bluuebunny/crossref_metadata_2025 huggingface dataset:
Spatio-Temporal Distribution of Environmental Health Risk of Heavy Metals in Industrial Wastewater of China during 1999–2018
Authors: Han Ruru , Zhou Beihai , Chen Huilun
Published: June 2021

In recent decades, environmental health risk caused by heavy metals in industrial wastewater (EHR-IHM) has become a serious issue globally, especially for China. Given the spatial difference of heavy metal emissions, hydrogeography, population distribution, etc., it is essential to estimate China’s EHR-IHM from a high-resolution perspective. Based on the framework of USEtox, this study constructs an environmental health risk assessment method for heavy metals discharged from industrial wastewater by coupling the Pollutant Accumulation Model (PAM). This method also considers the process of heavy metal flows between upstream and downstream areas. Based on this constructed method, we investigate the spatio-temporal distribution of EHR-IHM of As, Cd, Cr(VI), Hg, and Pb in China from 1999 to 2018. Results showed that the EHR-IHM in China increased rapidly during 1999–2007 and decreased gradually during 2007–2018, with the highest Damage Level (DL) of 6.8 × 104 disability-adjusted life years (DALY). As and Cr(VI) were the major heavy metal pollutants, which induced 58.9–70.6% and 23.9–36.2% of the total EHR-IHM, respectively. Intake of aquatic products was the dominant exposure route, accounting for over 84.1% of national EHR-IHM, followed by drinking water intake, accounting for 9.5–15.8%. Regarding spatial distribution, the regions with high EHR-IHM are mainly distributed in the middle–lower reaches of the Yangtze River, southeast coastal cities, Bohai Rim, etc.
Efficient Sequestration of Hexavalent Chromium by Graphene-Based Nanoscale Zero-Valent Iron Composite Coupled with Ultrasonic Pretreatment
Authors: Song Haiyan , Liu Wei , Meng Fansheng , Yang Qi , Guo Niandong
Published: June 2021

Nanoscale zero-valent iron (nZVI) has attracted considerable attention for its potential to sequestrate and immobilize heavy metals such as Cr(VI) from an aqueous solution. However, nZVI can be easily oxidized and agglomerate, which strongly affects the removal efficiency. In this study, graphene-based nZVI (nZVI/rGO) composites coupled with ultrasonic (US) pretreatment were studied to solve the above problems and conduct the experiments of Cr(VI) removal from an aqueous solution. SEM-EDS, BET, XRD, and XPS were performed to analyze the morphology and structures of the composites. The findings showed that the removal efficiency of Cr(VI) in 30 min was increased from 45.84% on nZVI to 78.01% on nZVI/rGO and the removal process performed coupled with ultrasonic pretreatment could greatly shorten the reaction time to 15 min. Influencing factors such as the initial pH, temperature, initial Cr(VI) concentration, and co-existing anions were studied. The results showed that the initial pH was a principal factor. The presence of HPO42−, NO3−, and Cl− had a strong inhibitory effect on this process, while the presence of SO42− promoted the reactivity of nZVI/rGO. Combined with the above results, the process of Cr(VI) removal in US-nZVI/rGO system consisted of two phases: (1) The initial stage is dominated by solution reaction. Cr(VI) was reduced in the solution by Fe2+ caused by ultrasonic cavitation. (2) In the following processes, adsorption, reduction, and coprecipitation coexisted. The addition of rGO enhanced electron transportability weakened the influence of passivation layers and improved the dispersion of nZVI particles. Ultrasonic cavitation caused pores and corrosion at the passivation layers and fresh Fe0 core was exposed, which improved the reactivity of the composites.
Four Weeks of Detraining Induced by COVID-19 Reverse Cardiac Improvements from Eight Weeks of Fitness-Dance Training in Older Adults with Mild Cognitive Impairment
Authors: Ammar Achraf , Boukhris Omar , Halfpaap Nicole , Labott Berit Kristin , Langhans Corinna , Herold Fabian , Grässler Bernhard , Müller Patrick , Trabelsi Khaled , Chtourou Hamdi , Zmijewski Piotr , Driss Tarak , Glenn Jordan M. , Müller Notger G. , Hoekelmann Anita
Published: June 2021

Physical training is considered as a low-cost intervention to generate cardioprotective benefits and to promote physical and mental health, while reducing the severity of acute respiratory infection symptoms in older adults. However, lockdown measures during COVID-19 have limited people’s opportunity to exercise regularly. The aim of this study was to investigate the effect of eight weeks of Fitness and Dance training, followed by four weeks of COVID-19-induced detraining, on cardiac adaptations and physical performance indicators in older adults with mild cognitive impairment (MCI). Twelve older adults (6 males and 6 females) with MCI (age, 73 ± 4.4 y; body mass, 75.3 ± 6.4 kg; height, 172 ± 8 cm; MMSE score: 24–27) participated in eight weeks of a combined Fitness-Dance training intervention (two sessions/week) followed by four weeks of training cessation induced by COVID-19 lockdowns. Wireless Polar Team Pro and Polar heart rate sensors (H10) were used to monitor covered distance, speed, heart rate (HR min, avg and max), time in HR zone 1 to 5, strenuousness (load score), beat-to-beat interval (max RR and avg RR) and heart rate variability (HRV-RMSSD). One-way ANOVA was used to analyze the data of the three test sessions (T1: first training session, T2: last training session of the eight-week training program, and T3: first training session after the four-week training cessation). Statistical analysis showed that eight weeks of combined Fitness-Dance training induced beneficial cardiac adaptations by decreasing HR (HR min, HR avg and HR max) with p < 0.001, ES = 0.5–0.6 and Δ = −7 to−9 bpm, and increasing HRV related responses (max and avg RR and RMSSD), with p < 0.01 and ES = 0.4. Consequently, participants spent more time in comfortable HR zones (e.g., p < 0.0005; ES = 0.7; Δ = 25% for HR zone 1) and showed reduced strenuousness (p = 0.02, Δ = −15% for load score), despite the higher covered total distance and average speed (p < 0.01; ES = 0.4). However, these changes were reversed after only four weeks of COVID-19 induced detraining, with values of all parameters returning to their baseline levels. In conclusion, eight weeks of combined Fitness-Dance training seems to be an efficient strategy to promote cardioprotective benefits in older adults with MCI. Importantly, to maintain these health benefits, training has to be continued and detraining periods should be reduced. During a pandemic, home-based exercise programs may provide an effective and efficient alternative of physical training.
Application of EN 16615 (4-Field Test) for the Evaluation of the Antimicrobial Activity of the Selected Commercial and Self-Made Disinfectant Wipes
Authors: Tyski Stefan , Grzybowska Wanda , Bocian Ewa
Published: June 2021

The purpose of disinfectants is to reduce microorganisms on a contaminated surface and to prevent the spread of microorganisms. The relatively new EN 16615 simulates disinfection by wiping and allows for assessing the recovery of microorganisms from the surface and, importantly, the degree of spread of microorganisms when the surface is disinfected by wiping. For the first time, using this standard, the tested products in the form of commercial disinfectant wipes were compared with self-made wipes soaked in respective disinfectant liquids. The disinfected surfaces were simulated by homogeneous polyvinyl chloride plates. The studies were carried out not only with the standard, but also with clinical multidrug-resistant microbial strains. Based on the research, it can be concluded that the most effective products in the disinfection process (log10 reduction of ≥5) with the shortest contact time (1 min) were products containing ethanol, propanol, and quaternary ammonium compounds (self-made wipes) and propanol (commercial wipes). The least effective products (log10 reduction of <5) in terms of the contact time declared by the manufacturer were products containing ethanol and sodium hypochlorite (commercial wipes). Much better antimicrobial activity of self-made wipes was observed in comparison to the activity of the commercial wipes.
Cardiac Parasympathetic Withdrawal and Sympathetic Activity: Effect of Heat Exposure on Heart Rate Variability
Authors: Abellán-Aynés Oriol , Manonelles Pedro , Alacid Fernando
Published: June 2021

Background: Research on heart rate variability has increased in recent years and the temperature has not been controlled in some studies assessing repeated measurements. This study aimed to analyze how heart rate variability may change based on environmental temperature during measurement depending on parasympathetic and sympathetic activity variations. Methods: A total of 22 volunteers participated in this study divided into an experimental (n = 12) and control group (n = 10). Each participant was assessed randomly under two different environmental conditions for the experimental group (19 °C and 35 °C) and two identical environmental conditions for the control group (19 °C). During the procedure, heart rate variability measurements were carried out for 10 min. Results: Significantly changes were observed for time and frequency domains as well as Poincaré plot variables after heat exposure (p < 0.05). These findings were not observed in the control group, whose conditions between measurements did not change. Conclusions: The reduction of heart rate variability due to exposure to hot conditions appears to be produced mostly by a parasympathetic withdrawal rather than a sympathetic activation. Therefore, if consecutive measurements have to be carried out, these should always be done under the same temperature conditions.
Association between Maternal Origin, Pre-Pregnancy Body Mass Index and Caesarean Section: A Nation-Wide Registry Study
Authors: Jatta Fatou , Sundby Johanne , Vangen Siri , Lindskog Benedikte Victoria , Sørbye Ingvil Krarup , Owe Katrine Mari
Published: June 2021

Aims: To explore the association between maternal origin and birthplace, and caesarean section (CS) by pre-pregnancy body mass index (BMI) and length of residence. Methods: We linked records from 118,459 primiparous women in the Medical Birth Registry of Norway between 2013 and 2017 with data from the National Population Register. We categorized pre-pregnancy BMI (kg/m2) into underweight (<18.5), normal weight (18.5–24.9) and overweight/obese (≥25). Multinomial regression analysis estimated crude and adjusted relative risk ratios (RRR) with 95% confidence intervals (CI) for emergency and elective CS. Results: Compared to normal weight women from Norway, women from Sub-Saharan Africa and Southeast Asia/Pacific had a decreased risk of elective CS (aRRR = 0.57, 95% CI 0.37–0.87 and aRRR = 0.56, 0.41–0.77, respectively). Overweight/obese women from Europe/Central Asia had the highest risk of elective CS (aRRR = 1.42, 1.09–1.86). Both normal weight and overweight/obese Sub-Saharan African women had the highest risks of emergency CS (aRRR = 2.61, 2.28-2.99; 2.18, 1.81-2.63, respectively). Compared to women from high-income countries, the risk of elective CS was increasing with a longer length of residence among European/Central Asian women. Newly arrived migrants from Sub-Saharan Africa had the highest risk of emergency CS. Conclusion: Women from Sub-Saharan Africa had more than two times the risk of emergency CS compared to women originating from Norway, regardless of pre-pregnancy BMI.
Trends in the Use of Anxiolytics in Castile and Leon, Spain, between 2015–2020: Evaluating the Impact of COVID-19
Authors: Sánchez Díaz Miryam , Martín-Calvo María Luisa , Mateos-Campos Ramona
Published: June 2021

Anxiolytics (N05B) are one of the most widely used pharmacological groups. This study aimed to analyze the progression of the consumption of anxiolytics (ATC classification: N05B) dispensed in pharmacies in Castile and Leon, Spain, from 2015 to 2020, with a special focus on the possible impact of COVID-19 on the use of these drugs. A quantitative-qualitative analysis of usage was carried out using the total number of packs and the packs per 1000 inhabitants. Overall, the use of anxiolytics grew by 14.41% during 2015–2020. The most commonly used drugs were the short-acting benzodiazepine derivatives lorazepam (whose use increased by 15.18%) and alprazolam (whose use increased by 21.40%), and the dispensing of the long-acting derivative diazepam increased the most, by 31.83%. Anxiolytics consumption increased significantly in 2020 and peaked in March. The pattern of use remained the same in 2020. The consumption of anxiolytics has continued to increase in Castile and Leon over the last six years. The COVID-19 pandemic situation affected the dispensing of these drugs, causing a sharp increase in prescriptions, especially during March, when the confinement of the population was initiated.
Technology-Supported University Courses for Increasing University Students’ Physical Activity Levels: A Systematic Review and Set of Design Principles for Future Practice
Authors: Sultoni Kuston , Peralta Louisa , Cotton Wayne
Published: June 2021

Physical activity levels tend to decrease as adolescents’ transition to adulthood. University course-based interventions utilising technology are a promising idea to combat this decrease. This review aims to systematically identify, critically appraise, and summarise the best available evidence regarding technology-supported university courses that aim to increase student’s physical activity levels. The second aim is to create initial design principles that will inform future practice in the area. Data Sources: CINAHL, ERIC, MEDLINE, ProQuest, PsycINFO, Scopus, SPORTDiscus, Web of Science. Search dates from January 2010 to December 2020. Study Inclusion: RCT or non-RCT or quasi-experimental studies describing university course-based interventions using technology that aim to increase the physical activity levels of university students. Data Extraction: Source (country), methods, participants, interventions, theoretical frameworks and type of technologies, outcome and measurement instrument, and results. Data Synthesis: Systematic review. Result: A total of 1939 articles were identified through databases. Six studies met the inclusion criteria. Conclusion: Four of the six included studies reported significant increases in university students’ physical activity levels. An analysis of the six included studies identified four design principles that future course designers could utilise as they develop technology-supported university courses that aim to increase the physical activity levels of university students. Further work is required to test the effectiveness of these four design principles.
NBM-BMX, an HDAC8 Inhibitor, Overcomes Temozolomide Resistance in Glioblastoma Multiforme by Downregulating the β-Catenin/c-Myc/SOX2 Pathway and Upregulating p53-Mediated MGMT Inhibition
Authors: Tsai Cheng-Yu , Ko Huey-Jiun , Chiou Shean-Jaw , Lai Yu-Ling , Hou Chia-Chung , Javaria Tehseen , Huang Zi-Yi , Cheng Tai-Shan , Hsu Tsung-I , Chuang Jian-Ying , Kwan Aij-Lie , Chuang Tsung-Hsien , Huang Chi-Ying F. , Loh Joon-Khim , Hong Yi-Ren
Published: June 2021

Although histone deacetylase 8 (HDAC8) plays a role in glioblastoma multiforme (GBM), whether its inhibition facilitates the treatment of temozolomide (TMZ)-resistant GBM (GBM-R) remains unclear. By assessing the gene expression profiles from short hairpin RNA of HDAC8 in the new version of Connectivity Map (CLUE) and cells treated by NBM-BMX (BMX)-, an HDAC8 inhibitor, data analysis reveals that the Wnt signaling pathway and apoptosis might be the underlying mechanisms in BMX-elicited treatment. This study evaluated the efficacy of cotreatment with BMX and TMZ in GBM-R cells. We observed that cotreatment with BMX and TMZ could overcome resistance in GBM-R cells and inhibit cell viability, markedly inhibit cell proliferation, and then induce cell cycle arrest and apoptosis. In addition, the expression level of β-catenin was reversed by proteasome inhibitor via the β-catenin/ GSK3β signaling pathway to reduce the expression level of c-Myc and cyclin D1 in GBM-R cells. BMX and TMZ cotreatment also upregulated WT-p53 mediated MGMT inhibition, thereby triggering the activation of caspase-3 and eventually leading to apoptosis in GBM-R cells. Moreover, BMX and TMZ attenuated the expression of CD133, CD44, and SOX2 in GBM-R cells. In conclusion, BMX overcomes TMZ resistance by enhancing TMZ-mediated cytotoxic effect by downregulating the β-catenin/c-Myc/SOX2 signaling pathway and upregulating WT-p53 mediated MGMT inhibition. These findings indicate a promising drug combination for precision personal treating of TMZ-resistant WT-p53 GBM cells.
Inferring Single-Cell 3D Chromosomal Structures Based on the Lennard-Jones Potential
Authors: Zha Mengsheng , Wang Nan , Zhang Chaoyang , Wang Zheng
Published: June 2021

Reconstructing three-dimensional (3D) chromosomal structures based on single-cell Hi-C data is a challenging scientific problem due to the extreme sparseness of the single-cell Hi-C data. In this research, we used the Lennard-Jones potential to reconstruct both 500 kb and high-resolution 50 kb chromosomal structures based on single-cell Hi-C data. A chromosome was represented by a string of 500 kb or 50 kb DNA beads and put into a 3D cubic lattice for simulations. A 2D Gaussian function was used to impute the sparse single-cell Hi-C contact matrices. We designed a novel loss function based on the Lennard-Jones potential, in which the ε value, i.e., the well depth, was used to indicate how stable the binding of every pair of beads is. For the bead pairs that have single-cell Hi-C contacts and their neighboring bead pairs, the loss function assigns them stronger binding stability. The Metropolis–Hastings algorithm was used to try different locations for the DNA beads, and simulated annealing was used to optimize the loss function. We proved the correctness and validness of the reconstructed 3D structures by evaluating the models according to multiple criteria and comparing the models with 3D-FISH data.
Alleviation of LPS-Induced Inflammation and Septic Shock by Lactiplantibacillus plantarum K8 Lysates
Authors: Kim Gayoung , Choi Kyeong-Hun , Kim Hangeun , Chung Dae-Kyun
Published: June 2021

We previously showed that Lactiplantibacillus plantarum K8 and its cell wall components have immunoregulatory effects. In this study, we demonstrate that pre-treatment of L. plantarum K8 lysates reduced LPS-induced TNF-α production in THP-1 cells by down-regulating the early signals of mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB). The down-regulation of signals may be caused by the induction of negative regulators involved in toll-like receptor (TLR)-mediated signaling. However, co-treatment with high concentrations of L. plantarum K8 lysates and lipopolysaccharide (LPS) activated the late signaling of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and NF-κB pathways and resulted in the induction of absent in melanoma 2 (AIM2) inflammasome-mediated interleukin (IL)-1β secretion. Intraperitoneal injection of L. plantarum K8 lysates in LPS-induced endotoxin shock mice alleviated mortality and reduced serum tumor-necrosis factor (TNF)-α, IL-1β, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels. In addition, the mRNA levels of TNF-α, IL-1β, and IL-6 decreased in livers from mice injected with L. plantarum K8 followed by LPS. Hematoxylin and eosin (H&E) staining of the liver showed that the cell size was enlarged by LPS injection and slightly reduced by L. plantarum K8 lysate pre-injection followed by LPS injection. Macrophage infiltration of the liver also decreased in response to the combination injection compared with mice injected with only LPS. Taken together, our results show that although L. plantarum K8 lysates differentially regulated the production of LPS-induced inflammatory cytokines in THP-1 cells, the lysates inhibited overall inflammation in mice. Thus, this study suggests that L. plantarum K8 lysates could be developed as a substance that modulates immune homeostasis by regulating inflammation.
Proangiogenic Effect of 2A-Peptide Based Multicistronic Recombinant Constructs Encoding VEGF and FGF2 Growth Factors
Authors: Gatina Dilara Z. , Garanina Ekaterina E. , Zhuravleva Margarita N. , Synbulatova Gulnaz E. , Mullakhmetova Adelya F. , Solovyeva Valeriya V. , Kiyasov Andrey P. , Rutland Catrin S. , Rizvanov Albert A. , Salafutdinov Ilnur I.
Published: June 2021

Coronary artery disease remains one of the primary healthcare problems due to the high cost of treatment, increased number of patients, poor clinical outcomes, and lack of effective therapy. Though pharmacological and surgical treatments positively affect symptoms and arrest the disease progression, they generally exhibit a limited effect on the disease outcome. The development of alternative therapeutic approaches towards ischemic disease treatment, especially of decompensated forms, is therefore relevant. Therapeutic angiogenesis, stimulated by various cytokines, chemokines, and growth factors, provides the possibility of restoring functional blood flow in ischemic tissues, thereby ensuring the regeneration of the damaged area. In the current study, based on the clinically approved plasmid vector pVax1, multigenic constructs were developed encoding vascular endothelial growth factor (VEGF), fibroblast growth factors (FGF2), and the DsRed fluorescent protein, integrated via picornaviruses’ furin-2A peptide sequences. In vitro experiments demonstrated that genetically modified cells with engineered plasmid constructs expressed the target proteins. Overexpression of VEGF and FGF2 resulted in increased levels of the recombinant proteins. Concomitantly, these did not lead to a significant shift in the general secretory profile of modified HEK293T cells. Simultaneously, the secretome of genetically modified cells showed significant stimulating effects on the formation of capillary-like structures by HUVEC (endothelial cells) in vitro. Our results revealed that when the multicistronic multigene vectors encoding 2A peptide sequences are created, transient transgene co-expression is ensured. The results obtained indicated the mutual synergistic effects of the growth factors VEGF and FGF2 on the proliferation of endothelial cells in vitro. Thus, recombinant multicistronic multigenic constructs might serve as a promising approach for establishing safe and effective systems to treat ischemic diseases.
Cord-Blood-Derived Professional Antigen-Presenting Cells: Functions and Applications in Current and Prospective Cell Therapies
Authors: Cunningham Sarah , Hackstein Holger
Published: June 2021

Human umbilical cord blood (UCB) represents a valuable source of hematopoietic stem cells, particularly for patients lacking a matching donor. UCB provides practical advantages, including a lower risk of graft-versus-host-disease and permissive human leukocyte antigen mismatching. These advantageous properties have so far been applied for stem cell, mesenchymal stromal cell, and chimeric antigen receptor T cell therapies. However, UCB-derived professional antigen-presenting cells are increasingly being utilized in the context of immune tolerance and regenerative therapy. Here, we review the cell-specific characteristics as well as recent advancements in UCB-based cell therapies focusing on dendritic cells, monocytes, B lymphocytes, innate lymphoid cells, and macrophages.
Gonadotropin Releasing Hormone (GnRH) Triggers Neurogenesis in the Hypothalamus of Adult Zebrafish
Authors: Ceriani Ricardo , Whitlock Kathleen E.
Published: June 2021

Recently, it has been shown in adult mammals that the hypothalamus can generate new cells in response to metabolic changes, and tanycytes, putative descendants of radial glia, can give rise to neurons. Previously we have shown in vitro that neurospheres generated from the hypothalamus of adult zebrafish show increased neurogenesis in response to exogenously applied hormones. To determine whether adult zebrafish have a hormone-responsive tanycyte-like population in the hypothalamus, we characterized proliferative domains within this region. Here we show that the parvocellular nucleus of the preoptic region (POA) labels with neurogenic/tanycyte markers vimentin, GFAP/Zrf1, and Sox2, but these cells are generally non-proliferative. In contrast, Sox2+ proliferative cells in the ventral POA did not express vimentin and GFAP/Zrf1. A subset of the Sox2+ cells co-localized with Fezf2:GFP, a transcription factor important for neuroendocrine cell specification. Exogenous treatments of GnRH and testosterone were assayed in vivo. While the testosterone-treated animals showed no significant changes in proliferation, the GnRH-treated animals showed significant increases in the number of BrdU-labeled cells and Sox2+ cells. Thus, cells in the proliferative domains of the zebrafish POA do not express radial glia (tanycyte) markers vimentin and GFAP/Zrf1, and yet, are responsive to exogenously applied GnRH treatment.
Mechanisms and Regulation of Cardiac CaV1.2 Trafficking
Authors: Westhoff Maartje , Dixon Rose E.
Published: June 2021

During cardiac excitation contraction coupling, the arrival of an action potential at the ventricular myocardium triggers voltage-dependent L-type Ca2+ (CaV1.2) channels in individual myocytes to open briefly. The level of this Ca2+ influx tunes the amplitude of Ca2+-induced Ca2+ release from ryanodine receptors (RyR2) on the junctional sarcoplasmic reticulum and thus the magnitude of the elevation in intracellular Ca2+ concentration and ultimately the downstream contraction. The number and activity of functional CaV1.2 channels at the t-tubule dyads dictates the amplitude of the Ca2+ influx. Trafficking of these channels and their auxiliary subunits to the cell surface is thus tightly controlled and regulated to ensure adequate sarcolemmal expression to sustain this critical process. To that end, recent discoveries have revealed the existence of internal reservoirs of preformed CaV1.2 channels that can be rapidly mobilized to enhance sarcolemmal expression in times of acute stress when hemodynamic and metabolic demand increases. In this review, we provide an overview of the current thinking on CaV1.2 channel trafficking dynamics in the heart. We highlight the numerous points of control including the biosynthetic pathway, the endosomal recycling pathway, ubiquitination, and lysosomal and proteasomal degradation pathways, and discuss the effects of β-adrenergic and angiotensin receptor signaling cascades on this process.
Nitrate- and Nitrite-Sensing Histidine Kinases: Function, Structure, and Natural Diversity
Authors: Gushchin Ivan , Aleksenko Vladimir A. , Orekhov Philipp , Goncharov Ivan M. , Nazarenko Vera V. , Semenov Oleg , Remeeva Alina , Gordeliy Valentin
Published: June 2021

Under anaerobic conditions, bacteria may utilize nitrates and nitrites as electron acceptors. Sensitivity to nitrous compounds is achieved via several mechanisms, some of which rely on sensor histidine kinases (HKs). The best studied nitrate- and nitrite-sensing HKs (NSHKs) are NarQ and NarX from Escherichia coli. Here, we review the function of NSHKs, analyze their natural diversity, and describe the available structural information. In particular, we show that around 6000 different NSHK sequences forming several distinct clusters may now be found in genomic databases, comprising mostly the genes from Beta- and Gammaproteobacteria as well as from Bacteroidetes and Chloroflexi, including those from anaerobic ammonia oxidation (annamox) communities. We show that the architecture of NSHKs is mostly conserved, although proteins from Bacteroidetes lack the HAMP and GAF-like domains yet sometimes have PAS. We reconcile the variation of NSHK sequences with atomistic models and pinpoint the structural elements important for signal transduction from the sensor domain to the catalytic module over the transmembrane and cytoplasmic regions spanning more than 200 Å.
Influence of Alkyl Chain Length on Thermal Properties, Structure, and Self-Diffusion Coefficients of Alkyltriethylammonium-Based Ionic Liquids
Authors: Markiewicz Roksana , Klimaszyk Adam , Jarek Marcin , Taube Michał , Florczak Patryk , Kempka Marek , Fojud Zbigniew , Jurga Stefan
Published: June 2021

The application of ionic liquids (ILs) has grown enormously, from their use as simple solvents, catalysts, media in separation science, or electrolytes to that as task-specific, tunable molecular machines with appropriate properties. A thorough understanding of these properties and structure–property relationships is needed to fully exploit their potential, open new directions in IL-based research and, finally, properly implement the appropriate applications. In this work, we investigated the structure–properties relationships of a series of alkyltriethylammonium bis(trifluoromethanesulfonyl)imide [TEA-R][TFSI] ionic liquids in relation to their thermal behavior, structure organization, and self-diffusion coefficients in the bulk state using DSC, FT-IR, SAXS, and NMR diffusometry techniques. The phase transition temperatures were determined, indicating alkyl chain dependency. Fourier-transformed infrared spectroscopy studies revealed the structuration of the ionic liquids along with alkyl chain elongation. SAXS experiments clearly demonstrated the existence of polar/non-polar domains. The alkyl chain length influenced the expansion of the non-polar domains, leading to the expansion between cation heads in polar regions of the structured IL. 1H NMR self-diffusion coefficients indicated that alkyl chain elongation generally caused the lowering of the self-diffusion coefficients. Moreover, we show that the diffusion of anions and cations of ILs is similar, even though they vary in their size.
Implications of SGLT Inhibition on Redox Signalling in Atrial Fibrillation
Authors: Bode David , Semmler Lukas , Oeing Christian U. , Alogna Alessio , Schiattarella Gabriele G. , M. Pieske Burkert , Heinzel Frank R. , Hohendanner Felix
Published: June 2021

Atrial fibrillation (AF) is the most common sustained (atrial) arrhythmia, a considerable global health burden and often associated with heart failure. Perturbations of redox signalling in cardiomyocytes provide a cellular substrate for the manifestation and maintenance of atrial arrhythmias. Several clinical trials have shown that treatment with sodium-glucose linked transporter inhibitors (SGLTi) improves mortality and hospitalisation in heart failure patients independent of the presence of diabetes. Post hoc analysis of the DECLARE-TIMI 58 trial showed a 19% reduction in AF in patients with diabetes mellitus (hazard ratio, 0.81 (95% confidence interval: 0.68–0.95), n = 17.160) upon treatment with SGLTi, regardless of pre-existing AF or heart failure and independent from blood pressure or renal function. Accordingly, ongoing experimental work suggests that SGLTi not only positively impact heart failure but also counteract cellular ROS production in cardiomyocytes, thereby potentially altering atrial remodelling and reducing AF burden. In this article, we review recent studies investigating the effect of SGLTi on cellular processes closely interlinked with redox balance and their potential effects on the onset and progression of AF. Despite promising insight into SGLTi effect on Ca2+ cycling, Na+ balance, inflammatory and fibrotic signalling, mitochondrial function and energy balance and their potential effect on AF, the data are not yet conclusive and the importance of individual pathways for human AF remains to be established. Lastly, an overview of clinical studies investigating SGLTi in the context of AF is provided.
PTX3 Effects on Osteogenic Differentiation in Osteoporosis: An In Vitro Study
Authors: Greggi Chiara , Cariati Ida , Onorato Federica , Iundusi Riccardo , Scimeca Manuel , Tarantino Umberto
Published: June 2021

Pentraxin 3 (PTX3) is a glycoprotein belonging to the humoral arm of innate immunity that participates in the body’s defence mechanisms against infectious diseases. It has recently been defined as a multifunctional protein, given its involvement in numerous physiological and pathological processes, as well as in the pathogenesis of age-related diseases such as osteoporosis. Based on this evidence, the aim of our study was to investigate the possible role of PTX3 in both the osteoblastic differentiation and calcification process: to this end, primary osteoblast cultures from control and osteoporotic patients were incubated with human recombinant PTX3 (hrPTX3) for 72 h. Standard osteinduction treatment, consisting of β-glycerophosphate, dexamethasone and ascorbic acid, was used as control. Our results showed that treatment with hrPTX3, as well as with the osteogenic cocktail, induced cell differentiation towards the osteoblastic lineage. We also observed that the treatment not only promoted an increase in cell proliferation, but also the formation of calcification-like structures, especially in primary cultures from osteoporotic patients. In conclusion, the results reported here suggest the involvement of PTX3 in osteogenic differentiation, highlighting its osteoinductive capacity, like the standard osteoinduction treatment. Therefore, this study opens new and exciting perspectives about the possible role of PTX3 as biomarker and therapeutic agent for osteoporosis.
Human-Induced Neural and Mesenchymal Stem Cell Therapy Combined with a Curcumin Nanoconjugate as a Spinal Cord Injury Treatment
Authors: Bonilla Pablo , Hernandez Joaquim , Giraldo Esther , González-Pérez Miguel A. , Alastrue-Agudo Ana , Elkhenany Hoda , Vicent María J. , Navarro Xavier , Edel Michael , Moreno-Manzano Victoria
Published: June 2021

We currently lack effective treatments for the devastating loss of neural function associated with spinal cord injury (SCI). In this study, we evaluated a combination therapy comprising human neural stem cells derived from induced pluripotent stem cells (iPSC-NSC), human mesenchymal stem cells (MSC), and a pH-responsive polyacetal–curcumin nanoconjugate (PA-C) that allows the sustained release of curcumin. In vitro analysis demonstrated that PA-C treatment protected iPSC-NSC from oxidative damage in vitro, while MSC co-culture prevented lipopolysaccharide-induced activation of nuclear factor-κB (NF-κB) in iPSC-NSC. Then, we evaluated the combination of PA-C delivery into the intrathecal space in a rat model of contusive SCI with stem cell transplantation. While we failed to observe significant improvements in locomotor function (BBB scale) in treated animals, histological analysis revealed that PA-C-treated or PA-C and iPSC-NSC + MSC-treated animals displayed significantly smaller scars, while PA-C and iPSC-NSC + MSC treatment induced the preservation of β-III Tubulin-positive axons. iPSC-NSC + MSC transplantation fostered the preservation of motoneurons and myelinated tracts, while PA-C treatment polarized microglia into an anti-inflammatory phenotype. Overall, the combination of stem cell transplantation and PA-C treatment confers higher neuroprotective effects compared to individual treatments.
Role of Satb1 and Satb2 Transcription Factors in the Glutamate Receptors Expression and Ca2+ Signaling in the Cortical Neurons In Vitro
Authors: Turovsky Egor A. , Turovskaya Maria V. , Fedotova Evgeniya I. , Babaev Alexey A. , Tarabykin Victor S. , Varlamova Elena G.
Published: June 2021

Transcription factors Satb1 and Satb2 are involved in the processes of cortex development and maturation of neurons. Alterations in the expression of their target genes can lead to neurodegenerative processes. Molecular and cellular mechanisms of regulation of neurotransmission by these transcription factors remain poorly understood. In this study, we have shown that transcription factors Satb1 and Satb2 participate in the regulation of genes encoding the NMDA-, AMPA-, and KA- receptor subunits and the inhibitory GABA(A) receptor. Deletion of gene for either Satb1 or Satb2 homologous factors induces the expression of genes encoding the NMDA receptor subunits, thereby leading to higher amplitudes of Ca2+-signals in neurons derived from the Satb1-deficient (Satb1fl/+ * NexCre/+) and Satb1-null mice (Satb1fl/fl * NexCre/+) in response to the selective agonist reducing the EC50 for the NMDA receptor. Simultaneously, there is an increase in the expression of the Gria2 gene, encoding the AMPA receptor subunit, thus decreasing the Ca2+-signals of neurons in response to the treatment with a selective agonist (5-Fluorowillardiine (FW)). The Satb1 deletion increases the sensitivity of the KA receptor to the agonist (domoic acid), in the cortical neurons of the Satb1-deficient mice but decreases it in the Satb1-null mice. At the same time, the Satb2 deletion decreases Ca2+-signals and the sensitivity of the KA receptor to the agonist in neurons from the Satb1-null and the Satb1-deficient mice. The Satb1 deletion affects the development of the inhibitory system of neurotransmission resulting in the suppression of the neuron maturation process and switching the GABAergic responses from excitatory to inhibitory, while the Satb2 deletion has a similar effect only in the Satb1-null mice. We show that the Satb1 and Satb2 transcription factors are involved in the regulation of the transmission of excitatory signals and inhibition of the neuronal network in the cortical cell culture.
The AtCRK5 Protein Kinase Is Required to Maintain the ROS NO Balance Affecting the PIN2-Mediated Root Gravitropic Response in Arabidopsis
Authors: Cséplő Ágnes , Zsigmond Laura , Andrási Norbert , Baba Abu Imran , Labhane Nitin M. , Pető Andrea , Kolbert Zsuzsanna , Kovács Hajnalka E. , Steinbach Gábor , Szabados László , Fehér Attila , Rigó Gábor
Published: June 2021

The Arabidopsis AtCRK5 protein kinase is involved in the establishment of the proper auxin gradient in many developmental processes. Among others, the Atcrk5-1 mutant was reported to exhibit a delayed gravitropic response via compromised PIN2-mediated auxin transport at the root tip. Here, we report that this phenotype correlates with lower superoxide anion (O2•−) and hydrogen peroxide (H2O2) levels but a higher nitric oxide (NO) content in the mutant root tips in comparison to the wild type (AtCol-0). The oxidative stress inducer paraquat (PQ) triggering formation of O2•− (and consequently, H2O2) was able to rescue the gravitropic response of Atcrk5-1 roots. The direct application of H2O2 had the same effect. Under gravistimulation, correct auxin distribution was restored (at least partially) by PQ or H2O2 treatment in the mutant root tips. In agreement, the redistribution of the PIN2 auxin efflux carrier was similar in the gravistimulated PQ-treated mutant and untreated wild type roots. It was also found that PQ-treatment decreased the endogenous NO level at the root tip to normal levels. Furthermore, the mutant phenotype could be reverted by direct manipulation of the endogenous NO level using an NO scavenger (cPTIO). The potential involvement of AtCRK5 protein kinase in the control of auxin-ROS-NO-PIN2-auxin regulatory loop is discussed.
Potential Contribution of Short Chain Fatty Acids to Hepatic Apolipoprotein A-I Production
Authors: Popeijus Herman E. , Zwaan Willem , Tayyeb Jehad Z. , Plat Jogchum
Published: June 2021

Apolipoprotein A-I (ApoA-I) is the major protein of high density lipoprotein (HDL) particles and has a crucial role in reverse cholesterol transport (RCT). It has been postulated that elevating production of de novo ApoA-I might translate into the formation of new functional HDL particles that could lower cardiovascular disease (CVD) risk via RCT. During inflammation, serum ApoA-I concentrations are reduced, which contributes to the development of dysfunctional HDL particles as Serum Amyloid A (SAA) overtakes the position of ApoA-I within the HDL particles. Therefore, instead of elevating serum HDL cholesterol concentrations, rescuing lower serum ApoA-I concentrations could be beneficial in both normal and inflamed conditions. Several nutritional compounds, amongst others short chain fatty acids (SCFAs), have shown their capacity to modulate hepatic lipoprotein metabolism. In this review we provide an overview of HDL and more specific ApoA-I metabolism, SCFAs physiology and the current knowledge regarding the influence of SCFAs on ApoA-I expression and synthesis in human liver cells. We conclude that the current evidence regarding the effect of SCFAs on ApoA-I transcription and secretion is promising, however there is a need to investigate which dietary fibres could lead to increased SCFAs formation and consequent elevated ApoA-I concentrations.
Combined Gemcitabine and Immune-Checkpoint Inhibition Conquers Anti-PD-L1 Resistance in Low-Immunogenic Mismatch Repair-Deficient Tumors
Authors: Salewski Inken , Henne Julia , Engster Leonie , Schneider Bjoern , Lemcke Heiko , Skorska Anna , Berlin Peggy , Henze Larissa , Junghanss Christian , Maletzki Claudia
Published: June 2021

Tumors arising in the context of Lynch Syndrome or constitutional mismatch repair deficiency are hypermutated and have a good response towards immune-checkpoint inhibitors (ICIs), including α-PD-L1 antibodies. However, in most cases, resistance mechanisms evolve. To improve outcomes and prevent resistance development, combination approaches are warranted. Herein, we applied a combined regimen with an α-PD-L1 antibody and gemcitabine in a preclinical tumor model to activate endogenous antitumor immune responses. Mlh1−/− mice with established gastrointestinal tumors received the α-PD-L1 antibody (clone 6E11; 2.5 mg/kg bw, i.v., q2wx3) and gemcitabine (100 mg/kg bw, i.p., q4wx3) in mono- or combination therapy. Survival and tumor growth were recorded. Immunological changes in the blood were routinely examined via multi-color flow cytometry and complemented by ex vivo frameshift mutation analysis to identify alterations in Mlh1−/−-tumor-associated target genes. The combined therapy of α-PD-L1 and gemcitabine prolonged median overall survival of Mlh1−/− mice from four weeks in the untreated control group to 12 weeks, accompanied by therapy-induced tumor growth inhibition, as measured by [18F]-FDG PET/CT. Plasma cytokine levels of IL13, TNFα, and MIP1β were increased and also higher than in mice receiving either monotherapy. Circulating splenic and intratumoral myeloid-derived suppressor cells (MDSCs), as well as M2 macrophages, were markedly reduced. Besides, residual tumor specimens from combi-treated mice had increased numbers of infiltrating cytotoxic T-cells. Frameshift mutations in APC, Tmem60, and Casc3 were no longer detectable upon treatment, likely because of the successful eradication of single mutated cell clones. By contrast, novel mutations appeared. Collectively, we herein confirm the safe application of combined chemo-immunotherapy by long-term tumor growth control to prevent the development of resistance mechanisms.
An Unbalanced Synaptic Transmission: Cause or Consequence of the Amyloid Oligomers Neurotoxicity?
Authors: Sciaccaluga Miriam , Megaro Alfredo , Bellomo Giovanni , Ruffolo Gabriele , Romoli Michele , Palma Eleonora , Costa Cinzia
Published: June 2021

Amyloid-β (Aβ) 1-40 and 1-42 peptides are key mediators of synaptic and cognitive dysfunction in Alzheimer’s disease (AD). Whereas in AD, Aβ is found to act as a pro-epileptogenic factor even before plaque formation, amyloid pathology has been detected among patients with epilepsy with increased risk of developing AD. Among Aβ aggregated species, soluble oligomers are suggested to be responsible for most of Aβ’s toxic effects. Aβ oligomers exert extracellular and intracellular toxicity through different mechanisms, including interaction with membrane receptors and the formation of ion-permeable channels in cellular membranes. These damages, linked to an unbalance between excitatory and inhibitory neurotransmission, often result in neuronal hyperexcitability and neural circuit dysfunction, which in turn increase Aβ deposition and facilitate neurodegeneration, resulting in an Aβ-driven vicious loop. In this review, we summarize the most representative literature on the effects that oligomeric Aβ induces on synaptic dysfunction and network disorganization.
Autophagy, Unfolded Protein Response, and Neuropilin-1 Cross-Talk in SARS-CoV-2 Infection: What Can Be Learned from Other Coronaviruses
Authors: Siri Morvarid , Dastghaib Sanaz , Zamani Mozhdeh , Rahmani-Kukia Nasim , Geraylow Kiarash Roustai , Fakher Shima , Keshvarzi Fatemeh , Mehrbod Parvaneh , Ahmadi Mazaher , Mokarram Pooneh , Coombs Kevin M. , Ghavami Saeid
Published: June 2021

The COVID-19 pandemic is caused by the 2019–nCoV/SARS-CoV-2 virus. This severe acute respiratory syndrome is currently a global health emergency and needs much effort to generate an urgent practical treatment to reduce COVID-19 complications and mortality in humans. Viral infection activates various cellular responses in infected cells, including cellular stress responses such as unfolded protein response (UPR) and autophagy, following the inhibition of mTOR. Both UPR and autophagy mechanisms are involved in cellular and tissue homeostasis, apoptosis, innate immunity modulation, and clearance of pathogens such as viral particles. However, during an evolutionary arms race, viruses gain the ability to subvert autophagy and UPR for their benefit. SARS-CoV-2 can enter host cells through binding to cell surface receptors, including angiotensin-converting enzyme 2 (ACE2) and neuropilin-1 (NRP1). ACE2 blockage increases autophagy through mTOR inhibition, leading to gastrointestinal complications during SARS-CoV-2 virus infection. NRP1 is also regulated by the mTOR pathway. An increased NRP1 can enhance the susceptibility of immune system dendritic cells (DCs) to SARS-CoV-2 and induce cytokine storm, which is related to high COVID-19 mortality. Therefore, signaling pathways such as mTOR, UPR, and autophagy may be potential therapeutic targets for COVID-19. Hence, extensive investigations are required to confirm these potentials. Since there is currently no specific treatment for COVID-19 infection, we sought to review and discuss the important roles of autophagy, UPR, and mTOR mechanisms in the regulation of cellular responses to coronavirus infection to help identify new antiviral modalities against SARS-CoV-2 virus.
The Therapeutic Effect of Intranasal Administration of Dexamethasone in Neuroinflammation Induced by Experimental Pulmonary Tuberculosis
Authors: Lara-Espinosa Jacqueline V. , Arce-Aceves María Fernanda , Mata-Espinosa Dulce , Barrios-Payán Jorge , Marquina-Castillo Brenda , Hernández-Pando Rogelio
Published: June 2021

Tuberculosis (TB) is an important infectious disease and a public health problem. The organs most frequently affected by TB are the lungs; despite this, it has been reported that TB patients suffer from depression and anxiety, which have been attributed to social factors. In previous experimental work, we observed that the extensive pulmonary inflammation characteristic of TB with high cytokine production induces neuroinflammation, neuronal death and behavioral abnormalities in the absence of brain infection. The objective of the present work was to reduce this neuroinflammation and avoid the psycho-affective disorders showed during pulmonary TB. Glucocorticoids (GCs) are the first-line treatment for neuroinflammation; however, their systemic administration generates various side effects, mostly aggravating pulmonary TB due to immunosuppression of cellular immunity. Intranasal administration is a route that allows drugs to be released directly in the brain through the olfactory nerve, reducing their doses and side effects. In the present work, dexamethasone’s (DEX) intranasal administration was evaluated in TB BALB /c mice comparing three different doses (0.05, 0.25 and 2.5 mg/kg BW) on lung disease evolution, neuroinflammation and behavioral alterations. Low doses of dexamethasone significantly decreased neuroinflammation, improving behavioral status without aggravating lung disease.