bluuebunny/crossref_metadata_2025 huggingface dataset:
Lymphatic activation of ACKR3 signaling regulates lymphatic response after ischemic heart injury
Authors: Balint Laszlo , Patel Shubhangi , Serafin D. Stephen , Zhang Hua , Quinn Kelsey E. , Aghajanian Amir , Kistner Bryan M. , Caron Kathleen M.
Published: December 2024

2.

Background

Ischemic heart disease is a prevalent cause of death and disability worldwide. Recent studies reported a rapid expansion of the cardiac lymphatic network upon ischemic heart injury and proposed that cardiac lymphatics may attenuate tissue edema and inflammatory mechanisms after ischemic heart injury. Nevertheless, the mechanisms through which hypoxic conditions affect cardiac lymphangiogenesis and function remain unclear. Here, we aimed to characterize the role of the adrenomedullin decoy receptor atypical chemokine receptor 3 (ACKR3) in the lymphatic response following ischemic heart injury.

Methods

Spatial assessment of ACKR3 signaling in the heart after ischemic heart injury was conducted using ACKR3-TangoGFP reporter mice. Roles of ACKR3 after ischemic heart injury were characterized inAckr3ΔLyve1mice and in cultured human lymphatic endothelial cells (LECs) exposed to hypoxia.

Results

Using the novel ACKR3-Tango-GFP reporter mice, we detected activation of ACKR3 signaling in cardiac lymphatics adjacent to the site of ischemic injury of left anterior descending artery (LAD) ligation.Ackr3ΔLyve1mice exhibited better survival and were protected from the formation of acute tissue edema after ischemic cardiac injury.Ackr3ΔLyve1mice exhibited a denser cardiac lymphatic network after LAD ligation, especially in the injured tissues. Transcriptomic analysis revealed changes in cardiac lymphatic gene expression patterns that have been associated with extracellular matrix remodeling and immune activation. We also found that ACKR3 plays a critical role in the regulating continuous cell-cell junction dynamics in LECs under hypoxic conditions.

Conclusions

Lymphatic expression of ACKR3 governs numerous processes following ischemic heart injury, including the lymphangiogenic response, edema protection and overall survival. These results expand our understanding of how the heart failure biomarker adrenomedullin, regulated by lymphatic ACKR3, may exert its cardioprotective roles after ischemic cardiac injury.
Prediction and annotation of alternative transcription starts and promoter shift in the chicken genome
Authors: Grushina Valentina A , Yevshin Ivan S , Gusev Oleg A , Kolpakov Fedor A , Pintus Sergey S
Published: December 2024

The promoter shift is a long known phenomenon which implies changes in the coordinates of a transcription start site (TSS). Analysis of CAGE experiments allows one to assess the impact and statistical significance of the shift. The promoter shift can be associated not only with the change of stages in early development or tissue differentiation, but also with the environmental influence on the cells. Differential promoter usage suggests non-constitutive expression activity of the regulated gene, which, in turn, suggests the usage of few sharp promoters. On the other hand, the housekeeping genes are assumed to demonstrate stable levels of expression while using multiple broad promoters. Additionally, the housekeeping genes are assumed to be normally expressed in most of the tissues. Our results show that many ubiquitously expressed genes use single sharp promoters and are subject to the significant promoter shift, which implies an additional level of complexity to the problem of definition of a housekeeping gene.

The reaction of genes in cells and tissues to external stimuli is often studied in the context of differential gene expression. Our study employs a different approach of differential promoter usage, which takes the genes whose promoters undergo significant promoter shifting as the signatures of tissue response and phenotypic effect. Our results suggest that the difference in growth rate of chickens is controlled by the rate of metabolism of nutrients via the differential usage of promoters of the relevant genes.
Cortical dynamics underlying initiation of rapid steps with contrasting postural demands
Authors: Giesbers Ilse , Billen Lucas , van der Cruijsen Joris , Corneil Brian D. , Weerdesteyn Vivian
Published: December 2024

Our ability to flexibly initiate rapid visually-guided stepping movements can be measured in the form of express visuomotor responses (EVRs), which are short-latency (∼100ms), goal-directed bursts of lower-limb muscle activity. Interestingly, we previously demonstrated that recruitment of anticipatory postural adjustments (APAs) interacted with the subcortically-generated EVRs in the lower limb, suggesting context-dependent top-down modulation.

We investigated the associated cortical dynamics prior to and during rapid step initiation towards a salient visual target in twenty-one young, healthy individuals. We adopted two contrasting postural conditions by manipulating the stepping direction. Anterolateral steps involved low postural demands, whereas anteromedial stepping involved high postural demands. We recorded high-density EEG, surface electromyography from gluteus medius and ground-reaction forces.

Independent component analysis and time-frequency statistics revealed significant, yet relatively modest differences between conditions in preparatory cortical dynamics, most evidently in primary motor areas. Following target presentation, we observed stronger theta and alpha power enhancement in the supplementary motor area, and stronger alpha and beta power decrease in primary motor, parietal and occipital clusters during APA recruitment that preceded steps under high postural demands. We found no differences in (pre)frontal areas associated with the observed EVR suppression in the high postural demand condition.

Together, our findings point towards greater cortical involvement in step initiation under high postural demands as compared to more reflexive, stimulus-driven steps. This notion may be particularly relevant for populations where postural control is impaired by age or disease, as more cortical resources may need to be allocated during stepping.
TRPM7 activity drives human CD4 T-cell activation and differentiation in a magnesium dependent manner
Authors: Hoelting Kilian , Madlmayr Anna , Hoeger Birgit , Lewitz Dorothea , Weng Marius , Haider Tanja , Duggan Michelle , Ross Rylee , Horgen F. David , Sperandio Markus , Dietrich Alexander , Gudermann Thomas , Zierler Susanna
Published: December 2024

T lymphocyte activation is a crucial process in the regulation of innate and adaptive immune responses. The ion channel-kinase TRPM7 has previously been implicated in cellular Mg2+homeostasis, proliferation, and immune cell modulation. Here, we show that pharmacological and genetic silencing of TRPM7 leads to diminished human CD4 T-cell activation and proliferation following TCR mediated stimulation. In both primary human CD4 T cells and CRISPR/Cas-9 engineered Jurkat T cells, loss of TRPM7 led to altered Mg2+homeostasis, Ca2+signaling, reduced NFAT translocation, decreased IL-2 secretion and ultimately diminished proliferation and differentiation. While the activation of primary human CD4 T cells was dependent on TRPM7, polarization of naïve CD4 T cells into regulatory T cells (Treg) was not. Taken together, these results highlight TRPM7 as a key protein of cellular Mg2+homeostasis and CD4 T-cell activation. Its role in lymphocyte activation suggests therapeutic potential for TRPM7 in numerous T-cell mediated diseases.

TRPM7 is crucial to maintaining cellular Mg2+homeostasis and regulates human CD4 T-cell activation by modulating early Ca2+signaling events in response to TCR-mediated stimulation subsequently, influencing T-cell differentiation in a Mg2+dependent manner.
In vitro neuroendocrine differentiation of BPH-1 cells under β2 adrenergic receptor stimulation
Authors: Pigat Natascha , Garrido Castillo Laura Nalleli , Lefevre Coline , Baures Manon , Goffin Vincent , Anract Julien , Armand Anne-Sophie , Capiod Thierry
Published: December 2024

Epidemiologic and experimental animal studies have shown that stress can alter tumor growth and that adrenergic fibers from the sympathetic nervous system, acting through stromal β2 adrenergic receptors, promote tumor cell survival during the initial phases of cancer development. Recent epidemiological data suggest that beta blocker intake improves survival of prostate cancer patients. Hypertension and high blood pressure have been suggested to increase likelihood of prostate cancer development, suggesting that the use of beta blockers in these patients could reduce prostate cancer risk. Signaling mediated by β adrenergic receptors promotes neuroendocrine differentiation in the LNCaP prostate cancer cell line. Although neuroendocrine cells are a minor population in the epithelial compartment of normal prostate glands, the population of neuroendocrine-like cells that express markers such as SYN, Bcl-2, Dll-3, and AMACR correlates with cancer progression, androgen-independent state, and poor prognosis in prostate cancer patients. As recent studies show that an increase in neuroendocrine cell density occurs before development of benign prostatic hyperplasia, a non-lethal disease affecting the transition zone, in hypertensive rats, we investigated whether neuroendocrine differentiation is associated with benign prostatic hyperplasia. Our results showed that isobutyl-methyl-xanthine, which blocks cAMP degradation, and forskolin, an adenylate cyclase activator, triggered sustained activation of the cAMP/PKA pathway and led to an increase in neuroendocrine differentiation markers in BPH-1 cells, which are a benign prostatic hyperplasia cell line. Similar results were observed by combining the β adrenergic receptors agonist isoproterenol with forskolin. The same treatments reduced BPH-1 cell proliferation rates by 40% and 60%, respectively. Effects on AMACR and SYN expression and cell proliferation were fully reversed by the β2 blocker carvedilol. These data suggest that β adrenergic receptors are linked to the development of neuroendocrine-like cells and benign prostatic hyperplasia. As 20% of the prostate cancer tumors occur in this zone, this observation warrants further investigation.
Snake venom metalloproteinases are predominantly responsible for the cytotoxic effects of certain African viper venoms
Authors: Bartlett Keirah E. , Westhorpe Adam , Wilkinson Mark C. , Casewell Nicholas R.
Published: December 2024

Abstract

Snakebite envenoming is a neglected tropical disease that causes substantial mortality and morbidity globally. The puff adder (Bitis arietans) and saw-scaled viper (Echis romani) have cytotoxic venoms that cause permanent injury via tissue-destructive dermonecrosis around the bite site. Identification of cytotoxic toxins within these venoms will allow development of targeted treatments, such as small molecule inhibitors or monoclonal antibodies to prevent snakebite morbidity. Venoms from both species were fractionated using gel filtration chromatography, and a combination of cell-based cytotoxicity approaches, SDS-PAGE gel electrophoresis, and enzymatic assays were applied to identify venom cytotoxins in the resulting fractions. Our results indicated that snake venom metalloproteinase (SVMP) toxins are predominately responsible for causing cytotoxic effects across both venoms, but that the PII subclass of SVMPs are likely the main driver of cytotoxicity following envenoming byB. arietans, whilst the structurally distinct PIII subclass of SVMPs are responsible for conveying this effect inE. romanivenom. Identification of distinct SVMPs as the primary cytotoxicity-causing toxins in these two African viper venoms will facilitate the future design and development of novel therapeutics targeting these medically important venoms, which in turn could help to mitigate the severe life and limb threatening consequences of tropical snakebite.

Key Contribution

SVMP toxins were identified as the primary cytotoxicity-causing toxins in the venoms of the puff adder (Bitis arietans) and saw-scaled viper (Echis romani); PII and PIII SVMPs, respectively. This cytotoxicity can be prevented using the metalloproteinase-inhibiting chelator EDTA, suggesting targeted drugs/antibodies may be a viable option for future treatment.
Comparative analysis of CRISPR/Cas9-targeted nanopore sequencing approaches in repeat expansion disorders
Authors: Benarroch Louise , Boëlle Pierre-Yves , Madry Hélène , Mohand Oumoussa Badreddine , Eura Noboyuki , Nishino Ichizo , Labrèche Karim , Bassez Guillaume , Stojkovic Tanya , Gourdon Geneviève , Bonne Gisèle , Tomé Stéphanie
Published: December 2024

More than 50 repeat expansion disorders have been identified, with long-read sequencing marking a new milestone in the diagnosis of these disorders. Despite these major achievements, the comprehensive characterization of short tandem repeats in a pathological context remains challenging, primarily due to their inherent characteristics such as motif complexity, high GC content, and variable length.

In this study, our aim was to thoroughly characterize repeat expansions in two neuromuscular diseases: myotonic dystrophy type 1 (DM1) and oculopharyngodistal myopathy (OPDM) using CRISPR/Cas9-targeted long-read sequencing (Oxford Nanopore Technologies, ONT). We conducted precise analyses of the DM1 and OPDM loci, determining repeat size, repeat length distribution, expansion architecture and DNA methylation, using three different basecallers (Guppy, Bonito and Dorado). We demonstrated the importance of the basecalling strategy in repeat expansion characterization. We proposed guidelines to perform CRISPR-Cas9 targeted long-read sequencing (no longer supported by ONT), from library preparation to bioinformatical analyses. Finally, we showed, for the first time, somatic mosaicism, hypermethylation ofLRP12loci in symptomatic patients and changes in the repeat tract structure of OPDM patients.

We propose a strategy based on CRISPR/Cas9-enrichment long-read sequencing for repeat expansion diseases, which could be readily applicable in research but also in diagnostic settings.
Adrenocortical Cancer Cell uptake of Iron Oxide Nanoparticles
Authors: Challapalli Ritihaas Surya , Hong Cong , Sorushanova Anna , Covarrubias-Zambrano Obdulia , Mullen Nathan , Feely Sarah , Covarrubias Jose , Varghese Sunita N. , Hantel Constanze , Owens Peter , O’Halloran Martin , Prakash Punit , Bossmann Stefan H. , Dennedy Michael Conall
Published: December 2024

Adrenocortical carcinoma (ACC) is a rare cancer with poor prognosis, treated primarily through surgery and chemotherapy. Other treatments like radiation or thermal ablation for metastases have limited success, and recurrence is common. More effective management options are needed. Magnetic iron oxide nanoparticles (IONP) show promise in cancer treatment due to their ability to be modified for selective uptake by cancer cells. This study investigated IONP uptake in ACC cell lines (H295R, HAC-15, MUC-1) using a multicellular model with endothelial cells (HUVEC) and monocytes. IONP uptake was concentration- and time-dependent, with optimal uptake at 10 µg/mL. IONP were found in the cytoplasm and intracellular vesicles of ACC cells. However, endothelial cells and monocytes also absorbed IONP, reducing uptake by ACC cells. These findings suggest ACC cells actively take up IONP, but better targeting is needed to enhance uptake specificity and efficiency.
Cell Type Differentiation Using Network Clustering Algorithms
Authors: Nasrollahi Fatemeh Sadat Fatemi , Silva Filipi Nascimento , Liu Shiwei , Chaudhuri Soumilee , Yu Meichen , Wang Juexin , Nho Kwangsik , Saykin Andrew J. , Bennett David A. , Sporns Olaf , Fortunato Santo
Published: December 2024

Single cell RNA-seq (scRNA-seq) technologies provide unprecedented resolution representing transcriptomics at the level of single cell. One of the biggest challenges in scRNA-seq data analysis is the cell type annotation, which is usually inferred by cell separation approaches. In-silico algorithms that accurately identify individual cell types in ongoing single-cell sequencing studies are crucial for unlocking cellular heterogeneity and understanding the biological basis of diseases. In this study, we focus on robustly identifying cell types in single-cell RNA sequencing data; we conduct a comparative analysis using methods established in biology, like Seurat, Leiden, and WGCNA, as well as Infomap, statistical inference via Stochastic Block Models (SBM), and single-cell Graph Neural Networks (scGNN). We also analyze preprocessing pipelines to identify and optimize key components in the process. Leveraging two independent datasets, PBMC and ROSMAP, we employ clustering algorithms on cell-cell networks derived from gene expression data. Our findings reveal that while clusters detected by WGCNA exhibit limited correspondence with cell types, those identified by multiresolution Infomap and Leiden, and SBM show a closer alignment, with Infomap standing out as a particularly effective approach. Infomap notably offers valuable insights for the precise characterization of cellular landscapes related to neurodegenration and immunology in scRNA-seq.
Diverging transposon activity among polar bear sub-populations inhabiting different climate zones
Authors: Godden Alice M. , Rix Benjamin T. , Immler Simone
Published: December 2024

A new subpopulation of polar bears (Ursus maritimus) was recently discovered in the South-East of Greenland (SEG). This isolated colony inhabits a warmer climate zone, akin to the predicted future environments of polar bears with vastly reduced sea ice habitats, rendering this population of bears particularly important. Over two-thirds of polar bears will be extinct by 2050 with total extinction predicted by the end of this century and understanding possible mechanisms of adaptation via genomic analyses and preservation are critical. Transposable elements (TEs) are parasitic mobile elements that may play a role in an adaptive response to environmental challenges. We analysed transcriptome data from polar bear sub-populations in North-East and South-East Greenland (NEG, SEG), who reside in cooler and warmer habitats respectively, to identify differentially expressed, divergent TE species, TE families and linked changes in gene expression with some overlapping significantly differentially expressed TEs and genes. We identified activity hotspots in the genome of regions with significantly differentially expressed TEs. LINE family TEs were the most abundant, and most differentially expressed and divergent in the SEG population compared to reference TEs. Our results provide insights into how a genomic response at the TE level may allow the SEG subpopulations adapt and survive to climate change and provides a useful resource for conservation in polar bears.
At-RS31 orchestrates hierarchical cross-regulation of splicing factors and integrates alternative splicing with TOR-ABA pathways
Authors: Köster Tino , Venhuizen Peter , Lewinski Martin , Petrillo Ezequiel , Marquez Yamile , Fuchs Armin , Ray Debashish , Nimeth Barbara A. , Riegler Stefan , Franzmeier Sophie , Zheng Hong , Hughes Timothy , Morris Quaid , Barta Andrea , Staiger Dorothee , Kalyna Maria
Published: December 2024

Alternative splicing is essential for plants, enabling a single gene to produce multiple transcript variants to boost functional diversity and fine-tune responses to environmental and developmental cues. At-RS31, a plant-specific splicing factor in the Serine/Arginine (SR)-rich protein family, responds to light and the Target of Rapamycin (TOR) signaling pathway, yet its downstream targets and regulatory impact remain unknown.

To identify At-RS31 targets, we applied individual-nucleotide resolution crosslinking and immunoprecipitation (iCLIP) and RNAcompete assays. Transcriptomic analyses of At-RS31 mutant and overexpressing plants further revealed its effects on alternative splicing.

iCLIP identified 4,034 At-RS31 binding sites across 1,421 genes, enriched in CU-rich and CAGA RNA motifs. Comparative iCLIP and RNAcompete data indicate that the RS domain of At-RS31 may influence its binding specificityin planta, underscoring the value of combiningin vivoandin vitroapproaches. Transcriptomic analysis showed that At-RS31 modulates diverse splicing events, particularly intron retention and exitron splicing, and influences other splicing modulators, acting as a hierarchical regulator.

By regulating stress-response genes and genes in both TOR and abscisic acid (ABA) signaling pathways, At-RS31 may help integrate these signals, balancing plant growth with environmental adaptability through alternative splicing.
Spike sorting biases and information loss in a detailed cortical model
Authors: Laquitaine Steeve , Imbeni Milo , Tharayil Joseph , Isbister James B. , Reimann Michael W.
Published: December 2024

Sorting electrical signals (spikes) from extracellular recordings of large groups of connected neurons is essential to understanding brain function. Despite transformative advances in dense extracellular recordings, the activity of most cortical neurons remains undetected. Small simulations with known neuron spike times offer critical ground truth data to improve spike sorting. Yet, current simulations underestimate neuronal heterogeneity and connectivity, which can potentially make spike sorting more challenging. We simulated recordings in a detailed large-scale cortical microcircuit model to link spike sorting accuracy to neuronal heterogeneity, evaluate the performance of state-of-the-art spike sorters and examine how spike sorting impacts the retrieval of information encoded in the cortical circuit. We found that modern spike sorters accurately isolated about 15% of neurons within 50 µm of the electrode shank, which contrasts with previous simulated yields but agrees with experiments. Neurons were unresolved because their spike trains were either missed (undersampling) or, when detected, incomplete or merged with other units’ (assignment biases). Neuron isolation quality was influenced by both anatomical and physiological factors (selection bias), improving with increased neuron firing rate, spike spatial extent, for neurons in layer 5, and excitatory neurons. We exposed the network to various stimuli to dissociate the impact of these biases on its stimulus discrimination ability. Surprisingly, undersampling did not affect discrimination capacity, but selection and assignment biases nearly reduced it by half. These findings posit realistic models as a complementary method to evaluate and improve spike sorting and, hence, brain activity representations.
Mapping of Multilineage Tumor Cell Populations in Mouse Bladder Cancer
Authors: Schrode Nadine , Hu Yang , Yu Haocheng , Galsky Matthew , Sfakianos John , Sebra Robert , Beaumont Kristin G. , Mulholland David J
Published: December 2024

In bladder cancer (BLCA), the cellular expression of lineage markers with predictive biomarker function can have important implications for tumor progression, treatment response, and survival. However, tumor heterogeneity and the coexistence of distinct tumor subpopulations can complicate the utility of using a primary, clinically assigned tumor signature. In this report, we have applied the reference atlas,Tabula Sapiens,and deep learning model, UniCell, to conduct in-depth transcriptional analysis of unique lineage marker-defined cell clusters in a carcinogen (BBN) induced bladder cancer model. UniCell deconvolution has identified tumor populations, including urothelial, adenocarcinoma, squamous cell carcinoma, and mesenchymal tumor populations, each with cell-intrinsic gene expression signatures relevant to human BLCA progression. The identified tumor clusters contain uniquely basal, luminal, stromal, or hybrid cells in cell lineage marker expression. To understand the significance of these populations during progression, we used trajectory and pseudo-time analysis to show that cells uniquely basal are plastic in lineage identity and can evolve to form tumor populations composed of other lineage marker-defined signatures. Finally, pathway and drug enrichment analysis of tumor cell clusters were used to identify therapeutics that may preferentially target the identified tumor cell populations.These data collectively define a molecular template that may uniquely profile molecular plasticity occurring during progression and response to therapy with important implications for human disease.

Significance

Tumor heterogeneity is a mechanism for treatment resistance. Our study defines unique tumor subpopulations having differential therapeutic sensitivities and potential for lineage plasticity. Our modeling may impact the treatment of BLCA patients.
Pigmentation and retinal pigment epithelium thickness: a study of the phenotypic and genotypic relationships between ocular and extraocular pigmented tissues
Authors: Julian Thomas , Fitzgerald Tomas ,   UK Biobank Eye and Vision Consortium, Birney Ewan , Sergouniotis Panagiotis I.
Published: December 2024

The retinal pigment epithelium (RPE) is a specialised monolayer of pigmented epithelial cells in the outer retina. The embryology and biology of pigmentation in the RPE differs from other pigmented tissues such as the hair, skin and iris. The extent to which RPE pigmentation is related to that of other tissues remains unclear, and this study aims to address this knowledge gap. Here, we utilised RPE thickness measured using optical coherence tomography (OCT) imaging as a surrogate phenotype for RPE melanin content. We used UK Biobank data to assess the phenotypic relationships between RPE thickness and fundus pigmentation (principally a measure of choroidal pigmentation), hair colour, skin colour, and ability to tan. We subsequently performed a genome-wide association study (GWAS) to identify genetic loci associated with RPE thickness. We utilised the obtained genetic data to explore the global and local genetic correlation between RPE thickness and other pigmentation-related traits. We found that RPE thickness is not phenotypically or globally genetically correlated with hair colour, skin colour or ability to tan. Whilst RPE thickness was phenotypically correlated with retinal pigmentation score, there was not significant global genetic correlation. Despite this, variants in key pigmentation loci includingTYR, andOCA2-HERC2were found to be significant in our GWAS of RPE thickness. Furthermore, we identified four genetic regions in which RPE thickness is locally genetically correlated with other pigmentation-related traits, all of which contain protein-coding genes that are central to melanogenesis and melanosome transport. In conclusion, our study supports our assertion that pigmentation plays a role in RPE thickness, and highlights both shared and divergent features of RPE and other pigmentation-related traits.
Integration of diverse bioactivity data into the Chemical Checker compound universe
Authors: Comajuncosa-Creus Arnau , Bertoni Martino , Duran-Frigola Miquel , Fernández-Torras Adrià , Guitart-Pla Oriol , Kurzawa Nils , Locatelli Martina , Martins Yasmmin , Pareja-Lorente Elena , Rojas-Granado Gema , Soler Nicolas , Viesi Eva , Aloy Patrick
Published: December 2024

Chemical signatures encode the physicochemical and structural properties of small molecules into numerical descriptors, forming the basis for chemical comparisons and search algorithms. The increasing availability of bioactivity data has improved compound representations to include biological effects, although bioactivity descriptors are often limited to a few well-documented molecules. To address this issue, we implemented a collection of deep neural networks able to leverage the experimentally determined bioactivity data associated to small molecules and infer the missing bioactivity signatures for any compound of interest. However, unlike static chemical descriptors, these bioactivity signatures dynamically evolve with new data and processing strategies. Here, we present a computational protocol to modify or generate novel bioactivity spaces and signatures, describing the main steps needed to leverage diverse bioactivity data with the current knowledge, as catalogued in the Chemical Checker (CC), using the predefined data curation pipeline. We illustrate the functioning of the protocol through four specific examples, including the incorporation of new compounds to an already existing bioactivity space, a change in the data pre-processing without altering the underlying experimental data, and the creation of two novel bioactivity spaces from scratch, which are completed in under 9 hours using GPU computing. Overall, this protocol offers a guideline for installing, testing and running the CC data integration approach on user-provided data, with the aim of extending the annotation presented for a limited number of small molecules to a larger chemical landscape.

Key points

The Chemical Checker is a large collection of processed, harmonized and integrated bioactivity signatures for over 1 million small molecules. Data are organized into 5 levels of increasing biological complexity and curation degrees: from chemical properties to clinical outcomes and from raw data representing explicit knowledge to embedded signatures inferred from observed bioactivity patterns.

The Chemical Checker package provides a predefined and versatile framework to integrate user-provided data to the Chemical Checker universe of small molecules and generate novel customized bioactivity signatures.

Key references

Duran-Frigolaet al. “Extending the small-molecule similarity principle to all levels of biology with the Chemical Checker.” Nature Biotechnology 38.9 (2020): 1087-1096.

Bertoniet al. “Bioactivity descriptors for uncharacterized chemical compounds.” Nature Communications 12.1 (2021): 3932.
Ecological networks across interaction types are modular and highly driven by sampling intensity at biogeographical scales
Authors: Garcia-Callejas David , Thebault Elisa , Lajaaiti Ismael , Martins Lucas P. , Laux Louise , Kefi Sonia
Published: December 2024

Understanding how the structure of ecological communities varies across biotic and abiotic dimensions is a fundamental goal in ecology. This challenge is now approachable due to the increasing availability of data on community structure across the globe. Ecological communities are often defined with respect to the guilds considered and the interactions they engage in, but it is unclear whether interactions of different types respond similarly to large-scale environmental gradients. Therefore, we don't know whether there exist differences in how the emergent structure of ecological networks varies across biogeographical gradients, depending on their constituent interaction types. Here, using a unique dataset of 952 networks across the globe, we provide a first comparison of network structural metrics and their large-scale variability for five overarching interaction types (feeding, frugivory, herbivory, parasitism, pollination). We show that networks of different types tend to be more modular than expected, but other structural metrics do not deviate from what is expected given the degree distributions of the networks. Our analysis also reveals that network sampling intensity is a particularly relevant factor influencing network degree distribution, and that food webs appear in general more sensitive to environmental factors than other interaction types. By analysing common descriptors from the degree distributions of ecological networks, this study underscores for the first time generalities and differences across different interaction types and their response to environmental, sampling, and anthropic factors.
Discovery of Novel and Selective GPR17 Antagonists as Pharmacological Tools for Developing New Therapeutic Strategies in Diabetes and Obesity
Authors: Zhu Hu , Conley Jason M. , Karavadhi Surendra , LaVigne Justin E. , Watts Val J. , Sun Hongmao , Shen Min , Hall Matthew D. , Ren Hongxia , Patnaik Samarjit
Published: December 2024

G protein coupled receptors (GPCRs) are promising targets for diabetes and obesity therapy due to their roles in metabolism and excellent potential for pharmacological manipulation. We previously reported thatGpr17ablation in the brain-gut axis leads to improved metabolic homeostasis, suggesting GPR17 antagonism could be developed for diabetes and obesity treatment. Here, we performed high throughput screening (HTS) and identified two new GPR17 antagonists (compound 978 and 527). Both compounds antagonized downstream Gαi/o, Gαq and β-arrestin signaling with high selectivity for GPR17, but not the closely related purinergic and cysteinyl leukotriene receptors. The molecular mechanisms of antagonism were revealed through Schild analysis, structure-activity relationship (SAR) studies and homology modelling. Compound 978 and its analog (793) attenuated GPR17 signaling and promoted glucagon-like peptide-1 (GLP-1) secretion in enteroendocrine cells. In summary, we identified selective GPR17 antagonists through HTS, which represent promising pharmacological tools for developing new therapeutic strategies in diabetes and obesity.

Significance

Our work highlights the therapeutic potential of GPR17 antagonism in the treatment of diabetes and obesity by leveraging its role in metabolic regulation. In previous studies, we have shown thatGpr17ablation improves metabolic homeostasis, and here we expanded our research by identifying two novel small molecule antagonists of GPR17 through high-throughput screening. The compounds inhibited multiple downstream signaling pathways of GPR17 with high selectivity over other closely related receptors. Of particular significance, compound 978 and its analogs not only attenuated GPR17 signaling but also increased glucagon-like peptide-1 (GLP-1) secretion, a critical hormone for glucose homeostasis and appetite regulation. These findings shed new light into the molecular mechanisms of GPR17 antagonism and introduce valuable pharmacological tools for further exploration of therapeutic strategies in diabetes and obesity.
Buca della Iena and Grotta del Capriolo: new chronological, lithic, and faunal analyses of two late Mousterian sites in Central Italy
Authors: Gennai Jacopo , Higham Tom , Romboni Marco , Fiorillo Angelica , Giannì Maddalena , van der Sluis Laura , Marchi Damiano , Starnini Elisabetta
Published: December 2024

New radiocarbon, lithic, faunal, and documentary analyses of two sites, Buca della Iena and Grotta del Capriolo, excavated in the 1970s, enhance our understanding of late Neanderthal settlement in the northwestern Italian peninsula and provide insights into their demise.

Reassessment of stratigraphical and fieldwork documentation identified areas of stratigraphic reliability, supporting robust interpretations. Radiocarbon dating reveals broadly contemporaneous occupations at both sites between 50–40 ka cal BP, with Buca della Iena showing occupation from approximately 47 to 42.5 ka cal BP. Lithic analyses demonstrate the consistent application of the samechaîne opératoireacross both sites. Faunal analyses indicate that carnivores, particularlyCrocuta spelaea, were the dominant accumulating agents in Buca della Iena, while limited preservation at Grotta del Capriolo prevents detailed taxonomic determination. However, hominin presence at both sites is evidenced by cut-marked bones. This study provides new perspectives on the Middle-to- Upper Palaeolithic transition in the northwestern Italian peninsula.
Role Of Pcdh15 In The Development Of Intrinsic Polarity Of Inner Ear Hair Cells
Authors: Kaushik Raman , Pandey Shivangi , Prakash Anubhav , Abe Takaya , Kiyonari Hiroshi , Ladher Raj K.
Published: December 2024

In vertebrates, auditory information is transduced in the cochlea by mechanosensory hair cells (HC) through an eccentrically organised structure known as the hair bundle. This consists of a true cilium, known as the kinocilium, and modified microvilli, known as stereocilia. The hair bundle has a distinct structure with stereocilia organised in graded rows, with the longest abutting the kinocilia. The hair bundles of all HC are aligned to the tissue axis and are planar polarised. Important in the development and physiology of HC are protein bridges consisting of cadherin-23 and protocadherin-15. These link the tips of stereocilia, where they play a role in mechanotransduction, and between the kinocilia and the stereocilia, where they are involved in development. Both cadherin-23 and protocadherin-15 mutations result in defects in planar polarity; however, the mechanism through which this defect arises is unclear. Using a novel mutant for the Pcdh15-CD2 isoform, we show that while the initial deflection of the kinocilium occurs, its peripheral migration to register with Gαi3 is perturbed. Pcdh15-CD2 genetically interacts with Gpsm2, perturbing vestibular function. We find that the earliest expression of Pcdh15-CD2 is at the base of the kinocilia, and the defects in morphogenesis occur before the formation of kinocilial links. By re-introducing functional Pcdh15-CD2, we show that polarity can be restored, suggesting that Pcdh15-CD2 couples kinocilial and stereocilial development through a mechanism independent of kinocilial links.
Strengthening evidence for text-based telehealth in post-operative care: A pragmatic study of the reach and effectiveness of two-way, text-based follow-up after voluntary medical male circumcision in South Africa
Authors: Feldacker Caryl , Fabens Isabella , Dong Tracy , Moyo Khumbulani , Makhele Calsile , Phohole Motshana , Igaba Nelson , Hlongwane Sizwe , Pienaar Jacqueline , Sardini Maria , Ndebele Felex , Tweya Hannock , Holec Marrianne , Waweru Evelyn , Setswe Geoffrey
Published: December 2024

Building upon evidence of safety and efficiency gains from a randomized control trial (RCT) in South Africa, we further scaled implementation of two-way, short message service (SMS), text-based (2wT) follow-up after voluntary medical male circumcision (VMMC). We aimed to determine if gains in adverse event (AE) identification and reduced follow-up visits could be maintained when 2wT was implemented in routine VMMC settings. A pragmatic, stepped wedge design (SWD) study was implemented across three districts in South Africa. Men ages 15 and older could opt into the 2wT telehealth follow-up approach when their facility was in the intervention period. Men in routine periods were offered the standard of care (SoC): in-person post-operative visits on days 2 and 7 as per national VMMC guidelines. 2wT participants were not required to attend any postoperative visits but could return for care if desired or referred. Two quality of care markers, safety (AE ascertainment rate) and efficiency (# in-person follow-up visits), were compared between groups. We aimed for at least 200 men per step to have 80% power to detect a change in AE rate from before to after 2wT was implemented. Secondary analysis explored response rates; client and site uptake; and AE details. Among 6842 clients in the intervention period, 2856 opted into 2wT (37.8%) across three intervention waves and two platforms (SMS or WhatsApp). Among those with post-operative follow-up, the AE ascertainment rate was higher among 2wT (0.60%) than SoC (0.13%) clients (p = 0.0018), demonstrating safety gains. On average, 2wT participants had 2.1 fewer visits compared to SoC clients (p<0.001), demonstrating gains in follow-up efficiency. Among 2wT men, 2069/2586 (80%) responded via 2wT over 14 days, demonstrating engagement in post-operative care. Of all intervention clients, 93 2wT (3.6%) and 342 (8.0%) SoC were considered lost to follow-up. In this expansion trial, we provided additional evidence that the 2wT approach maintains the quality of post-operative care for adult VMMC clients. 2wT should be scaled to augment in-person, post-operative visits after VMMC for eligible, interested males ages 15 and older. To achieve potential impact, effort is needed to improve access and uptake to 2wT among providers and sites, expanding the 2wT approach for other acute follow-up care especially among men.
Plasma proteomics for novel biomarker discovery in childhood tuberculosis
Authors: Fossati Andrea , Wambi Peter , Jaganath Devan , Calderon Roger , Castro Robert , Mohapatra Alexander , McKetney Justin , Luiz Juaneta , Nerurkar Rutuja , Nkereuwem Esin , Franke Molly F. , Mousavian Zaynab , Collins Jeffrey M. , Sigal George B. , Segal Mark R. , Kampman Beate , Wobudeya Eric , Cattamanchi Adithya , Ernst Joel D. , Zar Heather J. , Swaney Danielle L. ,   the COMBO Study
Published: December 2024

Failure to rapidly diagnose tuberculosis disease (TB) and initiate treatment is a driving factor of TB as a leading cause of death in children. Current TB diagnostic assays have poor performance in children, and identifying novel non-sputum-based TB biomarkers to improve pediatric TB diagnosis is a global priority. We sought to develop a plasma biosignature for TB by probing the plasma proteome of 511 children stratified by TB diagnostic classification and HIV status from sites in four low- and middle-income countries, using high-throughput data-independent acquisition mass-spectrometry (DIA-PASEF-MS). We identified 47 proteins differentially regulated (BH adjusted p-values < 1%) between children with microbiologically confirmed TB and children with non-TB respiratory diseases (Unlikely TB). We further employed machine learning to derive three parsimonious biosignatures encompassing 4, 5, or 6 proteins that achieved AUCs of 0.86-0.88 all of which exceeded the minimum WHO target product profile accuracy thresholds for a TB screening test (70% specificity at 90% sensitivity, PPV 0.65-0.74, NPV 0.92-0.95). This work provides insights into the unique host response in pediatric TB disease, as well as a non-sputum biosignature that could reduce delays in TB diagnosis and improve detection and management of TB in children worldwide.
Epigenome-wide Association Analysis of Mitochondrial Heteroplasmy Provides Insight into Molecular Mechanisms of Disease
Authors: Lai Meng , Kim Kyeezu , Zheng Yinan , Castellani Christina A. , Ratliff Scott M. , Wang Mengyao , Liu Xue , Haessler Jeffrey , Huan Tianxiao , Bielak Lawrence F. , Zhao Wei , Joehanes Roby , Ma Jiantao , Guo Xiuqing , Manson JoAnn E. , Grove Megan L. , Bressler Jan , Taylor Kent D. , Lappalainen Tuuli , Kasela Silva , Blackwell Thomas W. , Lake Nicole J. , Faul Jessica D. , Ferrier Kendra R. , Hou Lifang , Kooperberg Charles , Reiner Alexander P. , Zhang Kai , Peyser Patricia A. , Fornage Myriam , Boerwinkle Eric , Raffield Laura M. , Carson April P. , Rich Stephen S. , Liu Yongmei , Levy Daniel , Rotter Jerome I. , Smith Jennifer A. , Arking Dan E. , Liu Chunyu ,   NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium
Published: December 2024

The relationship between mitochondrial DNA (mtDNA) heteroplasmy and nuclear DNA (nDNA) methylation (CpGs) remains to be studied. We conducted an epigenome-wide association analysis of heteroplasmy burden scores across 10,986 participants (mean age 77, 63% women, and 54% non-White races/ethnicities) from seven population-based observational cohorts. We identified 412 CpGs (FDR p < 0.05) associated with mtDNA heteroplasmy. Higher levels of heteroplasmy burden were associated with lower nDNA methylation levels at most significant CpGs. Functional inference analyses of genes annotated to heteroplasmy-associated CpGs emphasized mitochondrial functions and showed enrichment in cardiometabolic conditions and traits. We developed CpG-scores based on heteroplasmy-count associated CpGs (MHC-CpG scores) using elastic net Cox regression in a training cohort. A one-unit higher level of the standardized MHC-CpG scores were associated with 1.26-fold higher hazard of all-cause mortality (95% CI: 1.14, 1.39) and 1.09-fold higher hazard of CVD (95% CI: 1.01–1.17) in the meta-analysis of testing cohorts, adjusting for age, sex, and smoking. These findings shed light on the relationship between mtDNA heteroplasmy and DNA methylation, and the role of heteroplasmy-associated CpGs as biomarkers in predicting all-cause mortality and cardiovascular disease.
Risk of root resorption between Invisalign and fixed orthodontic treatment: A retrospective study
Authors: Sabban Hanadi M. , Al-Labban Linah , Baeshen Nouf , Turkistani Khadijah A.
Published: December 2024

Objectives

The aim of our study is to evaluate and compare the presence and severity of external root resorption in patients treated with either clear aligners (Invisalign) versus conventional fixed orthodontic appliances.

Material and Methods

A retrospective study was performed on 203 patients, which includes 30 treated with Invisalign and 173 with fixed appliances. 60 cases (30 per group) were matched based on extraction status, treatment duration, gender, age, and malocclusion classification after inclusion criteria were applied. Radiographic evaluations were conducted with standardized periapical radiographs and Panoramic radiographs (OPG). Comparing radiographs taken before and after treatment allowed for the measurement of the extent of external root resorption.

Results

In the matched cases, external root resorption was present in 92% of patients in the Invisalign group and 77% of patients in the fixed appliance group. Maxillary incisors were the most afflicted teeth, particularly in situations involving tooth extractions. The greatest percentage of root resorption (100%) was recorded in Class II malocclusion, which was followed by Class I (84%) and Class III (77%). Although Invisalign treatments demonstrated an increased incidence of root resorption, fixed appliances were associated with more severe root reduction. There were not significant distinctions between the groups, according to statistical analysis (p > 0.05).

Conclusions

A frequent adverse effect of orthodontic treatments involving both fixed appliances and Invisalign is external root resorption. Root resorption was more common in Invisalign patients, but it was greater in fixed appliance cases. These results highlight the need for more expansive prospective studies to confirm these findings and enable clinicians minimize side effects associated with treatment.