bluuebunny/crossref_metadata_2025 huggingface dataset:
Cannabis use and the risk of primary open-angle glaucoma: a Mendelian randomization study
Authors: Katsimpris Andreas , Baumeister Sebastian-Edgar , Baurecht Hansjörg , Tatham Andrew J. , Nolde Michael
Published: November 2023

Several observational studies have investigated the association between cannabis use and intraocular pressure, but its association with primary open-angle glaucoma (POAG) remains unclear. In this study, we leveraged human genetic data to assess through Mendelian randomization (MR) whether cannabis use affects POAG. We used five single-nucleotide polymorphisms (SNPs) associated with lifetime cannabis use (P-value < 5 × 10–8) from a genome-wide association study (GWAS) (N = 184,765) by the International Cannabis Consortium, 23andMe, and UK Biobank and eleven SNPs associated with cannabis use disorder (P-value < 5 × 10–7) from a GWAS meta-analysis of (17,068 cases and 357,219 controls of European descent) from Psychiatric Genomics Consortium Substance Use Disorders working group, Lundbeck Foundation Initiative for Integrative Psychiatric Research, and deCode. We associated the selected five SNPs from the GWAS of lifetime cannabis use and the eleven SNPs from the GWAS of cannabis use disorder, with the largest to date GWAS meta-analysis of POAG (16,677 cases and 199,580 controls). MR analysis suggested no evidence for a causal association of lifetime cannabis use and cannabis use disorder with POAG (odds ratio (OR) of outcome per doubling of the odds of exposure (95% confidence interval): 1.04 (0.88; 1.23) for lifetime cannabis use and 0.97 (0.92; 1.03) for cannabis use disorder). Sensitivity analyses to address pleiotropy and weak instrument bias yielded similar estimates to the primary analysis. In conclusion, our results do not support a causal association between cannabis use and POAG.
An analysis of slippage effects on a solid sphere enclosed by a non-concentric cavity filled with a couple stress fluids
Authors: Al-Hanaya Amal , El-Sapa Shreen
Published: November 2023

This investigation shows the effect of slippage on the slow spinning of a rigid sphere covered by a non-concentric spherical hollow full of an incompressible couple stress fluid. Moreover, the velocity slip conditions are employed on surfaces of both the rigid sphere and the cavity. In addition, the solid sphere and the cavity are rotating axially at various angular speeds. The solution is obtained semi-analytically at low Reynolds numbers utilizing the superposition with the numerical collocation approach. This paper discusses the hydrodynamic couple exerted by the fluid on the internal particle. The dimensionless torque increases as the slip and spin slip increase by 99%, the couple stress parameter by 49%, and the separation parameter by 79%. Additionally, the non-dimensional torque decreases with the increase of the size ratio by 89%. Consequently, it is found that all the results agreed with the corresponding numerical analysis in the traditional viscous liquids and the revolving of two eccentric rigid spheres with no slippage (Al-Hanaya et al. in J. Appl Mech Tech Phys 63(5):1–9, 2022).
Clinacanthus nutans genetic diversity and its association with anti-apoptotic, antioxidant, and anti-bacterial activities
Authors: Chiangchin Salinee , Thongyim Saruda , Pandith Hataichanok , Kaewkod Thida , Tragoolpua Yingmanee , Inta Angkhana , Watthana Santi , Pongamornkul Wittaya , Jangsutthivorawat Siriphorn , Panya Aussara
Published: November 2023

Clinacanthus nutans (Burm. f.) Lindau has been extensively utilized in Thai folk medicine. However, there has been no prior exploration of its genetic diversity or its correlation with biological activity and phytochemical profiles. Herein, a total of 10 samples of C. nutans were collected from different geographic locations in different environments of Thailand, encompassing Northern, Northeastern, and Central regions. The genetic diversity study using sequence-related amplified polymorphism (SRAP) markers showed that all C. nutans samples were closely related, as indicated by UPGMA cluster analysis. When comparing the biological activities of C. nutans extracts, our findings demonstrated that those sourced from Northern Thailand exhibited the most potent activity in reducing lipopolysaccharide-inducing cell death, as accessed by cell viability assay. Furthermore, they showed remarkable antioxidant and antibacterial activities against Staphylococcus epidermidis, Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli. High-performance liquid chromatography (HPLC) analysis of phytochemical profiles revealed consistent chromatography peak patterns across all C. nutans extracts. However, they exhibited varying levels of phenolic contents, as judged by the Folin-Ciocalteu assay, which positively correlated with their observed activities. In conclusion, this study highlights the limited genetic variation within C. nutans population in Thailand. Furthermore, it underscores the association between the biological activity and the total phenolic contents which might be mainly impacted by environmental conditions.
IL-4 and IL-13 induce equivalent expression of traditional M2 markers and modulation of reactive oxygen species in human macrophages
Authors: Scott Tara E. , Lewis Caitlin V. , Zhu Mingyu , Wang Chao , Samuel Chrishan S. , Drummond Grant R. , Kemp-Harper Barbara K.
Published: November 2023

In cardiovascular disease, pathological and protective roles are reported for the Th2 cytokines IL-4 and IL-13, respectively. We hypothesised that differential effects on macrophage function are responsible. Type I and II receptor subunit (IL-2Rγ, IL-4Rα and IL-13Rα1) and M2 marker (MRC-1, CCL18, CCL22) expression was assessed via RT-qPCR in IL-4- and IL-13-treated human primary macrophages. Downstream signalling was evaluated via STAT1, STAT3 and STAT6 inhibitors, and IL-4- and IL-13-induced reactive oxygen species (ROS) generation assessed. IL-4 and IL-13 exhibited equivalent potency and efficacy for M2 marker induction, which was attenuated by STAT3 inhibition. Both cytokines enhanced PDBu-stimulated superoxide generation however this effect was 17% greater with IL-4 treatment. Type I IL-4 receptor expression was increased on M1-like macrophages but did not lead to a differing ability of these cytokines to modulate M1-like macrophage superoxide production. Overall, this study did not identify major differences in the ability of IL-4 and IL-13 to modulate macrophage function, suggesting that the opposing roles of these cytokines in cardiovascular disease are likely to be via actions on other cell types. Future studies should directly compare IL-4 and IL-13 in vivo to more thoroughly investigate the therapeutic validity of selective targeting of these cytokines.
Subtyping of COVID-19 samples based on cell-cell interaction in single cell transcriptomes
Authors: Jeong Kyeonghun , Kim Yooeun , Jeon Jaemin , Kim Kwangsoo
Published: November 2023

In single-cell transcriptome analysis, numerous biomarkers related to COVID-19 severity, including cell subtypes, genes, and pathways, have been identified. Nevertheless, most studies have focused on severity groups based on clinical features, neglecting immunological heterogeneity within the same severity level. In this study, we employed sample-level clustering using cell-cell interaction scores to investigate patient heterogeneity and uncover novel subtypes. The clustering results were validated using external datasets, demonstrating superior reproducibility and purity compared to gene expression- or gene set enrichment-based clustering. Furthermore, the cell-cell interaction score-based clusters exhibited a strong correlation with the WHO ordinal severity score based on clinical characteristics. By characterizing the identified subtypes through known COVID-19 severity-associated biomarkers, we discovered a “Severe-like moderate” subtype. This subtype displayed clinical features akin to moderate cases; however, molecular features, such as gene expression and cell-cell interactions, resembled those of severe cases. Notably, all patients who progressed from moderate to severe belonged to this subtype, underscoring the significance of cell-cell interactions in COVID-19 patient heterogeneity and severity.
Experimental production of K-rich metasomes through sediment recycling at the slab-mantle interface in the fore-arc
Authors: Gülmez Fatma , Prelević Dejan , Förster Michael W. , Buhre Stephan , Günther Jennifer
Published: November 2023

Sediment contribution to the mantle is the key step for the generation of orogenic magmatism to produce its isotopic and geochemical inventory. Even though they are exceptional for the post-collisional settings, there are worldwide examples of arc-related ultrapotassic mafic magmas which require complex multi-stage processes along with sediment melting e.g. in Italy or Pontides of Türkiye. To understand the metasomatism leading mantle to produce ultrapotassic mafic melts, we simulated the reactions of depleted (harzburgite) and fertile (lherzolite) mantle with subducted carbonate-rich sediment at relatively cold (800–850 °C) and shallow (2 GPa, 60–80 km) slab-mantle interfaces. The melting of sediments can trigger the formation of immiscible and conjugate carbonatitic and silicic melts which flux the mantle to develop hydrous minerals and dolomitic melt. The metasomatic growth product is a wehrlite composed of clinopyroxene, phlogopite, carbonate minerals and amphibole, representing a source of choice for Si-undersaturated ultrapotassic lavas. The occurrence of conjugate carbonatitic and silicic melts and their potential physical separation, offer a possibility for fractionation of several canonical trace element ratios such as Th/La, observed in Si-saturated ultrapotassic lavas. The synergy between peridotite-melt interaction and the physical separation of the carbonatitic and extremely K-enriched silicic melts are essential for the compositional evolution of ultrapotassic orogenic magmas and their mantle sources.
Activation-induced cytidine deaminase an antibody diversification enzyme interacts with chromatin modifier UBN1 in B-cells
Authors: Jaiswal Ankit , Roy Rajarshi , Tamrakar Anubhav , Singh Amit Kumar , Kar Parimal , Kodgire Prashant
Published: November 2023

Activation-induced cytidine deaminase (AID) is the key mediator of antibody diversification in activated B-cells by the process of somatic hypermutation (SHM) and class switch recombination (CSR). Targeting AID to the Ig genes requires transcription (initiation and elongation), enhancers, and its interaction with numerous factors. Furthermore, the HIRA chaperon complex, a regulator of chromatin architecture, is indispensable for SHM. The HIRA chaperon complex consists of UBN1, ASF1a, HIRA, and CABIN1 that deposit H3.3 onto the DNA, the SHM hallmark. We explored whether UBN1 interacts with AID using computational and in-vitro experiments. Interestingly, our in-silico studies, such as molecular docking and molecular dynamics simulation results, predict that AID interacts with UBN1. Subsequently, co-immunoprecipitation and pull-down experiments established interactions between UBN1 and AID inside B-cells. Additionally, a double immunofluorescence assay confirmed that AID and UBN1 were co-localized in the human and chicken B-cell lines. Moreover, proximity ligation assay studies validated that AID interacts with UBN1. Ours is the first report on the interaction of genome mutator enzyme AID with UBN1. Nevertheless, the fate of interaction between UBN1 and AID is yet to be explored in the context of SHM or CSR.
Drug screen identifies verteporfin as a regulator of lipid metabolism in macrophage foam cells
Authors: Hoeffner Nicholas , Paul Antoni , Goo Young-Hwa
Published: November 2023

Arterial macrophage foam cells are filled with cholesterol ester (CE) stored in cytosolic lipid droplets (LDs). Foam cells are central players in progression of atherosclerosis as regulators of lipid metabolism and inflammation, two major driving forces of atherosclerosis development. Thus, foam cells are considered plausible targets for intervention in atherosclerosis. However, a compound that directly regulates the lipid metabolism of LDs in the arterial foam cells has not yet been identified. In this study, we screened compounds that inhibit macrophage foam cell formation using a library of 2697 FDA-approved drugs. From the foam cells generated via loading of human oxidized low-density lipoprotein (oxLDL), we found 21 and 6 compounds that reduced and enhanced accumulations of lipids respectively. Among them, verteporfin most significantly reduced oxLDL-induced foam cell formation whereas it did not display a significant impact on foam cell formation induced by fatty acid. Mechanistically our data demonstrate that verteporfin acts via inhibition of oxLDL association with macrophages, reducing accumulation of CE. Interestingly, while other drugs that reduced foam cell formation did not have impact on pre-existing foam cells, verteporfin treatment significantly reduced their total lipids, CE, and pro-inflammatory gene expression. Together, our study identifies verteporfin as a novel regulator of foam cell lipid metabolism and inflammation and a potential compound for intervention in atherosclerosis.
Vision-related quality of life in patients with childhood-onset craniopharyngioma
Authors: Sowithayasakul Panjarat , Beckhaus Julia , Boekhoff Svenja , Friedrich Carsten , Calaminus Gabriele , Müller Hermann L.
Published: November 2023

Quality of life (QoL) is a critical component of aftercare in survivors of childhood-onset craniopharyngioma (CP). Visual impairment adversely affects QoL after CP. This study assessed the frequency of visual impairment in patients with CP and its association with QoL. This study analyzed vision-related QoL in patients recruited 2000–2019 in the prospective cohort studies KRANIOPHARYNGEOM 2000/2007. Ophthalmologic examinations were performed at diagnosis, three, 12, and 36 months, respectively after the diagnosis. The QoL (PEDQOL) scores, were also evaluated at three, 12, and 36 months, respectively after the CP diagnosis. Multivariable logistic regression was used to analyze factors associated with visual impairment during follow-up. One-hundred twenty patients were included in this study. On ophthalmological examination, visual impairment was observed in the majority of the patients (n = 84, 70%) at CP diagnosis. After surgery, vision was restored in 27 patients (32%) with visual impairment at diagnosis. In the first (p = 0.017) and third (p = 0.011) year after diagnosis, parents of patients with visual impairment reported lower social functioning (family). Reduced autonomy was found three years after diagnosis in self- (p = 0.029) and parental (p = 0.048) assessments. Next to visual impairment at diagnosis, no additional risk factors for visual impairment during follow-up could be identified. Visual impairment has a clinically relevant impact on QoL after CP. The visual status at CP diagnosis determines the visual outcome during follow-up. Early detection of visual impairment, regular QoL assessments, and risk-appropriate aftercare are recommended.

Clinical Trial Registration KRANIOPHARYNGEOM 2000 (Clinical trial registration number: NCT00258453) and KRANIOPHARYNGEOM 2007 (Clinical trial registration number: NCT01272622).
Local Bayesian Dirichlet mixing of imperfect models
Authors: Kejzlar Vojtech , Neufcourt Léo , Nazarewicz Witold
Published: November 2023

To improve the predictability of complex computational models in the experimentally-unknown domains, we propose a Bayesian statistical machine learning framework utilizing the Dirichlet distribution that combines results of several imperfect models. This framework can be viewed as an extension of Bayesian stacking. To illustrate the method, we study the ability of Bayesian model averaging and mixing techniques to mine nuclear masses. We show that the global and local mixtures of models reach excellent performance on both prediction accuracy and uncertainty quantification and are preferable to classical Bayesian model averaging. Additionally, our statistical analysis indicates that improving model predictions through mixing rather than mixing of corrected models leads to more robust extrapolations.
Proactive cues facilitate faster action reprogramming, but not stopping, in a response-selective stop signal task
Authors: Salomoni Sauro E. , Gronau Quentin F. , Heathcote Andrew , Matzke Dora , Hinder Mark R.
Published: November 2023

The ability to stop simple ongoing actions has been extensively studied using the stop signal task, but less is known about inhibition in more complex scenarios. Here we used a task requiring bimanual responses to go stimuli, but selective inhibition of only one of those responses following a stop signal. We assessed how proactive cues affect the nature of both the responding and stopping processes, and the well-documented stopping delay (interference effect) in the continuing action following successful stopping. In this task, estimates of the speed of inhibition based on a simple-stopping model are inappropriate, and have produced inconsistent findings about the effects of proactive control on motor inhibition. We instead used a multi-modal approach, based on improved methods of detecting and interpreting partial electromyographical responses and the recently proposed SIS (simultaneously inhibit and start) model of selective stopping behaviour. Our results provide clear and converging evidence that proactive cues reduce the stopping delay effect by slowing bimanual responses and speeding unimanual responses, with a negligible effect on the speed of the stopping process.
Histology-informed multiscale modeling of human brain white matter
Authors: Saeidi Saeideh , Kainz Manuel P. , Dalbosco Misael , Terzano Michele , Holzapfel Gerhard A.
Published: November 2023

In this study, we propose a novel micromechanical model for the brain white matter, which is described as a heterogeneous material with a complex network of axon fibers embedded in a soft ground matrix. We developed this model in the framework of RVE-based multiscale theories in combination with the finite element method and the embedded element technique for embedding the fibers. Microstructural features such as axon diameter, orientation and tortuosity are incorporated into the model through distributions derived from histological data. The constitutive law of both the fibers and the matrix is described by isotropic one-term Ogden functions. The hyperelastic response of the tissue is derived by homogenizing the microscopic stress fields with multiscale boundary conditions to ensure kinematic compatibility. The macroscale homogenized stress is employed in an inverse parameter identification procedure to determine the hyperelastic constants of axons and ground matrix, based on experiments on human corpus callosum. Our results demonstrate the fundamental effect of axon tortuosity on the mechanical behavior of the brain’s white matter. By combining histological information with the multiscale theory, the proposed framework can substantially contribute to the understanding of mechanotransduction phenomena, shed light on the biomechanics of a healthy brain, and potentially provide insights into neurodegenerative processes.
Identification of DNA damage response-related genes as biomarkers for castration-resistant prostate cancer
Authors: Oshima Masashi , Takayama Ken-ichi , Yamada Yuta , Kimura Naoki , Kume Haruki , Fujimura Tetsuya , Inoue Satoshi
Published: November 2023

Although hormone therapy is effective for the treatment of prostate cancer (Pca), many patients develop a lethal type of Pca called castration-resistant prostate cancer (CRPC). Dysregulation of DNA damage response (DDR)-related genes leads to Pca progression. Here, we explored DDR-related signals upregulated in CRPC tissues. We analyzed the gene expression profiles in our RNA-sequence (RNA-seq) dataset containing benign prostate, primary Pca, and CRPC samples. We identified six DDR-related genes (Ribonuclease H2 Subunit A (RNASEH2A), replication factor C subunit 2 (RFC2), RFC4, DNA Ligase 1 (LIG1), DNA polymerase D1 (POLD1), and DNA polymerase E4 (POLE4)) that were upregulated in CRPC compared with Pca tissues. By analyzing public databases and validation studies, we focused on RFC2 as a new biomarker. Functional analysis demonstrated that silencing of RFC2 expression inhibited cell proliferation and induced the expression of DNA damage and apoptosis markers in CRPC model cells. Furthermore, immunohistochemical (IHC) analysis revealed that high expression of RFC2 protein correlated with poor prognosis in patients with Pca and increased expression in CRPC tissues compared with localized Pca. Thus, our study suggests that six DDR-related genes would be important for Pca progression. RFC2 could be a useful biomarker associated with poor outcomes of patients with Pca.
Cell-free DNA as diagnostic and prognostic biomarkers for adult sepsis: a systematic review and meta-analysis
Authors: Charoensappakit Awirut , Sae-khow Kritsanawan , Rattanaliam Pongpera , Vutthikraivit Nuntanuj , Pecheenbuvan Monvasi , Udomkarnjananun Suwasin , leelahavanichkul Asada
Published: November 2023

Although cell-free DNA (cfDNA) is an emerging sepsis biomarker, the use of cfDNA, especially as diagnostic and prognostic indicators, has surprisingly not been systemically analyzed. Data of adult patients with sepsis that conducted cfDNA measurement within 24 h of the admission was collected from PubMed, ScienceDirect, Scopus, and Cochrane Library until October 2022. The Quality in Prognosis Studies (QUIPS) and Quality Assessment in Diagnostic Studies-2 (QUADAS-2) tools were used to reduce the risk of biased assessment. The mean difference (MD) of cfDNA concentration and the standardized mean difference (SMD) between populations was calculated using Review Manager (RevMan) version 5.4.1 package software. Pooled analysis from 18 included studies demonstrated increased serum cfDNA levels in sepsis when compared with healthy control (SMD = 1.02; 95% confidence interval (CI) 0.46–1.57) or non-sepsis patients in the intensive care unit (ICU) (SMD = 1.03; 95% CI 0.65–1.40), respectively. Meanwhile, a slight decrease in the statistical value was observed when compared with non-sepsis ICU patients with SIRS (SMD = 0.74; 95% 0.41–1.06). The lower cfDNA levels were also observed in sepsis survivors compared to the non-survivors (SMD at 1.43; 95%CI 0.69–2.17) with the pooled area under the receiver operating characteristic curve (AUC) of 0.76 (95% CI 0.64–0.87) for the mortality prediction. Levels of cfDNA showed a pooled sensitivity of 0.81 (95% CI 0.75–0.86) and specificity of 0.72 (95% CI 0.65–0.78) with pooled diagnostic odd ratio (DOR) at 25.03 (95% CI 5.48–114.43) for the identification of sepsis in critically ill conditions. The cfDNA levels were significantly higher in patients with sepsis and being a helpful indicator for the critically ill conditions of sepsis. Nevertheless, results of the test must be interpreted carefully with the context of all clinical situations.
Novel machine-learning analysis of SARS-CoV-2 infection in a subclinical nonhuman primate model using radiomics and blood biomarkers
Authors: Chu Winston T. , Castro Marcelo A. , Reza Syed , Cooper Timothy K. , Bartlinski Sean , Bradley Dara , Anthony Scott M. , Worwa Gabriella , Finch Courtney L. , Kuhn Jens H. , Crozier Ian , Solomon Jeffrey
Published: November 2023

Detection of the physiological response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is challenging in the absence of overt clinical signs but remains necessary to understand a full subclinical disease spectrum. In this study, our objective was to use radiomics (from computed tomography images) and blood biomarkers to predict SARS-CoV-2 infection in a nonhuman primate model (NHP) with inapparent clinical disease. To accomplish this aim, we built machine-learning models to predict SARS-CoV-2 infection in a NHP model of subclinical disease using baseline-normalized radiomic and blood sample analyses data from SARS-CoV-2-exposed and control (mock-exposed) crab-eating macaques. We applied a novel adaptation of the minimum redundancy maximum relevance (mRMR) feature-selection technique, called mRMR-permute, for statistically-thresholded and unbiased feature selection. Through performance comparison of eight machine-learning models trained on 14 feature sets, we demonstrated that a logistic regression model trained on the mRMR-permute feature set can predict SARS-CoV-2 infection with very high accuracy. Eighty-nine percent of mRMR-permute selected features had strong and significant class effects. Through this work, we identified a key set of radiomic and blood biomarkers that can be used to predict infection status even in the absence of clinical signs. Furthermore, we proposed and demonstrated the utility of a novel feature-selection technique called mRMR-permute. This work lays the foundation for the prediction and classification of SARS-CoV-2 disease severity.
Erosion behaviour of human, bovine and equine dental hard tissues
Authors: Hertel S. , Basche S. , Schmidt V. , Staszyk C. , Hannig C. , Sterzenbach T. , Hannig M.
Published: November 2023

Dental hard tissues from different species are used in dental research, but little is known about their comparability. The aim of this study was to compare the erosive behaviour of dental hard tissues (enamel, dentin) obtained from human, bovine and equine teeth. In addition, the protective effect of the pellicle on each hard tissue under erosive conditions was determined. In situ pellicle formation was performed for 30 min on enamel and dentin samples from all species in four subjects. Calcium and phosphate release was assessed during 120 s of HCl incubation on both native and pellicle-covered enamel and dentin samples. SEM and TEM were used to examine surface changes in native enamel and dentin samples after acid incubation and the ultrastructure of the pellicle before and after erosive exposure. In general, bovine enamel and dentin showed the highest degree of erosion after acid exposure compared to human and equine samples. Erosion of human primary enamel tended to be higher than that of permanent teeth, whereas dentin showed the opposite behaviour. SEM showed that eroded equine dentin appeared more irregular than human or bovine dentin. TEM studies showed that primary enamel appeared to be most susceptible to erosion.
24-Epibrassinolide alleviates diazinon oxidative damage by escalating activities of antioxidant defense systems in maize plants
Authors: Mehrian Saeed Karami , Karimi Nasser , Rahmani Fatemeh
Published: November 2023

Excessive use of pesticides against pests has contaminated agricultural crops and raised global concerns about food safety. This research investigates the alleviation effects of 24-epibrassinolide (EBL) seed priming on diazinon (DZ) pesticide toxicity. The experiment was conducted with eight groups including control, DZ, EBL (10 µM), EBL (0.1 µM), EBL (0.01 µM), EBL (10 µM) + DZ, EBL (0.1 µM) + DZ, and EBL (0.01 µM) + DZ. Plants grown with the lowest concentration of EBL (0.01 µM) exhibited an upward increase in the activity of SOD, CAT, POD, APX, GR, and GST enzymes under DZ toxicity stress. In contrast, higher concentrations of EBL showed some inhibitory effects on the activity of antioxidant enzymes. In addition, low concentrations of EBL elevated the free radical scavenging capacity (DPPH), iron-reducing antioxidant power (FRAP), photosynthesis rate (Pn), stomatal conductance (Gs) and proline, and protein contents. EBL also reduced lipid peroxidation (MDA levels) in the DZ-exposed plants, leading to membrane integrity. The favorable effects of EBL were more evident when plants were exposed to pesticides than normal growth conditions. The results indicated that EBL seed priming intensifies the antioxidant enzymes system activity, and helps maize plants against toxic effects of DZ under proper concentration.
Assessing causality between osteoarthritis and gastrointestinal disorders: a Mendelian randomization study
Authors: Xu Huiqing , Wei Jiahe , Chen Dingwan , Li Yingjun , Shen Qing
Published: November 2023

The association between osteoarthritis (OA) and gastrointestinal disorders was found in observational studies. However, the causality is still elusive. A bidirectional Mendelian randomization (MR) analysis using genome wide association studies data was conducted to assess the causal association between OA and gastrointestinal diseases [including peptic ulcer disease (PUD), gastroesophageal reflux disease (GORD), and inflammatory bowel disease (IBD)]. A two-step MR (TSMR) was conducted between OA, gastrointestinal diseases and drugs to explore the mediating effects of non-steroidal anti-inflammatory drugs (NSAIDs) and opioids use. We used multivariable MR (MVMR) analysis to further validate the impact of prescription history on diseases. Results had statistical significance at a Bonferroni corrected P-value below 0.008. We observed that genetically predicted OA had a significant positive association with GORD [odds ratio (OR) = 1.26, P = 5e−05], but not with PUD or IBD. Regarding the other direction, gastrointestinal disorders as exposure had a null association with OA. Using TSMR, OA patients tended to increase the use of NSAIDs (OR = 1.45, P = 0.001) and opioids (OR = 1.77, P = 2e−05), but only the use of opioids increased the risk of GORD (OR = 1.43, P = 5e−09). Further MVMR analysis showed that the adverse effect of OA on GORD was significantly reduced after adjusting for opioids use (OR = 1.20, P = 0.038). This study provides evidence for the causal association between OA and increased risk of GORD, which is partly attributed to opioids use in OA patients but not NSAIDs.
High pretransplant FGF23 level is associated with persistent vitamin D insufficiency and poor graft survival in kidney transplant patients
Authors: Ryu Jung-Hwa , Jeon Hee Jung , Han Ro , Jung Hee-Yeon , Kim Myung-Gyu , Huh Kyu Ha , Park Jae Berm , Kang Kyung Pyo , Han Seungyeup , Yang Jaeseok
Published: November 2023

Vitamin D3 (25[OH]D3) insufficiency and fibroblast growth factor 23 (FGF23) elevation are usually attenuated after kidney transplantation (KT). However, elevated FGF23 may be associated with poor graft outcomes and vitamin D insufficiency after KT. This study investigated the effect of pretransplant FGF23 levels on post-KT 25(OH)D3 status and graft outcomes. Serum FGF23 levels from 400 participants of the KoreaN Cohort Study for Outcome in Patients With Kidney Transplantation were measured. Annual serum 25(OH)D3 levels, all-cause mortality, cardiovascular event, and graft survival were assessed according to baseline FGF23 levels. Serum 25(OH)D3 levels were initially increased 1 year after KT (12.6 ± 7.4 vs. 22.6 ± 6.4 ng/mL). However, the prevalence of post-KT vitamin D deficiency increased again after post-KT 3 years (79.1% at baseline, 30.8% and 37.8% at 3 and 6 years, respectively). Serum FGF23 level was decreased 3 years post-KT. When participants were categorized into tertiles according to baseline FGF23 level (low, middle, high), 25(OH)D3 level in the low FGF23 group was persistently low at a median follow-up of 8.3 years. Furthermore, high baseline FGF23 level was a risk factor for poor graft survival (HR 5.882, 95% C.I.; 1.443–23.976, P = 0.013). Elevated FGF23 levels are associated with persistently low post-transplant vitamin D levels and poor graft survival.
The influence of insulin-related genetic variants on fetal growth, fetal blood flow, and placental weight in a prospective pregnancy cohort
Authors: Reim Pauline K. , Engelbrechtsen Line , Gybel-Brask Dorte , Schnurr Theresia M. , Kelstrup Louise , Høgdall Estrid V. , Hansen Torben
Published: November 2023

The fetal insulin hypothesis proposes that low birthweight and type 2 diabetes (T2D) in adulthood may be two phenotypes of the same genotype. In this study we aimed to explore this theory further by testing the effects of GWAS-identified genetic variants related to insulin release and sensitivity on fetal growth and blood flow from week 20 of gestation to birth and on placental weight at birth. We calculated genetic risk scores (GRS) of first phase insulin release (FPIR), fasting insulin (FI), combined insulin resistance and dyslipidaemia (IR + DLD) and insulin sensitivity (IS) in a study population of 665 genotyped newborns. Two-dimensional ultrasound measurements with estimation of fetal weight and blood flow were carried out at week 20, 25, and 32 of gestation in all 665 pregnancies. Birthweight and placental weight were registered at birth. Associations between the GRSs and fetal growth, blood flow and placental weight were investigated using linear mixed models. The FPIR GRS was directly associated with fetal growth from week 20 to birth, and both the FI GRS, IR + DLD GRS, and IS GRS were associated with placental weight at birth. Our findings indicate that insulin-related genetic variants might primarily affect fetal growth via the placenta.
Calculation of exact Shapley values for explaining support vector machine models using the radial basis function kernel
Authors: Mastropietro Andrea , Feldmann Christian , Bajorath Jürgen
Published: November 2023

Machine learning (ML) algorithms are extensively used in pharmaceutical research. Most ML models have black-box character, thus preventing the interpretation of predictions. However, rationalizing model decisions is of critical importance if predictions should aid in experimental design. Accordingly, in interdisciplinary research, there is growing interest in explaining ML models. Methods devised for this purpose are a part of the explainable artificial intelligence (XAI) spectrum of approaches. In XAI, the Shapley value concept originating from cooperative game theory has become popular for identifying features determining predictions. The Shapley value concept has been adapted as a model-agnostic approach for explaining predictions. Since the computational time required for Shapley value calculations scales exponentially with the number of features used, local approximations such as Shapley additive explanations (SHAP) are usually required in ML. The support vector machine (SVM) algorithm is one of the most popular ML methods in pharmaceutical research and beyond. SVM models are often explained using SHAP. However, there is only limited correlation between SHAP and exact Shapley values, as previously demonstrated for SVM calculations using the Tanimoto kernel, which limits SVM model explanation. Since the Tanimoto kernel is a special kernel function mostly applied for assessing chemical similarity, we have developed the Shapley value-expressed radial basis function (SVERAD), a computationally efficient approach for the calculation of exact Shapley values for SVM models based upon radial basis function kernels that are widely applied in different areas. SVERAD is shown to produce meaningful explanations of SVM predictions.
Identifying key genes related to the peritubular capillary rarefaction in renal interstitial fibrosis by bioinformatics
Authors: Zhang Yu , Shi Chuanbing , Yang Yiqiong , Hu Xiuxiu , Ni Haifeng , Li Li , Cheng Zhengyuan , Huang Jing , Chen Pingsheng
Published: November 2023

Renal interstitial fibrosis (RIF) is a key feature of progressive chronic kidney disease (CKD), characterized by tubular epithelial cell (TEC) hypoxia and peritubular capillary (PTC) rarefaction. However, the mechanisms underlying these processes remain poorly understood. To address this knowledge gap, we conducted a comparative transcriptome analysis of hypoxic and normoxic HK-2 cells, identifying 572 differentially expressed genes (DEGs). Subsequent Gene Ontology (GO), protein‒protein interaction (PPI) network, and hub gene analyses revealed significant enrichment of DEGs in the HIF-1 signaling pathway based on KEGG enrichment analysis. To further explore TEC modulation under hypoxic conditions, we performed chromatin immunoprecipitation (ChIP) sequencing targeting HIF-1α, identifying 2915 genes potentially regulated by HIF-1α. By comparing RNA sequencing and ChIP sequencing data, we identified 43 overlapping DEGs. By performing GO analysis and peak annotation with IGV, we identified two candidate molecules, VEGFA and BTG1, that are associated with angiogenesis and whose gene sequences were reliably bound by HIF-1α. Our study elucidates the molecular mechanisms underlying RIF, providing valuable insights for potential therapeutic interventions.
Growth and fatty acid composition of pikeperch (Sander lucioperca L., 1758) larvae under altered feeding protocol including the copepod Apocyclops panamensis (Marsh, 1913)
Authors: Ballesteros-Redondo Laura , Palm Harry W. , Bährs Hanno , Rapp Tobias , Stueeken Marcus , Wacker Alexander , Bischoff Adrian A.
Published: November 2023

Alternative live feeds for small and sensitive fish early life stages such as pikeperch (Sander lucioperca L., 1758) can improve the larval quantity, quality and performance in aquaculture. Therefore, this study evaluated the cyclopoid copepod Apocyclops panamensis (Marsh, 1913) as live feed for pikeperch larviculture from day 11 post hatch (dph) in two independent experiments. In both experiments, pikeperch larvae had the highest specific growth rate (SGR) when they fed on Brachionus plicatilis until dph 11 and A. panamensis until dph 16–18. SGR was related to a decrease in total fatty acids (FAs), saturated FAs and monounsaturated FAs in pikeperch larvae, indicating their use as energy for growth. Within the polyunsaturated FAs, docosahexaenoic acid (DHA) increased in larvae fed with A. panamensis and coincided with the highest SGR suggesting that DHA is accumulated in larvae as structural FA. Our study demonstrated a suitable pikeperch larval fatty acid composition for growth after feeding A. panamensis compared with Artemia sp. from dph 11 until dph 16 and previously fed with B. plicatilis. Moreover, it highlighted the importance of the dietary PUFAs in pikeperch rearing, specifically of linoleic acid (LA) from dph 4 until dph 11 and of DHA from dph 11 onwards.
Toward MR protocol-agnostic, unbiased brain age predicted from clinical-grade MRIs
Authors: Valdes-Hernandez Pedro A. , Laffitte Nodarse Chavier , Peraza Julio A. , Cole James H. , Cruz-Almeida Yenisel
Published: November 2023

The difference between the estimated brain age and the chronological age (‘brain-PAD’) could become a clinical biomarker. However, most brain age models were developed for research-grade high-resolution T1-weighted MRIs, limiting their applicability to clinical-grade MRIs from various protocols. We adopted a dual-transfer learning strategy to develop a model agnostic to modality, resolution, or slice orientation. We retrained a convolutional neural network (CNN) using 6281 clinical MRIs from 1559 patients, among 7 modalities and 8 scanner models. The CNN was trained to estimate brain age from synthetic research-grade magnetization-prepared rapid gradient-echo MRIs (MPRAGEs) generated by a ‘super-resolution’ method. The model failed with T2-weighted Gradient-Echo MRIs. The mean absolute error (MAE) was 5.86–8.59 years across the other modalities, still higher than for research-grade MRIs, but comparable between actual and synthetic MPRAGEs for some modalities. We modeled the “regression bias” in brain age, for its correction is crucial for providing unbiased summary statistics of brain age or for personalized brain age-based biomarkers. The bias model was generalizable as its correction eliminated any correlation between brain-PAD and chronological age in new samples. Brain-PAD was reliable across modalities. We demonstrate the feasibility of brain age predictions from arbitrary clinical-grade MRIs, thereby contributing to personalized medicine.
Dexamethasone with aggressive warming facilitates pain reduction, reduced blood loss, and quicker recovery after total hip arthroplasty
Authors: Li Fulin , Huang Xiao , Liu Wenhui , Huang Wenwen , Cheng Jinwen , Yin Dong
Published: November 2023

This study aimed to evaluate the optimal frequency of dexamethasone (DEX) administration and the efficacy of DEX with aggressive warming in total hip arthroplasty (THA), which remains unclear. A total of 150 patients were treated with DEX (10 mg) once before and once or twice after surgery with or without intraoperative aggressive warming. On postoperative day 3, the dynamic visual analogue scale scores and C-reactive protein (CRP) and interleukin-6 (IL-6) levels in participants administered with DEX twice after surgery were significantly lower than those who did not receive the second dose. The range of motion (ROM), postoperative fatigue based on Identity-Consequence-Fatigue Scale, average temperature at different stages, intraoperative blood loss, and postoperative drainage volume in patients who were subjected to warming were significantly higher than those who were not. The degree of satisfaction was also higher in the patients who received both second dose and warming than those who received neither. No differences in complications were observed based on the treatments. An additional dose of DEX at 48 h post-surgery has short-term advantages in terms of analgesia, anti-inflammatory effects, and accelerated rehabilitation after THA. DEX combined with aggressive warming further optimises short-term ROM and fatigue and improves the degree of satisfaction.

Clinical trial was registered in the International Clinical Trial Registry, and the date of registration is 2/12/2020 (ChiCTR2000040560).
Spring biomass burning in Indochina enhances summer Yangtze River Valley rainfall through land–atmosphere interactions
Authors: Wei Jiangfeng , Mao Qianqian , Shan Yufeng , Jin Qinjian , Yang Yang , Chen Haishan
Published: November 2023

Indochina is one of the regions with the most severe biomass burning (BB) in the world, which produces enormous amounts of atmospheric aerosols, mostly in spring. Moreover, the spring soil moisture anomalies in Indochina have been found to have a significant influence on the summer rainfall in the Yangtze River Valley (YRV). It is still partially unclear how spring BB in Indochina influences the local and regional climate and land–atmosphere interactions. Here, we use regional model experiments and observational data to show that the radiative effect of BB aerosols in Indochina stabilizes the atmosphere and reduces local precipitation and soil moisture. The dry soil in Indochina persists from spring to summer, which warms the land surface and the atmosphere. As a result, the western Pacific subtropical high (WPSH) is stronger and extends westward from spring to summer. This leads to stronger moisture transport to and more precipitation in the YRV (increases of approximately 5% in July and 10% in August). Thus, the effect of BB aerosols on the YRV rainfall is similar to that of the Indochina dry soil anomaly. Additionally, the increase in the YRV summer rainfall caused by the Indochina spring dry soil anomaly is almost doubled when there are BB aerosols compared to that without BB aerosols, suggesting the importance of BB aerosols in regulating the regional land–atmosphere interactions.
Deep learning-based image analysis identifies a DAT-negative subpopulation of dopaminergic neurons in the lateral Substantia nigra
Authors: Burkert Nicole , Roy Shoumik , Häusler Max , Wuttke Dominik , Müller Sonja , Wiemer Johanna , Hollmann Helene , Oldrati Marvin , Ramirez-Franco Jorge , Benkert Julia , Fauler Michael , Duda Johanna , Goaillard Jean-Marc , Pötschke Christina , Münchmeyer Moritz , Parlato Rosanna , Liss Birgit
Published: November 2023

Here we present a deep learning-based image analysis platform (DLAP), tailored to autonomously quantify cell numbers, and fluorescence signals within cellular compartments, derived from RNAscope or immunohistochemistry. We utilised DLAP to analyse subtypes of tyrosine hydroxylase (TH)-positive dopaminergic midbrain neurons in mouse and human brain-sections. These neurons modulate complex behaviour, and are differentially affected in Parkinson’s and other diseases. DLAP allows the analysis of large cell numbers, and facilitates the identification of small cellular subpopulations. Using DLAP, we identified a small subpopulation of TH-positive neurons (~5%), mainly located in the very lateral Substantia nigra (SN), that was immunofluorescence-negative for the plasmalemmal dopamine transporter (DAT), with ~40% smaller cell bodies. These neurons were negative for aldehyde dehydrogenase 1A1, with a lower co-expression rate for dopamine-D2-autoreceptors, but a ~7-fold higher likelihood of calbindin-d28k co-expression (~70%). These results have important implications, as DAT is crucial for dopamine signalling, and is commonly used as a marker for dopaminergic SN neurons.
Uncoupled evolution of the Polycomb system and deep origin of non-canonical PRC1
Authors: de Potter Bastiaan , Raas Maximilian W. D. , Seidl Michael F. , Verrijzer C. Peter , Snel Berend
Published: November 2023

Polycomb group proteins, as part of the Polycomb repressive complexes, are essential in gene repression through chromatin compaction by canonical PRC1, mono-ubiquitylation of histone H2A by non-canonical PRC1 and tri-methylation of histone H3K27 by PRC2. Despite prevalent models emphasizing tight functional coupling between PRC1 and PRC2, it remains unclear whether this paradigm indeed reflects the evolution and functioning of these complexes. Here, we conduct a comprehensive analysis of the presence or absence of cPRC1, nPRC1 and PRC2 across the entire eukaryotic tree of life, and find that both complexes were present in the Last Eukaryotic Common Ancestor (LECA). Strikingly, ~42% of organisms contain only PRC1 or PRC2, showing that their evolution since LECA is largely uncoupled. The identification of ncPRC1-defining subunits in unicellular relatives of animals and fungi suggests ncPRC1 originated before cPRC1, and we propose a scenario for the evolution of cPRC1 from ncPRC1. Together, our results suggest that crosstalk between these complexes is a secondary development in evolution.
First-principles microkinetic modeling of partial methane oxidation over graphene-stabilized single-atom Fe-catalysts
Authors: Hong Sungil , Kauppinen Minttu M. , Miu Evan V. , Mpourmpakis Giannis , Grönbeck Henrik
Published: November 2023

Detailed microkinetic modeling reveals complex mechanisms of room-temperature methanol synthesis from methane on FeN4/GN catalyst. Key factors for selectivity control are identified, providing guidelines for the design of catalysts.
Efficient and well-controlled ring opening polymerization of biobased ethylene brassylate by α-diimine FeCl3 catalysts via a coordination–insertion mechanism
Authors: Liu Lijia , Zhang Chunyu , Zhang Xuequan , Liu Heng , Wang Feng
Published: November 2023

A highly efficient late-transition metal based catalytic system of α-diimine FeCl3 for well-controlled ring opening polymerization of a cheap and biobased macrolactone, ethylene brassylate (EB), is described herein.
Recent advances in oral delivery systems of resveratrol: foreseeing their use in functional foods
Authors: Silva Pedro M. , Gonçalves Catarina , Pastrana Lorenzo M. , Coimbra Manuel A. , Vicente Antonio A. , Cerqueira Miguel A.
Published: November 2023

Herein, we review the current state-of-the-art on the use of micro- and nano-delivery systems, a possible solution to some of the drawbacks associated with the incorporation of resveratrol in foods.
Torreya grandis oil attenuates cognitive impairment in scopolamine-induced mice
Authors: Ma Jiachen , Yuan Tian , Gao Yuqi , Zeng Xiaoming , Liu Zhigang , Gao Jinming
Published: November 2023

The oil of Torreya grandis (TGO), a common nut in China, is considered to be a bioactive edible oil and has a great value in functional food development.
A cross-scale honeycomb architecture-based flexible piezoresistive sensor for multiscale pressure perception and fine-grained identification
Authors: Lu Chenxi , Gao Yuan , Chan Xiaoao , Yu Wei , Wang Haifeng , Hu Liang , Li Lingwei
Published: November 2023

A cross-scale honeycomb architecture (CHA) consisting of a microscale tip and macroscale base is proposed to achieve a trade-off between sensitivity and the pressure sensing range for flexible pressure sensors.