bluuebunny/crossref_metadata_2025_split huggingface dataset:
Blood mitochondrial health markers cf-mtDNA and GDF15 in human aging
Authors: Trumpff Caroline , Huang Qiuhan , Michelson Jeremy , Liu Cynthia C. , Shire David , Habeck Christian G. , Stern Yaakov , Picard Martin 
Published: January 2025

AbstractAltered mitochondria biology can accelerate biological aging, but scalable biomarkers of mitochondrial health for population studies are lacking. We examined two potential candidates: 1)cell-free mitochondrial DNA(cf-mtDNA), a marker of mitochondrial signaling elevated with disease states accessible as distinct biological entities from plasma or serum; and 2)growth differentiation factor 15(GDF15), an established biomarker of biological aging downstream of mitochondrial energy transformation defects and stress signaling. In a cohort of 430 participants aged 24-84 (54.2% women), we measured plasma and serum cf-mtDNA, and plasma GDF15 levels at two timepoints 5 years apart, then assessed their associations with age, BMI, diabetes, sex, health-related behaviors, and psychosocial factors. As expected, GDF15 showed a positive, exponential association with age (r=0.66, p<0.0001) and increased by 33% over five years. cf-mtDNA was not correlated with GDF15 or age. BMI and sex were also not related to cf-mtDNA nor GDF15. Type 2 diabetes was only positively associated with GDF15. Exploring potential drivers of systemic mitochondrial stress signaling, we report a novel association linking higher education to lower age-adjusted GDF15 (r=-0.14, p<0.0034), both at baseline and the 5-year follow up, highlighting a potential influence of psychosocial factors on mitochondrial health. Overall, our findings among adults spanning six decades of lifespan establish associations between age, diabetes and GDF15, an emerging marker of mitochondrial stress signaling. Further studies are needed to determine if the associations of blood GDF15 with age and metabolic stress can be moderated by psychosocial factors or health-related behaviors.
Enhanced Calcium Signaling in BLA Pyramidal Neurons Underlies a Sex and Circuit Specific Amygdala Dysfunction After Global Cerebral Ischemia
Authors: Vigil Jose J. , Tiemeier Erika , Chalmers Nicholas E. , Herson Paco S. , Quillinan Nidia 
Published: January 2025

AbstractWhile advances in resuscitation science have improved cardiac arrest survival, we lack therapies to improve cognitive-affective outcomes in this patient population. Our lab has previously identified cognitive dysfunction in a mouse model of global cerebral ischemia (GCI) which has been attributed to hippocampal neurodegeneration and impaired hippocampal plasticity. However, no study has attempted to identify amygdala dysfunction after GCI, despite clinical evidence of emotional dysfunction, such as anxiety and Post-Traumatic Stress Disorder (PTSD). Therefore, it is important to identify the effect that GCI has on the amygdala, the emotional center of the brain. Our lab has a well-developed, translatable mouse model of GCI, the cardiac arrest/cardiopulmonary resuscitation model (CA/CPR), that has been instrumental in assessing amygdala function after GCI. We have utilized the amygdala-dependent delay-fear conditioning (DFC) paradigm to assess associative learning and memory and have performed field excitatory post-synaptic potential (fEPSP) recordings in two circuits within the amygdala, as measures of amygdala function. We have found a sex- and circuit-specific deficit in LTP of the cortical input to the basolateral amygdala (BLA), after GCI, that corresponds with a male specific associative learning and memory deficit. We found no evidence that these deficits of amygdala function can be attributed to GCI-induced neurodegeneration within the amygdala or altered locomotor function. We did, however, find that neuronal dendritic spine calcium signaling dynamics are enhanced in male survivors of GCI and are likely contributing to the observed LTP deficit and ultimately the deficit in associative learning and memory processes.Significance StatementWhile cognitive dysfunction has been well characterized in CA/CPR survivors, the development of emotional dysfunction that may arise in survivors is understudied. Poor follow up of CA/CPR survivors has left a gap in our knowledge about the effect that GCI has on the amygdala, the emotional center of the brain. Thus, this study utilized a pre-clinical mouse model of CA/CPR to characterize amygdala dysfunction that arises from GCI. We found a male-specific deficit in associative learning and memory that corresponds with a circuit specific LTP deficit, which arises from elevated calcium signaling in dendritic spines. Thus, this study provides valuable information and rationale for extended follow up of CA/CPR survivors to identify and treat the development of GCI-induced affective disorders.
TiDHy: Timescale Demixing via Hypernetworks to learn simultaneous dynamics from mixed observations
Authors: Abe Elliott T. T. , Brunton Bingni W. 
Published: January 2025

AbstractNeural activity and behavior arise from multiple concurrent time-varying systems, including neuromodulation, neural state, and history; however, most current approaches model these data as one set of dynamics with a single timescale. Here we developTimescaleDemixing viaHypernetworks (TiDHy) as a new computational method to model spatiotemporal data, decomposing them into multiple simultaneous latent dynamical systems that may span orders-of-magnitude different timescales. Specifically, we train a hyper-network to dynamically reweigh linear combinations of latent dynamics. This approach enables accurate data reconstruction, converges to true latent dynamics, and captures multiple timescales of variation. We first demonstrate that TiDHy can demix dynamics and timescales from synthetic data comprising multiple independent switching linear dynamical systems, even when the observations are mixed. Next, with a simulated locomotion behavior dataset, we show that TiDHy accurately captures both the fast dynamics of movement kinematics and the slow dynamics of changing terrains. Finally, in an open-source multi-animal social behavior dataset, we show that the keypoint trajectory dynamics extracted with TiDHy can be used to accurately identify social behaviors of multiple mice. Taken together, TiDHy is a powerful new algorithm for demixing simultaneous latent dynamical systems with applications to diverse computational domains.
Unraveling latent cognitive, metacognitive, strategic, and affective processes underlying children’s problem-solving using Bayesian cognitive modeling
Authors: Mistry Percy K , Chang Hyesang , El-Said Dawlat , Menon Vinod 
Published: January 2025

AbstractChildren exhibit remarkable variability in their mathematical problem-solving abilities, yet the cognitive, metacognitive and affective mechanisms underlying these individual differences remain poorly understood. We developed a novel Bayesian model of arithmetic problem-solving (BMAPS) to uncover the latent processes governing children’s arithmetic strategy choice and efficiency. BMAPS inferred cognitive parameters related to strategy execution and metacognitive parameters related to strategy selection, revealing key mechanisms of adaptive problem solving. BMAPS parameters collectively explained individual differences in problem- solving performance, predicted longitudinal gains in arithmetic fluency and mathematical reasoning, and mediated the effects of anxiety and attitudes on performance. Clustering analyses using BMAPS parameters revealed distinct profiles of strategy use, metacognitive efficiency, and developmental change. By quantifying the fine-grained dynamics of strategy selection and execution and their relation to affective factors and academic outcomes, BMAPS provides new insights into the cognitive and metacognitive underpinnings of children’s mathematical learning. This work advances powerful computational methods for uncovering latent mechanisms of complex cognition in children.
Fast, flexible analysis of differences in cellular composition with crumblr
Authors: Hoffman Gabriel E. , Roussos Panos 
Published: January 2025

AbstractChanges in cell type composition play an important role in human health and disease. Recent advances in single-cell technology have enabled the measurement of cell type composition at increasing cell lineage resolution across large cohorts of individuals. Yet this raises new challenges for statistical analysis of these compositional data to identify changes in cell type frequency. We introducecrumblr(DiseaseNeurogenomics.github.io/crumblr), a scalable statistical method for analyzing count ratio data using precision-weighted linear mixed models incorporating random effects for complex study designs. Uniquely,crumblrperforms statistical testing at multiple levels of the cell lineage hierarchy using a multivariate approach to increase power over tests of one cell type. In simulations,crumblrincreases power compared to existing methods while controlling the false positive rate. We demonstrate the application ofcrumblrto published single-cell RNA-seq datasets for aging, tuberculosis infection in T cells, bone metastases from prostate cancer, and SARS-CoV-2 infection.
DECIPHERING THE DARK SIDE OF HISTONE ADP-RIBOSYLATION: WHAT STRUCTURAL FEATURES OF DAMAGED NUCLEOSOME REGULATE THE ACTIVITIES OF PARP1 AND PARP2
Authors: Tatyana A. Kurgina , Nina A. Moor , Mikhail M. Kutuzov , Anton V. Endutkin , Olga I. Lavrik 
Published: January 2025

ABSTRACTPoly(ADP-ribose) polymerases are critical enzymes contributing to regulation of numerous cellular processes, including DNA repair. Within the PARP family, PARP1 and PARP2 primarily facilitate PARylation in the nucleus, particularly responding to genotoxic stress. The activity of PARPs is influenced by the nature of DNA damage and multiple protein partners, with HPF1 being the important one. Forming a joint active site with PARP1 (PARP2), HPF1 contributes to histone PARylation and following chromatin remodelling during genotoxic stress events. This study elucidates interrelation between the presence and location of a one-nucleotide gap within the nucleosome core particle (NCP) and PARP activities in automodification and heteromodification of histones. Utilizing a combination of classical biochemical methods with fluorescence-based technique and a single-molecule mass photometry approach, we have shown that the NCP architecture impacts the efficiency and pattern of histone ADP-ribosylation and binding to the histones-associated damaged DNA more significantly for PARP2 than for PARP1. Analysis based on existing studies of HPF1-dependent ADP-ribosylome and NCP structural dynamics allows to suggest that the DNA damage location and the conformational flexibility of histone tails modulated by post-translational modifications are crucial for delineating the distinct roles of PARP1 and PARP2 during genotoxic stress responses.GRAPHICAL ABSTRACT
H-NS is a conserved repressor of the type VI secretion system inVibrio fischeri
Authors: Speare Lauren , Pavelsky Morgan , Jackson Aundre , Septer Alecia N. 
Published: January 2025

AbstractThe type VI secretion system (T6SS) is a broadly distributed interbacterial weapon found in both beneficial and pathogenic bacteria and can enhance a microbe’s ability to colonize a host.Vibrio fischeriis a beneficial symbiont of fish and squid and a model organism for T6SS function, which is activated in high-viscosity conditions. Previously, we isolated anhnsmutant in a transposon screen to identify regulators of the T6SS in the fish symbiontV. fischeriMJ11. Thehnsgene encodes the DNA-binding protein, H-NS, a conserved global regulator of gene expression that aids in adaptation to changing environments. Quantitative transcriptomes of thehnsmutant and parent strains grown in liquid or hydrogel media revealedhnsis required for the global transcriptional changes that occur during transition from lower to higher viscosity conditions. Furthermore, T6SS gene transcripts are more abundant in thehnsmutant in both conditions, suggesting H-NS represses T6SS in the parent. Single-cell fluorescence microscopy confirmedhnsmutant cells make more T6SS weapons in both liquid and hydrogel medium, where thehnsmutant is more proficient at killing a competitor strain, compared to the wild-type parent. Finally, disrupting thehnsgene in additional light organ isolates resulted in a similar derepression of T6SS, indicating H-NS is a conserved repressor of this interbacterial weapon. This work furthers our understanding of the role of H-NS as a global regulator during environmental shifts in a host-associated bacterial symbiont and expands the list of species where H-NS represses T6SS to includeV. fischeri.
Major antigenic differences inAeromonas salmonicidaisolates correlate with the emergence of a new strain causing furunculosis in Chilean salmon farms
Authors: Mancilla Marcos , Ojeda Adriana , Yuivar Yassef , Grandón Maritza , Grothusen Horst , Oyarzún Marcela , Bisquertt Alejandro , Ugalde Juan A. , Fuentes Francisco , Ibarra Pablo , Bustos Patricio 
Published: January 2025

ABSTRACTAeromonas salmonicidais the etiological agent of furunculosis, a septicemic disease with high mortality rates affecting salmonids and other teleost species worldwide. Reviewing molecular diagnostic protocols for routine diagnostics, we realized that the amplification of thevapAtarget gene failed in some cases of furunculosis. Therefore, we hypothesized that the emergence of a new strain may be involved in recent outbreaks. In this work, we demonstrate that thevapAlocus is absent in the new strain, which explains why it lacks the major membrane component VapA protein, a critical virulence factor. In addition, we found that thevapA-absent strain differs from its counterparts in outer membrane protein and lipopolysaccharide profiles, suggesting profound changes at the membrane structure level and in antigenic properties. These features along with sequence analysis information allowed us to infer that a complex genomic rearrangement, probably an indel encompassing the entirevapAlocus, gave rise to this membrane phenotype. Although the causes for pathogen evolution and emergence were not fully elucidated, our results strongly suggest that thevapA-absent strain is responsible for a raising proportion of recent furunculosis cases, and that it may be related to a less virulent disease and a low serological response upon vaccination with theA. salmonicidaantigen formulation currently used in Chile.
T7 RNA polymerase-based gene expression from a transcriptionally silent rDNA spacer in the endosymbiont-harboring trypanosomatidAngomonas deanei
Authors: Kröninger Lena , Maurya Anay K. , Stiebeling Christian , Stirba Florian P. , Kim Zio , Nowack Eva C. M. 
Published: January 2025

AbstractEukaryotic life has been shaped fundamentally by the integration of bacterial endosymbionts. The trypanosomatidAngomonas deaneithat contains a β-proteobacterial endosymbiont, represents an emerging model to elucidate initial steps in symbiont integration. Although the repertoire of genetic tools forA. deaneiis growing, no conditional gene expression system is available yet, which would be key for the functional characterization of essential or expression of toxic proteins. Development of a conditional expression system based on endogenous RNA polymerase II (POLII) is hampered by the absence of information on transcription signals inA. deaneias well as the unusual genetic system used in the Trypanosomatidae that relies on read-through transcription. This mode of transcription can result in polar effects when manipulating expression of genes in their endogenous loci. Finally, only few resistance markers are available forA. deaneiyet, restricting the number of genetic modifications that can be introduced into one strain. To increase the range of possible genetic manipulations inA. deanei, and in particular, build the base for a conditional expression system that does not interfere with the endogenous gene expression machinery, here we (i) implemented two new drug resistance markers, (ii) identified the spacer upstream of the rDNA array on chromosome 13 as transcriptionally silent genomic locus, and (iii) used this locus for engineering an ectopic expression system that depends on the T7 RNA polymerase expressed from the δ-amastin locus. We show that transgene expression in this system is independent of the activity of endogenous RNA polymerases, reaches expression levels similar to the previously described POLII-dependent expression from the γ-amastin locus, and can be applied for studying endosymbiosis. In sum, the new tools expand the possibilities for genetic manipulations ofA. deaneiand provide a solid base for the development of an ectopic conditional expression system.
Regulation of brassinosteroid signaling through Arabidopsis transcription factor TCP8 by a conserved post-translational mechanism
Authors: Spears Benjamin J. , Magnabosco Samuel A. , Mozal Raegan , Beauford Nyle M. , Baker Noah C. , Voeglie Quinn , Gassmann Walter 
Published: January 2025

AbstractThe ability of plants to respond to changing environmental conditions is dependent on their capacities to produce fast, transient, and reversible changes to stress-responsive gene expression profiles. Post-translation modification of transcription factors has been identified as a contributing mechanism to these responses but has yet to be explored mechanistically in the TCPs, a plant-specific TF family known to be broadly involved in phytohormone signaling governing biotic and abiotic stress responses. Here, we use a recombinant expression system and proteomic approach to identify the specific residues at which AtTCP8 is covalently modified by the small peptide SUMO and demonstrate that loss of key lysine residues abolishes modification of the TF. We validate these observations by demonstrating the failure of a sumoylation-site-deficient AtTCP8 mutant to complement a knowntcp8BR signaling deficiency phenotype natively inArabidopsisand reduced transcriptional activity of the protein at a known regulatory target promoter. Further, we show that class I TCP orthologs in the model non-vascular plantPhyscomitrium patensare sumoylated as well in our system, a novel finding for TFs in this organism. These data support a conserved model for post-translational regulation by SUMO of phytohormone-responsive gene expression between vascular and non-vascular plants.
Deuterium labeling enables proteome wide turnover kinetics analysis in cell culture
Authors: Alamillo Lorena , Ng Dominic C. M. , Currie Jordan , Black Alexander , Pandi Boomathi , Manda Vyshnavi , Pavelka Jay , Schaal Peyton , Travers Joshua G. , McKinsey Timothy A. , Lam Maggie P. Y. , Lau Edward 
Published: January 2025

SummaryThe half-life of proteins is tightly regulated and underlies many cellular processes. It remains unclear the extent to which proteins are dynamically synthesized and degraded in different cell types and cell states. We introduce an improved D2O labeling workflow and apply it to examine the landscape of protein turnover in pluripotent and differentiating human induced pluripotent stem cells (hiPSC). The majority of hiPSC proteins show minimal turnover beyond cell doubling rates, but we also identify over 100 new fast-turnover proteins not previously described as short-lived. These include proteins that function in cell division and cell cycle checkpoints, that are enriched in APC/C and SPOP degrons, and that are depleted upon pluripotency exit. Differentiation rapidly shifts the set of fast-turnover proteins toward including RNA binding and splicing proteins. The ability to identify fast-turnover proteins in different cell cultures also facilitates secretome analysis, as exemplified by studies of hiPSC-derived cardiac myocytes and primary human cardiac fibroblasts. The presented workflow is broadly applicable to protein turnover studies in diverse primary, pluripotent, and transformed cells.
A human organoid model of alveolar regeneration reveals distinct epithelial responses to interferon-gamma
Authors: Dost Antonella F.M. , Balážová Katarína , Casellas Carla Pou , van Rooijen Lisanne M. , Epskamp Wisse , van Son Gijs J.F. , van de Wetering Willine J. , Lopez-Iglesias Carmen , Begthel Harry , Peters Peter J. , Smakman Niels , van Es Johan. H. , Clevers Hans 
Published: January 2025

AbstractChronic obstructive pulmonary disease is characterized by inflammation and emphysema, leading to progressive alveolar destruction. Currently, no therapies effectively regenerate the alveolar epithelium. Here, we describe a feeder- and serum-free primary adult human organoid model to investigate how inflammation influences alveolar regeneration. We achieve long-term expansion of multipotent progenitor-like cells, while an alveolar type 2 (AT2) maturation protocol enhances surfactant production and supports tubular myelin formation. Introducing a LATS inhibitor to the expansion condition induces alveolar type 1 (AT1) differentiation while maintaining AT2 cells. Using this platform, we find that interferon-gamma exerts cytotoxic effects on AT1 cells while promoting the growth of regenerating AT2 cells, illustrating how a single inflammatory stimulus can have divergent effects on alveolar epithelial cell types. These findings underscore the nuanced influence of pro-inflammatory cytokines on alveolar regeneration. Our organoid model provides a reductionist platform for mechanistic studies, aimed to identify strategies to enhance alveolar regeneration.
Is efficiency of protein incorporations governed by membrane properties? Anα-synuclein and ceramide-1-phosphate investigation
Authors: Drabik Dominik , Hinc Piotr , Cierluk Karolina , Czogalla Aleksander 
Published: January 2025

ABSTRACTIn protein-membrane interactions membranes provide an environment that enables proteins to fulfill multiple functions. Yet our knowledge about specificity of protein-membrane interactions is not sufficient. It is our hipothesis that this specificity is governed to a large extend by the properties of membrane itself. This study investigates the protein-membrane interactions in the case ofα-synuclein (αS) and ceramide-1-phosphate (C1P) enriched membranes. The interactions betweenαS and lipids were reported to be governed by various factors, including lipid composition, membrane curvature, charge and fluidity. On the other hand, C1P is anionic lipid and the shape of its molecule is similar to that of PA, which was reported to strongly interact withαS. There are three main aspect of this work. First of all interactions betweenαS and C1P enriched membranes is investigated using microscale thermophoresis. Secondly, systematic characterization of membrane systems is performed using bothin vitroandin silicotechniques. Eventually, principal component analysis and multiple linear regression are used to determine phenomenological dependency of those interactions in function of membrane properties.