bluuebunny/crossref_metadata_2025_split huggingface dataset:
Two-hit mouse model of heart failure with preserved ejection fraction combining diet-induced obesity and renin-mediated hypertension
Authors: Berger Justin H. , Shi Yuji , Matsuura Timothy R. , Batmanov Kirill , Chen Xian , Tam Kelly , Marshall Mackenzie , Kue Richard , Patel Jiten , Taing Renee , Callaway Russell , Griffin Joanna , Kovacs Attila , Shanthappa Dinesh Hirenallur , Miller Russell , Zhang Bei B. , Roth Flach Rachel J. , Kelly Daniel P. 
Published: June 2024

ABSTRACTHeart failure with preserved ejection fraction (HFpEF) is increasingly common but its pathogenesis is poorly understood. The ability to assess genetic and pharmacologic interventions is hampered by the lack of robust preclinical mouse models of HFpEF. We have developed a novel “2-hit” model, which combines obesity and insulin resistance with chronic pressure overload to recapitulate clinical features of HFpEF. C57BL6/NJ mice fed a high fat diet for >10 weeks were administered an AAV8-driven vector resulting in constitutive overexpression of mouseRenin1d. Control mice, HFD only, Renin only and HFD-Renin (aka “HFpEF”) littermates underwent a battery of cardiac and extracardiac phenotyping. HFD-Renin mice demonstrated obesity and insulin resistance, a 2-3-fold increase in circulating renin levels that resulted in 30-40% increase in left ventricular hypertrophy, preserved systolic function, and diastolic dysfunction indicated by altered E/e’, IVRT, and strain measurements; increased left atrial mass; elevated natriuretic peptides; and exercise intolerance. Transcriptomic and metabolomic profiling of HFD-Renin myocardium demonstrated upregulation of pro-fibrotic pathways and downregulation of metabolic pathways, in particular branched chain amino acid catabolism, similar to findings in human HFpEF. Treatment of these mice with the sodium-glucose cotransporter 2 inhibitor empagliflozin, an effective but incompletely understood HFpEF therapy, improved exercise tolerance, left heart enlargement, and insulin homeostasis. The HFD-Renin mouse model recapitulates key features of human HFpEF and will enable studies dissecting the contribution of individual pathogenic drivers to this complex syndrome. Addition of HFD-Renin mice to the preclinical HFpEF model platform allows for orthogonal studies to increase validity in assessment of interventions.NEW & NOTEWORTHYHeart failure with preserved ejection fraction (HFpEF) is a complex disease to study due to limited preclinical models. We rigorously characterize a new two-hit HFpEF mouse model, which allows for dissecting individual contributions and synergy of major pathogenic drivers, hypertension and diet-induced obesity. The results are consistent and reproducible in two independent laboratories. This high-fidelity pre-clinical model increases the available, orthogonal models needed to improve our understanding of the causes and assessment treatments for HFpEF.
Assessing the distinct contributions of rostral and dorsomedial prefrontal cortex to cognitive control using temporal interference brain stimulation
Authors: Ryan Johnathan S. , Botzanowski Boris , Karkare Maya , Kubert Jessica R. , Liu Shiyin , Betters Samantha A. , Williamson Adam , Fani Negar , Treadway Michael T. 
Published: June 2024

AbstractThe medial prefrontal cortex has been strongly implicated in a diverse array of cognitive functions in humans, including cognitive control and emotion regulation. Numerous studies have further proposed distinct functions for dorsomedial and rostromedial areas, but direct evidence from neuromodulation studies in healthy humans has been lacking due to the limitations of commonly used non-invasive neuromodulation techniques. Temporal interference (TI) stimulation is a recently developed technique for non-invasive deep brain stimulation that utilizes the frequency difference Δƒ between pairs of high frequency electric fields to stimulate brain regions at depth and with improved precision compared to traditional techniques. Despite its theoretical potential, however, TI applications in humans have remained limited. Here, we examined the effects of TI stimulation to dorsomedial prefrontal cortex (dmPFC) and rostromedial prefrontal cortex (rmPFC) on cognitive control. Healthy adult participants (n = 32) were recruited and administered 20 Hz Δƒ TI stimulation and 0 Hz Δƒ sham stimulation in interleaved blocks while completing two variants of the Stroop Task, a well-established paradigm intended to measure cognitive control: the Color-Word and Affective Number Stroop. During the Color-Word Stroop, we found that 20 Hz Δƒ TI stimulation of dmPFC and rmPFC relative to sham stimulation slowed down reaction times, with a significantly more pronounced slowing effect specific to incongruent trials for dmPFC stimulation as well as reduced accuracy. Importantly, effects of TI on dmPFC targets localized with fMRI differed markedly from dmPFC targeting based on a generic model, highlighting the importance of individualized targeting. For the Affective Stroop, we found that stimulation of dmPFC relative to sham stimulation facilitated increased reaction times in a valence specific-manner. This research provides novel evidence for distinct effects of neuromodulation in sub-regions of medial prefrontal cortex in healthy humans and sheds light on the strengths of TI as a non-invasive stimulation method for human cognitive neuroscience.
Multiple allostery in the regulation of PDGFR beta kinase activities
Authors: Zhang Yanfeng , Wang Meimei , Shao Guangcan , Shang Qingbin , Dong Mengqiu , Qin Xiaohong , Mi Li-Zhi 
Published: June 2024

AbstractPlatelet-derived growth factor receptor beta (PDGFRβ), a type III receptor tyrosine kinase (RTK) with a featured kinase insert, regulates important cellular functions. Dysregulation of PDGFRβ is associated with cardiovascular and fibrosis diseases. Thus, its kinase activity needs to be precisely regulated under physiological conditions. Early studies demonstrated that its kinase was autoinhibited by its juxtamembrane segment and activated by transphosphorylation. However, additional mechanisms are required for the comprehensive regulation of the receptor kinase. Herein, we provide evidences that dimerization of activated kinases, autoinhibition by the kinase insert, and dimerization of inactive kinase, all contribute to the regulation of the receptor kinase. Moreover, we find such multiple allosteric regulation is also conserved in other type III RTKs, including colony stimulating factor 1 receptor (CSF1R). Impairing the allosteric regulation of CSF1R is associated with malfunctions of microglia and demyelination of neurons in Hereditary Diffuse Leukoencephalopathy with Spheroids (HDLS).
Mechanism of an Intrinsic Oscillation in Rat Geniculate Interneurons
Authors: Griffith Erica Y. , ElSayed Mohamed , Dura-Bernal Salvador , Neymotin Samuel A. , Uhlrich Daniel J. , Lytton William W. , Zhu J. Julius 
Published: June 2024

AbstractDepolarizing current injections produced a rhythmic bursting of action potentials – a bursting oscillation – in a set of local interneurons in the lateral geniculate nucleus (LGN) of rats. The current dynamics underlying this firing pattern have not been determined, though this cell type constitutes an important cellular component of thalamocortical circuitry, and contributes to both pathologic and non-pathologic brain states. We thus investigated the source of the bursting oscillation using pharmacological manipulations in LGN slicesin vitroandin silico.1. Selective blockade of calcium channel subtypes revealed that high-threshold calcium currents ILand IPcontributed strongly to the oscillation.2. Increased extracellular K+concentration (decreased K+currents) eliminated the oscillation.3. Selective blockade of K+channel subtypes demonstrated that the calcium-sensitive potassium current (IAHP) was of primary importance. A morphologically simplified, multicompartment model of the thalamic interneuron characterized the oscillation as follows:1. The low-threshold calcium current (IT) provided the strong initial burst characteristic of the oscillation.2. Alternating fluxes through high-threshold calcium channels andIAHPthen provided the continuing oscillation’s burst and interburst periods respectively. This interplay between ILand IAHPcontrasts with the current dynamics underlying oscillations in thalamocortical and reticularis neurons, which primarily involve ITand IH, or ITand IAHPrespectively. These findings thus point to a novel electrophysiological mechanism for generating intrinsic oscillations in a major thalamic cell type. Because local interneurons can sculpt the behavior of thalamocortical circuits, these results suggest new targets for the manipulation of ascending thalamocortical network activity.
Glycolytic Disruption Triggers Interorgan Signaling to Nonautonomously RestrictDrosophilaLarval Growth
Authors: Rai Madhulika , Li Hongde , Policastro Robert A. , Zentner Gabriel E. , Nemkov Travis , D’Alessandro Angelo , Tennessen Jason M. 
Published: June 2024

ABSTRACTDrosophilalarval growth requires efficient conversion of dietary nutrients into biomass. Lactate Dehydrogenase (Ldh) and Glycerol-3-phosphate dehydrogenase (Gpdh1) support larval biosynthetic metabolism by maintaining NAD+/NADH redox balance and promoting glycolytic flux. Consistent with the cooperative functions of Ldh and Gpdh1, the loss of both enzymes, but neither single enzyme, induces a developmental arrest. However, Ldh and Gpdh1 exhibit complex and often mutually exclusive expression patterns, suggesting that theGpdh1; Ldhdouble mutant lethal phenotype could be mediated nonautonomously. Here we find that the developmental arrest displayed by the double mutants extends beyond simple metabolic disruption and instead stems, in part, from changes in systemic growth factor signaling. Specifically, we demonstrate that this synthetic lethality is linked to the upregulation of Upd3, a cytokine involved in the Jak/Stat signaling pathway. Moreover, we demonstrate that either loss of the Upd3 or dietary administration of the steroid hormone 20-hydroxyecdysone (20E) rescue the synthetic lethal phenotype ofGpdh1; Ldhdouble mutants. Together, these findings demonstrate that metabolic disruptions within a single tissue can nonautonomously modulate interorgan signaling to ensure synchronous developmental growth.SUMMARY STATEMENTWe used the fruit flyDrosophila melanogasterto demonstrate that disruption of glycolysis within a single larval tissue alters systemic cytokine signaling and nonautonomously inhibits development of the entire animal.
Competitor-induced plasticity modifies the interactions and predicted competitive outcomes between annual plants
Authors: Gibbs Theo L. , Levine Jonathan M. , Turcotte Martin M. 
Published: June 2024

AbstractSpecies can modify their traits in response to changes in the environment – a process known as phenotypic plasticity. Because species traits can plastically respond to competition, the competitive effect of one individual on another involves not only reductions in performance, but also changes in morphology, behavior, phenology or physiology that affect interactions with other individuals. In this context, plasticity is often argued to favor species coexistence by increasing the niche differentiation between species, though experimental support that explicitly considers competitive outcomes is largely lacking. Here, we transiently subjected four annual plant species to early-season intraspecific or interspecific competition to explicitly induce plastic responses, and then examined the response of these individuals to other competitors. By measuring the interactions between the species with and without early-season competitors, we isolated the impact of plasticity on species interactions and coexistence. Growing with nearby competitors early in life impacted plant traits including height and morphology. These plastic responses tended to amplify the sensitivity of individuals to competition, and particularly so for interspecific competition. This increase in inter-relative to intraspecific competition caused plasticity to decrease the predicted likelihood of pairwise coexistence. By combining recent theory with a new experimental approach, we provide a pathway towards integrating phenotypic plasticity into our quantitative understanding of coexistence.
Precise Instruction and Consideration of the VerticalandHorizontal Force Component Increase Validity and Reliability of the 90:20 Isometric Posterior Chain Test
Authors: Rasp Dominic M. , Paternoster Florian K. , Kern Jan , Schwirtz Ansgar 
Published: June 2024

AbstractHamstring injuries are associated with decreased hamstring strength. Matinlauri et al.’s 90:20 Isometric Posterior Chain Test (90:20 IPCT) efficiently assesses hamstring strength, but has not been validated so far. Furthermore, their rather unprecise original instruction allows high variability in test execution. We added a new instruction and parameters and examined, whether this measure leads to increased reliability and validity.We assessed hamstring strength of 23 sport students via the 90:20 IPCT under the original instruction, to exert vertical force, and our new instruction, to exert verticalandhorizontal force. Instead of only using bare vertical force as outcome parameter under the original (Fz_V) and our new instruction (Fz_VH), we also calculated the resultant force (Fres_VH) and the applied torque onto the force place (M_F_ortho_VH). To test for validity, we correlated the outcome parameters with peak torque of gold standard dynamometry. Furthermore, we measured muscle activities of the mm. rectus femoris, biceps femoris, semitendinosus, and gluteus maximus under our new instruction and compared them to those under the original parameter (Fz_V) via one sample t-tests. To evaluate reliability, tests were repeated on two separate days, for which we calculated intra class correlation coefficients (ICCs) and coefficients of variation (CVs).Our new instruction and parameters (Fz_VH, Fres_VH, M_F_ortho_VH) showed better validity (mean r = 0.77, r = 0.81, and r = 0.85) and equally good or better reliability (ICCs: 0.87, 0.89, and 0.94; CVs: 4.7 %, 4.1 %, and 4.7 %) than the original instruction and parameter (Fz_V) (mean r = 0.70; ICC: 0.91; CV: 5.6 %). There were no differences in muscle activities between the parameters and instructions of the 90:20 IPCT.We recommend our new instruction and the applied torque onto the force plate as it makes the 90:20 IPCT a more reliable and valid tool to assess hamstring strength.
Global Progress in Competitive Co-Evolution: a Systematic Comparison of Alternative Methods
Authors: Nolfi Stefano , Pagliuca Paolo 
Published: June 2024

AbstractWe investigate the use of competitive co-evolution for synthesizing progressively better solutions. Specifically, we introduce a set of methods to measure historical and global progress. We discuss the factors that facilitate genuine progress. Finally, we compare the efficacy of four qualitatively different algorithms. The selected algorithms promote genuine progress by creating an archive of opponents used to evaluate evolving individuals, generating archives that include high-performing and well-differentiated opponents, identifying and discarding variations that lead to local progress only (i.e. progress against a subset of possible opponents and retrogressing against a larger set). The results obtained in a predator-prey scenario, commonly used to study competitive evolution, demonstrate that all the considered methods lead to global progress in the long term. However, the rate of progress and the ratio of progress versus retrogressions vary significantly among algorithms.
Comparative photosynthetic capacity, respiration rates, and nutrient content of micropropagated and wild-sourcedSphagnum
Authors: Keightley Anna T. , Field Chris D. , Rowson James G. , Caporn Simon J.M. 
Published: June 2024

AbstractRapid, effective restoration of degraded peatlands is urgently needed to reduce their current high levels of carbon loss. Re-introduction ofSphagnummoss, along with re-wetting, is key to returning carbon sequestration and retention capabilities to northern degraded bogs. Micropropagated (BeadaMoss®)Sphagnumhas already been applied in large quantities, and more is planned, for restoration projects in Britain and parts of Europe. Comparison with wild-sourcedSphagnummaterial is therefore pertinent to demonstrate its safety and suitability for wide-scale application. SixSphagnumspecies of micropropagated and wild-sourced origin were studied:S. capillifolium,S. fallax,S. palustre,S. papillosum,S. medium/divinumandS. squarrosum. MicropropagatedSphagnumhad significantly higher light-saturated photosynthesis (Pmax) rates, little colour expression, an open habit (shoots separated), higher numbers of chloroplasts, and more numerous, smaller shoot apices (capitula) than wild-sourcedSphagnum. Potentially, greater numbers of chloroplasts in micropropagatedSphagnumfacilitate higher photosynthesis rates, driving rapid growth in early-stage plants, particularly in optimum moisture conditions. Pmax rates were associated with lower bulk density (mass/volume) and higher nutrient concentrations in tissues. MicropropagatedSphagnum, grown with additional nutrients, showed no sign of nutrient toxicity or limited P or K, despite a N content approaching 30 mg g-1(well above the highest literature-reported concentration threshold), indicating its nutrient-demanding early growth stage. Ranking species according to their Pmax and respiration rates (expressed on a dry matter basis) found thatS. squarrosumwas the highest andS. medium/divinumwas the lowest, in both micropropagated and wild-sourcedSphagnum. MicropropagatedSphagnumis similar in form to wild-sourced, can be propagated in large quantities, and due to high photosynthesis rates and absorption of nutrients, is likely to establish well on application to a site where re-wetting has already occurred, therefore making it highly beneficial for restoration of degraded bogs.
Exploiting protein language model sequence representations for repeat detection
Authors: Qiu Kaiyu , Dunin-Horkawicz Stanislaw , Lupas Andrei 
Published: June 2024

AbstractDuplication is an essential evolutionary mechanism that operates at the scale of chromosomes, large chunks of DNA sequences, genes, protein domains, and shorter motifs. The study of duplication is central to understanding protein evolution, but the detection of repetitive sequence patterns is often challenging due to decreasing similarity between internal repeats resulting from long-term divergence. The most sensitive sequence-based repeat detection method, HHrepID, relies on the construction of multiple sequence alignments (MSAs) to enhance homology signals and thus facilitate the detection of very ancient duplications. However, such an alignment-based approach is slow and limits the ability to perform large-scale scans. Recent advances in protein representation learning have introduced sequence embeddings extracted from protein language models as a powerful and much faster alternative to MSAs. Protein sequence representations have been shown to be effective in homology detection, as exemplified by software such as our recently developed pLM-BLAST. In this study, we implement pLM-Repeat, a pipeline built upon pLM-BLAST, to identify repeats encoded in sequence embeddings. pLM-Repeat achieves comparable sensitivity to HHrepID in detecting the presence of repeats, while predicting many more repeat units and providing significantly better run times. We also trained an auxiliary neural network, DeepRepeat, to detect domains with patterns similar to well-characterized repeat folds to support rapid filtering. Using our newly developed tools, we scanned the AFDB90v4 database and identified a collection of novel and undescribed repeat domains.
Functional Imaging of Developing Brain in Mice and Non-Human Primates
Authors: Zhu Jiejun , He Dongming , Sun Mengzhu , Zheng Hanming , Chen Zihao , Yang Jin , Lin Chengqi , Yuan Qiwen , Shi Yun Stone , Sun Lei , Qiu Zhihai 
Published: June 2024

AbstractDespite significant advances in structural and genetic studies, investigations of early embryonic functions, such as brain activity, have long been constrained by technical challenges. Functional ultrasound (fUS) has emerged as a breakthrough modality, enabling real-time monitoring of brain activity with exceptional spatial and temporal resolution and offering unprecedented opportunities for studying functional embryonic development. In this study, we used fUS to monitor whole-embryo activity in mice from embryonic days E8.5 to E18.5, revealing patterns of neural activity throughout embryogenesis. This approach provides new opportunities to explore brain development dynamically as it unfolds. Moreover, we observed embryo responses to external stimuli, including sound, in both mice and cynomolgus macaques, offering insights into early sensory processing and neural maturation. In summary, our study establishes fUS as a powerful tool for studying embryonic brain functional development, with significant implications for scientific research, especially in non- human primate models, and clinical applications.
Visual Identification of Conspecifics Shapes Social Behavior in Mice
Authors: Greer Devon , Lei Tianhao , Kryshtal Anna , Jessen Zach , Schwartz Gregory William 
Published: June 2024

SummaryRecognizing conspecifics in order to determine how to interact with them appropriately is a fundamental goal of animal sensory systems. It has undergone selective pressure in nearly all species. Mice have a large repertoire of social behaviors that are the subject of a rapidly growing field of study in neuroscience. Mouse social interactions likely incorporate all available sensory modalities, and the vast majority of studies have not attempted to isolate them. Specifically the role of vision in mouse social interactions remains unclear. We developed a behavioral platform that allowed us to present a subject mouse the visual information of stimulus mice in isolation from olfactory, acoustic, and tactile cues. Our results indicate that the visual identification of the sex or individual identity of other mice influences behavior. These findings highlight the underappreciated role of vision in mouse social interactions and open new avenues to study the visual circuits underlying social behavior.
Electrostatic interactions in nucleosome and higher-order structures are regulated by protonation state of histone ionizable residue
Authors: Zhang Houfang , Guo Wenhan , Xu Wang , Li Anbang , Jiang Lijun , Li Lin , Peng Yunhui 
Published: June 2024

AbstractThe nucleosome serves as the fundamental unit of chromatin organization, with electrostatic interactions acting as the driving forces in the folding of nucleosomes into chromatin. Perturbations in cellular pH conditions can lead to changes in the protonation states of titratable histone residues, impacting nucleosome surface electrostatic potentials and interactions. However, the effects of proton uptake or release of histone ionizable groups on nucleosome-partner protein interactions and higher-order chromatin structures remain largely unexplored. Here, we conducted comprehensive analyses of histone titratable residue pKa values in various nucleosome contexts, utilizing 96 experimentally determined structures. We revealed that pH-induced changes in histone residue protonation states modulated nucleosome surface electrostatic potentials and significantly influenced nucleosome-partner protein interactions. Furthermore, we observed that proton uptake or release often accompanied nucleosome-partner protein interactions, facilitating their binding processes. Additionally, using a dataset of 1266 recurrent histone cancer mutations, we systematically characterized their impact on nucleosome surface electrostatics, demonstrating their profound effects on electrostatic interactions between nucleosomes and partner proteins. Finally, our findings suggest that alterations in histone protonation or cancer mutations can also regulate nucleosome self-association, thereby modulating the organization and dynamics of higher-order chromatin structure.