bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cellular underpinnings of the selective vulnerability to tauopathic insults in Alzheimer’s disease
Authors: Torok Justin , Maia Pedro D. , Anand Chaitali , Raj Ashish 
Published: July 2023

ABSTRACTNeurodegenerative diseases such as Alzheimer’s disease (AD) exhibit pathological changes in the brain that proceed in a stereotyped and regionally specific fashion, but the cellular and molecular underpinnings of regional vulnerability are currently poorly understood. Recent work has identified certain subpopulations of neurons in a few focal regions of interest, such as the entorhinal cortex, that are selectively vulnerable to tau pathology in AD. However, the cellular underpinnings of regional susceptibility to tau pathology are currently unknown, primarily because whole-brain maps of a comprehensive collection of cell types have been inaccessible. Here, we deployed a recent cell-type mapping pipeline, Matrix Inversion and Subset Selection (MISS), to determine the brain-wide distributions of pan-hippocampal and neocortical neuronal and non-neuronal cells in the mouse using recently available single-cell RNA sequencing (scRNAseq) data. We then performed a robust set of analyses to identify general principles of cell-type-based selective vulnerability using these cell-type distributions, utilizing 5 transgenic mouse studies that quantified regional tau in 12 distinct PS19 mouse models. Using our approach, which constitutes the broadest exploration of whole-brain selective vulnerability to date, we were able to discover cell types and cell-type classes that conferred vulnerability and resilience to tau pathology. Hippocampal glutamatergic neurons as a whole were strongly positively associated with regional tau deposition, suggesting vulnerability, while cortical glutamatergic and GABAergic neurons were negatively associated. Among glia, we identified oligodendrocytes as the single-most strongly negatively associated cell type, whereas microglia were consistently positively correlated. Strikingly, we found that there was no association between the gene expression relationships between cell types and their vulnerability or resilience to tau pathology. When we looked at the explanatory power of cell types versus GWAS-identified AD risk genes, cell type distributions were consistently more predictive of end-timepoint tau pathology than regional gene expression. To understand the functional enrichment patterns of the genes that were markers of the identified vulnerable or resilient cell types, we performed gene ontology analysis. We found that the genes that are directly correlated to tau pathology are functionally distinct from those that constitutively embody the vulnerable cells. In short, we have demonstrated that regional cell-type composition is a compelling explanation for the selective vulnerability observed in tauopathic diseases at a whole-brain level and is distinct from that conferred by risk genes. These findings may have implications in identifying cell-type-based therapeutic targets.
Protein Binding Leads to Reduced Stability and Solvated Disorder in the Polystyrene Nanoparticle Corona
Authors: Somarathne Radha P. , Amarasekara Dhanush L. , Kariyawasam Chathuri S. , Robertson Harley A. , Mayatt Railey , Fitzkee Nicholas C. 
Published: July 2023

AbstractUnderstanding the conformation of proteins in the nanoparticle corona has important implications in how organisms respond to nanoparticle-based drugs. These proteins coat the nanoparticle surface, and their properties will influence the nanoparticle’s interaction with cell targets and the immune system. While some coronas are thought to be disordered, two key unanswered questions are the degree of disorder and solvent accessibility. Here, using a comprehensive thermodynamic approach, along with supporting spectroscopic experiments, we develop a model for protein corona disorder in polystyrene nanoparticles of varying size. For two different proteins, we find that binding affinity decreases as nanoparticle size increases. The stoichiometry of binding, along with changes in the hydrodynamic size, support a highly solvated, disordered protein corona anchored at a small number of enthalpically-driven attachment sites. The scaling of the stoichiometry vs. nanoparticle size is consistent disordered polymer dimensions. Moreover, we find that proteins are destabilized less severely in the presence of larger nanoparticles, and this is supported by measurements of hydrophobic exposure, which becomes less pronounced at lower curvatures. Our observations hold for flat polystyrene surfaces, which, when controlled for total surface area, have the lowest hydrophobic exposure of all systems. Our model provides an explanation for previous observations of increased amyloid fibrillation rates in the presence of larger nanoparticles, and it may rationalize how cell receptors can recognize protein disorder in therapeutic nanoparticles.TOC Image
Prospects for a sequence-based taxonomy of influenza A virus subtypes
Authors: Poon Art F. Y. 
Published: July 2023

AbstractThe hemagglutinin (HA) and neuraminidase (NA) proteins are the primary antigenic targets of influenza A virus (IAV) infections. IAV infections are generally classified into subtypes of HA and NA proteins,e.g., H3N2. Most of the known subtypes were originally defined by a lack of antibody cross-reactivity. However, genetic sequencing has played an increasingly important role in characterizing the evolving diversity of IAV. Novel subtypes have recently been described solely by their genetic sequences, and IAV infections are routinely subtyped by molecular assays,e.g., real-time PCR, or the comparison of sequences to references. In this study, I carry out a phylogenetic analysis of all available IAV protein sequences in the Genbank database (over 1.1 million records) to determine whether the serologically-defined subtypes can be reproduced with sequence-based criteria. I show that a robust genetic taxonomy of HA and NA subtypes can be obtained with a simple clustering method, namely by progressively partitioning the phylogeny on its longest internal branches. However, this taxonomy also requires some amendments to the current nomenclature. For example, two IAV isolates from bats previously characterized as a divergent lineage of H9N2 should be separated into their own subtype. With the exception of these small and highly divergent lineages, the phylogenies relating each of the other six genomic segments do not support partitions into major subtypes.
Massive contractions of Myotonic Dystrophy Type 2-associated CCTG tetranucleotide repeats occur via double strand break repair with distinct requirements for helicases
Authors: Papp David , Hernandez Luis A. , Mai Theresa A. , Haanen Terrance J. , O’Donnell Meghan A. , Duran Ariel T. , Hernandez Sophia M. , Narvanto Jenni E. , Arguello Berenice , Onwukwe Marvin O. , Kolar Kara , Mirkin Sergei M. , Kim Jane C. 
Published: July 2023

AbstractMyotonic Dystrophy Type 2 (DM2) is a genetic disease caused by expanded CCTG DNA repeats in the first intron ofCNBP. The number of CCTG repeats in DM2 patients ranges from 75-11,000, yet little is known about the molecular mechanisms responsible for repeat expansions or contractions. We developed an experimental system inSaccharomyces cerevisiaethat enables selection of large-scale contractions of (CCTG)100within the intron of a reporter gene and subsequent genetic analysis. Contractions exceeded 80 repeat units, causing the final repetitive tract to be well below the threshold for disease. We found that Rad51 and Rad52 are required for these massive contractions, indicating a mechanism that involves homologous recombination. Srs2 helicase was shown previously to stabilize CTG, CAG, and CGG repeats. Loss of Srs2 did not significantly affect CCTG contraction rates in unperturbed conditions. In contrast, loss of the RecQ helicase Sgs1 resulted in a 6-fold decrease in contraction rate with specific evidence that helicase activity is required for large-scale contractions. Using a genetic assay to evaluate chromosome arm loss, we determined that CCTG and reverse complementary CAGG repeats elevate the rate of chromosomal fragility compared to a low-repeat control. Overall, our results demonstrate that the genetic control of CCTG repeat contractions is notably distinct among disease-causing microsatellite repeat sequences.
Using Published Pathway Figures in Enrichment Analysis and Machine Learning
Authors: Shin Min-Gyoung , Pico Alexander R. 
Published: July 2023

AbstractPathway Figure OCR (PFOCR) is a novel kind of pathway database approaching the breadth and depth of Gene Ontology while providing rich, mechanistic diagrams and direct literature support. PFOCR content is extracted from published pathway figures currently emerging at a rate of 1000 new pathways each month. Here, we compare the pathway information contained in PFOCR against popular pathway databases with respect to overall and disease-specific coverage. In addition to common pathways analysis use cases, we present two advanced case studies demonstrating unique advantages of PFOCR in terms of cancer subtype and grade prediction analyses.
The canonical single-stranded DNA binding protein SSB is not an essential replication protein but an RNA chaperon in the hyperthermophilic archaeonSaccharolobus islandicusREY15A
Authors: Xiao Yuanxi , Jiang Zhichao , Zhang Mengqi , Zhang Xuemei , Gan Qi , Yang Yunfeng , Wu Pengju , Feng Xu , Ni Jinfeng , Dong Xiuzhu , She Qunxin , Huang Qihong , Shen Yulong 
Published: July 2023

AbstractSingle-stranded DNA binding proteins (SSBs) have been regarded as indispensable factors in all three domains of life since they play vital roles in DNA replication. Herein, we report that genes coding for the canonical SSB (SisSSB) and the non-canonical SSB (SisDBP) in the hyperthermophilic archaeonSaccharolobus islandicusREY15A can both be deleted. The growth is not affected, and the cell cycle progression and genome stability of the deletion strains is not impaired, suggesting that SisSSB and SisDBP are not essential for cell viability. Interestingly, at a lower temperature (55°C), the protein level of SisSSB increases ∼1.8 fold in the wild type and the growth of ΔSisssband ΔSisssbΔSisdbpis retarded. SisSSB exhibits melting activity on dsRNA and DNA/RNA hybridin vitroand unwinding RNA hairpin inEscherichia coli. Furthermore, the core SisSSB domain is able to complement the absence of the cold shock proteins CspABGE inE. coli, suggesting that SisSSB functions as RNA chaperon. We show that a two-fold overexpression of SisSSB is beneficial to the cell growth at lower temperature, but it has detrimental effect on the cell growth and cell cycle progression at normal growth temperature, which differs from bacterial Csp proteins. Importantly, thesein vitroandin vivoactivities are conserved in SSB subtype SSB-1 in Crenarchaeota species that lack bacterial Csp homologs. Overall, we have clarified the function of the archaeal canonical SSB which does not function as a DNA processing factor, but plays a role in processes requiring dsRNA or DNA/RNA hybrid unwinding.
Genetic mixing and demixing on expanding spherical frontiers
Authors: Vázquez Alba García , Mitarai Namiko , Jauffred Liselotte 
Published: July 2023

ABSTRACTGenetic fluctuation during range expansion is a key process driving evolution. When a bacterial population is expanding on a 2D surface, random fluctuations in the growth of the pioneers at the front line cause a strong de-mixing of genotypes. Even when there is no selective advantage, sectors of low genetic diversity are formed. Experimental studies of range expansions in surface-attached colonies of fluorescently-labeled microorganisms have contributed significantly to our understanding of fundamental evolutionary dynamics. However, experimental studies on genetic fluctuations in 3D range expansions have been sparse, despite their importance for tumour or biofilm development. We encapsulated populations of two fluorescentEscherichia colistrains in inoculation droplets (volumes ∼0.1 nl). The confined ensemble of cells grew when embedded in a hydrogel – with nutrients – and developed 3D colonies with well-defined, sector-like regions. Using a confocal laser scanning microscope (CLSM), we imaged the development of 3D colonies and the emergence of sectors. We characterised how cell concentration in the inoculation droplet controls sectors, growth rate, and the transition from branched colonies to quasi-spherical colonies. We further analysed how sectors on the surface change over time. We complement these experimental results with a modified 3D Eden growth model. The model in 3D spherical growth predicts a phase, where sectors are merging, followed by a steady increase (constant rate), and the experimentally analysed sectors were consistent with this prediction. Ergo, our results demonstrate qualitative differences between radial (2D) and spherical (3D) range expansions and their importance in gene fixation processes.
Outer membrane vesicles as realistic models of bacterial membranes in interaction studies by Surface Plasmon Resonance
Authors: Bril’kov Maxim S. , Stenbakk Victoria , Jakubec Martin , Vasskog Terje , Kristoffersen Tone , Cavanagh Jorunn Pauline , Ericson Johanna U. , Isaksson Johan , Flaten Gøril Eide 
Published: July 2023

AbstractOne way to mitigate the ongoing antimicrobial resistance crisis is to discover and develop new classes of antibiotics. As all antibiotics at some point needs to either cross or interact with the bacterial membrane, there is a need for representative models of bacterial membranes and efficient methods to characterize the interactions to novel antimicrobials – both to generate new knowledge and to screen compound libraries. Since the bacterial cell envelope is a complex assembly of lipids, lipopolysaccharides, membrane proteins and other components, constructing realistic synthetic liposome-based models of the membrane is both difficult and expensive.We here propose to let the bacteria do the hard work for us. Outer membrane vesicles (OMVs) are naturally secreted by Gram-negative bacteria, playing a role in communication between bacteria, as virulence factors, molecular transport or being a part of the antimicrobial resistance mechanism. OMVs consist of the bacterial outer membrane and thus inherit many components and properties of the native outer cell envelope. In this work we have isolated and characterized OMVs fromE. colimutant strains and clinical isolates of the ESKAPE membersKlebsiella pneumoniae, Acinetobacter baumanniiandPseudomonas aeruginosa. The OMVs were shown to be representative models for the bacterial membrane in terms of lipid composition with strain specific variations. The OMVs were further used to probe the interactions between OMV and antimicrobial peptides (AMPs) as model compounds by Surface Plasmon Resonance (SPR) and provide proof-of-principle that OMVs can be used as an easily accessible and highly realistic model for the bacterial surface in interaction studies. This further enables direct monitoring of the effect of induction by antibiotics, or the response to host-pathogen interactions.
Characterization of Novel Peptides with Antimicrobial and Immunomodulatory Potential
Authors: Kakkerla Swetha , Kavela Sridhar , Kadivella Mohammad , Thupurani Murali Krishna , Chintalpani Sathvika 
Published: July 2023

AbstractIn this study, we designed six peptides based on the characteristics of natural antimicrobial peptides (AMPs), including small size, cationicity, amphipathicity, andα-helix structure. The peptides were evaluated for their antimicrobial activity, hemolytic potential, binding affinity to TLR4/MD-2 receptors, and immunomodulatory effects. Five out of the six designed peptides were classified as AMPs, while one peptide was predicted to be a non-antimicrobial peptide (NAMP) by the AxPEP server. The designed peptides exhibited varying degrees of antimicrobial activity against Escherichia coli, Staphylococcus aureus, Klebsiella pneumoniae, and Pseudomonas aeruginosa, with SK1217 and SK1260 demonstrating stronger antimicrobial potential. Hemolytic assays revealed minimal hemolytic activity for SK1203, SK1217, SK1260, and SK1281, indicating a low propensity to cause red blood cell (RBC) lysis. However, SK1286 and SK1283 exhibited significant hemolytic effects at higher concentrations, with SK1286 causing complete hemolysis at 100 μg/mL. Molecular docking analysis showed favourable binding affinities of SK1260, SK1217, and SK1286 with TLR4/MD-2 receptors. Furthermore, SK1260 displayed potent immunomodulatory activity, reducing the release of pro-inflammatory cytokines IL-6 and TNF-α in LPS-stimulated macrophage cells. Cell viability assays demonstrated minimal cytotoxicity of SK1260. In vivo studies on infected mice showed that SK1260 treatment increased leukocyte recruitment and cytokine levels (GM-CSF, INF-g, and MCP-1) in the peritoneal lavage fluid. Overall, these findings highlight the promising potential of these cationic AMPs as antimicrobial and immunomodulatory agents for further therapeutic exploration.
Deep FASTQ and BAM co-compression in Genozip 15
Authors: Lan Divon Mordechai , Hughes Daniel S.T. , Llamas Bastien 
Published: July 2023

AbstractWe introduce Genozip Deep, a method for losslessly co-compressing FASTQ and BAM files. Benchmarking demonstrates improvements of 75% to 96% versus the already-compressed source files, translating to 2.3X to 6.8X better compression than current state-of-the-art algorithms that compress FASTQ and BAM separately. The Deep method is independent of the underlying FASTQ and BAM compressors, and here we present its implementation in Genozip, an established genomic data compression software.
SALL4B, not targeted by IMiD, is important for SALL4-mediated tumorigenesis
Authors: L. Vu Kim Anh , Kumari Kalpana , Liu Bee Hui , Gao Chong , Li Feng , Tang Jing Ping , Maddalo Danilo , Auld Douglas S. , Casalena Dominick E. , Tian Xi , Liu Miao , Bassal Mahmoud A. , Moein Shiva , Iakovleva Viktoriia , Tan Justin L. , Stein Alicia J. , Zhou Qiling , Fischer Patrick D. , Sigua Logan H. , Qi Jun , Arthanari Haribabu , Tenen Daniel G. , Chai Li 
Published: July 2023

AbstractOncofetal transcription factor SALL4 is essential for cancer cell survival.1-5Recently, several groups reported that immunomodulatory imide drugs (IMiDs) could degrade SALL4 in a proteasome-dependent manner.6,7Intriguingly, we observed that IMiDs had no effect on SALL4-positive cancer cells. Further studies demonstrated that IMiDs could only degrade SALL4A, one of the SALL4 isoforms. This finding raises the possibility that SALL4B, the isoform not affected by IMiDs, may be essential for SALL4-mediated cancer cell survival. SALL4B knockdown led to an increase in apoptosis and inhibition of cancer cell growth. SALL4B gain-of-function alone led to liver tumor formation in mice. Our observation that protein degraders can possess isoform-specific effects exemplifies the importance of delineating drug action and oncogenesis at the isoform level to develop more effective cancer therapeutics.
Semi-supervised integration of single-cell transcriptomics data
Authors: Andreatta Massimo , Hérault Léonard , Gueguen Paul , Gfeller David , Berenstein Ariel J , Carmona Santiago J 
Published: July 2023

AbstractSingle-cell sequencing technologies offer unprecedented opportunities to characterize the complexity of biological samples with high resolution. At the same time, variations in sample processing and experimental protocols introduce technical variability – or “batch effects” – in the molecular readouts, hindering comparative analyses across samples and individuals. Although batch effect correction methods are routinely applied in single-cell omics analyses, data integration often leads to overcorrection, resulting in the loss of true biological variability. In this study, we present STACAS v2, a semi-supervised scRNA-seq data integration method that leverages prior knowledge in the form of cell type annotations to preserve biological variance. Through an open and reproducible benchmarking pipeline, we show that semi-supervised STACAS outperforms popular unsupervised methods such as Harmony, FastMNN, Seurat v4, scVI, and Scanorama, as well as supervised methods such as scANVI and scGen. Notably, STACAS is robust to incomplete and imprecise cell type annotations, which are commonly encountered in real-life integration tasks. Highlighting its scalability, we successfully applied semi-supervised STACAS to construct a high-resolution map of tumor-infiltrating CD8 T cells encompassing over 500,000 cells from 265 individuals. Based on our findings, we argue that the incorporation of prior cell type information should be a common practice in single-cell data integration, and we provide a flexible framework for semi-supervised batch effect correction. STACAS seamlessly integrates with Seurat pipelines and can be run with one command: Run.STACAS(seurat.list, cell.labels).
Dissociable encoding of motivated behavior by parallel thalamo-striatal projections
Authors: Beas Sofia , Khan Isbah , Gao Claire , Loewinger Gabriel , Macdonald Emma , Bashford Alison , Rodriguez-Gonzalez Shakira , Pereira Francisco , Penzo Mario A. 
Published: July 2023

SUMMARYThe successful pursuit of goals requires the coordinated execution and termination of actions that lead to positive outcomes. This process is thought to rely on motivational states that are guided by internal drivers, such as hunger or fear. However, the mechanisms by which the brain tracks motivational states to shape instrumental actions are not fully understood. The paraventricular nucleus of the thalamus (PVT) is a midline thalamic nucleus that shapes motivated behaviors via its projections to the nucleus accumbens (NAc)1–8and monitors internal state via interoceptive inputs from the hypothalamus and brainstem3,9–14. Recent studies indicate that the PVT can be subdivided into two major neuronal subpopulations, namely PVTD2(+)and PVTD2(–), which differ in genetic identity, functionality, and anatomical connectivity to other brain regions, including the NAc4,15,16. In this study, we used fiber photometry to investigate thein vivodynamics of these two distinct PVT neuronal types in mice performing a reward foraging-like behavioral task. We discovered that PVTD2(+)and PVTD2(−)neurons encode the execution and termination of goal-oriented actions, respectively. Furthermore, activity in the PVTD2(+)neuronal population mirrored motivation parameters such as vigor and satiety. Similarly, PVTD2(−)neurons, also mirrored some of these parameters but to a much lesser extent. Importantly, these features were largely preserved when activity in PVT projections to the NAc was selectively assessed. Collectively, our results highlight the existence of two parallel thalamo-striatal projections that participate in the dynamic regulation of goal pursuits and provide insight into the mechanisms by which the brain tracks motivational states to shape instrumental actions.