bluuebunny/crossref_metadata_2025_split huggingface dataset:
RAVER1 interconnects lethal EMT and miR/RISC activity by the control of alternative splicing
Authors: Wedler Alice , Bley Nadine , Glaß Markus , Müller Simon , Schian Laura , Obika Kingsley-Benjamin , Lederer Marcell , Misiak Claudia , Fuchs Tommy , Köhn Marcel , Jacob Roland , Gutschner Tony , Ihling Christian , Sinz Andrea , Hüttelmaier Stefan 
Published: June 2023

AbstractThe RAVER1 protein was proposed to serve as a co-factor in guiding the PTBP-dependent control of alternative splicing (AS). Whether RAVER1 solely acts in concert with PTBPs and how it affects cancer cell fate remained elusive. Here we provide the first comprehensive investigation of RAVER1-controlled AS in cancer cell models and reveal a pro-oncogenic role of RAVER1 in tumor growth. This unravels that RAVER1 guides AS in synergy with PTBPs but more prominently serves PTBP1-independent roles in splicing. In cancer cells, one major function of RAVER1 is the control of proliferation and apoptosis, which involves the modulation of AS events within the miR/RISC pathway. Associated with this regulatory role, RAVER1 antagonizes lethal, TGFB-driven epithelial-mesenchymal-transition (EMT) by limiting TGFB signaling. RAVER1-modulated splicing events affect the insertion of protein interaction modules in factors guiding miR/RISC-dependent gene silencing. Most prominently, in all three human TNRC6 proteins, RAVER1 controls AS of GW-enriched motifs, which are essential for AGO2-binding. Disturbance of RAVER1-guided AS events in TNRC6 proteins and other facilitators of miR/RISC activity compromise miR/RISC activity which is essential to restrict TGFB signaling and lethal EMT.
Sexual antagonism evolves when autosomes influence offspring sex ratio
Authors: Sloat Solomon , Rockman Matthew 
Published: June 2023

AbstractSex allocation theory generally assumes maternal control of offspring sex and makes few predictions for populations evolving under paternal control. Using population genetic simulations, we show that maternal and paternal control of the sex ratio lead to different equilibrium sex ratios in structured populations. Sex ratios evolved under paternal control are more female biased. This effect is dependent on the population subdivision; fewer founding individuals leads to both more biased sex ratios and a greater difference between the paternal and maternal equilibria. In addition, sexual antagonism evolves in simulations with both maternally- and paternally-acting loci. Maternally-acting loci continuously accumulate ever more female-biasing effects as male-biasing effects accumulate at paternally-acting loci. The difference in evolved sex-ratio equilibria and the evolution of sexual antagonism can be largely explained by differences in the between-group variance of maternal and paternal effects in the founding generation. These theoretical results apply to any system with biparental autosomal influence over offspring sex, opening up an exciting new line of questioning.
Alterations in the Mammary Gland and Tumor Microenvironment of Formerly Obese Mice
Authors: Kuziel Genevra , Moore Brittney N. , Haugstad Grace P. , Xiong Yue , Williams Abbey E. , Arendt Lisa M. 
Published: June 2023

ABSTRACTObesity is a risk factor for breast cancer, and women with obesity that develop breast cancer have a worsened prognosis. Within the mammary gland, obesity causes chronic, macrophage-driven inflammation and adipose tissue fibrosis. To examine the impact of weight loss on the mammary microenvironment, mice were fed high-fat diet to induce obesity, then switched to a low-fat diet. In formerly obese mice, we observed reduced numbers of crown-like structures and fibrocytes in mammary glands, while collagen deposition was not resolved with weight loss. Following transplant of TC2 tumor cells into the mammary glands of lean, obese, and formerly obese mice, diminished collagen deposition and cancer-associated fibroblasts were observed in tumors from formerly obese mice compared to obese mice. When TC2 tumor cells were mixed with CD11b+CD34+myeloid progenitor cells, collagen deposition within the tumors was significantly greater compared to when tumor cells were mixed with CD11b+CD34-monocytes, suggesting that fibrocytes contribute to early collagen deposition in mammary tumors of obese mice. Overall, these studies show that weight loss resolved some of the microenvironmental conditions within the mammary gland that may contribute to tumor progression.
Krause corpuscles of the genitalia are vibrotactile sensors required for normal sexual behavior
Authors: Qi Lijun , Iskols Michael , Handler Annie , Ginty David D. 
Published: June 2023

AbstractKrause corpuscles, first discovered in the 1850s, are enigmatic sensory structures with unknown physiological properties and functions found within the genitalia and other mucocutaneous tissues. Here, we identified two distinct somatosensory neuron subtypes that innervate Krause corpuscles of the mouse penis and clitoris and project to a unique sensory terminal region of the spinal cord. Usingin vivoelectrophysiology and calcium imaging, we found that both Krause corpuscle afferent types are A-fiber rapid-adapting low-threshold mechanoreceptors, optimally tuned to dynamic, light touch and mechanical vibrations (40-80 Hz) applied to the clitoris or penis. Optogenetic activation of male Krause corpuscle afferent terminals evoked penile erection, while genetic ablation of Krause corpuscles impaired intromission and ejaculation of males as well as reduced sexual receptivity of females. Thus, Krause corpuscles, which are particularly dense in the clitoris, are vibrotactile sensors crucial for normal sexual behavior.
Single-cell transcriptomic analysis of pea shoot development and cell-type-specific responses to boron deficiency
Authors: Chen Xi , Ru Yanqi , Takahashi Hirokazu , Nakazono Mikio , Shabala Sergey , Smith Steven M. , Yu Min 
Published: June 2023

SummaryUnderstanding how nutrient stress impacts plant growth is fundamentally important to the development of approaches to improve crop production under nutrient limitation. Here we applied single-cell RNA sequencing to shoot apices ofPisum sativumgrown under boron (B) deficiency. We identified up to fifteen cell clusters based on the clustering of gene expression profiles and verified cell identity with cell-type-specific marker gene expression. Different cell types responded differently to B deficiency. Specifically, the expression of photosynthetic genes in mesophyll cells (MCs) was down-regulated by B deficiency, consistent with impaired photosynthetic rate. Furthermore, the down-regulation of stomatal development genes in guard cells (GCs), including homologs ofMUTEandTOO MANY MOUTHS, correlated with a decrease in stomatal density under B deficiency. We also constructed the developmental trajectory of the shoot apical meristem (SAM) cells and a transcription factor (TF) interaction network. The developmental progression of SAM to MC was characterized by up-regulation of genes encoding histones and chromatin assembly and remodeling proteins including homologs of FASCIATA1 (FAS1) and SWITCH DEFECTIVE/SUCROSE NON-FERMENTABLE (SWI/SNF) complex. However, B deficiency suppressed their expression, which helps to explain impaired SAM development under B deficiency. These results represent a major advance over bulk-tissue RNA-seq analysis in which cell-type-specific responses are lost and hence important physiological responses to B deficiency are missed. The reported approach and resources have potential applications well beyondP. sativumspecies and could be applied to various legumes to improve their adaptability to multiple nutrient or abiotic stresses.
VIGA: an one-stop tool for eukaryotic Virus Identification and Genome Assembly from next-generation-sequencing data
Authors: Fu Ping , Wu Yifan , Zhang Zhiyuan , Qiu Ye , Wang Yirong , Peng Yousong 
Published: June 2023

AbstractIdentification of viruses and further assembly of viral genomes from the next-generation-sequencing (NGS) data are essential steps in virome studies. This study presented an one-stop tool named VIGA (available athttps://github.com/viralInformatics/VIGA) for eukaryotic virus identification and genome assembly from NGS data. It was composed of four modules including identification, taxonomic annotation, assembly and novel virus discovery which integrated the homology-based method for virus identification and both the reference-based andde novoassemblers for accurate and effective assembly of virus genomes. Evaluation on multiple simulated and real virome datasets showed that VIGA assembled more complete virus genomes than its competitors on both the metatranscriptomic and metagenomic data, and also performed well in assembling virus genomes at the strain level. Finally, VIGA was used to investigate the virome in metatranscriptomic data from the Human Microbiome Project and revealed different composition and positive rate of viromes in diseases of Prediabetes, Crohn’s disease and Ulcerative colitis. Overall, VIGA would help much in identification and characterization of viromes in future studies.
Hybrid Modeling of Engineered Biological Systems through Coupling Data-Driven Calibration of Kinetic Parameters with Mechanistic Prediction of System Performance
Authors: Cheng Zhang , Ronen Avner , Yuan Heyang 
Published: June 2023

ABSTRACTMechanistic models can provide predictive insight into the design and optimization of engineered biological systems, but the kinetic parameters in the models need to be frequently calibrated and uniquely identified. This limitation can be addressed by integrating mechanistic models with data-driven approaches, a strategy known as hybrid modeling. Herein, we developed a hybrid modeling strategy using bioelectrochemical systems as a platform system. The data-driven component of the model consisted of artificial neural networks (ANNs) that were trained by using mechanistically derived parameter values (e.g., the maximum specific growth rate µmaxand the maximum substrate utilization rate kmaxfor the fermentative, electroactive, and methanogenic populations, and the mediator yield for electroactive microbes YM) as outputs to compute error signals. The hybrid model was built using 148 samples collected from 25 publications. After ten-fold cross-validation, the model was tested with another 28 samples. Internal resistance was accurately predicted with a relative root-mean-square error (RMSE) of 3.9%. Microbial kinetic parameters were also calibrated using the data-driven component. They were fed into the mechanistic component to predict system performance. The R2between the predicted and observed organic removal and current production for systems fed with a simple substrate were 0.90 and 0.94, respectively, significantly higher than those obtained with a standalone data-driven model (0.51 and 0) and a standalone mechanistic model (0.07 and 0.15). The hybrid modeling strategy can potentially be applied to a variety of engineered biological systems forin silicosystem design and optimization.SYNOPSISA hybrid modeling strategy was developed to predict the performance of engineered biological systems without the need for laborious experiment-based parameter calibration.
EphB3 receptor negatively regulates osteogenesis in mice
Authors: Rodríguez-Sosa Mariano R. , Alfaro David , Castillo Luis M. del , Belarra Adrián , Zapata Agustín G. 
Published: June 2023

AbstractBone homeostasis is a complex process in which some Eph kinase receptors and their Ephrin ligands appear to be involved. In the present study, we address this issue by examining the capacity of adipose tissue-derived mesenchymal stromal cells (Ad-MSC) derived from either WT,EphB2-andEphB3-KO mice to differentiate into bone tissue. Differentiation capacities were evaluated in cultured MSC by RT-qPCR and histological staining, revealing that whereasEphB2-/-MSC cultured in a specific medium expressed mainly pro-adipogenic transcription factors,EphB3-/-MSC showed abundant osteogenic transcripts, such asRunx2,Msx2andOsterix.In addition, the lack of EphB3 signaling alters the genetic profile of differentiating Ad-MSC, reducing the expression of many inhibitory molecules and antagonists of the BMP signaling pathway, and increasingBmp7expression, a robust bone inductor. Then, to confirm the osteogenic role of EphB3in vivo, we studied the condition of two animal models of induced osteoporosis (ovariectomy or long-term glucocorticoid treatment). Interestingly, in both models, both WT andEphB2-/-mice equally developed the disease butEphB3-/-mice did not exhibit the typical bone loss, nor did they show increased urine Ca2+or blood serum CTX-1. The proportions of osteoprogenitor cells and pre-osteoblasts were also found to be significantly higher inEphB3-KO mice, and the osteoclasts significantly reduced, as compared to WT andEphB2-KO mice. We conclude that EphB3 acts as a negative regulator of the osteogenic differentiation, and its absence prevents the development of experimentally-induced osteoporosis.
Untargeted metabolomics reveals PTI-associated metabolites in tomato
Authors: Muñoz Hoyos Lina , Wan Petra Anisha , Meng Chen , Kleigrewe Karin , Dawid Corinna , Hückelhoven Ralph , Stam Remco 
Published: June 2023

AbstractPlants employ a multi-layered innate immune system to detect and fend off invading fungal pathogens. In one such layer, recognition of Pathogen- or Microbe-Associated Molecular Patterns or elicitors, triggers a signaling cascade that leads to defence against the pathogen and ultimately Pattern-Triggered Immunity (PTI). Secondary Metabolites (SMs) are expected to play an important role in this kind of resistance, because they are potentially mycotoxic compounds. Tomato plants inoculated withAlternaria solanishow clear symptoms of infection 5 days after inoculation. Whereas plants inoculated withAlternaria alternataremain symptomless. We hypothesized that pattern-triggered induction of resistance-related metabolites inSolanum lycopersicumcontribute to the resistance againstA. alternata, yet such SMs are suppressed in a compatible interaction. We compared the metabolomic profile (metabolome) ofS. lycopersicumat two time points (3 and 24 hours) after treatments withA. alternata, A. solaniand the fungal elicitor chitin and identified SMs that are involved in the early defence response of tomato plants. Our study revealed differential metabolome fingerprints and shows that the molecular composition ofA. alternataand chitin-induced indeed show larger overlap with each other than with theA. solani-induced metabolome. We identify 65 candidate metabolites possibly associated with pattern-triggered resistance in tomato plants, including the alkaloid, trigonelline, for which we can confirm that it inhibits fungal growthin vitrowhen supplied at physiological concentrations. Our findings show that a true, pattern-triggered, chemical defence is mounted againstA. alternataand that it contains mycotoxin compounds previously unidentified in tomato, that could be interesting for future crop protection strategies.
Anti-CD117 CAR T cells incorporating a safety switch eradicate human acute myeloid leukemia and hematopoietic stem cells
Authors: Magnani Chiara F. , Myburgh Renier , Brunn Silvan , Chambovey Morgane , Ponzo Marianna , Volta Laura , Pellegrino Christian , Pascolo Steve , Miskey Csaba , Ivics Zoltán , Shizuru Judith A. , Neri Dario , Manz Markus G. 
Published: June 2023

AbstractAcute Myeloid Leukemia originates from the accumulation of mutations in hematopoietic stem and progenitor cells, leading to the emergence of leukemia-initiating cells, which sustain blast formation. CAR T cells specific for the CD117 antigen can deplete malignant and healthy hematopoietic stem cells. Here we exploit non-viral technology to achieve early termination of CAR T cell activity to prevent incoming graft rejection. Transient expression of an anti-CD117 CAR by mRNA conferred T cells the ability to eliminate CD117+ targets in vitro and in vivo. As an alternative approach, we used a Sleeping Beauty transposon vector for the generation of CAR T cells incorporating an inducible Caspase 9 safety switch. Stable CAR expression was associated with high proportion of T memory stem cells, low levels of exhaustion markers, and potent cellular cytotoxicity. Anti-CD117 CAR T cells mediated depletion of leukemic cells and healthy hematopoietic stem cells in NSG mice reconstituted with human leukemia or CD34+ cord blood cells, respectively, and could be chemically terminated in vivo. The use of a non-viral technology to control CAR T cell pharmacokinetic properties is attractive for a first-in-human study in patients with acute myeloid leukemia prior to hematopoietic stem cell transplantation.
Vitamin B12 status and folic acid supplementation influence mitochondrial heteroplasmy levels in mice as they age
Authors: Walsh Darren J , Bernard David J , Fiddler Joanna L , Pangilinan Faith , Esposito Madison , Harold Denise , Field Martha S , Parle-McDermott Anne , Brody Lawrence C 
Published: June 2023

AbstractOne-carbon metabolism is a complex network of metabolic reactions that are essential for cellular function including DNA synthesis. Vitamin B12 and folate are micronutrients that are utilized in this pathway and their deficiency can result in the perturbation of one-carbon metabolism and subsequent perturbations in DNA replication and repair. This effect has been well characterized in nuclear DNA but to date, mitochondrial DNA (mtDNA) has not been investigated extensively. Mitochondrial variants have been associated with several inherited and age-related disease states; therefore, the study of factors that impact heteroplasmy are important for advancing our understanding of the mitochondrial genome’s impact on human health.Heteroplasmy studies require robust and efficient mitochondrial DNA enrichment to carry out in-depth mtDNA sequencing. Many of the current methods for mtDNA enrichment can introduce biases and false positive results. Here we use a method that overcomes these limitations and have applied it to assess mitochondrial heteroplasmy in mouse models of altered one-carbon metabolism. Vitamin B12 deficiency was found to cause increased levels of mitochondrial DNA heteroplasmy across all tissues that were investigated. Folic acid supplementation also contributed to elevated mitochondrial DNA heteroplasmy across all mouse tissues investigated. Heteroplasmy analysis of human data from the Framingham Heart Study suggested a potential sex-specific effect of folate and vitamin B12 status on mitochondrial heteroplasmy. This is a novel relationship that may have broader consequences for our understanding of one-carbon metabolism, mitochondrial related disease and the influence of nutrients on DNA mutation rates.Significance StatementUsing a sensitive method for mitochondrial heteroplasmy analysis, we show that both vitamin B12 and folic acid can impact mitochondrial DNA mutation. This effect requires further investigation of the potential impact on humans.
Improved RNA stability estimation through Bayesian modeling reveals mostSalmonellatranscripts have sub-minute half-lives
Authors: Jenniches Laura , Michaux Charlotte , Popella Linda , Reichardt Sarah , Vogel Jörg , Westermann Alexander J. , Barquist Lars 
Published: June 2023

AbstractRNA decay is a crucial mechanism for regulating gene expression in response to environmental stresses. In bacteria, RNA-binding proteins (RBPs) are known to be involved in post-transcriptional regulation, but their global impact on RNA half-lives has not been extensively studied. To shed light on the role of the major RBPs ProQ and CspC/E in maintaining RNA stability, we performed RNA sequencing ofSalmonella entericaover a time course following treatment with the transcription initiation inhibitor rifampicin (RIF-seq) in the presence and absence of these RBPs. We developed a hierarchical Bayesian model that corrects for confounding factors in rifampicin RNA stability assays and enables us to identify differentially decaying transcripts transcriptome-wide. Our analysis revealed that the median RNA half-life inSalmonellain early stationary phase is less than 1 minute, a third of previous estimates. We found that over half of the 500 most long-lived transcripts are bound by at least one major RBP, suggesting a general role for RBPs in shaping the transcriptome. Integrating differential stability estimates with CLIP-seq revealed that approximately 30% of transcripts with ProQ binding sites and more than 40% with CspC/E binding sites in coding or 3’ untranslated regions decay differentially in the absence of the respective RBP. Analysis of differentially destabilized transcripts identified a role for ProQ in the oxidative stress response. Our findings provide new insights into post-transcriptional regulation by ProQ and CspC/E, and the importance of RBPs in regulating gene expression.Significance StatementTogether with transcription and translation, RNA decay is one of the major processes governing protein production. Here, we have developed a new statistical approach that corrects for confounding effects when estimating RNA decay rates from RNA-seq in bacteria. Our more accurate decay rate estimates indicate thatSalmonellatranscripts have half-lives about three times shorter than previously thought. This approach allowed us to measure the effects of RNA-binding proteins (RBPs) on decay rates, identifying large cohorts of transcripts with changes in stability following RBP deletion and conditions where post-transcriptional regulation affects survival. Our method should lead to a reevaluation of RNA stability estimates across diverse bacteria and new insights into the role of RBPs in shaping the transcriptome.
DidMoldehaweraflowers evolve through mimicry with oil-producing Malpighiaceae?
Authors: de Queiroz Luciano Paganucci , Costa Jorge Antonio Silva , Costa Cristiana Barros Nascimento 
Published: June 2023

AbstractFloral mimicry is a captivating phenomenon wherein flowers imitate traits of other species to attract specific pollinators. The Caesalpinioideae legumes in general have relatively unspecialized flowers, which has allowed the development of disparate morphologies associated with adaptation to different types of pollinators. This study describes the pollination ofMoldenhawera nutansand explores its potential floral mimicry towards Malpighiaceae flowers. Our investigation revealed thatM. nutansis pollinated by species ofCentrisFabricius, 1804 andXylocopaLatreille, 1802. It also presents compelling evidence supporting the hypothesis of floral mimicry, including striking similarities in floral display, shared oil-collecting pollinators, oil collection behavior inM. nutansdespite the absence of oil production, and the reliance on exogenous pollen for reproduction. These findings suggest that species ofCentrisbees visitM. nutansflowers under the mistaken impression of oil availability, subsequently transitioning to pollen collection. We explored other potential cases of floral mimicry with Malpighiaceae in the Caesalpinioideae legumes by optimizing the Malpighiaceae-like floral display on a dated phylogeny of this subfamily. However, current information does not allow us to determine whether the similarities in floral morphology represent cases of floral mimicry, phylogenetic inertia, or simple convergence. Several hypothesis tests are suggested that can guide the study of these fascinating evolutionary processes in the group.