bluuebunny/crossref_metadata_2025_split huggingface dataset:
Frequency-dependent ecological interactions increase the prevalence, and shape the distribution, of pre-existing drug resistance
Authors: Maltas Jeff , Tadele Dagim Shiferaw , Durmaz Arda , McFarland Christopher D. , Hinczewski Michael , Scott Jacob G. 
Published: March 2023

ABSTRACTThe evolution of resistance remains one of the primary challenges for modern medicine from infectious diseases to cancers. Many of these resistance-conferring mutations often carry a substantial fitness cost in the absence of treatment. As a result, we would expect these mutants to undergo purifying selection and be rapidly driven to extinction. Nevertheless, pre-existing resistance is frequently observed from drug-resistant malaria to targeted cancer therapies in non-small cell lung cancer (NSCLC) and melanoma. Solutions to this apparent paradox have taken several forms from spatial rescue to simple mutation supply arguments. Recently, in an evolved resistant NSCLC cell line, we found that frequency-dependent ecological interactions between ancestor and resistant mutant ameliorate the cost of resistance in the absence of treatment. Here, we hypothesize that frequency-dependent ecological interactions in general play a major role in the prevalence of pre-existing resistance. We combine numerical simulations with robust analytical approximations to provide a rigorous mathematical framework for studying the effects of frequency-dependent ecological interactions on the evolutionary dynamics of pre-existing resistance. First, we find that ecological interactions significantly expand the parameter regime under which we expect to observe pre-existing resistance. Next, even when positive ecological interactions between mutants and ancestors are rare, these resistant clones provide the primary mode of evolved resistance because even weak positive interaction leads to significantly longer extinction times. We then find that even in the case where mutation supply alone is sufficient to predict pre-existing resistance, frequency-dependent ecological forces still contribute a strong evolutionary pressure that selects for increasingly positive ecological effects (negative frequency-dependent selection). Finally, we genetically engineer several of the most common clinically observed resistance mechanisms to targeted therapies in NSCLC, a treatment notorious for pre-existing resistance. We find that each engineered mutant displays a positive ecological interaction with their ancestor. As a whole, these results suggest that frequency-dependent ecological effects can play a crucial role in shaping the evolutionary dynamics of pre-existing resistance.
A mechanistic model of primer synthesis from catalytic structures of DNA polymerase α–primase
Authors: Mullins Elwood A. , Salay Lauren E. , Durie Clarissa L. , Bradley Noah P. , Jackman Jane E. , Ohi Melanie D. , Chazin Walter J. , Eichman Brandt F. 
Published: March 2023

AbstractThe mechanism by which polymerase α–primase (polα–primase) synthesizes chimeric RNA-DNA primers of defined length and composition, necessary for replication fidelity and genome stability, is unknown. Here, we report cryo-EM structures of polα–primase in complex with primed templates representing various stages of DNA synthesis. Our data show how interaction of the primase regulatory subunit with the primer 5′-end facilitates handoff of the primer to polα and increases polα processivity, thereby regulating both RNA and DNA composition. The structures detail how flexibility within the heterotetramer enables synthesis across two active sites and provide evidence that termination of DNA synthesis is facilitated by reduction of polα and primase affinities for the varied conformations along the chimeric primer/template duplex. Together, these findings elucidate a critical catalytic step in replication initiation and provide a comprehensive model for primer synthesis by polα–primase.
Projection-specific integration of convergent thalamic and retrosplenial signals in the presubicular head direction cortex
Authors: Richevaux Louis , Lim Dongkyun , Nassar Mérie , Rodrigues Léa Dias , Mauthe Constanze , Cohen Ivan , Sol-Foulon Nathalie , Fricker Desdemona 
Published: March 2023

SummaryHead-direction (HD) signals function as the brain’s internal compass. They are organized as an attractor, and anchor to the environment via visual landmarks. Here we examine how thalamic HD signals and visual landmark information from the retrosplenial cortex combine in the presubiculum. We find that monosynaptic excitatory connections from anterior thalamic nucleus and from retrosplenial cortex converge on single layer 3 pyramidal neurons in the dorsal portion of mouse presubiculum. Independent dual wavelength photostimulation of these inputs in slices leads to action potential generation preferentially for near-coincident inputs, indicating that layer 3 neurons can transmit a visually matched HD signal to medial entorhinal cortex. Layer 4 neurons, which innervate the lateral mammillary nucleus, form a second step in the association of HD and landmark signals. They receive little direct input from thalamic and retrosplenial axons. We show that layer 4 cells are excited di-synaptically, transforming regular spiking activity into bursts of action potentials, and that their firing is enhanced by cholinergic agonists. Thus, a coherent sense of orientation involves projection specific translaminar processing in the presubiculum, where neuromodulation facilitates landmark updating of HD signals in the lateral mammillary nucleus.
Actomyosin pulsing rescues embryonic tissue folding from disruption by myosin fluctuations
Authors: Zhu Hongkang , O’Shaughnessy Ben 
Published: March 2023

AbstractDuring early development, myosin II mechanically reshapes and folds embryo tissue. A much-studied example is ventral furrow formation inDrosophila, marking the onset of gastrulation. Furrowing is driven by contraction of actomyosin networks on apical cell surfaces, but how the myosin patterning encodes tissue shape is unclear, and elastic models failed to reproduce essential features of experimental cell contraction profiles. The myosin patterning exhibits substantial cell-to-cell fluctuations with pulsatile time-dependence, a striking but unexplained feature of morphogenesis in many organisms. Here, using biophysical modeling we find viscous forces offer the principle resistance to actomyosin-driven apical constriction. In consequence, tissue shape is encoded in the direction-dependent curvature of the myosin patterning which orients an anterior-posterior furrow. Tissue contraction is highly sensitive to cell-to-cell myosin fluctuations, explaining furrowing failure in genetically perturbed embryos whose fluctuations are temporally persistent. In wild-type embryos, this catastrophic outcome is averted by pulsatile myosin time-dependence, a time-averaging effect that rescues furrowing. This low pass filter mechanism may underlie the usage of actomyosin pulsing in diverse morphogenetic processes across many organisms.
Interferon restores replication fork stability and cell viability in BRCA-defective cells via ISG15
Authors: Biswas Uddipta , Moro Ramona N. , Kharat Suhas S. , Das Prosun , Chaudhuri Arnab Ray , Sharan Shyam K. , Penengo Lorenza 
Published: March 2023

AbstractDNA replication and repair defects or genotoxic treatments trigger interferon (IFN)-mediated inflammatory responses. However, whether and how IFN signaling in turn impacts the DNA replication process has remained elusive. Here we show that IFN promotes replication fork stability, cell proliferation and survival in BRCA1/2-defective cancer cells and rescues the lethality of BRCA2-deficient mouse embryonic stem cells. Although IFN activates hundreds of genes, these effects are specifically mediated by the ubiquitin-like modifier ISG15 (IFN-stimulated gene 15). Inactivation of ISG15 or of the enzymes promoting its conjugation, referred as ISGylation, completely suppresses the impact of IFN on the replication process. Depletion of ISG15 significantly reduces cell proliferation rates whereas its upregulation results in increased resistance to the chemotherapeutic drug cisplatin in human BRCA1-mutated triple-negative and mouse BRCA2-deficient breast cancer cells, respectively. Accordingly, cells carrying BRCA1/2 defects consistently show increased ISG15 levels, representing a novel, in-built mechanism of drug resistance linked to BRCAness.
Transcription regulation by CarD in mycobacteria is guided by basal promoter kinetics
Authors: Zhu Dennis X. , Stallings Christina L. 
Published: March 2023

ABSTRACTBacterial pathogens likeMycobacterium tuberculosis(Mtb) employ transcription factors to adapt their physiology to the diverse environments within their host. CarD is a conserved bacterial transcription factor that is essential for viability inMtb. Unlike classical transcription factors that recognize promoters by binding to specific DNA sequence motifs, CarD binds directly to the RNA polymerase (RNAP) to stabilize the open complex intermediate (RPo) during transcription initiation. We previously showed using RNA-sequencing that CarD is capable of both activating and repressing transcriptionin vivo. However, it is unknown how CarD achieves promoter specific regulatory outcomes inMtbdespite binding indiscriminate of DNA sequence. We propose a model where CarD’s regulatory outcome depends on the promoter’s basal RPostability and test this model usingin vitrotranscription from a panel of promoters with varying levels of RPostability. We show that CarD directly activates full-length transcript production from theMtbribosomal RNA promoterrrnAP3 (AP3) and that the degree of transcription activation by CarD is negatively correlated with RPostability. Using targeted mutations in the extended −10 and discriminator region of AP3, we show that CarD directly represses transcription from promoters that form relatively stable RPo. DNA supercoiling also influenced RPostability and affected the direction of CarD regulation, indicating that the outcome of CarD activity can be regulated by factors beyond promoter sequence. Our results provide experimental evidence for how RNAP-binding transcription factors like CarD can exert specific regulatory outcomes based on the kinetic properties of a promoter.
Polygenic pathogen networks control of host and pathogen transcriptional plasticity in the Arabidopsis-Botrytis pathosystem
Authors: Krishnan Parvathy , Caseys Celine , Soltis Nik , Zhang Wei , Burow Meike , Kliebenstein Daniel J. 
Published: March 2023

AbstractBidirectional flow of information shapes the outcome of the host-pathogen interactions and depends on the genetics of each organism. Recent work has begun to use co-transcriptomic studies to shed light on this bidirectional flow, but it is unclear how plastic the co-transcriptome is in response to genetic variation in both the host and pathogen. To study co-transcriptome plasticity, we conducted transcriptomics using natural genetic variation in the pathogen, Botrytis cinerea, and large effect genetic variation abolishing defense signaling pathways within the host, Arabidopsis thaliana. We show that genetic variation in the pathogen has a greater influence on the co-transcriptome than mutations that abolish defense signaling pathways in the host. Genome wide association mapping using the pathogens genetic variation and both organisms’ transcriptomes allowed an assessment of how the pathogen modulates plasticity in response to the host. This showed that the differences in both organism’s responses were linked to trans-eQTL hotspots within the pathogen’s genome. These hotspots control gene sets in either the host or pathogen and show differential allele sensitivity to the hosts genetic variation rather than qualitative host specificity. Interestingly, nearly all the trans-eQTL hotspots were unique to the host or pathogen transcriptomes. In this system of differential plasticity, the pathogen mediates the shift in the co-transcriptome more than the host.
Cell cycle perturbation uncouples mitotic progression and invasive behavior in a post-mitotic cell
Authors: Martinez Michael A. Q. , Zhao Chris Z. , Moore Frances E. Q. , Yee Callista , Zhang Wan , Shen Kang , Martin Benjamin L. , Matus David Q. 
Published: March 2023

ABSTRACTThe acquisition of the post-mitotic state is crucial for the execution of many terminally differentiated cell behaviors during organismal development. However, the mechanisms that maintain the post-mitotic state in this context remain poorly understood. To gain insight into these mechanisms, we used the genetically and visually accessible model ofC. elegansanchor cell (AC) invasion into the vulval epithelium. The AC is a terminally differentiated uterine cell that normally exits the cell cycle and enters a post-mitotic state, initiating contact between the uterus and vulva through a cell invasion event. Here, we set out to identify the set of negative cell cycle regulators that maintain the AC in this post-mitotic, invasive state. Our findings revealed a critical role for CKI-1 (p21CIP1/p27KIP1) in redundantly maintaining the post-mitotic state of the AC, as loss of CKI-1 in combination with other negative cell cycle regulators—including CKI-2 (p21CIP1/p27KIP1), LIN-35 (pRb/p107/p130), FZR-1 (Cdh1/Hct1), and LIN-23 (β-TrCP)—resulted in proliferating ACs. Remarkably, time-lapse imaging revealed that these ACs retain their ability to invade. Upon examination of a node in the gene regulatory network controlling AC invasion, we determined that proliferating, invasive ACs do so by maintaining aspects of pro-invasive gene expression. We therefore report that the requirement for a post-mitotic state for invasive cell behavior can be bypassed following direct cell cycle perturbation.
Perceived timing of postural instability onset
Authors: McIlroy Robert E , Barnett-Cowan Michael 
Published: March 2023

AbstractBackgroundThis study examines the perceived timing of postural instability onset, a crucial aspect of balance. Previous research using Temporal Order Judgment (TOJ) tasks found that postural perturbations need to occur significantly earlier than an auditory reference stimulus for individuals to perceive them as simultaneous. However, there are methodological concerns with this prior work, specifically regarding an unbalanced stimulus onset asynchrony (SOA) distribution.Research questionDoes the point of subjective simultaneity (PSS) between postural perturbation onset and an auditory reference stimulus differ for equal versus unequal SOA distributions?MethodsA repeated measures design was utilized, presenting two different SOA distributions to 10 participants using a TOJ task during both the equal (72 trials) and unequal (88 trials) SOA distributions. Paired t-tests were used to determine if there was a significant difference between the PSS of the equal and unequal SOA distributions. Additionally, one-sample t-tests were performed on the PSS values of both the equal and unequal SOA distributions in comparison to 0ms (defined as true simultaneity) to determine if perceptual responses were delayed.ResultsThe results indicate that the unequal SOA distribution resulted in a perceived delay of postural instability onset by 20.34ms, while the equal SOA distribution resulted in a perceived delay of the auditory stimulus of 3.52ms. However, neither condition was significantly different from each other nor from true simultaneity.SignificanceThese findings suggest that the perception of postural instability onset is not slow, as previously thought, and highlight the importance of controlling methodological parameters when investigating sensory cues. This knowledge highlights the importance of controlling methodological parameters when investigating the perception of sensory cues and will help inform falls prevention strategies.
Retinotopic connectivity maps of human visual cortex with unconstrained eye movements
Authors: Tangtartharakul Gene T. , Morgan Catherine A. , Rushton Simon K. , Schwarzkopf D. Samuel 
Published: March 2023

AbstractHuman visual cortex contains topographic visual field maps whose organization can be revealed with retinotopic mapping. Unfortunately, constraints posed by standard mapping hinders its use in patients, atypical subject groups, and individuals at either end of the lifespan. This severely limits the conclusions we can draw about visual processing in such individuals. Here we present a novel data-driven method to estimate connective fields, fine-grained maps of the functional connectivity between brain areas. We find that inhibitory connectivity fields accompany, and often surround, facilitatory fields. The visual field extent of these inhibitory subfields falls off with cortical magnification. We further show that our method is robust to large eye movements and myopic defocus. Importantly, freed from the controlled stimulus conditions in standard mapping experiments, using entertaining stimuli and unconstrained eye movements our approach can generate retinotopic maps, including the periphery visual field hitherto only possible to map with special stimulus displays. Generally, our results show that the connective field method can gain knowledge about retinotopic architecture of visual cortex in patients and participants where this is at best difficult and confounded, if not impossible, with current methods.
Polymer brush inspired by ribosomal RNA transcription
Authors: Yamamoto Tetsuya , Li Wei 
Published: March 2023

AbstractPre-ribosomal RNAs are synthesized during the transcription by RNA polymerase I molecules localized at the surfaces of a nucleolus subcompartment. Inspired by the ribosomal RNA transcription, we here develop a scaling theory of a brush of polymers, where monomers are added to their grafted ends in the steady state. Our theory predicts that monomers newly added to the polymers stay at the vicinity of the surface due to the slow dynamics of the polymers and thus the polymer volume fraction increases with increasing the polymerization rate. The excluded volume interaction between polymers and reactant monomers suppresses the diffusion of reactant monomers and thus decreases the polymerization rate. The extent of the suppression of monomer diffusion increases with increasing the polymerization rate because the diffusion length decreases, rather than the condensation of polymers due to their slow dynamics.
Over-eruption in marsupial carnivore teeth: compensation for a constraint
Authors: Jones Menna E. 
Published: March 2023

AbstractPronounced over-eruption of the canine teeth, much greater than in eco-morphologically equivalent placental carnivores, occurs with age and growth in Australian marsupial carnivores. Suppression of functional tooth replacement is a characteristic of marsupials and is frequent among diverse placentals, where the primitive therian pattern is two generations of incisor, canine and premolar teeth. Rapid determinate growth is one among multiple hypotheses proposed to explain the loss of tooth replacement in mammals. In this line of reasoning, the animal reaches a sufficient body or jaw size to accommodate adult-sized teeth by the time it requires functional dentition. Marsupial carnivores have a full set of adult anterior teeth at weaning, which erupt into a juvenile jaw that is 25 to 30 % adult size, compared with well grown in placental carnivores. Indeterminate over-eruption of the canine teeth in marsupial carnivores results in increasing canine height and diameter with increasing body size with age, suggesting this is a compensatory mechanism for the constraint of a single generation of anterior teeth. Patterns of over-eruption in different tooth types of marsupial carnivores are consistent with two non-exclusive mechanisms that operate in other mammals, a response to tooth wear and lack of an occlusal partner.
Biosynthetic Enzyme-guided Disease Correlation Connects Gut Microbial Metabolites Sulfonolipids to Inflammatory Bowel Disease Involving TLR4 Signaling
Authors: Older Ethan A. , Zhang Jian , Ferris Zachary E. , Xue Dan , Zhong Zheng , Mitchell Mary K. , Madden Michael , Wang Yuzhen , Chen Hexin , Nagarkatti Prakash , Nagarkatti Mitzi , Fan Daping , Ellermann Melissa , Li Yong-Xin , Li Jie 
Published: March 2023

AbstractThe trillions of microorganisms inhabiting the human gut are intricately linked to human health. At the species abundance level, correlational studies have connected specific bacterial taxa to various diseases. While the abundances of these bacteria in the gut serve as good indicators for disease progression, understanding the functional metabolites they produce is critical to decipher how these microbes influence human health. Here, we report a unique biosynthetic enzyme-guided disease correlation approach to uncover microbial functional metabolites as potential molecular mechanisms in human health. We directly connect the expression of gut microbial sulfonolipid (SoL) biosynthetic enzymes to inflammatory bowel disease (IBD) in patients, revealing a negative correlation. This correlation is then corroborated by targeted metabolomics, identifying that SoLs abundance is significantly decreased in IBD patient samples. We experimentally validate our analysis in a mouse model of IBD, showing that SoLs production is indeed decreased while inflammatory markers are increased in diseased mice. In support of this connection, we apply bioactive molecular networking to show that SoLs consistently contribute to the immunoregulatory activity of SoL-producing human microbes. We further reveal that sulfobacins A and B, two representative SoLs, primarily target Toll-like receptor 4 (TLR4) to mediate immunomodulatory activity through blocking TLR4’s natural ligand lipopolysaccharide (LPS) binding to myeloid differentiation factor 2, leading to significant suppression of LPS-induced inflammation and macrophage M1 polarization. Together, these results suggest that SoLs mediate a protective effect against IBD through TLR4 signaling and showcase a widely applicable biosynthetic enzyme-guided disease correlation approach to directly link the biosynthesis of gut microbial functional metabolites to human health.
Massively integrated coexpression analysis reveals transcriptional regulation, evolution and cellular implications of the noncanonical translatome
Authors: Rich April , Acar Omer , Carvunis Anne-Ruxandra 
Published: March 2023

AbstractBackgroundRecent studies uncovered pervasive transcription and translation of thousands of noncanonical open reading frames (nORFs) outside of annotated genes. The contribution of nORFs to cellular phenotypes is difficult to infer using conventional approaches because nORFs tend to be short, of recentde novoorigins, and lowly expressed. Here we develop a dedicated coexpression analysis framework that accounts for low expression to investigate the transcriptional regulation, evolution, and potential cellular roles of nORFs inSaccharomyces cerevisiae.ResultsOur results reveal that nORFs tend to be preferentially coexpressed with genes involved in cellular transport or homeostasis but rarely with genes involved in RNA processing. Mechanistically, we discover that youngde novonORFs located downstream of conserved genes tend to leverage their neighbors’ promoters through transcription readthrough, resulting in high coexpression and high expression levels. Transcriptional piggybacking also influences the coexpression profiles of youngde novonORFs located upstream of genes, but to a lesser extent and without detectable impact on expression levels. Transcriptional piggybacking influences, but does not determine, the transcription profiles ofde novonORFs emerging nearby genes. About 40% of nORFs are not strongly coexpressed with any gene but are transcriptionally regulated nonetheless and tend to form entirely new transcription modules. We offer a web browser interface (https://carvunislab.csb.pitt.edu/shiny/coexpression/) to efficiently query, visualize and download our coexpression inferences.ConclusionsOur results suggest that nORF transcription is highly regulated. Our coexpression dataset serves as an unprecedented resource for unraveling how nORFs integrate into cellular networks, contribute to cellular phenotypes, and evolve.