bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparative Genomics and Environmental Distribution of Large dsDNA Viruses in the Family Asfarviridae
Authors: Karki Sangita , Moniruzzaman Mohammad , Aylward Frank O.
Published: March 2021

The family Asfarviridae is a group of nucleo-cytoplasmic large DNA viruses (NCLDVs) of which African swine fever virus (ASFV) is well-characterized. Recently the discovery of several Asfarviridae members other than ASFV has suggested that this family represents a diverse and cosmopolitan group of viruses, but the genomics and distribution of this family have not been studied in detail. To this end we analyzed five complete genomes and 35 metagenome-assembled genomes (MAGs) of viruses from this family to shed light on their evolutionary relationships and environmental distribution. The Asfarvirus MAGs derive from diverse marine, freshwater, and terrestrial habitats, underscoring the broad environmental distribution of this family. We present phylogenetic analyses using conserved marker genes and whole-genome comparison of pairwise average amino acid identity (AAI) values, revealing a high level of genomic divergence across disparate Asfarviruses. Further, we found that Asfarviridae genomes encode genes with diverse predicted metabolic roles and detectable sequence homology to proteins in bacteria, archaea, and eukaryotes, highlighting the genomic chimerism that is a salient feature of NCLDV. Our read mapping from Tara oceans metagenomic data also revealed that three Asfarviridae MAGs were present in multiple marine samples, indicating that they are widespread in the ocean. In one of these MAGs we identified four marker genes with > 95% AAI to genes sequenced from a virus that infects the dinoflagellate Heterocapsa circularisquama (HcDNAV). This suggests a potential host for this MAG, which would thereby represent a reference genome of a dinoflagellate-infecting giant virus. Together, these results show that Asfarviridae are ubiquitous, comprise similar sequence divergence as other NCLDV families, and include several members that are widespread in the ocean and potentially infect ecologically important protists.
Long-Lived Species of Bivalves Exhibit Low MT-DNA Substitution Rates
Authors: Mortz Mathieu , Levivier Aurore , Lartillot Nicolas , Dufresne France , Blier Pierre U.
Published: March 2021

Bivalves represent valuable taxonomic group for aging studies given their wide variation in longevity (from 1–2 to >500 years). It is well known that aging is associated to the maintenance of Reactive Oxygen Species homeostasis and that mitochondria phenotype and genotype dysfunctions accumulation is a hallmark of these processes. Previous studies have shown that mitochondrial DNA mutation rates are linked to lifespan in vertebrate species, but no study has explored this in invertebrates. To this end, we performed a Bayesian Phylogenetic Covariance model of evolution analysis using 12 mitochondrial protein-coding genes of 76 bivalve species. Three life history traits (maximum longevity, generation time and mean temperature tolerance) were tested against 1) synonymous substitution rates (dS), 2) conservative amino acid replacement rates (Kc) and 3) ratios of radical over conservative amino acid replacement rates (Kr/Kc). Our results confirm the already known correlation between longevity and generation time and show, for the first time in an invertebrate class, a significant negative correlation between dS and longevity. This correlation was not as strong when generation time and mean temperature tolerance variations were also considered in our model (marginal correlation), suggesting a confounding effect of these traits on the relationship between longevity and mtDNA substitution rate. By confirming the negative correlation between dS and longevity previously documented in birds and mammals, our results provide support for a general pattern in substitution rates.
The Eminent Role of microRNAs in the Pathogenesis of Alzheimer's Disease
Authors: Samadian Mohammad , Gholipour Mahdi , Hajiesmaeili Mohammadreza , Taheri Mohammad , Ghafouri-Fard Soudeh
Published: March 2021

Alzheimer's disease (AD) is an irrevocable neurodegenerative condition characterized by the presence of senile plaques comprising amassed β-amyloid peptides (Aβ) and neurofibrillary tangles mainly comprising extremely phosphorylated Tau proteins. Recent studies have emphasized the role of microRNAs (miRNAs) in the development of AD. A number of miRNAs, namely, miR-200a-3p, miR-195, miR-338-5p, miR-34a-5p, miR-125b-5p, miR-132, miR-384, miR-339-5p, miR-135b, miR-425-5p, and miR-339-5p, have been shown to participate in the development of AD through interacting with BACE1. Other miRNAs might affect the inflammatory responses in the course of AD. Aberrant expression of several miRNAs in the plasma samples of AD subjects has been shown to have the aptitude for differentiation of AD subjects from healthy subjects. Finally, a number of AD-modifying agents affect miRNA profile in cell cultures or animal models. We have performed a comprehensive search and summarized the obtained data about the function of miRNAs in AD in the current review article.
Trans-Synaptic Regulation of Metabotropic Glutamate Receptors by Elfn Proteins in Health and Disease
Authors: Matsunaga Hayato , Aruga Jun
Published: March 2021

Trans-regulation of G protein-coupled receptors (GPCRs) by leucine-rich repeat (LRR) transmembrane proteins has emerged as a novel type of synaptic molecular interaction in the last decade. Several studies on LRR–GPCR interactions have revealed their critical role in synapse formation and in establishing synaptic properties. Among them, LRR–GPCR interactions between extracellular LRR fibronectin domain-containing family proteins (Elfn1 and Elfn2) and metabotropic glutamate receptors (mGluRs) are particularly interesting as they can affect a broad range of synapses through the modulation of signaling by glutamate, the principal excitatory transmitter in the mammalian central nervous system (CNS). Elfn–mGluR interactions have been investigated in hippocampal, cortical, and retinal synapses. Postsynaptic Elfn1 in the hippocampus and cerebral cortex mediates the tonic regulation of excitatory input onto somatostatin-positive interneurons (INs) through recruitment of presynaptic mGluR7. In the retina, presynaptic Elfn1 binds to mGluR6 and is necessary for synapse formation between rod photoreceptor cells and rod-bipolar cells. The repertoire of binding partners for Elfn1 and Elfn2 includes all group III mGluRs (mGluR4, mGluR6, mGluR7, and mGluR8), and both Elfn1 and Elfn2 can alter mGluR-mediated signaling through trans-interaction. Importantly, both preclinical and clinical studies have provided support for the involvement of the Elfn1–mGluR7 interaction in attention-deficit hyperactivity disorder (ADHD), post-traumatic stress disorder (PTSD), and epilepsy. In fact, Elfn1–mGluR7-associated disorders may reflect the altered function of somatostatin-positive interneuron inhibitory neural circuits, the mesolimbic and nigrostriatal dopaminergic pathway, and habenular circuits, highlighting the need for further investigation into this interaction.
Performance Variability During Motor Learning of a New Balance Task in a Non-immersive Virtual Environment in Children With Hemiplegic Cerebral Palsy and Typically Developing Peers
Authors: Cheng Minxin , Anderson Michael , Levac Danielle E.
Published: March 2021

Background:Motor impairments contribute to performance variability in children with cerebral palsy (CP) during motor skill learning. Non-immersive virtual environments (VEs) are popular interventions to promote motor learning in children with hemiplegic CP. Greater understanding of performance variability as compared to typically developing (TD) peers during motor learning in VEs may inform clinical decisions about practice dose and challenge progression.

Purpose:(1) To quantify within-child (i.e., across different timepoints) and between-child (i.e., between children at the same timepoint) variability in motor skill acquisition, retention and transfer in a non-immersive VE in children with CP as compared to TD children; and (2) To explore the relationship between the amount of within-child variability during skill acquisition and learning outcomes.

Methods:Secondary data analysis of 2 studies in which 13 children with hemiplegic CP and 67 TD children aged 7–14 years undertook repeated trials of a novel standing postural control task in acquisition, retention and transfer sessions. Changes in performance across trials and sessions in children with CP as compared to TD children and between younger (7–10 years) and older (11–14 years) children were assessed using mixed effects models. Raw scores were converted to z-scores to meet model distributional assumptions. Performance variability was quantified as the standard deviation of z-scores.

Results:TD children outperformed children with CP and older children outperformed younger children at each session. Older children with CP had the least between-child variability in acquisition and the most in retention, while older TD children demonstrated the opposite pattern. Younger children with CP had consistently high between-child variability, with no difference between sessions. Within-child variability was highest in younger children, regardless of group. Within-child variability was more pronounced in TD children as compared to children with CP. The relationship between the amount of within-child variability in performance and performance outcome at acquisition, retention and transfer sessions was task-specific, with a positive correlation for 1 study and a negative correlation in the other.

Conclusions:Findings, though preliminary and limited by small sample size, can inform subsequent research to explore VE-specific causes of performance variability, including differing movement execution requirements and individual characteristics such as motivation, attention and visuospatial abilities.
Analysis of Thrombolysis Process for Acute Ischemic Stroke in Urban and Rural Hospitals in Nova Scotia Canada
Authors: Bulmer Tessa , Volders David , Kamal Noreen
Published: March 2021

Background: Stroke is a devastating disease, but it is treatable with alteplase or tissue plasminogen activator (tPA). The effectiveness of tPA is highly time-dependent, meaning rapid treatment is critical. Fast treatment with tPA has been reported in many urban hospitals, but hospitals in rural locations struggle to reduce treatment times. This qualitative study examines current thrombolysis processes in one urban and two rural hospitals in Nova Scotia, Canada, by mapping and comparing the treatment process in these settings for acute ischemic stroke (AIS) patients, and by analyzing the healthcare professionals views on various treatment topics.

Methods: Structured interviews were conducted with healthcare professionals involved in stroke treatment across the three sites. The interviews focused on the various activities in the thrombolysis treatment at each site. Additionally, participants were asked about the following 10 topics: comfort treating acute ischemic stroke patients; perceptions about tPA; appropriate tPA treatment window; stroke patient priority; tPA availability; patient consent; urban-rural treatment differences; efficiency of their treatment process; treatment delays; and suggested process improvements. Results were analyzed using the Framework Method, as well as through the development of process maps.

Results: Twenty three healthcare professionals were interviewed at 2 rural hospitals and 1 urban hospital. Acute ischemic stroke patients are triaged as the highest or urgent priority at each included site. Physicians are more hesitant to treat with tPA in rural settings. A total of 11 urban-rural treatment differences were noted by the rural sites. Additionally, 11 patient-related and 29 system treatment delays were described. A process map was developed for each site, representing the arrival by ambulance and by private vehicle pathways.

Conclusions: Guidelines and clear protocols are critical in reducing treatment times and ensuring consistent access to treatment. The majority of treatment delays encountered are system delays, which can be appropriately planned for to reduce delays within the care pathway. There is a general consensus that there is an urban-rural treatment gap for acute ischemic stroke patients in Nova Scotia, and that continuing education is key in rural hospitals to improve Emergency Department (ED) physician comfort with treating patients with tPA.
Experience of After-Effect of Memory Update Reduces Sensitivity to Errors During Sensory-Motor Adaptation Task
Authors: Tanamachi Kenya , Izawa Jun , Yamamoto Satoshi , Ishii Daisuke , Yozu Arito , Kohno Yutaka
Published: March 2021

Motor learning is the process of updating motor commands in response to a trajectory error induced by a perturbation to the body or vision. The brain has a great capability to accelerate learning by increasing the sensitivity of the memory update to the perceived trajectory errors. Conventional theory suggests that the statistics of perturbations or the statistics of the experienced errors induced by the external perturbations determine the learning speeds. However, the potential effect of another type of error perception, a self-generated error as a result of motor command updates (i.e., an aftereffect), on the learning speeds has not been examined yet. In this study, we dissociated the two kinds of errors by controlling the perception of the aftereffect using a channel-force environment. One group experienced errors due to the aftereffect of the learning process, while the other did not. We found that the participants who perceived the aftereffect of the memory updates exhibited a significant decrease in error-sensitivity, whereas the participants who did not perceive the aftereffect did not show an increase or decrease in error-sensitivity. This suggests that the perception of the aftereffect of learning attenuated updating the motor commands from the perceived errors. Thus, both self-generated and externally induced errors may modulate learning speeds.
Multi-modal Mapping of the Face Selective Ventral Temporal Cortex–A Group Study With Clinical Implications for ECS, ECoG, and fMRI
Authors: Sanada Takahiro , Kapeller Christoph , Jordan Michael , Grünwald Johannes , Mitsuhashi Takumi , Ogawa Hiroshi , Anei Ryogo , Guger Christoph
Published: March 2021

Face recognition is impaired in patients with prosopagnosia, which may occur as a side effect of neurosurgical procedures. Face selective regions on the ventral temporal cortex have been localized with electrical cortical stimulation (ECS), electrocorticography (ECoG), and functional magnetic resonance imagining (fMRI). This is the first group study using within-patient comparisons to validate face selective regions mapping, utilizing the aforementioned modalities. Five patients underwent surgical treatment of intractable epilepsy and joined the study. Subdural grid electrodes were implanted on their ventral temporal cortices to localize seizure foci and face selective regions as part of the functional mapping protocol. Face selective regions were identified in all patients with fMRI, four patients with ECoG, and two patients with ECS. From 177 tested electrode locations in the region of interest (ROI), which is defined by the fusiform gyrus and the inferior temporal gyrus, 54 face locations were identified by at least one modality in all patients. fMRI mapping showed the highest detection rate, revealing 70.4% for face selective locations, whereas ECoG and ECS identified 64.8 and 31.5%, respectively. Thus, 28 face locations were co-localized by at least two modalities, with detection rates of 89.3% for fMRI, 85.7% for ECoG and 53.6 % for ECS. All five patients had no face recognition deficits after surgery, even though five of the face selective locations, one obtained by ECoG and the other four by fMRI, were within 10 mm to the resected volumes. Moreover, fMRI included a quite large volume artifact on the ventral temporal cortex in the ROI from the anatomical structures of the temporal base. In conclusion, ECS was not sensitive in several patients, whereas ECoG and fMRI even showed activation within 10 mm to the resected volumes. Considering the potential signal drop-out in fMRI makes ECoG the most reliable tool to identify face selective locations in this study. A multimodal approach can improve the specificity of ECoG and fMRI, while simultaneously minimizing the number of required ECS sessions. Hence, all modalities should be considered in a clinical mapping protocol entailing combined results of co-localized face selective locations.
Improving the Selectivity of an Osseointegrated Neural Interface: Proof of Concept For Housing Sieve Electrode Arrays in the Medullary Canal of Long Bones
Authors: Millevolte Augusto X. T. , Dingle Aaron M. , Ness Jared P. , Novello Joseph , Zeng Weifeng , Lu Yan , Minor Rashea L. , Nemke Brett , Markel Mark D. , Suminski Aaron J. , Williams Justin C. , Poore Samuel O.
Published: March 2021

Sieve electrodes stand poised to deliver the selectivity required for driving advanced prosthetics but are considered inherently invasive and lack the stability required for a chronic solution. This proof of concept experiment investigates the potential for the housing and engagement of a sieve electrode within the medullary canal as part of an osseointegrated neural interface (ONI) for greater selectivity toward improving prosthetic control. The working hypotheses are that (A) the addition of a sieve interface to a cuff electrode housed within the medullary canal of the femur as part of an ONI would be capable of measuring efferent and afferent compound nerve action potentials (CNAPs) through a greater number of channels; (B) that signaling improves over time; and (C) that stimulation at this interface generates measurable cortical somatosensory evoked potentials through a greater number of channels. The modified ONI was tested in a rabbit (n = 1) amputation model over 12 weeks, comparing the sieve component to the cuff, and subsequently compared to historical data. Efferent CNAPs were successfully recorded from the sieve demonstrating physiological improvements in CNAPs between weeks 3 and 5, and somatosensory cortical responses recorded at 12 weeks postoperatively. This demonstrates that sieve electrodes can be housed and function within the medullary canal, demonstrated by improved nerve engagement and distinct cortical sensory feedback. This data presents the conceptual framework for housing more sophisticated sieve electrodes in bone as part of an ONI for improving selectivity with percutaneous connectivity toward improved prosthetic control.
Changes in Phenolic Metabolites and Biological Activities of Pumpkin Leaves (Cucurbita moschata Duchesne ex Poir.) During Blanching
Authors: Mashitoa Florence M. , Shoko Tinotenda , Shai Jerry L. , Slabbert Retha M. , Sivakumar Dharini
Published: March 2021

Pumpkin leaves (Cucurbita moschata Duchesne ex Poir.) are popularly consumed in Sub-Saharan Africa and Asia. Blanching the leaves before drying is a method of preservation during off-season. In this study, different blanching treatments and media are used to test the changes in non-targeted phenolic compounds, antioxidant capacity (FRAP and ABTS activity), in vitro α-glucosidase activity and cell cytotoxicity of pumpkin leaves. Steam blanching in plain water led to the highest retention of total phenolic content and reduced the loss of quercetin 3-glucoside 7-rhamnoside (Rutin), kaempferol 7-neohesperidoside, isoorientin 2″-O-rhamnoside, isorhamnetin-3-O-rutinoside, quercetin 3-galactoside, coumaroyl glucaric acid, isorhamnetin-3-galactoside-6″-rhamnoside, 2-caffeoylisocitric acid, quercetin 3-galactoside 7-rhamnoside by (3.04%), (7.37%), (10.65%), (10.97%), (14.88%), (16.1%), (16.73%), (18.88%), and (23.15%), respectively, and coumaroyl isocitrate increased by 14.92%. Candidate markers, 2-O-caffeoylglucaric acid, 2-(E)-O-feruloyl-D-galactaric acid, quercetin 3-galactoside 7-rhamnoside (rutin) and unidentified compounds ([(M-H) 677.28 and at RT 21.78] were responsible for the separation of the steam blanched samples in plain water from the other blanching treatments. Steam blanching in plain water increased the antioxidant capacity (FRAP and ABTS activity). There were no cytotoxic effect or inhibitory effect of α-glucosidase activity detected in the raw or blanched pumpkin leaves. Thus, this study recommends steam blanching in plain water for African cuisine, and confirms it is safe to consume pumpkin leaves frequently.
Using Endoscopic Optical Coherence Tomography to Detect and Treat Early-Stage Pancreatic Cancers
Authors: Lu Lanchun , Hu Zhilin , Frankel Wendy , Shen Rulong , Chen Wei , Pan Xueliang , Grecula John C. , Bloomston Mark P. , Dillhoff Mary E.
Published: March 2021

We developed a novel technology capable of detecting early-stage pancreatic cancers using high-resolution three-dimensional endoscopic optical coherence tomography (Endo-OCT), and treating them using high dose rate brachytherapy (HDR) under the Endo-OCT image guidance. This technology integrates our custom-built ultra-high resolution endoscopic three-dimensional OCT diagnostic imaging device with a commercial high dose rate brachytherapy system (HDR), resulting in a compact, portable, easy-to-operate, and low-cost Endo-OCT image-guided high dose rate brachytherapy (OCT-IGHDR) system. The system has the dual functions of diagnosis and treatment that can precisely detect and measure the location and size of the early-stage pancreatic cancer or premalignant lesions and then treat them from the inside of the pancreatic duct with an accurate and focused dose while greatly reducing the radiation toxicity to the neighboring tissues and organs. This minimally-invasive treatment technology could avoid the potential complications from surgery and reduces the high operation cost. This technology could also be applied to treat diseases of the esophagus, rectum, bronchus, and other aerodigestive organs that are suitable for use with an endoscopic device. In this article, we describe the concept of this technology and the preliminary experiments that could demonstrate the concept by using this homemade Endo-OCT machine to image the pancreatic duct for diagnosis of early-stage pancreatic cancer or premalignant lesions and to perform Endo-OCT image-guided brachytherapy.
Efficacy and Safety of Anti-PD-1 Plus Anlotinib in Patients With Advanced Non–Small-Cell Lung Cancer After Previous Systemic Treatment Failure—A Retrospective Study
Authors: Wang Peiliang , Fang Xiaozhuang , Yin Tianwen , Tian Hairong , Yu Jinming , Teng Feifei
Published: March 2021

Background

Pre-clinical and clinical evidences support that simultaneous blockade of programmed death-1 (PD-1) and vascular endothelial growth factor receptor (VEGFR) can enhance antigen-specific T-cell migration, and show tolerable toxicity with favorable antitumor activity in patients. In this study, we aimed to assess the safety and efficacy of anlotinib, a novel multitarget tyrosine kinase inhibitor for VEGFR, platelet-derived growth receptor (PDGFR), and the stem cell-factor receptor (c-Kit), combined with anti-PD-1 treatment in patients with advanced NSCLC.

Methods

Sixty-seven patients with previously treated advanced NSCLC receiving anti-PD-1 agents concomitant with anlotinib were retrospectively enrolled in an IRB approved study. Anti-PD-1 agents including pembrolizumab, nivolumab, camrelizumab, toripalimab, sintilimab, and tislelizumab were administered every two or three weeks until disease progression or unacceptable toxicity was reached. Anlotinib was administered orally once daily on days 1–14 of a 21-day cycle. The safety and tolerability of the combination treatment were assessed by the incidence of adverse events. The efficacy of the treatment was assessed by the tumor response and survival.

Results

With a median follow-up period of 8.7 months, treatment-related adverse events occurred in 85% (57/67) of patients and grade 3–4 adverse events were observed in 27 patients (40%). No unexpected adverse events or significantly increased toxicities were observed. Complete response was not observed, 19 patients had partial response (28.4%), 39 had stable disease (58.2%) and 9 had progressive disease (13.4%). The overall response (ORR) and disease control rates (DCR) were 28.4% and 86.6%, respectively. The median progression-free survival (PFS) was 6.9 months (95% CI, 5.5-8.3 months) and overall survival (OS) was 14.5 months (95% CI, 10.9-18.1 months). The benefit of anti-PD-1 plus anlotinib was also observed in patients with EGFR mutation positive, liver metastases and brain metastases.

Conclusion

Anti-PD-1 treatment concomitant with anlotinib has tolerable toxicity and favorable antitumor activity in patients with previously treated advanced NSCLC. Our results add to the growing evidence that supports the benefits of combining immunotherapy with antiangiogenic drugs. This combination could be further evaluated with or without chemotherapy, since no additional toxicity was observed in the combination treatment.
Patient-Specific Quality Assurance Using a 3D-Printed Chest Phantom for Intraoperative Radiotherapy in Breast Cancer
Authors: Choi Yeonho , Lee Ik Jae , Park Kwangwoo , Park Kyung Ran , Cho Yeona , Kim Jun Won , Lee Ho
Published: March 2021

This study aims to confirm the usefulness of patient-specific quality assurance (PSQA) using three-dimensional (3D)-printed phantoms in ensuring the stability of IORT and the precision of the treatment administered. In this study, five patient-specific chest phantoms were fabricated using a 3D printer such that they were dosimetrically equivalent to the chests of actual patients in terms of organ density and shape around the given target, where a spherical applicator was inserted for breast IORT treatment via the INTRABEAM™ system. Models of lungs and soft tissue were fabricated by applying infill ratios corresponding to the mean Hounsfield unit (HU) values calculated from CT scans of the patients. The two models were then assembled into one. A 3D-printed water-equivalent phantom was also fabricated to verify the vendor-provided depth dose curve. Pieces of an EBT3 film were inserted into the 3D-printed customized phantoms to measure the doses. A 10 Gy prescription dose based on the surface of the spherical applicator was delivered and measured through EBT3 films parallel and perpendicular to the axis of the beam. The shapes of the phantoms, CT values, and absorbed doses were compared between the expected and printed ones. The morphological agreement among the five patient-specific 3D chest phantoms was assessed. The mean differences in terms of HU between the patients and the phantoms was 2.2 HU for soft tissue and −26.2 HU for the lungs. The dose irradiated on the surface of the spherical applicator yielded a percent error of −2.16% ± 3.91% between the measured and prescribed doses. In a depth dose comparison using a 3D-printed water phantom, the uncertainty in the measurements based on the EBT3 film decreased as the depth increased beyond 5 mm, and a good agreement in terms of the absolute dose was noted between the EBT3 film and the vendor data. These results demonstrate the applicability of the 3D-printed chest phantom for PSQA in breast IORT. This enhanced precision offers new opportunities for advancements in IORT.
Small Extracellular Vesicles: A Novel Avenue for Cancer Management
Authors: Gao Yanan , Qin You , Wan Chao , Sun Yajie , Meng Jingshu , Huang Jing , Hu Yan , Jin Honglin , Yang Kunyu
Published: March 2021

Extracellular vesicles are small membrane particles derived from various cell types. EVs are broadly classified as ectosomes or small extracellular vesicles, depending on their biogenesis and cargoes. Numerous studies have shown that EVs regulate multiple physiological and pathophysiological processes. The roles of small extracellular vesicles in cancer growth and metastasis remain to be fully elucidated. As endogenous products, small extracellular vesicles are an ideal drug delivery platform for anticancer agents. However, several aspects of small extracellular vesicle biology remain unclear, hindering the clinical implementation of small extracellular vesicles as biomarkers or anticancer agents. In this review, we summarize the utility of cancer-related small extracellular vesicles as biomarkers to detect early-stage cancers and predict treatment outcomes. We also review findings from preclinical and clinical studies of small extracellular vesicle-based cancer therapies and summarize interventional clinical trials registered in the United States Food and Drug Administration and the Chinese Clinical Trials Registry. Finally, we discuss the main challenges limiting the clinical implementation of small extracellular vesicles and recommend possible approaches to address these challenges.
Differentiation of Glioma Mimicking Encephalitis and Encephalitis Using Multiparametric MR-Based Deep Learning
Authors: Wu Wenli , Li Jiewen , Ye Junyong , Wang Qi , Zhang Wentao , Xu Shengsheng
Published: March 2021

Background

Computational aid for diagnosis based on convolutional neural network (CNN) is promising to improve clinical diagnostic performance. Therefore, we applied pretrained CNN models in multiparametric magnetic resonance (MR) images to classify glioma mimicking encephalitis and encephalitis.

Methods

A data set containing 3064 MRI brain images from 164 patients with a final diagnosis of glioma (n = 56) and encephalitis (n = 108) patients and divided into training and testing sets. We applied three MRI modalities [fluid attenuated inversion recovery (FLAIR), contrast enhanced-T1 weighted imaging (CE-T1WI) and T2 weighted imaging (T2WI)] as the input data to build three pretrained deep CNN models (Alexnet, ResNet-50, and Inception-v3), and then compared their classification performance with radiologists’ diagnostic performance. These models were evaluated by using the area under the receiver operator characteristic curve (AUC) of a five-fold cross-validation and the accuracy, sensitivity, specificity were analyzed.

Results

The three pretrained CNN models all had AUC values over 0.9 with excellent performance. The highest classification accuracy of 97.57% was achieved by the Inception-v3 model based on the T2WI data. In addition, Inception-v3 performed statistically significantly better than the Alexnet architecture (p<0.05). For Inception-v3 and ResNet-50 models, T2WI offered the highest accuracy, followed by CE-T1WI and FLAIR. The performance of Inception-v3 and ResNet-50 had a significant difference with radiologists (p<0.05), but there was no significant difference between the results of the Alexnet and those of a more experienced radiologist (p >0.05).

Conclusions

The pretrained CNN models can automatically and accurately classify these two diseases and further help to improving clinical diagnostic performance.
The Epigenetic Regulation of Microenvironment in Hepatocellular Carcinoma
Authors: Wang Fang , Malnassy Greg , Qiu Wei
Published: March 2021

Hepatocellular carcinoma (HCC) is a highly lethal and complex malignancy strongly influenced by the surrounding tumor microenvironment. The HCC microenvironment comprises hepatic stellate cells (HSCs), tumor-associated macrophages (TAMs), stromal and endothelial cells, and the underlying extracellular matrix (ECM). Emerging evidence demonstrates that epigenetic regulation plays a crucial role in altering numerous components of the HCC tumor microenvironment. In this review, we summarize the current understanding of the mechanisms of epigenetic regulation of the microenvironment in HCC. We review recent studies demonstrating how specific epigenetic mechanisms (DNA methylation, histone regulation, and non-coding RNAs mediated regulation) in HSCs, TAMs, and ECM, and how they contribute to HCC development, so as to gain new insights into the treatment of HCC via regulating epigenetic regulation in the tumor microenvironment.
Acute Kidney Injury in Critically Ill Children Is Not all Acute: Lessons Over the Last 5 Years
Authors: Hessey Erin , Melhem Nabil , Alobaidi Rashid , Ulrich Emma , Morgan Catherine , Bagshaw Sean M. , Sinha Manish D.
Published: March 2021

Acute kidney injury (AKI) in the pediatric intensive care unit (PICU) is an important risk factor for increased morbidity and mortality during hospitalization. Over the past decade, accumulated data on children and young people indicates that acute episodes of kidney dysfunction can have lasting consequences on multiple organ systems and health outcomes. To date, there are no guidelines for follow-up of surviving children that may be at risk of long-term sequelae following AKI in the PICU. This narrative review aims to describe literature from the last 5 years on the risk of medium and long-term kidney and non-kidney outcomes after AKI in the PICU. More specifically, we will focus on outcomes in children and young people following AKI in the general PICU population and children undergoing cardiac surgery. These outcomes include mortality, hypertension, proteinuria, chronic kidney disease, and healthcare utilization. We also aim to highlight current gaps in knowledge in medium and long-term outcomes in this pediatric population. We suggest a framework for future research to develop evidence-based guidelines for follow-up of children surviving an episode of critical illness and AKI.
Comparison of the Simulated Response of Three in Silico Human Stem Cell-Derived Cardiomyocytes Models and in Vitro Data Under 15 Drug Actions
Authors: Paci Michelangelo , Koivumäki Jussi T. , Lu Hua Rong , Gallacher David J. , Passini Elisa , Rodriguez Blanca
Published: March 2021

Objectives: Improvements in human stem cell-derived cardiomyocyte (hSC-CM) technology have promoted their use for drug testing and disease investigations. Several in silico hSC-CM models have been proposed to augment interpretation of experimental findings through simulations. This work aims to assess the response of three hSC-CM in silico models (Koivumäki2018, Kernik2019, and Paci2020) to simulated drug action, and compare simulation results against in vitro data for 15 drugs.

Methods: First, simulations were conducted considering 15 drugs, using a simple pore-block model and experimental data for seven ion channels. Similarities and differences were analyzed in the in silico responses of the three models to drugs, in terms of Ca2+ transient duration (CTD90) and occurrence of arrhythmic events. Then, the sensitivity of each model to different degrees of blockage of Na+ (INa), L-type Ca2+ (ICaL), and rapid delayed rectifying K+ (IKr) currents was quantified. Finally, we compared the drug-induced effects on CTD90 against the corresponding in vitro experiments.

Results: The observed CTD90 changes were overall consistent among the in silico models, all three showing changes of smaller magnitudes compared to the ones measured in vitro. For example, sparfloxacin 10 µM induced +42% CTD90 prolongation in vitro, and +17% (Koivumäki2018), +6% (Kernik2019), and +9% (Paci2020) in silico. Different arrhythmic events were observed following drug application, mainly for drugs affecting IKr. Paci2020 and Kernik2019 showed only repolarization failure, while Koivumäki2018 also displayed early and delayed afterdepolarizations. The spontaneous activity was suppressed by Na+ blockers and by drugs with similar effects on ICaL and IKr in Koivumäki2018 and Paci2020, while only by strong ICaL blockers, e.g. nisoldipine, in Kernik2019. These results were confirmed by the sensitivity analysis.

Conclusion: To conclude, The CTD90 changes observed in silico are qualitatively consistent with our in vitro data, although our simulations show differences in drug responses across the hSC-CM models, which could stem from variability in the experimental data used in their construction.
Sodium Selenite Attenuates Balloon Injury-Induced and Monocrotaline-Induced Vascular Remodeling in Rats
Authors: Cai Changhong , Wu Yonghui , Yang Lebing , Xiang Yijia , Zhu Ning , Zhao Huan , Hu Wuming , Lv Lingchun , Zeng Chunlai
Published: March 2021

Vascular remodeling (VR), induced by the massive proliferation and reduced apoptosis of vascular smooth muscle cells (VSMCs), is primarily responsible for many cardiovascular conditions, such as restenosis and pulmonary arterial hypertension. Sodium selenite (SSE) is an inorganic selenium, which can block proliferation and stimulate apoptosis of tumor cells; still, its protective effects on VR remains unknown. In this study, we established rat models with carotid artery balloon injury and monocrotaline induced pulmonary arterial hypertension and administered them SSE (0.25, 0.5, or 1 mg/kg/day) orally by feeding tube for 14 consecutive days. We found that SSE treatment greatly ameliorated the development of VR as evidenced by an improvement of its characteristic features, including elevation of the ratio of carotid artery intimal area to medial area, right ventricular hypertrophy, pulmonary arterial wall hypertrophy and right ventricular systolic pressure. Furthermore, PCNA and TUNEL staining of the arteries showed that SSE suppressed proliferation and enhanced apoptosis of VSMCs in both models. Compared with the untreated VR rats, lower expression of PCNA and CyclinD1, but higher levels of Cleaved Caspase-3 and Bax/Bcl-2 were observed in the SSE-treated rats. Moreover, the increased protein expression of MMP2, MMP9, p-AKT, p-ERK, p-GSK3β and β-catenin that occurred in the VR rats were significantly inhibited by SSE. Collectively, treatment with SSE remarkably attenuates the pathogenesis of VR, and this protection may be associated with the inhibition of AKT and ERK signaling and prevention of VSMC’s dysfunction. Our study suggest that SSE is a potential agent for treatment of VR-related diseases.
G6PD Variants and Haemolytic Sensitivity to Primaquine and Other Drugs
Authors: Bancone Germana , Chu Cindy S.
Published: March 2021

Restrictions on the cultivation and ingestion of fava beans were first reported as early as the fifth century BC. Not until the late 19th century were clinical descriptions of fava-induced disease reported and soon after characterised as “favism” in the early 20th century. It is now well known that favism as well as drug-induced haemolysis is caused by a deficiency of the glucose-6-phosphate dehydrogenase (G6PD) enzyme, one of the most common enzyme deficiency in humans. Interest about the interaction between G6PD deficiency and therapeutics has increased recently because mass treatment with oxidative 8-aminoquinolines is necessary for malaria elimination. Historically, assessments of haemolytic risk have focused on the clinical outcomes (e.g., haemolysis) associated with either a simplified phenotypic G6PD characterisation (deficient or normal) or an ill-fitting classification of G6PD genetic variants. It is increasingly apparent that detailed knowledge of both aspects is required for a complete understanding of haemolytic risk. While more attention has been devoted recently to better phenotypic characterisation of G6PD activity (including the development of new point-of care tests), the classification of G6PD variants should be revised to be clinically useful in malaria eliminating countries and in populations with prevalent G6PD deficiency. The scope of this work is to summarize available literature on drug-induced haemolysis among individuals with different G6PD variants and to highlight knowledge gaps that could be filled with further clinical and laboratory research.
Role of ATP in Extracellular Vesicle Biogenesis and Dynamics
Authors: Lombardi Marta , Gabrielli Martina , Adinolfi Elena , Verderio Claudia
Published: March 2021

Adenosine triphosphate (ATP) is among the molecules involved in the immune response. It acts as danger signal that promotes inflammation by activating both P2X and P2Y purinergic receptors expressed in immune cells, including microglia, and tumor cells. One of the most important receptors implicated in ATP-induced inflammation is P2X7 receptor (P2X7R). The stimulation of P2X7R by high concentration of ATP results in cell proliferation, inflammasome activation and shedding of extracellular vesicles (EVs). EVs are membrane structures released by all cells, which contain a selection of donor cell components, including proteins, lipids, RNA and ATP itself, and are able to transfer these molecules to target cells. ATP stimulation not only promotes EV production from microglia but also influences EV composition and signaling to the environment. In the present review, we will discuss the current knowledge on the role of ATP in the biogenesis and dynamics of EVs, which exert important functions in physiology and pathophysiology.
Calcium-Sensing Receptor Contributes to Hyperoxia Effects on Human Fetal Airway Smooth Muscle
Authors: Roesler Anne M. , Ravix Jovanka , Bartman Colleen M. , Patel Brijeshkumar S. , Schiliro Marta , Roos Benjamin , Nesbitt Lisa , Pabelick Christina M. , Martin Richard J. , MacFarlane Peter M. , Prakash Y. S.
Published: March 2021

Supplemental O2 (hyperoxia), necessary for maintenance of oxygenation in premature infants, contributes to neonatal and pediatric airway diseases including asthma. Airway smooth muscle (ASM) is a key resident cell type, responding to hyperoxia with increased contractility and remodeling [proliferation, extracellular matrix (ECM) production], making the mechanisms underlying hyperoxia effects on ASM significant. Recognizing that fetal lungs experience a higher extracellular Ca2+ ([Ca2+]o) environment, we previously reported that the calcium sensing receptor (CaSR) is expressed and functional in human fetal ASM (fASM). In this study, using fASM cells from 18 to 22 week human fetal lungs, we tested the hypothesis that CaSR contributes to hyperoxia effects on developing ASM. Moderate hyperoxia (50% O2) increased fASM CaSR expression. Fluorescence [Ca2+]i imaging showed hyperoxia increased [Ca2+]i responses to histamine that was more sensitive to altered [Ca2+]o, and promoted IP3 induced intracellular Ca2+ release and store-operated Ca2+ entry: effects blunted by the calcilytic NPS2143. Hyperoxia did not significantly increase mitochondrial calcium which was regulated by CaSR irrespective of oxygen levels. Separately, fASM cell proliferation and ECM deposition (collagens but not fibronectin) showed sensitivity to [Ca2+]o that was enhanced by hyperoxia, but blunted by NPS2143. Effects of hyperoxia involved p42/44 ERK via CaSR and HIF1α. These results demonstrate functional CaSR in developing ASM that contributes to hyperoxia-induced contractility and remodeling that may be relevant to perinatal airway disease.
Inhibiting Mitochondrial Cytochrome c Oxidase Downregulates Gene Transcription After Traumatic Brain Injury in Drosophila
Authors: Shah Ekta J. , Hüttemann Maik , Sanderson Thomas H. , Gurdziel Katherine , Ruden Douglas M.
Published: March 2021

Traumatic brain injuries (TBIs) caused by a sudden impact to the head alter behavior and impair physical and cognitive function. Besides the severity, type and area of the brain affected, the outcome of TBI is also influenced by the patient’s biological sex. Previous studies reporting mitochondrial dysfunction mainly focused on exponential reactive oxygen species (ROS) generation, increased mitochondrial membrane potential, and altered mitochondrial dynamics as a key player in the outcome to brain injury. In this study, we evaluated the effect of a near-infrared (NIR) light exposure on gene expression in a Drosophila TBI model. NIR interacts with cytochrome c oxidase (COX) of the electron transport chain to reduce mitochondrial membrane potential hyperpolarization, attenuate ROS generation, and apoptosis. We subjected w1118 male and female flies to TBI using a high-impact trauma (HIT) device and subsequently exposed the isolated fly brains to a COX-inhibitory wavelength of 750 nm for 2 hours (hr). Genome-wide 3′-mRNA-sequencing of fly brains revealed that injured w1118 females exhibit greater changes in transcription compared to males at 1, 2, and 4 hours (hr) after TBI. Inhibiting COX by exposure to NIR downregulates gene expression in injured females but has minimal effect in injured males. Our results suggest that mitochondrial COX modulation with NIR alters gene expression in Drosophila following TBI and the response to injury and NIR exposure varies by biological sex.
Left Ventricular Dimensions and Diastolic Function Are Different in Throwers, Endurance Athletes, and Sprinters From the World Masters Athletics Championships
Authors: Hoffmann Fabian , Moestl Stefan , Wooten Savannah V. , Stray-Gundersen Sten , Tomczak Corey R. , Tank Jens , Tanaka Hirofumi , Rittweger Jörn , Chilibeck Philip D.
Published: March 2021

There is controversy whether a lifetime of heavy resistance training, providing pressure-overload, is harmful for left ventricular function. We compared left ventricular dimensions and function in elite Masters athletes involved in throwing events (requiring strength; n = 21, seven females, 60 ± 14 years) to those involved in endurance events (n = 65, 25 females, 59 ± 10 years) and sprinting (n = 68, 21 females, 57 ± 13 years) at the 2018 World Masters Athletic Championships. Left ventricular dimensions and function were assessed with B-mode ultrasound and Doppler. The ratio of left ventricular early diastolic peak filling velocity to peak velocity during atrial contraction (E/A) across the mitral valve and the ratio of E to velocity of the E-wave (E’) across the lateral and septal mitral annulus (E/E’) were used as indexes of left ventricular diastolic function. Intra-ventricular septal wall thickness was greater in throwers compared to sprinters (11.9 ± 2.2 vs. 10.3 ± 2.3 mm; p = 0.01). Left ventricular end diastolic diameter/body surface area was higher in endurance athletes and sprinters vs. throwers (25.2 ± 3.0, 24.3 ± 3.1, and 22.0 ± 3.1 mm/m2, respectively, p < 0.01). The E/A was higher in endurance athletes and sprinters vs. throwers (1.35 ± 0.40, 1.37 ± 0.43, and 1.05 ± 0.41, respectively; p < 0.01). The E/E’ was lower in endurance athletes and sprinters vs. throwers (6.9 ± 1.8, 6.6 ± 1.9, and 8.1 ± 1.9, respectively, p < 0.05). Compared to age-matched historical controls (n > 1,000; E/A = 1.06; E/E’ = 7.5), left ventricular diastolic function was not different in throwers, but superior in endurance athletes and sprinters (p < 0.01). Masters throwers have altered left ventricular dimensions and function vs. other athletes, but a lifetime of heavy resistance training does not appear to alter left ventricular function compared to age-matched controls.
How Do Red Blood Cells Die?
Authors: Thiagarajan Perumal , Parker Charles J. , Prchal Josef T.
Published: March 2021

Normal human red blood cells have an average life span of about 120 days in the circulation after which they are engulfed by macrophages. This is an extremely efficient process as macrophages phagocytose about 5 million erythrocytes every second without any significant release of hemoglobin in the circulation. Despite large number of investigations, the precise molecular mechanism by which macrophages recognize senescent red blood cells for clearance remains elusive. Red cells undergo several physicochemical changes as they age in the circulation. Several of these changes have been proposed as a recognition tag for macrophages. Most prevalent hypotheses for red cell clearance mechanism(s) are expression of neoantigens on red cell surface, exposure phosphatidylserine and decreased deformability. While there is some correlation between these changes with aging their causal role for red cell clearance has not been established. Despite plethora of investigations, we still have incomplete understanding of the molecular details of red cell clearance. In this review, we have reviewed the recent data on clearance of senescent red cells. We anticipate recent progresses in in vivo red cell labeling and the explosion of modern proteomic techniques will, in near future, facilitate our understanding of red cell senescence and their destruction.