bluuebunny/crossref_metadata_2025_split huggingface dataset:
The developmental environment mediates adult seminal proteome allocation in maleDrosophila melanogaster
Authors: von Hellfeld Rebecca , Konietzny Rebecca , Charles Philip D. , Fischer Roman , Kessler Benedikt M. , Wigby Stuart , Sepil Irem , Morimoto Juliano 
Published: January 2025

AbstractEarly life conditions can have long-lasting fitness effects on organisms. In insects, crowding during larval stages impose a significant constraint on adult phenotypes due to increased intraspecific competition for resources, which can modulate males’ success in pre- and post-mating competition in adulthood. Evidence for larval crowding effects on male seminal fluid allocation exists but is limited to a small subset of well-known seminal fluid proteins (Sfps), and often overlooks the interactions between male and female phenotypes. We currently lack a comprehensive understanding of how male and female larval crowding interact to affect production, composition, and transfer of the wider seminal proteome. Here, we manipulatedDrosophila melanogasterlarval crowding (lowversushigh) of males and females to generate individuals with large and small body size, respectively. We mated individuals in a fully factorial design, and measured the abundance, composition, and transfer of Sfps. Large males produced Sfps in significantly higher abundances, yet this difference was marginal and not detected when Sfps were analysed individually. Conversely, small males transferred greater quantities of much of their seminal proteome to females than did large males. When analysing proteins individually, 10 Sfps were transferred in significantly higher abundances by small males than large males. Our results suggest that small males invest more on each mating opportunity, potentially as a response of overall fewer mating opportunities due to their reduced size, or due to the larval cues of high population density. This work provides an insight into early life effects on ejaculate allocation inD. melanogasterand sheds light on the physiological and behavioural responses to developmental conditions in insects.
Combined deletion of cytosolic 5’-nucleotidases IA and II lowers glycemia by improving skeletal muscle insulin action and by lowering hepatic glucose production
Authors: Jacobs R. , Herinckx G. , Galland N. , Balty C. , Vertommen D. , Rider M. H. , Johanns M. 
Published: January 2025

ABSTRACTObesity and type 2 diabetes (T2D)-linked hyperglycemia, along with their associated complications, have reached pandemic proportions, becoming a major public health issue. Genetic deletion or pharmacological inhibition of purine nucleotide-metabolizing enzymes has emerged as a potential strategy for treating diseases. We previously showed that cytosolic 5’-nucleotidase II (NT5C2)-deficient mice were protected against high-fat diet (HFD)-induced insulin resistance. In the present study, we investigated effects of dual deletion of cytosolic 5’-nucleotidase IA (NT5C1A) and NT5C2 in mice. We found that NT5C1A/NT5C2 double-knockout (NT5C-dKO) mice exhibited a hypoglycemic phenotype, displaying enhanced skeletal muscle insulin action and reduced hepatic glucose production. In addition to potential involvement of adenosine monophosphate (AMP)-activated protein kinase (AMPK) in their phenotype, NT5C-dKO mice displayed liver and skeletal muscle proteomic alterations most significantly linked to amino acid metabolism. Our findings support the development of novel anti-diabetic treatments using small-molecule cytosolic 5’-nucleotidase inhibitors.
Spatiotemporal variation in cutin polymerization and remodeling mediated by GDSL-hydrolase enzymes during tomato fruit development
Authors: Philippe Glenn , Sørensen Iben , Guérault Aurore , Cross Marcella J. , Domozych David S. , Clausen Mads H. , Rose Jocelyn K. C. 
Published: January 2025

AbstractLand plants produce a cuticle, an extracellular hydrophobic layer that covers aerial organs and is involved in many critical protective roles, most notably in preventing desiccation. The predominant component of the cuticle is the lipidic polyester, cutin, which is deposited in the epidermal primary cell wall. Most of cutin of tomato fruit, a model for cuticle research, is polymerized by the extracellular GDSL-hydrolase enzyme CUTIN SYNTHASE-LIKE 1 (CUS1). However, other enzymes involved in cutin assembly remain to be identified and characterized. In this current study, we investigated whether other GDSL-hydrolases that are highly expressed in fruit epidermis might also contribute to cutin polymerization and restructuring. Candidates include homologs ofArabidopsis thalianaCUTICLE DESTRUCTIVE FACTOR 1 (CDEF1), which has been reported to catalyze cutin hydrolysis, as well as other phylogenetically diverse and distantly related GDSL-hydrolases. We determined that members of the CUS and CDEF families can catalyze the transesterification of cutin precursorsin vitro, and can modify tomato fruit cutin structure in semi-in vivoassays. Tomato mutant knockout lines ofCUSandCDEFgenes generated by CRISPR/Cas9and cross mutations withcus1(previouslycd1) were found to exhibit different fruit and flower phenotypes related to cutin assembly, including an effect on cutin monomer esterification, composition and content, cutin nanoridge formation in flowers, fruit cuticle permeability and permeance. Characterization of the mutant phenotypes, in combination with the enzyme analysis and bioassays, revealed distinct differences in the contribution of CUS and CDEF enzymes to cutin biosynthesis and remodeling. Our analysis also revealed unexpected spatiotemporal variation in cutin polymerization and structure coordinated by distinct GDSL-hydrolase enzymes over the fruit surface, which further suggests great complexity in cutin deposition and cuticle functions during organ development.HighlightsCutin polymerization in tomato is catalyzed by coordinating the spatiotemporal expression of CUTIN SYNTHASE enzymes in different organs, including during fruit development.Extracellular cutin polymerization is not a function limited to the canonical CUTIN SYNTHASE family members but can be also be catalyzed by other GDSL-hydrolase enzymes, as suggested by evidencein vitro.Tomato CDEF enzymes, a clade within the GDSL-hydrolase superfamily, are involved in remodeling cutin structure during fruit development.The biosynthesis and remodeling of cutin over the tomato fruit surface is spatially heterogeneous.
Multiomics reveal associations between CpG methylation, histone modifications and transcription in a species that has lost DNMT3, the Colorado potato beetle
Authors: Länger Zoe M. , Israel Elisa , Engelhardt Jan , Kalita Agata I. , Valsecchi Claudia I. Keller , Kurtz Joachim , Prohaska Sonja J. 
Published: January 2025

AbstractInsects display exceptional phenotypic plasticity, which can be mediated by epigenetic modifications, including CpG methylation and histone modifications. In vertebrates, both are interlinked and CpG methylation is associated with gene repression. However, little is known about these regulatory systems in invertebrates, where CpG methylation is mainly restricted to gene bodies of transcriptionally active genes. A widely conserved mechanism involves the co-transcriptional deposition of H3K36 trimethylation and the targeted methylation of unmethylated CpGs by thede novoDNA methyltransferase DNMT3. However, DNMT3 has been lost multiple times in invertebrate lineages raising the question of how the links between CpG methylation, histone modifications and gene expression are affected by its loss.Here, we report the epigenetic landscape ofLeptinotarsa decemlineata,a beetle species that has lost DNMT3 but retained CpG methylation. We combine RNA-seq, enzymatic methyl-seq and CUT&Tag to study CpG methylation and patterns of H3K36me3 and H3K27ac histone modifications on a genome-wide scale. Despite the loss of DNMT3, H3K36me3 mirrors CpG methylation patterns. Together, they give rise to signature profiles for expressed and non-expressed genes. H3K27ac patterns, which show no association with CpG methylation, have a prominent peak at the transcription start site that is predictive of expressed genes. Our study provides new insights into the evolutionary flexibility of epigenetic modification systems that urge caution when generalizing across species.Research highlightsDespite lacking DNMT3, EM-seq revealed CpG methylation in the Colorado potato beetle. CUT&Tag showed an association of H3K36me3 and H3K27ac with transcription, while only H3K36me3 aligns with CpG methylation, demonstrating epigenetic flexibility.
Histone H4 lysine 20 monomethylation is not a mark of transcriptional silencers
Authors: Segert Julian A. , Bulyk Martha L. 
Published: January 2025

AbstractTranscriptional silencers arecis-regulatory elements that downregulate the expression of target genes. Although thousands of silencers have been identified experimentally, a predictive chromatin signature of silencers has not been found. H4K20me1 previously was reported to be highly enriched among human silencers, but our reanalysis of those data using an appropriate background revealed that the enrichment is only marginal. We generated H4K20me1 ChIP-seq profiles inDrosophilaS2 cells, which similarly showed that H4K20me1 does not markDrosophilasilencers and instead is associated with active transcription. Silencers remain a poorly annotated, difficult to predict class ofcis-regulatory elements whose specific chromatin features remain to be identified.
Loss of Effort in Chronic Low-Back Pain Patients: Motivational Anhedonia in Chronic Pain
Authors: Alldritt Samuel , Jammoul Mohammad , Makary Meena , Becker Susanne , Maeng Daniel , Keane Brian , Zald David , Geha Paul 
Published: January 2025

AbstractThe motivational and affective properties of chronic pain significantly impact patients’ lives and response to treatment but remain poorly understood. Most available phenotyping tools of chronic pain affect rely on patients’ self-report. Here we instead directly studied the willingness of chronic low-back pain (CLBP) patients to expend effort to win monetary rewards available for wins at different probabilities and different levels of difficulties in comparison to matched pain free controls and obtained functional brain imaging on a sub-group of our sample to link behavior to brain properties. We aimed to specifically test for a differential relationship of the functional connectivity in reward and effort related brain networks, and measures of effort in patients and pain free controls. Consistent with the hypothesis of “negative hedonic shift” in chronic pain we observed that CLBP patients are significantly less willing than pain free controls to expend effort to go for high cost/high reward choices and their reported low-back pain intensity predicted increased effort discounting. Furthermore, patients’ task performance was directly correlated to functional connectivity between the ventral striatum and ventro-medial prefrontal cortex, which are major nodes in the reward processing network. Patients’ performance was not explained by their self-reported depressive symptoms. Our results present new behavioral evidence characterizing the nature of anhedonia in chronic pain and links it directly to cortico-striatal connectivity highlighting the role of this circuitry in the pathophysiology of chronic pain.
Multi-omics analysis of keratinocytes reveals dermokine-dependent regulation of cell-cell adhesion via p120
Authors: Canbay Vahap , Wüstemann Till , Tian Weihua , Beyer Tobias A. , Elbæk Camilla Reiter , Stumpe Michael , Restivo Gaetana , Christiansen Chatpakorn , Herranz Anabel Migenda , Mailand Susanne , Hafner Jürg , Damgaard Rune Busk , Goletz Steffen , Dengjel Jörn , auf dem Keller Ulrich , Francavilla Chiara 
Published: January 2025

SummaryLoss of keratinocyte differentiation is a leading cause in several skin diseases and needs to be controlled in adult homeostasis by for instance growth factors and proteases. Among them, we studied the role of isoform-rich dermokine – a wound- and tumour-related matrix metalloproteinase 10 substrate – via functional multi-omics. We generated dermokine isoform-dependent keratinocyte knockouts and three dimensional (3D) organotypic skin cultures and analyzed changes in their proteome and phosphoproteome by quantitative mass spectrometry. Through functionalin vitroassays, we demonstrate that in the absence of dermokine-isoforms, p120 phosphorylation increases while cell-cell adhesion decreases in keratinocytes. Furthermore, we validate the link between decreased dermokine expression and phosphorylated p120-mediated adhesion in non-healing wounds samples derived from patients. Our data reveal a novel dermokine-p120-dependent cell-cell adhesion phenotype in keratinocytes and improve our understanding of wound-edge keratinocytes, expanding the hypothesis that dysregulated wounds resemble cancer.
Machine learning identifies routine blood tests as accurate predictive measures of pollution-dependent poor cognitive function
Authors: Johnson Hamish , Longden James , Cameron Gary , Waiter Gordon D. , Waldron Fergal M. , Gregory Jenna M. , Spence Holly 
Published: January 2025

AbstractBackgroundSeveral modifiable risk factors for dementia and related neurodegenerative diseases have been identified including education level, socio-economic status, and environmental exposures – however, how these population-level risks relate to individual risk remains elusive. To address this, we assess over 450 potential risk factors in one deeply clinically and demographically phenotyped cohort using random forest classifiers to determine predictive markers of poor cognitive function. This study aims to understand early risk factors for dementia by identifying predictors of poor cognitive performance amongst a comprehensive battery of imaging, blood, atmospheric pollutant and socio-economic measures.MethodsRandom forest modelling was used to determine significant predictors of poor cognitive performance in a cohort of 324 individuals (age 61.6 ± 4.8 years; 150 males, 174 females) without extant neurological disease. 457 features were assessed including brain imaging measures of volume and iron deposition, blood measures of anaemia, inflammation, and heavy metal levels, social deprivation indicators and atmospheric pollution exposure.ResultsRoutinely assessed markers of anaemia including mean corpuscular haemoglobin concentration were identified as robust predictors of poor general cognition, where both extremes (low and high) were associated with poor cognitive performance. The strongest, most consistent predictors of poor cognitive performance were environmental measures of atmospheric pollution, in particular, lead, carbon monoxide, and particulate matter. Feature analysis demonstrated a significant negative relationship between low mean corpuscular haemoglobin concentration and high levels of atmospheric pollutants highlighting the potential of routinely assessed blood tests as a predictive measure of pollution-dependent cognitive functioning, at an individual level.ConclusionsTaken together, these data demonstrate how routine, inexpensive medical testing and local authority initiatives could help to identify and protect at-risk individuals. These findings highlight the potential to identify individuals for targeted, cost effective medical and social interventions to improve population cognitive health.Graphical Abstract
The microbiota of fresh unfermented date palm sap: a culturomics and metagenomics investigation
Authors: Djemal S. , Gdoura M. , Mathlouthi N.E. , Gdoura R. , Cassagne C. , Hama H. Oumarou 
Published: January 2025

ABSTRACTPalm sap is an artisanal fermented beverage, the consumption of which has been historically attested for millennia. Despite this, the underlying fermentative microbiota is poorly known. Here, three date palm sap samples collected and bought in Tunisia were investigated for bacteria, methanogenic archaea, and fungi using culturomics and molecular detection techniques, including metagenomics. Metagenomics yielded 250 bacteria, two fungi, and no archaea. Culturomics yielded 36 bacteria, eight fungi, and no archaea. Taken together, these approaches detected 250 bacteria and nine fungi, including 28 bacteria and eight fungi which had been previously unreported in date palm sap, in addition to three potentially new bacteria. Specifically, the bacteriaZymomonas mobilisandLeuconostoc mesenteroidesand the fungusSaccharomyces cerevisiaewere the most abundant, fermentative species found in the three samples, by culturomics and metagenomics. While determining the source of these microbes of interest was beyond the scope of the study, the data reported here may pave the way for a better understanding of the organic and organoleptic qualities of date palm sap in productive countries.IMPORTANCEThis study provides valuable insights into the microbial composition of date palm sap, a traditional fermented beverage with deep historical roots. Despite its widespread consumption and cultural importance, the microbes driving its fermentation remain largely unexplored. Using advanced methods like metagenomics and culturomics, we uncovered a diverse array of bacteria and fungi, including species crucial for fermentation, such asZymomonas mobilis, Leuconostoc mesenteroides, andSaccharomyces cerevisiae. Moreover, the discovery of previously unreported microbes highlights the potential for further research into their roles in sap fermentation and quality. Improving our understanding of the microbial communities involved in the fermentation of date palm sap underscores its importance to the field of applied and environmental microbiology.
The trimeric thylakoidal Tat receptor complex consists of a homo-oligomeric TatC core with associated TatB subunits
Authors: Reimers Matthias , Jakob Mario , Klösgen Ralf Bernd 
Published: January 2025

AbstractThe Twin-arginine translocation (Tat) machinery, which is found in most cellular membranes containing a respiratory or photosynthetic electron transport chain, is characterized by its unique ability to catalyze membrane transport of folded proteins without impairing the membrane potential. In plant thylakoids, Tat machinery consists of three subunits, TatA, TatB, and TatC, with the latter two, TatB and TatC, forming membrane-integral multimeric TatBC receptor complexes. Here we have analyzed the stability and the subunit composition of these complexes after solubilization of thylakoids with the mild detergent digitonin as well as after additional affinity-purification. Employing different detergent combinations and/or heat treatment (40°C) followed by BN-PAGE and Western analysis we could identify four distinct Tat complexes with apparent molecular masses ranging from approximately 230 kDa to 620 kDa. Treatment of the largest Tat complex with either heat or detergents like DDM or Triton X-114 led to its stepwise breakdown into the three smaller complexes resulting from the successive release of TatB subunits from a relatively stable TatC core complex. From these data we conclude that the fully assembled, physiologically active TatBC receptor complex consists of a stable, trimeric TatC core to which three TatB subunits are bound independently from each other.
Encapsulation-enhanced genetic switches in lactobacilli
Authors: Blanch-Asensio Marc , Tadimarri Varun Sai , Martinez Roberto , Dahiya Gurvinder Singh , Lale Rahmi , Sankaran Shrikrishnan 
Published: January 2025

ABSTRACTLactiplantibacillus plantarum, a versatile member of the lactobacillus family, is widely recognized for its potential in healthcare, food production, and environmental biotechnology. Despite its inherent advantages and demonstrated potential as microbial chassis for biotechnological applications, its broader utility is constrained by a limited genetic toolbox, particularly the lack of robust genetic switches for inducible gene expression. Addressing this gap, we report the development of a novel genetic switch forL. plantarumbased on a strong bacteriophage-derived promoter and the food-grade inducer, cumate. The dynamic range and temporal profile of this switch exhibits interesting temperature and growth phase dependence that influence its leakiness and induced protein production levels. In the process of identifying ways to overcome both dependencies, we discovered that encapsulation ofL. plantarumin alginate seemingly traps them in a growth-phase that maximizes the performance of the switch. For the first time, we show how a material-oriented strategy can be leveraged to improve an engineered gene regulation function in bacteria. Furthermore, this engineered living material approach is promising for developingL. plantarumtowards advanced applications in biotechnology, pharmaceutics, and living therapeutics.
Corticosteroid resistance is predetermined by early immune response dynamics at acute Graft-versus-Host disease onset
Authors: Le Grand Sophie , Marie Yannick , Bouteiller Delphine , Robert Émilie , de Latour Régis Peffault , Socié Gérard , Vallet Nicolas , Michonneau David 
Published: January 2025

AbstractSteroid-resistant acute graft versus host disease (SR-aGVHD) is the leading life-threatening complication following allogeneic hematopoietic stem cell transplantation. Novel therapeutics development is impeded by scares knowledge on biological pathways leading to steroid resistance at time of aGVHD diagnosis. To gain insight into our understanding on circulating immune cell subsets and functions at time of aGVHD, a single cell deep phenotyping and transcriptome analysis was performed on peripheral blood mononuclear cells from patients with aGVHD before steroid treatment or without aGVHD. We aimed at identifying biological patterns associated with steroid resistance at early onset of aGVHD. First, circulating immune cell subsets were associated with increased incidence of aGVHD, but not with steroid sensitivity. Then, pathway analysis and inferred ligand/receptor interactions revealed major functional divergences between steroid-sensitive (SS-) and SR-aGVHD, including enrichment of TNFα activation in SR-GVHD, as well as TNF/TNFR, CCL3, CCL4 and IL18 signaling, and decreased interferon α and γ signaling pathways, suggesting that steroid resistance in an intrinsic property of immune cells before any treatment. To go deeper into the understanding of mechanisms at play during SR-aGVHD, we modeled immune trajectories within CD8+T cells and evidenced specific direct transition, from an early naive state to a highly activated one. By contrast, SS-aGVHD involved specific gene signatures across multiple intermediate differentiation stages during cell-to-cell transitions. These findings provide evidence that steroid resistance is driven by intrinsic mechanisms already present at the onset of alloimmune response, that may serve as potential new therapeutic targets.