bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of an internet-based insomnia intervention on suicidal ideation and associated correlates in veterans at elevated suicide risk
Authors: Nazem Sarra , Sun Shengnan , Barnes Sean M , Monteith Lindsey L , Hostetter Trisha A , Forster Jeri E , Brenner Lisa A , Galfalvy Hanga , Haghighi Fatemeh
Published: June 2024

Improving public health approaches to suicide prevention requires scalable evidence-based interventions that can be easily disseminated. Given empirical data supporting the association between insomnia and suicide risk, internet-delivered insomnia interventions are promising candidates to meet this need. The purpose of this study was to examine whether an unguided internet-delivered cognitive-behavioral therapy for insomnia (iCBT-I) improved insomnia severity, suicidal ideation (SI), and suicide risk correlates (depression, post-traumatic stress disorder, anxiety, hostility, belongingness, hopelessness, agitation, irritability, concentration) in a sample of veterans. Secondary data analysis of Operation Enduring Freedom, Operation Iraqi Freedom, and Operation New Dawn veterans (n = 50) with clinically significant insomnia and elevated SI drawn from a larger randomized controlled trial (RCT) of an iCBT-I, Sleep Healthy Using the Internet (SHUTi). Two-sample t-tests or Wilcoxon rank sum tests were used to evaluate between-group differences (SHUTi vs. Insomnia Education Website control) in symptom improvement from baseline to post-intervention. SHUTi participants experienced a significant improvement in insomnia severity (P < .001; d = −1.08) and a non-significant with small (subthreshold medium) effect size reduction of SI (P = .17, d = 0.40), compared to control participants. Significant improvement in hopelessness was observed (medium effect size), with non-significant small to medium effect size reductions in most remaining suicide risk correlates. Self-administered iCBT-I was associated with improvements in insomnia severity in veterans at elevated risk for suicide. These preliminary findings suggest that SI and suicide risk correlates may improve following an iCBT-I intervention, demonstrating the need for future well-powered iCBT-I RCTs targeted for populations at elevated suicide risk.
Cross study analyses of SEND data: toxicity profile classification
Authors: Carfagna Mark A , Ahmed Cm Sabbir , Butler Susan , Fukushima Tamio , Houser William , Jensen Nikolai , Paisley Brianna , Leuenroth-Quinn Stephanie , Snyder Kevin , Vispute Saurabh , Wang Wenxian , Ali Md Yousuf
Published: June 2024

A SEND toxicology data transformation, harmonization, and analysis platform were created to improve the identification of unique findings related to the intended target, species, and duration of dosing using data from multiple studies. The lack of a standardized digital format for data analysis had impeded large-scale analysis of in vivo toxicology studies. The CDISC SEND standard enables the analysis of data from multiple studies performed by different laboratories. This work describes methods to analyze data and automate cross-study analysis of toxicology studies. Cross-study analysis can be used to understand a single compound’s toxicity profile across all studies performed and/or to evaluate on-target versus off-target toxicity for multiple compounds intended for the same pharmacological target. This work involved development of data harmonization/transformation strategies to enable cross-study analysis of both numerical and categorical SEND data. Four de-identified SEND datasets from the BioCelerate database were used for the analyses. Toxicity profiles for key organ systems were developed for liver, kidney, male reproductive tract, endocrine system, and hematopoietic system using SEND domains. A cross-study analysis dashboard with a built-in user-defined scoring system was created for custom analyses, including visualizations to evaluate data at the organ system level and drill down into individual animal data. This data analysis provides the tools for scientists to compare toxicity profiles across multiple studies using SEND. A cross-study analysis of 2 different compounds intended for the same pharmacological target is described and the analyses indicate potential on-target effects to liver, kidney, and hematopoietic systems.
PRKC Fusion Melanocytic Tumors, a Subgroup of Melanocytic Tumors More Closely Aligned to Blue Nevi Than to PRKAR1A-inactivated Pigmented Epithelioid Melanocytomas
Authors: Patel Pragi , Chen Alice , Sharma Natasha , Zhang Yongzhan , Quan Victor L. , Olivares Shantel , Gerami Pedram
Published: June 2024

Tumors morphologically classified as pigmented epithelioid melanocytomas (PEMs) are genomically diverse, with the 2 most common genomic subtypes being PRKC fusions or PRKAR1A inactivating mutations. PRKC fusions activate the Gαq/11 pathway similar to blue nevi. Conversely, inactivating mutations in PRKAR1A activate the Gαs pathway. We hypothesize that PRKC fusions have greater genomic overlap with blue nevi compared with PRKAR1A-inactivated PEMs. We characterized the clinical and morphologic features of 21 PRKC and PRKACB fusion melanocytic tumors and compared this to PRKAR1A mutated PEMs. To test our hypothesis regarding greater genomic overlap between PRKC fusions and blue nevi relative to PRKAR1A mutated PEMs, we performed a principal component analysis (PCA) using mRNA expression data. Lastly, we performed a meta-analysis focusing on the outcome data of PRKC fusions. PRKC fusions occur at a younger median age than PRKAR1A mutated PEMs (16 vs. 27). Histologically, PRKC fusions have solid aggregates of epithelioid melanocytes not typical of PRKAR1A mutated PEMs. The PCA plot showed no overlap between the PRKC fusion group and the PRKAR1A-mutated PEMs. There was a significant overlap between PRKC fusions and blue nevi. A meta-analysis of PRKC fusion cases in the literature suggests melanoma is uncommon, but the loss of BAP-1 nuclear expression may be associated with an adverse prognosis as in tumors from the blue nevus family. PRKC fusion melanocytic tumors have greater genomic overlap with blue nevi compared with PRKAR1A mutated PEMs. We recommend categorizing benign PRKC fusion melanocytic tumors as blue fusion nevi/tumors.
Chimpanzees (
Pan troglodytes
) recognize that their guesses could be wrong and can pass a two-cup disjunctive syllogism task
Authors: Jones Benjamin , Call Josep
Published: June 2024

When chimpanzees search for hidden food, do they realize that their guesses may not be correct? We applied a post-decision wagering paradigm to a simple two-cup search task, varying whether we gave participants visual access to the baiting and then asking after they had chosen one of the cups whether they would prefer a smaller but certain reward instead of their original choice (experiment 1). Results showed that chimpanzees were more likely to accept the smaller reward in occluded than visible conditions. Experiment 2 found the same effect when we blocked visual access but manipulated the number of hiding locations for the food piece, showing that the effect is not owing to representation type. Experiments 3 and 4 showed that when given information about the contents of the unchosen cup, chimpanzees were able to flexibly update their choice behaviour accordingly. These results suggest that language is not a pre-requisite to solving the disjunctive syllogism and provides a valuable contribution to the debate on logical reasoning in non-human animals.
Elongation capacity of polyunsaturated fatty acids in the annelid
Platynereis dumerilii
Authors: Ramos-Llorens Marc , Bainour Khalida , Adelmann Leonie , Hontoria Francisco , Navarro Juan C. , Raible Florian , Monroig Óscar
Published: June 2024

Elongation of very long-chain fatty acid (Elovl) proteins plays pivotal functions in the biosynthesis of the physiologically essential long-chain polyunsaturated fatty acids (LC-PUFA). Polychaetes have important roles in marine ecosystems, contributing not only to nutrient recycling but also exhibiting a distinctive capacity for biosynthesizing LC-PUFA. To expand our understanding of the LC-PUFA biosynthesis in polychaetes, this study conducted a thorough molecular and functional characterization of Elovl occurring in the model organism
Platynereis dumerilii
. We identify six Elovl in the genome of
P. dumerilii
. The sequence and phylogenetic analyses established that four Elovl, identified as Elovl2/5, Elovl4 (two genes) and Elovl1/7, have putative functions in LC-PUFA biosynthesis. Functional characterization confirmed the roles of these elongases in LC-PUFA biosynthesis, demonstrating that
P. dumerilii
possesses a varied and functionally diverse complement of Elovl that, along with the enzymatic specificities of previously characterized desaturases, enables
P. dumerilii
to perform all the reactions required for the biosynthesis of the LC-PUFA. Importantly, we uncovered that one of the two Elovl4-encoding genes is remarkably long in comparison with any other animals' Elovl, which contains a C terminal KH domain unique among Elovl. The distinctive expression pattern of this protein in photoreceptors strongly suggests a central role in vision.
Sigh generation in preBötzinger Complex
Authors: Cui Yan , Bondarenko Evgeny , Perez Carolina Thörn , Chiu Delia N. , Feldman Jack L.
Published: June 2024

We explored neural mechanisms underlying sighing. Photostimulation of parafacial (pF) neuromedin B(NMB) or gastrin releasing peptide (GRP), or preBötzinger Complex (preBötC) NMBR or GRPR neurons elicited ectopic sighs with latency inversely related to time from preceding endogenous sigh. Of particular note, ectopic sighs could be produced without involvement of these peptides or their receptors in preBötC. Moreover, chemogenetic or optogenetic activation of preBötC SST neurons induced sighing, even in the presence of NMBR and/or GRPR antagonists. We propose that an increase in the excitability of preBötC NMBR or GRPR neurons not requiring activation of their peptide receptors activates partially overlapping pathways to generate sighs, and that preBötC SST neurons are a downstream element in the sigh generation circuit that converts normal breaths into sighs.
SK609, a novel dopamine D3 receptor agonist and norepinephrine transporter blocker with pro-cognitive actions, does not induce psychostimulant-like increases in risky choice during probabilistic discounting
Authors: Knapp Christopher P. , Fallon Brooke , Kortagere Sandhya , Waterhouse Barry D. , Floresco Stan B. , Navarra Rachel L.
Published: June 2024

Rationale

Psychostimulants, such as amphetamine (AMPH) and methylphenidate (MPH), non-selectively elevate extracellular concentrations of the catecholamine neurotransmitters, dopamine (DA) and norepinephrine (NE), and are common pharmacological strategies used to improve prefrontal cortex (PFC)-dependent cognitive dysfunction. However, this approach can be problematic given AMPH has been shown to increase preference for risky choices in a rodent assay of risk/reward decision making. SK609 is a novel NE reuptake blocker that selectively activates DA D3 receptors without affinity for the DA transporter. SK609 has been shown to improve cognitive performance without increasing psychostimulant-like spontaneous locomotor activity, suggesting SK609 may benefit neurocognitive function without psychostimulant-like side effect liability.

Objectives

We compared AMPH, MPH, and SK609 within dose ranges that display their cognitive enhancing properties in a probabilistic discounting task (PDT) of risk/reward decision making behavior to assess their potential to increase risky choice preference.

Methods

Rats chose between small/certain rewards delivered with 100% certainty and large/risky rewards delivered with descending probabilities across a session (100-6.25%) following administration of AMPH (0.25-1 mg/kg), MPH (2-8 mg/kg), and SK609 (4 mg/kg).

Results

AMPH and MPH increased risky choice behavior at doses previously reported to enhance cognition, whereas SK609 did not. AMPH and MPH also reduced sensitivity to non-rewarded risky choices.

Conclusions

These data highlight the combination of NE transporter blockade and selective D3 activation in pro-cognitive action without psychostimulant-like side effect liability. The absence of DA transporter blockade and non-selective dopaminergic activation are beneficial properties of SK609 that differentiates it from the traditional pro-cognitive psychostimulants.
Deciphering the Preeclampsia-Specific Immune Microenvironment: The Role of Pro-inflammatory Macrophages
Authors: Fei Haiyi , Lu Xiaowen , Shi Zhan , Liu Xiu , Yang Cuiyu , Zhu Xiaohong , Lin Yuhan , Jiang Ziqun , Wang Jianmin , Huang Dong , Liu Liu , Zhang Songying , Jiang Lingling
Published: June 2024

Preeclampsia (PE), a major cause of maternal and perinatal mortality with highly heterogeneous causes and symptoms, is usually complicated by gestational diabetes mellitus (GDM). However, a comprehensive understanding of the immune microenvironment in the placenta of PE and the differences between PE and GDM is still lacking. In this study, Cytometry by time of flight (CyTOF) indicated that the frequencies of memory-like Th17 cells (CD45RA-CCR7+IL-17A+CD4+), memory-like CD8+T cells (CD38+CXCR3-CCR7+Helios-CD127-CD8+) and pro-inflam Macs (CD206-CD163-CD38midCD107alowCD86midHLA-DRmidCD14+) were increased, while the frequencies of anti-inflam Macs (CD206+CD163-CD86midCD33+HLA-DR+CD14+) and granulocyte myeloid-derived suppressor cells (gMDSCs, CD11b+CD15hiHLA-DRlow) were decreased in the placenta of PE compared with that of NP, but not in that of GDM or GDM&PE. The pro-inflam Macs were positively correlated with memory-like Th17 cells and memory-like CD8+T cells but negatively correlated with gMDSCs. Single-cell RNA sequencing revealed that transferring the F4/80+CD206-pro-inflam Macs with a Folr2+Ccl7+Ccl8+C1qa+C1qb+C1qc+phenotype from the uterus of PE mice to normal pregnant mice induced the production of memory-like IL-17a+Rora+Il1r1+TNF+Cxcr6+S100a4+CD44+Th17 cells via IGF1-IGF1R, which contributed to the development and recurrence of PE. Pro-inflam Macs also induced the production of memory-like CD8+T cells but inhibited the production of Ly6g+S100a8+S100a9+Retnlg+Wfdc21+gMDSCs at the maternal-fetal interface, leading to PE-like symptoms in mice. In conclusion, this study revealed the PE-specific immune cell network, which was regulated by pro-inflam Macs, providing new ideas about the pathogenesis of PE.
TheArabidopsissplicing factor PORCUPINE/SmE1 orchestrates temperature-dependent root development via auxin homeostasis maintenance
Authors: El Arbi Nabila , Nardeli Sarah Muniz , Šimura Jan , Ljung Karin , Schmid Markus
Published: June 2024

Appropriate abiotic stress response is pivotal for plant survival and makes use of multiple signaling molecules and phytohormones to achieve specific and fast molecular adjustments. A multitude of studies has highlighted the role of alternative splicing in response to abiotic stress, including temperature, emphasizing the role of transcriptional regulation for stress response. Here we investigated the role of the core splicing factorPORCUPINE(PCP) on temperature-dependent root development.

We used marker lines and transcriptomic analyses to study the expression profiles of meristematic regulators and mitotic markers, and chemical treatments, as well as root hormone profiling to assess the effect of auxin signaling.

The loss ofPCPsignificantly alters RAM architecture in a temperature-dependent manner. Our results indicate that PCP modulates the expression of central meristematic regulators and is required to maintain appropriate levels of auxin in the RAM.

We conclude that alternative pre-mRNA splicing is sensitive to moderate temperature fluctuations and contributes to root meristem maintenance, possibly through the regulation of phytohormone homeostasis and meristematic activity.
Novel miRNA-inducing drugs enable differentiation of retinoic acid-resistant neuroblastoma cells
Authors: Nguyen Lien D. , Sengupta Satyaki , Cho Kevin , Floru Alexander , George Rani E. , Krichevsky Anna M.
Published: June 2024

Tumor cell heterogeneity in neuroblastoma, a pediatric cancer arising from neural crest-derived progenitor cells, poses a significant clinical challenge. In particular, unlike adrenergic (ADRN) neuroblastoma cells, mesenchymal (MES) cells are resistant to chemotherapy and retinoid therapy and thereby significantly contribute to relapses and treatment failures. Previous research suggested that overexpression or activation of miR-124, a neurogenic microRNA with tumor suppressor activity, can induce the differentiation of retinoic acid-resistant neuroblastoma cells. Leveraging our established screen for miRNA-modulatory small molecules, we validated PP121, a dual inhibitor of tyrosine and phosphoinositide kinases, as a robust inducer of miR-124. A combination of PP121 and BDNF-activating bufalin synergistically arrests proliferation, induces differentiation, and maintains the differentiated state of MES SK-N-AS cells for 8 weeks. RNA-seq and deconvolution analyses revealed a collapse of the ADRN core regulatory circuitry (CRC) and the emergence of novel CRCs associated with chromaffin cells and Schwann cell precursors. Using a similar protocol, we differentiated and maintained MES neuroblastoma GI-ME-N and SH-EP cell lines, as well as glioblastoma LN-229 and U-251 cell lines, for over 16 weeks. In conclusion, our novel protocol suggests a promising treatment for therapy-resistant cancers of the nervous system. Moreover, these long-lived, differentiated cells provide valuable models for studying mechanisms underlying differentiation, maturation, and senescence.
Diffusion of constructed resources and specialism promotes facilitation in spatial systems
Authors: Ardichvili Alice Nadia , Barot Sébastien , Lata Jean-Christophe , Loeuille Nicolas
Published: June 2024

Sessile organisms contend with locally limiting nutrients and neighbours. Increases in nutrient concentration due to niche construction and diffusion of resources change the interaction sign between neighbours usually thought to compete for resources. We investigate conditions under which the positive effect of niche construction outweighs the negative effect of resource consumption. Following the design of facilitation experiments, we model two patches connected by resource flows, and ask whether the presence of a niche constructor in one patch eases the colonisation of the other. Niche constructors positively affect neighbouring organisms when their niches are sufficiently differentiated, and when the constructed resource diffuses more than the non-constructed resource. Our work proposes mechanisms for the emergence of facilitation, which is increasingly recognised as a key process structuring plant and microbial communities. We discuss the implications for the spatial structure of communities and their functioning, including in an agricultural context.
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

The 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

Parkinson’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

Specific 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 BLURB

The 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

Fetal 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 Declarations

Competing Interests

Authors 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

Emotional 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

Complex 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 summary

Many 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

Ticks 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.

Highlights

Tick-borne diseases are significant concern across sub-Saharan Africa

Limited data on ticks of animals and people in Chad, Africa

A high diversity of tick species infested domestic dogs in Chad

Many 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.

Recent 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

If 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.

Highlights

We 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.
Plasticity in mosquito size and thermal tolerance across a latitudinal climate gradient
Authors: Lyberger Kelsey , Farner Johannah , Couper Lisa , Mordecai Erin A
Published: June 2024

Variation in heat tolerance among populations can determine whether a species is able to cope with ongoing climate change. Such variation may be especially important for ectotherms whose body temperatures, and consequently, physiological processes, are regulated by external conditions. Additionally, differences in body size are often associated with latitudinal clines, thought to be driven by climate gradients. While studies have begun to explore variation in body size and heat tolerance within species, our understanding of these patterns across large spatial scales, particularly regarding the roles of plasticity and genetic differences, remains incomplete. Here, we examine body size, as measured by wing length, and thermal tolerance, as measured by the time to immobilization at high temperatures ("thermal knockdown"), in populations of the mosquito Aedes sierrensis collected from across a large latitudinal climate gradient spanning 1300 km (34-44 N). We find that mosquitoes collected from lower latitudes and warmer climates were more tolerant of high temperatures than those collected from higher latitudes and colder climates. Moreover, body size increased with latitude and decreased with temperature, a pattern consistent with James' rule, which appears to be a result of plasticity rather than genetic variation. Our results suggest that warmer environments produce smaller and more thermally tolerant populations.
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

The 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

The 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.
The accuracy of species tree inference under gene tree dependence
Authors: He Wanting , Scornavacca Celine , Chan Yao-ban
Published: June 2024

When inferring the evolutionary history of species and the genes they contain, the phylogenetic trees of the genes can be different to that of the species and to each other, due to a variety of causes including incomplete lineage sorting. We often wish to infer the species tree, but only reconstruct the gene trees from sequences. We then combine the gene trees to produce a species tree; methods to do this are known as summary methods, of which ASTRAL is the currently among the most popular. ASTRAL has been shown to be practically accurate in many scenarios through extensive simulations. However, these simulations generally assume that the input gene trees are independent of each other. This is known to be unrealistic, as genes that are close to each other on the chromosome (or are related by function) have dependent phylogenies, due to the absence of unlimited recombination between the genes.

In this paper, we develop a model for generating dependent gene trees within a species tree, based on the coalescent with recombination. We then use these trees as input to ASTRAL to reassess its accuracy for dependent gene trees. Our results show that ASTRAL performs more poorly with greater dependence, both when gene trees are known and estimated from sequences. Indeed, the effect of dependence between gene trees is comparable to (if not larger than) the effect of gene tree estimation error. We then re-analyse a 37-taxon mammalian data set; under a realistic recombination rate, the estimated accuracy of ASTRAL decreases substantially (the Robinson-Foulds distance increases by a factor of 4.7) relative to the accuracy previously estimated with independent gene trees, and the effective sample size for this dataset is about one-third of the actual sample size. This shows that the impact of gene tree dependence on the accuracy of ASTRAL (and other summary methods) can be extensive.

Author summary

The study of the evolutionary history of species is important for understanding and reconstructing the history of life on Earth. These evolutionary histories are represented in the form of species trees, which can be reconstructed from the evolutionary histories of the genes contained in the species using so-called species tree inference methods. This is complicated by the fact that the histories of the genes (gene trees) can be related to each other, depending on their placement in the genome or their functions. Gene tree dependence is not taken into account in almost all studies of the accuracy of species tree inference. In this paper, we develop a statistical model to include gene tree dependence, and show that it can significantly affect the accuracy of species tree inference. This effect is at least as large as the impact of incorrect reconstruction of the gene trees themselves, a well-known issue in species tree inference.
Chromatin remodeling with combined FACT and BET inhibition disrupts oncogenic transcription in Diffuse Midline Glioma
Authors: Holliday Holly , Khan Aaminah , Ehteda Anahid , Ross Samuel E. , Jayatilleke Nisitha , Gopalakrishnan Anjana , Guo Xinyi , Liu Jie , Nguyen Hieu , Lee Alvin , Sanguino Yolanda Colino , Dinger Marcel E. , Mayoh Chelsea , Rayner Benjamin S. , Tsoli Maria , Ziegler David S.
Published: June 2024

Aberrant epigenetic regulation is a hallmark of Diffuse Midline Glioma (DMG), an incurable pediatric brain tumor. The H3K27M driver histone mutation leads to transcriptional dysregulation, indicating that targeting the epigenome and transcription may be key therapeutic strategies against this highly aggressive cancer. One such target is the Facilitates Chromatin Transcription (FACT) histone chaperone. We found FACT to be enriched at developmental gene promoters, coinciding with regions of open chromatin and binding motifs of core DMG regulatory transcription factors. Furthermore, FACT interacted and co-localized with the Bromodomain and Extra-Terminal Domain (BET) protein BRD4 at promoters and enhancers, suggesting functional cooperation between FACT and BRD4 in DMG.In vitro, a combinatorial therapeutic approach using the FACT inhibitor CBL0137, coupled with BET inhibition revealed potent and synergistic cytotoxicity across a range of DMG cultures, with H3K27M-mutant cells demonstrating heightened sensitivity. These results were recapitulatedin vivo, significantly extending survival in three independent orthotopic PDX models of DMG. Mechanistically, we show that CBL0137 treatment decreased chromatin accessibility, synergizing with BET inhibition to disrupt transcription, silencing several key oncogenes includingMYC, PDGFRAandMDM4, as well as causing alterations to the splicing landscape. Combined, these data highlight the therapeutic promise of simultaneously targeting FACT and BRD4 in DMG, proposing a novel strategy for combating this devastating pediatric brain tumor.