bluuebunny/crossref_metadata_2025_split huggingface dataset:
Patterns of low-complexity regions in human genes
Authors: Teekas Lokdeep , Vijay Nagarjun 
Published: December 2023

AbstractGenome evolution stands as a paramount determinant for species survival and overall biodiversity on Earth. Among the myriad processes orchestrating genome evolution, the dynamic attributes of length and compositional polymorphism within low-complexity regions (LCR) are the fastest. Clusters of LCR hotspots serve as pivotal conduits connecting different modes of genome evolution, specifically arising through gene duplication events and harboring pivotal sites susceptible to point mutations. Thus, they offer a holistic perspective on the panorama of genome evolution. Furthermore, LCR actively participates in a multifaceted spectrum of neurological, developmental, and cognitive disorders. Despite the substantial body of knowledge concerning the roles of individual LCR-containing genes in the causation of diseases, a comprehensive framework remains conspicuously absent, failing to provide a unified portrayal of LCR-containing genes and their interactions. Furthermore, our understanding of the intricate interplay between paralogy and LCR remains notably deficient. Within this study, we have identified nine clusters of LCR hotspots within the human genome. These clusters are predominantly comprised of closely positioned paralogs, characterized by a significantly higher prevalence of shared LCR and a lower degree of differentiation (FST) across diverse human populations. Moreover, we have unveiled intricate networks of LCR-containing genes engaged in mutual interactions, sharing associations with a spectrum of diseases and disorders, with a particular emphasis on hereditary cancer-predisposing syndromes. Our discoveries shed light on the compelling potential of LCR-containing interacting genes to collectively engender identical diseases or disorders, thereby underscoring their pivotal role in the manifestation of pathological conditions.Significance StatementAmong myriad genome evolution processes, low-complexity regions (LCR) are pivotal, being both the fastest and bridging other evolution modes like gene duplication and point mutations. Understanding LCR-containing paralogous genes is essential to comprehend genetic diseases. Here, we demonstrate that the human genome harbors clusters of LCR hotspots mainly composed of paralogous genes sharing LCR, indicating a role for segmental duplication. The degree of differentiation is significantly lower in clusters of LCR hotspots than in other regions. Moreover, we provide a detailed network of LCR-containing interacting genes associated with shared diseases. Instead of attributing a single disease to an LCR gene, a unified perspective on LCR-containing interacting genes causing the same disease enhances our understanding of LCR-induced disease mechanisms.
Barriers to cascade screening in people at risk of Thoracic Aortic Disease: a mixed methods evaluation from the DECIDE-TAD initiative
Authors: Abbasciano R. G. , Dionne J. , Miksza J. , Oczkowski S. , Barwell J. , Shannon N. , Grant R. , Clift P. , Proietti R. , Hope E. , Ahern U. , Hewytt K. , Ghosh L. , Kaur R. , Lewis M. , Cotton A. , Skinner L. , Saadia H. , McManus G. , Qureshi N. , Aujla H. , Page S. , Sayers R. , Bown M. , Maltby J. , Krasopoulos G. , Cameron D. , Oo A. , Elefteriades J. , Owens G. , Murphy G.J. 
Published: December 2023

BackgroundCascade genetic and imaging screening for relatives of people with non-syndromic thoracic aortic diseases (NS-TAD) is recommended by guidelines. However, the availability and uptake of cascade screening is low. The aim of this study was to use applied health research methods to identify barriers to screening, and strategies to overcome these.MethodsA cohort study using routinely collected health data evaluated barriers to imaging, genetic testing, and treatment for people with NS-TAD. Delphi consensus exercises and workshops evaluated the screening process and patient experience. Focus groups considered strategies to overcome individual and institutional barriers to uptake. A consensus exercise evaluated the evidence to support cascade screening.ResultsA cohort study of 33,793 patients with a TAD diagnosis between 2013 and 2018 demonstrated barriers to treatment and imaging surveillance in females, non-whites, and people from-low socioeconomic backgrounds. A survey of aortic dissection survivors and relatives in England reported that 33/70 (47%) of aortic dissection survivors who responded had undergone genetic testing, including 10/22 (45%) with a positive family history of TAD. In first- and second-degree relatives 66/150 (44%) and 32/155 (21%) of respondents were offered imaging or cascade genetic testing respectively. Only 19/70 (27%) probands and 20/155 (13%) relatives who responded reported that they were involved in shared decisions about their care. Barriers to the uptake of cascade screening included limited awareness of the disease and genetic aetiology, poor health literacy, concerns about cost-effectiveness of screening with low detection rates, requirements for life-long surveillance, and the management of uncertain test results. The consensus exercise demonstrated that the certainty of the evidence to guide cascade screening was Low or Very Low.ConclusionsBarriers to the implementation of cascade screening in people at high-risk for TAD occur at multiple levels suggesting that a complex intervention is required to improve equity of access.
The evolution and convergence of mutation spectra across mammals
Authors: Talenti A. , Wilkinson T. , Morrison L.J. , Prendergast J.G.D. 
Published: December 2023

AbstractDespite the key role genetic mutations play in shaping phenotypic differences between species, little is currently known about the evolution of germline mutation spectra across mammals. Domesticated species are likely particularly interesting case studies because of their high mutation rates and complex evolutionary histories, which can span multiple founding events and genetic bottlenecks. Here we have developed a new reusable workflow, nSPECTRa, that can undertake the key steps in characterising mutation spectra, from determining ancestral alleles to characterising multiple forms of variation. We apply nSPECTRa to seven species, including several that have undergone domestication, and highlight how nSPECTRa can provide important novel insights into mutation rate evolution. While mutation spectra most often show marked differences between species and even breeds, certain mutation types have risen to a high frequency in subpopulations of different species, indicative of convergent evolution in mutation rates. This includes the previously characterized TCC->TTC change enriched among European humans, which is also enriched among East Asian cattle. We show Indicine cattle are particularly interesting examples of how different mutation spectra segregate within a population and subsequently spread across the globe. Together, this work has important implications for understanding the control and evolution of mammalian mutation rates.
Towards the Clinical Translation of a Silver Sulfide Nanoparticle Contrast Agent: Large Scale Production with a Highly Parallelized Microfluidic Chip
Authors: Mossburg Katherine J. , Shepherd Sarah J. , Barragan Diego , O Nathaniel H. , Berkow Emily K. , Maidment Portia S. N. , Berrios Derick N. Rosario , Hsu Jessica C. , Siedlik Michael J. , Yadavali Sagar , Mitchell Michael J. , Issadore David , Cormode David P. 
Published: December 2023

AbstractUltrasmall silver sulfide nanoparticles (Ag2S-NP) have been identified as promising contrast agents for a number of modalities and in particular for dual-energy mammography. These Ag2S-NP have demonstrated marked advantages over clinically available agents with the ability to generate higher contrast with high biocompatibility. However, current synthesis methods are low-throughput and highly time-intensive, limiting the possibility of large animal studies or eventual clinical use of this potential imaging agent. We herein report the use of a scalable silicon microfluidic system (SSMS) for the large-scale synthesis of Ag2S-NP. Using SSMS chips with 1 channel, 10 parallelized channels, and 256 parallelized channels, we determined that the Ag2S-NP produced were of similar quality as measured by core size, concentration, UV-visible spectrometry, andin vitrocontrast generation. Moreover, by combining parallelized chips with increasing reagent concentration, we were able to increase output by an overall factor of 3,400. We also found thatin vivoimaging contrast generation was consistent across synthesis methods and confirmed renal clearance of the ultrasmall nanoparticles. Finally, we found best-in-class clearance of the Ag2S-NP occurred within 24 hours. These studies have identified a promising method for the large-scale production of Ag2S-NP, paving the way for eventual clinical translation.
A Unified Framework for Systematic Curation and Evaluation of Aging Biomarkers
Authors: Ying Kejun , Paulson Seth , Eames Alec , Tyshkovskiy Alexander , Li Siyuan , Perez-Guevara Martin , Emamifar Mehrnoosh , Martínez Maximiliano Casas , Kwon Dayoon , Kosheleva Anna , Snyder Michael P. , Gobel Dane , Herzog Chiara , Poganik Jesse R. ,   Biomarker of Aging Consortium, Moqri Mahdi , Gladyshev Vadim N. 
Published: December 2023

AbstractAging biomarkers are essential for understanding and quantifying the aging process and developing targeted longevity interventions. However, validation of these tools has been hindered by the lack of standardized approaches for cross-population validation, disparate biomarker designs, and inconsistencies in dataset structures. To address these challenges, we developed Biolearn, an open-source library that provides a unified framework for the curation, harmonization, and systematic evaluation of aging biomarkers. Leveraging Biolearn, we conducted a comprehensive evaluation of various aging biomarkers across multiple datasets. Our systematic approach involved three key steps: (1) harmonizing existing and novel aging biomarkers in standardized formats; (2) unifying public datasets to ensure coherent structuring and formatting; and (3) applying computational methodologies to assess the harmonized biomarkers against the unified datasets. This evaluation yielded valuable insights into the performance, robustness, and generalizability of aging biomarkers across different populations and datasets. The Biolearn python library, which forms the foundation of this systematic evaluation, is freely available athttps://Bio-Learn.github.io. Our work establishes a unified framework for the curation and evaluation of aging biomarkers, paving the way for more efficient and effective clinical validation and application in the field of longevity research.
A three-gene expression score for predicting clinical benefit to anti-PD-1 blockade in advanced renal cell carcinoma
Authors: Betancor Yoel Z. , Ferreiro-Pantín Miriam , Anido-Herranz Urbano , Fuentes-Losada Mar , León-Mateos Luis , García-Acuña Silvia Margarita , Vaamonde-Rodríguez Vanessa , García-Pinel Beatriz , Cebey-López Víctor , Villaverde-Viaño Rosa , Kotrulev Martín , Fernández-Díaz Natalia , Gomez-Tourino Iria , Fernández-Baltar Carlos , García-González Jorge , Tubio Jose M. C. , López-López Rafael , Ruiz-Bañobre Juan 
Published: December 2023

AbstractBackgroundIn the advanced renal cell carcinoma (RCC) scenario there are no consistent biomarkers to predict the clinical benefit patients derived from immune checkpoint blockade. We conducted a retrospective study in order to develop and to validate a gene expression score for predicting clinical benefit to nivolumab in the advanced clear cell RCC setting and to characterize its underlying clinical, molecular, and immune features.MethodsThis is apost hocpooled analysis of 311 patients with available clinical, molecular, and immune tumor data from the CheckMate-009, -010 and -025 trials. Efficacy endpoints were overall survival (OS), disease control rate, and overall response rate. Survival estimates were calculated by the Kaplan-Meier method, and groups were compared with the log-rank test. The Cox proportional hazards regression model was used to evaluate factors independently associated with OS. Factors associated with disease control and response were tested with logistic regression. Biomarker-treatment interaction was evaluated with the likelihood ratio test (LRT).ResultsFirst, a three-gene expression score (3GES) with prognostic value for OS integrating HMGA1, NUP62, and ARHGAP42 transcripts was developed in a cohort of patients treated with nivolumab. Favorable 3GES risk category was significantly associated with a better OS in univariable (HR = 0.32, 95% CI 0.21 - 0.48,P<0.001) and multivariable (HR = 0.36, 95% CI 0.24 - 0.56,P<0.001) analyses. Consistent and significant correlation was found with disease control (P=0.066) and response (P=0.002). The 3GES prognostic value was validated in the TCGA-KIRC cohort (HR=0.35,P<0.001). Next, the predictive value for nivolumab was confirmed in a set of patients from the CheckMate-025 trial (LRTP<0.001).ConclusionsIn accRCC, 3GES is not only an independent prognostic factor for OS but also a positive predictive biomarker for nivolumab. The predictive value deserves further validation in other retrospective and large-scale, randomized prospective studies.
ShapeProt: Top-down Protein Design with 3D Protein Shape Generative Model
Authors: Lee Youhan , Kim Jaehoon 
Published: December 2023

AbstractWith the fact that protein functionality is tied to its structure and shape, a protein design paradigm of generating proteins tailored to specific shape contexts has been utilized for various biological applications. Recently, researchers have shown that top-down strategies are possible with the aid of deep learning for the shape-conditioned design. However, state-of-the-art models have limitations because they do not fully consider the geometric and chemical constraints of the entire shape. In response, we propose ShapeProt, a pioneering end-to-end protein design framework that directly generates protein surfaces and generate sequences with considering the entire nature of the generated shapes. ShapeProt distinguishes itself from current protein deep learning models that primarily handle sequence or structure data because ShapeProt directly handles surfaces. ShapeProt framework employs mask-based inpainting and conditioning to generate diverse shapes at the desired location, and these shapes are then translated into sequences using a shape-conditioned language model. Drawing upon various experimental results, we first prove the feasibility of generative design directly on the three-dimensional molecular surfaces beyond sequences and structures.
Single-genome analysis reveals heterogeneous association of the Herpes Simplex Virus genome with H3K27me2 and the reader PHF20L1 following infection of human fibroblasts
Authors: Francois Alison K , Rohani Ali , Loftus Matt , Dochnal Sara , Hrit Joel , McFarlane Steven , Whitford Abigail , Lewis Anna , Krakowiak Patryk , Boutell Chris , Rothbart Scott B. , Kashatus David , Cliffe Anna R 
Published: December 2023

AbstractThe fate of herpesvirus genomes following entry into different cell types is thought to regulate the outcome of infection. For the Herpes simplex virus 1 (HSV-1), latent infection of neurons is characterized by association with repressive heterochromatin marked with Polycomb silencing-associated lysine 27 methylation on histone H3 (H3K27me). However, whether H3K27 methylation plays a role in repressing lytic gene expression in non-neuronal cells is unclear. To address this gap in knowledge, and with consideration that the fate of the viral genome and outcome of HSV-1 infection could be heterogeneous, we developed an assay to quantify the abundance of histone modifications within single viral genome foci of infected fibroblasts. Using this approach, combined with bulk epigenetic techniques, we were unable to detect any role for H3K27me3 during HSV-1 lytic infection of fibroblasts. In contrast, we could detect the lesser studied H3K27me2 on a subpopulation of viral genomes, which was consistent with a role for H3K27 demethylases in promoting lytic gene expression. This was consistent with a role for H3K27 demethylases in promoting lytic gene expression. In addition, viral genomes co-localized with the H3K27me2 reader protein PHF20L1, and this association was enhanced by inhibition of the H3K27 demethylases UTX and JMJD3. Notably, targeting of H3K27me2 to viral genomes was enhanced following infection with a transcriptionally defective virus in the absence of Promyelocytic leukemia nuclear bodies. Collectively, these studies implicate a role for H3K27me2 in fibroblast-associated HSV genome silencing in a manner dependent on genome sub-nuclear localization and transcriptional activity.ImportanceInvestigating the potential mechanisms of gene silencing for DNA viruses in different cell types is important to understand the differential outcomes of infection, particularly for viruses like herpesviruses that can undergo distinct types of infection in different cell types. In addition, investigating chromatin association with viral genomes informs on the mechanisms of epigenetic regulation of DNA processes. However, there is growing appreciation for heterogeneity in the outcome of infection at the single cell, and even single viral genome, level. Here we describe a novel assay for quantifying viral genome foci with chromatin proteins and show that a portion of genomes are targeted for silencing by H3K27me2 and associate with the reader protein PHF20L1. This study raises important questions regarding the mechanism of H3K27me2-specific targeting to viral genomes, the contribution of epigenetic heterogeneity to herpesvirus infection, and the role of PHF20L1 in regulating the outcome of DNA virus infection.
Structural Host-Virus Interactome Profiling of Intact Infected Cells
Authors: Bogdanow Boris , Mühlberg Lars , Gruska Iris , Vetter Barbara , Ruta Julia , Elofsson Arne , Wiebusch Lüder , Liu Fan 
Published: December 2023

ABSTRACTVirus-host protein-protein interactions (PPIs) are fundamental to viral infections, yet high-resolution identification within the native context of intact infected cells has remained an unsolved challenge. Here, we developed structural host-virus interactome profiling (SHVIP) that combinesin situcross-linking mass spectrometry with the enrichment of newly synthesized viral proteins from infected cells. We established SHVIP using herpes simplex virus type 1 and obtained 739 PPIs based on 6,194 cross-links from productively infected cells. SHVIP captures PPIs across intracellular compartments and at the intact host endomembrane system. It resolves PPIs to the protein domain level and seamlessly integrates with AlphaFold-based structural modeling, facilitating detailed predictions of PPI sites within structured and intrinsically disordered regions. We show that SHVIP captures parts of the virus-host PPI space that are elusive to traditional interaction proteomics approaches. By selectively disrupting several newly identified virus-host PPIs, we confirm SHVIP’s ability to uncover genuine virus-host PPIs in the intact complex environment of infected cells.
Multiple HP1 binding motifs in SUV420H2 heterochromatic targeting module
Authors: Nakao Masaru , Sato Yuko , Aizawa Arisa , Kimura Hiroshi 
Published: December 2023

AbstractConstitutive heterochromatin is transcriptionally repressed and densely packed chromatin, typically harboring histone H3 Lys9 trimethylation (H3K9me3) and heterochromatin protein 1 (HP1). SUV420H2, a histone H4 Lys20 methyltransferase, is recruited to heterochromatin by binding to HP1 through its Heterochromatic Targeting Module (HTM). Here, we have identified three HP1 binding motifs within the HTM. Both the full-length HTM and its N-terminal region (HTM-N), which contains the first and second motifs, stabilized HP1 on heterochromatin. The intervening region between the first and second HP1 binding motifs in HTM-N was also crucial for HP1 binding. In contrast, the C-terminal region of HTM (HTM-C), containing the third motif, destabilized HP1 on chromatin. An HTM V374D mutant, featuring a Val374 to Asp substitution in the second HP1 binding motif, localizes to heterochromatin without affecting HP1 stability. These data suggest that the second HP1 binding motif in the SUV420H2 HTM is critical for locking HP1 on H3K9me3-enriched heterochromatin. HTM V374D, tagged with a fluorescent protein, can serve as a live-cell probe to visualize HP1-bound heterochromatin.
Identification of 4-(6-((2-methoxyphenyl)amino)pyrazin-2-yl)benzoic acids as CSNK2A inhibitors with antiviral activity and improved selectivity over PIM3
Authors: Galal Kareem A. , Krämer Andreas , Strickland Benjamin G. , Smith Jeffery L. , Dickmander Rebekah J. , Moorman Nathaniel J. , Willson Timothy M. 
Published: December 2023

AbstractWe report the synthesis of 2,6-disubstituted pyrazines as potent cell active CSNK2A inhibitors. 4’-Carboxyphenyl was found to be the optimal 2-pyrazine substituent for CSNK2A activity, with little tolerance for additional modification. At the 6-position, modifications of the 6-isopropylaminoindazole substituent were explored to improve selectivity over PIM3 while maintaining potent CSNK2A inhibition. The 6-isopropoxyindole analogue6cwas identified as a nanomolar CSNK2A inhibitor with 30-fold selectivity over PIM3 in cells. Replacement of the 6-isopropoxyindole by isosteric ortho-methoxy anilines, such as7c, generated analogues with selectivity for CSNK2A over PIM3 and improved the kinome-wide selectivity. The optimized 2,6-disubstituted pyrazines showed inhibition of viral replication consistent with their CSNK2A activity.Graphical Abstract
Transcriptomic correlates of state modulation in GABAergic interneurons: A cross-species analysis
Authors: Keijser Joram , Hertäg Loreen , Sprekeler Henning 
Published: December 2023

AbstractGABAergic inhibitory interneurons comprise many subtypes that differ in their molecular, anatomical and functional properties. In mouse visual cortex, they also differ in their modulation with an animal’s behavioural state, and this state modulation can be predicted from the first principal component (PC) of the gene expression matrix. Here, we ask whether this link between transcriptome and state-dependent processing generalises across species. To this end, we analysed seven single-cell and single-nucleus RNA sequencing datasets from mouse, human, songbird, and turtle forebrains. Despite homology at the level of cell types, we found clear differences between transcriptomic PCs, with greater dissimilarities between evolutionarily distant species. These dissimilarities arise from two factors: divergence in gene expression within homologous cell types and divergence in cell type abundance. We also compare the expression of cholinergic receptors, which are thought to causally link transcriptome and state modulation. Several cholinergic receptors predictive of state modulation in mouse interneurons are differentially expressed between species. Circuit modelling and mathematical analyses suggest conditions under which these expression differences could translate into functional differences.