bluuebunny/crossref_metadata_2025 huggingface dataset:
Interaction Between LncRNA and UPF1 in Tumors
Authors: He Junjian , Ma Xiaoxin
Published: March 2021

Long non-coding RNAs (LncRNAs) can bind to other proteins or RNAs to regulate gene expression, and its role in tumors has been extensively studied. A common RNA binding protein, UPF1, is also a key factor in a variety of RNA decay pathways. RNA decay pathways serve to control levels of particular RNA molecules. The expression of UPF1 is often dysregulated in tumors, an observation which suggests that UPF1 contributes to development of a variety of tumors. Herein, we review evidence from studies of fourteen lncRNAs interact with UPF1. The interaction between lncRNA and UPFI provide fundamental basis for cell transformation and tumorigenic growth.
SARS-CoV-2 Causes a Different Cytokine Response Compared to Other Cytokine Storm-Causing Respiratory Viruses in Severely Ill Patients
Authors: Olbei Marton , Hautefort Isabelle , Modos Dezso , Treveil Agatha , Poletti Martina , Gul Lejla , Shannon-Lowe Claire D. , Korcsmaros Tamas
Published: March 2021

Hyper-induction of pro-inflammatory cytokines, also known as a cytokine storm or cytokine release syndrome (CRS), is one of the key aspects of the currently ongoing SARS-CoV-2 pandemic. This process occurs when a large number of innate and adaptive immune cells activate and start producing pro-inflammatory cytokines, establishing an exacerbated feedback loop of inflammation. It is one of the factors contributing to the mortality observed with coronavirus 2019 (COVID-19) for a subgroup of patients. CRS is not unique to the SARS-CoV-2 infection; it was prevalent in most of the major human coronavirus and influenza A subtype outbreaks of the past two decades (H5N1, SARS-CoV, MERS-CoV, and H7N9). With a comprehensive literature search, we collected changing the cytokine levels from patients upon infection with the viral pathogens mentioned above. We analyzed published patient data to highlight the conserved and unique cytokine responses caused by these viruses. Our curation indicates that the cytokine response induced by SARS-CoV-2 is different compared to other CRS-causing respiratory viruses, as SARS-CoV-2 does not always induce specific cytokines like other coronaviruses or influenza do, such as IL-2, IL-10, IL-4, or IL-5. Comparing the collated cytokine responses caused by the analyzed viruses highlights a SARS-CoV-2-specific dysregulation of the type-I interferon (IFN) response and its downstream cytokine signatures. The map of responses gathered in this study could help specialists identify interventions that alleviate CRS in different diseases and evaluate whether they could be used in the COVID-19 cases.
The SWI/SNF-Related, Matrix Associated, Actin-Dependent Regulator of Chromatin A4 Core Complex Represses Respiratory Syncytial Virus-Induced Syncytia Formation and Subepithelial Myofibroblast Transition
Authors: Xu Xiaofang , Qiao Dianhua , Dong Chenyang , Mann Morgan , Garofalo Roberto P. , Keles Sunduz , Brasier Allan R.
Published: March 2021

Epigenetics plays an important role in the priming the dynamic response of airway epithelial cells to infectious and environmental stressors. Here, we examine the epigenetic role of the SWI/SNF Related, Matrix Associated, Actin Dependent Regulator of Chromatin A4 (SMARCA4) in the epithelial response to RSV infection. Depletion of SMARCA4 destabilized the abundance of the SMARCE1/ARID1A SWI/SNF subunits, disrupting the innate response and triggering a hybrid epithelial/mesenchymal (E/M) state. Assaying SMARCA4 complex-regulated open chromatin domains by transposase cleavage -next generation sequencing (ATAC-Seq), we observed that the majority of cleavage sites in uninfected cells have reduced chromatin accessibility. Paradoxically, SMARCA4 complex-depleted cells showed enhanced RSV-inducible chromatin opening and gene expression in the EMT pathway genes, MMP9, SNAI1/2, VIM, and CDH2. Focusing on the key MMP9, we observed that SMARCA4 complex depletion reduced basal BRD4 and RNA Polymerase II binding, but enhanced BRD4/Pol II binding in response to RSV infection. In addition, we observed that MMP9 secretion in SMARCA4 complex deficient cells contributes to mesenchymal transition, cellular fusion (syncytia) and subepithelial myofibroblast transition. We conclude the SMARCA4 complex is a transcriptional repressor of epithelial plasticity, whose depletion triggers a hybrid E/M state that affects the dynamic response of the small airway epithelial cell in mucosal remodeling via paracrine MMP9 activity.
Follow-Up Study of the Chest CT Characteristics of COVID-19 Survivors Seven Months After Recovery
Authors: Liu Mengqi , Lv Fajin , Huang Yang , Xiao Kaihu
Published: March 2021

Background: It has remained a concern whether any long-term pulmonary sequelae exist for COVID-19 survivors.

Methods: Forty-one patients (22 men and 19 women, 50 ± 14 years) confirmed with COVID-19 performed follow-up chest CT and cardiopulmonary exercise testing at 7 months after discharge. Patients were divided into fibrosis group and non-fibrosis group according to the evidence of fibrosis on follow-up CT. The clinical data and the CT findings were recorded and analyzed.

Results: The predominant CT patterns of abnormalities observed at 7 months after discharge were parenchymal band (41%), interlobular septal thickening (32%), and traction bronchiectasis (29%). Sixty-one percent of the patients achieved complete radiological resolution, and 29% of patients developed pulmonary fibrosis. Compared with the patients in the non-fibrosis group, the patients in the fibrosis group were older, with a longer hospital stay, a higher rate of steroid and mechanical ventilation therapy, lower levels of lymphocyte and T cell count, higher levels of D-dimer and lactic dehydrogenase, and higher quantitative CT parameters (opacity score, volume of opacity, and percentage of opacity) at discharge. Besides, oxygen consumption and metabolic equations were decreased and ventilatory equivalent for carbon dioxide was increased in patients in the fibrosis group. Logistic regression analyses revealed that age, steroid therapy, presence of traction bronchiectasis on chest CT at discharge, and opacity score at discharge, were independent risk factors for developing pulmonary fibrosis at 7 months after discharge. Receiver operating characteristic analysis revealed that the combined clinical-radiological model was better than the clinical-only model in the prediction of pulmonary fibrosis.

Conclusions: The chest CT lesions could be absorbed without any sequelae for most patients with COVID-19, whereas older patients with severe conditions are more prone to develop fibrosis, which may further lead to cardiopulmonary insufficiency. The combined clinical-radiological model may predict the formation of pulmonary fibrosis early.
AtaT Improves the Stability of Pore-Forming Protein EspB by Acetylating Lysine 206 to Enhance Strain Virulence
Authors: He Zhili , Li Tao , Wang Jianxin , Luo Deyan , Ning Nianzhi , Li Zhan , Chen Fanghong , Wang Hui
Published: March 2021

A novel type II toxin of toxin–antitoxin systems (TAs), Gcn5-related N-acetyltransferase (GNAT) family, was reported recently. GNAT toxins are mainly present in pathogenic species, but studies of their involvement in pathogenicity are rare. This study discovered that the GANT toxin AtaT in enterohemorrhagic Escherichia coli (EHEC) can significantly enhance strain pathogenicity. First, we detected the virulence of ΔataT and ΔataR in cell and animal models. In the absence of ataT, strains showed a lower adhesion number, and host cells presented weaker attaching and effacing lesions, inflammatory response, and pathological injury. Next, we screened the acetylation substrate of AtaT to understand the underlying mechanism. Results showed that E. coli pore-forming protein EspB, which acts as a translocon in type III secretion system (T3SS) in strains, can be acetylated specifically by AtaT. The acetylation of K206 in EspB increases protein stability and maintains the efficiency of effectors translocating into host cells to cause close adhesion and tissue damage.
Dorsolateral Prefrontal Functional Connectivity Predicts Working Memory Training Gains
Authors: Faraza Sofia , Waldenmaier Julia , Dyrba Martin , Wolf Dominik , Fischer Florian U. , Knaepen Kristel , Kollmann Bianca , Tüscher Oliver , Binder Harald , Mierau Andreas , Riedel David , Fellgiebel Andreas , Teipel Stefan
Published: March 2021

Background: Normal aging is associated with working memory decline. A decrease in working memory performance is associated with age-related changes in functional activation patterns in the dorsolateral prefrontal cortex (DLPFC). Cognitive training can improve cognitive performance in healthy older adults. We implemented a cognitive training study to assess determinants of generalization of training gains to untrained tasks, a key indicator for the effectiveness of cognitive training. We aimed to investigate the association of resting-state functional connectivity (FC) of DLPFC with working memory performance improvement and cognitive gains after the training.

Method: A sample of 60 healthy older adults (mean age: 68 years) underwent a 4-week neuropsychological training, entailing a working memory task. Baseline resting-state functional MRI (rs-fMRI) images were acquired in order to investigate the FC of DLPFC. To evaluate training effects, participants underwent a neuropsychological assessment before and after the training. A second follow-up assessment was applied 12 weeks after the training. We used cognitive scores of digit span backward and visual block span backward tasks representing working memory function. The training group was divided into subjects who had and who did not have training gains, which was defined as a higher improvement in working memory tasks than the control group (N = 19).

Results: A high FC of DLPFC of the right hemisphere was significantly associated with training gains and performance improvement in the visuospatial task. The maintenance of cognitive gains was restricted to the time period directly after the training. The training group showed performance improvement in the digit span backward task.

Conclusion: Functional activation patterns of the DLPFC were associated with the degree of working memory training gains and visuospatial performance improvement. Although improvement through cognitive training and acquisition of training gains are possible in aging, they remain limited.
Elamipretide (SS-31) Improves Functional Connectivity in Hippocampus and Other Related Regions Following Prolonged Neuroinflammation Induced by Lipopolysaccharide in Aged Rats
Authors: Liu Yang , Fu Huiqun , Wu Yan , Nie Binbin , Liu Fangyan , Wang Tianlong , Xiao Wei , Yang Shuyi , Kan Minhui , Fan Long
Published: March 2021

Neuroinflammation has been recognized as a major cause for neurocognitive diseases. Although the hippocampus has been considered an important region for cognitive dysfunction, the influence of hippocampal neuroinflammation on brain functional connectivity (FC) has been rarely studied. In this study, lipopolysaccharide (LPS) was used to induce systemic inflammation and neuroinflammation in the aged rat brain, while elamipretide (SS-31) was used for treatment. Systemic and hippocampal inflammation were determined using ELISA, while astrocyte responses during hippocampal neuroinflammation were determined by interleukin 1 beta (IL-1β)/tumor necrosis factor alpha (TNFα) double staining immunofluorescence. Oxidative stress was determined by reactive oxidative species (ROS), electron transport chain (ETC) complex, and superoxide dismutase (SOD). Short- (<7 days) and long-term (>30 days) learning and spatial working memory were tested by the Morris water maze (MWM). Resting-state functional magnetic resonance imaging (rs-fMRI) was used to analyze the brain FC by placing seed voxels on the left and right hippocampus. Compared with the vehicle group, rats with the LPS exposure showed an impaired MWM performance, higher oxidative stress, higher levels of inflammatory cytokines, and astrocyte activation in the hippocampus. The neuroimaging examination showed decreased FC on the right orbital cortex, right olfactory bulb, and left hippocampus on day 3, 7, and 31, respectively, after treatment. In contrast, rats with SS-31 treatment showed lower levels of inflammatory cytokines, less astrocyte activation in the hippocampus, and improved MWM performance. Neuroimaging examination showed increased FC on the left-parietal association cortex (L-PAC), left sensory cortex, and left motor cortex on day 7 with the right flocculonodular lobe on day 31 as compared with those without SS-31 treatment. Our study demonstrated that inhibiting neuroinflammation in the hippocampus not only reduces inflammatory responses in the hippocampus but also improves the brain FC in regions related to the hippocampus. Furthermore, early anti-inflammatory treatment with SS-31 has a long-lasting effect on reducing the impact of LPS-induced neuroinflammation.
Impaired Learning and Memory Ability Induced by a Bilaterally Hippocampal Injection of Streptozotocin in Mice: Involved With the Adaptive Changes of Synaptic Plasticity
Authors: Qi Cong-Cong , Chen Xing-Xing , Gao Xin-Ran , Xu Jing-Xian , Liu Sen , Ge Jin-Fang
Published: March 2021

Background: Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive cognitive decline, psychiatric symptoms and behavioral disorders, resulting in disability, and loss of self-sufficiency.

Objective: To establish an AD-like mice model, investigate the behavioral performance, and explore the potential mechanism.

Methods: Streptozotocin (STZ, 3 mg/kg) was microinjected bilaterally into the dorsal hippocampus of C57BL/6 mice, and the behavioral performance was observed. The serum concentrations of insulin and nesfatin-1 were measured by ELISA, and the activation of hippocampal microglia and astrocytes was assessed by immunohistochemistry. The protein expression of several molecular associated with the regulation of synaptic plasticity in the hippocampus and the pre-frontal cortex (PFC) was detected via western blotting.

Results: The STZ-microinjected model mice showed a slower bodyweight gain and higher serum concentration of insulin and nesfatin-1. Although there was no significant difference between groups with regard to the ability of balance and motor coordination, the model mice presented a decline of spontaneous movement and exploratory behavior, together with an impairment of learning and memory ability. Increased activated microglia was aggregated in the hippocampal dentate gyrus of model mice, together with an increase abundance of Aβ1−42 and Tau in the hippocampus and PFC. Moreover, the protein expression of NMDAR2A, NMDAR2B, SynGAP, PSD95, BDNF, and p-β-catenin/β-catenin were remarkably decreased in the hippocampus and the PFC of model mice, and the expression of p-GSK-3β (ser9)/GSK-3β were reduced in the hippocampus.

Conclusion: A bilateral hippocampal microinjection of STZ could induce not only AD-like behavioral performance in mice, but also adaptive changes of synaptic plasticity against neuroinflammatory and endocrinal injuries. The underlying mechanisms might be associated with the imbalanced expression of the key proteins of Wnt signaling pathway in the hippocampus and the PFC.
Robotic Assessment of Wrist Proprioception During Kinaesthetic Perturbations: A Neuroergonomic Approach
Authors: D'Antonio Erika , Galofaro Elisa , Zenzeri Jacopo , Patané Fabrizio , Konczak Jürgen , Casadio Maura , Masia Lorenzo
Published: March 2021

Position sense refers to an aspect of proprioception crucial for motor control and learning. The onset of neurological diseases can damage such sensory afference, with consequent motor disorders dramatically reducing the associated recovery process. In regular clinical practice, assessment of proprioceptive deficits is run by means of clinical scales which do not provide quantitative measurements. However, existing robotic solutions usually do not involve multi-joint movements but are mostly applied to a single proximal or distal joint. The present work provides a testing paradigm for assessing proprioception during coordinated multi-joint distal movements and in presence of kinaesthetic perturbations: we evaluated healthy subjects' ability to match proprioceptive targets along two of the three wrist's degrees of freedom, flexion/extension and abduction/adduction. By introducing rotations along the pronation/supination axis not involved in the matching task, we tested two experimental conditions, which differed in terms of the temporal imposition of the external perturbation: in the first one, the disturbance was provided after the presentation of the proprioceptive target, while in the second one, the rotation of the pronation/ supination axis was imposed during the proprioceptive target presentation. We investigated if (i) the amplitude of the perturbation along the pronation/supination would lead to proprioceptive miscalibration; (ii) the encoding of proprioceptive target, would be influenced by the presentation sequence between the target itself and the rotational disturbance. Eighteen participants were tested by means of a haptic neuroergonomic wrist device: our findings provided evidence that the order of disturbance presentation does not alter proprioceptive acuity. Yet, a further effect has been noticed: proprioception is highly anisotropic and dependent on perturbation amplitude. Unexpectedly, the configuration of the forearm highly influences sensory feedbacks, and significantly alters subjects' performance in matching the proprioceptive targets, defining portions of the wrist workspace where kinaesthetic and proprioceptive acuity are more sensitive. This finding may suggest solutions and applications in multiple fields: from general haptics where, knowing how wrist configuration influences proprioception, might suggest new neuroergonomic solutions in device design, to clinical evaluation after neurological damage, where accurately assessing proprioceptive deficits can dramatically complement regular therapy for a better prediction of the recovery path.
Crosstalk Between ATP-P2X7 and Adenosine A2A Receptors Controlling Neuroinflammation in Rats Subject to Repeated Restraint Stress
Authors: Dias Liliana , Lopes Cátia R. , Gonçalves Francisco Q. , Nunes Ana , Pochmann Daniela , Machado Nuno J. , Tomé Angelo R. , Agostinho Paula , Cunha Rodrigo A.
Published: March 2021

Depressive conditions precipitated by repeated stress are a major socio-economical burden in Western countries. Previous studies showed that ATP-P2X7receptors (P2X7R) and adenosine A2Areceptors (A2AR) antagonists attenuate behavioral modifications upon exposure to repeated stress. Since it is unknown if these two purinergic modulation systems work independently, we now investigated a putative interplay between P2X7R and A2AR. Adult rats exposed to restraint stress for 14 days displayed an anxious (thigmotaxis, elevated plus maze), depressive (anhedonia, increased immobility), and amnesic (modified Y maze, object displacement) profile, together with increased expression of Iba-1 (a marker of microglia “activation”) and interleukin-1β (IL1β) and tumor necrosis factor α (TNFα; proinflammatory cytokines) and an up-regulation of P2X7R (mRNA) and A2AR (receptor binding) in the hippocampus and prefrontal cortex. All these features were attenuated by the P2X7R-preferring antagonist brilliant blue G (BBG, 45 mg/kg, i.p.) or by caffeine (0.3 g/L,p.o.), which affords neuroprotection through A2AR blockade. Notably, BBG attenuated A2AR upregulation and caffeine attenuated P2X7R upregulation. In microglial N9 cells, the P2X7R agonist BzATP (100 μM) or the A2AR agonist CGS26180 (100 nM) increased calcium levels, which was abrogated by the P2X7R antagonist JNJ47965567 (1 μM) and by the A2AR antagonist SCH58261 (50 nM), respectively; notably JNJ47965567 prevented the effect of CGS21680 and the effect of BzATP was attenuated by SCH58261 and increased by CGS21680. These results provide the first demonstration of a functional interaction between P2X7R and A2AR controlling microglia reactivity likely involved in behavioral adaptive responses to stress and are illustrative of a cooperation between the two arms of the purinergic system in the control of brain function.
Closed-Loop Deep Brain Stimulation to Treat Medication-Refractory Freezing of Gait in Parkinson’s Disease
Authors: Molina Rene , Hass Chris J. , Cernera Stephanie , Sowalsky Kristen , Schmitt Abigail C. , Roper Jaimie A. , Martinez-Ramirez Daniel , Opri Enrico , Hess Christopher W. , Eisinger Robert S. , Foote Kelly D. , Gunduz Aysegul , Okun Michael S.
Published: March 2021

Background: Treating medication-refractory freezing of gait (FoG) in Parkinson’s disease (PD) remains challenging despite several trials reporting improvements in motor symptoms using subthalamic nucleus or globus pallidus internus (GPi) deep brain stimulation (DBS). Pedunculopontine nucleus (PPN) region DBS has been used for medication-refractory FoG, with mixed findings. FoG, as a paroxysmal phenomenon, provides an ideal framework for the possibility of closed-loop DBS (CL-DBS).

Methods: In this clinical trial (NCT02318927), five subjects with medication-refractory FoG underwent bilateral GPi DBS implantation to address levodopa-responsive PD symptoms with open-loop stimulation. Additionally, PPN DBS leads were implanted for CL-DBS to treat FoG. The primary outcome of the study was a 40% improvement in medication-refractory FoG in 60% of subjects at 6 months when “on” PPN CL-DBS. Secondary outcomes included device feasibility to gauge the recruitment potential of this four-lead DBS approach for a potentially larger clinical trial. Safety was judged based on adverse events and explantation rate.

Findings: The feasibility of this approach was demonstrated as we recruited five subjects with both “on” and “off” medication freezing. The safety for this population of patients receiving four DBS leads was suboptimal and associated with a high explantation rate of 40%. The primary clinical outcome in three of the five subjects was achieved at 6 months. However, the group analysis of the primary clinical outcome did not reveal any benefit.

Interpretation: This study of a human PPN CL-DBS trial in medication-refractory FoG showed feasibility in recruitment, suboptimal safety, and a heterogeneous clinical effect in FoG outcomes.
Clinicopathological and Molecular Analysis of 45 Cases of Pure Mucinous Breast Cancer
Authors: Yim Hyun Ee , Kim Jang-Hee , Ahn Mi Sun , Jung Yongsik , Roh Jin , Park So Hyun , Kim Tae-Gyu , Choi Jin-Hyuk , Kang Seok Yun
Published: March 2021

Pure mucinous breast carcinoma (PMBC) is characterized by clusters of tumor cells floating in abundant extracellular mucin and can be classified into paucicellular (Type A) and hypercellular (Type B) subtypes. However, the clinicopathological and genomic differences between these two subtypes have not been well characterized. We retrospectively investigated the clinicopathologic features of 45 cases of surgically removed PMBC (31 Type A and 14 Type B). We also performed whole-exome sequencing (WES) in eight cases of PMBC. We found that Type B PMBC occurs at an older age and shows more aggressive clinical behavior than Type A. WES analysis revealed that HYDIN was the most frequently mutated gene in both types of PMBC. Although Type B PMBC showed a tendency toward more frequent genetic alterations, there were no statistically significant differences between the two subtypes in single nucleotide variants or insertions or deletions of bases associated with moderate or high effects. Our results provide additional evidence that PMBCs are clinicopathologically and genetically heterogeneous and lack pathognomonic genetic alterations. Further, Type B PMBC is more frequently associated with lymph node metastasis than Type A.
Immune-Related Adverse Events Predict the Efficacy of Immune Checkpoint Inhibitors in Lung Cancer Patients: A Meta-Analysis
Authors: Wang Donghui , Chen Cen , Gu Yanli , Lu Wanjun , Zhan Ping , Liu Hongbing , Lv Tangfeng , Song Yong , Zhang Fang
Published: March 2021

Background

Immune-related adverse events (irAEs) have been reported to be associated with the efficacy of immunotherapy. Herein, we conducted a meta-analysis to demonstrate that irAEs could predict the efficacy of immune checkpoint inhibitors (ICIs) in lung cancer patients.

Methods

Literature on the correlation between irAEs and the efficacy of immunotherapy in lung cancer patients were searched to collect the data on objective response rate (ORR), overall survival (OS), or progression-free survival (PFS) of the patients. These data were incorporated into the meta-analysis.

Results

A total of 34 records encompassing 8,115 patients were examined in this study. The irAEs occurrence was significantly associated with higher ORR {risk ratio (RR): 2.43, 95% confidence interval (CI) [2.06–2.88], p < 0.00001} and improved OS {hazard ratio (HR): 0.51, 95% CI [0.43–0.61], p < 0.00001}, and PFS (HR: 0.50, 95% CI [0.44–0.57], p < 0.00001) in lung cancer patients undergoing ICIs. Subgroup analysis revealed that OS was significantly longer in patients who developed dermatological (OS: HR: 0.53, 95%CI [0.42–0.65], p < 0.00001), endocrine (OS: HR: 0.55, 95%CI [0.45–0.67], p < 0.00001), and gastrointestinal irAEs (OS: HR: 0.58, 95%CI [0.42–0.80], p = 0.0009) than in those who did not. However, hepatobiliary, pulmonary, and high-grade (≥3) irAEs were not correlated with increased OS and PFS.

Conclusion

The occurrence of irAEs in lung cancer patients, particularly dermatological, endocrine, and gastrointestinal irAEs, is a predictor of enhanced ICIs efficacy.
Beyond PD-1: The Next Frontier for Immunotherapy in Melanoma
Authors: Rohatgi Anjali , Kirkwood John M.
Published: March 2021

The advent of first and second-generation immune checkpoint blockade (ICI) has resulted in improved survival of patients with metastatic melanoma over the past decade. However, the majority of patients ultimately progress despite these treatments, which has served as an impetus to consider a range of subsequent therapies. Many of the next generation of immunotherapeutic agents focus on modifying the immune system to overcome resistance to checkpoint blockade. ICI resistance can be understood as primary, or acquired—where the latter is the most common scenario. While there are several postulated mechanisms by which resistance, particularly acquired resistance, occurs, the predominant escape mechanisms include T cell exhaustion, upregulation of alternative inhibitory checkpoint receptors, and alteration of the tumor microenvironment (TME) into a more suppressive, anti-inflammatory state. Therapeutic agents in development are designed to work by combating one or more of these resistance mechanisms. These strategies face the added challenge of minimizing immune-related toxicities, while improving antitumor efficacy. This review focuses upon the following categories of novel therapeutics: 1) alternative inhibitory receptor pathways; 2) damage- or pathogen-associated molecular patterns (DAMPs/PAMPs); and 3) immune cell signaling mediators. We present the current state of these therapies, including preclinical and clinical data available for these targets under development.
Anti-High Mobility Group Box-1 Monoclonal Antibody Attenuates Seizure-Induced Cognitive Decline by Suppressing Neuroinflammation in an Adult Zebrafish Model
Authors: Paudel Yam Nath , Othman Iekhsan , Shaikh Mohd. Farooq
Published: March 2021

Epilepsy is a chronic brain disease afflicting around 70 million global population and is characterized by persisting predisposition to generate epileptic seizures. The precise understanding of the etiopathology of seizure generation is still elusive, however, brain inflammation is considered as a major contributor to epileptogenesis. HMGB1 protein being an initiator and crucial contributor of inflammation is known to contribute significantly to seizure generation via activating its principal receptors namely RAGE and TLR4 reflecting a potential therapeutic target. Herein, we evaluated an anti-seizure and memory ameliorating potential of an anti-HMGB1 monoclonal antibody (mAb) (1, 2.5 and 5 mg/kg, I.P.) in a second hit Pentylenetetrazol (PTZ) (80 mg/kg, I.P.) induced seizure model earlier stimulated with Pilocarpine (400 mg/kg, I.P.) in adult zebrafish. Pre-treatment with anti-HMGB1 mAb dose-dependently lowered the second hit PTZ-induced seizure but does not alter the disease progression. Moreover, anti-HMGB1 mAb also attenuated the second hit Pentylenetetrazol induced memory impairment in adult zebrafish as evidenced by an increased inflection ration at 3 and 24 h trail in T-maze test. Besides, decreased level of GABA and an upregulated Glutamate level was observed in the second hit PTZ induced group, which was modulated by pre-treatment with anti-HMGB1 mAb. Inflammatory responses occurred during the progression of seizures as evidenced by upregulated mRNA expression of HMGB1, TLR4, NF-κB, and TNF-α, in a second hit PTZ group, which was in-turn downregulated upon pre-treatment with anti-HMGB1 mAb reflecting its anti-inflammatory potential. Anti-HMGB1 mAb modulates second hit PTZ induced changes in mRNA expression of CREB-1 and NPY. Our findings indicates anti-HMGB1 mAb attenuates second hit PTZ-induced seizures, ameliorates related memory impairment, and downregulates the seizure induced upregulation of inflammatory markers to possibly protect the zebrafish from the incidence of further seizures through via modulation of neuroinflammatory pathway.
The Role of Prokineticin 2 in Oxidative Stress and in Neuropathological Processes
Authors: Lattanzi Roberta , Severini Cinzia , Maftei Daniela , Saso Luciano , Badiani Aldo
Published: March 2021

The prokineticin (PK) family, prokineticin 1 and Bv8/prokineticin 2 (PROK2), initially discovered as regulators of gastrointestinal motility, interacts with two G protein-coupled receptors, PKR1 and PKR2, regulating important biological functions such as circadian rhythms, metabolism, angiogenesis, neurogenesis, muscle contractility, hematopoiesis, immune response, reproduction and pain perception. PROK2 and PK receptors, in particular PKR2, are widespread distributed in the central nervous system, in both neurons and glial cells. The PROK2 expression levels can be increased by a series of pathological insults, such as hypoxia, reactive oxygen species, beta amyloid and excitotoxic glutamate. This suggests that the PK system, participating in different cellular processes that cause neuronal death, can be a key mediator in neurological/neurodegenerative diseases. While many PROK2/PKRs effects in physiological processes have been documented, their role in neuropathological conditions is not fully clarified, since PROK2 can have a double function in the mechanisms underlying to neurodegeneration or neuroprotection. Here, we briefly outline the latest findings on the modulation of PROK2 and its cognate receptors following different pathological insults, providing information about their opposite neurotoxic and neuroprotective role in different pathological conditions.
The Cranial Neural Crest in a Multiomics Era
Authors: Chong-Morrison Vanessa , Sauka-Spengler Tatjana
Published: March 2021

Neural crest ontogeny plays a prominent role in craniofacial development. In this Perspective article, we discuss recent advances to the understanding of mechanisms underlying the cranial neural crest gene regulatory network (cNC-GRN) stemming fromomics-based studies. We briefly summarize how parallel considerations of transcriptome, interactome, and epigenome data significantly elaborated the roles of key players derived from pre-omicsera studies. Furthermore, the growing cohort of cNC multiomics data revealed contribution of the non-coding genomic landscape. As technological improvements are constantly being developed, we reflect on key questions we are poised to address by taking advantage of the unique perspective a multiomics approach has to offer.
Advances in Understanding Defense Mechanisms in Persea americana Against Phytophthora cinnamomi
Authors: van den Berg Noëlani , Swart Velushka , Backer Robert , Fick Alicia , Wienk Raven , Engelbrecht Juanita , Prabhu S. Ashok
Published: March 2021

Avocado (Persea americana) is an economically important fruit crop world-wide, the production of which is challenged by notable root pathogens such as Phytophthora cinnamomi and Rosellinia necatrix. Arguably the most prevalent, P. cinnamomi, is a hemibiotrophic oomycete which causes Phytophthora root rot, leading to reduced yields and eventual tree death. Despite its’ importance, the development of molecular tools and resources have been historically limited, prohibiting significant progress toward understanding this important host-pathogen interaction. The development of a nested qPCR assay capable of quantifying P. cinnamomi during avocado infection has enabled us to distinguish avocado rootstocks as either resistant or tolerant - an important distinction when unraveling the defense response. This review will provide an overview of our current knowledge on the molecular defense pathways utilized in resistant avocado rootstock against P. cinnamomi. Notably, avocado demonstrates a biphasic phytohormone profile in response to P. cinnamomi infection which allows for the timely expression of pathogenesis-related genes via the NPR1 defense response pathway. Cell wall modification via callose deposition and lignification have also been implicated in the resistant response. Recent advances such as composite plant transformation, single nucleotide polymorphism (SNP) analyses as well as genomics and transcriptomics will complement existing molecular, histological, and biochemical assay studies and further elucidate avocado defense mechanisms.
Perceived vs. Actual Emotion Reactivity and Regulation in Individuals With and Without a History of NSSI
Authors: Mettler Jessica , Stern Melissa , Lewis Stephen P. , Heath Nancy L.
Published: March 2021

Non-suicidal self-injury (NSSI) has consistently been associated with self-reported difficulties in emotion reactivity and the regulation of negative emotions; however, less is known about the accuracy of these self-reports or the reactivity and regulation of positive emotions. The present study sought to investigate differences between women with and without a history of NSSI on: (a) self-reported general tendencies of negative and positive emotion reactivity, (b) self-reported general tendencies of negative and positive emotion regulation, and (c) emotion regulation reported in response to a positive and negative mood induction. The sample consisted of 36 women with a recent history of NSSI within the last 2 years (Mage = 20.06; SD = 1.51) and a comparison group with no history of NSSI (n = 34; Mage = 20.15; SD = 1.54). Participants completed self-report measures of negative and positive emotion reactivity and regulation. In a separate session, participants underwent both a negative and positive mood induction using a counterbalanced design and reported their experienced emotions. Results from two-way MANOVAs and ANOVAs revealed those with a history of NSSI reported significantly greater difficulties in negative emotion reactivity and regulation than the no-NSSI comparison group; however, no group differences emerged in self-reported reactivity or regulation of positive emotions. In contrast, repeated measures ANOVAs on data from the mood induction task found no group differences in reactivity or regulation for either negative or positive emotions. These findings highlight the possibility that although individuals with a history of NSSI evaluate their ability to manage negative emotions as significantly worse than individuals with no history of self-injury, this may not reflect their actual emotion regulatory processes.
The Three Teachings of East Asia (TTEA) Inventory: Developing and Validating a Measure of the Interrelated Ideologies of Confucianism, Buddhism, and Taoism
Authors: Lin Yi-Ying , Swanson Dena Phillips , Rogge Ronald David
Published: March 2021

Objectives:Buddhism, Taoism, and Confucianism have influenced societies and shaped cultures as they have spread across the span of history and ultimately across the world. However, to date, the interrelated nature of their impacts has yet to be examined largely due to the lack of a measure that comprehensively assesses their various tenets. Building on a conceptual integration of foundational texts on each ideology as well as on recent measure development work (much of which is unpublished), the current studies developed a comprehensive measure of these ideologies (the Three Teachings of East Asia Inventory; TTEA) and validated it across four languages.

Methods:A combined sample of 2,091 online respondents (Study 1: 322 Chinese respondents, Study 2: 400 Japanese respondents, Study 3: 362 Taiwanese respondents, Study 4: 688 White Americans and 319 Asian Americans) completed 25–35 min online survey in their preferred language: English, Traditional Mandarin, Simplified Mandarin, or Japanese.

Results:Exploratory Factor Analyses within a 122-item pool identified 18 stable dimensions across all samples. Measurement invariance analyses identified the final 61-items of the TTEA inventory (demonstrating reasonable invariance across all languages), confirming 18 individual tenet subscales that organize into four higher-order composites: Buddhism, Taoism, Restrictive Confucianism, and Empowering Confucianism. A shorter 36-item version of the TTEA inventory was also developed. The TTEA scales demonstrated (1) acceptable internal consistency, (2) discriminant validity, and (3) incremental predictive validity for current life satisfaction and vitality.

Conclusions:The TTEA inventory offers one of the first comprehensive, multilingual measures that will allow cross-cultural researchers to examine the influence of three related Eastern ideologies on societies across the world.
The Impact of the Covid-19 Pandemic on Consumers' Intention to Use Shared-Mobility Services in German Cities
Authors: Garaus Marion , Garaus Christian
Published: March 2021

One sector that severely suffers from the outbreak of the coronavirus is carsharing (i.e., short-term car access). The downswing of the carsharing industry may not only experience negative economic consequences but also ecological ones. Carsharing has the potential to reduce emissions, occupied space, and congestion and hence can actively contribute to mitigating climate change. As Bill Gates strikingly states: “Covid-19 is awful. Climate change could be worse.” For this reason, it is important to understand which underlying mechanisms drive carsharing usage during the Covid-19 pandemic. The current research has the overall objective to provide deeper insights into the mediating mechanisms that explain carsharing usage intention during the Covid-19 pandemic. In particular, we draw on signaling theory to explore how different claims (environmental claims, safety claims) that prompt two different opposing underlying processes (perceived ecological benefits, perceived physical risk) influence carsharing usage intention. An online experiment employing a 3 (environmental claim vs. safety claim vs. no claim) × 2 (high information diagnosticity vs. low information diagnosticity) between-subjects design with participants acquired by the online panel platform Clickworker was conducted in April 2020. Fictitious labels and fictitious advertisements served as stimulus material and constituted the five experimental conditions. The data were analyzed by a multicategorial moderated mediation analysis and a multivariate analysis of covariance. Results reveal that environmental claims can stimulate perceived ecological benefits, which, in turn, positively affect carsharing usage intention. Interestingly, our research demonstrates that safety claims cannot decrease perceived physical risk in the context of Covid-19 and carsharing. Nevertheless, perceived physical risk has a (marginal) negative influence on carsharing usage intention and hence should not be discarded altogether. The findings of this article offer new insights into the mental processes that guide consumer decision-making during the coronavirus crisis and also offer important policy implications by highlighting the relevance of environmental claims during the Covid-19 pandemic. Furthermore, the negative influence of perceived physical risk on carsharing usage intention points to the need for alternative measures to reduce users' risk perceptions.
Education for UN Sustainable Development Goal 12: A Cross-Curricular Program for Secondary Level Students
Authors: Kiely Lisa , Parajuly Keshav , Green James A. , Fitzpatrick Colin
Published: March 2021

Dealing with complex sustainability challenges requires an integrated approach to thinking and hence learning. Well-designed, integrated sustainability educational programs at the school level can have a significant positive impact on sensitizing students in this area. We present the case of a cross-curricular educational program designed and implemented at secondary level school with a focus on sustainability of material resources used in electronic products–a fast-growing sector with a significant environmental footprint. Over a 4-week period, teachers of five subjects (science, geography, business, technology and civic, social and political education) tailored their classes to focus on the topic of critical raw materials as it relates to these subjects. Examining a control group against the intervention group before and after the program, we use the New Ecological Paradigm (NEP) scale as a measure of students' environmental beliefs in order to find out the extent to which the program helped the cohort of students develop and retain such an ecological paradigm. Students' pro-NEP improved after the program, including on several facets, such as belief in limits to growth. Findings suggest that our cross-curricular approach was able to influence the young students' environmental orientation in a desirable direction.
Injury Incidence Across the Menstrual Cycle in International Footballers
Authors: Martin Dan , Timmins Kate , Cowie Charlotte , Alty Jon , Mehta Ritan , Tang Alicia , Varley Ian
Published: March 2021

Objectives: This study aimed to assess how menstrual cycle phase and extended menstrual cycle length influence the incidence of injuries in international footballers.

Methods: Over a 4-year period, injuries from England international footballers at training camps or matches were recorded, alongside self-reported information on menstrual cycle characteristics at the point of injury. Injuries in eumenorrheic players were categorized into early follicular, late follicular, or luteal phase. Frequencies were also compared between injuries recorded during the typical cycle and those that occurred after the cycle would be expected to have finished. Injury incidence rates (per 1,000 person days) and injury incidence rate ratios were calculated for each phase for all injuries and injuries stratified by type.

Results: One hundred fifty-six injuries from 113 players were eligible for analysis. Injury incidence rates per 1,000 person-days were 31.9 in the follicular, 46.8 in the late follicular, and 35.4 in the luteal phase, resulting in injury incidence rate ratios of 1.47 (Late follicular:Follicular), 1.11 (Luteal:Follicular), and 0.76 (Luteal:Late follicular). Injury incident rate ratios showed that muscle and tendon injury rates were 88% greater in the late follicular phase compared to the follicular phase, with muscle rupture/tear/strain/cramps and tendon injuries/ruptures occurring over twice as often during the late follicular phase compared to other phases 20% of injuries were reported as occurring when athletes were “overdue” menses.

Conclusion: Muscle and tendon injuries occurred almost twice as often in the late follicular phase compared to the early follicular or luteal phase. Injury risk may be elevated in typically eumenorrheic women in the days after their next menstruation was expected to start.
Case Report: Mediastinal Mass in SARS-COV-2 Pandemic: A Word of Caution
Authors: Baisi Alessandro , Mazzucco Alessandra , Caffarena Giovanni , Cioffi Gerardo , Guttadauro Angelo , Cioffi Ugo
Published: March 2021

Background: SARS-CoV-2 is a new disease with some manifestations not yet well-known. Sharing experiences in this topic is crucial for the optimal management of the patients.

Case Presentation: Left upper extremity deep vein thrombosis (UEDVT) due to a mediastinal mass strongly suspected of lymphoproliferative disease in a patient affected by SARS-CoV-2, disappearing at the resolution of the viral infection.

Conclusion: Before proceeding to surgical biopsy, mediastinal mass in SARS-CoV-2 patients must be revaluated after the resolution of the infection.
Changes in the Serum Protein Electrophoresis Profile in Dogs With Pyometra
Authors: Yoon Ji-Seon , Yu DoHyeon , Park Jinho
Published: March 2021

Serum proteins are involved in the regulation of inflammation, and therefore, serum protein profiling provides important insights in diverse inflammatory reactions. Accordingly, concentrations of single APPs, such as the C-reactive protein (CRP), serum amyloid A (SAA), and haptoglobin (Hp), have been described as indicators of inflammatory response in canine pyometra. However, there is little information regarding the overall serum protein profile obtained by SPE in canine pyometra. The present study was thus aimed to identify changes in the serum protein profile to monitor inflammation in dogs with pyometra using serum protein electrophoresis (SPE), in addition to the analysis of the concentration of single acute phase proteins (APPs). By SPE analysis, decreased levels of albumin and elevated levels of α2-globulin and β-globulin were noted in dogs with pyometra. In addition, the concentration of APPs, including the C-reactive protein (CRP), serum amyloid A (SAA), and haptoglobin (Hp), were also elevated in dogs with pyometra. The present study provides fundamental data for inflammatory indicators of canine pyometra.
Discrepancy Between In-clinic and Haemagglutination-Inhibition Tests in Detecting Maternally-Derived Antibodies Against Canine Parvovirus in Puppies
Authors: Dall'Ara Paola , Lauzi Stefania , Filipe Joel , Caseri Roberta , Beccaglia Michela , Desario Costantina , Cavalli Alessandra , Aiudi Giulio Guido , Buonavoglia Canio , Decaro Nicola
Published: March 2021

Canine parvovirus (CPV) is one of the most common causes of mortality in puppies worldwide. Protection against CPV infection is based on vaccination, but maternally-derived antibodies (MDA) can interfere with vaccination. The aim of this study was to evaluate the applicability of an in-clinic ELISA test to assess the CPV MDA in unvaccinated puppies and CPV antibodies in bitches, comparing the results with the gold standard haemagglutination inhibition (HI) test. Serum samples of 136 unvaccinated puppies were tested, along with sera of 16 vaccinated bitches. Five unvaccinated puppies were retested after vaccination. Both assays showed that the 16 vaccinated bitches had protective antibody levels against CPV. Conversely, significant discrepancies were observed for the MDA titers in unvaccinated puppies. Protective MDA titers were observed in 91.9% puppies using HI and in 40.4% by the in-clinic ELISA test, and only the latter one showed a decrease of MDA titers and percentages of protected puppies after the first weeks of age. Vaccination of five puppies with high HI and low in-clinic ELISA MDA titers resulted in seroconversion. Our results confirm the reliability of the in-clinic ELISA test in determining protective antibodies against CPV in adult dogs. Our findings also suggest that the in-clinic ELISA test kit may also be a useful tool to detect and quantify CPV MDA, thus allowing prediction of the best time to vaccinate puppies and reduction of the rate of vaccination failures due to interference by maternally-derived antibodies.