bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Mac1 ADP-ribosylhydrolase is a Therapeutic Target for SARS-CoV-2
Authors: Suryawanshi Rahul K. , Jaishankar Priyadarshini , Correy Galen J. , Rachman Moira M. , O’Leary Patrick C. , Taha Taha Y. , Zapatero-Belinchón Francisco J. , McCavitt-Malvido Maria , Doruk Yagmur U. , Stevens Maisie G. V. , Diolaiti Morgan E. , Jogalekar Manasi P. , Richards Alicia L. , Montano Mauricio , Rosecrans Julia , Matthay Michael , Togo Takaya , Gonciarz Ryan L. , Gopalkrishnan Saumya , Neitz R. Jeffrey , Krogan Nevan J. , Swaney Danielle L. , Shoichet Brian K. , Ott Melanie , Renslo Adam R. , Ashworth Alan , Fraser James S. 
Published: August 2024

AbstractSARS-CoV-2 continues to pose a threat to public health. Current therapeutics remain limited to direct acting antivirals that lack distinct mechanisms of action and are already showing signs of viral resistance. The virus encodes an ADP-ribosylhydrolase macrodomain (Mac1) that plays an important role in the coronaviral lifecycle by suppressing host innate immune responses. Genetic inactivation of Mac1 abrogates viral replicationin vivoby potentiating host innate immune responses. However, it is unknown whether this can be achieved by pharmacologic inhibition and can therefore be exploited therapeutically. Here we report a potent and selective lead small molecule, AVI-4206, that is effective in anin vivomodel of SARS-CoV-2 infection. Cellular models indicate that AVI-4206 has high target engagement and can weakly inhibit viral replication in a gamma interferon- and Mac1 catalytic activity-dependent manner; a stronger antiviral effect for AVI-4206 is observed in human airway organoids. In an animal model of severe SARS-CoV-2 infection, AVI-4206 reduces viral replication, potentiates innate immune responses, and leads to a survival benefit. Our results provide pharmacological proof of concept that Mac1 is a valid therapeutic target via a novel immune-restoring mechanism that could potentially synergize with existing therapies targeting distinct, essential aspects of the coronaviral life cycle. This approach could be more widely used to target other viral macrodomains to develop antiviral therapeutics beyond COVID-19.
Response diversity increases functional stability but decreases diversity and compositional stability of grassland communities
Authors: Zieschank Vincent , Junker Robert R. 
Published: August 2024

AbstractThe insurance hypothesis of biodiversity assumes that ecosystem stability rises with increasing biodiversity because functionally redundant species respond differently to environmental changes, allowing some species to compensate for the loss of others. We tested this hypothesis by combining extensive field data and a common garden experiment where sods originating from different regions were subjected to land-use treatments. Based on plant species-specific performance-environment relationships with abundance as performance proxy and land-use intensity as environmental variable, we calculated response dissimilarity of species-pairs. The resulting dissimilarity matrix was used to calculate response diversity (functional dispersion) of grass sods before and after land-use treatments. Our results showed that high land-use intensity decreased response diversity of plant communities both in the field as well as in the common garden. Response diversity in grass sods increased functional stability but decreased stability in terms of species diversity and composition as communities with high response diversity lost species without replacement in response to experimental land-use change, while those with low response diversity showed species turnover. We conclude that response diversity is an important component of biodiversity and discuss future research directions to refine and generalize the concept of response diversity and its role in ecosystem stability.
Complex genetic determination of male-fertility restoration in the gynodioecious snailPhysa acuta
Authors: Skarlou Elpida , Laugier Fanny , Béthune Kévin , Chenin Timothée , Donnay Jean-Marc , Froissard Céline , David Patrice 
Published: August 2024

AbstractMale fertility in plants is often controlled by the interaction between mitochondrial and nuclear genes. Some mitotypes confer cytoplasmic male sterility (CMS), making the individual male-sterile, unless the nuclear background contains alleles called restorers, that suppress the effects of CMS and restore the hermaphroditic condition. Restorers in cultivated crops are often alleles with strong and dominant effect, but in wild plants, data often suggest more complex systems. Here, we characterized the inheritance and specificity of restoration in a new CMS model, the freshwater snailPhysa acuta. We explored two different populations (i) a naive population i.e., without contact CMS in the past 80 generations, (ii) a non-naive population, where CMS is present and largely restored. We found that restoration potential was indeed heritable in both contexts and specific to a CMS type. However our results suggest that restoration of male fertility could be of a different nature depending on population history: in naïve populations not coevolved with CMS the background variation may include alleles that happen to act as weak quantitative modifiers of the penetrance of CMS, while in populations coevolved with CMS, selection may have favored, when such variants were available, the emergence of strong alleles with a dominant effect.
Alterations of the skeletal muscle nuclear proteome after acute exercise reveals a post-transcriptional influence
Authors: Martin Ryan A. , Viggars Mark R. , Sanford James A. , Taylor Zane W. , Hansen Joshua R. , Clair Geremy C. , Adkins Joshua N. , Douglas Collin M. , Esser Karyn A. 
Published: August 2024

AbstractExercise is firmly established as a key contributor to overall well-being and is frequently employed as a therapeutic approach to mitigate various health conditions. One pivotal aspect of the impact of exercise lies in the systemic transcriptional response, which underpins its beneficial adaptations. While extensive research has been devoted to understanding the transcriptional response to exercise, our knowledge of the protein constituents of nuclear processes that accompany gene expression in skeletal muscle remains largely elusive. We hypothesize that alterations in the nuclear proteome following exercise hold vital clues for comprehending the transcriptional regulation and other related nuclear functions. We isolated skeletal muscle nuclei from C57BL/6 mice both sedentary control and one-hour post 30-minute treadmill running, to gain insights into the nuclear proteome after exercise. A substantial number of the 2,323 proteins identified, were related to nuclear functions. For instance, we found 59 proteins linked to nucleocytoplasmic transport were higher in sedentary mice compared to exercise, hinting at an exercise-induced modulation to nuclear trafficking. Furthermore, 135 proteins exhibited increased abundance after exercise (FDR < 0.1) while 89 proteins decreased, with the most prominent changes in proteins linked to mRNA processing and splicing. Super resolution microscopy further highlights potential localization change in mRNA processing proteins post-exercise, further suggesting changes in nuclear transport dynamics. Nonetheless, our data provide important considerations for the study of the nuclear proteome and supports a paradigm through which exercise downregulated mRNA processing and splicing, offering valuable insights into the broader landscape of the impact from acute exercise.New & NoteworthyExercise plays a crucial role in promoting muscle health, but our understanding of nuclear proteins orchestrating exercise responses is limited. Isolation of skeletal muscle nuclei coupled with mass spectrometry enhanced the identification of nuclear proteins. This approach was used to investigate the effects of acute exercise, revealing changes in the muscle nuclear proteome 1-hour post-exercise, including proteins linked to post-transcriptional processing and splicing. Our findings offer insights into the exercise-induced changes within muscle nuclear proteins.
Interactions between neutrophils and macrophages harboring gram-negative bacteria promote obesity-associated breast cancer
Authors: Takle Sina T. , Grøndal Sturla Magnus , Lien Martin E. , Lianto Priscilia , Deng Wei , Lillestøl Reidun Kristine , Lønning Per , Lorens James B. , Knappskog Stian , Halberg Nils 
Published: August 2024

SUMMARYObesity promotes a more aggressive breast cancer phenotype. Through spatial and single-cell-based analysis of hormone receptor-negative breast cancers, we identify a subset of tumor-associated neutrophils (TANs) positive for granzyme B (GZMB) enriched in the tumor microenvironment of obese patients. In breast tumors evolved in obese environments, TANs are in proximity of M2 polarized macrophages containing lipopolysaccharides (LPS) from gram-negative bacteria. Pyroptosis of macrophages releases bacterial LPS, activating local GZMB+TANs. This induces release of the S100 family member S100A8 that promotes tumor progression. In sum, we describe an obesity associated cellular network of cancer cells, neutrophils and M2 polarized macrophages that promotes tumor growth.
Analytical Validation of a Circulating Tumor DNA Assay using PhasED-Seq Technology for Detecting Residual Disease in B-Cell Malignancies
Authors: Boehm Nina , Close Sandra , Kurtz David M. , Hockett Richard D. , Hyland Laura 
Published: August 2024

AbstractBackgroundCirculating tumor DNA (ctDNA) is a non-invasive biomarker that can be used as a tool to detect minimal residual disease (MRD). MRD can provide important prognostic information in diffuse large B-cell lymphomas (DLBCL). Here, we present an MRD assay with an improved detection method for ctDNA, Phased Variant Enrichment and Detection Sequencing (PhasED-Seq) which leverages phased variants (PVs) to detect ctDNA.MethodsPlasma samples from non-cancer controls were used to assess assay specificity. A limiting dilution series using DLBCL clinical-contrived samples was performed to assess assay sensitivity and precision. The accuracy of the PhasED-Seq-based assay was assessed using plasma samples from individuals with DLBCL and for whom MRD comparator assay results were also available. All samples were sourced from commercial vendors or academic studies.ResultsThe analytical and clinical performance of the MRD assay was evaluated using clinical and clinical-contrived DLBCL samples. The assay’s false positive rate was 0.24% and the background error rate was 1.95E-08. The limit of detection at 95% detection rate (LoD95) at 120 ng was 0.7 parts in 1,000,000 and precision was >96%. Clinical accuracy was 90.62% PPA and 77.78% NPA.ConclusionsThe PhasED-Seq-based MRD assay has strong analytical and clinical performance in B-cell dyscrasias. Through the development of improved ctDNA detection methods such as that presented here, patient outcomes may be improved through the detection of residual disease or early relapse which may be used to guide treatment decisions.Brief SummaryHere we present the analytical validation of a non-invasive minimal residual disease (MRD) assay which uses Phased Variant Enrichment and Detection Sequencing (PhasED-Seq) to improve the error profile and sensitivity of circulating tumor DNA (ctDNA) detection. The assay’s performance included a false positive rate of 0.24% and a background error rate of 1.95E-08. The limit of detection at 120 ng was 0.7 parts in 1,000,000 (6.61E-07 PVAF) with precision >96%. Positive and negative agreement were 90.62% and 77.78%, respectively. This suggests that the PhasED-Seq-based MRD assay is accurate and reproducible, thus appropriate for clinical use for individuals with B-cell malignancies.
A Literature Review and Pooled Case Analysis of Cardiofaciocutaneous Syndrome to Estimate Cancer Risk
Authors: Bess Jazmyn , Brown Toniya , Bhala Sonia , Faizer Anaqa , Ahmadzada Muzzammil , Livinski Alicia A , Pemov Alex , Kim Jung , Rosenberg Philip S , Ney Gina M , Stewart Douglas R 
Published: August 2024

AbstractBackgroundCardiofaciocutaneous syndrome (CFC) is a rare disorder with multiple congenital anomalies including macrocephaly, failure to thrive, and neurocognitive delay. CFC is part “RASopathy” syndromes caused by pathogenic germline variants inBRAF, KRAS, MAP2K1,andMAP2K2.To estimate cancer risk in CFC we conducted a systematic review using case reports and series.MethodsWe reviewed articles and abstracted CFC cases to form a retrospective cohort based on PRISMA guidelines. Genotype-pphenotype (cancer) correlations, standardized incidence ratios (SIR), cumulative incidence and cause-specific hazard rates for cancer and cancer-free in CFC were calculated.ResultsThis study includes 198 publications reporting 690 patients. Only 1.6% (11) had cancer, including acute lymphoblastic leukemia (ALL). Six cancer patients harbored pathogenic variants withinBRAF, MAP2K1, andMAP2K2. Cumulative incidence by age 10 was 5% for cancer or cancer-free death. Hazard Ratio (death) was 1-2% until age 3 and declined thereafter. Significant SIRs were found for all sites (SIR=4.96) and ALL (SIR=24.23).ConclusionsThis is the largest investigation of cancer in CFC to date. Cancer risk in the CFC population is elevated but appears limited to earlier childhood. Modest case and cancer numbers could pose limitations to accurately assess cancer risk in CFC and more studies are needed.Systematic Review RegistrationThe review was registered using PROSPERO under the identification tag CRD42023405823 (https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=405823)
Effect of cardiorespiratory exercise during rehabilitation on functional recovery early post-stroke: a cohort study
Authors: Thompson Sarah , Devasahayam Augustine J. , Danells Cynthia J. , Jagroop David , Inness Elizabeth L. , Mansfield Avril 
Published: August 2024

ABSTRACTBackgroundPeople with stroke often have low cardiorespiratory fitness, hindering daily activities and rehabilitation participation. Cardiorespiratory exercise (CRE) early post-stroke can improve fitness, facilitating participation in rehabilitation, and may promote neuroplasticity. This longitudinal observational study aimed to determine the effect of CRE during routine inpatient stroke rehabilitation on motor and cognitive function, functional ambulation, and motor impairment.MethodsData were collected from charts of patients (n=504) admitted to two rehabilitation hospitals in Ontario, Canada, over 14 month periods. Patients were classified into three groups: ‘Prescribed’, ‘Incidental’, or no cardiorespiratory exercise (‘None’). Functional independence Measure (FIM), Functional Ambulation Category (FAC), and Chedoke-McMaster Stroke Assessment (CMSA) scores were compared between groups at discharge from rehabilitation, controlling for age, length of stay, and scores at baseline.ResultsPatients who had cardiorespiratory exercise included in their treatment plan (i.e., Prescribed group) had higher FIM total and motor sub-scores at discharge than the None group (Site A; FIM total mean between-group difference: 13.2, p<0.0001; FIM motor mean between-group difference: 13.1, p<0.0001), or than those that completed cardiorespiratory exercise without a prescription (‘Incidental’ group; Site B; FIM Total mean between-group difference: 13.6, p=0.031; FIM motor mean between-group difference: 12.9, p=0.010). At both sites, FIM cognitive sub-scores and CMSA leg scores were higher at discharge for the Prescribed group than the None group (FIM cognitive mean between-group difference: 1.2, p=0.038; CMSA leg mean between-group difference: 0.5, p=0.0099). FAC scores were higher at discharge for the two exercise groups compared to the group that did not complete cardiorespiratory exercise at Site A only (p=0.0010).ConclusionsFindings support that cardiorespiratory exercise as part of routine in-patient rehabilitation early post-stroke is associated with improved functional independence and ambulation. However, the observational design limits causal inferences, highlighting the need for controlled studies to confirm cardiorespiratory exercise benefits in early stroke recovery.
An asymmetric nautilus-like HflK/C assembly controls FtsH proteolysis of membrane proteins
Authors: Ghanbarpour Alireza , Telusma Bertina , Powell Barrett M. , Zhang Jia Jia , Bolstad Isabella , Vargas Carolyn , Keller Sandro , Baker Tania , Sauer Robert T. , Davis Joseph H. 
Published: August 2024

ABSTRACTFtsH, a AAA protease, associates with HflK/C subunits to form a megadalton complex that spans the inner membrane and extends into the periplasm ofE. coli. How this complex and homologous assemblies in eukaryotic organelles recruit, extract, and degrade membrane-embedded substrates is unclear. Following overproduction of protein components, recent cryo-EM structures reveal symmetric HflK/C cages surrounding FtsH in a manner proposed to inhibit degradation of membrane-embedded substrates. Here, we present structures of native complexes in which HflK/C instead forms an asymmetric nautilus-like assembly with an entryway for membrane-embedded substrates to reach and be engaged by FtsH. Consistent with this nautilus-like structure, proteomic assays suggest that HflK/C enhances FtsH degradation of certain membrane-embedded substrates. The membrane curvature in our FtsH·HflK/C complexes is opposite that of surrounding membrane regions, a property that correlates with lipid-scramblase activity and possibly with FtsH’s function in the degradation of membrane-embedded proteins.
Tissue-specific modulation of CRISPR activity by miRNA-sensing guide RNAs
Authors: Garcia-Guerra Antonio , Sathyaprakash Chaitra , de Jong Olivier G. , Lim Wooi F. , Vader Pieter , El Andaloussi Samir , Bath Jonathan , Reine Jesus , Aoki Yoshitsugu , Turberfield Andrew J. , Wood Matthew J. A. , Rinaldi Carlo 
Published: August 2024

ABSTRACTNucleic acid nanostructures offer unique opportunities for biomedical applications due to their sequence-programmable structures and functions, which enable the design of complex responses to molecular cues. Control of the biological activity of therapeutic cargoes based on endogenous molecular signatures holds the potential to overcome major hurdles in translational research: cell specificity and off-target effects. Endogenous microRNAs can be used to profile cell type and cell state and are ideal inputs for RNA nanodevices. Here we present CRISPR MiRAGE (miRNA-activated genome editing), a tool comprising a dynamic single-guide RNA that senses miRNA complexed with Argonaute proteins and controls downstream CRISPR activity based on the detected miRNA signature. We study the operation of the miRNA-sensing single-guide RNA and attain muscle-specific activation of gene editing through CRISPR MiRAGE in models of Duchenne muscular dystrophy. By enabling RNA-controlled gene editing activity, this technology creates opportunities to advance tissue-specific CRISPR treatments for human diseases.
Spatial localization of CD16a at the human NK cell ADCC lytic synapse
Authors: Ross Patrick , Fatima Hijab , Leaman Dan P. , Matthias Jessica , Spencer Kathryn , Zwick Michael B. , Henderson Scott C. , Mace Emily M. , Murin Charles Daniel 
Published: August 2024

AbstractNatural Killer (NK) cells utilize effector functions, including antibody-dependent cellular cytotoxicity (ADCC), for the clearance of viral infection and cellular malignancies. NK cell ADCC is mediated by FcγRIIIa (CD16a) binding to the fragment crystallizable (Fc) region of immunoglobulin G (IgG) within immune complexes on a target cell surface. While antibody-induced clustering of CD16a is thought to drive ADCC, the molecular basis for this activity has not been fully described. Here we use MINFLUX nanoscopy to map the spatial distribution of stoichiometrically labeled CD16a across the NK cell membrane, revealing the presence of pairs of CD16a molecules with intra-doublet distance of approximately 17 nm. NK cells activated on supported lipid bilayers by Trastuzumab results in an increase of synaptic regions with greater CD16a density. Our results provide the highest spatial resolution yet described for CD16a imaging, offering new insight into how CD16a organization within the immune synapse could influence ADCC activity. MINFLUX holds great promise to further unravel the molecular details driving CD16a-based activation of NK cells.
Identification of Meibomian gland stem cell populations and mechanisms of aging
Authors: Zhu Xuming , Xu Mingang , Portal Celine , Lin Yvonne , Ferdinand Alyssa , Peng Tien , Morrisey Edward E. , Dlugosz Andrzej A. , Castellano Joseph M. , Lee Vivian , Seykora John T. , Iomini Carlo , Millar Sarah E 
Published: August 2024

SummaryMeibomian glands secrete lipid-rich meibum, which prevents tear evaporation. Aging-related Meibomian gland shrinkage may result in part from stem cell exhaustion and is associated with evaporative dry eye disease, a common condition lacking effective treatment. The identities and niche of Meibomian gland stem cells and the signals controlling their activity are poorly defined. Using snRNA-seq, in vivo lineage tracing, ex vivo live imaging, and genetic studies in mice, we identified markers for stem cell populations that maintain distinct regions of the gland and uncovered Hh signaling as a key regulator of stem cell proliferation. Consistent with this, human Meibomian gland carcinoma exhibited increased Hh signaling. Aged glands displayed decreased Hh and EGF signaling, deficient innervation, and loss of collagen I in niche fibroblasts, indicating that alterations in both glandular epithelial cells and their surrounding microenvironment contribute to age-related degeneration. These findings suggest new approaches to treat aging-associated Meibomian gland loss.
Triple Negative Breast Cancer Cells Acquire Lymphocyte Proteins and Genomic DNA During Trogocytosis with T Cells
Authors: Sivakoses Anutr , Marcarian Haley Q. , Arias Anika M. , Lam Allison R. , Ihedioha Olivia C. , Santamaria Juan A. , Gurtner Geoffrey C. , Bothwell Alfred L.M. 
Published: August 2024

AbstractTrogocytosis is the process by which a recipient cell siphons small membrane fragments and proteins from a donor cell and may be utilized by cancer cells to avoid immune detection. We observed lymphocyte specific protein expressed by TNBC cells via immunofluorescence imaging of patient samples. Image analysis of CD45RA expression, a T cell specific protein, revealed that all stages of TNBCs express CD45RA. Flow cytometry revealed TNBC cells trogocytose CD45 protein from T cells. We also showed that the acquisition of these lymphoid markers is contact dependent. Confocal and super-resolution imaging further revealed CD45+spherical structures containing T cell genomic DNA inside TNBC cells after co-culture. Trogocytosis between T cells and TNBC cells altered cancer cell gene expression. Our results revealed that CD45 is obtained by TNBC cells from T cells via trogocytosis and that TNBC cells express CD45 intracellularly and on the membrane.TeaserTNBC cells acquire small spherical structures from T cells containing lymphocyte-specific membrane proteins and genomic DNA.