bluuebunny/crossref_metadata_2025_split huggingface dataset:
The PHD3-FOXO3 axis modulates the interferon type I response in microglia aggravating Alzheimer’s disease progression
Authors: Sanchez-Garcia Manuel A. , Lara-Ureña Nieves , March-Diaz Rosana , Ortega-de San Luis Clara , Quiñones-Cañete Silvia , Barba-Reyes Juan M. , Cabello-Rivera Daniel , Muñoz-Cabello Ana M. , Mora-Romero Bella , Romero-Molina Carmen , Heras-Garvin Antonio , Navarro Victoria , Lopez-Barneo Jose , Vizuete Marisa , Vitorica Javier , Muñoz-Manchado Ana B. , Cokman Matthew , Rosales-Nieves Alicia E. , Pascual Alberto 
Published: October 2024

AbstractMicroglia respond to Alzheimer’s disease (AD) with a variety of transcriptional responses. However, the regulation of specific transcriptional signatures and the contribution of each individual response to disease progression is only starting to be characterized. We have previously shown that hypoxiaviahypoxia inducible factor 1 (HIF1) is a strong regulator of Aß plaque-associated microglia (AßAM). Here, we characterize the role of HIF1-mediated transcription ofEgln3, encoding for PHD3, in AßAM. We show that oligomeric Aß treatment (oAß)in vitroinduces the expression ofHif1aandEgln3in microglia, which correlates with the transcriptional activation of genes involved in the interferon type I signature (IFNS) in a PHD3-dependent manner. Mechanistically, we demonstrate FOXO3 to be an important repressor of IFNS in microglia, whose abundance decreases upon Aß presence, and, correspondingly, both in human single-nucleus (sn) and mouse AßAM transcriptomics, FOXO3 DNA binding sites define the IFNS. FOXO3 repression of the IFNS is dependent on PHD3, with our results suggesting a physical interaction between both proteinsin vitro.In vivo, loss of PHD3 correlate with abrogation of the IFNS and activation of the disease-associated microglia signature (DAM) in AßAM. Transcriptional changes in microglia associate with increased microglia proximity to Aß plaques, augmented phagocytosis of Aß by microglia, reduced parenchymal levels of Aß, and an increase in small-sized plaques. PHD3 deficiency also reduced the Aß plaque-associated neuropathology and rescued behavioural deficits of an AD mouse model. Finally, we also demonstrate that microglial PHD3 overexpression during development in the absence of Aß pathology is sufficient to induce the IFNS and to behavioural alterations. Altogether, our data strongly indicate that the PHD3-FOXO3 axis controls the microglial IFNS in a cell autonomous manner, contributing to the progression of AD.
Proteolysis-targeting vaccines (PROTAVs) for robust combination immunotherapy of melanoma
Authors: Wang Qiyan , Su Ting , Cheng Furong , Zhou Shurong , Liu Xiang , Wang Mi , Xu You , Tang Ri , Liao Shimiao , Dailey Jordan , Xiao Guolan , Yang Chunpeng , Wen Hanning , Zheng Weijia , Wen Bo , Tyc Katarzyna M , Liu Jinze , Sun Duxin , Wang Shaomeng , Zhu Guizhi 
Published: October 2024

AbstractProtein/peptide subunit vaccines are promising to promote the tumor therapeutic efficacy of immune checkpoint blockade (ICB). However, current protein/peptide vaccines elicit limited antitumor T cell responses, leading to suboptimal therapeutic efficacy. Here, we present proteolysis-targeting vaccines (PROTAVs) that facilitate antigen proteolytic processing and cross-presentation to potentiate T cell responses for robust ICB combination immunotherapy of melanoma. PROTAVs are modular conjugates of protein/peptide antigens, E3 ligase-binding ligands, and linkers. In antigen-presenting cells (APCs), PROTAVs bind to E3 ligases to rapidly ubiquitinate PROTAV antigens, facilitating antigen proteolytic processing by proteasome, and thereby promoting antigen cross-presentation to T cells and potentiating CD8+T cell responses. We developed a melanoma PROTAV using a tandem peptide of trivalent melanoma-associated antigens. Co-delivered by lipid nanoparticles (LNPs) with bivalent immunostimulant adjuvants, this PROTAV promotes the quantity and quality of melanoma-specific CD8+T cells in mice. Further, combining PROTAV and ICB ameliorates the immunosuppressive melanoma microenvironment. As a result, PROTAV and ICB combination enhances melanoma complete regression rates and eradicated 100% largeBrafV600Emelanoma without recurrence in syngeneic mice. PROTAVs hold the potential for robust tumor combination immunotherapy.
Regulatory T cells crosstalk with tumor and endothelium through lymphotoxin signaling
Authors: Piao Wenji , Wu Long , Xiong Yanbao , Zapas Gregory C. , Paluskievicz Christina M. , Oakes Robert S. , Pettit Sarah M. , Schmitz Jessica , Ivanyi Philipp , Shetty Amol C. , Song Yang , Kong Dejun , Sleeth Margaret , Hippen Keli L. , Lee Young , Li Lushen , Shirkey Marina W. , Kensiski Allison , Alvi Aamna , Ho Kevin , Saxena Vikas , Bräsen Jan H. , Jewell Christopher M. , Blazar Bruce R. , Abdi Reza , Bromberg Jonathan S. 
Published: October 2024

SUMMARYRegulatory T cells (Tregs) are suppressors of anti-tumor immunity that exert multifaceted functions by signaling surrounding cells. We revealed Tregs use their high-level surface lymphotoxin (LT)α1β2 to preferentially stimulate LTβ receptor (LTβR) nonclassical NFκB signaling on both tumor and lymphatic endothelial cells (LECs) to accelerate tumor growth and metastasis. Selectively targeting LTβR nonclassical NFκB pathways on both tumors and LECs cocultured with Tregs, inhibited tumor growth and migration in vitro. Further, we identified protumorigenic chemokines and interferon-stimulated response genes selectively driven by LTβR nonclassical NFκB in melanoma cells. Endothelial specific genes related to oncogenic process such as SOX18 and FLRT2 were identified to be driven under LTβR nonclassical NFκB in LECs. Leveragingin vivoTreg LTα1β2 interactions with LTβR on tumor and LECs, transfer of WT but not LTα-deficient Tregs promoted transplanted WT B16F10 growth and tumor cell-derived CXCL1 and CXCL10 secretion in LTβR-deficient host mice, and increased endothelial specific genes related to tumor angiogenesis and lymphangiogenesis, in WT mice bearing LTβR-depleted melanoma. Selectively blocking LTβR nonclassical NFκB pathways remarkably suppressed tumor growth and lymphatic metastasis by reducing tumor cell and LEC-derived CXCL1 and CXCL10 production, restricting Treg and myeloid-derived suppressor cell (MDSC) recruitment to tumor. It also retained intratumoral effector T cells, especially IFNγ+CD8 T cells by restraining Treg facilitated lymphatic vessel permeability. Our data revealed that Treg LTα1β2 promotes LTβR nonclassical NFκB signaling in tumor cells and LECs providing a rational strategy to modulate Treg-mediated protumorigenic molecules to prevent tumor growth and metastasis.
New Statistical Metric for Robust Target Detection in Cryo-EM Using 2DTM
Authors: Zhang Kexin , Cossio Pilar , Rangan Aaditya , Lucas Bronwyn , Grigorieff Nikolaus 
Published: October 2024

Abstract2D template matching (2DTM) can be used to detect molecules and their assemblies in cellular cryo-EM images with high positional and orientational accuracy. While 2DTM successfully detects spherical targets such as large ribosomal subunits, challenges remain in detecting smaller and more aspherical targets in various environments. In this work, a novel 2DTM metric, referred to as the 2DTM p-value, is developed to extend the 2DTM framework to more complex applications. The 2DTM p-value combines information from two previously used 2DTM metrics, namely the 2DTM signal-to-noise ratio (SNR) and z-score, which are derived from the cross-correlation coefficient between the target and the template. The 2DTM p-value demonstrates robust detection accuracies under various imaging and sample conditions and outperforms the 2DTM SNR and z-score alone. Specifically, the 2DTM p-value improves the detection of aspherical targets such as a modified artificial tubulin patch particle (500 kDa) and a much smaller clathrin monomer (193 kDa) in simulated data. It also accurately recovers mature 60S ribosomes in yeast lamellae samples, even under conditions of increased Gaussian noise. The new metric will enable the detection of a wider variety of targets in both purified and cellular samples through 2DTM.
Host Genome Drives the Diversity, Richness, and Beneficial Microbes in the Shrimp Microbiota: A Hologenome Perspective
Authors: Cornejo-Granados Fernanda , Gallardo-Becerra Luigui , Romero-Hidalgo Sandra , Lopez-Zavala Alonso A. , Sotelo-Mundo Rogerio R. , Cota-Huizar Andres , Ochoa-Leyva Adrian 
Published: October 2024

AbstractDespite the growing understanding of the factors influencing the shrimp microbiome, the impact of host genetics on modulating the intestinal microbiota still needs to be studied. Moreover, the existing studies were typically conducted using animal models and under laboratory conditions. Here, we investigated the effect of two shrimp genetics, fast-growth (Gen1) and disease-resistant (Gen2), on shaping the microbiota of the hepatopancreas and the intestine in open-pond aquaculture farming conditions. First, we identified significant genomic differences between the two genetic lines using genome-wide SNP analysis. Then, the microbiota analysis confirmed that organs had a more substantial impact, explaining 33.9% of the variability, followed by the genetic line, which explained 17.3%. The microbiota of the hepatopancreas was more significantly affected by the genetic line than the intestine. Gen1 exhibited higher richness, diversity, niche breadth, and abundance of beneficial microbes than Gen2, suggesting that Gen1 had a more generalist microbiota. By comparing the microbiota of another set of healthy and diseased shrimps, we confirmed that a higher presence of beneficial microbes was linked to a healthy shrimp status. Additionally, we genotyped and determined the microbiota of wild-type shrimps, proving that they differ from those observed in both genetic lines. Interestingly, ponds with Gen1 had better productivity than Gen2, suggesting a potential link between higher productivity and the microbiota selected by Gen1. Our study highlights the importance of the holobiome perspective in breeding and management programs. It suggests that a specific genetic line and its associated microbiota could be used to select the larvae to be cultivated, improving shrimp aquaculture production.
A multi-step completion process model of cell plasticity
Authors: Chen Chen M. , Yu Rosemary 
Published: October 2024

AbstractPlasticity is the potential for cells or cell populations to change their phenotypes and behaviours in response to internal or external cues. A common way to study a plasticity programme is to track the underlying molecular changes over time, by collecting omics time-series data. However, there remains a lack of mathematical models to elucidate and predict molecular behaviours in a plasticity programme using omics time-series data. Here we report a new mathematical framework that models cell plasticity as a multi-step completion process, where the system moves from the initial state along a path guided by multiple intermediate attractors until the final state (i.e. a new homeostasis) is reached. In benchmarking tests, we show that our developed Control Point (CP) model fits omics time-series data and identifies attractor states that are well-aligned with prior knowledge. Importantly, we show that the CP model can make non-trivial predictions such as the molecular outcomes of blocking a plasticity programme from reaching completion, in a quantitative and time-resolved manner.Significance statementCell plasticity is fundamental to a wide range of complex biological processes, for example in embryonic development, immunology, regenerative medicine, aging, cancer, and others. We developed a new mathematical model that leverages omics time-series data to understand and make accurate predictions about cell plasticity. This can lead to new discoveries and open up new avenues of research in medicine and bioengineering.
Potent and durable gene modulation in heart and muscle with chemically defined siRNAs
Authors: Fakih Hassan H. , Lochmann Clemens , Gagnon Rosemary , Summers Ashley , Caiazzi Jillian , Buchwald Julianna E. , Tang Qi , Maru Bruktawit , Hildebrand Samuel R. , UI Abideen Mohammad Zain , Furgal Raymond C. , Gross Katherine Y. , Yang Yen , Cooper David , Monopoli Kathryn R. , Echeverria Dimas , Shim JaeHyuck , Yamada Ken , Alterman Julia F. , Khvorova Anastasia 
Published: October 2024

ABSTRACTSmall interfering RNA (siRNAs) hold immense promise for treating cardiac and muscular diseases, but robust and scalable delivery to these tissues remains a challenge. Recent advances in delivery strategies to muscle include conjugation of biologics (antibody/antibody fragments, peptides), which are currently in clinical development. However, the manufacturing of biologic-siRNA conjugates is a challenging and complex process. By contrast, lipophilic siRNAs are readily chemically synthesized at scale and support sufficient cardiac and skeletal muscle delivery. In this work, we refine siRNA design elements to enhance potency and durability and support clinically relevant silencing in muscle. Applying this strategy for siRNAs targeting myostatin (MSTN), a key target in muscle-wasting conditions, we show that a single subcutaneous dose in mice achieved robust and durable silencing (∼80% inhibition up to 6 weeks, ∼30% at 14 weeks). Biweekly dosing resulted in >95% reduction of circulatingMSTNfor half a year, with no observed systemic or target-related toxicity.MSTNinhibition resulted in muscle growth and increased lean muscle mass, correlating with improved grip strength. Interestingly, the functional impact on muscle growth and strength significantly outlasts the target silencing, suggesting extended pharmacological effects. Systemic administration was equally efficacious in all muscle groups tested, including skeletal muscle, heart, tongue and diaphragm. The informational nature of the muscle-active chemically defined siRNA scaffold was confirmed by demonstrating muscle and heart efficacy with three additional targets. Our findings pave the way for potent and long-lasting gene modulation in muscle using chemically defined, lipophilic siRNAs, offering a new avenue for treating muscular diseases.
Atomic-Level Investigation ofKCNJ2Mutations Associated with Ventricular Arrhythmic Syndrome Phenotypes
Authors: Munawar Saba , Anderson Corey L , Reilly Louise , Woltz Ryan , Kayani Yusra Sajid , Chiamvimonvat Nipavan , Eckhardt Lee L. 
Published: October 2024

AbstractKCNJ2encodes the inward rectifying potassium channel (Kir2.1) that createsIK1which maintains the cardiac resting membrane potential and regulates excitability. Mutations inKCNJ2have been linked to several clinical phenotypes associated with ventricular arrhythmia and sudden death including Andersen-Tawil syndrome (ATS) related to loss of function mutations and Short QT Syndrome 3 related to gain of function mutations. Detailed structural-functional relationships to explain the arrhythmia phenotypes are understudied and limit the capacity to provide precision medicine. Here, we combine in-depth and complementary computational molecular modeling techniques with functional analysis from three patients with ATS that harborKCNJ2mutations R67Q, R218L, and G300D. Whole-cell patch-clamp experiments revealed loss of function in homomeric mutant channels. Full-length Kir2.1 models were developed for structure-based investigation, and mutations were introduced in both open and closed conformations. Site-directed mutagenesis identified altered interaction profiles contributing to structural perturbations. Molecular dynamics simulations assessed the impact of each mutation on overall channel conformation and stability. Principal component analysis and normal mode analysis revealed mutation-specific structural perturbations. These findings extend beyond previous studies, offering atomic-level characterization of mutation-specific perturbations. Our multifaceted approach provides first atomic-level insights into the molecular mechanisms underlying ATS, paving the way for targeted therapeutic strategies.Study Highlights1) Clinical mutation analysis confirmed loss-of-function.2) Mutation analysis revealed that these clinical mutations dramatically alter the interaction pattern of the mutated residue and subsequently disturbs channel stability.3) The molecular dynamics based RMSD and RMSF evaluations show that the open conformation state of the channel is more stable comparative to the closed state however, the mutations impact channel conformations regardless of conductance state.4) The PCA (principal component analysis) and PCA based NM (normal mode) analysis revealed that these clinicalKCNJ2mutations caused significant conformational changes, even distant from the specific residue.4) This study is the first extensivein silicoand experimental analysis ofKCNJ2clinical mutations that start from the arrhythmia phenotype and lead to an in-depth atomic-level investigation. These newly resolved features pave the way towards a better understanding of the molecular disease mechanism and new therapeutic strategies.
EDTA tubes are suitable for insulin and C-peptide measurement in resource-limited settings and can be stored at room temperature for up to 24 hours
Authors: Mubiru Nathan , Mukasa Rogers , Sekitoleko Isaac , Balungi Priscilla A , Kakumba Ronald M. , Ongaria Terry , Nkabura Hubert , Nyirenda Moffat , Niwaha Anxious J , Nakanga Wisdom P 
Published: October 2024

AbstractIntroductionInsulin and C-peptide assessment are important in characterization and management of diabetes. However, their adoption and increased clinical use in low resource settings (LRSs) is partly hindered by logistical factors including supplies required for pre-analytical sample handling and limited infrastructure. We aimed to determine the effects of altered sample processing conditions on stability of insulin and C-peptide at the pre-analytical stage.MethodsWe investigated the stability of C-peptide and insulin in serum and plasma collected, preservative type, time to centrifugation, storage conditions and duration of storage on the stability of C-peptide and insulin over 24 hours.ResultsBoth C-peptide and insulin levels remained stable above 90% from baseline p=1.000 & p=0.776 over 24 hours for samples stored in K2EDTA tubes, whether at room temperature or in a cooler box, both as centrifuged and uncentrifuged whole blood. In contrast, samples collected in plain serum tubes kept at room temperature and uncentrifuged C-peptide and insulin levels decreased significantly to 51%, p=0.006 and 62%, p=0. 083 respectively, similarly insulin levels for centrifuged samples declined to 64%, p=0.083 All iced and centrifuged serum samples remained above 90% of baseline concentration.ConclusionsIn resource limited settings where insulin and c-peptide tests are limited to central laboratories and highly dependent on sample referral systems, these tests can be reliably measured without the need for immediate centrifugation or processing from samples collected in whole blood K2EDTA tubes uncentrifuged kept at room temperature and processed within 24hours.MessageK2EDTA tubes can be used for sample collection in resource limited setting kept at room temperature for up to 24hrs for insulin and c-peptide assays.K2EDTA plasma is more stable than serum for insulin and c-peptide measurement and should be used in resource limited settings
Virtual epilepsy patient cohort: generation and evaluation
Authors: Dollomaja Borana , Wang Huifang E. , Guye Maxime , Makhalova Julia , Bartolomei Fabrice , Jirsa Viktor K. 
Published: October 2024

AbstractEpilepsy is a prevalent brain disorder, characterized by sudden, abnormal brain activity, making it difficult to live with. One-third of people with epilepsy do not respond to anti-epileptic drugs. Drug-resistant epilepsy is treated with brain surgery. Successful surgical treatment relies on identifying brain regions responsible for seizure onset, known as epileptogenic zones (EZ). Despite various methods for EZ estimation, evaluating their efficacy remains challenging due to a lack of ground truth for empirical data. To address this, we generated and evaluated a cohort of 30 virtual epilepsy patients, using patient-specific anatomical and functional data from 30 real drug-resistant epilepsy patients. This personalized modelling, based on the patient’s brain data, is called a virtual brain twin. For each virtual patient, we provided data that included anatomically parcellated brain regions, structural connectivity, reconstructed intracranial electrodes, simulated brain activity at both the brain region and electrode levels, and key parameters of the virtual brain twin. These key parameters, which include the EZ hypothesis, serve as the ground-truth for simulated brain activity. For each virtual brain twin, we generated synthetic spontaneous seizures, stimulation-induced seizures and interictal activity. We systematically evaluated these simulated brain signals by quantitatively comparing them against their corresponding empirical intracranial recordings. Simulated signals based on patient-specific EZ captured spatio-temporal seizure generation and propagation. Through in-silico exploration of stimulation parameters, we also demonstrated the role of patient-specific stimulation location and amplitude in reproducing empirically stimulated seizures. The virtual epileptic cohort is openly available, and can be directly used to systematically evaluate methods for the estimation of EZ or source localization using ground truth EZ parameters and source signals.
Fate plasticity of interneuron specification
Authors: Mostajo-Radji Mohammed A. , Leon Walter R. Mancia , Breevoort Arnar , Gonzalez-Ferrer Jesus , Schweiger Hunter E. , Lehrer Julian , Zhou Li , Schmitz Matthew T. , Perez Yonatan , Mukhtar Tanzila , Chu Julia , Andrews Madeline G. , Sullivan Frederika N. , Tejera Dario , Choy Eric C. , Paredes Mercedes F. , Teodorescu Mircea , Kriegstein Arnold R. , Alvarez-Buylla Arturo , Pollen Alex A. 
Published: October 2024

AbstractThe generation of neuronal subtypes in the mammalian central nervous system is driven by competing genetic programs. The medial ganglionic eminence (MGE) gives rise to two major cortical interneuron (cIN) populations, marked by Somatostatin (Sst) and Parvalbumin (Pvalb), which develop on different timelines. The extent to which external signals influence these identities remains poorly understood. Pvalb-positive cINs are particularly important for regulating cortical circuits through strong perisomatic inhibition, yet they have been difficult to modelin vitro. Here we investigated the role of the environment in shaping and maintaining Pvalb cINs. We grafted mouse MGE progenitors into a variety of 2D and 3D co-culture models, including mouse and human cortical, MGE, and thalamic systems with dissociated cells, organoids, organotypic cultures, and conditioned media. Across models, we observed distinct proportions of Sst- and Pvalb-positive cIN descendants. Strikingly, grafting MGE progenitors into 3D human, but not mouse, corticogenesis models led to efficient, non-autonomous differentiation of Pvalb-positive cINs. This differentiation was characterized by upregulation of Pvalb maturation markers, downregulation of Sst-specific markers, and the formation of perineuronal nets. Furthermore, lineage-traced postmitotic Sst-positive cINs, when grafted onto human cortical models, also upregulated Pvalb expression. These results reveal an unexpected level of fate plasticity in MGE-derived cINs, demonstrating that their identities can be dynamically shaped by the surrounding environment.