The plasma levels of interleukin (IL)-12p70, tumor necrosis factor, IL-6, and IL-10 did not change significantly after 6-OHDA treatment. Interferon-γ levels decreased evidently on days 4, 6, and 8 after 6-OHDA treatment. The absolute events of CD3+CD4+, CD3+CD8+, and CD3+NK1.1+cells of peripheral blood mononuclear cells were increased significantly in MP4-infected and 6-OHDA-treated mice compared to those without treatment. In splenocytes, the absolute cells of CD3−NK1.1+, CD3+NK1.1+and CD11b+Gr-1+cells of EV71-infected mice were increased significantly after 6-OHDA treatment. These findings suggested that 6-OHDA may be used a probe to explore clinical improvements and immune responses in the complicated EV71 infection. Taken together, peripheral chemical sympathectomy contribute to further understand the immunopathogenesis of EV71 BE with autonomic nervous system dysregulation.
Unraveling the Heterogeneity and Ontogeny of Dendritic Cells Using Single-Cell RNA Sequencing
Authors: Chen Binyao , Zhu Lei , Yang Shizhao , Su Wenru
Published: September 2021

Dendritic cells (DCs) play essential roles in innate and adaptive immunity and show high heterogeneity and intricate ontogeny. Advances in high-throughput sequencing technologies, particularly single-cell RNA sequencing (scRNA-seq), have improved the understanding of DC subsets. In this review, we discuss in detail the remarkable perspectives in DC reclassification and ontogeny as revealed by scRNA-seq. Moreover, the heterogeneity and multifunction of DCs during diseases as determined by scRNA-seq are described. Finally, we provide insights into the challenges and future trends in scRNA-seq technologies and DC research.
The Tec Kinase Itk Integrates Naïve T Cell Migration and In Vivo Homeostasis
Authors: Thelen Flavian , Wissmann Stefanie , Ruef Nora , Stein Jens V.
Published: September 2021

Naïve T cells (TN) constitutively recirculate through secondary lymphatic organs (SLOs), where they scan dendritic cells (DCs) for cognate peptide-loaded major histocompatibility complexes (pMHC). Continuous trafficking between SLOs not only enables rapid clonal selection but also ensures TN homeostasis by providing access to prosurvival signals from TCR, IL-7R, and the chemokine receptor CCR7. Inside the lymphoid tissue, CCR7-mediated TN motility is mainly driven by the Rac activator DOCK2, with a separate contribution by a phosphoinositide-3-kinase γ (PI3Kγ)-dependent pathway. Tec tyrosine kinases and the Rac activator Tiam1 constitute prominent downstream effectors of PI3K signaling. Yet, the precise role of Tec kinase versus Tiam1 signaling during CCR7-mediated TN migration and homeostasis remains incompletely understood. Here, we examined the function of the Tec family member interleukin-2-inducible T-cell kinase (Itk) and Tiam1 during TN migration in vitro and in vivo using intravital microscopy. Itk deficiency caused a mild decrease in CCR7-triggered TN migration, mirroring observations made with PI3Kγ;-/- T cells, while lack of Tiam1 did not affect TN motility. In silico modeling suggested that reduced migration in the absence of Itk does not result in a substantial decrease in the frequency of TN encounters with DCs within the lymphoid tissue. In contrast, Itk was important to maintain in vivo homeostasis of CD4+ TN, also in MHCII-deficient hosts. Taken together, our data suggest that Itk contributes to TN migration and survival by integrating chemokine receptor and TCR signaling pathways.
Immunoregulation by Artemisinin and Its Derivatives: A New Role for Old Antimalarial Drugs
Authors: Qiu Feifei , Liu Junfeng , Mo Xiumei , Liu Huazhen , Chen Yuchao , Dai Zhenhua
Published: September 2021

Artemisinin and its derivatives (ARTs) are known as conventional antimalarial drugs with clinical safety and efficacy. Youyou Tu was awarded a Nobel Prize in Physiology and Medicine due to her discovery of artemisinin and its therapeutic effects on malaria. Apart from antimalarial effects, mounting evidence has demonstrated that ARTs exert therapeutic effects on inflammation and autoimmune disorders because of their anti-inflammatory and immunoregulatory properties. In this aspect, tremendous progress has been made during the past five to seven years. Therefore, the present review summarizes recent studies that have explored the anti-inflammatory and immunomodulatory effects of ARTs on autoimmune diseases and transplant rejection. In this review, we also discuss the cellular and molecular mechanisms underlying the immunomodulatory effects of ARTs. Recent preclinical studies will help lay the groundwork for clinical trials using ARTs to treat various immune-based disorders, especially autoimmune diseases.
Distribution Patterns of Floating Microplastics in Open and Coastal Waters of the Eastern Mediterranean Sea (Ionian, Aegean, and Levantine Seas)
Authors: Adamopoulou Argyro , Zeri Christina , Garaventa Francesca , Gambardella Chiara , Ioakeimidis Christos , Pitta Elli
Published: September 2021

Microplastic pollution is a pervasive anthropogenic phenomenon at the ocean surface. Numerous studies have been performed worldwide; nevertheless, the distribution patterns, morphological properties, and sources of origin in the Eastern Mediterranean Sea are still poorly explored. The purpose of this study is to investigate the distribution patterns of surface floating microplastics (MPs) in the Ionian, Aegean, and Levantine Seas in relation to their sources and sea surface circulation. In total, eighty-four samples were collected using manta nets from 2014 to 2020, covering open waters, coastal waters, and enclosed gulfs (Corfu and Saronikos). MPs concentration measurements revealed high variability ranging from 0.012 to 1.62 items m–2 and did not present maximum concentrations close to MPs hotspot areas. The presence of sea surface slicks, as recorded visually during our samplings, seems to play a key role on the distribution pattern of MPs, and highest concentrations were recorded in samples affected by these formations. The dominant MPs shape type identified were fragments (50–60%), whilst filaments (1–23%), films (3–26%), and foams (0–34%) varied among the studied areas. The majority of MPs in open waters had sizes ≤2 mm peaking between 0.6 and 1.4 mm. Spectroscopic analysis of MPs revealed the presence of 11 polymer types in both open sea and gulfs; the most abundant type was polyethylene (PE), followed by polypropylene (PP), and polystyrene (PS). The relative abundance of polymer types was more diverse in Saronikos Gulf, compared to the open sea due to the proximity to major urban and industrial sources. Our findings suggest that the vicinity to coastal population centers determined the properties, size and polymer types of MPs and highlight that MPs concentrations are affected significantly by local oceanographic conditions, such as surface slicks.
An Asymmetric Silicon Grating Dual-Narrow-Band Perfect Absorber Based on Dielectric-Metal-Dielectric Structure
Authors: Xu Feng , Lin Lixia , Wei Dongwei , Xu Jing , Fang Jun
Published: September 2021

With the exhaustion of world energy, new energy has become the most important content of each country’s development strategy. How to efficiently use solar energy has become a research hotspot in current scientific research. Based on surface plasmon resonance and Fabry-Perot (FP) cavity, this paper proposes a design method of asymmetric silicon grating absorber, and uses finite difference time domain (FDTD) method for simulation calculation. By adjusting the geometric parameters, the asymmetric silicon grating absorber realizes two narrow-band absorption peaks with absorption greater than 99% in the optical wavelength range of 3,000–5,000 nm, and the absorption peak wavelengths are λ1 = 3,780 nm and λ2 = 4,135 nm, respectively. When the electromagnetic wave is incident on the surface of the metamaterial, it will excite the plasmon resonance of the metal to form a surface plasmon (SP) wave. When the SP wave propagates along the x axis, the silicon grating can reflect the SP wave back and forth. When the frequency of the SP wave and the incident light are equal, it will cause horizontal FP coupling resonance, resulting in different resonance wavelengths. This paper also discusses the influence of geometric parameters, incident angle and polarization angle on the performance of silicon grating absorbers. Finally, the sensing performance of the structure as a refractive index sensor is studied. The absorber can be used for various spectral applications such as photon detection, optical filtering and spectral sensing.
Case Report: Potential Role of Corticosteroids in the Management of Post-COVID-19 Pneumonia
Authors: Aissaoui Houari , Eskenazi Anaïs , Suteau Valentin , Adenis Antoine , Drak Alsibai Kinan
Published: September 2021

Certain patients who recover from severe pneumonia due to coronavirus disease 2019 (COVID-19) remain symptomatic in the post-infectious period, either clinically, radiologically, or respiratory. The post-COVID-19 period is characterized by clinical symptoms of varying duration from one subject to another and does not seem to depend on the severity of initial pneumonia. The persisting inflammatory and/or immune reactions in the post-COVID-19 period may play a role in the development of pulmonary lesions. Here, we report the case of a 61-year-old man with severe COVID-19 pneumonia, complicated by acute respiratory distress syndrome and pulmonary embolism, which required the patient's admission to the intensive care unit and high-flow oxygen therapy. The patient was hospitalized for 23 days for the management of his severe COVID-19 pneumonia. Afterwards, he was discharged home following a negative SARS-CoV-2 PCR test. The post-COVID-19 period was characterized by a complex respiratory symptomatology associating cough, resting dyspnea, and exertional dyspnea requiring oxygen therapy for several weeks. Surprisingly, the follow-up chest CT scan performed 4 weeks after discharge revealed bilateral interstitial lung lesions. After ruling out pulmonary superinfection, the patient was treated with oral corticosteroid for 3 months at a digressive dose. In our case, the use of corticosteroid therapy in the post-COVID19 phase had improved the outcome of the lung disease. These benefits are characterized by a rapid symptomatic improvement, accelerated repair of pulmonary images, rapid oxygen withdrawal, and rapid return to daily activities.
Higher-Order Conditioning: What Is Learnt and How it Is Expressed
Authors: Honey Robert C. , Dwyer Dominic M.
Published: September 2021

Pairing a neutral conditioned stimulus (CS) with a motivationally significant unconditioned stimulus (US) results in the CS coming to elicit conditioned responses (CRs). The widespread significance and translational value of Pavlovian conditioning are increased by the fact that pairing two neutral CSs (A and X) enables conditioning with X to affect behavior to A. There are two traditional informal accounts of such higher-order conditioning, which build on more formal associative analyses of Pavlovian conditioning. But, higher-order conditioning and Pavlovian conditioning have characteristics that are beyond these accounts: Notably, the two are influenced in different ways by the same experimental manipulations, and both generate conditioned responses that do not reflect the US per se. Here, we present a formal analysis that sought to address these characteristics.
Visual Explanation for Identification of the Brain Bases for Developmental Dyslexia on fMRI Data
Authors: Tomaz Da Silva Laura , Esper Nathalia Bianchini , Ruiz Duncan D. , Meneguzzi Felipe , Buchweitz Augusto
Published: September 2021

Problem: Brain imaging studies of mental health and neurodevelopmental disorders have recently included machine learning approaches to identify patients based solely on their brain activation. The goal is to identify brain-related features that generalize from smaller samples of data to larger ones; in the case of neurodevelopmental disorders, finding these patterns can help understand differences in brain function and development that underpin early signs of risk for developmental dyslexia. The success of machine learning classification algorithms on neurofunctional data has been limited to typically homogeneous data sets of few dozens of participants. More recently, larger brain imaging data sets have allowed for deep learning techniques to classify brain states and clinical groups solely from neurofunctional features. Indeed, deep learning techniques can provide helpful tools for classification in healthcare applications, including classification of structural 3D brain images. The adoption of deep learning approaches allows for incremental improvements in classification performance of larger functional brain imaging data sets, but still lacks diagnostic insights about the underlying brain mechanisms associated with disorders; moreover, a related challenge involves providing more clinically-relevant explanations from the neural features that inform classification.

Methods: We target this challenge by leveraging two network visualization techniques in convolutional neural network layers responsible for learning high-level features. Using such techniques, we are able to provide meaningful images for expert-backed insights into the condition being classified. We address this challenge using a dataset that includes children diagnosed with developmental dyslexia, and typical reader children.

Results: Our results show accurate classification of developmental dyslexia (94.8%) from the brain imaging alone, while providing automatic visualizations of the features involved that match contemporary neuroscientific knowledge (brain regions involved in the reading process for the dyslexic reader group and brain regions associated with strategic control and attention processes for the typical reader group).

Conclusions: Our visual explanations of deep learning models turn the accurate yet opaque conclusions from the models into evidence to the condition being studied.
Low Diastolic Blood Pressure Predicts Good Clinical Outcome in Patients With Cerebral Venous Thrombosis
Authors: Li Min , Pan Liqun , Gao Xiaogang , Hou Jiaojiao , Meng Ran , Ji Xunming
Published: September 2021

Background: Cerebral venous thrombosis (CVT) refers to a stroke subtype characterized by the disturbance of cerebral venous outflow caused by venous thrombosis. Previous studies have reported a range of factors that predict the prognosis of CVT. This study is aimed to find out whether systolic blood pressure (SBP) and diastolic blood pressure (DBP) are suitable as potential indicators of the severity and clinical outcome in CVT patients.

Methods: The CVT patients admitted to Xuanwu Hospital from January 2014 to December 2019 were enrolled. The severity of CVT was assessed by the National Institute of Health Stroke Scale (NIHSS) and intracranial pressure (ICP) at the time of admission. The modified Rankin score (mRS) was assessed at 6 months of follow-up.

Results: One hundred fifty-six CVT patients were enrolled with a mean age of 35.8 ± 12.8 years. A percentage of 55.8% of the CVT patients recruited were female, and 17.3% were either pregnant or in perinatal period. Headache was the most common symptom. SBP and DBP were not correlated with NIHSS at admission. Furthermore, SBP and DBP had no impact on the disturbance of consciousness, epilepsy, intracranial hemorrhage, and mental disorders. However, SBP and DBP were positively correlated with ICP at admission. SBP > 129.5 mmHg and/or DBP > 77.5 mmHg suggested the presence of intracranial hypertension (IH). Based on current results, SBP was not correlated with mRS at 6 months of follow-up. However, DBP was found to be positively correlated with mRS at 6 months of follow-up. DBP in CVT patients with good prognosis was significantly lower than in those with poor prognosis. DBP > 79.5 mmHg was identified as a cutoff value to predict a poor clinical outcome. A higher mRS and a higher rate of poor clinical outcome were found in CVT patients with SBP > 146 mmHg or DBP > 79.5 mmHg compared to those with SBP ≤ 146 mmHg or DBP ≤ 79.5 mmHg.

Conclusion: SBP > 129.5 mmHg and DBP > 77.5 mmHg suggested the presence of IH in CVT patients. DBP > 79.5 mmHg predicted a poor clinical outcome.
MRI Patterns Distinguish AQP4 Antibody Positive Neuromyelitis Optica Spectrum Disorder From Multiple Sclerosis
Authors: Clarke Laura , Arnett Simon , Bukhari Wajih , Khalilidehkordi Elham , Jimenez Sanchez Sofia , O'Gorman Cullen , Sun Jing , Prain Kerri M. , Woodhall Mark , Silvestrini Roger , Bundell Christine S. , Abernethy David A. , Bhuta Sandeep , Blum Stefan , Boggild Mike , Boundy Karyn , Brew Bruce J. , Brownlee Wallace , Butzkueven Helmut , Carroll William M. , Chen Cella , Coulthard Alan , Dale Russell C. , Das Chandi , Fabis-Pedrini Marzena J. , Gillis David , Hawke Simon , Heard Robert , Henderson Andrew P. D. , Heshmat Saman , Hodgkinson Suzanne , Kilpatrick Trevor J. , King John , Kneebone Christopher , Kornberg Andrew J. , Lechner-Scott Jeannette , Lin Ming-Wei , Lynch Christopher , Macdonell Richard A. L. , Mason Deborah F. , McCombe Pamela A. , Pereira Jennifer , Pollard John D. , Ramanathan Sudarshini , Reddel Stephen W. , Shaw Cameron P. , Spies Judith M. , Stankovich James , Sutton Ian , Vucic Steve , Walsh Michael , Wong Richard C. , Yiu Eppie M. , Barnett Michael H. , Kermode Allan G. K. , Marriott Mark P. , Parratt John D. E. , Slee Mark , Taylor Bruce V. , Willoughby Ernest , Brilot Fabienne , Vincent Angela , Waters Patrick , Broadley Simon A.
Published: September 2021

Neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS) are inflammatory diseases of the CNS. Overlap in the clinical and MRI features of NMOSD and MS means that distinguishing these conditions can be difficult. With the aim of evaluating the diagnostic utility of MRI features in distinguishing NMOSD from MS, we have conducted a cross-sectional analysis of imaging data and developed predictive models to distinguish the two conditions. NMOSD and MS MRI lesions were identified and defined through a literature search. Aquaporin-4 (AQP4) antibody positive NMOSD cases and age- and sex-matched MS cases were collected. MRI of orbits, brain and spine were reported by at least two blinded reviewers. MRI brain or spine was available for 166/168 (99%) of cases. Longitudinally extensive (OR = 203), “bright spotty” (OR = 93.8), whole (axial; OR = 57.8) or gadolinium (Gd) enhancing (OR = 28.6) spinal cord lesions, bilateral (OR = 31.3) or Gd-enhancing (OR = 15.4) optic nerve lesions, and nucleus tractus solitarius (OR = 19.2), periaqueductal (OR = 16.8) or hypothalamic (OR = 7.2) brain lesions were associated with NMOSD. Ovoid (OR = 0.029), Dawson's fingers (OR = 0.031), pyramidal corpus callosum (OR = 0.058), periventricular (OR = 0.136), temporal lobe (OR = 0.137) and T1 black holes (OR = 0.154) brain lesions were associated with MS. A score-based algorithm and a decision tree determined by machine learning accurately predicted more than 85% of both diagnoses using first available imaging alone. We have confirmed NMOSD and MS specific MRI features and combined these in predictive models that can accurately identify more than 85% of cases as either AQP4 seropositive NMOSD or MS.
Assessing the Relative Value of CT Perfusion Compared to Non-contrast CT and CT Angiography in Prognosticating Reperfusion-Eligible Acute Ischemic Stroke Patients
Authors: Bivard Andrew , Levi Christopher , Lin Longting , Cheng Xin , Aviv Richard , Spratt Neil J. , Kleinig Tim , Butcher Kenneth , Chen Chushuang , Dong Qiang , Parsons Mark
Published: September 2021

In the present study we sought to measure the relative statistical value of various multimodal CT protocols at identifying treatment responsiveness in patients being considered for thrombolysis. We used a prospectively collected cohort of acute ischemic stroke patients being assessed for IV-alteplase, who had CT-perfusion (CTP) and CT-angiography (CTA) before a treatment decision. Linear regression and receiver operator characteristic curve analysis were performed to measure the prognostic value of models incorporating each imaging modality. One thousand five hundred and sixty-two sub-4.5 h ischemic stroke patients were included in this study. A model including clinical variables, alteplase treatment, and NCCT ASPECTS was weak (R2 0.067, P < 0.001, AUC 0.605) at predicting 90 day mRS. A second model, including dynamic CTA variables (collateral grade, occlusion severity) showed better predictive accuracy for patient outcome (R2 0.381, P < 0.001, AUC 0.781). A third model incorporating CTP variables showed very high predictive accuracy (R2 0.488, P < 0.001, AUC 0.899). Combining all three imaging modalities variables also showed good predictive accuracy for outcome but did not improve on the CTP model (R2 0.439, P < 0.001, AUC 0.825). CT perfusion predicts patient outcomes from alteplase therapy more accurately than models incorporating NCCT and/or CT angiography. This data has implications for artificial intelligence or machine learning models.
Effect of Seat Backrest Inclination on the Muscular Pattern and Biomechanical Parameters of the Sit-to-Stand
Authors: Tebbache Nadège , Hamaoui Alain
Published: September 2021

Objectives:The sit-to-stand (STS) transfer mobilizes an extended part of the kinematic chain throughout a postural phase characterized by a flexion of the trunk and a focal phase consisting of a whole-body extension. The aim of this study was to analyze the variations of the global muscular pattern and the biomechanical parameters in both phases, in relation with seat backrest inclination.

Methods:Fifteen participants were asked to stand up from a seat with 5 backrest inclination settings and at 2 execution speeds. The ground reaction forces and the activity levels of fifteen muscles of the trunk and lower limbs were investigated.

Results:Backrest-induced modifications were mainly observed in the postural phase: inclining the backrest backward increased the phase duration and the activity level of the sternocleidomastoideus and the rectus abdominis, while it reduced the activity of the tibialis anterior. It also allowed for an increased maximal anteroposterior velocity of the body center of mass. Higher execution speed led to increased and earlier muscular activities of many trunk and lower limbs muscles, predominantly in the postural phase.

Discussion:Taken together, these results suggest that a greater backrest inclination increases the demand in the postural phase due to the increase of the upper body gravity torque about the ischial tuberosities, and requires an adaptation of muscular activity levels and timing, but with the same overall pattern. The kinetic energy gained during the longer excursion of the trunk may also require less activation of the lower limbs muscles involved in the generation of propulsive forces of the body.
Positive Effects of Education on Cognitive Functioning Depend on Clinical Status and Neuropathological Severity
Authors: Jansen Michelle G. , Geerligs Linda , Claassen Jurgen A. H. R. , Overdorp Eduard J. , Brazil Inti A. , Kessels Roy P. C. , Oosterman Joukje M.
Published: September 2021

Background: Variability in cognitive functions in healthy and pathological aging is often explained by educational attainment. However, it remains unclear to which extent different disease states alter protective effects of education. We aimed to investigate whether protective effects of education on cognition depend on (1) clinical diagnosis severity, and (2) the neuropathological burden within a diagnosis in a memory clinic setting.

Methods: In this cross-sectional study, we included 108 patients with subjective cognitive decline [SCD, median age 71, IQR (66–78), 43% men], 190 with mild cognitive impairment [MCI, median age 78, IQR (73–82), 44% men], and 245 with Alzheimer’s disease dementia (AD) [median age 80, IQR (76–84), 35% men]. We combined visual ratings of hippocampal atrophy, global atrophy, and white matter hyperintensities on MRI into a single neuropathology score. To investigate whether the contribution of education to cognitive performance differed across SCD, MCI, and AD, we employed several multiple linear regression models, stratified by diagnosis and adjusted for age, sex, and neurodegeneration. We re-ran each model with an additional interaction term to investigate whether these effects were influenced by neuropathological burden for each diagnostic group separately. False discovery rate (FDR) corrections for multiple comparisons were applied.

Results: We observed significant positive associations between education and performance for global cognition and executive functions (all adjusted p-values < 0.05). As diagnosis became more severe, however, the strength of these associations decreased (all adjusted p-values < 0.05). Education related to episodic memory only at relatively lower levels of neuropathology in SCD (β = −0.23, uncorrected p = 0.02), whereas education related to episodic memory in those with higher levels of neuropathology in MCI (β = 0.15, uncorrected p = 0.04). However, these interaction effects did not survive FDR-corrections.

Conclusions: Altogether, our results demonstrated that positive effects of education on cognitive functioning reduce with diagnosis severity, but the role of neuropathological burden within a particular diagnosis was small and warrants further investigation. Future studies may further unravel the extent to which different dimensions of an individual’s disease severity contribute to the waxing and waning of protective effects in cognitive aging.
Suppression and Rebound of Pallidal Beta Power: Observation Using a Chronic Sensing DBS Device
Authors: Cagle Jackson N. , Wong Joshua K. , Johnson Kara A. , Foote Kelly D. , Okun Michael S. , de Hemptinne Coralie
Published: September 2021

Pallidal deep brain stimulation (DBS) is an increasingly used therapy for Parkinson’s disease (PD). Here, we study the effect of DBS on pallidal oscillatory activity as well as on symptom severity in an individual with PD implanted with a new pulse generator (Medtronic Percept system) which facilitates chronic recording of local field potentials (LFP) through implanted DBS lead. Pallidal LFPs were recorded while delivering stimulation in a monopolar configuration using stepwise increments (0.5 mA, every 20 s). At each stimulation amplitude, the power spectral density (PSD) was computed, and beta power (13–30 Hz) was calculated and correlated with the degree of bradykinesia. Pallidal beta power was reduced when therapeutic stimulation was delivered. Beta power correlated to the severity of bradykinesia. Worsening of parkinsonism when excessive stimulation was applied was associated with a rebound in the beta band power. These preliminary results suggest that pallidal beta power might be used as an objective marker of the disease state in PD. The use of brain sensing from implanted neural interfaces may in the future facilitate clinical programming. Detection of rebound could help to optimize benefits and minimize worsening from overstimulation.
Single-Cell RNA-Seq of Cisplatin-Treated Adult Stria Vascularis Identifies Cell Type-Specific Regulatory Networks and Novel Therapeutic Gene Targets
Authors: Taukulis Ian A. , Olszewski Rafal T. , Korrapati Soumya , Fernandez Katharine A. , Boger Erich T. , Fitzgerald Tracy S. , Morell Robert J. , Cunningham Lisa L. , Hoa Michael
Published: September 2021

The endocochlear potential (EP) generated by the stria vascularis (SV) is necessary for hair cell mechanotransduction in the mammalian cochlea. We sought to create a model of EP dysfunction for the purposes of transcriptional analysis and treatment testing. By administering a single dose of cisplatin, a commonly prescribed cancer treatment drug with ototoxic side effects, to the adult mouse, we acutely disrupt EP generation. By combining these data with single cell RNA-sequencing findings, we identify transcriptional changes induced by cisplatin exposure, and by extension transcriptional changes accompanying EP reduction, in the major cell types of the SV. We use these data to identify gene regulatory networks unique to cisplatin treated SV, as well as the differentially expressed and druggable gene targets within those networks. Our results reconstruct transcriptional responses that occur in gene expression on the cellular level while identifying possible targets for interventions not only in cisplatin ototoxicity but also in EP dysfunction.
Optimization of γ-Aminobutyric Acid (GABA) Accumulation in Germinating Adzuki Beans (Vigna angularis) by Vacuum Treatment and Monosodium Glutamate, and the Molecular Mechanisms
Authors: Jiang Xiujie , Xu Qingpeng , Zhang Aiwu , Liu Yong , Zhao Liqin , Gu Liwei , Yuan Jianbin , Jia Hongdou , Shen Xinting , Li Zhijiang , Cao Dongmei , Zhang Dongjie
Published: September 2021

This study aimed to investigate the optimal hypoxic and monosodium glutamate (MSG) stress conditions for the enrichment of γ-Aminobutyric acid (GABA) in germinating adzuki beans and to reveal the potential underlying molecular mechanisms of GABA accumulation. Using single-factor experiments and response surface model, we investigated the effects of germination time, germination temperature, vacuum time, and MSG concentration on GABA contents, and further explored the activity and gene expression of glutamate decarboxylase (GAD) and polyamine oxidase (PAO) critical rate restriction enzymes during GABA synthesis. The optimal soaking temperature, soaking time, and pH conditions were 35°C, 16 h, and 5, respectively. Furthermore, the optimal germination conditions for optimal GABA enrichment were 48 h, 1.99 mg/ml MSG concentration, germination temperature of 31.49°C, and vacuum time of 15.83 h. Under such conditions, the predicted GABA concentration was 443.57 ± 7.18 mg/100 g, with no significant difference between the predicted and experimental data. The vacuum + MSG (FZM) treatment has a maximum contribution rate of GABA to 38.29%, which significantly increase GABA content, and the increase was associated with increased GAD and PAO activity. In addition, MSG in combination with vacuum treatment could significantly induce VaGAD4 and VaGAD6 genes in 2 days germination of adzuki beans. According to the results of the present study, vacuum + MSG treatment is an effective approach to enhancing GABA accumulation in germinating adzuki beans, which could be employed in enhancing the functional quality of germinating adzuki beans.
Xylo-Oligosaccharides, Preparation and Application to Human and Animal Health: A Review
Authors: Chen Yuxia , Xie Yining , Ajuwon Kolapo M. , Zhong Ruqing , Li Tao , Chen Liang , Zhang Hongfu , Beckers Yves , Everaert Nadia
Published: September 2021

Xylo-oligosaccharides (XOS) are considered as functional oligosaccharides and have great prebiotic potential. XOS are the degraded products of xylan prepared via chemical, physical or enzymatic degradation. They are mainly composed of xylose units linked by β-1, 4 bonds. XOS not only exhibit some specific physicochemical properties such as excellent water solubility and high temperature resistance, but also have a variety of functional biological activities including anti-inflammation, antioxidative, antitumor, antimicrobial properties and so on. Numerous studies have revealed in the recent decades that XOS can be applied to many food and feed products and exert their nutritional benefits. XOS have also been demonstrated to reduce the occurrence of human health-related diseases, improve the growth and resistance to diseases of animals. These effects open a new perspective on XOS potential applications for human consumption and animal production. Herein, this review aims to provide a general overview of preparation methods for XOS, and will also discuss the current application of XOS to human and animal health field.
Evaluation of Traditional Prognostic Factors for Stage I-III Colorectal Cancer Patients Who Survived for Over Five Years After Surgery
Authors: Luo Dakui , Yang Yufei , Shan Zezhi , Liu Qi , Cai Sanjun , Li Qingguo , Li Xinxiang
Published: September 2021

The aim of this study was to explore the prognostic factors in stage I-III colorectal cancer (CRC) patients who had survived for over five years. A total of 9754 stage I-III CRC patients who received curative surgery in the Department of Colorectal Surgery, Fudan University Shanghai Cancer Center were enrolled in this study. Of them, 3640 patients had survived for over five years after surgery. Univariate and multivariate Cox regression analyses were performed in the entire cohort and those who had survived for over five years. Compared with patients in the entire cohort, patients who had survived for over five years were more likely to be younger, have less disease of signet ring cell histology, perineural invasion and vascular invasion, more well differentiated tumors and stage I disease. In the entire cohort, increased age, signet ring cell, poor differentiation, more advanced pathological stage, perineural invasion and vascular invasion were inversely associated with disease-free survival (DFS) and overall survival (OS) using multivariable Cox regression analyses. Only age, pathological stage and perineural invasion remained significant in patients who had survived for over five years. Moreover, tumor location was an independent factor for OS in this subgroup. Predictors for prognosis of CRC change over time. Age, pathological stage and perineural invasion deserve more attention among patients who have survived for over five years.
Mammary Tumorigenesis and Metabolome in Male Adipose Specific Monocyte Chemotactic Protein-1 Deficient MMTV-PyMT Mice Fed a High-Fat Diet
Authors: Yan Lin , Sundaram Sneha , Rust Bret M. , Picklo Matthew J. , Bukowski Michael R.
Published: September 2021

Male breast cancer, while uncommon, is a highly malignant disease. Monocyte chemotactic protein-1 (MCP-1) is an adipokine; its concentration in adipose tissue is elevated in obesity. This study tested the hypothesis that adipose-derived MCP-1 contributes to male breast cancer. In a 2x2 design, male MMTV-PyMT mice with or without adipose-specific Mcp-1 knockout [designated as Mcp-1-/- or wild-type (WT)] were fed the AIN93G standard diet or a high-fat diet (HFD) for 25 weeks. Mcp-1-/- mice had lower adipose Mcp-1 expression than WT mice. Adipose Mcp-1 deficiency reduced plasma concentrations of MCP-1 in mice fed the HFD compared to their WT counterparts. Mcp-1-/- mice had a longer tumor latency (25.2 weeks vs. 18.0 weeks) and lower tumor incidence (19% vs. 56%), tumor progression (2317% vs. 4792%), and tumor weight (0.23 g vs. 0.64 g) than WT mice. Plasma metabolomics analysis identified 56 metabolites that differed among the four dietary groups, including 22 differed between Mcp-1-/- and WT mice. Pathway and network analyses along with discriminant analysis showed that pathways of amino acid and carbohydrate metabolisms are the most disturbed in MMTV-PyMT mice. In conclusion, adipose-derived MCP-1 contributes to mammary tumorigenesis in male MMTV-PyMT. The potential involvement of adipose-derived MCP-1 in metabolomics warrants further investigation on its role in causal relationships between cancer metabolism and mammary tumorigenesis in this male MMTV-PyMT model.
The Clinicopathological and Prognostic Significance of SOX9 Expression in Gastric Cancer: Meta-Analysis and TCGA Analysis
Authors: Zu Guo , Gao Jiacheng , Zhou Tingting
Published: September 2021

Background

The clinicopathological and prognostic significance of SRY-box transcription factor 9 (SOX9) expression in gastric cancer (GC) patients is still controversial. Our aim is to investigate the clinicopathological and prognostic value of SOX9 expression in GC patients.

Methods

A systemic literature search and meta-analysis were used to evaluate the clinicopathological significance and overall survival (OS) of SOX9 expression in GC patients. The Cancer Genome Atlas (TCGA) dataset was used to investigate the relationship between SOX9 expression and OS of stomach adenocarcinoma (STAD) patients.

Results

A total of 11 articles involving 3,060 GC patients were included. In GC patients, the SOX9 expression was not associated with age [odds ratio (OR) = 0.743, 95% CI = 0.507–1.089, p = 0.128], sex (OR = 0.794, 95% CI = 0.605–1.042, p = 0.097), differentiation (OR = 0.728, 95% CI = 0.475–1.115, p = 0.144), and lymph node metastasis (OR = 1.031, 95% CI = 0.793–1.340, p = 0.820). SOX9 expression was associated with depth of invasion (OR = 0.348, 95% CI = 0.247–0.489, p = 0.000) and TNM stage (OR = 0.428, 95% CI = 0.308–0.595, p = 0.000). The 1-year OS (OR = 1.507, 95% CI = 1.167–1.945, p = 0.002), 3-year OS (OR = 1.482, 95% CI = 1.189–1.847, p = 0.000), and 5-year OS (OR = 1.487, 95% CI = 1.187–1.862, p = 0.001) were significantly shorter in GC patients with high SOX9 expression. TCGA analysis showed that SOX9 was upregulated in STAD patients compared with that in normal patients (p < 0.001), and the OS of STAD patients with a high expression of SOX9 is poorer than that in patients with low expression of SOX9, but the statistical difference is not obvious (p = 0.31).

Conclusion

SOX9 expression was associated with the depth of tumor invasion, TNM stage, and poor OS of GC patients. SOX9 may be a potential prognostic factor for GC patients but needs further study.

Systematic Review Registration

PROSPERO, ID NUMBER 275712.
Identification of Iron Metabolism-Related Genes as Prognostic Indicators for Lower-Grade Glioma
Authors: Xu Shenbin , Wang Zefeng , Ye Juan , Mei Shuhao , Zhang Jianmin
Published: September 2021

Lower-grade glioma (LGG) is characterized by genetic and transcriptional heterogeneity, and a dismal prognosis. Iron metabolism is considered central for glioma tumorigenesis, tumor progression and tumor microenvironment, although key iron metabolism-related genes are unclear. Here we developed and validated an iron metabolism-related gene signature LGG prognosis. RNA-sequence and clinicopathological data from The Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA) were downloaded. Prognostic iron metabolism-related genes were screened and used to construct a risk-score model via differential gene expression analysis, univariate Cox analysis, and the Least Absolute Shrinkage and Selection Operator (LASSO)-regression algorithm. All LGG patients were stratified into high- and low-risk groups, based on the risk score. The prognostic significance of the risk-score model in the TCGA and CGGA cohorts was evaluated with Kaplan-Meier (KM) survival and receiver operating characteristic (ROC) curve analysis. Risk- score distributions in subgroups were stratified by age, gender, the World Health Organization (WHO) grade, isocitrate dehydrogenase 1 (IDH1) mutation status, the O6‐methylguanine‐DNA methyl‐transferase (MGMT) promoter-methylation status, and the 1p/19q co-deletion status. Furthermore, a nomogram model with a risk score was developed, and its predictive performance was validated with the TCGA and CGGA cohorts. Additionally, the gene set enrichment analysis (GSEA) identified signaling pathways and pathological processes enriched in the high-risk group. Finally, immune infiltration and immune checkpoint analysis were utilized to investigate the tumor microenvironment characteristics related to the risk score. We identified a prognostic 15-gene iron metabolism-related signature and constructed a risk-score model. High risk scores were associated with an age of > 40, wild-type IDH1, a WHO grade of III, an unmethylated MGMT promoter, and 1p/19q non-codeletion. ROC analysis indicated that the risk-score model accurately predicted 1-, 3-, and 5-year overall survival rates of LGG patients in the both TCGA and CGGA cohorts. KM analysis showed that the high-risk group had a much lower overall survival than the low-risk group (P < 0.0001). The nomogram model showed a strong ability to predict the overall survival of LGG patients in the TCGA and CGGA cohorts. GSEA analysis indicated that inflammatory responses, tumor-associated pathways, and pathological processes were enriched in high-risk group. Moreover, a high risk score correlated with the infiltration immune cells (dendritic cells, macrophages, CD4+ T cells, and B cells) and expression of immune checkpoint (PD1, PDL1, TIM3, and CD48). Our prognostic model was based on iron metabolism-related genes in LGG, can potentially aid in LGG prognosis, and provides potential targets against gliomas.
Case Report: Contrasting BCL2 Upregulation With Venetoclax in a Case of Refractory Lymphomatoid Papulosis and Progressive Chronic Lymphocytic Leukemia
Authors: Guarente Valerio , Martino Giovanni , Dorillo Erica , De Falco Filomena , Rompietti Chiara , Sorcini Daniele , Brogna Mariangela , Cardinali Valeria , Ascani Stefano , Marra Andrea , Sportoletti Paolo
Published: September 2021

A 57-year-old man affected by high-risk progressive chronic lymphocytic leukemia (CLL), primary resistant to first-line chemoimmunotherapy, developed a type A lymphomatoid papulosis (LyP) during a second progression of CLL. The two blood tumor entities were clonally unrelated. LyP presented with a diffuse (>90% body surface area) cutaneous rash and was characterized by intensely pruriginous dusky nodules (n = 10) and red flat-topped papules (n = 60). No response to topical corticosteroids and psoralen plus ultraviolet A (PUVA) phototherapy was observed. In order to effectively treat progressiveTP53-mutated CLL, the potent BCL2 inhibitor, venetoclax, was initiated with no treatment-related complications. While CLL only achieved a partial response, a complete remission of LyP-associated cutaneous rash and of the intractable pruritus was obtained within 2 months from venetoclax initiation. BCL2 immunostaining of the original cutaneous specimen showed a strong over-expression of the anti-apoptotic protein, restricted to CD30+lymphoid cells and reactive microenvironment. At 12 months follow-up, the patient is still in complete remission of LyP. Our findings underline the probable pathogenic role of BCL2 in LyP and the potential therapeutic efficacy of venetoclax for the treatment of this primary cutaneous CD30+lymphoproliferative disorder, especially in the setting of severe and refractory disease.
Comprehensive Molecular Analyses of a Six-Gene Signature for Predicting Late Recurrence of Hepatocellular Carcinoma
Authors: Zhang Yuyuan , Liu Zaoqu , Li Xin , Liu Long , Wang Libo , Han Xinwei , Li Zhen
Published: September 2021

A larger number of patients with stages I–III hepatocellular carcinoma (HCC) experience late recurrence (LR) after surgery. We sought to develop a novel tool to stratify patients with different LR risk for tailoring decision-making for postoperative recurrence surveillance and therapy modalities. We retrospectively enrolled two independent public cohorts and 103 HCC tissues. Using LASSO logical analysis, a six-gene model was developed in the The Cancer Genome Atlas liver hepatocellular carcinoma (TCGA-LIHC) and independently validated in GSE76427. Further experimental validation using qRT-PCR assays was performed to ensure the robustness and clinical feasible of this signature. We developed a novel LR-related signature consisting of six genes. This signature was validated to be significantly associated with dismal recurrence-free survival in three cohorts TCGA-LIHC, GSE76427, and qPCR assays [HR: 2.007 (1.200–3.357), p = 0.008; HR: 2.171 (1.068, 4.412), p-value = 0.032; HR: 3.383 (2.100, 5.450), p-value <0.001]. More importantly, this signature displayed robust discrimination in predicting the LR risk, with AUCs being 0.73 (TCGA-LIHC), 0.93 (GSE76427), and 0.85 (in-house cohort). Furthermore, we deciphered the specific landscape of molecular alterations among patients in nonrecurrence (NR) and LR group to analyze the mechanism contributing to LR. For high-risk group, we also identified several potential drugs with specific sensitivity to high- and low-risk groups, which is vital to improve prognosis of LR-HCC after surgery. We discovered and experimentally validated a novel gene signature with powerful performance for identifying patients at high LR risk in stages I–III HCC.
Paclitaxel Inhibits Synoviocyte Migration and Inflammatory Mediator Production in Rheumatoid Arthritis
Authors: Chen Xiaochen , Lin Haofeng , Chen Jinyang , Wu Lisheng , Zhu Junqing , Ye Yongnong , Chen Shixian , Du Hongyan , Li Juan
Published: September 2021

Activated fibroblast-like synoviocytes (FLSs) play a crucial role in the pathogenesis and progression of rheumatoid arthritis (RA). It is urgent to develop new drugs that can effectively inhibit the abnormal activation of RA-FLS. In our study, the RA-FLS cell line, MH7A, and mice with collagen-induced arthritis (CIA) were used to evaluate the effect of paclitaxel (PTX). Based on the results, PTX inhibited the migration of RA-FLS in a dose-dependent manner and significantly reduced the spontaneous expression of IL-6, IL-8, and RANKL mRNA and TNF-α-induced transcription of the IL-1β, IL-8, MMP-8, and MMP-9 genes. However, PTX had no significant effect on apoptosis in RA-FLS. Mechanistic studies revealed that PTX significantly inhibited the TNF-α-induced phosphorylation of ERK1/2 and JNK in the mitogen-activated protein kinase (MAPK) pathway and suppressed the TNF-α-induced activation of AKT, p70S6K, 4EBP1, and HIF-1α in the AKT/mTOR pathway. Moreover, PTX alleviated synovitis and bone destruction in CIA mice. In conclusion, PTX inhibits the migration and inflammatory mediator production of RA-FLS by targeting the MAPK and AKT/mTOR signaling pathways, which provides an experimental basis for the potential application in the treatment of RA.
Integrating Network Pharmacology and RT-qPCR Analysis to Investigate the Mechanisms Underlying ZeXie Decoction-Mediated Treatment of Non-alcoholic Fatty Liver Disease
Authors: Wu Jiashuo , Zhang Fangqing , Ruan Haonan , Chang Xiaoyan , Wang Jingxun , Li Zhuangzhuang , Jin Weiyi , Shi Yue
Published: September 2021

ZeXie Decoction (ZXD) is a traditional Chinese medicine composed ofAlisma orientalis(Sam.) Juzep. andAtractylodes macrocephalaKoidz. ZXD has been widely used to treat non-alcoholic fatty liver disease (NAFLD). The mechanistic basis for the pharmacological activity of ZXD, however, remains poorly understood. In this study, we used a network pharmacology approach and investigated the association between ZXD and NAFLD. We identified the active ingredients of ZXD and screened the potential targets of these ingredients, after which a database of relevant NAFLD-related targets were constructed and several enrichment analyses were performed. Furthermore, the ethanol and aqueous extracts of ZXD were prepared and experimental pharmacology validation was conducted using RT-qPCR of the non-alcoholic fatty liver disease (NAFLD) model in Sprague-Dawley (SD) rats. As a result, a herb-compound-target-pathway network model was developed, and HMGCR, SREBP-2, MAPK1, and NF-κBp65 targets were validated. The gene expression results of these four targets were consistent with those of the network pharmacology prediction. Using an integration strategy, we revealed that ZXD could treat NAFLD by targeting HMGCR, SREBP-2, MAPK1, and NF-κBp65.