bluuebunny/crossref_metadata_2025_split huggingface dataset:
Integrative analyses of neuroimaging, clinical, and multi-omics data identified meaningful Alzheimer’s disease progression subtypes
Authors: An Qiyuan , Zhang Mengliang , Hu Xinyue , Su Chang , Wang Fei , Zhu Yingying 
Published: November 2022

AbstractAlzheimer’s Disease (AD) is a common neurodegenerative disorder with diverse clinical manifestations. To better understand differences between diverse manifestations, we investigate from the difference in MRI ROI volumes among subtypes to their related different gene pathways. In this study, we identify three subtypes of AD development with fast, moderate, and slow progression rates from the MRI ROI volume biomarkers in the ADNI cohort. We further find differentially expressed proteins in CSF fluids among these AD patients and related significantly different genetic pathways. A total of 159 patients’ data are included for analysis. We identify three distinct subtypes from the hierarchical clustering on MRI ROI volume biomarkers. Subtype 1, characterized as fast progression, consists of 34 patients (21.9%). Subtype 2, as moderate progression, comprises 77 patients (49.6%). Subtype 3, as slow progression, consists of 44 patients (28.3%). These subtypes show significantly differences in cognitive test scores and corresponding genetic pathways.
KA-Search: Rapid and exhaustive sequence identity search of known antibodies
Authors: Olsen Tobias H. , Abanades Brennan , Moal Iain H. , Deane Charlotte M. 
Published: November 2022

ABSTRACTAntibodies with similar amino acid sequences, especially across their complementary-determining regions, often share properties. Finding that an antibody of interest has a similar sequence to naturally expressed antibodies in healthy or diseased repertoires is a powerful approach for the prediction of antibody properties, such as immunogenicity or antigen specificity. However, as the number of available antibody sequences is now in the billions and continuing to grow, repertoire mining for similar sequences has become increasingly computationally expensive. Existing approaches are limited by either being low-throughput, non-exhaustive, not antibody specific, or only searching against entire chain sequences. Therefore, there is a need for a specialized tool, optimized for a rapid and exhaustive search of any antibody region against all known antibodies, to better utilize the full breadth of available repertoire sequences.We introduce Known Antibody Search (KA-Search), a tool that allows for the rapid search of billions of antibody sequences by sequence identity across either the whole chain, the complementarity-determining regions, or a user defined antibody region. We show KA-Search in operation on the ∼2.4 billion antibody sequences available in the OAS database. KA-Search can be used to find the most similar sequences from OAS within 30 minutes using 5 CPUs. We give examples of how KA-Search can be used to obtain new insights about an antibody of interest. KA-Search is freely available athttps://github.com/oxpig/kasearch.
The evolution of the age of onset of resistance to infectious disease
Authors: Buckingham Lydia J. , Ashby Ben 
Published: November 2022

AbstractMany organisms experience an increase in disease resistance as they age but the time of life at which this change occurs varies. Increases in resistance are partially due to prior exposure and physiological constraints but these cannot fully explain the observed patterns of age-related resistance. An alternative explanation is that developing resistance at an earlier age incurs costs to other life-history traits. Here, we explore how trade-offs with host reproduction or mortality affect the evolution of the onset of resistance, depending on when during the host’s life-cycle the costs are paid (only when resistance is developing, only when resistant or throughout the lifetime). We find that the timing of the costs is crucial to determining evolutionary outcomes, often making the difference between resistance developing at an early or late age. Accurate modelling of biological systems therefore relies on knowing not only the shape of trade-offs but also when they take effect. We also find that the evolution of the rate of onset of resistance can result in evolutionary branching. This provides an alternative, possible evolutionary history of populations which are dimorphic in disease resistance, where the rate of onset of resistance has diversified rather than the level of resistance.
Model-driven optimal experimental design for calibrating cardiac electrophysiology models
Authors: Lei Chon Lok , Clerx Michael , Gavaghan David J. , Mirams Gary R. 
Published: November 2022

AbstractModels of the cardiomyocyte action potential (AP) have contributed immensely to the understanding of heart function, pathophysiology, and the origin of heart rhythm disturbances. However, AP models are nonlinear, complex, and can contain more than a hundred differential equations, making them difficult to parameterise. Therefore, cellular cardiac models have been limited to describing ‘average cell’ dynamics, when cell-specific models would be ideal to uncover inter-cell variability but are too experimentally challenging to be achieved. Here, we focus on automatically designing experimental protocols that allow us to better identify cell-specific maximum conductance values for each major current type—optimal experimental designs—for both voltage-clamp and current-clamp experiments. We show that optimal designs are able to perform better than many of the existing experiment designs in the literature in terms of identifying model parameters and hence model predictive power. For cardiac cellular electrophysiology, this approach will allow researchers to define their hypothesis of the dynamics of the system and automatically design experimental protocols that will result in theoretically optimal designs.
FkpA Enhances Membrane Protein Folding using an Extensive Interaction Surface
Authors: Devlin Taylor A. , Marx Dagan C. , Roskopf Michaela A. , Bubb Quenton R. , Plummer Ashlee M. , Fleming Karen G. 
Published: November 2022

AbstractOuter membrane protein (OMP) biogenesis in gram-negative bacteria is managed by a network of periplasmic chaperones that includes SurA, Skp, and FkpA. These chaperones bind unfolded OMPs (uOMPs) in dynamic conformational ensembles to suppress uOMP aggregation, facilitate diffusion across the periplasm, and enhance OMP folding. FkpA primarily responds to heat-shock stress, but its mechanism is comparatively understudied. To determine FkpA chaperone function, we monitored the folding of a cognate client uOmpA171and found that FkpA increases the folded uOmpA171population but also slows the folding rate, dual functions distinct from the other periplasmic chaperones. The results indicate that FkpA behaves as a chaperone and not as a folding catalyst to directly influence the uOmpA171folding trajectory. We determine the binding affinity between FkpA and uOmpA171by globally fitting sedimentation velocity titrations and found it to be intermediate between the known affinities of Skp and SurA for uOMP clients. Notably, complex formation steeply depends on the urea concentration, suggestive of an extensive binding interface. Initial characterizations of the complex using photo-crosslinking indicates that the binding interface spans the inner surfaces of the entire FkpA molecule. In contrast to prior findings, folding and binding experiments performed using subdomain constructs of FkpA demonstrate that the full-length chaperone is required for full activity. Together these results support that FkpA has a distinct and direct effect on uOMP folding and that it achieves this by utilizing an extensive chaperone-client interface.SignificanceThe periplasmic chaperone network is required for the survival and virulence of gram-negative bacteria. Here we find that the chaperone FkpA enhances outer membrane protein folding and tightly binds its clients with an extensive interaction interface. This modified holdase function of FkpA distinguishes it from other periplasmic chaperones and complements their functions to ensure robust outer membrane biogenesis.
A microwell platform for high-throughput longitudinal phenotyping and selective retrieval of organoids
Authors: Sockell Alexandra , Wong Wing , Longwell Scott , Vu Thy , Karlsson Kasper , Mokhtari Daniel , Schaepe Julia , Lo Yuan-Hung , Cornelius Vincent , Kuo Calvin , Van Valen David , Curtis Christina , Fordyce Polly M. 
Published: November 2022

SummaryOrganoids are powerful experimental models for studying the ontogeny and progression of diseases including cancer. Organoids are conventionally cultured in bulk using an extracellular matrix mimic. However, organoids in bulk culture physically overlap, making it impossible to track the growth of individual organoids over time in high throughput. Moreover, local spatial variations in bulk matrix properties make it difficult to assess whether observed phenotypic heterogeneity between organoids results from intrinsic cell differences or microenvironment variability. Here, we developed a microwell-based method that enables high-throughput quantification of image-based parameters for organoids grown from single cells, which can be retrieved from their microwells for sequencing and molecular profiling. Coupled with a deep-learning image processing pipeline, we characterized phenotypic traits including growth rates, cellular movement, and apical-basal polarity in two CRISPR-engineered human gastric organoid models, identifying genomic changes associated with increased growth rate and changes in accessibility and expression correlated with apical-basal polarity.
Integrated Multi-Omics Analysis of Brain Aging in Female Nonhuman Primates Reveals Altered Signaling Pathways Relevant to Age-Related Disorders
Authors: Cox Laura A. , Puppala Sobha , Chan Jeannie , Zimmerman Kip D. , Hamid Zeeshan , Ampong Isaac , Huber Hillary F. , Li Ge , Jadhav Avinash Y. L. , Wang Benlian , Li Cun , Baxter Mark G. , Shively Carol , Clarke Geoffrey D. , Register Thomas C. , Nathanielsz Peter W. , Olivier Michael 
Published: November 2022

AbstractThe prefrontal cortex (PFC) has been implicated as a key brain region responsible for age-related cognitive decline. Little is known about aging-related molecular changes in PFC that may mediate these effects. To date, no studies have used untargeted discovery methods with integrated analyses to determine PFC molecular changes in healthy female primates. We quantified PFC changes associated with healthy aging in female baboons by integrating multiple omics data types (transcriptomics, proteomics, metabolomics) from samples across the adult age span. Our integrated omics approach using unbiased weighted gene co-expression network analysis (WGCNA) to integrate data and treat age as a continuous variable, revealed highly interconnected known and novel pathways associated with PFC aging. We found GABA tissue content associated with these signaling pathways, providing one potential biomarker to assess PFC changes with age. These highly coordinated pathway changes during aging may represent early steps for aging-related decline in PFC functions, such as learning and memory, and provide potential biomarkers to assess cognitive status in humans.
A comprehensive survey of long-range tertiary interactions and motifs in non-coding RNA structures
Authors: Bohdan Davyd R. , Voronina Valeria V. , Bujnicki Janusz M. , Baulin Eugene F. 
Published: November 2022

ABSTRACTUnderstanding the 3D structure of RNA is key to understanding RNA function. RNA 3D structure is modular and can be seen as a composition of building blocks of various sizes called tertiary motifs. Currently, long-range motifs formed between distant loops and helical regions are largely less studied than the local motifs determined by the RNA secondary structure. We surveyed long-range tertiary interactions and motifs in a non-redundant set of non-coding RNA 3D structures. A new dataset of annotated LOng-RAnge RNA 3D modules (LORA) was built using an approach that does not rely on the automatic annotations of non-canonical interactions. An original algorithm, ARTEM, was developed for annotation-, sequence- and topology-independent superposition of two arbitrary RNA 3D modules. The proposed methods allowed us to identify and describe the most common long-range RNA tertiary motifs. Three basic interaction types were identified to be recurrent in the long-range RNA 3D modules: ribose-ribose interactions, canonical Type I and Type II A-minor interactions, and previously undescribed staple interactions. These three interaction types were found to be different building blocks of the same complex staple motifs common to non-coding RNA 3D structures.
Feasibility of intranasal delivery of thin-film freeze-dried, mucoadhesive AS01B-adjuvanted vaccine powders
Authors: Yu Yu-Sheng , AboulFotouh Khaled , Williams Gerallt , Suman Julie , Cano Chris , Warnken Zachary N. , Williams Robert O. , Cui Zhengrong 
Published: November 2022

AbstractIntranasal vaccination by directly applying a vaccine dry powder is appealing. However, a method that can be used to transform a vaccine from a liquid to a dry powder and a device that can be used to administer the powder to the desired region(s) of the nasal cavity are critical for a successful intranasal vaccination. In the present study, using a model vaccine that contains the liposomal AS01Bas an adjuvant and ovalbumin (OVA) as a model antigen, it was shown that thin-film freeze-drying can be applied to convert the liquid vaccine containing sucrose at a sucrose to lipid ratio of 15:1 (w/w), in the presence or absence of carboxymethyl cellulose sodium salt (CMC) as a mucoadhesive agent, into dry powders. Ultimately, the thin-film freeze-dried AS01B/OVA vaccine powder containing 1.9% w/w of CMC (i.e., TFF AS01B/OVA/CMC1.9%powder) was selected for additional evaluation because the TFF AS01B/OVA/CMC1.9%powder was mucoadhesive and maintained the integrity of the antigen and the physical properties of the vaccine. Compared to the TFF AS01B/OVA powder that did not contain CMC, the TFF AS01B/OVA/CMC1.9%powder had a lower moisture content and a higher glass transition temperature and was more porous. In addition, the TFF AS01B/OVA/CMC1.9%thin films were relatively thicker than the TFF AS01B/OVA thin films without CMC. When sprayed with the Unit Dose System Powder (UDSP) nasal device, the TFF AS01B/OVA powder and the TFF AS01B/OVA/CMC1.9%powder generated similar particle size distribution curves, spray patterns, and plume geometries. Importantly, after the TFF AS01B/OVA/CMC1.9%powder was sprayed with the UDSP nasal device, the integrity of the OVA antigen and the AS01Bliposomal adjuvant did not change. Finally, a Taguchi L8 orthogonal array was applied to identify the optimal parameters for using the UDSP device to deliver the TFF AS01B/OVA/CMC1.9%vaccine powder to the middle and lower turbinate and the nasopharynx regions in both adult and child nasal casts. Results from this study showed that it is feasible to apply the TFF technology to transform a nasal vaccine candidate from liquid to a dry powder and then use the UDSP nasal device to deliver the TFF vaccine powder to the desired regions in the nasal cavity for intranasal vaccination.
PdeMIXTA04triggers epidermal cells of placenta to differentiate into poplar catkins through forming MBW complexes withPdeMYCandPdeWD40
Authors: Zhou Fangwei , Wu Huaitong , Chen Yingnan , Tuskan Gerald A. , Yin Tongming 
Published: November 2022

AbstractDifferentiation of plant epidermal cells is a keen research topic in plant biology. Our study onPopulus deltoidesrevealed that epidermal cells of the female flower placenta protruded to form catkin fibers immediately after pollination. We discovered thatPdeMIXTA04was explicitly expressed in placenta of female poplar flowers. Heterologous expression ofPdeMIXTA04inArabidopsisdemonstrated that it significantly promoted the leaf epidermal cells to differentiate into trichomes. Compared with the wild type, significant increases in trichome density and trichome branches were observed on leaves of all35S:PdeMIXTA04transgenic lines. Furthermore, transformation ofPdeMIXTA04in the trichomelessArabidopsismutant(gl1)restored trichome development to that of the wild type. GUS expression in poplar, driven by the promoter ofPdeMIXTA04, also confirmed trichome-specific expression. We then screened a yeast library withPdeMIXTA04and captured two interacting genes,PdeMYCandPdeWD40. Interactions between these two proteins were verified by yeast two-hybrid (Y2H), biomolecular fluorescence complementation (BiFC), dual-luciferase (dual-LUC), and pull-down assays, indicating that PdeMIXTA04 functions through the MYB-BHLH-WD40 (MBW) ternary complex. Our work presents evidence ofPdeMIXTA04as a candidate gene for editing to resolve catkins associated pollution and provides distinctive understanding of the molecular mechanism triggering differentiation of plant epidermal cells.
Combination of Volasertib and Rapamycin Inhibits the Regrowth of TSC2-Deficient Tumors
Authors: Valianou Matthildi , Zhang Erik Y. , Johnson Daniel L. , Meyers Rhett , Markiewski Maciej M. , Karbowniczek Magdalena , Pfeffer Lawrence M. , Yu Jane J. , Bissler John J. , Astrinidis Aristotelis 
Published: November 2022

ABSTRACTMutations inTSC1andTSC2lead to hyperactivation of mTORC1 and cause Tuberous Sclerosis Complex (TSC) and pulmonary Lymphangioleiomyomatosis (LAM). Rapamycin and rapalogs are potent inhibitors of mTORC1 activity and are approved for the treatment of TSC and LAM. Nevertheless, rapalogs do not cause tumor cell death, and cessation of therapy leads to tumor regrowth. Polo-like kinase 1 (PLK1) interacts with and phosphorylates TSC1, and PLK1 inhibition induces apoptosis and attenuates autophagy in TSC1/TSC2-deficient cells. Here we report that the PLK1 inhibitor volasertib decreases the viability and survival and induces apoptosis in 621-101 cells, a TSC-deficient renal angiomyolipoma cell line from a LAM patient. Combined with rapamycin, volasertib further decreased the survival of 621-101 cells.In vivo, volasertib reduced short-term mouse lung colonization by TSC2-deficient cells and decreased the growth of TSC2-deficient subcutaneous tumors. Mice treated with a combination of volasertib and rapamycin had slower tumor relapse after discontinuation of treatment, compared to rapamycin only. Approximately 35 days after discontinuation of treatment, we observed persistent apoptotic markers and gene expression changes for type I interferon signaling in the regrowth tumors from combination-treated mice, compared to rapamycin only. Notably, combination treatment potently inhibited the growth of subcutaneous tumors derived from the rapamycin-refractory cell line ELT3-245. Taken together, our current work demonstrates that for the management of TSC and LAM disease combination of mTORC1 and PLK1 inhibitors in some cases may be advantageous over currently used rapalog monotherapies.
Plant protoplast-based assay to screen for salicylic acid response-modulating bacteria
Authors: Miebach Moritz , Jiang Renji , Jameson Paula E. , Remus-Emsermann Mitja N.P. 
Published: November 2022

ABSTRACTLeaves host remarkably diverse microbes, collectively referred to as the leaf microbiota. While many beneficial functions have been attributed to the plant microbiota, the individual contributions of leaf-colonising bacteria range from pathogenic to mutualistic interactions. Omics approaches demonstrated that some leaf-colonising bacteria evoke substantial changes in gene expression and metabolic profiles in the plant host, including plant immunity. While omic approaches provide a system level view on cellular functions, they are costly and laborious, thereby severely limiting the throughput of the number of bacterial strains that can be testedin planta. To enable cost-effective high-throughput screens, we have developed a plant protoplast-based assay to measure real-time target gene expression changes following bacterial inoculation. Here, protoplasts were isolated from leaves of stable transgenic plants containing a pPR1:eYFP-nls construct. Changes in yellow fluorescence were captured for up to 96 treatments using a plate reader. This allowed the monitoring of changes in the salicylic acid-dependent plant immune response over time. Protoplast isolation per se evoked mild fluorescence responses, likely linked to endogenous salicylic acid production. This is advantageous in a bacterial assay, as bidirectional changes in PR1 expression can be measured. Plate reader-generated data were validated via fluorescence microscopy and RT-qPCR. Fluorescence microscopy further demonstrated heterogeneity in the response of individual protoplasts, which is potentially linked to differences in cell-type. In summary, the protoplast assay is an affordable and easily up-scalable way of measuring changes in target gene expression to bacterial colonisation.
Early maturation and hyperexcitability is a shared phenotype of cortical neurons derived from different ASD-associated mutations
Authors: Hussein Yara , Tripathi Utkarsh , Choudhary Ashwani , Nayak Ritu , Peles David , Rosh Idan , Rabinski Tatiana , Djamus Jose , Vatine Gad , Spiegel Ronen , Garin-Shkolnik Tali , Stern Shani 
Published: November 2022

AbstractAutism Spectrum Disorder (ASD) is characterized mainly by social and sensory-motor abnormal and repetitive behavior patterns. Over hundreds of genes and thousands of genetic variants were reported to be highly penetrant and causative of ASD. Many of these mutations cause comorbidities such as epilepsy and intellectual disabilities (ID). In this study, we measured cortical neurons derived from induced pluripotent stem cells (iPSCs) of patients with four mutations in the genesGRIN2B, SHANK3, UBTF, as well as chromosomal duplication in the 7q11.23 region and compared them to neurons derived from a first-degree relative without the mutation. Using a whole-cell patch-clamp, we observed that the mutant cortical neurons demonstrated hyperexcitability and early maturation compared to control lines. These changes were characterized by increased sodium currents, increased amplitude and rate of excitatory postsynaptic currents (EPSCs), and more evoked action potentials in response to current stimulation in early-stage cell development (3-5 weeks post differentiation). These changes that appeared in all the different mutant lines, together with previously reported data, indicate that an early maturation and hyperexcitability may be a convergent phenotype of ASD cortical neurons.