bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sedation and Ventilator Weaning Bundle and Time to Extubation in Infants With Bronchiolitis: Secondary Analysis of the Sedation AND Weaning in Children (SANDWICH) Trial
Authors: Mitting Rebecca B. , McDowell Cliona , Blackwood Bronagh , Ray Samiran 
Published: January 2025

Objective:
The Sedation and Weaning in Children (SANDWICH) trial of a sedation weaning and ventilator liberation bundle had a primary outcome of time to successful extubation, and showed significant but small difference. We explored the impact of the intervention on infants with bronchiolitis.

Design:
Post hoc subgroup analysis of a cluster-randomized trial, 2018 to 2019 (ISRCTN16998143).

Patients:
Surviving patients with bronchiolitis under 1 year of age in the SANDWICH trial (n = 784).

Interventions:
Nil.

Measurements and Main Results:
Time to successful extubation, and rates of unplanned and failed extubation were compared in patients exposed and not exposed to the intervention. To explore a site-level effect, we tested the correlation between the rate of unplanned and failed extubation at each trial site with the median time to successful extubation at that site. Of 784 patients (48%), 376 were exposed to the intervention. Median (interquartile range [IQR]) time to successful extubation was 69.6 (IQR 50.4–110.4) hours in patients exposed to the intervention and 86.4 (IQR 60–124.8) hours in non-exposed. Exposure to the SANDWICH intervention was associated with a 13% (95% CI, 1%–26%) reduction in time to extubation following adjustment for confounders. Thirty (3.8%) patients experienced unplanned extubation and 112 (14%) failed extubation. Patients who experienced failed extubation had an increased time to successful extubation, which remained significant after adjustment for confounders. At the site level, there was a negative correlation between failed extubation rate and median time to successful extubation (Spearman rho –0.53 [95% CI, –0.8 to –0.08], p = 0.02).

Conclusions:
In a secondary analysis of the SANDWICH trial, the subgroup of bronchiolitis patients showed that exposure to the intervention was associated with a clinically significant reduction in time to successful extubation. Although failed extubation was associated with increased duration of ventilation in an individual, sites with higher rates of failed extubation had a lower median duration of ventilation.
Gadopiclenol Enables Reduced Gadolinium Dose While Maintaining Quality of Pulmonary Arterial Enhancement for Pulmonary MRA
Authors: Heidenreich Julius F. , Chu Sheena Y. , Grunz Jan-Peter , Starekova Jitka , Nagpal Prashant , Reeder Scott B. , Grist Thomas M. 
Published: January 2025

Rationale and Objectives
Pulmonary magnetic resonance angiography (MRA) is an imaging method with proven utility for the exclusion of pulmonary embolism and avoids the need for ionizing radiation and iodinated contrast agents. High-relaxivity gadolinium-based contrast agents (GBCAs), such as gadopiclenol, can be used to reduce the required gadolinium dose for pulmonary MRA. The aim of this study was to compare the contrast enhancement performance of gadopiclenol with an established gadobenate dimeglumine–enhanced pulmonary MRA protocol.

Materials and Methods
In this retrospective single-center study, data from 152 patients who underwent pulmonary MRA at 1.5 T were analyzed. Imaging was performed with either 0.05 mmol/kg gadopiclenol (n = 75) or 0.1 mmol/kg gadobenate dimeglumine (n = 77), using dedicated multiphasic imaging protocols with precontrast, pulmonary arterial phase, immediate delayed phase, and a low flip-angle T1-weighted spoiled gradient echo acquisition. Subjective image quality evaluation was performed blinded by 2 radiologists on a 5-point Likert scale. For the estimation of interrater reliability, Cohen weighted κ was calculated. For semiquantitative assessment, signal intensities were measured in the pulmonary arteries, and relative signal enhancement was calculated. Data from groups were compared with Mann-Whitney U tests using Bonferroni corrections.

Results
Signal enhancement relative to precontrast in the first-pass pulmonary arterial phase was higher with 0.05 mmol/kg gadopiclenol compared with 0.1 mmol/kg gadobenate dimeglumine (20.0-fold ± 5.6-fold vs 17.8-fold ± 5.8-fold; P = 0.015). Readers observed no difference in subjective rating in terms of intravascular contrast, peripheral vessel depiction, and diagnostic confidence with substantial interrater reliability (Cohen κ = 0.73 [95% confidence interval: 0.57–0.89], 0.65 [0.55–0.75], and 0.74 [0.65–0.84], all P's < 0.001). No severe adverse events were recorded for any clinical MRA examination.

Conclusions
The high-relaxivity contrast agent gadopiclenol can facilitate a reduction in gadolinium dose by 50% without compromising contrast enhancement for pulmonary MRA. This approach may enhance the safety and sustainability of pulmonary MRA in the long term.
Fenretinide targets GATA1 to induce cytotoxicity in GATA1 positive Acute Erythroid and Acute Megakaryoblastic Leukemic cells
Authors: Raza Yasharah , Yu GuiQin , Chiappone Sam Blake , Liu Suhu , Luberto Chiara 
Published: January 2025

ABSTRACTPatients with Acute Myeloid Leukemia (AML) subtypes, acute erythroleukemia and acute megakaryocytic leukemia (M6 and M7 AMLs, respectively) have a median survival of only a few months with no targeted effective treatment. Our gene expression analysis using the Cancer Cell Line Encyclopedia and CRISPR screen from DepMap showed that M6/M7 AMLs have high levels of the transcription factorGATA1and depend on GATA1 for survival. While GATA1 was shown to support AML cell proliferation and resistance to chemotherapy, GATA1 has long been considered “undruggable”. Here, we identify the small molecule N-(4-hydroxyphenyl)retinamide (4-HPR, Fenretinide) as a novel GATA1 targeting agent in M6 and M7 AML cells, with nM to low μM concentrations of 4-HPR causing loss of GATA1. In M6 AML OCIM1 cells, knock-down ofGATA1induced cytotoxicity similarly to low doses 4-HPR while overexpression of GATA1 significantly protected cells from 4-HPR-induced cytotoxicity. In M6 AML cells, 4-HPR synergized with the current standard-of-care (SOC), Azacytidine plus Venetoclax, overcoming cell resistance to the drugs. As single-agent, 4-HPR outperformed SOC. 4-HPR is a synthetic derivative of vitamin A, and numerous clinical trials have supported its safe profile in cancer patients; therefore, targeted use of 4-HPR against M6 and M7 AMLs may represent a novel therapeutic breakthrough.Key Points- Fenretinide (4-HPR) targets the transcription factor GATA1, which was previously thought to be “undruggable” and induces GATA1 loss.- M6 and M7 Acute Myeloid Leukemias (AML) have enriched expression of GATA1 and they can be considered GATA1 positive.- Loss of GATA1 contributes significantly to 4-HPR cytotoxicity in M6 OCIM1 cells.- 4-HPR treatment overcomes chemotherapeutic resistance in M6 Acute Myeloid Leukemia cells, synergizes with standard-of-care and outperforms standard-of-care as a single agent.
Inhibition of cathepsin B blocks amyloidogenesis in the mouse models of neurological lysosomal diseases mucopolysaccharidosis type IIIC and sialidosis
Authors: Viana Gustavo M. , Pan Xuefang , Fan Shuxian , Xu TianMeng , Wyatt Alexandra , Pshezhetsky Alexey V. 
Published: January 2025

AbstractNeuronal accumulation of amyloid aggregates is a hallmark of brain pathology in neurological lysosomal storage diseases (LSDs) including mucopolysaccharidoses (MPS), however, the molecular mechanism underlaying this pathology has not been understood. We demonstrate that elevated lysosomal cathepsin B (CTSB) levels and CTSB leakage to the cytoplasm triggers amyloidogenesis in two neurological LSDs. CTSB levels were elevated 3-5-fold in the cortices of mouse models of MPS IIIC (Hgsnat-GeoandHgsnatP304L) and sialidosis (Neu1ΔEx3), as well as in cortical samples of MPS I, IIIA, IIIC and IIID patients. CTSB was found in the cytoplasm of pyramidal layer IV-V cortical neurons containing Thioflavin-S-positive, β-amyloid-positive aggregates consistent with pro-senile phenotype. In contrast, CTSB-deficient MPS IIIC (HgsnatP304L/Ctsb-/-) mice as well asHgsnatP304LandNeu1ΔEx3mice chronically treated with irreversible brain-penetrable CTSB inhibitor, E64, showed a drastic reduction of neuronal Thioflavin-S-positive/APP-positive deposits. Neurons ofHgsnatP304L/Ctsb-/-mice and E64-treatedHgsnatP304Lmice also showed reduced levels of P62/LC3-positive puncta, GM2ganglioside and misfolded subunit C of mitochondrial ATP synthase (SCMAS) consistent with restored autophagy. E64 treatment also rescued hyperactivity and reduced anxiety inHgsnatP304Lmice implying that CTSB may become a novel pharmacological target for MPS III and similar LSDs.
An area-resolved phylogeography of bulbous barley (Hordeum bulbosum; Poaceae)
Authors: Blattner Frank R. , Pfanzelt Simon , Koch Christina , Himmelbach Axel , Sassone Agostina B. , Abdulkarim Abdulnaser Kh. , Shuka Lulëzim , Harpke Dörte 
Published: January 2025

SummaryHordeum bulbosum, the closest relative of barley (H. vulgare), is an important source of resistance genes for cereals in the Triticeae. This perennial and mainly outcrossing species occurs with two cytotypes: diploids thrive in the western and central parts of the Mediterranean, while autotetraploids extend from Greece mainly eastwards to western Asia. To elucidateH. bulbosum’s origin, colonization patterns, population relationships, and distinctions between the two cytotypes, we determined ploidy and performed genotyping-by-sequencing analyses on 314 individuals from across the species’ distribution range. Our results revealed two distinct lineages within diploidH. bulbosum: individuals from Libyavs. all other diploids. Southeastern Italian populations were the origin for the species expansion eastward into Albania/Greece and westward into mainland Italy, Sicily/Sardinia, Tunisia, and Spain. The tetraploid cytotype originated early in the evolution of the species, thus retaining alleles found in extant Libyan diploids. Tetraploids underwent local introgression from diploids in Greece, where also a secondary origin of tetraploids was detected. We found that ecoclimatic conditions alone cannot account for the clear geographic separation of the cytotypes, as habitats across much of the central Mediterranean would be suitable for both. We conclude that minority cytotype exclusion is the most plausible explanation for the distinct distribution patterns observed. While both cytotypes are morphologically indistinguishable, diploid populations typically occur in scattered stands within their range, while tetraploids tend to form larger, often contiguous populations.
SLAMF6 enables efficient attachment, synapse formation, and killing of HIV-1-infected CD4+T cells by virus-specific CD8+T cells
Authors: Monel Blandine , Lamothe Pedro A. , Meyo James , McLean Anna P. , Quinones-Alvarado Raymond , Laporte Mélanie , Boucau Julie , Walker Bruce D. , Kavanagh Daniel G. , Garcia-Beltran Wilfredo F. , Pacheco Yovana 
Published: January 2025

ABSTRACTEfficient recognition and elimination of HIV-1-infected CD4+T cells by cytotoxic CD8+T cells (CTLs) require target cell engagement and the formation of a well-organized immunological synapse. Surface proteins belonging to the SLAM family are known to be crucial for stabilizing the immunological synapse and regulating antiviral responses during lymphotropic viral infections. In the context of HIV-1, there have been reports of SLAMF6 down-regulation in HIV-1-infected CD4+T cells; however, the significance of this modulation for CTL function remains unclear. In this investigation, we used CTL lines from People living with HIV (PLWH) to examine the impact of SLAMF6 blockade on three pivotal processes: (1) the formation of CD8+-CD4+T-cell conjugates, (2) the establishment of the immunological synapse, and (3) the killing and cytokine production capacity of HIV-1-specific CTLs during HIV-1 infection. Our findings reveal that the inability to form CD8+-CD4+T-cell conjugates following incubation with an anti-SLAMF6 blocking antibody is primarily attributable to a defect in actin ring formation at the immunological synapse. Furthermore, SLAMF6 blockade leads to a reduction in the killing efficiency of HIV-1-infected CD4+T cells by HIV-1-specific CTLs, underscoring the critical role of SLAMF6 in cytolytic function. This study highlights the importance of SLAMF6 receptors in modulating cytotoxic antiviral responses, shedding light on potential avenues for manipulation and enhancement of this pathway in the context of HIV and other lymphotropic viral infections.
Lower spatial turnover of rare fungal taxa dominantly shaped by stochastic processes in grassland soils
Authors: Biao Zhang , Shutong Zhou , Kai Xue , Wenjing Liu , Shuo Chen , Li Tang , Linfeng Li , Jianqing Du , Yanbin Hao , Xiaoyong Cui , Yanfen Wang 
Published: January 2025

AbstractThe spatial pattern and community assembly of soil microbial taxa have notable meanings for biodiversity shaping and maintaining mechanisms. Rare fungal taxa may exhibit distinct patterns and assembly mechanisms compared to abundant taxa, but such information is limited, especially at large scales. Here, we investigated distance-decay patterns and underlying assembly mechanisms for abundant and rare fungal taxa in 129 soil samples collected across 4,000 km in Chinese Northern grasslands, based on high-throughput sequencing data. A total of 208 abundant OTUs (relative abundance > 0.1%, 2.73% of entire OTUs) and 5,779 rare OTUs (relative abundance < 0.01%, 75.85% of entire OTUs) were identified. Both abundant and rare fungal taxa showed significant distance-decay relationships (P < 0.001), but the turnover rate for rare taxa (0.0024 per 100 km) was nearly half that of abundant taxa (0.0054 per 100 km) based on the binary Bray-Curtis distance. The lower turnover of rare fungal taxa was likely due to their community assembly mechanism dominated by stochastic processes, which were less influenced by environmental gradients. In contrast, abundant taxa assembly was dominated by deterministic factors like soil variables and plant traits, which varied significantly along the geographic distance. Consistently, rare fungal taxa were also less sensitive to environmental changes, with a lower turnover rate by environmental distance (0.0027 vs. 0.0099) than abundant taxa. In summary, our findings revealed that rare fungal taxa, shaped mainly by stochastic processes, had lower spatial turnover compared to abundant taxa, dominated by deterministic processes, enhancing our understanding of rare microbial biogeography.
Thymic selection of the T cell receptor repertoire is biased toward autoimmunity in females
Authors: Vantomme Hélène , Quiniou Valentin , Adda Leslie , Jouannet Charline , Mhanna Vanessa , Albalaa Céline , Barennes Pierre , Coatnoan Nicolas , Diderot Vimala , Dubois Johanna , Fourcade Gwladys , Le Gouge Kenz , Nguekap Tchoumba Otriv Frédéric , Pezous Martin , Stys Paul , Six Adrien , Mariotti-Ferrandiz Encarnita , Klatzmann David 
Published: January 2025

AbstractWomen represent about 80% of patients with autoimmune diseases. This may partly result from sex-based differences in T cell receptor (TCR) selection during thymocyte development, potentially influenced by hormones and the lower expression of the Autoimmune Regulator (AIRE) transcription factor in females.To investigate this, we analyzed sex-specific differences in TCR generation and selection. We examined TCR repertoires in double-positive thymocytes and single-positive thymic cells, including CD8⁺ and CD4⁺ effector T cells and regulatory T cells (Tregs), derived from male and female organ donors. Minimal sex-based differences were observed in V and J gene usage, and there were no notable differences in TCR repertoire diversity, complementarity-determining region 3 (CDR3) length, amino acid composition, or network structure. No TCR sequences were exclusive to either sex.However, female effector T cells exhibited a significantly higher prevalence of TCRs specific to self-antigens implicated in autoimmunity compared to males, while female Tregs showed a reduced frequency of such TCRs. These differences were not observed for TCRs targeting self-antigens unrelated to autoimmunity or antigens associated with cancer or viruses.Our findings highlight a sex-specific imbalance in thymic selection of TCRs with autoimmunity-associated specificities, providing mechanistic insight into the increased susceptibility of women to autoimmune diseases.
Jack of all trades and master of most:Carpobrotustaxa show no trade-off in reproductive strategies
Authors: Canavan Susan , Rodríguez Jonatan , Skálová Hana , Le Roux Johannes J. , Brundu Giuseppe , Castillo María L. , D’Antonio Carla M. , González Luís , Hulme Philip E. , Richardson David M. , McLean Phill , Moodley-Maříková Desika , Moravcová Lenka , Parker Ingrid M , Pyšek Petr , Štajerová Kateřina , van Wyk Ernita , Novoa Ana 
Published: January 2025

AbstractThe ability to reproduce via multiple strategies is crucial for the invasion success of alien plant species. Here, we useCarpobrotustaxa (species and hybrids) to explore how trade-offs between and within these strategies may influence plant invasion dynamics. Native to South Africa,Carpobrotusplants are globally prominent in coastal ecosystems, reproducing by seed and clonally, and frequently hybridizing in both native and introduced regions. Three genetically distinct clusters were previously identified, with evidence of hybridization within and between these clusters in native and non-native ranges.We collected fruit samples from populations representing the genetic clusters and their hybrids across native and non-native ranges (i.e., Europe, California, and New Zealand). These genetic clusters reflect the complex taxonomy ofCarpobrotus, where species boundaries are unclear due to hybridization and morphological similarity. We then assessed seed set, seed mass, germination rates, and early growth under varying abiotic conditions alongside genetic estimates of clonality.Germination rates were influenced by temperature, moisture, and nutrient levels. Non-native populations demonstrated higher seed set, seed mass, and germination success compared to native populations, indicating a stronger investment in sexual reproduction. These populations also showed higher levels of clonality, shown by lower genotypic richness, suggesting that both reproductive strategies enhance invasive potential.High-clonality populations produced more seeds, demonstrating that the two reproductive strategies are not mutually exclusive. These results highlight the importance of multiple reproductive strategies for the establishment and spread ofCarpobrotustaxa and provide insights into the mechanisms driving their global success.
Multiple orthoflaviviruses secrete sfRNA in mosquito saliva to promote transmission by inhibiting MDA5-mediated early interferon response
Authors: Serrato-Pomar Idalba , Zoladek Jim , Medkour Hacène , Narpon Quentin , Rey-Cadilhac Felix , Rossi Solena , French Stephanie , Modahl Cassandra , Sornjai Wannapa , Miot Elliott , Hamel Rodolphe , Medianikov Oleg , Missé Dorothée , Nisole Sébastien , Pompon Julien 
Published: January 2025

AbstractNumerous orthoflaviviruses transmitted through the bites of different mosquito species infect more than 500 million people annually. Bite-initiated skin infection represents a critical and conserved step in transmission and a deeper understanding of this process will promote the design of broad-spectrum interventions to address diverse orthoflavivirus health threats. Here, we identify and characterize a transmission-enhancing viral factor in mosquito saliva that is shared across orthoflaviviruses. Saliva of West Nile virus-infectedCulexand Zika virus-infectedAedescontains a viral non-coding RNA, subgenomic orthoflaviviral RNA (sfRNA), within lipid vesicles distinct from virions. Higher concentration of sfRNA in infectious saliva positively correlates with infection intensity in human cells and skin explants. Early sfRNA delivery into transmission-relevant skin cell types and human skin explant demonstrate that sfRNA is responsible for the infection enhancement. Co-inoculation of sfRNA in a mouse model of transmission enhanced skin infection and worsened disease severity, evidencing the role of salivary sfRNA as a transmission-enhancer. Mechanistically, salivary sfRNA attenuates early interferon response in human skin cells and skin explants by altering MDA5-mediated signaling. Our results, derived from two distinct orthoflaviviruses and supported by prior studies, establish salivary sfRNA as a pan-orthoflavivirus transmission-enhancing factor driven by a conserved viral non-coding RNA.
Multiciliated cells adapt the mechanochemical Piezo1-Erk1/2-Yap1 cell proliferation axis to fine-tune centriole number
Authors: Narayanan Vani , Rao Venkatramanan G , Arrigo Angelo , Kulkarni Saurabh S 
Published: January 2025

AbstractMulticiliated cells (MCCs) are specialized epithelial cells that undergo massive amplification of centrioles, constructing several motile cilia to propel fluid flow. The abundance of cilia is critical for efficient fluid flow, yet how MCCs regulate centriole/cilia numbers remains a major knowledge gap. We have shown that mechanical tension plays a central role in regulating apical area and centriole number in MCCs. Here, we demonstrate that centriole amplification is controlled by a mechanochemical pathway essential for cell proliferation in cycling cells. Specifically, MCCs under tension use Piezo1-mediated calcium signaling to drive Erk½ phosphorylation via PKC and subsequent Yap1 activation. Remarkably, MCCs use this pathway to activate a cilia-specific transcription program, influencing the expression of Foxj1, a master regulator of motile ciliogenesis. Our work is the first to identify a novel function for an important mechanochemical pathway in centriole amplification in MCCs, offering new insights into ciliopathies and cancer, where aberrant centriole numbers are implicated.TeaserThis study demonstrates that multiciliated cells utilize the mechanochemical Piezo1-Erk1/2-Yap1 cell proliferation axis to activate the cilia-specific transcriptional factor Foxj1 and amplify centrioles in a tension- dependent manner.