bluuebunny/crossref_metadata_2025_split huggingface dataset:
Maternal-fetal interfaces transcriptome changes associated with placental insufficiency and a novel gene therapy intervention
Authors: Jones Helen N. , Davenport Baylea N. , Wilson Rebecca L. 
Published: June 2024

AbstractThe etiology of fetal growth restriction (FGR) is multifactorial, although many cases often involve placental insufficiency. Placental insufficiency is associated with inadequate trophoblast invasion resulting in high resistance to blood flow, decreased availability of nutrients, and increased hypoxia. We have developed a non-viral, polymer-based nanoparticle that facilitates delivery and transient gene expression ofhuman insulin-like 1 growth factor(hIGF1) in placental trophoblast for the treatment of placenta insufficiency and FGR. Using the established guinea pig maternal nutrient restriction (MNR) model of placental insufficiency and FGR, the aim of the study was to identify novel pathways in the sub-placenta/decidua that provide insight into the underlying mechanism driving placental insufficiency, and may be corrected withhIGF1nanoparticle treatment. Pregnant guinea pigs underwent ultrasound-guided sham orhIGF1nanoparticle treatment at mid-pregnancy, and sub-placenta/decidua tissue was collected 5 days later. Transcriptome analysis was performed using RNA Sequencing on the Illumina platform. The MNR sub-placenta/decidua demonstrated fewer maternal spiral arteries lined by trophoblast, shallower trophoblast invasion and downregulation of genelists involved in the regulation of cell migration.hIGF1nanoparticle treatment resulted in marked changes to transporter activity in the MNR +hIGF1sub-placenta/decidua when compared to sham MNR. Under normal growth conditions however,hIGF1nanoparticle treatment decreased genelists enriched for kinase signaling pathways and increased genelists enriched for proteolysis indicative of homeostasis. Overall, this study identified changes to the sub-placenta/decidua transcriptome that likely result in inadequate trophoblast invasion and increases our understanding of pathways thathIGF1nanoparticle treatment acts on in order to restore or maintain appropriate placenta function.
Internalized α-synuclein fibrils become truncated and resist degradation in neurons while glial cells rapidly degrade α-synuclein fibrils
Authors: Karim Md. Razaul , Gasparini Emilie , Tiegs Elizabeth , Schlichte Riley , Vermilyea Scott C. , Lee Michael K. 
Published: June 2024

AbstractParkinson’s disease (PD) and other α-synucleinopathies are characterized by the accumulation of α-synuclein (αS) pathology that can spread via the cell-to-cell transmission of αS aggregates. To better understand how various brain cells contribute to the spreading of αS pathology, we examined the metabolism of αS aggreges or pre-formed fibrils (PFFs) in neuronal and glial cells (microglia, astrocytes, and oligodendrocytes). In neurons, while the full-length αS rapidly disappeared following αS PFF uptake, truncated αS accumulated with a half-life of days rather than hours. Epitope mapping and fractionation studies indicate that αS PFF was truncated at the C-terminal region following uptake and remained insoluble/aggregated. In contrast, microglia and astrocytes rapidly metabolized αS PFF as the half-lives of αS PFF in these glial cells were <6 hours. Differential processing of αS by neurons was recapitulated in cell lines as differentiated CLU neuronal cell lines stably accumulate truncated αS while undifferentiated cells rapidly metabolize αS. Immunolocalization and subcellular fractionation studies show that internalized αS PFF is initially localized to endosomes followed by lysosomes. The lysosome is largely responsible for the degradation of internalized αS PFF as the inhibition of lysosomal function leads to the stabilization of αS in all cell types. Significantly, αS PFF causes lysosomal dysfunction in neurons. In summary, we show that neurons are inefficient in metabolizing internalized αS aggregates, partially because αS aggregates cause lysosomal dysfunction, potentially generating aggregation-prone truncated αS. In contrast, glial cells may protect neurons from αS aggregates by rapidly clearing αS aggregates.
Depletion of chemoresponsive mitochondrial fission mediator DRP1 does not mitigate sarcoma resistance
Authors: Borankova Karolina , Solny Matyas , Krchniakova Maria , Skoda Jan 
Published: June 2024

ABSTRACTSpecific patterns of mitochondrial dynamics have been repeatedly reported to promote drug resistance in cancer. However, whether targeting mitochondrial fission- and fusion-related proteins could be leveraged to combat multidrug-resistant pediatric sarcomas is poorly understood. Here, we demonstrated that the expression and activation of the mitochondrial fission mediator DRP1 are affected by chemotherapy exposure in common pediatric sarcomas, i.e., rhabdomyosarcoma and osteosarcoma. Unexpectedly, decreasing DRP1 activity through stable DRP1 knockdown did not attenuate sarcoma drug resistance or affect growth rate or the mitochondrial network morphology. The minimal impact on sarcoma cell physiology, combined with the upregulation of fission adaptor proteins (MFF and FIS1) detected in rhabdomyosarcoma cells, indicates that an alternative DRP1-independent mitochondrial fission mechanism may efficiently compensate for the lack of DRP1 activity. By exploring the upstream mitophagy and mitochondrial fission regulator, AMPKα1, we found that markedly reduced AMPKα1 levels are sufficient to maintain AMPK signaling capacity without affecting chemosensitivity. Collectively, our findings challenge the direct involvement of DRP1 in pediatric sarcoma drug resistance and highlight the complexity of yet-to-be-characterized noncanonical regulators of mitochondrial dynamics.SUMMARY BLURBThe mitochondrial fission mediator DRP1 levels and activation are modulated upon chemotherapy exposure, yet depleting DRP1 does not restore chemosensitivity in the most common pediatric sarcomas.
Mid-pregnancy placental transcriptome in a model of placental insufficiency with and without novel intervention
Authors: Wilson Rebecca L. , Davenport Baylea N. , Jones Helen N. 
Published: June 2024

AbstractFetal growth restriction (FGR) affects between 5-10% of all live births. Placental insufficiency is a leading cause of FGR, resulting in reduced nutrient and oxygen delivery to the fetus. Currently, there are no effective in utero treatment options for FGR, or placental insufficiency. We have developed a gene therapy to deliver, via a non-viral nanoparticle,human insulin-like 1 growth factor(hIGF1) to the placenta as potential treatment of placenta insufficiency and FGR. Using a guinea pig maternal nutrient restriction (MNR) model of FGR, we aimed to understand the transcriptional changes within the placenta associated with placental insufficiency that occur prior to/at initiation of FGR, and the impact of short-termhIGF1nanoparticle treatment. Using RNAsequencing, we analyzed protein coding genes of three experimental groups: Control and MNR dams receiving a sham treatment, and MNR dams receivinghIGF1nanoparticle treatment. Pathway enrichment analysis comparing differentially expressed genelists in sham-treated MNR placentas to Control revealed upregulation of pathways associated with degradation and repair of genetic information and downregulation of pathways associated with transmembrane transport. When compared to sham-treated MNR placentas, MNR +hIGF1placentas demonstrated changes to genelists associated with transmembrane transporter activity including ion, vitamin and solute carrier transport. Overall, this study identifies the key signaling and metabolic changes occurring in the placenta contributing to placental insufficiency prior to/at initiation of FGR, and increases our understanding of the pathways that our nanoparticle-mediated gene therapy intervention regulates.Statements and DeclarationsCompeting InterestsAuthors declare no conflicts of interest.
Emotional Distractors Capture Attention even at Very Low Contrast Levels: ERP evidence
Authors: Cipriani Germán A. , Kessel Dominique , Álvarez Fátima , Fernández-Folgueiras Uxía , Tapia Manuel , Carretié Luis 
Published: June 2024

ABSTRACTEmotional visual stimuli, whether appealing or aversive, preferentially capture exogenous attention due to their evolutionary significance. This study assessed whether such capacity persists at low contrast levels, where stimuli are minimally perceived. To this end, we recorded behavioral and electrophysiological (event-related potentials, ERPs) indices of attentional capture from 38 participants who were exposed to negative, neutral, and positive scenes, each presented at four distinct contrast levels. These contrast levels had previously resulted in a correct recognition rate of up to 25%, 50%, 75%, and 100% in a previous sample of 235 participants. Participants were presented with these scenes as distractors while simultaneously performing a perceptual task involving line orientation discrimination. The ERP results confirmed the expected emotional effect on exogenous attention and, critically, unveiled its persistence across all contrast levels. Specifically, occipito-parietal P1 (88-119 ms) was larger for negative than for positive distractors, while in a spreaded N2 component, positive distractors elicited larger amplitudes relative to both negative (213-354 ms) and neutral (213-525 ms) images. These findings reinforce the advantage of emotional distractors in accessing neural processing automatically and highlight the existence of a temporal negativity bias. Importantly, our novel findings emphasize the robustness of this exogenous attention pattern, present even under limited perceptual conditions.
Using lifestyle information in polygenic modeling of blood pressure traits: a simple method to reduce bias
Authors: Tiezzi Francesco , Goda Khushi , Morgante Fabio 
Published: June 2024

AbstractComplex traits are determined by the effects of multiple genetic variants, multiple environmental factors, and potentially their interaction. Predicting complex trait phenotypes from genotypes is a fundamental task in quantitative genetics that was pioneered in agricultural breeding for selection purposes. However, it has recently become important in human genetics. While prediction accuracy for some human complex traits is appreciable, this remains low for most traits. A promising way to improve prediction accuracy is by including not only genetic information but also environmental information in prediction models. However, environmental factors can, in turn, be genetically determined. This phenomenon gives rise to a correlation between the genetic and environmental components of the phenotype, which violates the assumption of independence between the genetic and environmental components of most statistical methods for polygenic modeling. In this work, we investigated the impact of including 27 lifestyle variables as well as genotype information (and their interaction) for predicting diastolic blood pressure, systolic blood pressure, and pulse pressure in older individuals in UK Biobank. The 27 lifestyle variables were included as either raw variables or adjusted by genetic and other non-genetic factors. The results show that including both lifestyle and genetic data improved prediction accuracy compared to using either piece of information alone. Both prediction accuracy and bias can improve substantially for some traits when the models account for the lifestyle variables after their proper adjustment. Our work confirms the utility of including environmental information in polygenic models of complex traits and highlights the importance of proper handling of the environmental variables.Author summaryMany traits of medical relevance are “complex” in that they are affected by both genetic and environmental factors. Thus, using genetic and environmental information in statistical methods has the potential to increase the accuracy of phenotypic prediction, the ultimate goal of precision medicine. However, the correlation between the genetic and environmental components (that arises when environmental variables are themselves genetically determined) and the correlations between environmental measures can be problematic for most statistical methods used for modeling complex traits. In this work, we investigated these issues using 27 lifestyle measures in addition to genetic information for predicting diastolic blood pressure, systolic blood pressure, and pulse pressure in older individuals. We show that including lifestyle and genetic data resulted in more accurate predictions than either data type alone. Moreover, adjusting the lifestyle measures for the genetic and other non-genetic effects can help improve the predictions further.
One Health in practice: Multi-season survey of ixodid tick species collected from domestic dogs in Chad
Authors: Cleveland Christopher A. , Friedman Morgan , Thompson Alec T. , Haynes Ellen , Coker Sarah M. , Bryan John A. , Sidouin Metinou K. , Ouakou Philip Tchindebet , Richard Ngandolo Bongo Nare , Yabsley Michael J. 
Published: June 2024

AbstractTicks are medically important vectors of pathogens, many of which are zoonotic or impact domestic animal and/or wildlife health. Climate change, landscape use, and increasing interactions between domestic animals, wildlife, and humans have resulted in changes in tick-host dynamics and the emergence of novel pathogens worldwide. Therefore, it is crucial to describe the host and geographic ranges of vector species to assess disease risk, particularly in areas where research is lacking. This task necessitates adopting a One Health approach. In sub-Saharan Africa, previous work on ticks has focused primarily on those species most relevant to domestic livestock or humans, highlighting a significant knowledge gap concerning species of ticks that infest peri-domestic animals in rural areas. The objective of this study was to investigate the species diversity of ticks on peri-domestic dogs in rural areas of Chad, Africa. From 2019-2022, we collected 3,412 ixodid ticks from 435 peri-domestic dogs from 23 villages in Chad, Africa during both dry and wet seasons. Ticks were identified to species using morphological techniques and/or molecular analyses of the 16S rRNA, 12S rRNA, and cytochrome oxidase I gene regions. We identified 11 species of ticks from dogs includingAmblyomma variegatum,Amblyomma marmoreum,Haemaphysalis leachi,aHaemaphysalissp.,Hyalomma impressum, Hyalomma truncatum, Rhipicephalus decoloratus, Rhipicephalus guilhoni, Rhipicephalus muhsamae, Rhipicephalus linnaei(=R. sanguineus‘tropical lineage’), and aRhipicephalussp. Several of these tick species are known vectors for important canine and zoonotic pathogens and some are more commonly associated with cattle hosts. Our results show that sampling ticks from peri-domestic dogs provides an opportunity to examine vectors that may infest domestic animals, agricultural animals, wildlife, and humans as hosts in an understudied area.HighlightsTick-borne diseases are significant concern across sub-Saharan AfricaLimited data on ticks of animals and people in Chad, AfricaA high diversity of tick species infested domestic dogs in ChadMany detected tick species associated with important pathogens
White Matter Microstructural Correlates of Cognitive and Motor Functioning Revealed via Multimodal Multivariate Analysis
Authors: Alasmar Z. , Tremblay S. A. , Baumeister T. R. , Carbonell F. , Iturria-Medina Y. , Gauthier C. J. , Steele C. J. 
Published: June 2024

1.AbstractRecent advances in cognitive neuroscience emphasise the importance of healthy white matter (WM) in optimal behavioural functioning. It is now widely accepted that brain connectivity via WM contributes to the emergence of behaviour. However, the association between the microstructure of WM fibres and behaviour is poorly understood. This is in part due to indirect and overlapping methods of assessing microstructure, and the use of overly simplistic approaches in assessing behaviour. Here, we used the Mahalanobis Distance (D2) to integrate 10 metrics of WM derived from multimodal neuroimaging that have strong ties to microstructure. The D2 metric was chosen because it accounts for metrics’ covariance as it measures the voxelwise distance between every subject and the average; thus providing a robust multiparametric assessment of microstructure. To examine WM-behaviour associations, we used multivariate correlation to examine the voxelwise correlates of 2 cognitive and 2 motor tasks, which allowed us to compare within and across domains in WM. We observed that behaviour is organised in cognitive, motor, and integrative variables that are widespread in their associations with WM, from frontal to parietal regions. Our results highlight the complex nature of microstructure and behaviour, and show the need for multivariate modelling when examining brain-behaviour associations.
Identity-by-descent segments in large samples
Authors: Temple Seth D. , Thompson Elizabeth A. 
Published: June 2024

AbstractIf two haplotypes share the same alleles for an extended gene tract, these haplotypes are likely to be derived identical-by-descent from a recent common ancestor. Identity-by-descent segment lengths are correlated via unobserved ancestral tree and recombination processes, which commonly presents challenges to the derivation of theoretical results in population genetics. We show that the proportion of detectable identity-by-descent segments around a locus is normally distributed when the sample size and the scaled population size are large. We generalize this central limit theorem to cover flexible demographic scenarios, multi-way identity-by-descent segments, and multivariate identity-by-descent rates. We use efficient simulations to study the distributional behavior of the detectable identity-by-descent rate. One consequence of non-normality in finite samples is that a genome-wide scan looking for excess identity-by-descent rates may be subject to anti-conservative control of family-wise error rates.HighlightsWe show the asymptotic normality of the detectable identity-by-descent rate, a mean of correlated binary random variables that arises in population genetics studies.We generalize our main central limit theorem to cover scenarios of nonconstant population sizes, multi-way identity-by-descent segments, and identity-by-descent rates of multiple samples from the same population.In enormous simulation studies, we use an efficient algorithm to characterize distributional properties of the detectable identity-by-descent rate.
Generation of the First Transgenic Line of the Iconic Coral Reef FishAmphiprion ocellaris
Authors: Graham Gabriel J. , Ibanez Emma M. , Mitchell Laurie J. , Weis Karen E. , Raetzman Lori T. , Cortesi Fabio , Rhodes Justin S. 
Published: June 2024

AbstractThe common clownfish,Amphiprion ocellaris, is an iconic coral reef fish, ubiquitous in the marine aquarium hobby and useful for studying a variety of biological processes (e.g., mutual symbiosis, ultraviolet vision, and protandrous sex change). Recently, CRISPR/Cas9 methods were developed for knocking out specific genes for mechanistic studies. Here, we expand the genetic toolkit forA. ocellarisby creating the first transgenic line using theTol2transposon system. Fertilized eggs were co-injected withTol2transposase mRNA and a plasmid encoding an Elongation factor 1α(Ef1α): Green fluorescent protein (GFP)cassette at various concentrations, needle tip dimensions and timepoints post-fertilization. We compared various injection parameters and sterilization methods to maximize the survival of injected eggs. F0s (n=10) that were genotyped GFP+ were then raised to 6 months of age and crossed with wild-type (WT) females to confirm germline transmission. F1 offspring were also raised and crossed in the same manner. The highly efficientTol2transposon system resulted in a 37% rate of transgenesis for surviving eggs amounting to a 2.7% yield of all injected eggs surviving and being GFP+ (n= 160). Of these, 10 were raised to adulthood, 8 spawned, and 5/8 (62.5 %) produced GFP+ offspring. Further, two F1s crossed with WT females produced 53.8% and 54.2% GFP+ offspring respectively, confirming the creation of a stable line. This is, to our knowledge, the first generation of a transgenic line in any coral reef fish. The ability to express transgenes of interest in the iconic anemonefish opens the door to a new era of exploration into their fascinating biology.
Energy-based Analysis of Biochemical Oscillators Using Bond Graphs and Linear Control Theory
Authors: Gawthrop Peter J. , Pan Michael 
Published: June 2024

AbstractThe bond graph approach has been recognised as a useful conceptual basis for understanding the behaviour of living entities modelled as a system with hierarchical interacting parts exchanging energy. One such behaviour is oscillation, which underpins many essential biological functions. In this paper, energy-based modelling of biochemical systems using the bond graph approach is combined with classical feedback control theory to give a novel approach to the analysis, and potentially synthesis, of biochemical oscillators. It is shown that oscillation is dependent on the interplay betweenactiveandpassivefeedback and this interplay is formalised using classical frequency-response analysis of feedback systems. In particular, thephase marginis suggested as a simple scalar indicator of the presence or absence of oscillations; it is shown how this indicator can be used to investigate the effect of both the structure and parameters of biochemical system on oscillation. It follows that the combination of classical feedback control theory and the bond graph approach to systems biology gives a novel analysis and design methodology for biochemical oscillators.The approach is illustrated using an introductory example similar to the Goodwin oscillator, the Sel’kov model of Glycolytic Oscillations and the Repressilator.