bluuebunny/crossref_metadata_2025 huggingface dataset:
The danger zone: the joint trap of incomplete lineage sorting and long-branch attraction in placing Rafflesiaceae
Authors: Cai Liming , Liu Liang , Davis Charles C.
Published: August 2024

Two key factors have been implicated as major impediments to phylogenomic inference: incomplete lineage sorting (ILS)—especially in cases where clades are in the anomaly zone—and erroneous gene tree estimation—commonly manifested by long-branch attraction in the Felsenstein zone. Seldom have these factors been analyzed when they occur simultaneously as in cases involving ancient adaptive radiations. Rafflesiaceae (Malpighiales) is an iconic holoparasitic plant clade growing west of Wallace’s line in tropical Southeast Asia. This clade has been notoriously difficult to place phylogenetically and is nested within an explosive ancient radiation in Malpighiales. To complicate matters, parasitic plants like Rafflesiaceae are well-known to exhibit accelerated rates of nucleotide substitution. Here, using 2,141 genes we identify for the first time that accelerated substitution rates is a genome-wide phenomenon in holoparasites. We demonstrate two orders of magnitude increase in substitution rates in Rafflesiaceae compared to its free-living relatives, rendering nearly every gene prone to long-branch attraction. Our analyses rejected the monophyletic (Rafflesiaceae, Euphorbiaceae) clade proposed in previous studies but favored an earlier divergence of Rafflesiaceae in close affinity with Euphorbiaceae, Peraceae, Putranjivaceae, and Pandaceae. Rafflesiaceae is therefore prey to a joint trap of the anomaly and Felsenstein zones. Moreover, owing to massive gene loss within Rafflesiaceae, our simulation suggests that this represents an intractable phylogenetic problem that will never achieve a single phylogenetic resolution. Our case study highlights a seemingly insurmountable confluence of factors—a danger zone—that hinders phylogenomic resolution and demonstrates the need to be flexible in cases where multiple phylogenomic placements are equally likely.
A principled approach to community detection in interareal cortical networks
Authors: Armas Jorge Martinez , Knoblauch Kenneth , Kennedy Henry , Toroczkai Zoltan
Published: August 2024

Structural connectivity between cortical areas, as revealed by tract-tracing is in the form of highly dense, weighted, directed, and spatially embedded complex networks. Extracting the community structure of these networks and aligning them with brain function is challenging, as most methods use local density measures, best suited for sparse graphs. Here we introduce a principled approach, based on distinguishability of connectivity profiles using the Hellinger distance, which is relatable to function. Applying it to tract-tracing data in the macaque, we show that the cortex at the interareal level is organized into a nested hierarchy of link-communities alongside with a node-community hierarchy. We find that the ½-Rényi divergence of connection profiles, a non-linear transform of the Hellinger metric, follows a Weibull-like distribution and scales linearly with the interareal distances, a quantitative expression between functional organization and cortical geometry. We discuss the relationship with the extensively studied SLN-based hierarchy.
PTEN Deletion in the Adult Dentate Gyrus Induces Epilepsy
Authors: Yonan Jennifer M. , Chen Kevin D. , Baram Tallie Z. , Steward Oswald
Published: August 2024

Embryonic and early postnatal promotor-driven deletion of the phosphatase and tensin homolog (PTEN) gene results in neuronal hypertrophy, hyperexcitable circuitry and development of spontaneous seizures in adulthood. We previously documented that focal, vector-mediated PTEN deletion in mature granule cells of adult dentate gyrus triggers dramatic growth of cell bodies, dendrites, and axons, similar to that seen with early postnatal PTEN deletion. Here, we assess the functional consequences of focal, adult PTEN deletion, focusing on its pro-epileptogenic potential. PTEN deletion was accomplished by injecting AAV-Cre either bilaterally or unilaterally into the dentate gyrus of double transgenic PTEN-floxed, ROSA-reporter mice. Hippocampal recording electrodes were implanted for continuous digital EEG with concurrent video recordings in the home cage. Electrographic seizures and epileptiform spikes were assessed manually by two investigators, and corelated with concurrent videos. Spontaneous electrographic and behavioral seizures appeared after focal PTEN deletion in adult dentate granule cells, commencing around 2 months post-AAV-Cre injection. Seizures occurred in the majority of mice with unilateral or bilateral PTEN deletion and led to death in several cases. PTEN-deletion provoked epilepsy was not associated with apparent hippocampal neuron death; supra-granular mossy fiber sprouting was observed in a few mice. In summary, focal, unilateral deletion of PTEN in the adult dentate gyrus suffices to provoke time-dependent emergence of a hyperexcitable circuit generating hippocampus-origin, generalizing spontaneous seizures, providing a novel model for studies of adult-onset epileptogenesis.
Effects of serotonergic psychedelics on synaptogenesis and immediate early genes expression - comparison with ketamine, fluoxetine and lithium
Authors: Vella Yana , Syrova Katerina , Petruskova Aneta , Koutrouli Isis , Kutna Viera , Pala Jan , Nikolic Marek , Sichova Klara , Mazoch Vladimir , Jurok Radek , Kuchar Martin , Bendova Zdenka , Palenicek Tomas
Published: August 2024

Background: Recent evidence suggests that psychedelics are able to induce rapid and long-lasting antidepressant effects. The generally acknowledged explanation for these traits is the phenomenon of neuroplasticity, although exact underlying molecular mechanisms remain unclear. Aims: This study investigates selected neuroplastic effects of psilocin, lysergic acid diethylamide (LSD) and N,N-dimethyltryptamine (DMT) in direct comparison with ketamine, fluoxetine and lithium after acute (1 h) and/or prolonged (24 h) treatment in vitro. Methods: Rat primary cortical cultures were treated with 10 uM psilocin, 1 uM lysergic acid diethylamide (LSD), 90 uM N, N-dimethyltryptamine (DMT), 1 uM ketamine, 10 uM fluoxetine and 5 mM lithium. Analysis of synaptic puncta was performed; puncta of presynaptic marker synapsin I/II, postsynaptic density protein 95 (PSD-95), and their co-localization (established synapse) were assessed 24 h after drug treatment. Next, expressions of immediate early genes (IEGs) encoding activity-regulated cytoskeleton-associated protein (Arc), early growth response 1 (Egr1), and neuronal PAS (Per-ArntSim) domain protein 4 (Npas4) were analysed 1 and 24 h after drug treatments. Results: Psilocin increased synaptic puncta count and induced Arc expression. The effect to promote synaptogenesis was comparable to ketamine and lithium; ketamine additionally increased PSD-95 puncta count. LSD and DMT didn't induce any significant effect. Interestingly, fluoxetine had no effect on synaptic puncta count, but upregulated Egr1 and Npas4. Conclusions: Psilocin demonstrated a significant neuroplastic effect comparable to that of ketamine and lithium, adding another piece of evidence to its profile as a promising therapeutic agent.
Research on the Mechanism of Lphn1 Knockout in Inhibiting Colorectal Cancer
Authors: Wang Yi
Published: August 2024

Decades ago, colorectal cancer was rarely diagnosed. Today, it is the fourth leading cause of cancer-related deaths worldwide, with nearly 90,000 fatalities each year.

By analyzing single-cell data from tumor-bearing colorectal cancer model mice with Lphn1 knockout and wild-type Lphn1, we identified five key target genes for anticancer therapy: Ulbp1, Klrk1, Ccl6, Tlr4, Cd48, Prdm5, VSTM2A, RET, OAS2, Hdac11 and Ptchd4, along with their corresponding cell types. Additionally, we discovered tumor-inhibiting cell subpopulations, including Cd244a_T_cells_subcluster_1, Cd48_Cd244a_NK_cells_subcluster_2, and C3_Macrophages_subcluster_1, which are potential candidates for therapeutic intervention. We propose that cancer-associated fibroblasts (CAFs) serve as the primary antigen presenters for MHC class I, providing antigens to macrophages, NK cells, and T cells to combat colorectal cancer. From a cellular perspective, the knockout of Lphn1 activates the anti-colorectal cancer functions of subpopulations of macrophages, NK cells, and T cells. Macrophages enhance antitumor immune activity by engaging the Ulbp1-Klrk1 receptor pair to activate NK cells. Additionally, macrophages activate downstream functions of T cells against colorectal cancer through CD48 signaling. After the knockout of Lphn1, macrophages are recruited by autocrine Ccl6 and Ccl6 secreted by CAFs. They exhibit high expression of Tlr4 and have the potential to transition into M1-type macrophages due to changes in their cellular state. After the knockout of Lphn1, the CAFs were reduced by half. CAFs, which are part of the cell network communication associated with tumor cells, typically play an immunosuppressive role. A reduction by half indicates that the immunosuppression in the Lphn1 knockout group has significantly decreased. This suggests that the efficacy of various cancer immunotherapy drugs can be significantly enhanced. These findings could open new avenues for the treatment of colorectal cancer and contribute to the development of personalized medicine.
Multi-Coloured Sequential Resonance Energy Transfer for Simultaneous Ligand Binding at G Protein-Coupled Receptors
Authors: Valentini Alice , Dibnah Bethany , Ciba Marija , Ulven Trond , Hudson Brian D. , Rexen Ulven Elisabeth
Published: August 2024

G protein coupled receptors (GPCRs) are the largest family of signalling proteins and highly successful drug targets. To date, most GPCR drugs interact with the binding pocket for the natural ligand, typically near the extracellular part of the transmembrane region. Recent advancements in structural biology have identified additional allosteric binding sites in other parts of these receptors. Allosteric sites provide several theoretical advantages, including the ability to modulate natural ligand function, and there is a need for better ways to study how ligands bind and interact with diVerent GPCR binding sites. We have developed an approach to study multiple ligands binding to the same receptor based on sequential resonance energy transfer between two fluorescent ligands bound simultaneously to a GPCR. We use this approach to gain insight into allosteric ligand interactions for a clinically relevant receptor. This method will provide important information to aid development of new GPCR drugs.
Neuropeptide oxytocin facilitates its own brain-to-periphery uptake by regulating blood flow dynamics and permeability
Authors: Rajamannar Preethi , Raz Oren , Levkowitz Gil
Published: August 2024

The hypothalamo-neurohypophyseal system is an important neuroendocrine brain-to-blood conduit through which the neurohormones oxytocin and arginine-vasopressin are released from the brain into the general circulation to affect peripheral physiological functions such as salt balance, metabolism and reproduction. However, the mechanism which executes fast and efficient neurohormone release to the periphery remains unsolved. We show, using live imaging in zebrafish, that a hyperosmotic physiological challenge elicits a local increase in neurohypophyseal blood flow velocities and a change in capillary diameter, which is dictated by the geometry of the hypophyseal vascular microcircuit. Genetic ablation of oxytocin neurons and inhibition of oxytocin receptor signaling attenuated changes in capillary blood flow and diameter. Optogenetic stimulation of oxytocin neurons resulted in an oxytocin receptor-dependent increase in blood flow velocities. Lastly, both osmotic challenge and oxytocin neuronal activation elicited a local rise in neurohypophyseal capillary permeability in an oxytocin signaling-dependent manner. Our study demonstrates that physiologically elicited changes in neurohypophyseal blood flow and permeability are regulated by oxytocin. We propose that oxytocin-dependent neuro-vascular coupling facilitates its efficient uptake into the blood circulation, suggesting a self-perpetuating mechanism of peripheral hormone transfer.
Releasing theoctoPus,an open-source digital tool to promote Integrated Pest Management
Authors: Bregaglio Simone , Rossi Eugenio , Ascari Lorenzo , Mongiano Gabriele , Cavallo Eleonora Del , Bajocco Sofia , Manici Luisa Maria , Pepe Antonio Gerardo , Bassi Chiara , Tiso Rocchina , Pietrangeli Fabio , Cattaneo Giovanna , Nigro Camilla , Gerardi Marco Secondo , Bussotti Simone , Sanchioni Angela , Tognetti Danilo , Sandra Mariangela , Lillo Irene De , Framarin Paolo , Ferdinando Sandra Di , Bugiani Riccardo
Published: August 2024

Meeting the EU targets to halve chemical pesticide use by 2030 necessitates European farmers to adopt Integrated Pest Management principles as the standard. Decision support systems are valuable tools to meet this target and rely on individual disease models to identify conducive conditions to fungal infections. These models are often proprietary assets of digital startups and agrochemical companies, leading to a lack of transparency for farmers and a bias towards chemical solutions over sustainable practices. We presentoctoPus, the first free digital tool designed to support the control of primary infections of grapevine downy mildew, and we evaluate its performance and behavior on a wide set of environmental conditions and agricultural contexts. We implemented eight models from scientific articles (Rule310, Laore, EPI, IPI, DMcast, UCSC, Misfits, Magarey, the “tentacles”), and evaluated them across Italian grapevine areas from 2001 to 2020. Model outputs were integrated with phenology and susceptibility models (the “eyes”), which were calibrated using data from regional extension services’ bulletins. The simulated infections serve as predictors in a Random Forest algorithm (“brain”) that elaborates an overall risk level (very low to very high). The Llama large language model is used to generate user-supportive messages (the “mouth”).

octoPusis released as an open-source software, which reads weather data, executes the models, and presents outputs in natural language and symbolic syntax. Our results showed reasonable accuracy in simulating grapevine phenology (RMSE = 9-10 days) and seasonal risk (RMSE ≈ 0.75). The infection models consistently identified a moisture and thermal north-south suitability gradient in Italy and accurately detected years with low or high downy mildew pressure. However, the models displayed significant differences in the number and dynamics of simulated infections, with two distinct patterns within the ensemble.

By developing and releasing the first free and open-source tool to support the control of grapevine downy mildew, we address a critical gap in the availability and transparency of decision support systems for European farmers. Unlike proprietary models that often lack transparency and may favor agribusiness’ logic,octoPusprovides a comprehensive and accessible alternative that promotes Integrated Pest Management practices. We propose the adoption ofoctoPusby plant health authorities to identify areas for performance refinement and capabilities expansion.
CD131 Contributes to Ulcerative Colitis Pathogenesis by Promoting Macrophage Infiltration
Authors: Wu Zhiyuan , Liu Lindi , He Chenchen , Xiao Lin , Yun Duo , Chen Junliang , Liu Zhihao , Li Wenjun , Lv Qingjie , Tan Xiaodong
Published: August 2024

Background

Ulcerative colitis (UC) is a group of chronic inflammatory bowel disease (IBD) mainly affecting the colon. The exact etiology of ulcerative colitis remains elusive. CD131 is a receptor subunit mediating the effects of hematopoietic growth factors GM-CSF and IL-3, which regulate various inflammatory responses. The pleiotropic effects of the cytokines on intestinal inflammation suggest that additional factors influence their overall function, where the receptor may play a role.

Methods

In the present study, we investigated the role of CD131 in the pathogenesis of ulcerative colitis, with the use of murine colitis model established by administration of DSS in the drinking water.

Results

By comparing the immune and inflammatory responses between wt and CD131-deficient mice, we found that CD131 contributed to DSS-induced murine colitis, which functioned in synergy with tissue- infiltrating macrophages. Besides, CD131 may have promoted the chemotaxis of macrophages and T cells into the colon through CCL4. In addition, we analyzed clinical data and pathology specimens from ulcerative colitis patients and found that CD131 was associated with the endoscopic and pathological severity of intestinal inflammation.

Conclusions

The present study provides a novel way to the understanding of the mechanisms of GM-CSF and IL-3 effects in the intestine, which will benefit the development of therapeutic approaches.
Boundary-Sensing Mechanism in Branched Microtubule Networks
Authors: Zaferani Meisam , Song Ryungeun , Wingreen Ned S. , Stone Howard A. , Petry Sabine
Published: August 2024

The self-organization of cytoskeletal networks in confined geometries requires sensing and responding to mechanical cues at nanometer to micron scales that allow for dynamic adaptation. Here, we show that the branching of microtubules (MTs) via branching MT nucleation combined with dynamic instability constitutes a boundary-sensing mechanism within confined spaces. Using a nanotechnology platform, we observe the self-organization of a branched MT network in a channel featuring a narrow junction and a closed end. Our observations reveal that branching MT nucleation occurs in the post-narrowing region only if that region exceeds a certain length before it terminates at the channel’s closed end. The length-dependent occurrence of branching MT nucleation arises from the dynamic instability of existing MTs when they interact with the channel’s closed end, combined with the specific timescale required for new MTs to nucleate at a point distant from the closed end, creating a mechanical feedback. Increasing the concentration of the base branching factor TPX2 accelerates nucleation kinetics and thus tunes the minimum length scale needed for occurrence of branching MT nucleation. As such, this feedback not only allows for adaptation to the local geometry, but also allows for tunable formation of MT networks in narrow (micron and submicron scale) channels. However, while a high concentration of TPX2 increases the kinetic rate of branching MT nucleation, it also stabilizes MTs at the channel’s closed end leading to MT growth and nucleation in the reversed direction, and thus hinders boundary sensing. After experimental characterization of boundary-sensing feedback, we propose a minimal model and execute numerical simulations. We investigate how this feedback, wherein growing MTs dynamically sense their physical environment and provide nucleation sites for new MTs, sets a length/time scale that steers the architecture of MT networks in confined spaces. This “search- and-branch” mechanism has implications for the formation of MT networks during neuronal morphogenesis, including axonal growth and the formation of highly branched dendritic networks, as well as for plant development and MT-driven guidance in fungi, and engineering nanotechnologies.
Hematophagy generates a convergent genomic signature in mosquitoes and sandflies
Authors: Devilliers Julien , Warren Ben , Rosato Ezio , Kyriacou Charalambos P. , Feuda Roberto
Published: August 2024

Blood-feeding (hematophagy) is widespread across Diptera (true flies), yet the underlying molecular mechanisms remain poorly understood. Using phylogenomics, we show that four gene families associated with neuro-modulation, immune responses, embryonic development, and iron metabolism have undergone independent expansions within mosquitoes and sandflies. Our findings illuminate the underlying genetic basis for blood-feeding adaptations in these important disease vectors.
UltraTimTrack: a Kalman-filter-based algorithm to track muscle fascicles in ultrasound image sequences
Authors: van der Zee Tim J. , Tecchio Paolo , Hahn Daniel , Raiteri Brent J.
Published: August 2024

Background

Brightness-mode (B-mode) ultrasound is a valuable tool to non-invasively image skeletal muscle architectural changes during movement, but automatically estimating architectural features such as fascicle length remains a major challenge. Existing fascicle tracking algorithms either require time-consuming drift corrections or yield noisy estimates that require post-processing. We therefore aimed to develop an algorithm that tracks fascicles without drift and noise across a range of experimental conditions and image acquisition settings.

Methods

We applied a Kalman filter to combine fascicle length and fascicle angle estimates from existing and openly available UltraTrack and TimTrack algorithms into a hybrid algorithm called UltraTimTrack. We applied the hybrid algorithm to ultrasound image sequences collected from the human medial gastrocnemius of healthy individuals (N=8, 4 women), who performed cyclical submaximal plantar flexion contractions or remained at rest during passive ankle joint rotations at given frequencies and amplitudes whilst seated in a dynamometer chair. We quantified the algorithm’s tracking accuracy, noise, and drift as the respective mean, cycle-to-cycle, and accumulated between-contraction variability in fascicle length and fascicle angle. We expected UltraTimTrack’s estimates to be less noisy and to drift less across experimental conditions and image acquisition settings, compared with estimates from its parent algorithms.

Results

The proposed algorithm had low-noise estimates like UltraTrack and was drift-free like TimTrack across the broad range of conditions we tested. Estimated fascicle length and fascicle angle deviations accumulated to 2.1 ± 1.3 mm (mean ± s.d.) and 0.8 ± 0.7 deg, respectively, over 120 cyclical contractions. Average cycle-to-cycle variability was 1.4 ± 0.4 mm and 0.6 ± 0.3 deg, respectively. In comparison, UltraTrack had similar cycle-to-cycle variability (1.1 ± 0.3 mm, 0.5 ± 0.1 deg) but greater cumulative deviation (67.0 ± 59.3 mm, 9.3 ± 8.6 deg), whereas TimTrack had similar cumulative deviation (1.9 ± 2.2 mm, 0.9 ± 1.0 deg) but greater variability (3.5 ± 1.0 mm, 1.4 ± 0.5 deg). UltraTimTrack was significantly less affected by experimental conditions and image acquisition settings than its parent algorithms. It also performed well on a previously published image sequence from the human tibialis anterior, yielding a smaller root-mean-square deviation from manual tracking (fascicle length: 2.7 mm, fascicle angle: 0.7 deg) than a recently proposed hybrid algorithm (fascicle length: 4.5 mm, fascicle angle: 0.8 deg) and a machine-learning (DL_Track) algorithm (fascicle length: 8.2 mm, fascicle angle: 4.8 deg).

Conclusion

We developed a Kalman-filter-based method to improve fascicle tracking from B-mode ultrasound image sequences. The proposed algorithm provides low-noise, drift-free estimates of muscle architectural changes that may better inform muscle function interpretations.
Genome Restructuring around Innate Immune Genes in Monocytes in Alcohol-associated Hepatitis
Authors: Kim Adam , McMullen Megan R. , Bellar Annette , Streem David , Dasarathy Jaividhya , Welch Nicole , Dasarathy Srinivasan
Published: August 2024

Many inflammatory genes in the immune system are clustered in the genome. The 3D genome architecture of these clustered genes likely plays a critical role in their regulation and alterations to this structure may contribute to diseases where inflammation is poorly controlled. Alcohol-associated hepatitis (AH) is a severe inflammatory disease that contributes significantly to morbidity in alcohol associated liver disease. Monocytes in AH are hyper-responsive to inflammatory stimuli and contribute significantly to inflammation. We performed high throughput chromatin conformation capture (Hi-C) technology on monocytes isolated from 4 AH patients and 4 healthy controls to better understand how genome structure is altered in AH. Most chromosomes from AH and healthy controls were significantly dissimilar from each other. Comparing AH to HC, many regions of the genome contained significant changes in contact frequency. While there were alterations throughout the genome, there were a number of hotspots containing a higher density of changes in structure. A few of these hotspots contained genes involved in innate immunity including the NK-gene receptor complex and the CXC-chemokines. Finally, we compare these results to scRNA-seq data from patients with AH challenged with LPS to predict how chromatin conformation impacts transcription of clustered immune genes. Together, these results reveal changes in the chromatin structure of monocytes from AH patients that perturb expression of highly clustered proinflammatory genes.
Tumor localization strategies of multi-cancer early detection tests: a quantitative assessment
Authors: Tyson Christopher , Li Kevin H. , Cao Xiting , O’Brien James M. , Fishman Elliot K. , O’Donnell Elizabeth K. , Duran Carlos , Parthasarathy Vijay , Rego Seema P. , Choudhry Omair A. , Beer Tomasz M.
Published: August 2024

Introduction

Blood-based multi-cancer early detection (MCED) tests may expand the number of “screenable” cancers. Defining an optimal approach to diagnostic resolution for individuals with positive MCED test results is critical. Two prospective trials employed distinct diagnostic resolution approaches; one employed a molecular signal to predict tissue of origin (TOO) and the other used an imaging-based diagnostic strategy. Using mathematical modeling, we compared the diagnostic burden of each approach and characterized the risk of excess cancer incidence that may be attributable to radiation exposure associated with a false positive (FP) MCED test result and an imaging-based diagnostic strategy.

Methods

A mathematical expression for diagnostic burden was derived using MCED test positive predictive value (PPV), molecular TOO localization accuracy, and the expected number of imaging procedures associated with each diagnostic outcome. Imaging and molecular TOO strategies were compared by estimating diagnostic burden across a wide range of MCED PPVs and TOO accuracies. Organ-specific radiation dose for diagnostic imaging was extracted from the literature and used as input to National Cancer Institute RADRat tool for estimating excess lifetime cancer risk due to radiation exposure.

Results

For the molecular TOO diagnostic approach, an average of 2.1 procedures are required to reach diagnostic resolution for correctly-localized TPs, 4.4 procedures for incorrectly-localized TPs, and 4 procedures for FPs, vs. an average of 2.75 procedures for TPs and 2.4 for FPs with an imaging-based diagnostic strategy. Across the entire range of possible PPV and localization performance, a molecular TOO strategy resulted in a higher mean diagnostic burden: 3.6 procedures (SD 0.445) vs. 2.6 procedures (SD 0.1) for the imaging strategy. Predicted diagnostic burden was higher for molecular TOO in 95.5% of all possible PPV and TOO accuracy combinations; 79% or higher PPV would be required for a 90% accurate molecular TOO strategy to be less burdensome than imaging. The maximum rate of excess cancer incidence from radiation exposure for FP results from MCED screening between the ages of 50-84 was estimated at 64.6 per 100,000 (annual testing, 99% specificity), 48.5 per 100,000 (biennial testing, 98.5% specificity), and 64.6 per 100,000 (biennial testing, 98% specificity).

Conclusions

This analysis demonstrates that an imaging-based diagnostic strategy is more efficient than a molecular TOO-informed approach across 95.5% of all possible MCED PPV and TOO accuracy combinations. The use of an imaging-based approach for cancer localization can be efficient and low risk compared to a molecular-based approach.
Multimodal AI/ML for discovering novel biomarkers and predicting disease using multi-omics profiles of patients with cardiovascular diseases
Authors: DeGroat William , Abdelhalim Habiba , Peker Elizabeth , Sheth Neev , Narayanan Rishabh , Zeeshan Saman , Liang Bruce T. , Ahmed Zeeshan
Published: August 2024

Cardiovascular diseases (CVDs) are multifactorial diseases, requiring personalized assessment and treatment. The advancements in multi-omics technologies, namely RNA-seq and whole genome sequencing, have offered translational researchers a comprehensive view of the human genome; utilizing this data, we can reveal novel biomarkers and segment patient populations based on personalized risk factors. Limitations in these technologies in failing to capture disease complexity can be accounted for by using an integrated approach, characterizing variants alongside expression related to emerging phenotypes. Designed and implemented data analytics methodology is based on a nexus of orthodox bioinformatics, classical statistics, and multimodal artificial intelligence and machine learning techniques. Our approach has the potential to reveal the intricate mechanisms of CVD that can facilitate patient-specific disease risk and response profiling. We sourced transcriptomic expression and variants from CVD and control subjects. By integrating these multi-omics datasets with clinical demographics, we generated patient-specific profiles. Utilizing a robust feature selection approach, we reported a signature of 27 transcripts and variants efficient at predicting CVD. Here, differential expression analysis and minimum redundancy maximum relevance feature selection elucidated biomarkers explanatory of the disease phenotype. We used Combination Annotation Dependent Depletion and allele frequencies to identify variants with pathogenic characteristics in CVD patients. Classification models trained on this signature demonstrated high-accuracy predictions for CVDs. Overall, we observed an XGBoost model hyperparameterized using Bayesian optimization perform the best (AUC 1.0). Using SHapley Additive exPlanations, we compiled risk assessments for patients capable of further contextualizing these predictions in a clinical setting. We discovered a 27-component signature explanatory of phenotypic differences in CVD patients and healthy controls using a feature selection approach prioritizing both biological relevance and efficiency in machine learning. Literature review revealed previous CVD associations in a majority of these diagnostic biomarkers. Classification models trained on this signature were able to predict CVD in patients with high accuracy. Here, we propose a framework generalizable to other diseases and disorders.
Diet driven differences in host tolerance are linked to shifts in global gene expression in a common avian host-pathogen system
Authors: Sauer Erin L. , Stacy Carson , Perrine Weston , Love Ashley C. , Lewis Jeffrey A. , DuRant Sarah E.
Published: August 2024

As humans alter the landscape, wildlife have become increasingly dependent on anthropogenic resources, altering interactions between individuals and subsequently disease transmission dynamics. Further, nutritional quantity and quality greatly impact an individual host’s immune capacity and ability to mitigate damage caused by infectious disease. Thus, understanding the impact of dietary nutrition on immune function is critical for predicting disease severity and transmission as human activity both facilitates the dispersal of pathogens and alters dietary options for wildlife. Here, we use transcriptomics to explore the previously unstudied molecular mechanisms underpinning diet-driven differences in pathogen tolerance using a widespread avian bacterial pathogen,Mycoplasma gallisepticum(MG). MG is an ideal model for understanding the dietary drivers of disease as the human supplementation that wild birds commonly rely on, bird feeders, are also an important source for MG transmission. Significant diet-driven differences in the expression of many genes encoding immune response and translational machinery proteins are seen both in the absence of MG and during the recovery period. Prior to infection, protein-fed birds are more transcriptionally primed for infection than lipid-fed birds which translates to greater tolerance in protein-fed birds during the recovery period. Given the significant importance of human supplemented food in wildlife disease systems, the molecular mechanisms by which interactions between diet and infection emerge provide insight into the ecological and immunological consequences of human behavior and wildlife disease.
Expanding kinetoplastid genome annotation through protein structure comparison
Authors: Trinidad-Barnech J.M. , José Sotelo-Silveira J.R. , Fernandez Do Porto D. , Smircich P.
Published: August 2024

Kinetoplastids belong to the supergroup Discobids, an early divergent eukaryotic clade. Although the amount of genomic information on these parasites has grown substantially, assigning gene functions through traditional sequence-based homology methods remains challenging. Recently, significant advancements have been made inin silicoprotein structure prediction and algorithms for rapid and precise large-scale protein structure comparisons. In this work, we developed a protein structure-based homology search pipeline (ASC, Annotation by Structural Comparisons) and applied it to annotate all kinetoplastid proteins available in TriTrypDB. Our pipeline assigned functional annotation to 23,000 hypothetical proteins across all 35 kinetoplastid species in the database. Among these, we identified ubiquitous eukaryotic proteins that had not been previously detected in kinetoplastid genomes. The resulting annotations (KASC, Kinetoplastid Annotation by Structural Comparison) are openly available to the community (kasc.fcien.edu.uy).

Author Summary

Kinetoplastids are a group of parasites that cause severe diseases in the poorest regions of the world. Despite the increasing amount of genomic information available on these parasites, predicting the function of many of their genes using traditional methods has been difficult. Recently, there have been significant advancements in predicting protein structures and comparing them on a large scale. In this study, we created a new method called ASC (Annotation by Structural Comparisons) to find functions for all the kinetoplastid genes listed in the TriTrypDB database. Our strategy successfully assigned functions to 23,000 proteins in kinetoplastids. Among these, we discovered important proteins found in all eukaryotes that had not been previously identified in kinetoplastids. This information (KASC, Kinetoplastid Annotation by Structural Comparison) is freely available at kasc.fcien.edu.uy.
Mixed outcomes in recombination rates after domestication: Revisiting theory and data
Authors: Bursell Madeline , Rohilla Manav , Ramirez Lucia , Cheng Yuhuan , Schwarzkopf Enrique J. , Guerrero Rafael F. , Heil Caiti Smukowski
Published: August 2024

The process of domestication has altered many phenotypes. Selection on these phenotypes has long been hypothesized to indirectly select for increases in recombination rate. This hypothesis is consistent with theory on the evolution of recombination rate, but empirical support has been unclear. We review relevant theory, lab-based experiments, and data comparing recombination rates in wild progenitors and their domesticated counterparts. We utilize population sequencing data and a deep learning method to infer genome-wide recombination rates for new comparisons of chicken/red junglefowl, sheep/mouflon, and goat/bezoar. We find evidence of increased recombination in domestic goats compared to bezoars, but more mixed results in chicken, and generally decreased recombination in domesticated sheep compared to mouflon. Our results add to a growing body of literature in plants and animals that finds no consistent evidence of an increase in recombination with domestication.
Design of a Soluble Multivalent Notch Agonist
Authors: Mout Rubul , Jing Ran , Egan Emily D , Eisenach Helen , Najia Mohamad Ali Toufic , Hensch Luca , Bingham Trevor , Kononov Martin A. , Gunage Rajesh , Zhao Yunliang , Edman Natasha I , Schlaeger Thorsten M , Zon Leonard I , North Trista E , Lendahl Urban , Baker David , Blacklow Stephen C , Daley George Q
Published: August 2024

Designed protein agonists can enhance the efficiency of endogenous signaling pathways, and provide a powerful means to control cellular functions and develop disease therapeutics. Designing a soluble cytokine-like agonist for Notch signaling, an evolutionarily conserved pathway that regulates cell fate in embryonic and adult development, is especially challenging because Notch receptor activation requires a mechanical force that is typically mediated by cell-associated transmembrane ligands at sites of cell-cell contact. Moreover, free soluble Notch ligand is signal inhibitory. Here, we exploit computationally designed protein oligomers with precise geometries and valencies to generate cytokine-like, ‘protein only,’ multivalent soluble Notch agonists. These tools promote cell-cell contact, cluster Notch proteins in synapses at the cell surface, and activate Notch signaling in reporter cell lines and cells expressing endogenous receptors. We demonstrate the utility of these soluble Notch agonists in T cell differentiation from cord blood (CB) and human induced pluripotent stem cells (iPSCs), and in bioreactor production of T cells in liquid suspension. Soluble multivalent Notch agonists can be applied broadly toin vitrocellular differentiation methods to generate clinical cell products and to develop immunotherapies.
TRCompDB: A reference of human tandem repeat sequence and composition variation from long-read assemblies
Authors: Gu Bida , Chaisson Mark J.P.
Published: August 2024

Tandem repeats (TRs), including short tandem repeats (STRs) and variable-number tandem repeats (VN-TRs), are hypermutable genetic elements consisting of tandem arrays of repeated motifs. TR variation can modify gene expression and has been implicated in over 50 diseases through repeat mutation and pathogenic expansion. Recent advances in long-read sequencing (LRS) enable the comprehensive profiling of TR variation in large cohorts. We previously developedvamos, a tool for annotating motif count and composition in LRS samples. Here, we expanded the functionality ofvamoswith new methods to construct motif databases that enhanced motif consistency, and a toolsettryvamosfor rapid analysis using vamos output. We demonstrate that thevamosmotif composition annotations more accurately reflect underlying genomes than other approaches for TR annotation. By applyingvamosto 360 LRS assemblies of diverse ancestries, we constructed TRCompDB, a reference database of tandem repeat variation across 805,485 STR and 370,468 VNTR loci on the CHM13 reference genome. Usingtryvamosfor genome-wide testing, we identified 6,039 loci exhibiting strong signatures of population divergence in length or composition, yielding insight into stratification of TR loci.
GPR43 in eosinophils prevents the emergence of pathogenic Siglec-Fhineutrophils in allergic airway inflammation
Authors: Yu Jihyun , Kim Seongryong , Song Hyun-Sup , Kim Hye-Young , Kim You-Me
Published: August 2024

Eosinophils are major effector cells in type 2 immune responses, contributing to host defense and allergic diseases. They also play critical roles in maintaining tissue homeostasis by regulating various immune cell types. However, evidence of the crosstalk between eosinophils and neutrophils is limited. Here, we show that eosinophils directly associate with neutrophils in the lungs of asthma-induced mice. Eosinophil-specific deficiency of the short-chain fatty acid receptor GPR43 results in hyperactivation of eosinophils and increases the expression of neutrophil chemoattractants and PECAM-1, thus enhancing the interaction between eosinophils and neutrophils. This binding event exposes the neutrophils to eosinophil-derived IL-4 and GM-CSF, which induces the conversion of conventional neutrophils into more pathogenic Siglec-Fhineutrophils that strongly enhance Th17 cell differentiation and aggravate asthma symptoms. These results reveal GPR43 as a critical regulator of eosinophils and highlight that eosinophils have a hitherto little-known ability to directly modulate neutrophil differentiation and function.

One Sentence Summary

Eosinophils directly recruit neutrophils and induce their differentiation into a pathogenic Siglec-Fhisubset in allergic airway inflammation.
Rapid Nanopore cloud-based monitoring and analysis of commercial aquaculture microbiomes
Authors: Strutt James P. B. , Bessarab Irina , Min Jamine Goh Ying , Marican Hana , Summers Stephen
Published: August 2024

Aquaculture stands as a crucial component of global food security and sustainable development, yet it faces challenges in disease management and ecological balance. Here, we present a novel approach using rapid nanopore sequencing, cloud-based monitoring and analysis for aquaculture microbiomes. Our study aimed to perform untargeted, agnostic biological monitoring of a commercial aquaculture facility, emphasizing rapidity, specificity, and sensitivity. We employed Oxford Nanopore Technologies’ MinION sequencer with an optimised rapid sequencing protocol, enabling on-site operation by facility staff. Three separate sampling efforts resulting in thirteen sequencing runs were conducted, revealing a representative microbiome baseline across aquaculture system components within a 24-hour timeframe. Our results demonstrated the feasibility of rapid monitoring and analysis of nitrogen-associated organisms, essential for same-day water quality management and infection event detection. Notably, Moving Bed Biofilm Reactor (MBBR media) or BioDiscs exhibited the highest diversity and abundance of nitrogen-associated organisms, confirming a pivotal role in nitrification processes. Critically, our approach addressed challenges in metagenomic sample purity and false positives, offering insights for future refinement and application. Our findings underscore the potential of rapid sequencing technologies in enhancing aquaculture management and sustainability. This approach holds promise for mitigating disease outbreaks, optimizing productivity, and advancing ecological balance in aquaculture systems.
Probing Autism and ADHD subtypes using cortical signatures of the T1w/T2w-ratio and morphometry
Authors: Norbom Linn B. , Syed Bilal , Kjelkenes Rikka , Rokicki Jaroslav , Beauchamp Antoine , Nerland Stener , Kushki Azadeh , Anagnostou Evdokia , Arnold Paul , Crosbie Jennifer , Kelley Elizabeth , Nicolson Robert , Schachar Russell , Taylor Margot J. , Westlye Lars T. , Tamnes Christian K. , Lerch Jason P.
Published: August 2024

Autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) are neurodevelopmental conditions that share genetic etiology and frequently co-occur. Given this comorbidity and well-established clinical heterogeneity, identifying individuals with similar brain signatures may be valuable for predicting clinical outcomes and tailoring treatment strategies. Cortical myelination is a prominent developmental process, and its disruption is a candidate mechanism for both disorders. Yet, no studies have attempted to identify subtypes using T1w/T2w-ratio, a magnetic resonance imaging (MRI) based proxy for intracortical myelin. Moreover, cortical variability arises from numerous biological pathways, and multimodal approaches can integrate cortical metrics into a single network. We analyzed data from 310 individuals aged 2.6-23.6 years, obtained from the Province of Ontario Neurodevelopmental (POND) Network consisting of individuals diagnosed with ASD (n=136), ADHD (n=100), and typically developing (TD) individuals (n=74). We first tested for differences in T1w/T2w-ratio between diagnostic categories and controls. We then performed unimodal (T1w/T2w-ratio) and multimodal (T1w/T2w-ratio, cortical thickness, and surface area) spectral clustering to identify diagnostic-blind subgroups. Linear models revealed no statistically significant case-control differences in T1w/T2w-ratio. Unimodal clustering mostly isolated single individual- or minority clusters, driven by image quality and intensity outliers. Multimodal clustering suggested three distinct subgroups, which transcended diagnostic boundaries, showing separate cortical patterns but similar clinical and cognitive profiles. T1w/T2w-ratio features were the most relevant for demarcation, followed by surface area. While our analysis revealed no significant case-control differences, multimodal clustering incorporating the T1w/T2w-ratio among cortical features holds promise for identifying biologically similar subsets of individuals with neurodevelopmental conditions.
Adverse events reported during weekly isoniazid-rifapentine (3HP) tuberculosis preventive treatment among people living with HIV in Uganda
Authors: Kadota Jillian L. , Musinguzi Allan , Aschmann Hélène E. , Akello Lydia , Welishe Fred , Nakimuli Jane , Berger Christopher A. , Kiwanuka Noah , Phillips Patrick PJ , Katamba Achilles , Dowdy David W. , Cattamanchi Adithya , Semitala Fred C.
Published: August 2024

Background

Short-course tuberculosis (TB) prevention regimens, including 12 weeks of isoniazid and rifapentine (3HP), are increasingly used in high TB-burden countries. Despite established safety and tolerability in efficacy trials, 3HP-related adverse events (AE) could differ in routine settings. Real-world data on AE type, frequency, and timing is crucial for health systems considering 3HP programmatic scale-up.

Methods

We reviewed AEs among people living with HIV (PLHIV) participating in a pragmatic implementation trial of facilitated 3HP taken by directly observed therapy (DOT) or self-administered therapy (SAT) in Kampala, Uganda, and classified them using the Common Terminology Criteria for Adverse Events. We assessed AE timing and summarized related clinical actions including lab tests, diagnoses made, medications prescribed, and treatment interruptions.

Results

Among 1655 PLHIV treated between July 2020-September 2022, 270 (16.3%) reported 451 events; main issues included general (7%), nervous system (6%), musculoskeletal (5%), gastrointestinal (5%), and dermatologic (3%) disorders. Most (61%) occurred within 6 weeks of initiating 3HP. Among those with events, 211 (78%) required further clinician evaluation, 202 (75%) required laboratory testing, 102 (38%) had medications prescribed, 40 (15%) had treatment paused, and 14 (5%) discontinued 3HP. Women, those multidimensionally impoverished, and DOT recipients were more likely to report an AE. SAT users and later enrollees were more likely to have 3HP interrupted or stopped due to an AE.

Conclusions

In a routine setting, 3HP was safe with 16% of PLHIV reporting AEs and only 3% requiring temporary or permanent treatment interruption. These findings support 3HP expansion in routine HIV/AIDS care settings for TB prevention.

3HP is being rolled out for TB prevention in high burden countries. We describe the incidence and clinical management of adverse events in a real-world clinical setting among people living with HIV participating in a pragmatic implementation study in Uganda.