bluuebunny/crossref_metadata_2025 huggingface dataset:
Analysis of gene expression profiles to elucidate racial differences in African American and White patients with Triple-negative breast cancer
Authors: McAndrew Hailey , Rigler Jessica , Yeguvapalli Suneetha , Chitrala Kumaraswamy Naidu
Published: June 2024

Triple-negative breast cancer (TNBC) is the second most diagnosed subtype of breast cancer. It is known to be the most aggressive one that lacks known targetable receptors. One of the concerns in TNBC is the disparities in its prevalence and tumor pathogenesis among women with non-Hispanic African American backgrounds. Despite extensive research, the genetic underpinnings that lead to these disparities remain elusive. The current study aims to provide initiative for further clinical research in the development of targeted therapy for TNBC. Gene expression profiles from African American (AA) and European American (EA) patients with TNBC were collected from Gene Expression Omnibus and performed differential gene expression (DEG)analysis. Candidate genes for a significant correlation between expression and survival rates for breast invasive carcinoma were analyzed using UALCAN. The DAVID annotation tool, Enrichr web server, KEGG database, and Gene Ontology (GO) database were used for functional enrichment analysis of target genes. The Network Analyst server was used to identify ligands with strong affinities, SeamDock server for molecular docking between the biomarkers/associated ligands and examined protein-protein interactions (PPI) from the STRING server. Data from public breast cancer cohorts was utilized to identify expression patterns associated with poor survival outcomes of AA patients with TNBC. Our results showed three genes of interest (CCT3,LSM2, andMRPS16) and potential ligands for molecular docking. Molecular docking was performed for the ICG001 ligand toCCT3(binding affinities of -9.3 kcal/mol and -8.9 kcal/mol) and other interacting proteins (CDC20andPPP2CA) with high degrees of connectivity. The results determined molecular docking of ICG001 to theCDC20protein resulted in the highest binding affinity. Our results demonstrated thatCCT3and its interacting partners could serve as potential biomarkers due to their association with the survival outcome of AA patients with TNBC and ICG 001 could be the therapeutic lead for these biomarkers.
Cardiac acetylcholinesterase and butyrylcholinesterase have distinct localization and function
Authors: Dingová Dominika , Kučera Matej , Hodbod Tibor , Fischmeister Rodolphe , Krejci Eric , Hrabovská Anna
Published: June 2024

Cholinesterase (ChE) inhibitors are under consideration to be used in the treatment of cardiovascular pathologies. A prerequisite to advancing ChE inhibitors into the clinic is their thorough characterization in the heart. The aim here was to provide a detailed analysis of cardiac ChE to understand their molecular composition, localization, and physiological functions. A battery of biochemical, microscopic, and physiological experiments was used to analyze two known ChE, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), in hearts of mutant mice lacking different ChE molecular forms. Overall, AChE activity was exceeded by BChE, while it was localized mainly in the atria and the ventricular epicardium of the heart base. AChE was anchored by ColQ in the basal lamina or by PRiMA at the plasma membrane and co-localized with the neuronal marker TUJ1. In absence of anchored AChE, heart rate was unresponsive to a ChE inhibitor. BChE, the major ChE in heart, was detected predominantly in ventricles, presumably as a precursor (soluble monomers/dimers). Mice lacking BChE were more sensitive to a ChE inhibitor. Nevertheless, the overall impact on heart physiology was subtle, showing mainly a role in cholinergic antagonism to the positive inotropic effect of β-adrenergic stimulation. Our results help to unravel the mechanisms of ChE in cardiovascular pathologies and provide a foundation to facilitate the design of a novel, more effective pharmacotherapies, which may reduce morbidity and mortality of patients with various heart diseases.

Abstract figure legend

Acetylcholinesterase (AChE) has the highest activity in the atria. It is present in the heart in molecular forms anchored by a proline-rich membrane anchor (PRiMA) and by collagen Q (ColQ) and hydrolyzes acetylcholine of neuronal origin (neuronal ACh). Butyrylcholinesterase (BChE) is predominant in the ventricles. It is secreted in the form of a soluble tetramer and hydrolyzes acetylcholine originating from cardiomyocytes (non-neuronal ACh).

Key points

Inhibition of cholinesterases has therapeutic potential in cardiovascular pathologies

Both known cholinesterases are present in heart

Each cholinesterase has distinct localization patterns in the heart and functions in cardiac physiology

Selective inhibition of acetylcholinesterase or butyrylcholinesterase may be used to alter specific cardiac functions

Butyrylcholinesterase polymorphism may have an impact on the outcome of the cholinesterase inhibitor treatment
Evaluating methods for B-cell clonal family assignment
Authors: Voss Katalin , Kaur Katrina M. , Banerjee Rituparna , Breden Felix , Pennell Matt
Published: June 2024

The adaptive immune response relies on a diverse repertoire of B-cell receptors, each of which is characterized by a distinct sequence resulting from VDJ-recombination. Upon binding to an antigen, B-cells undergo clonal expansion and in a process unique to B-cells the overall binding affinity of the repertoire is further enhanced by somatic hypermutations in the receptor sequence. For B-cell repertoires it is therefore particularly important to analyze the dynamics of clonal expansion and patterns of somatic hypermutations and thus it is necessary to group the sequences into distinct clones to determine the number and identity of expanding clonal families responding to an antigen. Multiple methods are currently used to identify clones from sequences, employing distinct approaches to the problem. Until now there has not been an extensive comparison of how well these methods perform under the same conditions. Furthermore, since this is fundamentally a phylogenetics problem, we speculated that the mPTP method, which delimits species based on an analysis of changes in the underlying process of diversification, might perform as well as or better than existing methods. Here we conducted extensive simulations of B-cell repertoires under a diverse set of conditions and studied errors in clonal assignment and in downstream ancestral state reconstruction. We demonstrated that SCOPer-H consistently yielded superior results across parameters. However, this approach relies on a good reference assembly for the germline immunoglobulin genes which is lacking for many species. Using mPTP had lower error rates than tailor-made immunogenetic methods and should therefore be considered by researchers studying antibody evolution in non-model organisms without a reference genome.
Proteomic analysis reveals dysregulation of peripheral blood neutrophils in patients with Multiple Sclerosis
Authors: Smith Katie J , Lim Zachary , Vermeren Sonja , Miron Veronique E. , Dimeloe Sarah , Davidson Donald J , Williams Anna , Findlay Emily Gwyer
Published: June 2024

Multiple Sclerosis (MS) is a complex auto-inflammatory disease affecting the brain and spinal cord, which results in axonal de-myelination and symptoms including fatigue, pain, and difficulties with vision and mobility. The involvement of the immune system in the pathology of MS is well established, particularly the adaptive T cell response, and there has been a particular focus on the IL-17-producing subset of Th17 cells and their role in driving disease. However, the importance of innate immune cells has not been so well characterised. Here we focused on neutrophils, which are innate immune cells and rapid responders to inflammation, and which have recently been linked to other chronic autoimmune conditions. Multiple strands of evidence in patients with MS and in mice with the experimental autoimmune encephalomyelitis MS model suggest neutrophils may play a role in driving MS inflammation. Here, we performed proteomic analysis on neutrophils from patients with MS and healthy donors, revealing striking differences. In particular, granule proteins were significantly more abundant in the MS neutrophils compared to the healthy controls, with a particular over-abundance of proteins in primary and secondary granules. In addition, members of the MAVS signalling pathway were differently regulated compared to healthy donor cells. Finally, we find that MS neutrophils do not suppress T cell activation equivalently to healthy neutrophils, and in particular are unable to suppress expression of CD161 on the T cells, indicative of Th17 differentiation. We propose that neutrophil dysregulation in MS may contribute to dysfunctional T cell responses.
Assessing the Sustainability of Pacific Walrus Harvest in a Changing Environment
Authors: Johnson Devin L. , Eisaguirre Joseph M. , Taylor Rebecca L. , Andersen Erik M. , Garlich-Miller Joel L.
Published: June 2024

Harvest sustainability is a primary goal of wildlife management and conservation, and in a changing world it is increasingly important to consider environmental drivers of population dynamics alongside harvest in cohesive management plans. This is particularly pertinent for harvested species that are acutely experiencing effects of climate change. The Pacific walrus (Odobenus rosmarus divergens), a critical traditional subsistence resource for indigenous communities, is simultaneously subject to rapid habitat loss associated with diminishing sea ice and an increasing anthropogenic footprint in the Arctic. We developed a theta-logistic population modeling-management framework to evaluate various harvest scenarios combined with four potential climate/disturbance scenarios (ranging from optimistic–pessimistic) which simulates Pacific walrus population dynamics to the end of the 21stcentury. We considered two types of harvest strategies: (1) adaptive harvest scenarios wherein harvest is calculated as a percentage of the population and annual harvests are updated at set intervals as the population is reassessed, and (2) non-adaptive harvest scenarios wherein annual harvest remains constant. All climate/disturbance scenarios indicated declines of varying severity in Pacific walrus abundance to the end of the 21stcentury, even in the absence of harvest. However, we found that an adaptive annual harvest of 1.23% of the independent-aged female subset of the population (e.g., 1,280 independent-aged females harvested in 2020, representing contemporary harvest levels) met our criterion for sustainability (>70% probability of maintaining population abundance above maximum net productivity level) under all climate/disturbance scenarios, accepting a medium risk tolerance level of 25%. This suggests that the present rate of Pacific walrus harvest is sustainable and will continue to be—provided the harvest adapts to match changes in population dynamics. Our simulations suggest that a sustainable non-adaptive harvest is also possible, but only at low levels if the population declines as expected. Applying a constant annual harvest of 1,280 independent-aged females (equivalent to contemporary harvest levels of 1.23) exceeded our criterion for sustainability and resulted in a >5% chance of quasi-extinction by the end of the 21stcentury under three of the four climate/disturbance scenarios we evaluated. Our results highlight the importance of adaptive co-management strategies, and we suggest such modeling frameworks are useful for managing for harvest sustainability in a changing climate.
Rapid Changes in Chromosome Counts in Fishes from the Spiral Egg Clade within the Gourami Family (Osphronemidae)
Authors: Mobley Brendan , Anderson Andrew P.
Published: June 2024

Identifying clades with numerous and noticeable changes in chromosome counts is an important step in unraveling the evolutionary mechanisms that shape cytogenetic processes. Here, we describe low chromosome counts in a group of teleost fishes delimited by their unique spiral egg structure and with a species with a known low chromosome count within the labyrinthine clade (Osphronemidae). We sampled seven of nine known species within this spiral egg clade, reporting novel chromosome counts for five species and confirming two others. Overall, we find high variability in both chromosome count and arm number, which suggests a rapid loss of chromosomes during the emergence of the clade and numerous large-scale mutations occurring across evolutionary time. Lastly, we offer some possible explanations for these changes based on current and ongoing empirical and theoretical research. These data provide important information in cataloguing rapid chromosomal shifts in teleost fishes and highlights this group for further study in chromosomal and genomic evolution due to their karyotypic heterogeneity.
Chromatin Capture Upsampling Toolbox - CCUT: A Versatile and unified Framework to Train Your Chromatin Capture Deep Learning Models
Authors: Sys Stanislav , Ceron-Noriega Alejandro , Kerber Anne , Weißbach Stephan , Schweiger Susann , Wand Michael , Everschor-Sitte Karin , Gerber Susanne
Published: June 2024

Chromatin Capture Experiments such as Hi-C and Micro-C have become popular methods for genome architecture exploration. Recently, also a protocol for long read sequencing, Pore-C, was introduced, allowing the characterization of three-dimensional chromatin structures using Oxford Nanopore Sequencing Technology. Here, we present a framework that focuses on the efficient reconstruction of low-resolution Pore-C data but can also process all other 3C data, such as Hi-C and Micro-C matrices, using models that can be trained on a consumer GPU. Furthermore, we integrate building blocks of popular super-resolution methods such as SWIN-Transformer or residual-in-residual-blocks to modify or build customized networks on the fly. Pre-built models were trained and evaluated on multiple publicly available gold-standard Micro-C and Pore-C datasets, allowing for fine-scale structure prediction. Our work aims to overcome the drawback of high sequencing costs to construct high resolution contact matrices, as well as the problem of mapping low-coverage libraries to high-resolution structures in the genome. Although there have been major breakthroughs regarding NGS-based methods for the reconstruction of high-resolution chromatin interaction matrices from low-resolution data, for data obtained by long-read sequencing, there is currently no solution to reconstruct missing and sparse information and to improve the quality.

Availability

The tool is available at (https://github.com/stasys-hub/CCUT)
Brain implantation of tissue-level-soft bioelectronics via embryonic development
Authors: Sheng Hao , Liu Ren , Li Qiang , Lin Zuwan , He Yichun , Blum Thomas S. , Zhao Hao , Tang Xin , Wang Wenbo , Jin Lishuai , Wang Zheliang , Hsiao Emma , Le Floch Paul , Shen Hao , Lee Ariel J. , Jonas-Closs Rachael Alice , Briggs James , Liu Siyi , Solomon Daniel , Wang Xiao , Lu Nanshu , Liu Jia
Published: June 2024

The design of bioelectronics capable of stably tracking brain-wide, single-cell, and millisecond-resolved neural activities in the developing brain is critical to the study of neuroscience and neurodevelopmental disorders. During development, the three-dimensional (3D) structure of the vertebrate brain arises from a 2D neural plate1,2. These large morphological changes previously posed a challenge for implantable bioelectronics to track neural activity throughout brain development3–9. Here, we present a tissue-level-soft, sub-micrometer-thick, stretchable mesh microelectrode array capable of integrating into the embryonic neural plate of vertebrates by leveraging the 2D-to-3D reconfiguration process of the tissue itself. Driven by the expansion and folding processes of organogenesis, the stretchable mesh electrode array deforms, stretches, and distributes throughout the entire brain, fully integrating into the 3D tissue structure. Immunostaining, gene expression analysis, and behavioral testing show no discernible impact on brain development or function. The embedded electrode array enables long-term, stable, brain-wide, single-unit-single-spike-resolved electrical mapping throughout brain development, illustrating how neural electrical activities and population dynamics emerge and evolve during brain development.
Electromigration of Charged Analytes Through Immiscible Fluids in Multiphasic Electrophoresis
Authors: Islam Md Nazibul , Liu Yang , Herr Amy E
Published: June 2024

Multiphasic buffer systems have been of greatest interest in electrophoresis and liquid-liquid electrotransfer; this study extends that foundation by exploring the interplay of the geometric and viscous properties of an interleaving oil layer on the electrotransfer of a charged analyte from an aqueous solution into a hydrogel. We utilized finite element analysis to examine two complementary configurations: one being electrotransfer of a charged analyte (protein) in an aqueous phase into a surrounding hydrogel layer and another being electrotransfer of the protein from that originating aqueous phase – through an interleaving oil layer of predetermined viscosity and thickness – and into a surrounding hydrogel layer. Results indicate that the presence of an oil layer leads to increased skew of the injected peak. To explain this difference in injection dispersion, we utilize Probstein’s framework and compare the Péclet (Pe) number with the ratio between length scales characteristic to the axial and radial dispersion, respectively. The formulation assigns electrotransfer conditions into six different dispersion regimes. We show that the presence or absence of an interleaving oil layer moves the observed peak dispersion into distinct electrotransfer regimes; the presence of an oil layer augments the electrophoretic mobility mismatch between the different phases, resulting in a five-fold increase in Pe and a six-fold increase in the ratio between the axial to radial dispersion characteristic lengths. We further show that oil viscosity significantly influences resultant injection dispersion. A decrease in oil-layer viscosity from 0.08 Pa·s to 0.02 Pa·s results in a >100% decrease in injection dispersion. Our theoretical predictions were experimentally validated by comparing the electrotransfer regimes of three different mineral oil samples. We show that lowering the oil viscosity to 0.0039 Pa·s results in an injection regime similar to that of the absence of an oil layer. Additionally, we measure the migration distance and show that average electromigration velocity over the transit duration is inversely proportional to the viscosity of an interleaving oil layer. Understanding of the impact of electrotransfer of charged species across multiple immiscible fluid layers on peak dispersion informs the design of multiphasic electrophoresis systems.
The association between street construction projects and community violence in New York City
Authors: Bushover Brady , Kim Andrew , Mehranbod Christina A. , Roberts Leah E. , Gobaud Ariana N. , Eschliman Evan L. , Fish Carolyn , Gao Xiang , Zadey Siddhesh , Morrison Christopher N.
Published: June 2024

Introduction

Community violence is a major cause of injury and death in the United States. Empirical studies have identified that some place-based interventions of urban private places, such as remediations of vacant lots and buildings, are associated with reductions in community violence in surrounding areas. The aim of this study was to examine whether routine maintenance and repair of urban public places (e.g., street construction projects) are also associated with reductions in community violence, proxied by violent crime.

Method

This staggered adoption difference-in-difference analysis investigated the association between street construction projects and community violence in New York City from 2010-2019, divided into 40 calendar quarters. The units of analysis were street-quarters (n = 155,280). Intervention street-quarters were those with completed projects in 2010-2019; control streets were those where projects were scheduled but not completed before 2019. The outcome of community violence was proxied by counts of crime and violence incidents reported to the New York Police Department, within street-quarters.

Results

There were 79,592 street-quarters with any community violence incidents (51.2%). We found that street construction projects were associated with a decrease in reckless endangerment (ATT = -0.013; 95% CI = -0.021, -0.004), robbery (ATT = -0.035; 95% CI = -0.063, -0.007), and weapons offenses (ATT = -0.016; 95% CI = -0.031, -0.001) occurring on street-quarters.

Conclusion

Street construction projects may be yet another type of place-based intervention to reduce community violence.
The Interplay of Prior Information and Motion Cues in Resolving Visual Ambiguity in Agent Perception
Authors: Er Sena , Elmas Hüseyin O. , Urgen Burcu A.
Published: June 2024

Agent perception is essential for social interaction, allowing individuals to interpret and respond to the actions of others within dynamic environments. In this study, we examined on how prior knowledge and motion cues are integrated to influence the temporal dynamics of perceiving agents. In order to make realistic but ambiguous stimuli in motion and form characteristics, we used human, robot, and android agents. Using temporal representational similarity analysis (RSA) on EEG recordings, we analyzed the representation of agent identities under varying conditions—Still versus Moving stimuli and Prior versus Naive contexts. Our findings revealed that prior knowledge and motion cues interact to produce distinct temporal patterns of representation. In the naive condition, information about the agent persisted longer during still presentations than during moving ones, suggesting that the processing of agents depends on the availability of motion information and prior information. Moreover, motion information affects the temporal processing of agents when no prior information about agents is available. These results highlight the critical roles of both bottom-up sensory inputs and top-down expectations and their interactions in resolving the ambiguities inherent in agent perception.
ProtEx: A Retrieval-Augmented Approach for Protein Function Prediction
Authors: Shaw Peter , Gurram Bhaskar , Belanger David , Gane Andreea , Bileschi Maxwell L. , Colwell Lucy J. , Toutanova Kristina , Parikh Ankur P.
Published: June 2024

Mapping a protein sequence to its underlying biological function is a critical problem of increasing importance in biology. In this work, we propose ProtEx, a retrieval-augmented approach for protein function prediction that leverages exemplars from a database to improve accuracy and robustness and enable generalization to unseen classes. Our approach relies on a novel multi-sequence pretraining task, and a fine-tuning strategy that effectively conditions predictions on retrieved exemplars. Our method achieves state-of-the-art results across multiple datasets and settings for predicting Enzyme Commission (EC) numbers, Gene Ontology (GO) terms, and Pfam families. Our ablations and analysis highlight the impact of conditioning predictions on exemplar sequences, especially for classes and sequences less well represented in the training data.
A diverse and distinct microbiome inside living trees
Authors: Arnold Wyatt , Gewirtzman Jonathan , Raymond Peter A. , Duguid Marlyse , Brodersen Craig , Brown Cade , Norbraten Naomi , Wood Qespi T’ika Vizcarra , Bradford Mark A. , Peccia Jordan
Published: June 2024

Despite significant advances in microbiome research across various environments1, the microbiome of Earth’s largest biomass reservoir– the wood of living trees2– remains largely unexplored. This oversight neglects a critical aspect of global biodiversity and potentially key players in tree health and forest ecosystem functions. Here we illuminate the microbiome inhabiting and adapted to wood, and further specialized to individual host species. We demonstrate that a single tree can host approximately a trillion microbes in its aboveground internal tissues, with microbial communities partitioned between heartwood and sapwood, each maintaining a distinct microbiome with minimal similarity to other plant tissues or nearby ecosystem components. Notably, the heartwood microbiome emerges as a unique ecological niche, distinguished in part by endemic archaea and anaerobic bacteria that drive consequential biogeochemical processes. Our research supports the emerging idea of a plant as a “holobiont”3,4—a single ecological unit comprising host and associated microorganisms—and parallels human microbiome research in its implications for host health, disease, and functionality5. By mapping the structure, composition, and potential sources and functions of the tree internal microbiome, our findings pave the way for novel insights into tree physiology and forest ecology, and establish a new frontier in environmental microbiology.
Dimensionality Reduction and Denoising of Spatial Transcriptomics Data Using Dual-Channel Masked Graph Autoencoder
Authors: Min Wenwen , Fang Donghai , Chen Jinyu , Zhang Shihua
Published: June 2024

Recent advances in spatial transcriptomics (ST) technology allow researchers to comprehensively measure gene expression patterns at the level of individual cells or even subcellular compartments while preserving the spatial context of their tissue. Spatial domain identification is a critical task in analyzing the ST data. However, effectively capturing distinctive gene expression features and relationships between genes poses a significant challenge. We develop a graph self-supervised learning method STMask for the analysis and exploration of the ST data. STMask combines the masking mechanism with a graph autoencoder, compelling the gene representation learning channel to acquire more expressive representations. Simultaneously, it combines the masking mechanism with graph self-supervised contrastive learning methods, pulling together the embedding distances between spatially adjacent points and pushing apart the representations of different clusters, allowing the gene relationship learning channel to learn more comprehensive relationships. The applications of STMask to four ST datasets demonstrate that STMask outperforms state-of-the-art methods in various tasks, including spatial clustering and trajectory inference. Source code is available athttps://github.com/donghaifang/STMask.

Author summary

Spatial Transcriptomics (ST) is an emerging transcriptomic sequencing technology aimed at revealing the spatial distribution of gene expression and cell types within tissues. This method enables the acquisition of gene expression profiles at the level of individual cells or spots within the tissue, uncovering the spatial expression patterns of genes. However, accurately identifying spatial domains in ST data remains challenging. In our study, we introduce STMask, a self-supervised learning method that combines a dual-channel masked graph autoencoder with masking and contrastive learning. Our work contributes primarily in two aspects: (1) We propose a novel graph self-supervised learning method (STMask) specifically tailored for the analysis and research of ST data, which enhances the ability to capture the unique features of gene expression and spatial relationships within tissues. (2) Through comprehensive experiments, STMask provides valuable insights into biological processes, particularly in the context of breast cancer. It identifies enrichment of various differentially expressed genes in tumor regions, such asIGHG1, which can serve as effective targets for cancer therapy.
Cell expansion-division under resource limitation: a novel framework for modeling fruit growth dynamics
Authors: Miele Leonardo , Roques Lionel , Constantinescu Dario , Génard Michel , Bertin Nadia
Published: June 2024

Fruit growth is determined by cell expansion and division, processes that are closely linked to the availability and allocation of resources. By influencing environmental and growing conditions, agricultural practices affect these processes and ultimately many key indicators of fruit quality and yield. Given the multifaceted complexity underlying fruit growth dynamics, a process-based framework that can link genetic and environmental inputs to observables of economic and nutritional interest has become essential for predicting and improving agricultural outcomes. Here we present a mathematical framework that integrates cellular dynamics with resource allocation mechanisms to model the interplay between division, expansion and resource limitation in fruit cells. The model captures the temporal evolution of total fruit mass, cell number and cell mass distribution, reflecting data across genotypes and environmental conditions from tomato growth experiments. This sheds light on the possible relationships between genetic traits, growth conditions and fruit traits, and provides a predictive tool for optimizing fruit yield and quality under agricultural practices. Our minimal but mechanistic approach has broader implications for understanding resource-limited growth in multicellular systems.
Improving Olfactory Receptor Structure Modeling via Hybrid Methods
Authors: Berwal Bhavika , Saha Pinaki , Kumar Ritesh
Published: June 2024

Understanding the structure of Olfactory Receptors (ORs) is pivotal in deciphering the molecular complexities of smell, a sense crucial for health, and survival, and holding immense therapeutic potential. However, the scarcity of detailed experimental data on ORs has hindered progress, demanding inventive approaches.

This study explores various structure prediction methods tailored to ORs based on their phylogenetic and structural characteristics, using OR51E2 as a reference. We employed a hybrid homology modeling approach, utilizing AlphaFold structures, yielding models with lower RMSD (1.019°A across pruned/significant pairs and 2.33°A over-all) and enhanced structural metrics compared to standalone AlphaFold (RMSD - 2.5°A) predictions. Our pipeline successfully replicated experimental findings for OR51E2 and was applied to homologous ORs: OR51E1, OR51D1, and OR51G2. Various tools were also used to predict potential binding sites for each receptor. Molecular dynamics simulations validated the stability of these OR models in a lipid bilayer environment, with biophysical analyses revealing that AlphaFold models exhibit relatively less ideal behavior compared to the Hybrid Model. Our study presents a targeted approach to investigate and generate optimum OR structures for further conformational analyses.
b-move: faster bidirectional character extensions in a run-length compressed index
Authors: Depuydt Lore , Renders Luca , Van de Vyver Simon , Veys Lennart , Gagie Travis , Fostier Jan
Published: June 2024

Due to the increasing availability of high-quality genome sequences, pan-genomes are gradually replacing single consensus reference genomes in many bioinformatics pipelines to better capture genetic diversity. Traditional bioinformatics tools using the FM-index face memory limitations with such large genome collections. Recent advancements in run-length compressed indices like Gagie et al.’s r-index and Nishimoto and Tabei’s move structure, alleviate memory constraints but focus primarily on backward search for MEM-finding. Arakawa et al.’s br-index initiates complete approximate pattern matching using bidirectional search in run-length compressed space, but with significant computational overhead due to complex memory access patterns. We introduce b-move, a novel bidirectional extension of the move structure, enabling fast, cache-efficient bidirectional character extensions in run-length compressed space. It achieves bidirectional character extensions up to 8 times faster than the br-index, closing the performance gap with FM-index-based alternatives, while maintaining the br-index’s favorable memory characteristics. For example, all available completeE. coligenomes on NCBI’s RefSeq collection can be compiled into a b-move index that fits into the RAM of a typical laptop. Thus, b-move proves practical and scalable for pan-genome indexing and querying. We provide a C++ implementation of b-move, supporting efficient lossless approximate pattern matching including locate functionality, available athttps://github.com/biointec/b-moveunder the AGPL-3.0 license.

Funding

Lore Depuydt: PhD Fellowship FR (1117322N), Research Foundation – Flanders (FWO)

Luca Renders: PhD Fellowship SB (1SE7822N), Research Foundation – Flanders (FWO)

Travis Gagie: NSERC Discovery Grant RGPIN-07185-2020 to Travis Gagie and NIH grant R01HG011392 to Ben Langmead
Cycling Cadence Selections at Different Saddle Heights Minimize Muscle Activation Rather Than Energy Cost
Authors: Riveros-Matthey Cristian D. , Connick Mark J. , Lichtwark Glen A. , Carroll Timothy J.
Published: June 2024

Unlike walking and running, people do not consistently choose cadences that minimize energy consumption when cycling. Assuming a common objective function for all forms of locomotion, this suggests either that the neural control system relies on indirect sensorimotor cues to energetic cost that are approximately accurate during walking but not cycling, or that an alternative objective function applies that correlates with energy expenditure in walking but not cycling. This study compared how objective functions derived as proxies to 1) energy cost or 2) an avoidance of muscle fatigue predicted self-selected cycling cadences (SSC) at different saddle heights. Saddle height systematically affected SSC, with lower saddles increasing SSC and higher saddles decreasing SSC. Both fatigue-avoidance and energy-expenditure cost functions derived from muscle activation measurements showed minima that closely approximated the SSCs. By contrast, metabolic power derived fromVO2uptake was minimal at cadences well below the SSC across all saddle height variations. The mismatch between the cadence versus muscle activation and the cadence versus metabolic energy relations is likely due to additional energy costs associated with performing mechanical work at higher cadences. The results suggest that the nervous system places greater emphasis on muscle activation than on energy consumption for action selections in cycling.
Bacterial growth dynamics on a surface having a particulate antimicrobial agent
Authors: Talebpour Cyrus , Fani Fereshteh , Salimnia Hossein , Ouellette Marc , Alamdari Houshang
Published: June 2024

The morphological dynamics of microbial cell proliferation on an antimicrobial surface at an early growth stage was studied withEscherichia colion the surface of a gel supplied with nanostructured AgNbO3antimicrobial particles. We demonstrated an inhibitory surface concentration, analogous to minimum inhibitory concentration, beyond which the growth of colonies and formation of biofilm are inhibited. In contrast, at lower concentrations, colonies circumvent the antimicrobial activity of the particles and grow with a short lag time of a few hours. The applicability of these findings, in terms of estimating inhibitory surface concentration, was tested in the case of antimicrobial polymethyl methacrylate (PMMA) bone cement.
Lysophosphatidylcholine acyltransferase 1 suppresses nanoclustering and function of KRAS
Authors: Arora Neha , Liang Hong , Yao Wantong , Ying Haoqiang , Liu Junchen , Zhou Yong
Published: June 2024

KRAS is frequently mutated in cancer, contributing to 20% of all human cancer especially pancreatic, colorectal and lung cancer. Signaling of the constitutively active KRAS oncogenic mutants is mostly compartmentalized to proteolipid nanoclusters on the plasma membrane (PM). Signaling nanoclusters of many KRAS mutants selectively enrich phosphatidylserine (PS) lipids with unsaturatedsn-2acyl chains, but not the fully saturated PS species. Thus, remodeling PS acyl chains may suppress KRAS oncogenesis. Lysophosphatidylcholine acyltransferases (LPCATs) remodelsn-2acyl chains of phospholipids, with LPCAT1 preferentially generating the fully saturated lipids. Here, we show that stable expression of LPCAT1 depletes major PS species with unsaturated sn-2 chains while decreasing minor phosphatidylcholine (PC) species with the corresponding acyl chains. LPCAT1 expression more effectively disrupts the nanoclustering of oncogenic GFP-KRASG12V, which is restored by acute addback of exogenous unsaturated PS. LPCAT1 expression compromises signaling and oncogenic activities of the KRAS-dependent pancreatic tumor lines. LPCAT1 expression sensitizes human pancreatic tumor MiaPaCa-2 cells to KRASG12Cspecific inhibitor, Sotorasib. Statistical analyses of patient data further reveal that pancreatic cancer patients with KRAS mutations express less LPCAT1. Higher LPCAT1 expression also improves survival probability of pancreatic and lung adenocarcinoma patients with KRAS mutations. Thus, PS acyl chain remodeling selectively suppresses KRAS oncogenesis.
Lipid loss and compositional change during preparation of liposomes by common biophysical methods
Authors: Kim Eunice , Graceffa Olivia , Broweleit Rachel , Ladha Ali , Boies Andrew , Rawle Robert J.
Published: June 2024

Liposomes are widely used as model lipid membrane platforms in many fields, ranging from basic biophysical studies to drug delivery and biotechnology applications. Various methods exist to prepare liposomes, but common procedures include thin-film hydration followed by extrusion, freeze-thaw, and/or sonication. These procedures have the potential to produce liposomes at specific concentrations and membrane compositions, and researchers often assume that the concentration and composition of their liposomes are similar to, if not identical, to what would be expected if no lipid loss occurred during preparation. However, lipid loss and concomitant biasing of lipid composition can in principle occur at any preparation step due to nonideal mixing, lipid-surface interactions, etc. Here, we report a straightforward method using HPLC-ELSD to quantify the lipid concentration and membrane composition of liposomes, and apply that method to study the preparation of simple POPC/cholesterol liposomes. We examine many common steps in liposome formation, including vortexing during re-suspension, hydration of the lipid film, extrusion, freeze-thaw, sonication, and the percentage of cholesterol in the starting mixture. We found that the resuspension step can play an outsized role in determining the overall lipid loss (up to ∼50% under seemingly rigorous procedures). The extrusion step yielded smaller lipid losses (∼10-20%). Freeze-thaw and sonication could both be employed to improve lipid yields. Hydration times up to 60 minutes and increasing cholesterol concentrations up to 50 mole% had little influence on lipid recovery. Fortunately, even conditions with large lipid loss did not substantially influence the target membrane composition more than ∼5% under the conditions we tested. From our results, we identify best practices for producing maximum levels of lipid recovery and minimal changes to lipid composition during liposome preparation protocols. We expect our results can be leveraged for improved preparation of model membranes by researchers in many fields.

Statement of Significance

Liposomes are spherical lipid membranes that can be prepared by a variety of biophysical techniques. Researchers use liposomes in a variety of ways, including fundamental biophysical studies of lipid membranes, in drug delivery, drug formulation, and other biotechnology applications. In this report, we study the process to prepare liposomes by several common techniques and validate how reliable each technique is at producing consistent liposome concentrations and lipid compositions. We identify best practices for researchers to produce reliable liposome preparations.
Cryo-EM and Solid State NMR Together Provide a More Comprehensive Structural Investigation of Protein Fibrils
Authors: Fonda Blake D. , Kato Masato , Li Yang , Murray Dylan T.
Published: June 2024

The Tropomyosin 1 isoform I/C C-terminal domain (Tm1-LC) fibril structure is studied jointly with cryogenic electron microscopy (cryo-EM) and solid state nuclear magnetic resonance (NMR). This study demonstrates the complementary nature of these two structural biology techniques. Chemical shift assignments from solid state NMR are used to determine the secondary structure at the level of individual amino acids, which is faithfully seen in cryo-EM reconstructions. Additionally, solid state NMR demonstrates that the region not observed in the reconstructed cryo-EM density is primarily in a highly mobile random coil conformation rather than adopting multiple rigid conformations. Overall, this study illustrates the benefit of investigations combining cryo-EM and solid state NMR to investigate protein fibril structure.

Significance

The use of multiple techniques to structurally characterize proteins provides models that accurately describe molecular conformations better than a technique used in isolation. Combination approaches allow for the study of proteins not only as rigid objects, but rather dynamic molecules that “breathe” over time. Cryogenic electron microscopy and solid state nuclear magnetic resonance are used jointly to provide a more detailed model of the same protein fibrils, and each technique provides novel insights.
Revealing biomolecular structure and motion with neural ab initio cryo-EM reconstruction
Authors: Levy Axel , Grzadkowski Michal , Poitevin Frederic , Vallese Francesca , Clarke Oliver B , Wetzstein Gordon , Zhong Ellen D
Published: June 2024

Proteins and other biomolecules form dynamic macromolecular machines that are tightly orchestrated to move, bind, and perform chemistry. Cryo-electron microscopy (cryo-EM) can access the intrinsic heterogeneity of these complexes and is therefore a key tool for understanding mechanism and function. However, 3D reconstruction of the resulting imaging data presents a challenging computational problem, especially without any starting information, a setting termed ab initio reconstruction. Here, we introduce a method, DRGN-AI, for ab initio heterogeneous cryo-EM reconstruction. With a two-step hybrid approach combining search and gradient-based optimization, DRGN-AI can reconstruct dynamic protein complexes from scratch without input poses or initial models. Using DRGN-AI, we reconstruct the compositional and conformational variability contained in a variety of benchmark datasets, process an unfiltered dataset of the DSL1/SNARE complex fully ab initio, and reveal a new "supercomplex" state of the human erythrocyte ankyrin-1 complex. With this expressive and scalable model for structure determination, we hope to unlock the full potential of cryo-EM as a high-throughput tool for structural biology and discovery.
Global analysis of protein turnover dynamics in single cells
Authors: Sabatier Pierre , Ye Zilu , Lechner Maico , Guzmán Ulises H. , Beusch Christian M. , Izaguirre Fabiana , Seth Anjali , Gritsenko Olga , Rodin Sergey , Grinnemo Karl-Henrik , Olsen Jesper V.
Published: June 2024

Even with recent improvements in sample preparation and instrumentation, single-cell proteomics (SCP) analyses mostly measure protein abundances, making the field unidimensional. In this study, we employ a pulsed stable isotope labeling by amino acids in cell culture (SILAC) approach to simultaneously evaluate protein abundance and turnover in single cells (SC-pSILAC). Using state-of-the-art SCP workflow, we demonstrated that two SILAC labels are detectable from ∼4000 proteins in single HeLa cells recapitulating known biology. We investigated drug effects on global and specific protein turnover in single cells and performed a large-scale time-series SC-pSILAC analysis of undirected differentiation of human induced pluripotent stem cells (iPSC) encompassing six sampling times over two months and analyzed >1000 cells. Abundance measurements highlighted cell-specific markers of stem cells and various organ-specific cell types. Protein turnover dynamics highlighted differentiation-specific co-regulation of core members of protein complexes with core histone turnover discriminating dividing and non-dividing cells with potential in stem cell and cancer research. Our study represents the most comprehensive SCP analysis to date, offering new insights into cellular diversity and pioneering functional measurements beyond protein abundance. This method distinguishes SCP from other single-cell omics approaches and enhances its scientific relevance in biological research in a multidimensional manner.
Smart Wristband Monitoring: A Caregiver-Oriented Mobile Application for Tracking Cognitive Decline in Mild Cognitive Impairment Patients
Authors: Ceyhan Barış , Bek Semai , Önal-Süzek Tuğba
Published: June 2024

Mild Cognitive Impairment (MCI) is the transitional phase between the typical expected memory problems related to age and the more serious decline of dementia. Therefore, monitoring progress from MCI to dementia is critical to slowing down this cognitive deterioration. Research shows that proper nutrition, routine brain, and physical exercise accompanied by proper care slow down the disease significantly. However, most of the patients do not perform these exercises regularly and their vital health data is not monitored properly, leaving patients most of the time with only basic care.

In this study, for the first time to our knowledge, we aimed to develop a mobile application that will enable caregivers to continuously monitor the vital health, medication, activity, and location of the patients with MCI with a smart wristband while enabling them caregivers to track the progress of the disease by a machine learning model that tracks MMSE of the patient using speech. Based on our research so far, this caregiver-oriented approach with the ability to track progress of the disease using the convenience of a mobile application is a unique attempt in the field. Patient profile along with collected data is correlated with tracked MMSE scores of the patients to come up with recommendations and findings about the patients. Caregivers are relieved to be notified about critical health data thresholds, progress, and condition of their patients.
WITHDRAWN: ChatGPT-4 as a Board-Certified Surgeon: A Pilot Study
Authors: Roshal Joshua , Silvestri Caitlin , Sathe Tejas , Townsend Courtney , Klimberg V. Suzanne , Perez Alexander
Published: June 2024

Withdrawal Statement

The authors have withdrawn their manuscript to update the methodology. Therefore, the authors do not wish this work to be cited as a reference for the project. If you have any questions, please contact the corresponding author.