bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prolactin receptor potentiates chemotherapy through miRNAs‐induced G6PD/TKT inhibition in pancreatic cancer
Authors: Liao Ying‐Na , Huang Pei‐Qi , Pan Hong , Gai Yan‐Zhi , Zhan Yun‐Fei , Li Shu‐Xin , Nie Hui‐Zhen 
Published: May 2024

AbstractPancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies, with a notoriously dismal prognosis. As a competitive inhibitor of DNA synthesis, gemcitabine is the cornerstone drug for treating PDAC at all stages. The therapeutic effect of gemcitabine, however, is often hindered by drug resistance, and the underlying mechanisms remain largely unknown. It is unclear whether their response to chemotherapeutics is regulated by endocrine regulators, despite the association between PDAC risk and endocrine deregulation. Here, we show that prolactin receptor (PRLR) synergizes with gemcitabine in both in vitro and in vivo treatment of PDAC. Interestingly, PRLR promotes the expression of miR‐4763‐3p and miR‐3663‐5p, two novel miRNAs whose functions are unknown. Furthermore, the analysis of transcriptome sequencing data of tumors from lactating mouse models enriches the PPP pathway, a multifunctional metabolic pathway. In addition to providing energy, the PPP pathway mainly provides a variety of raw materials for anabolism. We demonstrate that two key enzymes of the pentose phosphate pathway (PPP), G6PD and TKT, are directly targeted by miR‐4763‐3p and miR‐3663‐5p. Notably, miR‐4763‐3p and miR‐3663‐5p diminish the nucleotide synthesis of the PPP pathway, thereby increasing gemcitabine sensitivity. As a result, PRLR harnesses these two miRNAs to suppress PPP and nucleotide synthesis, subsequently elevating the gemcitabine sensitivity of PDAC cells. Also, PDAC tissues and tumors from LSL‐KrasG12D/+, LSL‐Trp53R172H/+, and PDX1‐cre (KPC) mice exhibit downregulation of PRLR. Bisulfite sequencing of PDAC tissues revealed that PRLR downregulation is due to epigenetic methylation. In this study, we show for the first time that the endocrine receptor PRLR improves the effects of gemcitabine by boosting two new miRNAs that block the PPP pathway and nucleotide synthesis by inhibiting two essential enzymes concurrently. The PRLR‐miRNAs‐PPP axis may serve as a possible therapeutic target to supplement chemotherapy advantages in PDAC.
First Experience of Radionuclide Therapy With 177Lu-FAPI-2286 in a Patient With Metastatic Mediastinal Sarcoma
Authors: Banihashemian Seyedeh Somayyeh , Bayat Mohadese , Pirayesh Elahe , Divband Ghasemali , Abolhosseini Abdolghafar , Akbari Mohammad Esmaeel 
Published: May 2024

Abstract
Fibroblast activation protein (FAP) is a new promising molecular target for theragnostic approach. FAP inhibitors (FAPIs) labeled with 177Lu could be potentially a therapeutic radiopharmaceutical. Here, we presented the experience of 4 cycles of 177Lu-FAPI in a 67-year-old man with an unresectable mediastinal sarcoma.
Efficacy and Safety Evaluation of 177Lu-FAP-2286 in the Treatment of Advanced Lung Cancer
Authors: Xie Yang , Ma Jiao , Tang Wenxin , Zhang Yu , Zhang Chunyin , Chen Yue 
Published: May 2024

Purpose
The aim of this study was to evaluate the efficacy and safety of peptide-targeted radionuclide therapy (PTRT) with 177Lu-FAP-2286 in advanced lung cancer.

Patients and Methods
This single-center prospective study included 9 patients diagnosed with advanced lung cancer. These patients met the inclusion criteria and received PTRT with 177Lu-FAP-2286. Short-term efficacy was assessed using RECIST 1.1 and PERCIST 1.0 criteria. Long-term efficacy was evaluated through overall survival, progression-free survival (PFS), overall response rate, EORTC QLQ-C30 v3.0, Eastern Cooperative Oncology Group, and Karnofsky Performance Status. Toxicity response was assessed using CTCAE v5.0.

Results
The results based on RECIST 1.1 and PERCIST 1.0 criteria were comparable, with 44% of patients showing a partial metabolic response, 33.3% with stable metabolic disease, and 22.22% with progressive metabolic disease. The highest metabolic response after treatment reached 66.89%, and the overall response rate could reach 77.78%. In the long-term efficacy assessment, the median overall survival and PFS were 10 months and 6 months, respectively. The 2 patients with the lowest PFS (3 months) started PTRT relatively late. EORTC QLQ-C30 v3.0, Eastern Cooperative Oncology Group, and Karnofsky Performance Status scores showed that the overall health status, symptom response, and quality of life of patients improved after 177Lu-FAP-2286 treatment. The most noticeable improvements in clinical symptoms were dyspnea and cancer-related pain. No grade III/IV toxicity events were observed during follow-up period, and fibrinogen decreased significantly after treatment.

Conclusions

177Lu-FAP-2286 has the potential to be a viable PTRT option for patients with advanced lung cancer.
Adapting Indirect Calorimetry to measure metabolic status of healthy and septic neonatal mice
Authors: Eynaud Adrien , Solomon Joan , Schoeman Elizna , Wu Ziyuan , Amenyogbe Nelly 
Published: May 2024

AbstractCommercially available platforms to measure murine pulmonary gas exchange have long been used to measure metabolic status of adult animals, thus providing insights into metabolic disease, diabetes, and infection. Metabolic status is increasingly being recognized as an important modulator of neonatal immunity, and capturing pulmonary gas exchange in neonatal animals provides a non-invasive way to capture physiological information in health and disease and may reveal metabolic determinants of immune-mediated diseases unique to this life stage. We evaluated an indirect calorimetry (IC) system, the Promethion Core CGF system outfitted with Respirometry Chambers (RC3) as a tool to accurately capture pulmonary gas exchange from individual healthy and septic murine neonatal pups in the first week of life. We assessed the technical variance of the platform, impact of the procedure of animal welfare, compared measurements performed either at room temperature or at 30°C, and determined the platform’s sensitivity to measure gas exchange from pups with very small lung capacity or low respiratory rate. While gas exchange was not captured above background levels in all pups with either very small lung volume (pups less than 4 days old) or with very low respiratory rates (septic pups with the most depressed respiratory status), measurements did capture physiologically relevant changes in gas exchange across age and disease states. The impost associated with frequent handling of septic animals for IC did not negatively impact clinical outcomes among pups challenged with a polymicrobial slurry. Further, while performing the IC readings at 30°C successfully stabilized animal body temperature, the VO2 and VCO2 values differed across temperature states for older pups. In conclusion, the Promethion Core system outfitted with RC3 chambers is a viable platform to integrate IC into murine neonatal health research.
Loss of neutrophil Shp1 produces hemorrhagic and lethal acute lung injury
Authors: Moussavi-Harami SF , Cleary SJ , Magnen M , Seo Y , Conrad C , English BC , Qiu L , Wang KM , Abram CL , Lowell CA , Looney MR 
Published: May 2024

AbstractThe acute respiratory distress syndrome (ARDS) is associated with significant morbidity and mortality and neutrophils are critical to its pathogenesis. Neutrophil activation is closely regulated by inhibitory tyrosine phosphatases including Src homology region 2 domain containing phosphatase-1 (Shp1). Here, we report that loss of neutrophil Shp1 in mice produced hyperinflammation and lethal pulmonary hemorrhage in sterile inflammation and pathogen-induced models of acute lung injury (ALI) through a Syk kinase-dependent mechanism. We observed large intravascular neutrophil clusters, perivascular inflammation, and excessive neutrophil extracellular traps in neutrophil-specific Shp1 knockout mice suggesting an underlying mechanism for the observed pulmonary hemorrhage. Targeted immunomodulation through the administration of a Shp1 activator (SC43) reduced agonist-induced reactive oxygen speciesin vitroand ameliorated ALI-induced alveolar neutrophilia and NETsin vivo. We propose that the pharmacologic activation of Shp1 has the potential to fine-tune neutrophil hyperinflammation that is central to the pathogenesis of ARDS.
Mechanism-based design of DNA-nanoparticle motor with high speed and processivity comparable to motor proteins
Authors: Harashima Takanori , Otomo Akihiro , Iino Ryota 
Published: May 2024

AbstractDNA-nanoparticle motor is a burnt-bridge Brownian ratchet moving on RNA-modified surface driven by Ribonuclease H (RNase H), and one of the fastest nanoscale artificial motors. However, its speed is still much lower than those of motor proteins. Here we resolve elementary processes of motion and reveal long pauses caused by slow RNase H binding are the bottleneck. As RNase H concentration ([RNase H]) increases, pause lengths shorten from ∼100 s to ∼0.1 s, while step sizes are constant (∼20 nm). At high [RNase H], speed reaches ∼100 nm s−1, however, processivity, run-length, and unidirectionality largely decrease. A geometry-based kinetic simulation reveals switching of bottleneck from RNase H binding to DNA/RNA hybridization at high [RNase H], and trade-off mechanism between speed and other performances. A mechanism-based newly-designed motor with 3.8-times larger DNA/RNA hybridization rate simultaneously achieves 30 nm s−1speed, 200 processivity, and 3 μm run-length comparable to motor proteins.
TIF1γ regulates stability of T regulatory cells during inflammation
Authors: Contreras-Castillo Eugenio , Zambrano-Romero Jesús Daniel , Pérez-Vázquez Diego , García-Patiño María Guadalupe , Tapia-Urzúa Gustavo , Candelario-Martínez Aurora , Ramos-Balderas Jose Luis , Licona-Limón Irma Ileana , Madera-Salcedo Iris , Rosetti-Scuitto Florencia , Crispin-Acuña Jose Carlos , Noriega-López Lilia , Nava Porfirio , Recillas-Targa Félix , Kaartinen Veesa , Henao-Mejía Jorge , Flavell Richard , Licona-Limón Paula 
Published: May 2024

AbstractT regulatory cells are a suppressor population critical to control inflammation and maintain tissue homeostasis. The TGF-β pathway is a fundamental signal for T regulatory cell differentiation, yet the molecular determinants of how TGF-β signals regulate all these processes are not completely understood. TIF1γ was demonstrated to promote a noncanonical TGF-β/Smad pathway in HSC, however the role of TIF1γ in Treg function has been largely ignored. Here we showed that TIF1γ deficient Tregs lose stability and acquire an effector phenotype in the presence of an inflammatory stimuli or upon activation. TIF1γ deficient T regs gain a Th1-like Treg phenotype or become pro-inflammatory exTregs, by losing Foxp3 expression and acquiring IFNγ expression in an autoimmune model. Loss of TIF1γ in Tregs was cell-intrinsic and was also accompanied by increased proliferation and enhanced glycolytic capacity upon activation. Additionally, we demonstrated that in the absence of TIF1γ, there was an increased methylation status in the CNS2 enhancer region of the Foxp3 locus, further suggesting increased susceptibility for loss of Foxp3 expression. Mechanistically, TGF-β was in part responsible to inhibit the Th1-like bias a Treg has in the absence of TIF1γ, however, the proliferative phenotype observed in these cells was mostly independent of TGF-β signaling. Finally, we identified the beta-catenin pathway as the molecular mechanism driving both TIF1γ-dependent Treg stability and proliferation upon inflammation. Altogether, our data demonstrated that TIF1γ is required for the maintenance of a suppressor phenotype and stability of Treg lymphocytes during inflammatory conditionsin vivoand represents a new modulatory pathway to manipulate Treg cells for therapeutic purposes.
SimpleMating: R-package for Prediction and Optimization of Breeding Crosses Using Genomic Selection
Authors: Peixoto Marco Antônio , Amadeu Rodrigo Rampazo , Bhering Leonardo Lopes , Ferrão Luís Felipe V. , Munoz Patrício R. , Resende Márcio F. R. 
Published: May 2024

ABSTRACTSelecting parents and crosses is a critical step for a successful breeding program. The ability to design crosses with high means that will maintain genetic variation in the population is the goal for long-term applications. Herein, we describe a new computational package for mate allocation in a breeding program. SimpleMating is a flexible and open-source R package originally designed to predict and optimize breeding crosses in crops with different reproductive systems and breeding designs. Divided into modules, SimpleMating first estimates the cross performance (criterion), such as mean parental average, cross total genetic value, and/or usefulness of a set of crosses. The second module implements an optimization algorithm to maximize a target criterion while minimizing next-generation inbreeding. The software is flexible, allowing users to specify the desired number of crosses, maximum/minimum number of crosses per parent, and the maximum value of the parent relationship for creating crosses. As an outcome, SimpleMating generates a mating plan from the target parental population using single or multi-trait criteria. As example, we implemented and tested SimpleMating in a simulated maize breeding program obtained through stochastic simulations. The crosses designed via SimpleMating showed large genetic mean over time (up to 22% more genetic gain than conventional genomic selection programs, with lower genetic diversity decrease over time), supporting the use of this tool, as well as the use of data-driven decisions in applied breeding programs.
Finding novel vulnerabilities of hypomorphic BRCA1 alleles
Authors: Schreuder Anne , de Lint Klaas , Góis Mariana M. , Kampen Rosalie A. , Martin Alonso Marta San , Nootenboom Ilse , Garzero Veronica , Wolthuis Rob M. F. , Noordermeer Sylvie M. 
Published: May 2024

ABSTRACTWith the recent rise in CRISPR/Cas9-mediated genome-wide synthetic lethality screens, many new synthetic lethal targets have been identified for diseases with underlying genetic causes such as tumours withBRCA1mutations. Such screens often use full deficiency of a protein to identify novel vulnerabilities. However, patient-derived mutations not only result in loss of the protein but often also concern missense mutations with hypomorphic phenotypes. Here we study the genetic vulnerabilities of two previously described hypomorphic BRCA1 missense mutations and compare these to a BRCA1-depleted setting to study whether this affects screening for synthetic lethal interactions. Our research showed that BRCA1I26Amutated cells have very similar vulnerabilities to BRCA1 wildtype cells, confirming its low tumorigenic effect. In contrast, the BRCA1R1699Qmutation induced a more similar phenotype to BRCA1-deficient cells. For this mutation, we also unveiled a unique vulnerability to the loss of NDE1. Specifically in BRCA1R1699Qmutated cells, and not BRCA1-proficient or -deficient cells, NDE1 loss leads to increased genomic instability. Altogether our findings highlight the importance to differentiate between patient-derived mutations when assessing novel treatment targets.
Dating the origin of a viral domestication event in parasitoid wasps attacking Diptera
Authors: Guinet Benjamin , Vogel Jonathan , Peters Ralph S. , Hrcek Jan , Buffington Matthew L. , Varaldi Julien 
Published: May 2024

AbstractOver the course of evolution, hymenopteran parasitoids have developed a close relationship with heritable viruses, sometimes even integrating viral genes into their chromosomes. For example, inDrosophilaparasitoids belonging to the Leptopilina genus, 13 viral genes from the Filamentoviridae family have been integrated and domesticated to deliver immunosuppressive factors to host immune cells, thereby protecting parasitoid offspring from host immune responses. The present study aims to comprehensively characterise this domestication event in terms of the viral genes involved, the wasp diversity affected by this event, and its chronology. Our genomic analysis of 41 Cynipoidea wasps from six subfamilies revealed 18 viral genes that were endogenised during the early radiation of the Eucoilini+Trichoplastini clade around 75 million years ago. Wasps from this highly diverse clade develop not only fromDrosophilabut also from a variety of Schizophora. This event coincides with the radiation of Schizophora, a highly speciose Diptera clade, suggesting that viral domestication facilitated wasp diversification in response to host diversification. Additionally, at least one viral gene was replaced by another Filamentovirus gene in one of the species, highlighting the dynamic nature of viral endogenisation. This study highlights the impact of viral domestication on the diversification of parasitoid wasps.
RUCova: Removal of Unwanted Covariance in mass cytometry data
Authors: Astaburuaga-García Rosario , Sell Thomas , Mutlu Samet , Sieber Anja , Lauber Kirsten , Blüthgen Nils 
Published: May 2024

High dimensional mass cytometry is confounded by unwanted covariance due to variations in cell size and staining efficiency, making analysis and interpretation challenging.We present RUCova, a novel method designed to address confounding factors in mass cytometry data. RUCova removes unwanted covariance using multivariate linear regression on Surrogates of Unwanted Covariance (SUCs), and Principal Component Analysis (PCA). We exemplify the use of RUCova and show that it effectively removes unwanted covariance while preserving genuine biological signals. Our results demonstrate the efficacy of RUCova in elucidating complex data patterns, facilitating the identification of activated signalling pathways, and improving the classification of important cell populations. By providing a robust framework for data normalization and interpretation, RUCova enhances the accuracy and reliability of mass cytometry analyses, contributing to advancements in our understanding of cellular biology and disease mechanisms. The R package is available onhttps://github.com/molsysbio/RUCova. Detailed documentation, data, and the code required to reproduce the results are available onhttps://doi.org/10.5281/zenodo.10913464. Supplementary material: Available at bioRxiv.
WITHDRAWN: Physiological modeling and biomechanical insights of cytokine modulation in COVID-19 and pulmonary fibrosis through a multi-dimensional graph-based approach
Authors: Ray Rajarshi , Bhowmik Ratul , Shyamal Sagar Singh , Manaithiya Ajay , Gong Wenping , Parkkila Seppo , Aspatwar Ashok 
Published: May 2024

Withdrawal StatementThe authors have withdrawn their manuscript owing to the inability to complete the revisions or follow up on the manuscript at this time, due to personal circumstances. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.
A multivariable Mendelian randomisation study of serum lipids and dementia risk within the UK Biobank
Authors: Pham Kitty , Mulugeta Anwar , Lumsden Amanda , Hyppӧnen Elina 
Published: May 2024

AbstractBackground and aimsAn unfavourable lipid profile has been associated with increased risk of dementia. However, it is challenging to investigate each serum lipid measure individually due to the high correlation between the traits. We tested for genetic evidence supporting associations between serum lipid measures and risk of dementia.MethodsWe conducted multivariable and univariable Mendelian randomisation (MR) analyses on 329,896 UK Biobank participants (age 37–73 years) to examine the associations between low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides, apolipoprotein-A1 (ApoA1) and apolipoprotein-B (ApoB), and the risk of dementia. The multivariable approach allows us to assess the association of each lipid measure with the outcome, including where the genetic variant-exposure associations are mediated by one another.ResultsIn the univariable MR analyses, we observed no association between genetically determined serum lipids and risk of dementia. However, in a multivariable MR model containing LDL-C, triglycerides, and ApoB, ApoB was associated with a higher risk of dementia (OR per 1 SD higher ApoB 1.63, 95% CI 1.12, 2.37). Multivariable findings were consistent across IVWMR and MR-Egger, but not weighted median MR or MR-Lasso. HDL-C and ApoA1 were not associated with dementia in univariable or multivariable MR.ConclusionsOur findings suggest that when considering the correlation between lipid measures, ApoB may play a role in the previously reported association between serum lipids and increased risk of dementia. Future studies should aim to confirm the findings in clinical/experimental studies and further explore the role of ApoB in dementia pathophysiology.
The Neurodegenerative Disease Knowledge Portal: Propelling Discovery Through the Sharing of Neurodegenerative Disease Genomic Resources
Authors: Dilliott Allison A. , Costanzo Maria C. , Bandres-Ciga Sara , Blauwendraat Cornelis , Casey Bradford , Hoang Quy , Iwaki Hirotaka , Jang Dongkeun , Kim Jonggeol Jeffrey , Leonard Hampton L. , Levine Kristin S. , Makarious Mary , Nguyen Trang T. , Rouleau Guy A. , Singleton Andrew B. , Smadbeck Patrick , Solle J , Vitale Dan , Nalls Mike A. , Flannick Jason , Burtt Noël P. , Farhan Sali M.K. 
Published: May 2024

AbstractAlthough large-scale genetic association studies have proven useful for the delineation of neurodegenerative disease processes, we still lack a full understanding of the pathological mechanisms of these diseases, resulting in few appropriate treatment options and diagnostic challenges. To mitigate these gaps, the Neurodegenerative Disease Knowledge Portal (NDKP) was created as an open-science initiative with the aim to aggregate, enable analysis, and display all available genomic datasets of neurodegenerative disease, while protecting the integrity and confidentiality of the underlying datasets. The portal contains 218 genomic datasets, including genotyping and sequencing studies, of individuals across ten different phenotypic groups, including neurological conditions such as Alzheimer’s disease, amyotrophic lateral sclerosis, Lewy body dementia, and Parkinson’s disease. In addition to securely hosting large genomic datasets, the NDKP provides accessible workflows and tools to effectively utilize the datasets and assist in the facilitation of customized genomic analyses. Here, we summarize the genomic datasets currently included within the portal, the bioinformatics processing of the datasets, and the variety of phenotypes captured. We also present example use-cases of the various user interfaces and integrated analytic tools to demonstrate their extensive utility in enabling the extraction of high-quality results at the source, for both genomics experts and those in other disciplines. Overall, the NDKP promotes open-science and collaboration, maximizing the potential for discovery from the large-scale datasets researchers and consortia are expending immense resources to produce and resulting in reproducible conclusions to improve diagnostic and therapeutic care for neurodegenerative disease patients.