bluuebunny/crossref_metadata_2025_split huggingface dataset:
Excitable dynamics in a molecularly-explicit model of cell motility: Mixed-mode oscillations and beyond
Authors: Plazen Lucie , Khadra Anmar 
Published: October 2022

AbstractMesenchymal cell motility is mainly regulated by two members of the Rho-family of GTPases, called Rac and Rho. The mutual inhibition exerted by these two proteins on each other’s activation and the promotion of Rac activation by an adaptor protein called paxillin have been implicated in driving cellular polarization comprised of front (high active Rac) and back (high active Rho) during cell migration. Mathematical modeling of this regulatory network has previously shown that bistability is responsible for generating a spatiotemporal pattern underscoring cellular polarity called wave-pinning when diffusion is included. We previously developed a 6D reaction-diffusion model of this network to decipher the role of Rac, Rho and paxillin (along with other auxiliary proteins) in generating wave-pinning. In this study, we simplify this model through a series of steps into an excitable 3D ODE model comprised of one fast variable (the scaled concentration of active Rac), one slow variable (the maximum paxillin phosphorylation rate – turned into a variable) and a very slow variable (a recovery rate – also turned into a variable). We then explore, through slow-fast analysis, how excitability is manifested by showing that the model can exhibit relaxation oscillations (ROs) as well as mixed-mode oscillations (MMOs) whose underlying dynamics are consistent with a delayed Hopf bifurcation. By reintroducing diffusion and the scaled concentration of inactive Rac into the model, we obtain a 4D PDE model that generates several unique spatiotemporal patterns that are relevant to cell motility. These patterns are then characterized and their impact on cell motility are explored by employing the cellular potts model (CPM). Our results reveal that wave pinning produces purely very directed motion in CPM, while MMOs allow for meandering and non-motile behaviours to occur. This highlights the role of MMOs as a potential mechanism for mesenchymal cell motility.
Polygenic Effects on the Z Chromosome Underlie Hybrid Incompatibility inPapilioandHeliconiusButterflies
Authors: Xiong Tianzhu , Tarikere Shreeharsha , Rosser Neil , Li Xueyan , Yago Masaya , Mallet James 
Published: October 2022

AbstractThe fitness of animal hybrids follows two empirical rules: hybrids of the heterogametic sex aremore unfit (Haldane’s Rule), and the sex chromosome is disproportionately involved in incompatibility (the large-X/Z effect). Whether these rules result from genetic mechanisms shared across taxa remains unknown, and existing explanations rarely consider female heterogametic taxa such as butterflies. Here, we investigate hybrid incompatibilities inPapilioandHeliconiusbutterflies, and show that defects coincide with unbalanced introgression between the Z chromosome and its genetic background. This polygenic mechanism predicts both rules because introgressed ancestry on the Z chromosome is more skewed in females, and is more variable than on all autosomes. Therefore, the explanation for both rules in butterflies shares little similarity with prevailing theories relying on dominance.
Quorum sensing peptidic inhibitor rescue host immune system eradication: a novel QS infectivity mechanism
Authors: Yehuda Avishag , Malach Einav , Slamti Leyla , Kuo Shanny Shuan , Lau Jonathan Z. , Oh Myung Whan , Adeoye John , Shlezinger Neta , Lau Gee W. , Lereclus Didier , Hayouka Zvi 
Published: October 2022

SummarySubverting the host immune system is a major task for any given pathogen to assure its survival and proliferation. For the opportunistic human pathogenBacillus cereus(Bc), immune evasion enables the establishment of potent infections. In various species of the Bc group, the pleiotropic regulator PlcR and its cognate cell–cell signaling peptide PapR7regulates virulence genes expression in response to fluctuations in population density,i.e., a quorum-sensing (QS) system. However, how QS exerts its effects during infections, and whether PlcR confers the immune evading ability remain unclear. Herein, we report how interception of the QS communication in Bc obliterates the ability to control the host immune system. Here we designed a peptide-based QS inhibitor that suppresses PlcR-dependent virulence factor expression and attenuates Bc infectivity in mouse models. We demonstrate that the QS peptidic inhibitor blocks host immune system-mediated eradication by reducing the expression of PlcR-regulated major toxins. Our findings provide the first evidence that Bc infectivity is regulated by QS circuit mediated destruction of the host immunity, thus reveal a new strategy to limit Bc virulence and enhance host defense. This peptidic quorum-quenching agent constitutes readily accessible chemical tool for studying how other pathogen QS systems modulate host immunity and forms a basis for development of anti-infective therapeutics.
Unified control of temporal and spatial scales of sensorimotor behavior through neuromodulation of short-term synaptic plasticity
Authors: Zhou Shanglin , Buonomano Dean V. 
Published: October 2022

AbstractNeuromodulators such as dopamine have been shown to modulate short-term synaptic plasticity (STP). Here we propose that the neuromodulation of STP provides a general mechanism to scale neural dynamics and motor outputs in time and space. We trained RNNs that incorporated STP to produce complex motor trajectories—handwritten digits—with different temporal (speed) and spatial (size) scales. The learned dynamics underwent temporal and spatial scaling when higher synaptic release probabilities corresponded to higher speed/size. Neuromodulation of STP enhanced temporal or spatial generalization compared to weight modulation alone. The model accounted for the data of two experimental studies involving flexible sensorimotor timing. Our results address a long-standing debate regarding the role of dopamine in timing and predict novel mechanisms by which dopamine may slow down neural dynamics and thus slow “clock” speed.
Adaptation to overflow metabolism by mutations that impair tRNA modification in experimentally evolved bacteria
Authors: Muraski Marc , Nilsson Emil M. , Fritz Melissa J , Richardson Anthony R. , Alexander Rebecca W. , Cooper Vaughn S. 
Published: October 2022

AbstractWhen microbes grow in foreign nutritional environments, selection may enrich mutations in unexpected pathways connecting growth and homeostasis. An evolution experiment designed to identify beneficial mutations inBurkholderia cenocepaciacaptured six independent nonsynonymous substitutions in the essential genetilS, which modifies tRNAIle2by adding a lysine to the anticodon for faithful AUA recognition. Further, five additional mutants acquired mutations in tRNAIle2, which strongly suggests that disrupting the TilS:tRNAIle2interaction was subject to strong positive selection. Mutated TilS incurred greatly reduced enzymatic function but retained capacity for tRNAIle2binding. Yet both mutant sets outcompeted wild-type by decreasing lag phase duration by ∼3.5 hours. We hypothesized that lysine demand could underlie fitness in the experimental conditions. As predicted, supplemental lysine complemented the ancestral fitness deficit, but so did additions of several other amino acids. Mutant fitness advantages were also specific to rapid growth on galactose using oxidative overflow metabolism that generates redox imbalance, not resources favoring more balanced metabolism. Remarkably, 13tilSmutations also evolved in the Long-Term Evolution Experiment withE. coli, including four fixed mutations. These results suggest that TilS or unknown binding partners contribute to improved growth under conditions of rapid sugar oxidation at the predicted expense of translational accuracy.
Defining the roles of pyruvate oxidation, TCA cycle, and mannitol metabolism in methicillin resistanceStaphylococcus aureuscatheter-associated urinary tract infection
Authors: Paudel Santosh , Guedry Sarah , Obernuefemann Chloe LP , Hultgren Scott , Walker Jennifer N , Kulkarni Ritwij 
Published: October 2022

AbstractMethicillin resistantStaphylococcus aureus(MRSA) is an important cause of complicated urinary tract infection (UTI) associated with the use of indwelling urinary catheters. Previous reports have revealed host and pathogen effectors critical for MRSA uropathogenesis. Here, we sought to determine the significance of specific metabolic pathways during MRSA UTI. First, we identified 16 mutants from the Nebraska transposon mutant library in the MRSA JE2 background with significantly reduced growth in pooled human urine (HU). Among these, five genes targeted by transposon mutation also showed significant upregulation upon exposure to HU for 2 h. This prompted us to generate transposon insertion mutants in the uropathogenic MRSA 1369 strain that were defective in TCA cycle (ΔsucD, ΔfumC), mannitol metabolism (ΔmtlD), and pyruvate oxidation and branched chain fatty acid synthesis (ΔlpdA). Compared to the WT, the ΔlpdAmutant showed a significant defect growth in HU and colonization of the urinary tract and dissemination to spleen in the mouse model of catheter-associated UTI (CAUTI), which may be attributed to its increased membrane hydrophobicity and higher susceptibility to killing in blood. MRSA 1369 ΔsucD, ΔfumC, and ΔmtlDmutants were not defective forin vitrogrowth in HU but showed significant fitness defects in the CAUTI mouse model. Overall, identification of novel metabolic pathways important for the urinary fitness and survival of MRSA can be used for the development of novel therapeutics.ImportanceWhileStaphylococcus aureushas historically not been considered a uropathogen,S. aureusurinary tract infection (UTI) is clinically significant in certain patient populations, including those with chronic indwelling urinary catheters. Moreover, mostS. aureusstrains causing catheter-associated UTI (CAUTI) are methicillin-resistantS. aureus(MRSA), which is difficult to treat as it limits treatment options and has the potential to deteriorate into life-threatening bacteremia, urosepsis, and shock. In this study, we found that pathways involved in pyruvate oxidation, TCA cycle, and mannitol metabolism are important for MRSA fitness and survival in the urinary tract. Improved understanding of the metabolic needs of MRSA in the urinary tract may help us develop novel inhibitors of MRSA metabolism that can be used to treat MRSA-CAUTI more effectively.
Incidence and Economic Burden of Retinal Tears in the United States
Authors: Taneja Kamil , Diaz Michael Joseph , Taneja Tanisha , Patel Karan , Batchu Sai , Oak Solomon , Zhang Alex , Joshi Aditya , Patel Urvish K. 
Published: October 2022

AbstractPurposeTo characterize retinal tears (RTs) and calculate the economic burden of RTs that present to the emergency department (ED) in the US.MethodsWe used a large national ED database to retrospectively analyze RTs that presented to the ED from 2006 to 2019. Using extrapolation methods, national estimates of RT incidence, demographics, comorbidities, disposition, inpatient (IP) costs, and ED costs were calculated.ResultsDuring the time period between 2006 and 2019, 15,841 patients presented to the ED with RT as the primary diagnosis. RT incidence was stable at 8.2 per million US population (95% Confidence Interval (CI): 5.3 - 21.0) in this time period. Most patients were males, Caucasian, paid with private insurance, and admitted to EDs in the Northeast. The most common comorbidities were hypertension (19%), a history of cataracts (15%), and diabetes (7.2%).During this time period, RTs costs added up to more than $79 million and $33 million in the ED and IP settings, respectively. Mean per-patient ED and IP costs increased by 145% (p=0.0008) and 86% (p=0.0047), respectively.ConclusionDespite the stable incidence of RTs, RTs place a significant economic burden to the healthcare system, which increases yearly. We recommend physicians and policy makers to work together to pass laws that could prevent the increasing healthcare costs.
Disentangling the role of NAc D1 and D2 cells in hedonic eating
Authors: Guillaumin Mathilde C. C. , Viskaitis Paulius , Bracey Ed , Burdakov Denis , Peleg-Raibstein Daria 
Published: October 2022

AbstractOvereating is driven by both the hedonic component (‘liking’) of food, and the motivation (‘wanting’) to eat it. The nucleus accumbens (NAc) is a key brain center implicated in these processes, but how distinct NAc cell populations encode ‘liking’ and ‘wanting’ to shape overconsumption remains unclear. Here, we probed the roles of NAc D1 and D2 cells in these processes using cell-specific recording and control in diverse behavioral paradigms that disentangle reward traits of ‘liking’ and ‘wanting’ related to food choice and overeating. NAc D2 cells encoded experience-dependent development of ‘liking’, while NAc D1 cells encoded innate ‘liking’ during the first food taste. Optogenetic control confirmed causal links of D1 and D2 cells to these aspects of ‘liking’. In relation to ‘wanting’, D1 and D2 cells encoded and promoted distinct aspects of food approach: D1 cells interpreted food cues while D2 cells also sustained food-visit-length that facilitates consumption. Finally, at the level of food choice, D1, but not D2, cell activity was sufficient to switch food preference, programming subsequent long-lasting overconsumption. By revealing complementary roles of D1 and D2 cells in consumption, these findings assign neural bases to ‘liking’ and ‘wanting’ in a unifying framework of D1 and D2 cell activity.
Increased neuron density in the midbrain of foveate birds results from profound change in tissue morphogenesis
Authors: Rodrigues Tania , Dib Linda , Bréthaut Émilie , Matter Michel M. , Matter-Sadzinski Lidia , Matter Jean-Marc 
Published: October 2022

ABSTRACTThe increase of brain neuron number in relation with brain size is currently considered to be the major evolutionary path to high cognitive power in amniotes. However, how changes in neuron density did contribute to the evolution of the information-processing capacity of the brain remains unanswered. High neuron densities are seen as the main reason why the fovea located at the optical center of the retina is responsible for sharp vision in birds and primates. The emergence of foveal vision is considered as a breakthrough innovation in visual system evolution. We found that neuron densities in the largest visual center of the midbrain – i.e., the optic tectum – are two to four times higher in modern birds with one or two foveae compared to birds deprived of this specialty. Interspecies comparisons enabled us to identify elements of a hitherto unknown developmental process set up by foveate birds for increasing neuron density in the upper layers of their optic tectum. The late progenitor cells that generate these neurons proliferate in a ventricular zone that can expand only radially. In this particular context, the number of cells in ontogenetic columns increases, thereby setting the conditions for higher cell densities in the upper layers once neurons did migrate.Graphical AbstractHighlightsThe presence of a fovea is associated with increased neuron density in the optic tectumFovea number and deepness influence neuron density in the optic tectumIncreased neuron density in the upper layers of the optic tectum requires major developmental changesPostponed cell migration, prolonged cell proliferation, hindered tissue growth are necessary settings for achieving high neuron density
Single-domain antibody delivery using an mRNA platform protects against lethal doses of botulinum neurotoxin A
Authors: Panova Eugenia A. , Kleymenov Denis A. , Shcheblyakov Dmitry V. , Bykonia Evgeniia N. , Mazunina Elena P. , Dzharullaeva Alina S. , Zolotar Anastasia N. , Derkaev Artem A. , Esmagambetov Ilias B. , Sorokin Ivan I. , Usachev Evgeny V. , Ivanov Igor A. , Zatsepin Timofei S , Dmitriev Sergey E. , Gushchin Vladimir A. , Logunov Denis Y. , Gintsburg Alexander L. 
Published: October 2022

ABSTRACTSingle-domain antibodies (sdAbs, VHHs, or nanobodies) are a promising tool for the treatment of both infectious and somatic diseases. Their small size greatly simplifies any genetic engineering manipulations. Such antibodies have the ability to bind hard-to-reach antigenic epitopes through long parts of the variable chains, the third complementarity-determining regions (CDR3s). VHH fusion with the canonical immunoglobulin Fc fragment allows the Fc-fusion single-domain antibodies (VHH-Fc) to significantly increase their neutralizing activity and serum half-life. Previously we have developed and characterized VHH-Fc specific to botulinum neurotoxin A (BoNT/A), that showed a 1000-fold higher protective activity than monomeric form when challenged with five times the lethal dose (5 LD50) of BoNT/A. During the COVID-19 pandemic, mRNA vaccines based on lipid nanoparticles (LNP) as a delivery system have become an important translational technology that has significantly accelerated the clinical introduction of mRNA platforms. We have developed an mRNA platform that provides long-term expression after both intramuscular and intravenous application. The platform has been extensively characterized using firefly luciferase (Fluc) as a reporter. An intramuscular administration of LNP-mRNA encoding VHH-Fc antibody made it possible to achieve its rapid expression in mice and resulted in 100% protection when challenged with up to 100 LD50of BoNT/A. The presented approach for the delivery of sdAbs using mRNA technology greatly simplifies drug development for antibody therapy and can be used for emergency prophylaxis.
Effects of inertia and switching costs on customer retention: a study of budget hotels in China
Authors: Li Zhiyong , Long Mang , Huang Songshan (Sam) , Duan Zhaohan , Hu Yingli , Cui Rui 
Published: October 2022

Purpose
This paper aims to examine the effect of consumer inertia – a tendency to adhere to prior purchase decisions despite the existence of preferable alternatives – on the relationships between switching costs and customer retention, and explain the controversy within them in the context of budget hotels.

Design/methodology/approach
An empirical test was conducted via structural equation modelling based on 337 self-administered questionnaires from customers at six of Chinese popular budget hotels.

Findings
Consumer inertia was a significant mediator between switching costs and customer retention. Specifically, consumer inertia completely mediated the effects of financial switching costs on customer retention, but partially did between procedural switching costs and customer retention. By introducing consumer inertia, the explanatory power of customer retention improved significantly by 19%.

Originality/value
This paper clarifies the effects of multiple dimensions of switching costs on customer retention via the mediating role of consumer inertia and partly addresses the inconsistency in the prior studies from an inertia perspective.
Efficacy of labile carbon addition to reduce fast‐growing, invasive non‐native plants: A review and meta‐analysis
Authors: Ossanna Lia Q. R. , Gornish Elise S. 
Published: October 2022

Abstract

Elevated soil nitrogen (N) resulting from pollution, fertilizer and woody encroachment in grasslands enhances invasion pressures from weedy plant species. Sawdust, sucrose and other labile carbon (C) sources can be used as a soil amendment to combat the growth of fast‐growing, invasive non‐native plants by immobilizing soil N.

Here, we present a systematic review of 83 publications, and a meta‐analysis from 48 publications. Using hierarchical mixed‐effects meta‐analytic models, we synthesized 655 responses from native plants and 486 responses from non‐native weeds to quantify the overall effect of C addition. We explored the possible explanations for variation in effect, such as differences in study conditions and how C was applied.

Carbon addition studies were almost exclusively reported from the United States, Australia and Canada (93%). The majority of papers (63%) did not include any cost information.

Overall, C addition significantly decreased non‐native weed abundance, but did not significantly affect native plant abundance. A C application rate of at least 210 g C m−2 year−1 (5 Mg sucrose ha−1 year−1 or 4.6 Mg sawdust ha−1 year−1) decreased non‐native weed abundance, but a rate of 2110–3000 g C m−2 year−1 (50–71 Mg sucrose ha−1 year−1 or 46–65 Mg sawdust ha−1 year−1) was required to significantly increase native plant abundance. Carbon addition was most effective in the western USA and southeastern Australia, and when used to suppress non‐native grasses (annual or perennial) and annual forbs. Simultaneous seeding of native species prevented an overall decrease in native plant abundance.

Synthesis and application. When there is a nearby and inexpensive source of C available, we recommend C addition with simultaneous seeding of native species to control invasive non‐native grasses and annual forbs in semi‐arid and arid regions of the western USA and southeast Australia. In contrast to other weed control measures, especially herbicide, C addition does not significantly harm native perennial plants. Future studies should implement longer‐term monitoring, establish larger plots and include cost analysis to improve guidance for land managers.
Improving variant prioritization in exome analysis by entropy‐weighted ensemble of multiple tools
Authors: Fan Yanjie , Zhou Ying , Liu Huili , Luo Xiaomei , Xu Ting , Sun Yu , Yang Tingting , Chen Linlin , Gu Xuefan , Yu Yongguo 
Published: October 2022

AbstractVariant prioritization is a crucial step in the analysis of exome and genome sequencing. Multiple phenotype‐driven tools have been developed to automate the variant prioritization process, but the efficacy of these tools in clinical setting with fuzzy phenotypic information and whether ensemble of these tools could outperform single algorithm remains to be assessed. A large rare disease cohort with heterogeneous phenotypic information, including a primary cohort of 1614 patients and a replication cohort of 1904 patients referred to exome sequencing, were recruited to assess the efficacy of variant prioritization and their ensemble. Three freely available tools—Exomiser, Xrare, and DeepPVP—and their ensemble were evaluated. The performance of all three tools was influenced by the attributes of phenotypic input. When combining these three tools by weighted‐sum entropy method (EWE3), the ensemble outperformed any single algorithm, achieving a rate of 78% diagnostic variants in top 3 (13% improvement over current best performer, compared to Exomiser: 63%, Xrare: 65%, and DeepPVP: 51%), 88% in top 10 and 96% in top 30. The results were replicated in another independent cohort. Our study supports using entropy‐weighted ensemble of multiple tools to improve variant prioritization and accelerate molecular diagnosis in exome/genome sequencing.