bluuebunny/crossref_metadata_2025_split huggingface dataset:
Potential pandemic risk of circulating swine H1N2 influenza viruses
Authors: Sage Valerie Le , Rockey Nicole C. , McCarthy Kevin R. , French Andrea J. , Shephard Meredith J. , McBride Ryan , Jones Jennifer E. , Walter Sydney G. , Doyle Joshua D. , Xu Lingqing , Barbeau Dominique J. , Wang Shengyang , Frizzell Sheila A. , Rigatti Lora H. , Myerburg Michael M. , Paulson James C. , McElroy Anita K. , Anderson Tavis K. , Baker Amy L. Vincent , Lakdawala Seema S. 
Published: January 2024

ABSTRACTInfluenza A viruses in swine have considerable genetic diversity and continue to pose a pandemic threat to humans. They were the source of the most recent influenza pandemic, and since 2010, novel swine viruses have spilled over into humans more than 400 times in the United States. Although these zoonotic infections generally result in mild illness with limited onward human transmission, the potential for sustained transmission of an emerging influenza virus between individuals due to lack of population level immunity is of great concern. Compiling the literature on pandemic threat assessment, we established a pipeline to characterize and triage influenza viruses for their pandemic risk and examined the pandemic potential of two widespread swine origin viruses. Our analysis revealed that a panel of human sera collected from healthy adults in 2020 has no cross-reactive neutralizing antibodies against an α-H1 clade strain but do against a γ-H1 clade strain. Swine H1N2 virus from the α-H1 clade (α-swH1N2) replicated efficiently in human airway cultures and exhibited phenotypic signatures similar to the human H1N1 pandemic strain from 2009 (H1N1pdm09). Furthermore, α-swH1N2 was capable of efficient airborne transmission to both naïve ferrets and ferrets with prior seasonal influenza immunity. Ferrets with H1N1pdm09 pre-existing immunity had reduced α-swH1N2 viral shedding from the upper respiratory tract and cleared the infection faster. Despite this, H1N1pdm09-immune ferrets that became infected via the air could still onward transmit α-swH1N2 with an efficiency of 50%. Taken together, these results indicate that this α-swH1N2 strain has a higher pandemic potential, but a moderate level of impact since there is reduced replication fitness in animals with prior immunity.
Tissue Inhibitor of Metalloproteinase 3 (TIMP3) mutations increase glycolytic activity and dysregulate glutamine metabolism in RPE cells
Authors: Grenell Allison , Singh Charandeep , Raju Monisha , Wolk Alyson , Dalvi Sonal , Jang Geeng-Fu , Crabb John S. , Hershberger Courtney E. , Manian Kannan , Crabb John W. , Singh Ruchira , Du Jianhai , Anand-Apte Bela 
Published: January 2024

AbstractMutations in Tissue Inhibitor of Metalloproteinases 3 (TIMP3) cause Sorsby’s Fundus Dystrophy (SFD), a dominantly inherited, rare form of macular degeneration that results in vision loss. TIMP3 is synthesized primarily by retinal pigment epithelial (RPE) cells, which constitute the outer blood-retinal barrier. Quantitative proteomics and RNAseq analysis on the choroid/RPE of mice expressing mutant TIMP3 identified a dysregulation in metabolic processes. We examined the effects of mutant TIMP3 on RPE metabolism using human ARPE-19 cells expressing mutant S179C TIMP3 and patient-derived induced pluripotent stem cell-derived RPE (iRPE) carrying the S204C TIMP3 mutation. Stable isotope tracing experiments demonstrated enhanced glucose utilization and glycolytic activity in mutant RPE concomitantly with altered glutamine utilization. This study provides important information on the dysregulation of the metabolome of RPE cells in SFD and implicates a potential commonality with other retinal degenerative diseases, emphasizing RPE cellular metabolism as a therapeutic target.
Climate change, age acceleration, and the erosion of fitness in polar bears
Authors: Newediuk Levi , Richardson Evan S , Biddlecombe Brooke A. , Kassim Haziqa , Kathan Leah , Lunn Nicholas , Rivkin L Ruth , Salama Ola E , Schmidt Chloé , Jones Meaghan J , Garroway Colin J 
Published: January 2024

AbstractClimate change is increasingly disrupting evolved life history strategies and reducing population viability in wild species. Using estimates of epigenetic age acceleration, a cellular biomarker of lifetime stress and the expression of age-related phenotypes, we found that polar bears aged approximately one year faster for each degree of warming since the 1960s. Age acceleration was also associated with reproducing early in life, linking this cellular process to well-established life history theory. However, we found evidence for the erosion of fitness as epigenetic aging accelerated and temperatures increased. Finally, using a large pedigree, we found adaptive potential in our study population was approximately zero. Global temperatures will soon reach the levels of warming currently experienced by Arctic species, which could impose widespread physiological costs and limit adaptive capacities worldwide.
A Supervised Contrastive Framework for Learning Disentangled Representations of Cell Perturbation Data
Authors: Tu Xinming , Hütter Jan-Christian , Wang Zitong Jerry , Kudo Takamasa , Regev Aviv , Lopez Romain 
Published: January 2024

AbstractCRISPR technology, combined with single-cell RNA-Seq, has opened the way to large scale pooled perturbation screens, allowing more systematic interrogations of gene functions in cells at scale. However, such Perturb-seq data poses many analysis challenges, due to its high-dimensionality, high level of technical noise, and variable Cas9 efficiency. The single-cell nature of the data also poses its own challenges, as we observe the heterogeneity of phenotypes in the unperturbed cells, along with the effect of the perturbations. All in all, these characteristics make it difficult to discern subtler effects. Existing tools, like mixscape and ContrastiveVI, provide partial solutions, but may oversimplify biological dynamics, or have low power to characterize perturbations with a smaller effect size. Here, we address these limitations by introducing the Supervised Contrastive Variational Autoencoder (SC-VAE). SC-VAE integrates guide RNA identity with gene expression data, ensuring a more discriminative analysis, and adopts the Hilbert-Schmidt Independence Criterion as a way to achieve disentangled representations, separating the heterogeneity in the control population from the effect of the perturbations. Evaluation on large-scale data sets highlights SC-VAE’s superior sensitivity in identifying perturbation effects compared to ContrastiveVI, scVI and PCA. The perturbation embeddings better reflect known protein complexes (evaluated on CORUM), while its classifier offers promise in identifying assignment errors and cells escaping the perturbation phenotype. SC-VAE is readily applicable across diverse perturbation data sets.
Graph Learning for Cortical Parcellation from Tensor Decompositions of Resting-State fMRI
Authors: Liu Yijun , Li Jian , Wisnowski Jessica L. , Leahy Richard M. 
Published: January 2024

ABSTRACTCortical parcellation has long been a cornerstone in the field of neuroscience, enabling the cerebral cortex to be partitioned into distinct, non-overlapping regions that facilitate the interpretation and comparison of complex neuroscientific data. In recent years, these parcellations have frequently been based on the use of resting-state fMRI (rsfMRI) data. In parallel, methods such as independent components analysis have long been used to identify large-scale functional networks with significant spatial overlap between networks. Despite the fact that both forms of decomposition make use of the same spontaneous brain activity measured with rsfMRI, a gap persists in establishing a clear relationship between disjoint cortical parcellations and brain-wide networks. To address this, we introduce a novel parcellation framework that integrates NASCAR, a three-dimensional tensor decomposition method that identifies a series of functional brain networks, with state-of-the-art graph representation learning to produce cortical parcellations that represent near-homogeneous functional regions that are consistent with these brain networks. Further, through the use of the tensor decomposition, we avoid the limitations of traditional approaches that assume statistical independence or orthogonality in defining the underlying networks. Our findings demonstrate that these parcellations are comparable or superior to established atlases in terms of homogeneity of the functional connectivity across parcels, task contrast alignment, and architectonic map alignment. Our methodological pipeline is highly automated, allowing for rapid adaptation to new datasets and the generation of custom parcellations in just minutes, a significant advancement over methods that require extensive manual input. We describe this integrated approach, which we refer to asUntamed, as a tool for use in the fields of cognitive and clinical neuroscientific research. Parcellations created from the Human Connectome Project dataset usingUntamed, along with the code to generate atlases with custom parcel numbers, are publicly available athttps://untamed-atlas.github.io.
Light-based juxtacrine signaling between synthetic cells
Authors: Moghimianavval Hossein , Loi Kyle J. , Hwang Sung-Won , Bashirzadeh Yashar , Liu Allen P. 
Published: January 2024

AbstractCell signaling through direct physical cell-cell contacts plays vital roles in biology during development, angiogenesis, and immune response. Intercellular communication mechanisms between synthetic cells constructed from the bottom up are majorly reliant on diffusible chemical signals, thus limiting the range of responses in receiver cells. Engineering contact-dependent signaling between synthetic cells promises to unlock more complicated signaling schemes with different types of responses. Here, we design and demonstrate a light-activated contact-dependent communication tool for synthetic cells. We utilize a split bioluminescent protein to limit signal generation exclusively to contact interfaces of synthetic cells, driving the recruitment of a photoswitchable protein in receiver cells, akin to juxtacrine signaling in living cells. Our modular design not only demonstrates contact-dependent communication between synthetic cells but also provides a platform for engineering orthogonal contact-dependent signaling mechanisms.
An expanded view of ligandability in the allosteric enzyme PTP1B from computational reanalysis of large-scale crystallographic data
Authors: (Skaist) Mehlman Tamar , Ginn Helen M. , Keedy Daniel A. 
Published: January 2024

AbstractThe recent advent of crystallographic small-molecule fragment screening presents the opportunity to obtain unprecedented numbers of ligand-bound protein crystal structures from a single high-throughput experiment, mapping ligandability across protein surfaces and identifying useful chemical footholds for structure-based drug design. However, due to the low binding affinities of most fragments, detecting bound fragments from crystallographic datasets has been a challenge. Here we report a trove of 65 new fragment hits across 59 new liganded crystal structures for PTP1B, an “undruggable” therapeutic target enzyme for diabetes and cancer. These structures were obtained from computational analysis of data from a large crystallographic screen, demonstrating the power of this approach to elucidate many (∼50% more) “hidden” ligand-bound states of proteins. Our new structures include a fragment hit found in a novel binding site in PTP1B with a unique location relative to the active site, one that validates another new binding site recently identified by simulations, one that links adjacent allosteric sites, and, perhaps most strikingly, a fragment that induces long-range allosteric protein conformational responses via a previously unreported intramolecular conduit. Altogether, our research highlights the utility of computational analysis of crystallographic data, makes publicly available dozens of new ligand-bound structures of a high-value drug target, and identifies novel aspects of ligandability and allostery in PTP1B.
Mesophyll-Specific Circadian Dynamics of CAM Induction in the Ice Plant Unveiled by Single-Cell Transcriptomics
Authors: Perron Noé , Dervinis Christopher , Pereira Wendell , Barbazuk Brad , Kirst Matias 
Published: January 2024

ABSTRACTCrassulacean acid metabolism (CAM) is an evolutionary modification of the C3photosynthetic carbon dioxide fixation pathway used by approximately 7% of terrestrial plants to live in drought-prone environments. Facultative CAM species, such asMesembryanthemum crystallinum(common ice plant), possess the unique ability to switch from C3to CAM photosynthesis in response to high-salinity and water-deficit stress. Here we characterized the environmentally-triggered transition from C3to CAM in the ice plant using single nucleus RNA sequencing (snRNA-seq) to identify its putative regulators, supported by a novel high-quality assembled and annotated genome. Analysis of snRNA-seq datasets from ice plant leaves transitioning between C3and CAM collected at dawn and dusk revealed substantial transcriptional changes in mesophyll cells at the onset of CAM induction. Notably, our findings identify mesophyll sub-cell types engaged in either CAM or C3photosynthesis at dusk. Cell trajectory inference analysis reconstructed both 24-hour CAM and C3cycles, enabling a direct comparison of gene expression profiles in these pathways. This comparative study uncovered divergent expression patterns of key circadian clock genes in CAM and C3cell trajectories, pointing to a connection between circadian regulation and CAM induction.
Balancing stability, dynamics and kinetics in phase separation of intrinsically disordered proteins
Authors: Zhang Guoqing , Chu Xiakun 
Published: January 2024

AbstractLiquid-liquid phase separation is a ubiquitous molecular phe-nomenon that plays crucial roles in a multitude of essential cellular activities. Intrinsically disordered proteins (IDPs), which lack well-defined three-dimensional structures, are prevalent participants in phase separation due to their inherent potential for promoting multivalent binding–the major driving force for this process. Understanding the underlying mechanisms of phase separation is challenging, as phase separation is a complex process, involving numerous molecules and various types of interactions. Here, we used a simplified coarse-grained model of IDPs to investigate the thermodynamic stability of the dense phase, conformational properties of IDPs, chain dynamics and kinetic rates of forming condensates. We focused on the IDP system, in which the oppositely charged IDPs are maximally segregated, inherently possessing a high propensity for phase separation. By varying interaction strengths, salt concentrations and temperatures, we observed that IDPs in the dense phase exhibited highly conserved conformational characteristics, which are more extended than those in the dilute phase. This implies that condensate formation acts as a protective shield, enabling IDPs to maintain conformational ensemble with high resistance to the changes in interactions and environmental conditions. Although the chain motions and global conformational dynamics of IDPs in the condensates are slow due to the high viscosity, local chain flexibility at the short timescales is largely preserved with respect to that at the free state. Strikingly, we observed a non-monotonic relationship between interaction strengths and kinetic rates for forming condensates. As strong interactions of IDPs result in high stable condensates, our results suggest that the thermodynamics and kinetics of phase separation are decoupled and optimized by the speed-stability balance through underlying molecular interactions. Our findings contribute to the molecular-level understanding of phase separation and offer valuable insights into the developments of engineering strategies for precise regulation of biomolecular condensates.
Heterozygosity for neurodevelopmental disorder-associatedTRIOvariants yields distinct deficits in behavior, neuronal development, and synaptic transmission in mice
Authors: Ishchenko Yevheniia , Jeng Amanda T. , Feng Shufang , Nottoli Timothy , Manriquez-Rodriguez Cindy , Nguyen Khanh K. , Carrizales Melissa G. , Vitarelli Matthew J. , Corcoran Ellen E. , Greer Charles A. , Myers Samuel A. , Koleske Anthony J. 
Published: January 2024

ABSTRACTGenetic variants inTRIOare associated with neurodevelopmental disorders (NDDs) including schizophrenia (SCZ), autism spectrum disorder (ASD) and intellectual disability. TRIO uses its two guanine nucleotide exchange factor (GEF) domains to activate GTPases (GEF1: Rac1 and RhoG; GEF2: RhoA) that control neuronal development and connectivity. It remains unclear how discreteTRIOvariants differentially impact these neurodevelopmental events. Here, we investigate how heterozygosity for NDD-associatedTriovariants –+/K1431M(ASD),+/K1918X(SCZ), and+/M2145T(bipolar disorder, BPD) – impact mouse behavior, brain development, and synapse structure and function. Heterozygosity for differentTriovariants impacts motor, social, and cognitive behaviors in distinct ways that align with clinical phenotypes in humans.Triovariants differentially impact head and brain size with corresponding changes in dendritic arbors of motor cortex layer 5 pyramidal neurons (M1 L5 PNs). Although neuronal structure was only modestly altered in theTriovariant heterozygotes, we observe significant changes in synaptic function and plasticity. We also identified distinct changes in glutamate synaptic release in+/K1431Mand+/M2145Tcortico-cortical synapses. The TRIO K1431M GEF1 domain has impaired ability to promote GTP exchange on Rac1, but+/K1431Mmice exhibit increased Rac1 activity, associated with increased levels of the Rac1 GEF Tiam1. Acute Rac1 inhibition with NSC23766 rescued glutamate release deficits in+/K1431Mvariant cortex. Our work reveals that discrete NDD-associatedTriovariants yield overlapping but distinct phenotypes in mice, demonstrates an essential role for Trio in presynaptic glutamate release, and underscores the importance of studying the impact of variant heterozygosity in vivo.
Auditory and visual gratings elicit distinct gamma responses
Authors: Gulati Divya , Ray Supratim 
Published: January 2024

AbstractSensory stimulation is often accompanied by fluctuations at high frequencies (>30Hz) in brain signals. These could be “narrowband” oscillations in the gamma band (30-70 Hz) or non-oscillatory “broadband” high-gamma (70-150 Hz) activity. Narrowband gamma oscillations, which are induced by presenting some visual stimuli such as gratings and have been shown to weaken with healthy aging and the onset of Alzheimer’s Disease, hold promise as potential biomarkers. However, since delivering visual stimuli is cumbersome as it requires head stabilization for eye tracking, an equivalent auditory paradigm could be useful. Although simple auditory stimuli have been shown to produce high-gamma activity, whether specific auditory stimuli can also produce narrowband gamma oscillations is unknown. We tested whether auditory ripple stimuli, which are considered an analogue to visual gratings, could elicit narrowband oscillations in auditory areas. We recorded 64-channel EEG from male and female (18 each) subjects while they either passively fixated on the monitor while viewing static visual gratings, or listened to stationary and moving ripples, played using loudspeakers, with their eyes open or closed. We found that while visual gratings induced narrowband gamma oscillations with suppression in the alpha band (8-12Hz), auditory ripples did not produce narrowband gamma but instead elicited very strong broadband high-gamma response and suppression in the beta band (14-26Hz). Even though we used equivalent stimuli in both modalities, our findings indicate that the underlying neuronal circuitry may not share ubiquitous strategies for stimulus processing.Significance statementIn the visual cortex, gratings can induce robust narrowband gamma oscillations (30-70Hz). These visual stimulus-induced oscillations can further be used as a biomarker for diagnosing neuronal disorders. However, tasks used to elicit these oscillations are challenging for elderly subjects, and therefore, we tested if we could use auditory stimuli instead. We hypothesized that auditory ripple stimuli, which are analogous to visual gratings, may elicit these narrowband oscillations. We found that ripples induce a broadband high-gamma response (70-150Hz) in human EEG, unlike visual gratings that produce robust gamma. Thus, the underlying neural circuitry in the two areas may not be canonical.
PHF6 suppresses self-renewal of leukemic stem cells in AML
Authors: Jalnapurkar Sapana S. , Pawar Aishwarya , George Subin S. , Antony Charles , Grana Jason , Gurbuxani Sandeep , Paralkar Vikram R. 
Published: January 2024

AbstractAcute myeloid leukemia is characterized by uncontrolled proliferation of self-renewing myeloid progenitors. PHF6 is a chromatin-binding protein mutated in myeloid leukemias, and its loss increases mouse HSC self-renewal without malignant transformation. We report here thatPhf6knockout increases the aggressiveness ofHoxa9-driven AML over serial transplantation, and increases the frequency of leukemia initiating cells. We define thein vivohierarchy ofHoxa9-driven AML and identify a population that we term the ‘LIC-e’ (leukemia initiating cells enriched) population. We find thatPhf6loss has context-specific transcriptional effects, skewing the LIC-e transcriptome to a more stem-like state. We demonstrate that LIC-e accumulation inPhf6knockout AML occurs not due to effects on cell cycle or apoptosis, but due to an increase in the fraction of its progeny that retain LIC-e identity. Overall, our work indicates thatPhf6loss increases AML self-renewal through context-specific effects on leukemia stem cells.Statement of SignificanceLeukemia stem cell self-renewal is critical to the pathophysiology of AML.Phf6deletion accelerates mouse AML by increasing LSC self-renewal, specifically by increasing the fraction of LSC progeny that retain LSC identity. Our work shows how a repressor of HSC self-renewal is inactivated in AML to drive LSC stemness.
An adaptive numerical method for multi–cellular simulations of tissue development
Authors: Osborne James M. 
Published: January 2024

AbstractIn recent years, multi–cellular models, where cells are represented as individual interacting entities, are becoming ever popular. This has led to a proliferation of novel methods and simulation tools. The first aim of this paper is to review the numerical methods utilised by multi–cellular modelling tools and to demonstrate which numerical methods are appropriate for simulations of tissue and organ development and disease. The second aim is to introduce an adaptive time–stepping algorithm and to demonstrate it’s efficiency and accuracy. We focus on off–lattice, mechanics based, models where cell movement is defined by a series of first order ordinary differential equations, derived by assuming over–damped motion and balancing forces. We see that many numerical methods have been used, ranging from simple Forward Euler approaches through to higher order single–step methods like Runge–Kutta 4 and multi–step methods like Adams–Bashforth 2. Through a series of exemplar multi–cellular simulations, we see that if: care is taken to have events (births deaths and re–meshing/re–arrangements) occur on common time–steps; and boundaries are imposed on all sub–steps of numerical methods or implemented using forces, then all numerical methods can converge with the correct order. We introduce an adaptive time–stepping method and demonstrate that the best compromise betweenL∞error and run–time is to use Runge–Kutta 4 with an increased time–step and moderate adaptivity. We see that a judicious choice of numerical method can speed the simulation up by a factor of 10–60 from the Forward Euler methods seen in Osborneet. al. [2017,https://doi.org/10.1371/journal.pcbi.1005387] and a further speed up by a factor of 4 can be achieved by using an adaptive time–step.