bluuebunny/crossref_metadata_2025_split huggingface dataset:
A neuroepithelial wave of BMP signalling drives anteroposterior specification of the tuberal hypothalamus
Authors: Chinnaiya Kavitha , Burbridge Sarah , Jones Aragorn , Kim Dong Won , Place Elsie , Manning Elizabeth , Groves Ian , Sun Changyu , Towers Matthew , Blackshaw Seth , Placzek Marysia 
Published: September 2022

AbstractThe tuberal hypothalamus houses several major hypothalamic nuclei, dozens of transcriptionally distinct cell types, and clinically relevant cell populations implicated in obesity and related metabolic disorders. Building on recent advances in the field, here we draw upon transcriptional, signalling, and fate mapping analyses of chicken embryos and neuroepithelial explants to analyze tuberal hypothalamic development. We show that a wave of BMP signalling sweeps through early floor plate-like progenitors overlying prospective Rathke’s pouch as they track anteriorly. The timing of BMP signalling correlates with cell fate, with anterior tuberal specification complete by Hamilton-Hamburger (HH) stage 10 but posterior tuberal progenitors requiring BMPs after this point. scRNA-Seq profiling of FGF10-expressing cells, a proxy for cells with active BMP signalling, through HH8-21 reveals transcriptional differences that may underlie their differing response to BMPs, and the switch from neuroepithelial progenitors to stem-like radial glial cells. This study provides an integrated account of the development of the tuberal hypothalamus.
Planarian dorsoventral Netrins control a muscle midline signaling center and regulate blastema formation
Authors: Schad Erik G. , Petersen Christian P. 
Published: September 2022

AbstractIntegration of positional information across body axes is likely critical for whole-body regeneration to define the territories of missing tissue in three dimensions with fidelity. The body-wall musculature in planarians expresses patterning factors regulating the anteroposterior, dorsoventral, and mediolateral axes, but how this information coordinates is not fully understood. We identify a previously described factor specifically expressed in dorsal midline muscle as a BMP/Activin decoy receptorbambi-2. Analysis of scRNAseq indicatesbambi-2+cells coexpress midline-specifying transcription factorpitxand longitudinal muscle-specifying factormyoD, and production ofbambi-2+cells requires these factors. In laterally amputated animals regenerating an entirely new midline,bambi-2+cells are initially formed at the wound site, then dynamically spread, and ultimately reset to restore bilateral symmetry. We further identify a system of dorsoventral Netrin and Netrin receptor signals expressed from body-wall muscle that control midline identity and blastema morphology. Ventral and laterally expressednetrins -1, -4,and-5signal via dorsally-enriched netrin repulsion receptorsunc5-C, unc5-E,anddcc-2, which together limit mediolateral spread ofbambi-2+dorsal midline muscle and influence the architecture of the muscle system. Our results suggest a model in which ventral determinants dictate mediolateral information important for blastema morphology.
Enhancers display constrained sequence flexibility and context-specific modulation of motif function
Authors: Reiter Franziska , de Almeida Bernardo P. , Stark Alexander 
Published: September 2022

AbstractThe information about when and where each gene is to be expressed is mainly encoded in the DNA sequence of enhancers, sequence elements that comprise binding sites (motifs) for different transcription factors (TFs). Most of the research on enhancer sequences has been focused on TF motif presence, while the enhancer syntax, i.e. the flexibility of important motif positions and how the sequence context modulates the activity of TF motifs, remain poorly understood. Here, we explore the rules of enhancer syntax by a two-pronged approach inDrosophila melanogasterS2 cells: we (1) replace important motifs by an exhaustive set of all possible 65,536 eight-nucleotide-long random sequences and (2) paste eight important TF motif types into 763 positions within 496 enhancers. These complementary strategies reveal that enhancers display constrained sequence flexibility and the context-specific modulation of motif function. Important motifs can be functionally replaced by hundreds of sequences constituting several distinct motif types, but only a fraction of all possible sequences and motif types restore enhancer activity. Moreover, TF motifs contribute with different intrinsic strengths that are strongly modulated by the enhancer sequence context (the flanking sequence, presence and diversity of other motif types, and distance between motifs), such that not all motif types can work in all positions. The context-specific modulation of motif function is also a hallmark of human enhancers and TF motifs, as we demonstrate experimentally. Overall, these two general principles of enhancer sequences are important to understand and predict enhancer function during development, evolution and in disease.
The rate of inversion fixation in plant genomes is highly variable
Authors: Hirabayashi Kaede , Owens Gregory L. 
Published: September 2022

AbstractChromosomal inversions are theorized to play an important role in adaptation by preventing recombination, but testing this hypothesis requires an understanding of the rate of inversion fixation. Here we use chromosome-level whole genome assemblies for 32 genera of plants to ask how fast inversions accumulate and what factors affect this rate. We find that on average species accumulate 4 to 28 inversions per million generations, but this rate is highly variable, and we find no correlation between sequence divergence or repeat content and the number of inversions and only a small correlation with chromosome size. We also find that inversion regions are depleted for genes and enriched for TEs compared to the genomic background. This suggests that idiosyncratic forces, like natural selection and demography, are controlling how fast inversions fix.
Conformational dynamics and putative substrate extrusion pathways of the N-glycosylated outer membrane factor CmeC from Campylobacter jejuni
Authors: Newman Kahlan E. , Khalid Syma 
Published: September 2022

AbstractThe outer membrane factor CmeC of the efflux machinery CmeABC plays an important role in conferring antibiotic and bile resistance to Campylobacter jejuni. Curiously, the protein is N-glycosylated, with the glycans playing a key role in the effective function of this system. In this work we have employed atomistic equilibrium molecular dynamics simulations of CmeC in a representative model of the C. jejuni outer membrane to characterise the dynamics of the protein and its associated glycans. We show that the glycans are more conformationally labile than had previously been thought. The extracellular loops of CmeC visit the open and closed states freely suggesting the absence of a gating mechanism on this side, while the narrow periplasmic entrance remains tightly closed, regulated via coordination to solvated cations. We identify several cation binding sites on the interior surface of the protein. Additionally, we used steered molecular dynamics simulations to elucidate translocation pathways for a bile acid and a macrolide antibiotic. These, and additional equilibrium simulations suggest that the anionic bile acid utilises multivalent cations to climb the ladder of acidic residues that line the interior surface of the protein.
In situ imaging across ecosystems to resolve the fine-scale oceanographic drivers of a globally significant planktonic grazer
Authors: Greer Adam T. , Schmid Moritz S. , Duffy Patrick I. , Robinson Kelly L. , Genung Mark A. , Luo Jessica Y. , Panaïotis Thelma , Briseño-Avena Christian , Frischer Marc E. , Sponaugle Su , Cowen Robert K. 
Published: September 2022

AbstractDoliolids are common gelatinous grazers in marine ecosystems around the world and likely influence carbon cycling due to their large population sizes with high growth and excretion rates. Aggregations or blooms of these organisms occur frequently, but they are difficult to measure or predict because doliolids are fragile, under sampled with conventional plankton nets, and can aggregate on fine spatial scales (1-10 m). Moreover, ecological studies typically target a single region or site that does not encompass the range of possible habitats favoring doliolid proliferation. To address these limitations, we combined in situ imaging data from six coastal ecosystems, including the Oregon shelf, northern California, southern California Bight, northern Gulf of Mexico, Straits of Florida, and Mediterranean Sea, to resolve and compare doliolid habitat associations during warm months when environmental gradients are strong and doliolid blooms are frequently documented. Higher ocean temperature was the strongest predictor of elevated doliolid abundances across ecosystems, with additional variance explained by chlorophyll-afluorescence and dissolved oxygen. For marginal seas with a wide range of productivity regimes, the nurse stage tended to comprise a higher proportion of the doliolids when total abundance was low. However, this pattern did not hold in ecosystems with persistent coastal upwelling. The doliolids tended to be most aggregated in oligotrophic systems (Mediterranean and southern California), suggesting that microhabitats within the water column favor proliferation on fine spatial scales. Similar comparative approaches can resolve the realized niche of fast-reproducing marine animals, thus improving predictions for population-level responses to changing oceanographic conditions.
Structural basis of nirmatrelvir and ensitrelvir resistance profiles against SARS-CoV-2 Main Protease naturally occurring polymorphisms
Authors: Noske Gabriela Dias , de Souza Silva Ellen , de Godoy Mariana Ortiz , Dolci Isabela , Fernandes Rafaela Sachetto , Guido Rafael Victório Carvalho , Sjö Peter , Oliva Glaucius , Godoy Andre Schutzer 
Published: September 2022

AbstractSARS-CoV-2 is the causative agent of COVID-19. Mpro is the main viral protease, with a critical role in replication and, therefore, an attractive target for antiviral drug discovery. The clinically approved drug nirmatrelvir from Pfizer, and the clinical candidate ensitrelvir from Shionogi Pharmaceuticals had so far showed great potential for treatment of viral infections. Despite the importance of new therapeutics, the broad use of antivirals is often associated with mutation selection and resistance generation. Herein, we characterized 14 naturally occurring polymorphisms that are already in circulation and are within the radius of action of these two antivirals. Nirmatrelvir retained most of its in vitro activity against most polymorphism tested, while mutants G143S and Q189K were associated with higher resistance. For ensitrelvir, higher resistance was observed for polymorphisms M49I, G143S and R188S, but not for Q189K, suggesting a distinct resistance profile difference between the two inhibitors. The crystal structures of selected polymorphism reveal the structural basis for resistance generation. Our data will assist the monitoring of potential resistant strains, support the design of combined therapy to avoid resistance, as well as assist the development of a next generation of Mpro inhibitors
Assessing biological network dynamics: Comparing numerical simulations with analytical decomposition of parameter space
Authors: Hari Kishore , Duncan William , Ibrahim Mohammed Adil , Jolly Mohit Kumar , Cummins Breschine , Gedeon Tomas 
Published: September 2022

AbstractMathematical modeling of the emergent dynamics of gene regulatory networks (GRN) faces a double challenge of (a) dependence of model dynamics on parameters, and (b) lack of reliable experimentally determined parameters. In this paper we compare two complementary approaches for describing GRN dynamics across unknown parameters: (1) parameter sampling and resulting ensemble statistics used by RACIPE (RAndom CIrcuit PErturbation), and (2) use of rigorous analysis of combinatorial approximation of the ODE models by DSGRN (Dynamic Signatures Generated by Regulatory Networks). We find a very good agreement between RACIPE simulation and DSGRN predictions for four different 2- and 3-node networks typically observed in cellular decision making. This observation is remarkable since the DSGRN approach assumes that the Hill coefficients of the models are very high while RACIPE assumes the values in the range 1-6. Thus DSGRN parameter domains, explicitly defined by inequalities between systems parameters, are highly predictive of ODE model dynamics within a biologically reasonable range of parameters.
Phenotypic Assessment of Clinical Escherichia coli Isolates Predicts Uropathogenic Potential
Authors: Shea A.E. , Frick-Cheng A.E. , Smith S.N. , Mobley H.L.T. 
Published: September 2022

AbstractFor women in the United States, urinary tract infections (UTI) are the most frequent diagnosis in emergency departments, comprising 21.3% of total visits. Uropathogenic Escherichia coli (UPEC) causes ∼80% of uncomplicated UTI. To combat this public health issue, it is vital to characterize UPEC strains as well as differentiate them from commensal strains to reduce the overuse of antibiotics. Surprisingly, no genetic signature has been identified which clearly separates UPEC from other E. coli. Therefore, we examined whether phenotypic data could be predictive of uropathogenic potential. We screened 13 clinical strains of UPEC, isolated from cases of uncomplicated UTI in young otherwise healthy women, in a series of microbiological phenotypic assays using UPEC prototype strain CFT073 and non-pathogenic E. coli strain MG1655 K12 as controls. Phenotypes included adherence, iron acquisition, biofilm formation, human serum resistance, motility, and stress resistance. These data were able to predict the severity of bacterial burden in both the urine and bladders using a well-established experimental mouse model of UTI. Multiple linear regression using three different phenotypic assays, growth in minimal medium, siderophore production, and type 1 fimbrial expression, was predictive of bladder colonization (adjusted r2=0.6411). Growth in ex vivo human urine, hemagglutination of red blood cells, and motility modeled urine colonization (adjusted r2=0.4821). These results showcase the utility of phenotypic characterization to predict the severity of infection these strains may cause. We predict that these methods will also be applicable to other complex, genetically redundant, pathogens.ImportanceUrinary tract infections are the second leading infectious disease worldwide, occurring in over half of the female population during their lifetime. Most infections are caused by uropathogenic Escherichia coli (UPEC). These strains can commensally colonize the gut, but upon introduction to the urinary tract, can infect the host and cause disease. Clinically, it would be beneficial to screen patient E. coli strains to understand their pathogenic potential, which may lead to the administration of prophylactic antibiotic treatment for those with increased risk. Others have proposed the use of PCR-based genetic screening methods to detect UPEC and differentiate them from other E. coli pathotypes; however, this method has not yielded a consistent uropathogenic signature. Here, we have used phenotypic characteristics such as growth rate, siderophore production, and expression of fimbriae to successfully predict uropathogenic potential.
Oculomotor and neural correlates of semantic and morphological priming in natural sentence reading
Authors: Marjanovič Katarina , Vidal Yamil , Crepaldi Davide 
Published: September 2022

AbstractOur current understanding of visual word identification is difficult to extend to text reading–both experiments and theories focus primarily, if not exclusively, on out–of–context individual words. Here, we try to fill this gap by studying cross–word semantic and morphological priming within sentences in natural reading, in a novel coregistration paradigm with simultaneous recording of eye movements and electroencephalography. We report results from both eye tracking measures, and, more importantly, from Fixation-Related potentials, time-locked to the fixation onset on the target word. In both, semantic facilitation clearly emerged, while we observed no effect of morphological priming. These results may indicate that morphological agreement is at least partially computed outside of the lexical-semantic system which gives rise to semantic priming. These results provide new insight into the neural correlates of semantic and morphological priming in natural reading, revealing lexical dynamics as they likely emerge in our everyday reading experience.
Preschool-located influenza vaccination and influenza-like illness surveillance: an Italian pilot experience
Authors: Amendola Antonella , Barcellini Lucia , Borghi Elisa , Bianchi Silvia , Garancini Nicolò , Nava Chiara , Mari Alessandra , Sala Anna , Fappani Clara , Gori Maria , Ottaviano Emerenziana , Colzani Daniela , Biganzoli Elia Mario , Tanzi Elisabetta , Zuccotti Gianvincenzo 
Published: September 2022

AbstractImproving influenza vaccination coverage in young children is crucial in reducing the spreading of influenza viruses, thus indirectly protecting the general population. Mass campaign needs to engage all the communities within the target population, overcoming socio-economic and cultural barriers. School-located interventions in some countries were successful in increasing vaccine acceptability and overall immunisation rates.Influenza-like illnesses (ILI) share several symptoms with the ongoing COVID-19 pandemic, posing an important challenge for both diagnostics and public health burden. Self-sampling using non-invasive saliva collection could represent a suitable tool for respiratory infection surveillance.This pilot study was carried out in a very densely populated Italian area, Milan, characterised by a high percentage of non-Italian citizens, often hard-to-reach by preventive programmes. We started a vaccine campaign with live-attenuated influenza vaccine (LAIV), recently recommended in Italy for children aged 2-6, coupled with a saliva-based ILI surveillance system in preschools.We enrolled 432 children from 5 schools in the Milan suburbs, 31.2% of which received the LAIV. Thanks to the undertaken multicultural approach, 59% of the vaccinated children were non-Italian citizens.Despite the COVID-19 preventive measures, i.e., school closure upon positive cases, highly affected the programmed surveillance, all the saliva samples from ILI cases, self-collected by parents at home, resulted adequate for viral molecular testing.With correction measures, this pilot experience could be broadened to a large population, simultaneously allowing for a widespread ILI surveillance and flu immunisation.
Evaluating prospective study registration and result reporting of trials conducted in Canada from 2009-2019
Authors: Alayche Mohsen , Cobey Kelly D. , Ng Jeremy Y. , Ardern Clare L. , Khan Karim M. , Chan An-Wen , Chow Ryan , Masalkhi Mouayad , Ayala Ana Patricia , Ebrahimzadeh Sanam , Ghossein Jason , Alayche Ibrahim , Willis Jessie V. , Moher David 
Published: September 2022

AbstractBackgroundAdherence to study registration and reporting best practices are vital to foster evidence-based medicine. Poor adherence to these standards in clinical trials conducted in Canada would be detrimental to patients, researchers, and the public alike.MethodsAll registered clinical trials on ClinicalTrials.gov conducted in Canada as of 2009 and completed by 2019 were identified. A cross-sectional analysis of those trials assessed prospective registration, subsequent result reporting in the registry, and subsequent publication of study findings. The lead sponsor, phase of study, clinical trial site location, total patient enrollment, number of arms, type of masking, type of allocation, year of completion, and patient demographics were examined as potential effect modifiers to these best practices.ResultsA total of 6,720 trials met the inclusion criteria. From 2009-2019, 59% (n=3,967) of them were registered prospectively and 39% (n=2,642) reported their results in the registry. Of the trials registered between 2009-2014, 55% (n=1,482) were subsequently published in an academic journal. Of the 3,763 trials conducted exclusively in Canada, 3% (n=123) met all 3 criteria of: prospective registration, reporting in the registry, and publishing findings. In contrast, of the remaining 2,957 trials with both Canadian and international sites, 41% (n=1,238) had an overall compliance to these three criteria. Overall, the odds of having adherence to all three practices concurrently in Canadian trials decreases by 95% when compared to international trials (OR = 0.05; 95CI: 0.04 – 0.06).ConclusionCanadian clinical trials substantially lacked adherence to study registration and reporting best practices. Knowledge of this widespread non-compliance should motivate stakeholders in the Canadian clinical trials ecosystem to address and continue to monitor this problem. The data presented provides a baseline against which to compare any improvement in the registration and reporting of clinical trials in Canada.
Porcn is essential for growth and invagination of the mammalian optic cup
Authors: Fuhrmann Sabine , Ramirez Sara , Abouda Mirna Mina , Campbell Clorissa D. 
Published: September 2022

AbstractMicrophthalmia, anophthalmia, and coloboma (MAC) are congenital ocular malformations causing 25% of childhood blindness. The X-linked disorder Focal Dermal Hypoplasia is frequently associated with MAC and results from mutations in Porcn, a membrane bound O-acyl transferase required for palmitoylation of Wnts to activate multiple Wnt-dependent pathways. Wnt/β-catenin signaling is suppressed in the anterior neural plate for initiation of eye formation and is subsequently required during differentiation of the retinal pigment epithelium (RPE). Non-canonical Wnts are critical for early eye formation in frog and zebrafish, however, it is unclear whether this also applies to mammals. We performed ubiquitous conditional inactivation of Porcn in mouse around the eye field stage. In PorcnCKO, optic vesicles (OV) arrest in growth and fail to form an optic cup. Ventral proliferation is significantly decreased in the mutant OV, with a concomitant increase in apoptotic cell death. While pan-ocular transcription factors such as PAX6, SIX3, LHX2, PAX2 are present, indicative of maintenance of OV identity, regional expression of VSX2, MITF, OTX2 and NR2F2 is downregulated. Failure of RPE differentiation in PorcnCKO is consistent with downregulation of the Wnt/β-catenin effector LEF1, starting around 2.5 days after inactivation. This suggests that Porcn inactivation affects signaling later than a potential requirement for Wnts to promote eye field formation. Altogether, our data shows a novel requirement for Porcn in regulating growth and morphogenesis of the OV, likely by controlling proliferation and survival. In FDH patients with ocular manifestations, growth deficiency during early ocular morphogenesis may be the underlying cause for microphthalmia.