bluuebunny/crossref_metadata_2025_split huggingface dataset:
Role of the NHE1 exchanger in the antitumor effects of copper(II) complexes and phenanthroline derivatives
Authors: Muñoz Garzón K.S. , Martínez V. , de Giusti V. , Pérez Visñuk D. , Villaverde M. , Alvarez N. , Facchin G. , Di Virgilio A.L. 
Published: January 2025

AbstractThree copper(II) complexes containing 1,10-phenanthroline ([CuCl2(phen)]·4H2O,1), neocuproine ([CuCl2(neo)]·4H2O,2) and tetramethyl-phenanthroline ([CuCl2(tmp)]·4H2O,3) as the primary ligand and another three copper(II) complexes with the L-Ala-Phe dipeptide as an auxiliary ligand: [Cu(L-Ala-Phe)(phen)]·4H2O (4), [Cu(L-Ala-Phe)(neo)]·4H2O (5) and [Cu(L-Ala-Phe)(tmp)]·4H2O (6), inhibited cell viability in breast cancer MCF-7 cell line, both in the monolayer and spheroid cell culture models. The pair with tetramethyl-phenanthroline displayed a better selectivity index than cisPt and non-cytotoxicity-related ROS induction and apoptosis in the monolayer breast cancer model. Cell proliferation was affected by all compounds in a concentration-dependent manner, with a more substantial effect on the tetramethyl-phenanthroline complexes. Cell viability on multicellular spheroids showed a concentration-dependent reduction from 1 μM, with IC50that were half the one for cisplatin. All copper complexes, except for1showed DNA damage, demonstrated by the comet assay at a concentration below the IC50. The role of NHE1 has been linked to many types of cancers. Our study revealed that all compounds inhibited NHE1 activity in MCF-7 cells. However, only complexes containing the dipeptide auxiliary ligand could extend their effect on cell migration (Wound Healing Assay) and MMP-9 activity studied by zimography. Wester Blot analysis showed that expressions of MMP-2, MMP-9, and NHE1 were affected when MCF7 cells were treated with the six compounds as well. Overall, our results reveal an antitumor effect of all copper(II) complexes studied in breast cancer cells and a fundamental role of NHE1 in cell migration.
Decreased BOLD signal variability in middle-aged and older adults on the Autism Spectrum
Authors: Pedrahita Stephanie , Linke Annika , Cordova Michaela , Wilkinson Molly , Hau Janice , Toro Gioia , Alemu Kalekirstos , Kohli Jiwandeep , Müller Ralph-Axel , Carper Ruth 
Published: January 2025

AbstractPurposeAutism spectrum disorder (ASD) is a lifelong neurodevelopmental disorder. Preliminary evidence suggests an increased risk for accelerated or early-onset cognitive and neurological decline in ASD. While it is well established that brain development in children, adolescents and young adults with ASD diverges from neurotypical (NT) peers, it is unknown how brain function is impacted in older adults with ASD. Understanding age-related changes of brain function in ASD is crucial to establish best practices for cognitive and health screenings in adults with ASD and develop interventions that might reduce the risk of accelerated decline. Decreases in blood-oxygenation-level-dependent (BOLD) signal variability (BSV) in typical aging have been shown across multiple studies, likely reflecting declining Gamma-Aminobutyric Acid (GABA) activity, and is associated with poorer cognitive performance. We hypothesized that adults with ASD would show reduced BSV compared to the NT group, with steeper negative age associations in the ASD than NT group.MethodsThe study assessed BSV in a cohort of adults (40-70 years), 28 with ASD and 39 age-matched NT. General linear models tested for main effects of diagnostic group (ASD, NT), age and group-by-age interactions (controlling for RMSD).LimitationsOur cross-sectional data and small sample size highlight the need for longitudinal analyses in larger cohorts, alongside exploring links to cognitive function. Additionally, psychotropic medications used by our cohort of adults on the autism spectrum may have affected BSV.ResultsSignificant group-by-age interactions were observed for the right insular, left temporal occipital fusiform, right frontal orbital and right inferior lateral occipital cortex, with BSV showing strong negative associations with age in the ASD but not NT group.ConclusionThese findings suggest that BSV decreases may occur earlier in adults on the autism spectrum compared to their neurotypical peers, possibly indicating accelerated aging. However, given limited prior research, additional longitudinal analyses will be necessary to determine if the results presented truly reflect accelerated aging or arise from lifelong persistent differences in brain function.
Analysis of plasma DNA fragmentation patterns from dried blood spots
Authors: Stephens Michelle D. , Dietmann Elise C. , McDonald Bradon R. , Nkadori Everlyne N. , Zafar Syed Nabeel , McGregor Stephanie M. , Murtaza Muhammed 
Published: January 2025

AbstractCirculating tumor DNA analysis holds promise for early detection of cancer. However, costs and complexity of genomic methods, and logistical requirements for blood collection and processing limit large scale implementation. Here, we evaluated the feasibility of genome-wide analysis of fragmentation patterns in plasma DNA obtained from dried blood spots (DBS). Across 75 individuals including 25 patients with cancer, we prepared conventional DBS, and plasma-separating DBS (psDBS) from whole blood samples, prior to plasma separation. In paired comparisons of plasma DNA between psDBS and blood tubes, we observed correlated concentrations, similar distributions of fragment lengths, correlated genome-wide fragmentation features, and equivalent performance of machine learning algorithms for cancer detection. Our results provide proof-of-principle that plasma DNA fragmentation analysis can be performed from small amounts of DNA obtained from psDBS. With further development and validation, this approach can expand the reach and impact of blood-based early cancer detection, particularly for resource constrained environments such as low- and middle-income countries and rural healthcare systems.
Arabidopsis EID1 E3 ubiquitin ligase regulates acquired thermotolerance by modulating HSBP translocation
Authors: Tu Yi-Tsung , Yen Ting-Chen , Chuo Guan-Lin , Wu Zhi-Qing , Jinn Tsung-Luo , Lee Chin-Mei 
Published: January 2025

AbstractClimate change is causing a rapid increase in global average temperatures and more frequent heatwaves, posing serious threats to agricultural production and global biodiversity. In response to heat stress (HS), plants can develop acquired thermotolerance (AT) by initiating a heat shock response (HSR) after mild HS priming, thereby enhancing their ability to withstand subsequent later lethal HS events. Central to this process are the HEAT SHOCK FACTORs (HSFs), which form trimeric complexes and activate the expression ofHEAT SHOCK PROTEINs (HSPs) and otherHSFsto maintain proper protein and cellular functionality. After heat stress subsides, the HSFs’ activities can be modulated to attenuate the negative effects of HSR during the heat. The SHOCK FACTOR BINDING PROTEIN (HSBP) is a conserved microprotein that plays a prominent role in modulating HSF activities. HSBP can translocate from the cytoplasm into the nucleus during heat stress to directly interact with HSFs and prevent the formation of HSF timers. However, the mechanism that regulates the HSBP cytoplasmic-nuclear shuttling remains unclear. Here, we identified an F-box E3 ubiquitin ligase, EMPFINDLICHER IM DUNKELROTEN LICHT 1 (EID1), whose mutant form shows reduced thermotolerance in AT. We showed that EID1 interacts with HSBP to modulate HSBP cytoplasm-nuclear localization during heat stress, possibly through modulating the K41 of HSBP. The decreased thermotolerance in theeid1mutant can be explained by alterations of someHSPsexpression caused by the mis-localization of HSBP. This finding provided a novel example of E3 ubiquitin-mediated regulation of heat stress in plants.
Clinical Profile of Vascular Behcet’s Disease Patients Over a 30-year Period: Insights from an Iranian Retrospective Cohort Study
Authors: Shadmanfar Soraya , Jazi Kimia , Faezi Seyedeh Tahereh , Akhlaghi Masoumeh , Kelarestaghi Hamidreza , Moghadam Zeynab Rastegar , Davatchi Fereydoun , Alavi Seyed Mojtaba , Masoumi Maryam 
Published: January 2025

AbstractVascular manifestations are rare and cause morbidity and mortality in patients with Behçet’s disease (BD). Owing to the lack of evidence, we aimed to retrospectively evaluate the clinical features and associated risk factors of vascular BD. This retrospective cohort study was conducted at the Rheumatology Research Center, Tehran, Iran, from 1982 to 2018. The demographics, laboratory results, severity at diagnosis, diagnosis interval, and clinical manifestations divided into major events as well as sub-events at each visit were recorded. Of 57 patients, 43 (75.44%) were male, with an M:F ratio of 3.07. The mean age at onset was 32.00 ± 8.05 years. The three major clinical events repeated during the study period were mucocutaneous (41.30%), ocular (17%), and vascular (16.8%). DVT (33.3 %), SVT (21.84 %), and thrombosis of the large vein extremities (17.24 %) were the most common vascular events. The presence of HLA-B51 was found to have a statistically significant impact on the distinct number of events (B=-0.39, 95% CI: -0.74, -0.03, p=0.039). Severity at diagnosis (Moderate Vs. mild and Severe Vs. mild) were found to be statistically significant predictors of the logarithm of distinct number of events (B=-0.68, 95% CI: -1.13, -0.24, p=0.004; B=-0.51, 95% CI: -0.93, -0.10, p=0.020). The odds of developing vasculitis decreased faster in patients with a family history of OA than in those without a family history of OA. The other variables were not found to have a statistically significant impact on the logarithm of distinct number of events. A family history of OA, HLA- B51 positivity, and disease severity at diagnosis were associated with the occurrence of vascular BD. Further longitudinal and large-sample size studies should be conducted to evaluate the risk factors for vascular events.
Nematode-Trapping FungusArthrobotrys oligosporais Hungry for COQ7 to Alleviate Environmentally Triggered Iron Overload
Authors: Wu Qunfu , Zhou Jiao , Wang Donglou , Xue Songhan , Li Ling , Wu Li , Yan Junxian , Niu Xuemei 
Published: January 2025

AbstractChoosing the right and appropriate amount of substances in a changing environment is essential for the growth and survival of all species. We found that elevated oxygen levels significantly enhanced the iron-rich trapping devices of a nematode-trapping fungus (NTF),Arthrobotrys oligospora. Interestingly, genomic analysis revealed that all NTFs lackedcoq7, a key gene involved in ubiquinol (UQ) biosynthesis and iron chelation. Notably,A. oligosporautilizes UQ instead of UQ for low-aerobic respiration. Transcriptional, metabolic, mutational, and phenotypic analyses revealed thatA. oligosporaproduces a chemotaxonomic class of highly oxygenated arthrobotrins with characteristics similar to UQ skeleton, for high-aerobic respiration. Disruption of arthrobotrin biosynthesis in the Δartmutant not only enhanced UQ biosynthesis, but also triggered trapping device formation and nematicidal activity under elevated oxygen conditions. The addition of UQ to both wild-type and Δartmutants strongly inhibited trapping device development. Remarkably, the iron-rich trapping devices preferentially capture N2 nematodes harboring iron-chelating COQ7 with ferritin properties. Time-calibrated evolutionary analyses, combined with geological data, indicated that the NTF ancestor lost thecoq7gene after acquiring the arthrobotrin biosynthetic gene cluster during the "superoligotrophy" period, characterized by dramatic shifts in global oxygen levels and temperature changes. Our results demonstrate that oxygen is a critical factor in inducing iron overload, highlighting the origin and role ofcoq7loss in the evolution of predatory behavior of NTFs. Our finding that NTFs capture nematodes for iron chelation therapy, rather than for food, explains a long standing debate about the limited carnivorous ability of trapping devices.
Insulation between adjacent TADs is controlled by the width of their boundaries through distinct mechanisms
Authors: Papale Andrea , Segueni Julie , Maroufi Hanae El , Noordermeer Daan , Holcman David 
Published: January 2025

AbstractTopologically Associating Domains (TADs) are sub-Megabase regions in vertebrate genomes with enriched intra-domain interactions that restrict enhancer-promoter contacts across their boundaries. However, the mechanisms that separate TADs remain incompletely understood. Most boundaries between TADs contain CTCF binding sites (CBSs), which individually contribute to the blocking of Cohesin-mediated loop extrusion. Using genome-wide classification, we show here that TAD boundary width forms a continuum from narrow to highly extended and correlates with CBS distribution, chromatin features, and gene regulatory elements. To investigate how these boundary widths emerge, we modified the Random Cross-Linker (RCL) polymer model to incorporate specific boundary configurations, enabling us to evaluate the differential impact of boundary composition on TAD insulation. Our analysis identifies three generic boundary categories, each influencing TAD insulation differently, with varying local and distal effects on neighboring domains. Notably, we find that increasing boundary width reduces long-range inter-TAD contacts, as confirmed by Hi-C data. While blocking loop extrusion at boundaries indirectly promotes spurious intermingling of neighboring TADs, extended boundaries counteract this effect, emphasizing their role in maintaining genome structure. In conclusion, TAD boundary width not only enhances the efficiency of loop extrusion blocking but may also modulate enhancer-promoter contacts over long distances across TADs boundaries, providing a mechanism for transcriptional regulation.Significance statementTopologically Associating Domains (TADs) compartmentalize vertebrate genomes to limit cross-domain enhancer-promoter loops. Our study reveals that boundaries between TADs are diverse genomic entities that range from narrow to highly extended. Using an interdisciplinary approach that combines genome-wide data analysis with biophysical polymer modeling, we find that wider TAD boundaries reduce spurious long-range interactions between neighboring domains. Moreover, we reveal how different boundary components can create this difference in insulating capacity. Our identification and characterization of TAD boundary width and composition suggests they have the potential to regulate the formation of enhancer-promoter loops across TAD boundaries at close and long distance.
Subtyping of Type 2 Diabetes from a large Middle Eastern Biobank: Implications for Precision Medicine
Authors: Al-Thani Nayra M. , Zaghlool Shaza B , Abou-Samra Abdul Badi , Suhre Karsten , Albagha Omar M E 
Published: January 2025

AbstractBackgroundType 2 diabetes (T2D) can be classified into Severe Insulin-Deficient Diabetes (SIDD), Severe Insulin-Resistant Diabetes (SIRD), Mild Obesity-related Diabetes (MOD), and Mild Age-related Diabetes (MARD). This classification predicts disease complications and determines the best treatment for individuals. However, the classification’s applicability to non-European populations and sensitivity to confounding factors remain unclear.MethodsWe applied k-means clustering to a large Middle Eastern biobank cohort (Qatar Biobank; QBB, comprising 13,808 individuals; 2,687 with T2D). We evaluated the efficacy of the European cluster coordinates and analyzed the impact of using actual age on clustering outcomes. We examined sex differences, analyzed insulin treatment frequency, investigated the clustering of maturity-onset diabetes of the young (MODY), and evaluated the incidence of chronic kidney disease (CKD) among T2D subtypes.ResultsWe identified the four T2D subtypes within a large Arab cohort. Data-derived centers outperformed European coordinates in classifying T2D. The use of actual age, as opposed to age of diagnosis, impacted MOD and MARD classification. Obesity prevalence was significantly higher in females, however, that did not translate to worse disease severity, as indicated by comparable levels of HbA1C and HOMA2-IR. Insulin was predominantly prescribed for individuals in SIDD and SIRD, which also displayed the highest risk of CKD, followed by MOD. Interestingly, most MODY individuals were clustered within MARD, further highlighting the need for precise classification and tailored interventions.ConclusionThe observed sex differences underscore the importance of tailoring treatment plans for females compared to males. For SIDD and SIRD individuals, who are at a higher risk of CKD, insulin therapy requires closer monitoring and physician oversight. Additionally, in populations without access to genetic testing, likely MODY individuals can be identified within the MARD cluster. These findings strongly support the need for a transition to more personalized, data-driven treatment approaches to minimize diabetes-related complications and improve patient outcomes.
Epigenetic Age among U.S. Adults with Chronic Respiratory Diseases: Results from NHANES 1999-2002
Authors: Perez-Garcia Javier , Khodasevich Dennis , De Matteis Sara , Rice Mary B. , Needham Belinda L , Rehkopf David H , Cardenas Andres 
Published: January 2025

ABSTRACTBackgroundChronic airway diseases are leading causes of mortality and morbidity worldwide. More evidence supports that lung aging can be reflected by changes in DNA methylation, which are relevant for lung diseases, given their ability to capture exposures over a lifetime.ObjectiveWe aimed to investigate the association and sex-specific associations of epigenetic age acceleration in whole blood with chronic respiratory diseases.MethodsWe analyzed public data from 2,402 adults from the National Health and Nutrition Examination Surveys (NHANES) 1999-2002 cycles. We examined the association between epigenetic age and respiratory traits using linear regression models corrected for age, age2, gender, race-ethnicity, survey cycles, and survey weights. Multiple comparisons were corrected using a false discovery rate <5%. We conducted stratified analyses by sex and sensitivity analyses adjusted by blood cell counts and clinical and socioeconomic status (SES) confounders.ResultsIndividuals with wheezing showed accelerated epigenetic aging of up to 3.1 years (95% Confidence Interval [CI], 2.1, 4.1,p=8.4×10-6). Participants with COPD exhibited an epigenetic age acceleration potentially mediated by smoking, while those with emphysema showed epigenetic aging of up to 4.4 years (95% CI: 3.1, 5.8,p=3.4×10-6) independent of SES factors. Participants with early-onset COPD and those who ever have asthma showed suggestive accelerated biological aging (p<0.05). The accelerated pace of biological aging in COPD participants and the telomere length reduction in wheezing subjects were stronger in males than females.ConclusionIndividuals with chronic respiratory diseases, such as wheezing, COPD, and asthma, have accelerated epigenetic aging in whole blood. Among COPD patients, those with emphysema might exhibit higher epigenetic age acceleration. These results suggest that different epigenetic clocks may capture aging mechanisms with sex-specific effects on chronic respiratory diseases.
Preventing premature deaths through polygenic risk scores
Authors: Chuong Melisa , Thompson Deborah , Weale Michael , Riveros-McKay Fernando , Samani Nilesh , Wells Daniel , Plagnol Vincent , McVean Gil , Ashley Euan A , Donnelly Peter , Harrison Seamus , O’Sullivan Jack W 
Published: January 2025

AbstractBackgroundPolygenic risk scores (PRS) have demonstrated predictive validity across a range of cohorts and diseases, but quantifying their clinical utility remains a challenge. As PRS can be derived from a single biological sample and remain stable throughout life, we explore the potential of PRS to optimize existing screening programs.MethodsUsing UK Biobank (n = 444,949), we quantified the potential clinical benefits arising from a knowledge of PRS across seven diseases with existing screening programs globally (breast cancer, prostate cancer, colorectal cancer, abdominal aortic aneurysm, type 2 diabetes, hypertension, and coronary artery disease). We identified individuals at high genetic risk (PRS OR>2) and very high genetic risk (PRS OR>3) and estimated the optimal screening ages for these genetically high risk individuals, based on the equivalent risk to population-level risk at recommended screening ages. We then leveraged published mortality estimates, with and without screening-based interventions, to assess the potential benefits of tailoring screening age based on genetic risk. We also estimated the case enrichment ratio, which is a ratio of the percentage of cases in the high PRS risk group and in the total population.FindingsVery high risk individuals reach the risk level associated with usual starting screening age on average 10.8 years earlier, high risk individuals 8.9 years earlier and reduced risk individuals (OR<0.5) 16.8 years later. During this time, case enrichment in the high risk group is between 1.7 and 3.0 depending on disease. Across all seven diseases, appropriate interventions following PRS-guided screening would reduce premature deaths in high risk individuals by 19.0%.ConclusionKnowledge of genetic risk, measured using PRS, has the potential to deliver substantial public health benefits when aggregated across conditions, and could reduce premature mortality by tailoring existing screening programs.
Sugarcane carries relatively larger family of CAMTA transcription factors, active against drought stress
Authors: Costa da Silva Vitor Luciano , Matinez Ana Maria , Vincente Melissa Azevedo , Alam Maqsood , Noman Muhammad , Chalfun-Junior Antonio 
Published: January 2025

AbstractAs the highly demanding complex genome of the hybrid sugarcane cultivar became publicly available last year (2023), it opened avenues to further study this important crop at molecular level. We are interested in digging the multiple stress responsive transcription factors family, the Calmodulin-Binding Transcription Activator (CAMTA) of sugarcane. This manuscript presents a comprehensive study ofScCAMTAfamily based on the latest sugarcane genome sequence information. Within the 10 gb genome, through HMM model prepared from sorghum CAMTA common domains, we found 48 genes, 46 out of which carry all the CAMTA-associated domains including CG-1, TIG, IQ and Ank. The phylogenetic analysis clustered then into seven classes. Keeping sorghum as reference, we named them asScCAMTA1–ScCAMTA7, while each one representing a class having 5-7 copies such asScCAMTA1A–ScCAMTA1E, present in each sub-genome (chromosome) within the hybrid sugarcane. In parallel to determining their physico-chemical attributes, gene structure, promoter sequences, protein domains, miRNA targets, protein interaction network, GO, genome collinearity, their expression pattern against drought was determined using the RNAseq data which flaunted thatScCAMTA7is highly active under drought. This study furthers the insights into complex sugarcane genome and will assist in developing its drought-tolerant varieties.