bluuebunny/crossref_metadata_2025 huggingface dataset:
Exogenous Oxidative Stress in Human Spermatozoa Induces Opening of the Mitochondrial Permeability Transition Pore: Effect on Mitochondrial Function, Sperm Motility and Induction of Cell Death
Authors: Bravo Anita , Sánchez Raúl , Zambrano Fabiola , Uribe Pamela
Published: June 2024

Oxidative stress (OS) and disrupted antioxidant defense mechanisms play a pivotal role in the etiology of male infertility. The alterations in reactive oxygen species (ROS) production and calcium (Ca2+) homeostasis are the main activators for the mitochondrial permeability transition pore (mPTP) opening. The mPTP opening is one of the main mechanisms involved in mitochondrial dysfunction in spermatozoa. This alteration in mitochondrial function adversely affects energy supply, sperm motility, and fertilizing capacity and contributes to the development of male infertility. In human spermatozoa, the mPTP opening has been associated with ionomycin-induced endogenous oxidative stress and peroxynitrite-induced nitrosative stress; however, the effect of exogenous oxidative stress on mPTP opening in sperm has not been evaluated. The aim of this study was to determine the effect of exogenous oxidative stress induced by hydrogen peroxide (H2O2) on mPTP opening, mitochondrial function, motility, and cell death markers in human spermatozoa. Human spermatozoa were incubated with 3 mmol/L of H2O2 for 60 min, and intracellular Ca2+ concentration, mPTP opening, mitochondrial membrane potential (ΔΨm), ATP levels, mitochondrial reactive oxygen species (mROS) production, phosphatidylserine (PS) externalization, DNA fragmentation, viability, and sperm motility were evaluated. H2O2-induced exogenous oxidative stress caused increased intracellular Ca2+, leading to subsequent mPTP opening and alteration of mitochondrial function, characterized by ΔΨm dissipation, decreased ATP levels, increased mROS production, and the subsequent alteration of sperm motility. Furthermore, H2O2-induced opening of mPTP was associated with the expression of apoptotic cell death markers including PS externalization and DNA fragmentation. These results highlight the role of exogenous oxidative stress in causing mitochondrial dysfunction, deterioration of sperm motility, and an increase in apoptotic cell death markers, including PS externalization and DNA fragmentation, through the mPTP opening. This study yielded new knowledge regarding the effects of this type of stress on mitochondrial function and specifically on mPTP opening, factors that can contribute to the development of male infertility, considering that the role of mPTP in mitochondrial dysfunction in human sperm is not completely elucidated. Therefore, these findings are relevant to understanding male infertility and may provide an in vitro model for further research aimed at improving human sperm quality.
Coreference Resolution Based on High-Dimensional Multi-Scale Information
Authors: Wang Yu , Ding Zenghui , Wang Tao , Xu Shu , Yang Xianjun , Sun Yining
Published: June 2024

Coreference resolution is a key task in Natural Language Processing. It is difficult to evaluate the similarity of long-span texts, which makes text-level encoding somewhat challenging. This paper first compares the impact of commonly used methods to improve the global information collection ability of the model on the BERT encoding performance. Based on this, a multi-scale context information module is designed to improve the applicability of the BERT encoding model under different text spans. In addition, improving linear separability through dimension expansion. Finally, cross-entropy loss is used as the loss function. After adding BERT and span BERT to the module designed in this article, F1 increased by 0.5% and 0.2%, respectively.
Evaluation of Heating Efficiency Increase Using a Simple Heat Recovery Unit
Authors: Stehlíková Beáta , Fecková Škrabuľáková Erika , Bogdanovská Gabriela , Fecko Matúš
Published: June 2024

Heating in the winter is one of the human activities that consumes the most energy, thereby affecting the environment and leaving a carbon footprint. An increase in heating efficiency results in a reduction in the energy demand of the process and environmental protection. This contribution aimed to determine and experimentally verify the possibility of obtaining and effectively using the heat from the chimney of a gas boiler generated during the heating of a family house. For this purpose, we used a simple heat exchanger and measured the relevant temperatures on an exchange unit for almost five months during the heating season. The air temperatures measured at the inlet and outlet of the exchanger unit together with the outside temperatures were statistically analyzed to determine the effect of using the exchanger unit to obtain additional heat that could be used for other purposes. In addition, this study investigated whether there was a statistically significant difference in the temperature of the air entering the heating system with different outdoor temperature values. In the discussion, these hypotheses are either confirmed or disproved. Finally, the effectiveness of the current household heating system is evaluated.
On the Necessity of Including the Dissociation Kinetics When Modelling Gas Hydrate Pipeline Plug Dissociation
Authors: Aguguo Johnbosco , Clarke Matthew
Published: June 2024

Gas hydrate plugs in petroleum fluid pipelines are a major flow assurance problem and thus, it is important for industry to have reliable mathematical models for estimating the time required to dissociate a hydrate pipeline plug. The existing mathematical models for modelling hydrate plug dissociation treat the problem as a pure heat transfer problem. However, an early study by Jamaluddin et al. speculated that the kinetics of gas hydrate dissociation could become the rate-limiting factor under certain operating conditions. In this short communication, a rigorous 2D model couples the equations of heat transfer and fluid flow with Clarke and Bishnoi’s model for the kinetics of hydrate dissociation. A distinguishing feature of the current work is the ability to predict the shape of the dissociating hydrate–gas interface. The model is used to correlate experimental data for both sI and sII hydrate plug dissociation, via single-sided depressurization and double-sided depressurization. As a preliminary examination on the necessity of including dissociation kinetics, this work is limited to conditions for which hydrate dissociation rate constants are available; kinetic rate constants for hydrate dissociation are available at temperatures above 273.15 K. Over the range of conditions that were investigated, it was found that including the intrinsic kinetics of hydrate dissociation led to only a very small improvement in the accuracy of the predictions of the cumulative gas volumes collected during dissociation. By contrast, a sensitivity study showed that the predictions of hydrate plug dissociation are very sensitive to the value of the porosity. Thus, it is concluded that unless values of the thermophysical properties of a hydrate plug are known, accounting for the dissociation kinetics need not be a priority.
Experimental Study on the Heat Pump Performance Combined with Dual-Purpose Solar Collector
Authors: Moon Kwang-Am , Kim Seong-Bhin , Choi Hwi-Ung , Choi Kwang-Hwan
Published: June 2024

In this study, we proposed and experimentally investigated a novel solar-assisted heat pump (SAHP) system integrated with a dual-purpose solar collector (DPSC). The DPSC is a solar collector designed to produce both heated air and hot water, and the proposed configuration of the SAHP utilizes both heated air and water simultaneously to improve the performance of the heat pump. The experiment was conducted under natural weather conditions on a clear day. The performance of the proposed system was evaluated and compared to that of a conventional air-type SAHP system. The results showed that the coefficient of performance (COP) of the proposed system, which takes into account the performance of the DPSC, heat pump, and the power consumption of both the blower and pump, was 3.14. In contrast, the system COP of the SAHP operated as conventional air-type SAHP was 2.33. This finding clearly demonstrated that the proposed SAHP performed better than the traditional SAHP mode. Additionally, the results of this research are useful as fundamental data related to SAHP combined with DPSC.
Development and Implementation of a Smart Charging System for Electric Vehicles Based on the ISO 15118 Standard
Authors: Santos Jóni B. , Francisco André M. B. , Cabrita Cristiano , Monteiro Jânio , Pacheco André , Cardoso Pedro J. S.
Published: June 2024

There is currently exponential growth in the electric vehicle market, which will require an increase in the electrical grid capacity to meet the associated charging demand. If, on the one hand, the introduction of energy generation from renewable energy sources can be used to meet that requirement, the intermittent nature of some of these sources will challenge the mandatory real-time equilibrium between generation and consumption. In order to use most of the energy generated via these sources, mechanisms are required to manage the charging of batteries in electric vehicles, according to the levels of generation. An effective smart charging process requires communication and/or control mechanisms between the supply equipment and the electric vehicle, enabling the adjustment of the energy transfer according to the generation levels. At this level, the ISO 15118 standard supports high-level communication mechanisms, far beyond the basic control solutions offered through the IEC 61851-1 specification. It is, thus, relevant to evaluate it in smart charging scenarios. In this context, this paper presents the development of a charge emulation system using the ISO 15118 communication protocol, and it discusses its application for demand response purposes. The system comprises several modules developed at both ends, supply equipment and electric vehicles, and allows the exchange of data during an emulated charging process. The system also includes human interfaces to facilitate interactions with users at both ends. Tests performed using the implemented system have shown that it supports a demand response when integrated with a photovoltaic renewable energy source. The dynamic adjustment to charging parameters, based on real-time energy availability, ensures efficient and sustainable charging processes, reducing the reliance on the grid and promoting the use of renewable energy.
Fed-Batch Bioreactor Cultivation of Bacillus subtilis Using Vegetable Juice as an Alternative Carbon Source for Lipopeptides Production: A Shift towards a Circular Bioeconomy
Authors: Gugel Irene , Vahidinasab Maliheh , Benatto Perino Elvio Henrique , Hiller Eric , Marchetti Filippo , Costa Stefania , Pfannstiel Jens , Konnerth Philipp , Vertuani Silvia , Manfredini Stefano , Hausmann Rudolf
Published: June 2024

In a scenario of increasing alarm about food waste due to rapid urbanization, population growth and lifestyle changes, this study aims to explore the valorization of waste from the retail sector as potential substrates for the biotechnological production of biosurfactants. With a perspective of increasingly contributing to the realization of the circular bioeconomy, a vegetable juice, derived from unsold fruits and vegetables, as a carbon source was used to produce lipopeptides such as surfactin and fengycin. The results from the shake flask cultivations revealed that different concentrations of vegetable juice could effectively serve as carbon sources and that the fed-batch bioreactor cultivation strategy allowed the yields of lipopeptides to be significantly increased. In particular, the product/substrate yield of 0.09 g/g for surfactin and 0.85 mg/g for fengycin was obtained with maximum concentrations of 2.77 g/L and 27.53 mg/L after 16 h, respectively. To conclude, this study provides the successful fed-batch cultivation of B. subtilis using waste product as the carbon source to produce secondary metabolites. Therefore, the consumption of agricultural product wastes might be a promising source for producing valuable metabolites which have promising application potential to be used in several fields of biological controls of fungal diseases.
A Mixture of Prebiotics, Essential Oil Blends, and Onion Peel Did Not Affect Greenhouse Gas Emissions or Nutrient Degradability, but Altered Volatile Fatty Acids Production in Dairy Cows Using Rumen Simulation Technique (RUSITEC)
Authors: Alabi Joel O. , Wuaku Michael , Anotaenwere Chika C. , Okedoyin Deborah O. , Adelusi Oludotun O. , Ike Kelechi A. , Gray DeAndrea , Kholif Ahmed E. , Subedi Kiran , Anele Uchenna Y.
Published: June 2024

This study evaluated the synergistic effects of prebiotics containing galacto-oligosaccharides (GOS) and/or mannan oligosaccharides (MOS), essential oil blend (EOB), and onion peel (OPE) on fermentation characteristics using the rumen simulation technique (RUSITEC) system. Three rumen-cannulated, non-lactating Holstein Friesian cows were the inoculum donors. The substrate used for the study was a total mixed ration (TMR), which consisted of corn silage, alfalfa hay, and concentrate at 6:2:2, respectively. Sixteen fermentation vessels were randomly allotted to four treatments with four replicates each over a 9-day period in a completely randomized design. The treatments assessed include: control [TMR only], GEO [TMR + GOS + EOB + OPE], MEO [TMR + MOS + EOB + OPE], and OLEO [TMR + OLG + EOB + OPE]. OLG comprises GOS and MOS in equal proportion. EOB was included at 3 µL/g, while OPE, GOS, MOS, and OLG were added at 30 mg/g TMR. Results showed that pH, gas volume, effluent volume, and ammonia-N were not affected (p > 0.05) by the different additives. Similarly, greenhouse gas (GHG) emissions and nutrient digestibility were not affected by the treatments. Compared to the control, total volatile fatty acids (VFA) were decreased (p < 0.05) by 14.8, 10.8, and 8.5% with GEO, MEO, and OLEO inclusion, respectively, while the molar proportion of acetate was increased (p = 0.011) by 3.3, 1.1, and 3.8% with GEO, MEO, and OLEO inclusion, respectively. MEO increased isobutyrate (p = 0.001) and branched chain VFA (p = 0.013) contents; however, GEO and OLEO inclusion reduced them. Overall, the interaction of EOB, OPE, GOS, and/or MOS did not affect nutrient digestibility or GHG emissions but reduced VFA production. Further research is recommended to assess the dose effect of the additives on GHG emissions and VFA production; and to determine the long-term effects of these interventions on the rumen microbiome and animal performance.
Determination of Imidazole Dipeptides and Related Amino Acids in Natural Seafoods by Liquid Chromatography–Tandem Mass Spectrometry Using a Pre-Column Derivatization Reagent
Authors: Onozato Mayu , Horinouchi Minori , Yoshiba Yuki , Sakamoto Tatsuya , Sugasawa Hiroshi , Fukushima Takeshi
Published: June 2024

Imidazole dipeptides (IDPs) and taurine (Tau) have several health benefits and are known to be contained in natural seafoods. However, their levels vary widely in different natural seafoods, making their simultaneous determination desirable. Herein, we employ a liquid chromatography–tandem mass spectrometry approach using a novel amino group derivatization reagent, succinimidyl 2-(3-((benzyloxy)carbonyl)-1-methyl-5-oxoimidazolidin-4-yl) acetate ((R)-CIMa-OSu), for the simultaneous quantification of IDPs (carnosine (Car) and anserine (Ans)), their related amino acids, and Tau in natural seafoods. Each seafood sample contained different concentrations of IDPs (Car: ND to 1.48 mmol/100 g-wet, Ans: ND to 4.67 mmol/100 g-wet). The Car levels were considerably higher in eel, while Tau was more abundant in squid, boiled octopus, and scallop. Thus, the derivatization reagent (R)-CIMa-OSu provides a new approach to accurately assess the nutritional composition of seafoods, thereby providing valuable insight into its dietary benefits.
Advances and Challenges in the Labor Markets for Healthcare Professionals
Authors: Groot Wim , van Merode Frits
Published: June 2024

A lack of nurses is a prevalent and persistent problem in many countries [...]
Water Uptake by Mountain Big Sagebrush (Artemisia tridentata subsp. vaseyana) and Environmental Variables Affecting Water Availability in Semiarid Rangeland Ecosystems
Authors: Ochoa Carlos G. , Abdallah Mohamed A. B. , Gómez Daniel G.
Published: June 2024

The sagebrush steppe ecosystem plays a critical role in water cycling in arid and semiarid landscapes of the western United States; yet, there is limited information regarding individual sagebrush plant water uptake. We used the stem heat balance (SHB) method to measure transpiration in mountain big sagebrush (Artemisia tridentata subsp. vaseyana) plants in a semiarid rangeland ecosystem in central Oregon, Pacific Northwest Region, USA. We evaluated the relationship between sagebrush transpiration and environmental factors from July 2022 to May 2023 for two individual plants representative of the average sagebrush stand height and crown width at the study site; transpiration rates varied by plant and by season. This study encompassed one below-average (2022; 278 mm) and one above-average (2023; 414 mm) precipitation years. Study results showed that the average water use during the entire period of study was 2.1 L d−1 for Plant 1 and 5.0 L d−1 for Plant 2. During the dry year, maximum transpiration was observed during the summer (Plant 1 = 4.8 L d−1; Plant 2 = 11.1 L d−1). For the wet year, both plants showed maximum transpiration levels at the end of the recording period in mid-May (Plant 1 = 9.6 L d−1; Plant 2 = 8.6 L d−1). The highest seasonal transpiration of both plants occurred in summer (2.87 L d−1), whereas the lowest transpiration was obtained in winter (0.21 L d−1). For all seasons but winter, soil moisture (SM), soil temperature (ST), and vapor pressure deficit (VPD) variables generally showed positive correlations with transpiration. Transpiration rates decreased in the summer of 2022 as the surface soil gradually dried. The two plants’ most significant water uptake differences were obtained during the dry year. It is possible that the larger stem diameter of plant 2 may have contributed to its higher transpiration rates during times of limited water availability. The study results add to the understanding of water use by sagebrush and its potential impact on the water balance of cool-climate rangeland ecosystems. The findings also highlight the sensitivity of sagebrush to variations in seasonal soil moisture availability, soil temperature, and vapor pressure deficit. Future research should involve studying the combined effects of water use by various dominant vegetation species and its effects on the water budget at the watershed scale.
Cinnamic Acid, Perillic Acid, and Tryptophan Metabolites Differentially Regulate Ion Transport and Serotonin Metabolism and Signaling in the Mouse Ileum In Vitro
Authors: Jiang Lili , Hao Youling , Li Qianjun , Dai Zhaolai
Published: June 2024

Phytochemicals and tryptophan (Trp) metabolites have been found to modulate gut function and health. However, whether these metabolites modulate gut ion transport and serotonin (5-HT) metabolism and signaling requires further investigation. The aim of this study was to investigate the effects of selected phytochemicals and Trp metabolites on the ion transport and 5-HT metabolism and signaling in the ileum of mice in vitro using the Ussing chamber technique. During the in vitro incubation, vanillylmandelic acid (VMA) reduced (p < 0.05) the short-circuit current, and 100 μM chlorogenic acid (CGA) (p = 0.12) and perillic acid (PA) (p = 0.14) had a tendency to reduce the short-circuit current of the ileum. Compared with the control, PA and N-acetylserotonin treatment upregulated the expression of tryptophan hydroxylase 1 (Tph1), while 100 μM cinnamic acid, indolelactic acid (ILA), and 10 μM CGA or indoleacetaldehyde (IAld) treatments downregulated (p < 0.05) the mRNA levels of Tph1. In addition, 10 μM IAld or 100 μM ILA upregulated (p < 0.05) the expression of monoamine oxidase A (Maoa). However, 10 μM CGA or 100 μM PA downregulated (p < 0.05) Maoa expression. All selected phytochemicals and Trp metabolites upregulated (p < 0.05) the expression of Htr4 and Htr7 compared to that of the control group. VMA and CGA reduced (p < 0.05) the ratios of Htr1a/Htr7 and Htr4/Htr7. These findings may help to elucidate the effects of phytochemicals and Trp metabolites on the regulation of gut ion transport and 5-HT signaling-related gut homeostasis in health and disease.
Trichinella spiralis Paramyosin Alleviates Collagen-Induced Arthritis in Mice by Modulating CD4+ T Cell Differentiation
Authors: Zhang Dongwan , Jiang Wang , Yu Yan , Huang Jingjing , Jia Zhihui , Cheng Yuli , Zhu Xinping
Published: June 2024

Rheumatoid arthritis (RA) is an autoimmune disease that significantly impacts quality of life by disrupting CD4+ T cell immune homeostasis. The identification of a low-side-effect drug for RA treatment is urgently needed. Our previous study suggests that Trichinella spiralis paramyosin (Ts-Pmy) has immunomodulatory effects, but its potential effect on CD4+ T cell response in RA remains unclear. In this study, we used a murine model to investigate the role of rTs-Pmy in regulating CD4+ T cell differentiation in collagen-induced arthritis (CIA). Additionally, we assessed the impact of rTs-Pmy on CD4+ T cell differentiation towards the Th1 and Th17 phenotypes, which are associated with inflammatory responses in arthritis, using in vitro assays. The results demonstrated that rTs-Pmy administration reduced arthritis severity by inhibiting Th1 and Th17 response while enhancing Treg response. Prophylactic administration of Ts-Pmy showed superior efficacy on CIA compared to therapeutic administration. Furthermore, in vitro assays demonstrated that rTs-Pmy could inhibit the differentiation of CD4+ T cells into Th1 and Th17 while inducing the production of Tregs, suggesting a potential mechanism underlying its therapeutic effects. This study suggests that Ts-Pmy may ameliorate CIA by restoring the immune balance of CD4+ T cells and provides new insights into the mechanism through which helminth-derived proteins exert their effects on autoimmune diseases.
Biomarkers in Thyroid Cancer: Emerging Opportunities from Non-Coding RNAs and Mitochondrial Space
Authors: Cabané Patricio , Correa Claudio , Bode Ignacio , Aguilar Rodrigo , Elorza Alvaro A.
Published: June 2024

Thyroid cancer diagnosis primarily relies on imaging techniques and cytological analyses. In cases where the diagnosis is uncertain, the quantification of molecular markers has been incorporated after cytological examination. This approach helps physicians to make surgical decisions, estimate cancer aggressiveness, and monitor the response to treatments. Despite the availability of commercial molecular tests, their widespread use has been hindered in our experience due to cost constraints and variability between them. Thus, numerous groups are currently evaluating new molecular markers that ultimately will lead to improved diagnostic certainty, as well as better classification of prognosis and recurrence. In this review, we start reviewing the current preoperative testing methodologies, followed by a comprehensive review of emerging molecular markers. We focus on micro RNAs, long non-coding RNAs, and mitochondrial (mt) signatures, including mtDNA genes and circulating cell-free mtDNA. We envision that a robust set of molecular markers will complement the national and international clinical guides for proper assessment of the disease.
Phytaspase Does Not Require Proteolytic Activity for Its Stress-Induced Internalization
Authors: Torosian Tatevik A. , Barsukova Anastasia I. , Chichkova Nina V. , Vartapetian Andrey B.
Published: June 2024

Phytaspases differ from other members of the plant subtilisin-like protease family by having rare aspartate cleavage specificity and unusual localization dynamics. Phytaspases are secreted from healthy plant cells but are re-internalized upon perception of death-inducing stresses. Although proteolytic activity is required for the secretion of plant subtilases, its requirement for the retrograde transportation of phytaspases is currently unknown. To address this issue, we employed an approach to complement in trans the externalization of a prodomain-less form of Nicotiana tabacum phytaspase (NtPhyt) with the free prodomain in Nicotiana benthamiana leaf cells. Using this approach, the generation of the proteolytically active NtPhyt and its transport to the extracellular space at a level comparable to that of the native NtPhyt (synthesized as a canonical prodomain-containing precursor protein) were achieved. The application of this methodology to NtPhyt with a mutated catalytic Ser537 residue resulted in the secretion of the inactive, although processed (prodomain-free), protein as well. Notably, the externalized NtPhyt Ser537Ala mutant was still capable of retrograde transportation into plant cells upon the induction of oxidative stress. Our data thus indicate that the proteolytic activity of NtPhyt is dispensable for stress-induced retrograde transport of the enzyme.
Repeated Infusions of Bone-Marrow-Derived Mesenchymal Stem Cells over 8 Weeks for Steroid-Refractory Chronic Graft-versus-Host Disease: A Prospective, Phase I/II Clinical Study
Authors: Kim Nayoun , Min Gi-June , Im Keon-Il , Nam Young-Sun , Song Yunejin , Lee Jun-Seok , Oh Eun-Jee , Chung Nack-Gyun , Jeon Young-Woo , Lee Jong Wook , Cho Seok-Goo
Published: June 2024

Chronic graft-versus-host disease (cGVHD) is a long-term complication of allogeneic hematopoietic stem cell transplantation associated with poor quality of life and increased morbidity and mortality. Currently, there are several approved treatments for patients who do not respond to steroids, such as ruxolitinib. Nevertheless, a significant proportion of patients fail second-line treatment, indicating the need for novel approaches. Mesenchymal stem cells (MSCs) have been considered a potential treatment approach for steroid-refractory cGVHD. To evaluate the safety and efficacy of repeated infusions of MSCs, we administered intravenous MSCs every two weeks to ten patients with severe steroid-refractory cGVHD in a prospective phase I clinical trial. Each patient received a total of four doses, with each dose containing 1 × 106 cells/kg body weight from the same donor and same passage. Patients were assessed for their response to treatment using the 2014 National Institutes of Health (NIH) response criteria during each visit. Ten patients with diverse organ involvement were enrolled, collectively undergoing 40 infusions as planned. Remarkably, the MSC infusions were well tolerated without severe adverse events. Eight weeks after the initial MSC infusion, all ten patients showed partial responses characterized by the amelioration of clinical symptoms and enhancement of their quality of life. The overall response rate was 60%, with a complete response rate of 20% and a partial response (PR) rate of 40% at the last follow-up. Overall survival was 80%, with a median follow-up of 381 days. Two patients died due to relapse of their primary disease. Immunological analyses revealed a reduction in inflammatory markers, including Suppression of Tumorigenicity 2 (ST2), C-X-C motif chemokine ligand (CXCL)10, and Secreted phosphoprotein 1(SPP1), following the MSC treatment. Repeated MSC infusions proved to be both feasible and safe, and they may be an effective salvage therapy in patients with steroid-refractory cGVHD. Further large-scale clinical studies with long-term follow-up are needed in the future to determine the role of MSCs in cGVHD.
IL-6 Inhibition as a Therapeutic Target in Aged Experimental Autoimmune Encephalomyelitis
Authors: Dema María , Eixarch Herena , Castillo Mireia , Montalban Xavier , Espejo Carmen
Published: June 2024

Multiple sclerosis (MS) onset at an advanced age is associated with a higher risk of developing progressive forms and a greater accumulation of disability for which there are currently no effective disease-modifying treatments. Immunosenescence is associated with the production of the senescence-associated secretory phenotype (SASP), with IL-6 being one of the most prominent cytokines. IL-6 is a determinant for the development of autoimmunity and neuroinflammation and is involved in the pathogenesis of MS. Herein, we aimed to preclinically test the therapeutic inhibition of IL-6 signaling in experimental autoimmune encephalomyelitis (EAE) as a potential age-specific treatment for elderly MS patients. Young and aged mice were immunized with myelin oligodendrocyte protein (MOG)35–55 and examined daily for neurological signs. Mice were randomized and treated with anti-IL-6 antibody. Inflammatory infiltration was evaluated in the spinal cord and the peripheral immune response was studied. The blockade of IL-6 signaling did not improve the clinical course of EAE in an aging context. However, IL-6 inhibition was associated with an increase in the peripheral immunosuppressive response as follows: a higher frequency of CD4 T cells producing IL-10, and increased frequency of inhibitory immune check points PD-1 and Tim-3 on CD4+ T cells and Lag-3 and Tim-3 on CD8+ T cells. Our results open the window to further studies aimed to adjust the anti-IL-6 treatment conditions to tailor an effective age-specific therapy for elderly MS patients.
Upscaling and Risk Evaluation of the Synthesis of the 3,5-Diamino-1H-Pyrazole, Disperazol
Authors: Jansen Charlotte Uldahl , Grier Katja Egeskov , Andersen Jens Bo , Hultqvist Louise Dahl , Nilsson Martin , Moser Claus , Graz Michael , Tolker-Nielsen Tim , Givskov Michael , Qvortrup Katrine
Published: June 2024

This paper presents the work performed to transition a lab-scale synthesis (1 g) to a large-scale (400 g) synthesis of the 3-5-diamino-1H-Pyrazole Disperazol, a new pharmaceutical for treatment of antibiotic-resistant Pseudomonas aeruginosa biofilm infections. The potentially hazardous diazotisation step in the lab-scale synthesis was transformed to a safe and easy-to-handle flow chemistry step. Additionally, the paper presents an OSHA-recommended safety assessment of active compound E, as performed by Fauske and Associates, LLC, Burr Ridge, IL, USA.
Adaptation of the Invasive Plant Sphagneticola trilobata to Flooding Stress by Hybridization with Native Relatives
Authors: Zhang Qilei , Chen Guangxin , Ke Weiqian , Peng Changlian
Published: June 2024

Hybridization is common between invasive and native species and may produce more adaptive hybrids. The hybrid (Sphagneticola × guangdongensis) of Sphagneticola trilobata (an invasive species) and S. calendulacea (a native species) was found in South China. In this study, S. trilobata, S. calendulacea, and Sphagneticola × guangdongensis were used as research materials to explore their adaptability to flooding stress. Under flooding stress, the ethylene content and the expression of key enzyme genes related to ethylene synthesis in Sphagneticola × guangdongensis and S. calendulacea were significantly higher than those in S. trilobata. A large number of adventitious roots and aerenchyma were generated in Sphagneticola × guangdongensis and S. calendulacea. The contents of reactive oxygen species and malondialdehyde in Sphagneticola × guangdongensis and S. calendulacea were lower than those in S. trilobata, and the leaves of S. trilobata were the most severely damaged under flooding stress. The results indicate that hybridization catalyzed the tolerance of Sphagneticola × guangdongensis to flooding stress, and the responses of Sphagneticola × guangdongensis to flooding stress were more similar to that of its native parent. This suggests that hybridization with native relatives is an important way for invasive species to overcome environmental pressure and achieve invasion.
A Quantitative Human Red Blood Cell Agglutination Assay for Characterisation of Galectin Inhibitors
Authors: Gasson Rhianna , Roper James A. , Slack Robert J.
Published: June 2024

Galectins are a family of beta-galactoside-binding proteins that are characterised by their carbohydrate recognition domain (CRD) and include galectin-1 and galectin-3. These galectins have been implicated in numerous diseases due to their pleiotropic nature, including cancer and fibrosis, with therapeutic inhibitors being clinically developed to block the CRD. One of the early methods developed to characterise these galectins was the hemagglutination of red blood cells. Although it is insightful, this approach has been hampered by a lack of sensitivity and accurate quantification of the agglutination observed. In this study, we aimed to validate a more precise and quantitative method to enable the further investigation of differences between galectins in respect to agglutination induction in different blood groups, as well as the characterisation of small molecule inhibitors. Quantification of hemagglutination was shown to be optimal using U-bottom plates imaged and analysed with FIJI ImageJ rather than flat-bottom plates read for absorbance on an optical density plate reader. Galectin-3-induced red blood cell agglutination efficacy increased significantly from blood group O to A to B. However, for both the galectin-1 monomer and concatemer, a more comparable effect was observed between blood group B and O, but with more potent effects than in blood group A. Inhibition assays for both galectin-3 and galectin-1 induced-hemagglutination were able to demonstrate clear concentration responses and expected selectivity profiles for a set of small-molecule glycomimetics, confirming the historical profiles obtained in biochemical binding and functional cellular assays.
Gibberellin Signaling through RGA Suppresses GCN5 Effects on Arabidopsis Developmental Stages
Authors: Balouri Christina , Poulios Stylianos , Tsompani Dimitra , Spyropoulou Zoe , Ketikoglou Maria-Christina , Kaldis Athanasios , Doonan John H. , Vlachonasios Konstantinos E.
Published: June 2024

Histone acetyltransferases (HATs) modify the amino-terminal tails of the core histone proteins via acetylation, regulating chromatin structure and transcription. GENERAL CONTROL NON-DEREPRESSIBLE 5 (GCN5) is a HAT that specifically acetylates H3K14 residues. GCN5 has been associated with cell division and differentiation, meristem function, root, stem, foliar, and floral development, and plant environmental response. The flowers of gcn5 plants display a reduced stamen length and exhibit male sterility relative to the wild-type plants. We show that these effects may arise from gibberellin (GA)-signaling defects. The signaling pathway of bioactive GAs depends on the proteolysis of their repressors, DELLA proteins. The repressor GA (RGA) DELLA protein represses plant growth, inflorescence, and flower and seed development. Our molecular data indicate that GCN5 is required for the activation and H3K14 acetylation of genes involved in the late stages of GA biosynthesis and catabolism. We studied the genetic interaction of the RGA and GCN5; the RGA can partially suppress GCN5 action during the whole plant life cycle. The reduced elongation of the stamen filament of gcn5–6 mutants is reversed in the rga–t2;gcn5–6 double mutants. RGAs suppress the GCN5 effect on the gene expression and histone acetylation of GA catabolism and GA signaling. Interestingly, the RGA and RGL2 do not suppress ADA2b function, suggesting that ADA2b acts downstream of GA signaling and is distinct from GCN5 activity. In conclusion, we propose that the action of GCN5 on stamen elongation is partially mediated by RGA and GA signaling.
Deciphering Key microRNA Regulated Pathways in Tissue-Engineered Blood Vessels: Implications for Vascular Scaffold Production
Authors: Rodrigues Lenize da Silva , Felix Tainara Francini , Minutentag Iael Weissberg , Reis Patricia Pintor , Bertanha Matheus
Published: June 2024

MicroRNAs (miRNAs) are non-coding RNAs involved in the regulation of gene expression associated with cell differentiation, proliferation, adhesion, and important biological functions such as inflammation. miRNAs play roles associated with the pathogenesis of chronic degenerative disorders including cardiovascular diseases. Understanding the influence of miRNAs and their target genes can effectively streamline the identification of key biologically active pathways that are important in the development of vascular grafts through the tissue engineering of blood vessels. To determine miRNA expression levels and identify miRNA target genes and pathways with biological roles in scaffolds that have been repopulated with adipose-derived stem cells (ASCs) generated through tissue engineering for the construction of blood vessels. miRNA quantification assays were performed in triplicate to determine miRNA expression in a total of 20 samples: five controls (natural inferior vena cava), five scaffolds recellularized with ASCs and differentiated into the endothelium (luminal layer), five samples of complete scaffolds seeded with ASCs differentiated into the endothelium (luminal layer) and smooth muscle (extraluminal layer), and five samples of ASC without cell differentiation. Several differentially expressed miRNAs were identified and predicted to modulate target genes with roles in key pathways associated with angiogenesis, vascular system control, and endothelial and smooth muscle regulation, including migration, proliferation, and growth. These findings underscore the involvement of these pathways in the regulatory mechanisms that are essential for vascular scaffold production through tissue engineering. Our research contributes to the knowledge of miRNA-regulated mechanisms, which may impact the design of vascular substitutes, and provide valuable insights for enhancing clinical practice. The molecular pathways regulated by miRNAs in tissue engineering of blood vessels (TEBV) allowed us to elucidate the main phenomena involved in cellular differentiation to constitute a blood vessel, with the main pathways being essential for angiogenesis, cellular differentiation, and differentiation into vascular smooth muscle.
The Ubiquinone-Ubiquinol Redox Cycle and Its Clinical Consequences: An Overview
Authors: Mantle David , Dewsbury Mollie , Hargreaves Iain P.
Published: June 2024

Coenzyme Q10 (CoQ10) plays a key role in many aspects of cellular metabolism. For CoQ10 to function normally, continual interconversion between its oxidised (ubiquinone) and reduced (ubiquinol) forms is required. Given the central importance of this ubiquinone–ubiquinol redox cycle, this article reviews what is currently known about this process and the implications for clinical practice. In mitochondria, ubiquinone is reduced to ubiquinol by Complex I or II, Complex III (the Q cycle) re-oxidises ubiquinol to ubiquinone, and extra-mitochondrial oxidoreductase enzymes participate in the ubiquinone–ubiquinol redox cycle. In clinical terms, the outcome of deficiencies in various components associated with the ubiquinone–ubiquinol redox cycle is reviewed, with a particular focus on the potential clinical benefits of CoQ10 and selenium co-supplementation.
Effects of Liquid Fructose Supplementation and Chronic Unpredictable Stress on Uterine Contractile Activity in Nonpregnant Rats
Authors: Oreščanin Dušić Zorana , Kovačević Sanja , Ristić Nataša , Vojnović Milutinović Danijela , Vidonja Uzelac Teodora , Blagojević Duško , Djordjevic Ana , Brkljačić Jelena
Published: June 2024

Increased fructose consumption and chronic stress, the major characteristics of modern lifestyle, impact human health; however, the consequences of their combination on the uterus remain understudied. In this study, we investigated contractile activity, morphology, and intracellular activity of antioxidant enzymes in uteri from virgin Wistar rats subjected to liquid fructose supplementation and/or unpredictable stress over 9 weeks. Contractile activity and uterine response to oxytocin or adrenaline were examined ex vivo using isolated bath chambers. Fructose supplementation, irrespective of stress, affected uterine morphology by increasing endometrium while decreasing myometrium volume density, attenuated uterine response to increasing doses of oxytocin, and increased glutathione peroxidase activity. Stress, irrespective of fructose, attenuated dose-dependent adrenaline-induced uterine relaxation. Stress, when applied solely, decreased mitochondrial superoxide dismutase activity. In the combined treatment, irregular estrous cycles and both reduced response to oxytocin and to adrenaline (as a consequence of fructose consumption and exposure to stress), along with fructose-related alteration of uterine morphology, were detected. In conclusion, fructose and stress affect uterine contractile activity, irrespective of each other, by inducing completely distinct responses in isolated uteri. In the combined treatment, the effects of both factors were evident, suggesting that the combination exerts more detrimental effects on the uterus than each factor individually.
Advancing Landslide Susceptibility Mapping in the Medea Region Using a Hybrid Metaheuristic ANFIS Approach
Authors: Debiche Fatiha , Benbouras Mohammed Amin , Petrisor Alexandru-Ionut , Baba Ali Lyes Mohamed , Leghouchi Abdelghani
Published: June 2024

Landslides pose significant risks to human lives and infrastructure. The Medea region in Algeria is particularly susceptible to these destructive events, which result in substantial economic losses. Despite this vulnerability, a comprehensive landslide map for this region is lacking. This study aims to develop a novel hybrid metaheuristic model for the spatial prediction of landslide susceptibility in Medea, combining the Adaptive Neuro-Fuzzy Inference System (ANFIS) with four novel optimization algorithms (Genetic Algorithm—GA, Particle Swarm Optimization—PSO, Harris Hawks Optimization—HHO, and Salp Swarm Algorithm—SSA). The modeling phase was initiated by using a database comprising 160 landslide occurrences derived from Google Earth imagery; field surveys; and eight conditioning factors (lithology, slope, elevation, distance to stream, land cover, precipitation, slope aspect, and distance to road). Afterward, the Gamma Test (GT) method was used to optimize the selection of input variables. Subsequently, the optimal inputs were modeled using hybrid metaheuristic ANFIS techniques and their performance evaluated using four relevant statistical indicators. The comparative assessment demonstrated the superior predictive capabilities of the ANFIS-HHO model compared to the other models. These results facilitated the creation of an accurate susceptibility map, aiding land use managers and decision-makers in effectively mitigating landslide hazards in the study region and other similar ones across the world.
Yttria-Stabilized Zirconia Composite Coating as Barrier to Reduce Hydrogen Permeation into Steel
Authors: Wu Jianmeng , Xie Jiaqi , He Mengyuan , Zhang Jingyi , Li Songjie
Published: June 2024

Hydrogen atoms can enter into metallic materials through penetration and diffusion, leading to the degradation of the mechanical properties of the materials, and the application of hydrogen barrier coatings is an effective means to alleviate this problem. Zirconia coatings (ZrO2) have been widely studied as a common hydrogen barrier coating, but zirconia undergoes a crystalline transition with temperature change, which can lead to volumetric changes in the coating and thus cause problems such as cracking and peeling of the coating. In this work, ZrO2 coating was prepared on a Q235 matrix using a sol-gel method, while yttria-stabilized zirconia (YSZ) coatings with different contents of rare earth elements were prepared in order to alleviate a series of problems caused by the crystal form transformation of ZrO2. The coating performances were evaluated by the electrochemical hydrogen penetration test, pencil hardness test, scratch test, and high-temperature oxidation test. The results show that yttrium can improve the stability of the high-temperature phase of ZrO2, alleviating the cracking problem of the coating due to the volume change triggered by the crystalline transition; improve the consistency of the coating; and refine the grain size of the oxide. The performance of YSZ coating was strongly influenced by the yttria doping mass, and the coating with 10 wt% yttria doping had the best hydrogen barrier performance, the best antioxidant performance, and the largest adhesion. Compared with the matrix, the steady-state hydrogen current density of the YSZ coating decreased by 72.3%, the antioxidant performance was improved by 65.8%, and the ZrO2 coating hardness and adhesion levels were B and 4B, respectively, while YSZ coating hardness and adhesion were upgraded to 2H and 5B. With the further increase in yttrium doping mass, the hardness of the coating continued to improve, but the defects of the coating increased, resulting in a decrease in the hydrogen barrier performance, antioxidant performance, and adhesion. In this work, the various performances of ZrO2 coating were significantly improved by doping with the rare earth element, which provides a reference for further development and application of oxide coatings.
Separation of Damage Mechanisms in Full Forward Rod Extruded Case-Hardening Steel 16MnCrS5 Using 3D Image Segmentation
Authors: Lingnau Lars , Heermant Johannes , Otto Johannes , Donnerbauer Kai , Sauer Lukas , Lücker Lukas , Macias Barrientos Marina , Walther Frank
Published: June 2024

In general, formed components are lightweight as well as highly economic and resource efficient. However, forming-induced ductile damage, which particularly affects the formation and growth of pores, has not been considered in the design of components so far. Therefore, an evaluation of forming-induced ductile damage would enable an improved design and take better advantage of the lightweight nature as it affects the static and dynamic mechanical material properties. To quantify the amount, morphology and distribution of the pores, advanced scanning electron microscopy (SEM) methods such as scanning transmission electron microscopy (STEM) and electron channeling contrast imaging (ECCI) were used. Image segmentation using a deep learning algorithm was applied to reproducibly separate the pores from inclusions such as manganese sulfide inclusions. This was achieved via layer-by-layer ablation of the case-hardened steel 16MnCrS5 (DIN 1.7139, AISI/SAE 5115) with a focused ion beam (FIB). The resulting images were reconstructed in a 3D model to gain a mechanism-based understanding beyond the previous 2D investigations.