bluuebunny/crossref_metadata_2025 huggingface dataset:
Thermal acclimation of spreading depolarization in the CNS ofDrosophila melanogaster
Authors: Andersen Mads Kuhlmann , Robertson R. Meldrum , MacMillan Heath A.
Published: June 2024

During exposure to extreme stress, the CNS of mammals and insects fails through a phenomenon known as spreading depolarization (SD). SD is characterized by an abrupt disruption of ion gradients across neural and glial membranes that spreads through the CNS, silencing neural activity. In humans, SD is associated with neuropathological conditions like migraine and stroke. In insects, it is coincident with critical thermal limits for activity and can be conveniently monitored by observing the transperineurial potential (TPP). We used the TPP to explore the temperature-dependence and plasticity of SD thresholds and SD-induced changes to the TPP in fruit flies (Drosophila melanogaster) acclimated to different temperatures. Specifically, we characterized the effects of thermal acclimation on the TPP characteristics of cold-induced SD, after which we induced SDviaanoxia at different temperatures in both acclimation groups to examine the interactive effects of temperature and acclimation status. Lastly, we investigated these effects on the rate of SD propagation across the fruit fly CNS. Cold acclimation enhanced resistance to both cold- and anoxic SD and our TPP measurements revealed independent and interactive effects of temperature and acclimation on the TPP and SD propagation. This suggests thermodynamic processes and physiological mechanisms interact to modulate the threshold for activity through SD and its electrophysiological phenomenology. These findings are discussed in relation to conceptual models for SD and established mechanisms for variation in the thermal threshold for SD.
CAMSAP3 Forms Dimers via its α-helix Domain that Directly Stabilize Non-centrosomal Microtubule Minus Ends
Authors: Li Yuejia , Zhang Rui , Ren Jinqi , Chen Wei , Zhou Zhengrong , Xu Honglin , Li Dong , Cheng Haisu , Xie Qi , Ji Wei , Feng Wei , Liang Xin , Meng Wenxiang
Published: June 2024

Microtubules are vital components of the cytoskeleton. Their plus ends are dynamic and respond to changes in cell morphology, while the minus ends are stable and serve a crucial role in microtubule seeding and maintaining spatial organization. In mammalian cells, the calmodulin-regulated spectrin-associated proteins (CAMSAPs), play a key role in directly regulating the dynamics of non-centrosomal microtubules minus ends. However, the molecular mechanisms are not yet fully understood. Our study reveals that CAMSAP3 forms dimers through its C-terminal α-helix; this dimerization not only enhances the microtubule-binding affinity of the CKK domain but also enables the CKK domain to regulate the dynamics of microtubules. Furthermore, CAMSAP3 also specializes in decorating at the minus end of microtubules through the combined action of the microtubule-binding domain (MBD) and the C-terminal α-helix, thereby achieving dynamic regulation of the minus ends of microtubules. These findings are crucial for advancing our understanding and treatment of diseases associated with non-centrosomal microtubules.

Significance

Our study reveals the molecular mechanism of how CAMSAP3, a key regulator of non-centrosomal microtubule dynamics, directly regulates the dynamics of non-centrosomal microtubule minus ends through CKK domain. CAMSAP3 forms dimers through its C-terminal α-helix, which enhances the CKK domain of CAMSAP3 binding to microtubule minus ends and confers stability of them. This finding is not limited to CAMSAP3, but can also be applied to the understanding of the regulation of non-centrosomal microtubule minus end stability by CAMSAP family proteins. Our findings deepen our comprehension of cellular structure and function, offering insights into the role of microtubules in cellular integrity and disease. This study fills a significant knowledge gap and lays the foundation for future research into the complex balance of microtubule dynamics required for cellular health and disease prevention.
Food webs can deliver win-win strategies for tropical agroforestry and biodiversity conservation
Authors: Jarrett Crinan , Powell Luke L. , Claire Tabe Tiku Regine , Kowo Cyril , Ferreira Diogo F. , Quiñones Alma L.S. , Welch Andreanna J. , Haydon Daniel T. , Matthiopoulos Jason
Published: June 2024

Balancing biodiversity conservation and agricultural productivity is commonly regarded as a trade-off, but such analyses overlook ecosystem services that functional biodiverse communities provide in agroecosystems, and the possibility that win-win strategies may exist. We developed a dynamic mechanistic community model of the bird-insect food web associated with African cocoa agroforestry, structurally informed by metabarcoding data on bird diets, and fitted to trapping data on species abundances. We used the model to predict equilibrium community composition under varying intensities of shade management and pesticide use. Our results indicate that low-intensity farming favours forest bird species, and potential pollinator abundance, with no increase in pest biomass. Furthermore, using simulations of pesticide application, we found that pesticides do not effectively reduce pest biomass, and result in forest bird extinction. Our mechanistic framework combines the influence of management and the direct and indirect effects of species’ interactions, and demonstrates that low intensity agriculture may provide a win-win for biodiversity and ecosystem services.
Early life adversity promotes gastrointestinal dysfunction through a sex-dependent phenotypic switch in enteric glia
Authors: Gonzales Jacques , Dharshika Christine , Mazhar Khadijah , Morales-Soto Wilmarie , McClain Jonathon L. , Moeser Adam J. , Nault Rance , Price Theodore J. , Gulbransen Brian D.
Published: June 2024

Irritable bowel syndrome and related disorders of gut-brain interaction (DGBI) are common and exhibit a complex, poorly understood etiology that manifests as abnormal gut motility and pain. Risk factors such as biological sex, stressors during critical periods, and inflammation are thought to influence DGBI vulnerability by reprogramming gut-brain circuits, but the specific cells affected are unclear. Here, we used a model of early life stress to understand cellular mechanisms in the gut that produce DGBIs. Our findings identify enteric glia as a key cellular substrate in which stress and biological sex converge to dictate DGBI susceptibility. Enteric glia exhibit sexual dimorphism in genes and functions related to cellular communication, inflammation, and disease susceptibility. Experiencing early life stress has sex-specific effects on enteric glia that cause a phenotypic switch in male glia toward a phenotype normally observed in females. This phenotypic transformation is followed by physiological changes in the gut, mirroring those observed in DGBI in humans. These effects are mediated, in part, by alterations to glial prostaglandin and endocannabinoid signaling. Together, these data identify enteric glia as a cellular integration site through which DGBI risk factors produce changes in gut physiology and suggest that manipulating glial signaling may represent an attractive target for sex-specific therapeutic strategies in DGBIs.
Homologous Recombination Shapes the Architecture and Evolution of Bacterial Genomes
Authors: Torrance Ellis L. , Diop Awa , Bobay Louis-Marie
Published: June 2024

Homologous recombination is a key evolutionary force that varies considerably across bacterial species. However, how the landscape of homologous recombination varies across genes and within individual genomes has only been studied in a few species. Here, we used Approximate Bayesian Computation to estimate the recombination rate along the genomes of 145 bacterial species. Our results show that homologous recombination varies greatly along bacterial genomes and shapes many aspects of genome architecture and evolution. The genomic landscape of recombination presents several key signatures: rates are highest near the origin of replication in most species, patterns of recombination generally appear symmetrical in both replichores (i.e.replicational halves of circular chromosomes) and most species have genomic hotpots of recombination. Furthermore, many closely related species share conserved landscapes of recombination across orthologs indicating that recombination landscapes are conserved over significant evolutionary distances. We show evidence that recombination drives the evolution of GC-content through increasing the effectiveness of selection and not through biased gene conversion, thereby contributing to an ongoing debate. Finally, we demonstrate that the rate of recombination varies across gene function and that many hotspots of recombination are associated with adaptive and mobile regions often encoding genes involved in pathogenicity.
Characterizing population structure and documenting rapid loss of genetic diversity in Chiricahua Leopard Frogs (Lithobates chiricahuensis) with high throughput microsatellite genotyping
Authors: Beimfohr Caleb , Moreno Linet Rivas , Anderson Regan , Cardwell Raina , Seeman Zach , Spry Ryan , Holding Matthew L , Owens Audrey , Denton Robert
Published: June 2024

The use of molecular markers to assess genetic diversity has become a common component of recovery action plans for threatened and endangered species. In this study, we use an unusually large number of microsatellite markers (N=91) to characterize the genetic variation of Chiricahua Leopard Frogs (Lithobates chiricahuensis) across their range in order to understand their distribution of genetic variation, identify genetic bottlenecks, and measure genetic changes over time in a single, highly-managed population. Populations were best divided into three genetically distinct clusters, with the southeastern Arizona and New Mexico populations forming distinct genetic clusters. While there is moderate genetic variation distributed across the sampled populations, each population on its own shows relatively low allelic diversity. Most populations displayed strong genetic signals of recent genetic bottlenecks or a deficiency of heterozygous genotypes that is typically associated with frequent inbreeding. Populations that have a history of no management through translocations harbored the greatest number of unique alleles and overall allelic richness, especially in a subset of the Mexican populations. Finally, long-term cohort sampling at one specific site (the Southwestern Research Station in Portal, Arizona) allowed us to demonstrate how rapidly genetic diversity can decrease across a matter of years in a population with few founders. This work shows how microsatellite markers can provide important context for conservation agencies, but even a large suite of markers beyond what is typical may not be enough for populations that are extremely bottlenecked and have low levels of standing genetic diversity.
Metabolic control by the Bithorax Complex-Wnt signaling crosstalk inDrosophila
Authors: Hemba-Waduge Rajitha-Udakara-Sampath , Liu Mengmeng , Li Xiao , Sun Jasmine L. , Budslick Elisabeth A. , Bondos Sarah E. , Ji Jun-Yuan
Published: June 2024

Adipocytes distributed throughout the body play crucial roles in lipid metabolism and energy homeostasis. Regional differences among adipocytes influence normal function and disease susceptibility, but the mechanisms driving this regional heterogeneity remain poorly understood. Here, we report a genetic crosstalk between theBithorax Complex(BX-C) genes and Wnt/Wingless signaling that orchestrates regional differences among adipocytes inDrosophilalarvae. Abdominal adipocytes, characterized by the exclusive expression ofabdominal A(abd-A) andAbdominal B(Abd-B), exhibit distinct features compared to thoracic adipocytes, with Wnt signaling further amplifying these disparities. Depletion ofBX-Cgenes in adipocytes reduces fat accumulation, delays larval-pupal transition, and eventually leads to pupal lethality. Depleting Abd-A or Abd-B reduces Wnt target gene expression, thereby attenuating Wnt signaling-induced lipid mobilization. Conversely, Wnt signaling stimulatedabd-Atranscription, suggesting a feedforward loop that amplifies the interplay between Wnt signaling andBX-Cin adipocytes. These findings elucidate how the crosstalk between cell-autonomousBX-Cgene expression and Wnt signaling define unique metabolic behaviors in adipocytes in different anatomical regions of fat body, delineating larval adipose tissue domains.
Perturbation-driven transcriptional heterogeneity impacts cell fitness
Authors: Nadal-Ribelles Mariona , Solé Carme , Diez-Villanueva Anna , Stephan-Otto Attolini Camille , Matas Yaima , Steinmetz Lars , de Nadal Eulalia , Posas Francesc
Published: June 2024

Heterogeneity is inherent to living organisms and it determines cell fate and phenotypic variability1–3. Indeed, even isogenic cell populations vary in quantifiable phenotypes. Here we generated a high-resolution single-cell yeast transcriptome atlas using genotype and clone RNA barcoded deletions to profile 3500 mutants under control and stress conditions in a genome-scale genetic and environmental perturbation screen. We uncovered a myriad of cell states within a population with specific transcriptional architectures that are both intrinsically and extrinsically regulated, thereby suggesting a continuum of cell states. Cell state occupancy and transition can be genetically modulated with specific mutants that act as state attractors, resulting in differential fitness. By exploiting the power of intra-genetic variability, we identified regulators of transcriptional heterogeneity that are functionally diverse and influenced by the environment.

One-Sentence Summary

The yeast single cell-transcriptome atlas based on RNA-traceable genetic perturbations served to map cellular states and define their underlying genetic basis.
Insights into Immune Gene Prediction and Function Through the Evolutionary History ofADFGene Family
Authors: Chen Huan , Day Brad
Published: June 2024

ACTIN DEPOLYMERIZING FACTORS (ADFs) are key regulators of actin cytoskeletal dynamics and plant immunity.

We predicted the potential immune-associated function of 38 genes fromArabidopsisusing gene expression values from 24,123 RNA-Seq datasets and 34 single-cell datasets through machine learning algorithms.

The evolutionary relationships ofADFfamily members from 38 eukaryotic species were evaluated, including an assessment of the sub-function(s) of these members.

Our results show that theADFclade in plant and other kingdoms are separated, withADF3, 5, 7, 9,and10possessing collinear relationships within species, andADF 2,3,4,6,7, and 10possessing evolved, new, sub-functions related to response to Fe, copper-deficiency, and ABA signaling inArabidopsis. Expanded, multiple, roles forADF1,4,and6were also identified.

This study not only provides an analysis of the expanded role for the ADF family of genes/proteins, but also provides insight into, and a framework for, the identification and study of the evolutionary history of genes having putative roles in immune signaling.
Cell-scale porosity in microporous annealed particle (MAP) scaffolds modulates immune response and promotes formation of innervated muscle fibers in volumetric muscle loss injuries
Authors: Ayala Areli Rodriguez , Christ George , Griffin Donald
Published: June 2024

Volumetric muscle loss (VML) is caused by severe traumatic injuries to skeletal muscle and is characterized by the irreversible loss of contractile tissue and permanent functional deficits. VML injuries cannot be healed by endogenous mechanisms and are exceptionally difficult to treat in the clinic due to the excessive upregulation of the inflammatory response, which leads to fibrosis, denervation of muscle fibers, and impaired regeneration. These injuries lead to long-term disability. Using a rodent model of VML in the tibialis anterior, this study presents microporous annealed particle (MAP) hydrogel scaffolds as a biomaterial platform for improved muscle regeneration in VML injuries, specifically highlighting the benefits of cell-scale porosity. In contrast to bulk (i.e., nanoporous) hydrogel scaffolds, MAP scaffolds promote integration by avoiding the foreign body response, decreasing the rate of implant degradation, and shifting macrophage polarization to favor regeneration. In addition, cell migration and angiogenesis throughout the implant precede the degradation of MAP scaffolds, including the formation of muscle fibers and neuromuscular junctions within MAP scaffolds prior to degradation. These fibers and junctions continue to develop as the implant degrades, indicating that MAP hydrogel scaffolds are a promising therapeutic approach for VML injuries.
Root System Architecture Reorganization Under Decreasing Soil Phosphorus Lowers Root System Conductance ofZea mays
Authors: Bauer Felix Maximilian , Baker Dirk Norbert , Giraud Mona , Baca Cabrera Juan Carlos , Vanderborght Jan , Lobet Guillaume , Schnepf Andrea
Published: June 2024

The global supply of phosphorus is decreasing. At the same time, climate change reduces the water availability in most regions of the world. Insights on how decreasing phosphorus availability influences plant architecture is crucial to understand its influence on plant functional properties, such as the root system’s water uptake capacity. In this study we investigated the structural and functional responses ofZea maysto varying phosphorus fertilization levels focusing especially on the root system’s conductance. A rhizotron experiment with soils ranging from severe phosphorus deficiency to sufficiency was conducted. We measured architectural parameters of the whole plant and combined them with root hydraulic properties to simulate time-dependent root system conductance of growing plants under different phosphorus levels. We observed changes of the root system architecture, characterized by decreasing crown root elongation and reduced axial root radii with declining phosphorus availability. Modeling revealed that only plants with optimal phosphorus availability sustained a high root system conductance, while all other phosphorus levels led to a significantly lower root system conductance, both under light and severe phosphorus deficiency. We postulate that phosphorus deficiency initially enhances root system function for drought mitigation but eventually reduce biomass and impairs root development and water uptake in prolonged or severe cases of drought. Our results also highlight the fact that root system organization, rather than its total size, is critical to estimate important root functions.
Understanding Complex Chromatin Dynamics of Primary Human Neutrophils During PMA Induced NETosis
Authors: Atteberry Brandi , Berman Benjamin P. , Kelly Theresa K , Cayford Justin
Published: June 2024

Background

Primary human neutrophils play a pivotal role in innate immunity, mainly through the formation of neutrophil extracellular traps (NETs) in a process known as NETosis. This cell-death pathway is crucial for combating infections but is also implicated in many inflammatory diseases such as sepsis, systemic lupus erythematosus, rheumatoid arthritis, and others.

Methods

The study presented here investigates chromatin dynamics during NETosis by stimulating primary human neutrophils with phorbol 12-myristate 13-acetate (PMA). We adapt the ATAC-seq (Assay for Transposase-Accessible Chromatin using sequencing) method to isolated neutrophils and characterize a time-dependent chromatin response.

Results

We find that chromatin accessibility patterns are consistent across individual donors and most chromatin changes occur within 30 minutes, with many continuing across the 90 minutes assessed in this study. Regulatory regions gaining accessibility are associated with activity of pathways that have been implicated in NOX-dependent NET formation.

Conclusions

Our findings enhance the understanding of the chromatin changes underlying NETosis and also identify potential early-acting targets for modulating this process in inflammatory diseases.
ARTEM: a method for RNA and DNA tertiary motif identification with backbone permutations, and its example application to kink-turn-like motifs
Authors: Baulin Eugene F. , Bohdan Davyd R. , Kowalski Dawid , Serwatka Milena , Świerczyńska Julia , Żyra Zuzanna , Bujnicki Janusz M.
Published: June 2024

The functions of non-coding RNAs are largely defined by their three-dimensional structures. RNA 3D structure is organized hierarchically and consists of recurrent building blocks called tertiary motifs. The computational problem of RNA tertiary motif search remains largely unsolved, as standard approaches are restrained by sequence, interaction network, or backbone topology. We developed the ARTEM superposition algorithm, which is free from these limitations. Here, we present a version of ARTEM that allows automated searches of RNA and DNA structure databases to identify 3D structure motifs. We exemplify it by a search of motifs isosteric to the kink-turn motif. This widespread motif plays a role in many aspects of RNA function, and its mutations are known to cause several human syndromes. With ARTEM, we discovered two new kink-turn topologies, multiple no-kink variants of the motif, and showed that a ribosomal junction in bacteria forms either a kink or a no-kink variant depending on the species. Additionally, we identified kink-turns in the catalytic core of group II introns, whose structures have not previously been characterized as containing kink-turns. ARTEM opens a fundamentally new way to study RNA and DNA 3D folds and motifs and analyze their correlations and variations.
Robust virtual staining of landmark organelles
Authors: Liu Ziwen , Hirata-Miyasaki Eduardo , Pradeep Soorya , Rahm Johanna , Foley Christian , Chandler Talon , Ivanov Ivan , Woosley Hunter , Lao Tiger , Balasubramanian Akilandeswari , Marreiros Rita , Liu Chad , Leonetti Manu , Aviner Ranen , Arias Carolina , Jacobo Adrian , Mehta Shalin B.
Published: June 2024

Correlative dynamic imaging of cellular landmarks, such as nuclei and nucleoli, cell membranes, nuclear envelope and lipid droplets is critical for systems cell biology and drug discovery, but challenging to achieve with molecular labels. Virtual staining of label-free images with deep neural networks is an emerging solution for correlative dynamic imaging. Multiplexed imaging of cellular landmarks from scattered light and subsequent demultiplexing with virtual staining leaves the light spectrum for imaging additional molecular reporters, photomanipulation, or other tasks. Current approaches for virtual staining of landmark organelles are fragile in the presence of nuisance variations in imaging, culture conditions, and cell types. We report training protocols for virtual staining of nuclei and membranes robust to variations in imaging parameters, cell states, and cell types. We describe a flexible and scalable convolutional architecture, UNeXt2, for supervised training and self-supervised pre-training. The strategies we report here enable robust virtual staining of nuclei and cell membranes in multiple cell types, including human cell lines, neuromasts of zebrafish and stem cell (iPSC)-derived neurons, across a range of imaging conditions. We assess the models by comparing the intensity, segmentations, and application-specific measurements obtained from virtually stained and experimentally stained nuclei and cell membranes. The models rescue missing labels, non-uniform expression of labels, and photobleaching. We share three pre-trained models (VSCyto3D, VSNeuromast, and VSCyto2D) and a PyTorch-based pipeline (VisCy) for training, inference, and deployment that leverages current community standards for image data and metadata.
Peptide sequencing via reverse translation of peptides into DNA
Authors: Zheng Liwei , Sun Yujia , Eisenstein Michael , Soh Hyongsok Tom
Published: June 2024

Scalable methods that can accurately sequence peptides at single-amino acid resolution could significantly advance proteomic studies. We present a protein sequencing method based on the “reverse translation” of peptide sequence information into DNA barcodes that document the identity, position, and the originating peptide of each amino acid. We employ a modified Edman degradation process that converts peptides into DNA-barcoded amino acids, which are subsequently detected by proximity extension assay, yielding multi-barcoded DNA outputs that can be PCR amplified and sequenced. Using our method, we sequenced multiple consecutive amino acids within a model peptide. This method also enables the differentiation of single amino acid substitutions, and the identification of post-translational modifications and their positions within multiple peptides simultaneously. With further development, we anticipate that this method will enable highly parallelde novoprotein sequencing with single-molecule sensitivity.
Prot2Token: A multi-task framework for protein language processing using autoregressive language modeling
Authors: Pourmirzaei Mahdi , Esmaili Farzaneh , Pourmirzaei Mohammadreza , Wang Duolin , Xu Dong
Published: June 2024

This paper proposes a versatile tokenization method and introduces Prot2Token, a model that combines autoregressive language modeling with protein language models (PLMs) to tackle various protein prediction tasks using protein sequences. Leveraging our tokenization method, Prot2Token adapts existing PLMs for multiple tasks such as protein-level prediction, residue-level prediction, and protein-protein interaction prediction through next-token prediction of tokenized target label sequences. By incorporating prompt tokens into the decoder, Prot2Token enables multi-task training in a single end-to-end session. Our results demonstrate that Prot2Token not only matches the performance of specialized models across various tasks but also paves the way for integrating protein tasks with large language models (LLMs), representing an important step towards creating general-purpose PLMs for advanced protein language processing (PLP). Additionally, we use Prot2Token to develop S-ESM, a structure-aware version of the ESM model, which achieves competitive performance with state-of-the-art methods in 3D structure-related tasks using only protein sequences. Code is available at:https://github.com/mahdip72/prot2token.
A Neuropathology Case Report of a Woman with Down Syndrome who Remained Cognitively Stable
Authors: Liou Jr-Jiun , Lou Jerry , Nakagiri Jamie , Yong William , Hom Christy L. , Doran Eric W. , Totoiu Minodora , Lott Ira , Mapstone Mark , Keator David B. , Brickman Adam M. , Wright Sierra , Nelson Brittany , Lai Florence , Xicota Laura , Dang Lam-Ha T. , Li Jinghang , Santini Tales , Mettenburg Joseph M. , Ikonomovic Milos D. , Kofler Julia , Ibrahim Tamer , Head Elizabeth ,   the Alzheimer Biomarker Consortium - Down Syndrome
Published: June 2024

In this neuropathology case report, we present findings from an individual with Down syndrome (DS) who remained cognitively stable despite Alzheimer’s disease (AD) neuropathology. Clinical assessments, fluid biomarkers, neuroimaging, and neuropathological examinations were conducted to characterize her condition. Notably, her ApoE genotype was E2/3, which is associated with a decreased risk of dementia. Neuroimaging revealed stable yet elevated amyloid profiles and moderately elevated tau levels, while neuropathology indicated intermediate AD neuropathologic change with Lewy body pathology and cerebrovascular pathology. Despite the presence of AD pathology, the participant demonstrated intact cognitive functioning, potentially attributed to factors such as genetic variations, cognitive resilience, and environmental enrichment. The findings suggest a dissociation between clinical symptoms and neuropathological changes, emphasizing the complexity of AD progression in DS. Further investigation into factors influencing cognitive resilience in individuals with DS, including comorbidities and social functioning, is warranted. Understanding the mechanisms underlying cognitive stability in DS could offer insights into resilience to AD neuropathology in people with DS and in the general population and inform future interventions.
DALSO: domain ALS ontology
Authors: Podsiadły-Marczykowska Teresa , Andersen Peter , Gromicho Marta , Grosskreutz Julian , Kuźma-Kozakiewicz Magdalena , Petri Susanne , Szacka Katarzyna , Uysal Hilmi , de Carvalho Mamede , Piotrkiewicz Maria
Published: June 2024

Amyotrophic lateral sclerosis (ALS) is an incurable, rapidly progressive neurodegenerative disease. During the course of ALS, virtually all skeletal muscles are gradually affected, including the respiratory muscles, and the disease is usually fatal within 2–5 years of symptom onset. Unequivocal and conclusive tests for ALS do not exist, its disease etiology is still unknown, and therapeutic options are limited. This paper presents the ALS domain ontology (DALSO), model containing formalized, semantic descriptions of a wide range of modeled disease related notions such as patient demographics, clinical findings and history, disease clinical features and diagnostic classifications, risk factors, genetics and pathophysiological mechanisms of motor neuron degeneration. The DALSO’s aim and information scope, design assumption, structure and implementation details are also described. DALSO covers the broad range of significant biomedical concepts ranging from clinical to molecular feature of the modeled disease, it represents a comprehensive, structured knowledge source for the ALS disease domain. To the best of authors’ knowledge, the DALSO is the first attempt to develop a formal, computational model representing knowledge of this fatal motor neuron disease. It provides the means for integrating and annotating clinical and research data, not only at the generic domain knowledge level, but also at the level of individual patient case studies. The DALSO is expressed in OWL2 language, contains 910 classes, is consistent and free of logical errors. Its syntactic correctness was validated by the Fact++ reasoner.
The Predictors of COVID-19 Case Fatalities in Nigerian Health Systems: A Secondary Data Analysis
Authors: Akinjeji Adewale , Oladigbolu Remi , Adedokun Adetunji , Onuorah Ogonna , Emerenini Franklin
Published: June 2024

Background

COVID-19, caused by the novel SARS-CoV-2 is the worst catastrophe in this century that affected more than 800 million people and caused more than 7 million deaths. During the pandemic, the burden of COVID-19 increased significantly, posing a threat to public health infrastructure, testing protocols, national healthcare capacity, and disease control measures. To assess the impacts of the Nigerian Health Systems on COVID-19 fatalities, the researchers evaluated the association between healthcare system capability and mortality rate of COVID-19 patients through adjustments for healthcare spending as a proportion of the GDP, population density, and the proportion of the population that are 65 years and above across the 36 States and Abuja, FCT.

Methods

The study utilized secondary data abstracted from the World Bank records, Worldometer, and Post-Pandemic Health Financing by the States in Nigeria (2020 to 2022). It used data from the 36 States of the country and the FCT, Abuja. The dependent variable was COVID-19 case fatality (Case Fatality Rate across the study areas), the predictor variable was Healthcare Capacity Index (aggregate of number of doctors/nurses/midwives/hospital bed space per 1,000 population categorized into low, middle, and high Healthcare Capacity index), and the covariates were population density, health expenditure as a percentage of GDP, and the proportion of the population that are 65 years and above. A negative binomial regression model was used to assess the predictors of case fatality after adjusting for other covariates at an alpha of <0.05 and 95% confidence interval.

Results

Almost half of the States in Nigeria were in the middle Healthcare Capacity Index 16 (43.2%) with only 7 (18.9%) in the high Healthcare Capacity Index (HCI). The regression analysis shows that HCI was a predictor of COVID-19 case fatality as the States with high HCI compared with low HCI were 9.4 times more likely to have lower COVID-19 case fatalities (AOR=0.106, p=0.063, 95% CI[0.010-1.131]), and those with middle HCI compared with low were 6.4 times more likely to have lower COVID-19 case fatality (aOR=0.156, p=0.006, 95% CI [0.041-0.593]). Although States with a higher proportion of the population that were 65 years and above were about 2 times more likely to have higher COVID-19 case fatality (aOR 1.99, p=0.154, 95% CI [0.771-5.172]), this was not statistically significant due to the small sample size (37 States)

Conclusion

The research further buttressed the pivotal role that effective multidimensional healthcare capacity is a pertinent strategy to mitigate future case fatalities from Public Health Events of International Concerns (PHEICs).
Bayesian marker-based principal component ridge regression – a flexible multipurpose framework for quantitative genetics in wild study systems
Authors: Aspheim Janne C. H. , Aase Kenneth , Bolstad Geir H. , Jensen Henrik , Muff Stefanie
Published: June 2024

As larger genomic data sets become available for wild study populations, the need for flexible and efficient methods to estimate and predict quantitative genetic parameters, such as the adaptive potential and measures for genetic change, increases. Animal breeders have produced a wealth of methods, but wild study systems often face challenges due to larger effective population sizes, environmental heterogeneity and higher spatio-temporal variation. Here we adapt methods previously used for genomic prediction in animal breeding to the needs of wild study systems. The core idea is to approximate the breeding values as a linear combination of principal components (PCs), where the PC effects are shrunk with Bayesian ridge regression. Thanks to efficient implementation in a Bayesian framework using integrated nested Laplace approximations (INLA), it is possible to handle models that include several fixed and random effects in addition to the breeding values. Applications to a Norwegian house sparrow meta-population, as well as simulations, show that this method efficiently estimates the additive genetic variance and accurately predicts the breeding values. A major benefit of this modeling framework is computational efficiency at large sample sizes. The method therefore suits both current and future needs to analyze genomic data from wild study systems.
Identification of functional non-coding variants associated with orofacial cleft
Authors: Kumari Priyanka , Friedman Ryan Z. , Pi Lira , Curtis Sarah W. , Paraiso Kitt , Visel Axel , Rhea Lindsey , Dunnwald Martine , Patni Anjali P. , Mar Daniel , Bomsztyk Karol , Mathieu Julie , Ruohola-Baker Hannele , Leslie Elizabeth J. , White Michael A. , Cohen Barak A. , Cornell Robert A.
Published: June 2024

Oral facial cleft (OFC) is a multifactorial disorder that can present as a cleft lip with or without cleft palate (CL/P) or a cleft palate only. Genome wide association studies (GWAS) of isolated OFC have identified common single nucleotide polymorphisms (SNPs) at the 1q32/IRF6locus and many other loci where, likeIRF6, the presumed OFC-relevant gene is expressed in embryonic oral epithelium. To identify the functional subset of SNPs at eight such loci we conducted a massively parallel reporter assay in a cell line derived from fetal oral epithelium, revealing SNPs with allele-specific effects on enhancer activity. We filtered these against chromatin-mark evidence of enhancers in relevant cell types or tissues, and then tested a subset in traditional reporter assays, yielding six candidates for functional SNPs in five loci (1q32/IRF6, 3q28/TP63, 6p24.3/TFAP2A, 20q12/MAFB, and 9q22.33/FOXE1). We further tested two SNPs nearIRF6and one nearFOXE1by engineering the genome of induced pluripotent stem cells, differentiating the cells into embryonic oral epithelium, and measuring expression ofIRF6orFOXE1and binding of transcription factors; the results strongly supported their candidacy. Conditional analyses of a meta-analysis of GWAS suggest that the two functional SNPs nearIRF6account for the majority of risk for CL/P associated with variation at this locus. This study connects genetic variation associated with orofacial cleft to mechanisms of pathogenesis.
Elucidation of the life cycle of a saprotrophic inoperculate discomycete that is associated with pinesap, using a polyphasic taxonomic approach#
Authors: Demir Özge , Chen Yanpeng , Lambert Christopher , Schüffler Anja , Surup Frank , Stadler Marc
Published: June 2024

This study deals with the elucidation of the life cycle of an inoperculate discomycete that was eventually collected from conifer wood in South Germany and has become famous for the extraordinary diversity of its secondary metabolites when it was studied extensively during the 1990s. It had then been identified asLachnum papyraceum(Lachnaceae,Helotiales) based on morphological traits, and extracts from its mycelial cultures were found to possess extraordinary nematicidal and antibiotic activities. Over 60 different secondary metabolites were finally identified from this fungus after extensive variation of culture media and scale up of production up to 100 litre scale. Among the main active principles were mycorrhizin A and chloromycorrhizin A, which had first been reported in 1987 from an unnamed “mycorrhizal” fungus of the hemiparasitic plant,Monotropa hypopitys(pinesap) that was isolated in Sweden. We noted that both theLachnumstrain and the original mycorrhizin producer were still available in the public domain, and decided to study them for comparison, using a multilocus phylogeny and also generated secondary metabolite profiles of both strains using analytical high performance liquid chromatography coupled to diode array and mass spectrometric detection (HPLC-DAD/MS). Surprisingly, the sequence data as well as the secondary metabolite profiles of both strains were highly similar, and it was also confirmed by phylogenetic methods that the strains are indeed nested within the genusLachnumby comparison of their ITS, LSU and RBP2 sequences. The specimen calledL. papyraceumin the old publications was tentatively re-identified by Hans-Otto Baral asL. cf.subvirgineum,but substantial further work on the taxonomy of the genus remains to be done, anyway. We conclude that someLachnumspecies have a highly complex but all the more interesting life cycle, and the mycorrhizal symbiont partner may invade the host plant, where it may persist as an endophyte and finally turn saprotrophic on the wood of the senescent pine tree. The taxonomy of these fungi should also be further resolved in the future, using a polythetic concept that includes chemotaxonomic data and a multi-locus genealogy.
Stem cell-like memory T cells are closely related to follicular helper T lymphocytes
Authors: Lalinde-Ruiz Nicolás , Padillo-Fino David Santiago , Parra-López Carlos Alberto
Published: June 2024

Adoptive cell therapy has the potential to increase antitumor immunity by modifying cellsin-vitroto expand lymphocytes that recognize and attack the tumor. The functional capacity and survival of the cells transferred to the patient heavily depends on the memory subpopulations that are being expanded in the laboratory, hence, obtaining early memory cells is desirable. The main objective of our work was to determine a strategy forin-vitroexpansion of human stem cell-like memory T CD4 lymphocytes. Starting from naive cells, stimulated with a polyclonal agent supplemented with different combinations of cytokines from the common gamma family, we found that the combination of IL-7, IL-15 and IL-21 or IL-7 and IL-21 were the cocktails that produced a greater number of cells with a stem memory phenotype, measured by flow cytometry. Additionally, through the measurement of membrane proteins andin-silicoanalysis, a close relationship between stem cell-like memory and the follicular helper T cells differentiation program was established, which we believe contributes to a better understanding of the processes that underlie the generation and maintenance of memory and, therefore, may improve current strategies of expansion of T cells for immunotherapy purposes.
Cross Tissue DNAm Biomarker Prediction using Transfer Learning
Authors: Mcgreevy Kristen M , Chen Brian H , Horvath Steve , Telesca Donatello
Published: June 2024

DNA methylation (DNAm) is an epigenetic mechanism vital for regulating gene expression and influencing disease states. Developing accurate DNAm biomarkers often requires data from specific tissues, which are sometimes difficult to access. This study explores the use of Transfer Learning (TL) to predict blood DNAm biomarkers using saliva DNAm data, aiming to overcome limitations posed by sample size and tissue accessibility. We developed TL-based algorithms that integrate DNAm data from multiple tissues. These algorithms were evaluated against traditional Lasso regression and direct saliva DNAm estimates. Our results show that TL significantly improves the prediction accuracy of DNAm biomarkers, outperforming traditional methods in 20 out of 26 biomarkers. We further validated our models using independent datasets, demonstrating that TL-derived predictions reflect known biological relationships, such as sex differences in telomere length and the impact of smoking on DNAm biomarkers. Our findings highlight the potential of TL in enhancing DNAm biomarker prediction across tissues, providing a valuable tool for epigenetic research. The developed algorithms and methodologies are accessible to researchers, fostering advancements in personalized medicine and aging research. This study establishes a framework for utilizing TL to bridge the gap between accessible and pertinent tissue data, paving the way for more accurate and versatile DNAm biomarker applications.

ACM Reference Format

Kristen M McGreevy, Brian H Chen, Steve Horvath, and Donatello Telesca. 2024. Cross Tissue DNAm Biomarker Prediction using Transfer Learning. 1, 1 (June 2024), 43 pages.https://doi.org/10.1145/nnnnnnn.nnnnnnn
Assessment of false discovery rate control in tandem mass spectrometry analysis using entrapment
Authors: Wen Bo , Freestone Jack , Riffle Michael , MacCoss Michael J. , Noble William S. , Keich Uri
Published: June 2024

A pressing statistical challenge in the field of mass spectrometry proteomics is how to assess whether a given software tool provides accurate error control. Each software tool for searching such data uses its own internally implemented methodology for reporting and controlling the error. Many of these software tools are closed source, with incompletely documented methodology, and the strategies for validating the error are inconsistent across tools. In this work, we identify three different methods for validating false discovery rate (FDR) control in use in the field, one of which is invalid, one of which can only provide a lower bound rather than an upper bound, and one of which is valid but under-powered. The result is that the field has a very poor understanding of how well we are doing with respect to FDR control, particularly for the analysis of data-independent acquisition (DIA) data. We therefore propose a theoretical formulation of entrapment experiments that allows us to rigorously characterize the behavior of the various entrapment methods. We also propose a more powerful method for evaluating FDR control, and we employ that method, along with other existing techniques, to characterize a variety of popular search tools. We empirically validate our entrapment analysis in the fairly well-understood DDA setup before applying it in the DIA setup. We find that none of the DIA search tools consistently controls the FDR at the peptide level, and the tools struggle particularly with analysis of single cell datasets.
Next generation AMA1-based plasmids for enhanced heterologous expression in filamentous fungi
Authors: Roux Indra , Woodcraft Clara , Sbaraini Nicolau , Pepper Amy , Wong Emily , Bracegirdle Joe , Chooi Yit-Heng
Published: June 2024

Episomal AMA1-based plasmids are increasingly used for expressing biosynthetic pathways and CRISPR/Cas systems in filamentous fungi cell factories due to their high transformation efficiency and multicopy nature. However, gene expression from AMA1 plasmids has been observed to be highly heterogeneous in growing mycelia. To overcome this limitation, here we developed next-generation AMA1-based plasmids that ensure homogenous and strong expression. We achieved this by evaluating various degradation tags fused to the auxotrophic marker gene on the AMA1 plasmid, which introduces a more stringent selection pressure throughout multicellular fungal growth. With these improved plasmids, we observed inAspergillus nidulansa 5-fold increase in the expression of a fluorescent reporter, a doubling in the efficiency of a CRISPRa system for genome mining, and a up to a 10-fold increase in the production of heterologous natural product metabolites. This strategy has the potential to be applied to diverse filamentous fungi.
Evaluating sustainable feeds for aquaculture by simulating Atlantic salmon lipid metabolism
Authors: Rotnes Filip , Vik Jon Olav , Øyås Ove
Published: June 2024

Atlantic salmon aquaculture is an important food source globally, but its sustainability is challenged by environmental impacts and the nutritional demands of farmed fish, particularly when it comes to fatty acids. Salmon feeds still rely heavily on fish or soybean meal, which poses sustainability concerns due to overfishing and carbon footprint. Innovations in feed composition seek to address these challenges, e.g., by using more sustainable ingredients, but the impacts of alternative feeds on fish and environment can be hard to quantify. Here, we developed a model with detailed and flexible accounting for lipids – Simulated Salmon Lipid Metabolism (SimSaLipiM) – to predict the nutritional and environmental outcomes of feed formulations. Integrating SimSaLipiM with feed ingredient databases enabled detailed analysis of anin vivofeed trialin silico. The model predicted optimal feed efficiency in agreement with observations as well as a detailed energy budget and fish biomass lipid composition for each feed. We also used the model to formulate novel sustainable feeds and feed supplements by minimising CO2footprint. Thus, SimSaLipiM makes it easy to identify recipes that optimize key feed properties such as efficiency and environmental impacts. This could be a valuable tool for feed manufacturers, guiding the formulation of feeds that are both sustainable and cost effective. By bridging the gap between feed formulation and the flexible growth and energy requirements of a fish, SimSaLipiM can contribute to advancing sustainable aquaculture.