bluuebunny/crossref_metadata_2025 huggingface dataset:
Driver Behavior When Overtaking Cyclists Riding in Different Group Configurations on Two-Lane Rural Roads
Authors: Pérez-Zuriaga Ana María , Moll Sara , López Griselda , García Alfredo
Published: December 2021

The presence of cyclists on Spanish rural roads is ever increasing and currently frequent, and thus becoming a serious safety concern. In rural environments, the risk of a crash is higher than in rural areas. The main cause is the higher speed of motor vehicles during overtaking manoeuvres. This manoeuvre is especially challenging when cyclists ride in groups as they may change size, length, shape, and speed along their route. These variables and those related to road cross-section can influence driver behaviour when overtaking a group of cyclists. To study this, instrumented bicycles were used to ride along five road segments with different geometric and traffic characteristics. Cyclists rode individually and in groups. Overtaking was evaluated by analysing the lateral distance, the speed, and other characteristics of the manoeuvre. Wider roads presented higher lateral clearances and overtaking speeds. Narrower roads had a high opposing lane invasion but a high level of compliance with the minimum lateral clearance. A higher clearance and lower speed of overtaking vehicles was registered when cyclists rode in line. Compliance with the 1.5 m clearance depended on the group configuration, being higher when cyclists rode in line. However, overtaking cyclists riding two abreast presented more accelerative manoeuvres, especially on narrow roads.
Leisure Time Use and Adolescent Mental Well-Being: Insights from the COVID-19 Czech Spring Lockdown
Authors: Cosma Alina , Pavelka Jan , Badura Petr
Published: December 2021

Background: As leisure—one of the crucial life domains—was completely disrupted by the COVID-19 pandemic, our study aimed to investigate how adolescents spent their leisure time during the Spring 2020 lockdown. Secondly, we aimed to investigate the associations between the perceived changes in leisure time use, the leisure activities adolescents engaged in, and the associations with well-being during the Spring 2020 lockdown in Czechia. Methods: Data from 3438 participants were included in this study (54.2% girls; mean age = 13.45, SD = 1.62). First, the initial number of items measuring leisure, electronic media use, and sports was reduced through Principal Component Analysis (PCA). Multivariate linear regression models tested the associations between leisure domains and mental well-being Results: The amount of leisure time, together with socially active leisure and sports and physical activity, formed the strongest positive predictors of mental well-being, whereas idle activities and time spent on electronic media acted as negative predictors. The amount of time spent doing schoolwork was unrelated to mental well-being. Conclusions: Overall, our results support the idea that leisure as a promoting factor for well-being is not just a matter of its amount but rather of engagement in meaningful and fulfilling activities.
Substitute Behaviors following Residential Substance Use Treatment in the Western Cape, South Africa
Authors: Sinclair Deborah Louise , Sussman Steve , De Schryver Maarten , Samyn Cedric , Adams Sabirah , Florence Maria , Savahl Shazly , Vanderplasschen Wouter
Published: December 2021

The dynamics of substitute behaviors and associated factors remain poorly understood globally, and particularly in low- and middle-income contexts. This prospective study describes the prevalence and types of substitute behaviors as well as predictors, correlates, and motivations associated with substitution in persons (n = 137) admitted to residential substance use treatment in the Western Cape province of South Africa. The brief assessment of recovery capital, overall life satisfaction scale, and an adapted version of the addiction matrix self-report measure were completed during and post-treatment. Results indicate that substitutes were employed consciously for anticipated appetitive effects, for time-spending, (re)connecting with others, and enjoyment. At follow-up, 36% of service users had substituted their primary substance(s) with another substance or behavior; 23% had relapsed and 40% had maintained abstinence. While some service users may be especially vulnerable to developing substitute behaviors, targeted prevention and intervention efforts can reduce this risk.
Predicted Impact of the Lockdown Measure in Response to Coronavirus Disease 2019 (COVID-19) in Greater Bangkok, Thailand, 2021
Authors: Uansri Sonvanee , Tuangratananon Titiporn , Phaiyarom Mathudara , Rajatanavin Nattadhanai , Suphanchaimat Rapeepong , Jaruwanno Warisara
Published: December 2021

In mid-2021, Thailand faced a fourth wave of Coronavirus Disease 2019 (COVID-19) predominantly fueled by the Delta and Alpha variants. The number of cases and deaths rose exponentially, alongside a sharp increase in hospitalizations and intubated patients. The Thai Government then implemented a lockdown to mitigate the outbreak magnitude and prevent cases from overwhelming the healthcare system. This study aimed to model the severity of the outbreak over the following months by different levels of lockdown effectiveness. Secondary analysis was performed on data primarily obtained from the Ministry of Health; the data were analyzed using both the deterministic compartmental model and the system dynamics model. The model was calibrated against the number of daily cases in Greater Bangkok during June–July 2021. We then assessed the outcomes (daily cases, daily deaths, and intubated patients) according to hypothetical lockdowns of varying effectiveness and duration. The findings revealed that lockdown measures could reduce and delay the peak of COVID-19 cases and deaths. A two-month lockdown with 60% effectiveness in the reduction in reproduction number caused the lowest number of cases, deaths, and intubated patients, with a peak about one-fifth of the size of a no-lockdown peak. The two-month lockdown policy also delayed the peak until after December, while in the context of a one-month lockdown, cases peaked during the end of September to early December (depending on the varying degrees of lockdown effectiveness in the reduction in reproduction number). In other words, the implementation of a lockdown policy did not mean the end of the outbreak, but it helped delay the peak. In this sense, implementing a lockdown helped to buy time for the healthcare system to recover and better prepare for any future outbreaks. We recommend further studies that explore the impact of lockdown measures at a sub-provincial level, and examine the impact of lockdowns on parameters not directly related to the spread of disease, such as quality of life and economic implications for individuals and society.
In-Season Internal Load and Wellness Variations in Professional Women Soccer Players: Comparisons between Playing Positions and Status
Authors: Fernandes Renato , Brito João Paulo , Vieira Luiz H. Palucci , Martins Alexandre Duarte , Clemente Filipe Manuel , Nobari Hadi , Reis Victor Machado , Oliveira Rafael
Published: December 2021

The internal intensity monitoring in soccer has been used more in recent years in men’s football; however, in women’s soccer, the existing literature is still scarce. The aims of this study were threefold: (a) to describe the weekly variations of training monotony, training strain and acute: chronic workload ratio through session Rated Perceived Exertion (s-RPE); (b) to describe weekly variations of Hooper Index [stress, fatigue, Delayed Onset Muscle Soreness (DOMS) and sleep]; and (c) to compare those variations between playing positions and player status. Nineteen players (24.1 ± 2.7 years) from a Portuguese BPI League professional team participated in this study. All variables were collected in a 10-week in-season period with three training sessions and one match per week during the 2019/20 season. Considering the overall team, the results showed that there were some associations between Hooper Index categories and s-RPE like stress or fatigue (0.693, p < 0.01), stress or DOMS (0.593, p < 0.01), stress or s-RPE (−0.516, p < 0.05) and fatigue or DOMS (0.688, p < 0.01). There were no differences between all parameters in playing positions or player status. In conclusion, the study revealed that higher levels of fatigue and DOMS occur concurrently with better nights of sleep. Moreover, any in-season variations concerning internal load and perceived wellness seems independent of position or status in outfield players. The data also showed that the higher the players’ reported stress, the lower the observed s-RPE, thus possibly indicating a mutual interference of experienced stress levels on the assimilation of training intensity by elite women soccer players.
Internal Modifications to Optimize Pollution and Emissions of Internal Combustion Engines through Multiple-Criteria Decision-Making and Artificial Neural Networks
Authors: Galdo María Isabel Lamas , Miranda Javier Telmo , Lorenzo José Manuel Rebollido , Caccia Claudio Giovanni
Published: December 2021

The present work proposes several modifications to optimize both emissions and consumption in a commercial marine diesel engine. A numerical model was carried out to characterize the emissions and consumption of the engine under several performance parameters. Particularly, five internal modifications were analyzed: water addition; exhaust gas recirculation; and modification of the intake valve closing, overlap timing, and cooling water temperature. It was found that the result on the emissions and consumption presents conflicting criteria, and thus, a multiple-criteria decision-making model was carried out to characterize the most appropriate parameters. In order to analyze a high number of possibilities in a reasonable time, an artificial neural network was developed.
Combining Global Geopotential Models, Digital Elevation Models, and GNSS/Leveling for Precise Local Geoid Determination in Some Mexico Urban Areas: Case Study
Authors: Alcantar-Elizondo Norberto , Garcia-Lopez Ramon Victorino , Torres-Carillo Xochitl Guadalupe , Vazquez-Becerra Guadalupe Esteban
Published: December 2021

This work shows improvements of geoid undulation values obtained from a high-resolution Global Geopotential Model (GGM), applied to local urban areas. The methodology employed made use of a Residual Terrain Model (RTM) to account for the topographic masses effect on the geoid. This effect was computed applying the spherical tesseroids approach for mass discretization. The required numerical integration was performed by 2-D integration with 1DFFT technique that combines DFT along parallels with direct numerical integration along meridians. In order to eliminate the GGM commission error, independent geoid undulations values obtained from a set of GNSS/leveling stations are employed. A corrector surface from the associated geoid undulation differences at the stations was generated through a polynomial regression model. The corrector surface, in addition to the GGM commission error, also absorbs the GNSS/leveling errors as well as datum inconsistencies and systematic errors of the data. The procedure was applied to five Mexican urban areas that have a geodetic network of GNSS/leveling points, which range from 166 to 811. Two GGM were evaluated: EGM2008 and XGM2019e_2159. EGM2008 was the model that showed relatively better agreement with the GNSS/leveling stations having differences with RMSE values in the range of 8–60 cm and standard deviations of 5–8 cm in four of the networks and 17 cm in one of them. The computed topographic masses contribution to the geoid were relatively small, having standard deviations on the range 1–24 mm. With respect to corrector surface estimations, they turned out to be fairly smooth yielding similar residuals values for two geoid models. This was also the case for the most recent Mexican gravity geoid GGM10. For the three geoid models, the second order polynomial regression model performed slightly better than the first order with differences up to 1 cm. These two models produced geoid correction residuals with a standard deviation in one test area of 14 cm while for the others it was of about 4–7 cm. However, the kriging method that was applied for comparison purposes produced slightly smaller values: 8 cm for one area and 4–6 cm for the others.
Circulating Tumor Cells in Hepatocellular Carcinoma: A Comprehensive Review and Critical Appraisal
Authors: Espejo-Cruz María Lola , González-Rubio Sandra , Zamora-Olaya Javier , Amado-Torres Víctor , Alejandre Rafael , Sánchez-Frías Marina , Ciria Rubén , De la Mata Manuel , Rodríguez-Perálvarez Manuel , Ferrín Gustavo
Published: December 2021

Hepatocellular carcinoma (HCC) is the fifth most common neoplasm and a major cause of cancer-related death worldwide. There is no ideal biomarker allowing early diagnosis of HCC and tumor surveillance in patients receiving therapy. Liquid biopsy, and particularly circulating tumor cells (CTCs), have emerged as a useful tool for diagnosis and monitoring therapeutic responses in different tumors. In the present manuscript, we evaluate the current evidence supporting the quantitative and qualitative assessment of CTCs as potential biomarkers of HCC, as well as technical aspects related to isolation, identification, and classification of CTCs. Although the dynamic assessment of CTCs in patients with HCC may aid the decision-making process, there are still many uncertainties and technical caveats to be solved before this methodology has a true impact on clinical practice guidelines. More studies are needed to identify the optimal combination of surface markers, to increase the efficiency of ex-vivo expansion of CTCs, or even to target CTCs as a potential therapeutic strategy to prevent HCC recurrence after surgery or to hamper tumor progression and extrahepatic spreading.
Gut Microbiota as a Mediator of Essential and Toxic Effects of Zinc in the Intestines and Other Tissues
Authors: Skalny Anatoly V. , Aschner Michael , Lei Xin Gen , Gritsenko Viktor A. , Santamaria Abel , Alekseenko Svetlana I. , Prakash Nagaraja Tejo , Chang Jung-Su , Sizova Elena A. , Chao Jane C. J. , Aaseth Jan , Tinkov Alexey A.
Published: December 2021

The objective of the present study was to review the existing data on the association between Zn status and characteristics of gut microbiota in various organisms and the potential role of Zn-induced microbiota in modulating systemic effects. The existing data demonstrate a tight relationship between Zn metabolism and gut microbiota as demonstrated in Zn deficiency, supplementation, and toxicity studies. Generally, Zn was found to be a significant factor for gut bacteria biodiversity. The effects of physiological and nutritional Zn doses also result in improved gut wall integrity, thus contributing to reduced translocation of bacteria and gut microbiome metabolites into the systemic circulation. In contrast, Zn overexposure induced substantial alterations in gut microbiota. In parallel with intestinal effects, systemic effects of Zn-induced gut microbiota modulation may include systemic inflammation and acute pancreatitis, autism spectrum disorder and attention deficit hyperactivity disorder, as well as fetal alcohol syndrome and obesity. In view of both Zn and gut microbiota, as well as their interaction in the regulation of the physiological functions of the host organism, addressing these targets through the use of Zn-enriched probiotics may be considered an effective strategy for health management.
Current and Novel Antiplatelet Therapies for the Treatment of Cardiovascular Diseases
Authors: Jourdi Georges , Lordkipanidzé Marie , Philippe Aurélien , Bachelot-Loza Christilla , Gaussem Pascale
Published: December 2021

Over the last decades, antiplatelet agents, mainly aspirin and P2Y12 receptor antagonists, have significantly reduced morbidity and mortality associated with arterial thrombosis. Their pharmacological characteristics, including pharmacokinetic/pharmacodynamics profiles, have been extensively studied, and a significant number of clinical trials assessing their efficacy and safety in various clinical settings have established antithrombotic efficacy. Notwithstanding, antiplatelet agents carry an inherent risk of bleeding. Given that bleeding is associated with adverse cardiovascular outcomes and mortality, there is an unmet clinical need to develop novel antiplatelet therapies that inhibit thrombosis while maintaining hemostasis. In this review, we present the currently available antiplatelet agents, with a particular focus on their targets, pharmacological characteristics, and patterns of use. We will further discuss the novel antiplatelet therapies in the pipeline, with the goal of improved clinical outcomes among patients with atherothrombotic diseases.
Korean Red Ginseng Improves Astrocytic Mitochondrial Function by Upregulating HO-1-Mediated AMPKα–PGC-1α–ERRα Circuit after Traumatic Brain Injury
Authors: Kim Minsu , Kim Joohwan , Moon Sunhong , Choi Bo Young , Kim Sueun , Jeon Hui Su , Suh Sang Won , Kim Young-Myeong , Choi Yoon Kyung
Published: December 2021

Heme oxygenase-1 (HO-1) exerts beneficial effects, including angiogenesis and energy metabolism via the peroxisome proliferator-activating receptor-γ coactivator-1α (PGC-1α)–estrogen-related receptor α (ERRα) pathway in astrocytes. However, the role of Korean red ginseng extract (KRGE) in HO-1-mediated mitochondrial function in traumatic brain injury (TBI) is not well-elucidated. We found that HO-1 was upregulated in astrocytes located in peri-injured brain regions after a TBI, following exposure to KRGE. Experiments with pharmacological inhibitors and target-specific siRNAs revealed that HO-1 levels highly correlated with increased AMP-activated protein kinase α (AMPKα) activation, which led to the PGC-1α-ERRα axis-induced increases in mitochondrial functions (detected based on expression of cytochrome c oxidase subunit 2 (MTCO2) and cytochrome c as well as O2 consumption and ATP production). Knockdown of ERRα significantly reduced the p-AMPKα/AMPKα ratio and PGC-1α expression, leading to AMPKα–PGC-1α–ERRα circuit formation. Inactivation of HO by injecting the HO inhibitor Sn(IV) protoporphyrin IX dichloride diminished the expression of p-AMPKα, PGC-1α, ERRα, MTCO2, and cytochrome c in the KRGE-administered peri-injured region of a brain subjected to TBI. These data suggest that KRGE enhanced astrocytic mitochondrial function via a HO-1-mediated AMPKα–PGC-1α–ERRα circuit and consequent oxidative phosphorylation, O2 consumption, and ATP production. This circuit may play an important role in repairing neurovascular function after TBI in the peri-injured region by stimulating astrocytic mitochondrial biogenesis.
The Complex Functions of the NME Family—A Matter of Location and Molecular Activity
Authors: Schlattner Uwe
Published: December 2021

The family of NME proteins represents a quite complex group of multifunctional enzymes [...]
Effects of Arbuscular Mycorrhiza on Primary Metabolites in Phloem Exudates of Plantago major and Poa annua and on a Generalist Aphid
Authors: Stallmann Jana , Schweiger Rabea
Published: December 2021

Arbuscular mycorrhiza (AM), i.e., the interaction of plants with arbuscular mycorrhizal fungi (AMF), often influences plant growth, physiology, and metabolism. Effects of AM on the metabolic composition of plant phloem sap may affect aphids. We investigated the impacts of AM on primary metabolites in phloem exudates of the plant species Plantago major and Poa annua and on the aphid Myzus persicae. Plants were grown without or with a generalist AMF species, leaf phloem exudates were collected, and primary metabolites were measured. Additionally, the performance of M. persicae on control and mycorrhizal plants of both species was assessed. While the plant species differed largely in the relative proportions of primary metabolites in their phloem exudates, metabolic effects of AM were less pronounced. Slightly higher proportions of sucrose and shifts in proportions of some amino acids in mycorrhizal plants indicated changes in phloem upload and resource allocation patterns within the plants. Aphids showed a higher performance on P. annua than on P. major. AM negatively affected the survival of aphids on P. major, whereas positive effects of AM were found on P. annua in a subsequent generation. Next to other factors, the metabolic composition of the phloem exudates may partly explain these findings.
Differential Expression of PD-L1 during Cell Cycle Progression of Head and Neck Squamous Cell Carcinoma
Authors: Schulz Daniela , Wetzel Martin , Eichberger Jonas , Piendl Gerhard , Brockhoff Gero , Wege Anja K. , Reichert Torsten E. , Ettl Tobias , Bauer Richard J.
Published: December 2021

The expression of PD-L1 by tumor cells is mainly associated with its immunosuppressive effect. In fact, PD-1/PD-L1 immune checkpoint inhibitors demonstrated remarkable effects in advanced cancer patients including HNSCC. In this context, irradiation is currently being investigated as a synergistic treatment modality to immunotherapy. However, the majority of HNSCC patients still show little improvement or even hyperprogression. Interestingly, there is increasing evidence for additional cell-intrinsic functions of PD-L1 in tumor cells. In previous studies, we showed that PD-L1 has a strong influence on proliferation, migration, invasion, and survival after irradiation. We demonstrated that cellular expression and localization of PD-L1 differed depending on sensitivity to irradiation. Here, we show that PD-L1 is also differentially expressed during cell cycle progression of HNSCC. Furthermore, cellular localization of PD-L1 also changes depending on a particular cell cycle phase. Moreover, distinct observations occurred depending on the general differentiation status. Overall, the function of PD-L1 cannot be generalized. Rather, it depends on the differentiation status and microenvironment. PD-L1 expression and localization are variable, depending on different factors. These findings may provide insight into why differential response to PD-1/PD-L1 antibody therapy can occur. Detailed understanding of cell-intrinsic PD-L1 functions will further allow antibody-based immunotherapy to be optimized.
Identification of New Compounds with Anticonvulsant and Antinociceptive Properties in a Group of 3-substituted (2,5-dioxo-pyrrolidin-1-yl)(phenyl)-Acetamides
Authors: Abram Michał , Jakubiec Marcin , Rapacz Anna , Mogilski Szczepan , Latacz Gniewomir , Szulczyk Bartłomiej , Szafarz Małgorzata , Socała Katarzyna , Nieoczym Dorota , Wyska Elżbieta , Wlaź Piotr , Kamiński Rafał M. , Kamiński Krzysztof
Published: December 2021

We report herein a series of water-soluble analogues of previously described anticonvulsants and their detailed in vivo and in vitro characterization. The majority of these compounds demonstrated broad-spectrum anticonvulsant properties in animal seizure models, including the maximal electroshock (MES) test, the pentylenetetrazole-induced seizure model (scPTZ), and the psychomotor 6 Hz (32 mA) seizure model in mice. Compound 14 showed the most robust anticonvulsant activity (ED50 MES = 49.6 mg/kg, ED50 6 Hz (32 mA) = 31.3 mg/kg, ED50scPTZ = 67.4 mg/kg). Notably, it was also effective in the 6 Hz (44 mA) model of drug-resistant epilepsy (ED50 = 63.2 mg/kg). Apart from favorable anticonvulsant properties, compound 14 revealed a high efficacy against pain responses in the formalin-induced tonic pain, the capsaicin-induced neurogenic pain, as well as in the oxaliplatin-induced neuropathic pain in mice. Moreover, compound 14 showed distinct anti-inflammatory activity in the model of carrageenan-induced aseptic inflammation. The mechanism of action of compound 14 is likely complex and may result from the inhibition of peripheral and central sodium and calcium currents, as well as the TRPV1 receptor antagonism as observed in the in vitro studies. This lead compound also revealed beneficial in vitro ADME-Tox properties and an in vivo pharmacokinetic profile, making it a potential candidate for future preclinical development. Interestingly, the in vitro studies also showed a favorable induction effect of compound 14 on the viability of neuroblastoma SH-SY5Y cells.
Redefining the Role of ADAM17 in Renal Proximal Tubular Cells and Its Implications in an Obese Mouse Model of Pre-Diabetes
Authors: Palau Vanesa , Villanueva Sofia , Jarrín Josué , Benito David , Márquez Eva , Rodríguez Eva , Soler María José , Oliveras Anna , Gimeno Javier , Sans Laia , Crespo Marta , Pascual Julio , Barrios Clara , Riera Marta
Published: December 2021

Acute and chronic kidney lesions induce an increase in A Disintegrin And Metalloproteinase domain 17 (ADAM17) that cleaves several transmembrane proteins related to inflammatory and fibrotic pathways. Our group has demonstrated that renal ADAM17 is upregulated in diabetic mice and its inhibition decreases renal inflammation and fibrosis. The purpose of the present study was to analyze how Adam17 deletion in proximal tubules affects different renal structures in an obese mice model. Tubular Adam17 knockout male mice and their controls were fed a high-fat diet (HFD) for 22 weeks. Glucose tolerance, urinary albumin-to-creatinine ratio, renal histology, and pro-inflammatory and pro-fibrotic markers were evaluated. Results showed that wild-type mice fed an HFD became obese with glucose intolerance and renal histological alterations mimicking a pre-diabetic condition; consequently, greater glomerular size and mesangial expansion were observed. Adam17 tubular deletion improved glucose tolerance and protected animals against glomerular injury and prevented podocyte loss in HFD mice. In addition, HFD mice showed more glomerular macrophages and collagen accumulation, which was prevented by Adam17 deletion. Galectin-3 expression increased in the proximal tubules and glomeruli of HFD mice and ameliorated with Adam17 deletion. In conclusion, Adam17 in proximal tubules influences glucose tolerance and participates in the kidney injury in an obese pre-diabetic murine model. The role of ADAM17 in the tubule impacts on glomerular inflammation and fibrosis.
Recombinant Bovine Growth Hormone-Induced Metabolic Remodelling Enhances Growth of Gilthead Sea-Bream (Sparus aurata): Insights from Stable Isotopes Composition and Proteomics
Authors: Blasco Josefina , Vélez Emilio J. , Perelló-Amorós Miquel , Azizi Sheida , Capilla Encarnación , Fernández-Borràs Jaume , Gutiérrez Joaquim
Published: December 2021

Growth hormone and insulin-like growth factors (GH/IGF axis) regulate somatic growth in mammals and fish, although their action on metabolism is not fully understood in the latter. An intraperitoneal injection of extended-release recombinant bovine growth hormone (rbGH, Posilac®) was used in gilthead sea bream fingerlings and juveniles to analyse the metabolic response of liver and red and white muscles by enzymatic, isotopic and proteomic analyses. GH-induced lipolysis and glycogenolysis were reflected in liver composition, and metabolic and redox enzymes reported higher lipid use and lower protein oxidation. In white and red muscle reserves, rBGH increased glycogen while reducing lipid. The isotopic analysis of muscles showed a decrease in the recycling of proteins and a greater recycling of lipids and glycogen in the rBGH groups, which favoured a protein sparing effect. The protein synthesis capacity (RNA/protein) of white muscle increased, while cytochrome-c-oxidase (COX) protein expression decreased in rBGH group. Proteomic analysis of white muscle revealed only downregulation of 8 proteins, related to carbohydrate metabolic processes. The global results corroborated that GH acted by saving dietary proteins for muscle growth mainly by promoting the use of lipids as energy in the muscles of the gilthead sea bream. There was a fuel switch from carbohydrates to lipids with compensatory changes in antioxidant pathways that overall resulted in enhanced somatic growth.
The N-Acetylglucosamine Kinase from Yarrowia lipolytica Is a Moonlighting Protein
Authors: Flores Carmen-Lisset , Ariño Joaquín , Gancedo Carlos
Published: December 2021

In Yarrowia lipolytica, expression of the genes encoding the enzymes of the N-acetylglucosamine (NAGA) utilization pathway (NAG genes) becomes independent of the presence of NAGA in a Ylnag5 mutant lacking NAGA kinase. We addressed the question of whether the altered transcription was due to a lack of kinase activity or to a moonlighting role of this protein. Glucosamine-6-phosphate deaminase (Nag1) activity was measured as a reporter of NAG genes expression. The NGT1 gene encoding the NAGA transporter was deleted, creating a Ylnag5 ngt1 strain. In glucose cultures of this strain, Nag1 activity was similar to that of the Ylnag5 strain, ruling out the possibility that NAGA derived from cell wall turnover could trigger the derepression. Heterologous NAGA kinases were expressed in a Ylnag5 strain. Among them, the protein from Arabidopsis thaliana did not restore kinase activity but lowered Nag1 activity 4-fold with respect to a control. Expression in the Ylnag5 strain of YlNag5 variants F320S or D214V with low kinase activity caused a repression similar to that of the wild-type protein. Together, these results indicate that YlNag5 behaves as a moonlighting protein. An RNA-seq analysis revealed that the Ylnag5 mutation had a limited transcriptomic effect besides derepression of the NAG genes.
Heat Shock Factor 1 Directly Regulates Postsynaptic Scaffolding PSD-95 in Aging and Huntington’s Disease and Influences Striatal Synaptic Density
Authors: Zarate Nicole , Intihar Taylor A. , Yu Dahyun , Sawyer Jacob , Tsai Wei , Syed Maha , Carlson Luke , Gomez-Pastor Rocio
Published: December 2021

PSD-95 (Dlg4) is an ionotropic glutamate receptor scaffolding protein essential in synapse stability and neurotransmission. PSD-95 levels are reduced during aging and in neurodegenerative diseases like Huntington’s disease (HD), and it is believed to contribute to synaptic dysfunction and behavioral deficits. However, the mechanism responsible for PSD-95 dysregulation under these conditions is unknown. The Heat Shock transcription Factor 1 (HSF1), canonically known for its role in protein homeostasis, is also depleted in both aging and HD. Synaptic protein levels, including PSD-95, are influenced by alterations in HSF1 levels and activity, but the direct regulatory relationship between PSD-95 and HSF1 has yet to be determined. Here, we showed that HSF1 chronic or acute reduction in cell lines and mice decreased PSD-95 expression. Furthermore, Hsf1(+/−) mice had reduced PSD-95 synaptic puncta that paralleled a loss in thalamo-striatal excitatory synapses, an important circuit disrupted early in HD. We demonstrated that HSF1 binds to regulatory elements present in the PSD-95 gene and directly regulates PSD-95 expression. HSF1 DNA-binding on the PSD-95 gene was disrupted in an age-dependent manner in WT mice and worsened in HD cells and mice, leading to reduced PSD-95 levels. These results demonstrate a direct role of HSF1 in synaptic gene regulation that has important implications in synapse maintenance in basal and pathological conditions.
The Effect of 17α-Ethynilestradiol and GPER1 Activation on Body and Muscle Growth, Muscle Composition and Growth-Related Gene Expression of Gilthead Seabream, Sparus aurata L
Authors: Ayala Maria D. , Gómez Victoria , Cabas Isabel , García Hernández María P. , Chaves-Pozo Elena , Arizcun Marta , Garcia de la Serrana Daniel , Gil Francisco , García-Ayala Alfonsa
Published: December 2021

Endocrine-disrupting chemicals include natural and synthetic estrogens, such as 17α-ethynilestradiol (EE2), which can affect reproduction, growth and immunity. Estrogen signalling is mediated by nuclear or membrane estrogen receptors, such as the new G-protein-coupled estrogen receptor 1 (GPER1). The present work studies the effect of EE2 and G1 (an agonist of GPER1) on body and muscle parameters and growth-related genes of 54 two-year-old seabreams. The fish were fed a diet containing EE2 (EE2 group) and G1 (G1 group) for 45 days and then a diet without EE2 or G1 for 122 days. An untreated control group was also studied. At 45 days, the shortest body length was observed in the G1 group, while 79 and 122 days after the cessation of treatments, the shortest body growth was observed in the EE2 group. Hypertrophy of white fibers was higher in the EE2 and G1 groups than it was in the control group, whereas the opposite was the case with respect to hyperplasia. Textural hardness showed a negative correlation with the size of white fibers. At the end of the experiment, all fish analyzed in the EE2 group showed a predominance of the gonadal ovarian area. In addition, the highest expression of the mafbx gene (upregulated in catabolic signals) and mstn2 (myogenesis negative regulator) was found in EE2-exposed fish.
Designing Cardiovascular Implants Taking in View the Endothelial Basement Membrane
Authors: Lau Skadi , Gossen Manfred , Lendlein Andreas
Published: December 2021

Insufficient endothelialization of cardiovascular grafts is a major hurdle in vascular surgery and regenerative medicine, bearing a risk for early graft thrombosis. Neither of the numerous strategies pursued to solve these problems were conclusive. Endothelialization is regulated by the endothelial basement membrane (EBM), a highly specialized part of the vascular extracellular matrix. Thus, a detailed understanding of the structure–function interrelations of the EBM components is fundamental for designing biomimetic materials aiming to mimic EBM functions. In this review, a detailed description of the structure and functions of the EBM are provided, including the luminal and abluminal interactions with adjacent cell types, such as vascular smooth muscle cells. Moreover, in vivo as well as in vitro strategies to build or renew EBM are summarized and critically discussed. The spectrum of methods includes vessel decellularization and implant biofunctionalization strategies as well as tissue engineering-based approaches and bioprinting. Finally, the limitations of these methods are highlighted, and future directions are suggested to help improve future design strategies for EBM-inspired materials in the cardiovascular field.
UMPred-FRL: A New Approach for Accurate Prediction of Umami Peptides Using Feature Representation Learning
Authors: Charoenkwan Phasit , Nantasenamat Chanin , Hasan Md Mehedi , Moni Mohammad Ali , Manavalan Balachandran , Shoombuatong Watshara
Published: December 2021

Umami ingredients have been identified as important factors in food seasoning and production. Traditional experimental methods for characterizing peptides exhibiting umami sensory properties (umami peptides) are time-consuming, laborious, and costly. As a result, it is preferable to develop computational tools for the large-scale identification of available sequences in order to identify novel peptides with umami sensory properties. Although a computational tool has been developed for this purpose, its predictive performance is still insufficient. In this study, we use a feature representation learning approach to create a novel machine-learning meta-predictor called UMPred-FRL for improved umami peptide identification. We combined six well-known machine learning algorithms (extremely randomized trees, k-nearest neighbor, logistic regression, partial least squares, random forest, and support vector machine) with seven different feature encodings (amino acid composition, amphiphilic pseudo-amino acid composition, dipeptide composition, composition-transition-distribution, and pseudo-amino acid composition) to develop the final meta-predictor. Extensive experimental results demonstrated that UMPred-FRL was effective and achieved more accurate performance on the benchmark dataset compared to its baseline models, and consistently outperformed the existing method on the independent test dataset. Finally, to aid in the high-throughput identification of umami peptides, the UMPred-FRL web server was established and made freely available online. It is expected that UMPred-FRL will be a powerful tool for the cost-effective large-scale screening of candidate peptides with potential umami sensory properties.
Current Status of Biomarkers in Anti-N-Methyl-D-Aspartate Receptor Encephalitis
Authors: Ciano-Petersen Nicolás Lundahl , Cabezudo-García Pablo , Muñiz-Castrillo Sergio , Honnorat Jérôme , Serrano-Castro Pedro Jesús , Oliver-Martos Begoña
Published: December 2021

The discovery of biomarkers in rare diseases is of paramount importance to allow a better diagnosis, improve predictions of outcomes, and prompt the development of new treatments. Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a rare autoimmune disorder associated with the presence of antibodies targeting the GluN1 subunit of the NMDAR. Since it was discovered in 2007, large efforts have been made towards the identification of clinical, paraclinical, and molecular biomarkers to better understand the immune mechanisms that govern the course of the disease as well as to define predictors of treatment response and long-term outcomes. However, most of these biomarkers are still in an exploratory phase, with only a few candidates reaching the final phases of the always-complex process of biomarker development, mainly due to the low incidence of the disease and its recent description. Clinical and paraclinical markers are probably the most widely explored in anti-NMDAR encephalitis, five of them combined in a clinical score to predict 1 year outcome. On the contrary, soluble molecules, such as persistent antibody positivity, antibody titers, cytokines, and other inflammatory mediators, have been proposed as biomarkers of clinical activity, inflammation, prognosis, and treatment response, but further studies are required for their clinical validation including larger and more homogenous cohorts of patients. Similarly, genetic susceptibility biomarkers are still in the exploratory phase and, therefore, weak conclusions can for now only be achieved. Thus, further studies are warranted to define biomarkers and unravel the underlying mechanisms driving rare diseases such as anti-NMDAR encephalitis. Future international collaborative studies with prospective designs that enable the enrollment of large cohorts will allow for the identification and validation of novel biomarkers for clinical decision-making.
Methylmercury plus Ethanol Exposure: How Much Does This Combination Affect Emotionality?
Authors: Luz Diandra Araújo , Cartágenes Sabrina de Carvalho , da Silveira Cinthia Cristina Sousa de Menezes , Pinheiro Bruno Gonçalves , Ferraro Kissila Márvia Matias Machado , Fernandes Luanna de Melo Pereira , Fontes-Júnior Enéas Andrade , Maia Cristiane do Socorro Ferraz
Published: December 2021

Mercury is a heavy metal found in organic and inorganic forms that represents an important toxicant with impact on human health. Mercury can be released in the environment by natural phenoms (i.e., volcanic eruptions), industrial products, waste, or anthropogenic actions (i.e., mining activity). Evidence has pointed to mercury exposure inducing neurological damages related to emotional disturbance, such as anxiety, depression, and insomnia. The mechanisms that underlie these emotional disorders remain poorly understood, although an important role of glutamatergic pathways, alterations in HPA axis, and disturbance in activity of monoamines have been suggested. Ethanol (EtOH) is a psychoactive substance consumed worldwide that induces emotional alterations that have been strongly investigated, and shares common pathophysiological mechanisms with mercury. Concomitant mercury and EtOH intoxication occur in several regions of the world, specially by communities that consume seafood and fish as the principal product of nutrition (i.e., Amazon region). Such affront appears to be more deleterious in critical periods of life, such as the prenatal and adolescence period. Thus, this review aimed to discuss the cellular and behavioral changes displayed by the mercury plus EtOH exposure during adolescence, focused on emotional disorders, to answer the question of whether mercury plus EtOH exposure intensifies depression, anxiety, and insomnia observed by the toxicants in isolation.
Strategies and Perspectives for UV Resonance Raman Applicability in Clinical Analyses of Human Sperm RNA
Authors: Pachetti Maria , D’Amico Francesco , Zupin Luisa , Luppi Stefania , Martinelli Monica , Crovella Sergio , Ricci Giuseppe , Pascolo Lorella
Published: December 2021

Developing a deeper knowledge about the impact of DNA and RNA epigenetic mutations on sperm production and fertilization performance is essential for selecting best quality samples in Assisted Reproductive Technologies (ART). Indeed, sperm RNAs adenine and guanine are likely to be methylated in low quality RNA sperm samples and their study requires the employment of techniques able to isolate high quality nucleic acids. UV resonance Raman spectroscopy represents a valuable tool that is able to monitor peculiar molecular modifications occurring predominantly in nucleic acids, being less sensitive to the presence of other biological compounds. In this work, we used an UV Resonance Raman (UVRR) setup coupled to a synchrotron radiation source tuned at 250 nm, in order to enhance sperm RNAs adenine and guanine vibrational signals, reducing also the impact of a fluorescence background typically occurring at lower energies. Despite that our protocol should be further optimized and further analyses are requested, our results support the concept that UVRR can be applied for setting inexpensive tools to be employed for semen quality assessment in ART.
Genetic Background Influences Severity of Colonic Aganglionosis and Response to GDNF Enemas in the Holstein Mouse Model of Hirschsprung Disease
Authors: Soret Rodolphe , Lassoued Nejia , Bonnamour Grégoire , Bernas Guillaume , Barbe Aurélie , Pelletier Mélanie , Aichi Manon , Pilon Nicolas
Published: December 2021

Hirschsprung disease is a congenital malformation where ganglia of the neural crest-derived enteric nervous system are missing over varying lengths of the distal gastrointestinal tract. This complex genetic condition involves both rare and common variants in dozens of genes, many of which have been functionally validated in animal models. Modifier loci present in the genetic background are also believed to influence disease penetrance and severity, but this has not been frequently tested in animal models. Here, we addressed this question using Holstein mice in which aganglionosis is due to excessive deposition of collagen VI around the developing enteric nervous system, thereby allowing us to model trisomy 21-associated Hirschsprung disease. We also asked whether the genetic background might influence the response of Holstein mice to GDNF enemas, which we recently showed to have regenerative properties for the missing enteric nervous system. Compared to Holstein mice in their original FVB/N genetic background, Holstein mice maintained in a C57BL/6N background were found to have a less severe enteric nervous system defect and to be more responsive to GDNF enemas. This change of genetic background had a positive impact on the enteric nervous system only, leaving the neural crest-related pigmentation phenotype of Holstein mice unaffected. Taken together with other similar studies, these results are thus consistent with the notion that the enteric nervous system is more sensitive to genetic background changes than other neural crest derivatives.
Overview of Drug Transporters in Human Placenta
Authors: Yamashita Michiko , Markert Udo R.
Published: December 2021

The transport of drugs across the placenta is a point of great importance in pharmacotherapy during pregnancy. However, the knowledge of drug transport in pregnancy is mostly based on experimental clinical data, and the underlying biological mechanisms are not fully understood. In this review, we summarize the current knowledge of drug transporters in the human placenta. We only refer to human data since the placenta demonstrates great diversity among species. In addition, we describe the experimental models that have been used in human placental transport studies and discuss their availability. A better understanding of placental drug transporters will be beneficial for the health of pregnant women who need drug treatment and their fetuses.
Differential Actions of Muscarinic Receptor Subtypes in Gastric, Pancreatic, and Colon Cancer
Authors: Schledwitz Alyssa , Sundel Margaret H. , Alizadeh Madeline , Hu Shien , Xie Guofeng , Raufman Jean-Pierre
Published: December 2021

Cancers arising from gastrointestinal epithelial cells are common, aggressive, and difficult to treat. Progress in this area resulted from recognizing that the biological behavior of these cancers is highly dependent on bioactive molecules released by neurocrine, paracrine, and autocrine mechanisms within the tumor microenvironment. For many decades after its discovery as a neurotransmitter, acetylcholine was thought to be synthesized and released uniquely from neurons and considered the sole physiological ligand for muscarinic receptor subtypes, which were believed to have similar or redundant actions. In the intervening years, we learned this former dogma is not tenable. (1) Acetylcholine is not produced and released only by neurons. The cellular machinery required to synthesize and release acetylcholine is present in immune, cancer, and other cells, as well as in lower organisms (e.g., bacteria) that inhabit the gut. (2) Acetylcholine is not the sole physiological activator of muscarinic receptors. For example, selected bile acids can modulate muscarinic receptor function. (3) Muscarinic receptor subtypes anticipated to have overlapping functions based on similar G protein coupling and downstream signaling may have unexpectedly diverse actions. Here, we review the relevant research findings supporting these conclusions and discuss how the complexity of muscarinic receptor biology impacts health and disease, focusing on their role in the initiation and progression of gastric, pancreatic, and colon cancers.