bluuebunny/crossref_metadata_2025_split huggingface dataset:
A CAG repeat threshold for therapeutics targeting somatic instability in Huntington’s disease
Authors: Aldous Sarah G. , Smith Edward J. , Landles Christian , Osborne Georgina F. , Cañibano-Pico Maria , Nita Iulia M. , Phillips Jemima , Zhang Yongwei , Jin Bo , Hirst Marissa B. , Benn Caroline L. , Bond Brian C. , Edelmann Winfried , Greene Jonathan R. , Bates Gillian P. 
Published: December 2023

AbstractThe Huntington’s disease mutation is a CAG repeat expansion in the huntingtin gene that results in an expanded polyglutamine tract in the huntingtin protein. The CAG repeat is unstable, and expansions of hundreds of CAGs have been detected in Huntington’s diseasepost-mortembrains. The age of disease onset can be predicted partially from the length of the CAG repeat as measured in blood. Onset age is also determined by genetic modifiers, which in six cases involve variation in DNA mismatch repair pathways genes. Knocking-out specific mismatch repair genes in mouse models of Huntington’s disease prevents somatic CAG repeat expansion. Taken together, these results have led to the hypothesis that somatic CAG repeat expansion in Huntington’s disease brains is required for pathogenesis. Therefore, the pathogenic repeat threshold in brain is longer than (CAG)40, as measured in blood, and is currently unknown.The mismatch repair geneMSH3has become a major focus for therapeutic development, as unlike other mismatch repair genes, nullizygosity forMSH3does not cause malignancies associated with mismatch repair deficiency. Potential treatments targetingMSH3currently under development include gene therapy, biologics and small molecules, which will be assessed for efficacy in mouse models of Huntington’s disease. The zQ175 knock-in model carries a mutation of approximately (CAG)185and develops early molecular and pathological phenotypes that have been extensively characterised. Therefore, we crossed the mutant huntingtin allele onto heterozygous and homozygousMsh3knock-out backgrounds to determine the maximum benefit of targetingMsh3in this model. Ablation ofMsh3prevented somatic expansion throughout the brain and periphery, and reduction ofMsh3by 50% decreased the rate of expansion. This had no effect on the deposition of huntingtin aggregation in the nuclei of striatal neurons, nor on the dysregulated striatal transcriptional profile. This contrasts with ablatingMsh3in knock-in models with shorter CAG repeat expansions. Therefore, further expansion of a (CAG)185repeat in striatal neurons does not accelerate the onset of molecular and neuropathological phenotypes. It is striking that highly expanded CAG repeats of a similar size in humans cause disease onset before 2 years of age, indicating that somatic CAG repeat expansion in the brain is not required for pathogenesis. Given that the trajectory for somatic CAG expansion in the brains of Huntington’s disease mutation carriers is unknown, our study underlines the importance of administering treatments targeting somatic instability as early as possible.
Prognostic pan-cancer and single-cancer models: A large-scale analysis using a real-world clinico-genomic database
Authors: McGough Sarah F. , Lyalina Svetlana , Incerti Devin , Huang Yunru , Tyanova Stefka , Mace Kieran , Harbron Chris , Copping Ryan , Narasimhan Balasubramanian , Tibshirani Robert 
Published: December 2023

AbstractPrognostic models in oncology have a profound impact on personalized cancer care and patient profiling, but tend to be heterogeneously developed and implemented in narrow patient cohorts. Here, we develop and benchmark multiple machine learning models to predict survival in pan-cancer and 16 single-cancer settings using a de-identified clinico-genomic database of 28,079 US patients with cancer. We identify key predictors of cancer prognosis, including 15 shared across seven or more cancer types, revealing strong consistency in cancer prognostic factors. We demonstrate that pan-cancer models generally outperform or match single-cancer models in predicting survival and risk stratifying patients, especially in smaller cancer cohorts, suggesting a unique transfer learning advantage of pan-cancer models. This work demonstrates the potential of pan-cancer approaches in enhancing the accuracy and applicability of prognostic models in oncology, paving the way for more personalized and effective cancer care strategies.
Interferon signaling in the nasal epithelium distinguishes among lethal and common cold respiratory viruses and is critical for viral clearance
Authors: Otter Clayton J. , Renner David M. , Fausto Alejandra , Tan Li Hui , Cohen Noam A. , Weiss Susan R. 
Published: December 2023

SUMMARYAll respiratory viruses establish primary infections in the nasal epithelium, where efficient innate immune induction may prevent dissemination to the lower airway and thus minimize pathogenesis. Human coronaviruses (HCoVs) cause a range of pathologies, but the host and viral determinants of disease during common cold versus lethal HCoV infections are poorly understood. We model the initial site of infection using primary nasal epithelial cells cultured at air-liquid interface (ALI). HCoV-229E, HCoV-NL63 and human rhinovirus-16 are common cold-associated viruses that exhibit unique features in this model: early induction of antiviral interferon (IFN) signaling, IFN-mediated viral clearance, and preferential replication at nasal airway temperature (33°C) which confers muted host IFN responses. In contrast, lethal SARS-CoV-2 and MERS-CoV encode antagonist proteins that prevent IFN-mediated clearance in nasal cultures. Our study identifies features shared among common cold-associated viruses, highlighting nasal innate immune responses as predictive of infection outcomes and nasally-directed IFNs as potential therapeutics.
Neuropathological assessment of the olfactory bulb and tract in individuals with COVID-19
Authors: Lengacher Nathalie A. , Tomlinson Julianna J. , Jochum Ann-Kristin , Franz Jonas , Ali Omar Hasan , Flatz Lukas , Jochum Wolfram , Penninger Josef ,   aSCENT-PD Investigators, Stadelmann-Nessler Christine , Woulfe John M. , Schlossmacher Michael G. 
Published: December 2023

SummaryThe majority of patients with Parkinson disease (PD) experience a loss in their sense of smell and accumulate insoluble α-synuclein aggregates in their olfactory bulbs (OB). Subjects affected by a SARS-CoV-2-linked illness (COVID-19) frequently experience hyposmia. We previously hypothesized that α-synuclein and tau misprocessing could occur following host responses to microbial triggers. Using semiquantitative measurements of immunohistochemical signals, we examined OB and olfactory tract specimens collected serially at autopsies between 2020 and 2023. Deceased subjects comprised 50 adults, which included COVID19+ patients (n=22), individuals with Lewy body disease (e.g., PD and dementia with Lewy bodies (DLB; n=6)), Alzheimer disease (AD; n=3), other non-synucleinopathy-linked degenerative diseases (e.g., progressive supranuclear palsy (PSP; n=2) and multisystem atrophy (MSA; n=1)). Further, we included neurologically healthy controls (HCO; n=9) and those with an inflammation-rich brain disorder as neurological controls (NCO; n=7). When probing for inflammatory changes focusing on anterior olfactory nuclei (AON) using anti-CD68 immunostaining, scores were consistently elevated in NCO and AD cases. In contrast, inflammation on average was not significantly altered in COVID19+ patients relative to controls, although anti-CD68 reactivity in their OB and tracts declined with progression in age. Mild-to-moderate increases in phospho-αSyn and phospho-tau signals were detected in the AON of tauopathy-and synucleinopathy-afflicted brains, respectively, consistent with mixed pathology, as described by others. Lastly, when both sides were available for comparison in our case series, we saw no asymmetry in the degree of pathology of the left versus right OB and tracts. We concluded from our autopsy series that after a fatal course of COVID-19, microscopic changes -when present-in the rostral, intracranial portion of the olfactory circuitry generally reflected neurodegenerative processes seen elsewhere in the brain. In general, inflammation correlated best with the degree of Alzheimer’s-linked tauopathy and declined with progression of age in COVID19+ patients.
Assessing yellow fever outbreak potential and implications for vaccine strategy
Authors: Fraser Keith , Hamlet Arran , Jean Kévin , Ramos Daniel Garkauskas , Romano Alessandro , Horton Jennifer , Cibrelus Laurence , Ferguson Neil , Gaythorpe Katy A.M. 
Published: December 2023

AbstractBackgroundYellow fever (YF), a vector-borne viral hemorrhagic fever, is endemic in tropical regions of Africa and South America, with large vaccination programmes being used for control. However, significant outbreaks have occurred in recent years. Data on infection rates and seroprevalence is often sparse, requiring robust mathematical models to estimate the burden of yellow fever. In particular, modelling is required to estimate the risk of outbreaks and inform policy decisions regarding the targeting of vaccination.MethodsWe present a dynamic, stochastic model of YF transmission which uses environ-mental covariates to estimate the force of infection due to spillover from the sylvatic (non-human primate) reservoir and the basic reproduction number for human-to-human transmission. We examine the potential for targets identified by the World Health Organization EYE Strategy (50%, 60% or 80% vaccination coverage in 1-60 year olds) to achieve different threshold values for the effective reproduction number. Threshold values are chosen to reflect the potential for seasonal and/or climatic variation in YF transmission even in a scenario where vaccination lowers the median reproduction number below 1.ResultsBased on parameter estimates derived from epidemiological data, it is found that the 2022 EYE Strategy target coverage is sufficient to reduce the static averaged annual effective reproduction numberRbelow 1 across most or all regions in Africa depending on the effectiveness of reported vaccinations, but insufficient to reduce it below 0.5 and thereby eliminate outbreaks in areas with high seasonal range. Coverage levels aligned with the 2026 targets are found to significantly decrease the proportion of regions whereRis greater than 0.5.
The molecular landscape of premature aging diseases defined by multilayer network exploration
Authors: Beust Cécile , Valdeolivas Alberto , Baptista Anthony , Brière Galadriel , Lévy Nicolas , Ozisik Ozan , Baudot Anaïs 
Published: December 2023

AbstractPremature Aging (PA) diseases are rare genetic disorders that mimic some aspects of physiological aging at an early age. Various causative genes of PA diseases have been identified in recent years, providing insights into some dysfunctional cellular processes. However, the identification of PA genes also revealed significant genetic heterogeneity and highlighted the gaps in our understanding of PA-associated molecular mechanisms. Furthermore, many patients remain undiagnosed. Overall, the current lack of knowledge about PA diseases hinders the development of effective diagnosis and therapies and poses significant challenges to improving patient care.Here, we present a network-based approach to systematically unravel the cellular functions disrupted in PA diseases. Leveraging a network community identification algorithm, we delved into a vast multilayer network of biological interactions to extract the communities of 67 PA diseases from their 132 associated genes. We found that these communities can be grouped into six distinct clusters, each reflecting specific cellular functions: DNA repair, cell cycle, transcription regulation, inflammation, cell communication, and vesicle-mediated transport. We propose that these clusters collectively represent the landscape of the molecular mechanisms that are perturbed in PA diseases, providing a framework for better understanding their pathogenesis. Intriguingly, most clusters also exhibited a significant enrichment in genes associated with physiological aging, suggesting a potential overlap between the molecular underpinnings of PA diseases and natural aging.
Neratinib Synergizes with Trastuzumab Antibody Drug Conjugate or with Vinorelbine to Treat HER2 Mutated Breast Cancer Patient Derived Xenografts and Organoids
Authors: Li Shunqiang , Primeau Tina M. , Highkin Maureen K. , Pratt Stephanie L. , Tipton Ashley R. , Vemalapally Nagalaxmi , Monsey John , Tao Yu , Luo Jingqin , Hagemann Ian S. , Lin Chieh-Yu , Eli Lisa D. , Ma Cynthia X. , Bose Ron 
Published: December 2023

AbstractHER2 (ERBB2) is a major therapeutic drug target in breast cancer and The Cancer Genome Atlas (TCGA) Breast Cancer project and other studies have identified HER2 activating mutations in breast cancers without HER2 gene amplification. HER2 activating mutations occur in 2-5% of metastatic breast cancer patients (MBC), and clinical trials have shown that the irreversible pan-HER tyrosine kinase inhibitor, neratinib, produces a 31-40% clinical benefit rate for HER2 mutated MBC patients. We developed breast cancer patient-derived xenografts (PDX) from ER+, HER2 mutated MBC patients and used them to test neratinib-based drug combinations. Using organoid culture of these PDX breast cancer cells, we performed rapid, high-throughputex vivoscreening assays to test novel drug combinations. These organoid culture experiments identified drug synergy with the neratinib plus ado-trastuzumab emtansine (T-DM1) and neratinib plus vinorelbine combinations and we validated these results within vivoPDX experiments.Statement of SignificancePDX’s are a ready source of human cancer organoids, and with thousands of PDX’s already available worldwide, PDX derived organoids (PDxO’s) can dramatically accelerate cancer drug testing. This strategy of PDxO drug testing is particularly useful for rare cancer subtypes or mutations to identify the most promising treatment strategies for clinical trials testing.
Conformational states of the microtubule nucleator, the γ-tubulin ring complex
Authors: Romer Brianna , Travis Sophie M. , Mahon Brian P. , McManus Collin T. , Jeffrey Philip D. , Coudray Nicolas , Raghu Rishwanth , Rale Michael J. , Zhong Ellen D. , Bhabha Gira , Petry Sabine 
Published: December 2023

ABSTRACTMicrotubules (MTs) perform essential functions in the cell, and it is critical that they are made at the correct cellular location and cell cycle stage. This nucleation process is catalyzed by the γ-tubulin ring complex (γ-TuRC), a cone-shaped protein complex composed of over 30 subunits. Despite recent insight into the structure of vertebrate γ-TuRC, which shows that its diameter is wider than that of a MT, and that it exhibits little of the symmetry expected for an ideal MT template, the question of how γ-TuRC achieves MT nucleation remains open. Here, we utilized single particle cryo-EM to identify two conformations of γ-TuRC. The helix composed of 14 γ-tubulins at the top of the γ-TuRC cone undergoes substantial deformation, which is predominantly driven by bending of the hinge between the GRIP1 and GRIP2 domains of the γ-tubulin complex proteins. However, surprisingly, this deformation does not remove the inherent asymmetry of γ-TuRC. To further investigate the role of γ-TuRC conformational change, we used cryo electron-tomography (cryo-ET) to obtain a 3D reconstruction of γ-TuRC bound to a nucleated MT, providing insight into the post-nucleation state. Rigid-body fitting of our cryo-EM structures into this reconstruction suggests that the MT lattice is nucleated by spokes 2 through 14 of the γ-tubulin helix, which entails spokes 13 and 14 becoming more structured than what is observed in apo γ-TuRC. Together, our results allow us to propose a model for conformational changes in γ-TuRC and how these may facilitate MT formation in a cell.
Regulation of lactose and galactose growth: Insights from a unique metabolic gene cluster inCandida intermedia
Authors: Peri Kameshwara V. R. , Yuan Le , Oliveira Fábio Faria , Persson Karl , Alalam Hanna D , Olsson Lisbeth , Larsbrink Johan , Kerkhoven Eduard J , Geijer Cecilia 
Published: December 2023

AbstractLactose assimilation is a relatively rare trait in yeasts, andKluyveromycesyeast species have long served as model organisms for studying lactose metabolism. Meanwhile, the metabolic strategies of most other lactose-assimilating yeasts remain unknown. In this work, we have elucidated the genetic determinants of the superior lactose-growing yeastCandida intermedia. Through genomic and transcriptomic analyses and deletion mutant phenotyping, we identified three interdependent gene clusters responsible for the metabolism of lactose and its hydrolysis product galactose: the conservedLACcluster (LAC12, LAC4) for lactose uptake and hydrolysis, the conservedGALcluster (GAL1, GAL7, GAL10) for galactose catabolism, and a unique “GALLAC”cluster. This novelGALLACcluster, which has evolved through gene duplication and divergence, proved indispensable forC. intermedia’sgrowth on lactose and galactose. The cluster contains the transcriptional activator geneLAC9, second copies ofGAL1andGAL10and theXYL1gene encoding an aldose reductase involved in carbon overflow metabolism. Notably, the regulatory network inC. intermedia, governed by Lac9 and Gal1 from theGALLACcluster, differs significantly from the (ga)lactose regulons inSaccharomyces cerevisiae,Kluyveromyces lactisandCandida albicans. Moreover, although lactose and galactose metabolism are closely linked inC. intermedia, our results also point to important regulatory differences. This study paves the way to a better understanding of lactose and galactose metabolism inC. intermediaand provides new evolutionary insights into yeast metabolic pathways and regulatory networks. In extension, the results will facilitate future development and use ofC. intermediaas a cell-factory for conversion of lactose-rich whey into value-added products.
The potential role of liquid-liquid phase separation in the cellular fate of the compartments for unconventional protein secretion
Authors: Mendes Luis Felipe S. , Gimenes Carolina O. , Silva Marília D. O. da , Rout Saroj K. , Riek Roland , Costa-Filho Antonio J. 
Published: December 2023

AbstractEukaryotic cells have developed sophisticated mechanisms for biomolecule transport, particularly under stress conditions. This study focuses on the unconventional protein secretion (UPS) pathways activated during starvation stress, facilitating the export of soluble leaderless proteins. Specifically, we examine the role of the GRASP family, which is crucial in these processes but has largely unexplored mechanisms, especially regarding the biogenesis and cargo recruitment for the vesicular-like compartment for UPS. Our results reveal that under the circumstances mimicking starvation conditions in yeast, liquid-liquid phase separation (LLPS) is instrumental in the self-association of Grh1, the yeast homologue of GRASP. This association is likely a precursor to the biogenesis of the so-called Compartment for Unconventional Protein Secretion. We demonstrate that Grh1’s self-association involves complex interactions and is regulated by electrostatic, hydrophobic, and hydrogen-bonding forces. Importantly, our study shows that phase-separated states of Grh1 can recruit UPS cargo under starvation-like situations, a significant finding given the minimal interaction between these proteins under normal conditions. Additionally, we address how droplet ageing might affect the ability of cells to return to normal post-stress states. Our findings can potentially enhance our understanding of intracellular protein dynamics and their adaptive responses to stress in eukaryotic cells.
CDCA7 is a hemimethylated DNA adaptor for the nucleosome remodeler HELLS
Authors: Wassing Isabel E. , Nishiyama Atsuya , Hiruta Moeri , Jia Qingyuan , Shikimachi Reia , Kikuchi Amika , Sugimura Keita , Hong Xin , Chiba Yoshie , Peng Junhui , Jenness Christopher , Nakanishi Makoto , Zhao Li , Arita Kyohei , Funabiki Hironori 
Published: December 2023

AbstractMutations of the SNF2 family ATPase HELLS and its activator CDCA7 cause immunodeficiency-centromeric instability-facial anomalies (ICF) syndrome, characterized by hypomethylation at heterochromatin. The unique zinc-finger domain, zf-4CXXC_R1, of CDCA7 is widely conserved across eukaryotes but is absent from species that lack HELLS and DNA methyltransferases, implying its specialized relation with methylated DNA. Here we demonstrate that zf-4CXXC_R1 acts as a hemimethylated DNA sensor. The zf-4CXXC_R1 domain of CDCA7 selectively binds to DNA with a hemimethylated CpG, but not unmethylated or fully methylated CpG, and ICF disease mutations eliminated this binding. CDCA7 and HELLS interact via their N-terminal alpha helices, through which HELLS is recruited to hemimethylated DNA. While placement of a hemimethylated CpG within the nucleosome core particle can hinder its recognition by CDCA7, cryo-EM structure analysis of the CDCA7-nucleosome complex suggests that zf-4CXXC_R1 recognizes a hemimethylated CpG in the major groove at linker DNA. Our study provides insights into how the CDCA7-HELLS nucleosome remodeling complex uniquely assists maintenance DNA methylation.
Network-based anomaly detection algorithm reveals proteins with major roles in human tissues
Authors: Kagan Dima , Jubran Juman , Yeger-Lotem Esti , Fire Michael 
Published: December 2023

AbstractBackgroundAnomaly detection in graphs is critical in various domains, notably in medicine and biology, where anomalies often encapsulate pivotal information. Here, we focused on network analysis of molecular interactions between proteins, which is commonly used to study and infer the impact of proteins on health and disease. In such a network, an anomalous protein might indicate its impact on the organism’s health.ResultsWe propose Weighted Graph Anomalous Node Detection (WGAND), a novel machine learning-based method for detecting anomalies in weighted graphs. WGAND is based on the observation that edge patterns of anomalous nodes tend to deviate significantly from expected patterns. We quantified these deviations to generate features, and utilized the resulting features to model the anomaly of nodes, resulting in node anomaly scores. We created four variants of the WGAND methods and compared them to two previously-published (baseline) methods. We evaluated WGAND on data of protein interactions in 17 human tissues, where anomalous nodes corresponded to proteins with major roles in tissue contexts. In 13 of the tissues, WGAND obtained higher AUC and P@K than baseline methods. We demonstrate that WGAND effectively identified proteins that participate in tissue-specific processes and diseases.ConclusionWe present WGAND, a new approach to anomaly detection in weighted graphs. Our results underscore its capability to highlight critical proteins within protein-protein interaction networks. WGAND holds the promise to enhance our understanding of intricate biological processes and might pave the way for novel therapeutic strategies targeting tissue-specific diseases. Its versatility ensures its applicability across diverse weighted graphs, making it a robust tool for detecting anomalous nodes.