bluuebunny/crossref_metadata_2025 huggingface dataset:
Mistranslating tRNA variants have anticodon- and sex-specific impacts onDrosophila melanogaster
Authors: Isaacson Joshua R. , Berg Matthew D. , Jagiello Jessica , Yeung William , Charles Brendan , Villén Judit , Brandl Christopher J. , Moehring Amanda J.
Published: June 2024

Transfer RNAs (tRNAs) are vital in determining the specificity of translation. Mutations in tRNA genes can result in the misincorporation of amino acids into nascent polypeptides in a process known as mistranslation. Since mistranslation has different impacts, depending on the type of amino acid substitution, our goal here was to compare the impact of different mistranslating tRNAServariants on fly development, lifespan, and behaviour. We established two mistranslating fly lines, one with a tRNAServariant that misincorporates serine at valine codons (V➔S) and the other that misincorporates serine at threonine codons (TàS). While both mistranslating tRNAs increased development time and developmental lethality, the severity of the impacts differed depending on amino acid substitution and sex. The V➔S variant extended embryonic, larval, and pupal development whereas the T➔S only extended larval and pupal development. Females, but not males, containing either mistranslating tRNA presented with significantly more anatomical deformities than controls. Mistranslating females also experienced extended lifespan whereas mistranslating male lifespan was unaffected. In addition, mistranslating flies from both sexes showed improved locomotion as they aged, suggesting delayed neurodegeneration. Therefore, although mistranslation causes detrimental effects, we demonstrate that mistranslation also has positive effects on complex traits such as lifespan and locomotion. This has important implications for human health given the prevalence of tRNA variants in humans.

PLAIN LANGUAGE SUMMARY

Mutant tRNA genes can cause mistranslation, the misincorporation of amino acids into proteins, and are associated with several human diseases. This study investigated the role of two tRNA variants that cause threonine-to-serine (T➔S) or valine-to-serine (V➔S) substitution. Both variants caused developmental delays and lethality in both sexes and increase prevalence of deformities in females. Surprisingly, female T➔S and V➔S flies experienced increased lifespan and mistranslating males and females showed improved locomotion. These results suggest that mistranslation has both positive and negative effects that depend on the tRNA variant and sex of the fly.
Combined effects of matrix stiffness and obesity-associated signaling directs progressive phenotype in PANC-1 pancreatic cancer cellsin vitro
Authors: Jones A.E. , Netto J.F. , Foote T.L. , Ruliffson B.N.K. , Whittington C.F.
Published: June 2024

Obesity is a leading risk factor of pancreatic ductal adenocarcinoma (PDAC) that contributes to poor disease prognosis and outcomes. Retrospective studies have identified this link, but interactions surrounding obesity and PDAC are still unclear. Research has shifted to contributions of fibrosis (desmoplasia) on malignancy, which involves increased deposition of collagens and other extracellular matrix (ECM) molecules and increased ECM crosslinking, all of which contribute to increased tissue stiffening. However, fibrotic stiffening is underrepresented as a model feature in current PDAC models. Fibrosis is shared between PDAC and obesity, and can be leveraged forin vitromodel design, as current animal obesity models of PDAC are limited in their ability to isolate individual components of fibrosis to study cell behavior. In the current study, methacrylated type I collagen (PhotoCol®) was photo-crosslinked to pathological stiffness levels to recapitulate fibrotic ECM stiffening. PANC-1 cells were encapsulated within PhotoCol®, and the tumor-tissue constructs were prepared to represent normal (healthy) (∼600 Pa) and pathological (∼2000 Pa) tissues. Separately, human mesenchymal stem cells were differentiated into adipocytes representing lean (2D differentiation) and obese fat tissue (3D collagen matrix differentiation), and conditioned media was applied to PANC-1 tumor-tissue constructs. Conditioned media from obese adipocytes showed increased vimentin expression, a hallmark of invasiveness and progression, that was not seen after exposure to media from lean adipocytes or control media. Characterization of the obese adipocyte secretome suggested that some PANC-1 differences may arise from increased interleukin-8 and -10 compared to lean adipocytes. Additionally, high matrix stiffness associated induced an amoeboid morphology in PANC-1 cells that was not present at low stiffness. Amoeboid morphology is an accessory to epithelial-to-mesenchymal transition and is used to navigate complex ECM environments. This plasticity has greater implications for treatment efficacy of metastatic cancers. Overall, this work 1) highlights the importance of investigating PDAC-obesity interactions to study the effects on disease progression and persistence, 2) establishes PhotoCol® as a matrix material that can be leveraged to study amoeboid morphology and invasion in PDAC, and 3) emphasizes the importance of integrating both biophysical and biochemical interactions associated within both pathologies forin vitroPDAC models.
Early transatlantic movement of horses and donkeys at Jamestown
Authors: Treal Taylor William Timothy , Delsol Nicolas , Oelze Vicky M. , Mitchell Peter , Stricker Leah , Lavin Michael , Ogundiran Akin , Hosek Lauren , Barrón-Ortiz Christina Isabelle , Ojediran Olumide , Quintero-Bisono Diana , Magoon Dane , Hill Matthew E. , Thomas Ariane E. , Waterman Anna , Peate David W. , Chauvey Lorelei , Schiavinato Stéphanie , Tonasso-Calvière Laure , Borges Luis , Brito-Mayor Aitor , Santana Jonathan , Kamenov George , Orlando Ludovic , Krigbaum John
Published: June 2024

Domestic horses and donkeys played a key role in the initial colonization of the Atlantic seaboard of the Americas, a process partially chronicled by historical records. While Spanish colonists brought horses to the Caribbean and southern latitudes earlier, the transport of domestic horses to the English colony at Jamestown, Virginia in 1606 was among the first dispersals to the eastern seaboard. Archaeozoological analysis, isotope analysis, and radiocarbon dating of identifiable domestic equid remains from two contexts associated with the initial occupation of Jamestown demonstrate intense processing and consumption of the first Jamestown horses during the “Starving Time” winter of 1609, while paleopathological data show evidence of their use in transport. Osteological, genetic, and isotopic study of these equid remains reveal the presence of at least one adult domestic donkey with mixed European and West African ancestry, possibly supplied through undocumented exchange during a trans-Atlantic stopover. These results reveal the importance of equids in the survival of early European settlers and the global connectivity of early trans-Atlantic exchange in horses and donkeys, showing Caribbean and African links in the founding livestock populations and pointing towards an important and ecologically-anchored role for donkeys in the early colonial lifeways along the Eastern seaboard.
Ocular biomarker profiling after complement factor I gene therapy in geographic atrophy secondary to age-related macular degeneration
Authors: Hallam Thomas M , Gardenal Emanuela , McBlane Fraser , Cho GaEun , Ferraro Lucy Lee , Pekle Eva , Lu Darlene , Carney Kate , Wenden Claire , Beadsmoore Hannah , Kaiser Sergio , Drage Lauren , Haye Thomas , Kassem Iris , Rangaswamy Nalini , Obeidat Ma’en , Grosskreutz Cyndy , Saint-Geniez Magali , Steel David H , MacLaren Robert E , Ellis Scott , Harris Claire L , Poor Stephen , Jones Amy V
Published: June 2024

Objective

Complement biomarker analysis in ocular fluid samples from subjects with geographic atrophy (GA) in a Phase I/II clinical trial of subretinal AAV2 complement factor I (CFI; FI) gene therapy, PPY988 (formerly GT005), to understand target pharmacokinetics/pharmacodynamics. Clinical findings were subsequently utilized to investigate the therapeutic dose in anin vitrocomplement activation assay.

Design, setting and participants

Biomarker data were evaluated from 28 subjects in FOCUS, a Phase I/II clinical trial evaluating the safety and efficacy of three ascending doses of PPY988.

Main outcomes and measures

Vitreous humor (VH), and aqueous humor (AH) from subjects before surgery and at serial timepoints (week 5 or 12, 36, 96) were evaluated for changes in levels of intact complement factors I, B and H (FI, FB, FH) components C3, C4, and C1q and breakdown products (Ba, C3a, C3b/iC3b, C4b) using validated assays and OLINK®proteomics.

A modifiedin vitroassay of complement activation modelling VH complement concentrations was used to compare PPY988 potency to the approved intravitreal C3 inhibitor pegcetacoplan (Apellis) and complement Factor H (FH).

Results

An average 2-fold increase in VH FI was observed post-treatment at week 36 and week 96. This correlated with a marked post-treatment reduction in VH concentration of the FB breakdown product Ba and Ba:FB ratio, but minimal changes in C3a and C3b/iC3b levels. Variable concordance in complement biomarker levels in VH versus AH suggest AH is not a reliable proxy for VH for complement activation. During the experimental comparison of doses, a 2-fold increase of FI achieved in the vitreous had only a minor effect on the complement amplification loopin vitro, indicating limited impact [IC50: 1229nM]. Pegcetacoplan completely blocks C3a generation at concentrations much lower than the estimated trough level for monthly intravitreal injections [IC50: 2nM]. Supplementation with FH in the assay revealed similar potency to pegcetacoplan [IC50: 6nM].

Conclusions and relevance

PPY988 subretinal gene therapy may not have provided sufficient FI protein to meaningfully modulate complement activation to slow GA growth. Reviewing VH biomarkers is important for understanding target expression, pathway engagement, and determining optimal dose, thereby informing future clinical development.
Dual targeting of KDM1A and antioxidants is an effective anticancer strategy
Authors: Mudambi Shaila , Fitzgerald Megan E , Washington Deschana L , Pera Paula J , Huss Wendy J , Paragh Gyorgy
Published: June 2024

Abstract

Lysine Specific Demethylase 1 (KDM1A / LSD1) regulates mitochondrial respiration and stabilizes HIF-1A (hypoxia-inducible factor 1A). HIF-1A modulates reactive oxygen species (ROS) levels by increasing cellular glucose uptake, glycolysis, and endogenous antioxidants. The role of KDM1A in cellular ROS response has not previously been described. We determined the role of KDM1A in regulating the ROS response and the utility of KDM1A inhibitors in combination with ROS-inducing cancer therapies. Our results show that KDM1A inhibition sensitized cells to oxidative stress and increased total cellular ROS, which was mitigated by treatment with the antioxidant N-acetyl cysteine. KDM1A inhibition decreased basal mitochondrial respiration and impaired induction of HIF-1A after ROS exposure. Overexpression of HIF-1A salvaged cells from KDM1A inhibition enhanced sensitivity to ROS. Thus we found that increased sensitivity of ROS after KDM1A inhibition was mediated by HIF-1A and depletion of endogenous glutathione. We also show that KDM1A-specific inhibitor bizine synergized with antioxidant-depleting therapies, buthionine sulfoximine, and auranofin in rhabdomyosarcoma cell lines (Rh28 and Rh30). In this study, we describe a novel role for KDM1A in regulating HIF- 1A functions under oxidative stress and found that dual targeting of KDM1A and antioxidant systems may serve as an effective combination anticancer strategy.
Vegetation density is the main driver of insect species richness and diversity in small private urban front gardens
Authors: Morpurgo Joeri , Huurdeman Margot , Oostermeijer J. Gerard B. , Remme Roy P.
Published: June 2024

Urbanisation changes the natural ecosystems and vegetation to urban green spaces, and causes insect communities to experience novel challenges for survival. New evidence suggests that urban green spaces, no matter how small, can provide meaningful habitats for insects. Information on design and management of small gardens (<10m2) in dense urban areas is still scarce. In particular, it is hardly known which garden designs provide most benefits to insects. We surveyed 65 small private urban front gardens (μ=1.7m2) in Amsterdam and The Hague in The Netherlands and measured a series of garden attributes thought to be relevant for general, flower-visiting and herbivorous insect species richness and diversity. Plant coverage and richness were the strongest predictors for insect biodiversity and species richness. We found no support for associations with native vs. exotic plants or garden size.

Synthesis and applications

To strengthen insect biodiversity in the urban environment, we recommend future design of urban green spaces to focus on maximising coverage and richness of vegetation, potentially even using exotic species to fill in the gaps where native plant species cannot survive.

Highlights

Small urban gardens hold large potential for supporting urban insect communities

Total vegetation cover was the strongest predictor for insect diversity and richness

Plant richness was the second strongest predictor, but not for herbivorous insects

Garden size had no effect on insect diversity or richness

Native vegetation did not impact insect diversity or richness

Abstract Figure

Graphical abstract. Shown are either plus or minus signs indicating a positive or negative trends from the models that predict species richness and Shannon biodiversity of insects, pollinators or herbivores by the design of small urban gardens.

*indicates a statistically significant trend at p-value < 0.05. A plus or minus sign without*means a visible statistically non-significant trend. A greyed out square indicates exclusion of the term in the model. A white square indicates non-significant and non-visible trend.
Recent speciation and adaptation to aridity in the ecologically diverse Pilbara region of Australia enabled the native tobaccos (Nicotiana; Solanaceae) to colonize all Australian deserts
Authors: Cauz-Santos Luiz Augusto , Samuel Rosabelle , Metschina Dominik , Christenhusz Maarten J. M. , Dixon Kingsley W. , Conran John G. , Paun Ovidiu , Chase Mark W.
Published: June 2024

For the last six million years, the arid Australian Eremaean Zone (EZ) has been as dry as today. A hypothesis, applied to arid regions worldwide, suggests that flora and fauna were more broadly distributed before aridification began. In Australia, this aridification process started around 20 million years ago (Mya), leading to gradual speciation processes via vicariance as the climate became increasingly arid. Here, we use genomic data to investigate the biogeography and timing of divergence of native allotetraploid tobaccos, Nicotiana section Suaveolentes (Solanaceae), which putatively entered the EZ 5 Mya. The original allotetraploid migrants from South America were adapted to mesic areas of Australia and putatively radiated recently in the EZ, including sandy dune fields (only 1.2 My old), after developing drought adaptations. Based on coalescent and maximum likelihood analyses designed to corroborate timing of the Australian radiation independently, arrival of Nicotiana section Suaveolentes on the continent occurred approximately 6 Mya, and ancestors of the Pilbara (Western Australian) lineages radiated there at the onset of extreme aridity 5 Mya by locally adapting to these various ancient, highly stable habitats. The Pilbara thus served as both a mesic refugium and cradle for adaptations to harsher conditions. This dual role is due to its high topographical diversity, providing microhabitats with varying moisture levels, and its proximity to the ocean, which buffers against extreme aridity. Consequently, species like Nicotiana have been able to survive in mesic refugia during arid periods and subsequently adapt to more arid conditions. These results demonstrate that initially poorly adapted plant groups can develop novel adaptations in situ, permitting extensive and rapid wide dispersal despite the highly variable and unpredictable extremes of heat and drought in the EZ.
Effective anti-tumor immune responses are orchestrated by immune cell partnership network that functions through tissue homeostatic pathways, not direct cytotoxicity
Authors: Koelsch Nicholas , Mirshahi Faridoddin , Aqbi Hussein F. , Seneshaw Mulugeta , Idowu Michael O. , Olex Amy L. , Sanyal Arun J. , Manjili Masoud H.
Published: June 2024

The liver hosts a diverse array of immune cells that play pivotal roles in both maintaining tissue homeostasis and responding to disease. However, the precise contributions of these immune cells in the progression of nonalcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma (HCC) remain unclear. Utilizing a systems immunology approach, we reveal that liver immune responses are governed by a dominant-subdominant hierarchy of ligand-receptor-mediated homeostatic pathways. In healthy individuals, inflammatory immune responses operate within these pathways, challenging the notion of the liver as a purely tolerogenic organ. Chronic consumption of a Western diet (WD) disrupts hepatocyte function and reconfigures immune interactions, resulting in hepatic stellate cells (HSCs), cancer cells, and NKT cells driving 80% of the immune activity during NAFLD. In HCC, 80% of immune response involves NKT cells and monocytes collaborating with hepatocytes and myofibroblasts to restore disrupted homeostasis. Interestingly, dietary correction during NAFLD yields nonlinear outcomes: tumor progression coincides with the failure of mounting homeostatic immune responses, whereas tumor prevention is associated with sustained immune responses, predominantly orchestrated by monocytes. These monocytes actively target fibroblasts and myofibroblasts, creating a tumor-suppressive microenvironment. Notably, only 5% of T cells displayed apoptosis-inducing activity, selectively contributing to the turnover of hepatic stromal cells, particularly myofibroblasts and fibroblasts. Our findings suggest that effective anti-tumor immune responses in the liver are primarily mediated by immune cells sustaining tissue homeostasis, rather than relying on direct cytotoxic mechanisms.
The ENCODE mouse postnatal developmental time course identifies regulatory programs of cell types and cell states
Authors: Rebboah Elisabeth , Rezaie Narges , Williams Brian A. , Weimer Annika K. , Shi Minyi , Yang Xinqiong , Liang Heidi Yahan , Dionne Louise A. , Reese Fairlie , Trout Diane , Jou Jennifer , Youngworth Ingrid , Reinholdt Laura , Morabito Samuel , Snyder Michael P. , Wold Barbara J. , Mortazavi Ali
Published: June 2024

Postnatal genomic regulation significantly influences tissue and organ maturation but is under-studied relative to existing genomic catalogs of adult tissues or prenatal development in mouse. The ENCODE4 consortium generated the first comprehensive single-nucleus resource of postnatal regulatory events across a diverse set of mouse tissues. The collection spans seven postnatal time points, mirroring human development from childhood to adulthood, and encompasses five core tissues. We identified 30 cell types, further subdivided into 69 subtypes and cell states across adrenal gland, left cerebral cortex, hippocampus, heart, and gastrocnemius muscle. Our annotations cover both known and novel cell differentiation dynamics ranging from early hippocampal neurogenesis to a new sex-specific adrenal gland population during puberty. We used an ensemble Latent Dirichlet Allocation strategy with a curated vocabulary of 2,701 regulatory genes to identify regulatory “topics,” each of which is a gene vector, linked to cell type differentiation, subtype specialization, and transitions between cell states. We find recurrent regulatory topics in tissue-resident macrophages, neural cell types, endothelial cells across multiple tissues, and cycling cells of the adrenal gland and heart. Cell-type-specific topics are enriched in transcription factors and microRNA host genes, while chromatin regulators dominate mitosis topics. Corresponding chromatin accessibility data reveal dynamic and sex-specific regulatory elements, with enriched motifs matching transcription factors in regulatory topics. Together, these analyses identify both tissue-specific and common regulatory programs in postnatal development across multiple tissues through the lens of the factors regulating transcription.
Evaluating the Roles of Drift and Selection in Trait Loss along an Elevational Gradient
Authors: Buysse Sophia F. , Pérez Samuel G. , Puzey Joshua R. , Garrison Ava , Bradburd Gideon S. , Oakley Christopher G. , Tonsor Stephen J. , Picó F. Xavier , Josephs Emily B. , Conner Jeffrey K
Published: June 2024

Traits that have lost function sometimes persist through evolutionary time. These traits may persist if there is not enough standing genetic variation for the trait to allow a response to selection, if selection against the trait is weak relative to drift, or if the trait has a residual function. To determine the evolutionary processes shaping whether nonfunctional traits are retained or lost, we investigated short stamens in 16 populations ofArabidopsis thalianaalong an elevational cline in northeast Spain. We found a cline in short stamen number from retention of short stamens in high elevation populations to incomplete loss in low elevation populations. We did not find evidence that limited genetic variation constrains the loss of short stamens at high elevations, nor evidence for divergent selection on short stamens between high and low elevations. Finally, we identified loci associated with short stamens in northeast Spain that are different from loci associated with variation in short stamen number across latitudes from a previous study. Overall, we did not identify the evolutionary mechanisms contributing to an elevational cline in short stamen number but did identify different genetic loci underlying variation in short stamen along similar phenotypic clines.

Teaser text

The evolutionary mechanisms underlying loss or retention of traits that have lost function are poorly understood. Short stamens inArabidopsis thalianaprovide a compelling system to investigate the roles of genetic drift and selection in trait loss across latitudinal and elevational clines. This study investigates how drift and selection shape short stamen loss in 16 populations ofA. thalianaalong an elevational gradient in Northeast Spain. An investigation of the loci underlying variation in short stamen number suggests variants in different genes may cause trait loss in similar phenotypic clines within a species.
Xenometabolome of Early-Life Stage Salmonids Exposed to 6PPD-Quinone
Authors: Ankley Phillip J. , da Silva Francisco C. , Hunnie Blake , Roberts Catherine , Eriksson Andreas N. M. , Kohlman Evan , Corker Jennifer , Westcott Jodi , Germain Bradlee , Martin Michael J. , Dubiel Justin , Anderson-Bain Katherine , Urrutia Rayen M. , Hogan Natacha , Giesy John P. , Wiseman Steve , Krol Ed , Hecker Markus , Brinkmann Markus
Published: June 2024

N-(1,3-Dimethylbutyl)-N′-phenyl-p-phenylenediamine-quinone (6PPD-Q) is a ubiquitous transformation product (TP) derived from the rubber tire antioxidantN-(1,3-Dimethylbutyl)-N′-phenyl-p-phenylenediamine (6PPD) and is acutely toxic to certain species ofSalmonidae. Not all salmonids are sensitive to acute lethality caused by 6PPD-Q, with 6PPD-Q potency varying by several orders of magnitude among teleosts. The main driver(s) of species sensitivity differences is (are) a pressing question, with one area of interest examining whether differences in teleosts ability to biotransform and detoxify 6PPD-Q could be a key factor. This study utilized liquid-chromatography high-resolution mass spectrometry (LC-HRMS) to assess biotransformation and metabolome-wide effects of 6PPD-Q on early-life stage salmonids, including two sensitive species, rainbow trout (Oncorhynchus mykiss) and lake trout (Salvelinus namaycush), and one tolerant species, brown trout (Salmo trutta). Three phase I TPs and seven phase II TPs were detected, with differences in peak areas revealing that brown trout had the greatest ability to detoxify 6PPD-Q. Monohydroxylated TPs were verified using co-developed analytical standards that will be of use for future biomonitoring and exposure assessment. Several endogenous metabolites were found to be dysregulated in rainbow and lake trout, indicative of mitochondrial dysfunction, altered metabolism, and disrupted membrane permeability. Results of this study indicate a difference in the biotransformation capability of 6PPD-Q amongSalmonidaefish species and subsequent unique metabolome responses.

Graphical Abstract

Synopsis

Inter-species salmonid differences in the biotransformation capability of 6PPD-Q leads to sensitivity variability and subsequent unique metabolome responses.
Inferring single-cell spatial gene expression with tissue morphology via explainable deep learning
Authors: Zhao Yue , Alizadeh Elaheh , Liu Yang , Xu Ming , Mahoney J Matthew , Li Sheng
Published: June 2024

The spatial arrangement of cells is vital in developmental processes and organogenesis in multicellular life forms. Deep learning models trained with spatial omics data uncover complex patterns and relationships among cells, genes, and proteins in a high-dimensional space, providing new insights into biological processes and diseases. State-of-the-artin silicospatialmulti-cellgene expression methods using histological images of tissue stained with hematoxylin and eosin (H&E) to characterize cellular heterogeneity. These computational techniques offer the advantage of analyzing vast amounts of spatial data in a scalable and automated manner, thereby accelerating scientific discovery and enabling more precise medical diagnostics and treatments.

In this work, we developed a vision transformer (ViT) framework to map histological signatures to spatialsingle-celltranscriptomic signatures, named SPiRiT (Spatial OmicsPrediction andReproducibility integratedTransformer). Our framework was enhanced by integrating cross validation with model interpretation during hyper-parameter tuning. SPiRiT predicts single-cell spatial gene expression using the matched histopathological image tiles of human breast cancer and whole mouse pup, evaluated by Xenium (10x Genomics) datasets. Furthermore, ViT model interpretation reveals the high-resolution, high attention area (HAR) that the ViT model uses to predict the gene expression, including marker genes for invasive cancer cells (FASN), stromal cells (POSTN), and lymphocytes (IL7R). In an apple-to-apple comparison with the ST-Net Convolutional Neural Network algorithm, SPiRiT improved predictive accuracy by 40% using human breast cancer Visium (10x Genomics) dataset. Cancer biomarker gene prediction and expression level are highly consistent with the tumor region annotation. In summary, our work highlights the feasibility to infer spatial single-cell gene expression using tissue morphology in multiple-species, i.e., human and mouse, and multi-organs, i.e., mouse whole body morphology. Importantly, incorporating model interpretation and vision transformer is expected to serve as a general-purpose framework for spatial transcriptomics.
Estrogen-induced chromatin looping changes identify a subset of functional regulatory elements
Authors: Abewe Hosiana , Richey Alexandra , Vahrenkamp Jeffery M , Ginley-Hidinger Matthew , Rush Craig M , Kitchen Noel , Zhang Xiaoyang , Gertz Jason
Published: June 2024

Transcriptional enhancers can regulate individual or multiple genes through long-range three-dimensional (3D) genome interactions, and these interactions are commonly altered in cancer. Yet, the functional relationship between changes in 3D genome interactions associated with regulatory regions and differential gene expression appears context-dependent. In this study, we used HiChIP to capture changes in 3D genome interactions between active regulatory regions of endometrial cancer cells in response to estrogen treatment and uncovered significant differential long-range interactions strongly enriched for estrogen receptorα(ER) bound sites (ERBS). The ERBS anchoring differential chromatin loops with either a gene’s promoter or distal regions were correlated with larger transcriptional responses to estrogen compared to ERBS not involved in differential 3D genome interactions. To functionally test this observation, CRISPR- based Enhancer-i was used to deactivate specific ERBS, which revealed a wide range of effects on the transcriptional response to estrogen. However, these effects are only subtly and not significantly stronger for ERBS in differential chromatin loops. In addition, we observed an enrichment of 3D genome interactions between the promoters of estrogen upregulated genes and found that looped promoters can work together cooperatively. Overall, our work reveals that estrogen treatment causes large changes in 3D genome structure in endometrial cancer cells; however, these changes are not required for a regulatory region to contribute to an estrogen transcriptional response.
ParallelEvolCCM: Quantifying co-evolutionary patterns among genomic features
Authors: Beiko Robert G. , Liu Chaoyue , Cavalcante João Vitor , Fink Ryan C.
Published: June 2024

Concerted gains and losses of genomic features such as genes and mobile genetic elements can provide key clues into related functional roles and shared evolutionary trajectories. By capturing phylogenetic signals, a co-evolutionary model can outperform comparative methods based on shared presence and absence of features.We previously developed the Community Coevolution Model, which represents the gain/loss probability of each feature as a combination of its own intrinsic rate, combined the joint probabilities of gain and loss with all other features. Originally implemented as an R library, we have now developed a R wrapper that adds parallelization and several options to pre-filter the features to increase the efficiency of comparisons. Here we describe the functionality of EvolCCM and apply it to a dataset of 1000 genomes of the genus Bifidobacterium. ParallelEvolCCM is released under the MIT license and available athttps://github.com/beiko-lab/arete/blob/master/bin/ParallelEvolCCM.R.

Significance Statement

Patchy phylogenetic distributions of genes, mobile genetic elements, and other genomic features can constitute evidence for lateral gene transfer. Comparing the presence/absence patterns of multiple features can reveal important associations among them, but the phylogenetic relationships must be taken into consideration in order to avoid spurious correlations. Our new ParallelEvolCCM software embeds these comparisons in a coevolutionary framework, offers a range of options to optimize the speed and comparisons, and offers helper scripts to visualize relationships among features.
Wolbachiastrain wMelM disrupts egg retention byAedes aegyptifemales prevented from ovipositing
Authors: Ross Perran A. , Yeatman Ella , Gu Xinyue , Hoffmann Ary A. , van Heerwaarden Belinda
Published: June 2024

Aedes aegyptimosquitoes are well adapted to dry climates and can retain their eggs for extended periods in the absence of suitable habitat.Wolbachiastrains transferred from other insects to mosquitoes can be released to combat dengue transmission by blocking virus replication and spreading through populations, but host fitness costs imposed byWolbachia, particularly under some environments, can impede spread. We therefore assessed the impact of twoWolbachiastrains being released for dengue control (wAlbB andwMelM) on fecundity and egg viability following extended egg retention (12 or 18 d) under laboratory conditions. Egg viability decreased to a greater extent in females carryingwMelM compared to uninfected orwAlbB females. Fertility fully recovered in uninfected females following a second blood meal after laying retained eggs, whilewMelM females experienced only partial recovery. Effects ofwMelM on egg retention were similar regardless of whether females were crossed to uninfected orwMelM males, suggesting that fitness costs were triggered byWolbachiapresence in females. The fecundity and hatch proportions of eggs ofwMelM females declined with age, regardless of whether females used stored sperm or were recently inseminated. Costs of someWolbachiastrains during egg retention may affect the invasion and persistence ofWolbachiain release sites where larval habitats are scarce and/or intermittent.
Latrophilin-2 mediates fluid shear stress mechanotransduction at endothelial junctions
Authors: Tanaka Keiichiro , Chen Minghao , Prendergast Andrew , Zhuang Zhenwu , Nasiri Ali , Joshi Divyesh , Hintzen Jared , Chung Minhwan , Kumar Abhishek , Mani Arya , Koleske Anthony , Crawford Jason , Nicoli Stefania , Schwartz Martin A.
Published: June 2024

Endothelial cell responses to fluid shear stress from blood flow are crucial for vascular development, function and disease. A complex of PECAM-1, VE-cadherin, VEGF receptors (VEGFRs) and PlexinD1 located at cell-cell junctions mediates many of these events. But available evidence suggests that another mechanosensor upstream of PECAM-1 initiates signaling. Hypothesizing that GPCR and Gα proteins may serve this role, we performed siRNA screening of Gα subunits and found that Gαi2 and Gαq/11 are required for activation of the junctional complex. We then developed a new activation assay, which showed that these G proteins are activated by flow. We next mapped the Gα residues required for activation and developed an affinity purification method that used this information to identify latrophilin-2 (Lphn-2/ADGRL2) as the upstream GPCR. Latrophilin-2 is required for all PECAM-1 downstream events tested. In both mice and zebrafish, latrophilin-2 is required for flow-dependent angiogenesis and artery remodeling. Furthermore, endothelial specific knockout demonstrates that latrophilin plays a role in flow-dependent artery remodeling. Human genetic data reveal a correlation between the latrophilin-2-encodingAdgrl2gene and cardiovascular disease. Together, these results define a pathway that connects latrophilin-dependent G protein activation to subsequent endothelial signaling, vascular physiology and disease.
Deep brain stimulation induces white matter remodeling and functional changes to brain-wide networks
Authors: Fujimoto Satoka H. , Fujimoto Atsushi , Elorette Catherine , Seltzer Adela , Andraka Emma , Verma Gaurav , Janssen William GM , Fleysher Lazar , Folloni Davide , Choi Ki Sueng , Russ Brian E. , Mayberg Helen S. , Rudebeck Peter H.
Published: June 2024

Deep brain stimulation (DBS) is an emerging therapeutic option for treatment resistant neurological and psychiatric disorders, most notably depression. Despite this, little is known about the anatomical and functional mechanisms that underlie this therapy. Here we targeted stimulation to the white matter adjacent to the subcallosal anterior cingulate cortex (SCC-DBS) in macaques, modeling the location in the brain proven effective for depression. We demonstrate that SCC-DBS has a selective effect on white matter macro- and micro-structure in the cingulum bundle distant to where stimulation was delivered. SCC-DBS also decreased functional connectivity between subcallosal and posterior cingulate cortex, two areas linked by the cingulum bundle and implicated in depression. Our data reveal that white matter remodeling as well as functional effects contribute to DBS’s therapeutic efficacy.
Multi-dimensionality of tree communities structure host-parasitoid networks and their phylogenetic composition
Authors: Wang Ming-Qiang , Guo Shi-Kun , Guo Peng-Fei , Yang Juan-Juan , Chen Guo-Ai , Chesters Douglas , Orr Michael , Niu Ze-Qing , Staab Michael , Chen Jing-Ting , Li Yi , Zhou Qing-Song , Fornoff Felix , Shi Xiaoyu , Li Shan , Martini Massimo , Klein Alexandra-Maria , Schuldt Andreas , Liu Xiaojuan , Ma Keping , Bruelheide Helge , Luo Arong , Zhu Chao-Dong
Published: June 2024

Environmental factors can influence ecological networks, but these effects are poorly understood in the realm of the phylogeny of host-parasitoid interactions. Especially, we lack a comprehensive understanding of the ways that biotic factors, including plant species richness, overall community phylogenetic and functional composition of consumers, and abiotic factors such as microclimate, determining host–parasitoid network structure and host–parasitoid community dynamics. To address this, we leveraged a five-year dataset of trap-nesting bees and wasps and their parasitoids collected in a highly-controlled, large-scale subtropical tree biodiversity experiment. We tested for effects of tree species richness, tree phylogenetic and functional diversity, and species and phylogenetic composition on species and phylogenetic diversity of both host and parasitoid communities and the composition of their interaction networks. We show that multiple components of tree diversity and canopy cover impacted both, species and phylogenetic composition of hosts and parasitoids. Generally, phylogenetic associations between hosts and parasitoids reflected non-randomly structured interactions between phylogenetic trees of hosts and parasitoids. Further, host-parasitoid network structure was influenced by tree species richness, tree phylogenetic diversity, and canopy cover. Our study indicates that the composition of higher trophic levels and corresponding interaction networks are determined by plant diversity and canopy cover especially via trophic links in species-rich ecosystems.
Cerebrospinal Fluid Dynamics: Uncovering Alternative Blood Vessel Clearance Mechanisms
Authors: Yuan Qiuju , Satyanarayanan Senthil Kumaran , Lee Suki Man-Yan , Yan Lingli , Wang Yaofeng , Xian Yan-Fang , He Liumin , Zhou Yingying , Wu Wutian , Song You-Qiang , Su Huanxing , Lin Zhi-Xiu , Qin Dajiang
Published: June 2024

The pathways that run along the olfactory nerves crossing the cribriform plate and connecting to lymphatic vessels in the nasal cavity, have been identified as a crucial route for cerebrospinal fluid (CSF) outflow. However, the presence of a CSF efflux pathway through blood vessels in this region has yet to be clarified. This study aimed to elucidate the anatomical connections between the subarachnoid space and the bloodstream at the nasal epithelium and the venous drainage routes of the nasal epithelium in mice. Our findings demonstrated that CSF tracers could be drained not only through lymphatic vessels in the nasal cavity and cervical lymph nodes (CLNs), but also through the blood vessels in this area that extend to its venous drainage routes, including the facial and jugular veins. Additionally, we showed that ligation of CLNs neither impeded the influx and efflux of CSF tracers nor exacerbated Alzheimer’s disease (AD)-related pathology in AD mice. Our work reveals a previously unrecognized pathway for CSF drainage through blood vessels within the nasal mucosa. These findings provide insight into the efficient removal of waste products, facilitating optimal functioning of neural tissue within the susceptible tissue of our brains.
Neuromodulation with Ultrasound: Hypotheses on the Directionality of Effects and Community Resource
Authors: Caffaratti Hugo , Slater Ben , Shaheen Nour , Rhone Ariane , Calmus Ryan , Kritikos Michael , Kumar Sukhbinder , Dlouhy Brian , Oya Hiroyuki , Griffiths Tim , Boes Aaron D. , Trapp Nicholas , Kaiser Marcus , Sallet Jérôme , Banks Matthew I. , Howard Matthew A. , Zanaty Mario , Petkov Christopher I.
Published: June 2024

Low-intensity Transcranial Ultrasound Stimulation is a promising non-invasive technique for brain stimulation and focal neuromodulation. Research with humans and animal models has raised the possibility that TUS can be biased towards enhancing or suppressing neural function. Here, we first collate a set of hypotheses on the directionality of TUS effects and conduct an initial meta-analysis on the availablehealthy human participantTUS studies reporting stimulation parameters and outcomes (n =47 studies, 52 experiments). In these initial exploratory analyses, we find that parameters such as the intensity and continuity of stimulation (duty cycle) with univariate tests show only statistical trends towards likely enhancement or suppressed of function with TUS. Multivariate machine learning analyses are currently limited by the small sample size. Given that human TUS sample sizes will continue to increase, predictability on the directionality of TUS effects could improve if this database can continue to grow as TUS studies more systematically explore the TUS stimulation parameter space and report outcomes. Therefore, we establish aninTUSdatabase and resource for the systematic reporting of TUS parameters and outcomes to assist in greater precision in TUS use for brain stimulation and neuromodulation. The paper concludes with a selective review ofhuman clinical TUSstudies illustrating how hypotheses on the directionality of TUS effects could be developed for empirical testing in the intended clinical application, not limited to the examples provided.

Highlights

Collated set of hypotheses on using TUS to bias towards enhancement or suppression

Meta-analysis results identify parameters that may bias directionality of TUS effects

inTUSresource established for systematic reporting of TUS parameters and outcomes

Selective review of patient TUS studies for enhancing or suppressing neural function
Functional dysconnectivity of visual and somatomotor networks yields a simple and robust biomarker for psychosis
Authors: Keane Brian P. , Abrham Yonatan , Cole Michael W. , Johnson Brent A. , Hu Boyang , Cocuzza Carrisa V.
Published: June 2024

People with psychosis exhibit thalamo-cortical hyperconnectivity and cortico-cortical hypoconnectivity with sensory networks, however, it remains unclear if this applies to all sensory networks, whether it arises from other illness factors, or whether such differences could form the basis of a viable biomarker. To address the foregoing, we harnessed data from the Human Connectome Early Psychosis Project and computed resting-state functional connectivity (RSFC) matrices for 54 healthy controls and 105 psychosis patients. Primary visual, secondary visual (“visual2”), auditory, and somatomotor networks were defined via a recent brain network partition. RSFC was determined for 718 regions via regularized partial correlation. Psychosis patients— both affective and non-affective—exhibited cortico-cortical hypoconnectivity and thalamo-cortical hyperconnectivity in somatomotor and visual2 networks but not in auditory or primary visual networks. When we averaged and normalized the visual2 and somatomotor network connections, and subtracted the thalamo-cortical and cortico-cortical connectivity values, a robust psychosis biomarker emerged (p=2e-10, Hedges’ g=1.05). This “somato-visual” biomarker was present in antipsychotic-naive patients and did not depend on confounds such as psychiatric comorbidities, substance/nicotine use, stress, anxiety, or demographics. It had moderate test-retest reliability (ICC=.61) and could be recovered in five-minute scans. The marker could discriminate groups in leave-one-site-out cross-validation (AUC=.79) and improve group classification upon being added to a well-known neurocognition task. Finally, it could differentiate later-stage psychosis patients from healthy or ADHD controls in two independent data sets. These results introduce a simple and robust RSFC biomarker that can distinguish psychosis patients from controls by the early illness stages.
Developing Consensus for an Upper and Lower Limb Athlete Pain Assessment Framework – A Real-time Delphi Study with International Sports Physiotherapists
Authors: Purcell Ciarán , Fullen Brona M , Ward Tomás , Caulfield Brian M
Published: June 2024

Objectives

There is no current consensus on the key items sports physiotherapists should consider when completing a comprehensive biopsychosocial upper or lower limb pain assessment with athletes. We sought to develop recommendations to inform a framework for the assessment of upper and lower limb pain in athletes.

Design

Real-time Delphi

Methods

We recruited sports physiotherapists currently working with athletes through the International Society of Sports Physical Therapists and Irish Society of Chartered Physiotherapists. Participants voted on 86 pain assessment items chosen using best available evidence. The real-time Delphi method facilitated independent anonymous voting, commenting and immediate review of consensus. Participants indicated level of agreement for inclusion in an upper and lower limb athlete pain assessment framework on a 6-point Likert scale from Strongly Disagree to Strongly Agree, and how often they are/will be required in practice on a 5-point scale fromNevertoAlways.Criteria for consensus agreement and inclusion were i) >70% sports physiotherapists voting agree/strongly agree AND ii) median vote selected by physiotherapists was Agree or Strongly Agree.

Results

41 sports physiotherapists (female n=20, male n=21), visited the survey an average of 5.3 times (±5), resulting in a completion rate of 98%. 64 assessment items (neurophysiological n=20, biomechanical n=15, affective n=8, cognitive n=3, socioenvironmental n=10, general assessment aspects of assessment n=8) met the criteria for consensus. Frequency of use in practice wasAlwaysfor 28 itemsOftenfor 32 items andSometimesfor 4 items.

Conclusion

We have presented stakeholder-generated recommendations and priorities for athlete pain assessment.
Evaluation of ComBat harmonization for reducing across-tracer differences in regional amyloid PET analyses
Authors: Yang Braden , Earnest Tom , Kumar Sayantan , Kothapalli Deydeep , Benzinger Tammie , Gordon Brian , Sotiras Aristeidis
Published: June 2024

Introduction Differences in amyloid positron emission tomography (PET) radiotracer pharmacokinetics and binding properties lead to discrepancies in amyloid-β uptake estimates. Harmonization of tracer-specific biases is crucial for optimal performance of downstream tasks. Here, we investigated the efficacy of ComBat, a data-driven harmonization model, for reducing tracer-specific biases in regional amyloid PET measurements from [18F]-florbetapir (FBP) and [11C]-Pittsburgh Compound-B (PiB). Methods One-hundred-thirteen head-to-head FBP-PiB scan pairs, scanned from the same subject within ninety days, were selected from the Open Access Series of Imaging Studies 3 (OASIS-3) dataset. The Centiloid scale, ComBat with no covariates, ComBat with biological covariates, and GAM-ComBat with biological covariates were used to harmonize both global and regional amyloid standardized uptake value ratios (SUVR). Variants of ComBat, including longitudinal ComBat and PEACE, were also tested. Intraclass correlation coefficient (ICC) and mean absolute error (MAE) were computed to measure the absolute agreement between tracers. Additionally, longitudinal amyloid SUVRs from an anti-amyloid drug trial were simulated using linear mixed effects modeling. Differences in rates-of-change between simulated treatment and placebo groups were tested, and change in statistical power/Type-I error after harmonization was quantified. Results In the head-to-head tracer comparison, ComBat with no covariates was the best at increasing ICC and decreasing MAE of both global summary and regional amyloid PET SUVRs between scan pairs of the same group of subjects. In the clinical trial simulation, harmonization with both Centiloid and ComBat increased statistical power of detecting true rate-of-change differences between groups and decreased false discovery rate in the absence of a treatment effect. The greatest benefit of harmonization was observed when groups exhibited differing FBP-to-PiB proportions. Conclusion ComBat outperformed the Centiloid scale in harmonizing both global and regional amyloid estimates. Additionally, ComBat improved the detection of rate-of-change differences between clinical trial groups. Our findings suggest that ComBat is a viable alternative to Centiloid for harmonizing regional amyloid PET analyses.