bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dual function of the O-antigen WaaL ligase ofAggregatibacter actinomycetemcomitans
Authors: Danforth David R. , Melloni Marcella , Thorpe Richard , Cohen Avi , Voogt Richard , Tristano Jake , Mintz Keith P. 
Published: November 2022

AbstractProtein glycosylation is critical to the quaternary structure and collagen binding activity of the extracellular matrix protein adhesin A (EmaA) associated withAggregatibacter actinomycetemcomitans. The glycosylation of this large, trimeric autotransporter adhesin is postulated to be mediated by WaaL, an enzyme with the canonical function to ligate the O-polysaccharide (O-PS) antigen with a terminal sugar of the lipid A-core oligosaccharide of lipopolysaccharide (LPS). In this study, we have determined that theEscherichia coli waaLortholog (rflA) does not restore collagen binding of awaaLmutant strain ofA. actinomycetemcomitansbut does restore O-PS ligase activity following transformation of a plasmid expressingwaaL. Therefore, a heterologousE. coliexpression system was developed constituted of two independently replicating plasmids expressing eitherwaaLoremaAofA. actinomycetemcomitansto directly demonstrate the necessity of ligase activity for EmaA collagen binding. Proper expression of the protein encoded by each plasmid was characterized, and the individually transformed strains did not promote collagen binding. However, co-expression of the two plasmids resulted in a strain with a significant increase in collagen binding activity and a change in the biochemical properties of the protein. These results provide additional data supporting the novel hypothesis that the WaaL ligase ofA. actinomycetemcomitansshares a dual role as a ligase in LPS biosynthesis and is required for collagen binding activity of EmaA.ImportanceThe human oral pathogenA. actinomycetemcomitansis a causative agent of periodontal and several systemic diseases. The organism expresses an adhesin, EmaA, important for the colonization of this pathobiont via collagen binding and biofilm formation. EmaA is suggested to be modified with sugars and the modification is mediated using the same enzymes involved in lipopolysaccharide (LPS) biosynthesis. In this study, evidence is presented which suggests that the WaaL ligase, the enzyme that ligates the O-polysaccharide (O-PS) antigen with a terminal sugar of the lipid A-core oligosaccharide of LPS, is required for the collagen binding activity of EmaA. This finding represents a new paradigm for the posttranslational modification of this type of autotransporter protein.
Chromatin loop dynamics during cellular differentiation are associated with changes to both anchor and internal regulatory features
Authors: Bond Marielle L. , Davis Eric S. , Quiroga Ivana Y. , Love Michael I. , Won Hyejung , Phanstiel Douglas H. 
Published: November 2022

ABSTRACT3D chromatin structure has been shown to play a role in regulating gene transcription during biological transitions. While our understanding of loop formation and maintenance is rapidly improving, much less is known about the mechanisms driving changes in looping and the impact of differential looping on gene transcription. One limitation has been a lack of well powered differential looping data sets. To address this, we conducted a deeply sequenced Hi-C time course of megakaryocyte development comprising 4 biological replicates and 6 billion reads per time point. Statistical analysis revealed 1,503 differential loops. Gained loops were enriched for AP-1 occupancy and correlated with increased expression of genes at their anchors. Lost loops were characterized by increases in expression of genes within the loop boundaries. Linear modeling revealed that changes in histone H3 K27 acetylation, chromatin accessibility, and JUN binding in between the loop anchors were as predictive of changes in loop strength as changes to CTCF and/or cohesin occupancy at loop anchors. Finally, we built linear models and found that incorporating the dynamics of enhancer acetylation and loop strength increased accuracy of gene expression predictions.
Computed tomography analysis of vulnerable carotid atherosclerotic plaque and relationship to clinical characteristics
Authors: Giannotti N. , McNulty J.P. , Foley S.J. , Barry M. , Crowe M. , Dolan E. , Harbison J. , Horgan G. , Kavanagh E. , O’Connell M , Marnane M. , Murphy S. , McDonnell C. , O’Donohoe M. , Williams D. , Kelly P.J. 
Published: November 2022

AbstractObjectiveThe presence of atherosclerotic plaque components such as lipid rich necrotic core and intraplaque haemorrhage is associated with increased plaque vulnerability, and may be used to stratify the risk of future cerebrovascular events. Our aim was to investigate the relationship between selected carotid plaque components imaged with CTA, patient characteristics, and clinical outcomes.MethodsSymptomatic patients underwent carotid CTA as part of the BIOVASC study. Images were analysed for plaque volume composition with a semi-automatic Hounsfield Unit (HU)-based algorithm. Plaque components were classified based on their attenuation values: lipids <61 HU, fibrous tissue 61-129 HU and calcium >131 HU. Parametric and non-parametric tests were performed to compare plaque measurements to clinical characteristics and outcomes.ResultsOne-hundred and two symptomatic carotids were analysed (avg. age 69y, 54.9% Male, 29.4% severe stenosis). Mean plaque volume was 480±230 mm3, and the mean LRNC volume was 170±100 mm3. A difference in LRNC volume was identified between moderate and severe stenosis (190–150 mm3, p=0.012). Regression analysis showed that age and gender may predict increased plaque volume (p<0.001). A trend for reduced mean plaque LRNC was identified in patients receiving statins (130-210 mm3, p=0.08). Intra-reader reliability showed good agreement (0.62-0.78, p<0.001) between CTA plaque measurements.ConclusionsIn-vivo CTA plaque volume composition assessment is feasible with good intra-reader reliability. Our findings suggest that CTA-HU measurements may be used to provide improved mechanistic and diagnostic insights into atherosclerotic disease, and facilitate the quantification of selected plaque components whose presence may be associated with increased plaque vulnerability.Key PointsPlaque CTA Hounsfield Unit (HU) measurement and segmentation techniques can provide improved mechanistic and diagnostic insights into atherosclerotic disease.Plaque components characterisation using CTA HU measurements may help clinicians to identify patients presenting with high-risk vulnerable plaque.CTA plaque volume composition assessment is feasible with good reliability observed between measurements taken at different time-points.
DNA-PKcs is required for cGAS/STING-dependent viral DNA sensing in human cells
Authors: Hristova Dayana , Oliveira Marisa , Wagner Emma , Melcher Alan , Harrington Kevin , Belot Alexandre , Ferguson Brian J 
Published: November 2022

AbstractTo mount an efficient interferon response to virus infection, intracellular pattern recognition receptors (PRRs) sense viral nucleic acids and activate anti-viral gene transcription. The mechanisms by which intracellular DNA and DNA viruses are sensed are relevant not only to antiviral innate immunity, but also to autoinflammation and anti-tumour immunity through initiation of sterile inflammation by self-DNA recognition. The PRRs that directly sense and respond to viral or damaged self-DNA function by signalling to activate interferon regulatory factor (IRF)-dependent type one interferon (IFN-I) transcription. We and others have previously defined DNA-dependent protein kinase (DNA-PK) as an essential component of the DNA-dependent antiviral innate immune system. Here, we show that DNA-PK is essential for STING-dependent IFN-I responses in human cells during stimulation with exogenous DNA and infection with DNA viruses.
The effect of lysergic acid diethylamide (LSD) on whole-brain functional and effective connectivity
Authors: Bedford Peter , Hauke Daniel J. , Wang Zheng , Roth Volker , Nagy-Huber Monika , Holze Friederike , Ley Laura , Vizeli Patrick , Liechti Matthias E. , Borgwardt Stefan , Müller Felix , Diaconescu Andreea O. 
Published: November 2022

AbstractPsychedelics have emerged as promising candidate treatments for various psychiatric conditions, and given their clinical potential, there is a need to identify biomarkers that underlie their effects. Here, we investigate the neural mechanisms of lysergic acid diethylamide (LSD) using regression dynamic causal modelling (rDCM), a novel technique that assesses whole-brain effective connectivity (EC) during resting-state functional magnetic resonance imaging (fMRI). We modelled data from two randomized, placebo-controlled, double-blind, cross-over trials, in which 45 participants were administered 100μg LSD and placebo in two resting-state fMRI sessions. We compared EC against whole-brain functional connectivity (FC) using classical statistics and machine learning methods. Multivariate analyses of EC parameters revealed widespread increases in interregional connectivity and reduced self-inhibition under LSD compared to placebo, with the notable exception of primarily decreased interregional connectivity and increased self-inhibition in occipital brain regions. This finding suggests that LSD perturbs the Excitation/Inhibition balance of the brain. Moreover, random forests classified LSD vs. placebo states based on FC and EC with comparably high accuracy (FC: 85.56%, EC: 91.11%) suggesting that both EC and FC are promising candidates for clinically-relevant biomarkers of LSD effects.
Ketamine induces multiple individually distinct whole-brain functional connectivity signatures
Authors: Moujaes Flora , Ji Jie Lisa , Rahmati Masih , Burt Joshua , Schleifer Charles H. , Adkinson Brendan , Savič Aleksandar , Santamauro Nicole , Tamayo Zailyn , Diehl Caroline , Kolobaric Antonija , Flynn Morgan , Rieser Nathalie M. , Fonteneau Clara , Camarro Terry , Xu Junqian , Cho Youngsun T. , Repovš Grega , Fineberg Sarah K. , Morgan Peter , Seifritz Erich , Vollenweider Franz X. , Krystal John , Murray John D. , Preller Katrin H. , Anticevic Alan 
Published: November 2022

BackgroundKetamine has emerged as one of the most promising therapies for treatment-resistant depression. However, inter-individual variability in response to ketamine is still not well understood and it is unclear how ketamine’s molecular mechanisms connect to its neural and behavioral effects.MethodsWe conducted a double-blind placebo-controlled study in which 40 healthy participants received acute ketamine (initial bolus 0.23 mg/kg, continuous infusion 0.58 mg/kg/hour). We quantified resting-state functional connectivity via data-driven global brain connectivity, related it to individual ketamine-induced symptom variation, and compared it to cortical gene expression targets.ResultsWe found that: i) both the neural and behavioral effects of acute ketamine are multi-dimensional, reflecting robust inter-individual variability; ii) ketamine’s data-driven principal neural gradient effect matched somatostatin (SST) and parvalbumin (PVALB) cortical gene expression patterns in humans, implicating the role of SST and PVALB interneurons in ketamine’s acute effects; and iii) behavioral data-driven individual symptom variation mapped onto distinct neural gradients of ketamine, which were resolvable at the single-subject level.ConclusionsCollectively, these findings support the possibility for developing individually precise pharmacological biomarkers for treatment selection in psychiatry.FundingThis study was supported by NIH grants DP5OD012109-01 (A.A.), 1U01MH121766 (A.A.), R01MH112746 (J.D.M.), 5R01MH112189 (A.A.), 5R01MH108590 (A.A.), NIAAA grant 2P50AA012870-11 (A.A.); NSF NeuroNex grant 2015276 (J.D.M.); Brain and Behavior Research Foundation Young Investigator Award (A.A.); SFARI Pilot Award (J.D.M., A.A.); Heffter Research Institute (Grant No. 1–190420); Swiss Neuromatrix Foundation (Grant No. 2016–0111m Grant No. 2015 – 010); Swiss National Science Foundation under the frame-work of Neuron Cofund (Grant No. 01EW1908), Usona Institute (2015 – 2056).
ERK-dependent DICER1 phosphorylation promotes open chromatin state and lineage plasticity to mediate tumor progression
Authors: Reyes-Castro Raisa A. , Chen Shin-Yu , Seemann Jacob , Arur Swathi 
Published: November 2022

AbstractDICER1 controls micro(mi)RNA-mediated epithelial-to-mesenchymal transition (EMT) to regulate tumorigenesis of lung adenocarcinomas (LUADs). We discovered that DICER1 is phosphorylated by ERK and nuclear translocated and phospho-DICER1 contributes to tumorigenesis. Mechanisms through which phospho-DICER1 regulates tumor progression remain undefined. We show that phospho-nuclear DICER1 associates with invasive human LUADs with oncogenicKRASmutations and promotes late-stage tumor progression in mice with oncogenicKrasmutations. Surprisingly, phosphomimetic DICER1 regulates LUAD progression independent of miRNAs and EMT. Integrating single-cell RNA sequencing, fluorescentin situRNA hybridization, immunofluorescence, and ATAC-sequencing, in mice, we discovered that phosphomimetic DICER1 generates an open chromatin state in the lung tumor alveolar cells leading to expression of gastrointestinal genes and altered AT2 cell identity. Strikingly, we also observe the gastric gene signature in human LUADs with phospho-DICER1 andKRASmutations. We propose that phosphorylated nuclear DICER1 regulates chromatin remodeling leading to tumor cell reprogramming which drives lung cancer progression.
Transcranial magnetic stimulation to frontal but not occipital cortex disrupts endogenous attention
Authors: Fernández Antonio , Hanning Nina M. , Carrasco Marisa 
Published: November 2022

ABSTRACTCovert endogenous (voluntary) attention improves visual performance. Human neuroimaging studies suggest that the putative human homolog of macaque FEF (FEF+) is critical for this improvement, whereas early visual areas are not. Yet, MRI methods are correlational, as they do not manipulate brain function. Here we investigated whether rFEF+ or V1/V2 play acausalrole in endogenous attention. We used transcranial magnetic stimulation (TMS) to alter activity in visual cortex (Exp.1) or rFEF+ (Exp.2) when observers performed an orientation discrimination task while attention was manipulated. On every trial, they received double-pulse TMS at a predetermined site (stimulated region) around the occipital pole or the rFEF+. Two cortically magnified gratings were presented, one in the stimulated region (contralateral to the stimulated cortical area) and another in the symmetric (ipsilateral) non-stimulated region. Grating contrast was varied to measure contrast response functions (CRFs) for all attention and stimulation combinations. InExp.1, the CRFs were similar at the stimulated and non-stimulated regions, indicating that early visual areas do not modulate endogenous attention during stimulus presentation. In contrast, occipital TMS eliminates exogenous (involuntary) attention effects on performance (1). InExp.2, rFEF+ stimulation decreased the overall attentional effect; neither benefits at the attended location nor cost at the unattended location were significant. This pattern is mimicked in the frequency and directionality of microsaccades: Whereas occipital stimulation did not affect microsaccades, rFEF+ stimulation caused a higher microsaccade rate selectively directed toward the stimulated hemifield. These results providecausalevidence of the role of this frontal region for endogenous attention.SIGNIFICANCE STATEMENTHuman neuroimaging studies have revealed activity in frontal regions (e.g., FEF+) as a neural correlate of endogenous (voluntary) attention, and early visual areas (V1/V2) as neural correlates of both endogenous and exogenous (involuntary) attention. Using a causal manipulation–transcranial magnetic stimulation–we show that briefly disrupting activity in rFEF+ weakens endogenous attention’s benefits at attended and costs at unattended locations. In contrast, V1/V2 stimulation did not alter endogenous attention (although we have previously demonstrated that it eliminates effects of exogenous attention). Correspondingly, whereas stimulation to rFEF+ increased the rate of microsaccades directed toward the stimulated hemifield, occipital stimulation did not. Together, these results providecausalevidence for the role of rFEF+ but not V1/V2 in endogenous attention.
Letrozole delays acquisition of water maze task in female BALB/c mice: possible involvement of anxiety
Authors: Mamczarz Jacek , Lane Malcolm , Merchenthaler Istvan 
Published: November 2022

AbstractLetrozole, an aromatase inhibitor (AI), is used as an adjuvant therapy in estrogen receptor-positive (ER+) breast cancer patients. Similar to other AIs, it induces many side effects, including impaired cognition. Despite its negative effect in humans, results from animal models are inconsistent and suggest that letrozole can either impair or improve cognition. Here we studied effects of letrozole on cognitive behavior of adult female BALB/c mice, a relevant animal model for breast cancer studies. Mice were continuously treated with once-a-day subcutaneous (s.c.) injections of letrozole (0.1 or 0.3 mg/kg/day) or vehicle and subjected to behavioral testing starting on day 21 after treatment initiation. During the treatments, vaginal smears were taken from the mice to evaluate estrous cyclicity. Both doses of letrozole suspended cyclicity and the smears showed that the mice were in constant metestrus. Exposure to letrozole did not significantly affect response to novelty measured as a locomotor activity in open field. However, repeated testing in open field (4 days × 15 min) revealed that letrozole 0.3 mg/kg facilitated locomotor habituation (a form of non-associative learning), significantly reducing locomotor activity on 3rd and 4th day of testing. These findings suggest that certain doses of letrozole may have positive effects on cognitive behavior. Training to find a hidden platform in the Morris water maze (15 days x 4 trials), however, indicated that letrozole 0.1 mg/kg-treated mice had significant learning impairment, as, throughout the training, they swam longer times than vehicle-treated mice to reach the hidden platform. Similarly, in a probe test performed 72 h after the last day of the training, letrozole 0.1 mg/kg-treated mice did not show preference for the training platform zones. These results indicate that cognitive impairments reported by women treated with letrozole can be captured in BALB/c mice treated with clinically relevant doses of the drug. Interestingly, most of the letrozole 0.1 mg/kg-treated mice were able to learn the new platform position in reversal training and performed similar to control mice in a reversal probe test. Results of the reversal test suggest that letrozole did not completely disrupt spatial navigation but rather delayed acquisition of spatial information. The current study shows that letrozole dose dependently modulates behavioral response and that its effects are task dependent.
Enterobacteriaceae isolated from patients share antibiotic resistance conferring plasmids recently acquired from those isolated from sinks in the same treatment room
Authors: Taylor Bradford P , Che You , Passarelli Hemanoel , Smollan Gill , Cohen Carmit , Rapaport Rotem , Tal Ilana , Zade Nani Pinas , Jaber Hanaa , Keller Nati , Hanage William P , Regev-Yochay Gili 
Published: November 2022

AbstractIdentifying how and where pathogens acquire antibiotic resistance is crucial to developing effective strategies to limit its spread. Many bacterial species carry and share plasmids harboring antibiotic resistant genes. Plasmids are mobile genetic elements whose horizontal transmission is difficult to assess through genomic comparison due to assembly issues when using short-read sequencing alone. In this study, we use hybrid assembly to fully assemble plasmids that are shared between different Enterobacteriaceae isolated from patients and sinks in the same hospital rooms. We isolated and sequenced pairs of carbapenem resistantEnterobacter hormaecheisubsp.xiangfangensisandKlebsiella pneumoniaefrom patients and sinks within the same hospital room. The isolate pairs share plasmids that putatively confer antibiotic resistance, including carbapenem resistance. These plasmids differ by few mutations and structural changes, while the isolates carry unique plasmids. Together, this suggests that plasmids can act as vectors of antibiotic resistance spread from sink reservoirs to patients.
Podocyte lineage marker expression is preserved across Wilms tumor subtypes and enhanced in tumors harboring the SIX1/2 p.Q177R mutation
Authors: Stevenson Matthew J. , Phanor Sabrina K. , Patel Urvi , Gisselbrecht Stephen S. , Bulyk Martha L. , O’Brien Lori L. 
Published: November 2022

SUMMARYWilms tumors present as an amalgam of varying proportions of three tissues normally located within the developing kidney, one being the multipotent nephron progenitor population. While incomplete differentiation of the nephron progenitors is widely-considered the underlying cause of tumor formation, where this barrier occurs along the differentiation trajectory and how this might promote therapeutic resistance in high-risk blastemal-predominant tumors is unclear. Comprehensive integrated analysis of genomic datasets from normal human fetal kidney and high-risk Wilms tumors has revealed conserved expression of genes indicative of podocyte lineage differentiation in tumors of all subtypes. Comparatively upregulated expression of several of these markers, including the non-canonical WNT ligandWNT5A, was identified in tumors with the relapse-associated mutation SIX1/2 p.Q177R. These findings highlight the shared progression of cellular differentiation towards the podocyte lineage within Wilms tumors and enhancement of this differentiation program through promotion of non-canonical WNT/planar cell polarity signaling in association with SIX1/2 p.Q177R.
Determinants of white and fatty fish consumption by Croatian and Italian consumers
Authors: Krešić Greta , Dujmić Elena , Lončarić Dina , Zrnčić Snježana , Liović Nikolina , Pleadin Jelka 
Published: November 2022

PurposeThis study aims to investigate the influence of sociodemographic characteristics, perceived risks, health and nutritional motives and taste preference on at-home fish consumption.Design/methodology/approachData were collected from a nationally representative sample of people responsible for food purchasing in households, using the CAWI (computer-aided web interviewing) method. The eligible study sample comprised 977 participants in Croatia and 967 in Italy, who reported fishery products consumption in the previous 12 months. A questionnaire was used to examine sociodemographic characteristics, fish consumption frequency and factors affecting fish consumption. Determinants of white and fatty fish consumption were estimated with ordered probit models, along with marginal effects for each factor in the models.FindingsCommon positive determinants of white and fatty fish consumption in Croatia and Italy were health and nutritional motives (p < 0.001, p = 0.001, p < 0.001, p = 0.010), taste preference (p < 0.001, p < 0.001, p = 0.001, p = 0.001) and maritime nature of the living region. The common negative determinant of white and fatty fish consumption in Croatia and Italy was financial risk (p < 0.001, p < 0.001, p < 0.001, p = 0.005). The country-specific positive determinant in Croatia was the number of household members (p < 0.001), while negative determinants for white and fatty fish were functional risk (p = 0.004, p = 0.013), number of children (p = 0.030, p = 0.001) and female gender (for fatty fish) (p = 0.028). In Italy, older age negatively affected (p < 0.001) fish consumption, while number of children (p = 0.009) and household income positively affected white fish consumption.Originality/valueAn adequate probabilistic model of national representative samples ensures credibility of results. Policy and marketing activities are proposed that can encourage higher fish consumption.