bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pre-vaccination transcriptomic profiles of immune responders to the MUC1 peptide vaccine for colon cancer prevention
Authors: Cameron Cheryl M. , Raghu Vineet , Richardson Brian , Zagore Leah L. , Tamilselvan Banumathi , Golden Jackelyn , Cartwright Michael , Schoen Robert E. , Finn Olivera J. , Benos Panayiotis V. , Cameron Mark J. 
Published: May 2024

AbstractSelf-antigens abnormally expressed on tumors, such as MUC1, have been targeted by therapeutic cancer vaccines. We recently assessed in two clinical trials in a preventative setting whether immunity induced with a MUC1 peptide vaccine could reduce high colon cancer risk in individuals with a history of premalignant colon adenomas. In both trials, there were immune responders and non-responders to the vaccine. Here we used PBMC pre-vaccination and 2 weeks after the first vaccine of responders and non-responders selected from both trials to identify early biomarkers of immune response involved in long-term memory generation and prevention of adenoma recurrence. We performed flow cytometry, phosflow, and differential gene expression analyses on PBMCs collected from MUC1 vaccine responders and non-responders pre-vaccination and two weeks after the first of three vaccine doses. MUC1 vaccine responders had higher frequencies of CD4 cells pre-vaccination, increased expression of CD40L on CD8 and CD4 T-cells, and a greater increase in ICOS expression on CD8 T-cells. Differential gene expression analysis revealed that iCOSL, PI3K AKT MTOR, and B-cell signaling pathways are activated early in response to the MUC1 vaccine. We identified six specific transcripts involved in elevated antigen presentation, B-cell activation, and NF-κB1 activation that were directly linked to finding antibody response at week 12. Finally, a model using these transcripts was able to predict non-responders with accuracy. These findings suggest that individuals who can be predicted to respond to the MUC1 vaccine, and potentially other vaccines, have greater readiness in all immune compartments to present and respond to antigens. Predictive biomarkers of MUC1 vaccine response may lead to more effective vaccines tailored to individuals with high risk for cancer but with varying immune fitness.
MonoallelicTYROBPdeletion is a novel risk factor for Alzheimer’s disease
Authors: Martiskainen Henna , Willman Roosa-Maria , Heikkinen Sami , Müller Stephan A. , Sinisalo Rosa , Takalo Mari , Mäkinen Petra , Kuulasmaa Teemu , Pekkala Viivi , Galván del Rey Ana , Harju Päivi , Juopperi Sini-Pauliina , Jeskanen Heli , Kervinen Inka , Saastamoinen Kirsi ,   FinnGen, Niiranen Marja , Heikkinen Sami V. , Kurki Mitja I. , Marttila Jarkko , Mäkinen Petri I. , Ngandu Tiia , Lehtisalo Jenni , Bellenguez Céline , Lambert Jean-Charles , Haass Christian , Rinne Juha , Hakumäki Juhana , Rauramaa Tuomas , Krüger Johanna , Soininen Hilkka , Haapasalo Annakaisa , Lichtenthaler Stefan F. , Leinonen Ville , Solje Eino , Hiltunen Mikko 
Published: May 2024

AbstractBiallelic loss-of-function variants inTYROBPandTREM2cause autosomal recessive presenile dementia with bone cysts known as Nasu-Hakola disease (NHD, alternatively polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy, PLOSL). Some otherTREM2variants contribute to the risk of Alzheimer’s disease (AD) and frontotemporal dementia, while deleteriousTYROBPvariants are globally extremely rare and their role in neurodegenerative diseases remains unclear. The population history of Finns has favored the enrichment of deleterious founder mutations, including a 5.2 kb deletion encompassing exons 1-4 ofTYROBPand causing NHD in homozygous carriers. We used here a proxy marker to identify monoallelicTYROBPdeletion carriers in the Finnish biobank study FinnGen combining genome and health registry data of 520,210 Finns. We show that monoallelicTYROBPdeletion associates with an increased risk and earlier onset age of AD and dementia when compared to noncarriers. In addition, we present the first reported case of a monoallelicTYROBPdeletion carrier with NHD-type bone cysts. Mechanistically, monoallelicTYROBPdeletion leads to decreased levels of DAP12 protein (encoded byTYROBP) in myeloid cells. Using transcriptomic and proteomic analyses of human monocyte-derived microglia-like cells, we show that upon lipopolysaccharide stimulation monoallelicTYROBPdeletion leads to the upregulation of the inflammatory response and downregulation of the unfolded protein response when compared to cells with two functional copies ofTYROBP. Collectively, our findings indicateTYROBPdeletion as a novel risk factor for AD and suggest specific pathways for therapeutic targeting.One Sentence SummaryNasu-Hakola disease causingTYROBPdeletion increases the risk of Alzheimer’s disease in elderly monoallelic carriers in the Finnish population.
Improvement in quality of life and cognitive function in Post Covid Syndrome after online occupational therapy: results from a randomized controlled pilot study
Authors: Schröder Dominik , Stölting Andrea , Müllenmeister Christina , Behrens Georg M.N. , Klawitter Sandra , Klawonn Frank , Cook Aisha , Wegner Nadja , Wetzke Martin , Schmachtenberg Tim , Dopfer-Jablonka Alexandra , Müller Frank , Happle Christine 
Published: May 2024

AbstractBackgroundPost-COVID-Syndrome (PCS) poses enormous clinical challenges. Occupational therapy (OT) is recommended in PCS, but structural validation of this concept is pending.MethodsIn an unblinded randomized pilot study (clinical trial # DRKS0026007), feasibility and effects of online OT in PCS were tested. Probands received structured online OT over 12 weeks either via interactive online treatment sessions (interactive group) or prerecorded videos (video group). 50% of probands received no online OT (control group). At week 0, 12, and 24, we analyzed study experience, health-related quality of life, and impairment in performance, participation, and cognitive functions.ResultsN=158 probands (mean age 38 yrs., 86% female) were included into the analyses. 83.3% of probands in the interactive versus 48.1% of probands in the video group described their study experience as positive or very positive (p=0.001). After 12 weeks, all groups displayed significant improvement in concentration, memory, and performance of daily tasks. After 24 weeks, significant improvement in concentration and memory were observed in control- and video-probands, and social participation had improved after video-OT. However, only probands that had received interactive online OT showed improvement of all measured endpoints including concentration, memory, quality of life, and social participation.ConclusionWe show that online OT is feasible and that interactive online OT is a promising treatment strategy for affected patients. We present exploratory data on its efficacy and describe variables that can be employed for further investigations in confirmatory trials.
Naa10 regulates hippocampal neurite outgrowthviaBtbd3 N-α-acetylation-mediated actin dynamics
Authors: Chou Chien-Te , Kang Ming-Lun , Lee Chen-Cheng , Hsu Pang-Hung , Juan Li-Jung 
Published: May 2024

AbstractProtein N-α-acetylation is widespread in eukaryotes, yet its neuronal role remains unclear. Mutations in human N-α-acetyltransferase 10 (NAA10) lead to developmental defects affecting brain function, such as intellectual disability and autism. We found that hippocampal CA1-specificNaa10-knockout mice exhibit anxiety and reduced hippocampal dendritic complexity. Mechanistically, Naa10 promotes neurite outgrowth by acetylating BTB/POZ domain-containing protein 3 (Btbd3), crucial for the interaction of Btbd3 with filamentous actin (F-actin)-capping protein subunit beta (CapZb). Disrupting the Btbd3/CapZb interaction, either throughNaa10knockout or by expressing an N-α-acetylation-defective Btbd3 mutant, diminishes CapZb binding to F-actin and reduces neurite outgrowth. Moreover, cytochalasin D, a compound like CapZb in capping the barbed end of F-actin, rescues theNaa10knockout-induced neurite reduction in hippocampal primary neurons. These findings unveil the role of Naa10 in enhancing hippocampal neurite outgrowth through the Btbd3-CapZb-F-actin axis, shedding light on potential mechanisms underlying X-linked Ogden syndrome resulting from humanNAA10mutations.eTOCChou et al. demonstrate that Naa10 promotes neurite outgrowth by N-acetylating Btbd3, facilitating the binding of the filamentous actin capping protein subunit beta (CapZb) to F-actin. Their study establishes a connection between protein N-α-acetylation and neuronal function, providing insight into the mechanism underlying brain disorders associated with human NAA10 mutations.HIGHLIGHTSHippocampal CA1-specificNaa10KO leads to anxietyHippocampal CA1-specificNaa10KO reduces hippocampal dendritic complexityNaa10 promotes neurite outgrowth by N-acetylating Btbd3Naa10-mediated Btbd3 N-α-acetylation promotes CapZb binding to F-actinGraphical Abstract
Single-Cell multiomics reveals ENL mutation perturbs kidney developmental trajectory by rewiring gene regulatory landscape
Authors: Song Lele , Li Qinglan , Xia Lingbo , Sahay Arushi , Qiu Qi , Li Yuanyuan , Li Haitao , Sasaki Kotaro , Susztak Katalin , Wu Hao , Wan Liling 
Published: May 2024

AbstractCell differentiation during organogenesis relies on precise epigenetic and transcriptional control. Disruptions to this regulation can result in developmental abnormalities and malignancies, yet the underlying mechanisms are not well understood. Wilms tumors, a type of embryonal tumor closely linked to disrupted organogenesis, harbor mutations in epigenetic regulators in 30-50% of cases. However, the role of these regulators in kidney development and pathogenesis remains unexplored. By integrating mouse modeling, histological characterizations, and single-cell transcriptomics and chromatin accessibility profiling, we show that a Wilms tumor-associated mutation in the chromatin reader protein ENL disrupts kidney development trajectory by rewiring the gene regulatory landscape. Specifically, the mutant ENL promotes the commitment of nephron progenitors while simultaneously restricting their differentiation by dysregulating key transcription factor regulons, particularly theHOXclusters. It also induces the emergence of abnormal progenitor cells that lose their chromatin identity associated with kidney specification. Furthermore, the mutant ENL might modulate stroma-nephron interactions via paracrine Wnt signaling. These multifaceted effects caused by the mutation result in severe developmental defects in the kidney and early postnatal mortality in mice. Notably, transient inhibition of the histone acetylation binding activity of mutant ENL with a small molecule displaces transcriptional condensates formed by mutant ENL from target genes, abolishes its gene activation function, and restores developmental defects in mice. This work provides new insights into how mutations in epigenetic regulators can alter the gene regulatory landscape to disrupt kidney developmental programs at single-cell resolutionin vivo. It also offers a proof-of-concept for the use of epigenetics-targeted agents to rectify developmental defects.
An empirical evaluation of simulated gastrointestinal digestion platforms for use in plant breeding, using common bean (Phaseolus vulgarisL.) as a model
Authors: Bolt Tayah M. , Riggs Margaret , Sun Weiyi , Tian Li , Gepts Paul , Palkovic Antonia , Parker Travis , Bornhorst Gail M. , Diepenbrock Christine 
Published: May 2024

AbstractThere remains a disconnect in plant breeding between increasing nutrient levels in crops at time of harvest and increasing bioaccessible levels of those nutrients during digestion. This study aims to develop and compare simulated digestion models for use in plant breeding and examine bioaccessible nutrient levels in common bean samples with differing seed coat coloration and patterning. The highest trait values (starch and protein hydrolysis, total phenolics, and antioxidant power) were observed from more dynamic digestion models, but even simple dynamic models showed higher trait values than a commonly used static digestion model. The use of these models provided insight on nutrient bioaccessibility; e.g., differences were observed during digestion between common bean genotypes for protein hydrolysis and between growing environments for both total phenolics and protein hydrolysis. Together, these results inform potential future pathways for applying simulated digestion models in plant breeding to improve bioaccessible nutrient levels in crops.
Linear ubiquitin chains remodel the proteome and influence the levels of hundreds of regulators inDrosophila
Authors: Nuga Oluwademilade , Richardson Kristin , Patel Nikhil , Wang Xusheng , Pagala Vishwajeeth , Stephan Anna , Peng Junmin , Demontis Fabio , Todi Sokol V. 
Published: May 2024

ABSTRACTUbiquitin controls many cellular processes via its post-translational conjugation onto substrates. Its use is highly variable due to its ability to form poly-ubiquitin with various topologies. Among them, linear chains have emerged as important regulators of immune responses and protein degradation. Previous studies inDrosophila melanogasterfound that expression of linear poly-ubiquitin that cannot be dismantled into single moieties leads to their own ubiquitination and degradation or, alternatively, to their conjugation onto proteins. However, it remains largely unknown which proteins are sensitive to linear poly-ubiquitin. To address this question, here we expanded the toolkit to modulate linear chains and conducted ultra-deep coverage proteomics from flies that express non-cleavable, linear chains comprising 2, 4, or 6 moieties. We found that these chains regulate shared and distinct cellular processes inDrosophilaby impacting hundreds of proteins. Our results provide key insight into the proteome subsets and cellular pathways that are influenced by linear poly-ubiquitin with distinct lengths and suggest that the ubiquitin system is exceedingly pliable.
Systematic Development of Reprogrammed Modular Integrases Enables Precise Genomic Integration of Large DNA Sequences
Authors: Fauser Friedrich , Arangundy-Franklin Sebastian , Davis Jessica E , Liu Lifeng , Schmidt Nicola J , Rodriguez Luis , Scarlott Nicholas A , Mureli Rakshaa , Xia Danny F , Hinkley Sarah J , Kadam Bhakti N , Nguyen Nga , Lam Stephen , Bourgeois Bryan , Tait Emily , Qasim Mohammad , Vaidya Vishvesha , Chen Adeline , Nguyen Andrew , Li Patrick , Paschon David E , Davis Gregory D , Miller Jeffrey C 
Published: May 2024

SummaryDespite recent progress in the ability to manipulate the genomes of eukaryotic cells1–3, there is still no effective and practical method to precisely integrate large synthetic DNA constructs into desired chromosomal sites using a programmable integrase. Serine integrases can perform the necessary molecular steps4, but only if their natural target site is first installed into the recipient genome by other methods. A more elegant approach would be to directly reprogram the serine integrase itself to target a desired site endogenous to the genome that is different from the natural recognition site of the integrase5. Here, we describe the development of a platform of Modular Integrases (the MINT platform), a versatile protein-guided genome editing method that can facilitate site-directed targeted integration of synthetic DNA into chromosomal sites. Through a combination of structural modeling, directed evolution, and screening in human cells we have reprogrammed the specificity of the serine integrase Bxb1. We then utilized these reprogrammed Bxb1 variants to enable precise integration of kilobase-sized constructs into multiple endogenous locations within the human genome with up to 35% efficiency and promising genome-wide specificity. We demonstrate the therapeutic potential of the MINT platform by retargeting Bxb1 to the human TRAC and AAVS1 loci where wild-type Bxb1 has no detectable activity.
Proinsulin C-peptide is a major source of HLA-DQ8 restricted HIPs recognized by human Islet-Infiltrating CD4+T cells
Authors: Bhattacharjee Pushpak , Pakusch Miha , Lacorcia Matthew , Tresoldi Eleonora , Rubin Alan F. , Foster Abby , King Laura S. , Chiu Chris , Kay Thomas W.H. , Karas John A. , Cameron Fergus J. , Mannering Stuart I. 
Published: May 2024

ABSTRACTType 1 diabetes (T1D) is an autoimmune disease that develops when T cells destroy the pancreatic insulin-producing beta cells that reside in the pancreatic islets. Immune cells, including T cells infiltrate the islets and gradually destroy the beta cells. Human islet-infiltrating CD4+T cells recognize peptide epitopes derived from proinsulin, particularly C-peptide. Hybrid Insulin peptides (HIPs) are neoepitopes formed by the fusion of two peptides derived from beta-cell granule proteins and are known to be the targets of pathogenic CD4+T cells in the NOD mouse and human islet-infiltrating CD4+T cells. Proinsulin is widely recognized as a central antigen in T1D, but its role in forming HIPs is unclear. We developed a method to functionally screen TCRs derived from human islet-infiltrating CD4+T cells and applied this to the identification of new proinsulin-derived HIPs. We generated a library of 4,488 candidate HIPs formed by fusion of proinsulin fragments and predicted to bind to HLA-DQ8. This library was screened against 109 islet-infiltrating CD4+T-cell TCRs isolated from four organ donors who had T1D. We identified 13 unique HIPs recognized by 9 different TCRs from two organ donors. HIP specific T-cell avatars responded specifically to a peptide extract from human islets. These new HIPs predominantly stimulated CD4+T-cell proliferation in PBMCs from people with T1D in contrast to HLA-matched controls. This is the first unbiased functional, islet-infiltrating T-cell based, screen to identify proinsulin derived HIPs. It has revealed many new HIPs and a central role of proinsulin C-peptide in their formation.SUMMARYType 1 diabetes is an autoimmune disease caused by T cells destroying the pancreatic insulin-producing beta cells. The antigens/epitopes seen by disease promoting CD4+T cells are poorly understood. Hybrid insulin peptides (HIPs) are a new class of CD4+antigen recognized by pathogenic NOD mouse CD4+T cells. In humans very few HIPs recognized by human islet-infiltrating CD4+T cells are known. We show that proinsulin HIPs are recognized by human islet-infiltrating CD4+T cells from T1D donors and describe 13 new HIPs formed by fusion of proinsulin peptides. This work shows that proinsulin, particularly C-peptide, is a major contributor to the pool HIPs recognized by human islet-infiltrating CD4+T cells and are therefore central to autoimmunity in T1D.
Impairments in proprioceptively-referenced limb and eye movements in chronic stroke
Authors: Tulimieri Duncan T. , Decarie Amelia , Singh Tarkeshwar , Semrau Jennifer A. 
Published: May 2024

AbstractBackgroundUpper limb proprioceptive impairments are common after stroke and can affect daily function. Recent work has shown that stroke survivors have difficulty using visual information to improve proprioception. It is unclear how eye movements are impacted to guide action of the arm after stroke. Here, we aimed to understand how upper limb proprioceptive impairments impact eye movements in individuals with stroke.MethodsControl (N=20) and stroke participants (N=20) performed a proprioceptive matching task with upper limb and eye movements. A KINARM exoskeleton with eye tracking was used to assess limb and eye kinematics. The upper limb was passively moved by the robot and participants matched the location with either an arm or eye movement. Accuracy was measured as the difference between passive robot movement location and the active limb matching (Hand-End Point Error) or the active eye movement matching (Eye-End Point Error).ResultsWe found that individuals with stroke had significantly larger Hand and Eye-End Point Errors compared to controls. Further, we found that stroke participants had proprioceptive errors of the hand and eye were highly correlated [r=0.67, p=0.001], a relationship not observed for controls.ConclusionsEye movement accuracy declined as a function of proprioceptive impairment of the more-affected limb, which was used as a proprioceptive reference. The inability to use proprioceptive information of the arm to coordinate eye movements suggests that disordered proprioception impacts integration of sensory information across different modalities. These results have important implications for how vision is used to actively guide limb movement during rehabilitation.
High Throughput Screening with a Primary Human Mucociliary Airway Model Identifies a Small Molecule with Anti-SARS-CoV-2 Activity
Authors: Sen Chandani , Rickabaugh Tammy M. , Jeyachandran Arjit Vijey , Yuen Constance , Ghannam Maisam , Durra Abdo , Aziz Adam , Castillo Kristen , Garcia Gustavo , Purkayastha Arunima , Han Brandon , Boulton Felix W. , Chekler Eugene , Garces Robert , Wolff Karen C. , Riva Laura , Kirkpatrick Melanie G. , Gebara-Lamb Amal , McNamara Case W. , Betz Ulrich A.K. , Arumugaswami Vaithilingaraja , Damoiseaux Robert , Gomperts Brigitte N. 
Published: May 2024

SummaryRespiratory viruses (e.g. influenza, RSV, SARS etc.) attack the proximal airway and cause a wide spectrum of diseases for which we have limited therapies. To date, a few primary human stem cell-based models of the proximal airway have been reported for drug discovery but scaling them up to a higher throughput platform remains a significant challenge. Here we present a microscale, primary human stem cell-based proximal airway model of SARS-CoV-2 infection, which is amenable to moderate-to-high throughput drug screening. The model recapitulates the heterogeneity of infection seen among different patients and with different SARS-CoV-2 variants. We applied this model to screen 2100 compounds from targeted drug libraries using an image-based quantification method. While there were heterogeneous responses across variants for host factor targeting compounds, the direct acting antivirals showed a consistent response and we characterized a new antiviral drug that is effective against both the parental strain and the Omicron variant.
Amyloid fibril polymorphism in the heart of an ATTR amyloidosis patient with polyneuropathy attributed to the V122Δ variant
Authors: Ahmed Yasmin , Nguyen Binh An , Afrin Shumaila , Singh Virender , Evers Bret , Singh Preeti , Pedretti Rose , Wang Lanie , Bassett Parker , Fernandez-Ramirez Maria del Carmen , Pekala Maja , Kluve-Beckerman Barbara , Saelices Lorena 
Published: May 2024

AbstractATTR amyloidosis is a phenotypically heterogeneous disease characterized by the pathological deposition of transthyretin in the form of amyloid fibrils into various organs. ATTR amyloidosis may stem from mutations in variant (ATTRv) amyloidosis, or aging in wild-type (ATTRwt) amyloidosis. ATTRwt generally manifests as a cardiomyopathy phenotype, whereas ATTRv may present as polyneuropathy, cardiomyopathy, or mixed, in combination with many other symptoms deriving from secondary organ involvement. Over 130 different mutational variants of transthyretin have been identified, many of them being linked to specific disease symptoms. Yet, the role of these mutations in the differential disease manifestation remains elusive. Using cryo-electron microscopy, here we structurally characterized fibrils from the heart of an ATTRv patient carrying the V122Δ mutation, predominantly associated with polyneuropathy. Our results show that these fibrils are polymorphic, presenting as both single and double filaments. Our study alludes to a structural connection contributing to phenotypic variation in ATTR amyloidosis, as polymorphism in ATTR fibrils may manifest in patients with predominantly polyneuropathic phenotypes.