bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transcriptomic analysis reveals lipid metabolism and macrophage involvement associated with nintedanib treatment in a rat bleomycin model
Authors: Bonatti Martina , Pitozzi Vanessa , Caruso Paola , Pontis Silvia , Pittelli Maria Gloria , Frati Caterina , Madeddu Denise , Quaini Federico , Lagrasta Costanza Anna Maria , Minato Ilaria , Bocchi Emanuela , Civelli Maurizio , Villetti Gino , Trevisani Marcello , Montanini Barbara 
Published: November 2024

ABSTRACTINTRODUCTIONIdiopathic pulmonary fibrosis (IPF) is a progressive and irreversible lung disease with a poor prognosis. While pirfenidone and nintedanib offer some benefits, they cannot cure IPF. Nintedanib inhibits various proliferative pathways and has antifibrotic effects, but its molecular mechanisms and impact on the lung transcriptome in vivo remain unclear. This study aims to evaluate nintedanib’s transcriptomic profile in a rat model of bleomycin-induced lung fibrosis.METHODOLOGY/PRINCIPAL FINDINGSLung fibrosis was induced by two intratracheal administrations of bleomycin. Nintedanib protocol included three weeks of daily oral treatments beginning seven days after the first bleomycin dose. Left lungs were processed for histological evaluation using an automated fibrosis quantification system and the Ashcroft Score, while the right lungs were used for RNA sequencing to conduct differential expression and correlation network analysis (WGCNA). WGCNA modules were examined by cell and pathway enrichment analysis. Lipid peroxidation was assessed through the measurement of malondialdehyde in right lung lysates.Bleomycin induced significant fibrotic lesions, as confirmed by the histological evaluations. Nintedanib reduced fibrotic lesion size by about 15% and decreased severe Ashcroft scores. When compared to controls, the number of differentially expressed genes decreased from over 2000 to barely more than 400 after nintedanib treatment. WGCNA identified two gene clusters correlated to histological parameters, with nintedanib-treated animals showing gene expression levels similar to control animals. One cluster was associated with mesenchymal cells and extracellular matrix-related pathways, in line with the known anti-fibrotic effect of nintedanib. The second cluster, involving principally macrophages, was related to lipid metabolism, potentially uncovering a new mechanistic role of nintedanib in modulating lung fibrosis.CONCLUSIONS/SIGNIFICANCEThe mechanisms involving macrophages and lipid metabolism, influenced by nintedanib in this study, may open new research directions to better inquire the role of this cellular type in tissue repair and pathological lung fibrosis.
Pangenome biology and evolution in harmful algal-bloom-forming pelagophyte algae
Authors: Sibbald Shannon J. , Lawton Maggie , Maclean Charlotte , Roger Andrew J. , Archibald John M. 
Published: November 2024

ABSTRACTIn prokaryotes lateral gene transfer (LGT) is a key mechanism leading to intra-species variability in gene content and the phenomenon of pangenomes. In microbial eukaryotes, however, the extent to which LGT-driven pangenomes exist is unclear. Pelagophytes are ecologically important marine algae that includeAureococcus anophagefferens– a species notorious for causing harmful algal blooms. To investigate genome evolution across Pelagophyceae and withinAureococcus anophagefferens, we used long-read sequencing to produce high-quality genome assemblies for five strains ofAc. anophagefferens(52-54 megabase-pairs; Mbp), a telomere-to-telomere assembly forPelagomonas calceolata(32 Mbp), and the first reference genome forAureoumbra lagunensis(41 Mbp). Using comparative genomics and phylogenetics, we show remarkable strain level genetic variation inAc. anophagefferenswith a pangenome (23,356 orthogroups) that is 81.1% core and 18.9% accessory. Although gene content variation withinAc. anophagefferensdoes not appear to be largely driven by recent prokaryotic LGTs (2.6% of accessory orthogroups), 368 orthogroups were acquired from bacteria in a common ancestor of all analyzed strains and are not found inP. calceolataorAu. lagunensis. 1,077 recent LGTs from prokaryotes and viruses were identified within Pelagophyceae overall, constituting 3.5-4.0% of the orthogroups in each species. This includes genes likely contributing to the ecological success of pelagophytes globally and in long-lasting harmful blooms.
Inflammatory molecules in the glomerular endothelium in mild IgA-Nephropathy identified by single-cell and spatial transcriptome
Authors: Hasegawa Kumi , Kawashima Nagako , Kawabata Ayako , Sakakura Megumi , Onoda Naoki , Sano Takashi , Urakawa Itaru , Matsubara Masahiro , Naito Shokichi 
Published: November 2024

AbstractImmunoglobulin A nephropathy (IgA-N) is a primary glomerulonephritis characterized by mesangial cell proliferation and expansion. It still leads to end-stage renal disease over the long course of the disease in many patients. Although glomerular endothelial cells (GE) have been implicated in the pathogenesis of IgA-N, their role remains poorly understood. We conducted single-cell and spatial transcriptomic analysis using human specimens with mild IgA-N compared with normal. We observed the significantly higher expression of several inflammation-associated molecules which have been reported and not reported to be involved in IgA-N pathogenesis, respectively. Furthermore, we show that several important molecules were also highly expressed in GE of IgA-N at protein level by tissue immunostaining. Our analysis suggests that the characteristic pathways identified in GE that involve these molecules are associated with the progression of IgA-N. These findings offer important insights on both the pathogenesis of IgA-N and its treatment at an early stage.
Breaking barriers: the fungal toxin candidalysin disrupts epithelial integrity and induces inflammation in a gut-on-chip model
Authors: Morelli Moran , Queiroz Karla 
Published: November 2024

AbstractCandida albicansis an opportunistic pathogenic yeast commonly found in the gastrointestinal tract, vagina, and mouth of healthy humans. Under certain conditions, it can become invasive, causing mucosal or life-threatening systemic infections. One mechanism used byC.albicansto breach the epithelial barrier is the secretion of candidalysin, a cytolytic peptide toxin. Candidalysin damages epithelial membranes and activates the innate epithelial immune response, making it key toC.albicans’pathogenicity and a promising therapeutic target. Although candidalysin mediatesC. albicanstranslocation through intestinal layers, its impact on epithelial responses is not fully understood.This study aims to characterize this response and develop scalable, quantitative methodologies to assess candidalysin’s toxicological effects using gut-on-chip models.We used the OrganoPlate®, a microfluidic platform to culture up to 64 perfused, membrane-free intestinal epithelial tubes. We exposed Caco-2 tubes to candidalysin and evaluated their response with trans-epithelial electrical resistance (TEER), protein detection, and immunostaining. We then validated our findings in a proof-of-concept experiment using human intestinal organoid tubules.Candidalysin impaired barrier integrity, as indicated by decreased TEER and increased permeability in a fluorescent dye assay. It also induced actin remodeling and DRAQ7™ dye uptake, a marker of cell permeability. This disruption was associated with the release of LDH, cytokines, and the antimicrobial peptide LL37, suggesting cellular damage, inflammation, and antimicrobial activity.This study strengthens our understanding of candidalysin’s role inC. albicanspathogenesis and suggests new therapeutic strategies targeting this toxin. Moreover, the use of patient-derived organoids shows promise for capturing patient heterogeneity and developing personalized treatments.Graphical Abstract
The impacts of climate variability on the niche concept and distributions of species
Authors: Berti Emilio , Rosenbaum Benjamin , Reuman Daniel C. 
Published: November 2024

1AbstractInter-annual climate variability affects the long-term growth rate and thus the viability of populations. Despite the importance of climate variability, niche models and species distribution models (SDMs) typically do not account for it. This causes systematic biases in the projected distributions of species and can mislead conservation measures. Here, we use ideas from stochastic demography to quantify the effects of inter-annual climate variability on population performance and distributions of species, developing a new SDM framework which we call XSDM. The new framework expands the traditional deterministic notion of the fundamental niche, re-conceptualizing the niche to account for stochasticity. XSDM can be applied widely, requiring only occurrence data, e.g. from GBIF, and it shows superior performance to commonly-used SDMs in simulation studies. Using XSDM, we assessed the impacts of inter-annual climate variability on 10 North-American species chosen as illustrative examples. We found that climate variability reduces the potential distribution of the species on average by 26% and up to 57%. SDMs and niche concepts that do not incorporate variability cannot account for this reduction and can thus be strongly biased. Because climate change is altering not only average conditions, but also the frequency and intensity of extreme events, which are aspects of variability, it is paramount to better understand how climate variability influences the distributions of species in order to help mitigate future biodiversity losses due to climate change. Our new XSDM approach provides a new foundation for such a research program by helping re-orient niche theory to include stochastic effects.2Significance statementInter-annual climate variability influences populations’ long-term viability and, therefore, species’ distributional ranges. However, existing niche concepts and species distribution models (SDMs) typically do not account for such variability and therefore cannot accurately predict species’ distributions. Here, we developed the new SDM framework “XSDM” that accounts for climate variability when assessing the ecological niche of a species and predicting its distribution. We tested XSDM using simulations, where it performs better than traditional SDMs. By applying XSDM to 10 example species, we found that climate variability impacts their distribution, reducing potential range by up to half. As global change alters climate variability, e.g., through increased frequency and intensity of extreme events, our new paradigm provides better tools for countering future biodiversity losses.
Beyond size dimorphism: the past, present, and future of Rensch’s Rule
Authors: Toyama Ken S. 
Published: November 2024

Abstract‘Rensch’s Rule’ is known as a pattern of allometry in which the degree of male-biased sexual size dimorphism (SSD) increases with species body size. Over the last decades, a growing amount of Rensch’s Rule studies has advanced our understanding of SSD, its prevalence in nature, and the mechanisms underlying its evolution. However, Bernhard Rensch, when describing the pattern for the first time, considered the allometry of SSD only as a special case of a more general pattern in which dimorphism in any relative sexual difference increased with body size. In this perspective I revisit the history of Rensch’s Rule, starting with its popularization in recent decades, then diving into the original works by Rensch to rediscover his original observations, and finally discussing the implications of studying Rensch’s pattern beyond its applications to SSD. The strong bias towards body size in the study of Rensch’s Rule has proven valuable regarding our understanding of the evolution of SSD. Using empirical examples I propose, however, that expanding the study of the pattern to other traits might prove insightful for the general study of sexual dimorphism and phenotypic diversity.
An integrative RNA spliceosomic landscape of pancreatic neuroendocrine tumors unveils novel clinicomolecular associations
Authors: Blázquez-Encinas Ricardo , García-Vioque Víctor , Mafficini Andrea , Landoni Luca , Moreno-Montilla María Trinidad , Alcala Nicolas , Ventura Sebastián , Eyras Eduardo , Paiella Salvatore , Salvia Roberto , Rovite Vita , Foll Matthieu , Luchini Claudio , Fernandez-Cuesta Lynnette , Lawlor Rita T. , Scarpa Aldo , Ibáñez-Costa Alejandro , Pedraza-Arevalo Sergio , Castaño Justo P. 
Published: November 2024

ABSTRACTAlterations in alternative splicing are emerging as a novel hallmark in cancer biology, offering new insights. However, integrative analyses of splicing are still scarce, particularly in rare cancers such as pancreatic neuroendocrine tumors (PanNETs). These tumors are highly heterogeneous, complicating diagnosis and treatment. This study is the first to comprehensively investigate the RNA splicing landscape in PanNETs, identifying distinct spliceosomic profiles correlated with unique clinical and molecular characteristics. We analyzed RNA-seq data from 174 samples, identifying three distinct spliceosomic groups (SPN1, SPN2, SPN3) with unique clinical and molecular characteristics. SPN1 exhibited intermediate clinical features and specific splicing machinery profile, SPN2 was associated with frequent mutations inMEN1andDAXX/ATRXgenes, and SPN3 showed a prevalence of well-differentiated tumors with distinct splicing patterns. These groups were linked to different clinical outcomes and activated key biological processes like mTOR signaling and hormone secretion pathways. Our findings underscore the significant impact of RNA splicing on PanNET heterogeneity and suggest that detailed splicing profiles could serve as valuable tools for identifying novel biomarkers and therapeutic targets. This study provides crucial insights into PanNET molecular biology and paves the way for personalized therapies based on splicing features.
Reaction norm fitness peak tracking applied on sparse time series in the fossil record
Authors: Ergon Rolf 
Published: November 2024

AbstractSpecies that have existed over millions of years have done so because of sufficient mean fitness for survival through the ages, such that the mean phenotypic traits continuously have been tracking the optimal phenotypic values that maximize fitness. These optimal values are predominantly functions of the environment, for example the sea temperature. The mean phenotypic traits over time will thus predominantly be determined by the environment over time, and the trait history may be found in the fossil record. Here, I simulate such a tracking system by use of a univariate intercept-slope reaction norm model and show how both linear and nonlinear mean phenotype vs. environment functions can be found also from quite sparse and short time series from the fossil record, and I also discuss how this methodology can be extended to multivariate systems. The simulations also include cases with a constraint on the individual trait values and with other factors than environment influencing the optimal phenotypic values. The methodology is finally applied on two time-varying mean traits in a record of bryozoanMicroporella agonistesfossils spanning 2.3 million years, using the∂18Omeasure as environmental variable. From few irregular samples of phenotypic mean traits found in the fossil record, it was possible to identify linear mean phenotype vs. environment functions, and thus to predict the continuous mean phenotypic traits as functions of time.
Immunologic comparisons of strain and induction method in an improved mouse model of intrauterine fibrosis
Authors: Hernandez Jamie L. , Daniel Jonathan , Stelzel Jessica L. , Prasad Neeti R. , Soares Vance V. , Doloff Joshua C. 
Published: November 2024

AbstractIntrauterine adhesions are growths of fibrotic tissue within the uterine cavity and can arise from a variety of tissue-damaging stimuli. Immune cells are known to mediate fibrotic responses, but specific mechanisms require further elucidation. Here, we compared intrauterine fibrosis development and immune responses across different mouse strains and induction methods. We aimed to identify a consistent and more clinically relevant mouse model of intrauterine fibrosis, whether immune responses differ in response to different stimuli, and which potential key immune cell populations are responsible for intrauterine fibrosis susceptibility. Intrauterine fibrosis induction methods were compared using surgical curettage or transcervically administered chemical (quinacrine) models. Measurements of tissue morphology and collagen gene expression indicate BALB/c mice are more susceptible than C57BL/6 mice to intrauterine fibrosis. In chemically induced BALB/c uterine tissues, gene expression and flow cytometry data show greater pro-inflammatory macrophage responses, implicating a possible role in fibrogenesis consistent with human intrauterine adhesion data. Findings from this study demonstrate the importance of mouse strain selection in studies of intrauterine adhesions. Furthermore, we show that a new hormone-synchronized, chemically induced mouse model can more uniformly and reliably provoke fibrotic tissue response. This model may allow for greater elucidation of mechanisms involved in intrauterine adhesion development, and exploratory therapeutic studies for treatment intervention.
Conditional activation of NK cell function using chemically synthetic constrained bicyclic peptides directed against NKp46 and tumor-expressed antigens
Authors: Dufort Fay J. , Leitheiser Christopher J. , Rezvaya Alexandra , Ezell Tucker R. , Ho Kathleen Q.W. , Bezerra Gustavo A. , Blakeman Ben J. F. , Uhlenbroich Sandra , Zammit William H. , Stanczuk Lukas , Brown Peter N. , Mudd Gemma E. , McDonnell Kevin , Keen Nicholas , Brandish Philip E. 
Published: November 2024

ABSTRACTNatural killer (NK) cells have the unique potential to recognize and kill tumor cells independently of MHC-I presentation of antigens, as well as to secrete cytokines that engage adaptive anti-tumor immunity and the function of cytolytic T cells. We have discovered and characterized chemically synthetic, constrained bicyclic peptides that bind with high affinity and specificity to NKp46, an activating receptor expressed selectively on NK cells in the tumor microenvironment. Chemical coupling to other bicyclic peptides specific for the tumor antigens EphA2 or MT-1 created NKp46 agonists whose function was completely conditional on binding to the tumor antigen. These chemical conjugates effectively convert the tumor antigen into a “kill me” signal for NK cells. Not only did these newly created tumor-immune cell agonists (TICAs) direct potent and efficient killing of human tumor cells by primary human NK cells in vitro, but they also caused secretion of the pro-inflammatory cytokines TNFα and IFNγ. Importantly, the TICAs directed production of FLT3 ligand, an essential mitogen for conventional dendritic cells which are central to the development of anti-tumor immunity in cancer. We illustrate the TICA-directed interaction of NK cells with tumor cells using confocal microscopy and we show that TICAs enable sustained function over multiple rounds of killing. These novel tools are well positioned to harness the potential of NK cells in the treatment of cancer.
How partial phenotyping to reduce generation intervals can help to increase annual genetic gain in selected honeybee populations
Authors: Kistler Tristan , Brascamp Evert W. , Basso Benjamin , Phocas Florence , Bijma Piter 
Published: November 2024

AbstractHoneybee breeding is organized around annual cycles, following seasonal change. Generation intervals are thus commonly multiples of whole years. Most queens are generally raised during spring or early summer in temperate climates. A generation interval of 1 year limits phenotyping to early recordable traits, before the spring following queens’ births. Some traits, however, can only be recorded later, as is typically the case for total honey yield. Their recording on selection candidates thus increases the generation interval to at least 2 years, a common interval on the dam path. Using stochastic simulation, we investigated the impact of halving the dam generation interval and therefore recording only early traits on candidate dams. The generation interval on the sire path remained at 2 years with complete phenotyping. Breeding goals with varying weights on early and late traits were considered, as well as different genetic correlations between traits, from negative to positive. The acceleration of the breeding scheme generally resulted in an increased genetic gain for the two-trait breeding goals, from 0% up to +47% after 20 years of selection. Although inbreeding rates per generation were slightly lower in the accelerated breeding scheme, associate inbreeding levels were about 20-30% higher after 20 years of selection due to the 33% increased generation turnover. To avoid too high inbreeding, shortening the generation interval should thus be accompanied by strategies to limit inbreeding while still retaining most of the genetic gain, such as increasing the breeding nucleus size by relaxing selection intensity.
Genetic Diversity Analysis for Heat Stress Tolerance in Chili (Capsicum annumL.)
Authors: Usmani Saad Farid , Saddique Muhammad Abu Bakar , Tahir Muhammad Hammad Nadeem , Faried Hafiz Nazar 
Published: November 2024

ABSTRACTChili (Capsicum annuum L.) also known as hot pepper and red pepper is a valuable condiment all around the world. It holds significant importance in the global economy and is used in a variety of products such as sauces, pickles, medicines, and insect-repellent sprays. Pakistan is 4thlargest chili producer worldwide. Global warming a is an important issue around the globe that causes losses to global agricultural productivity. In this study, chili germplasm was screened to identify heat-tolerant genotypes. The experiment was carried out following factorial under RCBD (randomized complete block design) having 785 with two treatments and three repeats. The genotypes were sown in nursery trays in November 2023 and transplanted in the field in February 2024. The data recording was performed twice. The data collected in March-April was considered as data from controlled treatment while data recorded during June-July was considered as heat-stressed treatment. The data was recorded for Days to flowering, NDVI value, plant height (cm), number of primary branches per plant, fruit length (cm), fruit diameter (cm), individual fruit weight (g), number of fruits per plant, fruit yield per plant, and pollen viability. Heat susceptibility indices for all traits were calculated. The data was subjected to analysis of variance, path coefficient, and biplot analysis. Genotypes D1, D4, D7, D12, 12, 42, 75, 76, 118, 172, 217, 229, 424, 497, 514, 532, and 772 are selected as heat tolerant genotypes because the yield of these genotypes was unaffected or slightly affected due to heat stress during the experiment, while on the other hand, the genotypes 41, 44, 57, 63, 94, 123, 141, 154, 285, 347, 516, 540, 601 and 663 are selected as heat susceptible because these genotypes have high heat susceptibility index and there was a huge decrease in the yield in heat-stressed condition as compared to non-stressed condition.