bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting B and T lymphocyte attenuator regulates lupus disease development in NZB/W mice
Authors: Gherardi Léa , Aubergeon Lucie , Sayah Mélanie , Fauny Jean-Daniel , Dumortier Hélène , Monneaux Fanny 
Published: June 2024

ABSTRACTB and T Lymphocyte Attenuator (BTLA) is a co-inhibitory receptor expressed by most immune cells, playing a role in negatively regulating immune responses. Studies in MRL/lpr lupus mice deficient for BTLA, indicate that BTLA has a protective role in lupus. We have previously shown an altered BTLA expression by regulatory T cells and an impaired capacity of BTLA to inhibit CD4+T cell activation in lupus patients. In this study, we thoroughly analyzed BTLA expression and function in the NZB/W lupus-mouse model. We found that diseased NZB/W mice exhibit a BTLA expression and function pattern similar to that observed in lupus patients, emphasizing the importance of this mouse model in evaluating the therapeutic potential of targeting BTLA. Administration of a monoclonal anti-BTLA antibody (clone 6F7, which displays agonist propertiesex vivo) into pre-diseased NZB/W mice resulted in a delayed onset of proteinuria, limited kidney damages and an increased survival rate compared to isotype-treated mice. This beneficial effect was associated with a decrease in circulating B cell frequency and required continuous exposure to the antibody. Regarding its mode of action, we demonstrated that the 6F7 antibody is not a depleting antibody and does not block HVEM binding to BTLA, but instead induces BTLA down modulation, leading to a selective reduction of follicular B cell numbers, and exhibitsin vivoagonist activity. Overall, our data confirm the involvement of BTLA in lupus pathogenesis and provide the first evidence that BTLA is a potential therapeutic target for the treatment of lupus.
DockQ v2: Improved automatic quality measure for protein multimers, nucleic acids, and small molecules
Authors: Mirabello Claudio , Wallner Björn 
Published: June 2024

AbstractIt is important to assess the quality of modeled biomolecules to benchmark and assess the performance of different prediction methods. DockQ has emerged as the standard tool for assessing the quality of protein interfaces in model structures against given references. However, as predictions of large multimers with multiple chains become more common, there is a need to update DockQ with more functionality for robustness and speed. Moreover, as the field progresses and more methods are released to predict interactions between proteins and other types of molecules, such as nucleic acids and small molecules, it becomes necessary to have a tool that can assess all types of interactions. Here, we present a complete reimplementation of DockQ in pure Python. The updated version of DockQ is more portable, faster and introduces novel functionalities, such as automatic DockQ calculations for multiple interfaces and automatic chain mapping with multi-threading. These enhancements are designed to facilitate comparative analyses of protein complexes, particularly large multi-chain complexes. Furthermore, DockQ is now also able to score interfaces between proteins, nucleic acids, and small molecules.Codehttps://wallnerlab.org/DockQ
Predicting metal-protein interactions using cofolding methods: Status quo
Authors: Dürr Simon L. , Rothlisberger Ursula 
Published: June 2024

AbstractMetals play important roles for enzyme function and many therapeutically relevant proteins. Despite the fact that the first drugs developed via computer aided drug design were metalloprotein inhibitors, many computational pipelines for drug discovery still discard metalloproteins due to the difficulties of modelling them computationally. New “cofolding” methods such as AlphaFold3 (AF3) (Abramson et al., 2024) and RoseTTAfold-AllAtom (RFAA) (Krishna et al., 2024) promise to improve this issue by being able to dock small molecules in presence of multiple complex cofactors including metals or covalent modifications. Here, we analyze the current status for metal ion prediction using these methods. We find that currently only AF3 provides realistic predictions for metal ions, RFAA in contrast does perform worse than more specialized models such as AllMetal3D in predicting the location of metal ions accurately. We find that AF3 predictions are consistent with expected physico-chemical trends/intuition whereas RFAA often also predicts unrealistic metal ion locations.
Contributions of action potentials to scalp EEG: theory and biophysical simulations
Authors: Brake Niklas , Khadra Anmar 
Published: June 2024

AbstractDifferences in the apparent 1/f component of neural power spectra require correction depending on the underlying neural mechanisms, which remain incompletely understood. Past studies suggest that neuronal spiking produces broadband signals and shapes the spectral trend of invasive macroscopic recordings, but it is unclear to what extent action potentials (APs) influence scalp EEG. Here, we combined biophysical simulations with statistical modelling to examine the amplitude and spectral content of scalp potentials generated by the electric fields from spiking activity. We found that under physiological conditions, synchronized aperiodic spiking can account for at most 1% of the spectral density observed in EEG recordings, suggesting that the EEG spectral trend reflects only external noise at high frequencies. Indeed, by analyzing previously published data from pharmacologically paralyzed subjects, we confirmed that the EEG spectral trend is entirely explained by synaptic timescales and electromyogram contamination. We also investigated rhythmic EEG generation, finding that APs can generate narrowband power between approximately 60 and 600 Hz, thus reaching frequencies much faster than the timescales of excitatory synaptic currents. Our results imply that different spectral detrending strategies are required for high frequency oscillations compared to slower synaptically generated EEG rhythms.
Obg-like ATPase 1 Genetic Deletion Leads to Dilated Cardiomyopathy in Mice and Structural Changes in Drosophila Heart
Authors: Dubey Praveen K , Singh Sarojini , Khalil Hussain , Kommini Goutham K , Bhat Krishna Moorthi , Krishnamurthy Prasanna 
Published: June 2024

AbstractCardiomyopathy, disease of the heart muscle, is a significant contributor to heart failure. The pathogenesis of cardiomyopathy is multifactorial and involves genetic, environmental, and lifestyle factors. Identifying and characterizing novel genes that contribute to cardiac pathophysiology are crucial for understanding cardiomyopathy and effective therapies.In this study, we investigated the role of a novel gene,Obg-like ATPase 1(Ola1), in cardiac pathophysiology using a cardiac-specific knockout mouse model as well as a Drosophila model. Our previous work demonstrated that OLA1 modulates the hypertrophic response of cardiomyocytes through the GSK-beta/beta-catenin signaling pathway. Furthermore, recent studies have suggested that OLA1 plays a critical role in organismal growth and development. For example,Ola1null mice exhibit increased heart size and growth retardation. It is not known, however, if loss of function forOla1leads to dilated cardiomyopathy.We generated cardiac-specificOla1knockout mice (OLA1-cKO) to evaluate the role of OLA1 in cardiac pathophysiology. We found thatOla1-cKO in mice leads to dilated cardiomyopathy (DCM) and left ventricular (LV) dysfunction. These mice developed severe LV dilatation, thinning of the LV wall, reduced LV function, and, in some cases, ventricular wall rupture and death. In Drosophila, RNAi-mediated knock-down specifically in developing heart cells led to the change in the structure of pericardial cells from round to elongated, and abnormal heart function. This also caused significant growth reduction and pupal lethality. Thus, our findings suggest that OLA1 is critical for cardiac homeostasis and that its deficiency leads to dilated cardiomyopathy and dysfunction. Furthermore, our study highlights the potential of theOla1gene as a therapeutic target for dilated cardiomyopathy and heart failure.
DrugGym: A testbed for the economics of autonomous drug discovery
Authors: Retchin Michael , Wang Yuanqing , Takaba Kenichiro , Chodera John D. 
Published: June 2024

AbstractDrug discovery is stochastic. The effectiveness of candidate compounds in satisfying design objectives is unknown ahead of time, and the tools used for prioritization—predictive models and assays—are inaccurate and noisy. In a typical discovery campaign, thousands of compounds may be synthesized and tested before design objectives are achieved, with many others ideated but deprioritized. These challenges are well-documented, but assessing potential remedies has been difficult. We introduceDrugGym, a frame-work for modeling the stochastic process of drug discovery. Emulating biochemical assays with realistic surrogate models, we simulate the progression from weak hits to sub-micromolar leads with viable ADME. We use this testbed to examine how different ideation, scoring, and decision-making strategies impact statistical measures of utility, such as the probability of program success within predefined budgets and the expected costs to achieve target candidate profile (TCP) goals. We also assess the influence of affinity model inaccuracy, chemical creativity, batch size, and multi-step reasoning. Our findings suggest that reducing affinity model inaccuracy from 2 to 0.5 pIC50 units improves budget-constrained success rates tenfold. DrugGym represents a realistic testbed for machine learning methods applied to the hit-to-lead phase. Source code is available atwww.drug-gym.org.
A glial circadian gene expression atlas reveals cell type and disease-specific reprogramming in response to amyloid pathology or aging
Authors: Sheehan Patrick W. , Fass Stuart , Sapkota Darshan , Kang Sylvia , Hollis Henry C. , Lawrence Jennifer H. , Anafi Ron C. , Dougherty Joseph D. , Fryer Jon D. , Musiek Erik S. 
Published: June 2024

AbstractWhile circadian rhythm disruption may promote neurodegenerative disease, how aging and neurodegenerative pathology impact circadian gene expression patterns in different brain cell types is unknown. Here, we used translating ribosome affinity purification methods to define the circadian translatomes of astrocytes, microglia, and bulk cerebral cortex, in healthy mouse brain and in the settings of amyloid-beta plaque pathology or aging. Our data reveal that glial circadian translatomes are highly cell type-specific and exhibit profound, context-dependent reprogramming of rhythmic transcripts in response to amyloid pathology or aging. Transcripts involved in glial activation, immunometabolism, and proteostasis, as well as nearly half of all Alzheimer Disease (AD)-associated risk genes, displayed circadian oscillations, many of which were altered by pathology. Amyloid-related differential gene expression was also dependent on time of day. Thus, circadian rhythms in gene expression are cell- and context dependent and provide important insights into glial gene regulation in health, AD, and aging.
IL1A enhances TNF-induced retinal ganglion cell death
Authors: Andersh Katherine M. , MacLean Michael , Howell Gareth R. , Libby Richard T. 
Published: June 2024

AbstractGlaucoma is a neurodegenerative disease that leads to the death of retinal ganglion cells (RGCs). A growing body of literature suggests a role for neuroinflammation in RGC death after glaucoma-relevant insults. For instance, it was shown that deficiency of three proinflammatory cytokines, complement component 1, subcomponent q (C1q), interleukin 1 alpha (Il1a), and tumor necrosis factor (Tnf), resulted in near complete protection of RGCs after two glaucoma-relevant insults, optic nerve injury and ocular hypertension. While TNF and C1Q have been extensively investigated in glaucoma-relevant model systems, the role of IL1A in RGC is not as well defined. Thus, we investigated the direct neurotoxicity of IL1A on RGCs in vivo. Intravitreal injection of IL1A did not result in RGC death at either 14 days or 12 weeks after insult. Consistent with previous studies, TNF injection did not result in significant RGC loss at 14 days but did after 12 weeks. Interestingly, IL1A+TNF resulted in a relatively rapid RGC death, driving significant RGC loss two weeks after injection. JUN activation and SARM1 have been implicated in RGC death in glaucoma and after cytokine insult. Using mice deficient in JUN or SARM1, we show RGC loss after IL1A+TNF insult is JUN-independent and SARM1-dependent. Furthermore, RNA-seq analysis showed that RGC death by SARM1 deficiency does not stop the neuroinflammatory response to IL1A+TNF. These findings indicate that IL1A can potentiate TNF-induced RGC death after combined insult is likely driven by a SARM1-dependent RGC intrinsic signaling pathway.
Precise cell recovery by cell nucleus united transcript (CellCUT) for enhanced spatial transcriptomics
Authors: Hong Bei , Zeng Bo , Feng Huimin , Liu Zeyuan , Ni Qi , Wang Wei , Li Mayuqing , Yang Meng , Wang Mengdi , Sun Le , Zhong Suijuan , Wu Qian , Wang Xiaoqun 
Published: June 2024

AbstractCell segmentation is the first step in parsing spatial transcriptomic data, often a challenging task. Existing cell segmentation methods do not fully leverage spatial cues between nuclear images and transcripts, tending to produce undesirable cell profiles for densely packed cells. Here, we propose CellCUT to perform cell segmentation and transcript assignment without additional manual annotations. CellCUT provides a flexible computational framework that maintains high segmentation accuracy across diverse tissues and spatial transcriptomics protocols, showing superior capabilities compared to state-of-the-art methods. CellCUT is a robust model to deal with undesirable data such as low contrast intensity, localized absence of transcripts, and blurred images. CellCUT supports a human-in-the-loop workflow to enhance its generalizability to customized datasets. CellCUT identifies subcellular structures, enabling insights at both the single-cell and subcellular levels.
Dihydromyricetin promotes GLP-1 secretion to improve insulin resistance via “gut microbiota-CDCA”
Authors: Li Pengfei , Zhang Yong , Lang Hedong , Hou Pengfei , Yao Yu , Zhang Ruiliang , Wang Xiaolan , Zhang QianYong , Mi Mantian , Yi Long 
Published: June 2024

AbstractDihydromyricetin (DHM) is a polyphenolic phytochemical found mainly in plants such asAmpelopsis grossedentata,which has beneficial effects on insulin resistance. However, the specific mechanism has not been clarified. In this study, C57BL/6 mice were exposed to a high-fat diet (HFD) for eight weeks. DHM could improve insulin resistance via enhancing the incretin effect. DHM increased serum GLP-1 by improving intestinal GLP-1 secretion and inhibiting GLP-1 decomposition, associated with the alteration of intestinal intraepithelial lymphocytes (IELs) proportions and decreased expression of CD26 in IELs and TCRαβ+CD8αβ+IELs in HFD-induced mice. Meanwhile, DHM could ameliorate GLP-1 level and insulin resistance by modulation of gut microbiota and the metabolites, particularly the regulation of intestinal bile acid CDCA content, followed by the inhibition of FXR expression in intestinal L cells as well as increased Gcg mRNA expression and the secretion of GLP-1. These findings clarify the role of the “gut microbiota-CDCA” pathway in the improvement of intestinal GLP-1 levels in HFD-induced mice by DHM administration, providing a new pharmacological target for the prevention of insulin resistance.
A temporally restricted function of the Dopamine receptor Dop1R2 during memory formation
Authors: Kaldun Jenifer C. , Fritsch Cornelia , Komarov Nikita , Sprecher Simon G. 
Published: June 2024

SUMMARYDopamine is a crucial neuromodulator, which is involved in many brain processes, including learning and the formation of memories. Dopamine acts through multiple receptors and controls an intricate signaling network to regulate different tasks. While the diverse functions of dopamine are intensely studied, the interplay and role of the distinct dopamine receptors to regulate different processes is less well understood. An interesting candidate is the dopamine receptor Dop1R2 (also known as Damb), as it could connect to different downstream pathways. Dop1R2 is reported to be involved in forgetting and memory maintenance, however, the circuits requiring the receptors are unknown. To study Dop1R2 and its role in specific spatial and temporal contexts, we generated a conditional knock-out line using the CRISPR-Cas9 technique. Two FRT sites were inserted, allowing flippase-mediated excision of the dopamine receptor in neurons of interest. To study the function of Dop1R2, we knocked it out conditionally in the Mushroom body ofDrosophila melanogaster, a well-studied brain region for memory formation. We show that Dop1R2 is required for later memory forms but not for short-term memories for both aversive and appetitive memories. Moreover, Dop1R2 is specifically required in the the α/β-lobe and the α’/β’-lobe but not in the γ-lobe of the Mushroom body. Our findings show a spatially and temporally restricted role of Dop1R2 in the process of memory formation highlighting the differential requirement of receptors during distinct phases of learning.
Emergence of activation or repression in transcriptional control under a fixed molecular context
Authors: Martinez-Corral Rosa , Friedrich Dhana , Frömel Robert , Velten Lars , Gunawardena Jeremy , DePace Angela H. 
Published: June 2024

AbstractFor decades, studies have noted that transcription factors (TFs) can behave as either activators or repressors of different target genes. More recently, evidence suggests TFs can act on transcription simultaneously in positive and negative ways. Here we use biophysical models of gene regulation to define, conceptualize and explore these two aspects of TF action: “duality”, where TFs can be overall both activators and repressors at the level of the transcriptional response, and “coherent and incoherent” modes of regulation, where TFs act mechanistically on a given target gene either as an activator or a repressor (coherent) or as both (incoherent). For incoherent TFs, the overall response depends on three kinds of features: the TF’s mechanistic effects, the dynamics and effects of additional regulatory molecules or the transcriptional machinery, and the occupancy of the TF on DNA. Therefore, activation or repression can be tuned by just the TF-DNA binding affinity, or the number of TF binding sites, given an otherwise fixed molecular context. Moreover, incoherent TFs can cause non-monotonic transcriptional responses, increasing over a certain concentration range and decreasing outside the range, and we clarify the relationship between non-monotonicity and common assumptions of gene regulation models. Using the mammalian SP1 as a case study and well controlled, synthetically designed target sequences, we find experimental evidence for incoherent action and activation, repression or non-monotonicity tuned by affinity. Our work highlights the importance of moving from a TF-centric view to a systems view when reasoning about transcriptional control.
Bio-inspired augmented reality: an interactive, digital twin ofC. elegans
Authors: Sacristán Daniel , Jenderny Sebastian , Hövel Philipp , Albers Christian , Beyer Isabella , Ochs Karlheinz 
Published: June 2024

AbstractThis work presents a digital twin of the nematodeCaenorhabditis elegans(C. elegans), an organism whose biology has been extensively studied. The digital twin can emulate neuronal activity and the corresponding muscle activity, and performs basic locomotion movement. The underlying mathematical model ofC. eleganscan be realized directly as an electronic circuit and is additionally implemented as a ready-to-use simulation in software. We implemented the digital twin in augmented reality (AR) as a novel format that extends the content of a traditional paper with an interactive visualization in the real world. The figures in the paper are the anchor point for the AR that can be accessed by the readers via an open-source app, which is freely available for tablets, phones, and AR glasses. This enables immersive experiences of the three-dimensional visualization in the real world from a perspective chosen by the reader, supplementing the traditional, flat figure layout of the paper. For researchers, the digital twin further provides a useful tool that is highly relevant and versatile for future developments. At the same time, its manifold possibilities for scientific outreach also aim at making the topic more engaging for a broader audience.
Folding of mRNA-DNA origami for controlled translation and viral vector packaging
Authors: Seitz Iris , Saarinen Sharon , Wierzchowiecka Julia , Cornelissen Jeroen J. L. M. , Linko Veikko , Kostiainen Mauri A. 
Published: June 2024

AbstractmRNA is an important molecule in vaccine development and treatment of genetic disorders. Its capability to hybridize with DNA oligonucleotides in a programmable manner facilitates the formation of RNA-DNA origami structures, which can possess a well-defined morphology and serve as rigid supports for mRNA delivery. However, to date, compre- hensive studies on the requirements for efficient folding of mRNA into distinct mRNA-DNA structures while preserving its translation func- tionality remain elusive. Here, we systematically investigate the impact of design parameters on the folding of protein-encoding mRNA into mRNA-DNA origami structures and demonstrate the importance of the availability of ribosome-binding sequences on the translation effi- ciency. Furthermore, these hybrid structures can be encapsulated inside virus capsids for protecting them against nuclease degradation and also for enhancing their cellular uptake. This multicomponent system therefore showcases a modular and versatile nanocarrier. Our work pro- vides valuable insight into the design of mRNA-DNA origami structures contributing to the development of mRNA-based gene delivery platforms.