bluuebunny/crossref_metadata_2025_split huggingface dataset:
PCSK9 inhibition protects mice from food allergy
Authors: Lorant Victoria , Klein Martin , Garçon Damien , Sotin Thibaud , Frey Samuel , Cheminant Marie-Aude , Ayer Audrey , Croyal Mikaël , Flet Laurent , Colas Luc , Cariou Bertrand , Bouchaud Grégory , Le May Cédric 
Published: October 2023

AbstractThe Proprotein Convertase Subtilisin Kexin of type 9 (PCSK9) has been identified in 2003 as the third gene involved in familial hypercholesterolemia. PCSK9 binds to the membrane low-density lipoprotein receptor (LDLR) and promotes its cellular internalization and lysosomal degradation. Beyond this canonical role, PCSK9 was recently described to be involved in several immune responses. However, to date, the contribution of PCSK9 in food allergy remains unknown. Here, we showed thatPcsk9deficiency or pharmacological inhibition of circulating PCSK9 with a specific monoclonal antibody (m-Ab) protected mice against symptoms of gliadin-induced-food allergy, such as increased intestinal transit time and ear oedema. Furthermore, specific PCSK9 inhibition during the elicitation steps of allergic process was sufficient to ensure anti-allergic effects in mice. Interestingly, the protective effect of PCSK9 inhibition against food allergy symptoms was independent of the LDLR as PCSK9 inhibitors remained effective inLdlrdeficient mice.In vitro, we showed that recombinant gain of function PCSK9 (PCSK9 D374Y) increased the percentage of mature bone marrow derived dendritic cells (BMDCs), promoted naïve T cell proliferation and potentiated the gliadin induced basophils degranulation. Altogether, our data demonstrate that PCSK9 inhibition is protective against gliadin induced food allergy in a LDLR-independent manner.
Pervasive Influence of Hormonal Contraceptives on the Human Plasma Proteome in a Broad Population Study
Authors: Dordevic Nikola , Dierks Clemens , Hantikainen Essi , Farztdinov Vadim , Amari Fatma , Verri Hernandes Vinicius , De Grandi Alessandro , Domingues Francisco S. , Mülleder Michael , Pramstaller Peter Paul , Rainer Johannes , Ralser Markus 
Published: October 2023

AbstractBackgroundPlasma proteomics offers new avenues to explore non-genetic associations, such as biomarkers for lifestyle and environmental exposure in population studies. To date, most proteomic investigations in population studies have utilized affinity-reagent based technologies, which are ideal to quantify the low abundant fraction of the circulating proteome but may omit several of the abundant proteins that function in plasma.MethodsUtilizing high throughput mass spectrometry, we quantified 148 highly abundant protein groups including immunoglobulins, coagulation factors, metabolic proteins, and components of the innate immune system, in the plasma of 3,632 participants from the Cooperative Health Research in South Tyrol (CHRIS) study. Using multiple regression analyses we then investigated associations with various factors including common medications.ResultsBeyond age and sex, the high abundant plasma proteome is predominantly influenced by hormonal contraceptives. For instance, Angiotensinogen (AGT) levels exhibit significant alteration with this treatment, suggesting that AGT levels could be a potential biomarker for contraceptive use. The effect of this drug class is more pronounced than other common medications or covariates. Furthermore, our analysis does not reveal any enduring signature associated with the use of these contraceptives.ConclusionIn contrast to most used drugs, hormonal contraceptives exert a pronounced effect on the high abundant plasma proteome. Given its high prevalence among young female participants, the impact of hormonal contraceptives might be misconstrued as sex-or age-related effects on the plasma proteome. One should thus account for their use in any epidemiological or clinical plasma proteome study to prevent misleading results.
A visual efference copy-based navigation algorithm inDrosophilafor complex visual environments
Authors: Canelo Angel , Kim Yeon , Park Jeongmin , Kim Anmo J 
Published: October 2023

AbstractDrosophilavisuomotor processing has been intensively studied in recent years, leading to a qualitative understanding of individual neural circuits. However, the collective operation of these circuits during naturalistic behaviors, in which flies encounter a mixture of complex visual stimuli—including those caused by their own actions—remains unexplored. In this study, we developed an integrative model ofDrosophilavisuomotor processing, wherein multiple visuomotor circuits interconnect through an efference copy (EC) mechanism. To derive the model experimentally, we analyzed the wingbeat responses of flyingDrosophilato individual, rotating visual patterns. We then combined these models to build an integrative model for superposed visual patterns, using three different strategies: the addition-only, the graded EC, and the all-or-none EC models. We compared orientation behaviors of these models with those of flyingDrosophilathat rotates their body freely in response to complex visual patterns. Results of these experiments support the all-or-none EC model, in which the amplitude of the flight turn is unimpeded by the background scene, irrespective of the visual environment. Together, our “virtual fly” model provides a formal description of vision-based navigation strategies ofDrosophilain complex visual environments and offers a novel framework for assessing the role of constituent visuomotor neural circuits in real-world contexts.
Scarring hair follicle destruction is driven by the collapse of EGFR-protected JAK-STAT1-sensitive stem cell immune privilege
Authors: Strobl Karoline , Klufa Jörg , Jin Regina , Artner-Gent Lena , Krauß Dana , Novoszel Philipp , Strobl Johanna , Stary Georg , Vujic Igor , Griss Johannes , Holcmann Martin , Farlik Matthias , Homey Bernhard , Sibilia Maria , Bauer Thomas 
Published: October 2023

AbstractThe hair follicle stem cell niche is an immune-privileged microenvironment, characterised by suppressed antigen presentation, thus shielding against permanent immune-mediated tissue damage. In this study, we demonstrate the protective role of hair follicle-specific epidermal growth factor receptor (EGFR) from scarring hair follicle degeneration. Mechanistically, disruption of EGFR signalling generates a cell intrinsic hypersensitivity within the JAK-STAT1 pathway, compromising the immune privilege in the context of CD8 T cell and NK cell-mediated inflammation. Genetic depletion of either JAK1/2 or STAT1 or topical therapeutic inhibition of JAK1/2 restores the immune privilege and activates stem cells to resume hair growth in mouse models of epidermal and hair follicle specific EGFR deletion. Skin biopsies from EGFR inhibitor-treated and from EGFR-independent cicatricial alopecia patients indicate active STAT1 signalling within the hair follicles. Notably, a case study of folliculitis decalvans, characterised by progressive hair loss, scaling and perifollicular erythema, demonstrates successful treatment with systemic JAK1/2 inhibition. Our findings offer mechanistic insights and present a therapeutic strategy for addressing scarring hair follicle destruction associated with EGFR-inhibitor therapy and cicatricial alopecia.
Extraordinary levels of per- and polyfluoroalkyl substances (PFAS) in vertebrate animals at a New Mexico desert oasis: multiple pathways for wildlife and human exposure
Authors: Witt Christopher C. , Gadek Chauncey R. , Cartron Jean-Luc E. , Andersen Michael J. , Campbell Mariel L. , Castro-Farías Marialejandra , Gyllenhaal Ethan F. , Johnson Andrew B. , Malaney Jason L. , Montoya Kyana N. , Patterson Andrew , Vinciguerra Nicholas T. , Williamson Jessie L. , Cook Joseph A. , Dunnum Jonathan L. 
Published: October 2023

AbstractPer- and polyfluoroalkyl substances (PFAS) threaten human and wildlife health, but their movement through food webs remains poorly understood. Contamination of the physical environment is widespread, but particularly concentrated at military installations. Here we measured 17 PFAS in wild, free-living mammals and migratory birds at Holloman Air Force Base (AFB), New Mexico, USA, where wastewater catchment lakes form biodiverse oases. PFAS concentrations were among the highest ever reported in animal tissues, and high levels have persisted for at least three decades. The hazardous long carbon-chain form, perfluorooctanosulfonic acid (PFOS), was most abundant, with liver concentrations averaging tens of thousands of ng/g wet weight (ww), reaching as high 97,000 ng/g (ww) in a 1994 specimen of white-footed mouse (Peromyscus leucopus) and 38,000 ng/g ww in a duck, the American wigeon (Mareca americana). Perfluorohexanesulfonic acid (PFHxS) averaged thousands of ng/g ww in the livers of birds and house mice, but one order of magnitude lower in the livers of upland desert rodent species. PFAS levels were strikingly lower at control sites, even for highly mobile migratory species. Tissue concentrations were correlated within individuals, and consistently higher in liver than in muscle or blood. Twenty of 23 vertebrate species sampled at Holloman AFB were heavily contaminated, representing multiple trophic levels and microhabitats, and implicating a range of pathways for PFAS spread: ingestion of surface water, sediments, and dust; foraging on aquatic invertebrates and plants by secondary consumers; and preying upon small vertebrates by higher level consumers, including consumption of game species by hunters. Unlike in other aquatic systems, piscivory was not an important pathway of PFAS uptake. In sum, legacy PFAS at a desert wetland have permeated the local food web across a period of decades, severely contaminating resident and migrant animals, and likely exposing humans via game meat consumption and outdoor recreation.Five highlightsA biodiverse, wetland food web at a military base is heavily contaminated with PFAS.Littoral-zone mice and aquatic birds had high liver PFOS, up to 97,000 ng/g ww.Species and ecological variation were high among 16 PFAS detected in animal tissues.Game species had dangerously contaminated meat and can transport it long distances.Biorepositories provide key temporal and spatial sampling for contaminant studies.Graphical abstract
Robust estimation of cancer and immune cell-type proportions from bulk tumor ATAC-Seq data
Authors: Gabriel Aurélie AG , Racle Julien , Falquet Maryline , Jandus Camilla , Gfeller David 
Published: October 2023

AbstractAssay for Transposase-Accessible Chromatin sequencing (ATAC-Seq) is a widely used technique to explore gene regulatory mechanisms. For most ATAC-Seq data from healthy and diseased tissues such as tumors, chromatin accessibility measurement represents a mixed signal from multiple cell types. In this work, we derive reliable chromatin accessibility marker peaks and reference profiles for most non-malignant cell types frequently observed in the micro-environment of human tumors. We then integrate these data into the EPIC deconvolution framework (Racleet al., 2017) to quantify cell-type heterogeneity in bulk ATAC-Seq data. Our EPIC-ATAC tool accurately predicts non-malignant and malignant cell fractions in tumor samples. When applied to a human breast cancer cohort, EPIC-ATAC accurately infers the immune contexture of the main breast cancer subtypes.
Early Neolithic forest farming at Seven Springs, Martlesham, Suffolk inferred from sedaDNA and pollen
Authors: Hudson Samuel M. , Allen Steven J. , Alsos Inger Greve , Curl Julie , Heintzman Peter D. , Hughes Paul , Gardiner Lynne , Lloyd-Smith Lindsay , Pears Ben , Scaife Rob , Stoof-Leichsenring Kathleen R. , Brown Antony 
Published: October 2023

AbstractThe importance of small wetlands and springs to Mesolithic cultures is well established. However, few studies have focused on their significance and use by Early Neolithic agro-pastoralists. Here we present a multiproxy palaeoenvironmental analysis, including ‘authenticated’ sedimentary ancient DNA (sedaDNA), at Seven Springs, Martlesham, UK, indicating that the springs provided an attractive location for pastoral and ritual activity around a palaeochannel surrounded by dense woodland. We demonstrate that sedaDNA can be preserved well within stratigraphically complex wetland sediment sequences, allowing archaeologically valuable insights into crucial periods of change in the prehistoric, where other forms of environmental evidence can be scarce.
Xbra modulates the activity of linker region phosporlated Smad1 duringXenopussomitogenesis
Authors: Kumar Santosh , Umair Zobia , Goutam Ravi Shankar , Lee Unjoo , Kim Jaebong 
Published: October 2023

AbstractThe Bmp/Smad1 pathway plays a crucial role in developmental processes and tissue homeostasis. Mitogen-activated protein kinase (Mapk)/Erk mediated phosphorylation of Smad1 in the linker region leads to Smad1 degradation, cytoplasmic retention and inhibition of Bmp/Smad1 signaling. While Fgf/Erk pathway has been documented to inhibit Bmp/Smad1 signaling, several studies also suggests the cooperative interaction between these two pathways in different context. However, the precise role and molecular pathway of this collaborative interaction remain obscure. Here, we identified Xbra induced by Fgf/Erk signaling as a factor in a protective mechanism for Smad1. Xbra physically interacted with the linker region phosphorylated Smad1 to make Xbra/Smad1/Smad4 trimeric complex, leading to Smad1 nuclear localization and protecting it from ubiquitin-mediated proteasomal degradation. This interaction of Xbra/Smad1/Smad4 led to sustained nuclear localization of Smad1 and the upregulation of lateral mesoderm genes, while concurrently suppression of neural and blood forming genes. Taken together, the results suggests Xbra-dependent cooperative interplays between Fgf/Erk and Bmp/Smad1 signaling during lateral mesoderm specification inXenopusembryos.
Characterization of Alternative Splicing During Mammalian Brain Development Reveals the Magnitude of Isoform Diversity and its Effects on Protein Conformational Changes
Authors: Alieh Leila Haj Abdullah , Cardoso de Toledo Beatriz , Hadarovich Anna , Toth-Petroczy Agnes , Calegari Federico 
Published: October 2023

ABSTRACTRegulation of gene expression is critical for fate commitment of stem and progenitor cells during tissue formation. In the context of mammalian brain development, a plethora of studies have described how changes in the expression of individual genes characterize cell types across ontogeny and phylogeny. However, little attention was paid to the fact that different transcripts can arise from any given gene through alternative splicing (AS). Considered a key mechanism expanding transcriptome diversity during evolution, assessing the full potential of AS on isoform diversity and protein function has been notoriously difficult. Here we capitalize on the use of a validated reporter mouse line to isolate neural stem cells, neurogenic progenitors and neurons during corticogenesis and combine the use of short- and long-read sequencing to reconstruct the full transcriptome diversity characterizing neurogenic commitment. Extending available transcriptional profiles of the mammalian brain by nearly 50,000 new isoforms, we found that neurogenic commitment is characterized by a progressive increase in exon inclusion resulting in the profound remodeling of the transcriptional profile of specific cortical cell types. Most importantly, we computationally infer the biological significance of AS on protein structure by using AlphaFold2 and revealing how radical protein conformational changes can arise from subtle changes in isoforms sequence. Together, our study reveals that AS has a greater potential to impact protein diversity and function than previously thought independently from changes in gene expression.
Regulatory T cells limit age-associated retinal inflammation and neurodegeneration
Authors: Llorián-Salvador María , de Fuente Alerie G , McMurran Christopher E. , Penalva Rosana , Dombrowski Yvonne , Stitt Alan W. , Fitzgerald Denise C 
Published: October 2023

AbstractAging is the principal risk factor for retinal degenerative diseases, which are the commonest cause of blindness in the developed countries. These conditions include age-related macular degeneration or diabetic retinopathy. Regulatory T cells play a vital role in immunoregulation of the nervous system by limiting inflammation and tissue damage in health and disease. Because the retina was long-considered an immunoprivileged site, the precise contribution of regulatory T cells in retinal homeostasis and in age-related retinal diseases remains unknown. Our study shows that regulatory T cell elimination leads to retinal pigment epithelium cell dysmorphology, and accumulation of phagocytes in the subretinal space of young and aged mice. However, only aged mice experience retinal neurodegeneration and gliosis. Surprisingly, adoptive transfer of young but not aged regulatory T cells reverse these changes. This study reveals a previously unknown protective role of regulatory T cells in maintaining aged retinal homeostasis.
Regulation of Hepatic Xenosensor Function by HNF4alpha
Authors: Kotulkar Manasi , Cabrera Diego Paine , Robarts Dakota , Apte Udayan 
Published: October 2023

AbstractNuclear receptors including Aryl hydrocarbon Receptor (AhR), Constitutive Androstane Receptor (CAR), Pregnane X Receptor (PXR), and Peroxisome Proliferator-Activated Receptor-alpha (PPARα) function as xenobiotic sensors. Hepatocyte nuclear factor 4alpha (HNF4α) is a highly conserved orphan nuclear receptor essential for liver function. We tested the hypothesis that HNF4α is essential for function of these four major xenosensors.Wild-type (WT) and hepatocyte-specific HNF4α knockout (HNF4α-KO) mice were treated with the mouse-specific activators of AhR (TCDD, 30 µg/kg), CAR (TCPOBOP, 2.5 µg/g), PXR, (PCN, 100 µg/g), and PPARα (WY-14643, 1 mg/kg). Blood and liver tissue samples were collected to study nuclear receptor activation.TCDD (AhR agonist) treatment did not affect the liver-to-body weight ratio (LW/BW) in either WT or HNF4α-KO mice. Further, TCDD activated AhR in both WT and HNF4-KO mice, confirmed by increase in expression of its target genes. TCPOBOP (CAR agonist) significantly increased the LW/BW ratio and CAR target gene expression in WT mice, but not in HNF4α-KO mice. PCN (a mouse PXR agonist) significantly increased LW/BW ratio in both WT and HNF4α-KO mice however, it failed to induce PXR target genes in HNF4 KO mice. The treatment of WY-14643 (PPARα agonist) increased LW/BW ratio and PPARα target gene expression in WT mice but not in HNF4α-KO mice.Together, these data indicate that the function of CAR, PXR, and PPARα but not of AhR was disrupted in HNF4α-KO mice. These results demonstrate that HNF4α function is critical for the activation of hepatic xenosensors, which are critical for toxicological responses.
Assembly and annotation of two high-quality columbid reference genomes from sequencing of aColumba liviaxColumba guineaF1hybrid
Authors: Maclary Emily T. , Holt Carson , Concepcion Gregory T. , Sović Ivan , Vickrey Anna I. , Yandell Mark , Kronenberg Zev , Shapiro Michael D. 
Published: October 2023

ABSTRACTPigeons and doves (family Columbidae) are one of the most diverse extant avian lineages, and many species have served as key models for evolutionary genomics, developmental biology, physiology, and behavioral studies. Building genomic resources for colubids is essential to further many of these studies. Here, we present high-quality genome assemblies and annotations for two columbid species,Columba liviaandC. guinea. We simultaneously assembledC. liviaandC. guineagenomes from long-read sequencing of a single F1hybrid individual. The newC. liviagenome assembly (Cliv_3) shows improved completeness and contiguity relative to Cliv_2.1, with an annotation incorporating long-read IsoSeq data for more accurate gene models. Intensive selective breeding ofC. liviahas given rise to hundreds of breeds with diverse morphological and behavioral characteristics, and Cliv_3 offers improved tools for mapping the genomic architecture of interesting traits. TheC. guineagenome assembly is the first for this species and is a new resource for avian comparative genomics. Together, these assemblies and annotations provide improved resources for functional studies of columbids and avian comparative genomics in general.ARTICLE SUMMARYPigeons and doves are important models for evolutionary genomics, developmental biology, physiology, and behavioral studies. Here, we present high-quality reference genome assemblies and annotations for two pigeon species, the domestic rock pigeon (Columba livia) and the African speckled pigeon (C. guinea). These assemblies and annotations provide improved resources for both comparative genomics and functional studies.
A 5’ UTR Language Model for Decoding Untranslated Regions of mRNA and Function Predictions
Authors: Chu Yanyi , Yu Dan , Li Yupeng , Huang Kaixuan , Shen Yue , Cong Le , Zhang Jason , Wang Mengdi 
Published: October 2023

AbstractThe 5’ UTR, a regulatory region at the beginning of an mRNA molecule, plays a crucial role in regulating the translation process and impacts the protein expression level. Language models have showcased their effectiveness in decoding the functions of protein and genome sequences. Here, we introduced a language model for 5’ UTR, which we refer to as the UTR-LM. The UTR-LM is pre-trained on endogenous 5’ UTRs from multiple species and is further augmented with supervised information including secondary structure and minimum free energy. We fine-tuned the UTR-LM in a variety of downstream tasks. The model outperformed the best-known benchmark by up to 42% for predicting the Mean Ribosome Loading, and by up to 60% for predicting the Translation Efficiency and the mRNA Expression Level. The model also applies to identifying unannotated Internal Ribosome Entry Sites within the untranslated region and improves the AUPR from 0.37 to 0.52 compared to the best baseline. Further, we designed a library of 211 novel 5’ UTRs with high predicted values of translation efficiency and evaluated them via a wet-lab assay. Experiment results confirmed that our top designs achieved a 32.5% increase in protein production level relative to well-established 5’ UTR optimized for therapeutics.
Keratin 17- and PKCα-dependent transient amplification of neutrophil influx after repeated stress to the skin
Authors: Xu Yang , Cohen Erez , Johnson Craig N. , Parent Carole A. , Coulombe Pierre A. 
Published: October 2023

AbstractNeutrophils contribute to the pathogenesis of chronic inflammatory skin diseases. Little is known about the source and identity of the signals mediating their recruitment in inflamed skin. We used the phorbol ester TPA and UVB, alone or in combination, to induce sterile inflammation in mouse skin and assess whether keratinocyte-derived signals impact neutrophil recruitment. A single TPA treatment results in a neutrophil influx in the dermis that peaks at 12h and resolves within 24h. A second TPA treatment or a UVB challenge, when applied at 24h but not 48h later, accelerates, amplifies, and prolongs neutrophil infiltration. This transient amplification response (TAR) is mediated by local signals in inflamed skin, can be recapitulated inex vivoculture, and involves the K17-dependent sustainment of protein kinase Cα (PKCα) activity and release of neutrophil chemoattractants by stressed keratinocytes. We show that K17 binds RACK1, a scaffold essential for PKCα activity. Finally, analyses of RNAseq data reveal the presence of a transcriptomic signature consistent with TAR and PKCα activation in chronic inflammatory skin diseases. These findings uncover a novel, transient, and keratin-dependent mechanism that amplifies neutrophil recruitment to the skin under stress, with direct implications for inflammatory skin disorders.