bluuebunny/crossref_metadata_2025 huggingface dataset:
Neutrophilic Asthma Is Associated With Smoking, High Numbers of IRF5+, and Low Numbers of IL10+ Macrophages
Authors: Turan Nil , van der Veen T. Anienke , Draijer Christina , Fattahi Fatemeh , ten Hacken Nick H. , Timens Wim , van Oosterhout Antoon J. , van den Berge Maarten , Melgert Barbro N.
Published: June 2021

Asthma is a heterogenous disease with different inflammatory subgroups that differ in disease severity. This disease variation is hampering treatment and development of new treatment strategies. Macrophages may contribute to asthma phenotypes by their ability to activate in different ways, i.e., T helper cell 1 (Th1)-associated, Th2-associated, or anti-inflammatory activation. It is currently unknown if these different types of activation correspond with specific inflammatory subgroups of asthma. We hypothesized that eosinophilic asthma would be characterized by having Th2-associated macrophages, whereas neutrophilic asthma would have Th1-associated macrophages and both having few anti-inflammatory macrophages. We quantified macrophage subsets in bronchial biopsies of asthma patients using interferon regulatory factor 5 (IRF5)/CD68 for Th1-associated macrophages, CD206/CD68 for Th2-associated macrophages and interleukin 10 (IL10)/CD68 for anti-inflammatory macrophages. Macrophage subset percentages were investigated in subgroups of asthma as defined by unsupervised clustering using neutrophil/eosinophil counts in sputum and tissue and forced expiratory volume in 1 s (FEV1). Asthma patients clustered into four subgroups: mixed-eosinophilic/neutrophilic, paucigranulocytic, neutrophilic with normal FEV1, and neutrophilic with low FEV1, the latter group consisting mainly of smokers. No differences were found for CD206+ macrophages within asthma subgroups. In contrast, IRF5+ macrophages were significantly higher and IL10+ macrophages lower in neutrophilic asthmatics with low FEV1 as compared to those with neutrophilic asthma and normal FEV1 or mixed-eosinophilic asthma. This study shows that neutrophilic asthma with low FEV1 is associated with high numbers of IRF5+, and low numbers of IL10+ macrophages, which may be the result of combined effects of smoking and having asthma.
Coactosin Promotes F-Actin Protrusion in Growth Cones Under Cofilin-Related Signaling Pathway
Authors: Hou Xubin , Nozumi Motohiro , Nakamura Harukazu , Igarashi Michihiro , Sugiyama Sayaka
Published: June 2021

During brain development, axon outgrowth and its subsequent pathfinding are reliant on a highly motile growth cone located at the tip of the axon. Actin polymerization that is regulated by actin-depolymerizing factors homology (ADF-H) domain-containing family drives the formation of lamellipodia and filopodia at the leading edge of growth cones for axon guidance. However, the precise localization and function of ADF-H domain-containing proteins involved in axon extension and retraction remain unclear. We have previously shown that transcripts and proteins of coactosin-like protein 1 (COTL1), an ADF-H domain-containing protein, are observed in neurites and axons in chick embryos. Coactosin overexpression analysis revealed that this protein was localized to axonal growth cones and involved in axon extension in the midbrain. We further examined the specific distribution of coactosin and cofilin within the growth cone using superresolution microscopy, structured illumination microscopy, which overcomes the optical diffraction limitation and is suitable to the analysis of cellular dynamic movements. We found that coactosin was tightly associated with F-actin bundles at the growth cones and that coactosin overexpression promoted the expansion of lamellipodia and extension of growth cones. Coactosin knockdown in oculomotor neurons resulted in an increase in the levels of the inactive, phosphorylated form of cofilin and dysregulation of actin polymerization and axonal elongation, which suggests that coactosin promoted axonal growth in a cofilin-dependent manner. Indeed, the application of a dominant-negative form of LIMK1, a downstream effector of GTPases, reversed the effect of coactosin knockdown on axonal growth by enhancing cofilin activity. Combined, our results indicate that coactosin functions promote the assembly of protrusive actin filament arrays at the leading edge for growth cone motility.
The Role of BMP Signaling in Endothelial Heterogeneity
Authors: Han Orjin , Pak Boryeong , Jin Suk-Won
Published: June 2021

Bone morphogenetic proteins (BMPs), which compose the largest group of the transforming growth factor-β (TGF-ß) superfamily, have been implied to play a crucial role in diverse physiological processes. The most intriguing feature of BMP signaling is that it elicits heterogeneous responses from cells with equivalent identity, thus permitting highly context-dependent signaling outcomes. In endothelial cells (ECs), which are increasingly perceived as a highly heterogeneous population of cells with respect to their morphology, function, as well as molecular characteristics, BMP signaling has shown to elicit diverse and often opposite effects, illustrating the innate complexity of signaling responses. In this review, we provide a concise yet comprehensive overview of how outcomes of BMP signaling are modulated in a context-dependent manner with an emphasis on the underlying molecular mechanisms and summarize how these regulations of the BMP signaling promote endothelial heterogeneity.
The Mechanical Interplay Between Differentiating Mesenchymal Stem Cells and Gelatin-Based Substrates Measured by Atomic Force Microscopy
Authors: Meng Hongxu , Chowdhury Tina T. , Gavara Núria
Published: June 2021

Traditional methods to assess hMSCs differentiation typically require long-term culture until cells show marked expression of histological markers such as lipid accumulation inside the cytoplasm or mineral deposition onto the surrounding matrix. In parallel, stem cell differentiation has been shown to involve the reorganization of the cell’s cytoskeleton shortly after differentiation induced by soluble factors. Given the cytoskeleton’s role in determining the mechanical properties of adherent cells, the mechanical characterization of stem cells could thus be a potential tool to assess cellular commitment at much earlier time points. In this study, we measured the mechanical properties of hMSCs cultured on soft gelatin-based hydrogels at multiple time points after differentiation induction toward adipogenic or osteogenic lineages. Our results show that the mechanical properties of cells (stiffness and viscosity) and the organization of the actin cytoskeleton are highly correlated with lineage commitment. Most importantly, we also found that the mechanical properties and the topography of the gelatin substrate in the vicinity of the cells are also altered as differentiation progresses toward the osteogenic lineage, but not on the adipogenic case. Together, these results confirm the biophysical changes associated with stem cell differentiation and suggest a mechanical interplay between the differentiating stem cells and their surrounding extracellular matrix.
Emerging Role of Long Non-Coding RNAs in Diabetic Vascular Complications
Authors: Tanwar Vinay Singh , Reddy Marpadga A. , Natarajan Rama
Published: June 2021

Chronic metabolic disorders such as obesity and diabetes are associated with accelerated rates of macrovascular and microvascular complications, which are leading causes of morbidity and mortality worldwide. Further understanding of the underlying molecular mechanisms can aid in the development of novel drug targets and therapies to manage these disorders more effectively. Long non-coding RNAs (lncRNAs) that do not have protein-coding potential are expressed in a tissue- and species-specific manner and regulate diverse biological processes. LncRNAs regulate gene expression in cis or in trans through various mechanisms, including interaction with chromatin-modifying proteins and other regulatory proteins and via posttranscriptional mechanisms, including acting as microRNA sponges or as host genes of microRNAs. Emerging evidence suggests that major pathological factors associated with diabetes such as high glucose, free fatty acids, proinflammatory cytokines, and growth factors can dysregulate lncRNAs in inflammatory, cardiac, vascular, and renal cells leading to altered expression of key inflammatory genes and fibrotic genes associated with diabetic vascular complications. Here we review recent reports on lncRNA characterization, functions, and mechanisms of action in diabetic vascular complications and translational approaches to target them. These advances can provide new insights into the lncRNA-dependent actions and mechanisms underlying diabetic vascular complications and uncover novel lncRNA-based biomarkers and therapies to reduce disease burden and mortality.
Prognostic Nomograms for Predicting Overall Survival and Cancer‐Specific Survival of Patients With Malignant Pheochromocytoma and Paraganglioma
Authors: Zheng Lei , Gu Yalong , Silang Jiangcun , Wang Jinlong , Luo Feng , Zhang Baopeng , Li Chuanhong , Wang Feng
Published: June 2021

Background

Malignant pheochromocytoma and paraganglioma (PPGL) are rare tumors with few prognostic tools. This study aimed to construct nomograms for predicting 3- and 5-year survival for patients with malignant PPGL.

Methods

The patient data was retrieved from the Surveillance, Epidemiology, and End Results (SEER) database. A total of 764 patients diagnosed with malignant PPGL from 1975 to 2016 were included in this study. The patients were randomly divided into two cohorts; the training cohort (n = 536) and the validation cohort (n = 228). Univariate analysis, Lasso regression, and multivariate Cox analysis were used to identify independent prognostic factors, which were then utilized to construct survival nomograms. The nomograms were used to predict 3- and 5-year overall survival (OS) and cancer-specific survival (CSS) for patients with malignant PPGL. The prediction accuracy of the nomogram was assessed using the concordance index (C-index), receiver operating characteristic (ROC) curves and calibration curves. Decision curve analysis (DCAs) was used to evaluate the performance of survival models.

Results

Age, gender, tumor type, tumor stage, or surgery were independent prognostic factors for OS in patients with malignant PPGL, while age, tumor stage, or surgery were independent prognostic factors for CSS (P <.05). Based on these factors, we successfully constructed the OS and CSS nomograms. The C-indexes were 0.747 and 0.742 for the OS and CSS nomograms, respectively. In addition, both the calibration curves and ROC curves for the model exhibited reliable performance.

Conclusion

We successfully constructed nomograms for predicting the OS and CSS of patients with malignant PPGL. The nomograms could inform personalized clinical management of the patients.
Fate of four Different Classes of Chemicals Under Aerobic and Anaerobic Conditions in Biological Wastewater Treatment
Authors: Komolafe Oladapo , Mrozik Wojciech , Dolfing Jan , Acharya Kishor , Vassalle Lucas , Mota Cesar R. , Davenport Russell
Published: June 2021

The removal mechanisms and extent of degradation of 28 chemicals (triclosan, fifteen polycyclic aromatic hydrocarbons, four estrogens, and eight polybrominated diphenyl ether congeners) in different biological treatment systems [activated sludge, up-flow anaerobic sludge blanket reactor (UASB) and waste stabilization pond (WSP)] was investigated to provide insights into the limits of engineered biological treatment systems. This was done through degradation experiments with inhibition and abiotic controls in static reactors under aerobic and anaerobic conditions. Estrogens showed higher first order degradation rates (0.1129 h−1) under aerobic conditions with activated sludge inocula followed by low molecular weight (LMW) PAHs (0.0171 h−1), triclosan (0.0072 h−1), middle (MMW) (0.0054 h−1) and high molecular weight PAHs (HMW) (0.0033 h−1). The same trend was observed under aerobic conditions with a facultative inoculum from a WSP, although at a much slower rate. Biodegradation was the major removal mechanism for these chemicals in the activated sludge and WSP WWTPs surveyed. Photodegradation of these chemicals was also observed and varied across the group of chemicals (estrogens (light rate = 0.4296 d−1; dark = 0.3900 d−1) degraded faster under light conditions while reverse was the case for triclosan (light rate = 0.0566 d−1; dark = 0.1752 d−1). Additionally, all the chemicals were resistant to anaerobic degradation with UASB sludge, which implies that their removal in the UASB of the surveyed WWTP was most likely via sorption onto solids. Importantly, the first order degradation rate determined in this study was used to estimate predicted effluent concentrations (PECs). The PECs showed good agreement with the measured effluent concentrations from a previous study for these treatment systems.
A 14-Year Italian Experience in DM2 Genetic Testing: Frequency and Distribution of Normal and Premutated CNBP Alleles
Authors: Botta Annalisa , Visconti Virginia Veronica , Fontana Luana , Bisceglia Paola , Bengala Mario , Massa Roberto , Bagni Ilaria , Cardani Rosanna , Sangiuolo Federica , Meola Giovanni , Antonini Giovanni , Petrucci Antonio , Pegoraro Elena , D’Apice Maria Rosaria , Novelli Giuseppe
Published: June 2021

Myotonic dystrophy type 2 (DM2) is a multisystemic disorder caused by a (CCTG)n in intron 1 of the CNBP gene. The CCTG repeat tract is part of a complex (TG)v(TCTG)w(CCTG)x(NCTG)y(CCTG)z motif generally interrupted in CNBP healthy range alleles. Here we report our 14-year experience of DM2 postnatal genetic testing in a total of 570 individuals. The DM2 locus has been analyzed by a combination of SR-PCR, TP-PCR, LR-PCR, and Sanger sequencing of CNBP alleles. DM2 molecular diagnosis has been confirmed in 187/570 samples analyzed (32.8%) and is mainly associated with the presence of myotonia in patients. This set of CNBP alleles showed unimodal distribution with 25 different alleles ranging from 108 to 168 bp, in accordance with previous studies on European populations. The most frequent CNBP alleles consisted of 138, 134, 140, and 136 bps with an overall locus heterozygosity of 90%. Sequencing of 103 unexpanded CNBP alleles in DM2-positive patients revealed that (CCTG)5(NCTG)3(CCTG)7 and (CCTG)6(NCTG)3(CCTG)7 are the most common interruption motifs. We also characterized five CNBP premutated alleles with (CCTG)n repetitions from n = 36 to n = 53. However, the molecular and clinical consequences in our cohort of samples are not unequivocal. Data that emerged from this study are representative of the Italian population and are useful tools for National and European centers offering DM2 genetic testing and counseling.
Integrative Analysis of lncRNA-mRNA Profile Reveals Potential Predictors for SAPHO Syndrome
Authors: Sun Yuxiu , Li Chen , Lu Qingyi , Jiang Haixu , Zhu Mengmeng , Huang Guangrui , Wang Ting
Published: June 2021

Synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome is known as a rare disease characterized by inflammatory lesions on bones and skin. Polymorphism of clinical manifestation and lack of molecular biomarkers have both limited its diagnosis. Our study performed RNA sequencing (RNA-seq) and integrative bioinformatics analysis of long noncoding RNA (lncRNA)-messenger RNA (mRNA) profile in patients with SAPHO syndrome and healthy controls. A total of 4,419 differentially expressed (DE) mRNAs and 2,713 lncRNAs were identified (p < 0.05, fold change > 2) and a coexpression network was constructed to further investigate their regulatory interactions. The DE lncRNAs were predicted to interact with mRNAs in both cis and trans manners. Functional prediction found that the lncRNA-targeted genes may function in SAPHO syndrome by participating in biological process such as adipocytokine signaling pathway, ErbB signaling pathway, FoxO signaling pathway, as well as production and function of miRNAs. The expression levels of three pairs of coexpressed lncRNA-mRNAs were validated by qRT-PCR, and their relative expression levels were consistent with the RNA-seq data. The deregulated RNAs GAS7 and lnc-CLLU1.1-1:2 may serve as potential diagnostic biomarkers, and the combined receiver operating characteristic (ROC) curve of the two showed more reliable diagnostic ability with an AUC value of 0.871 in distinguishing SAPHO patients from healthy controls. In conclusion, this study provides a first insight into long noncoding RNA transcriptome profile changes associated with SAPHO syndrome and inspiration for further investigation on clinical biomarkers and molecular regulators of this inadequately understood clinical entity.
Mind the Seat Limit: On Capacity Management in Public Automated Shuttles
Authors: Mirnig Alexander G. , Gärtner Magdalena , Wallner Vivien , Füssl Elisabeth , Ausserer Karin , Rieß Jannik , Meschtscherjakov Alexander
Published: June 2021

With ever growing automation of public transport automated shuttles offer an attractive alternative in areas where traffic regulations limit the deployment of large buses (city centres) or where low degrees of utilization renders the manual vehicles operation non-economical (last mile). The low capacities of shuttles in combination with the human factor (driver or conductor) makes capacity management a greater challenge for the user. Capacity management describes the allocation of available seats in a vehicle, e.g., when buying a ticket. In this paper, we present the results of series of studies where capacity management in automated shuttles has been tested via instruments that are currently available in public transit (audio announcements, in-shuttle displays, booking apps). We found that measures during and after boarding are not sufficient and that capacity management in automated shuttle requires a more detailed planning of pre-boarding stages; when boarding automated shuttles as opposed to non-automated public buses the flexibility is reduced. The paper concludes with discussion and recommendations for an optimal capacity management d.
Meta-Ribosomalomics: RNA Sequencing Is an Unbiased Method for Parasite Detection of Different Sample Types
Authors: Wylezich Claudia , Höper Dirk
Published: June 2021

In this perspective article, we review the past use of ribosomal sequences to address scientific and diagnostic questions. We highlight a variety of sequencing approaches including metagenomics and DNA barcoding and their different demands and requirements. Meta-ribosomalomics is introduced as an unbiased approach to exploit high-throughput sequencing datasets for eukaryotic and prokaryotic ribosomal sequences. Prerequisites, benefits, drawbacks, and future perspectives are elaborated and compared to other sequencing approaches.
Prevalence of the NTEKPC-I on IncF Plasmids Among Hypervirulent Klebsiella pneumoniae Isolates in Jiangxi Province, South China
Authors: Huang Qi-Sen , Liao Wenjian , Xiong Zhijuan , Li Dan , Du Fang-Ling , Xiang Tian-xin , Wei DanDan , Wan La-Gen , Liu Yang , Zhang Wei
Published: June 2021

Infection caused by carbapenem-resistant hypervirulent Klebsiella pneumoniae (CR-hvKP) has become a tricky health care threat in China and KPC-2 enzyme is a main factor mediating resistance to carbapenems of K. pneumoniae. Here, we report the characterization of the genetic environment of the blaKPC-2 gene in CR-hvKP clinical isolates from South China. Forty-five non-duplicated CR-hvKP isolates collected in Jiangxi Province from 2018 to 2019 were analyzed. Each of them were multidrug-resistant due to the presence not only of blaKPC-2 gene but also of other resistance determinants, including Metallo-β-lactamases (NDM-1), extended-spectrum β-lactamases (TEM-1, CTX-M-14, SHV-1), and plasmid-mediated quinolone resistance determinants (qnrS, aac(6′)-Ib-cr). After plasmid analyses of PCR-based replicon typing (PBRT), mapping PCR, amplicon sequencing, and whole-genome sequencing (WGS) were used to analyze the genetic environment of the blaKPC-2 gene. PCR analysis of pLVPK-like plasmids, Southern Blot, and mouse lethality assay were used to characterize the virulence phenotype of K. pneumoniae. Multilocus sequence typing (MLST) analysis showed ST11 CR-hvKP was the predominant clone. In conclusion, this is the first analysis of diverse genetic structures blaKPC-2 gene in CR-hvKP isolates from south China. Both the NTEKPC-I on the IncF plasmids and pLVPK-like virulence plasmids make contributions to the formation of CR-hvKP especially ST11 which need more attention.
Impact of the Expression System on Recombinant Protein Production in Escherichia coli BL21
Authors: Lozano Terol Gema , Gallego-Jara Julia , Sola Martínez Rosa Alba , Martínez Vivancos Adrián , Cánovas Díaz Manuel , de Diego Puente Teresa
Published: June 2021

Recombinant protein production for medical, academic, or industrial applications is essential for our current life. Recombinant proteins are obtained mainly through microbial fermentation, with Escherichia coli being the host most used. In spite of that, some problems are associated with the production of recombinant proteins in E. coli, such as the formation of inclusion bodies, the metabolic burden, or the inefficient translocation/transport system of expressed proteins. Optimizing transcription of heterologous genes is essential to avoid these drawbacks and develop competitive biotechnological processes. Here, expression of YFP reporter protein is evaluated under the control of four promoters of different strength (PT7lac, Ptrc, Ptac, and PBAD) and two different replication origins (high copy number pMB1′ and low copy number p15A). In addition, the study has been carried out with the E. coli BL21 wt and the ackA mutant strain growing in a rich medium with glucose or glycerol as carbon sources. Results showed that metabolic burden associated with transcription and translation of foreign genes involves a decrease in recombinant protein expression. It is necessary to find a balance between plasmid copy number and promoter strength to maximize soluble recombinant protein expression. The results obtained represent an important advance on the most suitable expression system to improve both the quantity and quality of recombinant proteins in bioproduction engineering.
Case Report: Formation of 3D Osteoblast Spheroid Under Magnetic Levitation for Bone Tissue Engineering
Authors: Gaitán-Salvatella Iñigo , López-Villegas Edgar Oliver , González-Alva Patricia , Susate-Olmos Fernando , Álvarez-Pérez Marco Antonio
Published: June 2021

Skeletal reconstruction is necessary in cases of bone defects created by tumors, trauma, and abnormalities. Regeneration of bone defects remains a critical problem, and current approaches are based on biocompatible scaffolds. Spheroids represent a simple 3D system since no supporting material is required for cell growth. Different techniques are used to generate spheroids, such as hanging drop, low-attachment plates, and magnetic nanoparticles. The idea of using magnetic nanoparticles is to cross-link through cell membrane overnight to create complex 3D cellular spheroid by using magnets to guide the cellular response. Herein, the current study aimed to achieve 3D human fetal osteoblast (hFOB) spheroid under magnetic levitation. Formation of 3D spheroid culture under magnetic levitation was evaluated by cell viability at 3, 7, and 14 days. Morphology of the 3D hFOB spheroid was analyzed by SEM and fluorescence microscopy and the differentiation towards mineralized lineage by ALP assay, qPCR, and alizarin red staining. The cell viability indicated that the 3D hFOB spheroid still viable after 14 days of culture. ALP assay, qPCR analysis expression of Col1, ALP, and Itg-β1 molecules, and calcium deposition with alizarin red showed a high level of bioactivity of the 3D hFOB spheroid. SEM images allowed the morphological analysis of the 3D microtissue-like spheroid with the presence of matrix deposition. These results indicate that magnetic levitation culture enables 3D stable osteoblast spheroids and could be a promising strategy for engineering application in the 3D construct in surgery regeneration of mineralized tissue.
Case Report: Ruptured Middle Cerebral Artery Aneurysm With Intrasylvian Hematoma Successfully Treated by Coil Embolization and Minimally Invasive Puncture and Drainage
Authors: Li Zhen , Hu Quan , Zhao Li , Huang Huayun , Zhang Shizhong , Zheng Limin , Wang Guojun
Published: June 2021

Up to one-third (12–35%) of patients with aneurysmal subarachnoid hemorrhage experience intracerebral hematoma. Ruptured middle cerebral artery (MCA) aneurysm with hematoma is usually accompanied by progressive cerebral swelling with poor outcomes; however, it can be successfully treated by coil embolization and minimally invasive puncture and drainage. From February 2012 to March 2019, six surgeries for ruptured MCA aneurysms with intrasylvian hematoma were performed at our clinic. All patients had intracranial hematomas of <30 ml and GCS scores >8. The patients were treated by coil embolization and minimally invasive puncture and drainage. The aneurysms in all patients were completely embolized and the hematomas were mostly removed by minimally invasive puncture. The Glasgow outcome scale (GOS) scores of all patients were more than 4 at discharge when they discharged. Coil embolization and minimally invasive puncture and drainage are viable treatments for ruptured MCA aneurysms with hematomas, especially if the patient is too old, in a complicated state to undergo craniotomy, is unwilling to undergo craniotomy, or is at a greater risk of bleeding 3 days after surgery.
Angiogenin in the Neurogenic Subventricular Zone After Stroke
Authors: Gabriel-Salazar Marina , Lei Ting , Grayston Alba , Costa Carme , Medina-Gutiérrez Esperanza , Comabella Manuel , Montaner Joan , Rosell Anna
Published: June 2021

Ischemic stroke is a leading cause of death and disability worldwide with effective acute thrombolytic treatments. However, brain repair mechanisms related to spontaneous or rehabilitation-induced recovery are still under investigation, and little is known about the molecules involved. The present study examines the potential role of angiogenin (ANG), a known regulator of cell function and metabolism linked to neurological disorders, focusing in the neurogenic subventricular zone (SVZ). Angiogenin expression was examined in the mouse SVZ and in SVZ-derived neural stem cells (NSCs), which were exposed to exogenous ANG treatment during neurosphere formation as well as in other neuron-like cells (SH-SY5Y). Additionally, male C57Bl/6 mice underwent a distal permanent occlusion of the middle cerebral artery to study endogenous and exercise-induced expression of SVZ-ANG and neuroblast migration. Our results show that SVZ areas are rich in ANG, primarily expressed in DCX+ neuroblasts but not in nestin+NSCs. In vitro, treatment with ANG increased the number of SVZ-derived NSCs forming neurospheres but could not modify SH-SY5Y neurite differentiation. Finally, physical exercise rapidly increased the amount of endogenous ANG in the ipsilateral SVZ niche after ischemia, where DCX-migrating cells increased as part of the post-stroke neurogenesis process. Our findings position for the first time ANG in the SVZ during post-stroke recovery, which could be linked to neurogenesis.
Changes in Corticospinal Circuits During Premovement Facilitation in Physiological Conditions
Authors: Cirillo Giovanni , Di Vico Ilaria Antonella , Emadi Andani Mehran , Morgante Francesca , Sepe Giovanna , Tessitore Alessandro , Bologna Matteo , Tinazzi Michele
Published: June 2021

Changes in corticospinal excitability have been well documented in the preparatory period before movement, however, their mechanisms and physiological role have not been entirely elucidated. We aimed to investigate the functional changes of excitatory corticospinal circuits during a reaction time (RT) motor task (thumb abduction) in healthy subjects (HS). 26 HS received single pulse transcranial magnetic stimulation (TMS) over the primary motor cortex (M1). After a visual go signal, we calculated RT and delivered TMS at three intervals (50, 100, and 150 ms) within RT and before movement onset, recording motor evoked potentials (MEP) from the abductor pollicis brevis (APB) and the task-irrelevant abductor digiti minimi (ADM). We found that TMS increased MEPAPB amplitude when delivered at 150, 100, and 50 ms before movement onset, demonstrating the occurrence of premovement facilitation (PMF). MEP increase was greater at the shorter interval (MEP50) and restricted to APB (no significant effects were detected recording from ADM). We also reported time-dependent changes of the RT and a TMS side-dependent effect on MEP amplitude (greater on the dominant side). In conclusion, we here report changes of RT and side-dependent, selective and facilitatory effects on the MEPAPB amplitude when TMS is delivered before movement onset (PMF), supporting the role of excitatory corticospinal mechanisms at the basis of the selective PMF of the target muscle during the RT protocol.
Prefrontal Theta-Phase Synchronized Brain Stimulation With Real-Time EEG-Triggered TMS
Authors: Gordon Pedro Caldana , Dörre Sara , Belardinelli Paolo , Stenroos Matti , Zrenner Brigitte , Ziemann Ulf , Zrenner Christoph
Published: June 2021

Background

Theta-band neuronal oscillations in the prefrontal cortex are associated with several cognitive functions. Oscillatory phase is an important correlate of excitability and phase synchrony mediates information transfer between neuronal populations oscillating at that frequency. The ability to extract and exploit the prefrontal theta rhythm in real time in humans would facilitate insight into neurophysiological mechanisms of cognitive processes involving the prefrontal cortex, and development of brain-state-dependent stimulation for therapeutic applications.

Objectives

We investigate individual source-space beamforming-based estimation of the prefrontal theta oscillation as a method to target specific phases of the ongoing theta oscillations in the human dorsomedial prefrontal cortex (DMPFC) with real-time EEG-triggered transcranial magnetic stimulation (TMS). Different spatial filters for extracting the prefrontal theta oscillation from EEG signals are compared and additional signal quality criteria are assessed to take into account the dynamics of this cortical oscillation.

Methods

Twenty two healthy participants were recruited for anatomical MRI scans and EEG recordings with 18 composing the final analysis. We calculated individual spatial filters based on EEG beamforming in source space. The extracted EEG signal was then used to simulate real-time phase-detection and quantify the accuracy as compared to post-hoc phase estimates. Different spatial filters and triggering parameters were compared. Finally, we validated the feasibility of this approach by actual real-time triggering of TMS pulses at different phases of the prefrontal theta oscillation.

Results

Higher phase-detection accuracy was achieved using individualized source-based spatial filters, as compared to an average or standard Laplacian filter, and also by detecting and avoiding periods of low theta amplitude and periods containing a phase reset. Using optimized parameters, prefrontal theta-phase synchronized TMS of DMPFC was achieved with an accuracy of ±55°.

Conclusion

This study demonstrates the feasibility of triggering TMS pulses during different phases of the ongoing prefrontal theta oscillation in real time. This method is relevant for brain state-dependent stimulation in human studies of cognition. It will also enable new personalized therapeutic repetitive TMS protocols for more effective treatment of neuropsychiatric disorders.
Assessment of Autonomic Nervous System Dysfunction in the Early Phase of Infection With SARS-CoV-2 Virus
Authors: Milovanovic Branislav , Djajic Vlado , Bajic Dragana , Djokovic Aleksandra , Krajnovic Tatjana , Jovanovic Sladjana , Verhaz Antonija , Kovacevic Pedja , Ostojic Miodrag
Published: June 2021

Background

We are facing the outburst of coronavirus disease 2019 (COVID-19) defined as a serious, multisystem, disorder, including various neurological manifestations in its presentation. So far, autonomic dysfunction (AD) has not been reported in patients with COVID-19 infection.

Aim

Assessment of AD in the early phase of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 virus).

Patients and methods

We analyzed 116 PCR positive COVID-19 patients. After the exclusion of 41 patients with associate diseases (CADG), partitioned to patients with diabetes mellitus, hypertension, and syncope, the remaining patients were included into a severe group (45 patients with confirmed interstitial pneumonia) and mild group (30 patients). Basic cardiovascular autonomic reflex tests (CART) were performed, followed by beat-to-beat heart rate variability (HRV) and systolic and diastolic blood pressure variability (BPV) analysis, along with baroreceptor sensitivity (BRS). Non-linear analysis of HRV was provided by Poincare Plot. Results were compared to 77 sex and age-matched controls.

Results

AD (sympathetic, parasympathetic, or both) in our study has been revealed in 51.5% of severe, 78.0% of mild COVID-19 patients, and the difference compared to healthy controls was significant (p = 0.018). Orthostatic hypotension has been established in 33.0% COVID-19 patients compared to 2.6% controls (p = 0.001). Most of the spectral parameters of HRV and BPV confirmed AD, most prominent in the severe COVID-19 group. BRS was significantly lower in all patients (severe, mild, CADG), indicating significant sudden cardiac death risk.

Conclusion

Cardiovascular autonomic neuropathy should be taken into account in COVID-19 patients’ assessment. It can be an explanation for a variety of registered manifestations, enabling a comprehensive diagnostic approach and further treatment.
Desire for Success Awakens: Proof of Competence Restoration in a Non-competitive Environment
Authors: Meng Liang , Pei Guanxiong , Zhang Yupei , Jin Jia
Published: June 2021

Pioneering studies reported that individuals who worked on a highly difficult task and experienced competence frustration beforehand would activate a restorative process and show enhanced autonomous motivation in a subsequent irrelevant activity. In this follow-up study, we explored the effect of prior competition outcome on one’s autonomous motivation in a subsequent non-competitive environment. According to our experimental manipulation, participants were randomly assigned to two treatment groups (a winning group and a losing group) and a control group. The experiment lasted for three sessions. Participants in the control group completed a single-player stop-watch (SW) task all along, while those in both treatment groups worked on a competitive SW task and competed for monetary rewards during Session 2 only. Electrophysiological data in Session 1 serve as the baseline and measure one’s trait-level autonomous motivation towards the SW game. For participants in the losing group, more pronounced difference wave of feedback-related negativity was observed in Session 3 compared with Session 1, suggesting enhanced autonomous motivation in Session 3. Such a pattern was observed in neither the winning group nor the control group. These results suggested that failure in a prior competition would activate one’s competence restoration in a subsequent non-competitive environment. Task difficulty and social competition are varied sources of competence frustration. Thus, our findings advanced understanding of the competence restorative process and helped clarify the dynamics between competition and human motivation.
Application of Interactive and Intelligent Packaging for Fresh Fish Shelf-Life Monitoring
Authors: Ibrahim Saber , Fahmy Hager , Salah Shimaa
Published: June 2021

Smart packaging, also known as intelligent packaging, is responsive to external stimuli, moisture, light, oxygen, heat, pH, and bacterial growth. It has evolved from extensive applications in food safety, bacterial response, and medical packaging. Interactive packaging has a scientific basis for additional information about food products because these codes give all required data. This work deals with a combination of frontline food sciences, smart and interactive packaging that are applicable for future production of nutrition packages through smart detection of food spooling. Additionally, it verifies the best degree of food safety and population demands as the third generation of packaging technology. High qualified duplex laminated package with a nano-encapsulated pH monitoring label for fresh fish was printed. The interactive Quick Response code icon was combined in a designed package with important information about cooking, smart packaging, and fish quality. Therefore, particle size, zeta potential, and surface area are measured for a nanoencapsulated indicator which exhibits 74.4 nm, 23.6 mV, and 88.9 m2/g, respectively: overall migration, water vapor, and oxygen permeability. The properties of printing for 11 color spots are evaluated by x-rite before and after the cold storage period without any detectable changes in the rate of color change (ΔE). The bacterial count of the tested sample is examined by counting the microbial colonies in the agar plate media. There is good agreement between microbial count and smart indicator color change as an effective direct detection tool for sustainable food quality and safety.
How to Better Understand the Influence of Host Genetics on Developing an Effective Immune Response to Thoracic Cancers
Authors: Behrouzfar Kiarash , Burton Kimberley , Mutsaers Steve E. , Morahan Grant , Lake Richard A. , Fisher Scott A.
Published: June 2021

Thoracic cancers pose a significant global health burden. Immune checkpoint blockade therapies have improved treatment outcomes, but durable responses remain limited. Understanding how the host immune system interacts with a developing tumor is essential for the rational development of improved treatments for thoracic malignancies. Recent technical advances have improved our understanding of the mutational burden of cancer cells and changes in cancer-specific gene expression, providing a detailed understanding of the complex biology underpinning tumor-host interactions. While there has been much focus on the genetic alterations associated with cancer cells and how they may impact treatment outcomes, how host genetics affects cancer development is also critical and will greatly determine treatment response. Genome-wide association studies (GWAS) have identified genetic variants associated with cancer predisposition. This approach has successfully identified host genetic risk factors associated with common thoracic cancers like lung cancer, but is less effective for rare cancers like malignant mesothelioma. To assess how host genetics impacts rare thoracic cancers, we used the Collaborative Cross (CC); a powerful murine genetic resource designed to maximize genetic diversity and rapidly identify genes associated with any biological trait. We are using the CC in conjunction with our asbestos-induced MexTAg mouse model, to identify host genes associated with mesothelioma development. Once genes that moderate tumor development and progression are known, human homologues can be identified and human datasets interrogated to validate their association with disease outcome. Furthermore, our CC−MexTAg animal model enables in-depth study of the tumor microenvironment, allowing the correlation of immune cell infiltration and gene expression signatures with disease development. This strategy provides a detailed picture of the underlying biological pathways associated with mesothelioma susceptibility and progression; knowledge that is crucial for the rational development of new diagnostic and therapeutic strategies. Here we discuss the influence of host genetics on developing an effective immune response to thoracic cancers. We highlight current knowledge gaps, and with a focus on mesothelioma, describe the development and application of the CC-MexTAg to overcome limitations and illustrate how the knowledge gained from this unique study will inform the rational design of future treatments of mesothelioma.
First-in-Human Trial of EphA2-Redirected CAR T-Cells in Patients With Recurrent Glioblastoma: A Preliminary Report of Three Cases at the Starting Dose
Authors: Lin Qingtang , Ba Teer , Ho Jinyuan , Chen Dandan , Cheng Ye , Wang Leiming , Xu Geng , Xu Lixin , Zhou Yiqiang , Wei Yukui , Li Jianqiang , Ling Feng
Published: June 2021

Glioblastoma is the most common primary brain malignancy with limited treatment options. EphA2 is a tumor-associated-antigen overexpressed in glioblastoma. Pre-clinical studies have demonstrated the promise of EphA2-redirected CAR T-cells against glioblastoma. We conduct the first-in-human trial of EphA2-redirected CAR T-cells in patients with EphA2-positive recurrent glioblastoma and report the results of three patients enrolled as the first cohort receiving the starting dosage (1×106 cells/kg). A single infusion of EphA2-redirected CAR T-cells was administrated intravenously, with the lymphodepletion regimen consisting of fludarabine and Cyclophosphamide. In two patients, there was grade 2 cytokine release syndrome accompanied by pulmonary edema, which resolved completely with dexamethasone medication. Except that, there was no other organ toxicity including neurotoxicity. In both the peripheral blood and cerebral-spinal-fluid, we observed the expansion of CAR T-cells which persisted for more than four weeks. In one patient, there was a transit diminishment of the tumor. Among these three patients, one patient reported SD and two patients reported PD, with overall survival ranging from 86 to 181 days. At the tested dose level (1×106 cells/kg), intravenously infusion of EphA2-rediretected CAR T-cells were preliminary tolerable with transient clinical efficacy. Future study with adjusted dose and infusion frequency of CAR T-cells is warranted.

Trial Registration Numbers

NCT 03423992
Efficacy of Intravenous Immunoglobulin/Exchange Transfusion Therapy on Gestational Alloimmune Liver Disease
Authors: Yeh Pai-Jui , Huang Shiu-Feng , Chiang Ming-Chou , Wang Chao-Jan , Lai Ming-Wei
Published: June 2021

Background: Gestational alloimmune liver disease (GALD) is a rare but critical cause of neonatal liver failure. After discovering the maternal–fetal alloimmune mechanism, intravenous immunoglobulin (IVIG) with or without exchange transfusion (ET) has gradually replaced antioxidant cocktails as the first-line therapy. Whether such therapy changes the outcome of neonates with GALD is yet to be defined.

Method: We reported a pair of twins with discordant presentations, mild and self-limited in the older, whereas liver failure in the younger, who was successfully rescued by ET and IVIG. To investigate the outcome after therapeutic alteration, 39 cases between 2005 and 2020 from literature research were collected.

Results: Half of the collected cases (47.1%) were preterm. Common presentations were ascites, jaundice, respiratory distress, hepatomegaly, and edema. Leading laboratory abnormalities were coagulopathy, hypoalbuminemia, and elevated serum ferritin. Salivary gland biopsy and magnetic resonance imaging detected extrahepatic siderosis in 70% (14/20) and 56% (14/25), respectively. IVIG, ET, and liver transplantation were performed in 19 (48.7%), 15 (38.5%), and 8 (20.5%) patients, respectively. The overall survival (OS) rate and native liver survival (NLS) rate were 64.1% (25/39) and 43.6% (17/39), respectively. Although the compiled results did not support a significant benefit, the OS and NLS were higher in the IVIG with/without ET group compared with those treated with conventional therapy [OS (70 vs. 57.9%) and NLS (55 vs. 31.6%), respectively].

Conclusion: A high index of suspicion for GALD is crucial when facing a neonate with liver failure. Despite no significant influence on the outcome over conventional therapy in such a rare and detrimental disease, IVIG with or without ET can be worth trying before resorting to liver transplantation, which is resource-demanding and technique-challenging in small infants.
Quantification of Inter-Limb Symmetries With Rate of Force Development and Relaxation Scaling Factor
Authors: Smajla Darjan , Žitnik Jure , Šarabon Nejc
Published: June 2021

The inter-limb (a)symmetries have been most often assessed with the tests that quantify the maximal muscle capacity. However, the rapid force production and relaxation during submaximal tasks is equally important for successful sports performance. This can be evaluated with an established rate of force development and relaxation scaling factor (RFD-SF/RFR-SF). The aims of our study were (1) to assess the intra-session reliability of shortened RFD-SF/RFR-SF protocol and its absolute and symmetry outcome measures, (2) to compare the main absolute RFD-SF/RFR-SF outcome measures (slopes of RFD-SF and RFR-SF: kRTD–SF and kRFR–SF, theoretical peak RFD/RFR: TPRFD and TPRFR) across gender and sports groups, and (3) to compare inter-limb symmetries across gender and sports groups for main outcome measures (kRFD–SF, kRFR–SF, TPRFD, and TPRFR). A cross-sectional study was conducted on a group of young health participants (basketball and tennis players, and students): 30 in the reliability study and 248 in the comparison study. Our results showed good to excellent relative and excellent absolute reliability for the selected absolute and symmetry outcome measures (kRFD–SF, kRFR–SF, TPRFD, and TPRFR). We found significantly higher absolute values for kRFD–SF and TPRFD in males compared to females for the preferred (kRFD–SF: 9.1 ± 0.9 vs. 8.6 ± 0.9/s) and the non-preferred leg (kRFD–SF: 9.1 ± 0.9 vs. 8.5 ± 0.8/s), while there was no effect of sport. Significantly lower symmetry values for kRFR–SF (88.4 ± 8.6 vs. 90.4 ± 8.0%) and TPRFR (90.9 ± 6.8 vs. 92.5 ± 6.0%) were found in males compared to females. Moreover, tennis players had significantly higher symmetry values for kRFR–SF (91.1 ± 7.7%) and TPRFR (93.1 ± 6.0%) compared to basketball players (kRFR–SF: 88.4 ± 8.7% and TPRFR: 90.9 ± 6.7%) and students (kRFR–SF: 87.6 ± 8.7% and TPRFR: 90.5 ± 6.7%). Our results suggest that the reduced RFD-SF/RFR-SF protocol is a valuable and useful tool for inter-limb (a)symmetry evaluation. Differences in symmetry values in kRFR–SF and TPRFR (relaxation phase) were found between different sports groups. These may be explained by different mechanisms underlying the muscle contraction and relaxation. We suggest that muscle contraction and relaxation should be assessed for in-depth inter-limb symmetry investigation.