bluuebunny/crossref_metadata_2025 huggingface dataset:
Heat Shock Proteins in Lymphoma Immunotherapy
Authors: Albakova Zarema , Mangasarova Yana , Sapozhnikov Alexander
Published: March 2021

Immunotherapy harnessing the host immune system for tumor destruction revolutionized oncology research and advanced treatment strategies for lymphoma patients. Lymphoma is a heterogeneous group of cancer, where the central roles in pathogenesis play immune evasion and dysregulation of multiple signaling pathways. Immunotherapy-based approaches such as engineered T cells (CAR T), immune checkpoint modulators and NK cell-based therapies are now in the frontline of lymphoma research. Even though emerging immunotherapies showed promising results in treating lymphoma patients, low efficacy and on-target/off-tumor toxicity are of a major concern. To address that issue it is suggested to look into the emerging role of heat shock proteins. Heat shock proteins (HSPs) showed to be highly expressed in lymphoma cells. HSPs are known for their abilities to modulate immune responses and inhibit apoptosis, which made their successful entry into cancer clinical trials. Here, we explore the role of HSPs in Hodgkin and Non-Hodgkin lymphoma and their involvement in CAR T therapy, checkpoint blockade and NK cell- based therapies. Understanding the role of HSPs in lymphoma pathogenesis and the ways how HSPs may enhance anti-tumor responses, may help in the development of more effective, specific and safe immunotherapy.
An Ethology of Adaptation: Dolphins Stop Feeding but Continue Socializing in Construction-Degraded Habitat
Authors: Weaver Ann
Published: March 2021

Adaptation is a biological mechanism by which organisms adjust physically or behaviorally to changes in their environment to become more suited to it. This is a report of free-ranging bottlenose dolphins’ behavioral adaptations to environmental changes from coastal construction in prime habitat. Construction was a 5-year bridge removal and replacement project in a tidal inlet along west central Florida’s Gulf of Mexico coastline. It occurred in two consecutive 2.5-year phases to replace the west and east lanes, respectively. Lane phases involved demolition/removal of above-water cement structures, below-water cement structures, and reinstallation of below + above water cement structures (N= 2,098 photos). Data were longitudinal (11 years: 2005–2016,N= 1,219 surveys 2–4 times/week/11 years,N= 4,753 dolphins, 591.95 h of observation in the construction zone, 126 before-construction surveys, 568 during-construction surveys, 525 after-construction surveys). The dependent variable was numbers of dolphins (count) in the immediate construction zone. Three analyses examined presence/absence, total numbers of dolphins, and numbers of dolphins engaged in five behavior states (forage-feeding, socializing, direct travel, meandering travel, and mixed states) across construction. Analyses were GLIMMIX generalized linear models for logistic and negative binomial regressions to account for observation time differences as an exposure (offset) variable. Results showed a higher probability of dolphin presence than absence before construction began, more total dolphins before construction, and significant decreases in the numbers of feeding but not socializing dolphins. Significant changes in temporal rhythms also revealed finer-grained adaptations. Conclusions were that the dolphins adapted to construction in two ways, by establishing feeding locations beyond the disturbed construction zone and shifting temporal rhythms of behaviors that they continued to exhibit in the construction zone to later in the day when construction activities were minimized. This is the first study to suggest that the dolphins learned to cope with coastal construction with variable adjustments.
The Importance of Marine Research Infrastructures in Capturing Processes and Impacts of Extreme Events
Authors: Lo Bue Nadia , Best Mairi M. R. , Embriaco Davide , Abeysirigunawardena Dilumie , Beranzoli Laura , Dewey Richard K. , Favali Paolo , Feng Ming , Heesemann Martin , Leijala Ulpu , Ó’Conchubhair Diarmuid , Scherwath Martin , Scoccimarro Enrico , Wernberg Thomas
Published: March 2021

Extreme events have long been underestimated in the extent to which they shape the surface of our planet, our environment, its ecological integrity, and the sustainability of human society. Extreme events are by definition rarely observed, of significant impact and, as a result of their spatiotemporal range, not always easily predicted. Extremes may be short-term catastrophic events such as tsunamis, or long-term evolving events such as those linked to climate change; both modify the environment, producing irreversible changes or regime shifts. Whatever the driver that triggers the extreme event, the damages are often due to a combination of several processes and their impacts can affect large areas with secondary events (domino effect), whose effects in turn may persist well beyond the duration of the trigger event itself. Early studies of extreme events were limited to opportunistic approaches: observations were made within the context of naturally occurring events with high societal impact. Given that climate change is now moving us out of a relatively static climate regime during the development of human civilization, extreme events are now a function of underlying climate shifts overlain by catastrophic processes. Their impacts are often due to synergistic factors, all relevant in understanding process dynamics; therefore, an integrated methodology has become essential to enhance the reliability of new assessments and to develop strategies to mitigate societal impacts. Here we summarize the current state of extreme event monitoring in the marine system, highlighting the advantages of a multidisciplinary approach using Research Infrastructures for providing the temporal and spatial resolution required to monitor Earth processes and enhance assessment of associated impacts.
Combination of Angiotensin (1-7) Agonists and Convalescent Plasma as a New Strategy to Overcome Angiotensin Converting Enzyme 2 (ACE2) Inhibition for the Treatment of COVID-19
Authors: Issa Hawraa , Eid Ali H. , Berry Bassam , Takhviji Vahideh , Khosravi Abbas , Mantash Sarah , Nehme Rawan , Hallal Rawan , Karaki Hussein , Dhayni Kawthar , Faour Wissam H. , Kobeissy Firas , Nehme Ali , Zibara Kazem
Published: March 2021

Coronavirus disease-2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently the most concerning health problem worldwide. SARS-CoV-2 infects cells by binding to angiotensin-converting enzyme 2 (ACE2). It is believed that the differential response to SARS-CoV-2 is correlated with the differential expression of ACE2. Several reports proposed the use of ACE2 pharmacological inhibitors and ACE2 antibodies to block viral entry. However, ACE2 inhibition is associated with lung and cardiovascular pathology and would probably increase the pathogenesis of COVID-19. Therefore, utilizing ACE2 soluble analogs to block viral entry while rescuing ACE2 activity has been proposed. Despite their protective effects, such analogs can form a circulating reservoir of the virus, thus accelerating its spread in the body. Levels of ACE2 are reduced following viral infection, possibly due to increased viral entry and lysis of ACE2 positive cells. Downregulation of ACE2/Ang (1-7) axis is associated with Ang II upregulation. Of note, while Ang (1-7) exerts protective effects on the lung and cardiovasculature, Ang II elicits pro-inflammatory and pro-fibrotic detrimental effects by binding to the angiotensin type 1 receptor (AT1R). Indeed, AT1R blockers (ARBs) can alleviate the harmful effects associated with Ang II upregulation while increasing ACE2 expression and thus the risk of viral infection. Therefore, Ang (1-7) agonists seem to be a better treatment option. Another approach is the transfusion of convalescent plasma from recovered patients with deteriorated symptoms. Indeed, this appears to be promising due to the neutralizing capacity of anti-COVID-19 antibodies. In light of these considerations, we encourage the adoption of Ang (1-7) agonists and convalescent plasma conjugated therapy for the treatment of COVID-19 patients. This therapeutic regimen is expected to be a safer choice since it possesses the proven ability to neutralize the virus while ensuring lung and cardiovascular protection through modulation of the inflammatory response.
Diagnostic Accuracy of Pleural Effusion Mononuclear Cells/Leukocyte Ratio in Tuberculous Pleurisy
Authors: Lei Xiaoli , Wang Junli , Yang Zhigang
Published: March 2021

Background: Tuberculous pleurisy (TBP) is a common clinical type of tuberculosis (TB) in China. TBP is difficult to diagnose. Whether the mononuclear cell/leukocyte (MNC/LEU) ratio in pleural effusion can contribute to accurate TBP diagnosis remains yet unclear.

Objective: To explore the diagnostic value of MNC/LEU ratio in pleural effusion for TBP in China.

Methods: This study was a retrospective case-control study involving 406 patients with pleural effusion of unknown cause who were hospitalized at the Henan Provincial People's Hospital. Using histopathological examination of thoracoscopic pleural biopsy as the gold standard for TBP diagnosis, a final total of 215 subjects were included in this study including 91 cases of TBP and 124 cases of non-TBP. The receiver operating characteristic (ROC) curve of pleural effusion MNC/LEU ratio for TBP diagnosis was plotted and the area under curve (AUC) and the optimal cutoff value were determined. In addition, the sensitivity, specificity and accuracy of the MNC/LEU ratio at the optimal cutoff value for TBP diagnosis were also evaluated.

Results: The MNC/LEU ratio was significantly higher in TB pleural effusion [95.9% (89.7–98.0%)] than in non-TB pleural effusion [77.8% (39.3–93.2%)] (P < 0.001). The AUC was 0.776 (95% CI, 0.714–0.830), and the sensitivity, specificity and accuracy for TBP diagnosis at the 93.7% cutoff value were 64.83%, 79.03%, and 0.730, respectively.

Conclusion: The pleural effusion MNC/LEU ratio may be a new and valuable laboratory indicator for the diagnosis of tuberculous pleurisy in China.
The Limited Establishment of Native Ectomycorrhizal Fungi in Exotic Eucalyptus spp. Stands in Japan
Authors: Sugiyama Yoriko , Sato Hirotoshi
Published: March 2021

Host specificity may potentially limit the distribution expansion of ectomycorrhizal (ECM) fungi into areas where their original host plants are absent. To test this hypothesis, we investigated whether populations of native ECM fungi may establish in stands of exotic host trees, namely those of theEucalyptusspecies, in Japan. ECM fungal communities associated with eucalyptus and surrounding native host species (Pinus thunbergiiand Fagaceae spp.) were investigated at two sites; one site in which eucalyptus and native trees were growing in isolation, and a second site in which these species were mixed. To identify fungal taxa, the nuclear ribosomal internal transcribed spacer region 1 was sequenced for the ECM fungi from the root tips and clustered into operational taxonomic units (OTUs). To confirm whether the retrieved OTUs were native to Japan, they were queried against the entire database of the National Center for Biotechnology Information, UNITE, and GlobalFungi, whereby sampling locations and associated hosts were obtained from sequences with ≥97% similarity. Eucalyptus trees were associated with seven and 12 ECM fungal OTUs, including putatively exotic OTUs in isolated and mixed sites, respectively. Among the 36 and 63 native ECM fungal OTUs detected from native hosts at isolated and mixed sites, only one OTU was shared with eucalyptus at the respective sites. This means that most native ECM fungi in Japan may be incapable of forming an association with exoticEucalyptusspp. Notably, even ECM fungi associated with bothPinusandQuercuswere not detected from eucalyptus, suggesting that host-fungus incompatibility is determined not only by host phylogenetic relatedness but also by host biogeographic affinities. Our findings show that the incompatibility with eucalyptus as well as dispersal limitation may prevent the distribution expansion of native ECM fungi in Japan into the distribution ranges ofEucalyptusspp., where the original hosts are absent.
Rapid and Visual Identification of Chlorophyllum molybdites With Loop-Mediated Isothermal Amplification Method
Authors: Wang Nan , Zhao Zhiyong , Gao Jie , Tian Enjing , Yu Wenjie , Li Hui , Zhang Juan , Xie Ruibin , Zhao Xiaoyan , Chen Ailiang
Published: March 2021

Chlorophyllum molybdites is a kind of common poisonous mushroom in China that is widely distributed in different areas. Food poisoning caused by accidentally eating C. molybdites has become more frequent in recent years. In 2019, there were 55 food poisoning incidents caused by eating this mushroom in China. Mushroom poisoning continues to be a common health issue of global concern. When mushroom poisoning occurs, an effective, simple, and rapid detection method is required for accurate clinical treatment or forensic analysis. For the first time, we established a loop-mediated isothermal amplification (LAMP) assay for the visual detection of C. molybdites. A set of specific LAMP primers was designed, and the specificity was confirmed against 43 different mushroom species. The LAMP method could detect as low as 1 pg of genomic DNA. Boiled mushrooms and artificial gastric-digested mushroom samples were prepared to test the applicability of the method, and the results showed that as low as 1% C. molybdites in boiled and digested samples could be successfully detected. The LAMP method can also be completed within 45 min, and the reaction results could be directly observed based on a color change under daylight by the naked eye. Therefore, the LAMP assay established in this study provides an accurate, sensitive, rapid, and low-cost method for the detection of C. molybdites.
Phylogenomics of Plant-Associated Botryosphaeriaceae Species
Authors: Garcia Jadran F. , Lawrence Daniel P. , Morales-Cruz Abraham , Travadon Renaud , Minio Andrea , Hernandez-Martinez Rufina , Rolshausen Philippe E. , Baumgartner Kendra , Cantu Dario
Published: March 2021

The Botryosphaeriaceae is a fungal family that includes many destructive vascular pathogens of woody plants (e.g., Botryosphaeria dieback of grape, Panicle blight of pistachio). Species in the genera Botryosphaeria, Diplodia, Dothiorella, Lasiodiplodia, Neofusicoccum, and Neoscytalidium attack a range of horticultural crops, but they vary in virulence and their abilities to infect their hosts via different infection courts (flowers, green shoots, woody twigs). Isolates of seventeen species, originating from symptomatic apricot, grape, pistachio, and walnut were tested for pathogenicity on grapevine wood after 4 months of incubation in potted plants in the greenhouse. Results revealed significant variation in virulence in terms of the length of the internal wood lesions caused by these seventeen species. Phylogenomic comparisons of the seventeen species of wood-colonizing fungi revealed clade-specific expansion of gene families representing putative virulence factors involved in toxin production and mobilization, wood degradation, and nutrient uptake. Statistical analyses of the evolution of the size of gene families revealed expansions of secondary metabolism and transporter gene families in Lasiodiplodia and of secreted cell wall degrading enzymes (CAZymes) in Botryosphaeria and Neofusicoccum genomes. In contrast, Diplodia, Dothiorella, and Neoscytalidium generally showed a contraction in the number of members of these gene families. Overall, species with expansions of gene families, such as secreted CAZymes, secondary metabolism, and transporters, were the most virulent (i.e., were associated with the largest lesions), based on our pathogenicity tests and published reports. This study represents the first comparative phylogenomic investigation into the evolution of possible virulence factors from diverse, cosmopolitan members of the Botryosphaeriaceae.
Development and Validation of a Predictive Model for Early Refractoriness of Transarterial Chemoembolization in Patients With Hepatocellular Carcinoma
Authors: Wang Tian-Cheng , An Tian-Zhi , Li Jun-Xiang , Zhang Zi-Shu , Xiao Yu-Dong
Published: March 2021

Objectives: To develop and validate a predictive model for early refractoriness of transarterial chemoembolization (TACE) in patients with hepatocellular carcinoma (HCC).

Methods: In this multicenter retrospective study, a total of 204 consecutive patients who initially underwent TACE were included. Early TACE refractoriness was defined as patients presented with TACE refractoriness after initial two consecutive TACE procedures. Of all patients, 147 patients (approximately 70%) were assigned to a training set, and the remaining 57 patients (approximately 30%) were assigned to a validation set. Predictive model was established using forward stepwise logistic regression and nomogram. Based on factors selected by logistic regression, a one-to-one propensity score matching (PSM) was conducted to compare progression-free survival (PFS) between patients who were present or absent of early TACE refractoriness. PFS curve was estimated by Kaplan-Meier method and compared by log-rank test.

Results: Logistic regression revealed that bilobar tumor distribution (p = 0.002), more than three tumors (p = 0.005) and beyond up-to-seven criteria (p = 0.001) were significantly related to early TACE refractoriness. The discriminative abilities, as determined by the area under the receiver operating characteristic (ROC) curve, were 0.788 in the training cohort and 0.706 in the validation cohort. After PSM, the result showed that patients who were absent of early TACE refractoriness had a significantly higher PFS rate than those of patients who were present (p < 0.001).

Conclusion: This study presents a predictive model with moderate accuracy to identify patients with high risk of early TACE refractoriness, and patients with early TACE refractoriness may have a poor prognosis.
Structural and Biochemical Analysis of OrfG: The VirB8-like Component of the Conjugative Type IV Secretion System of ICESt3 From Streptococcus thermophilus
Authors: Cappele Julien , Mohamad Ali Abbas , Leblond-Bourget Nathalie , Mathiot Sandrine , Dhalleine Tiphaine , Payot Sophie , Savko Martin , Didierjean Claude , Favier Frédérique , Douzi Badreddine
Published: March 2021

Conjugative transfer is a major threat to global health since it contributes to the spread of antibiotic resistance genes and virulence factors among commensal and pathogenic bacteria. To allow their transfer, mobile genetic elements including Integrative and Conjugative Elements (ICEs) use a specialized conjugative apparatus related to Type IV secretion systems (Conj-T4SS). Therefore, Conj-T4SSs are excellent targets for strategies that aim to limit the spread of antibiotic resistance. In this study, we combined structural, biochemical and biophysical approaches to study OrfG, a protein that belongs to Conj-T4SS of ICESt3 from Streptococcus thermophilus. Structural analysis of OrfG by X-ray crystallography revealed that OrfG central domain is similar to VirB8-like proteins but displays a different quaternary structure in the crystal. To understand, at a structural level, the common and the diverse features between VirB8-like proteins from both Gram-negative and -positive bacteria, we used an in silico structural alignment method that allowed us to identify different structural classes of VirB8-like proteins. Biochemical and biophysical characterizations of purified OrfG soluble domain and its central and C-terminal subdomains indicated that they are mainly monomeric in solution but able to form an unprecedented 6-mer oligomers. Our study provides new insights into the structural analysis of VirB8-like proteins and discusses the interplay between tertiary and quaternary structures of these proteins as an essential component of the conjugative transfer.
Motor Training Using Mental Workload (MWL) With an Assistive Soft Exoskeleton System: A Functional Near-Infrared Spectroscopy (fNIRS) Study for Brain–Machine Interface (BMI)
Authors: Asgher Umer , Khan Muhammad Jawad , Asif Nizami Muhammad Hamza , Khalil Khurram , Ahmad Riaz , Ayaz Yasar , Naseer Noman
Published: March 2021

Mental workload is a neuroergonomic human factor, which is widely used in planning a system's safety and areas like brain–machine interface (BMI), neurofeedback, and assistive technologies. Robotic prosthetics methodologies are employed for assisting hemiplegic patients in performing routine activities. Assistive technologies' design and operation are required to have an easy interface with the brain with fewer protocols, in an attempt to optimize mobility and autonomy. The possible answer to these design questions may lie in neuroergonomics coupled with BMI systems. In this study, two human factors are addressed: designing a lightweight wearable robotic exoskeleton hand that is used to assist the potential stroke patients with an integrated portable brain interface using mental workload (MWL) signals acquired with portable functional near-infrared spectroscopy (fNIRS) system. The system may generate command signals for operating a wearable robotic exoskeleton hand using two-state MWL signals. The fNIRS system is used to record optical signals in the form of change in concentration of oxy and deoxygenated hemoglobin (HbO and HbR) from the pre-frontal cortex (PFC) region of the brain. Fifteen participants participated in this study and were given hand-grasping tasks. Two-state MWL signals acquired from the PFC region of the participant's brain are segregated using machine learning classifier—support vector machines (SVM) to utilize in operating a robotic exoskeleton hand. The maximum classification accuracy is 91.31%, using a combination of mean-slope features with an average information transfer rate (ITR) of 1.43. These results show the feasibility of a two-state MWL (fNIRS-based) robotic exoskeleton hand (BMI system) for hemiplegic patients assisting in the physical grasping tasks.
TMAO Aggregates Neurological Damage Following Ischemic Stroke by Promoting Reactive Astrocytosis and Glial Scar Formation via the Smurf2/ALK5 Axis
Authors: Su Haibo , Fan Shaoping , Zhang Lingqiong , Qi Hui
Published: March 2021

Ischemic stroke has been reported to cause significant changes to memory, thinking, and behavior. Intriguingly, recently reported studies have indicated the association of Trimethylamine N-oxide (TMAO) with the acute phase of ischemic stroke. However, the comprehensive underlying mechanism remained unknown. The objective of the present study was to investigate the association between TMAO and recovery of neurological function after ischemic stroke. For this purpose, a middle cerebral artery occlusion/reperfusion (MCAO/R) rat model was established and treated with TMAO or/and sh-ALK5, followed by the neurological function evaluation. Behaviors of rats were observed through staircase and cylinder tests. Moreover, the expression of Smurf2 and ALK5 was detected by immunohistochemistry while expression of GFAP, Neurocan, and Phosphacan in brain tissues was determined by immunofluorescence. Thereafter, gain- and loss-of-function assays in astrocytes, the proliferation, viability, and migration were evaluated by the EdU, CCK-8, and Transwell assays. Besides, Smurf2 mRNA expression was determined by the RT-qPCR, whereas, Smurf2, ALK5, GFAP, Neurocan, and Phosphacan expression was evaluated by the Western blotting. Finally, the interaction of Smurf2 with ALK5 and ALK5 ubiquitination was assessed by the co-immunoprecipitation. Notably, our results showed that TMAO promoted the proliferation of reactive astrocyte and formation of glial scar in MCAO/R rats. However, this effect was abolished by the Smurf2 overexpression or ALK5 silencing. We further found that TMAO upregulated the ALK5 expression by inhibiting the ubiquitination role of Smurf2. Overexpression of ALK5 reversed the inhibitory effect of Smurf2 on astrocyte proliferation, migration, and viability. Collectively, our work identifies the evolutionarily TMAO/Smurf2/ALK5 signaling as a major genetic factor in the control of reactive astrocyte proliferation and glial scar formation in ischemic stroke, thus laying a theoretical foundation for the identification of ischemic stroke.
Waterfall Forest Environment Regulates Chronic Stress via the NOX4/ROS/NF-κB Signaling Pathway
Authors: Zhu Zixin , Zhao Xueke , OuYang Qiuyue , Wang Yinghui , Xiong Yan , Cong Shuo , Zhou Mingyu , Zhang Manman , Luo Xinhua , Cheng Mingliang
Published: March 2021

Background: Forest therapy has been proven to have beneficial effects on people with depression and anxiety. However, it remains unknown whether the waterfall forest environment (WF) affects the physical and psychological health of patients with chronic fatigue and how the WF regulates chronic stress.

Methods: Twenty-four patients with chronic fatigue were randomly divided into two groups: the WF group and the urban (U) group. Scores on the Hamilton Anxiety Scale (HAMA), Hamilton Depression Scale (HAMD), and Fatigue Scale-14 (FS-14) were evaluated before and after environmental intervention. Detection of physiological indexes and inflammatory factor levels and immunological analysis were also performed. In addition, the chronic stress rat model was constructed, and the effects of the WF on hopelessness and liver damage of rats were investigated.

Results: Patients with chronic fatigue in the WF group showed a significant decrease in FS-14, HAMA, and HAMD scores compared with the U group. The expression levels of glutathione peroxidase and superoxide dismutase were remarkably higher in the WF group than in the U group. However, the expression levels of malondialdehyde and inflammatory factors (IL-1β, TNF-α, IL-6, and IL-10) were remarkably decreased after the intervention of the WF. In addition, animal experiments confirmed that the WF improved hopelessness, liver damage, and excitability of neurons of chronic stress rats. Mechanistically, the WF reduced the liver damage caused by chronic stress in rats by inhibiting the NOX4/ROS/NF-κB signaling pathway.

Conclusions: Collectively, the WF had a positive effect on immune enhancement and physical and psychological health in patients with chronic fatigue and might inhibit chronic stress by regulating the NOX4/ROS/NF-κB signaling pathway.
Can a Theater Acting Intervention Enhance Inhibitory Control in Older Adults? A Brain-Behavior Investigation
Authors: Rajesh Aishwarya , Noice Tony , Noice Helga , Jahn Andrew , Daugherty Ana M. , Heller Wendy , Kramer Arthur F.
Published: March 2021

Purpose: Studies of reactive and proactive modes of inhibitory control tend to show age-related declines and are accompanied by abnormalities in the prefrontal cortex. We explored which mode of inhibitory control would be more amenable to change and accrue greater benefits following engagement in a 4-week theater acting intervention in older adults. These gains were evaluated by performance on the AX-CPT task. We hypothesized that an increase in proactive control would relate to an increase in AY errors and a decrease in BX errors. In contrast, an increase in reactive control would be associated with a decrease in AY errors, no change in AY reaction time, and an increase in BX response time. Further, we posited that an increase in behavioral proactive control would accompany greater cue versus probe activity for previously identified regions in the prefrontal cortex. In contrast, an increase in behavioral reactive control would be accompanied by greater probe activation in these identified brain areas.

Materials and Methods: The participants were 179 community-dwelling adults aged 60–89 years who were on average, college-educated. Participants were pseudo-randomly assigned to either an active-experiencing acting intervention condition (n = 93) or the active control condition (n = 86); participant assignment was subject to time of enrollment. Participants in both groups were trained by theater-actor researchers with expertise in acting interventions. In contrast to the active control participants who attended a course on theater acting, the acting-intervention group was required to consistently deploy proactive and reactive control mechanisms. Both groups met two times/week for 75-min for 4 weeks. Participant brain-behavioral performance on the AX-CPT task was evaluated prior to and after this four-week period.

Results: No intervention effects were found in favor of proactive control. Behavioral evidence in favor of reactive control was weak. Brain-related benefits to reactive control was illustrated by greater probe-activation in Brodmann areas 6 and 8, relative to controls and pre-intervention.

Conclusion: We found some evidence for improvements in reactive control via brain measures, attributed to engagement in the acting intervention.
Neural Correlates of the Shamanic State of Consciousness
Authors: Huels Emma R. , Kim Hyoungkyu , Lee UnCheol , Bel-Bahar Tarik , Colmenero Angelo V. , Nelson Amanda , Blain-Moraes Stefanie , Mashour George A. , Harris Richard E.
Published: March 2021

Psychedelics have been recognized as model interventions for studying altered states of consciousness. However, few empirical studies of the shamanic state of consciousness, which is anecdotally similar to the psychedelic state, exist. We investigated the neural correlates of shamanic trance using high-density electroencephalography (EEG) in 24 shamanic practitioners and 24 healthy controls during rest, shamanic drumming, and classical music listening, followed by an assessment of altered states of consciousness. EEG data were used to assess changes in absolute power, connectivity, signal diversity, and criticality, which were correlated with assessment measures. We also compared assessment scores to those of individuals in a previous study under the influence of psychedelics. Shamanic practitioners were significantly different from controls in several domains of altered states of consciousness, with scores comparable to or exceeding that of healthy volunteers under the influence of psychedelics. Practitioners also displayed increased gamma power during drumming that positively correlated with elementary visual alterations. Furthermore, shamanic practitioners had decreased low alpha and increased low beta connectivity during drumming and classical music and decreased neural signal diversity in the gamma band during drumming that inversely correlated with insightfulness. Finally, criticality in practitioners was increased during drumming in the low and high beta and gamma bands, with increases in the low beta band correlating with complex imagery and elementary visual alterations. These findings suggest that psychedelic drug-induced and non-pharmacologic alterations in consciousness have overlapping phenomenal traits but are distinct states of consciousness, as reflected by the unique brain-related changes during shamanic trance compared to previous literature investigating the psychedelic state.
18F-FDG PET Combined With MR Spectroscopy Elucidates the Progressive Metabolic Cerebral Alterations After Blast-Induced Mild Traumatic Brain Injury in Rats
Authors: Li Yang , Liu Kaijun , Li Chang , Guo Yu , Fang Jingqin , Tong Haipeng , Tang Yi , Zhang Junfeng , Sun Jinju , Jiao Fangyang , Zhang Qianhui , Jin Rongbing , Xiong Kunlin , Chen Xiao
Published: March 2021

A majority of blast-induced mild traumatic brain injury (mTBI) patients experience persistent neurological dysfunction with no findings on conventional structural MR imaging. It is urgent to develop advanced imaging modalities to detect and understand the pathophysiology of blast-induced mTBI. Fluorine-18 fluorodeoxyglucose positron emission tomography (18F-FDG PET) could detect neuronal function and activity of the injured brain, while MR spectroscopy provides complementary information and assesses metabolic irregularities following injury. This study aims to investigate the effectiveness of combining 18F-FDG PET with MR spectroscopy to evaluate acute and subacute metabolic cerebral alterations caused by blast-induced mTBI. Thirty-two adult male Sprague–Dawley rats were exposed to a single blast (mTBI group) and 32 rats were not exposed to the blast (sham group), followed by 18F-FDG PET, MRI, and histological evaluation at baseline, 1–3 h, 1 day, and 7 days post-injury in three separate cohorts. 18F-FDG uptake showed a transient increase in the amygdala and somatosensory cortex, followed by a gradual return to baseline from day 1 to 7 days post-injury and a continuous rise in the motor cortex. In contrast, decreased 18F-FDG uptake was seen in the midbrain structures (inferior and superior colliculus). Analysis of MR spectroscopy showed that inflammation marker myo-inositol (Ins), oxidative stress marker glutamine + glutamate (Glx), and hypoxia marker lactate (Lac) levels markedly elevated over time in the somatosensory cortex, while the major osmolyte taurine (Tau) level immediately increased at 1–3 h and 1 day, and then returned to sham level on 7 days post-injury, which could be due to the disruption of the blood–brain barrier. Increased 18F-FDG uptake and elevated Ins and Glx levels over time were confirmed by histology analysis which showed increased microglial activation and gliosis in the frontal cortex. These results suggest that 18F-FDG PET and MR spectroscopy can be used together to reflect more comprehensive neuropathological alterations in vivo, which could improve our understanding of the complex alterations in the brain after blast-induced mTBI.
40 Years of CSF Toxicity Studies in ALS: What Have We Learnt About ALS Pathophysiology?
Authors: Ng Kee Kwong Koy Chong , Harbham Pratap K. , Selvaraj Bhuvaneish T. , Gregory Jenna M. , Pal Suvankar , Hardingham Giles E. , Chandran Siddharthan , Mehta Arpan R.
Published: March 2021

Based on early evidence of in vitro neurotoxicity following exposure to serum derived from patients with amyotrophic lateral sclerosis (ALS), several studies have attempted to explore whether cerebrospinal fluid (CSF) obtained from people with ALS could possess similar properties. Although initial findings proved inconclusive, it is now increasingly recognized that ALS-CSF may exert toxicity both in vitro and in vivo. Nevertheless, the mechanism underlying CSF-induced neurodegeneration remains unclear. This review aims to summarize the 40-year long history of CSF toxicity studies in ALS, while discussing the various mechanisms that have been proposed, including glutamate excitotoxicity, proteotoxicity and oxidative stress. Furthermore, we consider the potential implications of a toxic CSF circulatory system in the pathophysiology of ALS, and also assess its significance in the context of current ALS research.
Gentle Sterilization of Carrot-Based Purees by High-Pressure Thermal Sterilization and Ohmic Heating and Influence on Food Processing Contaminants and Quality Attributes
Authors: Gratz Maximilian , Sevenich Robert , Hoppe Thomas , Schottroff Felix , Vlaskovic Nevena , Belkova Beverly , Chytilova Lucie , Filatova Maria , Stupak Michal , Hajslova Jana , Rauh Cornelia , Jaeger Henry
Published: March 2021

Pressure-enhanced sterilization (PES) and ohmic heating (OH) are two emerging sterilization techniques, currently lacking implementation in the food industry. However, both technologies offer significant benefits in terms of spore inactivation using reduced thermal intensity in food products, as well as minimized effects on sensory and nutritional profiles. In this study, PES and OH were tested based on possible food safety process windows in comparison to thermal retorting, to optimize the food quality of carrot-based purees. The following parameters related to food quality were tested: texture, carotenoid content, color, and detectable amount of food processing contaminants (FPC) formed. Application of the innovative sterilization techniques resulted in a better retention of color, texture, and carotenoids (for PES) as well as a reduced formation of food processing contaminants. Importantly, a significant reduction in the formation of furan and its derivates was observed, compared to the retorted samples. Hence, both sterilization technologies showed promising results in the mitigation of potential toxic processing contaminants and retention of quality attributes.
The Looming Effects of Estrogen in Covid-19: A Rocky Rollout
Authors: Al-kuraishy Hayder M. , Al-Gareeb Ali I. , Faidah Hani , Al-Maiahy Thabat J. , Cruz-Martins Natália , Batiha Gaber El-Saber
Published: March 2021

In the face of the Covid-19 pandemic, an intensive number of studies have been performed to understand in a deeper way the mechanisms behind better or worse clinical outcomes. Epidemiologically, men subjects are more prone to severe acute respiratory syndrome-coronavirus type 2 (SARS-CoV-2) infections than women, with a similar scenario being also stated to the previous coronavirus diseases, namely, SARS-CoV in 2003 and Middle East Respiratory Syndrome coronavirus diseases (MERS-CoV) in 2012. In addition, and despite that aging is regarded as an independent risk factor for the severe form of the disease, even so, women protection is evident. In this way, it has been expected that sex hormones are the main determinant factors in gender differences, with the immunomodulatory effects of estrogen in different viral infections, chiefly in Covid-19, attracting more attention as it might explain the case-fatality rate and predisposition of men for Covid-19 severity. Here, we aim to provide a mini-review and an overview on the protective effects of estrogen in Covid-19. Different search strategies were performed including Scopus, Web of Science, Medline, Pubmed, and Google Scholar database to find relative studies. Findings of the present study illustrated that women have a powerful immunomodulating effect against Covid-19 through the effect of estrogen. This study illustrates that estrogens have noteworthy anti-inflammatory and immuno-modulatory effects in Covid-19. Also, estrogen hormone reduces SARS-CoV-2 infectivity through modulation of pro-inflammatory signaling pathways. This study highlighted the potential protective effect of estrogen against Covid-19 and recommended for future clinical trial and prospective studies to elucidate and confirm this protective effect.
Extensive-Stage Small Cell Carcinoma Transformation From EGFR Del19-Mutant Lung Adenocarcinoma on Gefitinib at the Twelfth-Year Follow-Up Case Report
Authors: Kok Victor C. , Lee Chien-Kuan , Chiang Yu-Hsin , Wang Ming-Chih , Lu Yen-Te , Cherng Chiu-Chun , Lee Pei-Yu , Wang Ke-Bin
Published: March 2021

Introduction

The acquired resistance mechanisms in patients with epidermal growth factor receptor (EGFR)-mutant lung cancer, particularly adenocarcinoma (ADC), following treatment with an EGFR tyrosine kinase inhibitor (TKI) have received extensive investigations. The phenotypic transformation to small cell carcinoma (SCCT) has been estimated to occur in approximately 3 to 10% of patients treated with an EGFR-TKI. The prognosis after SCCT is extremely poor.

Case Study

We report about SCCT that occurred 45 months after the initial diagnosis of ADC in an East Asian never-smoker woman with advanced-stage EGFR Del-19-mutant lung ADC treated with combined chemoradiotherapy before the era of insurance coverage for EGFR-TKIs in this country and subsequently gefitinib; deletion at codon 746–750 in exon 19 of the EGFR gene was ascertained in the original formalin-fixed paraffin-embedded lung biopsy tissue. Spinal cord compression at thoracic-12 level from SCCT was successfully relieved with neurosurgical treatment, chemotherapy with etoposide and cisplatin, and radiotherapy, while gefitinib treatment was maintained. Eleven months later, SCCT relapsed in the lung parenchyma, which was resected and was found to be sensitive to second-line weekly topotecan. Prophylactic cranial irradiation was subsequently administered. SCCT was confirmed by MALDI-TOF MS analysis of formalin-fixed paraffin-embedded tissues demonstrating the same exon 19 deletion. At the 12th-year follow-up, the patient remains relapse free with very good performance status. The novelty of this case is the successful interdisciplinary team effort to correct the spinal cord compression by maintaining the patient in an ambulatory state, non-stop use of gefitinib justified by the presence of activating EGFR mutation in SCCT tumor cells, and aggressive dose-intensive chemotherapy and radiotherapy for the SCCT that leads to an unprecedented prolonged remission and survival. This case also supports the observation that SCCT is chemotherapy sensitive, and thus, re-biopsy or complete tumor excision is recommended to understand the mutation profiles of the current tumor. Aggressive prudent administration of systemic chemotherapy obtaining optimal dose intensity leads to the successful management of the patient.
MEKK1 Regulates Chemokine Expression in Mammary Fibroblasts: Implications for the Breast Tumor Microenvironment
Authors: Gentile Saverio , Eskandari Najmeh , Rieger Michael A. , Cuevas Bruce D.
Published: March 2021

Breast tumors contain both transformed epithelial cells and non-transformed stroma cells producing secreted factors that can promote metastasis. Previously, we demonstrated that the kinase MEKK1 regulates cell migration and gene expression, and that transgene-induced breast tumor metastasis is markedly inhibited in MEKK1-deficient mice. In this report, we examined the role of MEKK1 in stroma cell gene expression and the consequent effect on breast tumor cell function. Using a heterotypic cell system to quantify the effect of stroma cells on breast tumor cell function, we discovered that MEKK1−/− fibroblasts are significantly less effective at inducing tumor cell invasion than MEKK1+/+ fibroblasts. Expression array analysis revealed that both baseline and tumor cell-induced expression of the chemokines CCL3, CCL4, and CCL5 were markedly reduced in MEKK1−/− mammary fibroblasts. By focusing on the role of MEKK1 in CCL5 regulation, we discovered that MEKK1 kinase activity promotes CCL5 expression, and inactive mutant MEKK1 strongly inhibits CCL5 transcription. CCL5 and the other MEKK1-dependent chemokines are ligands for the GPCR CCR5, and we show that the CCR5 antagonist Maraviroc strongly inhibits fibroblast-induced tumor cell migration. Finally, we report that fibroblast growth factor 5 (FGF-5) is secreted by MDA-MB 231 cells, that FGF-5 activates MEKK1 effectors ERK1/2 and NFκB in fibroblasts, and that chemical inhibition of NFκB inhibits CCL5 expression. Our results suggest that MEKK1 contributes to the formation of a breast tumor microenvironment that supports metastasis by promoting expression of stroma cell chemokine genes in response to tumor cell-induced paracrine signaling.
Clinical and Prognostic Pan-Cancer Analysis of N6-Methyladenosine Regulators in Two Types of Hematological Malignancies: A Retrospective Study Based on TCGA and GTEx Databases
Authors: Zhang Xiangsheng , Zhong Liye , Zou Zhilin , Liang Guosheng , Tang Zhenye , Li Kai , Tan Shuzhen , Huang Yongmei , Zhu Xiao
Published: March 2021

N6-methyladenosine (m6A) is one of the most active modification factors of mRNA, which is closely related to cell proliferation, differentiation, and tumor development. Here, we explored the relationship between the pathogenesis of hematological malignancies and the clinicopathologic parameters. The datasets of hematological malignancies and controls were obtained from the TCGA [AML (n = 200), DLBCL (n = 48)] and GTEx [whole blood (n = 337), blood vascular artery (n = 606)]. We analyzed the m6A factor expression differences in normal tissue and tumor tissue and their correlations, clustered the express obvious clinical tumor subtypes, determined the tumor risk score, established Cox regression model, performed univariate and multivariate analysis on all datasets. We found that the AML patients with high expression of IGF2BP3, ALKBH5, and IGF2BP2 had poor survival, while the DLBCL patients with high expression of METTL14 had poor survival. In addition, “Total” datasets analysis revealed that IGF2BP1, ALKBH5, IGF2BP2, RBM15, METTL3, and ZNF217 were potential oncogenes for hematologic system tumors. Collectively, the expressions of some m6A regulators are closely related to the occurrence and development of hematologic system tumors, and the intervention of specific regulatory factors may lead to a breakthrough in the treatment in the future.
TMPRSS4 Promotes Cell Proliferation and Inhibits Apoptosis in Pancreatic Ductal Adenocarcinoma by Activating ERK1/2 Signaling Pathway
Authors: Gu Jianyou , Huang Wenjie , Zhang Junfeng , Wang Xianxing , Tao Tian , Yang Ludi , Zheng Yao , Liu Songsong , Yang Jiali , Zhu Liwei , Wang Huaizhi , Fan Yingfang
Published: March 2021

Transmembrane protease serine 4 (TMPRSS4) is upregulated in various kinds of human cancers, including pancreatic cancer. However, its biological function in pancreatic ductal adenocarcinoma (PDAC) remains unclear. In the current study, real-time qPCR, immunohistochemical staining, Western blotting, and database (Cancer Genome Atlas and Gene Expression) analysis revealed remarkable overexpression of TMPRSS4 in PDAC tissue as compared to non-tumor tissue. The TMPRSS4 overexpression was associated with poor prognosis of PDAC patients. Moreover, multivariate analysis revealed that TMPRSS4 serves as an independent risk factor in PDAC. We performed gain-and loss-of-function analysis and found that TMPRSS4 promotes cellular proliferation and inhibits apoptosis of PDAC cells both in vitro and in vivo. Furthermore, we showed that TMPRSS4 might promote cell proliferation and inhibit apoptosis through activating ERK1/2 signaling pathway in pancreatic cancer cells. These findings were validated by using ERK1/2 phosphorylation inhibitor SCH772984 both in vitro and in vivo. Taken together, this study suggests that TMPRSS4 is a proto-oncogene, which promotes initiation and progression of PDAC by controlling cell proliferation and apoptosis. Our findings indicate that TMPRSS4 could be a promising prognostic biomarker and a therapeutic target for the treatment of pancreatic cancer.
Vildagliptin Attenuates Myocardial Dysfunction and Restores Autophagy via miR-21/SPRY1/ERK in Diabetic Mice Heart
Authors: Li Xiaochen , Meng Cheng , Han Fei , Yang Juhong , Wang Jingyu , Zhu Yanjuan , Cui Xiao , Zuo Minxia , Xu Jie , Chang Baocheng
Published: March 2021

Aim: Vildagliptin (vild) improves diastolic dysfunction and is associated with a lower relative risk of major adverse cardiovascular events in younger patients. The present study aimed to evaluate whether vild prevents the development of diabetic cardiomyopathy in type 2 diabetic mice and identify its underlying mechanisms.

Methods: Type 2 diabetic mouse model was generated using wild-type (WT) (C57BL/6J) and miR-21 knockout mice by treatment with HFD/STZ. Cardiomyocyte-specific miR-21 overexpression was achieved using adeno-associated virus 9. Echocardiography was used to evaluate cardiac function in mice. Morphology, autophagy, and proteins levels in related pathway were analyzed. qRT-PCR was used to detect miR-21. Rat cardiac myoblast cell line (H9c2) cells were transfected with miR-21 mimics and inhibitor to explore the related mechanisms of miR-21 in diabetic cardiomyopathy.

Results: Vild restored autophagy and alleviated fibrosis, thereby enhancing cardiac function in DM mice. In addition, miR-21 levels were increased under high glucose conditions. miR-21 knockout DM mice with miR-21 knockout had reduced cardiac hypertrophy and cardiac dysfunction compared to WT DM mice. Overexpression of miR-21 aggravated fibrosis, reduced autophagy, and attenuated the protective effect of vild on cardiac function. In high-glucose-treated H9c2 cells, the downstream effectors of sprouty homolog 1 (SPRY1) including extracellular signal-regulated kinases (ERK) and mammalian target of rapamycin showed significant changes following transfection with miR-21 mimics or inhibitor.

Conclusion: The results of our study indicate that vild prevents DCM by restoring autophagy through the miR-21/SPRY1/ERK/mTOR pathway. Therefore, miR-21 is a target in the development of DCM, and vild demonstrates significant potential for clinical application in prevention of DCM.