bluuebunny/crossref_metadata_2025_split huggingface dataset:
Using Dynamic Bayesian Optimization to Induce Desired Effects in the Presence of Motor Learning: a Simulation Study
Authors: Kim GilHwan , Chishty Haider A. , Sergi Fabrizio 
Published: August 2024

AbstractHuman-in-the-loop (HIL) optimization is a control paradigm used for tuning the control parameters of human-interacting devices while accounting for variability among individuals. A limitation of state-of-the-art HIL optimization algorithms such as Bayesian Optimization (BO) is that they assume that the relationship between control parameters and user response does not change over time. BO can be modified to account for the dynamics of the user response by implementing time into the kernel function, a method known as Dynamic Bayesian Optimization (DBO). However, it is unknown if DBO outperforms BO when the human response is characterized by models of human motor learning.In this work, we simulated runs of HIL optimization using BO and DBO towards establishing if DBO is a suitable paradigm for HIL optimization in the presence of motor learning. Simulations were conducted assuming either purely time-dependent participant responses, or assuming that responses would arise from state-space models of motor learning capable of describing both adaptation and use-dependent learning behavior.Statistical comparisons indicated that DBO was never inferior to BO, and, after a certain number of iterations, generally outperformed BO in convergence to optimal inputs and outputs. The number of iterations beyond which DBO was superior to BO occurred earlier when the input-output relationship of the simulated responses was more dynamic. Our results suggest that DBO may improve the performance of HIL optimization over BO when a sufficient number of iterations can be evaluated to accurately distinguish between unstructured variability (noise) and learning.
A Biologically Inspired Attention Model for Neural Signal Analysis
Authors: Skatchkovsky Nicolas , Glazman Natalia , Sadeh Sadra , Iacaruso Florencia 
Published: August 2024

AbstractUnderstanding how the brain represents sensory information and triggers behavioural responses is a fundamental goal in neuroscience. Recent advances in neuronal recording techniques aim to progress towards this milestone, yet the resulting high dimensional responses are challenging to interpret and link to relevant variables. In this work, we introduce SPARKS, a model capable of generating low dimensional latent representations of high dimensional neural recordings. SPARKS adapts theself-attentionmechanism of large language models to extract information from the timing of single spikes and the sequence in which neurons fire using Hebbian learning. Trained with a criterion inspired by predictive coding to enforce temporal coherence, our model produces interpretable embeddings that are robust across animals and sessions. Behavioural recordings can be used to inform the latent representations of the neural data, and we demonstrate state-of-the-art predictive capabilities across diverse electrophysiology and calcium imaging datasets from the motor, visual and entorhinal cortices. We also show how SPARKS can be applied to large neuronal networks by revealing the temporal evolution of visual information encoding across the hierarchy of the visual cortex. Overall, by integrating biological mechanisms into a machine learning model, we provide a powerful tool to study large-scale network dynamics. SPARKS’ capacity to generalize across animals and behavioural states suggests it is capable of estimating the internal latent generative model of the world in animals, paving the way towards a foundation model for neuroscience.
Exacerbation of influenza virus induced lung injury by alveolar macrophages and its suppression by pyroptosis blockade in a human lung alveolus chip
Authors: Man Yuncheng , Zhai Yunhao , Jiang Amanda , Bai Haiqing , Gulati Aakanksha , Plebani Roberto , Mannix Robert J. , Merry Gwenn E. , Goyal Girija , Belgur Chaitra , Hall Sean R. R. , Ingber Donald E. 
Published: August 2024

AbstractAlveolar macrophages (AMs) are the major sentinel immune cells in human alveoli and play a central role in eliciting host inflammatory responses upon distal lung viral infection. Here, we incorporated peripheral human monocyte-derived macrophages within a microfluidic human Lung Alveolus Chip that recreates the human alveolar-capillary interface under an air-liquid interface along with vascular flow to study how residential AMs contribute to the human pulmonary response to viral infection. When Lung Alveolus Chips that were cultured with macrophages were infected with influenza H3N2, there was a major reduction in viral titers compared to chips without macrophages; however, there was significantly greater inflammation and tissue injury. Pro-inflammatory cytokine levels, recruitment of immune cells circulating through the vascular channel, and expression of genes involved in myelocyte activation were all increased, and this was accompanied by reduced epithelial and endothelial cell viability and compromise of the alveolar tissue barrier. These effects were partially mediated through activation of pyroptosis in macrophages and release of pro-inflammatory mediators, such as interleukin (IL)-1β, and blocking pyroptosisviacaspase-1 inhibition suppressed lung inflammation and injury on-chip. These findings demonstrate how integrating tissue resident immune cells within human Lung Alveolus Chip can identify potential new therapeutic targets and uncover cell and molecular mechanisms that contribute to the development of viral pneumonia and acute respiratory distress syndrome (ARDS).
Low concentrations of the food contaminant Deoxynivalenol trigger apoptosis and impair GnRH-induced LH secretion in pituitary gonadotrope-like cells
Authors: Cai Guodong , Yang Lingchen , Marien-Bourgeois Francis , Boerboom Derek , Zamberlam Gustavo , Alassane-Kpembi Imourana 
Published: August 2024

AbstractTheFusariummycotoxin deoxynivalenol (DON) is one of the most frequently occurring food contaminants. Nearly all individuals are exposed to DON, due to it widespread presence in grains and grain-based products. Chronic DON poisoning is associated with growth retardation, immunotoxicity as well as impaired reproduction and fetal development. At the molecular level, DON alters intracellular signaling by activating mitogen-activated protein kinases (MAPKs) that modulate cell growth, differentiation, and apoptosis. Of note, these MAPKs are also critical mediators of gonadotrophin-releasing hormone (GnRH)-induced synthesis and secretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) by pituitary gonadotrope cells. So far, no research has explored the potential endocrine-disrupting effects of DON on pituitary gonadotropins production. Herein, we show the first evidence that DON affects LH production by the immortalized gonadotrope-like cell line LβT2 in a concentration-dependent manner. Taken together, our experiments demonstrated that low concentrations of DON affect GnRH-induced signaling through a mechanism that, at least in part, involves apoptosis and inhibition of GnRH-induced phosphorylation of ERK-MAPK. Consequently, DON also affects the GnRH-induced expression ofCgaandLhb, two critical genes for LH synthesis and secretion by gonadotrope cells in mammals. This research broadens our knowledge of the toxicity of DON and brings a new depth to the potential neuroendocrine implications for reproduction.Graphical abstract
Improving the accuracy of cerebral blood flow measurement by phase contrast MRI
Authors: Yang Xiuli 
Published: August 2024

AbstractCerebral blood flow (CBF) is a critical hemodynamic marker for natural aging and pathological conditions. It can be assessed non-invasively by the phase-contrast (PC) magnetic resonance imaging (MRI) technique. Although the technical principle of PC MRI is straightforward, related experimental settings, e.g., spatial resolution, partial volume effect, slice positioning angle, and signal-to-noise ratio (SNR), require deliberate considerations to ensure measurement accuracy. In this study, we performed simulations to systematically investigate the dependence of measurement accuracy of PC MRI on the spatial resolution, extent of partial volume effect, slice imperfection angle, and SNR. It has been found that at least 6 voxels along the vessel diameter are required to ensure accurate CBF measurements. Partial volume effect acts to underestimate CBF measurements. The tolerance against slice imperfection angle is ≤15 degree for the commonly seen artery in mice under isoflurane anesthesia. A normalized SNR of 25.47 dB is required to ensure the accuracy of CBF measurement. Our study will promote the utilization of CBF as a pathophysiological marker for future studies by delineating the factors affecting measurement accuracy in PC MRI.
ComBat-met: Adjusting Batch Effects in DNA Methylation Data
Authors: Wang Junmin 
Published: August 2024

AbstractIntegration of genomics data is routinely hindered by unwanted technical variations known as batch effects. Despite wide availability, existing batch correction methods often fall short in capturing the unique characteristics of DNA methylation data. We present ComBat-met, a beta regression framework to adjust batch effects in DNA methylation studies. Our method fits beta regression models to the data, calculates batch-free distributions, and maps the quantiles of the estimated distributions to their batch-free counterparts. Compared to traditional methods, ComBat-met followed by differential methylation analysis shows improved statistical power without compromising false positive rates based on simulated data. Additionally, we demonstrate the ability of ComBat-met to remove cross-batch variations and recover biological signals using data from The Cancer Genome Atlas.
Targeting Interferon-Driven Inflammatory Memory Prevents Epigenetic Evolution of Cancer Immunotherapy Resistance
Authors: Qiu Jingya , Ye Darwin , Chen Xinyi E. , Dangle Nathan , Yoshor Benjamin , Zhang Thomas , Shao Yue , Nallamala Vamshidhar C. , Wang Shangshang , Ren Diqiu , Xu Yuanming , Chen Jie , Zhang Nancy R. , Shi Junwei , Greenberg Roger A. , Minn Andy J. 
Published: August 2024

SUMMARYAcquired resistance is a growing obstacle to durable responses after cancer immune checkpoint blockade (ICB). The mechanisms by which heterogeneous tumors evolve under immunotherapy pressure and strategies targeting key populations to prevent relapse are poorly understood. We show that chronic interferon (IFN) enables a subpopulation of cancer cells to acquire inflammatory memory and express memory ISGs, a subset of IFN-stimulated genes enriched for immune evasion properties, leading to subclonal epigenetic evolution of ICB-resistant states. Inflammatory memory is epigenetically encoded through chronic virus mimicry – feedforward MDA5 signaling likely activated by endogenous retroelements. While JAK inhibitors can improve ICB response, combining them with TBK1 inhibitors collapses this feedforward mechanism, erasing inflammatory memory and preventing differentiation into resistance states. Across human cancers, small subpopulations of memory ISG-expressing cells are prevalent and coupled to T cell exhaustion, suggesting inflammatory memory may be a common mechanism of acquired resistance targetable by JAK plus TBK1 inhibition.
E-cigarette market share by nicotine claims
Authors: Ma Shaoying , Brinkman Marielle C. , Berman Micah , Wagener Theodore , Shang Ce 
Published: August 2024

AbstractBackgroundNicotine forms (salt vs. freebase) and isomers (synthetic vs. tobacco-derived) are key characteristics of e-cigarettes that manufacturers manipulate, and “tobacco-free” claims may have served to attract new consumers and increase their intention to use.MethodThis study presents a snapshot of nicotine marketing claims for e-cigarettes using Nielsen ScanTrack data from brick-and-mortar stores. Market share was calculated as the ratio of unit sales of each nicotine claim category to the total unit sales of e-cigarettes during the four weeks ending 1-20-2024.ResultsWe summarized the market share for the following six nicotine form/isomer category: 1) nicotine (77%), 2) nicotine salt (10%), 3) synthetic nicotine (2%), 4) zero tobacco or tobacco-free (2%), 5) zero nicotine or nicotine-free (0.03%), and 6) no claim or CBD/hemp/cannabis (9%).ConclusionThe market share of products that explicitly carried nicotine salt claims (10%) or synthetic nicotine or tobacco-free claims (2% each) was notable. This study informs regulatory authorities on the recent trend of nicotine claims marketed by the e-cigarette industry, which may be contributing to the use of these products or addiction to nicotine among young people and non-users.
PhyClone: Accurate Bayesian reconstruction of cancer phylogenies from bulk sequencing
Authors: Hurtado Emilia , Bouchard-Côté Alexandre , Roth Andrew 
Published: August 2024

AbstractMotivationCancer is driven by somatic mutations that result in the expansion of genomically distinct sub-populations of cells called clones. Identifying the clonal composition of tumours and understanding the evolutionary relationships between clones is a crucial task in cancer genomics. Bulk DNA sequencing is commonly used for studying the clonal composition of tumours, but it is challenging to infer the genetic relationship between different clones due to the mixture of different cell populations.ResultsIn this work, we introduce a new probabilistic model called PhyClone that can infer clonal phylogenies from bulk sequencing data. We demonstrate the performance of PhyClone on simulated and real-world datasets and show that it outperforms previous methods in terms of accuracy and scalability.Availability and implementationSource code is available on Github at:https://github.com/Roth-Lab/PhyCloneunder the GPL v3.0 license.Contactaroth@bccrc.ca
GENOMICON-Seq: A comprehensive tool for the simulation of mutations in amplicon and whole exome sequencing
Authors: Stosic Milan S. , Costanzi Jean-Marc , Ambur Ole Herman , Rounge Trine B. 
Published: August 2024

AbstractGENOMICON-Seq is a comprehensive genomic sequencing simulation tool that enables the assessment of laboratory and bioinformatics parameters influencing the detection of mutations. The tool generates genomes with mutations, mimicking processes such as low-frequency mutations, APOBEC3 activity in viruses, somatic mutations and single base substitution (SBS) mutational signals. GENOMICON-Seq adds amplicon and whole exome sequencing biases and errors. It outputs sequencing reads compatible with mutation detection tools and a report on mutation origin (generated mutations and PCR errors), nucleotide context, and position. GENOMICON-Seq aids in the evaluation of bioinformatics tools and experimental designs, reducing the need for costly real-world sequencing experiments.
The transcription factor TCF21 is necessary for adoption of cell fates by Foxd1+ stromal progenitors during kidney development
Authors: Finer Gal , Khan Mohammad D. , Zhou Yalu , Gadhvi Gaurav , Yacu George S. , Park Joo-Seop , Gomez R. Ariel , Sequeira-Lopez Maria Luisa S. , Quaggin Susan E. , Winter Deborah R. 
Published: August 2024

ABSTRACTNormal kidney development requires the coordinated interactions between multiple progenitor cell lineages. Among these, Foxd1+ stromal progenitors are essential for nephrogenesis, giving rise to diverse cell types including the renal stroma, capsule, mesangial cells, renin cells, pericytes, and vascular smooth muscle cells (VSMCs). However, the molecular mechanisms governing their differentiation remain poorly understood. This study investigates the role of Tcf21, a mesoderm-specific bHLH transcription factor, in Foxd1+ cell fate determination.Using single-cell RNA sequencing (scRNA-seq), we analyzed 32,461 GFP+ cells from embryonic day 14.5 (E14.5)Foxd1Cre/+;Rosa26mTmG;Tcf21f/fkidneys (Tcf21-cKO) and controls. Clustering identified a predominant stromal population, further divided into six subpopulations associated with healthy kidney development: nephrogenic zone-associated stroma, proliferating stroma, medullary/perivascular stroma, collecting duct-associated stroma, differentiating stroma, and ureteric stroma. Loss of Tcf21 resulted in marked depletion of medullary/perivascular stroma, collecting duct-associated stroma, proliferating stroma, and nephrogenic zone-associated stroma stromal subpopulations, confirmed by immunostaining, which revealed severe constriction of medullary and collecting duct stromal spaces.Additionally, we identified a novel cluster unique toTcf21-cKOkidneys, characterized by high expression of Endomucin (Emcn), a vascular endothelial marker. These cells spanned across pseudotime trajectories and were distributed broadly across the mutant kidney. The emergence of Emcn-expressing cells inTcf21-cKOkidneys coincided with a reduction in Acta2-expressing medullary stromal cells, suggesting a population shift.Our findings highlight the critical role of Tcf21 in directing Foxd1+ progenitor differentiation. Loss of Tcf21 disrupts stromal cell fates, leading to aberrant kidney development and providing new insights into the mechanisms underlying congenital kidney anomalies.TRANSLATIONAL STATEMENTThis study reveals critical insights into kidney development and congenital anomalies by identifying the developmental origins of stromal heterogeneity and the key role of Tcf21 in stromal progenitor differentiation. These findings enhance our understanding of stromal cell fate decisions and their relevance to congenital disorders. Additionally, this work provides valuable information for improving the recapitulation of the stromal compartment ex vivo, a current challenge in kidney organoid models. The role of Tcf21 in stromal phenotypic modulation underscores its broader significance in tissue repair and fibrotic diseases, suggesting potential avenues for therapeutic intervention.
Large protein databases reveal structural complementarity and functional locality
Authors: Szczerbiak Paweł , Szydlowski Lukasz M. , Wydmański Witold , Renfrew P. Douglas , Koehler Leman Julia , Kosciolek Tomasz 
Published: August 2024

AbstractRecent breakthroughs in protein structure prediction have led to an unprecedented surge in high-quality 3D models, highlighting the need for efficient computational solutions to manage and analyze this wealth of structural data. In our work, we comprehensively examine the structural clusters obtained from the AlphaFold Protein Structure Database (AFDB), a high-quality subset of ESMAtlas, and the Microbiome Immunity Project (MIP). We create a single cohesive low-dimensional representation of the resulting protein space. Our results show that, while each database occupies distinct regions within the protein structure space, they collectively exhibit significant overlap in their functional profiles. High-level biological functions tend to cluster in particular regions, revealing a shared functional landscape despite the diverse sources of data. To facilitate exploration and improve access to our data, we developed an open-access web server. Our findings lay the groundwork for more in-depth studies concerning protein sequence-structure-function relationships, where various biological questions can be asked about taxonomic assignments, environmental factors, or functional specificity.
Temporal and spatial niche partitioning in a retrotransposon community of the Drosophila genome
Authors: Varoqui Marion , Mohamed Mourdas , Mugat Bruno , Gourion Daniel , Lemoine Maëlys , Pélisson Alain , Grimaud Charlotte , Chambeyron Séverine 
Published: August 2024

SummaryTransposable elements (TEs), widespread genetic parasites, pose potential threats to the stability of their host genomes. Hence, the interactions observed today between TEs and their host genomes, as well as among the different TE species coexisting in the same host, likely reflect those that did not lead to the extinction of either the host or the TEs. It is not clear to what extent the expression and integration steps of the TE replication cycles are involved in this ‘peaceful’ coexistence. Here, we show that four Drosophila LTR RetroTransposable Elements (LTR-RTEs), although sharing the same overall integration mechanism, preferentially integrate into distinct open chromatin domains of the host germline. Notably, the differential expressions of the gtwin and ZAM LTR-RTEs in ovarian and embryonic somatic tissues, respectively, result in differential integration timings and targeting of accessible chromatin landscapes that differ between early and late embryonic nuclei, highlighting connections between temporal and spatial LTR-RTEs niche partitionings.
An epigenetic memory at theCYP1Agene in cancer-resistant, pollution-adapted killifish
Authors: Carrothers Samantha , Trevisan Rafael , Jayasundara Nishad , Pelletier Nicole , Weeks Emma , Meyer Joel N. , Di Giulio Richard , Weinhouse Caren 
Published: August 2024

AbstractHuman exposure to polycyclic aromatic hydrocarbons (PAH) is a significant and growing public health problem. Frequent, high dose exposures are likely to increase due to a warming climate and increased frequency of large-scale wildfires. Here, we characterize an epigenetic memory at thecytochrome P450 1A(CYP1A) gene in a population of wildFundulus heteroclitusthat has adapted to chronic, extreme PAH pollution. In wild-type fish,CYP1Ais highly induced by PAH. In PAH-tolerant fish,CYP1Ainduction is blunted. Since CYP1A metabolically activates PAH, this memory protects these fish from PAH-mediated cancer. However, PAH-tolerant fish reared in clean water recoverCYP1Ainducibility, indicating that blunted induction is a non-genetic memory of prior exposure. To explore this possibility, we bred depurated wild fish from PAH-sensitive and -tolerant populations, manually fertilized exposure-naïve embryos, and challenged them with PAH. We observed epigenetic control of the reversible memory of generational PAH stress in F1PAH-tolerant embryos. Specifically, we observed a bivalent domain in theCYP1Apromoter enhancer comprising both activating and repressive histone post-translational modifications. Activating modifications, relative to repressive ones, showed greater increases in response to PAH in sensitive embryos, relative to tolerant, consistent with greater gene activation. Also, PAH-tolerant adult fish showed persistent induction ofCYP1Along after exposure cessation, which is consistent with defectiveCYP1Ashutoff and recovery to baseline. SinceCYP1Aexpression is inversely correlated with cancer risk, these results indicate that PAH-tolerant fish have epigenetic protection against PAH-induced cancer in early life that degrades in response to continuous gene activation.SignificanceEpigenetic memory, or the inheritance across cell division within an organism or across generations, of environmental exposure response is a compelling phenomenon with limited understanding of mechanism. Here, we characterized an epigenetic memory at theCYP1Agene in pollution-adaptedFundulus heteroclitus. We found that theCYP1Apromoter enhancer contains a bivalent domain, comprising both active and repressive histone modifications, that shows reduced function correlating with reduced gene induction by its pollutant activator. In early life, this memory protects fish against pollution-induced cancer. However, this reduced function carries a cost; adult fish show defective transcriptional recovery ofCYP1A, which increases cancer risk later in life. These results provide an initial mechanism for a model epigenetic memory and highlight potential costs.