bluuebunny/crossref_metadata_2025 huggingface dataset:
Unveiling the double-edged sword: SOD1 trimers possess tissue-selective toxicity and bind septin-7 in motor neuron-like cells
Authors: Choi Esther Sue , Hnath Brianna Leigh , Sha Congzhou Mike , Dokholyan Nikolay V
Published: March 2024

Misfolded soluble trimeric species of superoxide dismutase 1 (SOD1) are associated with increased death in neuron-like cell models and greater disease severity in amyotrophic lateral sclerosis (ALS) patients compared to insoluble protein aggregates. The mechanism by which structurally independent SOD1 trimers cause cellular toxicity is unknown but may be a driver of disease pathology. Here, we uncovered the SOD1 trimer interactome – a map of potential tissue-selective protein binding partners in the brain, spinal cord, and skeletal muscle. We identified binding partners and key pathways associated with SOD1 trimers, comparing them to those of wild-type SOD1 dimers. We found that trimers may affect normal cellular functions such as dendritic spine morphogenesis and synaptic function in the central nervous system and cellular metabolism in skeletal muscle. We also identified key pathways using transcriptomic data from motor neuron-like cells (NSC-34s) expressing SOD1 trimers. We discovered differential gene expression in cells that express SOD1 trimers with selective enrichment of genes responsible for protein localization to membranes and a global upregulation of cellular senescence pathways. We performed detailed computational and biochemical characterization of protein binding for septin-7, an SOD1 trimer binding partner. We found that septin-7 preferentially binds SOD1 trimers and co-localizes in neuron-like cells. We explore a double-edged sword theory regarding the toxicity of SOD1 trimers. These trimers are implicated in causing dysfunction not only in the central nervous system but also in muscle tissues. Our investigation highlights key protein factors and pathways within each system, revealing a plausible intersection of genetic and pathophysiological mechanisms in ALS through interactions involving SOD1 trimers.

In amyotrophic lateral sclerosis (ALS), misfolded soluble species of superoxide dismutase 1 (SOD1) are associated with disease severity and, specifically, trimeric forms of SOD1 are toxic in neuron-like cells compared to insoluble aggregates. The role of toxic SOD1 trimers in cells is unknown. Using molecular engineering and pull-down experiments, we found that SOD1 trimers have tissue-selective protein interactions that affect pathways such as dendritic spine morphogenesis and synaptic function in the nerves, energy, and amino acid metabolism in skeletal muscle. We investigated the SOD1 trimer transcriptome to reveal a global upregulation of genes associated with cellular senescence compared to SOD1 dimers. We further validated septin-7, a shared brain and spinal cord protein binding hit, using integrative computational and biochemical approaches, and confirmed that septin-7 binds SOD1 trimers and not native dimers. Taken together, we show evidence that SOD1 trimers play a central role in the convergence of ALS pathophysiology.

Graphical abstract
Efficient differentiation of human retinal pigment epithelium cells from chemically induced pluripotent stem cells
Authors: Zhang Ke , Wang Yanqiu , An Qi , Ji Hengjing , Wu Defu , Li Xuri , Dong Xuran , Zhang Chun
Published: March 2024

Human induced pluripotent stem cells (hiPSCs) hold considerable promise for autologous cellular therapies, particularly in ocular disease treatment, because of the low numbers of cells required for transplantation and the non-invasive nature of graft monitoring. However, the use of hiPSCs in ocular disease treatment faces challenges because the production of clinical-grade autologous hiPSCs via genetic techniques remains expensive, time-consuming, and subject to safety concerns. Here, we utilize a recently reported chemical method to derive human chemically induced pluripotent stem cells (hCiPSCs), demonstrating that hiPSC lines can be generated using small molecules in a simple and robust manner. Moreover, we show that these cell lines can be efficiently differentiated into retinal pigment epithelium (RPE) cells, which may aid in the treatment of age-related macular degeneration (AMD). Our study provides a foundation for cost-effective, fast, and safe methods that enable efficient production of autologous retinal cell types for ocular disease treatment.
TAK1-mediated phosphorylation of PLCE1 represses PIP2 hydrolysis to impede esophageal squamous cancer metastasis
Authors: Ju Qianqian , Sheng Wenjing , Zhang Meichen , Chen Jing , Wu Liucheng , Liu Xiaoyu , Fang Wentao , Shi Hui , Sun Cheng
Published: March 2024

TAK1 is a serine/threonine protein kinase that is a key regulator in a wide variety of cellular processes. However, the functions and mechanisms involved in cancer metastasis are still not well understood. Here, we found that TAK1 knockdown promoted esophageal squamous cancer cell (ESCC) migration and invasion, whereas TAK1 overexpression resulted in the opposite outcome. Thesein vitrofindings were recapitulatedin vivoin a xenograft metastatic mouse model. Mechanistically, co-immunoprecipitation and mass spectrometry demonstrated that TAK1 interacted with phospholipase C epsilon 1 (PLCE1), and phosphorylated PLCE1 at serine 1060 (S1060). Functional studies revealed that phosphorylation at S1060 in PLCE1 resulted in decreased enzyme activity, leading to the repression of PIP2 hydrolysis. As a result, the degradation products of PIP2 including diacylglycerol (DAG) and inositol IP3 were reduced, which thereby suppressed signal transduction in the axis of PKC/GSK-3β/β-Catenin. Consequently, expression of cancer metastasis-related genes was impeded by TAK1. Overall, our data indicate that TAK1 plays a negative role in ESCC metastasis, which depends on the TAK1 induced phosphorylation of PLCE1 at S1060.
From presence/absence to reliable prey proportions: A field test of dietary DNA for characterizing seabird diets
Authors: Clucas Gemma V , Stillman Andrew , Craig Elizabeth C
Published: March 2024

Climate change and human impacts are causing rapid shifts in species’ distributions and abundance, potentially disrupting predator-prey relationships. Monitoring animal diets can elucidate these relationships and potentially provide a mechanistic understanding of population declines, but efficient methods to monitor diets are needed. Dietary DNA can be used to gather data on species’ diets with high-taxonomic resolution, but the question of whether it can provide quantitative information on animal diets has so far limited its applications. Here we show that dietary DNA can efficiently provide quantitative information on the relative proportions of fish in the diets of piscivorous seabirds. Over three breeding seasons, we observed common tern chick feeding events and collected fecal samples from chicks. We compared the frequency of occurrence (FOO) and relative read abundance (RRA) of fish prey in the fecal samples to the relative biomass recorded through visual observations and found a high correlation (R = 0.94) between RRA and relative biomass at the colony level. We also found that RRA outperformed FOO in capturing interannual changes in relative prey biomass, and that FOO systematically over-estimated the relative importance across all prey categories. The high taxonomic resolution provided by dietary DNA and the high correlation between RRA and relative biomass we found here suggest that dietary DNA can be used as a quantitative metric to monitor seabird diets. This has important applications for studying the impact of changing forage fish availability on seabird populations, but also for harnessing seabirds as sentinels of ecosystem health. Since quantitative diet data can be collected highly efficiently using dietary DNA, this method could provide key information about food web dynamics and forage fish availability as we move towards ecosystem-based fisheries management.
Effect of temperature on circadian clock functioning of trees in the context of global warming
Authors: Estravis-Barcala Maximiliano , Gaischuk Sofía , Gonzalez-Polo Marina , Martínez-Meier Alejandro , Gutiérrez Rodrigo A. , Yanovsky Marcelo , Bellora Nicolás , Arana María Verónica
Published: March 2024

Plant survival in a warmer world requires the timely adjustment of biological processes to cyclical changes in the new environment. Circadian oscillators have been proposed to contribute to thermal adaptation and plasticity in plants, due to their ability to maintain periodicity in biological rhythms over a wide temperature range, promoting fitness. However, the influence of temperature and circadian clock performance on plant behaviour in natural ecosystems is not well understood. Here we used two co-occurringNothofagustree species from the Patagonian forests that are adapted to contrasting thermal environments derived from their different altitudinal profiles. We revealed that the upper thermal limits for accurate clock function are linked to the species’ thermal niches and contribute to seedling plasticity in natural environments. We computationally identified 24 circadian clock-related genes, which showed a high degree of structural conservation with clock genes from both annual and perennial species, and very similar patterns of gene expression to those ofArabidopsis thaliana. Warm temperatures produced a strong transcriptomic rearrangement, which affected the expression of clock-related genes and direct clock targets, evidencing the extent of clock functioning disruption by temperature.N. pumilio, the species from colder environments, showed reduced ability to keep rhythmicity at high temperatures compared toN. obliqua, which inhabits warmer zones. Accordingly,N. pumilio, but notN. obliqua, showed a limited oscillator function in warmer zones of the forest, reduced survival, and growth. Together, our results highlight the potential role of a resonating oscillator in ecological adaptation to a warming environment.
Functional characterization of Lipid storage droplets 1 (LSD1) in growth and lipolysis ofHermetia illucens
Authors: Jiang Yuguo , Kou Zongqing , Chen Bihui , Xingyu Luo , Huang Yongping
Published: March 2024

As intracellular organelles in adipose tissue, lipids droplets manage the balance between triglyceride accumulation and energy consumption in animals. Perilipin family members, associated with surface of lipid droplets, participate the regulation of lipid metabolism. Lipid storage droplet-1 (LSD1)/Perilipin-1 acts as a gatekeeper for adipose lipid storage in animals. Despite extensive studies in fruit fly, the function ofLSD1in insect larval stage remain indistinct. In this study, we characterized the function ofLSD1in black soldier flyHermetia illucens, a nova resource insect to recycle organic wastes. We found thatLSD1was broadly present in dipteran species and evolved with divergence between mosquitos and flies. We further constructedin vivomutagenesis mediated by CRISPR/Cas9 and found that mutations inLSD1increased the larval weight and did not bring any defects in development. Raw fat content was also not significantly influenced in late larval stage and new-emerged adults. Our results not only extend our knowledge ofLSD1in insects, but also help for better understanding of the lipid homeostasis in BSF.
Exploiting De Novo Serine Synthesis as a Metabolic Vulnerability to Overcome Sunitinib Resistance in Advanced Renal Cell Carcinoma
Authors: Teisseire Manon , Sahu Umakant , Parola Julien , Tsai Meng-Chen , Vial Valérie , Durivault Jérôme , Grépin Renaud , Cormerais Yann , Pagès Gilles , Ben-Sahra Issam , Giuliano Sandy
Published: March 2024

Sunitinib, an oral tyrosine kinase inhibitor used in advanced renal cell carcinoma (RCC), exhibits significant efficacy but faces resistance in 30% of patients. Yet, the molecular mechanisms underlying this therapy resistance remain elusive. Here, we show that sunitinib induces a metabolic shift leading to increased serine synthesis in RCC cells. The activation of the GCN2-ATF4 stress response pathway is identified as the mechanistic link between sunitinib treatment and elevated serine production. Inhibiting key enzymes in the serine synthesis pathway, such as PHGDH and PSAT1, enhances the sensitivity of resistant cells to sunitinib. The study underscores the role of serine biosynthesis in nucleotide synthesis, influencing cell proliferation, migration, and invasion. Beyond RCC, similar activation of serine synthesis occurs in other cancer types, suggesting a shared adaptive response to sunitinib therapy. This research identifies serine synthesis as a potential target to overcome sunitinib resistance, offering insights into therapeutic strategies applicable across diverse cancer contexts.

Graphical abstract

Highlights

Sunitinib induces an increase in endogenous serine production in metastatic ccRCC.

The heightened serine biosynthesis promoted by sunitinib facilitates nucleotide synthesis, thereby sustaining tumor cell proliferation.

Sunitinib-induced enhancement of serine biosynthesis enables cell migration and invasion.

The stimulation in serine synthesis is also observed in other cancer models treated with sunitinib.
The FAIR-Device - a non-lethal and generalist semi-automatic Malaise trap for insect biodiversity monitoring: Proof of concept
Authors: Chiavassa Juan A. , Kraft Martin , Noack Patrick , Walther Simon , Kirse Ameli , Scherber Christoph
Published: March 2024

Field monitoring plays a crucial role in understanding insect dynamics within ecosystems. It facilitates pest distribution assessment, control measure evaluation, and prediction of pest outbreaks. Additionally, it provides important information on bioindicators with which the state of biodiversity and ecological integrity in specific habitats and ecosystems can be accurately assessed. However, traditional monitoring systems can present various difficulties, leading to a limited temporal and spatial resolution of the obtained information. Despite recent advancements in automatic insect monitoring traps, also called e-traps, most of these systems focus exclusively on studying agricultural pests, rendering them unsuitable for monitoring diverse insect populations. To address this issue, we introduce the Field Automatic Insect Recognition (FAIR)-Device, a novel non-lethal field tool that relies on semi-automatic image capture and species identification using artificial intelligence via the iNaturalist platform. Our objective was to develop an automatic, cost-effective, and non-specific monitoring solution capable of providing high-resolution data for assessing insect diversity. During a 26-day proof-of-concept evaluation, the FAIR-Device recorded 24.8 GB of video, identifying 431 individuals from 9 orders, 50 families, and 69 genera. While improvements are possible, our device demonstrated potential as a cost-effective, non-lethal tool for monitoring insect biodiversity. Looking ahead, we envision new monitoring systems such as e-traps as valuable tools for real-time insect monitoring, offering unprecedented insights for ecological research and agricultural practices.
Cerebrovascular reactivity mapping using breath-hold BOLD-fMRI: comparison of signal models combined with voxelwise lag optimization
Authors: Domingos Catarina , Esteves Inês , Fouto Ana R. , Ruiz-Tagle Amparo , Caetano Gina , Figueiredo Patrícia
Published: March 2024

Cerebrovascular reactivity (CVR) can be mapped noninvasively using blood oxygenation level dependent (BOLD) fMRI during a breath-hold (BH) task. Previous studies showed that the BH BOLD response is best modeled as the convolution of the partial pressure of end-tidal CO2 (PetCO2) with a canonical hemodynamic response function (HRF). However, previous model comparisons employed a global bulk time lag, which is now well accepted to provide only a rough approximation of the heterogeneous distribution of response latencies across the brain. Here, we investigate the best modeling approach for mapping CVR based on BH BOLD-fMRI data, when using a lagged general linear model approach combined with voxelwise lag optimization. In a group of fourteen healthy participants, we compared models considering: two types of regressors (PetCO2 and Block), three convolution models (no convolution; convolution with a single gamma HRF; and convolution with a double gamma HRF), and a variable HRF delay (3-11s). We found no significant improvements in model fit with other delays, and hence selected the canonical delay of 6s. Although the two regressor types yielded similar model fits, PetCO2 produced significantly greater CVR values than Block models. Interestingly, a single gamma HRF yielded the greatest CVR values in PetCO2 models, while block models benefited from convolution with a double gamma HRF. In conclusion, when modeling BH BOLD-fMRI signals with voxelwise lag optimization, PetCO2 regressors convolved with a single gamma HRF should be preferentially used. In case good quality PetCO2 recordings are unavailable, a block-based model convolved with the canonical HRF may be a good alternative. In conclusion, our manuscript reports the first systematic signal model comparison, providing evidence to support the use of specific modeling approaches for CVR mapping based on BH BOLD-fMRI.
Aging amplifies a gut microbiota immunogenic signature linked to heightened inflammation
Authors: Caetano-Silva Maria Elisa , Shrestha Akriti , Duff Audrey F. , Kontic Danica , Brewster Patricia C. , Kasperek Mikaela C. , Lin Chia-Hao , Wainwright Derek A. , Hernandez-Saavedra Diego , Woods Jeffrey A. , Bailey Michael T. , Buford Thomas W. , Allen Jacob M.
Published: March 2024

Aging is associated with low-grade inflammation that increases the risk of infection and disease, yet the underlying mechanisms remain unclear. Gut microbiota composition shifts with age, harboring microbes with varied immunogenic capacities. We hypothesized the gut microbiota acts as an active driver of low-grade inflammation during aging. Microbiome patterns in aged mice strongly associated with signs of bacterial-induced barrier disruption and immune infiltration, including marked increased levels of circulating lipopolysaccharide (LPS)-binding protein (LBP) and colonic calprotectin.Ex vivoimmunogenicity assays revealed that both colonic contents and mucosa of aged mice harbored increased capacity to activate toll-like receptor 4 (TLR4) whereas TLR5 signaling was unchanged. We found patterns of elevated innate inflammatory signaling (colonicIl6, Tnf, Tlr4) and endotoxemia (circulating LBP) in young germ-free mice after 4 weeks of colonization with intestinal contents from aged mice compared with young counterparts, thus providing a direct link between aging-induced shifts in microbiota immunogenicity and host inflammation. Additionally, we discovered that the gut microbiota of aged mice exhibited unique responses to a broad-spectrum antibiotic challenge (Abx), with sustained elevation inEscherichia(Proteobacteria)and altered TLR5 immunogenicity 7 days post-Abx cessation. Together, these data indicate that old age results in a gut microbiota that differentially acts on TLR signaling pathways of the innate immune system. We found that these age-associated microbiota immunogenic signatures are less resilient to challenge and strongly linked to host inflammatory status. Gut microbiota immunogenic signatures should be thus considered as critical factors in mediating chronic inflammatory diseases disproportionally impacting older populations.
Elucidating the sustainability of 700 years of Inuvialuit beluga whale hunting in the Mackenzie River Delta, Northwest Territories, Canada
Authors: Skovrind Mikkel , Louis Marie , Ferguson Steven H. , Glazov Dmitry M. , Litovka Dennis I. , Loseto Lisa , Meschersky Ilya G. , Miller Mariah M. , Postma Lianne , Rozhnov Viatcheslav V. , Scott Michael , Westbury Michael V. , Szpak Paul , Friesen T. Max , Lorenzen Eline D.
Published: March 2024

Beluga whales play a critical role in the subsistence economies and cultural heritage of Indigenous communities across the Arctic, yet the effects of Indigenous hunting on beluga whales remains unknown. Here, we integrate paleogenomics and stableδ13C andδ15N isotope analysis to investigate 700 years of beluga subsistence hunting in the Mackenzie Delta area of northwestern Canada. Genetic identification of the zooarchaeological remains, which based on radiocarbon dating span three time periods (1290-1440 CE; 1450-1650 CE; 1800-1870 CE), indicate shifts across time in the sex ratio of the harvested belugas. The equal number of females and males harvested in 1450-1650 CEversusmore males harvested in the two other time periods may reflect changes in hunting practices or temporal shifts in beluga availability. We find temporal shifts and sex-based differences in δ13C of the harvested belugas across time, suggesting historical adaptability in the foraging ecology of the whales. Although we uncovered novel mitochondrial diversity in the Mackenzie Delta belugas, we found no changes in nuclear genomic diversity nor any substructuring across time. Our findings indicate the genomic stability and continuity of the Mackenzie Delta beluga population across the 700 years surveyed, indicating the impact of Inuvialuit subsistence harvests on the genetic diversity of contemporary beluga individuals has been negligible.

Significance Statement

Since colonizing the Mackenzie Delta in northwestern Canada ∼1200 CE, Inuvialuit have been heavily reliant on belugas for their livelihoods and cultural heritage. However, little is known of the impact of centuries of sustained Inuvialuit subsistence hunting on the beluga population inhabiting the Mackenzie Delta. Using palaeogenomic and stable isotope analysis of zooarchaeological remains, and comparing the findings with contemporary data, we investigate temporal changes in beluga diversity, structuring, and foraging ecology. We show Inuvialuit harvests had a negligible impact on the genetic diversity of contemporary Mackenzie belugas, and highlight the applicability of combining genomic sexing and isotope analysis of zooarchaeological remains for advancing our understanding of past hunting practices and faunal ecologies.
DUAL ACTION ELECTROCHEMICAL BANDAGE OPERATED by a PROGRAMMABLE MULTIMODAL WEARABLE POTENTIOSTAT
Authors: Bozyel Ibrahim , Fleming Derek , Kim Won-Jun , Rosen Peter F. , Gelston Suzanne , Ozdemir Dilara , Ay Suat U. , Patel Robin , Beyenal Haluk
Published: March 2024

Electrochemical bandages (e-bandages) can be applied to biofilm-infected wounds to generate reactive oxygen species, such as hypochlorous acid (HOCl) or hydrogen peroxide (H2O2). The e-bandage-generated HOCl or H2O2kills biofilmsin vitroand in infected wounds on mice. The HOCl-generating e-bandage is more active against biofilmsin vitro, although this distinction is less apparentin vivo. The H2O2-generating e-bandage, more than the HOCl-generating e-bandage, is associated with improved healing of infected wounds. A strategy in which H2O2and HOCl are generated alternately—for dual action—was explored. The goal was to develop a programmable multimodal wearable potentiostat (PMWP) that could be programmed to generate HOCl or H2O2, as needed. An ultralow-power microcontroller unit managed operation of the PMWP. The system was operated with a 260-mAh capacity coin battery and weighed 4.6 grams, making it suitable for small animal experiments or human use. The overall cost of a single wearable potentiostat was $6.50 (USD). The device was verified using established electrochemical systems and functioned comparably to a commercial potentiostat. To determine antimicrobial effectiveness, PMWP-controlled e-bandages were tested against clinical isolates of four prevalent chronic wound bacterial pathogens, methicillin-resistantStaphylococcus aureus(MRSA),Pseudomonas aeruginosa, Acinetobacter baumannii, andEnterococcus faecium, and one fungal pathogen of emerging concern,Candida auris. PMWP-controlled e-bandages exhibited broad-spectrum activity against biofilms of all study isolates tested when programmed to deliver HOCl followed by H2O2. These results show that the PMWP operates effectively and is suitable for animal testing.
Intracellular pH regulates β-catenin with low pHi increasing adhesion and signaling functions
Authors: Czowski Brandon J. , White Katharine A.
Published: March 2024

Intracellular pH (pHi) dynamics are linked to cell processes including proliferation, migration, and differentiation. The adherens junction (AJ) and signaling protein β-catenin has decreased abundance at high pHi due to increased proteasomal-mediated degradation. However, the effects of low pHi on β-catenin abundance and functions have not been characterized. Here, we show that low pHi stabilizes β-catenin in epithelial cells using population-level and single-cell assays. β-catenin abundance is increased at low pHi and decreased at high pHi. We also assay single-cell protein degradation rates to show that β-catenin half-life is longer at low compared to high pHi. Importantly, we show that AJs are not disrupted by β-catenin loss at high pHi due to rescue by plakoglobin. Finally, we show that low pHi increases β-catenin transcriptional activity in single cells and is indistinguishable from a Wnt-on state. This work characterizes pHi as a rheostat regulating β-catenin abundance, stability, and funcion and implicates β-catenin as a molecular mediator of pHi-dependent cell processes.

Intracellular pH (pHi) regulates the degradation rate of the pH sensor β-catenin, altering protein abundance, localization, and function in epithelial cells. This work shows pHi acts as a rheostat to alter both adhesion and signaling functions of β-catenin.
Deep Learning and GBLUP Integration: An Approach that Identifies Nonlinear Genetic Relationships Between Traits
Authors: Shokor Fatima , Croiseau Pascal , Gangloff Hugo , Saintilan Romain , Tribout Thierry , Mary-Huard Tristan , C.D. Cuyabano Beatriz
Published: March 2024

Background

Genomic prediction aims to predict the breeding values of multiple complex traits, usually assumed to be normally distributed by the largely used statistical methods, thus imposing linear genetic correlations between traits. While statistical methods are of great value for genomic prediction, these methods do not account for nonlinear genetic relationships between traits. If such relationships exist, although statistical models do perform a fair linear approximation, their prediction accuracy is limited due to the nonlinearity. Deep learning (DL) is a promising methodology for predicting multiple complex traits, in scenarios where nonlinear genetic relationships are present, due to its capacity to capture complex and nonlinear patterns in large data. We proposed a novel hybrid DLGBLUP model which uses the output of the traditional GBLUP, and enhances its PGV by accounting for nonlinear genetic relationships between traits using DL. Using simulated data, we compared the accuracy of the PGV obtained with the proposed hybrid DLGBLUP model, a DL model, and the traditional GBLUP model – the latter being our baseline reference.

Results

We found that both DL and DLGBLUP models either outperformed GBLUP, or presented equally accurate PGV, with a particular greater accuracy for traits presenting a strongly characterized nonlinear genetic relationship. Overall, DLGBLUP presented the highest prediction accuracy, up to 0.2 points higher than GBLUP, and smallest mean squared error of the PGV for all traits. Additionally, we evolved a base population over seven generations and compared the genetic progress when selecting individuals based on the additive PGV obtained by either DL, DLGBLUP or GBLUP. For all traits with a nonlinear genetic relationship, after the fourth generation, the observed genetic gain when selection was based on the additive PGV from GBLUP was always inferior to the one achieved from either DL or DLGBLUP.

Conclusions

The integration of DL into genomic prediction enables the possibility of modeling nonlinear relationships between traits. Moreover, by identifying these nonlinear genetic relationships, our DL and DLGBLUP models improved prediction accuracy, when compared to GBLUP. The possibility of nonlinear relationships between traits offers a different perspective into multi-trait evaluations and prediction, as well as into the traits’ evolution over generations, with potential to further improve selection strategies in commercial livestock breeding programs. Moreover, DLGBLUP shows that DL can be used as a complement to statistical methods, by enhancing their performance.
STING-Activating Polymer-Drug Conjugates for Cancer Immunotherapy
Authors: Sheehy Taylor L. , Kwiatkowski Alexander J. , Arora Karan , Kimmel Blaise R. , Schulman Jacob A. , Gibson-Corley Katherine N. , Wilson John T.
Published: March 2024

The stimulator of interferon genes (STING) pathway links innate and adaptive antitumor immunity and therefore plays an important role in cancer immune surveillance. This has prompted widespread development of STING agonists for cancer immunotherapy, but pharmacological barriers continue to limit the clinical impact of STING agonists and motivate the development of drug delivery systems to improve their efficacy and/or safety. To address these challenges, we developed SAPCon, a STING-activating polymer-drug conjugate platform based on strain-promoted azide-alkyne cycloaddition of dimeric-amidobenzimidazole (diABZI) STING agonists to hydrophilic polymer chains through an enzyme-responsive chemical linker. To synthesize a first-generation SAPCon, we designed a diABZI prodrug modified with a DBCO reactive handle with a cathepsin B-cleavable spacer for intracellular drug release and conjugated this to pendant azide groups on a 100kDa poly(dimethyla acrylamide-co-azide methacrylate) copolymer backbone to increase circulation time and enable passive tumor accumulation. We found that intravenously administered SAPCon accumulated at tumor sites, where it was endocytosed by tumor-associated myeloid cells, resulting in increased STING activation in tumor tissue. Consequently, SAPCon promoted an immunogenic tumor microenvironment, characterized by increased frequency of activated macrophages and dendritic cells and improved infiltration of CD8+T cells, resulting in inhibition of tumor growth, prolonged survival, and enhanced response to anti-PD-1 immune checkpoint blockade in orthotopic breast cancer models. Collectively, these studies position SAPCon as a modular and programmable platform for improving the efficacy of systemically administered STING agonists for cancer immunotherapy.
Compromised retinoic acid receptor beta (RARβ) accelerates the onset of motor, cellular and molecular abnormalities in mouse model of Huntington’s disease
Authors: Zinter Nicolas , Ye Tao , Fraulob Valerie , Plassard Damien , Krezel Wojciech
Published: March 2024

The mechanisms underlying detrimental effects of mutant huntingtin on striatal dysfunction in Huntington’s disease (HD) are not well understood. Although retinoic acid receptor beta (RARβ) emerged recently as one of the top regulators of transcriptionally downregulated genes in the striatum of HD patients and mouse models of HD its involvement in disease progression remains elusive. We report that genetically compromised RARβ signaling accelerates onset of motor abnormalities in R6/1 mouse model of HD. Transcriptional profiling revealed that downregulation of RARβ expression inRarβ+/-; R6/1 mice also accelerates transcriptional signature of disease progression by emergence of upregulated cluster of genes related to cell-cycle, stem cell maintenance and telencephalon development with concomitant downregulation of striatal cell-identity genes. The reactivation of proliferative activity demonstrated in the neurogenic niche and development-related transcriptional programs in the striatum prompt an attempt of lineage infidelity in HD striatum which may lead in consequence to disease-driving energy crisis as suggested by concomitant downregulation of transcripts essential for oxidative phosphorylation, a well-accepted correlate of HD physiopathology, and a metabolic change required for maintenance of proliferative activity and differentiation but not compatible with high energetic demand of differentiated and active neurons.

Highlights

Compromising RARβ expression in R6/1 mouse model of HD accelerates onset of HD-like motor abnormalities

Compromised RARβ signaling contributes to the progression of disease-related transcriptional changes in R6/1 mice

RARβ supports cell-identity maintenance in HD mouse model
Investigating Cryopreserved PBMC Functionality in an Antigen-Induced Model of Sarcoidosis Granuloma Formation
Authors: Seman Sarah G. , Bicer Sabahattin , Julian Mark W. , Kramer Patrick J. , Mitchell Jonah R. , Crouser Elliott D. , Locke Landon W.
Published: March 2024

Sarcoidosis, a systemic inflammatory disease, poses challenges in understanding its etiology and variable clinical courses. Despite ongoing uncertainty about causative agents and genetic predisposition, granuloma formation remains its hallmark feature. To address this complexity, we developed a validated in vitro human granuloma model using peripheral blood mononuclear cells (PBMCs), providing a dynamic platform for studying sarcoidosis pathogenesis. While cryopreservation is a common method for long-term sample preservation, the biological effects of freezing and thawing PBMCs on granuloma formation remain unclear. This study aimed to assess the viability and functionality of cryopreserved sarcoidosis PBMCs within the granuloma model, revealing similar granulomatous responses to fresh cells and highlighting the potential of cryopreserved PBMCs as a valuable tool for studying sarcoidosis and related diseases.
Initiation and Formation of Stereocilia during the Development of Mouse Cochlear Hair Cells
Authors: Chakravarthy Suraj Ranganath , van Zanten Thomas S. , Ladher Raj K
Published: March 2024

Stereocilia are apically located actin-protrusions found on the hair cells of the inner ear. At least three rows of stereocilia are arranged in a graded staircase pattern, which is vital for mechanosensation. Stereocilia form soon after the specification of hair cells. While these steps have been well-characterized in the avian auditory epithelium, the equivalent information in mice is lacking. Using scanning electron microscopy and super-resolution microscopy, we investigate stereocilia formation from hair cell specification stages in the mouse organ of Corti. Even before differentiation, we find that sensory progenitors, which will give rise to both hair cells and support cells, have a dense lawn of microvilli. Hair cell specialisation is first apparent as an enrichment in junctional actin, followed by the relocalisation of kinocilium into an eccentric position and the thickening of hair cell microvilli closest to the kinocilium. To determine actin signatures associated with hair cell development, we use a new analytical method to map cellular actin filament distribution during development. By nomalising relative actin filament density, we obtain insights into cuticular plate development and actin redistribution during the earliest phases of hair cell specialisation.
TreeCompR: Tree competition indices for inventory data and 3D point clouds
Authors: Rieder Julia S. , Link Roman M. , Köthe Konstantin , Seidel Dominik , Ullmann Tobias , Žmegač Anja , Zang Christian , Schuldt Bernhard
Published: March 2024

In times of more frequent global-change-type droughts and associated tree mortality events, competition release is one silvicultural measure discussed to have an impact on the resilience of managed forest stands. Understanding how trees compete with each other is therefore crucial, but different measurement options and competition indices leave users with the agony of choice, as no single competition index has proven universally superior.

To help users with the choice and computation of appropriate indices, we present the open-sourceTreeCompRpackage, which can handle 3D point clouds in various formats as well as classical forest inventory data and serves as a centralized platform for exploring and comparing different competition indices (CIs). Within a common interface, users can efficiently select the most suitable CI for their specific research questions. The package facilitates the integration of both traditional distance-dependent and novel point cloud-based indices.

To evaluate the package, we usedTreeCompRto quantify the competition situation of 308 European beech trees from 13 sites in Central Europe. Based on this dataset, we discuss the interpretation, comparability and sensitivity of the different indices to their parameterization and identify possible sources of uncertainty and ways to minimize them.

The compatibility ofTreeCompRwith different data formats and different data collection methods makes it accessible and useful for a wide range of users, specifically ecologists and foresters. Due to the flexibility in the choice of input formats as well as the emphasis on tidy, well-structured output, our package can easily be integrated into existing data-analysis workflows both for 3D point cloud and classical forest inventory data.
Augmented Doubly Robust Post-Imputation Inference for Proteomic data
Authors: Moon Haeun , Du Jin-Hong , Lei Jing , Roeder Kathryn
Published: March 2024

Quantitative measurements produced by mass spectrometry proteomics experiments offer a direct way to explore the role of proteins in molecular mechanisms. However, analysis of such data is challenging due to the large proportion of missing values. A common strategy to address this issue is to utilize an imputed dataset, which often introduces systematic bias into down-stream analyses if the imputation errors are ignored. In this paper, we propose a statistical framework inspired by doubly robust estimators that offers valid and efficient inference for proteomic data. Our framework combines powerful machine learning tools, such as variational autoencoders, to augment the imputation quality with high-dimensional peptide data, and a parametric model to estimate the propensity score for debiasing imputed outcomes. Our estimator is compatible with the double machine learning framework and has provable properties. Simulation studies verify its empirical superiority over other existing procedures. In application to both single-cell proteomic data and bulk-cell Alzheimer’s Disease data our method utilizes the imputed data to gain additional, meaningful discoveries and yet maintains good control of false positives.
No Evidence of Altered Language Laterality in People Who Stutter across Different Brain Imaging Studies of Speech and Language
Authors: Demirel Birtan , Chesters Jennifer , Connally Emily , Gough Patricia , Ward David , Howell Peter , Watkins Kate E.
Published: March 2024

A long-standing neurobiological explanation of stuttering is the incomplete cerebral dominance theory, which refers to competition between two hemispheres for “dominance” over handedness and speech, causing altered language lateralisation. Renewed interest in these ideas came from brain imaging findings in people who stutter (PWS) of increased activity in the right hemisphere during speech production or of shifts in activity from right to left when fluency increased. Here, we revisited this theory using functional MRI data from children and adults who stutter, and typically fluent speakers (119 participants in total) during four different speech and language tasks: overt sentence reading, overt picture description, covert sentence reading and covert auditory naming. Laterality indices (LIs) were calculated for the frontal and temporal lobes using the LI toolbox running in Statistical Parametric Mapping. We also repeated the analyses with more specific language regions, namely the pars opercularis (Brodmann Area 44) and pars triangularis (Brodmann Area 45). Laterality indices in PWS and typically fluent speakers (TFS) did not differ and Bayesian analyses provided moderate to anecdotal levels of support for the null hypothesis (i.e., no differences in laterality in PWS compared with TFS). The proportions of the PWS and TFS who were left lateralised or had atypical rightwards or bilateral lateralisation did not differ. We found no support for the theory that language laterality is reduced or differs in PWS compared with TFS.
Diversity and abundance of tree microhabitats in the tropical forests of southern Western Ghats, India
Authors: Patel Bharati , Sivaraman Sreejith , Hrideek T.K. , Balakrishnan Peroth
Published: March 2024

Tree microhabitats (TMHs) are proven tools for assessing and monitoring diversity. These structures on trees are potential indicators of biota, but there is a huge gap in TMH-related knowledge from the tropical regions, the cradles of biodiversity. Thus, an inventory was made to document the TMHs in the tropical forests of southern Western Ghats, India. In evergreen forests, 3,637 TMH host and 450 cavity host trees were identified from the 6,363 trees sampled. The density of TMHs was 972.57±341.25 ha-1and cavity density was 63.13±11.91 ha-1. In moist deciduous forests, out of 1,545 trees sampled, 1,108 hosted TMHs and 212 trees hosted cavities. The density of TMHs was 493.67±133.28 ha-1and cavity density was 42.00±15.01 ha-1. TMHs were categorised into nine categories and 33 sub-categories. The TMH and cavity occurrences were significantly influenced by species richness, stand density, basal area, diameter and height of trees, and density of healthy, unhealthy and dead trees. Dominant and codominant individuals hosted more TMHs and cavities in the deciduous stands while in evergreen, intermediate and overtopped trees had more TMHs and intermediate and codominant had more cavities. In both the habitats the important species of the habitat were also major hosts for TMHs and cavities.

Highlights

Primary inventory of diversity of TMHs and their host trees in tropical forests

TMH and cavity occurrences are significantly influenced by stand characteristics

Key species in the habitats also form major hosts for TMHs and cavities

Dominant and codominant individuals host more TMHs and cavities in deciduous stands

Intermediate and overtopped trees host more TMHs, intermediate and codominant host more cavities in evergreen
Pharmacological stimulation of infralimbic cortex after fear conditioning facilitates subsequent fear extinction
Authors: Bayer Hugo , Hassell James E. , Oleksiak Cecily R. , Garcia Gabriela M. , Vaughan Hollis L. , Juliano Vitor A. L. , Maren Stephen
Published: March 2024

The infralimbic (IL) division of the medial prefrontal cortex (mPFC) is a crucial site for extinction of conditioned fear memories in rodents. Recent work suggests that neuronal plasticity in the IL that occurs during (or soon after) fear conditioning enables subsequent IL-dependent extinction learning. We therefore hypothesized that pharmacological activation of the IL after fear conditioning would promote the extinction of conditioned fear. To test this hypothesis, we characterized the effects of post-conditioning infusions of the GABAAreceptor antagonist, picrotoxin, into the IL on extinction of auditory conditioned freezing in male and female rats. In four experiments, we found that picrotoxin injections performed immediately, 24 hours, or 13 days after fear conditioning reduced conditioned freezing to the auditory conditioned stimulus (CS) during both extinction training and extinction retrieval; this effect was observed up to two weeks after picrotoxin infusions. Interestingly, inhibiting protein synthesis inhibition in the IL immediately after fear conditioning prevented the inhibition of freezing by picrotoxin injected 24 hours later. Our data suggest that the IL encodes an inhibitory memory during the consolidation of fear conditioning that is necessary for future fear suppression.
Altered patterning of neural activity in a tauopathy mouse model
Authors: Hoffman C. , Cheng J. , Morales R. , Ji D. , Dabaghian Y.
Published: March 2024

Alzheimer’s disease (AD) is a complex neurodegenerative condition that manifests at multiple levels and involves a spectrum of abnormalities ranging from the cellular to cognitive. Here, we investigate the impact of AD-related tau-pathology on hippocampal circuits in mice engaged in spatial navigation, and study changes of neuronal firing and dynamics of extracellular fields. While most studies are based on analyzing instantaneous or time-averaged characteristics of neuronal activity, we focus on intermediate timescales—spike trains and waveforms of oscillatory potentials, which we consider as single entities. We find that, in healthy mice, spike arrangements and wave patterns (series of crests or troughs) are coupled to the animal’s location, speed, and acceleration. In contrast, in tau-mice, neural activity is structurally disarrayed: brainwave cadence is detached from locomotion, spatial selectivity is lost, the spike flow is scrambled. Importantly, these alterations start early and accumulate with age, which exposes progressive disinvolvement the hippocampus circuit in spatial navigation. These features highlight qualitatively different neurodynamics than the ones provided by conventional analyses, and are more salient, thus revealing a new level of the hippocampal circuit disruptions.

Significance

We expose differences in WT and tau brains, emerging at the circuit level, using a novel, morphological perspective on neural activity. This approach allows identifying qualitative changes in spiking patterns and in extracellular field oscillations, that are not discernible through traditional time-localized or time-averaged analyses. In particular, analyses of activity patterns facilitates detection of neurodegenerative deviations, conspicuously linking their effects to behavior and locomotion, thus opening a new venue for understanding how the architecture of neural activity shifts from normal to pathological.