bluuebunny/crossref_metadata_2025_split huggingface dataset:
Beneficial effects of intermittent fasting in NASH and subsequent HCC development are executed by concerted PPARα and PCK1 action in hepatocytes
Authors: Gallage Suchira , Ali Adnan , Barragan Avila Jose Efren , Seymen Nogayhan , Ramadori Pierluigi , Joerke Vera , Zizmare Laimdota , Kosla Jan , Li Xin , Focaccia Enrico , Yousuf Suhail , Sijmonsma Tjeerd , Rahbari Mohammad , Kommoss Katharina S. , Billeter Adrian , Prokosch Sandra , Rothermel Ulrike , Mueller Florian , Hetzer Jenny , Heide Danijela , Machauer Tim , Malek Nisar P. , Longerich Thomas , Rose Adam J. , Roth Susanne , Schwenck Johannes , Trautwein Christoph , Karimi Mohammad M , Heikenwalder Mathias 
Published: October 2023

AbstractThe role and molecular mechanisms of intermittent fasting (IF) in non-alcoholic steatohepatitis (NASH) and its transition to hepatocellular carcinoma (HCC) are unknown. Here, we identified that an IF 5:2 regimen (two non-consecutive days of food deprivation per week), initiated in the active phase of mice, prevents/ameliorates NASH and fibrosis as well as reduces subsequent HCC development without affecting total calorie intake. The timing, length and number of fasting cycles as well as the type of NASH diet were all critical parameters determining the effectiveness of the fasting benefits. Combined proteomic, transcriptomic and metabolomic analyses identified that PPARα and glucocorticoid receptor (GR)-PCK1 act co-operatively as hepatic executors of the fasting response by promoting fatty acid catabolism and gluconeogenesis whilst suppressing anabolic lipogenesis. In line, PPARα targets and PCK1 were reduced in human NASH. Additionally, dynamic [18F]FDG-PET analysisin vivorevealed increased [18F]FDG uptake/retention and enhanced gluconeogenesis in the liver upon fasting (in accordance with PPARα and GR-PCK1 activation) when assessed by compartmental modelling. Hepatocyte-specificGRdeletion only partially abrogated the hepatic fasting response. In contrast, the combined knockdown ofPparaandPck1 in vivoabolished the beneficial outcomes of fasting against inflammation and fibrosis, confirming their causal relationship in integrating systemic signalling in hepatocytes. Notably, PPARα agonist pemafibrate recapitulated key aspects of hepatic fasting signalling at a molecular level. Therefore, IF or pharmacological mimetics of the PPARα and/or GR-PCK1 axis could be a viable intervention against NASH and subsequent liver cancer.One-Sentence SummaryIntermittent fasting protects against fatty liver disease and liver cancer through concerted PPARα and GR-PCK1 action in hepatocytes.
Dynamic model of carbon dioxide-induced stomatal closure reveals a feedback core for cellular decision-making
Authors: Gan Xiao , Sengottaiyan Palanivelu , Park Kyu Hyong , Assmann Sarah M. , Albert Réka 
Published: October 2023

AbstractStomata are pores on plant aerial surfaces, each bordered by a pair of guard cells. They control gas exchange vital for plant survival. Understanding how guard cells respond to environmental signals such as atmospheric carbon dioxide (CO2) levels is not only insightful to fundamental biology but also relevant to real-world issues of crop productivity under global climate change. In the past decade, multiple important signaling elements for stomatal closure induced by elevated CO2have been identified. Yet, there is no comprehensive understanding of high CO2induced stomatal closure. In this work we assemble a cellular signaling network underlying high CO2-induced stomatal closure by integrating evidence from a comprehensive literature analysis. We further construct a Boolean dynamic model of the network, which allowsin silicosimulation of the stomatal closure response to high CO2in wild-typeArabidopsis thalianaplants and in cases of pharmacological or genetic manipulation of network nodes. Our model has a 91% accuracy in capturing known experimental observations. We perform network-based logical analysis and reveal a feedback core of the network, which dictates cellular decisions in closure response to high CO2. Based on these analyses, we predict and experimentally confirm that applying nitric oxide (NO) induces stomatal closure in ambient CO2and causes hypersensitivity to elevated CO2. Moreover, we predict a negative regulatory relationship between NO and the protein phosphatase ABI2 and find experimentally that NO inhibits ABI2 phosphatase activity. The experimental validation of these model predictions demonstrates the effectiveness of network-based modeling and highlights the decision-making role of the feedback core of the network in signal transduction. We further explore the model’s potential in predicting targets of signaling elements not yet connected to the CO2network. Our combination of network science,in silicomodel simulation, and experimental assays demonstrates an effective interdisciplinary approach to understanding system-level biology.
De novogenome assemblies from two Indigenous Americans from Arizona identify new polymorphisms in non-reference sequences
Authors: Köroğlu Çiğdem , Chen Peng , Traurig Michael , Altok Serdar , Bogardus Clifton , Baier Leslie J 
Published: October 2023

ABSTRACTThere is a collective push to diversify human genetic studies by including underrepresented populations. However, analyzing DNA sequence reads involves the initial step of aligning the reads to the GRCh38/hg38 reference genome which is inadequate for non-European ancestries. To help address this issue, we created a modified hg38 reference map usingde novosequence assemblies from Indigenous Americans living in Arizona (IAZ). Using HiFi SMRT long-read sequencing technology, we generatedde novogenome assemblies for one female and one male IAZ individual. Each assembly included ∼17 Mb of DNA sequence not present (non-reference sequence; NRS) in hg38, which consists mostly of repeat elements. Forty NRSs totaling 240 kb were uniquely anchored to the hg38 primary assembly generating a modified hg38-NRS reference genome. DNA sequence alignment and variant calling were then conducted with WGS sequencing data from 387 IAZ cohorts using both the hg38 and modified hg38-NRS reference maps. Variant calling with the hg38-NRS map identified ∼50,000 single nucleotide variants present in at least 5% of the WGS samples which were not detected with the hg38 reference map. We also directly assessed the NRSs positioned within genes. Seventeen NRSs anchored to regions including an identical 187 bp NRS found in both de novo assemblies. The NRS is located inHCN279 bp downstream of exon 3 and contains several putative transcriptional regulatory elements. Genotyping of theHCN2-NRS revealed that the insertion is enriched in IAZ (MAF = 0.45) compared to Caucasians (MAF = 0.15) and African Americans (MAF = 0.03). This study shows that inclusion of population-specific NRSs can dramatically change the variant profile in an under-represented ethnic groups and thereby lead to the discovery of previously missed common variations.AUTHOR SUMMARYGRCh38/hg38 reference genome has been the standard reference for large-scale human genetics studies. However, it does not adequately represent sequences of non-European ancestry. In this study, using long-read sequencing technology, we constructedde novosequence assemblies from two Indigenous Americans from Arizona. We then compared thede novoassemblies to the hg38 reference genome to identify non-reference sequences (NRSs). We integrated these NRSs into our whole-genome sequencing (WGS) variant calling pipeline to improve read alignment and variant detection. We also directly assessed the NRSs positioned within genes. Inclusion of population-specific NRSs dramatically changed the variant profile of our study group with under-represented ethnicity, revealing common variation not detected by our previous population-level WGS and genotyping studies.
Quantitative dynamics of intracellular NMN by genetically encoded biosensor
Authors: Chen Liuqing , Wang Pei , Huang Guan , Cheng Wenxiang , Liu Kaijing , Yu Qiuliyang 
Published: October 2023

AbstractNicotinamide mononucleotide (NMN) is a major precursor for NAD+metabolism with promising effects in treating NAD+- and aging-related pathologies. However, measuring live cell NMN dynamics was not possible, leaving key questions in intracellular NMN uptake and regulation unanswered. Here we developed a genetically encoded bioluminescent sensor to quantify subcellular NMN in live cells by fusing engineered NMN-responsive binding domain to bioluminescent and fluorescent proteins from BRET pairs. The sensor dissected the multimechanistic uptake of extracellular NMN and precursors in live cells. We then captured the notably low mitochondrial NMN content and the thereafter vulnerable NMN/NAD+ratio and SARM1 activation in mitochondria, establishing NMN/NAD+ratio as an important parameter in evaluating NAD+boosting strategies. Moreover, we characterized the signature of major NAD+regulating enzymes on NMN and NMN/NAD+ratios, in which Slc25a45 was identified to be a potential mitochondrial NMN transporter for its unique fingerprint on mitochondrial NMN/NAD+ratio.
Improving forest ecosystem functions by optimizing tree species spatial arrangement
Authors: Beugnon Rémy , Albert Georg , Hähn Georg , Haider Sylvia , Hättenschwiler Stephan , Davrinche Andréa , Rosenbaum Benjamin , Gauzens Benoit , Eisenhauer Nico 
Published: October 2023

AbstractReforestation and afforestation programs are promoted as strategies to mitigate rising atmospheric CO2concentrations and enhance ecosystem services. Planting diverse forests is supposed to foster such benefits, but optimal tree planting techniques, especially regarding species spatial arrangement, are underexplored.Here, using field measurements from the subtropical BEF-China experiment, we simulated leaf litterfall and decomposition, as a function of various spatial arrangements of tree species, from clusters of species to random distributions.We show that increasing tree species spatial heterogeneity in forests composed of nine tree species led to more evenly distributed litterfall, increased litter decomposition and associated nitrogen cycling by 45%. These effects were amplified with increasing plot species richness, while species functional trait identity and diversity modulated these relationships.The spatial arrangement of tree species is a critical component determining biodiversity-ecosystem functioning relationships, and considering such spatial aspects is crucial for operationalizing biodiversity-ecosystem functioning theory in realistic re-/afforestation projects.
Sex and species associated differences in Complement-mediated immunity in Humans and Rhesus macaques
Authors: Kelkar Natasha S. , Goldberg Benjamin S. , Dufloo Jérémy , Bruel Timothée , Schwartz Olivier , Hessell Ann J. , Ackerman Margaret E. 
Published: October 2023

AbstractThe complement system can be viewed as a ‘moderator’ of innate immunity, ‘instructor’ of humoral immunity, and ‘regulator’ of adaptive immunity. While sex and aging are known to affect humoral and cellular immune systems, their impact on the complement pathway in humans and rhesus macaques, a commonly used non-human primate model system, have not been well-studied. To address this knowledge gap, we analyzed serum samples from 90 humans and 75 rhesus macaques for the abundance and activity of the complement system components. While sequences of cascade proteins were highly conserved, dramatically different levels were observed between species. Whereas the low levels detected in rhesus samples raised questions about the suitability of the test, differences in levels of complement proteins were observed in male and female humans. Levels of total and antibody-dependent deposition of C1q and C3b on a glycosylated antigen differed between human and rhesus, suggesting differential recognition of glycans. Functional differences in complement-mediated lysis of antibody-sensitized cells were observed in multiple assays and showed that human females frequently exhibited higher lytic activity than human males or rhesus macaques, which typically did not exhibit such sexual dimorphism. Other differences between species and sexes were observed in more narrow contexts—for only certain antibodies, antigens, or assays. Collectively, these results expand our knowledge of sexual dimorphism in the complement system in humans, identifying differences that appear to be absent from rhesus macaques.
Multi-Factor Coral Disease Risk Forecasting for Early Warning and Management
Authors: Caldwell Jamie M , Liu Gang , Geiger Erick , Heron Scott F , Eakin C Mark , De La Cour Jacqueline , Greene Austin , Raymundo Laurie , Dryden Jen , Schlaff Audrey , Stella Jessica S , Kindinger Tye L , Couch Courtney S , Fenner Douglas , Hoot Whitney , Manzello Derek , Donahue Megan J 
Published: October 2023

AbstractEcological forecasts are becoming increasingly valuable tools for conservation and management. However, there are few examples of near real-time forecasting systems that account for the wide range of ecological complexities. We developed a new coral disease ecological forecasting system that explores a suite of ecological relationships and their uncertainty and investigates how forecast skill changes with shorter lead times. The Multi-Factor Coral Disease Risk product introduced here uses a combination of ecological and marine environmental conditions to predict risk of white syndromes and growth anomalies across reefs in the central and western Pacific and along the east coast of Australia and is available through the U.S. National Oceanic and Atmospheric Administration Coral Reef Watch program. This product produces weekly forecasts for a moving window of six months at ∼5 km resolution based on quantile regression forests. The forecasts show superior skill at predicting disease risk on withheld survey data from 2012-2020 compared with predecessor forecast systems, with the biggest improvements shown for predicting disease risk at mid-to high-disease levels. Most of the prediction uncertainty arises from model uncertainty and therefore prediction accuracy and precision do not improve substantially with shorter lead times. This result arises because many predictor variables cannot be accurately forecasted, which is a common challenge across ecosystems. Weekly forecasts and scenarios can be explored through an online decision support tool and data explorer, co-developed with end-user groups to improve use and understanding of ecological forecasts. The models provide near real-time disease risk assessments and allow users to refine predictions and assess intervention scenarios. This work advances the field of ecological forecasting with real world complexities, and in doing so, better supports near term decision making for coral reef ecosystem managers and stakeholders. Secondarily, we identify clear needs and provide recommendations to further enhance our ability to forecast coral disease risk.
A Germline Point Mutation in the MYC-FBW7 Phosphodegron Initiates Hematopoietic Malignancies
Authors: Freie Brian , Carroll Patrick A. , Varnum-Finney Barbara J. , Ramani Vijay , Bernstein Irwin , Eisenman Robert N. 
Published: October 2023

ABSTRACTOncogenic activation of MYC in cancers predominantly involves increased transcription rather than coding region mutations. However, MYC-dependent lymphomas frequently contain point mutations in the MYC phospho-degron, including at threonine-58 (T58), where phosphorylation permits binding by the FBW7 ubiquitin ligase triggering MYC degradation. To understand how T58 phosphorylation functions in normal cell physiology, we introduced an alanine mutation at T58 (T58A) into the endogenousc-Myclocus in the mouse germline. While MYC-T58A mice develop normally, lymphomas and myeloid leukemias emerge in ∼60% of adult homozygous T58A mice. We find that primitive hematopoietic progenitor cells from MYC-T58A mice exhibit aberrant self-renewal normally associated with hematopoietic stem cells (HSCs) and upregulate a subset of Myc target genes important in maintaining stem/progenitor cell balance. Genomic occupancy by MYC-T58A was increased at all promoters, compared to WT MYC, while genes differentially expressed in a T58A-dependent manner were significantly more proximal to MYC-bound enhancers. MYC-T58A lymphocyte progenitors exhibited metabolic alterations and decreased activation of inflammatory and apoptotic pathways. Our data demonstrate that a single point mutation in Myc is sufficient to produce a profound gain of function in multipotential hematopoietic progenitors associated with self-renewal and initiation of lymphomas and leukemias.
Intrinsic properties of spinal motoneurons degrade ankle torque control in humans
Authors: Beauchamp James. A. , Pearcey Gregory E. P. , Khurram Obaid U. , Negro Francesco , Dewald Julius P.A. , Heckman CJ. 
Published: October 2023

AbstractMotoneurons are the final common pathway for all motor commands and possess intrinsic electrical properties that must be tuned to control muscle across the full range of motor behaviors. Neuromodulatory input from the brainstem is likely essential for adapting motoneuron properties to match this diversity of motor tasks. A primary mechanism of this adaptation, control of dendritic persistent inward currents (PICs) in motoneurons by brainstem monoaminergic systems, generates both amplification and prolongation of synaptic inputs. While essential, there is an inherent tension between this amplification and prolongation. Although amplification by PICs allows for quick recruitment and acceleration of motoneuron discharge during discrete motor tasks, PICs must be deactivated to de-recruit motoneurons upon movement cessation. In contrast, during stabilizing or postural tasks, PIC-induced prolongation of synaptic inputs is likely critical for sustained motoneuron discharge. Here, we designed two motor tasks that show PIC amplification and prolongation may conflict and generate errors that degrade the precision of motor output in humans. This included a paradigm comprised of a discrete motor task superimposed atop a stabilizing task and a paradigm with muscle length-induced changes to the balance of excitatory and inhibitory inputs available for controlling PICs. We show that prolongation from PICs introduces deficits in ankle torque control and that these deficits are further degraded at shorter muscle lengths when PIC prolongation is greatest. These results highlight the necessity for inhibitory control of PICs and showcase issues that are introduced when inhibitory control is perturbed or constrained. Our findings suggest that, like sensory systems, errors are inherent in motor systems. These errors are not due to problems in the perception of movement-related sensory input but are embedded in the final stage of motor output.
A geometrical model of cell fate specification in the mouse blastocyst
Authors: Raju Archishman , Siggia Eric D. 
Published: October 2023

AbstractThe lineage decision that generates the epiblast and primitive endoderm from the inner cell mass (ICM) is a paradigm for cell fate specification. Recent mathematics has formalized Waddington’s landscape metaphor and proven that lineage decisions in detailed gene network models must conform to a small list of low dimensional stereotypic changes called bifurcations. The most plausible bifurcation for the ICM is the so-called heteroclinic flip that we define and elaborate here. Our reanalysis of recent data suggests that there is sufficient cell movement in the ICM so the FGF signal, which drives the lineage decision, can be treated as spatially uniform. We thus extend the bifurcation model for a single cell to the entire ICM by means of a self-consistently defined time-dependent FGF signal. This model is consistent with available data and we propose additional dynamic experiments to test it further. This demonstrates that simplified, quantitative, and intuitively transparent descriptions are possible when attention is shifted from specific genes to lineages. The flip bifurcation is a very plausible model for any situation where the embryo needs control over the relative proportions of two fates by a morphogen feedback.
Acoustomechanically activatable liposomes for ultrasonic drug uncaging
Authors: Purohit Mahaveer P. , Roy Kanchan Sinha , Xiang Yun , Yu Brenda J. , Azadian Matine M. , Muwanga Gabriella , Hart Alex R. , Taoube Ali K. , Lopez Diego Gomez , Airan Raag D. 
Published: October 2023

AbstractUltrasound-activatable drug-loaded nanocarriers enable noninvasive and spatiotemporally-precise on-demand drug delivery throughout the body. However, most systems for ultrasonic drug uncaging utilize cavitation or heating as the drug release mechanism and often incorporate relatively exotic excipients into the formulation that together limit the drug-loading potential, stability, and clinical translatability and applicability of these systems. Here we describe an alternate strategy for the design of such systems in which the acoustic impedance and osmolarity of the internal liquid phase of a drug-loaded particle is tuned to maximize ultrasound-induced drug release. No gas phase, cavitation, or medium heating is necessary for the drug release mechanism. Instead, a non-cavitation-based mechanical response to ultrasound mediates the drug release. Importantly, this strategy can be implemented with relatively common pharmaceutical excipients, as we demonstrate here by implementing this mechanism with the inclusion of a few percent sucrose into the internal buffer of a liposome. Further, the ultrasound protocols sufficient for in vivo drug uncaging with this system are achievable with current clinical therapeutic ultrasound systems and with intensities that are within FDA and society guidelines for safe transcranial ultrasound application. Finally, this current implementation of this mechanism should be versatile and effective for the loading and uncaging of any therapeutic that may be loaded into a liposome, as we demonstrate for four different drugs in vitro, and two in vivo. These acoustomechanically activatable liposomes formulated with common pharmaceutical excipients promise a system with high clinical translational potential for ultrasonic drug uncaging of myriad drugs of clinical interest.One Sentence SummaryIncorporating a few percent sucrose into a liposome transforms it into an immediately translatable vehicle for noninvasive, on-demand ultrasound-targeted drug delivery.
Decoding Genetics, Ancestry, and Geospatial Context for Precision Health
Authors: Koyama Satoshi , Wang Ying , Paruchuri Kaavya , Uddin Md Mesbah , Cho So Mi J. , Urbut Sarah M. , Haidermota Sara , Hornsby Whitney E. , Green Robert C. , Daly Mark J. , Neale Benjamin M. , Ellinor Patrick T. , Smoller Jordan W. , Lebo Matthew S. , Karlson Elizabeth W. , Martin Alicia R. , Natarajan Pradeep 
Published: October 2023

AbstractMass General Brigham, an integrated healthcare system based in the Greater Boston area of Massachusetts, annually serves 1.5 million patients. We established the Mass General Brigham Biobank (MGBB), encompassing 142,238 participants, to unravel the intricate relationships among genomic profiles, environmental context, and disease manifestations within clinical practice. In this study, we highlight the impact of ancestral diversity in the MGBB by employing population genetics, geospatial assessment, and association analyses of rare and common genetic variants. The population structures captured by the genetics mirror the sequential immigration to the Greater Boston area throughout American history, highlighting communities tied to shared genetic and environmental factors. Our investigation underscores the potency of unbiased, large-scale analyses in a healthcare-affiliated biobank, elucidating the dynamic interplay across genetics, immigration, structural geospatial factors, and health outcomes in one of the earliest American sites of European colonization.