bluuebunny/crossref_metadata_2025_split huggingface dataset:
A reaction norm for flowering time plasticity reveals physiological footprints of maize adaptation
Authors: Drouault Justine , Palaffre Carine , Millet Emilie J. , Rodriguez Jonas , Martre Pierre , Johnson Kristian , Parent Boris , Welcker Claude , Wisser Randall J. 
Published: July 2024

AbstractUnderstanding how plant phenotypes are shaped by their environments is crucial for addressing questions about crop adaptation to new environments. This study focused on analyzing the genetic variability underlying genotype-by-environment interactions and adaptation for flowering time in maize. We developed the use of a physiological reaction norm for flowering time plasticity (PRN-FTP) modeled from multi-environment trial networks, with genotype-specific parameters putatively linked to different regulatory modules for flowering time. We show how genotype-specific differences in developmental responses to temperature fluctuations condition differences in photoperiod perceived among genotypes. This occurs not only across but also within common environments, as the perception of photoperiod is altered by variation in rates of development and durations for becoming sensitized to photoperiod. Using a new metric for envirotyping sensed photoperiods for maize, it was found that, at high latitudes, different genotypes in the same environment can experience up to hours-long differences in photoperiod. This emphasizes the importance of considering genotype-specific differences in the experienced environment when investigating plasticity. Modeling the PRN-FTP for global breeding material of maize showed that tropical and temperate germplasm occupy distinct territories of the trait space for PRN-FTP parameters, supporting that the geographical spread and adaptation of maize was differentially mediated by distinct pathways for flowering time regulation. Our results have implications for understanding crop adaptation and for future crop improvement efforts.Article SummaryMaize adjusts its flowering time across environments using genetic pathways tuned to cues like temperature and day length. This study models how different varieties perceive and respond to these factors, revealing that genotypes can perceive the same environment in distinct ways. By examining the physiological underpinnings of genetic and environmental interactions, the research highlights how maize’s historical spread and artificial selection have shaped diverse strategies for flowering time regulation in tropical and temperate varieties.
Submaximal eccentric resistance training increases serial sarcomere number and improves dynamic muscle performance in old rats
Authors: Hinks Avery , Vlemmix Ethan , Power Geoffrey A. 
Published: July 2024

AbstractThe age-related loss of muscle mass is partly accounted for by the loss of sarcomeres in series. Serial sarcomere number (SSN) influences muscle mechanical function including the force-length and force-velocity-power relationships, and the age-related loss of SSN contributes to declining performance. Resistance training biased to active lengthening (eccentric) contractions increases SSN in young muscle, however, we showed maximal eccentric training in old rats did not alter SSN and further worsened performance. A submaximal eccentric training stimulus may be more conducive to adaptation for aged muscle. Therefore, the purpose of this study was to assess whether submaximal eccentric training can increase SSN and improve mechanical function in old rats. Twelve 32-month-old male F344/BN rats completed 4 weeks of submaximal (60% maximum) isokinetic eccentric plantar-flexion training 3 days/week. Pre- and post-training, we assessedin-vivomaximum isometric torque at a stretched and neutral ankle angle, the passive torque-angle relationship, and the isotonic torque-angular velocity-power relationship. The soleus and MG were harvested for SSN measurements via laser diffraction, with the untrained leg as a control. SSN increased 11% and 8%, and muscle wet weight increased 14% and 13% in the soleus and MG, respectively. Maximum isometric torque and shortening velocity were unaltered, but there was a shift towards longer muscle lengths for the optimal angle of torque production, a 42% reduction of passive torque, and 23% increase in peak isotonic power. Eccentric training at 60% maximum was beneficial for aged muscle, increasing SSN and muscle mass, reducing muscle passive tension, and improving dynamic performance.New & NoteworthyFour weeks of submaximal (60% of maximum) eccentric resistance training increased serial sarcomere number and muscle mass in old ratsIncreased serial sarcomere number corresponded to broadening of the torque-angle relationship following training, which contributed to increased peak isotonic powerSubmaximal eccentric training also led to a large reduction in passive torque throughout the range of motion
High-throughput drug screening for inhibition of influenza A virus infection based on human SIRT1 promoter and Genipin suppressing influenza A virus by activation of AMPK-SIRT1-PGC-1α signaling pathway
Authors: Ye Jinghan , Liu Dekun , Wang Qianwen , Dai Jianping 
Published: July 2024

AbstractThe energy metabolism crisis is considered an important risk factor for severe influenza A virus (IAV) infection. During virus replication, the host cell’s “metabolic reprogramming” is beneficial for increasing the energy demand of the virus. SIRT1 plays a major role in altering metabolic reprogramming, and upregulation of SIRT1 expression can defend against viral infection. This study established a high-throughput drug screening method for human SIRT1 promoter. Nine natural medicines were selected from 134 traditional Chinese medicines. Among them, the activity ofGardenia jasminoidesEllis was relatively high. Further research has found that the plant extract and its active compound Genipin and its derivatives can significantly inhibit IAV replication, improve the survival rate of infected mice, and inhibit pneumonia. In addition, Genipin significantly increased the levels of energy metabolism core regulatory factors SIRT1, PPAR γ, PGC-1 α, and p-AMPK, inhibited IAV induced activation of MAPKs and NF-κB, and alleviated inflammatory response. The pharmacological antagonists of SIRT1 and PGC-1 α, as well as siRNA, significantly counteracted the effects of Genipin on IAV replication and inflammation. In summary, we found that Genipin and its derivatives could significantly inhibit IAV replication and inflammation, possibly by activating the AMPK-SIRT1-PGC-1α signaling pathway and altering metabolic reprogramming.
Effects of clinically relevant radionuclides on the activation of a type I interferon response by radiopharmaceuticals in syngeneic murine tumor models
Authors: Kerr Caroline P. , Sheehan-Klenk Julia , Grudzinski Joseph J. , Adam David P. , Nguyen Thanh Phuong T. , Ferreira Carolina A. , Bates Amber M. , Jin Won Jong , Kwon Ohyun , Olson Aeli P. , Lin Wilson , Hyun Meredith , Jagodinsky Justin C. , Powers Maria , Sriramaneni Raghava N. , Clark Paul A. , Shea Amanda G. , Rojas Hansel Comas , Choi Cynthia , Massey Christopher F. , Zangl Luke M. , Pinchuk Anatoly N. , Aluicio-Sarduy Eduardo , Kim KyungMann , Engle Jonathan W. , Hernandez Reinier , Bednarz Bryan P. , Weichert Jamey P. , Morris Zachary S. 
Published: July 2024

AbstractRadiopharmaceutical therapies (RPT) activate a type I interferon (IFN1) response in tumor cells. We hypothesized that the timing and amplitude of this response varies by isotope. We compared equal doses delivered by90Y,177Lu, and225Acin vitroas unbound radionuclides andin vivowhen chelated to NM600, a tumor-selective alkylphosphocholine. Response in murine MOC2 head and neck carcinoma and B78 melanoma was evaluated by qPCR and flow cytometry. Therapeutic response to225Ac-NM600+anti-CTLA4+anti-PD-L1 immune checkpoint inhibition (ICI) was evaluated in wild-type and stimulator of interferon genes knockout (STING KO) B78. The timing and magnitude of IFN1 response correlated with radionuclide half-life and linear energy transfer. CD8+/Treg ratios increased in tumors 7 days after90Y- and177Lu-NM600 and day 21 after225Ac-NM600.225Ac-NM600+ICI improved survival in mice with WT but not with STING KO tumors, relative to monotherapies. Immunomodulatory effects of RPT vary with radioisotope and promote STING-dependent enhanced response to ICIs in murine models.TeaserThis study describes the time course and nature of tumor immunomodulation by radiopharmaceuticals with differing physical properties.
CrypToth: Cryptic pocket detection through mixed-solvent molecular dynamics simulations based topological data analysis
Authors: Koseki Jun , Motono Chie , Yanagisawa Keisuke , Kudo Genki , Yoshino Ryunosuke , Hirokawa Takatsugu , Imai Kenichiro 
Published: July 2024

ABSTRACTSome functional proteins undergo conformational changes to expose hidden binding sites when a binding molecule approaches their surface. Such binding sites are called cryptic sites and are important targets for drug discovery. However, it is still difficult to correctly predict cryptic sites. Therefore, we introduce a new method, CrypToth, for the precise identification of cryptic sites utilizing the persistent homology method. This method integrates topological data analysis and mixed-solvent molecular dynamics (MSMD) simulations. To identify hotspots corresponding to cryptic sites, we conducted MSMD simulations using six probes with different chemical properties: benzene, isopropanol, phenol, imidazole, acetonitrile, and ethylene glycol. Subsequently, we applied our topological data analysis method to rank hotspots based on the possibility of harboring cryptic sites. Evaluation of CrypToth using nine target proteins containing well-defined cryptic sites revealed its superior performance compared to recent machine-learning methods. As a result, in 7 out of 9 cases, hotspots associated with cryptic sites were ranked highest. CrypToth can explore hotspots on the protein surface favorable to ligand binding using MSMD simulations with six different probes and then identify hotspots corresponding to cryptic sites by assessing the protein’s conformational variability using the topological data analysis. This synergistic approach facilitates the prediction of cryptic sites with high accuracy.
Platelet integrin αIIbβ3 plays a key role in venous thrombogenesis in a mouse model
Authors: Adair Brian D. , Field Conroy O. , Alonso José L. , Xiong Jian-Ping , Deng Shi-Xian , Ahn Hyun Sook , Mashin Eivgeni , Clish Clary B. , van Agthoven Johannes , Yeager Mark , Guo Youzhong , Tess David A , Landry Donald W , Poncz Mortimer , Arnaout M. Amin 
Published: July 2024

AbstractVenous thrombosis (VT) is a common vascular disease associated with reduced survival and a high recurrence rate. Previous studies have shown that the accumulation of platelets and neutrophils at sites of endothelial cell activation is a primary event in VT, but a role for platelet αIIbβ3 in the initiation of venous thrombosis has not been established. This task has been complicated by the increased bleeding linked to partial agonism of current αIIbβ3 inhibitory drugs such as tirofiban (Aggrastat®). Here, we show that m-tirofiban, an engineered version of tirofiban, is not a partial agonist of αIIbβ3. This is based on its cryo-EM structure in complex with human full-length αIIbβ3 and its inability to increase expression of an activation-sensitive epitope on platelet αIIbβ3. m-tirofiban abolished agonist-induced platelet aggregationex vivoat concentrations that preserved clot retraction and markedly suppressed the accumulation of platelets, neutrophils, and fibrin on thrombin-activated endothelium in real-time using intravital microscopy in a mouse model of venous thrombogenesis. Unlike tirofiban, however, m-tirofiban did not increase bleeding at the thrombosis-inhibitory dose. These findings establish a key role for αIIbβ3 in the initiation of VT, provide a guiding principle for designing potentially safer inhibitors for other integrins, and suggest that pure antagonists of αIIbβ3 like m-tirofiban merit further consideration as potential thromboprophylaxis agents in patients at high-risk for VT and hemorrhage.
Unbiased functional genetic screens reveal essential RNA modifications in human cancer and drug resistance
Authors: Pauli Cornelius , Kienhöfer Michael , Blank Maximilian Felix , Begik Oguzhan , Rohde Christian , Heid Daniel , Xu Fu , Zimmermann Sarah Miriam Naomi , Weidenauer Katharina , Delaunay Sylvain , Krall Nadja , Trunk Katrin , Zhao Duoduo , Zhou Fengbiao , Heit-Mondrzyk Anke , Platzbecker Uwe , Baldus Claudia , Serve Hubert , Bornhäuser Martin , Vågbø Cathrine Broberg , Aznar Benitah Salvador , Krijgsveld Jeroen , Novoa Eva Maria , Müller-Tidow Carsten , Frye Michaela 
Published: July 2024

AbstractRNA modification pathways are mis-regulated in multiple types of human cancer. To comprehensively identify cancer-relevant RNA modifications and their regulators, we screened all 150 annotated human RNA modifying proteins across 18 different normal and cancer cell lines using a CRISPR-based genetic knockout system. Fifty RNA modifying proteins were essential for survival of at least one cell type. A third of these essential genes were amplified in 38 different human primary cancer types and potentially drive cancer growth. Unexpectedly, the number of essential genes per cell line varied considerably, and this variation was not due to tissue of origin. Instead, we found that cancer cell-specific mitochondrial metabolic plasticity was responsible for the unique requirement of certain RNA modifications. For example, leukemia cells with high intrinsic drug tolerance required mitochondrial flexibility to survive treatment with the anti-leukemic drugs cytarabine and venetoclax. Synthetic lethality screens revealed that drug-resistance is abolished by deleting the mitochondrial methyltransferase TRMT5, which is responsible for the formation of N1-methylguanosine (m1G) in the tRNA anticodon loop. In summary, our study identifies cancer-relevant RNA modifying enzymes, and reveals a novel promising drug target for therapy-resistant acute myeloid leukemia.
Effect of the COVID-19 pandemic and maternal SARS-CoV-2 status on breastfeeding practices in the COMBO cohort
Authors: Walzer Lauren , Nichols Presley , Amoo-Achampong Monica K. , Glassman Melissa E. , Kyle Margaret H. , Hussain Maha , Abreu Wanda , Scripps Tessa , Khan Adrita , Hanft Erin , Xu Ruiyang L. , LoFrumento Mary Ann , Kataria Anglina , Stockwell Melissa S. , Dumitriu Dani , Fernández Cristina R. 
Published: July 2024

AbstractObjectivesTo investigate the role of prenatal maternal SARS-CoV-2 infection and delivery during the COVID-19 pandemic on breastfeeding practices through 6 months postpartum.Study designA cohort of mother-infant dyads who delivered at a large medical center in New York City and who had either documented history of prenatal SARS-CoV-2 infection, no history of SARS-CoV-2 infection, or who delivered in February 2020 prior to the COVID-19 pandemic were invited to participate in the COVID-19 Mother Baby Outcomes (COMBO) Initiative. These three groups of mothers completed surveys about their breastfeeding practices at 1, 2, 4, and/or 6 months postpartum, and responses were compared across enrollment group at each postpartum assessment period.ResultsData from 557 mother-infant dyads was included. The SARS-CoV-2 infected group reported significantly lower rates of mostly or exclusively breastfeeding at 1 month, 2 months, and 4 months postpartum. When analyses were separated by birth timing and maternal ethnicity, these differences between infected and uninfected mothers were only significant in the second pandemic wave delivery group and in Latina mothers.Conclusions for practiceMaternal SARS-CoV-2 infection during pregnancy was associated with lower rates of mostly or exclusively breastfeeding through 4 months postpartum. These differences may have been driven by delivery timing during the pandemic and self-reported maternal ethnicity. These results suggest a need to increase resources and support for breastfeeding during healthcare-disruptive events such as the pandemic, particularly for those belonging to groups historically underserved in healthcare.
Training community home care workers to deliver a tailored falls prevention Education and Exercise program to home care clients – TrEdEx an effectiveness-implementation study protocol
Authors: Francis-Coad Jacqueline , Hill Anne-Marie , Flicker Leon , Etherton-Beer Christopher , Burton Elissa , Wharton Philippa , Wilkinson Jo , Norman Richard , Xu Daniel , Vaz Sharmila , Jessup Vanessa 
Published: July 2024

ABSTRACTFrail, older people receiving supportive care in the home are at high risk of falls and functional decline that leads to either unplanned hospital admissions or permanent residential care, making it difficult to safely remain at home. Community home care organisations are well positioned to deliver high quality falls prevention programs if staff are suitably trained. This research aims to train community home care workers to deliver a fall prevention program to home care clients and evaluate program implementation and effectiveness.A 2-phase hybrid effectiveness-implementation, pre- post design using a realist approach will be undertaken with a home care organisation. Home care workers, comprising community therapy assistants and community support workers, employed by the organisation will be trained to deliver the program by the organisation’s allied health professional staff using a train the trainer model. A multi-media falls prevention program (education and exercises) will be tailored to the client’s falls risk profile to raise falls awareness and promote physical activity and self-management. Clients receiving home care from the organisation will be recruited. Implementation of the program will be guided by the Consolidated Framework for Implementation Research, barriers and enablers will be identified at the client, staff, and organisation levels. Program effectiveness will be determined through client engagement, program satisfaction, knowledge acquisition, attitudes and enactment of falls prevention strategies, changes in functional mobility, falls and falls injuries and a cost-consequence analysis.If successful, home care clients may enhance their functional mobility and reduce their risk of falling, allowing them to stay safely at home. Home care organisations could positively contribute to the sustainable development of a well-trained workforce delivering evidence-based programs.
GWAS and 3D chromatin mapping identifies multicancer risk genes associated with hormone-dependent cancers
Authors: Rivera Isela Sarahi , French Juliet D. , Bitar Mainá , Sivakumaran Haran , Nair Sneha , Kaufmann Susanne , Hillman Kristine M. , Marjaneh Mahdi Moradi , Beesley Jonathan , Edwards Stacey L. 
Published: July 2024

ABSTRACTHormone-dependent cancers (HDCs) share several risk factors, suggesting a common aetiology. Using data from genome-wide association studies, we showed spatial clustering of risk variants across four HDCs (breast, endometrial, ovarian and prostate cancers), contrasting with genetically uncorrelated traits. We identified 44 multi-HDC risk regions across the genome, defined as overlapping risk regions for at least two HDCs: two regions contained risk variants for all four HDCs, 13 for three HDCs and 28 for two HDCs. Integrating GWAS data, epigenomic profiling and high-resolution promoter capture HiC maps from diverse cell line models, we annotated 53 candidate risk genes at 22 multi-HDC risk regions. These targets were enriched for established genes from the COSMIC Cancer Gene Census, but many had no previously reported pleiotropic roles. Additionally, we pinpointed lncRNAs as potential HDC targets and identified risk alleles in several regions that altered transcription factors motifs, suggesting regulatory mechanisms. Known drug targets were over-represented among the candidate multi-HDC risk genes, implying that some may serve as targets for therapeutic development or facilitate the repurposing of existing treatments for HDC. Our comprehensive approach provides a framework for identifying common target genes driving complex traits and enhances understanding of HDC susceptibility.AUTHOR SUMMARYWhile hormone-dependent cancers (HDCs) share several risk factors, our understanding of the complex genetic interactions contributing to their development is limited. In this study, we leveraged large-scale genetic studies of cancer risk, high-throughput sequencing methods and computational analyses to identify genes associated with four HDCs: breast, endometrial, ovarian and prostate cancers. We identified known cancer genes and discovered many that were not previously linked to cancer. These findings are significant because identifying genes associated with risk of multiple cancer types can enhance the gene mapping accuracy and highlight new therapeutic targets.
Catecholaminergic modulation of large-scale network dynamics is tied to the reconfiguration of corticostriatal connectivity
Authors: Hill Justine A. , Korponay Cole , Salmeron Betty Jo , Ross Thomas J. , Janes Amy C. 
Published: July 2024

ABSTRACTLarge-scale brain network function is critical for healthy cognition, yet links between such network function, neurochemistry, and smaller-scale neurocircuitry are unclear. Here, we evaluated 59 healthy individuals using resting-state fMRI to determine how network-level temporal dynamics were impacted by two well-characterized pharmacotherapies targeting catecholamines: methylphenidate (20mg) and haloperidol (2mg). Network dynamic changes were tested for links with drug-induced alterations in complex corticostriatal connections as this circuit is a primary site of action for both drugs. A randomized, double-blind, placebo-controlled design was used. Methylphenidate enhanced time spent in the default mode network (DMN p<0 .001) and dorsal attention network (DAN p<0.001) and reduced time in the frontoparietal network (p<0.01). Haloperidol increased time in a sensory motor-DMN state (p<0.01). The magnitude of change in network dynamics induced by methylphenidate vs. placebo was correlated with the magnitude of methylphenidate-induced rearrangement of complex corticostriatal connectivity (R=0.32, p=0.014). Haloperidol did not alter complex corticostriatal connectivity. Methylphenidate increased time in networks involved in internal (DMN) and external attention (DAN), aligning with methylphenidate’s established role in attention. Methylphenidate also significantly changed complex corticostriatal connectivity by altering the relative strength between multiple corticostriatal connections, indicating that methylphenidate may shift which corticostriatal connections are prioritized relative to others. Findings further show that these local circuit changes are linked with large scale network function. Collectively, these findings provide a deeper understanding of large-scale network function, set a stage for mechanistic understanding of network engagement, and provide needed information to potentially guide medication use based on network-level effects.