bluuebunny/crossref_metadata_2025 huggingface dataset:
Medically Tailored Grocery Deliveries to Improve Food Security and Hypertension in Underserved Groups: A Student-Run Pilot Randomized Controlled Trial
Authors: Lapay Elaijah R. , Sytsma Trevor M. , Hutchinson Haley M. , Yoon Elliot J. , Brummel Scott A. , Tang Linda Y. , Suarez Elena G. , Mitra Kishen , Kane Ryan M. , Hemming J. Patrick
Published: January 2025

Background/Objectives: Randomized controlled trials (RCTs) are needed to evaluate the impact of food is medicine (FIM) programs, such as medically tailored groceries (MTGs) to treat hypertension among diverse populations. Partnerships between academic centers’ student-run organizations (SROs) and community-based organizations (CBOs) offer critical safety nets for historically underserved groups, positioning these organizations to effectively undertake FIM programs among populations disproportionately affected by hypertension. We conducted an unblinded pilot RCT whose objectives were to assess the feasibility and acceptability of an SRO-coordinated, CBO-partnered MTGs intervention targeting blood pressure (BP) and food insecurity (FI) in underserved groups. Methods: Adult Black/African American and Hispanic/Latinx patients in Durham, North Carolina, where essential hypertension and FI were randomized (parallel arm, computerized 1:1 ratio) to 12 weeks of home-delivered, hypertension-focused MTGs plus in-person nutrition education sessions with compensation (intervention) versus data collection sessions with compensation (control). We offered transportation, childcare, and home visits to facilitate session attendance. The primary outcomes were the eligibility, enrollment, and retention rates (feasibility), and the survey feedback from the participants and CBO partners (acceptability). The secondary outcomes included the changes in the mean BP and median FI score with associated 95% confidence intervals. Results: Medical record screening identified 1577 eligible participants. Of the 94 reached to confirm eligibility, 77 met the enrollment criteria, and 50 were randomized (82% post-screen eligibility, 65% enrollment). A conventional content analysis of 15 participant surveys and CBO partner feedback affirmed the acceptability, noting intervention components that enhanced the retention (e.g., home delivery, transportation support, home visits). Pre–post analyses of secondary outcomes for 13/25 intervention and 15/25 control participants completing ≥2 sessions ≥2 months apart were performed. The intervention was associated with an average change in systolic BP of −14.2 mmHg (−27.5, −4.5) versus −3.5 mmHg (−11.7, 5.9) in the control group. The FI scores improved by −2 (−2.2, −0.5) in the intervention group and −1 (−1.3, −0.2) in the control group. No adverse events were reported. Conclusions: SRO-CBO partnerships could be feasible and acceptable avenues for conducting FIM trials among underserved populations. This multi-component FIM approach enhanced the study equity by addressing the participants’ disease-related social needs and warrants expansion into a powered RCT.
The Application of Three Dimensional Digital Technologies in Historic Gardens and Related Cultural Heritage: A Scoping Review
Authors: Li Fangming , Achille Cristiana , Vassena Giorgio Paolo Maria , Fassi Francesco
Published: January 2025

This paper presents a comprehensive scoping review of the application of 3D digital technologies in the documentation, conservation, and management of historic gardens and related cultural heritage. By analyzing a curated selection of literature, this study assessed the current state of research, highlighting trends in publications, the geographic distribution of contributors, and the key technologies employed. Using bibliometric methods and visualization tools, followed by a case study review, this review identified significant research hotspots and technical methodologies, particularly focusing on advanced techniques such as mobile laser scanning, UAV photogrammetry, and point cloud processing and their relationships with end users. The findings emphasize the importance of integrating multiple technologies to capture the diverse elements of historic gardens, including architectural features, vegetation, and topography. This review also underscores the significance of dynamic landscapes facing challenges posed by environmental degradation and urban development pressures. Moreover, it discusses the limitations of existing research and outlines future opportunities, such as the development of 4D documentation systems and the incorporation of AI for improving heritage management. This paper concludes by recommending interdisciplinary collaboration and public engagement to enhance the accessibility, understanding, and sustainable management of historic gardens through innovative technological applications.
Novel Alleles of the Potato Leaf Gene Identified in Italian Traditional Varieties Conferring Potato-like Leaf Shape in Tomato
Authors: Mancini Lorenzo , Farinon Barbara , Fumelli Ludovica , Picarella Maurizio Enea , Mazzucato Andrea , Olivieri Fabrizio
Published: January 2025

The genetic diversity of tomato in Italy and the growing interest in high-quality food products highlight the importance of establishing varietal distinctiveness through molecular strategies to ensure agrifood product quality and traceability. In this study, four Italian potato-like leaf (PL) landraces were analyzed: “Spagnoletta di Formia e di Gaeta” (SPA) from southern Lazio, “Giagiù” (GIA) and “Patanara” (PTN) from Campania, and “Pomodoro di Mola” (MOL) from Apulia. These landraces were genotyped for the potato leaf gene (C), with two PL American genotypes and a non-allelic PL mutant line included as outgroups. Nagcarlang served as control. An allelism test confirmed C as determinant gene. The SCAR marker for C revealed that the Italian landraces presented determinants other than the most representative one responsible for PL. Whole-genome sequencing of SPA identified a private novel nonsense SNP variant allele, confirmed through dCAPS marker analysis. Additionally, two novel PL alleles responsible for missense variations were identified in GIA/PTN and MOL. In silico protein analysis suggested that novel C alleles could be functional determinants for the protein activity. Overall, PL mutations identified for the first time could serve as molecular tools for agrifood chain traceability, enabling early differentiation and recognition of genotypically similar varieties.
Effective Tomato Spotted Wilt Virus Resistance Assessment Using Non-Destructive Imaging and Machine Learning
Authors: Kim Sang Gyu , Lee Sang-Deok , Lee Woo-Moon , Jeong Hyo-Bong , Yu Nari , Lee Oak-Jin , Lee Hye-Eun
Published: January 2025

There is a growing need to establish a breed reassessment system responding to tomato spotted wilt virus (TSWV) mutations. Conventional visual survey methods allow for assessing TSWV severity and disease incidence, while enzyme-linked Immunosorbent Assay (ELISA) data analysis can replace and validate visual surveys. This study proposes a non-destructive evaluation technique for TSWV using an open software platform based on image processing and machine learning. Many studies have evaluated resistance to the TSWV. However, as strains that destroy TSWV resistance emerge, an evaluation technique that can identify new genetic resources with resistance to the variants is needed. Evaluation techniques based on images and machine learning have the strength to respond quickly and accurately to the emergence of new variants. However, studies on resistance to viruses rely on empirical judgment based on visual surveys. The accuracy of the training model using Support Vector Machine (SVM), Logistic Regression (LR), and neural networks (NNs) was excellent, in the following order: NNs (0.86), LR (0.81), SVM (0.65). Meanwhile, the accuracy of the validation model was good, in the following order NN (0.84), LR (0.79), SVM (0.71). NNs’ prediction performance was verified through ELISA data analysis, showing a causal relationship between the two data sets with an R² of 0.86 with statistical significance. Imaging and NN-based TSWV resistance assessment technologies show significant potential as key tools in genetic resource reassessment systems that ensure a rapid and accurate response to the emergence of new TSWV strains.
“Omics” and Postmortem Interval Estimation: A Systematic Review
Authors: Secco Laura , Palumbi Stefano , Padalino Pasquale , Grosso Eva , Perilli Matteo , Casonato Matteo , Cecchetto Giovanni , Viel Guido
Published: January 2025

Postmortem interval (PMI) estimation is a challenge of utmost importance in forensic daily practice. Traditional methods face limitations in accuracy and reliability, particularly for advanced decomposition stages. Recent advances in “omics” sciences, providing a holistic view of postmortem biochemical changes, offer promising avenues for overcoming these challenges. This systematic review aims at investigating the role of mass-spectrometry-based “omics” approaches in PMI estimation to elucidate molecular mechanisms underlying predictable time-dependent biochemical alterations occurring after death. A systematic search was performed, adhering to PRISMA guidelines, through “free-text” protocols in the databases PubMed, SCOPUS and Web of Science. The inclusion criteria were as follows: experimental studies analyzing, as investigated samples, animal or human corpses in toto or in parts and estimating PMI through MS-based untargeted omics approaches, with full texts in the English language. Quality assessment was performed using STROBE and ARRIVE critical appraisal checklists. A total of 1152 papers were screened and 26 included. Seventeen papers adopted a proteomic approach (65.4%), nine focused on metabolomics (34.6%) and two on lipidomics (7.7%). Most papers (57.7%) focused on short PMIs (<7 days), the remaining papers explored medium (7–120 days) (30.77%) and long PMIs (>120 days) (15.4%). Muscle tissue was the most frequently analyzed substrate (34.6% of papers), followed by liver (19.2%), bones (15.4%), cardiac blood and leaking fluids (11.5%), lung, kidney and serum (7.7%), and spleen, vitreous humor and heart (3.8%). Predictable time-dependent degradation patterns of macromolecules in different biological substrates have been discussed, with special attention to molecular insights into postmortem biochemical changes.
Prenatal Constant Light Exposure Induces Behavioral Deficits in Male and Female Rat Offspring: Effects of Prenatal Melatonin Treatment
Authors: Stoyanova Tsveta , Nocheva Hristina , Nenchovska Zlatina , Krushovlieva Desislava , Ivanova Petya , Tchekalarova Jana
Published: January 2025

Prenatal constant light exposure (CLE) impaired the anxiety response and circadian rhythms of testicular enzymes in adult male rat offspring, while melatonin corrected these deficiencies. However, the mechanism by which CLE induces these long-term behavioral consequences and the impact of melatonin system have not been examined. The aim of the present study was to investigate the effects of prenatal CLE and melatonin treatment on anxiety- and depression-like behaviors, and the melatonin system in male and female adult rat offspring. Six groups of male and female rat offspring (P60) exposed to either light/dark (LD) or CL regimes, and treated with vehicle or melatonin (10 mg/kg, s.c.) were evaluated for anxiety by open field (OF), elevated plus maze (EPM), and light/dark (LD) tests, and depressive-like response by splash test and sucrose preference test. Plasma adrenocorticotropic hormone (ACTH), corticosterone (CORT) and melatonin expression, and hippocampal MT1A and MT1b receptor expression were assessed by ELISA. Prenatal CLE induced behavioral deficits and elevated plasma CORT levels, while melatonin levels, their circadian rhythmicity, and hippocampal MT receptor expression were not altered in male and female offspring in the CLE regime. However, prenatal melatonin treatment corrected behavioral deficits in a sex-specific manner by up-regulating hippocampal MT receptors, even without altering systemic melatonin levels or normalizing CORT in either sex. The results of this study suggest critical insights into how prenatal environmental factors and therapeutic interventions shape physiological and behavioral outcomes.
Multifunctional Role of Cytokinin in Horticultural Crops
Authors: Hussain Shahid , Chang Jingjing , Li Jing , Chen Lei , Ahmad Sheraz , Song Zhao , Zhang Baige , Chen Xiao
Published: January 2025

Cytokinins (CKs) are a class of phytohormones identified in the early 1960s and are mainly responsible for stimulating cell division. Following the discovery, research to help understand the pluralistic roles of CKs in plant growth and stress biology increased. With their fascinating ability, CKs serve as an important element in regulating the defense–growth trade-off. Herein, we demonstrate how the CK fine-tuning the organogenesis of different parts of horticultural plants is discussed. CK’s role in tailoring reproductive biology (flowering, sex differentiation, fruit set, and fruit attributes) has been presented. An extensive explanation of the CK-mediated response of horticultural crops to abiotic (temperature, drought, and salinity) and biotic stresses (fungal, bacterial, and nematodes) is provided. Finally, we posit the unexplored roles of CKs and highlight the research gaps worth addressing.
SARS-CoV-2 S, M, and E Structural Glycoproteins Differentially Modulate Endoplasmic Reticulum Stress Responses
Authors: Albalawi Wejdan , Thomas Jordan , Mughal Farah , Kotsiri Aurelia , Roper Kelly J. , Alshehri Abdullateef , Kelbrick Matthew , Pollakis Georgios , Paxton William A.
Published: January 2025

We have previously shown that the hepatitis C virus (HCV) E1E2 envelope glycoprotein can regulate HIV-1 long-terminal repeat (LTR) activity through disruption to NF-κB activation. This response is associated with upregulation of the endoplasmic reticulum (ER) stress response pathway. Here, we demonstrate that the SARS-CoV-2 S, M, and E but not the N structural protein can perform similar downmodulation of HIV-1 LTR activation, and in a dose-dependent manner, in both HEK293 and lung BEAS-2B cell lines. This effect is highest with the SARS-CoV-2 Wuhan S strain and decreases over time for the subsequent emerging variants of concern (VOC), with Omicron providing the weakest effect. We developed pseudo-typed viral particle (PVP) viral tools that allowed for the generation of cell lines constitutively expressing the four SARS-CoV-2 structural proteins and utilising the VSV-g envelope protein to deliver the integrated gene construct. Differential gene expression analysis (DGEA) was performed on cells expressing S, E, M, or N to determine cell activation status. Gene expression differences were found in a number of interferon-stimulated genes (ISGs), including IF16, IFIT1, IFIT2, and ISG15, as well as for a number of heat shock protein (HSP) genes, including HSPH1, HSPA6, and HSPBP1, with all four SARS-CoV-2 structural proteins. There were also differences observed in expression patterns of transcription factors, with both SP1 and MAVS upregulated in the presence of S, M, and E but not the N protein. Collectively, the results indicate that gene expression patterns associated with ER stress pathways can be activated by SARS-CoV-2 envelope glycoprotein expression. The results suggest the SARS-CoV-2 infection can modulate an array of cell pathways, resulting in disruption to NF-κB signalling, hence providing alterations to multiple physiological responses of SARS-CoV-2-infected cells.
Bioanalytical Application of the Total-Reflection X-Ray Fluorescence Spectrometry
Authors: Fernández-Ruiz Ramón
Published: January 2025

This paper briefly overviews the application of total-reflection X-ray fluorescence (TXRF) spectrometry in the biosciences, focusing on key bioanalytical applications. It seeks to review and update the current state of TXRF’s use in biomedical, biochemical, and pharmacological research. The review highlights relevant works in the field, summarising past achievements and incorporating the latest developments. The goal is to demonstrate how the analytical application of TXRF spectrometry in this area has evolved and what its role is in analysing trace elements and other biomolecules in diverse biological samples and diseases. Physical foundations to understand its analytical power and its comparison with related analytical techniques are presented to gain objective knowledge of the benefits, limitations, and drawbacks that TXRF spectrometry can offer.
Overexpression of Apolipoprotein A-I Alleviates Insulin Resistance in MASLD Mice Through the PPARα Pathway
Authors: Wang Yifan , Zhang Yudian , Wang Yutong
Published: January 2025

Insulin resistance (IR) is one of the important causes of metabolic dysfunction-associated steatotic liver disease (MASLD). Apolipoprotein A-I (apoA-I) is secreted primarily by hepatocytes and plays an essential role in reverse cholesterol transport. Our previous studies revealed that apoA-I can mitigate the progression of metabolic dysfunction-associated steatohepatitis (MASH). However, there is no clear evidence to explain the relationship between apoA-I and IR. Here, we investigated the effects of apoA-I overexpression on IR in both HepG2 cells and mice. In vitro experiment results revealed that apoA-I overexpression can promote cellular glucose uptake in oleic acid-induced IR in HepG2 cells. High-fat, high-cholesterol, and high-fructose diets were used to induce IR in mice. The results showed that apoA-I overexpression improved glucose tolerance, reduced serum insulin levels, and ameliorated IR in diet-induced MASLD mice. Moreover, apoA-I promoted the expression of peroxisome proliferator-activated receptor α (PPARα) in the nucleus both in vitro and in vivo. In conclusion, apoA-I could alleviate MASLD by reducing IR in mice and might exert this effect through the PPARα pathway.
Transcriptomics Unveil Canonical and Non-Canonical Heat Shock-Induced Pathways in Human Cell Lines
Authors: Reinschmidt Andrew , Solano Luis , Chavez Yonny , Hulsy William Drew , Nikolaidis Nikolas
Published: January 2025

The cellular stress response (CSR) is a conserved mechanism that protects cells from -environmental and physiological stressors. The heat shock response (HSR), a critical component of the CSR, utilizes molecular chaperones to mitigate proteotoxic stress caused by elevated temperatures. We hypothesized that while the canonical HSR pathways are conserved across cell types, specific cell lines may exhibit unique transcriptional responses to heat shock. To test this, we compared the transcriptomic responses of HEK293, HepG2, and HeLa cells under control conditions immediately following heat shock and after an 8-h recovery period. RNA sequencing revealed the conserved activation of canonical HSR pathways, including the unfolded protein response, alongside the -enrichment of the non-canonical “Receptor Ligand Activity” pathway across all cell lines. Cell-line-specific variations were observed, with HepG2 cells exhibiting significantly higher ex-pression levels of certain genes compared to other cell lines under stress conditions, as well as greater fold changes in gene expression relative to its control conditions. Validation by qPCR confirmed the activation of key genes within the “Receptor Ligand Activity” pathway across time points. These findings provide insights into conserved and context-specific aspects of the HSR, contributing to a more comprehensive understanding of stress response mechanisms across mammalian cells.
Integrated Analysis of Terpenoid Profiles and Full-Length Transcriptome Reveals the Central Pathways of Sesquiterpene Biosynthesis in Atractylodes chinensis (DC.) Koidz
Authors: Zhang Zheng , Tian Yelin , Qiao Xu , Li Hanqiu , Ouyang Lizhi , Li Xinyu , Geng Xin , Xiao Li , Ma Yimian , Li Yuan
Published: January 2025

Atractylodes chinensis (DC.) Koidz. is an aromatic and medicinal plant in East Asia. The primary bioactive compounds in this species are sesquiterpenes, particularly β-eudesmol, hinesol, and atractylon. Cultivation techniques require improvement to meet the medicinal demands of this species. In this study, gas chromatography–mass spectrometry analysis of an A. chinensis germplasm showed its essential oil contained various sesquiterpenes, including a high relative ratio of β-eudesmol. Full-length transcriptome profiling of A. chinensis revealed 26 genes related to terpenoid biosynthesis. These genes belonged to 13 gene families, including five in the isopentenyl pyrophosphate synthase gene family and four in the terpene synthase gene family. The functions of the four terpene synthase genes were proposed based on gene expression patterns and phylogenetic relationships: one was thought to encode monoterpene synthase and three to encode sesquiterpene synthase. Based on the results, the central biosynthesis pathways of the major sesquiterpenes in the A. chinensis rhizome were proposed, and three sesquiterpene synthase genes were identified as expressed in the rhizome for the first time. AcHMGR, AcFPPS, and the three sesquiterpene synthase genes were proposed as potential targets for molecular breeding in A. chinensis to enhance its sesquiterpene content.
Characterization of CK2, MYC and ERG Expression in Biological Subgroups of Children with Acute Lymphoblastic Leukemia
Authors: Lo Nigro Luca , Arrabito Marta , Andriano Nellina , Iachelli Valeria , La Rosa Manuela , Bonaccorso Paola
Published: January 2025

Despite the excellent survival rate, relapse occurs in 20% of children with ALL. Deep analyses of cell signaling pathways allow us to identify new markers and/or targets promising more effective and less toxic therapy. We analyzed 61 diagnostic samples collected from 35 patients with B- and 26 with T-ALL, respectively. The expression of CK2, MYC and ERG genes using Sybr-Green assay and the comparative 2-ΔΔCt method using 20 healthy donors (HDs) was evaluated. We observed a statistically significant difference in CK2 expression in non-HR (p = 0.010) and in HR (p = 0.0003) T-ALL cases compared to HDs. T-ALL patients with PTEN-Exon7 mutation, IKZF1 and CDKN2A deletions showed high CK2 expression. MYC expression was higher in pediatric T-ALL patients than HDs (p = 0.019). Surprisingly, we found MYC expression to be higher in non-HR than in HR T-ALL patients. TLX3 (HOX11L2)-rearranged T-ALLs (27%) in association with CRLF2 overexpression (23%) showed very high MYC expression. In B-ALLs, we detected CK2 expression higher than HDs and MYC overexpression in HR compared to non-HR patients, particularly in MLL-rearranged B-ALLs. We observed a strong difference in ERG expression between pediatric T- and B-ALL cases. In conclusion, we confirmed CK2 as a prognostic marker and a therapeutic target.
Pharmacological Inhibition of MDM2 Induces Apoptosis in p53-Mutated Triple-Negative Breast Cancer
Authors: On Jasmin Linh , Ghaderi Sahel , Rittmann Carina , Hoffmann Greta , Gier Franziska , Woloschin Vitalij , Tu Jia-Wey , Bhatia Sanil , Kulik Andrea , Niederacher Dieter , Neubauer Hans , Kurz Thomas , Fehm Tanja , Esser Knud
Published: January 2025

Triple-negative breast cancer (TNBC) represents the most aggressive breast carcinoma subtype lacking efficient therapeutic options. A promising approach in cancer treatment is the pharmacological inhibition of murine double minute 2 (MDM2)-p53 interaction inducing apoptosis in p53 wild-type tumors. However, the role of MDM2 in TNBC with primarily mutant p53 is not well understood. We here selected the clinical-stage MDM2 inhibitors Idasanutlin and Milademetan and investigated their anti-tumoral effects in TNBC. When we analyzed anti-tumor activity in the TNBC cell lines MDA-MB-231, MDA-MB-436, and MDA-MB-468, cellular viability was efficiently reduced, with half maximal inhibitory concentration (IC50) values ranging between 2.00 and 7.62 µM being up to 11-fold lower compared to the well-characterized non-clinical-stage MDM2 inhibitor Nutlin-3a. Furthermore, caspase-3/7 activity was efficiently induced. Importantly, the IC50 values for MDM2 inhibition were equally observed in HCT116 p53+/+ or HCT116 p53−/− cells. Finally, the IC50 was significantly higher in non-malignant MCF-10A cells than in TNBC cells. Taken together, Idasanutlin and Milademetan show a potent anti-tumor activity in TNBC cell culture models by efficiently inducing tumor cell death via apoptosis. This effect was observed despite an inactivating p53 mutation and was apparently independent of p53 expression. Our data suggest that MDM2 is a promising target in TNBC and clinical-stage MDM2 inhibitors should be further evaluated for their potential therapeutic application.
Antitumor Activities of a Humanized Cancer-Specific Anti-HER2 Monoclonal Antibody, humH2Mab-250 in Human Breast Cancer Xenografts
Authors: Kaneko Mika K. , Suzuki Hiroyuki , Ohishi Tomokazu , Nakamura Takuro , Yanaka Miyuki , Tanaka Tomohiro , Kato Yukinari
Published: January 2025

Monoclonal antibody (mAb) and cell-based immunotherapies represent cutting-edge strategies for cancer treatment. However, safety concerns persist due to the potential targeting of normal cells that express reactive antigens. Therefore, it is crucial to develop cancer-specific mAbs (CasMabs) that can bind to cancer-specific antigens and exhibit antitumor activity in vivo, thereby reducing the risk of adverse effects. We previously screened mAbs targeting human epidermal growth factor receptor 2 (HER2) and successfully developed a cancer-specific anti-HER2 mAb, H2Mab-250/H2CasMab-2 (mouse IgG1, kappa). In this study, we assessed both the in vitro and in vivo antitumor efficacy of the humanized H2Mab-250 (humH2Mab-250). Although humH2Mab-250 showed lower reactivity to HER2-overexpressed Chinese hamster ovary-K1 (CHO/HER2) and breast cancer cell lines (BT-474 and SK-BR-3) than trastuzumab in flow cytometry, both humH2Mab-250 and trastuzumab showed similar antibody-dependent cellular cytotoxicity (ADCC) against CHO/HER2 and the breast cancer cell lines in the presence of effector splenocytes. In addition, humH2Mab-250 exhibited significant complement-dependent cellular cytotoxicity (CDC) in CHO/HER2 and the breast cancer cell lines compared to trastuzumab. Furthermore, humH2Mab-250 possesses compatible in vivo antitumor effects against CHO/HER2 and breast cancer xenografts with trastuzumab. These findings highlight the distinct roles of ADCC and CDC in the antitumor effects of humH2Mab-250 and trastuzumab and suggest a potential direction for the clinical development of humH2Mab-250 for HER2-positive tumors.
Serum KL-6 and SP-D: Markers of Lung Function in Autoimmune-Related Interstitial Lung Diseases
Authors: Miądlikowska Ewa , Miłkowska-Dymanowska Joanna , Białas Adam Jerzy , Makowska Joanna Samanta , Lewandowska-Polak Anna , Puła Anna , Kumor-Kisielewska Anna , Piotrowski Wojciech Jerzy
Published: January 2025

This study evaluates the usefulness of serum KL-6, SP-D and TGF-β1 levels in assessing lung impairment and predicting interstitial lung disease (ILD) short-term progression in patients with interstitial pneumonia with autoimmune features (IPAF). A total of 24 patients with IPAF, 21 with connective tissue disease-associated ILD (CTD-ILD) and 23 with CTD without ILD were followed for 1 year. Serum levels of KL-6, SP-D and TGF-β1 were measured and their associations with disease severity and progression were analysed. KL-6, SP-D and TGF-β1 levels were significantly higher in IPAF and CTD-ILD patients compared to CTD without ILD (p < 0.0001, p = 0.0005 and p = 0.0001, respectively). KL-6 (r = 0.45, p = 0.002) and SP-D (r = 0.35, p = 0.02) levels correlated with lung involvement in HRCT in the ILD group. In IPAF, KL-6 levels correlated with pulmonary function tests (FVC%, TLCO%, and 6MWD) and SpO2, while SP-D correlated with 6MWD and SpO2. In CTD-ILD, KL-6 and SP-D levels were positively correlated with BAL cell count (KL-6: r = 0.58, p = 0.04; SP-D: r = 0.63, and p = 0.02). KL-6 also showed a negative correlation with the time since symptom onset (r = −0.51, p = 0.02). No significant associations were found between the baseline biomarker levels and ILD progression risk. KL-6 and SP-D may serve as potential biomarkers for assessing lung impairment in IPAF, though their predictive value for short-term prognosis remains uncertain.
Identification of DDR1 Inhibitors from Marine Compound Library Based on Pharmacophore Model and Scaffold Hopping
Authors: Hu Honghui , Tao Jiahua , Luo Lianxiang
Published: January 2025

Ulcerative colitis (UC) is a chronic inflammatory condition that affects the intestines. Research has shown that reducing the activity of DDR1 can help maintain intestinal barrier function in UC, making DDR1 a promising target for treatment. However, the development of DDR1 inhibitors as drugs has been hindered by issues such as toxicity and poor binding stability. As a result, there are currently no DDR1-targeting drugs available for clinical use, highlighting the need for new inhibitors. In a recent study, a dataset of 85 DDR1 inhibitors was analyzed to identify key characteristics for effective inhibition. A pharmacophore model was constructed and validated to screen a library of marine natural products for potential DDR1 inhibitors. Through high-throughput virtual screening and precise docking, 17 promising compounds were identified from a pool of over 52,000 molecules in the marine database. To improve binding affinity and reduce potential toxicity, scaffold hopping was employed to modify the 17 compounds, resulting in the generation of 1070 new compounds. These new compounds were further evaluated through docking and ADMET analysis, leading to the identification of three compounds—39713a, 34346a, and 34419a—with superior predicted activity and drug-like properties compared to the original 17 compounds. Further analysis showed that the binding free energy values of the three candidate compounds were less than −12.200 kcal/mol, which was similar to or better than −12.377 kcal/mol of the known positive compound VU6015929, and the drug-like properties were better than those of the positive compounds. Molecular dynamics simulations were then conducted on these three candidate compounds, confirming their stable interactions with the target protein. In conclusion, compounds 39713a, 34346a, and 34419a show promise as potential DDR1 inhibitors for the treatment of ulcerative colitis.
The Molecular Mechanism of Clock in Thermal Adaptation of Two Congeneric Oyster Species
Authors: Jiang Zhuxiang , Wang Chaogang , Du Mingyang , Cong Rihao , Li Ao , Wang Wei , Zhang Guofan , Li Li
Published: January 2025

Clock genes regulate physiological and metabolic processes by responding to changes in environmental light and temperature, and genetic variations in these genes may facilitate environmental adaptation, offering opportunities for resilience to climate change. However, the genetic and molecular mechanisms remain unclear in marine organisms. In this study, we investigated the role of a key clock gene, the circadian locomotor output cycles kaput (Clock), in thermal adaptation using DNA affinity purification sequencing (DAP-Seq) and RNA interference (RNAi)-based transcriptome analysis. In cold-adapted Crassostrea gigas and warm-adapted Crassostrea angulata, Clock was subject to environmental selection and exhibited contrasting expression patterns. The transcriptome analysis revealed 2054 differentially expressed genes (DEGs) following the knockdown of the Clock expression, while DAP-Seq identified 150,807 genes regulated by Clock, including 5273 genes located in promoter regions. The combined analyses identified 201 overlapping genes between the two datasets, of which 98 were annotated in public databases. These 98 genes displayed distinct expression patterns in C. gigas and C. angulata under heat stress, which were potentially regulated by Clock, indicating its role in a molecular regulatory network that responds to heat stress. Notably, a heat-shock protein 70 family gene (Hsp12b) and a tripartite motif-containing protein (Trim3) were significantly upregulated in C. angulata but showed no significant changes in C. gigas, further highlighting their critical roles in thermal adaptation. This study preliminarily constructs a thermal regulatory network involving Clock, providing insights into the molecular mechanisms of clock genes in thermal adaptation.
Ligustrazine hydrochloride Prevents Ferroptosis by Activating the NRF2 Signaling Pathway in a High-Altitude Cerebral Edema Rat Model
Authors: Han Yue , Li Wenting , Duan Huxinyue , Jia Nan , Liu Junling , Zhang Hongying , Song Wenqian , Li Meihui , He Yang , Wu Chunjie , He Yacong
Published: January 2025

High-altitude cerebral edema (HACE) is a disorder caused by low pressure and hypoxia at high altitudes. Nevertheless, as of now, there is still a scarcity of safe and effective prevention and treatment methods. The active component of Ligusticum Chuanxiong, namely Ligustrazine hydrochloride (LH), has shown potential in the prevention and treatment of HACE due to its anti-inflammatory, antioxidant, and neuroprotective effects in nervous system disorders. Consequently, the potential protective effect of LH on HACE and its mechanism still need to be further explored. Prior to modeling, 90 male Sprague-Dawley rats were pretreated with different doses of drugs, including LH (100 mg/kg and 50 mg/kg), dexamethasone (4 mg/kg), and ML385 (30 mg/kg). Subsequently, the pretreated rats were placed in a low-pressure anoxic chamber simulating a plateau environment to establish the rat HACE model. The effects and mechanisms of LH on HACE rats were further elucidated through determination of brain water content, HE staining, ELISA, immunofluorescence, molecular docking, molecular dynamics simulation, western blot, and other techniques. The results showed, first of all, that LH pretreatment can effectively reduce brain water content; down-regulate the expression of AQP4, HIF-1α, and VEGF proteins; and alleviate damage to brain tissue and nerve cells. Secondly, compared with the HACE group, LH pretreatment can significantly reduce MDA levels and increase GSH and SOD levels. Additionally, LH decreased the levels of inflammatory factors IL-1β, IL-6, and TNF-α; reduced total iron content in brain tissue; increased the expression of ferroptosis-related proteins such as SLC7A11, GPX4, and FTH1; and alleviated ferroptosis occurrence. Molecular docking and molecular dynamics simulations show that LH has a strong binding affinity for NRF2 signaling. Western blot analysis further confirmed that LH promotes the translocation of NRF2 from the cytoplasm to the nucleus and activates the NRF2 signaling pathway to exert an antioxidant effect. The NRF2 inhibitor ML385 can reverse the anti-oxidative stress effect of LH and its protective effect on HACE rat brain tissue. In summary, LH may have a protective effect on HACE rats by activating the NRF2 signaling pathway, inhibiting ferroptosis, and resisting oxidative stress.
Newborn Screening for Sickle Cell Disease: Results from a Pilot Study in the Portuguese Population
Authors: Rodrigues Diogo , Marcão Ana , Lopes Lurdes , Ventura Ana , Faria Teresa , Ferrão Anabela , Gonçalves Carolina , Kjöllerström Paula , Castro Ana , Fraga Sofia , Almeida Marta , Maia Tabita , Gomes João , Lachado Ana , Guerra Isabel , Ferreira Fátima , Trigo Fernanda , Bento Celeste , Vilarinho Laura
Published: January 2025

The Portuguese Newborn Screening Program currently includes 28 pathologies: congenital hypothyroidism, cystic fibrosis, 24 inborn errors of metabolism, sickle cell disease and spinal muscular atrophy. This pilot study for sickle cell disease newborn screening, including 188,217 samples, was performed between May 2021 and December 2023, with phase I, including 24,130 newborns, in the Lisbon and Setubal districts and phase II, including 164,087 newborns, in the whole country. DBS samples were analyzed through capillary electrophoresis. In phase I, a high birth incidence of sickle cell disease was found (1:928 NBs), resulting from the identification of 24 HbSS and 2 HbSC patients. This birth incidence decreased but remained significant when the pilot study for sickle cell disease newborn screening was expanded to a national level, with the identification of 67 sickle cell disease patients (59 HbSS and 8 HbSC), revealing a birth incidence of 1:2449 NBs. These data suggest that this condition is becoming increasingly relevant in Portugal, thus reflecting a general European trend, where sickle cell disease is already recognized as a public health problem. Therefore, it highlights the importance of its integration into the Portuguese National Newborn Screening Program panel in January 2024, thus allowing the early identification and clinical follow-up of these patients.
Relationships Between Common Distresses in Flexible Pavements and Physical Properties of Construction Materials Using an Ordinal Logistic Regression Model
Authors: Gazder Uneb , Shah Muhammad Zafar Ali , Barbieri Diego Maria , Junaid Muhammad , Saleh Muhammad Sohail
Published: January 2025

Analytical models to predict distresses and service conditions of road pavements can greatly contribute to the development of an effective pavement management system. These models allow the transportation agencies to monitor and track the deterioration of pavements and consequently determine the needed maintenance operations to preserve the performance of the network. In this research, the pavement distresses and service conditions of the Indus Highway N-55 located in Karak district, Pakistan were examined. Distresses were identified by visual observation, and then their severity and extent were measured individually by using a Vernier caliper and a measuring scale. For each distress type, the corresponding PCR was calculated. The compaction densities of the base and wearing courses were considered as input parameters to develop an ordinal logistic regression model for two dominant distresses, namely rutting and potholes. Rutting severity and extent were divided into three levels, while pothole severity was divided into four levels. Bulk and maximum specific gravity were found to have a significant impact on the models of both distresses. The model can be used to predict their development in terms of severity and extent. The proposed formulation provides valuable insights into monitoring and predicting pavement distresses by assessing the densities of road construction materials.
Deciphering the Microbiota of Edible Insects Sold by Street Vendors in Thailand Using Metataxonomic Analysis
Authors: Rampanti Giorgia , Cardinali Federica , Ferrocino Ilario , Milanović Vesna , Garofalo Cristiana , Osimani Andrea , Aquilanti Lucia
Published: January 2025

The aim of the present study was to investigate the microbiota of processed ready-to-eat (fried or boiled) edible insects sold by street vendors at local green markets in Thailand (Bangkok and Koh Samui). To this end, samples of 4 insect species (rhino beetle adults, silkworm pupae, giant waterbugs adults, and black scorpions) were collected and analyzed through viable counting and metataxonomic analysis. Enterobacteriaceae showed counts below 1 log cfu g−1 in all samples, except for black scorpions, which showed elevated counts reaching up to 4 log cfu g−1. Total mesophilic aerobes counts were up to 8 log cfu g−1 in all the analyzed samples. Counts below 1 log cfu g−1 were observed for Escherichia coli, Staphylococcus aureus, sulfite-reducing clostridia viable cells and spores, and Bacillus cereus. All the samples showed the absence of Listeria monocytogenes and Salmonella spp. According to metataxonomic analysis, 14 taxa were consistently present across all insect samples, including Dellaglioa algida, Latilactobacillus curvatus, Latilactobacillus sakei, Acetobacteraceae, Apilactobacillus kunkeei, Bombilactobacillus spp., Enterobacteriaceae, Gilliamella spp., Lactobacillus spp., Lactobacillus apis, Streptococcus thermophilus, Lacticaseibacillus rhamnosus, Lactiplantibacillus plantarum, and Weissella spp. Minority taxa included Alcaligenes spp., Brochothrix thermosphacta, Psychrobacter spp., Staphylococcus saprophyticus, Lactobacillus melliventris, Pediococcus spp., Levilactobacillus brevis, and Snodgrassella alvi.
Wound Healing in Butterfly Pupal Wing Tissues: Real-Time In Vivo Imaging of Long-Range Cell Migration, Cluster Formation, and Calcium Oscillations
Authors: Nagai Shuka , Otaki Joji M.
Published: January 2025

Insects can repair wounds and regenerate body parts in response to physical damage. Wound healing in butterfly pupal wing tissues is developmentally interesting because ectopic color patterns develop during healing, suggesting that normal and damage-induced color patterns may use similar mechanisms. Here we physiologically investigated wound healing and ectopic color pattern formation in butterfly pupal wing tissues using the blue pansy butterfly Junonia orithya. In response to physical puncture damage, various ectopic color patterns are formed around the damage site. After the wounding operation, we observed hemocytes migrating over long distances along the wing veins (lacunae) toward the damage site, where hemocytes and epidermal cells formed cellular clusters. Calcium oscillations were observed in cells at and near the damage site. Calcium oscillations were transiently affected by ruthenium red, an inhibitor of calcium transporters and channels, and ruthenium red caused various abnormalities in the scales of adult wings. These results suggest that cell migration, cluster formation, and calcium oscillations play important roles in wound healing and scale development at and near the damage site. Ectopic color patterns may develop in response to local calcium oscillations as a consequence of the evolutionary co-option of the healing process for normal development.
New Data Indicate Larger Decline in Morphological Diversity in Split-Footed Lacewing Larvae than Previously Estimated
Authors: Buchner Laura , Linhart Simon , Braig Florian , Haug Gideon T. , Weiterschan Thomas , Haug Carolin , Haug Joachim T.
Published: January 2025

Modern insect decline sparks interest in similar declines of the past. Neuroptera, the group of lacewings, has been suggested to have undergone decline after the Cretaceous, and quantitative studies of larval morphology have supported this view. One of the groups within Neuroptera seeing a major decline is that of split-footed lacewings, Nymphidae. We here report 13 new larval specimens of split-footed lacewings from about 100-million-year-old Kachin amber, Myanmar. We explore how enlarging the data set to 60 specimens and expanding the investigated morphological structures affect the recognition of decline. The expanded data set has an increased morphospace, indicating a lack of saturation. The decline is, therefore, likely even larger than so far anticipated for Nymphidae. The study of head and mouthparts provides the strongest signal for a loss of diversity, which is feasible due to the direct coupling to feeding ecology. Analysis of the trunk region cannot recover a signal for loss of diversity. Sampling issues play a role here: the trunk of the larvae is less often well preserved, and the fossil larvae are more likely in early developmental stages due to the constraints of preservation.
Utilizing C. elegans Spermatogenesis and Fertilization Mutants as a Model for Human Disease
Authors: Perez Sofia M. , Augustineli Helena S. , Marcello Matthew R.
Published: January 2025

The nematode C. elegans is a proven model for identifying genes involved in human disease, and the study of C. elegans reproduction, specifically spermatogenesis and fertilization, has led to significant contributions to our understanding of cellular function. Approximately 70 genes have been identified in C. elegans that control spermatogenesis and fertilization (spe and fer mutants). This review focuses on eight genes that have human orthologs with known pathogenic phenotypes. Using C. elegans to study these genes has led to critical developments in our understanding of protein domain function and human disease, including understanding the role of OTOF (the ortholog of C. elegans fer-1) in hearing loss, the contribution of the spe-39 ortholog VIPAS39 in vacuolar protein sorting, and the overlapping functions of spe-26 and KLHL10 in spermatogenesis. We discuss the cellular function of both the C. elegans genes and their human orthologs and the impact that C. elegans mutants and human variants have on cellular function and physiology. Utilizing C. elegans to understand the function of the genes reviewed here, and additional understudied and undiscovered genes, represents a unique opportunity to understand the function of variants that could lead to better disease diagnosis and clinical decision making.
Tennis Timing Assessment by a Machine Learning-Based Acoustic Detection System: A Pilot Study
Authors: Caprioli Lucio , Najlaoui Amani , Campoli Francesca , Dhanasekaran Aatheethyaa , Edriss Saeid , Romagnoli Cristian , Zanela Andrea , Padua Elvira , Bonaiuto Vincenzo , Annino Giuseppe
Published: January 2025

Background/Objectives: In tennis, timing plays a crucial factor as it influences the technique and effectiveness of strokes and, therefore, matches results. However, traditional technical evaluation methods rely on subjective observations or video motion-tracking technology, mainly focusing on spatial components. This study evaluated the reliability of an acoustic detection system in analyzing key temporal elements of the game, such as the rally rhythm and timing of strokes. Methods: Based on a machine learning algorithm, the proposed acoustic detection system classifies the sound of the ball’s impact on the racket and the ground to measure the time between them and give immediate feedback to the player. We performed trials with expert and amateur players in controlled settings. Results: The ML algorithm showed a detection accuracy higher than 95%, while the average accuracy of the whole system that was applied on-court was 85%. Moreover, this system has proven effective in evaluating the technical skills of a group of players on the court and highlighting their areas for improvement, showing significant potential for practical applications in player training and performance analysis. Conclusions: Quantitatively assessing timing offers a new perspective for coaches and players to improve performance and technique, providing objective data to set training regimens and optimize game strategies.
The Verbal Irony Questionnaire: An Initial Approach to the Conceptualization and Measurement of Verbal Irony in High Intellectual Ability
Authors: Sastre-Riba Sylvia , Ruiz de Mendoza Ibáñez Francisco J. , Navarro i Ferrando Ignasi , Urraca-Martínez María Luz , Cladellas-Pros Ramon
Published: January 2025

Figurative language is a complex construct related to intelligence. Psychology and psycholinguistics are trying to understand it from an interdisciplinary perspective, but studies are still scarce, methodologies are heterogeneous, and results are difficult to integrate. Some studies suggest that understanding the cognitive processes underlying figurative language and its forms could provide a new approach to understanding intellectual differences, such as high intellectual ability (HIA), and new instruments to assess it. The language of HIA children develops earlier and includes the use of irony, which involves metalinguistic skills. In this context, the present study aims to offer an instrument, called the verbal irony questionnaire (or VIrQ), to test the comprehension of verbal irony in students with HIA. A convenience sample of n = 169 students with HIA, aged between 7 and 15 years, responded to the VIrQ. An exploratory factor analysis was conducted. The results revealed that 33 items were retained and categorized into four factors. F1, ironic dissociation (14 items); F2, ironic attitude (8 items); F3, ironic constructions (7 items); and F4, reinforced irony echo (4 items). All factors have adequate reliability indices above 0.70 and below 0.95. Finally, new perspectives are also discussed.