bluuebunny/crossref_metadata_2025_split huggingface dataset:
An Evaluation Protocol of ‘Replicability Model’ project for detection and treatment of leprosy and related disability in Chhattisgarh, India
Authors: Darlong Joydeepa , Govindasamy Karthikeyan , Ilozumba Onaedo , Choudhury Sopna , Shrivastva Anjali , Griffiths Frances , Watson Samuel , Sartori Jo , Lilford Richard 
Published: September 2022

AbstractIntroductionPeople affected by leprosy are at increased risk of impairments and deformities from peripheral nerve damage. This mostly occurs if diagnosis and treatment is delayed and contributes to continued transmission within the community. Champa district of Chhattisgarh state in India is an endemic area with the highest national annual case detection and disability rates for leprosy. The Replicability Model is a system strengthening intervention implemented by the Leprosy Mission Trust India in Champa that aims to promote early diagnosis and treatment of leprosy, improve on-going management of the effects of leprosy and improve welfare for the people affected by leprosy. This protocol presents a plan to describe the overall implementation of the Replicability Model and describe the barriers and facilitators encountered in the process. We will also quantify the effect of the program on one of its key aims- early leprosy diagnosis.MethodsWe have two Work Packages (WPs). In WP1, we will conduct a process evaluation. This will include three methods i) observations of replicability model implementation teams’ monthly meetings ii) key informant interviews (n=10) and interviews with stakeholders (n=30) iii) observations of key actors (n=15).Our purpose is to describe the implementation process and identify barriers and facilitators to successful implementation.WP2 will be a quantitative study to track existing and new cases of leprosy using routinely collected data. If the intervention is successful, we expect to see an increase in cases (with a higher proportion detected at an early clinical stage) followed by a decrease in total cases.ConclusionThis study will enable us to improve and disseminate the Replicability Model by identifying factors that promote success. It will also identify its effectiveness in fulfilling one of its aims: reducing the incidence of leprosy by finding and tracking cases at an earlier stage in the disease.
A 1D Model Characterizing the Role of Spatiotemporal Contraction Distributions on Lymph Transport
Authors: Sedaghati Farbod , Dixon J. Brandon , Gleason Rudolph L. 
Published: September 2022

ABSTRACTBackgroundLymphedema is a condition in which the two primary functions of the lymphatic system, immunity and lymph transport, are compromised. Computational models of lymphatic function to characterize lymph transport have proved useful in quantifying changes in lymph transport in health and disease; however, much is unknown regarding the regulation of contractions throughout a lymphatic network. The purpose of this paper is to study the role of pacemaking cells and contractile wave propagation on lymph transport using a 1-D mathematical model.MethodA 1D fluid-solid modeling framework with constitutive relationships were employed to characterize the interaction between the contracting vessel wall and the lymph flow during contractions. The time-space distribution of contraction waves along the length of a three-lymphangion chain, was determined by prescribing the location of pacemaking cells and parameters that govern the contractile wave propagation, with the total contractile response at each location determined as the summation of the local electrical signals.ResultsSpatiotemporal changes in radius and lymphangion ejection fraction from our illustrative simulations mimic well values reported in isolated lymphatics from the wild-type (WT) and Smmhc-CreERT2;Cx45fx/fx knock-out (KO) reported in the literature. The flow rate is 5.43 and 2.45 μL/hr in the WT and the KO (average) models, respectively. The average and the peak WSS in the WT model are 0.08 and 4 dyn/cm2 and −0.03 and 0.87 dyn/cm2 in the KO (average) models, respectively.ConclusionsThe factors that govern the timing of lymphatic contractions remain largely unknown; but these factors likely play a central role in health and disease. This modeling framework captures well lymphatic contractile wave propagations and how it relates to lymph transport and may motivate novel assays and experimental endpoints to evaluate subtle changes in lymphatic pumping function in the development and progression of lymphedema.
DNA methylation at a single cytosine embedded in the W-box cis-element repels binding of WRKY transcription factors through steric hindrance
Authors: Charvin Magali , Halter Thierry , Blanc-Mathieu Romain , Barraud Pierre , Aumont-Nicaise Magali , Parcy François , Navarro Lionel 
Published: September 2022

ABSTRACTPreviously, we showed that the Arabidopsis active demethylase ROS1 prunes DNA methylation at the promoters of a subset of immune-responsive genes to facilitate their transcriptional activation during antibacterial defence (Halter et al., 2021). In particular, ROS1 was shown to demethylate the RLP43 promoter in a region carrying a functional W-box cis-element, thereby ensuring a tight binding of WRKY transcriptional factors (TFs) onto DNA. Here, we first extend these findings by showing that DNA methylation at W-box elements decreases the binding of several Arabidopsis WRKY TFs in vitro. Furthermore, we provide evidence that DNA methylation at a single cytosine located in the W-box of the RLP43 promoter strongly repels DNA binding of an Arabidopsis WRKY TF in vitro. Using structural modelling, we demonstrate that this cytosine interacts through van der Waals contacts with the conserved tyrosine of WRKY DNA binding domains. Significantly, our model predicts steric hindrance when a 5-methyl group is present on this specific cytosine, thereby likely preventing tight binding of WRKY DNA binding domains. Finally, because the WRKY motif and the residues involved in DNA contacts are conserved, we propose that this methylation-dependent WRKY-DNA binding inhibitory mechanism must be widespread across plant species.
The maternal brain is more flexible and responsive at rest: effective connectivity of the parental caregiving network in postpartum mothers
Authors: Orchard Edwina R , Voigt Katharina , Chopra Sidhant , Thapa Tribikram , Ward Phillip GD , Egan Gary F , Jamadar Sharna D 
Published: September 2022

AbstractThe field of neuroscience has largely overlooked the impact of motherhood on brain function outside the context of responses to infant stimuli. Here, we apply spectral dynamic causal modelling (spDCM) to resting-state fMRI data to investigate differences in brain function between a group of 40 first-time mothers at one-year postpartum and 39 age- and education-matched women who have never been pregnant. Using spDCM, we investigate the directionality (top-down vs bottom-up) and valence (inhibition vs excitation) of functional connections between six key brain regions implicated in motherhood: the dorsomedial prefrontal cortex, ventromedial prefrontal cortex, posterior cingulate cortex, parahippocampal gyrus, amygdala, and nucleus accumbens. We show a selective modulation of inhibitory pathways related to differences between (1) mothers and non-mothers, (2) the interactions between group and cognitive performance and (3) group and social cognition, and (4) differences related to maternal caregiving behaviour. Across analyses, we show consistent disinhibition between cognitive and affective regions suggesting more efficient, flexible, and responsive behaviour, subserving cognitive performance, social cognition, and maternal caregiving. Together our results support the interpretation of these key regions as constituting a parental caregiving network. The nucleus accumbens and the parahippocampal gyrus emerging as ‘hub’ regions of this network, highlighting the global importance of the affective limbic network for maternal caregiving, social cognition, and cognitive performance in the postpartum period.
GOLVEN peptides regulate lateral root spacing as part of a negative feedback loop on the establishment of auxin maxima
Authors: Jourquin Joris , Fernandez Ana Ibis , Xu Ke , Šimura Jan , Ljung Karin , Beeckman Tom 
Published: September 2022

AbstractThe initiation of lateral roots in Arabidopsis requires the accumulation of auxin in lateral root founder cells, yielding a local auxin maximum. The positioning of these auxin maxima along the primary root determines the density and spacing of lateral roots. The GOLVEN6 (GLV6) and GLV10 signaling peptides and their receptors have been established as regulators of lateral root spacing via an inhibitory effect on lateral root initiation. However, it remained unclear how these GLV peptides interfere with auxin signaling or homeostasis. Here we show that GLV6/10 signaling regulates the expression of a subset of auxin response genes during lateral root initiation, downstream of the canonical auxin signaling pathway, while simultaneously inhibiting the establishment of auxin maxima in xylem-pole pericycle cells. We present genetic evidence that this inhibitory effect relies on the activity of the PIN3 and PIN7 auxin export proteins. Furthermore, GLV6/10 peptide signaling was found to enhance PIN7 abundance in the plasma membrane of xylem-pole pericycle cells, which likely stimulates auxin efflux from these cells. Based on these findings, we propose a model in which the GLV6/10 signaling pathway serves as a negative feedback loop that contributes to the robust patterning of auxin maxima along the primary root.
Impact of vancomycin loading doses and dose escalation on glomerular function and kidney injury biomarkers in a translational rat model
Authors: Chang Jack , Pais Gwendolyn M. , Engel Patti L. , Klimek Patryk , Marianski Sylwia , Valdez Kimberly , Scheetz Marc H. 
Published: September 2022

AbstractVancomycin induced kidney injury is common, and outcomes in humans are well predicted by animal models. This study employed our translational rat model to investigate temporal changes in glomerular filtration rate (GFR) and correlation with kidney injury biomarkers related to various vancomycin dosing strategies. First, Sprague Dawley rats received allometrically scaled loading doses or standard doses. Rats that received a loading dose had lower GFR and increased urinary injury biomarkers (kidney injury molecule 1 [KIM-1] and clusterin) that persisted through day 2, compared to those that did not receive a loading dose. Second, we compared low and high allometrically scaled vancomycin doses to a positive acute kidney injury control of high dose folic acid. Rats in both the low and high vancomycin dose groups had higher GFRs on all dosing days versus the positive control group. When the two vancomycin groups were compared, rats that received the low dose had significantly higher GFR on days 1, 2, and 4. Compared to low dose vancomycin, KIM-1 was elevated in high dose rats on dosing day 3. GFR correlated most closely with the urinary injury biomarker KIM-1, on all experimental days.Vancomycin loading doses were associated with significant loss of kidney function and elevation of urinary injury biomarkers. In our translational rat model, both the degree of kidney function decline and urinary biomarker rise corresponded to the magnitude of vancomycin dose (i.e. higher dose resulted in more kidney function decline and greater degree of urinary injury biomarker increase).
Rheumatoid arthritis and idiopathic pulmonary fibrosis: a bidirectional Mendelian randomisation study
Authors: Leavy Olivia C , Kawano-Dourado Leticia , Stewart Iain D , Quint Jennifer K , Solomon Joshua J , Borie Raphael , Crestani Bruno , Wain Louise V , Jenkins R Gisli , Dieudé Philippe , Minelli Cosetta 
Published: September 2022

AbstractIntroductionA usual interstitial pneumonia (UIP) pattern of lung injury is a key feature of idiopathic pulmonary fibrosis (IPF) and is also observed in up to 40% of individuals with rheumatoid arthritis (RA) related Interstitial Lung Disease (RA-ILD). The RA-UIP phenotype could result from either a causal relationship of RA on UIP or vice versa, or from a simple co-occurrence of RA and IPF due to shared demographic, genetic or environmental risk factors.MethodsWe used two-sample bidirectional Mendelian Randomisation (MR) to investigate the causal effects of RA on UIP and of UIP on RA, using variants from genome-wide association studies of RA (separately for seropositive and seronegative RA) and of IPF as genetic instruments. We conducted inverse-variance-weighted fixed-effect MR as a primary analysis and undertook sensitivity analyses to assess potential violations of the key MR assumption of no (horizontal) pleiotropy.ResultsSeropositive RA showed a significant protective effect on IPF (Odds Ratio, OR = 0.93; 95% Confidence Interval, CI: 0.87-0.99; P=0.032), while the MR in the other direction showed a strongly significant causal effect of IPF on seropositive RA (OR = 1.06, 95% CI: 1.04-1.08, P=1.22×10−11).ConclusionOur findings support the hypothesis that RA-UIP may be due to a cause-effect relationship between IPF and RA, rather than due to a coincidental occurrence of IPF in patients with RA. The causal effect of IPF on seropositive RA suggests that patho-mechanisms involved in the development of UIP may promote RA and would suggest that screening for UIP in asymptomatic RA patients may be warranted and may influence therapy management of patients with RA-UIP.
Major Contribution of Myeloid Cells In TB specific Host Gene Signature: Revelations from Re-Analysis of Publicly Available Datasets
Authors: Gautam Anuradha , Mohapatra Saroj Kant , Pandit Bhaswati 
Published: September 2022

AbstractIntroductionInteraction of human host and its pathogen M.tuberculosis drives tuberculosis disease, resulting in dysregulation of host gene expression. We re-analyzed host gene expression datasets of TB to identify and validate a cellular circuit by interlinking the DEGs with their target miRNAs, GWAS hits associated with immunological phenotypes mapping to the DEGs and associated cellular subtypes through bioinformatic and experimental approaches.MethodologyDEGs were identified systematically through re-analysis of whole blood host transcriptomic datasets of treatment-naive TB patients, obtained from public repositories having at least 1.2 fold change of expression and FDR corrected p-value <0.05. Using well characterized M.tb antigens: Ag85 complex, LAM, CFP10 and ESAT6, we evaluated their effect on the expression of a subset of the top DEGs with at least two fold change of expression in a monocytic cell line THP1 with or without differentiation into a macrophage-like state with PMA and a T cell line Jurkat E6-1.ResultsWe discovered 305 DEGs (236 up and 69 down-regulated genes) out of which 23 (21 up and 2 down-regulated genes) were top DEGs. Overall, innate immune and myeloid cell associated pathways were enriched for up-regulated genes while T cell associated pathways were enriched for down-regulated genes. Among top DEGs, EPSTI1 was predominantly up-regulated in macrophages while SERPING1 was universally up-regulated in the monocyte model by all antigens. The down-regulation of gene expression was replicated by ESAT6 in T cell line by significantly down-regulating a top down-regulated gene LRRN3.
DREAMS: Deep Read-level Error Model for Sequencing data applied to low-frequency variant calling and circulating tumor DNA detection
Authors: Christensen Mikkel H. , Drue Simon , Rasmussen Mads H. , Frydendahl Amanda , Lyskjær Iben , Demuth Christina , Nors Jesper , Gotschalck Kåre A. , Iversen Lene H. , Andersen Claus L. , Pedersen Jakob Skou 
Published: September 2022

AbstractCirculating tumor DNA detection using Next-Generation Sequencing (NGS) data of plasma DNA is promising for cancer identification and characterization. However, the tumor signal in the blood is often low and difficult to distinguish from errors. We present DREAMS (Deep Read-level Modelling of Sequencing-errors) for estimating error rates of individual read positions. Using DREAMS, we developed statistical methods for variant calling (DREAMS-vc) and cancer detection (DREAMS-cc).For evaluation, we generated deep targeted NGS data of matching tumor and plasma DNA from 85 colorectal cancer patients. The DREAMS approach performed better than state-of-the-art methods for variant calling and cancer detection.
Machine learning and hypothesis driven optimization of bull semen cryopreservation media
Authors: Tu Frankie , Bhat Maajid , Blondin Patrick , Vincent Patrick , Sharafi Mohsen , Benson James D 
Published: September 2022

AbstractCryopreservation provides a critical tool for dairy herd genetics management. Due to widely varying inter- and within-bull post thaw fertility, recent research on cryoprotectant extender medium has not dramatically improved suboptimal post-thaw recovery in industry. This progress is stymied by the interactions between samples and the many components of extender media and is often compounded by industry irrelevant sample sizes. To address these challenges, here we demonstrate blank-slate optimization of bull sperm cryopreservation media by supervised machine learning. We considered two supervised learning models: artificial neural networks and Gaussian process regression (GPR). Eleven media components and initial concentrations were identified from publications in bull semen cryopreservation, and an initial 200 extender-post-thaw motility pairs were used to train and 32 extender-post-thaw motility pairs to test the machine learning algorithms. The median post-thaw motility after coupling differential evolution with GPR the increased from 52.6 ± 6.9% to 68.3 ± 6.0% at generations 7 and 17 respectively, with several media performing dramatically better than control media counterparts. This is the first study in which machine learning was used to determine the best combination of constituents to optimize bull sperm cryopreservation media, and provides a template for optimization in other cell types.
Vascular-water-exchange MRI (VEXI) enables the detection of subtle BBB breakdown in Alzheimer’s disease without MRI contrast agent
Authors: Zhang Yifan , Wang Yue , Li Zhaoqing , Wang Zejun , Cheng Juange , Bai Xiaoyan , Hsu Yi-Cheng , Sun Yi , Li Shiping , Shi Jiong , Sui Binbin , Bai Ruiliang 
Published: September 2022

AbstractBlood-brain barrier (BBB) impairment is an important pathophysiological process in Alzheimer’s disease (AD) and a potential biomarker for early diagnosis of AD. However, most current neuroimaging methods assessing BBB function need the injection of exogenous contrast agents (or tracers), which limits the application of these methods in a large population. In this study, we aim to explore the feasibility of vascular water exchange MRI (VEXI), a diffusion-MRI-based method to assess the BBB permeability to water molecules without using a contrast agent, in the detection of the BBB breakdown in AD. We tested VEXI on a 3T MRI scanner on three groups: AD patients (AD group), mild cognitive impairment (MCI) patients due to AD (MCI group), and the age-matched normal cognition subjects (NC group). Interestingly, we find that VEXI can detect the BBB permeability to water molecules increase in MCI and this BBB breakdown happens specifically in the hippocampus. This BBB breakdown gets worse and extends to more brain regions (orbital frontal cortex and thalamus) from MCI group to the AD group. Furthermore, we find that the BBB breakdown of these three regions detected by VEXI is correlated significantly with impairment of respective cognitive domains independent of age, sex and education. These results suggest VEXI is a promising method to assess the BBB breakdown in AD.HighlightsThe vascular water exchange MRI (VEXI) is a contrast-agent-free method to assess BBB permeabilityBBB breakdown happens specifically in the hippocampus, orbital frontal cortex, and thalamus in ADBBB breakdown detected by VEXI is significantly correlated with cognitive dysfunction
The RNA binding proteins ZFP36L1 and ZFP36L2 modulate transcriptional and post-transcriptional genome-wide effects of glucocorticoids
Authors: Rynne Jennifer , Ortiz-Zapater Elena , Khooshemehri Paniz , Ponde Nicole O. , Bucca Giselda , Hesketh Andrew , Platé Manuela , Chambers Rachel , Smith Colin , Martinez-Nunez Rocio T. 
Published: September 2022

AbstractGlucocorticoids (GCs) are one of the most used anti-inflammatory drugs worldwide. Despite their widespread use, our understanding of their post-transcriptional effects remains poorly understood. The tristetraprolin (TTP) RNA binding protein (RBP) family (ZFP36, ZFP36L1 and ZFP36L2) has been implicated in inflammation regulation via binding to AU-rich elements (ARE) in mRNAs, with TTP being implicated in GC modulation. We hypothesised that ZFP36L1 and ZFP36L2 are part of the GC pathway and tested this hypothesis in bronchial epithelium, which commonly encounters GC in vivo upon inhalation. Our data show that dexamethasone, a commonly used GC, modulated the levels, subcellular localisation and RNA binding of ZFP36L1/L2. Employing Frac-seq (subcellular fractionation and RNA-sequencing), we show that GC modulated distinct subsets of RNAs in a subcellular-dependent manner. In addition to their mostly known transcriptional effects (116 differentially expressed genes, DEGs), GCs modified the binding to monosomes of myriad mRNAs (83 differentially bound genes, DBGs). We also demonstrate that ZFP36L1/L2 modulated gene expression mainly at the total cytoplasmic and polyribosome binding levels. ZFP36L1/L2 down-regulation led to an increase in ARE-containing mRNAs and a pronounced modification of the effects of GC on gene expression. We observed a small overlap of genes modulated by GCs when comparing control and ZFP36L1/L2 knockdown cells, in a subcellular-dependent manner Our data also suggest a novel role for these RBPs and GCs in epithelial biology via regulation of mRNAs encoding proteins important for epithelial cell function including cellular structure. We believe that our data has further implications in how we investigate gene expression. We show the power of employing sub-cellular fractionation when analysing genome-wide effects for known ‘transcriptional modulators’ such as GCs, as well as a tool to demonstrate the extent of the effect of RBPs on gene expression modulation beyond total RNA levels.