bluuebunny/crossref_metadata_2025 huggingface dataset:
Metabolic Profiling and Molecular Mechanisms Underlying Melatonin-Induced Secondary Metabolism of Postharvest Goji Berry (Lycium barbarum L.)
Authors: Wang Junjie , Zhang Huaiyu , Hou Jie , Yang En , Zhao Lunaike , Zhou Yueli , Ma Wenping , Ma Danmei , Li Jiayi
Published: November 2023

Postharvest decay of goji berries, mainly caused by Alternaria alternata, results in significant economic losses. To investigate the effects of melatonin (MLT) on resistance to Alternaria rot in goji berries, the fruits were immersed in the MLT solutions with varying concentrations (0, 25, 50, and 75 μmol L−1) and then inoculated with A. alternata. The results showed that the fruits treated with 50 μmol L−1 MLT exhibited the lowest disease incidence and least lesion diameter. Meanwhile, endogenous MLT in the fruits treated with 50 μmol L−1 MLT showed higher levels than in the control fruits during storage at 4 ± 0.5 °C. Further, the enzymatic activities and expressions of genes encoding peroxidase, phenylalanine ammonia-lyase, cinnamate 4-hydroxylase, 4-coumarate-CoA ligase, chalcone synthase, chalcone isomerase, and cinnamyl alcohol dehydrogenase were induced in the treated fruit during storage. UPLC-ESI-MS/MS revealed that secondary metabolites in the fruits on day 0, in order of highest to lowest levels, were rutin, p-coumaric acid, chlorogenic acid, ferulic acid, caffeic acid, naringenin, quercetin, kaempferol, and protocatechuic acid. MLT-treated fruits exhibited higher levels of secondary metabolites than the control. In conclusion, MLT treatment contributed to controlling the postharvest decay of goji fruit during storage by boosting endogenous MLT levels, thus activating the antioxidant system and secondary metabolism.
Factors in Learning Dynamics Influencing Relative Strengths of Strategies in Poker Simulation
Authors: Foote Aaron , Gooyabadi Maryam , Addleman Nikhil
Published: November 2023

Poker is a game of skill, much like chess or go, but distinct as an incomplete information game. Substantial work has been done to understand human play in poker, as well as the optimal strategies in poker. Evolutionary game theory provides another avenue to study poker by considering overarching strategies, namely rational and random play. In this work, a population of poker playing agents is instantiated to play the preflop portion of Texas Hold’em poker, with learning and strategy revision occurring over the course of the simulation. This paper aims to investigate the influence of learning dynamics on dominant strategies in poker, an area that has yet to be investigated. Our findings show that rational play emerges as the dominant strategy when loss aversion is included in the learning model, not when winning and magnitude of win are of the only considerations. The implications of our findings extend to the modeling of sub-optimal human poker play and the development of optimal poker agents.
MiR-217 Regulates SIRT1 Expression and Promotes Inflammatory and Apoptotic Responses in Osteoarthritis
Authors: Papageorgiou Aliki-Alexandra , Roussos Athanasios , Papathanasiou Ioanna , Balis Charalampos , Karachalios Theophilos , Varitimidis Sokratis E. , Malizos Konstantinos N. , Tsezou Aspasia
Published: November 2023

Previous studies have reported miR-217 uregulation in age-related pathologies. We investigated the impact of miR-217-5p on sirtuin 1 (SIRT1) regulation in human osteoarthritic (OA) chondrocytes. MiR-217 target enrichment analyses were performed using three public databases, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes. MiR-217-5p expression levels were quantified in normal and OA chondrocytes. SIRT1 expression levels, nuclear factor kappa-B p65 subunit (NF-κBp65) and p53 acetylation levels, and expression levels of OA-related pro-inflammatory markers [tumor necrosis factor α (TNFα), interleukin 1β (IL-1β), IL-6], pro-apoptotic markers [Bax, pro-caspase 3, cleaved caspase 3] and matrix regulators [matrix metalloproteinase (MMP)-1, MMP-13, MMP-9, Collagen 2 (COL2A1), Aggrecan (ACAN)] were evaluated in miR-217 mimic-treated and/or miR-217 inhibitor-treated OA chondrocytes, with/without subsequent treatment with siRNA against SIRT1 (siSIRT1). MiR-217-5p was upregulated in OA chondrocytes, while target prediction/enrichment analyses revealed SIRT1 as miR-217 target-gene. Deacetylation of NF-κBp65 and p53 in miR-217 inhibitor-treated OA chondrocytes was reversed by siSIRT1 treatment. MiR-217 inhibitor-treated OA chondrocytes showed increased COL2A1, ACAN and decreased IL-1β, IL-6, TNFα, Bax, cleaved caspase 3 and MMPs expression levels, which were reversed following miR-217 inhibitor/siSIRT1 treatment. Our findings highlight the impact of miR-217-5p on SIRT1 downregulation contributing to OA pathogenesis.
Duplication at 19q13.32q13.33 Segregating with Neuropsychiatric Phenotype in a Three-Generation Family: Towards the Definition of a Critical Region
Authors: Guadagnolo Daniele , Mastromoro Gioia , Torres Barbara , Marchionni Enrica , di Palma Francesca , Goldoni Marina , Cocciadiferro Dario , Novelli Antonio , Bernardini Laura , Pizzuti Antonio
Published: November 2023

Chromosomal submicroscopic imbalances represent well-known causes of neurodevelopmental disorders. In some cases, these can cause specific autosomal dominant syndromes, with high-to-complete penetrance and de novo occurrence of the variant. In other cases, they result in non-syndromic neurodevelopmental disorders, often acting as moderate-penetrance risk factors, possibly inherited from unaffected parents. We describe a three-generation family with non-syndromic neuropsychiatric features segregating with a novel 19q13.32q13.33 microduplication. The propositus was a 28-month-old male ascertained for psychomotor delay, with no dysmorphic features or malformations. His mother had Attention-Deficit/Hyperactivity Disorder and a learning disability. The maternal uncle had an intellectual disability. Chromosomal microarray analysis identified a 969 kb 19q13.32q13.33 microduplication in the proband. The variant segregated in the mother, the uncle, and the maternal grandmother of the proband, who also presented neuropsychiatric disorders. Fragile-X Syndrome testing was negative. Exome Sequencing did not identify Pathogenic/Likely Pathogenic variants. Imbalances involving 19q13.32 and 19q13.33 are associated with neurodevelopmental delay. A review of the reported microduplications allowed to propose BICRA (MIM *605690) and KPTN (MIM *615620) as candidates for the neurodevelopmental delay susceptibility in 19q13.32q13.33 copy number gains. The peculiarities of this case are the small extension of the duplication, the three-generation segregation, and the full penetrance of the phenotype.
A Proposal of the Ur-RNAome
Authors: Palacios-Pérez Miryam , José Marco
Published: November 2023

It is widely accepted that the earliest RNA molecules were folded into hairpins or mini-helixes. Herein, we depict the 2D and 3D conformations of those earliest RNA molecules with only RNY triplets, which Eigen proposed as the primeval genetic code. We selected 26 species (13 bacteria and 13 archaea). We found that the free energy of RNY hairpins was consistently lower than that of their corresponding shuffled controls. We found traces of the three ribosomal RNAs (16S, 23S, and 5S), tRNAs, 6S RNA, and the RNA moieties of RNase P and the signal recognition particle. Nevertheless, at this stage of evolution there was no genetic code (as seen in the absence of the peptidyl transferase centre and any vestiges of the anti-Shine–Dalgarno sequence). Interestingly, we detected the anticodons of both glycine (GCC) and threonine (GGU) in the hairpins of proto-tRNA.
Co-Creating Nature: Tourist Photography as a Creative Performance
Authors: Lund Katrín Anna
Published: November 2023

This article examines tourism nature photography as a creative and sensual activity. Based on a collection of photographs gathered from tourists in the Strandir region in northwest Iceland, I demonstrate how photographing nature is a more-than-human practice in which nature has full agency. Much has been written about tourist photography since John Urry theorised about the tourist gaze in the early 1990s; this view has been criticised, especially in the light of the performance turn in tourism studies.It has, for example, been noted that tourist photography is not just about the gazing tourist, but also about social relations that the surrounding landscape partly directs and stages. It has also been argued that, as photographing tourists, we become ‘concerned with the artistic production of ourselves’. Photography is thus a practise that is relational and sensual and that cannot be reduced to the seeing eye. However, whilst emphasising the tourist as a creative being, the surrounding landscape has been left out as a stage and its active agency ignored. I address the complex, more-than-human relations that emerge in the photographs collected in Strandir. I argue that the act of photographing, as a performative practice, is improvisational and co-creative, and the material surroundings have a direct and active agency. As has been demonstrated, photography communicates ‘not through the realist paradigm but through lyrical expressiveness’ and, thus, it may be argued that tourist photography is a poetic practice of making, as it weaves together the sensing self and the vital surroundings in the moving moment that the photograph captures.
The Impact of COVID-19 Infection on Trauma Patients in South Korea
Authors: Jang Myungjin , Lee Mina , Choi Woosung , Choi Kangkook
Published: November 2023

Background: The COVID-19 pandemic has significantly affected societies worldwide, including the medical healthcare system and trauma care. This study explores the impact of COVID-19 infection on trauma patients in South Korea, a country with effective pandemic management. Methods: A retrospective cohort study of 4206 trauma patients from June 2020 to May 2022 was conducted. Patients were categorized into COVID-19-positive and COVID-19-negative groups. Various clinical parameters, complications, and mortality rates were analyzed. Results: COVID-19-positive patients exhibited higher rates of complications, such as pressure sores (8.8% vs. 2.3%, p < 0.001), surgical site infections (2.4% vs. 0.8%, p = 0.044), and pneumonia (8.8% vs. 4.1%, p = 0.007). There was no significant difference in mortality between COVID-19-positive and -negative groups (4% vs. 5.6%, p = 0.439). Factors influencing mortality included COVID-19 status, age, Glasgow Coma Scale, Injury Severity Score, and transfusion status. Conclusion: COVID-19 positivity may have adverse clinical effects on trauma patients, but the impact varies based on public health factors. Additional studies in different contexts are crucial to elucidate these complexities.
Recent Advances and Applications of Textile Technology in Patient Monitoring
Authors: Stern Lindsay , Roshan Fekr Atena
Published: November 2023

Sleep monitoring has become a prevalent area of research where body position and physiological data, such as heart rate and respiratory rate, are monitored. Numerous critical health problems are associated with poor sleep, such as pressure sore development, sleep disorders, and low sleep quality, which can lead to an increased risk of falls, cardiovascular diseases, and obesity. Current monitoring systems can be costly, laborious, and taxing on hospital resources. This paper reviews the most recent solutions for contactless textile technology in the form of bed sheets or mats to monitor body positions, vital signs, and sleep, both commercially and in the literature. This paper is organized into four categories: body position and movement monitoring, physiological monitoring, sleep monitoring, and commercial products. A detailed performance evaluation was carried out, considering the detection accuracy as well as the sensor types and algorithms used. The areas that need further research and the challenges for each category are discussed in detail.
Temperature and Daylength Effects on Growth and Floral Initiation in Biennial-Fruiting Blackberry
Authors: Sønsteby Anita , Heide Ola M.
Published: November 2023

Little is known about the environmental control of growth and flower bud initiation (FBI) in commercial blackberries. We studied the processes in the cultivars ‘Lock Ness’, ’Ouachita’ and ‘Sweet Royalla’ at 12, 16 and 20 °C in a daylight phytotron under naturally decreasing autumn daylength at Ås, Norway (59°40′ N). Growth rate increased with increasing temperature but was much lower at all temperatures in the erect ‘Ouachita’ than in the trailing cultivars ‘Lock Ness’ and ‘Sweet Royalla’. In all cultivars, FBI occurred earliest at 16 °C, whereas little or no FBI took place in ‘Ouachita’ and ‘Lock Ness’ at 12 °C. Growth cessation was earliest at 16 °C where it occurred in early September in all cultivars, suggesting a critical daylength of approximately 14 h. At variance from earlier statements, FBI started in lateral buds situated several nodes below the apex and progressed in both acropetal and basipetal directions as previously reported for red raspberry. Winter chill at 0 °C enhanced flowering in spring in marginally induced plants of all cultivars except ‘Ouachita’ grown at 12 °C, which remained vegetative in spring. The results suggest that temperature is as important as daylength for FBI in biennial-fruiting blackberry, and that winter chilling may enhance flowering and yield potential in partially induced plants.
The Prospect of Hydrolytic Enzymes from Bacillus Species in the Biological Control of Pests and Diseases in Forest and Fruit Tree Production
Authors: Ajuna Henry B. , Lim Hyo-In , Moon Jae-Hyun , Won Sang-Jae , Choub Vantha , Choi Su-In , Yun Ju-Yeol , Ahn Young Sang
Published: November 2023

Plant diseases and insect pest damage cause tremendous losses in forestry and fruit tree production. Even though chemical pesticides have been effective in the control of plant diseases and insect pests for several decades, they are increasingly becoming undesirable due to their toxic residues that affect human life, animals, and the environment, as well as the growing challenge of pesticide resistance. In this study, we review the potential of hydrolytic enzymes from Bacillus species such as chitinases, β-1,3-glucanases, proteases, lipases, amylases, and cellulases in the biological control of phytopathogens and insect pests, which could be a more sustainable alternative to chemical pesticides. This study highlights the application potential of the hydrolytic enzymes from different Bacillus sp. as effective biocontrol alternatives against phytopathogens/insect pests through the degradation of cell wall/insect cuticles, which are mainly composed of structural polysaccharides like chitins, β-glucans, glycoproteins, and lipids. This study demonstrates the prospects for applying hydrolytic enzymes from Bacillus sp. as effective biopesticides in forest and fruit tree production, their mode of biocidal activity and dual antimicrobial/insecticidal potential, which indicates a great prospect for the simultaneous biocontrol of pests/diseases. Further research should focus on optimizing the production of hydrolytic enzymes, and the antimicrobial/insecticidal synergism of different Bacillus sp. which could facilitate the simultaneous biocontrol of pests and diseases in forest and fruit tree production.
SPTBN1 Mediates the Cytoplasmic Constraint of PTTG1, Impairing Its Oncogenic Activity in Human Seminoma
Authors: Teveroni Emanuela , Di Nicuolo Fiorella , Vergani Edoardo , Oliva Alessandro , Vodola Emanuele Pierpaolo , Bianchetti Giada , Maulucci Giuseppe , De Spirito Marco , Cenci Tonia , Pierconti Francesco , Gulino Gaetano , Iavarone Federica , Urbani Andrea , Milardi Domenico , Pontecorvi Alfredo , Mancini Francesca
Published: November 2023

Seminoma is the most common testicular cancer. Pituitary tumor-transforming gene 1 (PTTG1) is a securin showing oncogenic activity in several tumors. We previously demonstrated that nuclear PTTG1 promotes seminoma tumor invasion through its transcriptional activity on matrix metalloproteinase 2 (MMP-2) and E-cadherin (CDH1). We wondered if specific interactors could affect its subcellular distribution. To this aim, we investigated the PTTG1 interactome in seminoma cell lines showing different PTTG1 nuclear levels correlated with invasive properties. A proteomic approach upon PTTG1 immunoprecipitation uncovered new specific securin interactors. Western blot, confocal microscopy, cytoplasmic/nuclear fractionation, sphere-forming assay, and Atlas database interrogation were performed to validate the proteomic results and to investigate the interplay between PTTG1 and newly uncovered partners. We observed that spectrin beta-chain (SPTBN1) and PTTG1 were cofactors, with SPTBN1 anchoring the securin in the cytoplasm. SPTBN1 downregulation determined PTTG1 nuclear translocation, promoting its invasive capability. Moreover, a PTTG1 deletion mutant lacking SPTBN1 binding was strongly localized in the nucleus. The Atlas database revealed that seminomas that contained higher nuclear PTTG1 levels showed significantly lower SPTBN1 levels in comparison to non-seminomas. In human seminoma specimens, we found a strong PTTG1/SPTBN1 colocalization that decreases in areas with nuclear PTTG1 distribution. Overall, these results suggest that SPTBN1, along with PTTG1, is a potential prognostic factor useful in the clinical management of seminoma.
Crosstalk between Endothelial Cells and Tumor Cells: A New Era in Prostate Cancer Progression
Authors: Ji Shiyu , Wu Wenbo , Jiang Qi
Published: November 2023

Prostate cancer stands as one of the most prevalent malignancies afflicting men worldwide. The tumor microenvironment plays a pivotal role in tumor progression, comprising various cell types including endothelial cells, tumor-associated fibroblasts, and macrophages. Recent accumulating evidence underscores the indispensable contribution of endothelial cells to prostate cancer development. Both endothelial cells and tumor cells release a multitude of factors that instigate angiogenesis, metastasis, and even drug resistance in prostate cancer. These factors serve as regulators within the tumor microenvironment and represent potential therapeutic targets for managing prostate cancer. In this review, we provide an overview of the crucial functions of endothelial cells in angiogenesis, metastasis, and drug resistance, and their prospective therapeutic applications in combating this disease.
Quantitative Trait Loci Mapping Identified Candidate Genes Involved in Plant Height Regulation in Rice
Authors: Park Jae-Ryoung , Jang Yoon-Hee , Kim Eun-Gyeong , Hur Sang-Sun , Kim Kyung-Min
Published: November 2023

Rice plant height is an agricultural trait closely related to biomass, lodging tolerance, and yield. Identifying quantitative trait loci (QTL) regions related to plant height regulation and developing strategies to screen potential candidate genes can improve agricultural traits in rice. In this study, a double haploid population (CNDH), derived by crossing ‘Cheongcheong’ and ‘Nagdong’ individuals, was used, and a genetic map was constructed with 222 single-sequence repeat markers. In the RM3482-RM212 region on chromosome 1, qPh1, qPh1-1, qPh1-3, qPh1-5, and qPh1-6 were identified for five consecutive years. The phenotypic variance explained ranged from 9.3% to 13.1%, and the LOD score ranged between 3.6 and 17.6. OsPHq1, a candidate gene related to plant height regulation, was screened in RM3482-RM212. OsPHq1 is an ortholog of gibberellin 20 oxidase 2, and its haplotype was distinguished by nine SNPs. Plants were divided into two groups based on their height, and tall and short plants were distinguished and clustered according to the expression level of OsPHq1. QTLs and candidate genes related to plant height regulation, and thus, biomass regulation, were screened and identified in this study, but the molecular mechanism of the regulation remains poorly known. The information obtained in this study will help develop molecular markers for marker-assisted selection and breeding through rice plant height control.
Hypericin-Based Photodynamic Therapy Displays Higher Selectivity and Phototoxicity towards Melanoma and Squamous Cell Cancer Compared to Normal Keratinocytes In Vitro
Authors: Woźniak Marta , Nowak-Perlak Martyna
Published: November 2023

The aim of this study was to explore the potential of hypericin, a naturally occurring photosensi-tizer, for photodynamic therapy (PDT) in skin cancer, investigating its phototoxic effects and mechanisms of action in cancer cells compared to normal skin keratinocytes, squamous cell cancer (SCC-25) cells and melanoma (MUG-Mel2) cells. Hypericin was applied at concentrations ranging from 0.1–40 μM to HaCaT, SCC-25, and MUG-Mel2 cells. After 24 h of incubation, the cells were exposed to orange light at 3.6 J/cm2 or 7.2 J/cm2. Phototoxicity was assessed using MTT and SRB tests. Cellular uptake was measured by flow cytometry. Apoptosis-positive cells were estimated through TUNEL for apoptotic bodies’ visualization. Hypericin exhibited a higher phototoxic reaction in cancer cells compared to normal keratinocytes after irradiation. Cancer cells demonstrated increased and selective uptake of hypericin. Apoptosis was observed in SCC-25 and MUG-Mel2 cells following PDT. Our findings suggest that hypericin-based PDT is a promising and less invasive approach for treating skin cancer. The higher phototoxic reaction, selective uptake by cancer cells, and observed proapoptotic properties support the promising role of hypericin-based PDT in skin cancer treatment.
Predictive Performances of Blood-Count-Derived Inflammatory Markers for Liver Fibrosis Severity in Psoriasis Vulgaris
Authors: Tiucă Oana Mirela , Morariu Silviu Horia , Mariean Claudia Raluca , Tiucă Robert Aurelian , Nicolescu Alin Codrut , Cotoi Ovidiu Simion
Published: November 2023

Psoriasis is an immune-mediated, chronic disorder that significantly alters patients’ quality of life and predisposes them to a higher risk of comorbidities, including liver fibrosis. Various non-invasive tests (NITs) have been validated to assess liver fibrosis severity, while blood-count-derived inflammatory markers have been proven to be reliable in reflecting inflammatory status in psoriatic disease. The fibrosis-4 (FIB-4) index became part of the newest guideline for monitoring psoriasis patients undergoing systemic treatment. Patients with psoriasis vulgaris and fulfilling inclusion criteria were enrolled in this study, aiming to assess for the first time in the literature whether such inflammatory markers are useful in predicting liver fibrosis. Based on internationally validated FIB-4 index values, patients were divided into two study groups: a low risk of significant fibrosis (LR-SF) and a high risk of significant fibrosis (HR-SF). Patients from HR-SF were significantly older and had higher values of the monocyte-to-lymphocyte ratio (MLR) (p < 0.001), which further significantly correlated with fibrosis severity (p < 0.001). Platelet-to-lymphocyte ratio (PLR), systemic immune inflammation index (SII), platelet-to-white blood cell ratio (PWR), and aggregate index of systemic inflammations (AISI) significantly correlated negatively with liver fibrosis (p < 0.001). PWR proved to be the most reliable inflammatory predictor of fibrosis severity (AUC = 0.657). MLR, PWR, and AISI were independent inflammatory markers in multivariate analysis (p < 0.001), while the AST to platelet ratio index (APRI) and AST to ALT ratio (AAR) can be used as additional NITs for significant liver fibrosis (p < 0.001). In limited-resources settings, blood-count-derived inflammatory markers such as MLR, PWR, and AISI, respectively, and hepatic indexes APRI and AAR prove to be of particular help in predicting significant liver fibrosis.
Pharmacological Inhibition of PIP4K2 Potentiates Venetoclax-Induced Apoptosis in Acute Myeloid Leukemia
Authors: Lima Keli , Carvalho Maria Fernanda Lopes , Pereira-Martins Diego Antonio , Nogueira Frederico Lisboa , de Miranda Lívia Bassani Lins , Nascimento Mariane Cristina do , Cavaglieri Rita de Cássia , Schuringa Jan Jacob , Machado-Neto João Agostinho , Rego Eduardo Magalhães
Published: November 2023

Phosphatidylinositol-5-phosphate 4-kinase type 2 (PIP4K2) protein family members (PIP4K2A, PIP4K2B, and PIP4K2C) participate in the generation of PIP4,5P2, which acts as a secondary messenger in signal transduction, a substrate for metabolic processes, and has structural functions. In patients with acute myeloid leukemia (AML), high PIP4K2A and PIP4K2C levels are independent markers of a worse prognosis. Recently, our research group reported that THZ-P1-2 (PIP4K2 pan-inhibitor) exhibits anti-leukemic activity by disrupting mitochondrial homeostasis and autophagy in AML models. In the present study, we characterized the expression of PIP4K2 in the myeloid compartment of hematopoietic cells, as well as in AML cell lines and clinical samples with different genetic abnormalities. In ex vivo assays, PIP4K2 expression levels were related to sensitivity and resistance to several antileukemia drugs and highlighted the association between high PIP4K2A levels and resistance to venetoclax. The combination of THZ-P1-2 and venetoclax showed potentiating effects in reducing viability and inducing apoptosis in AML cells. A combined treatment differentially modulated multiple genes, including TAp73, BCL2, MCL1, and BCL2A1. In summary, our study identified the correlation between the expression of PIP4K2 and the response to antineoplastic agents in ex vivo assays in AML and exposed vulnerabilities that may be exploited in combined therapies, which could result in better therapeutic responses.
Concurrent Infection of the Human Brain with Multiple Borrelia Species
Authors: Golovchenko Maryna , Opelka Jakub , Vancova Marie , Sehadova Hana , Kralikova Veronika , Dobias Martin , Raska Milan , Krupka Michal , Sloupenska Kristyna , Rudenko Natalie
Published: November 2023

Lyme disease (LD) spirochetes are well known to be able to disseminate into the tissues of infected hosts, including humans. The diverse strategies used by spirochetes to avoid the host immune system and persist in the host include active immune suppression, induction of immune tolerance, phase and antigenic variation, intracellular seclusion, changing of morphological and physiological state in varying environments, formation of biofilms and persistent forms, and, importantly, incursion into immune-privileged sites such as the brain. Invasion of immune-privileged sites allows the spirochetes to not only escape from the host immune system but can also reduce the efficacy of antibiotic therapy. Here we present a case of the detection of spirochetal DNA in multiple loci in a LD patient’s post-mortem brain. The presence of co-infection with Borrelia burgdorferi sensu stricto and Borrelia garinii in this LD patient’s brain was confirmed by PCR. Even though both spirochete species were simultaneously present in human brain tissue, the brain regions where the two species were detected were different and non-overlapping. The presence of atypical spirochete morphology was noted by immunohistochemistry of the brain samples. Atypical morphology was also found in the tissues of experimentally infected mice, which were used as a control.
Lacticaseibacillus rhamnosus CRL1505 Peptidoglycan Modulates the Inflammation-Coagulation Response Triggered by Poly(I:C) in the Respiratory Tract
Authors: Zelaya Hortensia , Arellano-Arriagada Luciano , Fukuyama Kohtaro , Matsumoto Kaho , Marranzino Gabriela , Namai Fu , Salva Susana , Alvarez Susana , Agüero Graciela , Kitazawa Haruki , Villena Julio
Published: November 2023

Lacticaseibacillus rhamnosus CRL1505 beneficially modulates the inflammation-coagulation response during respiratory viral infections. This study evaluated the capacity of the peptidoglycan obtained from the CRL1505 strain (PG-Lr1505) to modulate the immuno-coagulative response triggered by the viral pathogen-associated molecular pattern poly(I:C) in the respiratory tract. Adult BALB/c mice were nasally treated with PG-Lr1505 for two days. Treated and untreated control mice were then nasally challenged with poly(I:C). Mice received three doses of poly(I:C) with a 24 h rest period between each administration. The immuno-coagulative response was studied after the last administration of poly(I:C). The challenge with poly(I:C) significantly increased blood and respiratory pro-inflammatory mediators, decreased prothrombin activity (PT), and increased von Willebrand factor (vWF) levels in plasma. Furthermore, tissue factor (TF), tissue factor pathway inhibitor (TFPI), and thrombomodulin (TM) expressions were increased in the lungs. PG-Lr1505-treated mice showed significant modulation of hemostatic parameters in plasma (PT in %, Control = 71.3 ± 3.8, PG-Lr1505 = 94.0 ± 4.0, p < 0.01) and lungs. Moreover, PG-Lr1505-treated mice demonstrated reduced TF in F4/80 cells from lungs, higher pro-inflammatory mediators, and increased IL-10 compared to poly(I:C) control mice (IL-10 in pg/mL, Control = 379.1 ± 12.1, PG-Lr1505 = 483.9 ± 11.3, p < 0.0001). These changes induced by PG-Lr1505 correlated with a significant reduction in lung tissue damage. Complementary in vitro studies using Raw 264.7 cells confirmed the beneficial effect of PG-Lr1505 on poly(I:C)-induced inflammation, since increased IL-10 expression, as well as reduced damage, production of inflammatory mediators, and hemostatic parameter expressions were observed. In addition, protease-activated receptor-1 (PAR1) activation in lungs and Raw 264.7 cells was observed after TLR3 stimulation, which was differentially modulated by PG-Lr1505. The peptidoglycan from L. rhamnosus CRL1505 is able to regulate inflammation, the procoagulant state, and PAR1 activation in mice and macrophages in the context of the activation of TLR3 signaling pathways, contributing to a beneficial modulation of inflammation-hemostasis crosstalk.
Refining Immunogenicity through Intradermal Delivery of Outer Membrane Vesicles against Shigella flexneri in Mice
Authors: Pastor Yadira , Calvo Alba , Salvador-Erro Josune , Gamazo Carlos
Published: November 2023

Shigellosis remains a global health concern, especially in low- and middle-income countries. Despite improvements in sanitation, the absence of a licensed vaccine for human use has prompted global health organizations to support the development of a safe and effective multivalent vaccine that is cost-effective and accessible for limited-resource regions. Outer Membrane Vesicles (OMVs) have emerged in recent years as an alternative to live attenuated or whole-inactivated vaccines due to their immunogenicity and self-adjuvating properties. Previous works have demonstrated the safety and protective capacity of OMVs against Shigella flexneri infection in mouse models when administered through mucosal or intradermal routes. However, some immunological properties, such as the cellular response or cross-protection among different Shigella strains, remained unexplored. In this study, we demonstrate that intradermal immunization of OMVs with needle-free devices recruits a high number of immune cells in the dermis, leading to a robust cellular response marked by antigen-specific cytokine release and activation of effector CD4 T cells. Additionally, functional antibodies are generated, neutralizing various Shigella serotypes, suggesting cross-protective capacity. These findings highlight the potential of OMVs as a promising vaccine platform against shigellosis and support intradermal administration as a simple and painless vaccination strategy to address this health challenge.
Deep-Brain Subthalamic Nucleus Stimulation Enhances Food-Related Motivation by Influencing Neuroinflammation and Anxiety Levels in a Rat Model of Early-Stage Parkinson’s Disease
Authors: Grembecka Beata , Majkutewicz Irena , Harackiewicz Oliwia , Wrona Danuta
Published: November 2023

Deep-brain subthalamic nucleus stimulation (DBS-STN) has become a well-established therapeutic option for advanced Parkinson’s disease (PD). While the motor benefits of DBS-STN are widely acknowledged, the neuropsychiatric effects are still being investigated. Beyond its immediate effects on neuronal circuits, emerging research suggests that DBS-STN might also modulate the peripheral inflammation and neuroinflammation. In this work, we assessed the effects of DBS-STN on food-related motivation, food intake pattern, and the level of anxiety and compared them with markers of cellular and immune activation in nigrostriatal and mesolimbic areas in rats with the 6-OHDA model of early PD. To evaluate the potential mechanism of observed effects, we also measured corticosterone concentration in plasma and leukocyte distribution in peripheral blood. We found that DBS-STN applied during neurodegeneration has beneficial effects on food intake pattern and motivation and reduces anxiety. These behavioral effects occur with reduced percentages of IL-6-labeled cells in the ventral tegmental area and substantia nigra pars compacta in the stimulated brain hemisphere. At the same brain structures, the cFos cell activations were confirmed. Simultaneously, the corticosterone plasma concentration was elevated, and the peripheral blood lymphocytes were reduced after DBS-STN. We believe that comprehending the relationship between the effects of DBS-STN on inflammation and its therapeutic results is essential for optimizing DBS therapy in PD.
The Potential of Endophytes in Improving Salt–Alkali Tolerance and Salinity Resistance in Plants
Authors: Guo Xueying , Peng Wanrong , Xu Xinyi , Xie Kangwei , Yang Xingyong
Published: November 2023

Ensuring food security for the global population is a ceaseless and critical issue. However, high-salinity and high-alkalinity levels can harm agricultural yields throughout large areas, even in largely agricultural countries, such as China. Various physical and chemical treatments have been employed in different locations to mitigate high salinity and alkalinity but their effects have been minimal. Numerous researchers have recently focused on developing effective and environmentally friendly biological treatments. Endophytes, which are naturally occurring and abundant in plants, retain many of the same characteristics of plants owing to their simultaneous evolution. Therefore, extraction of endophytes from salt-tolerant plants for managing plant growth in saline–alkali soils has become an important research topic. This extraction indicates that the soil environment can be fundamentally improved, and the signaling pathways of plants can be altered to increase their defense capacity, and can even be inherited to ensure lasting efficacy. This study discusses the direct and indirect means by which plant endophytes mitigate the effects of plant salinity stress that have been observed in recent years.
Enzyme Databases in the Era of Omics and Artificial Intelligence
Authors: Prešern Uroš , Goličnik Marko
Published: November 2023

Enzyme research is important for the development of various scientific fields such as medicine and biotechnology. Enzyme databases facilitate this research by providing a wide range of information relevant to research planning and data analysis. Over the years, various databases that cover different aspects of enzyme biology (e.g., kinetic parameters, enzyme occurrence, and reaction mechanisms) have been developed. Most of the databases are curated manually, which improves reliability of the information; however, such curation cannot keep pace with the exponential growth in published data. Lack of data standardization is another obstacle for data extraction and analysis. Improving machine readability of databases is especially important in the light of recent advances in deep learning algorithms that require big training datasets. This review provides information regarding the current state of enzyme databases, especially in relation to the ever-increasing amount of generated research data and recent advancements in artificial intelligence algorithms. Furthermore, it describes several enzyme databases, providing the reader with necessary information for their use.
The Role of microRNAs in Gene Expression and Signaling Response of Tumor Cells to an Acidic Environment
Authors: Riemann Anne , Rauschner Mandy , Reime Sarah , Thews Oliver
Published: November 2023

Many tumors are characterized by marked extracellular acidosis due to increased glycolytic metabolism, which affects gene expression and thereby tumor biological behavior. At the same time, acidosis leads to altered expression of several microRNAs (Mir7, Mir183, Mir203, Mir215). The aim of this study was to analyze whether the acidosis-induced changes in cytokines and tumor-related genes are mediated via pH-sensitive microRNAs. Therefore, the expression of Il6, Nos2, Ccl2, Spp1, Tnf, Acat2, Aox1, Crem, Gls2, Per3, Pink1, Txnip, and Ypel3 was examined in acidosis upon simultaneous transfection with microRNA mimics or antagomirs in two tumor lines in vitro and in vivo. In addition, it was investigated whether microRNA expression in acidosis is affected via known pH-sensitive signaling pathways (MAPK, PKC, PI3K), via ROS, or via altered intracellular Ca2+ concentration. pH-dependent microRNAs were shown to play only a minor role in modulating gene expression. Individual genes (e.g., Ccl2, Txnip, Ypel3) appear to be affected by Mir183, Mir203, or Mir215 in acidosis, but these effects are cell line-specific. When examining whether acid-dependent signaling affects microRNA expression, it was found that Mir203 was modulated by MAPK and ROS, Mir7 was affected by PKC, and Mir215 was dependent on the intracellular Ca2+ concentration. Mir183 could be increased by ROS scavenging. These correlations could possibly result in new therapeutic approaches for acidotic tumors.
Phytohormones as Regulators of Mitochondrial Gene Expression in Arabidopsis thaliana
Authors: Bychkov Ivan A. , Pojidaeva Elena S. , Doroshenko Anastasia S. , Khripach Vladimir A. , Kudryakova Natalia V. , Kusnetsov Victor V.
Published: November 2023

The coordination of activities between nuclei and organelles in plant cells involves information exchange, in which phytohormones may play essential roles. Therefore, the dissection of the mechanisms of hormone-related integration between phytohormones and mitochondria is an important and challenging task. Here, we found that inputs from multiple hormones may cause changes in the transcript accumulation of mitochondrial-encoded genes and nuclear genes encoding mitochondrial (mt) proteins. In particular, treatments with exogenous hormones induced changes in the GUS expression in the reporter line possessing a 5′-deletion fragment of the RPOTmp promoter. These changes corresponded in part to the up- or downregulation of RPOTmp in wild-type plants, which affects the transcription of mt-encoded genes, implying that the promoter fragment of the RPOTmp gene is functionally involved in the responses to IAA (indole-3-acetic acid), ACC (1-aminocyclopropane-1-carboxylic acid), and ABA (abscisic acid). Hormone-dependent modulations in the expression of mt-encoded genes can also be mediated through mitochondrial transcription termination factors 15, 17, and 18 of the mTERF family and genes for tetratricopeptide repeat proteins that are coexpressed with mTERF genes, in addition to SWIB5 encoding a mitochondrial SWI/SNF (nucleosome remodeling) complex B protein. These genes specifically respond to hormone treatment, displaying both negative and positive regulation in a context-dependent manner. According to bioinformatic resources, their promoter region possesses putative cis-acting elements involved in responses to phytohormones. Alternatively, the hormone-related transcriptional activity of these genes may be modulated indirectly, which is especially relevant for brassinosteroids (BS). In general, the results of this study indicate that hormones are essential mediators that are able to cause alterations in the transcript accumulation of mt-related nuclear genes, which, in turn, trigger the expression of mt genes.
Postischemic Infusion of Apigenin Reduces Seizure Burden in Preterm Fetal Sheep
Authors: Cho Kenta H. T. , Hounsell Natalya , McClendon Evelyn , Riddle Art , Basappa  , Dhillon Simerdeep K. , Bennet Laura , Back Stephen , Sherman Larry S. , Gunn Alistair J. , Dean Justin M.
Published: November 2023

Seizures are common in preterm newborns and are associated with poor neurodevelopmental outcomes. Current anticonvulsants have poor efficacy, and many have been associated with upregulation of apoptosis in the developing brain. Apigenin, a natural bioactive flavonoid, is a potent inhibitor of hyaluronidase and reduces seizures in adult animal models. However, its impact on perinatal seizures is unclear. In the present study, we examined the effect of apigenin and S3, a synthetic, selective hyaluronidase inhibitor, on seizures after cerebral ischemia in preterm fetal sheep at 0.7 gestation (98–99 days, term ~147 days). Fetuses received sham ischemia (n = 9) or ischemia induced by bilateral carotid occlusion for 25 min. Immediately after ischemia, fetuses received either a continuous infusion of vehicle (0.036% dimethyl sulfoxide, n = 8) or apigenin (50 µM, n = 6). In a pilot study, we also tested infusion of S3 (2 µM, n = 3). Fetuses were monitored continuously for 72 h after ischemia. Infusion of apigenin or S3 were both associated with reduced numbers of animals with seizures, total seizure time, and mean seizure burden. S3 was also associated with a reduction in the total number of seizures over the 72 h recovery period. In animals that developed seizures, apigenin was associated with earlier cessation of seizures. However, apigenin or S3 treatment did not alter recovery of electroencephalographic power or spectral edge frequency. These data support that targeting brain hyaluronidase activity with apigenin or S3 may be an effective strategy to reduce perinatal seizures following ischemia. Further studies are required to determine their effects on neurohistological outcomes.
Defect of TIMP4 Is Associated with High Myopia and Participates in Rat Ocular Development in a Dose-Dependent Manner
Authors: Zhou Wenhui , Jiang Zixuan , Yi Zhen , Ouyang Jiamin , Li Xueqing , Zhang Qingjiong , Wang Panfeng
Published: November 2023

Thinning of the sclera happens in myopia eyes owing to extracellular matrix (ECM) remodeling, but the initiators of the ECM remodeling in myopia are mainly unknown. The matrix metalloproteinase (MMPs) and tissue inhibitors of matrix metalloproteinase (TIMPs) regulate the homeostasis of the ECM. However, genetic studies of the MMPs and TIMPs in the occurrence of myopia are poor and limited. This study systematically investigated the association between twenty-nine genes of the TIMPs and MMPs families and early-onset high myopia (eoHM) based on whole exome sequencing data. Two TIMP4 heterozygous loss-of-function (LoF) variants, c.528C>A in six patients and c.234_235insAA in one patient, were statistically enriched in 928 eoHM probands compared to that in 5469 non-high myopia control (p = 3.7 × 10−5) and that in the general population (p = 2.78 × 10−9). Consequently, the Timp4 gene editing rat was further evaluated to explore the possible role of Timp4 on ocular and myopia development. A series of ocular morphology abnormalities in a dose-dependent manner (Timp4−/− < Timp4+/− < Timp4+/+) were observed in a rat model, including the decline in the retinal thickness, the elongation in the axial length, more vulnerable to the form deprivation model, morphology changes in sclera collagen bundles, and the decrease in collagen contents of the sclera and retina. Electroretinogram revealed that the b-wave amplitudes of Timp4 defect rats were significantly reduced, consistent with the shorter length of the bipolar axons detected by HE and IF staining. Heterozygous LoF variants in the TIMP4 are associated with early onset high myopia, and the Timp4 defect disturbs ocular development by influencing the morphology and function of the ocular tissue.
Circulating Proteins as Diagnostic Markers in Gastric Cancer
Authors: Repetto Ombretta , Vettori Roberto , Steffan Agostino , Cannizzaro Renato , De Re Valli
Published: November 2023

Gastric cancer (GC) is a highly malignant disease affecting humans worldwide and has a poor prognosis. Most GC cases are detected at advanced stages due to the cancer lacking early detectable symptoms. Therefore, there is great interest in improving early diagnosis by implementing targeted prevention strategies. Markers are necessary for early detection and to guide clinicians to the best personalized treatment. The current semi-invasive endoscopic methods to detect GC are invasive, costly, and time-consuming. Recent advances in proteomics technologies have enabled the screening of many samples and the detection of novel biomarkers and disease-related signature signaling networks. These biomarkers include circulating proteins from different fluids (e.g., plasma, serum, urine, and saliva) and extracellular vesicles. We review relevant published studies on circulating protein biomarkers in GC and detail their application as potential biomarkers for GC diagnosis. Identifying highly sensitive and highly specific diagnostic markers for GC may improve patient survival rates and contribute to advancing precision/personalized medicine.
Nucleic Acid-Based Approaches to Tackle KRAS Mutant Cancers
Authors: Kim Jimi
Published: November 2023

Activating mutations in KRAS are highly relevant to various cancers, driving persistent efforts toward the development of drugs that can effectively inhibit KRAS activity. Previously, KRAS was considered ‘undruggable’; however, the recent advances in our understanding of RNA and nucleic acid chemistry and delivery formulations have sparked a paradigm shift in the approach to KRAS inhibition. We are currently witnessing a large wave of next-generation drugs for KRAS mutant cancers—nucleic acid-based therapeutics. In this review, we discuss the current progress in targeting KRAS mutant tumors and outline significant developments in nucleic acid-based strategies. We delve into their mechanisms of action, address existing challenges, and offer insights into the current clinical trial status of these approaches. We aim to provide a thorough understanding of the potential of nucleic acid-based strategies in the field of KRAS mutant cancer therapeutics.