bluuebunny/crossref_metadata_2025 huggingface dataset:
Expanding the Associations between Landscape Characteristics and Aesthetic Sensory Perception for Traditional Village Public Space
Authors: Chen Guodong , Yan Jiayu , Wang Chongxiao , Chen Shuolei
Published: January 2024

Traditional village landscapes have a cultural and regional significance, and the visual aesthetic quality of the landscape is widely regarded as a valuable resource to benefit the health and well-being of urban residents. Although the literature has analyzed the influential mechanism of landscape features on aesthetic senses, most were from a single dimension. To improve the precision of the landscape aesthetic evaluation method, this study expanded the indicators for landscape characteristics of public spaces in traditional villages by incorporating multiple dimensions, such as landscape visual attraction elements and landscape color. It explored their associations with sensory preferences in a case study in Dongshan (a peninsula) and Xishan (an island) of Taihu Lake. We used multi-source data, a semantic segmentation model, and R language to identify landscape characteristic indicators quantitatively. The research results indicated that the accuracy of the aesthetic sensory assessment model integrating multi-dimensional landscape characteristic indicators was significantly improved; in the open space of traditional villages, the public preferred a scenario with a high proportion of trees, relatively open space, mild and uniform color tones, suitability for movement, and the ability to produce a restorative and peaceful atmosphere. This study can provide a guarantee for the efficient use of village landscape resources, the optimization of rural landscapes, and the precise enhancement of traditional village habitat.
Crosslinking Mechanism of Tannin-Based Adhesives Based on Model Compounds: Copolycondensation of Resorcinol with Dimethylol Urea
Authors: Liang Jiankun , Li De , Zhong Xiao , Wu Zhigang , Cao Ming , Yang Guifen , Yin Shuang , Gong Feiyan
Published: January 2024

This study focuses on the competition reaction rules of a system containing resorcinol (as a tannin model compound) and dimethylol urea (as a urea–formaldehyde resin model compound) under various alkaline and acidic environments. The aim is to investigate the crosslinked modification mechanism of urea–formaldehyde resin with tannin adhesive. The study delves into the competitive relationship between self-condensation polymerization reactions and co-condensation polymerization reactions. It specifically highlights the conditions for the copolycondensation reaction of dimethylolurea and resorcinol and validates its rationality through an examination of the resorcinol–urea–formaldehyde system’s reaction rules. The results show that (1) under strongly acidic conditions, the activity of carbocation intermediates produced by hydroxymethyl resorcinol for the resorcinol phenol ring is higher than the electrophilic reactivity of nitrogen atoms on hydroxymethyl urea, which is more beneficial for the resorcinol–formaldehyde self-polycondensation reaction, and the co-polycondensation structures do not play a dominant role. (2) Under weakly acidic conditions, the co-polycondensation structures are evidently advantageous over self-polycondensation structures, and the degree of the co-polycondensation reaction is positively correlated with pH below the neutral point of resorcinol. (3) Under alkaline conditions, the self-polycondensation between resorcinol and formaldehyde is dominant in the system. (4) The concentration of hydroxymethyl urea carbocation is the key factor to determine the degree of the co-polycondensation reaction.
Effect of Nature Space on Enhancing Humans’ Health and Well-Being: An Integrative Narrative Review
Authors: Zhang Zhiyong , Ye Bing , Yang Wenjuan , Gao Yue
Published: January 2024

With the progress of science and technology, humans’ ability to transform and create has been greatly enhanced, but so have the physical and mental ailments associated with environmental degradation and urbanization. Human survival and health are strongly linked to nature, and there is growing evidence that exposure to nature promotes health and well-being. However, there is currently a lack of synthesis among empirical studies on these aspects for the findings to be sufficient for informing public health strategies and social policy. Here, following basic guidelines for systematic review and meta-analysis, we searched PubMed, Web of Science, ScienceDirect, and Scopus databases in January 2023. The results of our search and analysis show that nature can improve people’s health and well-being from two aspects: physical (reduces CVDs, increases immunity, improves autonomic nervous system function, and improves sleep quality) and psychological (restores attention, improves mood, reduces stress, and improves cognitive development). The ways in which people derive health from nature are varied, and tailored, personalized, symptom-specific exposure can further increase the health benefits. More importantly, it seems that people can gain the health benefits of nature by only being exposed to it for a short time. We incorporate the existing scientific evidence in our review and develop a new heuristic point of view on the necessity of exposure to natural environments for the health of individuals.
Quantifying Spatial Heterogeneities of Surface Heat Budget and Methane Emissions over West-Siberian Peatland: Highlights from the Mukhrino 2022 Campaign
Authors: Chechin Dmitry G. , Repina Irina A. , Artamonov Arseniy Yu. , Drozd Ilya D. , Dyukarev Egor A. , Kazantsev Vladimir S. , Krivenok Liudmila A. , Larina Arina V. , Pashkin Artem D. , Shmonin Kirill N. , Stepanenko Victor M. , Varentsov Mikhail I.
Published: January 2024

The study presents the first results from the multi-platform observational campaign carried out at the Mukhrino peatland in June 2022. The focus of the study is the quantification of spatial contrasts of the surface heat budget terms and methane emissions across the peatland, which arise due to the presence of microlandscape heterogeneities. It is found that surface temperature contrasts across the peatland exceeded 10 °C for clear-sky conditions both during day and night. Diurnal variation of surface temperature was strongest over ridges and drier hollows and was smallest over the waterlogged hollows and shallow lakes. This resulted in strong spatial variations of sensible heat flux (H) and Bowen ratio, while the latent heat varied much less. During the clear-sky days, H over ryam exceeded the one over the waterlogged hollow by more than a factor of two. The Bowen ratio amounted to about unity over ryam, which is similar to values over forests. Methane emissions estimated using the static-chamber method also strongly varied between various microlandscapes, being largest at a hollow within a ridge-hollow complex and smallest at a ridge. A strong nocturnal increase in methane mixing ratio was observed and was used in the framework of the atmospheric boundary layer budget method to estimate nocturnal methane emissions, which were found to be in the same order of magnitude as daytime emissions. Finally, the directions for further research are outlined, including the verification of flux-aggregation techniques, parameterizations of surface roughness and turbulent exchange, and land-surface model evaluation and development.
Biocontrol of L. monocytogenes with Selected Autochthonous Lactic Acid Bacteria in Raw Milk Soft-Ripened Cheese under Different Water Activity Conditions
Authors: Martín-Miguélez José M. , Robledo Jurgen , Martín Irene , Castaño Cristina , Delgado Josué , Córdoba Juan J.
Published: January 2024

The effect of selected autochthonous Lactic Acid Bacteria (LAB) against Listeria monocytogenes was evaluated in two elaborations of soft-ripened cheese performed under high and low relative humidity (RH) elaborations, to achieve aw ranging from 0.97 to 0.94 in ripened cheeses. Two selected autochthonous strains of Lacticaseibacillus casei 31 and 116 were used. In each elaboration, 8 batches were physicochemically and microbiologically evaluated throughout the ripening process. The aw and pH decreased during ripening to final values ranging from 0.944 to 0.972 aw and 5.0 to 5.3 pH, respectively. LAB was the only microbial group that increased throughout the ripening in high and low RH elaborations. In batches that were uninoculated with LAB strains, L. monocytogenes was either maintained at the initial inoculation level or showed a slight reduction by the end of the ripening process. However, in LAB-inoculated batches in the two elaborations, steady decreases of L. monocytogenes were observed throughout maturation. L. casei 31 alone or in combination with strain 116 provoked reductions of 2 to 4 log CFU/g in L. monocytogenes over 60 days of ripening, which could be enough as a strategy for biocontrol to deal with the usual contamination by L. monocytogenes during cheese processing.
The Use of Educational Games to Promote Learning in Geology: Conceptions of Middle and Secondary School Teachers
Authors: Teixeira Isabel , Vasconcelos Clara
Published: January 2024

Studies highlight researchers’ concerns about how science should be taught today. It is recognised that teachers have difficulty involving and motivating students to learn about different complex topics, such as geology. Schools must promote skills development to develop citizens who can be active and informed in society. One way of undertaking this is to use active methodologies such as educational games, in which students play an essential role in developing activities. Games encourage changes in conceptions regarding the relevance of this scientific topic that is often undervalued by students. Games have gained space in recent years in several disciplines, and it is essential that this tool is thought out and planned within a consistent pedagogical proposal. This educational resource is used to increase motivation for learning, as well as enhance and strengthen the effects of learning. An intervention plan can be framed within game-based teaching. Teachers have been underrepresented in the game-based learning literature, with more emphasis on games’ effects. However, the pedagogical issue of games has been particularly relevant in recent decades. The current investigation used a survey given to geology teachers (n = 112) from public and private middle and secondary schools in Portugal. Its purpose was to assess teachers’ perceptions regarding game-based teaching and its potential to promote active learning. Our sample ages ranged from 24 to 64 years (average of 48.9 years old); 81.3% were women and 18.8% were men. The analysis of the results seems to confirm that although they do not always use games to promote learning in geology, most teachers still recognise their potential to motivate, enhance, and reinforce the learning of geological content, with digital games being the preferred option. They emphasise the importance of teacher training in this area and the inclusion of game applications in school textbooks to approach different geology-related themes. Our results seem to indicate some lack of consistency in teachers’ opinions on the impact of games on student learning.
How Does a Collective Body Arrive, Move, and Learn? Becoming through Practice-Based Research as a Stringing-(Em)bodying Process
Authors: Ludevid Llop Mireia , Martin Jonathan , McDonnell Ben , Ortolani Sara , Pardoe Molly , Stanhope Clare , Vicente Richards Ana
Published: January 2024

This practice-based paper explores the methods of answering the question: what is our collective body? This article offers a case study of collaborative research and seeks to enact a collective body as a means of transgressing and occupying individuated neoliberal spaces of higher education. Understanding the processes through which knowledge is collectively built highlights the in-becoming nature of practice-based research and the enabling forces of this inquiry. The methods enacted access a particular rendering of how we understand ourselves as a collective; we answer the question through doing together. The ways we encounter the collective enable understanding around the shifting boundaries of the individual–collective connection, made palpable by a string. Through playful forms of dissent, such as embodied, remembered, and writing encounters, enable connections with others and inspire a refocusing of our individual practices.
Work-Related Musculoskeletal Disorders Risk Assessment during Manual Lymphatic Drainage with Compressive Bands among Physiotherapists
Authors: Jacquier-Bret Julien , Gorce Philippe
Published: January 2024

Background: Complete decongestive therapy is the standard treatment for lymphedema. Manual lymphatic drainage and short-stretch multilayer compression bandaging are two daily stages of complete decongestive therapy during which physiotherapists work with patients. Objective: The aim of this study was to assess the risks of musculoskeletal disorders to which physiotherapists are exposed during these two phases. Method: Five physiotherapists performed five 20 min manual lymphatic drainages, followed by the compression bandaging phase. From the video recordings, 8477 postures defined by 13 joint angles were grouped into clusters using hierarchical cluster analysis. The risk of musculoskeletal disorders in physiotherapists’ postures was assessed using ergonomic tools. Results: Seven clusters, called generic postures (GP), were identified and defined throughout the mean joint angle values and standard deviation. Four seated GPs were found for the drainage phase, and three standing GPs were identified for the bandaging phase. This phase corresponded to a quarter of the total duration. The GP’s ergonomic scores ranged from 4.51 to 5.63 and from 5.08 to 7.12, respectively, for the Rapid Upper Limb Assessment (RULA) and Rapid Entire Body Assessment (REBA). GP1, GP3, and GP4 presented the highest ergonomic scores (RULA scores: 5.27 to 5.63; REBA scores: 6.25 to 7.12). The most affected areas were the neck (flexion > 20° for all GPs), trunk (flexion between 25 and 30° for GP2, and GP7 during the bandaging phase and GP4 during the drainage phase), and shoulder (flexion and abduction >20° for all GPs except GP5). Conclusions: These results highlighted that the two complete decongestive therapy phases could be described as a combination of GP. Ergonomic assessment showed that compression bandaging as well as drainage phases expose physiotherapists to moderate musculoskeletal disorder risks that require “further investigation and change soon”.
Stakeholder Insights into Czech Performance-Based Managed Entry Agreements: Potential for Transformative Change in Pharmaceutical Access?
Authors: Hospodková Petra , Karásek Pavel , Tichopád Aleš
Published: January 2024

Managed Entry Agreements (MEAs) play a pivotal role in addressing the challenges arising from escalating prices of innovative medical technologies, especially in areas like oncology, immunology, and rare diseases. Among MEAs, Performance-Based MEAs (PB MEAs) and Outcome-Based MEAs (OB MEAs) stand out as innovative strategies. This study examines the adoption of PB MEAs in the Czech Republic post a 2022 legislative change. Interviews with key stakeholders, including the Ministry of Health, pharmaceutical companies, insurers, and patient groups, were conducted to explore perceptions and challenges. Stakeholders expressed concerns about legislation completeness, data quality, transparency, and methodology. Interestingly, pharmaceutical companies were less concerned about transparency and methodology, likely due to their multinational experience. Despite legislative progress, challenges persist, especially in data infrastructure, risk-sharing perceptions, and stakeholder readiness. Addressing these issues requires collaboration between pharmaceutical companies and payers. Patient involvement, though mandated, remains limited, potentially due to a lack of awareness. This study emphasizes the need for a comprehensive transformation beyond legislation for a successful PB MEA implementation. Trust, technical infrastructure, and data availability are crucial, necessitating a holistic approach. It contributes to the global discourse on PB MEAs, stressing the adjustment of financial frameworks, embracing value-based healthcare principles, and ensuring high-quality health data metrics. A more holistic, value-based MEA approach could reshape pharmaceutical reimbursement in the future.
Mid-Term Results of an Italian Multicentric Experience with the RoadsaverTM Dual-Layer Carotid Stent System
Authors: Silvestri Olga , Accarino Giulio , Turchino Davide , Squizzato Francesco , Piazza Michele , Bastianon Martina , Di Gregorio Sara , Pratesi Giovanni , Antonello Michele , Costa Davide , Serra Raffaele , Bracale Umberto Marcello
Published: January 2024

Background: Carotid artery stenting (CAS) using first-generation single-layer stents is widely accepted as a good alternative to standard carotid endarterectomy (CEA) but it is associated with worse outcomes in terms of both plaque prolapse and cerebral embolization. Aim: To evaluate the perioperative and midterm outcomes of CAS using the new-generation RoadsaverTM dual-layer micromesh-covered carotid stent. Methods: Herein, we present the results of an observational, retrospective, multicentric study on non-consecutive patients who underwent the CAS procedure between January 2017 and December 2022 at three Italian, high-volume vascular surgery centers. The inclusion criteria were the patients’ eligibility for the CAS procedure in accordance with the current Italian guidelines, and the implantation of a Roadsaver stent. Both symptomatic and asymptomatic patients were included in the study. The patients requiring reintervention for carotid restenosis following CEA were also included. Perioperative data regarding procedural success was defined as the successful implantation of the device in the desired position, less than 30% residual stenosis, and the absence of intraoperative neurological complications. The primary outcome was any adverse cerebrovascular event such as stroke or transient ischemic attack (TIA) during the procedure and/or after discharge. The secondary outcomes were the need for further intervention, and all-cause death following procedure. Results: Three-hundred-fifty-three (353) patients were included in our study; the mean age was 74.3 years. A total of 5.9% of the patients were symptomatic on their operated side, while 7.3% had contralateral carotid occlusion. A cerebral embolic protection device (CPD) was employed in all patients. A total of 13.3% of the patients were operated on for restenosis after CEA Technical success was achieved in 96.9% of the cases with an intraoperative report of six TIAs (1.7%) and six ipsilateral strokes (1.7%). The mean hospital stay was 1.8 days. The thirty-day follow up showed one TIA and one more stroke. At the mean 35-month follow-up time, the primary outcome was present in six patients (1.7%), where four TIAs (1.1%) and two strokes (0.5%) were reported. Restenosis occurred in five patients (1.4%). Death for any cause was reported in 11 patients (3.1%). Conclusions: As most recent, high-quality studies show, the CAS procedure with second-generation devices such as the Roadsaver stent is safe and effective in preventing carotid-related cerebrovascular events in both symptomatic and asymptomatic patients. The intraoperative and postoperative cerebrovascular complication rate in high volume centers is very low, ensuring confidence in its employment for the CAS procedure along with a CPD as a valid alternative to CEA.
Plasmacytoma in the Maxillary Jaw: A Diagnostic and Therapeutic Challenge
Authors: Bernardi Sara , Bianchi Serena , Lupi Ettore , Gerardi Davide , Macchiarelli Guido , Varvara Giuseppe
Published: January 2024

Plasmacytoma is a neoplastic disorder originating from plasma cells, with bone and soft tissue being common sites of manifestation. This report presents the clinical and radiological findings of a 65-year-old female patient who presented with an exophytic lesion in the upper right lateral incisor region. The lesion appeared as a unilocular radiotransparent area in imaging tests. Following an excisional biopsy, histological and immunohistochemical evaluations confirmed the presence of mature plasmacellular elements and small infiltrates of B and T lymphocytes. The patient did not exhibit systemic manifestations of multiple myeloma. Surgical intervention, in the form of enucleation of the lesion combined with root canal treatment and apicoectomy, was performed. This case underscores the rare occurrence of plasmacytoma in the jaw region and highlights the importance of surgical management in cases where structural damage or functional impairment is present. Further research on novel treatment approaches is also mentioned, including targeted therapies, immunomodulatory agents, and monoclonal antibodies. The patient is currently under the care of a hematologist for further investigation and the choice of the most appropriate therapy.
An Integrated Framework to Assess the Environmental and Economic Impact of Fertilizer Restrictions in a Nitrate-Contaminated Aquifer
Authors: Siarkos Ilias , Mallios Zisis , Latinopoulos Pericles
Published: January 2024

Groundwater nitrate contamination caused by the excessive use of nitrogen-based fertilizers has been widely recognized as an issue of significant concern in numerous rural areas worldwide. To mitigate nitrate contamination, corrective management practices, such as regulations on fertilizer usage, should be implemented. However, these measures often entail economic consequences that impact farmers’ income, and thus should be properly assessed. Within this context, an integrated framework combining the environmental and economic assessment of fertilization restrictions through multi-criteria decision analysis is presented in an effort to efficiently manage groundwater nitrate contamination in rural areas. For this task, various scenarios involving reductions (10%, 20%, 30%, 40% and 50%) in fertilizer application were investigated, evaluated and ranked in order to determine the most suitable option. The environmental assessment considered occurrences of nitrates in groundwater, with a specific emphasis on nitrate concentrations in water-supply wells, as obtained by a nitrate fate and transport model, while the economic analysis focused on the losses experienced by farmers due to the reduced fertilizer usage. Our case-study implementation showed that a 30% reduction in fertilization is the most appropriate option for the area being studied, highlighting the importance of adopting such an approach when confronted with conflicting outcomes among alternatives.
The Epigenomic Features and Potential Functions of PEG- and PDS-Favorable DNA G-Quadruplexes in Rice
Authors: Huang Ranran , Feng Yilong , Gao Zhicheng , Ahmed Asgar , Zhang Wenli
Published: January 2024

A G-quadruplex (G4) is a typical non-B DNA structure and involved in various DNA-templated events in eukaryotic genomes. PEG and PDS chemicals have been widely applied for promoting the folding of in vivo or in vitro G4s. However, how PEG and PDS preferentially affect a subset of G4 formation genome-wide is still largely unknown. We here conducted a BG4-based IP-seq in vitro under K++PEG or K++PDS conditions in the rice genome. We found that PEG-favored IP-G4s+ have distinct sequence features, distinct genomic distributions and distinct associations with TEGs, non-TEGs and subtypes of TEs compared to PDS-favored ones. Strikingly, PEG-specific IP-G4s+ are associated with euchromatin with less enrichment levels of DNA methylation but with more enriched active histone marks, while PDS-specific IP-G4s+ are associated with heterochromatin with higher enrichment levels of DNA methylation and repressive marks. Moreover, we found that genes with PEG-specific IP-G4s+ are more expressed than those with PDS-specific IP-G4s+, suggesting that PEG/PDS-specific IP-G4s+ alone or coordinating with epigenetic marks are involved in the regulation of the differential expression of related genes, therefore functioning in distinct biological processes. Thus, our study provides new insights into differential impacts of PEG and PDS on G4 formation, thereby advancing our understanding of G4 biology.
Atp6v1h Deficiency Blocks Bone Loss in Simulated Microgravity Mice through the Fos-Jun-Src-Integrin Pathway
Authors: Zhao Zanyan , Wang Xiangpu , Ma Yu , Duan Xiaohong
Published: January 2024

The microgravity conditions in outer space are widely acknowledged to induce significant bone loss. Recent studies have implicated the close relationship between Atp6v1h gene and bone loss. Despite this, the role of Atp6v1h in bone remodeling and its molecular mechanisms in microgravity have not been fully elucidated. To address this, we used a mouse tail suspension model to simulate microgravity. We categorized both wild-type and Atp6v1h knockout (Atp6v1h+/-) mice into two groups: regular feeding and tail-suspension feeding, ensuring uniform feeding conditions across all cohorts. Analysis via micro-CT scanning, hematoxylin-eosin staining, and tartrate-resistant acid phosphatase assays indicated that wild-type mice underwent bone loss under simulated microgravity. Atp6v1h+/- mice exhibited bone loss due to Atp6v1h deficiency but did not present aggravated bone loss under the same simulated microgravity. Transcriptomic sequencing revealed the upregulation of genes, such as Fos, Src, Jun, and various integrin subunits in the context of simulated microgravity and Atp6v1h knockout. Real-time quantitative polymerase chain reaction (RT-qPCR) further validated the modulation of downstream osteoclast-related genes in response to interactions with ATP6V1H overexpression cell lines. Co-immunoprecipitation indicated potential interactions between ATP6V1H and integrin beta 1, beta 3, beta 5, alpha 2b, and alpha 5. Our results indicate that Atp6v1h level influences bone loss in simulated microgravity by modulating the Fos-Jun-Src-Integrin pathway, which, in turn, affects osteoclast activity and bone resorption, with implications for osteoporosis. Therefore, modulating Atp6v1h expression could mitigate bone loss in microgravity conditions. This study elucidates the molecular mechanism of Atp6v1h’s role in osteoporosis and positions it as a potential therapeutic target against environmental bone loss. These findings open new possibilities for the treatment of multifactorial osteoporosis.
Genome-Wide Identification and Expression Analysis of Chitinase Genes in Watermelon under Abiotic Stimuli and Fusarium oxysporum Infection
Authors: Xuan Changqing , Feng Mengjiao , Li Xin , Hou Yinjie , Wei Chunhua , Zhang Xian
Published: January 2024

Chitinases, which catalyze the hydrolysis of chitin, the primary components of fungal cell walls, play key roles in defense responses, symbiotic associations, plant growth, and stress tolerance. In this study, 23 chitinase genes were identified in watermelon (Citrullus lanatus [Thunb.]) and classified into five classes through homology search and phylogenetic analysis. The genes with similar exon-intron structures and conserved domains were clustered into the same class. The putative cis-elements involved in the responses to phytohormone, stress, and plant development were identified in their promoter regions. A tissue-specific expression analysis showed that the ClChi genes were primarily expressed in the roots (52.17%), leaves (26.09%), and flowers (34.78%). Moreover, qRT-PCR results indicate that ClChis play multifaceted roles in the interaction between plant/environment. More ClChi members were induced by Race 2 of Fusarium oxysporum f. sp. niveum, and eight genes were expressed at higher levels on the seventh day after inoculation with Races 1 and 2, suggesting that these genes play a key role in the resistance of watermelon to Fusarium wilt. Collectively, these results improve knowledge of the chitinase gene family in watermelon species and help to elucidate the roles played by chitinases in the responses of watermelon to various stresses.
Eternal Youth: A Comprehensive Exploration of Gene, Cellular, and Pharmacological Anti-Aging Strategies
Authors: Kitaeva Kristina V. , Solovyeva Valeriya V. , Blatt Nataliya L. , Rizvanov Albert A.
Published: January 2024

The improvement of human living conditions has led to an increase in average life expectancy, creating a new social and medical problem—aging, which diminishes the overall quality of human life. The aging process of the body begins with the activation of effector signaling pathways of aging in cells, resulting in the loss of their normal functions and deleterious effects on the microenvironment. This, in turn, leads to chronic inflammation and similar transformations in neighboring cells. The cumulative retention of these senescent cells over a prolonged period results in the deterioration of tissues and organs, ultimately leading to a reduced quality of life and an elevated risk of mortality. Among the most promising methods for addressing aging and age-related illnesses are pharmacological, genetic, and cellular therapies. Elevating the activity of aging-suppressing genes, employing specific groups of native and genetically modified cells, and utilizing senolytic medications may offer the potential to delay aging and age-related ailments over the long term. This review explores strategies and advancements in the field of anti-aging therapies currently under investigation, with a particular emphasis on gene therapy involving adeno-associated vectors and cell-based therapeutic approaches.
The Mechanisms of Altered Blood–Brain Barrier Permeability in CD19 CAR T–Cell Recipients
Authors: Pinto Soniya N. , Krenciute Giedre
Published: January 2024

Cluster of differentiation 19 (CD19) chimeric antigen receptor (CAR) T cells are a highly effective immunotherapy for relapsed and refractory B-cell malignancies, but their utility can be limited by the development of immune effector cell-associated neurotoxicity syndrome (ICANS). The recent discovery of CD19 expression on the pericytes in the blood–brain barrier (BBB) suggests an important off-target mechanism for ICANS development. In addition, the release of systemic cytokines stimulated by the engagement of CD19 with the CAR T cells can cause endothelial activation and decreased expression of tight junction molecules, further damaging the integrity of the BBB. Once within the brain microenvironment, cytokines trigger a cytokine-specific cascade of neuroinflammatory responses, which manifest clinically as a spectrum of neurological changes. Brain imaging is frequently negative or nonspecific, and treatment involves close neurologic monitoring, supportive care, interleukin antagonists, and steroids. The goal of this review is to inform readers about the normal development and microstructure of the BBB, its unique susceptibility to CD19 CAR T cells, the role of individual cytokines on specific elements of the brain’s microstructural environment, and the clinical and imaging manifestations of ICANS. Our review will link cellular pathophysiology with the clinical and radiological manifestations of a complex clinical entity.
Nanoparticle-Encapsulated Epirubicin Efficacy in the Inhibition of Growth of Orthotopic Ovarian Patient-Derived Xenograft in Immunocompromised Mice
Authors: Kośnik Wioletta , Sikorska Hanna , Kiciak Adam , Ciach Tomasz
Published: January 2024

Epirubicin hydrochloride (EPI) is an anticancer drug widely used in the treatment of many solid tumors, including ovarian cancer. Because of its anatomical location, ovarian cancer shows symptoms when it is already in an advanced stage and is thus more difficult to treat. Epirubicin hydrochloride kills cancer cells effectively, but its dose escalation is limited by its severe toxicity. By encapsulating epirubicin in dextran-based nanoparticles (POLEPI), we expected to deliver higher and thus clinically more effective doses directly to tumors, where epirubicin would be released and retained longer in the tumor. The antitumor activity of POLEPI compared to EPI was first tested ex vivo in a series of ovarian cancer patient-derived tumor xenografts (PDX). The most promising PDX was then implanted orthotopically into immunocompromised mice, and tumor growth was monitored via magnetic resonance imaging (MRI). Although we succeeded in suppressing the growth of ovarian cancer derived from a patient, in a mouse model by 70% compared to 40% via EPI in 5 days after only one injection, we could not eliminate serious side effects, and the study was terminated prematurely for humane reasons.
ULK2 Is a Key Pro-Autophagy Protein That Contributes to the High Chemoresistance and Disease Relapse in FLT3-Mutated Acute Myeloid Leukemia
Authors: Lai Justine , Yang Claire , Shang Chuquan , Chen Will , Chu Michael P. , Brandwein Joseph , Lai Raymond , Wang Peng
Published: January 2024

We recently demonstrated that a small subset of cells in FLT3-mutated acute myeloid leukemia (AML) cell lines exhibit SORE6 reporter activity and cancer stem-like features including chemoresistance. To study why SORE6+ cells are more chemoresistant than SORE6− cells, we hypothesized that these cells carry higher autophagy, a mechanism linked to chemoresistance. We found that cytarabine (Ara-C) induced a substantially higher protein level of LC3B-II in SORE6+ compared to SORE6− cells. Similar observations were made using a fluorescence signal-based autophagy assay. Furthermore, chloroquine (an autophagy inhibitor) sensitized SORE6+ but not SORE6− cells to Ara-C. To decipher the molecular mechanisms underlying the high autophagic flux in SORE6+ cells, we employed an autophagy oligonucleotide array comparing gene expression between SORE6+ and SORE6− cells before and after Ara-C treatment. ULK2 was the most differentially expressed gene between the two cell subsets. To demonstrate the role of ULK2 in conferring higher chemoresistance in SORE6+ cells, we treated the two cell subsets with a ULK1/2 inhibitor, MRT68921. MRT68921 significantly sensitized SORE6+ but not SORE6− cells to Ara-C. Using our in vitro model for AML relapse, we found that regenerated AML cells contained higher ULK2 expression compared to pretreated cells. Importantly, inhibition of ULK2 using MRT68921 prevented in vitro AML relapse. Lastly, using pretreatment and relapsed AML patient bone marrow samples, we found that ULK2 expression was higher in relapsed AML. To conclude, our results supported the importance of autophagy in the relapse of FLT3-mutated AML and highlighted ULK2 in this context.
Degradation of Polylactic Acid/Polypropylene Carbonate Films in Soil and Phosphate Buffer and Their Potential Usefulness in Agriculture and Agrochemistry
Authors: Szymanek Izabela , Cvek Martin , Rogacz Diana , Żarski Arkadiusz , Lewicka Kamila , Sedlarik Vladimir , Rychter Piotr
Published: January 2024

Blends of poly(lactic acid) (PLA) with poly(propylene carbonate) (PPC) are currently in the phase of intensive study due to their promising properties and environmentally friendly features. Intensive study and further commercialization of PPC-based polymers or their blends, as usual, will soon face the problem of their waste occurring in the environment, including soil. For this reason, it is worth comprehensively studying the degradation rate of these polymers over a long period of time in soil and, for comparison, in phosphate buffer to understand the difference in this process and evaluate the potential application of such materials toward agrochemical and agricultural purposes. The degradation rate of the samples was generally accompanied by weight loss and a decrease in molecular weight, which was facilitated by the presence of PPC. The incubation of the samples in the aqueous media yielded greater surface erosions compared to the degradation in soil, which was attributed to the leaching of the low molecular degradation species out of the foils. The phytotoxicity study confirmed the no toxic impact of the PPC on tested plants, indicating it as a “green” material, which is crucial information for further, more comprehensive study of this polymer toward any type of sustainable application.
Large-Scale Biogeographical Shifts of Abundance of Antibiotic Resistance Genes and Marine Bacterial Communities as Their Carriers along a Trophic Gradient
Authors: Dželalija Mia , Fredotović Željana , Udiković-Kolić Nikolina , Kalinić Hrvoje , Jozić Slaven , Šamanić Ivica , Ordulj Marin , Maravić Ana
Published: January 2024

The role of marine environments in the global spread of antibiotic resistance still remains poorly understood, leaving gaps in the One Health-based research framework. Antibiotic resistance genes (ARGs) encoding resistance to five major antibiotic classes, including sulfonamides (sul1, sul2), tetracyclines (tetA, tetB), β-lactams (blaCTX-M, blaTEM blaVIM), macrolides (ermB, mphA), aminoglycosides (aac3-2), and integrase gene (intl1) were quantified by RT-qPCR, and their distribution was investigated in relation to environmental parameters and the total bacterial community in bottom layer and surface waters of the central Adriatic (Mediterranean), over a 68 km line from the wastewater-impacted estuary to coastal and pristine open sea. Seasonal changes (higher in winter) were observed for antibiotic resistance frequency and the relative abundances of ARGs, which were generally higher in eutrophic coastal areas. In particular, intl1, followed by blaTEM and blaVIM, were strongly associated with anthropogenic influence and Gammaproteobacteria as their predominant carriers. Water column stratification and geographic location had a significant influence on ARGs distribution in the oligotrophic zone, where the bacterial community exhibited a seasonal shift from Gammaproteobacteria in winter to Marine group II in summer.
Molecular Signal Transfer of Highly Diluted Antibodies to Interferon-Gamma Regarding Kind, Time, and Distance of Exposition
Authors: Jerman Igor , Ogrizek Linda , Krapež Vesna Periček , Jan Luka
Published: January 2024

Physicochemical examinations of very high dilution (UHD) solutions subjected to certain physical factors (such as shaking) are becoming more frequent and are increasingly producing conclusive results. A much less studied phenomenon is the transfer of molecular information (i.e., UHD signals of dilute substances) from one liquid to another without an intermediate liquid phase. The aim of this study was to investigate the possibility of such a transfer of the UHD signal from the UHD solutions to the receiver solution, in particular, if the molecular source used in the donor solutions was the biologically active antibodies to interferon-gamma molecule. We were especially interested in how the transfer of the UHD signal is affected by the time of exposure of the receiver to the donor, the distance between the two, and how the transfer is affected by activation (striking) versus exposure alone. Signal transfer was evaluated by differential measurements of electrical conductivity, ORP, pH, and UV/VIS spectroscopy of the exposed liquid. The results showed that activation strongly influences signal transfer and that this can be compensated to some extent by prolonged direct exposure. In principle, exposure time has a positive effect on signal transfer. Interestingly, the results of different distances between the donor and receiver showed similar changes in the parameters in the range of 0–4 cm, as estimated in this study. While the study mainly confirms the two hypotheses, it also raises a number of new questions and provides clues for further research.
Targeted Radium Alpha Therapy in the Era of Nanomedicine: In Vivo Results
Authors: Trencsényi György , Csikos Csaba , Képes Zita
Published: January 2024

Targeted alpha-particle therapy using radionuclides with alpha emission is a rapidly developing area in modern cancer treatment. To selectively deliver alpha-emitting isotopes to tumors, targeting vectors, including monoclonal antibodies, peptides, small molecule inhibitors, or other biomolecules, are attached to them, which ensures specific binding to tumor-related antigens and cell surface receptors. Although earlier studies have already demonstrated the anti-tumor potential of alpha-emitting radium (Ra) isotopes—Radium-223 and Radium-224 (223/224Ra)—in the treatment of skeletal metastases, their inability to complex with target-specific moieties hindered application beyond bone targeting. To exploit the therapeutic gains of Ra across a wider spectrum of cancers, nanoparticles have recently been embraced as carriers to ensure the linkage of 223/224Ra to target-affine vectors. Exemplified by prior findings, Ra was successfully bound to several nano/microparticles, including lanthanum phosphate, nanozeolites, barium sulfate, hydroxyapatite, calcium carbonate, gypsum, celestine, or liposomes. Despite the lengthened tumor retention and the related improvement in the radiotherapeutic effect of 223/224Ra coupled to nanoparticles, the in vivo assessment of the radiolabeled nanoprobes is a prerequisite prior to clinical usage. For this purpose, experimental xenotransplant models of different cancers provide a well-suited scenario. Herein, we summarize the latest achievements with 223/224Ra-doped nanoparticles and related advances in targeted alpha radiotherapy.
Brief Electrical Stimulation Promotes Recovery after Surgical Repair of Injured Peripheral Nerves
Authors: Gordon Tessa
Published: January 2024

Injured peripheral nerves regenerate their axons in contrast to those in the central nervous system. Yet, functional recovery after surgical repair is often disappointing. The basis for poor recovery is progressive deterioration with time and distance of the growth capacity of the neurons that lose their contact with targets (chronic axotomy) and the growth support of the chronically denervated Schwann cells (SC) in the distal nerve stumps. Nonetheless, chronically denervated atrophic muscle retains the capacity for reinnervation. Declining electrical activity of motoneurons accompanies the progressive fall in axotomized neuronal and denervated SC expression of regeneration-associated-genes and declining regenerative success. Reduced motoneuronal activity is due to the withdrawal of synaptic contacts from the soma. Exogenous neurotrophic factors that promote nerve regeneration can replace the endogenous factors whose expression declines with time. But the profuse axonal outgrowth they provoke and the difficulties in their delivery hinder their efficacy. Brief (1 h) low-frequency (20 Hz) electrical stimulation (ES) proximal to the injury site promotes the expression of endogenous growth factors and, in turn, dramatically accelerates axon outgrowth and target reinnervation. The latter ES effect has been demonstrated in both rats and humans. A conditioning ES of intact nerve days prior to nerve injury increases axonal outgrowth and regeneration rate. Thereby, this form of ES is amenable for nerve transfer surgeries and end-to-side neurorrhaphies. However, additional surgery for applying the required electrodes may be a hurdle. ES is applicable in all surgeries with excellent outcomes.
H2O2 Significantly Affects Larix kaempferi × Larix olgensis Somatic Embryogenesis
Authors: Zhu Junjie , Zhang Kaikai , Xiong Huiru , Xie Yunhui , Li Rui , Wu Xinru , Yang Yun , Wu Hua , Hao Zhaodong , Sun Xiaomei , Chen Jinhui
Published: January 2024

Larch is widely distributed throughout the world and is an important species for timber supply and the extraction of industrial raw materials. In recent years, the hybrid breeding of Larix kaempferi and Larix olgensis has shown obvious heterosis in quick-growth, stress resistance and wood properties. However, its growth and development cycle is too long to meet general production needs. In order to shorten the breeding cycle, we have for the first time successfully established and optimized a somatic embryogenesis system for Larix kaempferi × Larix olgensis. We found that the highest rate of embryonal-suspensor mass (ESM) induction was observed when late cotyledonary embryos were used as explants. The induced ESMs were subjected to stable proliferation, after which abscisic acid (ABA) and polyethylene glycol (PEG) were added to successfully induce somatic embryos. Treatment with PEG and ABA was of great importance to somatic embryo formation and complemented each other’s effect. ABA assisted embryo growth, whereas PEG facilitated the formation of proembryo-like structures. On top of this, we studied in more detail the relationship between redox homeostasis and the efficiency of somatic embryogenesis (frequency of ESM induction). During subculture, we observed the gradual formation of three distinct types of ESM. The Type I ESM is readily able to form somatic embryos. In contrast to type I, the type III ESM suffers from severe browning, contains a higher level of hydrogen peroxide (H2O2) and demonstrates a decreased ability to form somatic embryos. External treatment with H2O2 decreased the somatic embryogenesis efficiency of Type I and type III ESMs, or the higher the exogenous H2O2 content, the lower the resulting somatic embryogenesis efficiency. We found that treatment with the H2O2 scavenger DMTU (dimethylthiourea) could significantly increase the somatic embryogenesis efficiency of the type III ESM, as a result of a decline in endogenous H2O2 content. Overall, these findings have contributed to setting up a successful somatic embryogenesis system for larch production.
Methanogenic Archaea in the Pediatric Inflammatory Bowel Disease in Relation to Disease Type and Activity
Authors: Cisek Agata Anna , Szymańska Edyta , Wierzbicka-Rucińska Aldona , Aleksandrzak-Piekarczyk Tamara , Cukrowska Bożena
Published: January 2024

The inflammatory bowel disease (IBD) is associated with gut microbiota dysbiosis; however, studies on methanogens—especially those focused on children—are extremely limited. The aim of this study was to determine the abundance of total methanogenic archaea and their three subgroups: Methanobrevibacter (Mb.) smithii, Methanosphaera (Ms.) stadtmanae, and Methanomassiliicoccales, in the feces of children with both active and inactive Crohn’s disease (CD) and ulcerative colitis (UC). The results of a quantitative real-time PCR were cross-referenced with the disease type (CD vs. UC) and activity assessed with the use of Pediatric Crohn’s Disease Activity Index (PCDAI) and Pediatric Ulcerative Colitis Activity Index (PUCAI) indices, and fecal calprotectin (FCP) concentration, and compared with controls. There was a significant decrease in the number of total methanogens in CD and UC compared to controls. The prevalence of total methanogens was also lower in UC compared to controls. Furthermore, patients from the inactive UC group were colonized by a lower number of Mb. smithii, and demonstrated the most pronounced positive correlation between the number of Ms. stadtmanae and the FCP concentration. Our results demonstrate that gut methanogens are related to the type and activity of pediatric IBD.
Secondary Beams at High-Intensity Electron Accelerator Facilities
Authors: Battaglieri Marco , Bianconi Andrea , Bondí Mariangela , De Vita Raffaella , Fulci Antonino , Gosta Giulia , Grazzi Stefano , Jo Hyon-Suk , Lee Changhui , Mandaglio Giuseppe , Mascagna Valerio , Nagorna Tetiana , Pilloni Alessandro , Spreafico Marco , Tagliapietra Luca J. , Venturelli Luca , Vittorini Tommaso
Published: January 2024

The interaction of a high-current O(100 µA), medium energy O(10 GeV) electron beam with a thick target O(1m) produces an overwhelming shower of standard model particles in addition to hypothetical light dark matter particles. While most of the radiation (gamma, electron/positron) is contained in the thick target, deep penetrating particles (muons, neutrinos, and light dark matter particles) propagate over a long distance, producing high-intensity secondary beams. Using sophisticated Monte Carlo simulations based on FLUKA and GEANT4, we explored the characteristics of secondary muons and neutrinos and (hypothetical) dark scalar particles produced by the interaction of the Jefferson Lab 11 GeV intense electron beam with the experimental Hall-A beam dump. Considering the possible beam energy upgrade, this study was repeated for a 22 GeV CEBAF beam.