bluuebunny/crossref_metadata_2025_split huggingface dataset:
Understanding end-user preferences for hand hygiene enabling technologies: a mixed-methods study in peri-urban Lusaka
Authors: Kazimbaya Katayi , Davies Katherine , Mwenge Mwamba M. , Tadiri Elisabeth , Chipungu Jenala , Dreibelbis Robert 
Published: October 2024

AbstractIntroductionHandwashing facilities (HWFs) are associated with higher rates of handwashing with soap, and the presence of a HWF is the global proxy indicator of household handwashing behaviour. There is limited information on attributes of HWFs important to end-users with few comparative assessments of HWFs from a user-perspective. We aimed to identify attributes of HWFs important to end-users and determine how pre-manufactured HWFs ranked against these attributes.MethodWe identified eight pre-existing HWFs: two locally manufactured (Kalingalinga bucket and Tippy tap) and six industrially produced designs (Jengu, SatoTap, SaniTap, HappyTap, SpaTap, and Kohler Cleanse). Two rounds of focus group discussions were conducted with a diverse group of targeted end-users in two peri-urban communities in Lusaka, Zambia. In the first, participants discussed aspects of each HWF they liked and disliked, and thematic analysis was used to define nine attributes for comparision across each HWF. In the second round, participants individually ranked each HWF against the identified attributes, their overall preference, and overall preference once estimated retail prices were revealed. Participants also ranked attributes by importance. Ranking data were modelled using rank-ordered logistic regression.ResultsDiscussions revealed nine attributes important to end users: appearance, water management, hygienic use, convenience, water disposal, vulnerability to theft or breakage, ease of use, price and maintenance. Hygienic use and water management were considered most important attributes. Excluding price, facilities resembling a sink, such as the Happy Tap (34%) and Jengu (28%), had the highest probability of being ranked first. With consideration for price, participants preferred lower-cost HWFs such as the Kalingalinga bucket (44%), Tippy Tap (13%) and SATO Tap (10%).ConclusionThis study identified nine attributes important to end-users that can inform future design efforts. Future work will explore user preferencesin situby rotating households through specific HWF for an extended period. Potential manufacturers should continue to iterate on HWF designs emphasizing on reducing costs.
Infections are not alike: the effects of covariation between individual susceptibility and transmissibility on epidemic dynamics
Authors: Harris Jeremy D. , Gallmeier Esther , Dushoff Jonathan , Beckett Stephen J. , Weitz Joshua S. 
Published: October 2024

AbstractIndividual-level variation in susceptibility to infection and transmissibility of infection can affect population-level dynamics in epidemic outbreaks. Prior work has incorporated independent variation in susceptibility or transmissibility of individuals into epidemic compartmental models. Here, we develop and assess a mathematical framework that includes covariation in susceptibility and transmissibility. We show that uncorrelated variation in susceptibility and transmissibility leads to an effective transmissibility distribution that has a constant coefficient of variation such that the epidemic dynamics match those with variation in susceptibility alone, providing a baseline for comparison across different correlation structures. Increasing the correlation between susceptibility and transmissibility increases both the speed and strength of the outbreak – and is indicative of outbreaks which might be strongly structured by contact rate variation. In contrast, negative correlations between susceptibility and transmissibility lead to overall weaker outbreaks – with the caveat that the strength of effective transmission increases over time. In either case, correlations can shift the transmissibility distribution, thereby modifying the speed of the epidemic as the susceptible population is depleted. Overall, this work demonstrates how (often unaccounted) covariation in susceptibility and transmission can shape the course of outbreaks and final outbreak sizes.HighlightsDeveloped models incorporating susceptibility and transmissibility covariation.Identified eigendistributions of the force of infection.Uncorrelated transmissibility reduces to variation in susceptibility alone.Positive correlations lead to increases in the basic reproduction number.Positive correlations give faster, stronger, more likely outbreaks.Effective transmission rates increase over time with negative correlations.
Enhanced anti-tumor activity by Zinc Finger Repressor-driven epigenetic silencing of immune checkpoints and TGFBR2 in CAR-T cells and TILs
Authors: David Marion , Schiele Phillip , Monteferrario Davide , Saviane Gaëlle , Martelli Angélique E. , Dupont Coralie F. , Jeanneau Caroline , Marchetti Irène , Tadi Satish K. , Vahldick Julia , Truong Lynn N. , Zhou Yuanyue , Sauer Igor M. , Schöning Wenzel , Na Il-Kang , Reik Andreas , Frentsch Marco , de la Rosa Maurus , Fenard David 
Published: October 2024

ABSTRACTCAR-T therapies have shown remarkable success in treating hematological malignancies. However, effectiveness against solid tumors remains limited due to the immunosuppressive tumor microenvironment (TME), such as TGF-β signaling and upregulated immune checkpoints (ICs). Furthermore, identifying universal, tumor-specific targets for CAR-T cells in solid tumors is challenging, but using reinvigorated, immunosuppressive-resistant tumor-infiltrating lymphocytes (TILs) could be a promising alternative approach. Unlike nucleases, which may induce genotoxic DNA double-strand breaks, multiplexed Zinc Finger Repressors (ZFR) offer a safer alternative for knocking out TME-related immunosuppressive factors. We epigenetically repressed PD-1 expression both in CAR-T cells and TILs from colorectal liver metastases. PD-1 repression did not affect T cell viability, proliferation, or functionality. In a murine B cell lymphoma model, PD-1-repressed CD19-CAR-T cells exhibited enhanced anti-tumor activity and improved survival. Notably, PD-1 repression alone did not increase cytotoxicity against a PD-L1-positive colorectal cell line in vitro. To further increase anti-tumor potency in this context, ZFR-expressing lentiviral vectors targeting PD-1 and other ICs (LAG-3, TIM-3, TIGIT) or TGFBR2 were developed, improving significantly the cytotoxic activity in TILs. This strategy highlights the potential to enhance tumor-reactive T cells and improve anti-cancer immunotherapies by epigenetically repressing immunosuppressive factors in the TME using multiplexed ZFRs.
Ruxolitinib clears CRYAB p.Arg120Gly aggregates through the ubiquitin-proteasome system
Authors: Alizoti Erda , Ewald Leonie , Parretta Simona , Meyer-Jens Moritz , Orthey Ellen , Conze Christian , Carrier Lucie , Robbins Jeffrey , Singh Sonia R 
Published: October 2024

AbstractRationaleProtein accumulation is a hallmark of many neurodegenerative and muscular diseases. Desmin-related (cardio-) myopathy (DRM), a well-studied model for cardiac muscle protein accumulation, is an autosomal dominant-inherited disease presenting with progressive muscle weakness, reduced quality of life, and shortened life span. To date, DRM patients are treated symptomatically and there is no causal treatment available. Independent of the genetic cause, most DRM patients display intracellular accumulation of desmin and its chaperone αB-crystallin (CRYAB). We previously conducted an unbiased high-throughput screen to identify novel effectors that reduce cardiomyocyte aggregate levels and found that downregulation of Janus kinase 1 (JAK1) resulted in lower aggregate load in neonatal mouse cardiomyocytes.ObjectiveIn this study, we tested if the approved JAK inhibitor ruxolitinib ameliorates the disease phenotype in rodent and human CRYAB p.Arg120Gly DRM models.Methods and ResultsWe found that the mRNA levels ofJak1andStat3were higher than any other JAK-signal transducer and activator of transcription (STAT) family members in neonatal rat ventricular myocytes (NRVMs) and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). The approved JAK1/2 inhibitor ruxolitinib and the JAK1 inhibitors solcitinib, upadacitinib, and filgotinib prevented accumulation of and cleared pre-existing CRYAB p.Arg120Gly protein aggregates in NRVMs and hiPSC-CMs. Importantly, the knockdown ofJak1andStat3, but notJak2resulted in fewer aggregates. Moreover, ruxolitinib,Jak1orStat3siRNA treatment enhanced the ubiquitin-proteasome system (UPS)-mediated degradation. Blocking UPS function blunted the effect of ruxolitinib orJak1siRNA on CRYAB p.Arg120Gly accumulation. RNAseq of NRVMs treated withJak1siRNA extracts revealed higher gene expression of important muscle E3 ubiquitinating enzymes. Knockdown of the E3 ligaseAsb2(Ankyrin Repeat And SOCS Box Protein 2) abolished the effect of ruxolitinib on CRYAB p.Arg120Gly aggregates. In DRM mice, phospho-STAT3 levels were markedly higher than in non-transgenic (NTG) mice with age. Ruxolitinib treatment orJak1knockout prevented cardiac dysfunction and reduced CRYAB p.Arg120Gly aggregate load in DRM mice.ConclusionIn this study, we uncovered the previously unknown effect of the approved drug ruxolitinib to enhance UPS-mediated degradation and prevent protein aggregates in cardiomyocytes.
Mapping the Temporal Landscape of Breast Cancer Using Epigenetic Entropy
Authors: Monyak Daniel L. , Holloway Shannon T. , Gumbert Graham J. , Grimm Lars J. , Hwang E. Shelley , Marks Jeffrey R. , Shibata Darryl , Ryser Marc D. 
Published: October 2024

ABSTRACTAlthough generally unknown, the age of a newly diagnosed tumor encodes valuable etiologic and prognostic information. Here, we estimate the age of breast cancers, defined as the time from the start of growth to detection, using a measure of epigenetic entropy derived from genome-wide methylation arrays. Based on an ensemble of neutrally fluctuating CpG (fCpG) sites, this stochastic epigenetic clock differs from conventional clocks that measure age-related increases in methylation. We show that younger tumors exhibit hallmarks of aggressiveness, such as increased proliferation and genomic instability, whereas older tumors are characterized by elevated immune infiltration, indicative of enhanced immune surveillance. These findings suggest that the clock captures a tumor’s effective growth rate resulting from the evolutionary-ecological competition between intrinsic growth potential and external systemic pressures. Because of the clock’s ability to delineate old and stable from young and aggressive tumors, it has potential applications in risk stratification of early-stage breast cancers and guiding early detection efforts.
Fibromyalgia patients have altered lipid concentrations associated with disease symptom severity and anti-satellite glial cell IgG antibodies
Authors: Jakobsson Jenny E. , Menezes Joana , Krock Emerson , Hunt Matthew A. , Carlsson Henrik , Vaivade Aina , Emami Khoonsari Payam , Agalave Nilesh M. , Sandström Angelica , Kadetoff Diana , Tour Jeanette , Erngren Ida , Al-Grety Asma , Freyhult Eva , Sandor Katalin , Kosek Eva , Svensson Camilla I. , Kultima Kim 
Published: October 2024

AbstractAutoimmunity and immunoglobulin G (IgG) autoantibodies may contribute to pain in a subset of fibromyalgia (FM) patients. Previously, we saw that IgG from FM patients induces pain-like behavior in mice and binds to satellite glial cells (anti-SGC IgG). The anti-SGC IgG levels were also associated with more severe symptomatology. Lipid metabolism in FM subjects is altered with lysophosphatidylcholines (LPCs) acting as pain mediators. The relationship between autoantibodies, lipid metabolism, and FM symptomatology remains unclear. We analyzed serum lipidomics with liquid chromatography mass spectrometry, anti-SGC IgG levels, and clinical measures in 35 female FM subjects and 33 age- and body mass index-balanced healthy controls (HC). Fibromyalgia subjects with higher anti-SGC IgG levels experienced more intense pain than those with lower levels. Sixty-three lipids were significantly altered between FM subjects and HC or between FM subjects with severe (FM severe) and mild symptoms (FM mild). Compared to HC, FM subjects had lower concentrations of lipid species belonging to the classes LPC (n = 10), lysophosphatidylethanolamine (n = 7), phosphatidylcholine (n = 4), and triglyceride (n = 5), but higher concentrations of diglyceride (n = 3). Additionally, FM severe had higher LPC 19:0, 22:0, and 24:1 and lower sphingomyelin (n = 9) concentrations compared to FM mild. A positive association was seen for LPC 22:0 and 24:1 with pain intensity and anti-SGC IgG levels in FM subjects. Taken together, our results suggest an association between altered lipid metabolism and autoimmune mechanisms in FM.PerspectiveOur results suggest an association between the postulated autoimmunity in FM and lipids that can act as pain mediators.
Phosphoproteomics highlights complex resource management upon inflammatory stimulation of fibroblasts
Authors: Janker-Bortel Patricia , Martinez-Val Ana , Hagn Gerhard , Skos Lukas , Olsen Jesper V. , Gerner Christopher 
Published: October 2024

ABSTRACTThe stimulation of cells by inflammatory mediators gives rise to intricate signaling cascades, inducing specific biological functions. The role of kinase activation for the establishment of specific inflammatory functions has only scarcely been established. A time-course analysis of human fetal fibroblasts stimulated with Interleukin-1β (IL-1β) and/or Dexamethasone (Dex) was conducted using mass spectrometry-based proteomics and phosphoproteomics in conjunction with lysolipid and oxylipin profiling. The IL-1β induced proteome alterations indicated metabolic, transcriptional, and translational activation, including inflammatory marker proteins such as NOS1, THBS1, and STING1. The induction of mitochondrial proteins and the formation of numerous lysolipids indicated an increase in beta-oxidation. In addition to the NF-κB and STAT signaling pathways, which are characteristic of inflammatory activation, the MAP and AKT kinase signaling pathways were found to be strongly induced. Six hours after treatment, the observed signaling events exhibited a notable decline, nearly returning to their initial states after 24 hours. It is noteworthy that nearly all of these signaling activities were also observed in cells treated with Dex alone. Additionally, the proteome exhibited transient alterations, which included proteins otherwise characteristic of an inflammatory response, such as MMP3 and NFKB2. Activation of the kinase PIKFYVE was apparently specific for dexamethasone but constituted a minority of the total phosphorylation events. Only after 24 hours was the induction of proteins characteristic of glucocorticoids, such as TSC22D3 and MAOA, observed. The analysis of the effects of dexamethasone on the background of established inflammatory signaling verified the known inhibitory functions and resulted in the expression of anti-inflammatory proteins and oxylipins, but hardly affected the signaling events involving MAP and AKT kinases. In conclusion, this data demonstrates that a majority of inflammation-associated signaling events in fibroblasts needs to be attributed to resource and stress management rather than the establishment of specific inflammatory effector functions.
Inconsistencies in the published rabbit ribosomal rRNAs: a proposal for uniformity in sequence and site numbering
Authors: De Swastik , Zhou Michelle , Brown Zuben P , Burton-Smith Raymond N. , Hashem Yaser , Pestova Tatyana , Hellen Christopher U T , Frank Joachim 
Published: October 2024

AbstractExamination of all publicly availableOryctolagus cuniculus(rabbit) ribosome cryo-EM structures reveals numerous confusing inconsistencies. First, there are a plethora of single nucleotide differences among the various rabbit 28S and 18S rRNA structures. Second, two nucleotides are absent from the NCBI Reference Sequence for the 18S rRNA gene. Moving forward, we propose using the Broad Institute’s rabbit whole genome shotgun sequence and numbering to reduce modeling ambiguity and improve consistency between ribosome models.
Population structure limits inferences from genomic prediction and genome-wide association studies in a forest tree
Authors: Slavov Gancho T. , Macaya-Sanz David , DiFazio Stephen P. , Howe Glenn T. 
Published: October 2024

AbstractThere is overwhelming evidence that forest trees are locally adapted to climate. Thus, genecological models based on population phenotypes have been used to measure local adaptation, assess risks of genetic maladaptation to climate, and guide assisted migration. However, instead of phenotypes, there is increasing interest in using genomic data for gene resource management. We used whole-genome resequencing and a replicated common- garden experiment to understand the genetic architecture of adaptive traits in black cottonwood. We studied the potential of using genome-wide association studies (GWAS) and genomic prediction to detect causal loci, identify climate-adapted phenotypes, and practice assisted migration. We analyzed hierarchical population structure by partitioning phenotypic and genomic (SNP) variation among 840 genotypes collected from 91 stands along 16 rivers. Most phenotypic variation (60-81%) occurred at the population level and was strongly associated with climate. Population phenotypes were predicted well using genomic data (e.g., predictive abilityr> 0.9) but almost as well using climate or geography (r> 0.8). In contrast, genomic prediction within populations was poor (r< 0.2). Similarly, we identified many GWAS associations among populations, but most appeared to be spurious based on pooled within-population analyses. Hierarchical partitioning of linkage disequilibrium and haplotype sharing suggested that within-population genomic prediction and GWAS were poor because allele frequencies of causal loci and linked markers differed among populations. Our results highlight the difficulty of using GWAS to identify causal loci when there is population structure, and the limitations of using genomic information alone to guide assisted migration.
An Adverse Outcome Pathway for Food Nanomaterial-induced Intestinal Barrier Disruption
Authors: Stanco Deborah , Lipsa Dorelia , Bogni Alessia , Bremer-Hoffmann Susanne , Clerbaux Laure-Alix 
Published: October 2024

AbstractIntroductionIngestion of nanomaterials (NMs) might impair intestinal barrier, but the underlying mechanisms remain evasive, and evidence is not systematically gathered or produced. A mechanistic-based approach would be instrumental to assess if relevant NMs disrupt intestinal barrier to support NM risk assessment in the food sector.MethodsHere, we developed an adverse outcome pathway (AOP) based on biological plausibility and by leveraging existing information of an existing NM relevant AOP leading to hepatic outcomes. We then extracted the current evidence existing in the literature for a targeted selection of NMs with high food sector relevance, namely ZnO, CuO, FeO, SiO2, Ag NMs and nanocellulose.ResultsWe propose a new AOP (AOP530) that starts with endocytic lysosomal uptake leading to lysosomal disruption inducing mitochondrial dysfunction. Mitochondrial impairments can lead to cell injury/death and disrupt the intestinal barrier. The evidence collected supports that those food NMs can be taken up by intestinal cells and indicates that intestinal barrier disruption by Ag, CuO, SiO2NMs might occur whilst only few studies support that outcome for FeO, ZnO. Lysosomal disruption and mitochondrial dysfunction are rarely evaluated. For nanocellulose, none of the studies report toxic-related events.ConclusionsCollecting the existing scientific evidence supporting our AOP linking NM uptake to intestinal barrier impairments allowed us to highlight current evidence gaps but also data inconsistencies. Those latter could be associated with the variety of stressors, biological systems and KE-related assays used in the different studies, calling for further harmonized methodologies and production of mechanistic evidence in the safety regulatory assessment of NMs in the food sector.
GATA1-deficient human pluripotent stem cells generate neutrophils with improved antifungal immunity that is mediated by the integrin CD18
Authors: Wagner Andrew S. , Smith Frances M. , Bennin David A. , Votava James A. , Datta Rupsa , Giese Morgan A. , Zhao Wenxuan , Skala Melissa C. , Fan Jing , Keller Nancy P. , Huttenlocher Anna 
Published: October 2024

AbstractNeutrophils are critical for host defense against fungi. However, the short life span and lack of genetic tractability of primary human neutrophils has limitedin vitroanalysis of neutrophil-fungal interactions. Human induced pluripotent stem cell (iPSC)-derived neutrophils (iNeutrophils) are a genetically tractable alternative to primary human neutrophils. Here, we show that deletion of the transcription factor GATA1 from human iPSCs results in iNeutrophils with improved antifungal activity againstAspergillus fumigatus. GATA1 knockout (KO) iNeutrophils have increased maturation, antifungal pattern recognition receptor expression and more readily execute neutrophil effector functions compared to wild-type iNeutrophils. iNeutrophils also show a shift in their metabolism following stimulation with fungal β-glucan, including an upregulation of the pentose phosphate pathway (PPP), similar to primary human neutrophilsin vitro. Furthermore, we show that deletion of the integrin CD18 attenuates the ability of GATA1-KO iNeutrophils to killA. fumigatusbut is not necessary for the upregulation of PPP. Collectively, these findings support iNeutrophils as a robust system to study human neutrophil antifungal immunity and has identified specific roles for CD18 in the defense response.Author SummaryNeutrophils are important first responders to fungal infections, and understanding their antifungal functions is essential to better elucidating disease dynamics. Primary human neutrophils are short lived and do not permit genetic manipulation, limiting their use to study neutrophil-fungal interactionsin vitro. Human induced pluripotent stem cell (iPSC)-derived neutrophils (iNeutrophils) are a genetically tractable alternative to primary human neutrophils forin vitroanalyses. In this report we show that GATA1-deficient iPSCs generate neutrophils (iNeutrophils) that are more mature than wild-type iNeutrophils and display increased antifungal activity against the human fungal pathogenAspergillus fumigatus. We also show that GATA1-deficient iNeutrophils have increased expression of antifungal receptors than wild-type cells and shift their metabolism and execute neutrophil antifungal functions at levels comparable to primary human neutrophils. Deletion of the integrin CD18 blocks the ability of GATA1-deficient iNeutrophils to kill and control the growth ofA. fumigatus, demonstrating an important role for this integrin in iNeutrophil antifungal activity. Collectively, these findings support the use of iNeutrophils as a model to study neutrophil antifungal immunity.