bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characteristics of ectopic alveolar basal cells relative to airway basal cells in fibrosis
Authors: Blumer Sabrina , Khan Petra , Roux Julien , Artysh Nataliia , Plappert Linda , Prasse Antje , Hostettler Katrin E. 
Published: September 2024

ABSTRACTRationaleBasal cells (BC) appear ectopically within the lung parenchyma of interstitial lung disease (ILD) patients, potentially through migration of airway BC or though trans-differentiation of alveolar epithelial type 2 (AT2) cells. The exact origin and function of these ectopic alveolar BC remains elusive. By comparing ectopic alveolar to “classical” airway BC, we aimed to get a better understanding of the origin and characteristics of alveolar BC in ILD.MethodsAlveolar and airway BC were isolated from transbronchial and airway mucosal biopsies, respectively, from the same ILD patients and expanded in culture. Samples were analyzed by single cell RNA sequencing (scRNA-seq), TaqMan RT-PCR, and immunochemistry.ResultsscRNA-seq analysis revealed several differences in gene expression that suggested a shift to a more mesenchymal-like phenotype and a decrease in keratinization genes in alveolar compared to airway BC. Specific AT2 cell marker genes were not expressed in either BC type. While the morphology, wound repair and proliferation capacities of BC from both origins were not significantly different, alveolar BC formed significantly fewer organoids, expressing more MUC5B. After instillation into bleomycin-injured mice, alveolar and airway BC showed similar engraftment, differentiation capacity and effects on fibrosis.ConclusionDespite similar overall functionality in vitro and after instillation into bleomycin-injured mice, alveolar and airway BC differed in their transcriptomes and in their capacities to form and to differentiate in organoids. Our data provide no evidence to support their potential derivation from AT2 cells.Take home messageAlveolar and airway basal cells differ in their transcriptomes and in their capacities to form and to differentiate in organoids, although with no indication of an AT2 cell origin.
Evolvoid: A genetic algorithm for shaping optimal cellular constructs
Authors: Mancini P. , Fontana F. , Botte E. , Magliaro C. , Ahluwalia A. 
Published: September 2024

AbstractWe describe anin-silicopipeline, Evolvoid, based on Genetic Algorithms (GAs) for identifying the optimal morphologies of cell-laden constructs. Driven by an ad hoc selection rule (i.e., the so-called fitness function (FF)), Evolvoid iteratively identifies the characteristics (i.e., the genome) of the ‘survival of the fittest’ individual of a given population throughout generations. The FF is based on universally observed biophysical laws, representing the optimal trade-off betweeni)high cell viability and robustness to changes in environmental oxygen andii)a low surface energy. The Shannon entropy is used to evaluate genome complexity, with the most complex fittest individuals showing quantitative and qualitative biological resemblance toin vitroconstructs. Evolvoid paves the way for the development of “lab on a laptop”: high-fidelity and cost-effective digital twins of cellular constructs which could augment or even substitute costlyin vitromodels.
Assessment of drive efficiency and resistance allele formation of a homing gene drive in the mosquitoAedes aegypti
Authors: Yang Xiaozhen , Xu Xuejiao , Chen Yixian , Wei Jiajia , Huang Wanting , Wu Songqing , Champer Jackson , Wang Junxiang 
Published: September 2024

AbstractAedes aegypti, known for transmitting viruses such as dengue, zika, and yellow fever, poses a significant public health threat. Conventional insecticides give rise to a range of issues, including ecological contamination and insect resistance. Hence, there is a pressing demand for environmentally friendly, safer, and more efficacious strategies for mosquito control. With the rapid advancement of the CRISPR/Cas9 system in gene function exploration and pest population control, substantial progress has been achieved in utilizing CRISPR/Cas9-based gene drive systems across various mosquito species. Only a few studies on gene drive technology have been conducted inA. aegypti. In this study, we constructed two complete drives forA. aegyptiwith different Cas9 promoters, each targetingkmo. Our drive based onPub-Cas9 had limited activity, but one withexu-Cas9 exhibited super-Mendelian inheritance rates of approximately 60%. We observed low but detectable somatic activity of the drive and no evidence of maternally deposited Cas9. Germline resistance allele formation rates were similar to drive conversion rates, but most wild-type alleles in the germline remained uncut. Injections into theexu-Cas9 drive line had 100% knockout efficiency among surviving offspring at three separate target genes. These results support the development and application of novel genetic pest control technologies aimed at combatingA. aegypti.
Transcription elongation factor ELOF1 is required for efficient somatic hypermutation and class switch recombination
Authors: Wu Lizhen , Yadavalli Anurupa Devi , Matos-Rodrigues Gabriel , Xu Dijin , Pintado-Urbanc Andreas P. , Simon Matthew D. , Wu Wei , Nussenzweig André , Schatz David G. 
Published: September 2024

SummarySomatic hypermutation (SHM) and class switch recombination (CSR) diversify immunoglobulin (Ig) genes and are initiated by the activation induced deaminase (AID), a single-stranded DNA cytidine deaminase that is thought to engage its substrate in the context of RNA polymerase II (RNAPII) transcription. Through a loss of function genetic screen, we identified numerous potential factors involved in SHM including ELOF1, a component of the RNAPII elongation complex that has been shown to function in DNA repair and transcription elongation. Loss of ELOF1 strongly compromises SHM, CSR, and AID targeting and alters RNAPII transcription by reducing RNAPII pausing downstream of transcription start sites and levels of serine 5 but not serine 2 phosphorylated RNAPII throughout transcribed genes. ELOF1 must bind to RNAPII to be a proximity partner for AID and to function in SHM and CSR. We propose that ELOF1 helps create the appropriate stalled RNAPII substrate on which AID acts.HighlightsA CRISPR knockout screen has identified numerous potential SHM factors.SHM, CSR, and AID targeting are strongly compromised in the absence of ELOF1.ELOF1 must interact with RNAPII to be an AID proximity partner and support AID targeting.ELOF1 supports RNAPII pausing and generation of the substrate for AID action.
The Proteostasis Network is a Therapeutic Target in Acute Myeloid Leukemia
Authors: Lam Kentson , Kim Yoon Joon , Ong Carlo M. , Liu Andrea Z. , Zhou Fanny J. , Sunshine Mary Jean , Chua Bernadette A. , Vicenzi Silvia , Ford Pierce W. , Zhou Jie-Hua , Hong Yuning , Bennett Eric J. , Crews Leslie A. , Ball Edward D. , Signer Robert A.J. 
Published: September 2024

ABSTRACTOncogenic growth places great strain and dependence on the proteostasis network. This has made proteostasis pathways attractive therapeutic targets in cancer, but efforts to drug these pathways have yielded disappointing clinical outcomes. One exception is proteasome inhibitors, which are approved for frontline treatment of multiple myeloma. However, proteasome inhibitors are largely ineffective for treatment of other cancers, including acute myeloid leukemia (AML), although reasons for these differences are unknown. Here, we determined that proteasome inhibitors are ineffective in AML due to inability to disrupt proteostasis. In response to proteasome inhibition, AML cells activated HSF1 and autophagy, two key stem cell proteostasis pathways, to prevent unfolded protein accumulation. Inactivation ofHSF1sensitized human AML cells to proteasome inhibition, marked by unfolded protein accumulation, activation of the PERK-mediated integrated stress response, severe reductions in protein synthesis, proliferation and cell survival, and significant slowing of disease progression and extension of survivalin vivo. Similarly, combined autophagy and proteasome inhibition suppressed proliferation, synergistically killed AML cells, and significantly reduced AML burden and extended survivalin vivo. Furthermore, autophagy and proteasome inhibition preferentially suppressed protein synthesis and induced apoptosis in primary patient AML cells, including AML stem/progenitor cells, without severely affecting normal hematopoietic stem/progenitor cells. Combined autophagy and proteasome inhibition also activated the integrated stress response, but surprisingly this occurred in a PKR-dependent manner. These studies unravel how proteostasis pathways are co-opted to promote AML growth, progression and drug resistance, and reveal that disabling the proteostasis network is a promising strategy to therapeutically target AML.
Sanctioning of bacterial cheaters by the host plant in nitrogen-fixing symbiosis betweenMedicago truncatulaandSinorhizobium meliloti
Authors: Chen Min , Raisin Axelle , Judkins Nathalie , Allard Pierre-Marie , Défossez Emmanuel , Stumpe Michael , Yruela Inmaculada , Becana Manuel , Reinhardt Didier 
Published: September 2024

AbstractIn plant-microbe interactions, the host plant invests considerable amounts of resources in the microbial partner until the symbiotic machinery is established. If the microbial partner does not reciprocate with a comparable symbiotic benefit, the interaction represents a parasitic relationship. This is thought to elicit a plant’s response to prevent the selective disadvantage of being parasitized by such microbial cheaters. Indeed, negative feedback against bad mutualists, known as sanctioning, has been observed in interactions such as the arbuscular mycorrhizal and legume-rhizobium symbioses. Here, to study sanctioning by the plant host, we manipulate the exchange of resources between the model legumeMedicago truncatulaand its bacterial partnerSinorhizobium melilotiby three ways: mutating the bacterial nitrogenase enzyme, replacing nitrogen in the atmosphere with argon gas, and supplying high nitrate to the host. Then, we follow the consequences for the interaction by examining the metabolome, proteome, and phosphoproteome of nodules. We find that such cheating conditions result in sanctioning of the bacterial partner, and observe characteristic shifts including induced defense markers, repressed symbiotic markers, and changes in central metabolism that may be relevant for microbial fitness and that could therefore contribute to sanctioning.
Colorectal Cancer Screening in Adults 45-49: Provider Availability, CT Colonography Access, and Screening Rates
Authors: Liu-Galvin Rachel , Xie Zhigang , Hong Young-Rock 
Published: September 2024

AbstractBackgroundThe US Preventive Services Task Force updated colorectal cancer (CRC) screening guidelines in 2021, recommending screening for adults aged 45-49. This study aimed to evaluate CRC screening prevalence among this newly eligible population and examine associations with healthcare provider supply and CT colonography facility availability in 2022.MethodsUsing 2022 Behavioral Risk Factor Surveillance System data (n=25,592), we estimated CRC screening prevalence among adults aged 45-49. We examined associations between screening rates and state-level healthcare provider supply using 2021-2022 Area Health Resources File data. Spearman rank-order correlations assessed relationships between provider supply, CT colonography facility availability, and screening prevalence.ResultsOverall CRC screening prevalence was 34.5% (95% CI: 33.4%-35.8%). Endoscopic tests were most common (74.9%), followed by stool-based tests (9.3%) and CT colonography (0.5%). Significant variations in screening modalities were observed across sociodemographic factors. Gastroenterology physician supply positively correlated with overall CRC screening prevalence (ρ=0.42, P=.002) and endoscopy screening prevalence (ρ=0.39, P=.005). CT colonography facility availability weakly correlated with CT colonography screening prevalence (ρ=0.18, P=.22).ConclusionsCRC screening rates among newly eligible adults aged 45-49 appear to be suboptimal in 2022. Disparities in screening methods across sociodemographic factors highlight potential access barriers. The association between gastroenterology physician supply and screening rates emphasizes the importance of addressing projected workforce shortages. Targeted efforts are needed to increase CRC screening uptake in this age group and ensure equitable access to screening services.
An Automation Framework for Clinical Codelist Development Validated with UK Data from Patients with Multiple Long-term Conditions
Authors: Aslam A. , Walker L. , Abaho M. , Cant H. , O’Connell M. , Abuzour A. S. , Hama L. , Schofield P. , Mair F.S. , Ruddle R.A. , Popoola O. , Sperrin M. , Tsang J.Y. , Shantsila E. , Gabbay M. , Clegg A. , Woodall A.A. , Buchan I. , Relton S. D. 
Published: September 2024

AbstractBackgroundCodelists play a crucial role in ensuring accurate and standardized communication within healthcare. However, preparation of high-quality codelists is a rigorous and time-consuming process. The literature focuses on transparency of clinical codelists and overlooks the utility of automation.Method and Automated Framework DesignHere we present a Codelist Generation Framework that can automate generation of codelists with minimal input from clinical experts. We demonstrate the process using a specific project, DynAIRx, producing appropriate codelists and a framework allowing 1future projects to take advantage of automated codelist generation. Both the framework and codelist are publicly available.Use-case: DynAIRxDynAIRx is an NIHR-funded project aiming to develop AIs to help optimise prescribing of medicines in patients with multiple long-term conditions. DynAIRx requires complex codelists to describe the trajectory of each patient, and the interaction between their conditions. We promptly generated≈200 codelists for DynAIRx using the proposed framework and validated them with a panel of experts, significantly reducing the amount of time required by making effective use of automation.Findings and ConclusionThe framework reduced the clinician time required to validate codes, automatically shrunk codelists using trusted sources and added new codes for review against existing codelists. In the DynAIRx case study, a codelist of≈9600 codes required only 7-9 hours of clinician’s time in the end (while existing methods takes months), and application of the automation framework reduced the workload by>80%.
Effect of Immunoadsorption on clinical presentation and immune alterations in COVID-19–associated ME/CFS
Authors: Anft Moritz , Wiemers Lea , Rosiewicz Kamil , Doevelaar Adrian , Skrzypczyk Sarah , Kurek Julia , Kaliszczyk Sviatlana , Seidel Maximilian , Stervbo Ulrik , Seibert Felix S. , Westhoff Timm H. , Babel Nina 
Published: September 2024

AbstractAutoreactive antibodies (AAB) are currently being investigated as causative or aggravating factors during post-COVID. In this study we analyze the effect of immunoadsorption therapy on symptom improvement and the relationship with immunological parameters in post-COVID patients exhibiting symptoms of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). This observational study includes 12 post-COVID patients exhibiting a predominance of ME/CFS symptoms alongside increased concentrations of autonomic nervous system receptors (ANSR) autoantibodies and neurological impairments. We found that following immunoadsorption therapy, the ANSR autoantibodies were nearly eliminated from the patients’ blood. The removal of IgG antibodies was accompanied by a decrease of pro-inflammatory cytokines including IL4, IL2, IL1β, TNF and IL17A serum levels, and a significant reduction of soluble spike protein. Notably, a strong positive correlation between pro-inflammatory cytokines and ASNR-AABs β1, β2, M3, and M4 was observed in spike protein-positive patients, whereas no such correlation was evident in spike protein-negative patients. 30 days post-immunoadsorption therapy, patients exhibited notable improvement in neuropsychological function and a substantial amelioration of hand grip strength was observed. However, neither self-reported symptoms nor scores on ME/CSF questionnaires showed a significant improvement and a rebound of the removed proteins occurring within a month.
The family as a health producer: household composition and health behaviours in a Southern Europe population
Authors: Alves Ricardo , Gonçalves Judite , Perelman Julian 
Published: September 2024

AbstractObjectivesIn the context of rapid transformations in family structures, understanding how household composition can affect adults’ health behaviours is crucial, particularly when considering the potential role of such close social relationships in shaping those behaviours. This paper documents how household structure relates to individual health behaviours.Study designWe pooled cross-sectional data from the Portuguese National Health Interview Surveys of 2014 and 2019, covering 26,000+ households.MethodsLinear and logistic regression models were used to assess the association between different household compositions (single dwelling adults, single parents, couples with or without children) and adherence to the Mediterranean diet, frequency of physical activity, likelihood of risky alcohol consumption, and smoking, distinguishing between men and women.ResultsPeople living alone and single parents were significantly less likely to adhere to the Mediterranean diet than individuals living in couple. Single dwellers had significantly higher likelihood of engaging in risky alcohol consumption or being smokers than individuals living in couple and/or with children. Analyses by gender revealed that women in couples with children were less likely to practice physical activity than women in couples without children; this difference was not observed among men.ConclusionsOverall, family contexts strongly correlate with individual health behaviours, with people living alone or in single-parent households appearing at higher risk of having less healthy diets, risky alcohol consumption, and smoking. This study identifies key target groups for policies aiming to improve population health (behaviours) including, critically, single dwellers and single parent households.Key massagesWhat is already known on this topicSocial relationships, particularly within the family, play a significant role in shaping individuals’ health behaviors. With rapid changes in family structures, understanding how household composition influences adult behaviors is crucial.What this study addsThis study reveals that single dwellers generally exhibit unhealthier behaviors, except in the case of physical activity. Additionally, it highlights that having children tends to promote healthier lifestyles among couples.How this study might affect research, practice, or policyThe findings underscore the importance of considering household composition in health interventions and policy development. Specifically, attention may need to be directed towards individuals living alone and single-parent households to address potential health disparities and promote healthier behaviors.
Single-cell RNA sequencing reveals immunosuppressive pathways associated with metastatic breast cancer
Authors: Ozmen Furkan , Ozmen Tugba Y. , Ors Aysegul , Janghorban Mahnaz , Rames Matthew J. , Li Xi , Behbod Fariba , Mills Gordon B. , Mohammed Hisham 
Published: September 2024

AbstractMetastatic breast cancer remains largely incurable, and the mechanisms underlying the transition from primary to metastatic breast cancer remain elusive. We analyzed the complex landscape of primary and metastatic breast cancer using scRNA-seq data from twenty-three female patients with either primary or metastatic disease to elucidate the genetic and molecular mechanisms underlying changes in the metastatic tumor ecosystem. We identify specific subtypes of stromal and immune cells critical to forming a pro-tumor microenvironment in metastatic lesions, including CCL2+ macrophages, cytotoxic T cells with an exhausted gene signature, and FOXP3+ regulatory T cells. Analysis of cell-cell communication highlights a marked decrease in tumor-immune cell interactions in metastatic tissues, likely strengthening the immunosuppressive microenvironment. In contrast, primary breast cancer samples displayed increased activation of the TNF-α signaling pathway via NF-kB, indicating a potential therapeutic target. Our study comprehensively characterizes the transcriptional landscape encompassing primary and metastatic breast cancer.
STRIVE-ON: Safety and ToleRability of GTX-104 (Nimodipine Injection for IV Infusion) ComparEd with Oral Nimodipine in Patients Hospitalized for Aneurysmal Subarachnoid Hemorrhage (aSAH): a Prospective, Randomized Trial (STRIVE-ON)
Authors: Choi A , Chou SH-Y , Ducruet AF , Kimberly WT , Macdonald RL , Rabinstein AA 
Published: September 2024

ABSTRACTOral nimodipine is the only drug approved in North America for treatment of patients with aneurysmal subarachnoid hemorrhage (aSAH). However, bioavailability is variable and frequently poor, leading to fluctuations in peak plasma concentrations that cause dose-limiting hypotension. Furthermore, administration is problematic in patients who cannot swallow capsules. An oral liquid formulation exists but causes gastrointestinal complications. An intravenous nimodipine formulation (GTX-104) has been developed that has bioavailability approaching 100% and is not affected by feeding or gastointestinal absorption. GTX-104 causes less hypotension and has more consistent peak plasma concentrations than oral nimodipine in healthy human volunteers.Herein we describe the protocol of a prospective, randomized, open-label safety and tolerability study of GTX-104 compared to oral nimodipine in patients with aSAH (STRIVE-ON,NCT05995405). Inclusion and exclusion criteria match the prescribing information for oral nimodipine and include adult patients with aSAH of all Hunt and Hess grades who can receive investigational product within 96 hours of aSAH. Subjects at imminent risk of death are excluded. Subjects are randomized 1:1 to GTX-104 or oral nimodipine for up to 21 days. The primary endpoint is the proportion of subjects in each group with clinically significant hypotension, defined as hypotension requiring any medical treatment, with a reasonable likelihood of being due to investigational product as determined by an independent, blinded endpoint adjudication committee. No statistical analysis of the endpoint is planned. Secondary endpoints include all episodes of hypotension, all adverse events, delayed cerebral ischemia, rescue therapy and suicidal ideation. Clinical and health economic outcomes include quality of life using the EQ-5D-3L, modified Rankin scale at 30 and 90 days after aSAH and hospital resource use. The planned sample size is 100 subjects across 25 sites in the United States and Canada.DETAILS PAGEWe confirm that manuscript complies with all instructions to authors.We confirm that authorship requirements have been met and the final manuscript is approved by all authors.We confirm that this manuscript has not been published elsewhere and is not under consideration by another journal. It is planned to post it onWe confirm adherence to ethical guidelines and indicate ethical approvals and use of informed consent.All conflicts of Interest for all authors are disclosed.We confirm the use of the Standard Protocol Items: Recommended for Interventional Trials (SPIRIT) checklist.The source of funding for the study is disclosed. It is Acasti Pharma.