bluuebunny/crossref_metadata_2025 huggingface dataset:
PDG-Arena: An ecophysiological model for characterizing tree-tree interactions in heterogeneous and mixed stands
Authors: Rouet Camille , Davi Hendrik , Druel Arsène , Fady Bruno , Morin Xavier
Published: February 2024

In the context of the ongoing climate and biodiversity crises, mixed forest stands are increasingly considered as a sustainable management alternative to monocultures. We developed a new individual-based and process-based forest growth model, PDG-Arena, to simulate mixed forest functioning and test ecophysiological interactions among trees in mixed stands. The model builds upon the validated ecophysiological stand-scale model CASTANEA and integrates tree competition for light and water. We evaluated the performance of PDG-Arena by comparing the simulated growth with annual dendrochronological growth data from 37 common beech and silver fir monospecific and mixed plots in the French Alps. PDG-Arena showed a slightly better performance than CASTANEA when simulating even-age and monospecific forests (r2of 32.1 versus 29.5%). When using structure-diverse and species-diverse inventories, PDG-Arena performed better than CASTANEA in pure beech (38.3 versus 22.9%) and mixed stands (40.5 versus 36.3%), but not in pure fir stands (39.8 versus 42.0%). The new model also showed a significant positive effect of species mixing on gross primary production (+5.5%), canopy absorbance (+11.1%) and transpiration (+15.8%). Our results thus show that tree-level process-based models such as PDG-Arena, formally simulating interspecific interactions, can serve as a valuable tool to understand and simulate the carbon, light and water dynamics of mixed stands.
TL1A/DR3 signaling regulates the generation of pathogenic Th9 cells in experimental inflammatory bowel disease
Authors: Menghini Paola , Butto Ludovica , Gomez-Nguyen Adrian , Aladyshkina Natalia , Buela Kristine-Ann , Osme Abdullah , Chan Ricky , Bamias Giorgos , Pizarro Theresa T , Cominelli Fabio
Published: February 2024

Objective: Death receptor 3 (DR3) and its ligand tumor necrosis factor like ligand 1A (TL1A), are involved in the regulation of the balance between effector and regulatory T cells in IBD. New evidence suggests a role of IL-9-secreting Th9 cells in the pathogenesis of ulcerative colitis (UC), although the molecular pathways through which IL-9 and Th9 cells may mediate intestinal inflammation in Crohn's disease (CD) are still unclear. Design: We investigated the role of DR3 signaling in the differentiation of Th9 cells in mouse models of CD-like ileitis and colitis, including SAMP1/YitFc (SAMP) mice. Results: Polarized-Th9 cells with functional DR3 from SAMP WT (Th9WT) harbor a pro-inflammatory signature compared to DR3-deficient Th9 cells that were obtained from DR3-/-xSAMP mice (Th9KO). Conversely, ablation of DR3 signaling generated anti-inflammatory responses, as reflected by higher numbers of IL-10 producing cells in DR3-/-xSAMP mice. Additionally, RNA-seq and phosphoproteomic analyses showed that inflammatory pathways are significantly more activated in Th9WT than in Th9KO cells. Finally, in the T-cell adoptive transfer model, Th9KO cells were less colitogenic than Th9WT, while IL-9 blockade diminished the severity of intestinal inflammation, indicating a crucial role of functional DR3 receptor in Th9 cells pathogenicity. Conclusion: We describe herein that a functional DR3 receptor is required for the pathogenicity of Th9 cells, thus, constituting a novel mechanism by which TL1A/DR3 signaling mediates experimental CD-like ileitis. The TL1A/DR3/Th9 pro-inflammatory pathway may offer a novel therapeutic target for patients with CD.
Identification of novel genes regulating the development of the palate
Authors: Bhaskar Ashwin , Astrof Sophie
Published: February 2024

The International Mouse Phenotyping Consortium (IMPC) has generated thousands of knockout mouse lines, many of which exhibit embryonic or perinatal lethality. Using micro-computed tomography (micro-CT), the IMPC has created and publicly released 3D image datasets of embryos from these lethal and subviable lines. In this study, we leveraged this dataset to screen homozygous null mutants for anomalies in secondary palate development. We analyzed optical sections from 2,987 embryos at embryonic days E15.5 and E18.5, representing 484 homozygous mutant lines. Our analysis identified 45 novel genes implicated in palatogenesis. Gene set enrichment analysis highlighted biological processes and pathways relevant to palate development and uncovered 18 genes jointly regulating the development of the eye and the palate. These findings present a valuable resource for further research, offer novel insights into the molecular mechanisms underlying palatogenesis, and provide important context for understanding the etiology of rare human congenital disorders involving simultaneous malformations of the palate and other organs, including the eyes, ears, kidneys, and lungs.
Microbial responses to stress cryptically alter natural selection on plants
Authors: Bolin Lana G. , Lau Jennifer A.
Published: February 2024

Microbial communities can rapidly respond to stress, meaning plants may encounter altered soil microbial communities in stressful environments. These altered microbial communities may then affect natural selection on plants. Because stress can cause lasting changes to microbial communities, microbes may also cause legacy effects on plant selection that persist even after the stress ceases.

To explore how microbial responses to stress and persistent microbial legacy effects of stress affect natural selection, we grewChamaecrista fasciculataplants in stressful (salt, herbicide, or herbivory) or non-stressful conditions with microbes that had experienced each of these environments in the previous generation.

Microbial community responses to stress generally counteracted the effects of stress itself on plant selection, thereby weakening the strength of stress as a selective agent. Microbial legacy effects of stress altered plant selection in non-stressful environments, suggesting that stress-induced changes to microbes may continue to affect selection after stress is lifted.

These results suggest that soil microbes may play a cryptic role in plant adaptation to stress, potentially reducing the strength of stress as a selective agent and altering the evolutionary trajectory of plant populations.
Myosin-I Synergizes with Arp2/3 Complex to Enhance Pushing Forces of Branched Actin Networks
Authors: Xu Mengqi , Rutkowski David M. , Rebowski Grzegorz , Boczkowska Malgorzata , Pollard Luther W. , Dominguez Roberto , Vavylonis Dimitrios , Ostap E. Michael
Published: February 2024

Myosin-Is colocalize with Arp2/3 complex-nucleated actin networks at sites of membrane protrusion and invagination, but the mechanisms by which myosin-I motor activity coordinates with branched actin assembly to generate force are unknown. We mimicked the interplay of these proteins using the “comet tail” bead motility assay, where branched actin networks are nucleated by Arp2/3 complex on the surface of beads coated with myosin-I and the WCA domain of N-WASP. We observed that myosin-I increased bead movement efficiency by thinning actin networks without affecting growth rates. Remarkably, myosin-I triggered symmetry breaking and comet-tail formation in dense networks resistant to spontaneous fracturing. Even with arrested actin assembly, myosin-I alone could break the network. Computational modeling recapitulated these observations suggesting myosin-I acts as a repulsive force shaping the network’s architecture and boosting its force-generating capacity. We propose that myosin-I leverages its power stroke to amplify the forces generated by Arp2/3 complex-nucleated actin networks.
Processing-bias correction with DEBIAS-M improves cross-study generalization of microbiome-based prediction models
Authors: Austin George I. , Kav Aya Brown , Park Heekuk , Biermann Jana , Uhlemann Anne-Catrin , Korem Tal
Published: February 2024

Every step in common microbiome profiling protocols has variable efficiency for each microbe. For example, different DNA extraction kits may have different efficiency for Gram-positive and -negative bacteria. These variable efficiencies, combined with technical variation, create strong processing biases, which impede the identification of signals that are reproducible across studies and the development of generalizable and biologically interpretable prediction models. “Batch-correction” methods have been used to alleviate these issues computationally with some success. However, many make strong parametric assumptions which do not necessarily apply to microbiome data or processing biases, or require the use of an outcome variable, which risks overfitting. Lastly and importantly, existing transformations used to correct microbiome data are largely non-interpretable, and could, for example, introduce values to features that were initially mostly zeros. Altogether, processing bias currently compromises our ability to glean robust and generalizable biological insights from microbiome data. Here, we present DEBIAS-M (Domain adaptation with phenotypeEstimation andBatchIntegrationAcrossStudies of theMicrobiome), an interpretable framework for inference and correction of processing bias, which facilitates domain adaptation in microbiome studies. DEBIAS-M learns bias-correction factors for each microbe in each batch that simultaneously minimize batch effects and maximize cross-study associations with phenotypes. Using benchmarks of HIV and colorectal cancer classification from gut microbiome data, and cervical neoplasia prediction from cervical microbiome data, we demonstrate that DEBIAS-M outperforms batch-correction methods commonly used in the field. Notably, we show that the inferred bias-correction factors are stable, interpretable, and strongly associated with specific experimental protocols. Overall, we show that DEBIAS-M allows for better modeling of microbiome data and identification of interpretable signals that are reproducible across studies.
Discovery of Phenyl-β-D-glucuronide Medical Function for in Vivo Producing Handheld Gas Sensor Detectable Phenol-like Breath Marker: The Future of Induced Volatolomics in Cancer Risk Pre-warning
Authors: Xue Cuili , Yan Yufei , Ni Huiyan , Yi Chenghan , Xu Yuli , Xiang Siyi , Wu Yuejun , Jin Han , Cui Daxiang
Published: February 2024

Induced volatolomics provides a promising approach for cancer risk pre-warning. Nevertheless, continues to be questioned bio-compatibility of the synthetic exogenous agents and sophisticated instrument solely detectable isotopes labeled volatile compounds restrained induced volatolomics in clinic application. Here, we report phenyl-β-D-glucuronide as a potential exogenous agent of induced volatolomics. As a nature product, phenyl-β-D-glucuronide demonstrates satisfactory bio-compatibility in pilot study and metabolizes into volatile phenol under the action of tumor micro-environment highly accumulated β-glucuronidase. For conveniently recording breath signal, handheld breath-analyzer based on electrochemical phenol sensor is developed. After administrating healthy or tumor bearing mice with phenyl-β-D-glucuronide, breath signal given by breath-analyzer is verified to be capable of not only predicting various tumor risk with specificity/sensitivity/accuracy above 94.3% in 10 min, but also speculating tumor stage.
The Impact of Gender on Pediatric Surgical Access and Outcomes in Africa
Authors: Williams Sacha , Serhan Olivia , Wang Jenny , Guindi Christian , Guadagno Elena , Trudeau Maeve , Ameh Emannuel , Lakhoo Kokila , Poenaru Dan
Published: February 2024

Introduction

Girls, whose care is often affected by barriers steeped in gender inequity, may be at higher risk of poor surgical outcomes. This study explored the impact of gender on pediatric surgical care in Africa.

Methods

Differences in access to care and clinical outcomes for boys and girls were examined for pediatric surgical conditions that do not differ by physiological sex. A systematic review of African pediatric surgical studies ensued, followed by a random effects meta-analysis, and risk of bias assessment.

Results

Of the 12281 records retrieved, 54 were selected for review. Most studies were retrospective (57.4%), single-site (94.4%), from Egypt, Nigeria, Ghana, or Ethiopia (55.6%), focussed on gastrointestinal conditions (63.0%), published in 2010 or sooner (85.1%), had study durations of 5 years or less (68.5%), and cohorts of less than 200 children (57.4%). Sixty percent reported the outcome of mortality. Meta-analysis odds ratios revealed surgery was performed 3.6 times more often on boys (95% CI: 2.6, 4.9); and mortality was 1.6 times greater for girls (95% CI: 1.3, 2.0).

Conclusion

African girls appear to face gender inequities in pediatric surgical care. Findings will be further explored in a mixed-methods study.

Level of evidence

I

Highlights

Gender disparities in global surgical care have been documented in the African adult population. However gender specific differentials in surgical access and outcomes have yet to be documented for African pediatric populations.

This study provides first-time evidence of gender inequity in pediatric surgical care in Africa.
Cell non-autonomous signaling through the conservedC. elegansglycopeptide hormone receptor FSHR-1 regulates cholinergic neurotransmission
Authors: Buckley Morgan , Jacob William P. , Bortey Letitia , McClain Makenzi , Ritter Alyssa L. , Godfrey Amy , Munneke Allyson S. , Ramachandran Shankar , Kenis Signe , Kolnik Julie C. , Olofsson Sarah , Adkins Ryan , Kutoloski Tanner , Rademacher Lillian , Heinecke Olivia , Alva Alexandra , Beets Isabel , Francis Michael M. , Kowalski Jennifer R.
Published: February 2024

Modulation of neurotransmission is key for organismal responses to varying physiological contexts such as during infection, injury, or other stresses, as well as in learning and memory and for sensory adaptation. Roles for cell autonomous neuromodulatory mechanisms in these processes have been well described. The importance of cell non-autonomous pathways for inter-tissue signaling, such as gut-to-brain or glia-to-neuron, has emerged more recently, but the cellular mechanisms mediating such regulation remain comparatively unexplored. Glycoproteins and their G protein-coupled receptors (GPCRs) are well-established orchestrators of multi-tissue signaling events that govern diverse physiological processes through both cell-autonomous and cell non-autonomous regulation. Here, we show that follicle stimulating hormone receptor, FSHR-1, the soleCaenorhabditis elegansortholog of mammalian glycoprotein hormone GPCRs, is important for cell non-autonomous modulation of synaptic transmission. Inhibition offshr-1expression reduces muscle contraction and leads to synaptic vesicle accumulation in cholinergic motor neurons. The neuromuscular and locomotor defects infshr-1loss-of-function mutants are associated with an underlying accumulation of synaptic vesicles, build-up of the synaptic vesicle priming factor UNC-10/RIM, and decreased synaptic vesicle release from cholinergic motor neurons. Restoration of FSHR-1 to the intestine is sufficient to restore neuromuscular activity and synaptic vesicle localization tofshr-1-deficient animals. Intestine-specific knockdown of FSHR-1 reduces neuromuscular function, indicating FSHR-1 is both necessary and sufficient in the intestine for its neuromuscular effects. Re-expression of FSHR-1 in other sites of endogenous expression, including glial cells and neurons, also restored some neuromuscular deficits, indicating potential cross-tissue regulation from these tissues as well. Genetic interaction studies provide evidence that downstream effectorsgsa-1/GαS,acy-1/adenylyl cyclase andsphk-1/sphingosine kinase and glycoprotein hormone subunit orthologs, GPLA-1/GPA2 and GPLB-1/GPB5, are important for FSHR-1 modulation of the NMJ. Together, our results demonstrate that FSHR-1 modulation directs inter-tissue signaling systems, which promote synaptic vesicle release at neuromuscular synapses.
Natural variation in infection specificity ofCaenorhabditis briggsaeisolates by two RNA viruses
Authors: Alkan Cigdem , Brésard Gautier , Frézal Lise , Richaud Aurélien , Ruaud Albane , Zhang Gaotian , Félix Marie-Anne
Published: February 2024

Antagonistic relationships such as host-virus interactions potentially lead to rapid evolution and specificity in interactions. The Orsay virus is so far the only horizontal virus naturally infecting the nematodeC. elegans. In contrast, several related RNA viruses infect its congenerC. briggsae, including Santeuil (SANTV) and Le Blanc (LEBV) viruses. Here we focus on the host’s intraspecific variation in sensitivity to these two intestinal viruses. Many temperate-originC. briggsaestrains, including JU1264 and JU1498, are sensitive to both, while many tropical strains, such as AF16, are resistant to both. Interestingly, someC. briggsaestrains exhibit a specific resistance, such as the HK104 strain, specifically resistant to LEBV. The viral sensitivity pattern matches the strains’ geographic and genomic relationships. The heavily infected strains mount a seemingly normal small RNA response that is insufficient to suppress viral infection, while the resistant strains show no small RNA response, suggesting an early block in viral entry or replication. We use a genetic approach from the host side to map genomic regions participating in viral resistance polymorphisms. Using Advanced Intercrossed Recombinant Inbred Lines (RILs) between virus-resistant AF16 and SANTV-sensitive HK104, we detect Quantitative Trait Loci (QTLs) on chromosomes IV and III. Building RILs between virus-sensitive JU1498 and LEBV-resistant HK104 followed by bulk segregant analysis, we identify a chromosome II QTL. In both cases, further introgressions of the regions confirmed the QTLs. This diversity provides an avenue for studying virus entry, replication, and exit mechanisms, as well as host-virus specificity and the host response to a specific virus infection.
Key unprotected areas for carnivore conservation in Mexico
Authors: Gonzalez Germar , Harris Nyeema C.
Published: February 2024

Area-based conservation remains a pivotal component of global wildlife protection efforts. Mexico hosts a diverse array of area-based approaches, encompassing protected areas (PAs) and other effective area-based conservation measures (OECMs) such as voluntary conservation areas (VCAs) and wildlife management units (UMAs). Indigenous Territories (ITs) also provide heightened conservation potential through traditional ecological knowledge systems. These conservation spaces exhibit significant variations in community involvement, national coverage, and governance. Here, we evaluate the conservation potential of these land management types for 29 terrestrial carnivores, focusing on spatial co-occurrence. We determine areas in Mexico lacking area-based protection and calculate carnivore richness per land management type. Analyzing overlap between land management types and carnivore ranges, we employ heat maps to visualize overlap occurrence and key unprotected areas. We found that across all carnivore ranges, 87% of the area remains unprotected under designated protection areas (PAs & VCAs), decreasing to 65.2% after including non-designated types (ITs and UMAs). We identified several key gaps in the protection estate for Mexican carnivores, most notably on the eastern Mexican coast in the state of Veracruz. Our findings corroborate the importance of including Indigenous Peoples and Local Communities in conservation efforts, emphasizing their contributions to the stewardship of Mexican ecosystems. As the global protected area estate continues to expand under the post-2020 global biodiversity targets, and the importance of a well-designed and diverse portfolio of practices for conservation is recognized, the need for collective action, increased collaboration and inclusivity, and effective communication amongst stakeholders becomes necessary for carnivore conservation.
Unifying approaches from statistical genetics and phylogenetics for mapping phenotypes in structured populations
Authors: Schraiber Joshua G. , Edge Michael D. , Pennell Matt
Published: February 2024

In both statistical genetics and phylogenetics, a major goal is to identify correlations between genetic loci or other aspects of the phenotype or environment and a focal trait. In these two fields, there are sophisticated but disparate statistical traditions aimed at these tasks. The disconnect between their respective approaches is becoming untenable as questions in medicine, conservation biology, and evolutionary biology increasingly rely on integrating data from within and among species, and once-clear conceptual divisions are becoming increasingly blurred. To help bridge this divide, we derive a general model describing the covariance between the genetic contributions to the quantitative phenotypes of different individuals. Taking this approach shows that standard models in both statistical genetics (e.g., Genome-Wide Association Studies; GWAS) and phylogenetic comparative biology (e.g., phylogenetic regression) can be interpreted as special cases of this more general quantitative-genetic model. The fact that these models share the same core architecture means that we can build a unified understanding of the strengths and limitations of different methods for controlling for genetic structure when testing for associations. We develop intuition for why and when spurious correlations may occur using analytical theory and conduct population-genetic and phylogenetic simulations of quantitative traits. The structural similarity of problems in statistical genetics and phylogenetics enables us to take methodological advances from one field and apply them in the other. We demonstrate this by showing how a standard GWAS technique—including both the genetic relatedness matrix (GRM) as well as its leading eigenvectors, corresponding to the principal components of the genotype matrix, in a regression model—can mitigate spurious correlations in phylogenetic analyses. As a case study of this, we re-examine an analysis testing for co-evolution of expression levels between genes across a fungal phylogeny, and show that including covariance matrix eigenvectors as covariates decreases the false positive rate while simultaneously increasing the true positive rate. More generally, this work provides a foundation for more integrative approaches for understanding the genetic architecture of phenotypes and how evolutionary processes shape it.
Proteus: Exploring Protein Structure Generation for Enhanced Designability and Efficiency
Authors: Wang Chentong , Qu Yannan , Peng Zhangzhi , Wang Yukai , Zhu Hongli , Chen Dachuan , Cao Longxing
Published: February 2024

Diffusion-based generative models have been successfully employed to create proteins with novel structures and functions. However, the construction of such models typically depends on large, pre-trained structure prediction networks, like RFdiffusion. In contrast, alternative models that are trained from scratch, such as FrameDiff, still fall short in performance. In this context, we introduce Proteus, an innovative deep diffusion network that incorporates graph-based triangle methods and a multi-track interaction network, eliminating the dependency on structure prediction pre-training with superior efficiency. We have validated our model’s performance onde novoprotein backbone generation through comprehensive in silico evaluations and experimental characterizations, which demonstrate a remarkable success rate. These promising results underscore Proteus’s ability to generate highly designable protein backbones efficiently. This capability, achieved without reliance on pre-training techniques, has the potential to significantly advance the field of protein design. Codes are available athttps://github.com/Wangchentong/Proteus.
Carbon nanoparticle exposure strengthens water-relation parameters by stimulating abscisic acid pathway and aquaporins genes in rice
Authors: Kumar Aman , Lekshmi Manasa S , Kashyap Jyotiprabha , Mandal Sikha , Mishra Gayatri , Rath Jnanendra , Rout Gyana Ranjan , Panigrahi Kishore CS , Panigrahy Madhusmita
Published: February 2024

Mechanism of action and molecular basis of positive growth effects including yield increase due to carbon nanoparticle (CNP) treatment in rice plants is dissected here. CNP at 500 -750 µg/mL were found to be the optimum dosages showing best seedling growth. CNP treatment resulted increase in stomata size, gaseous exchange and water use efficiency along with decrease in stomata frequency, relative humidity, internal CO2concentration. CNP treatment exerted cold tolerance in seedlings and water stress tolerance in reproductive stage. CNP-coupled with water uptake was found to be endocytosis mediated, although CNP uptake was not affected by endocytosis inhibitor application in roots. Genomic analysis resulted major involvement of ABA pathway and stomata size and frequency genes inArabidopsisand rice. Elevated endogenous ABA in rice seedlings and flag leaves along with increased expression of ABA biosynthetic genes inArabidopsisand riceAtNCED3,AtNCED6,OsNCED1confirmed increased ABA synthesis. Negative regulators of ABA pathway,OsSNRK2down-regulation and up-regulation of stomagen (OsEPFL9) reconfirmed ABA’s involvement. CNP treatment resulted water stress tolerance by maintaining lower stomatal conductance, transpiration rate and higher relative water content. Increased ABA (OsSNRK1,OsSNRK2) and aquaporin (OsPIP2-5) genes’ expressions could explain the better water stress tolerance in rice plants treated with CNP. Altogether, due to thermomorphogenesis, down-regulation of Phytochrome B resulted altered the ABA pathway and stomatal distribution with size. These changes resulted improved water relation parameters and WUE showing improvement in yield. Detailed mechanism of action of CNP in abiotic stress tolerance can be exploited in in nano-agriculture.
BPTF cooperates with MYCN and MYC to link neuroblastoma cell cycle control to epigenetic cellular states
Authors: Felipe Irene , Martínez-de-Villarreal Jaime , Patel Khushbu , Martínez-Torrecuadrada Jorge , Grossmann Liron D. , Roncador Giovanna , Cubells Mariona , Farrell Alvin , Kendsersky Nathan , Sabroso-Lasa Sergio , Sancho-Temiño Lucía , Torres Kyabeth , Martinez Daniel , Perez Javier Muñoz , García Fernando , Pogoriler Jenny , Moreno Lucas , Maris John M. , Real Francisco X.
Published: February 2024

The nucleosome remodeling factor BPTF is required for the deployment of the MYC-driven transcriptional program. Deletion of oneBptfallele delays tumor progression in mouse models of pancreatic cancer and lymphoma. In neuroblastoma, MYCN cooperates with the transcriptional core regulatory circuitry (CRC). HighBPTFlevels are associated with high-risk features and decreased survival. BPTF depletion results in a dramatic decrease of cell proliferation. Bulk RNA-seq, single-cell sequencing, and tissue microarrays reveal a positive correlation ofBPTFand CRC transcription factor expression. Immunoprecipitation/mass spectrometry shows that BPTF interacts with MYCN and the CRC proteins. Genome-wide distribution analysis of BPTF and CRC in neuroblastoma reveals a dual role for BPTF: 1) it co-localizes with MYCN/MYC at the promoter of genes involved in cell cycle and 2) it co-localizes with the CRC at super-enhancers to regulate cell identity. The critical role of BPTF across neuroblastoma subtypes supports its relevance as a therapeutic target.
Profiling IOP-responsive genes in anterior and posterior ocular tissues in the rat CEI glaucoma model
Authors: Lozano Diana C. , Yang Yong-Feng , Cepurna William O. , Smoody Barbara F. , Ing Eliesa , Morrison John C. , Keller Kate E.
Published: February 2024

Purpose

The rat Controlled Elevation of Intraocular pressure (CEI) model allows study ofin vivoresponses to defined intraocular pressures (IOP). In this study, we use Nanostring technology to investigatein vivoIOP-related gene responses in the trabecular meshwork (TM) and optic nerve head (ONH) simultaneously from the same animals.

Methods

Male and female rats (N=35) were subject to CEI for 8-hours at pressures simulating mean, daytime normotensive rat IOP (CEI-20), or 2.5x IOP (CEI-50). Naïve animals, receiving no anesthesia or surgical interventions, served as controls. Immediately after CEI, TM and ONH tissues were dissected, RNA isolated, and samples were analyzed with a Nanostring panel containing 770 genes. Post-processing, raw count data were uploaded to Rosalind® for differential gene expression analyses.

Results

For the TM, 45 IOP-related genes were significant in the “CEI-50 vs. CEI-20” and “CEI-50 vs. naïve” comparisons, with 15 genes common to both comparisons. Bioinformatics analysis identified Notch and TGFβ pathways to be the most up- and down-regulated KEGG pathways, respectively. For ONH, 22 significantly regulated genes were identified in the “CEI-50 vs. naïve” comparison. Pathway analysis identified ‘defense response’ and ‘immune response’ as two significantly upregulated biological process pathways.

Conclusions

This study demonstrates the ability to assay IOP-responsive genes in both TM and ONH tissues simultaneously. In the TM, downregulation of TGFβ pathway genes suggest that TM responses may prevent TGFβ-induced extracellular matrix synthesis. For ONH, the initial response to elevated IOP may be protective, with astrocytes playing a key role in these gene responses.
DNA barcoding affirms the presence of invasiveParachanna obscuraand new records of some species in the Mweru-Luapula fishery
Authors: Seemani Bornwell , Katongo Cyprian , Bloomer Paulette , Klopper Arrie W. , Oosthuizen Carel J.
Published: February 2024

DNA barcoding has recently been instrumental in identifying both invasive and undetected species in aquatic environments. This study aimed at analysing collected fish fin clips to ascertain the identity of native species and theParachannaspecies that have invaded the Mweru-Luapula (ML) fishery of Zambia. The identification process was carried out through field phenotypic analysis using species guides and DNA barcoding, with the mitochondrial DNA (mtDNA) cytochrome C oxidase 1 (COI) gene fragment. Of the 28 specimens for which DNA was successfully PCR amplified, five matched the reference sequences of species and 22 matched the reference sequences of genera on the NCBI GenBank. Five unexpected species, namelyOreochromis niloticus, Coptodon zillii, Mormyrus kannume, Thoracochromis buysiandTylochromis polylepiswere identified. The study further affirmed the presence of invasiveParachanna obscurain the fishery and its interconnected water bodies.Parachanna obscurainvaded the fishery through annual flooding from aquacultural facilities in the Democratic Republic of Congo (DRC). There is a need to investigate this invasion further by using large sample sizes and also by applying the gonadosomatic index (GSI) to determine invasive species occupancy and impact on native species throughout the fishery. This study provides a platform for further detailed taxonomic verification and species inventory of the entire ML fishery. This will facilitate the development of a viable and sustainable strategy to appropriately curb the impact of invasive species, and will thus contribute to the conservation of the ML aquatic biodiversity.
Integrated transcriptomic analysis of human induced pluripotent stem cell-derived osteogenic differentiation reveals a regulatory role of KLF16
Authors: Ru Ying , Ma Meng , Zhou Xianxiao , Kriti Divya , Cohen Ninette , D’Souza Sunita , Schaniel Christoph , Motch Perrine Susan M. , Kuo Sharon , Pichurin Oksana , Pinto Dalila , Housman Genevieve , Holmes Greg , Schadt Eric , van Bakel Harm , Zhang Bin , Jabs Ethylin Wang , Wu Meng
Published: February 2024

Osteogenic differentiation is essential for bone development, metabolism, and repair; however, the underlying regulatory relationships among genes remain poorly understood. To elucidate the transcriptomic changes and identify novel regulatory genes involved in osteogenic differentiation, we differentiated mesenchymal stem cells (MSCs) derived from 20 human iPSC lines into preosteoblasts (preOBs) and osteoblasts (OBs). We then performed transcriptome profiling of MSCs, preOBs and OBs. The iPSC-derived MSCs and OBs showed similar transcriptome profiles to those of primary human MSCs and OBs, respectively. Differential gene expression analysis revealed global changes in the transcriptomes from MSCs to preOBs, and then to OBs, including the differential expression of 840 genes encoding transcription factors (TFs). TF regulatory network analysis uncovered a network comprising 451 TFs, organized into five interactive modules. Multiscale embedded gene co-expression network analysis (MEGENA) identified gene co-expression modules and key network regulators (KNRs). From these analyses,KLF16emerged as an important TF in osteogenic differentiation. We demonstrate that overexpression ofKlf16in vitro inhibited osteogenic differentiation and mineralization, whileKlf16+/-mice exhibited increased bone mineral density, trabecular number, and cortical bone area. Our study underscores the complexity of osteogenic differentiation and identifies novel regulatory genes such asKLF16, which plays an inhibitory role in osteogenic differentiation both in vitro and in vivo.
Impaired drainage through capillary-venous networks contributes to age-related white matter loss
Authors: Stamenkovic Stefan , Schmid Franca , Weitermann Nicolas , Takasaki Kevin , Bonney Stephanie K. , Sosa Maria J. , Li Yuandong , Bennett Hannah C. , Kim Yongsoo , Waters Jack , Shih Andy Y.
Published: February 2024

The gradual loss of cerebral white matter contributes to cognitive decline during aging. However, microvascular networks that support the metabolic demands of white matter remain poorly defined. We usedin vivodeep multi-photon imaging to characterize microvascular networks that perfuse cortical layer 6 and corpus callosum, a highly studied region of white matter in the mouse brain. We show that these deep tissues are exclusively drained by sparse and wide-reaching venules, termed principal cortical venules, which mirror vascular architecture at the human cortical-U fiber interface. During aging, capillary networks draining into deep branches of principal cortical venules are selectively constricted, reduced in density, and diminished in pericyte numbers. This causes hypo-perfusion in deep tissues, and correlates with gliosis and demyelination, whereas superficial tissues become relatively hyper-perfused. Thus, age-related impairment of capillary-venular drainage is a key vascular deficit that contributes to the unique vulnerability of cerebral white matter during brain aging.
DNA methylation-dependent and -independent binding of CDX2 directs activation of distinct developmental and homeostatic genes
Authors: Lorzadeh Alireza , Ye George , Sharma Sweta , Jadhav Unmesh
Published: February 2024

Precise spatiotemporal and cell type-specific gene expression is essential for proper tissue development and function. Transcription factors (TFs) guide this process by binding to developmental stage-specific targets and establishing an appropriate enhancer landscape. In turn, DNA and chromatin modifications direct the genomic binding of TFs. However, how TFs navigate various chromatin features and selectively bind a small portion of the millions of possible genomic target loci is still not well understood. Here we show that Cdx2 - a pioneer TF that binds distinct targets in developing versus adult intestinal epithelial cells - has a preferential affinity for a non-canonical CpG-containing motifin vivo. A higher frequency of this motif at embryonic and fetal Cdx2 target loci and the specifically methylated state of the CpG during development allows selective Cdx2 binding and activation of developmental enhancers and linked genes. Conversely, demethylation at these enhancers prohibits ectopic Cdx2 binding in adult cells, where Cdx2 binds its canonical motif without a CpG. This differential Cdx2 binding allows for corecruitment of Ctcf and Hnf4, facilitating the establishment of intestinal superenhancers during development and enhancers mediating adult homeostatic functions, respectively. Induced gain of DNA methylation in the adult mouse epithelium or cultured cells causes ectopic recruitment of Cdx2 to the developmental target loci and facilitates cobinding of the partner TFs. Together, our results demonstrate that the differential CpG motif requirements for Cdx2 binding to developmental versus adult target sites allow it to navigate different DNA methylation profiles and activate cell type-specific genes at appropriate times.

Graphical Abstract
Graph-based Nanopore Adaptive Sampling with GNASTy enables sensitive pneumococcal serotyping in complex samples
Authors: Horsfield Samuel T. , Fok Basil , Fu Yuhan , Turner Paul , Lees John A. , Croucher Nicholas J.
Published: February 2024

Serotype surveillance ofStreptococcus pneumoniae(the pneumococcus) is critical for understanding the effectiveness of current vaccination strategies. However, existing methods for serotyping are limited in their ability to identify co-carriage of multiple pneumococci and detect novel serotypes. To develop a scalable and portable serotyping method that overcomes these challenges, we employed Nanopore Adaptive Sampling (NAS), an on-sequencer enrichment method which selects for target DNA in real-time, for direct detection ofS. pneumoniaein complex samples. Whereas NAS targeting the wholeS. pneumoniaegenome was ineffective in the presence of non-pathogenic streptococci, the method was both specific and sensitive when targeting the capsular biosynthetic locus (CBL), the operon that determinesS. pneumoniaeserotype. NAS significantly improved coverage and yield of the CBL relative to sequencing without NAS, and accurately quantified the relative prevalence of serotypes in samples representing co-carriage. To maximise the sensitivity of NAS to detect novel serotypes, we developed and benchmarked a new pangenome-graph algorithm, named GNASTy. We show that GNASTy outperforms the current NAS implementation, which is based on linear genome alignment, when a sample contains a serotype absent from the database of targeted sequences. The methods developed in this work provide an improved approach for novel serotype discovery and routineS. pneumoniaesurveillance that is fast, accurate and feasible in low resource settings. GNASTy therefore has the potential to increase the density and coverage of global pneumococcal surveillance.

One sentence summary

Pangenome graph-based Nanopore Adaptive Sampling, presented in our tool GNASTy, is a sensitive, portable and cost-effective method forStreptococcus pneumoniaesurveillance.
The impact of face masks on face-to-face neural tracking of speech: auditory and visual obstacles
Authors: Fantoni M. , Federici A. , Camponogara I. , Handjaras G. , Martinelli A. , Bednaya E. , Ricciardi E. , Pavani F. , Bottari D.
Published: February 2024

Face masks provide fundamental protection against the transmission of respiratory viruses but hamper communication. We estimated auditory and visual obstacles generated by face masks on communication by measuring the neural tracking of face-to-face speech. To this end, we recorded the EEG while participants were exposed to naturalistic audio-visual speech, embedded in multi-talker noise, in three contexts: (i) no-mask (audio-visual information was fully available), (ii) virtual mask (occluded lips, but intact audio), and (iii) real mask (occluded lips and degraded audio). The neural tracking of lip movements and the sound envelope of speech was measured through backward modeling, that is, by reconstructing stimulus properties from neural activity. Behaviorally, face masks increased listening -phonological-errors in speech content retrieval and perceived listening difficulty. At the neural level, we observed that the occlusion of the mouth abolished lip tracking and dampened neural tracking of the speech envelope at the earliest processing stages. Degraded acoustic information due to face mask filtering altered neural tracking at later processing stages instead. Finally, a consistent link emerged between the increment of listening perceived difficulty and the drop in reconstruction performance of speech envelope when attending to a speaker wearing a face mask. Results clearly dissociated the visual and auditory impacts of face masks on face-to-face neural tracking of speech. While face masks hampered the ability to predict and integrate audio-visual speech, the auditory filter generated by face masks impacted the neural processing stages typically associated with auditory selective attention. The link between perceived difficulty and neural tracking drop provided evidence of a major impact of face masks on the metacognitive levels subtending speech processing.
Age-dependent dynamics of neuronal VAPBALSinclusions in the adult brain
Authors: Thulasidharan Aparna , Garg Lovleen , Tendulkar Shweta , Ratnaparkhi Girish S
Published: February 2024

Amyotrophic Lateral Sclerosis (ALS) is a relentlessly progressive and fatal disease, caused by the degeneration of upper and lower motor neurons within the brain and spinal cord in the ageing human. The dying neurons contain cytoplasmic inclusions linked to the onset and progression of the disease. Here, we use aDrosophilamodel ofALS8 (VAPP58S)to understand the modulation of these inclusions in the ageing adult brain.

The adultVAPP58Sfly shows progressive deterioration in motor function till its demise 25 days post-eclosion. The density of VAPP58S-positive brain inclusions is stable for 5-15 days of age. In contrast, adding a single copy ofVAPWTto theVAPP58Sanimal leads to a large decrease in inclusion density with concomitant rescue of motor function and lifespan. ER stress, a contributing factor in disease, shows reduction with ageing for the disease model. Autophagy, rather than the Ubiquitin Proteasome system, is the dominant mechanism for aggregate clearance.

We explored the ability ofDrosophilaValosin-containing protein (VCP/TER94), theALS14locus, which is involved in cellular protein clearance, to regulate age-dependent aggregation. Contrary to expectation,TER94overexpression increased VAPP58Spunctae density, while its knockdown led to enhanced clearance. Expression of a dominant positive allele,TER94R152H,further stabilised VAPP58Spuncta, cementing roles for anALS8-ALS14axis. Our results are explained by a mechanism where autophagy is modulated byTER94knockdown.

Our study sheds light on the complex regulatory events involved in the neuronal maintenance of ALS8 aggregates, suggesting a context-dependent switch between proteasomal and autophagy-based mechanisms as the larvae develop into an adult. A deeper understanding of the nucleation and clearance of the inclusions, which affect cellular stress and function, is essential for understanding the initiation and progression of ALS.
Modeling Hereditary Diffuse Leukoencephalopathy with Axonal Spheroids using microglia-sufficient brain organoids
Authors: Wong Wei Jie , Zhu Yi Wen , Wang Hai Ting , Qian Jia Wen , Li Ziyi , Li Song , Liu Zhao Yuan , Guo Wei , Zhang Shuang Yan , Su Bing , He Fang Ping , Wang Kang , Ginhoux Florent
Published: February 2024

Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) is a rare, fatal, adult-onset neurodegenerative disease that is most often caused by mutations affecting the Colony Stimulating factor-1 Receptor (CSF-1R). To understand how CSF-1R-mutation affects human microglia – the specialized brain-resident macrophages of the central nervous system – and the downstream consequences for neuronal cells, we used a macrophage and forebrain organoid co-culture system based on induced pluripotent stem cells generated from two patients with HDLS, withCSF-1Rgene-corrected isogenic organoids as controls. Macrophages derived from iPSC (iMacs) of patients exhibited a metabolic shift towards the glycolytic pathway and reduced CSF-1 sensitivity, which was associated with higher levels of IL-1β production and an activated inflammatory phenotype. Single-cell RNA sequencing revealed that iMacs adopt a reactive state that leads to impaired regulation of neuronal cell populations in organoid cultures, thereby identifying microglial dysregulation and specifically IL-1β production as key contributors to the degenerative neuro-environment in HDLS.
Continuous Bump Attractor Networks Require Explicit Error Coding for Gain Recalibration
Authors: Secer Gorkem , Knierim James J. , Cowan Noah J.
Published: February 2024

Representations of continuous variables are crucial to create internal models of the external world. A prevailing model of how the brain maintains these representations is given by continuous bump attractor networks (CBANs) in a broad range of brain functions across different areas, such as spatial navigation in hippocampal/entorhinal circuits and working memory in prefrontal cortex. Through recurrent connections, a CBAN maintains a persistent activity bump, whose peak location can vary along a neural space, corresponding to different values of a continuous variable. To track the value of a continuous variable changing over time, a CBAN updates the location of its activity bump based on inputs that encode the changes in the continuous variable (e.g., movement velocity in the case of spatial navigation)—a process akin to mathematical integration. This integration process is not perfect and accumulates error over time. For error correction, CBANs can use additional inputs providing ground-truth information about the continuous variable’s correct value (e.g., visual landmarks for spatial navigation). These inputs enable the network dynamics to automatically correct any representation error. Recent experimental work on hippocampal place cells has shown that, beyond correcting errors, ground-truth inputs also fine-tune the gain of the integration process, a crucial factor that links the change in the continuous variable to the updating of the activity bump’s location. However, existing CBAN models lack this plasticity, offering no insights into the neural mechanisms and representations involved in the recalibration of the integration gain. In this paper, we explore this gap by using a ring attractor network, a specific type of CBAN, to model the experimental conditions that demonstrated gain recalibration in hippocampal place cells. Our analysis reveals the necessary conditions for neural mechanisms behind gain recalibration within a CBAN. Unlike error correction, which occurs through network dynamics based on ground-truth inputs, gain recalibration requires an additional neural signal that explicitly encodes the error in the network’s representation via a rate code. Finally, we propose a modified ring attractor network as an example CBAN model that verifies our theoretical findings. Combining an error-rate code with Hebbian synaptic plasticity, this model achieves recalibration of integration gain in a CBAN, ensuring accurate representation for continuous variables.