bluuebunny/crossref_metadata_2025_split huggingface dataset:
Single nucleotide polymorphisms and Zn transport by nuclear ZIP11 shape cancer phenotypes in HeLa cells
Authors: Kim Elizabeth Y. , Verdejo-Torres Odette , Diaz-Rodriguez Karla , Hasanain Farah , Caromile Leslie , Padilla-Benavides Teresita 
Published: August 2023

ABSTRACTZinc (Zn) is an essential micronutrient that regulates critical biological processes such as enzymatic function, gene expression, and cell signaling and provides structural stability to proteins. Under physiological conditions, Zn is a divalent cation (Zn2+) in an inactive redox state. Maintaining Zn homeostasis is essential for normal cell development and function, and any dysregulation in supply and transport can lead to pathophysiological conditions. Zn transporters, such as ZIP11, are critical regulators in Zn homeostasis. In mammals, ZIP11 belongs to the GufA subfamily of ZIP transporters and is primarily found in the nucleus and the Golgi apparatus. Our laboratory recently reported an essential role of ZIP11 in maintaining nuclear Zn levels in the cervical cancer cell line HeLa that supports various hallmark phenotypes of cancer. Genomic analysis of publicly available cervical and ovarian cancer patient datasets identified several single-nucleotide polymorphisms (SNPs) in the ZIP11 coding region that correlated with disease severity. We hypothesized that these SNPs might have potentially deleterious consequences as they are in coding regions that could affect ZIP11 function by increasing substrate accessibility, potentially enhancing the carcinogenic phenotype of HeLa cells. In addition, we identified a classic Zn-metal binding site (MBS) composed of three relevant residues which may be required for transmembrane Zn-transport, maintenance of metal homeostasis, and the carcinogenic properties of HeLa cells. To address these questions, we utilized our well-established model of stably knock down (KD)ZIP11in HeLa cells and overexpressed ZIP11 encoding single mutations corresponding to the SNPs and the MBS. Overexpression of ZIP11 encoding SNPs restored the Zn levels and the proliferation, migration, and invasive defects ofZIP11KD cells. On the other hand, cells expressing ZIP11 with single MBS mutations exhibited a phenotype similar to KD cells, suggesting that Zn transport by this transporter is necessary for establishing and maintaining carcinogenic properties. The work highlights the functional relevance of nuclear Zn transport by ZIP11 to maintain homeostasis and support carcinogenic properties in ovarian cancer cells.
A model of calcium-induced calcium release from the sarcoplasmic reticulum in the smooth muscle cell and its investigation by mathematical modeling
Authors: Zhuk P. F. , Karakhim S. O. , Kosterin S. O. 
Published: August 2023

AbstractA model of calcium-induced calcium release (CICR) from the sarcoplasmic reticulum was developed, simulating the behavior of the smooth muscle cell under conditions of its agonist stimulation. The mathematical model is a system of thirteen differential equations. In the initial (basal) state, the parameters of active and passive transport of Ca2+through both the plasma membrane and the sarcoplasmic reticulum membrane are adjusted.A study of the model showed that, depending on the model parameters, the cell system can demonstrate two types of calcium concentration changes in the cytosol: a single Ca2+transient and an oscillatory mode.After stimulation is completed, the cell system returns to the basal state (underin vivoconditions) or goes to a new steady-state level (underin vitroconditions), except when the cell system is in oscillatory mode. It is shown that the sarcoplasmic reticulum can act both as a passive participant in the process of Ca2+accumulation in the smooth muscle cell, acting as a buffer, and play a major role in this process by significantly increasing the Ca2+concentration in the cytosol, which is initiated by Ca2+entry from the extracellular space.It was found that after stimulation of the smooth muscle cell, the net Ca2+flux from the cytosol increases due to an increase in Ca2+concentration in the cytosol, while the net Ca2+flux into the cytosol first increases due to an increase in the number of open calcium channels located on the membrane of the sarcoplasmic reticulum. It then begins to decrease due to a decrease in the Ca2+concentration gradient across the membrane of the sarcoplasmic reticulum. Therefore, at a certain time point these fluxes become equal and the process of Ca2+accumulation in the cytosol is terminated. Thus, calcium-induced calcium release is terminated spontaneously, resulting in the formation of a single cytosolic Ca2+transient. As a result of calcium-induced calcium release, the sarcoplasmic reticulum is not completely emptied, but retains quite significant amounts of Ca2+.The possibility of Ca2+redistribution between the three compartments (extracellular space, cytosol and sarcoplasmic reticulum) creates the possibility of oscillation of cytosolic Ca2+concentration. The oscillation amplitude and frequency can remain practically unchanged for a considerable period.The developed model qualitatively reproduces the results of experimental studies conducted to identify store-operated calcium channels using the inhibitors of the calcium pump of the sarcoplasmic reticulum in a calcium-free medium.
Addressing biases in gene-set enrichment analysis: a case study of Alzheimer’s Disease
Authors: Bakulin Artemy , Teyssier Noam B , Kampmann Martin , Khoroshkin Matvei , Goodarzi Hani 
Published: August 2023

SUMMARYInferring the driving regulatory programs from comparative analysis of gene expression data is a cornerstone of systems biology. Many computational frameworks were developed to address this problem, including our iPAGE (information-theoreticPathwayAnalysis ofGeneExpression) toolset that uses information theory to detect non-random patterns of expression associated with given pathways or regulons1. Our recent observations, however, indicate that existing approaches are susceptible to the biases and artifacts that are inherent to most real world annotations. To address this, we have extended our information-theoretic framework to account for specific biases in biological networks using the concept of conditional information. This novel implementation, called pyPAGE, provides an unbiased way for the estimation of the activity of transcriptional and post-transcriptional regulons.To showcase pyPAGE, we performed a comprehensive analysis of regulatory perturbations that underlie the molecular etiology of Alzheimer’s disease (AD). pyPAGE successfully recapitulated several known AD-associated gene expression programs. We also discovered several additional regulons whose differential activity is significantly associated with AD. We further explored how these regulators relate to pathological processes in AD through cell-type specific analysis of single cell gene expression datasets.
Meteora sporadica, a protist with incredible cell architecture, is related to Hemimastigophora
Authors: Eglit Yana , Shiratori Takashi , Jerlström-Hultqvist Jon , Williamson Kelsey , Roger Andrew J. , Ishida Ken-Ichiro , Simpson Alastair G. B. 
Published: August 2023

Summary‘Kingdom-level’ branches are being added to the tree of eukaryotes at a rate approaching one per year, with no signs of slowing down1–4. Some are completely new discoveries, while others are morphologically unusual protists that were previously described but lacked molecular data. For example, Hemimastigophora are predatory protists with two rows of flagella that were known since the 19thcentury, but proved to represent a new deep-branching eukaryote lineage when phylogenomic analyses were conducted2.Meteora sporadicaHausmann et al. 20025is a protist with a unique morphology and motility; cells glide over substrates along a long axis of anterior and posterior projections, and have a pair of lateral ‘arms’ that swing back and forth. Originally,Meteorawas described by light microscopy only, from a short-term enrichment of deep-sea sediment. A small subunit ribosomal RNA (SSU rRNA) sequence was reported recently, but the phylogenetic placement ofMeteoraremained unresolved6. Here, we investigated two cultivatedMeteora sporadicaisolates in detail. Transmission electron microscopy showed that the anterior-posterior projections are supported by microtubules originating from a cluster of subnuclear MTOCs. Likewise, the arms are supported by microtubules, and neither have a flagellar axoneme-like structure. Sequencing the mitochondrial genome showed this to be amongst the most gene-rich known, outside jakobids. Remarkably, phylogenomic analyses of 254 nuclear protein-coding genes robustly support a close relationship with Hemimastigophora. Our study suggests thatMeteoraand Hemimastigophora together represent a morphologically diverse ‘supergroup’, and thus are important for resolving the tree of eukaryote life and early eukaryote evolution.
Neural correlates of confidence during decision formation in a perceptual judgment task
Authors: Ko Yiu Hong , Zhou Andong , Niessen Eva , Stahl Jutta , Weiss Peter H. , Hester Robert , Bode Stefan , Feuerriegel Daniel 
Published: August 2023

AbstractWhen we make a decision, we also estimate the probability that our choice is correct or accurate. This probability estimate is termed our degree of decision confidence. Recent work has reported event-related potential (ERP) correlates of confidence both during decision formation (the centro-parietal positivity component; CPP) and after a decision has been made (the error positivity component; Pe). However, there are several measurement confounds that complicate the interpretation of these findings. More recent studies that overcome these issues have so far produced conflicting results. To better characterise the ERP correlates of confidence we presented participants with a comparative brightness judgment task while recording electroencephalography. Participants judged which of two flickering squares (varying in luminance over time) was brighter on average. Participants then gave confidence ratings ranging from “surely incorrect” to “surely correct”. To elicit a range of confidence ratings we manipulated both the mean luminance difference between the brighter and darker squares (relative evidence) and the overall luminance of both squares (absolute evidence). We found larger CPP amplitudes in trials with higher confidence ratings. This association was not simply a by-product of differences in relative evidence (which covaries with confidence) across trials. We did not identify postdecisional ERP correlates of confidence, except when they were artificially produced by pre-response ERP baselines. These results provide further evidence for neural correlates of processes that inform confidence judgments during decision formation.
Pantothenate Kinase 4 controls efficient skeletal muscle energy substrate metabolism via acetyl-CoA
Authors: Miranda-Cervantes Adriana , Fritzen Andreas M. , Raun Steffen H. , Hodek Ondřej , Møller Lisbeth L. V. , Johann Kornelia , Deisen Luisa , Gregorevic Paul , Gudiksen Anders , Artati Anna , Adamski Jerzy , Andersen Nicoline R. , Schjerling Peter , Cebrian-Serrano Alberto , Jähnert Markus , Gottmann Pascal , Burtscher Ingo , Lickert Heiko , Pilegaard Henriette , Schürmann Annette , Tschöp Matthias H. , Moritz Thomas , Müller Timo D. , Sylow Lykke , Kiens Bente , Richter Erik A. , Kleinert Maximilian 
Published: August 2023

AbstractMetabolic inflexibility in skeletal muscle (SkM) is closely linked to metabolic diseases. Exercise improves metabolic flexibility, rendering it a valuable discovery tool of mechanisms promoting efficient metabolism of glucose and lipids. We herein discover pantothenate kinase 4 (PanK4) as a conserved exercise target with high abundance in SkM. We go on to show that murine musclePank4is dysregulated with high-fat diet feeding, and identify humanPANK4variants that associate with glycemic control and body mass index traits, indicating important roles of PanK4 in glucose metabolism and growth. Consistent with the latter, germline deletion of PanK4 reduces circulating IGF-1 and stunts growth in mice. Deletion specifically in mouse SkM reveals that PanK4 facilitates fatty acid oxidation by acting as a regulator of SkM acetyl-CoA, a key node in metabolism of both glucose and lipids. Consequently, without PanK4, elevated SkM acetyl-CoA levels allosterically gridlock key enzymes required for efficient lipid and glucose utilization, and these SkM metabolic perturbations manifest in whole-body insulin resistance. As proof of principle, we show that an increase in muscle PanK4 lowers SkM acetyl-CoA and increases SkM glucose utilization. Our findings identify PanK4 as a novel regulator of SkM energy substrate metabolism, warranting inclusion in comprehensive strategies against metabolic disease.
Single-protein optical holography
Authors: Thiele Jan Christoph , Pfitzner Emanuel , Kukura Philipp 
Published: August 2023

AbstractLight scattering by nanoscale objects is a fundamental physical property defined by their scattering cross-section and thus polarisability. Over the past decade, a number of studies have demonstrated single molecule sensitivity, by imaging the interference between coherent scattering from the object of interest with a reference field. This approach has enabled mass measurements of single biomolecules in solution owing to the linear scaling of the image contrast with the molecular polarisability. Nevertheless, all implementations to date based on a common-path interferometer cannot separate and independently tune the reference and scattered light field, prohibiting access to the rich toolbox available to holographic imaging. Here, we demonstrate comparable sensitivity using a non-common path geometry based on a dark-field scattering microscope, similar to a Mach-Zehnder interferometer. We separate the scattering and reference light into four parallel, inherently phase stable detection channels, delivering a five orders of magnitude boost in sensitivity in terms of scattering cross-section over the state-of-the-art, demonstrating detection and mass measurement of single proteins below 100 kDa. Amplitude and phase measurement yields direct information on sample identity and the first experimental determination of the polarisability of single biomolecules.
A scalable, low-cost phenotyping strategy to assess tuber size, shape, and the colorimetric features of tuber skin and flesh in potato breeding populations
Authors: Feldman Max J. , Park Jaebum , Miller Nathan , Wakholi Collins , Greene Katelyn , Abbasi Arash , Rippner Devin A. , Navarre Duroy , Carley Cari Schmitz , Shannon Laura M. , Novy Rich 
Published: August 2023

AbstractTuber size, shape, colorimetric characteristics, and defect susceptibility are all factors that influence the acceptance of new potato cultivars. Despite the importance of these characteristics, our understanding of their inheritance is substantially limited by our inability to precisely measure these features quantitatively on the scale needed to evaluate breeding populations. To alleviate this bottleneck, we developed a low-cost, semi-automated workflow to capture data and measure each of these characteristics using machine vision. This workflow was applied to assess the phenotypic variation present within 189 F1 progeny of the A08241 breeding population. Our results provide an example of quantitative measurements acquired using machine vision methods that are reliable, heritable, and can be used to understand and select upon multiple traits simultaneously in structured potato breeding populations.
Early life high fructose exposure disrupts microglia function and impedes neurodevelopment
Authors: Wang Zhaoquan , Lipshutz Allie , Liu Zong-Lin , Trzeciak Alissa J. , Miranda Isabella C. , Martínez de la Torre Celia , Schild Tanya , Lazarov Tomi , Rojas Waleska Saitz , Saavedra Pedro H. V. , Romero-Pichardo Jesús E. , Baako Ann , Geissmann Frederic , Faraco Giuseppe , Gan Li , Etchegaray Jon Iker , Lucas Christopher D. , Parkhurst Christopher N. , Zeng Melody Y. , Keshari Kayvan R. , Perry Justin S. A. 
Published: August 2023

AbstractDespite the success of fructose as a low-cost food additive, recent epidemiological evidence suggests that high fructose consumption by pregnant mothers or during adolescence is associated with disrupted neurodevelopment1–7. An essential step in appropriate mammalian neurodevelopment is the synaptic pruning and elimination of newly-formed neurons by microglia, the central nervous system’s (CNS) resident professional phagocyte8–10. Whether early life high fructose consumption affects microglia function and if this directly impacts neurodevelopment remains unknown. Here, we show that both offspring born to dams fed a high fructose diet and neonates exposed to high fructose exhibit decreased microglial density, increased uncleared apoptotic cells, and decreased synaptic pruningin vivo. Importantly, deletion of the high affinity fructose transporter SLC2A5 (GLUT5) in neonates completely reversed microglia dysfunction, suggesting that high fructose directly affects neonatal development. Mechanistically, we found that high fructose treatment of both mouse and human microglia suppresses synaptic pruning and phagocytosis capacity which is fully reversed in GLUT5-deficient microglia. Using a combination ofin vivoandin vitronuclear magnetic resonance- and mass spectrometry-based fructose tracing, we found that high fructose drives significant GLUT5-dependent fructose uptake and catabolism, rewiring microglia metabolism towards a hypo-phagocytic state. Importantly, mice exposed to high fructose as neonates exhibited cognitive defects and developed anxiety-like behavior which were rescued in GLUT5-deficient animals. Our findings provide a mechanistic explanation for the epidemiological observation that early life high fructose exposure is associated with increased prevalence of adolescent anxiety disorders.
Llgl1 mediates timely epicardial emergence and establishment of an apical laminin sheath around the trabeculating cardiac ventricle
Authors: Pollitt Eric JG , Derrick Christopher J , Sánchez-Posada Juliana , Noël Emily S 
Published: August 2023

AbstractDuring heart development, the embryonic ventricle becomes enveloped by the epicardium, a layer of mesothelium which adheres to the outer apical surface of the heart. This is concomitant with onset of ventricular trabeculation, where a subset of cardiomyocytes lose apicobasal polarity and delaminate basally from the ventricular wall, projecting into the cardiac lumen to begin building the muscle mass necessary for adult cardiac function. Lethal(2) giant larvae homolog 1 (Llgl1) regulates the formation of apical cell junctions and apicobasal polarity, and we investigated its role in ventricular wall maturation, including trabeculation and epicardial establishment. We found thatllgl1mutant zebrafish embryos exhibit aberrantly positioned cardiomyocytes during early trabeculation, some of which extrude apically into the pericardial space. While investigating apical cardiomyocyte extrusion we identified a basal to apical shift in laminin deposition in the ventricular wall. Initially laminin deposition occurs on the luminal (basal) surface of the heart but concomitant with the onset of trabeculation basal laminin is removed and is instead deposited on the exterior (apical) surface of the ventricle. We find that epicardial cells express several laminin subunits as they adhere to the ventricular wall, and show that the epicardium is required for laminin deposition on the ventricular surface. Inllgl1mutants the timing of the basal-apical laminin shift is delayed, in line with a delay in establishment of the epicardial layer. Analysis of earlier epicardial development reveals that while both Llgl1 and laminin are not required for specification of the proepicardial organ, they are instead required for dissemination of epicardial cells to the ventricular surface. Together our analyses reveal an unexpected role for Llgl1 in correct timing of epicardial development, supporting integrity of the myocardial wall during early trabeculation.
Crowdsourcing and phylogenetic modelling reveal parrot tool use is not rare
Authors: Bastos Amalia P. M. , Claessens Scott , Nelson Ximena J. , Welch David , Atkinson Quentin D. , Taylor Alex H. 
Published: August 2023

AbstractStudying the prevalence of putatively rare behaviours, such as tool use, is challenging because absence of evidence can arise either from a species’ inability to produce the behaviour or from insufficient research effort. Here, we tackle this challenge by combining crowdsourcing and phylogenetic modelling to approximate actual rates of a rarely observed behaviour based on limited data, targeting tool use in parrots. Crowdsourcing on a social media platform revealed novel instances of tool use in 17 parrot species, more than doubling the confirmed number of tool-using parrot species from 11 (3%) to 28 (7%). Phylogenetic modelling ranked additional species that are most likely to be unobserved tool users, suggesting that between 11% and 17% of extant parrot species may be tool users. These discoveries have implications for inferences about the evolutionary drivers and origins of tool use in parrots, revealing associations with relative brain size and feeding generalism and indicating several genera where tool use was likely an ancestral trait. Overall, our findings challenge the assumption that current sampling effort captures the full distribution of putatively rare animal behaviours. Combining our sampling and analysis methods offers a fruitful approach for investigating the distribution, drivers, and origins of other rare behaviours.This working paper has not yet been peer-reviewed.
Intein-based thermoregulated meganucleases for biocontainment of genetic material
Authors: Foo Gary W. , Leichthammer Christopher D. , Saita Ibrahim M. , Lukas Nicholas D. , Batko Izabela Z. , Heinrichs David E. , Edgell David R. 
Published: August 2023

ABSTRACTLimiting the spread of synthetic genetic information outside of the intended use is essential for applications where biocontainment is critical. In particular, biocontainment of engineered probiotics and plasmids that are excreted from the mammalian gastrointestinal tract is needed to prevent escape and acquisition of genetic material that could confer a selective advantage to microbial communities. Here, we built a simple and lightweight biocontainment system that post-translationally activates a site-specific DNA endonuclease to degrade DNA at 18°C and not at higher temperatures. We constructed an orthogonal set of temperature sensitive-meganucleases, or TSMs, by inserting the yeast VMA1 L212P temperature-sensitive intein into the coding regions of LAGLIDADG homing endonucleases. We showed that the TSMs eliminated plasmids carrying the cognate TSM target site from laboratory strains ofEscherichia coliat the permissive 18°C but not at higher restrictive temperatures. Plasmid elimination is dependent on both TSM endonuclease activity and intein splicing. We demonstrated that TSMs eliminated plasmids from theE. coliNissle 1917 strain after passage through the mouse gut when fecal resuspensions were incubated at 18°C but not at 37°C. Collectively, our data demonstrates the potential of thermoregulated meganucleases as a means of restricting engineered plasmids and probiotics to the mammalian gut.