bluuebunny/crossref_metadata_2025_split huggingface dataset:
Seeing the future: connectome strength and network efficiency in visual network predict individual ability of episodic future thinking
Authors: Hu Bowen , Zhang Rong , Feng Tingyong 
Published: October 2022

AbstractEpisodic future thinking (EFT) refers to the critical ability that people construct vivid mental imagery about future events and pre-experience it, which helps with individual and group decision-making. Although EFT is generally believed to have a visual nature by theorists, little neuroscience evidence had been provided to verify this assumption. Here, by employing the approach of connectome-based predictive modeling (CPM) and graph-theoretical analysis, we analyzed resting-state functional brain image from 191 participants to predict their variability of EFT ability (leave-one-out cross-validation), and validated the results by applying different parcellation schemas and feature selection thresholds. At the connectome strength level, CPM-based analysis revealed that EFT ability could be predicted by the connectome strength of visual network. Further at the network level, graph-theoretical analysis showed that EFT ability could be predicted by the network efficiency of visual network. Moreover, these findings were replicated using different parcellation schemas and feature selection thresholds. These results robustly and collectively supported the visual network being the neural substrates underlying EFT ability from a comprehensive perspective of resting-state functional connectivity strength and the neural network. This study provides indications on how the function of visual network supports EFT ability, and helps to understand the EFT ability from a neural basis perspective.
Expectation-Maximization enables Phylogenetic Dating under a Categorical Rate Model
Authors: Mai Uyen , Charvel Eduardo , Mirarab Siavash 
Published: October 2022

AbstractDating phylogenetic trees to obtain branch lengths in time unit is essential for many downstream applications but has remained challenging. Dating requires inferring substitution rates that can change across the tree. While we can assume to have information about a small subset of nodes from the fossil record or sampling times (for fast-evolving organisms), inferring the ages of the other nodes essentially requires extrapolation and interpolation. Assuming a clock model that defines a distribution over rates, we can formulate dating as a constrained maximum likelihood (ML) estimation problem. While ML dating methods exist, their accuracy degrades in the face of model misspecification where the assumed parametric statistical clock model vastly differs from the true distribution. Notably, existing methods tend to assume rigid, often unimodal rate distributions. A second challenge is that the likelihood function involves an integral over the continuous domain of the rates and often leads to difficult non-convex optimization problems. To tackle these two challenges, we propose a new method called Molecular Dating using Categorical-models (MD-Cat). MD-Cat uses a categorical model of rates inspired by non-parametric statistics and can approximate a large family of models by discretizing the rate distribution into k categories. Under this model, we can use the Expectation-Maximization (EM) algorithm to co-estimate rate categories and branch lengths time units. Our model has fewer assumptions about the true clock model than parametric models such as Gamma or LogNormal distribution. Our results on two simulated and real datasets of Angiosperms and HIV and a wide selection of rate distributions show that MD-Cat is often more accurate than the alternatives, especially on datasets with nonmodal or multimodal clock models.Code availabilityThe MD-Cat software is available athttps://github.com/uym2/MD-Cat.Data availabilityData are available on Githubhttps://github.com/uym2/MD-Cat-paperand Dryadhttps://doi.org/10.5061/dryad.pk0p2ngs0.
The differential impacts of dataset imbalance in single-cell data integration
Authors: Maan Hassaan , Zhang Lin , Yu Chengxin , Geuenich Michael , Campbell Kieran R , Wang Bo 
Published: October 2022

AbstractSingle-cell transcriptomic data measured across distinct samples has led to a surge in computational methods for data integration. Few studies have explicitly examined the common case of cell-type imbalance between datasets to be integrated, and none have characterized its impact on downstream analyses. To address this gap, we developed theIniquitatepipeline for assessing the stability of single-cell RNA sequencing (scRNA-seq) integration results after perturbing the degree of imbalance between datasets. Through benchmarking 5 state-of-the-art scRNA-seq integration techniques in 1600 perturbed integration scenarios for a multi-sample peripheral blood mononuclear cell (PBMC) dataset, our results indicate that sample imbalance has significant impacts on downstream analyses and the biological interpretation of integration results. We observed significant variation in clustering, cell-type classification, marker gene-based annotation, and query-to-reference mapping in imbalanced settings. Two key factors were found to lead to quantitation differences after scRNA-seq integration - the cell-type imbalance within and between samples (relative cell-type support) and the relatedness of cell-types across samples (minimum cell-type center distance). To account for evaluation gaps in imbalanced contexts, we developed novel clustering metrics robust to sample imbalance, including the balanced Adjusted Rand Index (bARI) and balanced Adjusted Mutual Information (bAMI). Our analysis quantifies biologically-relevant effects of dataset imbalance in integration scenarios and introduces guidelines and novel metrics for integration of disparate datasets. The Iniquitate pipeline and balanced clustering metrics are available athttps://github.com/hsmaan/Iniquitateandhttps://github.com/hsmaan/balanced-clustering, respectively.
Preprint peer review enhances undergraduate biology students’ disciplinary literacy and sense of belonging in STEM
Authors: Otto Josie L. , McDowell Gary S , Balgopal Meena M. , Lijek Rebeccah S 
Published: October 2022

AbstractUndergraduate education on science publishing and peer review is limited compared to the focus on experimental research. Since peer review is integral to the scientific process and central to the identity of a scientist, we envision a paradigm shift that makes teaching peer review integral to undergraduate science education, and hypothesize that this may facilitate the development of students’ scientific literacy and identity formation. To this end, we developed a curriculum for biology undergraduates to learn about the mechanisms of peer review, then write and publish their own peer reviews as a way to authentically join the scientific community of practice. The curriculum was implemented as a semester-long intervention in one class and as a module intervention embedded into a discipline-based class on vaccines. Before and after both interventions, we measured students’ scientific literacy, including peer review ability, using quantitative methods. We also carried out a longitudinal qualitative assessment of students’ perceptions of their scientific literacy and identity using thematic analysis of students’ writing. Here, we present data on the improvement in peer review ability of undergraduates in both classes, and data on the curriculum’s interrelated impact on students’ development of scientific literacy, identity, and belonging in academic and professional spaces. These data suggest that undergraduates can and should be trained in peer review to foster the interrelated development of their scientific literacy, scientific identity, and sense of belonging in science.
Neuronal E93 regulates metabolic homeostasis
Authors: Yip Cecilia , Wyler Steven , Yamazaki Shin , Rothenfluh Adrian , Lee Syann , You Young-Jai , Elmquist Joel 
Published: October 2022

AbstractMetamorphosis is a transition from growth to reproduction, through which an animal adopts adult behavior and metabolism. Yet the mechanisms underlying the switch is unclear. Here we report that neuronalE93, a transcription factor essential for metamorphosis, regulates the adult metabolism and circadian rhythm inDrosophila melanogaster. WhenE93is specifically knocked down in neurons, the flies become hyperphagic and obese with increased energy stores and disrupted circadian rhythms. A screen of Gal4 lines targeting subsets of neurons and endocrine cells identified neurons producing GABA and myoinhibitory peptide (MIP) as the main sites ofE93action. Knockdown of the ecdysone receptor specifically in MIP neurons partly phenocopies the MIP neuron-specific knockdown ofE93suggesting the steroid signal coordinates adult metabolism viaE93. The circadian disruption caused by neuronal knockdown ofE93is also observed whenE93is knockdown in GABA and MIP neurons. Based on these results we suggest that neuronalE93is a key switch for metabolic transition representing an intersectional node between metabolism and circadian biology.
Genome-Wide Epigenomic Profiling of Primary Non-Small Cell Lung Cancer Reveals Specific and Recurrent DNA Methylation Alterations in Smoker Versus Never-Smoker Patients
Authors: Karlow Jennifer A. , Pehrsson Erica C. , Xing Xiaoyun , Watson Mark , Devarakonda Siddhartha , Govindan Ramaswamy , Wang Ting 
Published: October 2022

AbstractEpigenetic alterations are widespread in cancer and can complement genetic alterations to influence cancer progression and treatment. To better understand the potential contribution of DNA methylation alterations to tumor phenotype in non-small cell lung cancer (NSCLC) in both smoker and never-smoker patients, we performed a comprehensive, genome-wide profiling of DNA methylation in 17 primary non-small cell lung cancer and 10 matched normal lung samples using the complementary methylation assays MeDIP-seq and MRE-seq. Compared to patient-matched non-malignant lung tissue, we report recurrent methylation changes of several gene promoters, many previously implicated in cancer, including FAM83A and SEPT9 (hypomethylation), and PCDH7, NKX2-1, and SOX17 (hypermethylation). Although smoker and never-smoker patients shared many methylation changes, several were specific and recurrent within a particular smoking status. In particular, never-smokers displayed a greater proportion of hypoDMRs and exhibited a greater number of recurrently hypomethylated promoters, including the promoter of the oncogene ASPSCR1, and others previously linked to cancer, including TOP2A, DPP9, and USP39. Methylation changes outside of promoters were also widespread and often recurrent, particularly the loss of methylation over repetitive elements, highly enriched for ERV1 subfamilies. Recurrent hypoDMRs were also enriched for several transcription factor (TF) binding motifs, often for genes involved in signaling and cell proliferation, including 71% encoding a binding site of NKX2-1, which was found to be significantly upregulated in TCGA LUAD samples. Furthermore, the overwhelming majority of DMRs identified in this study were found to reside in an active chromatin state in at least one tissue profiled using the Roadmap Epigenome data, suggesting that methylation changes may contribute to altered regulatory programs through the adaptation of cell type-specific expression programs.
User-friendly high-content imaging analysis on a single desktop: R package H5CellProfiler
Authors: Wink Steven , Burger Gerhard A. , Le Dévédec Sylvia E. , Beltman Joost B. , van de Water Bob 
Published: October 2022

AbstractTechnological development has led to ever-increasing amounts of data in high-content screening. For utilizing such data in an efficient, thorough, and user-friendly manner we developed the R package H5CellProfiler. H5CellProfiler is based on R packages data.table, ggvis, ggplot2 and shiny. H5CellProfiler launches a browser that allows scientists to analyze large single-cell datasets and make statistical summaries and graphs on their local desktop in a fast and memory-efficient manner. In addition, single-cell track labels are calculated and broken tracks are re-connected based on user-defined thresholds resulting in unique sets of annotated tracks.
Elephant trunks use an adaptable prehensile grip
Authors: Schulz Andrew K. , Reidenberg Joy S. , Wu Jia Ning , Tang Cheuk Ying , Seleb Benjamin , Mancebo Josh , Elgart Nathan , Hu David L. 
Published: October 2022

AbstractElephants have long been observed to grip objects with their trunk, but little is known about how they adjust their strategy for different weights. In this study, we challenge a female African elephant at Zoo Atlanta to lift 20 to 60 kg barbell weights with only its trunk. We measure the trunk’s shape and wrinkle geometry from a frozen elephant trunk at the Smithsonian. We observe several strategies employed to accommodate heavier weights, including accelerating less, orienting the trunk more vertically, and wrapping the barbell with a greater trunk length. Mathematical models show that increasing barbell weights are associated with constant trunk tensile force and an increasing barbell-wrapping surface area due to the trunk’s wrinkles. Our findings may inspire the design of more adaptable soft robotic grippers that can improve grip using surface morphology such as wrinkles.
Multiple Postsynaptic Protein Levels in Adult Superior Colliculus Are Unaffected by Dark Rearing from Birth
Authors: Juvale Parag S. , Mudd David B. , Shree Nitheyaa , Pallas Sarah L. 
Published: October 2022

AbstractVisual deprivation by dark rearing in kittens and monkeys delays visual pathway development and prolongs the critical period. In contrast, receptive fields (RFs) in superior colliculus (SC) of Syrian hamsters(Mesocricetus auratus)refine normally with spontaneous activity alone, requiring only brief juvenile visual experience to maintain refined RFs in adulthood (Carrasco et al., 2005). Extending dark rearing past puberty leads to lower GAD and GABA levels due to reduced BDNF-TrkB signaling, resulting in RF re-enlargement (Carrasco et al., 2011; Mudd et al., 2019). Previous studies in kittens and monkeys have reported that dark rearing is associated with changes in both GABA ligand and GABAAreceptor levels. Given the reduced GABA levels in SC of dark reared adult hamsters, we asked if dark rearing also causes changes in GABAAreceptor levels. We examined expression of GABAAreceptor subunits, their anchoring protein gephyrin, and the cation-chloride co-transporters KCC2 and NKCC1 in dark reared hamsters. Surprisingly, we found that dark rearing from birth until puberty had no effect on the levels of any of these postsynaptic elements, revealing a new form of maladaptive, presynaptic only inhibitory plasticity in which, rather than extending the critical period as seen in kittens and monkeys, hamster receptive fields refine normally and then lose refinement in adulthood. These results suggest that attempts to increase plasticity in adulthood for rehabilitation or recovery from injury should consider the possibility of unintended negative consequences. In addition, our results demonstrate the interesting finding that changes in neurotransmitter levels are not necessarily coordinated with changes in postsynaptic components.
Enzymatic reactions of AGO4 in RNA-directed DNA methylation: siRNA duplex loading, passenger strand elimination, target RNA slicing and sliced target retention
Authors: Wang Feng , Huang Hsiao-Yun , Huang Jie , Singh Jasleen , Pikaard Craig S. 
Published: October 2022

AbstractRNA-directed DNA methylation in plants is guided by 24 nt siRNAs generated in parallel with 23 nt RNAs of unknown function. We show that 23 nt RNAs function as passenger strands during 24 nt siRNA incorporation into AGO4. The 23 nt RNAs are then sliced into 11 and 12 nt fragments, with 12 nt fragments remaining associated with AGO4. Slicing recapitulated with recombinant AGO4 and synthetic RNAs reveals that siRNAs of 21-24 nt, with any 5’ terminal nucleotide, can guide slicing, with sliced RNAs then retained by AGO4. In vivo, RdDM target locus RNAs that copurify with AGO4 also display a sequence signature of slicing. Comparing plants expressing slicing-competent versus slicing-defective AGO4 shows that slicing elevates cytosine methylation levels at virtually all RdDM loci. We propose that siRNA passenger strand elimination and AGO4 tethering to sliced target RNAs are distinct modes by which AGO4 slicing enhances RNA-directed DNA methylation.
Gene knock-outs in human CD34+ hematopoietic stem and progenitor cells and in the human immune system of mice
Authors: Kuppers Daniel A. , Linton Jonathan , Espinosa Sergio Ortiz , McKenna Kelly M. , Rongvaux Anthony , Paddison Patrick J. 
Published: October 2022

AbstractHuman CD34+hematopoietic stem and progenitor cells (HSPCs) are a standard source of cells for clinical HSC transplantations as well as experimental xenotransplantation to generate “humanized mice”. To further extend the range of applications of these humanized mice, we developed a protocol to efficiently edit the genomes of human CD34+HSPCs before transplantation. In the past, manipulating HSPCs has been complicated by the fact that they are inherently difficult to transduce with lentivectors, and rapidly lose their stemness and engraftment potential duringin vitroculture. However, with optimized nucleofection of sgRNA:Cas9 ribonucleoprotein complexes, we are now able to edit a candidate gene in CD34+HSPCs with almost 100% efficiency, and without affecting their potential for engraftment and multilineage differentiation in mice. The result is a humanized mouse from which we knocked out a gene of interest from their human immune system.
A multiparametric anti-aging CRISPR screen uncovers a role for BAF in protein translation
Authors: Breusegem Sophia Y. , Houghton Jack , Romero-Bueno Raquel , Fragoso-Luna Adrián , Kentistou Katherine A. , Ong Ken K. , Janssen Anne F. J. , Bright Nicholas A. , Riedel Christian G. , Perry John R. B. , Askjaer Peter , Larrieu Delphine 
Published: October 2022

AbstractProgeria syndromes are very rare, incurable premature aging conditions recapitulating most aging features. Here, we report the first whole genome, multiparametric CRISPR anti-aging screen, identifying 43 new genes that can reverse multiple aging phenotypes in progeria. The screen was implemented in fibroblasts from Néstor- Guillermo Progeria Syndrome (NGPS) patients, carrying a homozygous p.Ala12Thr mutation in barrier-to-autointegration factor (BAF A12T). The hits were enriched for genes involved in protein translation, protein and RNA transport and osteoclast formation. We further confirmed that BAF A12T drives increased protein translation and translational errors that could directly contribute to premature aging in patients. This work has highlighted the power of multiparametric whole genome synthetic rescue screens to identify new anti-aging genes and uncover novel biology behind progeria-associated cellular dysfunction.One-Sentence SummaryA whole genome multiparametric screen in progeria identifies new pathways that can reverse cellular aging phenotypes.
Tuning of cytokine signaling through imbalanced abundances of receptors and kinases
Authors: Sta Léa , Voisinne Guillaume , Cotari Jesse , Adamer Michael F. , Molina-París Carmen , Altan-Bonnet Grégoire 
Published: October 2022

Cells use surface receptors to detect extra-cellular ligands (e.g., growth factors or cytokines) and engender signaling cascades. We explore the effect of cell-to-cell variability in receptor subunit copy number for cells responding to γc cytokines (e.g., IL-2, IL-7 and IL-15). We find that primary T cells expressing higher levels of the common γc receptor chain have weaker responses to IL-7, both in terms of lowered STAT5 phosphorylation amplitude and higher EC50. A mathematical model that accounts for abundance imbalance (e.g., insufficient expression of JAK kinases compared to the number of receptors, or γc competition for other receptor subunit chains) predicts the formation of non-signalling complexes, consistent with the observed cellular behaviour. This type of built-in limit on signaling responses illustrates how phenotypic heterogeneity generates biological functional diversity.Significance StatementCells rely on cytokines to coordinate their activation, differentiation, proliferation and survival. In particular, γc cytokines (interleukins IL-2, 4, 7, 9, 15, and 21) regulate the fate of leukocytes. The signaling cascade induced by these cytokines is relatively simple, and involves the phosphorylation of receptor-associated Janus-like kinases (JAK). Here, we explore the cell-to-cell variability of cytokine responses in primary mouse T cells, and find a paradoxical and quantitative imprint of receptor expression levels and other signaling components. For instance, high abundance of the common γc chain reduces cytokine responses (both in terms of signaling amplitudes and characteristic cytokine concentrations triggering 50% of the response). We develop mathematical models to quantify how limited abundances of signaling components (e.g., JAK or other cytokine receptor subunit chains) may explain our experimental observations. We conclude by generalizing this observation of cell-to-cell signaling variability to other ligand-receptor-kinase systems.
Selecting a new electron transfer pathway for nitrogen fixation uncovers an electron bifurcating-like enzyme involved in anaerobic aromatic compound degradation
Authors: Lewis Nathan M. , Sarne Abigail , Fixen Kathryn R. 
Published: October 2022

AbstractNitrogenase is the key enzyme involved in nitrogen fixation and uses low potential electrons delivered by ferredoxin (Fd) or flavodoxin (Fld) to reduce dinitrogen gas (N2) to produce ammonia and hydrogen. Although the phototrophic alphaproteobacterium Rhodopseudomonas palustris encodes multiple proteins that can reduce Fd, the FixABCX complex is the only one shown to support nitrogen fixation, and R. palustris Fix- mutants grow poorly in nitrogen-fixing conditions. To investigate how native electron transfer chains (ETCs) can be redirected towards nitrogen fixation, we leveraged the strong selective pressure of nitrogen limitation to isolate a suppressor of R. palustris ΔfixC that grows under nitrogen-fixing conditions. We found two mutations were required to restore growth under nitrogen-fixing conditions in the absence of functional FixABCX. One mutation was in the gene encoding the primary Fd involved in nitrogen fixation, fer1, and the other mutation was in aadN, which encodes a homolog of NAD+-dependent Fd:NADPH oxidoreductase (Nfn). We present evidence that AadN plays a role in electron transfer to benzoyl-CoA reductase, the key enzyme involved in anaerobic aromatic compound degradation. Our data support a model where the ETC for anaerobic aromatic compound degradation was re-purposed to support nitrogen fixation in the suppressor strain.ImportanceThere is increasing evidence that protein electron carriers like Fd have evolved to form specific partnerships with select electron donors and acceptors to keep native electron transfer pathways insulated from one another. This makes it challenging to integrate a Fd-dependent pathway like biological nitrogen fixation into non-nitrogen-fixing organisms and provide the high-energy reducing power needed to fix nitrogen. Here we show that amino acid substitutions in an electron donor for anaerobic aromatic compound degradation and a Fd involved in nitrogen fixation enabled electron transfer to nitrogenase. This work provides a model system to understand electron transfer chain specificity and how new electron transfer pathways can be evolved for biotechnologically valuable pathways like nitrogen fixation.