bluuebunny/crossref_metadata_2025_split huggingface dataset:
Adaptations to water stress and pastoralism in the Turkana of northwest Kenya
Authors: Lea AJ , Caldas IV , Garske KM , Echwa J , Gurven M , Handley C , Kahumbu J , Kamau  , Kinyua P , Lotukoi F , Lopurudoi A , Lowasa S , Mallarino R , Martins D , Messer PW , Miano C , Muhoya B , Peng J , Phung T , Rabinowitz JD , Roichman A , Siford R , Stone A , Oill AM Taravella , Mathew S , Wilson MA , Ayroles JF 
Published: January 2023

AbstractThe Turkana people inhabit arid regions of east Africa—where temperatures are high and water is scarce—and they practice subsistence pastoralism, such that their diet is primarily composed of animal products. Working with Turkana communities, we sequenced 367 genomes and identified 8 regions putatively involved in adaptation to water stress and pastoralism. One of these regions includes a putative enhancer for STC1—a kidney-expressed gene involved in the response to dehydration and the metabolism of purine-rich foods such as red meat. We show that STC1 is induced by antidiuretic hormone in humans, is associated with urea levels in the Turkana themselves, and is under strong selection in this population (s∼0.041). This work highlights that partnerships with subsistence-level groups can lead to new models of human physiology with biomedical relevance.
Predictive Motor Control Based on a Generative Adversarial Network
Authors: Lenninger Movitz , Choi Whan-Hyuk , Choi Hansol 
Published: January 2023

ABSTRACTPredictive processing models suggest that a brain decides actions through inference using its internal generative model over the world’s states and their transitions. Most of the predictive processing models have been formalized using explicit representations of the probability distributions, with explicit structures and parameters. They are difficult to learn in general and needs explanation about representation of structure and parameters of distributions, and the method for statistical arithmetic on them, each of which are questions not easy to answer. In this study, we explore an alternative representation for predictive processing which is based on an implicit model known as generative adversarial networks, which has been widely explored recently in machine learning studies as they can learn a distribution directly from data. We demonstrate how a generative adversarial network can be trained to learn an implicit generative model of motor dynamics. And then, we show that such a model can perform approximate inference using the trained model, providing the necessary computations for both the forward and inverse model of motor control. Our framework may provide another formalization for brain’s inference model, especially for learning process. Additionally, we suggest that the functional architecture of the cortical-basal ganglia circuit may modeled as the generator and discriminator in the generative adversarial network model.
Bromodomain-containing Protein 4 Regulates Innate Inflammation in Airway Epithelial Cells via Modulation of Alternative Splicing
Authors: Mann Morgan , Fu Yao , Xu Xiaofang , Roberts David S. , Li Yi , Zhou Jia , Ge Ying , Brasier Allan R. 
Published: January 2023

AbstractBromodomain-containing Protein 4 (BRD4) is a transcriptional regulator which coordinates gene expression programs controlling cancer biology, inflammation, and fibrosis. In airway viral infection, non-toxic BRD4-specific inhibitors (BRD4i) block the release of pro-inflammatory cytokines and prevent downstream remodeling. Although the chromatin modifying functions of BRD4 in inducible gene expression have been extensively investigated, its roles in post-transcriptional regulation are not as well understood. Based on its interaction with the transcriptional elongation complex and spliceosome, we hypothesize that BRD4 is a functional regulator of mRNA processing. To address this question, we combine data-independent analysis - parallel accumulation-serial fragmentation (diaPASEF) with RNA-sequencing to achieve deep and integrated coverage of the proteomic and transcriptomic landscapes of human small airway epithelial cells exposed to viral challenge and treated with BRD4i. The transcript-level data was further interrogated for alternative splicing analysis, and the resulting data sets were correlated to identify pathways subject to post-transcriptional regulation. We discover that BRD4 regulates alternative splicing of key genes, including Interferon-related Developmental Regulator 1 (IFRD1) and X-Box Binding Protein 1 (XBP1), related to the innate immune response and the unfolded protein response, respectively. These findings extend the transcriptional elongation-facilitating actions of BRD4 in control of post-transcriptional RNA processing in innate signaling.
Lateral membrane organization as target of an antimicrobial peptidomimetic compound
Authors: Melcrová Adéla , Maity Sourav , Melcr Josef , de Kok Niels A. W. , Gabler Mariella , van der Eyden Jonne , Stensen Wenche , Svendsen John S. M. , Driessen Arnold J. M. , Marrink Siewert J. , Roos Wouter H. 
Published: January 2023

AbstractAntimicrobial resistance is one of the leading concerns in medical care. Here we resolve the functional mechanism of the antimicrobial action of the cationic tripeptide AMC-109 by combining high speed-atomic force microscopy, molecular dynamics, fluorescence assays, and lipidomic analysis. We show that AMC-109 activity on the negatively charged plasma membrane ofStaphylococcus aureusconsists of two crucial steps. First, AMC-109 self-assembles into stable aggregates with specificity for negatively charged membranes. Second, by incorporation into theS. aureusmembrane the lateral membrane organization is affected, dissolving membrane nanodomains. Domain dissolution affects membrane functions such as protein sorting and cell wall synthesis, and is suggested to cause a loss of resistance of methicillin-resistantS. aureus(MRSA) to methicillin. As the AMC-109 mode of action is similar to the activity of the disinfectant benzalkonium chloride (BAK), a broad applicability, but with low cytotoxicity to human cells, is expected.
The prevalence of dementia in humans could be the result of a functional adaptation
Authors: Holt Alan G , Davies Adrian M 
Published: January 2023

AbstractIn this paper we propose that high copy number of the mitochondrial genome in neurons is a functional adaptation. We simulated the proliferation of deletion mutants of the human mitochondrial genome in a virtual mitochondrion and recorded the cell loss rates due to deletions overwhelming the wild-type.Our results showed that cell loss increased with mtDNA copy number. Given that neuron loss equates to cognitive dysfunction, it would seem counter-intuitive that there would be a selective pressure for high copy number over low. However, for a low copy number, the onset of cognitive decline, while mild, started early in life. Whereas, for high copy number, it did not start until middle age but progressed rapidly. There could have been an advantage to high copy number in the brain if it delayed the onset of cognitive decline until after reproductive age. The prevalence of dementia in our aged population is a consequence of this functional adaptation.
MOXD1 is a gate-keeper of organ homeostasis and functions as a tumor-suppressor in neuroblastoma
Authors: Fredlund Elina , Andersson Stina , Hilgert Elien , Álvarez-Hernán Guadalupe , Monferrer Ezequiel , Karakaya Sinan , Gregor Tomas , Loontiens Siebe , Bek Jan Willem , Lecomte Estelle , Magnusson Emma , Miltenyte Enrika , Cabirol Marie , Kyknas Michail , Engström Niklas , Henriksson Marie Arsenian , Hammarlund Emma , Noguera Rosa , Speleman Frank , van Nes Johan , Mohlin Sofie 
Published: January 2023

AbstractNeuroblastoma is a childhood cancer believed to result from dysfunctional development. Its origin during embryogenesis remains poorly understood. The lack of appropriate models has hindered in-depth mapping of tumor-driving events. Here, we identify a novel tumor-suppressor gene that predicts poor survival in high-risk disease, by applying bulk and single cell RNA sequencing data of neuroblastoma and human fetal adrenal glands. Trunk neural crest-specific MOXD1 discriminates cell populations during normal and tumor development, with implications for deciphering neuroblastoma cell origin. We created an embryonic conditional knockout model and show that cell type-specific loss ofMOXD1leads to disrupted organ homeostasis and failed adrenal gland formation, home for neuroblastoma. We show that MOXD1 is a tumor suppressor gene in zebrafish, chick, and micein vivomodels.One-Sentence SummaryNeural crest-specific MOXD1 is ade novotumor-suppressor gene in childhood cancers arising during embryogenesis.
Low level of antioxidant capacity biomarkers but not target overexpression predicts vulnerability to ROS-inducing drugs
Authors: Samarin Jana , Fabrowski Piotr , Kurilov Roman , Nuskova Hana , Hummel-Eisenbeiss Johanna , Pink Hannelore , Li Nan , Weru Vivienn , Alborzinia Hamed , Yildiz Umut , Grob Laura , Taubert Minerva , Czech Marie , Morgen Michael , Brandstädter Christina , Becker Katja , Mao Lianghao , Jayavelu Ashok Kumar , Goncalves Angela , Uhrig Ulrike , Seiler Jeanette , Lyu Yanhong , Diederichs Sven , Klingmüller Ursula , Muckenthaler Martina , Kopp-Schneider Annette , Teleman Aurelio , Miller Aubry K , Gunkel Nikolas 
Published: January 2023

AbstractDespite a strong rationale for why cancer cells are susceptible to redox-targeting drugs, such drugs often face tumor resistance or dose-limiting toxicity in preclinical and clinical studies. An important reason is the lack of specific biomarkers to better select susceptible cancer entities and stratify patients. Using a large panel of lung cancer cell lines, we identified a set of “antioxidant-capacity” biomarkers (ACB), which were tightly repressed, partly by STAT3 and STAT5A/B in sensitive cells, rendering them susceptible to multiple redox-targeting and ferroptosis-inducing drugs. Contrary to expectation, constitutively low ACB expression was not associated with an increased steady state level of reactive oxygen species (ROS) but a high level of nitric oxide, which is required to sustain high replication rates. Using ACBs, we identified cancer entities with a high percentage of patients with favorable ACB expression pattern, making it likely that more responders to ROS-inducing drugs could be stratified for clinical trials.
Motor cortex retains and reorients neural dynamics during motor imagery
Authors: Dekleva Brian M. , Chowdhury Raeed H. , Batista Aaron P. , Chase Steven M. , Yu Byron M. , Boninger Michael L. , Collinger Jennifer L. 
Published: January 2023

AbstractThe most prominent role of motor cortex is generating patterns of neural activity that lead to movement, but it is also active when we simply imagine movements in the absence of actual motor output. Despite decades of behavioral and imaging studies, it is unknown how the specific activity patterns and temporal dynamics within motor cortex during covert motor imagery relate to those during motor execution. Here we recorded intracortical activity from the motor cortex of two people with residual wrist function following incomplete spinal cord injury as they performed both actual and imagined isometric wrist extensions. We found that we could decompose the population-level activity into orthogonal subspaces such that one set of components was similarly active during both action and imagery, and others were only active during a single task type—action or imagery. Although they inhabited orthogonal neural dimensions, the action-unique and imagery-unique subspaces contained a strikingly similar set of dynamical features. Our results suggest that during motor imagery, motor cortex maintains the same overall population dynamics as during execution by recreating the missing components related to motor output and/or feedback within a unique imagery-only subspace.
Size tuning of neural response variability in laminar circuits of macaque primary visual cortex
Authors: Nurminen Lauri , Bijanzadeh Maryam , Angelucci Alessandra 
Published: January 2023

ABSTRACTA defining feature of the cortex is its laminar organization, which is likely critical for cortical information processing. For example, visual stimuli of different size evoke distinct patterns of laminar activity. Visual information processing is also influenced by the response variability of individual neurons and the degree to which this variability is correlated among neurons. To elucidate laminar processing, we studied how neural response variability across the layers of macaque primary visual cortex is modulated by visual stimulus size. Our laminar recordings revealed that single neuron response variability and the shared variability among neurons are tuned for stimulus size, and this size-tuning is layer-dependent. In all layers, stimulation of the receptive field (RF) reduced single neuron variability, and the shared variability among neurons, relative to their pre-stimulus values. As the stimulus was enlarged beyond the RF, both single neuron and shared variability increased in supragranular layers, but either did not change or decreased in other layers. Surprisingly, we also found that small visual stimuli could increase variability relative to baseline values. Our results suggest multiple circuits and mechanisms as the source of variability in different layers and call for the development of new models of neural response variability.
PEGylated recombinantAplysia punctataink toxin depletes arginine and lysine and inhibits growth of tumor xenografts
Authors: Wolkersdorfer Alena M. , Bergmann Birgit , Adelmann Juliane , Ebbinghaus Matthias , Günther Eckhard , Gutmann Marcus , Hahn Lukas , Hurwitz Robert , Krähmer Ralf , Leenders Frank , Lühmann Tessa , Schueler Julia , Schmidt Luisa , Teifel Michael , Meinel Lorenz , Rudel Thomas 
Published: January 2023

AbstractIn recent years, a novel treatment method for cancer emerged, which is based on the starvation of tumors of amino acids like arginine. The deprivation of arginine in serum is based on enzymatic degradation and can be realized by arginine deaminases like the L-amino acid oxidase found in the ink toxin of the sea hareAplysia punctata. Previously isolated from the ink, the L-amino acids oxidase was described to oxidate the essential amino acid L-lysine and L-arginine to their corresponding deaminated alpha-keto acids. Here, we present the recombinant production and functionalization of amino acid oxidaseAplysia Punctataink toxin (APIT). PEGylated APIT (APIT-PEG) increased the blood circulation time. APIT-PEG treatment of patient-derived xenografted mice shows a significant dose dependent reduction of tumor growth over time mediated by amino acid starvation of the tumor. Treatment of mice with APIT-PEG which lead to deprivation of arginine was well tolerated.
Dynamic Effects of Ventral Hippocampal NRG3/ERBB4 Signaling on Nicotine Withdrawal-Induced Responses
Authors: Fisher Miranda L. , Prantzalos Emily R. , O’Donovan Bernadette , Anderson Tanner , Sahoo Pabitra K. , Twiss Jeffery L. , Ortinski Pavel I. , Turner Jill R. 
Published: January 2023

AbstractTobacco smoking remains a leading cause of preventable death in the United States, with a less than 5% success rate for smokers attempting to quit. High relapse rates have been linked to several genetic factors, indicating that the mechanistic relationship between genes and drugs of abuse is a valuable avenue for the development of novel smoking cessation therapies. For example, various single nucleotide polymorphisms (SNPs) in the gene for neuregulin 3 (NRG3) and its cognate receptor, the receptor tyrosine-protein kinase erbB-4 (ERBB4), have been linked to nicotine addiction. Our lab has previously shown that ERBB4 plays a role in anxiety-like behavior during nicotine withdrawal (WD); however, the neuronal mechanisms and circuit-specific effects of NRG3-ERBB4 signaling during nicotine and WD are unknown. The present study utilizes genetic, biochemical, and functional approaches to examine the anxiety-related behavioral and functional role of NRG3-ERBB4 signaling, specifically in the ventral hippocampus (VH). We report that 24hWD from nicotine is associated with altered synaptic expression of VH NRG3 and ERBB4, and genetic disruption of VHErbB4leads to an elimination of anxiety-like behaviors induced during 24hWD. Moreover, we observed attenuation of GABAergic transmission as well as alterations in Ca2+-dependent network activity in the ventral CA1 area of VHErbB4knock-down mice during 24hWD. Our findings further highlight contributions of the NRG3-ERBB4 signaling pathway to anxiety-related behaviors seen during nicotine WD.
Caffeine-tolerant mutations selected through an at-home yeast experimental evolution teaching lab
Authors: Moresi Naomi G. , Geck Renee C. , Skophammer Ryan , Godin Dennis ,   yEvo Students, Taylor M. Bryce , Dunham Maitreya J. 
Published: January 2023

ABSTRACTyEvo is a curriculum for high school students centered around evolution experiments inS. cerevisiae. To adapt the curriculum for remote instruction, we created a new protocol to evolve non-GMO yeast in the presence of caffeine. Evolved strains had increased caffeine tolerance and distinct colony morphologies. Many possessed copy number variations, transposon insertions, and mutations affecting genes with known relationships to caffeine and TOR signaling - which is inhibited by caffeine - and in other genes not previously connected with caffeine. This demonstrates that our accessible, at-home protocol is sufficient to permit novel insights into caffeine tolerance.
Defining T cell receptor repertoires using nanovial-based affinity and functional screening
Authors: Koo Doyeon , Mao Zhiyuan , Dimatteo Robert , Tsubamoto Natalie , Noguchi Miyako , McLaughlin Jami , Tran Wendy , Lee Sohyung , Cheng Donghui , de Rutte Joseph , Sojo Giselle Burton , Witte Owen N. , Carlo Dino Di 
Published: January 2023

AbstractThe ability to selectively bind to antigenic peptides and secrete cytokines can define populations of cells with therapeutic potential in emerging T cell receptor (TCR) immunotherapies. We leverage cavity-containing hydrogel microparticles, called nanovials, each coated with millions of peptide-major histocompatibility complex (pMHC) monomers to isolate antigen-reactive T cells. T cells are captured and activated by pMHCs and secrete cytokines on nanovials, allowing sorting based on both affinity and function. The TCRs of sorted cells on nanovials are sequenced, recovering paired αβ-chains using microfluidic emulsion-based single-cell sequencing. By labeling nanovials having different pMHCs with unique oligonucleotide-barcodes we could link TCR sequence to targets with 100% accuracy. We identified with high specificity an expanded repertoire of functional TCRs targeting viral antigens compared to standard techniques.One-sentence SummaryAffinity and secretion-based screening of antigen-specific T cells using nanovials defines a functional TCR repertoire
The evolution of the gliotoxin biosynthetic gene cluster inPenicilliumfungi
Authors: Balamurugan Charu , Steenwyk Jacob L. , Goldman Gustavo H. , Rokas Antonis 
Published: January 2023

AbstractFungi biosynthesize a diversity of secondary metabolites, small organic bioactive molecules that play diverse roles in fungal ecology. Fungal secondary metabolites are often encoded by physically clustered sets of genes known as biosynthetic gene clusters (BGCs). Fungi in the genusPenicilliumproduce diverse secondary metabolites that have been both useful (e.g., the antibiotic penicillin and the cholesterol-lowering drug mevastatin) and harmful (e.g., the mycotoxin patulin and the immunosuppressant gliotoxin) to human affairs. BGCs often also encode resistance genes that confer self-protection to the secondary metabolite-producing fungus. SomePenicilliumspecies, such asPenicillium lilacinoechinulatumandPenicillium decumbens, are known to produce gliotoxin, a secondary metabolite with known immunosuppressant activity; however, an evolutionary characterization of the BGC responsible for gliotoxin biosynthesis amongPenicilliumspecies is lacking. Here, we examine the conservation of genes involved in gliotoxin biosynthesis and resistance in 35Penicilliumgenomes from 23 species. We found homologous, less fragmented gliotoxin BGCs in 12 genomes, mostly fragmented remnants of the gliotoxin BGC in 21 genomes, whereas the remaining twoPenicilliumgenomes lacked the gliotoxin BGC altogether. In contrast, we observed broad conservation of homologs of resistance genes that reside outside the BGC acrossPenicilliumgenomes. Evolutionary rate analysis revealed that BGCs with higher numbers of genes evolve slower than BGCs with few genes. Even though the gliotoxin BGC is fragmented to varying degrees in nearly all genomes examined, ancestral state reconstruction suggests that the ancestor ofPenicilliumspecies possessed the gliotoxin BGC. Our analyses suggest that genes that are part of BGCs can be retained in genomes long after the loss of secondary metabolite biosynthesis.
Predicting tumor immune microenvironment and checkpoint therapy response of head & neck cancer patients from blood immune single-cell transcriptomics
Authors: Cao Yingying , Chang Tiangen , Schischlik Fiorella , Wang Kun , Sinha Sanju , Hannenhalli Sridhar , Jiang Peng , Ruppin Eytan 
Published: January 2023

AbstractThe immune state of tumor microenvironment is crucial for determining immunotherapy response but is not readily accessible. Here we investigate if we can infer the tumor immune state from the blood and further predict immunotherapy response. First, we analyze a dataset of head and neck squamous cell carcinoma (HNSCC) patients with matched scRNA-Seq of peripheral blood mononuclear cells (PBMCs) and tumor tissues. We find that the tumor immune cell fractions of different immune cell types and many of the genes they express can be inferred from the matched PBMC scRNA-Seq. Second, analyzing another HNSCC dataset with PBMC scRNA-Seq and immunotherapy response, we find that the inferred ratio between tumor memory B and regulatory T cell fractions is predictive of immunotherapy response and is superior to the well-established cytolytic and exhausted T-cell signatures. Overall, these results showcase the potential of scRNA-Seq liquid biopsies in cancer immunotherapy, calling for their larger-scale testing.SignificanceThis head and neck cancer study demonstrates the potential of using blood single-cell transcriptomics to (1) infer the tumor immune status and (2) predict immunotherapy response from the tumor immune status inferred from blood. These results showcase the potential of single-cell transcriptomics liquid biopsies for further advancing personalized cancer immunotherapy.
Specific and non-linear effects of glaucoma on optic radiation tissue properties
Authors: Kruper John , Richie-Halford Adam , Benson Noah C. , Caffarra Sendy , Owen Julia , Wu Yue , Lee Aaron Y. , Lee Cecilia S. , Yeatman Jason D. , Rokem Ariel 
Published: January 2023

AbstractChanges in sensory input with aging and disease affect brain tissue properties. To establish the link between glaucoma, the most prevalent cause of irreversible blindness, and changes in major brain connections, we characterized white matter tissue properties in diffusion MRI measurements in a large sample of subjects with glaucoma (N=905; age 49-80) and healthy controls (N=5,292; age 45-80) from the UK Biobank. Confounds due to group differences were mitigated by matching a sub-sample of controls to glaucoma subjects. A convolutional neural network (CNN) accurately classified whether a subject has glaucoma using information from the primary visual connection to cortex (the optic radiations, OR), but not from non-visual brain connections. On the other hand, regularized linear regression could not classify glaucoma, and the CNN did not generalize to classification of age-group or of age-related macular degeneration. This suggests a unique non-linear signature of glaucoma in OR tissue properties.