bluuebunny/crossref_metadata_2025_split huggingface dataset:
Connectome-Based Attractor Dynamics Underlie Brain Activity in Rest, Task, and Disease
Authors: Englert Robert , Kincses Balint , Kotikalapudi Raviteja , Gallitto Giuseppe , Li Jialin , Hoffschlag Kevin , Woo Choong-Wan , Wager Tor D. , Timmann Dagmar , Bingel Ulrike , Spisak Tamas 
Published: November 2023

AbstractUnderstanding large-scale brain dynamics is a grand challenge in neuroscience. We propose functional connectome-based Hopfield Neural Networks (fcHNNs) as a model of macro-scale brain dynamics, arising from recurrent activity flow among brain regions. An fcHNN is neither optimized to mimic certain brain characteristics, nor trained to solve specific tasks; its weights are simply initialized with empirical functional connectivity values. In the fcHNN framework, brain dynamics are understood in relation to so-called attractor states, i.e. neurobiologically meaningful low-energy activity configurations. Analyses of 7 distinct datasets demonstrate that fcHNNs can accurately reconstruct and predict brain dynamics under a wide range of conditions, including resting and task states and brain disorders. By establishing a mechanistic link between connectivity and activity, fcHNNs offer a simple and interpretable computational alternative to conventional descriptive analyses of brain function. Being a generative framework, fcHNNs can yield mechanistic insights and hold potential to uncover novel treatment targets.Key PointsWe present a simple yet powerful phenomenological model for large-scale brain dynamicsThe model uses a functional connectome-based Hopfield artificial neural network (fcHNN) architecture to compute recurrent “activity flow” through the network of brain regionsfcHNN attractor dynamics accurately reconstruct several characteristics of resting state brain dynamicsfcHNNs conceptualize both task-induced and pathological changes in brain activity as a non-linear alteration of these dynamicsOur approach is validated using large-scale neuroimaging data from seven studiesfcHNNs offers a simple and interpretable computational alternative to conventional descriptive analyses of brain function
Calibrated Identification of Feature Dependencies in Single-cell Multiomics
Authors: Boyeau Pierre , Bates Stephen , Ergen Can , Jordan Michael I. , Yosef Nir 
Published: November 2023

AbstractData-driven identification of functional relationships between cellular properties is an exciting promise of single-cell genomics, especially given the increasing prevalence of assays for multiomic and spatial transcriptomic analysis. Major challenges include dealing with technical factors that might introduce or obscure dependencies between measurements, handling complex generative processes that require nonlinear modeling, and correctly assessing the statistical significance of discoveries.VI-VS(Variational Inference for Variable Selection) is a comprehensive framework designed to strike a balance between robustness and interpretability.VI-VSemploys nonlinear generative models to identify conditionally dependent features, all while maintaining control over false discovery rates. These conditional dependencies are more stringent and more likely to represent genuine causal relationships.VI-VSis openly available athttps://github.com/YosefLab/VIVS, offering a no-compromise solution for identifying relevant feature relationships in multiomic data, advancing our understanding of molecular biology.
PANAMA enabled high sensitivity dual nanoflow LC/MS metabolomics and proteomics analysis
Authors: Lin Weiwei , Mousavi Fatemeh , Blum Benjamin C. , Heckendorf Christian F. , Lampl Noah , Heckman Ryan , Guo Hongbo , McComb Mark , Emili Andrew 
Published: November 2023

SummaryHigh sensitivity nanoflow liquid chromatography (nLC) is seldom employed in untargeted metabolomics because current sample preparation techniques are inefficient to prevent nanocapillary column performance degradation. Here, we describe an nLC-based tandem mass spectrometry workflow that enables seamless joint analysis and integration of metabolomics (including lipidomics) and proteomics from the same samples without instrument duplication. This workflow is based on robust solid phase micro-extraction step for routine sample clean-up and bioactive molecule enrichment. Our method, termed PANAMA, improves compound resolution and detection sensitivity without compromising depth of coverage as compared with existing widely used analytical procedures. Notably, PANAMA can be applied to a broad array of specimens including biofluids, cell line and tissue samples. It generates high quality, information rich metabolite-protein datasets while bypassing the need for specialized instrumentation.MotivationThe ability to routinely, sensitively and reproducibly analyze both cellular proteins and metabolite mixtures from the same biospecimens can enhance the discovery of biomolecules associated with basic biochemical processes and pathobiological states. Yet existing mass spectrometry-based profiling methods rely on specialized protocols and duplicated instrumentation platforms, resulting in increased time, sample consumption and costs. We sought to generate an effective platform for both metabolomic and proteomic studies on the same samples by enabling nanoflow liquid chromatography for small molecules. The resulting approach was extensively optimized and benchmarked to provide in depth molecular coverage, along with improved chromatographic separations, sensitivity and reliability as compared to existing methods. The cost benefit ratio of PANAMA is substantial because the platform bypasses the need for specialized instrumentation stemming from incompatible procedures.
Purinergic Ca2+signaling as a novel mechanism of drug tolerance in BRAF mutant melanoma
Authors: Stauffer Philip E. , Brinkley Jordon , Jacobson David , Quaranta Vito , Tyson Darren R. 
Published: November 2023

SUMMARYDrug tolerance is a major cause of relapse after cancer treatment. In spite of intensive efforts1–9, its molecular basis remains poorly understood, hampering actionable intervention. We report a previously unrecognized signaling mechanism supporting drug tolerance in BRAF-mutant melanoma treated with BRAF inhibitors that could be of general relevance to other cancers. Its key features are cell-intrinsic intracellular Ca2+signaling initiated by P2X7 receptors (purinergic ligand-gated cation channels), and an enhanced ability for these Ca2+signals to reactivate ERK1/2 in the drug-tolerant state. Extracellular ATP, virtually ubiquitous in living systems, is the ligand that can initiate Ca2+spikes via P2X7 channels. ATP is abundant in the tumor microenvironment and is released by dying cells, ironically implicating treatment-initiated cancer cell death as a source of trophic stimuli that leads to ERK reactivation and drug tolerance. Such a mechanism immediately offers an explanation of the inevitable relapse after BRAFi treatment in BRAF-mutant melanoma, and points to actionable strategies to overcome it.
Mutation of NOTCH1 is selected within normal esophageal tissues, yet leads to selective epistasis suppressive of further evolution into cancer
Authors: Glasmacher Kira A. , Cannataro Vincent L. , Mandell Jeffrey D. , Jackson Mia , Fisk J. Nic , Townsend Jeffrey P. 
Published: November 2023

AbstractSequencing of tissues from histologically normal esophagus, among other organs, has revealed that normal tissues harbor somatic variants that are also found in cancers arising from the same tissue types. Our understanding of how somatic mutations commonly found in normal tissue can contribute to tumorigenesis is limited: common somatic mutations may or may not confer phenotypes compatible with oncogenesis. However, the strength of selection for somatic variants that appear in both normal and cancer tissues can be quantified in each context using evolutionary modeling approaches. We studied the evolutionary trajectory from normal esophageal tissue to esophageal squamous-cell carcinoma (ESCC) by analysis of 2171 sequenced samples from previous studies on normal esophageal epithelium and ESCC to reveal the stepwise contributions of somatic mutations to increased cellular division and survival. We also analyzed pairwise selective epistasis between somatically mutated genes that may lead to stepwise substitution patterns. We found thatNOTCH1substitutions are highly selected along the trajectory from embryogenesis to adult normal esophageal tissue, explaining their high prevalence in the tissue. In contrast, there is little to no positive selection forNOTCH1mutations along the trajectory from adult normal tissue to ESCC, suggesting thatNOTCH1substitutions do not drive tumorigenesis. Furthermore, mutations in NOTCH1 exhibit antagonistic epistasis with well-known cancer drivers including TP53, reducing selection for progressive mutations in tumorigenesis. This antagonistic epistasis likely corresponds with a low likelihood of tumor progression in the presence ofNOTCH1mutations in the esophagus.
A novel exopolysaccharide pathway from a freshwaterSphingomonasisolate
Authors: Goetsch Alexandra G. , Ufearo Daniel , Keiser Griffin , Heiss Christian , Azadi Parastoo , Hershey David M. 
Published: November 2023

AbstractBacteria embellish their cell envelopes with a variety of specialized polysaccharides. Biosynthesis pathways for these glycans are complex, and final products vary greatly in their chemical structures, physical properties and biological activities. This tremendous diversity comes from the ability to arrange complex pools of monosaccharide building blocks into polymers with many possible linkage configurations. Due to the complex chemistry of bacterial glycans, very few biosynthetic pathways have been defined in detail. To better understand the breadth of polysaccharide production in nature we isolated a bacterium from Lake Michigan calledSphingomonas sp.LM7 that is proficient in exopolysaccharide (EPS) production. We identified genes that contribute to EPS biosynthesis in LM7 by screening a transposon mutant library for colonies displaying altered colony morphology. A gene cluster was identified that appears to encode a completewzy/wzx-dependent polysaccharide assembly pathway. Deleting individual genes in this cluster caused a non-mucoid phenotype and a corresponding loss of EPS secretion, confirming that LM7 assembles a novelwzy/wzx-dependent polysaccharide. We extracted EPS from LM7 cultures and showed that it contains a linear chain of 3- and 4-linked glucose, galactose, and glucuronic acid residues. Finally, we found that the EPS pathway we identified diverges from those of adhesive polysaccharides such as the holdfast that are conserved in higherAlphaproteobacteria.Our approach of characterizing complete biosynthetic pathways holds promise for engineering of polysaccharides with valuable properties.ImportanceBacteria produce complex polysaccharides that serve a range of biological functions. These polymers often have properties that make them attractive for industrial applications, but they remain woefully underutilized. In this work, we studied a novel polysaccharide called promonan that is produced bySphingomonas sp.LM7, a bacterium we isolated from Lake Michigan. We extracted promonan from LM7 cultures and identified which sugars are present in the polymer. We also identified the genes responsible for polysaccharide production. Comparing the promonan genes to those of other bacteria showed that promonan is distinct from previously characterized polysaccharides. We conclude by discussing how the promonan pathway could be used to produce new polysaccharides through genetic engineering.
Heterogeneity in Neutrophil Extracellular Traps from Healthy Human Subjects
Authors: Collins Margaret S. , Imbrogno Michelle A. , Kopras Elizabeth J. , Howard James A. , Zhang Nanhua , Kramer Elizabeth L. , Hudock Kristin M. 
Published: November 2023

AbstractNeutrophil Extracellular Traps (NETs), a key component of early defense against microbial infection, are also associated with tissue injury. NET composition has been reported to vary with some disease states, but the composition and variability of NETs across many healthy subjects provides a critical comparison that has not been well investigated. We evaluated NETs from twelve healthy subjects of varying ages isolated from multiple blood draws over a three and one half-year period to delineate the variability in extracellular DNA, protein, enzymatic activities, and susceptibility to protease inhibitors. We calculated correlations for NET constituents and loss of human bronchial epithelial barrier integrity, measured by transepithelial electrical resistance, after NET exposure. We found that although there was some variability within the same subject over time, the mean numbers of neutrophils, protein, LDH, serine protease activities, and cytokines IL-8, IL-1RA, and G-CSF in isolated NETs were consistent across subjects. Total DNA and double stranded DNA content in NETs were different across donors. NETs had little or no TNFα, IL-17A, or GM-CSF. NET DNA concentration correlated with increased NET neutrophil elastase activity and higher NET IL-1RA concentrations. NET serine protease activity varied considerably within the same donor from day-to-day. Mean response to protease inhibitors was significantly different across donors. NET DNA concentration correlated best with reductions in barrier integrity of human bronchial epithelia. Defining NET concentration by DNA content correlates with other NET components and reductions in NET-driven epithelial barrier dysfunction, suggesting DNA is a reasonable surrogate measurement for these complex structures in healthy subjects.
PARP knockdown promotes synapse reformation after axon injury
Authors: Belew Micah Y. , Huang Wenjia , Florman Jeremy T. , Alkema Mark J. , Byrne Alexandra B. 
Published: November 2023

AbstractInjured nervous systems are often incapable of self-repairing, resulting in permanent loss of function and disability. To restore function, a severed axon must not only regenerate, but must also reform synapses with target cells. Together, these processes beget functional axon regeneration. Progress has been made towards a mechanistic understanding of axon regeneration. However, the molecular mechanisms that determine whether and how synapses are formed by a regenerated motor axon are not well understood. Using a combination ofin vivolaser axotomy, genetics, and high-resolution imaging, we find that poly (ADP-ribose) polymerases (PARPs) inhibit synapse reformation in regenerating axons. As a result, regeneratedparp(-)axons regain more function than regenerated wild-type axons, even though both have reached their target cells. We find that PARPs regulate both axon regeneration and synapse reformation in coordination with proteolytic calpain CLP-4. These results indicate approaches to functionally repair the injured nervous system must specifically target synapse reformation, in addition to other components of the injury response.
How resource abundance and stochasticity affect organisms’ range sizes
Authors: Mezzini Stefano , Fleming Chris H. , Medici E. Patrícia , Noonan Michael J. 
Published: November 2023

AbstractThe amount of space organisms use is thought to be tightly linked to the availability of resources within their habitats, such that organisms living in productive habitats generally require less space than those in resource-poor habitats. This hypothesis has widespread em-pirical support, but existing studies have focused primarily on responses to the mean amount of resources, while responses to the variance around the mean are still largely unknown. This is not a trivial oversight. Organisms adjust to variable environmental conditions, so failing to consider the effects of resource (un)predictability can result in a limited understanding of an organism’s range size, which challenges ecological theory and applied conservation alike. In this study, we leverage the available literature to provide a unifying framework and hypotheses for the effect of mean and variance in resources on range sizes. Next, we use simulated movement data to demonstrate how the combined effects of mean and variance in resource abundance interact to shape predictable patterns in range size. Finally, we use real-world tracking data on a lowland tapir (Tapirus terrestris) from the Brazilian Cerrado to show how this framework can be applied to better understand the movement ecology of free-ranging animals.
The membrane-associated ubiquitin ligase MARCHF8 stabilizes the human papillomavirus oncoprotein E7 by degrading CUL1 and UBE2L3 in head and neck cancer
Authors: Khalil Mohamed I. , Yang Canchai , Vu Lexi , Chadha Smriti , Nabors Harrison , James Claire D. , Morgan Iain M. , Pyeon Dohun 
Published: November 2023

ABSTRACTThe human papillomavirus (HPV) oncoprotein E7 is a relatively short-lived protein required for HPV-driven cancer development and maintenance. E7 is degraded through ubiquitination mediated by cullin 1 (CUL1) and the ubiquitin-conjugating enzyme E2 L3 (UBE2L3). However, E7 proteins are maintained at high levels in most HPV-positive cancer cells. A previous proteomics study has shown that UBE2L3 and CUL1 protein levels are increased by the knockdown of the E3 ubiquitin ligase membrane-associated ring-CH-type finger 8 (MARCHF8). We have recently demonstrated that HPV upregulates MARCHF8 expression in HPV-positive keratinocytes and head and neck cancer (HPV+ HNC) cells. Here, we report that MARCHF8 stabilizes the E7 protein by degrading the components of the SKP1-CUL1-F-box (SCF) ubiquitin ligase complex in HPV+ HNC cells. We found thatMARCHF8knockdown in HPV+ HNC cells drastically decreases the E7 protein level while increasing the CUL1 and UBE2L3 protein levels. We further revealed that the MARCHF8 protein binds to and ubiquitinates CUL1 and UBE2L3 proteins and that MARCHF8 knockdown enhances the ubiquitination of the E7 protein. Conversely, the overexpression of CUL1 and UBE2L3 in HPV+ HNC cells decreases E7 protein levels and suppresses tumor growth in vivo. Our findings suggest that HPV-induced MARCHF8 prevents the degradation of the E7 protein in HPV+ HNC cells by ubiquitinating and degrading CUL1 and UBE2L3 proteins.IMPORTANCESince HPV oncoprotein E7 is essential for virus replication, HPV has to maintain high levels of E7 expression in HPV-infected cells. However, HPV E7 can be efficiently ubiquitinated by a ubiquitin ligase and degraded by proteasomes in the host cell. Mechanistically, the components of the E3 ubiquitin ligase complex CUL1 and UBE2L3 play an essential role in E7 ubiquitination and degradation. Here, we show that the membrane ubiquitin ligase MARCHF8 induced by HPV E6 stabilizes the E7 protein by degrading CUL1 and UBE2L3 and blocking E7 degradation through proteasomes. MARCHF8 knockout restores CUL1 and UBE2L3 expression, decreasing E7 protein levels and inhibiting the proliferation of HPV-positive cancer cells. Additionally, overexpression of CUL1 or UBE2L3 decreases E7 protein levels and suppresses in vivo tumor growth. Our results suggest that HPV maintains high E7 protein levels in the host cell by inducing MARCHF8, which may be critical for cell proliferation and tumorigenesis.
A blood-brain-barrier penetrant AAV gene therapy rescues neurological deficits in mucolipidosis IV mice
Authors: Sangster Madison , Bishop Martha , Yao Yizheng , Feitor Jessica , Shahriar Sanjid , Miller Maxwell , Chekuri Anil K. , Budnik Bogdan , Bei Fengfeng , Grishchuk Yulia 
Published: November 2023

AbstractMucolipidosis IV (MLIV) is a rare, autosomal recessive, lysosomal disease characterized by intellectual disability, motor deficits and progressive vision loss. Using AAV9 and AAV-PHP.B as delivery vectors, we previously demonstrated the feasibility of modifying disease course in a mouse model of MLIV by the humanMCOLN1gene transfer. Here, using a primate-enabling capsid AAV.CPP.16 (CPP16), we constructed a new, clinic-orientedMCOLN1gene expression vector and demonstrated its efficacy in the preclinical model of MLIV. Systemic administration of CPP16-MCOLN1in adult symptomaticMcoln1-/-mice at a dose of 1e12 vg per mouse resulted inMCOLN1expression in the brain and peripheral tissues, alleviated brain pathology, rescued neuromotor function, and completely prevented paralysis. Notable expression ofMCOLN1transcripts was also detected in the retina of the mouse that had exhibited significant degeneration at the time of the treatment. However, no increase of retinal thickness was observed after the gene therapy treatment. Our results suggest a new AAV-based systemic gene replacement therapy for the treatment of MLIV that could be translated into clinical studies.
IL-2Rα KO mice exhibit maternal microchimerism and reveal nuclear localization of IL-2Rα in lymphoid and non-lymphoid cells
Authors: Wong Victoria A. , Dinh Kristie N. , Chen Guangchun , Wrenshall Lucile E. 
Published: November 2023

AbstractIL-2Rα KO mice have been instrumental to discovering the immunoregulatory properties of IL-2Rα. While initially thought of only as a stimulatory cytokine, IL-2 and IL-2Rα knock out (KO) mice revealed that this cytokine-receptor system controls immune responses through restimulation-induced cell death and by promoting the survival of T regulatory cells. Although described mostly in the context of lymphocytes, recent studies by our laboratory showed that IL-2R is expressed in smooth muscle cells. Given this finding, we sought to use IL-2Rα knock mice to determine the function of this receptor in vascular smooth muscle cells. Surprisingly, we found that IL-2Rα knock out vascular smooth muscle cells had detectable IL-2Rα. Further studies suggested that the source of IL-2Rα protein was likely maternal heterozygous cells present in KO offspring due to maternal microchimerism. Because the KO was generated by using a neomycin resistance gene insert, we treated cells with G418 and were able to eliminate the majority of IL-2Rα expressing cells. This elimination revealed that IL-2Rα KO vascular smooth muscle cells exhibited increased proliferation, decreased size, and hypodiploid DNA content when compared to wildtype cells. Our findings suggest that the phenotype of complete IL-2Rα loss is more severe than demonstrated by IL-2Rα KO mice, and that IL-2Rα plays a here-to-fore unrecognized role in regulating cell proliferation in non-lymphoid cells.