bluuebunny/crossref_metadata_2025_split huggingface dataset:
The antagonistic transcription factors, EspM and EspN, regulate the ESX-1 secretion system inM. marinum
Authors: Nicholson Kathleen R. , Cronin Rachel M. , Prest Rebecca J. , Menon Aruna R. , Yang Yuwei , Jennisch Madeleine K. , Champion Matthew M. , Tobin David M. , Champion Patricia A. 
Published: January 2024

AbstractBacterial pathogens use protein secretion systems to transport virulence factors and regulate gene expression. Among pathogenic mycobacteria, includingMycobacterium tuberculosisandMycobacterium marinum,ESX-1 (ESAT-6 system 1) secretion is crucial for host interaction. Secretion of protein substrates by the ESX-1 secretion system disrupts phagosomes, allowing mycobacteria cytoplasmic access during macrophage infections. Deletion or mutation of the ESX-1 system attenuates mycobacterial pathogens. Pathogenic mycobacteria respond to the presence or absence of the ESX-1 system in the cytoplasmic membrane by altering transcription. Under laboratory conditions, the EspM repressor and WhiB6 activator control transcription of specific ESX-1-responsive genes, including the ESX-1 substrate genes. However, deleting theespMorwhiB6genes does not phenocopy the deletion of the ESX-1 substrate genes during macrophage infection byM. marinum. In this study, we identified EspN, a critical transcription factor whose activity is masked by the EspM repressor under laboratory conditions. In the absence of EspM, EspN activates transcription ofwhiB6and ESX-1 genes both during laboratory growth and during macrophage infection. EspN is also independently required forM. marinumgrowth within and cytolysis of macrophages, similar to the ESX-1 genes, and for disease burden in a zebrafish larval model of infection. These findings suggest that EspN and EspM coordinate to counterbalance the regulation of the ESX-1 system and support mycobacterial pathogenesis.ImportancePathogenic mycobacteria, which are responsible for tuberculosis and other long-term diseases, use the ESX-1 system to transport proteins that control the host response to infection and promote bacterial survival. In this study, we identify an undescribed transcription factor that controls the expression of ESX-1 genes and is required for both macrophage and animal infection. However, this transcription factor is not the primary regulator of ESX-1 genes under standard laboratory conditions. These findings identify a critical transcription factor that likely controls expression of a major virulence pathway during infection, but whose effect is not detectable with standard laboratory strains and growth conditions.
Mutations in yeast are deleterious on average regardless of the degree of adaptation to the testing environment
Authors: Bao Kevin , Strayer Brant R. , Braker Neil P. , Chan Alexandra A. , Sharp Nathaniel P. 
Published: January 2024

AbstractThe role of spontaneous mutations in evolution depends on the distribution of their effects on fitness. Despite a general consensus that new mutations are deleterious on average, a handful of mutation accumulation experiments in diverse organisms instead suggest that of beneficial and deleterious mutations can have comparable fitness impacts, i.e., the product of their respective rates and effects can be roughly equal. We currently lack a general framework for predicting when such a pattern will occur. One idea is that beneficial mutations will be more evident in genotypes that are not well adapted to the testing environment. We tested this prediction experimentally in the laboratory yeastSaccharomyces cerevisiaeby allowing nine replicate populations to adapt to novel environments with complex sets of stressors. After >1000 asexual generations interspersed with 41 rounds of sexual reproduction, we assessed the mean effect of induced mutations on yeast growth in both the environment to which they had been adapting and the alternative novel environment. The mutations were deleterious on average, with the severity depending on the testing environment. However, we find no evidence that the adaptive match between genotype and environment is predictive of mutational fitness effects.
The landscape of paediatric infectious disease exposure in a rural sub-Saharan Africa setting in Kilifi, Kenya: longitudinal serological analysis over two decades and priorities for future vaccine development
Authors: Foley Deirdre F , Chege Timothy K , Kabagenyi Joyce , McCarthy Karen , Gicheru Elijah T , Kibinge Nelson , Maina Angela W , Waeni Jacqueline M , Clemens Ralf , Clemens Sue-Ann Costa , Tuju James , Sande Charles J 
Published: January 2024

AbstractBackgroundThe paucity of data on the contemporary causes of serious infection among the world’s most vulnerable children means the landscape of emerging paediatric infectious disease remains largely undefined and out of focus on the global vaccine research and development agenda.MethodsWe aimed to partially define the paediatric infectious disease landscape in a typical low-income setting in sub-Saharan Africa in Kilifi, Kenya by simultaneously estimating antibody prevalence for 38 infectious diseases using a longitudinal birth cohort that was sampled between 2002 and 2008 and a paediatric inpatient cohort that was sampled between 2006 and 2017.FindingsAmong the infectious diseases with the highest antibody prevalence in the first year of life were vaccine-preventable diseases such as RSV (57.4%), mumps (31.5%) and influenza H3N2 (37.3%). Antibody prevalence forPlasmodium falciparumshifted substantially over time, from 47% in the mid 2000s to 13% approximately 10 years later corresponding to a documented decline in parasite transmission. A high prevalence of antibodies was also observed in the first year of life for infections for which no licenced vaccines are currently available, including norovirus (34.2%), cytomegalovirus (44.7%), EBV (29.3%) and coxsackie B virus (40.7%). The prevalence to antibodies to vaccine antigens in the local immunisation schedule was generally high but varied by antigen.InterpretationThe data show a high and temporally stable infection burden of RSV, mumps and influenza, providing a compelling evidence base to support progress towards the introduction of these vaccines into the local immunization schedule. The high prevalence of norovirus, EBV, CMV and Coxsackie B provide rationale for increased vaccine research and development investment.FundingThis research was funded by the Wellcome Trust (grant no. WT105882MA).
The contribution of animal antibiotic use to antibiotic resistance in humans: Panel evidence from Denmark
Authors: Emes Eve , Belay Dagim , Knight Gwenan M 
Published: January 2024

AbstractAntibiotic use (ABU) in animals is postulated to be a major contributor to selection of antibiotic resistance (ABR) which subsequently causes infections in human populations. However, there are few quantifications of the size of this association. Denmark, as a country with high levels of pig production and good surveillance data, is an ideal case study for exploring this association.In this paper, we compile a dataset on ABU across several animal species and antibiotic classes, and data on the rate of antibiotic resistance (ABR) in humans across key pathogens, in Denmark over time (2010 - 2020). We run panel data regressions (fixed effects, random effects, first difference and pooled ordinary least squares) to test the association between the level of ABR in human infections and the level of ABU in animals.Between ABR in humans and ABU in animal species, we find a positive relationship for cattle, some evidence of a positive relationship for poultry and companion animals, and a negative relationship for fish, although the latter is likely driven by confounding factors. When lagging ABU by one year, the effect of ABU in cattle and companion animals remained similar, the effect of ABU in poultry fell in size, and ABU in fish was no longer significant, perhaps due to differences in life cycle length among animal species. Additional covariates were explored, including pet populations, agricultural production and GDP per capita (at purchasing power parity), but these results were limited by the statistical power of the dataset. Under all models, animal ABU determined only a minority of the change in human ABR levels in this context with adjusted R2 ranging from 0.19 to 0.44.This paper supports the role of animal ABU in determining human ABR levels but suggests that, despite comprising a large portion of systemwide ABU, it only explains a minority of the variation. This is likely driven in part by data limitations, and could also be due to a persistence of ABR once resistance has emerged, suggesting a significant role for socioeconomic and transmission factors in bringing ABR down to desirable levels.Highlights- We use panel regression to explore the link between animal ABU and human ABR in Denmark- ABU was linked to ABR in cattle, and potentially in poultry and companion animals- However, animal ABU did not appear to be the main determinant of human ABR- This could be due to poor data, or persistence of ABR after reaching a certain level- Animal ABU reductions alone may be insufficient to curb ABR
Unexpected Transmission Dynamics in a University Town: Lessons from COVID-19
Authors: Clancey Erin , Mietchen Matthew S. , McMichael Corrin , Lofgren Eric T. 
Published: January 2024

AbstractInstitutions of higher education faced a number of challenges during the COVID-19 pandemic. Chief among them was whether or not to re-open during the second wave of COVID-19 in the fall of 2020, which was controversial because incidence in young adults was on the rise. The migration of students back to campuses worried many that transmission within student populations would spread into surrounding communities. In light of this, many colleges and universities implemented mitigation strategies, with varied degrees of success. Washington State University (WSU), located in the city of Pullman in Whitman County, WA, is an example of this type of university-community co-location, where the role of students returning to the area for the fall 2020 semester was contentious. Using COVID-19 incidence reported to Whitman County, we retrospectively study the transmission dynamics that occurred between the student and community subpopulations in fall 2020. We develop a two-population ordinary differential equation mechanistic model to infer transmission rates within and across the university student and community subpopulations. We use results from Bayesian parameter estimation to determine if sustained transmission of COVID-19 occurred in Whitman County and the magnitude of cross-transmission from students to community members. We find these results are consistent with estimation of the time-varying reproductive number and conclude that the students returning to WSU-Pullman did not place the surrounding community at disproportionate risk of COVID-19 during fall 2020 when mitigation efforts were in place.
Use of electronic health record data to identify hospital-associatedClostridioides difficileinfections: a validation study
Authors: Ray Michael J. , Lacanilao Kathleen L. , Lazaro Maela Robyne , Strnad Luke C. , Furuno Jon P. , Royster Kelly , McGregor Jessina C. 
Published: January 2024

AbstractBackgroundClinical research focused on the burden and impact ofClostridioides difficileinfection (CDI) often relies upon accurate identification of cases using existing health record data. Use of diagnosis codes alone can lead to misclassification of cases. Our goal was to develop and validate a multi-component algorithm to identify hospital-associated CDI (HA-CDI) cases using electronic health record (EHR) data.MethodsWe performed a validation study using a random sample of adult inpatients at a large academic hospital setting in Portland, Oregon from January 2018 to March 2020. We excluded patients with CDI on admission and those with short lengths of stay (< 4 days). We tested a multi-component algorithm to identify HA-CDI; case patients were required to have received an inpatient course of metronidazole, oral vancomycin, or fidaxomicin and have at least one of the following: a positiveC. difficilelaboratory test or the International Classification of Diseases, Tenth Revision (ICD-10) code for non-recurrent CDI. For a random sample of 80 algorithm-identified HA-CDI cases and 80 non-cases, we performed manual EHR review to identify gold standard of HA-CDI diagnosis. We then calculated overall percent accuracy, sensitivity, specificity, and positive and negative predictive value for the algorithm overall and for the individual components.ResultsOur case definition algorithm identified HA-CDI cases with 94% accuracy (95% Confidence Interval (CI): 88% to 97%). We achieved 100% sensitivity (94% to 100%), 89% specificity (81% to 95%), 88% positive predictive value (78% to 94%), and 100% negative predictive value (95% to 100%). Requiring a positiveC. difficiletest as our gold standard further improved diagnostic performance (97% accuracy [93% to 99%], 93% PPV [85% to 98%]).ConclusionsOur algorithm accurately detected true HA-CDI cases from EHR data in our patient population. A multi-component algorithm performs better than any isolated component. Requiring a positive laboratory test forC. difficilestrengthens diagnostic performance even further. Accurate detection could have important implications for CDI tracking and research.
Novel Mechanisms of Strigolactone-Induced DWARF14 Degradation inArabidopsis thaliana
Authors: Sánchez Martín-Fontecha Elena , Cardinale Francesca , Bürger Marco , Prandi Cristina , Cubas Pilar 
Published: January 2024

AbstractStrigolactones (SLs) are carotenoid-derived compounds that regulate various aspects of plant development, physiological responses and plant interactions with microorganisms. In angiosperms, the SL receptor is the α/β hydrolase D14 that, upon SL binding, undergoes conformational changes, triggers SL-dependent responses and hydrolyses SLs. Arabidopsis SL signalling involves the formation of a complex between SL-bound D14, the E3-ubiquitin ligase SCFMAX2and the transcriptional corepressors SMXL6/7/8 (SMXLs), which become ubiquitinated and degraded by the proteasome. However, the sequence of events that result in SL signalling and the requirement of SL hydrolysis for this process remain unclear. In addition, SL destabilises the D14 receptor. The biological significance of SL-induced D14 degradation is unclear, although it has been proposed to create a negative feedback loop in SL signalling. The current model proposes that D14 degradation occurs after SMXLs ubiquitination and proteolysis, via the same E3-ubiquitin ligase that targets the repressors.In this work we quantitatively studied the degradation dynamics of Arabidopsis D14 in response to SLsin planta. For this, we conducted fluorescence and luminescence assays to monitor D14 stability dynamics upon SL treatments, in transgenic lines expressingD14fused toGREEN FLUORESCENT PROTEIN(GFP) orLUCIFERASE(LUC), in wild-type and SL-signalling mutant backgrounds. Mutant D14 proteins predicted to be non-functional for SL signalling were also examined, and their capability to bind SLsin vitrowas studied using Differential Scanning Fluorimetry (DSF). Finally, we used a non-hydrolysable SL to test the requirements of SL hydrolysis for D14 and SMXL7 degradation. Our research revealed that SL-induced D14 degradation may occur in the absence of SCFMAX2and/or SMXLs by a proteasome-independent mechanism. Additionally, we observed conditions in which the efficiency of SL-induced degradation of D14 is not aligned with that of SMXL7 degradation. Finally, our results indicate that the hydrolysis of SLs is not a prerequisite to trigger either D14 or SMXL7 degradation. These findings suggest the existence of a regulatory mechanism governing D14 degradation more complex than anticipated, and provide novel insights into the dynamics of SL signalling in Arabidopsis.
Genome - nuclear lamina interactions are multivalent and cooperative
Authors: Dauban Lise , Eder Mathias , de Haas Marcel , Franceschini-Santos Vinícius H. , Yañez-Cuna J. Omar , van Schaik Tom , Leemans Christ , Rademaker Koen , Ara Miguel Martinez , Martinovic Moreno , de Wit Elzo , van Steensel Bas 
Published: January 2024

AbstractLamina-associated domains (LADs) are megabase-sized genomic regions that interact with the nuclear lamina (NL). It is not yet understood how their interactions with the NL are encoded in their DNA. Here, we designed an efficient LAD “scrambling” approach, based on transposon-mediated local hopping of loxP recombination sites, to generate series of large deletions and inversions that span LADs and flanking sequences. Mapping of NL interactions in these rearrangements revealed that a single LAD contacts the NL through multiple regions that act cooperatively or redundantly; some have more affinity for the NL than others and can pull neighbouring sequences to the NL. Genes drawn towards the NL showed often, but not always, reduced expression and increased H3K9me3 levels. Furthermore, neighbouring LADs can cooperatively interact with the NL when placed close enough to each other. These results elucidate principles that govern the positioning of megabase-sized genomic regions inside the cell nucleus.HighlightsEfficient generation of LAD rearrangements by transposon hopping ofloxPelements.NL interactions are multivalent, with some subregions being more potent tethers than others.LADs can cooperate to promote their association to the NL.Changes in NL association are often accompanied by changes in gene activity and H3K9me3.
Late consolidation of rRNA structure during co-transcriptional assembly inE. coliby time-resolved DMS footprinting
Authors: Hao Yumeng , Hulscher Ryan M. , Zinshteyn Boris , Woodson Sarah A. 
Published: January 2024

AbstractThe production of new ribosomes requires proper folding of the rRNA and the addition of more than 50 ribosomal proteins. The structures of some assembly intermediates have been determined by cryo-electron microscopy, yet these structures do not provide information on the folding dynamics of the rRNA. To visualize the changes in rRNA structure during ribosome assembly inE. colicells, transcripts were pulse-labeled with 4-thiouridine and the structure of newly made rRNA probed at various times by dimethyl sulfate modification and mutational profiling sequencing (4U-DMS-MaPseq). The in-cell DMS modification patterns revealed that many long-range rRNA tertiary interactions and protein binding sites through the 16S and 23S rRNA remain partially unfolded 1.5 min after transcription. By contrast, the active sites were continually shielded from DMS modification, suggesting that these critical regions are guarded by cellular factors throughout assembly. Later, bases near the peptidyl tRNA site exhibited specific rearrangements consistent with the binding and release of assembly factors. Time-dependent structure-probing in cells suggests that many tertiary interactions throughout the new ribosomal subunits remain mobile or unfolded until the late stages of subunit maturation.
Nonlocal Finite-Depth Circuits for Constructing Symmetry-Protected Topological States and Quantum Cellular Automata
Authors: Stephen David T. , Dua Arpit , Lavasani Ali , Nandkishore Rahul 
Published: January 2024

Whether a given target state can be prepared by starting with a simple product state and acting with a finite-depth quantum circuit is a key question in condensed matter physics and quantum information science. It underpins classifications of topological phases, as well as the understanding of topological quantum codes, and has obvious relevance for device implementations. Traditionally, this question assumes that the quantum circuit is made up of unitary gates that are . Inspired by the advent of noisy intermediate-scale quantum devices, we reconsider this question with k- gates, i.e., gates that act on no more than k degrees of freedom but are not restricted to be geometrically local. First, we construct explicit finite-depth circuits of symmetric k-local gates that create symmetry-protected topological (SPT) states from an initial product state. Our construction applies to SPT states protected by global symmetries or subsystem symmetries but not to those with higher-form symmetries, which we conjecture remain nontrivial. Next, we show how to implement arbitrary translationally invariant quantum cellular automata in any dimension using finite-depth circuits of k-local gates. These results imply that the topological classifications of SPT phases and quantum cellular automata both collapse to a single trivial phase in the presence of k-local interactions. We furthermore argue that SPT phases are fragile to k-local symmetric perturbations. We conclude by discussing the implications for other phases, such as fracton phases, and surveying future directions. Our analysis opens a new experimentally motivated conceptual direction examining the stability of phases and the feasibility of state preparation without the assumption of geometric locality.

Published by the American Physical Society
2024
Monetization of first questions by text mining: how do peer patients respond to online health information in a Q&A forum?
Authors: Shi Dingyu , Zhang Xiaofei , Liu Libo , Hansen Preben , Li Xuguang 
Published: January 2024

PurposeOnline health question-and-answer (Q&A) forums have developed a new business model whereby listeners (peer patients) can pay to read health information derived from consultations between askers (focal patients) and answerers (physicians). However, research exploring the mechanism behind peer patients' purchase decisions and the specific nature of the information driving these decisions has remained limited. This study aims to develop a theoretical model for understanding how peer patients make such decisions based on limited information, i.e. the first question displayed in each focal patient-physician interaction record, considering argument quality (interrogative form and information details) and source credibility (patient experience of focal patients), including the contingent role of urgency.Design/methodology/approachThe model was tested by text mining 1,960 consultation records from a popular Chinese online health Q&A forum on the Yilu App. These records involved interactions between focal patients and physicians and were purchased by 447,718 peer patients seeking health-related information until this research.FindingsPatient experience embedded in focal patients' questions plays a significant role in inducing peer patients to purchase previous consultation records featuring exchanges between focal patients and physicians; in particular, increasingly detailed information is associated with a reduced probability of making a purchase. When focal patients demonstrate a high level of urgency, the effect of information details is weakened, while the interrogative form is strengthened.Originality/valueThe originality of this study lies in its exploration of the monetization mechanism forming the trilateral relationship between askers (focal patients), answerers (physicians) and listeners (peer patients) in the business model “paying to view others' answers” in the online health Q&A forum and the moderating role of urgency in explaining the mechanism of how first questions influence peer patients' purchasing behavior.