bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cell competition for cancer treatment with Urine Progenitor Cells
Authors: Bagó Juli R. , Radhakrishnan Dhwani , Hrdinka Matouš , Cichoń Tomasz , Smolarczyk Ryszard , Charvátová Sandra , Motais Benjamin , Giebel Sebastian , Hájek Roman 
Published: August 2023

AbstractHere, we provide evidence that urine progenitor cells (UPCs) might offer a novel therapeutic strategy for treating different types of cancer. We found that UPCs have inherent antitumor properties due to cell-cell competition, and we described their mechanism of action against different tumor cell lines.In vitrotime-lapse analysis showed that the UPCs have tumor tropic properties, homing to various tumor-conditioned mediums. Besides, UPCs engineered for the expression of cytotoxic agents (the Tumor Necrosis Factor ligand superfamily member 10 and Herpesvirus-thymidine kinase) significantly increased their antitumor properties against several tumor cell lines and proved to serve as highly effective drug-delivery vehicles. Finally, using a mouse model of human triple-negative breast cancer, we observed a 150-fold decrease in tumor volumes in mice treated with engineered UPCs compared to controls. Collectively, our findings demonstrate for the first time the antitumor properties of the UPCs and form a foundation to continue exploring the new concept of cell-cell competition in progenitor cells to treat different types of cancer.
Functional annotation of a divergent genome using sequence and structure-based homology
Authors: Svedberg Dennis , Winiger Rahel R. , Berg Alexandra , Sharma Himanshu , Tellgren-Roth Christian , Debrunner-Vossbrinck Bettina A. , Vossbrinck Charles R. , Barandun Jonas 
Published: August 2023

AbstractBackgroundMicrosporidia are a large taxon of intracellular pathogens characterized by extraordinarily streamlined genomes with unusually high sequence divergence and many species-specific adaptations. These unique factors pose challenges for traditional genome annotation methods based on sequence homology. As a result, many of the microsporidian genomes sequenced to date contain numerous genes of unknown function. Recent innovations in rapid and accurate structure prediction and comparison, together with the growing amount of data in structural databases, provide new opportunities to assist in the functional annotation of newly sequenced genomes.ResultsIn this study, we established a workflow that combines sequence and structure-based functional gene annotation approaches employing a ChimeraX plugin, allowing for visual inspection and manual curation. We employed this workflow on a high-quality telomere-to-telomere sequenced tetraploid genome ofVairimorpha necatrix. First, the 3080 predicted open reading frames, of which 89 % were confirmed with RNA sequencing data, were used as input. Next, ColabFold was used to create protein structure predictions, followed by a Foldseek search for structural matching to the PDB and AlphaFold databases. The subsequent manual curation, using sequence and structure-based hits, increased the accuracy and quality of the functional genome annotation compared to results using only traditional annotation tools. Our workflow resulted in a comprehensive description of theV. necatrixgenome, along with a structural summary of the most prevalent protein groups, such as the ricin B lectin family. In addition, and to test our tool, we identified the functions of several previously uncharacterizedEncephalitozoon cuniculigenes.ConclusionWe provide a new functional annotation tool for divergent organisms and employ it on a newly sequenced, high-quality microsporidian genome to shed light on this uncharacterized intracellular pathogen of Lepidoptera. The addition of a structure-based annotation approach can serve as a valuable template for studying other microsporidian or similarly divergent species.
Prior Uncertainty Impedes Discrete Locomotor Adaptation
Authors: Jiang Aojun , Grover Francis M. , Bucklin Mary , Deol Jasjit , Shafer Anna , Gordon Keith E. 
Published: August 2023

AbstractThe impact of environmental uncertainty on locomotor adaptation remains unclear. Environmental uncertainty could either aid locomotor adaptation by prompting protective control strategies that stabilize movements to assist learning or impede adaptation by reducing error sensitivity and fostering hesitance to pursue corrective movements. To explore this, we investigated participants’ adaptation to a consistent viscous force field after experiencing environmental uncertainty in the form of unpredictable balance perturbations. We compared the performance of this group (Perturbation) to the adaptive performance of a Control group that did not experience any unpredictable perturbations. Perturbations were delivered using a cable-driven robotic device applying lateral forces to the pelvis. We assessed whole-body center of mass (COM) trajectory (COM signed deviation), anticipatory postural adjustments (COM lateral offset), and first step width. The Perturbation group exhibited larger disruptions in COM trajectory (greater COM signed deviations) than the Control group when first walking in the force field. While the COM signed deviations of both groups decreased towards baseline values, only the Control group returned to baseline levels. The Perturbation groups COM signed deviations remained higher, indicating they failed to fully adapt to the force field before the end. The Perturbation group also did not adapt their COM lateral offset to counter the predictable effects of the force field as the Control group did, and their first step width increased more slowly. Our findings suggest that exposure to unpredictable perturbations impeded future sensorimotor adaptations to consistent perturbations.
A novel, N2-fixing cyanobacterium present and active in the global oceans
Authors: Cleveland Catie S. , Turk-Kubo Kendra A. , Zhao Yiming , Zehr Jonathan P. , Webb Eric A. 
Published: August 2023

AbstractMarine N2-fixing cyanobacteria, including the unicellular genusCrocosphaera, are considered keystone species in marine food webs.Crocosphaeraare globally distributed and provide new sources of nitrogen (N) and carbon (C), which fuel oligotrophic microbial communities and upper trophic levels. Despite their ecosystem importance, only one species,Crocosphaera watsonii, has ever been identified and characterized as widespread in the oligotrophic oceans. Herein, we present a novel species, candidatusCrocosphaera waterburyi(C. waterburyihereafter), enriched from the North Pacific Ocean, activein situ, and globally distributed in environmental datasets.C. waterburyiis morphologically, phylogenetically, and physiologically distinct fromC. watsonii; therefore, description of this novel species provides a new window into previously uncharacterized diversity and ecology of unicellular N2-fixing cyanobacterial taxa and further highlights their importance in the global N cycle.
Endothelial mechanobiology under controlled disturbed flows
Authors: Paddillaya Neha , Mahulkar Suyog , Arakeri Jaywant H , Gundiah Namrata 
Published: August 2023

AbstractEarly atherosclerotic lesions often develop in areas of disturbed flow within arterial curvatures and bifurcations. Complex flows alter the signaling of inflammatory and other signaling molecules that may exacerbate the disease phenotype. Microfluidic platforms to assess changes in endothelial mechanobiology generally employ laminar unidirectional or oscillatory flows generated in straight channels; such platforms do not however mimic the complex time-varying bi-directional shear patterns on arterial walls. We fabricated an endothelium-on-chip device to generate “controlled” disturbed flows, characterized using a wall shear rosette, such as those reported in aneurysmal vessels and in regions with atherosclerotic plaques. We cultured human aortic endothelial cells (HAEC) in the device and subjected the monolayer to a circular shear rosette which represents bidirectional and oscillatory shear stresses. Immunofluorescence results show large cuboidal cells with significantly higher nuclear areas, changes in the localization of VE-Cadherin, elevated actin and NF-kB expressions in the device as compared to cell monolayers subjected to laminar flow, unidirectional oscillatory flow, and No-flow conditions. The creation of a dysfunctional endothelial monolayer due to bidirectional oscillatory flows also correlated with dramatic changes to the lamin A/C distribution and heterochromatin organization in the nucleus that have not been reported earlier. Such studies are potentially useful to assess novel therapeutics, mitigate effects of vascular disease for personalized medicine, study thrombus creation in the vicinity of inflamed endothelial monolayers, and reduce ourreliance on animal trials. Our device and analytical method represent the first successful demonstration of generating controlled disturbed flows in microfluidic devices
Prolonged survival of a patient with active MDR-TB HIV co-morbidity: Insights from a Mycobacterium tuberculosis strain with a unique genomic deletion
Authors: Rubinstein Mor , Makhon Andrei , Losev Yelena , Valenci Gal Zizelski , Gatt Yair E. , Margalit Hanah , Fass Ephraim , Kutikov Ina , Murik Omer , Zeevi David A. , Savyon Michal , Tau Luba , Shwartz Hasia Kaidar , Dveyrin Zeev , Rorman Efrat , Nissan Israel 
Published: August 2023

AbstractCoinfection of HIV and multidrug-resistant tuberculosis (MDR-TB) presents significant challenges in terms of the treatment and prognosis of tuberculosis, leading to complexities in managing the disease and impacting the overall outcome for TB patients. This study presents a remarkable case of a patient with MDR-TB and HIV coinfection who survived for over eight years, despite poor treatment adherence and comorbidities. Whole genome sequencing (WGS) of the infectingMycobacterium tuberculosis(Mtb) strain revealed a unique genomic deletion, spanning 18 genes, including key genes involved in hypoxia response, intracellular survival, immunodominant antigens and dormancy. This deletion, that we have called “Del-X”, potentially exerts a profound influence on the bacterial physiology and its virulence. Only few similar deletions were detected in other non-relatedMtbgenomes worldwide.In vivoevolution analysis identified drug resistance and metabolic adaptation mutations and their temporal dynamics during the patient’s treatment course.
A platform for standardized, online delivered, clinically applicable neurocognitive assessment: Webneuro
Authors: Williams Leanne M. 
Published: August 2023

ABSTRACTWe are in the midst of a paradigm shift in which we see a precision mental health and the emergence of brain-based assessments for personalizing treatments. The precision emphasis of precision mental health includes a focus on measurement. Within the biopsychosocial domains of measurement, objective measures of cognitive function have an important role in disorders of mental health. Here, data integrating the development, norming, validation, psychometric testing and clinical application of a web-delivered neurocognitive assessment (WebNeuro) are presented. Data are from 1,000 healthy participants and over 500 clinical participants across diagnoses. Results provide norms across nine decades, and demonstrate the construct validity, internal consistency, and test-retest reliability of WebNeuro. Findings also show that WebNeuro identifies neurocognitive impairments across multiple neuropsychiatric disorders.
Brain-Derived CCN3 Is An Osteoanabolic Hormone That Sustains Bone in Lactating Females
Authors: Babey Muriel E. , Krause William C. , Herber Candice B. , Chen Kun , Nikkanen Joni , Rodriquez Ruben , Zhang Xiao , Castro-Navarro Fernanda , Wang Yuting , Villeda Saul , Lane Nancy E. , Scheller Erica L. , Chan Charles K.F. , Ambrosi Thomas H. , Ingraham Holly A. 
Published: August 2023

ABSTRACTIn lactating mothers, the high calcium (Ca2+) demand for milk production triggers significant bone resorption. While estrogen would normally counteract excessive bone loss and maintain sufficient bone formation during this postpartum period, this sex steroid drops precipitously after giving birth. Here, we report that brain-derived CCN3 (Cellular Communication Network factor 3) secreted from KISS1 neurons of the arcuate nucleus (ARCKISS1) fills this void and functions as a potent osteoanabolic factor to promote bone mass in lactating females. Using parabiosis and bone transplant methods, we first established that a humoral factor accounts for the female-specific, high bone mass previously observed by our group after deleting estrogen receptor alpha (ERα) from ARCKISS1neurons1. This exceptional bone phenotype in mutant females can be traced back to skeletal stem cells (SSCs), as reflected by their increased frequency and osteochondrogenic potential. Based on multiple assays, CCN3 emerged as the most promising secreted pro-osteogenic factor from ARCKISS1neurons, acting on mouse and human SSCs at low subnanomolar concentrations independent of age or sex. That brain-derived CCN3 promotes bone formation was further confirmed by in vivo gain- and loss-of-function studies. Notably, a transient rise in CCN3 appears in ARCKISS1neurons in estrogen-depleted lactating females coincident with increased bone remodeling and high calcium demand. Our findings establish CCN3 as a potentially new therapeutic osteoanabolic hormone that defines a novel female-specific brain-bone axis for ensuring mammalian species survival.
Discovery and engineering of AiEvo2, a novel Cas12a nuclease for human gene editing applications
Authors: Sharrar Allison , Arake de Tacca Luisa , Meacham Zuriah , Staples-Ager Johanna , Collingwood Trevor , Rabuka David , Schelle Michael 
Published: August 2023

AbstractThe precision of gene editing technology is critical to creating safe and effective therapies for treating human disease. While the programmability of CRISPR-Cas systems has allowed for rapid innovation of new gene editing techniques, the off-target activity of these enzymes has hampered clinical development for novel therapeutics. Here we report the identification and characterization of a novel CRISPR-Cas12a enzyme fromAcinetobacter indicus(AiCas12a). We then engineer the nuclease (termed AiEvo2) for increased specificity, PAM recognition, and efficacy on a variety of human clinical targets. AiEvo2 is highly precise and able to efficiently discriminate between normal and disease-causing alleles in Huntington’s patient derived cells by taking advantage of a single nucleotide polymorphism on the disease-associated allele. AiEvo2 efficiently edits several liver-associated target genes including PCSK9 and TTR when delivered to primary hepatocytes as mRNA encapsulated in a lipid nanoparticle. The enzyme also engineers an effective CD19 CAR-T therapy from primary human T cells using multiplexed simultaneous editing and CAR insertion. To further ensure precise editing, we engineered an anti-CRISPR protein (ErAcr) to selectively inhibit off-target gene editing while retaining therapeutic on-target editing. The engineered AiEvo2 nuclease coupled with a novel ErAcr protein represents a new way to control the fidelity of editing and improve the safety and efficacy of gene editing therapies.
Dark adaptation is not necessary to drive the proliferative regeneration response in the adult zebrafish retina
Authors: Hemerson Marlo , Muhr Jeremy , Pferdmenges Lauren , Jiudice Sarah , Ackerman Kristin M. 
Published: August 2023

AbstractMacular degeneration, retinal detachment, and retinitis pigmentosa are eye diseases which cause damage to the photoreceptors and are considered leading causes of vision loss worldwide (National Eye Institute, 2022). Thus, developing animal models to study processes related to retinal damage, specifically loss of photoreceptors and their pending degeneration/regeneration is critical. This study aims to modify current light-induced retinal degeneration (LIRD) protocols within the zebrafish model to more efficiently replicate the proliferative response that drives regeneration. The most common LIRD model incorporates a 10-14 day dark adaptation period followed by multiple days of constant intense light exposure designed to damage the retinas and induce a proliferation response (Thomas et al., 2012; Vihtelic & Hyde, 2000). Modified procedures have been published and demonstrate that shortened 24-hour dark adaptation periods still result in cellular damage via apoptosis, but the proliferation response (i.e., pending regeneration) was not examined (Khan et al., 2020). Therefore, our study aims to fully eliminate dark adaptation and will use changes in retinal morphology and proliferation as the hallmark of a successfully initiated regeneration response. Dark-adapted (DA-control fish) and non-dark-adapted (NDA-experimental fish) were taken off their housing system and exposed to constant intense light for 24, 36, and 48 hr. to ensure enough time for damage and proliferation to proceed. Retinas were cross-sectioned to include dorsal and ventral retina, immunohistochemically labeled, and the outer nuclear layer (ONL), inner nuclear layer (INL), cones, and proliferation cell nuclear antigen (PCNA)-positive cells were analyzed to determine the level of structural integrity, if cell photoreceptor numbers were altered, and if proliferation occurred in response to light exposure. Dark-adapted (DA) and non-dark-adapted (NDA) zebrafish retinas displayed similar damage and increased proliferation responses to the constant intense light, indicating that the 10–14-day dark adaptation period is not necessary to induce regeneration in adult zebrafish retinas, reducing experimental timing by two weeks.
MoMA: Large scale network model of Microbes, Metabolites and Aging hallmarks
Authors: Menon Sarvesh , Bapatdhar Nishad , Kumar Bipin Pradeep , Ghosh Samik 
Published: August 2023

AbstractThe gut microbiome is known to be a driver of age-related health decline. Various studies have shone light on the role of the gut microbiome as a marker as well as modulator of aging processes. However, the mechanisms by which the microbiome affects aging are still unclear. We have developed a Microbiome Metabolite Aging (MMA) fusion network by building upon a metabolic interaction network of gut microbiota to develop associations with the hallmarks of aging. The MMA, consisting of 238 metabolite-aging hallmark interactions serves as a tool to investigate the mammalian (and in particular human) gut microbiome as an effector of aging at a systems-level. The network further identifies 249 microbes that unequivocally affect the hallmarks of aging. The results highlight how the underlying biology of microbial metabolite mediated interactions, in conjunction with the topological properties at a network level, differentially regulate the aging hallmarks. This detailed microbial and metabolite association to the hallmarks of aging provides a foundation which is envisaged to be instrumental in advancing our knowledge of the physiology of aging, and for the development of novel therapeutic tools.
The utility of CRISPR activation as a platform to identify interferon stimulated genes with anti-viral function
Authors: Kirby Emily N. , Montin Xavier B. , Allen Timothy P. , Densumite Jaslan , Trowbridge Brooke N. , Beard Michael R. 
Published: August 2023

AbstractInterferon Stimulated Genes (ISGs) play key roles in the control of viral replication and dissemination. Understanding this dynamic relationship between the pathogen and host is critical to our understanding of viral life-cycles and development of potential novel anti-viral strategies. Traditionally, plasmid based exogenous prompter driven expression of ISGs has been used to investigate anti-viral ISG function, however there are deficiencies in this approach. To overcome this, we investigated the utility of CRISPR activation (CRISPRa), which allows for targeted transcriptional activation of a gene from its endogenous promoter. Using the CRISPRa-SAM system to induce targeted expression of a panel of anti-viral ISGs we showed robust induction of mRNA and protein expression. We then employed our CRISPRa-SAM ISG panel in several antiviral screen formats to test for the ability of ISGs to prevent viral induced cytopathic cell death (CPE) and replication of Dengue Virus (DENV), Zika Virus (ZIKV), West Nile Virus Kunjin (WNVKUNV), Hepatitis A Virus (HAV) and Human Coronavirus 229E (HCoV-229E). Our CRISPRa approach confirmed the anti-viral activity of ISGs like IFI6, IFNβ and IFNλ2 that prevented viral induced CPE, which was supported by high-content immunofluorescence imaging analysis. This work highlights CRISPRa as a rapid, agile, and powerful methodology to identify and characterise ISGs and viral restriction factors.
The human AMPKγ3 R225W mutation does neither enhance basal AMPKγ3-associated activity nor glycogen in human or mouse skeletal muscle
Authors: Eskesen Nicolas O. , Kjøbsted Rasmus , Birk Jesper B. , Henriksen Nicolai S. , Andersen Nicoline R. , Ringholm Stine , Pilegaard Henriette , Pehmøller Christian K. , Wojtaszewski Jørgen F. P. 
Published: August 2023

AbstractBackgroundAMP-activated protein kinase (AMPK) is activated during cellular energy perturbation. AMPK is composed of three subunits and several variants of AMPK complexes are expressed in skeletal muscle. The regulatory AMPKγ3 subunit is predominantly expressed in fast-twitch muscle fibers. A human AMPKγ3 R225W mutation has been described in two families. In cultured cells derived from R225W carrier muscle, the mutation was reported to increase total AMPK activity. In addition, elevated glycogen levels were observed in skeletal muscle. This led to the idea of AMPKγ3 being involved in glycogen levels in skeletal muscle. Evidence for such a causative link has never been provided.ResultsWe studied newly obtained muscle biopsies from three human carriers of the AMPKγ3 R225W mutation and matched controls and we developed a novel knock-in mouse model carrying the AMPKγ3 R225W mutation (KI HOM). In all three human pairs, the basal AMPKγ3-associated activity was reduced when assayed in the absence of exogenous AMP. No difference was observed when assayed under AMP saturation, which was supported by findings in muscle of KI HOM mice. Furthermore, the well-established stimulatory effects of AICAR/muscle contraction on AMPKγ3-associated activity were absent in muscle from KI HOM mice. Muscle glycogen levels were not affected by the mutation in human carriers or in KI HOM mice.ConclusionsThe AMPKγ3 R225W mutation does not impact AMPK-associated activity in mature human skeletal muscle and the mutation is not linked to glycogen accumulation. The R225W mutation ablates AMPKγ3-associated activation by AICAR/muscle contractions, presumably through loss of nucleotide binding.