bluuebunny/crossref_metadata_2025 huggingface dataset:
TMS-Induced Central Motor Conduction Time at the Non-Infarcted Hemisphere Is Associated with Spontaneous Motor Recovery of the Paretic Upper Limb after Severe Stroke
Authors: Hoonhorst Maurits H. J. , Nijland Rinske H. M. , Emmelot Cornelis H. , Kollen Boudewijn J. , Kwakkel Gert
Published: May 2021

Background: Stroke affects the neuronal networks of the non-infarcted hemisphere. The central motor conduction time (CMCT) induced by transcranial magnetic stimulation (TMS) could be used to determine the conduction time of the corticospinal tract of the non-infarcted hemisphere after a stroke. Objectives: Our primary aim was to demonstrate the existence of prolonged CMCT in the non-infarcted hemisphere, measured within the first 48 h when compared to normative data, and secondly, if the severity of motor impairment of the affected upper limb was significantly associated with prolonged CMCTs in the non-infarcted hemisphere when measured within the first 2 weeks post stroke. Methods: CMCT in the non-infarcted hemisphere was measured in 50 patients within 48 h and at 11 days after a first-ever ischemic stroke. Patients lacking significant spontaneous motor recovery, so-called non-recoverers, were defined as those who started below 18 points on the FM-UE and showed less than 6 points (10%) improvement within 6 months. Results: CMCT in the non-infarcted hemisphere was prolonged in 30/50 (60%) patients within 48 h and still in 24/49 (49%) patients at 11 days. Sustained prolonged CMCT in the non-infarcted hemisphere was significantly more frequent in non-recoverers following FM-UE. Conclusions: The current study suggests that CMCT in the non-infarcted hemisphere is significantly prolonged in 60% of severely affected, ischemic stroke patients when measured within the first 48 h post stroke. The likelihood of CMCT is significantly higher in non-recoverers when compared to those that show spontaneous motor recovery early post stroke.
One-Year Demographical and Clinical Indices of Patients with Chronic Disorders of Consciousness
Authors: Nekrasova Julia , Kanarskii Mikhail , Borisov Ilya , Pradhan Pranil , Shunenkov Denis , Vorobiev Alexey , Smirnova Maria , Pasko Vera , Petrova Marina V. , Luginina Elena , Pryanikov Igor
Published: May 2021

This work aims to evaluate the prognostic value of the demographical and clinical data on long-term outcomes (up to 12 months) in patients with severe acquired brain injury with vegetative state/unresponsive wakefulness syndrome (VS/UWS/UWS) or a minimally conscious state (MCS). Patients (n = 211) with VS/UWS/UWS (n = 123) and MCS (n = 88) were admitted to the Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology after anoxic brain injury (n = 53), vascular lesions (n = 59), traumatic brain injury (n = 93), and other causes (n = 6). At the beginning of the 12-month study, younger age and a higher score by the Coma Recovery Scale-Revised (CRS-R) predicted a survival. However, no reliable markers of significant positive dynamics of consciousness were found. Based on the etiology, anoxic brain injury has the most unfavorable prognosis. For patients with vascular lesions, the first three months after injury have the most important prognostic value. No correlations were found between survival, increased consciousness, and gender. The demographic and clinical characteristics of patients with chronic DOC can be used to predict long-term mortality in patients with chronic disorders of consciousness. Further research should be devoted to finding reliable predictors of recovery of consciousness.
Developmental Language Disorder: Early Predictors, Age for the Diagnosis, and Diagnostic Tools. A Scoping Review
Authors: Sansavini Alessandra , Favilla Maria Elena , Guasti Maria Teresa , Marini Andrea , Millepiedi Stefania , Di Martino Maria Valeria , Vecchi Simona , Battajon Nadia , Bertolo Laura , Capirci Olga , Carretti Barbara , Colatei Maria Paola , Frioni Cristina , Marotta Luigi , Massa Sara , Michelazzo Letizia , Pecini Chiara , Piazzalunga Silvia , Pieretti Manuela , Rinaldi Pasquale , Salvadorini Renata , Termine Cristiano , Zuccarini Mariagrazia , D’Amico Simonetta , De Cagno Anna Giulia , Levorato Maria Chiara , Rossetto Tiziana , Lorusso Maria Luisa
Published: May 2021

Background. Developmental Language Disorder (DLD) is frequent in childhood and may have long-term sequelae. By employing an evidence-based approach, this scoping review aims at identifying (a) early predictors of DLD; (b) the optimal age range for the use of screening and diagnostic tools; (c) effective diagnostic tools in preschool children. Methods. We considered systematic reviews, meta-analyses, and primary observational studies with control groups on predictive, sensitivity and specificity values of screening and diagnostic tools and psycholinguistic measures for the assessment of DLD in preschool children. We identified 37 studies, consisting of 10 systematic reviews and 27 primary studies. Results. Delay in gesture production, receptive and/or expressive vocabulary, syntactic comprehension, or word combination up to 30 months emerged as early predictors of DLD, a family history of DLD appeared to be a major risk factor, and low socioeconomic status and environmental input were reported as risk factors with lower predictive power. Optimal time for screening is suggested between age 2 and 3, for diagnosis around age 4. Because of the high variability of sensitivity and specificity values, joint use of standardized and psycholinguistic measures is suggested to increase diagnostic accuracy. Conclusions. Monitoring risk situations and employing caregivers’ reports, clinical assessment and multiple linguistic measures are fundamental for an early identification of DLD and timely interventions.
Digital Modelling and Accuracy Verification of a Complex Architectural Object Based on Photogrammetric Reconstruction
Authors: Ozimek Agnieszka , Ozimek Paweł , Skabek Krzysztof , Łabędź Piotr
Published: May 2021

Data concerning heritage buildings are necessary for all kinds of building surveying and design. This paper presents a method for creating a precise model of a historical architectural and landscape object with complex geometry. Photogrammetric techniques were used, combining terrestrial imaging and photographs taken using UAVs. In large-scale objects, it is necessary to divide the reconstruction into smaller parts and adopt an iterative approach based on the gradual completion of missing fragments, especially those resulting from occlusions. The model developed via the reconstruction was compared with geometrically reliable data (LAS point clouds) available in the public domain. The degree of accuracy it achieved can be used in conservation, for example, in construction cost estimates. Despite extensive research on photogrammetric techniques and their applicability in reconstructing cultural heritage sites, the results obtained have not yet been compared by other researchers with LAS point clouds from the information system for land cover (ISOK).
Orai1 Channel Regulates Human-Activated Pancreatic Stellate Cell Proliferation and TGFβ1 Secretion through the AKT Signaling Pathway
Authors: Radoslavova Silviya , Folcher Antoine , Lefebvre Thibaut , Kondratska Kateryna , Guénin Stéphanie , Dhennin-Duthille Isabelle , Gautier Mathieu , Prevarskaya Natalia , Ouadid-Ahidouch Halima
Published: May 2021

Activated pancreatic stellate cells (aPSCs), the crucial mediator of pancreatic desmoplasia, are characterized, among others, by high proliferative potential and abundant transforming growth factor β1 (TGFβ1) secretion. Over the past years, the involvement of Ca2+ channels in PSC pathophysiology has attracted great interest in pancreatic cancer research. We, thus, aimed to investigate the role of the Orai1 Ca2+ channel in these two PSC activation processes. Using the siRNA approach, we invalided Orai1 expression and assessed the channel functionality by Ca2+ imaging, the effect on aPSC proliferation, and TGFβ1 secretion. We demonstrated the functional expression of the Orai1 channel in human aPSCs and its implication in the store-operated Ca2+ entry (SOCE). Orai1 silencing led to a decrease in aPSC proliferation, TGFβ1 secretion, and AKT activation. Interestingly, TGFβ1 induced a higher SOCE response by increasing Orai1 mRNAs and proteins and promoted both AKT phosphorylation and cell proliferation, abolished by Orai1 silencing. Together, our results highlight the role of Orai1-mediated Ca2+ entry in human aPSC pathophysiology by controlling cell proliferation and TGFβ1 secretion through the AKT signaling pathway. Moreover, we showed a TGFβ1-induced autocrine positive feedback loop by promoting the Orai1/AKT-dependent proliferation via the stimulation of Orai1 expression and function.
Endosomal mTORC2 Is Required for Phosphoinositide-Dependent AKT Activation in Platelet-Derived Growth Factor-Stimulated Glioma Cells
Authors: Kim Suree , Heo Sukyeong , Brzostowski Joseph , Kang Dongmin
Published: May 2021

The serine/threonine kinase AKT is a major effector during phosphatidylinositol 3-kinase (PI3K)-driven cell signal transduction in response to extracellular stimuli. AKT activation mechanisms have been extensively studied; however, the mechanism underlying target of rapamycin complex 2 (mTORC2) phosphorylation of AKT at Ser473 in the cellular endomembrane system remains to be elucidated. Here, we demonstrate that endocytosis is required for AKT activation through phosphorylation at Ser473 via mTORC2 using platelet-derived growth factor-stimulated U87MG glioma cells. mTORC2 components are localized to early endosomes during growth factor activation, and the association of mTORC2 with early endosomes is responsible for the local activation of AKT, which is critical for specific signal transduction through glycogen synthase kinase-3 beta and forkhead box O1/O3 phosphorylation. Furthermore, endosomal phosphoinositide, represented by PtdIns(3,4)P2, provides a binding platform for mTORC2 to phosphorylate AKT Ser473 in endosomes through mammalian Sty1/Spc1-interacting protein (mSIN), a pleckstrin homology domain-containing protein, and is dispensable for AKT phosphorylation at Thr308. This PtdIns(3,4)P2-mediated endosomal AKT activation provides a means to integrate PI3K activated by diverse stimuli to mTORC2 assembly. These early endosomal events induced by endocytosis, together with the previously identified AKT activation by PtdIns(3,4,5)P3, contribute to the strengthening of the transduction of AKT signaling through phosphoinositide.
Sustained Complete Response after Biological Downstaging in Patients with Hepatocellular Carcinoma: XXL-Like Prioritization for Liver Transplantation or “Wait and See” Strategy?
Authors: Vitale Alessandro , Scolari Federica , Bertacco Alessandra , Gringeri Enrico , D’Amico Francesco , Bassi Domenico , D’Amico Francesco Enrico , Angeli Paolo , Burra Patrizia , Lai Quirino , Cillo Umberto
Published: May 2021

The XXL trial represents the first prospective validation of “biological downstaging” in liver transplantation (LT) for hepatocellular carcinoma. The aim of this study was to compare the Padua downstaging protocol to the XXL protocol in terms of downstaging failure rates and patient outcome. A total of 191 patients undergoing aggressive surgical downstaging and potentially eligible for LT from 2012 to 2018 at our center were retrospectively selected according to XXL trial criteria. Unlike the XXL trial, patients with a complete response to downstaging did not receive any prioritization for LT. Downstaging failure was defined as stable progressive disease or post-treatment mortality. The statistical method of “matching-adjusted indirect comparison” was used to match the study group to the XXL population. Downstaging failure rate was considerably lower in the study group than in the XXL trial (12% vs. 32%, d value = |0.683|). The survival curves of our LT group (n = 68) overlapped with those of the LT-XXL group (p = 0.846). Survival curves of non-LT candidates with a sustained complete response (n = 64) were similar to those of transplanted patients (p = 0.281). Our study represents a validation of the current Padua and Italian policies of denying rapid prioritization to patients with complete response to downstaging. Such a policy seems to spare organs without worsening patient outcome.
Histone Acetyltransferases and Stem Cell Identity
Authors: He Ruicen , Dantas Arthur , Riabowol Karl
Published: May 2021

Acetylation of histones is a key epigenetic modification involved in transcriptional regulation. The addition of acetyl groups to histone tails generally reduces histone-DNA interactions in the nucleosome leading to increased accessibility for transcription factors and core transcriptional machinery to bind their target sequences. There are approximately 30 histone acetyltransferases and their corresponding complexes, each of which affect the expression of a subset of genes. Because cell identity is determined by gene expression profile, it is unsurprising that the HATs responsible for inducing expression of these genes play a crucial role in determining cell fate. Here, we explore the role of HATs in the maintenance and differentiation of various stem cell types. Several HAT complexes have been characterized to play an important role in activating genes that allow stem cells to self-renew. Knockdown or loss of their activity leads to reduced expression and or differentiation while particular HATs drive differentiation towards specific cell fates. In this study we review functions of the HAT complexes active in pluripotent stem cells, hematopoietic stem cells, muscle satellite cells, mesenchymal stem cells, neural stem cells, and cancer stem cells.
SEGHI Study: Defining the Best Surveillance Strategy in Hodgkin Lymphoma after First-Line Treatment
Authors: Bastos Oreiro Mariana , Martín Reyes , Gomez Pilar , López Muñoz Nieves , Rodriguez Antonia , Liébana Marta , Navarro Belén , Sánchez-González Blanca , Marí Pilar , Pérez de Oteiza Jaime , Gutiérrez Antonio , Bento Leyre , Domingo Doménech Eva , Vidal María , Del Campo Raquel , Pérez Ceballos Elena , Infante María , Roldán Alicia , García Belmonte Daniel , Santero Miriam , Sureda Anna , Sanz Ramón ,   on behalf of the GELTAMO Group
Published: May 2021

The optimal strategy for early surveillance after first complete response is unclear in Hodgkin lymphoma. Thus, we compared the various follow-up strategies in a multicenter study. All the included patients had a negative positron emission tomography/computed tomography at the end of induction therapy. From January 2007 to January 2018, we recruited 640 patients from 15 centers in Spain. Comparing the groups in which serial imaging were performed, the clinical/analytical follow-up group was exposed to significantly fewer imaging tests and less radiation. With a median follow-up of 127 months, progression-free survival at 60 months of the entire series was 88% and the overall survival was 97%. No significant differences in survival or progression-free survival were found among the various surveillance strategies. This study suggests that follow-up approaches with imaging in Hodgkin lymphoma provide no benefits for patient survival, and we believe that clinical/analytical surveillance for this group of patients could be the best course of action.
Blood Oxygenation Level Dependent Magnetic Resonance Imaging (MRI), Dynamic Contrast Enhanced MRI, and Diffusion Weighted MRI for Benign and Malignant Breast Cancer Discrimination: A Preliminary Experience
Authors: Fusco Roberta , Granata Vincenza , Mattace Raso Mauro , Vallone Paolo , De Rosa Alessandro , Siani Claudio , Di Bonito Maurizio , Petrillo Antonella , Sansone Mario
Published: May 2021

Purpose. To combine blood oxygenation level dependent magnetic resonance imaging (BOLD-MRI), dynamic contrast enhanced MRI (DCE-MRI), and diffusion weighted MRI (DW-MRI) in differentiation of benign and malignant breast lesions. Methods. Thirty-seven breast lesions (11 benign and 21 malignant lesions) pathologically proven were included in this retrospective preliminary study. Pharmaco-kinetic parameters including Ktrans, kep, ve, and vp were extracted by DCE-MRI; BOLD parameters were estimated by basal signal S0 and the relaxation rate R2*; and diffusion and perfusion parameters were derived by DW-MRI (pseudo-diffusion coefficient (Dp), perfusion fraction (fp), and tissue diffusivity (Dt)). The correlation coefficient, Wilcoxon-Mann-Whitney U-test, and receiver operating characteristic (ROC) analysis were calculated and area under the ROC curve (AUC) was obtained. Moreover, pattern recognition approaches (linear discrimination analysis and decision tree) with balancing technique and leave one out cross validation approach were considered. Results. R2* and D had a significant negative correlation (−0.57). The mean value, standard deviation, Skewness and Kurtosis values of R2* did not show a statistical significance between benign and malignant lesions (p > 0.05) confirmed by the ‘poor’ diagnostic value of ROC analysis. For DW-MRI derived parameters, the univariate analysis, standard deviation of D, Skewness and Kurtosis values of D* had a significant result to discriminate benign and malignant lesions and the best result at the univariate analysis in the discrimination of benign and malignant lesions was obtained by the Skewness of D* with an AUC of 82.9% (p-value = 0.02). Significant results for the mean value of Ktrans, mean value, standard deviation value and Skewness of kep, mean value, Skewness and Kurtosis of ve were obtained and the best AUC among DCE-MRI extracted parameters was reached by the mean value of kep and was equal to 80.0%. The best diagnostic performance in the discrimination of benign and malignant lesions was obtained at the multivariate analysis considering the DCE-MRI parameters alone with an AUC = 0.91 when the balancing technique was considered. Conclusions. Our results suggest that the combined use of DCE-MRI, DW-MRI and/or BOLD-MRI does not provide a dramatic improvement compared to the use of DCE-MRI features alone, in the classification of breast lesions. However, an interesting result was the negative correlation between R2* and D.
Kinetic Study of 17α-Estradiol Activity in Comparison with 17β-Estradiol and 17α-Ethynylestradiol
Authors: Bosakova Tereza , Tockstein Antonin , Bosakova Zuzana , Komrskova Katerina
Published: May 2021

17α-estradiol (αE2), an endogenous stereoisomer of the hormone 17β-estradiol (E2), is capable of binding to estrogen receptors (ER). We aimed to mathematically describe, using experimental data, the possible interactions between αE2 and sperm ER during the process of sperm capacitation and to develop a kinetic model. The goal was to compare the suggested kinetic model with previously published results of ER interactions with E2 and 17α-ethynylestradiol (EE2). The HPLC-MS/MS method was developed to monitor the changes of αE2 concentration during capacitation. The calculated relative concentrations Bt were used for kinetic analysis. Rate constants k and molar ratio n were optimized and used for the construction of theoretical B(t) curves. Modifications in αE2–ER interactions were discovered during comparison with models for E2 and EE2. These new interactions displayed autocatalytic formation of an unstable adduct between the hormone and the cytoplasmic receptors. αE2 accumulates between the plasma membrane lipid bilayer with increasing potential, and when the critical level is reached, αE2 penetrates through the inner layer of the plasma membrane into the cytoplasm. It then rapidly reacts with the ER and creates an unstable adduct. The revealed dynamics of αE2–ER action may contribute to understanding tissue rejuvenation and the cancer-related physiology of αE2 signaling.
Hydrothermal Sintering and Oxidation of an Alumina-Supported Nickel Methanation Catalyst Studied Using In Situ Magnetometry
Authors: Maphutha Malebelo , de Oliveira Dominic , Nyathi Thulani M. , Fadlalla Mohamed I. , Henkel Robert , Fischer Nico , Claeys Michael
Published: May 2021

The presented study investigated the effects of temperature (350–650 °C) and gas environment (pure Ar versus a H2O/H2 partial pressure ratio (PH2O/PH2) of 5) on the extent of sintering and oxidation of Al2O3-supported Ni0 nanoparticles (≈4 nm). We note that a PH2O/PH2 of 5 corresponds to a simulated CO conversion of 94% during methanation. Sintering and oxidation were studied using in situ magnetometry, while ex situ TEM analyses confirmed the particle sizes before and after the magnetometry-based experiments. It was found that increasing the temperature from 350 to 650 °C in Ar at atmospheric pressure causes a negligible change to the average size and degree of reduction (DOR) of the starting Ni0 nanoparticles. However, studying the same temperature window under hydrothermal conditions at 10 bar causes significant particle growth (≈9 nm) and the development of a bimodal distribution. Furthermore, the presence of steam decreases the DOR of Ni0 from 86.2% after initial activation to 22.2% due to oxidation. In summary, this study reports on the expected sintering and oxidation of Ni-based catalysts under high CO conversion conditions at elevated temperatures during methanation. Importantly, we were able to demonstrate how magnetometry-based analyses can provide similar size information (and changes thereof) as those observed with TEM but with the added advantage that this information can be obtained in situ.
Immunology of Cell Death in Cancer Immunotherapy
Authors: Galluzzi Lorenzo , Garg Abhishek D.
Published: May 2021

Over the last two decades, a large volume of studies has established that dying and dead cancer cells exert a potent immunomodulatory effect on their immediate microenvironment, which has a major influence on the anticancer immunity [...]
In Vivo Stimulation of α- and β-Adrenoceptors in Mice Differentially Alters Small RNA Content of Circulating Extracellular Vesicles
Authors: Kwon Jin-Sook , Barr Eric W. , Chuprun J. Kurt , Koch Walter J.
Published: May 2021

When myocardial function is compromised as in heart failure (HF), there is activation of the sympathetic nervous system with elevated circulating catecholamine levels. These catecholamines activate cardiac and extra-cardiac adrenergic receptors (ARs). Interest in secreted extracellular vesicles (EVs) from the heart is growing and in HF, it is not known whether excessive activation of α- or β-adrenergic receptors (ARs) could induce specific changes in EV content. In this study, we have evaluated, by next generation sequencing, the small RNA content, including micro-RNAs (miRs), of circulating EVs of mice exposed to chronic selective α- or β- AR stimulation. EVs from mouse blood were purified by differential ultracentrifugation resulting in EVs with an average size of 116.6 ± 4.8 nm that by immunoblotting included protein markers of EVs. We identified the presence of miRs in blood EVs using miR-21-5p and -16-5p real-time PCR as known constituents of blood exosomes that make up a portion of EVs. We next performed next generation sequencing (NGS) of small non-coding RNAs found in blood EVs from mice following 7 days of chronic treatment with isoproterenol (ISO) or phenylephrine (PE) to stimulate α- or β-ARs, respectively. PE increased the percent of genomic repeat region reads and decreased the percent of miR reads. In miR expression analysis, PE and ISO displayed specific patterns of miR expression that suggests differential pathway regulation. The top 20 KEGG pathways predicted by differential expressed miRs show that PE and ISO share 11 of 20 pathways analyzed and reveal also key differences including three synapse relative pathways induced by ISO relative to PE treatment. Both α-and β-AR agonists can alter small RNA content of circulating blood EVs/exosomes including differential expression and loading of miRs that indicate regulation of distinct pathways. This study provides novel insight into chronic sympathetic nervous system activation in HF where excessive catecholamines may not only participate in pathological remodeling of the heart but alter other organs due to secretion of EVs with altered miR content.
Spatiotemporal Patterns of Menin Localization in Developing Murine Brain: Co-Expression with the Elements of Cholinergic Synaptic Machinery
Authors: Batool Shadab , Zaidi Jawwad , Akhter Basma , Ulfat Anosha Kiran , Visser Frank , Syed Naweed I.
Published: May 2021

Menin, a product of MEN1 (multiple endocrine neoplasia type 1) gene is an important regulator of tissue development and maintenance; its perturbation results in multiple tumors—primarily of the endocrine tissue. Despite its abundance in the developing central nervous system (CNS), our understanding of menin’s role remains limited. Recently, we discovered menin to play an important role in cholinergic synaptogenesis in the CNS, whereas others have shown its involvement in learning, memory, depression and apoptosis. For menin to play these important roles in the CNS, its expression patterns must be corroborated with other components of the synaptic machinery imbedded in the learning and memory centers; this, however, remains to be established. Here, we report on the spatio-temporal expression patterns of menin, which we found to exhibit dynamic distribution in the murine brain from early development, postnatal period to a fully-grown adult mouse brain. We demonstrate here that menin expression is initially widespread in the brain during early embryonic stages, albeit with lower intensity, as determined by immunohistochemistry and gene expression. With the progression of development, however, menin expression became highly localized to learning, memory and cognition centers in the CNS. In addition to menin expression patterns throughout development, we provide the first direct evidence for its co-expression with nicotinic acetylcholine, glutamate and GABA (gamma aminobutyric acid) receptors—concomitant with the expression of both postsynaptic (postsynaptic density protein PSD-95) and presynaptic (synaptotagamin) proteins. This study is thus the first to provide detailed analysis of spatio-temporal patterns of menin expression from initial CNS development to adulthood. When taken together with previously published studies, our data underscore menin’s importance in the cholinergic neuronal network assembly underlying learning, memory and cognition.
Redox Control in Acute Lymphoblastic Leukemia: From Physiology to Pathology and Therapeutic Opportunities
Authors: Chen Yongfeng , Li Jing , Zhao Zhiqiang
Published: May 2021

Acute lymphoblastic leukemia (ALL) is a hematological malignancy originating from B- or T-lymphoid progenitor cells. Recent studies have shown that redox dysregulation caused by overproduction of reactive oxygen species (ROS) has an important role in the development and progression of leukemia. The application of pro-oxidant therapy, which targets redox dysregulation, has achieved satisfactory results in alleviating the conditions of and improving the survival rate for patients with ALL. However, drug resistance and side effects are two major challenges that must be addressed in pro-oxidant therapy. Oxidative stress can activate a variety of antioxidant mechanisms to help leukemia cells escape the damage caused by pro-oxidant drugs and develop drug resistance. Hematopoietic stem cells (HSCs) are extremely sensitive to oxidative stress due to their low levels of differentiation, and the use of pro-oxidant drugs inevitably causes damage to HSCs and may even cause severe bone marrow suppression. In this article, we reviewed research progress regarding the generation and regulation of ROS in normal HSCs and ALL cells as well as the impact of ROS on the biological behavior and fate of cells. An in-depth understanding of the regulatory mechanisms of redox homeostasis in normal and malignant HSCs is conducive to the formulation of rational targeted treatment plans to effectively reduce oxidative damage to normal HSCs while eradicating ALL cells.
The PI3K/Akt Pathway: Emerging Roles in Skin Homeostasis and a Group of Non-Malignant Skin Disorders
Authors: Teng Yan , Fan Yibin , Ma Jingwen , Lu Wei , Liu Na , Chen Yingfang , Pan Weili , Tao Xiaohua
Published: May 2021

The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway regulates cell proliferation, differentiation, and migration, along with angiogenesis and metabolism. Additionally, it could mediate skin development and homeostasis. There is much evidence to suggest that dysregulation of PI3K/Akt pathway is frequently associated with several human cutaneous malignancies like malignant melanoma (MM), basal cell carcinoma (BCC), and cutaneous squamous cell carcinoma (SCC), as well as their poor outcomes. Nevertheless, emerging roles of PI3K/Akt pathway cascade in a group of common non-malignant skin disorders including acne and psoriasis, among others, have been recognized. The enhanced understanding of dysfunction of PI3K/Akt pathway in patients with these non-malignant disorders has offered a solid foundation for the progress of updated therapeutic targets. This article reviews the latest advances in the roles of PI3K/Akt pathway and their targets in the skin homeostasis and progression of a wide range of non-malignant skin disorders and describes the current progress in preclinical and clinical researches on the involvement of PI3K/Akt pathway targeted therapies.
Differential Tropism in Roots and Shoots of Resistant and Susceptible Cassava (Manihot esculenta Crantz) Infected by Cassava Brown Streak Viruses
Authors: Sheat Samar , Margaria Paolo , Winter Stephan
Published: May 2021

Cassava brown streak disease (CBSD) is a destructive disease of cassava in Eastern and Central Africa. Because there was no source of resistance in African varieties to provide complete protection against the viruses causing the disease, we searched in South American germplasm and identified cassava lines that did not become infected with the cassava brown streak viruses. These findings motivated further investigations into the mechanism of virus resistance. We used RNAscope® in situ hybridization to localize cassava brown streak virus in cassava germplasm lines that were highly resistant (DSC 167, immune) or that restricted virus infections to stems and roots only (DSC 260). We show that the resistance in those lines is not a restriction of long-distance movement but due to preventing virus unloading from the phloem into parenchyma cells for replication, thus restricting the virus to the phloem cells only. When DSC 167 and DSC 260 were compared for virus invasion, only a low CBSV signal was found in phloem tissue of DSC 167, indicating that there is no replication in this host, while the presence of intense hybridization signals in the phloem of DSC 260 provided evidence for virus replication in companion cells. In neither of the two lines studied was there evidence of virus replication outside the phloem tissues. Thus, we conclude that in resistant cassava lines, CBSV is confined to the phloem tissues only, in which virus replication can still take place or is arrested.
Anti-Vascular Endothelial Growth Factor C Antibodies Efficiently Inhibit the Growth of Experimental Clear Cell Renal Cell Carcinomas
Authors: Dumond Aurore , Montemagno Christopher , Vial Valérie , Grépin Renaud , Pagès Gilles
Published: May 2021

Despite improvement during the last ten years in the longevity of patients with metastatic clear cell renal cell carcinoma (mccRCC) the disease remains incurable. Hence, new therapeutic strategies are urgently needed. Relapse following anti-angiogenic treatment depends on the over-expression of vascular endothelial growth factor C (VEGFC), one of the main drivers of lymphangiogenesis. Therefore, we developed specific mouse monoclonal antibodies and evaluated their therapeutic efficacy in vitro and in vivo. Immunization of mice with the domain of VEGFC that stimulates the VEGF receptor 3 (VEGFR3) led to the selection of one hybridoma producing specific anti-VEGFC monoclonal antibodies. The selected 1E9 antibodies were sequenced, and the corresponding variable light and heavy chains were subcloned into expression vectors in frame with sequences encoding the human IgG1 constant heavy and light chains. CHO cells were stably transfected and cloned to produce chimeric antibodies. These antibodies inhibited the activation of VEGFR3 signaling, and therefore the proliferation and migration of VEGFC-stimulated endothelial cells. Moreover, they inhibited the proliferation of VEGFC-expressing renal cancer cells through NRP2 signaling. 1E9 antibodies inhibited the growth of experimental RCC, and their therapeutic efficacy was enhanced by the anti-VEGF antibody bevacizumab. Hence, our results suggest that targeting VEGFC could have a relevant therapeutic impact on mccRCC that relapse following anti-angiogenic treatment.
From Laboratory Studies to Clinical Trials: Temozolomide Use in IDH-Mutant Gliomas
Authors: Sun Xueyuan , Turcan Sevin
Published: May 2021

In this review, we discuss the use of the alkylating agent temozolomide (TMZ) in the treatment of IDH-mutant gliomas. We describe the challenges associated with TMZ in clinical (drug resistance and tumor recurrence) and preclinical settings (variabilities associated with in vitro models) in treating IDH-mutant glioma. Lastly, we summarize the emerging therapeutic targets that can potentially be used in combination with TMZ.
Glutamatergic Mechanisms in Glioblastoma and Tumor-Associated Epilepsy
Authors: Lange Falko , Hörnschemeyer Max Frederik , Kirschstein Timo
Published: May 2021

The progression of glioblastomas is associated with a variety of neurological impairments, such as tumor-related epileptic seizures. Seizures are not only a common comorbidity of glioblastoma but often an initial clinical symptom of this cancer entity. Both, glioblastoma and tumor-associated epilepsy are closely linked to one another through several pathophysiological mechanisms, with the neurotransmitter glutamate playing a key role. Glutamate interacts with its ionotropic and metabotropic receptors to promote both tumor progression and excitotoxicity. In this review, based on its physiological functions, our current understanding of glutamate receptors and glutamatergic signaling will be discussed in detail. Furthermore, preclinical models to study glutamatergic interactions between glioma cells and the tumor-surrounding microenvironment will be presented. Finally, current studies addressing glutamate receptors in glioma and tumor-related epilepsy will be highlighted and future approaches to interfere with the glutamatergic network are discussed.
Can Sexual Selection Drive the Evolution of Sperm Cell Structure?
Authors: Simmons Leigh W. , Garcia-Gonzalez Francisco
Published: May 2021

Sperm cells have undergone an extraordinarily divergent evolution among metazoan animals. Parker recognized that because female animals frequently mate with more than one male, sexual selection would continue after mating and impose strong selection on sperm cells to maximize fertilization success. Comparative analyses among species have revealed a general relationship between the strength of selection from sperm competition and the length of sperm cells and their constituent parts. However, comparative analyses cannot address causation. Here, we use experimental evolution to ask whether sexual selection can drive the divergence of sperm cell phenotype, using the dung beetle Onthophagus taurus as a model. We either relaxed sexual selection by enforcing monogamy or allowed sexual selection to continue for 20 generations before sampling males and measuring the total length of sperm cells and their constituent parts, the acrosome, nucleus, and flagella. We found differences in the length of the sperm cell nucleus but no differences in the length of the acrosome, flagella, or total sperm length. Our data suggest that different sperm cell components may respond independently to sexual selection and contribute to the divergent evolution of these extraordinary cells.
Pathological Role of Pin1 in the Development of DSS-Induced Colitis
Authors: Matsunaga Yasuka , Hasei Shun , Yamamotoya Takeshi , Honda Hiroaki , Kushiyama Akifumi , Sakoda Hideyuki , Fujishiro Midori , Ono Hiraku , Ito Hisanaka , Okabe Takayoshi , Asano Tomoichiro , Nakatsu Yusuke
Published: May 2021

Inflammatory bowel diseases (IBDs) are serious disorders of which the etiologies are not, as yet, fully understood. In this study, Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (Pin1) protein was shown to be dramatically upregulated in the colons of dextran sodium sulfate (DSS)-induced ulcerative colitis model mice. Interestingly, Pin1 knockout (KO) mice exhibited significant attenuation of DSS-induced colitis compared to wild-type (WT) mice, based on various parameters, including body weight, colon length, microscopic observation of the intestinal mucosa, inflammatory cytokine expression, and cleaved caspase-3. In addition, a role of Pin1 in inflammation was suggested because the percentage of M1-type macrophages in the colon was decreased in the Pin1 KO mice while that of M2-type macrophages was increased. Moreover, Pin1 KO mice showed downregulation of both Il17 and Il23a expression in the colon, both of which have been implicated in the development of colitis. Finally, oral administration of Pin1 inhibitor partially but significantly prevented DSS-induced colitis in mice, raising the possibility of Pin1 inhibitors serving as therapeutic agents for IBD.
SMARTIES Project: The Survey of Needs for Municipalities and Trainers for Smart Cities
Authors: Xydis George , Pagliaricci Luca , Paužaitė Živilė , Grinis Vygintas , Sallai Gyula , Bakonyi Peter , Vician Radoslav
Published: May 2021

In an aim to contribute to already existing knowledge upon the subject of smart cities and the public sector’s wider knowledge in Europe, this study investigates the perception by the municipalities and the wider public sector, responsible for implementing smart solutions in the environment. The understanding of the concept of smart cities/villages by municipalities is on a low level due to the fact that the problem is too wide, not well described, solutions even wider, accompanied by the lack of experts able to offer comprehensive solutions to municipalities. The study presents factors according to the current municipalities’ knowledge (environmental awareness, knowledge and prior experience) and the existing market, of whether these factors can be said that affect the acceptance of smart cities. The public is already aware of the smart cities as a general concept, however, the study sheds light upon the established knowledge that the decision makers have in five countries, Hungary, Slovakia, Italy, Lithuania, and Denmark.
Respiratory Trajectory after Invasive Interventions for Patent Ductus Arteriosus of Preterm Infants
Authors: Wei Yu-Jen , Chen Yen-Ju , Lin Yung-Chieh , Kan Chung-Dann , Hsieh Min-Ling , Lin Yuh-Jyh , Wu Jing-Ming , Wang Jieh-Neng
Published: May 2021

Invasive interventions have been conducted in preterm infants with significant patent ductus arteriosus (PDA) when medical treatment has failed, and methods of invasive intervention have been reported. Surgical ligation via lateral thoracotomy has been a well-established procedure for decades. Recently, transcatheter occlusion has been safely and feasibly applied to the premature population. However, little research has been conducted on the benefits of transcatheter occlusion in very-low-birth-weight (VLBW) infants compared to surgical ligation. This study compared transcatheter and surgical techniques in VLBW infants in terms of short-term respiratory outcomes. The medical records of 401 VLBW infants admitted to a tertiary hospital between September 2014 and January 2019 were retrospectively reviewed. Patients who were diagnosed with a congenital anomaly, a chromosomal anomaly, or congenital heart disease, except for an inter-atrial shunt, were excluded. The perinatal conditions, neonatal morbidities, periprocedural vital signs, and respiratory support trajectories were compared between the transcatheter-treated and surgically ligated group. A total of 31 eligible VLBW infants received invasive intervention: 14 were treated with transcatheter occlusion (Group A), and 17 infants were treated with surgical ligation (Group B). Respiratory outcomes were not statistically significant between the two groups, despite Group A showing a trend toward early improvement in post-intervention respiratory trajectory. In this small case study, a different trend in post-intervention respiratory trajectories was observed. Future research with larger case numbers should be conducted to address our preliminary observations in more detail.
Impact of Perceived Social Support on the Relationship between ADHD and Depressive Symptoms among First Year Medical Students: A Structural Equation Model Approach
Authors: Karawekpanyawong Nuntaporn , Wongpakaran Tinakon , Wongpakaran Nahathai , Boonnag Chiraphat , Siritikul Sirinut , Chalanunt Sirikorn , Kuntawong Pimolpun
Published: May 2021

Background: Attention deficit hyperactivity disorder (ADHD) is associated with depression among college students, while perceived social support is also associated with depression, especially among young adults. This study aimed to examine to what extent perceived social support mediated the relationship between ADHD symptoms and depressive symptoms. Methods: In total, 124 first year medical students completed the Adult ADHD Self-Report Scale Screener (ASRS), the Patient Health questionnaire-9 and the revised Thai Multidimensional scale of perceived social support reflecting ADHD symptoms, depressive symptoms, and perceive social support, i.e., family members, friends and other significant people, respectively. Structural equation modeling was used to investigate the hypothesized mediation model. Results: ADHD symptoms exhibited a significant indirect effect on depressive symptoms via perceived social support. ADHD symptoms initially had a direct effect on depression; thereafter, it reduced to a non-significance effect after perceived social support was added. The total variance explained by this model was 35.2%. The mediation model with family support as a mediator showed the highest effect size. Conclusions: The study highlighted the importance of perceived social support, particularly family support, on depressive symptoms among young medical students experiencing ADHD symptoms. The model suggests promising relationships for further research on ADHD-related depression and potential treatment in the future.
Analysis of Latvian Households’ Potential Participation in the Energy Market as Prosumers
Authors: Lebedeva Kristina , Krumins Andris , Tamane Antra , Dzelzitis Egils
Published: May 2021

The European Union sets targets for the extensive use of renewable energy. Meanwhile, the energy production network is changing and transferring from the classic “producer to consumer” scheme to new operation models, where a small consumer with local renewable energy systems becomes a producer–prosumer, an active energy consumer who is also an energy producer. This study evaluated a potential of Latvian households’ participation in the energy market as prosumers. The analysis was based on an informal prospective extrapolation data evaluation method, based on real historical data from the Central Statistical Bureau of Latvia, annual reports of distribution and transmission system operators, assessments, and the conclusions of relevant experts. In addition, the real performance of a photovoltaic (PV) system was evaluated to get information on the whole year’s energy balance, and to compare it with seasonal electricity price fluctuation. The Latvian electricity transmission system is able to accept about 800 MW of additional new renewable energy source (RES) capacity, so there is a great potential for prosumers. The biggest obstacle for a household’s involvement in the energy market is the lack of support mechanisms and relatively high cost of RES technologies. The results show that with the current dynamics of new microgenerator connections, Latvia will achieve the set goals regarding the involvement of prosumers in the achievement of RES goals only in the next century. In order to attract the public to energy production, the concept of energy community needs to be defined in Latvian legislation, a balanced peer trading mechanism needs to be developed for various RES self-consumption groups willing to sell surplus electricity, and tax policy conditions need to be reviewed for electricity transactions outside the NET (payment system), in order to fully ensure the rights of prosumers.
ZnOTe Compounds Grown by DC-Magnetron Co-Sputtering
Authors: Sánchez Olga , Hernández-Vélez Manuel
Published: May 2021

ZnOTe compounds were grown by DC magnetron cosputtering from pure Tellurium (Te) and Zinc (Zn) cathodes in O2/Ar atmosphere. The applied power on the Zn target was constant equal to 100 W, while the one applied on the Te target took two values, i.e., 5 W and 10 W. Thus, two sample series were obtained in which the variable parameter was the distance from the Te targets to the substrate. Sample compositions were determined by Rutherford Backscattering Spectroscopy (RBS) experiments. Structural analysis was done using X-Ray diffraction (XRD) spectrometry and the growth of the hexagonal w-ZnO phase was identified in the XRD spectra. RBS results showed high bulk homogeneity of the samples forming ZnOTe alloys, with variable Te molar fraction (MF) ranging from 0.48–0.6% and from 1.9–3.1% for the sample series obtained at 5 W and 10 W, respectively. The results reflect great differences between the two sample series, particularly from the structural and optical point of view. These experiments point to the possibility of Te doping ZnO with the permanence of intrinsic defects, as well as the possibility of the formation of other Te solid phases when its content increases. The results and appreciable variations in the band gap transitions were detected from Photoluminescence (PL) measurements.
Effectiveness of a Selective Etching Technique in Reducing White Spots Formation around Lingual Brackets: A Prospective Cohort Clinical Study
Authors: Dalessandri Domenico , Bindi Marino , Massetti Francesca , Isola Gaetano , Migliorati Marco , Visconti Luca , Paganelli Corrado , Bonetti Stefano
Published: May 2021

The risk of developing white spot lesions (WSLs) after orthodontic treatment with lingual brackets is generally considered lower than with labial ones, even if plaque accumulation is frequently higher due to the increased difficulty level in oral hygiene maintenance. In this prospective clinical study, selective enamel etching technique effectiveness in reducing plaque accumulation and WSLs was tested. Thirty patients were bonded with a split-mouth approach: two randomly selected opposite quadrants were used as the test sides, using customized plastic etching guides, and the other two as control sides, applying traditional direct etching methods. The plaque presence around the braces was recorded after 1, 3, 6, and 12 months according to a lingual plaque accumulation index (LPAI), as was the presence of WSLs. PAI measured values were significantly higher in the control sides during the observation period. Test and control sides differed significantly for new WSL onset only after 12 months of treatment. Therefore, the present research demonstrated that this guided enamel etching technique allowed for significant reduction in plaque accumulation around the lingual brackets and reduced onset of white spots after one year of treatment.