bluuebunny/crossref_metadata_2025 huggingface dataset:
Relationship between Tilt Sensation Ability and Lower Limb Injuries in Junior Athletes
Authors: Tanaka Maki , Inoue Yuka , Gonno Megumi , Nomura Teruo , Oku Kyosuke , Matsui Tomoyuki , Hiramoto Machiko , Miyazaki Tetsuya , Koda Hitoshi , Watanabe Yuya , Kai Yoshihiro , Morihara Toru , Kida Noriyuki
Published: July 2024

The purpose of this study was to devise a tilt sensation measurement method to evaluate ankle proprioception and to examine its reliability. It was also used to determine the relationship among tilt sensation abilities, physical development, and lower limb injuries in junior athletes. In this study, a step platform created tilt angles. Participants with eye masks answered “yes” or “no” to sensing a tilt, evaluated over nine or seven trials. Experiment 1 involved 22 university students (20.6 ± 0.9 years). The minimum angle at which a tilt could be sensed while standing on both feet was determined, and measurements were taken again to examine reliability. Experiment 2 involved 40 junior athletes (12.3 ± 2.0 years), where the minimum angle for tilt sensation was obtained, and medical checks were conducted to assess injuries in the knee, lower leg, and foot. Reliability studies showed a moderately significant correlation between the first and second sessions (r = 0.504, p = 0.017), suggesting the reliability of the experimental method. The proportion capable of sensing a tilt of 1.1° and 1.6° was significantly higher in junior high school students than in elementary school students (1.1°; χ2 = 8.839, p = 0.003. 1.6°; χ2 = 4.038, p = 0.044). The group unable to sense a tilt of 1.6° and 2.1° had a significantly higher positive rate of knee injuries compared to the sensed group among junior high school students (1.6°; χ2 = 4.622, p = 0.032. 2.1°; χ2 = 4.622, p = 0.032). Our findings suggested that a reduced tilt sensation ability was associated with knee injuries in junior high school students. Utilizing our devised tilt sensation assessment could play a crucial role in preventing and detecting early injuries in junior high school students.
[18F]Flotaza for Aβ Plaque Diagnostic Imaging: Evaluation in Postmortem Human Alzheimer’s Disease Brain Hippocampus and PET/CT Imaging in 5xFAD Transgenic Mice
Authors: Sandhu Yasmin K. , Bath Harman S. , Shergill Jasmine , Liang Christopher , Syed Amina U. , Ngo Allyson , Karim Fariha , Serrano Geidy E. , Beach Thomas G. , Mukherjee Jogeshwar
Published: July 2024

The diagnostic value of imaging Aβ plaques in Alzheimer’s disease (AD) has accelerated the development of fluorine-18 labeled radiotracers with a longer half-life for easier translation to clinical use. We have developed [18F]flotaza, which shows high binding to Aβ plaques in postmortem human AD brain slices with low white matter binding. We report the binding of [18F]flotaza in postmortem AD hippocampus compared to cognitively normal (CN) brains and the evaluation of [18F]flotaza in transgenic 5xFAD mice expressing Aβ plaques. [18F]Flotaza binding was assessed in well-characterized human postmortem brain tissue sections consisting of HP CA1-subiculum (HP CA1-SUB) regions in AD (n = 28; 13 male and 15 female) and CN subjects (n = 32; 16 male and 16 female). Adjacent slices were immunostained with anti-Aβ and analyzed using QuPath. In vitro and in vivo [18F]flotaza PET/CT studies were carried out in 5xFAD mice. Post-mortem human brain slices from all AD subjects were positively IHC stained with anti-Aβ. High [18F]flotaza binding was measured in the HP CA1-SUB grey matter (GM) regions compared to white matter (WM) of AD subjects with GM/WM > 100 in some subjects. The majority of CN subjects had no decipherable binding. Male AD exhibited greater WM than AD females (AD WM♂/WM♀ > 5; p < 0.001) but no difference amongst CN WM. In vitro studies in 5xFAD mice brain slices exhibited high binding [18F]flotaza ratios (>50 versus cerebellum) in the cortex, HP, and thalamus. In vivo, PET [18F]flotaza exhibited binding to Aβ plaques in 5xFAD mice with SUVR~1.4. [18F]Flotaza is a new Aβ plaque PET imaging agent that exhibited high binding to Aβ plaques in postmortem human AD. Along with the promising results in 5xFAD mice, the translation of [18F]flotaza to human PET studies may be worthwhile.
Comparative Analysis of Breast Cancer Metabolomes Highlights Fascin’s Central Role in Regulating Key Pathways Related to Disease Progression
Authors: AlMalki Reem H. , Al-Nasrallah Huda K. , Aldossry Alanoud , Barnawi Rayanah , Al-Khaldi Samiyah , Almozyan Sheema , Al-Ansari Mysoon M. , Ghebeh Hazem , Abdel Rahman Anas M. , Al-Alwan Monther
Published: July 2024

Omics technologies provide useful tools for the identification of novel biomarkers in many diseases, including breast cancer, which is the most diagnosed cancer in women worldwide. We and others have reported a central role for the actin-bundling protein (fascin) in regulating breast cancer disease progression at different levels. However, whether fascin expression promotes metabolic molecules that could predict disease progression has not been fully elucidated. Here, fascin expression was manipulated via knockdown (fascinKD+NORF) and rescue (fascinKD+FORF) in the naturally fascin-positive (fascinpos+NORF) MDA-MB-231 breast cancer cells. Whether fascin dysregulates metabolic profiles that are associated with disease progression was assessed using untargeted metabolomics analyses via liquid chromatography–mass spectrometry. Overall, 12,226 metabolic features were detected in the tested cell pellets. Fascinpos+NORF cell pellets showed 2510 and 3804 significantly dysregulated metabolites compared to their fascinKD+NORF counterparts. Fascin rescue (fascinKD+FORF) revealed 2710 significantly dysregulated cellular metabolites compared to fascinKD+NORF counterparts. A total of 101 overlapped cellular metabolites between fascinKD+FORF and fascinpos+NORF were significantly dysregulated in the fascinKD+NORF cells. Analysis of the significantly dysregulated metabolites by fascin expression revealed their involvement in the metabolism of sphingolipid, phenylalanine, tyrosine, and tryptophan biosynthesis, and pantothenate and CoA biosynthesis, which are critical pathways for breast cancer progression. Our findings of fascin-mediated alteration of metabolic pathways could be used as putative poor prognostic biomarkers and highlight other underlying mechanisms of fascin contribution to breast cancer progression.
Robust CXCL10/IP-10 and CCL5/RANTES Production Induced by Tick-Borne Encephalitis Virus in Human Brain Pericytes Despite Weak Infection
Authors: Prančlová Veronika , Hönig Václav , Zemanová Marta , Růžek Daniel , Palus Martin
Published: July 2024

Tick-borne encephalitis virus (TBEV) targets the central nervous system (CNS), leading to potentially severe neurological complications. The neurovascular unit plays a fundamental role in the CNS and in the neuroinvasion of TBEV. However, the role of human brain pericytes, a key component of the neurovascular unit, during TBEV infection has not yet been elucidated. In this study, TBEV infection of the primary human brain perivascular pericytes was investigated with highly virulent Hypr strain and mildly virulent Neudoerfl strain. We used Luminex assay to measure cytokines/chemokines and growth factors. Both viral strains showed comparable replication kinetics, peaking at 3 days post infection (dpi). Intracellular viral RNA copies peaked at 6 dpi for Hypr and 3 dpi for Neudoerfl cultures. According to immunofluorescence staining, only small proportion of pericytes were infected (3% for Hypr and 2% for Neudoerfl), and no cytopathic effect was observed in the infected cells. In cell culture supernatants, IL-6 production was detected at 3 dpi, together with slight increases in IL-15 and IL-4, but IP-10, RANTES and MCP-1 were the main chemokines released after TBEV infection. These chemokines play key roles in both immune defense and immunopathology during TBE. This study suggests that pericytes are an important source of these signaling molecules during TBEV infection in the brain.
Nucleic Acids-Based Biomarkers for Alzheimer’s Disease Diagnosis and Novel Molecules to Treat the Disease
Authors: Bivona Giulia , Sammataro Selene , Ghersi Giulio
Published: July 2024

Alzheimer’s disease (AD) represents the most common form of dementia and affects million people worldwide, with a high social burden and considerable economic costs. AD diagnosis benefits from a well-established panel of laboratory tests that allow ruling-in patients, along with FDG and amyloid PET imaging tools. The main laboratory tests used to identify AD patients are Aβ40, Aβ42, the Aβ42/Aβ40 ratio, phosphorylated Tau 181 (pTau181) and total Tau (tTau). Although they are measured preferentially in the cerebrospinal fluid (CSF), some evidence about the possibility for blood-based determination to enter clinical practice is growing up. Unfortunately, CSF biomarkers for AD and, even more, the blood-based ones, present a few flaws, and twenty years of research in this field did not overcome these pitfalls. The tale even worsens when the issue of treating AD is addressed due to the lack of effective strategies despite the many decades of attempts by pharmaceutic industries and scientists. Amyloid-based drugs failed to stop the disease, and no neuroinflammation-based drugs have been demonstrated to work so far. Hence, only symptomatic therapy is available, with no disease-modifying treatment on hand. Such a desolate situation fully justifies the active search for novel biomarkers to be used as reliable tests for AD diagnosis and molecular targets for treating patients. Recently, a novel group of molecules has been identified to be used for AD diagnosis and follow-up, the nuclei acid-based biomarkers. Nucleic acid-based biomarkers are a composite group of extracellular molecules consisting of DNA and RNA alone or in combination with other molecules, including proteins. This review article reports the main findings from the studies carried out on these biomarkers during AD, and highlights their advantages and limitations.
The Regulatory Impact of CFLAR Methylation Modification on Liver Lipid Metabolism
Authors: Ye Chen , Jiang Wen , Hu Ting , Liang Jichao , Chen Yong
Published: July 2024

Non-alcoholic fatty liver disease (NAFLD) has emerged as the leading cause of chronic liver disease worldwide. Caspase 8 and FADD-like apoptosis regulator (CFLAR) has been identified as a potent factor in mitigating non-alcoholic steatohepatitis (NASH) by inhibiting the N-terminal dimerization of apoptosis signal-regulating kinase 1 (ASK1). While arginine methyltransferase 1 (PRMT1) was previously reported to be associated with increased hepatic glucose production, its involvement in hepatic lipid metabolism remains largely unexplored. The interaction between PRMT1 and CFLAR and the methylation of CFLAR were verified by Co-IP and immunoblotting assays. Recombinant adenoviruses were generated for overexpression or knockdown of PRMT1 in hepatocytes. The role of PRMT1 in NAFLD was investigated in normal and high-fat diet-induced obese mice. In this study, we found a significant upregulation of PRMT1 and downregulation of CFLAR after 48h of fasting, while the latter significantly rebounded after 12h of refeeding. The expression of PRMT1 increased in the livers of mice fed a methionine choline-deficient (MCD) diet and in hepatocytes challenged with oleic acid (OA)/palmitic acid (PA). Overexpression of PRMT1 not only inhibited the expression of genes involved in fatty acid oxidation (FAO) and promoted the expression of genes involved in fatty acid synthesis (FAS), resulting in increased triglyceride accumulation in primary hepatocytes, but also enhanced the gluconeogenesis of primary hepatocytes. Conversely, knockdown of hepatic PRMT1 significantly alleviated MCD diet-induced hepatic lipid metabolism abnormalities and liver injury in vivo, possibly through the upregulation of CFLAR protein levels. Knockdown of PRMT1 suppressed the expression of genes related to FAS and enhanced the expression of genes involved in FAO, causing decreased triglyceride accumulation in OA/PA-treated primary hepatocytes in vitro. Although short-term overexpression of PRMT1 had no significant effect on hepatic triglyceride levels under physiological conditions, it resulted in increased serum triglyceride and fasting blood glucose levels in normal C57BL/6J mice. More importantly, PRMT1 was observed to interact with and methylate CFLAR, ultimately leading to its ubiquitination-mediated protein degradation. This process subsequently triggered the activation of c-Jun N-terminal kinase 1 (JNK1) and lipid deposition in primary hepatocytes. Together, these results suggested that PRMT1-mediated methylation of CFLAR plays a critical role in hepatic lipid metabolism. Targeting PRMT1 for drug design may represent a promising strategy for the treatment of NAFLD.
Expanding the Phenotypic Spectrum of Pathogenic KIAA0586 Variants: From Joubert Syndrome to Hydrolethalus Syndrome
Authors: Deconte Desirée , Diniz Bruna Lixinski , Hartmann Jéssica K. , de Souza Mateus A. , Zottis Laira F. F. , Zen Paulo Ricardo Gazzola , Rosa Rafael F. M. , Fiegenbaum Marilu
Published: July 2024

KIAA0586 variants have been associated with a wide range of ciliopathies, mainly Joubert syndrome (JS, OMIM #616490) and short-rib thoracic dysplasia syndrome (SRTD, OMIM #616546). However, the hypothesis that this gene is involved with hydrolethalus syndrome (HSL, OMIM #614120) and orofaciodigital syndrome IV (OMIM #258860) has already been raised. Ciliopathies’ clinical features are often overlapped despite differing in phenotype severity. Besides KIAA0586, HYLS1 and KIF7 are also known for being causative of ciliopathies, indicating that all three genes may have similar or converging genomic pathways. Overall, the genotypic and phenotypic spectrum of ciliopathies becomes wider and conflicting while more and more new variants are added to this group of disorders’ molecular pot. In this case report we discuss the first Brazilian individual clinically diagnosed with hydrolethalus syndrome and molecular findings that demonstrate the role of KIAA0586 as a causative gene of a group of genetic disorders. Also, recent reports on individuals with intronic and exonic variants combined leading to ciliopathies support our patient’s molecular diagnosis. At the same time, we discuss variable expressivity and overlapping features in ciliopathies.
Primary Cell Culture as a Model System for Evolutionary Molecular Physiology
Authors: Harper James M.
Published: July 2024

Primary cell culture is a powerful model system to address fundamental questions about organismal physiology at the cellular level, especially for species that are difficult, or impossible, to study under natural or semi-natural conditions. Due to their ease of use, primary fibroblast cultures are the dominant model system, but studies using both somatic and germ cells are also common. Using these models, genome evolution and phylogenetic relationships, the molecular and biochemical basis of differential longevities among species, and the physiological consequences of life history evolution have been studied in depth. With the advent of new technologies such as gene editing and the generation of induced pluripotent stem cells (iPSC), the field of molecular evolutionary physiology will continue to expand using both descriptive and experimental approaches.
Tau beyond Tangles: DNA Damage Response and Cytoskeletal Protein Crosstalk on Neurodegeneration
Authors: Asada-Utsugi Megumi , Urushitani Makoto
Published: July 2024

Neurons in the brain are continuously exposed to various sources of DNA damage. Although the mechanisms of DNA damage repair in mitotic cells have been extensively characterized, the repair pathways in post-mitotic neurons are still largely elusive. Moreover, inaccurate repair can result in deleterious mutations, including deletions, insertions, and chromosomal translocations, ultimately compromising genomic stability. Since neurons are terminally differentiated cells, they cannot employ homologous recombination (HR) for double-strand break (DSB) repair, suggesting the existence of neuron-specific repair mechanisms. Our research has centered on the microtubule-associated protein tau (MAPT), a crucial pathological protein implicated in neurodegenerative diseases, and its interplay with neurons’ DNA damage response (DDR). This review aims to provide an updated synthesis of the current understanding of the complex interplay between DDR and cytoskeletal proteins in neurons, with a particular focus on the role of tau in neurodegenerative disorders.
Exploiting Glycyrrhiza glabra L. (Licorice) Flavanones: Licoflavanone’s Impact on Breast Cancer Cell Bioenergetics
Authors: Frattaruolo Luca , Lauria Graziantonio , Aiello Francesca , Carullo Gabriele , Curcio Rosita , Fiorillo Marco , Campiani Giuseppe , Dolce Vincenza , Cappello Anna Rita
Published: July 2024

Research on the energy metabolism of cancer cells is becoming a central element in oncology, and in recent decades, it has allowed us to better understand the mechanisms underlying the onset and chemoresistance of oncological pathologies. Mitochondrial bioenergetic processes, in particular, have proven to be fundamental for the survival of tumor stem cells (CSC), a subpopulation of tumor cells responsible for tumor recurrence, the onset of metastasis, and the failure of conventional anticancer therapies. Over the years, numerous natural products, in particular flavonoids, widely distributed in the plant kingdom, have been shown to interfere with tumor bioenergetics, demonstrating promising antitumor effects. Herein, the anticancer potential of Licoflavanone, a flavanone isolated from the leaves of G. glabra, was explored for the first time in breast cancer cells. The results obtained highlighted a marked antitumor activity that proved to be greater than that mediated by Glabranin or Pinocembrin, flavanones isolated from the same plant matrix. Furthermore, the investigation of Licoflavanone’s effects on breast cancer energy metabolism highlighted the inhibitory activity of this natural product on tumor bioenergetics, a mechanism that could underlie its ability to reduce tumor proliferation, invasiveness, and stemness.
The Advantage of Targeted Next-Generation Sequencing over qPCR in Testing for Druggable EGFR Variants in Non-Small-Cell Lung Cancer
Authors: Szpechcinski Adam , Moes-Sosnowska Joanna , Skronska Paulina , Lechowicz Urszula , Pelc Magdalena , Szolkowska Malgorzata , Rudzinski Piotr , Wojda Emil , Maszkowska-Kopij Krystyna , Langfort Renata , Orlowski Tadeusz , Sliwinski Pawel , Polaczek Mateusz , Chorostowska-Wynimko Joanna
Published: July 2024

The emergence of targeted therapies in non-small-cell lung cancer (NSCLC), including inhibitors of epidermal growth factor receptor (EGFR) tyrosine kinase, has increased the need for robust companion diagnostic tests. Nowadays, detection of actionable variants in exons 18–21 of the EGFR gene by qPCR and direct DNA sequencing is often replaced by next-generation sequencing (NGS). In this study, we evaluated the diagnostic usefulness of targeted NGS for druggable EGFR variants testing in clinical NSCLC material previously analyzed by the IVD-certified qPCR test with respect to DNA reference material. We tested 59 NSCLC tissue and cytology specimens for EGFR variants using the NGS ‘TruSight Tumor 15’ assay (Illumina) and the qPCR ‘cobas EGFR mutation test v2’ (Roche Diagnostics). The sensitivity and specificity of targeted NGS assay were evaluated using the biosynthetic and biological DNA reference material with known allelic frequencies (VAF) of EGFR variants. NGS demonstrated a sufficient lower detection limit for diagnostic applications (VAF < 5%) in DNA reference material; all EGFR variants were correctly identified. NGS showed high repeatability of VAF assessment between runs (CV% from 0.02 to 3.98). In clinical material, the overall concordance between NGS and qPCR was 76.14% (Cohen’s Kappa = 0.5933). The majority of discordant results concerned false-positive detection of EGFR exon 20 insertions by qPCR. A total of 9 out of 59 (15%) clinical samples showed discordant results for one or more EGFR variants in both assays. Additionally, we observed TP53 to be a frequently co-mutated gene in EGFR-positive NSCLC patients. In conclusion, targeted NGS showed a number of superior features over qPCR in EGFR variant detection (exact identification of variants, calculation of allelic frequency, high analytical sensitivity), which might enhance the basic diagnostic report.
The Next Frontier in Tuberculosis Investigation: Automated Whole Genome Sequencing for Mycobacterium tuberculosis Analysis
Authors: Ng Justin H. J. , Castro Lina , Gorzalski Andrew , Allred Adam , Siao Danielle , Wong Edwina , Lin Andrew , Shokralla Shadi , Pandori Mark , Masinde Godfred , Khaksar Ramin
Published: July 2024

A fully automated bacteria whole genome sequencing (WGS) assay was evaluated to characterize Mycobacterium tuberculosis (MTB) and non-tuberculosis Mycobacterium (NTM) clinical isolates. The results generated were highly reproducible, with 100% concordance in species and sub-lineage classification and 92% concordance between antimicrobial resistance (AMR) genotypic and phenotypic profiles. Using extracted deoxyribonucleic acid (DNA) from MTB clinical isolates as starting material, these findings demonstrate that a fully automated WGS assay, with a short turnaround time of 24.5 hours, provides timely and valuable insights into MTB outbreak investigation while providing reliable genotypic AMR profiling consistent with traditional antimicrobial susceptibility tests (AST). This study establishes a favorable proposition for the adoption of end-to-end fully automated WGS solutions for decentralized MTB diagnostics, thereby aiding in World Health Organization’s (WHO) vision of tuberculosis eradication.
Difamilast, a Topical Phosphodiesterase 4 Inhibitor, Produces Soluble ST2 via the AHR–NRF2 Axis in Human Keratinocytes
Authors: Tsuji Gaku , Yumine Ayako , Kawamura Koji , Takemura Masaki , Kido-Nakahara Makiko , Yamamura Kazuhiko , Nakahara Takeshi
Published: July 2024

Difamilast, a phosphodiesterase 4 (PDE4) inhibitor, has been shown to be effective in the treatment of atopic dermatitis (AD), although the mechanism involved remains unclear. Since IL-33 plays an important role in the pathogenesis of AD, we investigated the effect of difamilast on IL-33 activity. Since an in vitro model of cultured normal human epidermal keratinocytes (NHEKs) has been utilized to evaluate the pharmacological potential of adjunctive treatment of AD, we treated NHEKs with difamilast and analyzed the expression of the suppression of tumorigenicity 2 protein (ST2), an IL-33 receptor with transmembrane (ST2L) and soluble (sST2) isoforms. Difamilast treatment increased mRNA and protein levels of sST2, a decoy receptor suppressing IL-33 signal transduction, without affecting ST2L expression. Furthermore, supernatants from difamilast-treated NHEKs inhibited IL-33-induced upregulation of TNF-α, IL-5, and IL-13 in KU812 cells, a basophil cell line sensitive to IL-33. We also found that difamilast activated the aryl hydrocarbon receptor (AHR)–nuclear factor erythroid 2-related factor 2 (NRF2) axis. Additionally, the knockdown of AHR or NRF2 abolished the difamilast-induced sST2 production. These results indicate that difamilast treatment produces sST2 via the AHR–NRF2 axis, contributing to improving AD symptoms by inhibiting IL-33 activity.
Sex-Specific Changes to Brain Fatty Acids, Plasmalogen, and Plasma Endocannabinoids in Offspring Exposed to Maternal and Postnatal High-Linoleic-Acid Diets
Authors: Ezechukwu Henry C. , Ney Luke J. , Jarvis Madeline A. , Shrestha Nirajan , Holland Olivia J. , Cuffe James S. M. , Perkins Anthony V. , Yau Suk-Yu , McAinch Andrew J. , Hryciw Deanne H.
Published: July 2024

Linoleic acid (LA) is required for neuronal development. We have previously demonstrated sex-specific changes in cardiovascular and hepatic function in rat offspring from mothers consuming a high-LA diet, with some effects associated with reduced LA concentration in the postnatal diet. At this time, the impact of a high-maternal-LA diet on offspring brain development and the potential for the postnatal diet to alter any adverse changes are unknown. Rat offspring from mothers fed low- (LLA) or high-LA (HLA) diets during pregnancy and lactation were weaned at postnatal day 25 (PN25) and fed LLA or HLA diets until sacrifice in adulthood (PN180). In the offspring’s brains, the postnatal HLA diet increased docosapentaenoate in males. The maternal HLA diet increased LA, arachidonate, docosapentaenoate, C18:0 dimethylacetal (DMA), C16:0 DMA, C16:0 DMA/C16:0, and C18:0 DMA/C18:0, but decreased eoicosenoate, nervoniate, lignocerate, and oleate in males. Maternal and postnatal HLA diets reduced oleate and vaccenate and had an interaction effect on myristate, palmitoleate, and eicosapentaenoate in males. In females, maternal HLA diet increased eicosadienoate. Postnatal HLA diet increased stearate and docosapentaenoate. Maternal and postnatal HLA diets had an interaction effect on oleate, arachidate, and docosahexaenoic acid (DHA)/omega (n)-6 docosapentaenoic acid (DPA) in females. Postnatal HLA diet decreased DHA/n-6 DPA in males and females. Postnatal HLA diet increased plasma endocannabinoids (arachidonoyl ethanolamide and 2-arachidonoyl glycerol), as well as other N-acyl ethanolamides and testosterone. HLA diet alters brain fatty acids, plasma endocannabinoids, and plasmalogen concentrations in a development-specific and sex-specific manner.
Human Neutrophil Elastase: Characterization of Intra- vs. Extracellular Inhibition
Authors: Birk Denise , Siepmann Erika , Simon Stefan , Sommerhoff Christian P.
Published: July 2024

Neutrophil elastase (HNE), like other members of the so-called GASPIDs (Granule-Associated Serine Peptidases of Immune Defense), is activated during protein biosynthesis in myeloid precursors and stored enzymatically active in cytoplasmic granules of resting neutrophils until secreted at sites of host defense and inflammation. Inhibitors thus could bind to the fully formed active site of the protease intracellularly in immature progenitors, in circulating neutrophils, or to HNE secreted into the extracellular space. Here, we have compared the ability of a panel of diverse inhibitors to inhibit HNE in the U937 progenitor cell line, in human blood-derived neutrophils, and in solution. Most synthetic inhibitors and, surprisingly, even a small naturally occurring proteinaceous inhibitor inhibit HNE intracellularly, but the extent and dynamics differ markedly from classical enzyme kinetics describing extracellular inhibition. Intracellular inhibition of HNE potentially affects neutrophil functions and has side effects, but it avoids competition of inhibitors with extracellular substrates that limit its efficacy. As both intra- and extracellular inhibition have advantages and disadvantages, the quantification of intracellular inhibition, in addition to classical enzyme kinetics, will aid the design of novel, clinically applicable HNE inhibitors with targeted sites of action.
Effect of Ho3+ Substitution on Magnetic Properties of ZnCr2Se4
Authors: Jendrzejewska Izabela , Groń Tadeusz , Tomaszewicz Elżbieta , Stokłosa Zbigniew , Goryczka Tomasz , Goraus Jerzy , Pilch Michał , Pietrasik Ewa , Witkowska-Kita Beata
Published: July 2024

A series of ZnCr2−xHoxSe4 microcrystalline spinels (where x = 0.05, 0.075, and 0.10) containing holmium ions in octahedral coordination were obtained by sintering of adequate reactants at high temperatures. The obtained doped materials were characterized by X-ray diffraction, Scanning Electron Microscopy, UV–Vis–NIR, molecular field approximation, and XPS spectroscopies. Their thermal properties were also investigated. The doping of the ZnCr2S4 matrix with paramagnetic Ho3+ ions with a content of not more than 0.1 and a screened 4f shell revealed a significant effect of orbital and Landau diamagnetism, a strong reduction in short-range ferromagnetic interactions, and a broadening and shift of the peak of the first critical field by simultaneous stabilization of the sharp peak in the second critical field. These results correlate well with FPLO calculations, which show that Cr sites have magnetic moments of 3.19 µB and Ho sites have significantly larger ones with a value of 3.95 µB. Zn has a negligible magnetic polarization of 0.02 µB, and Se induces a polarization of approximately −0.12 µB.
Genome-Wide Association Studies on Resistance to Pea Weevil: Identification of Novel Sources of Resistance and Associated Markers
Authors: Osuna-Caballero Salvador , Cobos María J. , Ruiz Carmen M. , Wohor Osman Z. , Rispail Nicolas , Rubiales Diego
Published: July 2024

Little resistance to the pea weevil insect pest (Bruchus pisorum) is available in pea (Pisum sativum) cultivars, highlighting the need to search for sources of resistance in Pisum germplasm and to decipher the genetic basis of resistance. To address this need, we screened the response to pea weevil in a Pisum germplasm collection (324 accession, previously genotyped) under field conditions over four environments. Significant variation for weevil seed infestation (SI) was identified, with resistance being frequent in P. fulvum, followed by P. sativum ssp. elatius, P. abyssinicum, and P. sativum ssp. humile. SI tended to be higher in accessions with lighter seed color. SI was also affected by environmental factors, being favored by high humidity during flowering and hampered by warm winter temperatures and high evapotranspiration during and after flowering. Merging the phenotypic and genotypic data allowed genome-wide association studies (GWAS) yielding 73 markers significantly associated with SI. Through the GWAS models, 23 candidate genes were found associated with weevil resistance, highlighting the interest of five genes located on chromosome 6. These included gene 127136761 encoding squalene epoxidase; gene 127091639 encoding a transcription factor MYB SRM1; gene 127097033 encoding a 60S ribosomal protein L14; gene 127092211, encoding a BolA-like family protein, which, interestingly, was located within QTL BpLD.I, earlier described as conferring resistance to weevil in pea; and gene 127096593 encoding a methyltransferase. These associated genes offer valuable potential for developing pea varieties resistant to Bruchus spp. and efficient utilization of genomic resources through marker-assisted selection (MAS).
Novel Piperazine Derivatives of Vindoline as Anticancer Agents
Authors: Zsoldos Bernadett , Nagy Nóra , Donkó-Tóth Viktória , Keglevich Péter , Weber Márton , Dékány Miklós , Nehr-Majoros Andrea , Szőke Éva , Helyes Zsuzsanna , Hazai László
Published: July 2024

A series of novel vindoline–piperazine conjugates were synthesized by coupling 6 N-substituted piperazine pharmacophores at positions 10 and 17 of Vinca alkaloid monomer vindoline through different types of linkers. The in vitro antiproliferative activity of the 17 new conjugates was investigated on 60 human tumor cell lines (NCI60). Nine compounds presented significant antiproliferative effects. The most potent derivatives showed low micromolar growth inhibition (GI50) values against most of the cell lines. Among them, conjugates containing [4-(trifluoromethyl)benzyl]piperazine (23) and 1-bis(4-fluorophenyl)methyl piperazine (25) in position 17 of vindoline were outstanding. The first one was the most effective on the breast cancer MDA-MB-468 cell line (GI50 = 1.00 μM), while the second one was the most effective on the non-small cell lung cancer cell line HOP-92 (GI50 = 1.35 μM). The CellTiter-Glo Luminescent Cell Viability Assay was performed with conjugates 20, 23, and 25 on non-tumor Chinese hamster ovary (CHO) cells to determine the selectivity of the conjugates for cancer cells. These compounds exhibited promising selectivity with estimated half-maximal inhibitory concentration (IC50) values of 2.54 μM, 10.8 μM, and 6.64 μM, respectively. The obtained results may have an impact on the design of novel vindoline-based anticancer compounds.
Toward Robust Arabic AI-Generated Text Detection: Tackling Diacritics Challenges
Authors: Alshammari Hamed , Elleithy Khaled
Published: July 2024

Current AI detection systems often struggle to distinguish between Arabic human-written text (HWT) and AI-generated text (AIGT) due to the small marks present above and below the Arabic text called diacritics. This study introduces robust Arabic text detection models using Transformer-based pre-trained models, specifically AraELECTRA, AraBERT, XLM-R, and mBERT. Our primary goal is to detect AIGTs in essays and overcome the challenges posed by the diacritics that usually appear in Arabic religious texts. We created several novel datasets with diacritized and non-diacritized texts comprising up to 9666 HWT and AIGT training examples. We aimed to assess the robustness and effectiveness of the detection models on out-of-domain (OOD) datasets to assess their generalizability. Our detection models trained on diacritized examples achieved up to 98.4% accuracy compared to GPTZero’s 62.7% on the AIRABIC benchmark dataset. Our experiments reveal that, while including diacritics in training enhances the recognition of the diacritized HWTs, duplicating examples with and without diacritics is inefficient despite the high accuracy achieved. Applying a dediacritization filter during evaluation significantly improved model performance, achieving optimal performance compared to both GPTZero and the detection models trained on diacritized examples but evaluated without dediacritization. Although our focus was on Arabic due to its writing challenges, our detector architecture is adaptable to any language.
AI Language Models: An Opportunity to Enhance Language Learning
Authors: Cong Yan
Published: July 2024

AI language models are increasingly transforming language research in various ways. How can language educators and researchers respond to the challenge posed by these AI models? Specifically, how can we embrace this technology to inform and enhance second language learning and teaching? In order to quantitatively characterize and index second language writing, the current work proposes the use of similarities derived from contextualized meaning representations in AI language models. The computational analysis in this work is hypothesis-driven. The current work predicts how similarities should be distributed in a second language learning setting. The results suggest that similarity metrics are informative of writing proficiency assessment and interlanguage development. Statistically significant effects were found across multiple AI models. Most of the metrics could distinguish language learners’ proficiency levels. Significant correlations were also found between similarity metrics and learners’ writing test scores provided by human experts in the domain. However, not all such effects were strong or interpretable. Several results could not be consistently explained under the proposed second language learning hypotheses. Overall, the current investigation indicates that with careful configuration and systematic metrics design, AI language models can be promising tools in advancing language education.
VOC Characterization of Byasa hedistus (Lepidoptera: Papilionidae) and Its Visual and Olfactory Responses during Foraging and Courtship
Authors: Li Mingtao , Liu Jie , Chen Shunan , Yao Jun , Shi Lei , Chen Hang , Chen Xiaoming
Published: July 2024

Color and odor are crucial cues for butterflies during foraging and courtship. While most sexual dimorphic butterflies rely more on vision, our understanding of how butterflies with similar coloration use different signals remains limited. This study investigated the visual and olfactory behavioral responses of the similarly colored butterfly Byasa hedistus during foraging and courtship. While visiting artificial flowers of different colors, we found that B. hedistus exhibits an innate color preference, with a sequence of preferences for red, purple, and blue. The frequency of flower visits by B. hedistus significantly increased when honey water was sprayed on the artificial flowers, but it hardly visited apetalous branches with honey water. This proves that locating nectar sources by odor alone is difficult in the absence of floral color guides. During courtship, males are active while females hardly chase; only two models were observed: males chasing males and males chasing females. The courtship process includes four behaviors: slowing approach, straight chasing, hovering, and spinning. B. hedistus cannot distinguish between sexes based on color, as there is no significant difference in color and shape between them. Twenty-three VOCs (>1%) were identified in B. hedistus, with 21 shared by both sexes, while ketones are specific to males. These VOCs are principally represented by cineole, β-pinene, and linalool. When cineole was added to butterfly mimics, many butterflies were attracted to them, but the butterflies did not seem to distinguish between males and females. This suggests that cineole may be the feature VOC for identifying conspecific groups. Adding β-pinene and linalool to mimics induced numerous butterflies to chase, hover, spin around, and attempt to mate with them. This suggests that β-pinene and linalool are crucial cues indicating the presence of females.
The Relationship between Selective Digestive Decontamination and Nosocomial Infections in Patients Receiving Continuous Renal Replacement Therapy in ICUs: A Multicenter Study
Authors: Vicente Arranz Juan Luis , Sánchez-Ramírez Catalina , Saavedra Pedro , Rivero Perdomo Yasmina , Lorenzo-Martín María Victoria , Blanco-López José , Domínguez Cabrera Casimira , Hernández-Socorro Carmen-Rosa , Ruiz-Santana Sergio
Published: July 2024

Background: Nosocomial infections are a worldwide healthcare issue, especially in intensive care units (ICUs), and they had a prevalence of 21.1% in 2023 in Spain. Numerous predisposing risk factors have been identified, with the most relevant being invasive techniques, including renal replacement therapies (RRTs). Several outstanding strategies have been published that prevent or reduce their incidence, including the nationwide ZERO in Spain, which consists of structured guidelines to be implemented to tackle this problem. One of these strategies, which is defined as ‘highly recommended’ in these projects, is selective digestive decontamination (SDD). The main aim of this study is to compare the incidences of ICU-acquired infections, including those due to multidrug-resistant bacteria (MDRB), in two cohorts of RRT with or without SDD. Methods: We conducted a multicenter, prospective, observational study at two tertiary hospitals in Spain. In total, 140 patients treated with RRT were recruited based on their exposure to SDD. Surveillance microbiological samples and nosocomial infection risk factors were obtained. Infection rates per 1000 days of exposure and the MDRB incidence density ratio were determined. Results: SDD statistically significantly reduced RRT-associated nosocomial infections (OR: 0.10, 95% CI: (0.04–0.26)) and the MDRB incidence density ratio (IDR: 0.156, 95% CI = 0.048–0.506). However, mechanical ventilation (OR: 7.91, 95% CI: (2.54–24.66)) and peripheral vascular disease (OR: 3.17, 95% CI: (1.33–7.56)) were significantly associated with increases in infections. Conclusions: Our results favor the use of SDD in ICU patients with renal failure undergoing CRRT as a tool for infection control.
Functional and Structural Changes in Patients with Spinal Muscular Atrophy Treated in Poland during 12-Month Follow-Up: A Prospective Cohort Study
Authors: Bieniaszewska Aleksandra , Sobieska Magdalena , Gajewska Ewa
Published: July 2024

Background: In recent years, rapid advances in diagnosis and treatment have been observed in spinal muscular atrophy (SMA) patients. The introduction of modern therapies and screening tests has significantly changed the clinical picture of the disease. The previous classification has, therefore, been replaced by new phenotypes: non-sitters, sitters, and walkers, defined by the patient’s functional level. However, despite the change in the clinical picture of the disease, patients still suffer from accompanying structural disorders such as scoliosis or joint contractures. Their presence also significantly affects the acquisition of subsequent motor skills. Due to this, monitoring structural changes and ensuring therapists are aware of improvements or declines in patient functionality are essential components of clinical practice. This study aims to compare the assessment of structural and functional changes after a 12-month follow-up in SMA patients who have already experienced the effects of the disease and are now receiving modern therapy. Methods: We present a study of 34 SMA patients being treated with modern therapies and tested twice 12 months apart. The participants were tested using structural measurements and validated scales such as The Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) and Hammersmith Functional Motor Scale–Expanded (HFMSE). Results: During the 12-month follow-up, patients showed deteriorating, non-statistically significant structural changes. We also proved that patients showed a trend toward functional improvement. Analyzing the individual scale items, we distinguished which participants obtained the maximum score for a given parameter and no longer had an opportunity to improve during the second examination. Conclusions: Our study proved that most patients improved overall motor function. The examination of structural measurements should become a standard in the evaluation of SMA patients.
A Parallelized Climatological Drifter-Based Model of Sargassum Biomass Dynamics in the Tropical Atlantic
Authors: Payne Karl , Greene Khalil , Oxenford Hazel A.
Published: July 2024

The movement and biomass fluctuations of sargassum across the Tropical Atlantic have profound implications when influxes reach the Eastern Caribbean. These influxes have cross-cutting impacts across ecological, economic, and social systems. The objective of this work is to quantify sargassum biomass accumulation in the Eastern Caribbean, accounting for the spatial variability in sea surface temperature and morphotype diversity. A parallel implementation of a climatological drifter-based model was used to simulate advection of sargassum across the model domain. After determining the trajectory of virtual sargassum particles, Monte Carlo simulations using 1000 realizations were run to quantify biomass accumulations along these tracks. For simulations with a single morphotype, the biomass accumulation as predicted by the model effectively reproduced the seasonal distributions of sargassum for the simulated period (May 2017 to August 2017). The model closely approximated an observed increase during the period from May to July 2017, followed by a subsequent decline in sargassum abundance. A major factor that led to the discrepancy between the simulated and observed biomass accumulation is the occlusion of the optical satellite signal from cloud cover, which led to underestimates of sargassum abundance. The mean maximum growth rate required to reproduce the observed sargassum biomass was 0.05 day−1, which is consistent with other published experimental and computational studies that have reported similar growth rates for sargassum populations under comparable environmental conditions. An innovative aspect of this study was the investigation of the biomass dynamics of the three dominant morphotypes found in the study area. The results from these simulations show that the accumulation of the fastest growing morphotype, Sargassum fluitans var. fluitans, closely approximates the profiles of the overall prediction with a single morphotype.
Research on the Construction of a Digital Twin System for the Long-Term Service Monitoring of Port Terminals
Authors: Bi Jinqiang , Wang Peiren , Zhang Wenjia , Bao Kexin , Qin Liu
Published: July 2024

Structural damage is a prevalent issue in long-term operations of harbor terminals. Addressing the lack of transparency in terminal infrastructure components, the limited integration of sensor monitoring data, and the insufficient support for feedback on service performance, we propose a novel digital twin system construction methodology tailored for the long-term monitoring of port terminals. This study elaborates on the organization and processing of foundational geospatial data, sensor monitoring information, and oceanic hydrometeorological data essential for constructing a digital twin of the terminal. By mapping relationships between physical and virtual spaces, we developed comprehensive dynamic and static models of terminal facilities. Employing a “particle model” approach, we visually represented oceanic and meteorological elements. Additionally, we developed a multi-source heterogeneous data fusion model to facilitate the rapid creation of data indexes for harbor elements under high concurrency conditions, effectively addressing performance issues related to scene-rendering visualization and real-time sensor data storage efficiency. Experimental validation demonstrates that this method enables the rapid construction of digital twin systems for port terminals and supports practical application in business scenarios. Data analysis and comparison confirm the feasibility of the proposed method, providing an effective approach for the long-term monitoring of port terminal operations.
Standard Total Ankle Arthroplasty vs. Patient-Specific Instrumentation: A Comparative Study
Authors: Arceri Alberto , Abdi Pejman , Mazzotti Antonio , Zielli Simone Ottavio , Artioli Elena , Langone Laura , Sgubbi Federico , Faldini Cesare
Published: July 2024

Purpose: This retrospective study aims to compare surgical outcomes between two cohorts of patients who underwent total ankle arthroplasty (TAA) using either standard technique or patient-specific instrumentation (PSI). Methods: A consecutive series of patients who affected of end-staged ankle osteoarthritis were retrospectively assessed and divided into two groups based on TAA techniques: a TAA standard technique group and a TAA-using PSI group. The two groups were compared in terms of operative time, additional procedures, complications (neurovascular and wound problems, infection, loosening and osteolysis, revision and explantation rates, and perioperative fracture), clinical scores, and range of motion (ROM). Result: Fifty-one patients underwent standard TAA, while 13 patients underwent TAA with PSI. At 1-year follow-up, there were no significant differences in complication rates between the two groups (p > 0.05). AOFAS scores were similar, with the standard TAA group scoring 83.33 ± 7.55 and the PSI group scoring 82.92 ± 9.7 (p = 0.870). Likewise, the postoperative ROM did not differ significantly, with 15.12 ± 7.6 degrees for the standard TAA group and 16.05 ± 6.7 degrees for the PSI group (p = 0.689). However, the standard TAA group experienced significantly longer operative time (107.1 ± 22.1 min) compared to the PSI group (91.92 ± 22.9 min, p = 0.032). Additionally, the standard TAA group required more adjunctive procedures (29.7%) compared to the PSI group (7.7%, p = 0.04). Residual pain was also more frequently reported in the standard TAA group (62.7%) than in the PSI group (30.7%, p = 0.038). Conclusion: While both techniques resulted in comparable complication rates, clinical scores and ROM, the PSI group reported significantly shorter operative time and less residual pain, thus requiring fewer postoperative procedures.