bluuebunny/crossref_metadata_2025 huggingface dataset:
Longitudinal Changes of CT-radiomic and Systemic Inflammatory Features Predict Survival in Advanced Non–Small Cell Lung Cancer Patients Treated With Immune Checkpoint Inhibitors
Authors: Balbi Maurizio , Mazzaschi Giulia , Leo Ludovica , Moron Dalla Tor Lucas , Milanese Gianluca , Marrocchio Cristina , Silva Mario , Mura Rebecca , Favia Pasquale , Bocchialini Giovanni , Trentini Francesca , Minari Roberta , Ampollini Luca , Quaini Federico , Roti Giovanni , Tiseo Marcello , Sverzellati Nicola
Published: August 2024

Purpose:

This study aims to determine whether longitudinal changes in CT radiomic features (RFs) and systemic inflammatory indices outperform single-time-point assessment in predicting survival in advanced non–small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICIs).

Materials and Methods:

We retrospectively acquired pretreatment (T0) and first disease assessment (T1) RFs and systemic inflammatory indices from a single-center cohort of stage IV NSCLC patients and computed their delta (Δ) variation as [(T1-T0)/T0]. RFs from the primary tumor were selected for building baseline-radiomic (RAD) and Δ-RAD scores using the linear combination of standardized predictors detected by LASSO Cox regression models. Cox models were generated using clinical features alone or combined with baseline and Δ blood parameters and integrated with baseline-RAD and Δ-RAD. All models were 3-fold cross-validated. A prognostic index (PI) of each model was tested to stratify overall survival (OS) through Kaplan-Meier analysis.

Results:

We included 90 ICI-treated NSCLC patients (median age 70 y [IQR=42 to 85], 63 males). Δ-RAD outperformed baseline-RAD for predicting OS [c-index: 0.632 (95%CI: 0.628 to 0.636) vs. 0.605 (95%CI: 0.601 to 0.608) in the test splits]. Integrating longitudinal changes of systemic inflammatory indices and Δ-RAD with clinical data led to the best model performance [Integrated-Δ model, c-index: 0.750 (95% CI: 0.749 to 0.751) in training and 0.718 (95% CI: 0.715 to 0.721) in testing splits]. PI enabled significant OS stratification within all the models (P-value <0.01), reaching the greatest discriminative ability in Δ models (high-risk group HR up to 7.37, 95% CI: 3.9 to 13.94, P<0.01).

Conclusion:

Δ-RAD improved OS prediction compared with single-time-point radiomic in advanced ICI-treated NSCLC. Integrating Δ-RAD with a longitudinal assessment of clinical and laboratory data further improved the prognostic performance.
Objective Analysis of Predictive Value of Ultrasound Quantitative Scoring System for Treatment Method Selection in Cesarean Scar Pregnancy
Authors: Zhang Jieying , Liu Yingying , Wan Hui , Lu Yue , Xin Yanli , Du Jianwen , Wang Hong
Published: August 2024

This study aimed to explore the feasibility of using the ultrasound quantitative scoring system to guide the selection of surgical methods for a cesarean scar ectopic pregnancy (CSEP). A retrospective analysis was conducted of the medical records of 117 cases of patients with a CSEP. All patients underwent transvaginal ultrasound examination before treatment, and the ultrasound results were compared with the results of surgical exploration. The treatment methods that were delivered for the 2 patient groups with CSEP were analyzed, and agreement between the predicted and actual treatment protocols was tested using the kappa consistency test. Residual myometrial thickness at the scar site was mainly concentrated above 3 mm in the low-risk group, with 70 cases accounting for 76.9%, while in the high-risk group, this was primarily in the range of 1–3 mm with 18 cases accounting for 69.2%. The grading of nourishing blood supply to the gestational sac showed that 96.7% of patients in the low-risk group had Grade I and Grade II blood flow, while 84.6% of the high-risk group had Grade I and Grade II blood flow; Grade II blood flow was predominant in the high-risk group. The majority of patients in both the low- and high-risk groups experienced intraoperative blood loss of ≤50 mL (93.9% vs 80.6%, respectively). The consistency test between the actual and predicted treatment methods yielded a kappa coefficient of 0.644, indicating consistency between the two. For patients with CSEP in the low-risk group (score <4), the ultrasound quantitative scoring system could provide individualized assessment and offer clinically valuable treatment protocols.
Presurgical Maxillary Segmented Orthodontics Associated With 3-Piece Le Fort 1 Osteotomy for Palatal Expansion
Authors: Ricard Daniel , Ferri Joël , Schlund Matthias
Published: August 2024

Objective:

The aim of this study is to assess maxillary transverse dimension following presurgical maxillary segmented orthodontics associated with 3-piece Le Fort 1 osteotomy in a cohort of “long face syndrome” patients with palatal constriction.

Methods:

Patients with maxillary transverse insufficiency were retrospectively included. They all underwent maxillary segmented orthodontics followed by a 3-piece Le Fort 1 osteotomy with palatal expansion. Palatal width dimensions were collected preoperatively, postoperatively, and at the time of the final follow-up, the stability of the expansion was analyzed.

Results:

Nineteen patients were included. There was no complication. The mean postoperative expansion was 6 mm (range: 3.1–8.7 mm) in the canine region and 4.3 mm (range: 0–9.1 mm) in the second molar region. The mean relapse was 0.36 mm (range: 0–1.4 mm) or 6% (range: 0%–16.1%) in the canine region and 0.17 mm (range: 0–1.3 mm) or 4% (range: 0%–14%) in the second molar region.

Conclusion:

Presurgical maxillary segmented orthodontics with 3-piece Le Fort 1 osteotomy has shown high stability of the maxillary transverse dimension in a 1-step surgery without dental tipping. It should be considered as an alternative to rapid palatal expansion.
Planning for implementation success: insights from conducting an implementation needs assessment
Authors: Graham Nicole D. , Graham Ian D. , Vanderspank-Wright Brandi , Nadalin-Penno Letitia , Fergusson Dean A. , Squires Janet E.
Published: August 2024

Aim:

The aim of this paper is to provide insights into conducting an implementation needs assessment using a case example in a less-research-intensive setting.

Design and methods:

In the case example, an implementation needs assessment was conducted, including (1) an environmental scan of the organization's website and preliminary discussions with key informants to learn about the implementation context, and (2) a formal analysis of the evidence–practice gap (use of sedation interruptions) deploying a chart audit methodology using legal electronic reports.

Results:

Our needs assessment was conducted over 5 months and demonstrated how environmental scans reveal valuable information that can inform the evidence–practice gap analysis. A well-designed gap analysis, using suitable indicators of best practice, can reveal compliance rates with local protocol recommendations, even with a small sample size. In our case, compliance with the prescribed practices for sedation interruptions ranged from 65% (n=53) to as high as 84% (n=69).

Conclusions:

Implementation needs assessments provide valuable information that can inform implementation planning. Such assessments should include an environmental scan to understand the local context and identify both current recommended best practices and local best practices for the intervention of interest. When addressing an evidence–practice gap, analyses should quantify the difference between local practice and desired best practice.

Impact:

The insights gained from the case example presented in this paper are likely transferrable to implementation research or studies conducted in similar, less-research-intensive settings.

Spanish abstract:

http://links.lww.com/IJEBH/A257
Molecular basis of urostyle development in frogs: genes and gene regulation underlying an evolutionary novelty
Authors: Senevirathne Gayani , Shubin Neil H.
Published: August 2024

Evolutionary novelties entail the origin of morphologies that enable new functions. These features can arise through changes to gene function and regulation. One key novelty is the fused rod at the end of the vertebral column in anurans, the urostyle. This feature is composed of a coccyx and a hypochord, both of which ossify during metamorphosis. To elucidate the genetic basis of these features, we used laser capture microdissection of these tissues and did RNA-seq and ATAC-seq at three developmental stages in tadpoles of
Xenopus tropicalis
. RNA-seq reveals that the coccyx and hypochord have two different molecular signatures. Neuronal (
TUBB3
) and muscle markers (
MYH3
) are upregulated in coccygeal tissues, whereas T-box genes (
TBXT
,
TBXT.2
), corticosteroid stress hormones (
CRCH.1
) and matrix metallopeptidases (
MMP1
,
MMP8
and
MMP13
) are upregulated in the hypochord. ATAC-seq reveals potential regulatory regions that are observed in proximity to candidate genes that regulate ossification identified from RNA-seq. Even though an ossifying hypochord is only present in anurans, this ossification between the vertebral column and the notochord resembles a congenital vertebral anomaly seen prenatally in humans caused by an ectopic expression of the
TBXT
/
TBXT.2
gene. This work opens the way to functional studies that can elucidate anuran
bauplan
evolution.
The rise of dietary diversity in coral reef fishes
Authors: Ng Isabelle , Bellwood David R. , Strugnell Jan M. , Parravicini Valeriano , Siqueira Alexandre C.
Published: August 2024

Diet has been identified as a major driver of reef fish lineage diversification, producing one of the most speciose vertebrate assemblages today. Yet, there is minimal understanding of how, when and why diet itself has evolved. To address this, we used a comprehensive gut content dataset, alongside a recently developed phylogenetic comparative method to assess multivariate prey use across a diverse animal assemblage, coral reef fishes. Specifically, we investigated the diversification, transitions and phylogenetic conservatism of fish diets through evolutionary time. We found two major pulses of diet diversification: one at the end-Cretaceous and one during the Eocene, suggesting that the Cretaceous–Palaeogene mass extinction probably provided the initial ecological landscape for fish diets to diversify. The birth of modern families during the Eocene then provided the foundation for a second wave of dietary expansion. Together, our findings showcase the role of extinction rebound events in shaping the dietary diversity of fishes on present-day coral reefs.
Mycovorax composti gen. nov., sp. nov., a member of the family Chitinophagaceae isolated from button mushroom compost
Authors: Thai Meghann , Bell Tina L. , Kertesz Michael A.
Published: August 2024

Two Gram-stain-negative, aerobic, rod-shaped, orange-coloured bacterial strains, designated strain C216T and strain M2295, were isolated from mature mushroom compost from composting facilities in Victoria and South Australia, Australia, respectively. External structures such as flagella or pili were not observed on the cells under scanning electron microscopy. Optimal growth was found to occur at 45 °C, at pH 7.25 and in the absence of NaCl on Emerson’s 350 YpSs medium. The genome sequence of strain C216T was 3 342 126 bp long with a G+C content of 40.5 mol%. Functional analysis of the genome of strain C216T revealed genes encoding chitinolytic and hemi-cellulolytic functions, with 166 predicted genes associated with carbohydrate metabolism (8.9% of the predicted genes). These functions are important for survival in the mushroom compost environment, which is rich in hemicelluloses. No antibiotic resistance genes were found in the genome sequence. The major fatty acids of strain C216T were iso-C15 : 0 (56.7%), iso-C17 : 0 3-OH (15.6%), C16 : 1
 ω7c/iso-C15 : 0 2-OH (7.3%) and iso-C15 : 1 G (6.1%). The only respiratory quinone was MK-7. The major polar lipid of strain C216T was phosphatidylethanolamine, but three unidentified phospholipids, four unidentified aminophospholipids/aminolipids and one unidentified glycolipid were also detected. Phylogenetic analysis based on proteins encoded by the core genome (bac120, 120 conserved bacterial genes) showed that strain C216T forms a distinct lineage in the family Chitinophagaceae and that the closest identified relative is Niabella soli (69.69% ANI). These data demonstrate that strain C216T represents a novel genus and novel species within the family Chitinophagaceae, for which we propose the name Mycovorax composti. The type strain is C216T (=DSM 114558T=LMG 32998T).
Cyclic Electromagnetic DNA Simulation (CEDS) can enhance the Functions of Anticancer miR-26a-5p and miR-126-5p in RAW 264.7 cells
Authors: Kim Yeon Sook , Lee Suk Keun
Published: August 2024

Since cyclic electromagnetic DNA simulation (CEDS) was found to increase the hybridization potential of double-stranded DNA (dsDNA) and affect the functions of plasmid DNA (1), in this study, Dodecagonal CEDS was applied to RAW 264.7 cells to target anticancer miRNAs, miR-26a-5p and miR-126-5p, at 20-25 Gauss for 20 min during cell culture, followed by cytological observation, quantitative polymerase chain reaction (qPCR), and immunoprecipitation-based high-performance liquid chromatography (IP-HPLC). Both of miR-26a-5p*-CEDS and miR-126-5p*-CEDS induced significant decrease in cell number, and strong immunoreaction of c-caspase 3 in the remaining cells compared to oncogenic miR-21-5p*-CEDS and untreated control. In qPCR results, miR-26a-5p*-CEDS and miR-126-5p*-CEDS markedly increased the expression of target primary and mature miRNAs. IP-HPLC analysis showed that both miR-26a-5p*-CEDS and miR-126-5p*-CEDS induced potent anticancer effect on RAW 264.7 cells by suppressing RAS signaling, proliferation-growth-cytodifferentiation signaling axis, and angiogenesis-survival-oncogenesis-chronic inflammation axis compared to the untreated control and the positive control performed with non-specific poly-A 12A*-CEDS. MiR-26a-5p*-CEDS increased miRNA biogenesis and ER stress signaling more than miR-126-5p*-CEDS, while miR-126-5p*-CEDS increased NFkB signaling-immunity-apoptosis signaling axis more than miR-26a-5p*-CEDS. Therefore, it is proposed that the sequential treatment of miR-26a-5p*-CEDS and miR-126-5p*-CEDS may give a synergistic anticancer effect on RAW 264.7 cells. It is postulated that CEDS using a miRNA sequence can stimulate hybridization between miRNA and target mRNA and also increase the expression of target miRNA, and subsequently decrease the expression of miRNA target proteins, resulting in the alteration of protein signaling pathways in cells.
Cyclic Electromagnetic DNA Simulation (CEDS) targeting Telomere Repeat Sequence can enhance Anticancer Effect, while CEDS targeting Canonical E-box Sequence induce Oncogenic Effect in Cells
Authors: Kim Yeon Sook , Lee Suk Keun
Published: August 2024

Cyclic electromagnetic DNA simulation (CEDS) was used in the previous study (1) to stimulate the base pair polarities of oligo-dsDNAs, plasmid DNAs, and miRNAs. This study applied dodecagonal CEDS to target telomere repeat sequence (TTAGGG*-CEDS), canonical E-box sequence (CACGTG*-CEDS) in genomic DNA of RAW 264.7 cells and KB cells. During cell culture, CEDS was performed at 20-25 Gauss for 20 min, and followed by cytological observation and immunoprecipitation high-performance liquid chromatography (IP-HPLC) using 350 antisera. KB cells treated with TTAGGG*-CEDS showed a significant decrease in cell density and metachromasia in toluidine blue staining compared to untreated control, while only a slight decrease in cell density and metachromasia was observed by telomere mutation sequence, TTTGGG*-CEDS. Conversely, CACGTG*-CEDS induced almost no change in cell density, cell number, metachromasia in toluidine blue staining compared to random sequence*-CEDS (2(ACGT)*-CEDS) and untreated control. IP-HPLC results showed that TTAGGG*-CEDS induced a potent anticancer effect by downregulating RAS, oncogenesis, and telomere signaling, and activating NFkB signaling-p53-and FAS-mediated apoptosis-innate and cellular immunity signaling axis compared to untreated control and positive control performed with nonspecific poly-A 12A*-CEDS. In contrast, CACGTG*-CEDS exhibited a significant oncogenic effect by enhancing of RAS and NFkB signaling and resulting oncogenesis-glycolysis-chronic inflammation signaling axis. Therefore, it is suggested that CEDS is able to target DNA motif sequences in genomic DNA, and that TTAGGG*-CEDS and CACGTG*-CEDS are favorable candidates to regulate important genes involved in oncogenesis, inflammation, apoptosis, etc.
pyVIPER: A fast and scalable Python package for rank-based enrichment analysis of single-cell RNASeq data
Authors: Wang Alexander L.E. , Lin Zizhao , Zanella Luca , Vlahos Lukas , Anglada Girotto Miquel , Zafar Aziz , Noh Heeju , Califano Andrea , Vasciaveo Alessandro
Published: August 2024

Single-cell sequencing has revolutionized biomedical research by offering insights into cellular heterogeneity at unprecedented resolution. Yet, the low signal-to-noise ratio, characteristic of single-cell RNA sequencing (scRNASeq), challenges quantitative analyses. We have shown that gene regulatory network (GRN) analysis can help overcome this obstacle and support mechanistic elucidation of cellular state determinants, for example by using the VIPER algorithm to identify Master Regulator (MR) proteins from gene expression data. A key challenge, as the size and complexity of scRNASeq datasets grow, is the need for highly scalable tools supporting the analysis of large-scale datasets with up to hundreds of thousands of cells. To address it, we introduce pyVIPER, a fast, memory-efficient, and highly scalable Python toolkit for assessing protein activity in large-scale scRNASeq datasets. pyVIPER supports multiple enrichment analysis algorithms, data transformation/postprocessing modules, a novel data structure for GRNs manipulation, and seamless integration with AnnData, Scanpy and several widely adopted machine learning libraries. Compared to VIPER, benchmarking reveals orders of magnitude runtime reduction for large datasets—i.e., from hours to minutes— thus supporting VIPER-based analysis of virtually any large-scale single-cell dataset, as well as integration with other Python-based tools.

Availability and Implementation

pyVIPER is available on GitHub (https://github.com/alevax/pyviper) and PyPI (https://pypi.org/project/viper-in-python/).

Contact

av2729@cumc.columbia.edu

Supplementary information

Supplementary data are available at Bioinformatics online. Accompanying data for the tutorials are available on Zenodo (https://zenodo.org/records/10059791).
PCDHGC3silencing promotes clear cell renal cell carcinoma metastasis via mTOR/HIF2α and lipid metabolism reprogramming
Authors: Celada Lucía , Cubiella Tamara , Salerno Laura , San-Juan-Guardado Jaime , Murias Eduardo , Da Silva Torres Marina , Suárez-Priede Álvaro , Weiner Joshua A. , Herrada-Manchón Helena , Fernández M. Alejando , Chiara María-Dolores
Published: August 2024

Clustered protocadherins (cPCDH) are widely expressed in the nervous system with known functions, but their roles in cancer, particularly metastasis, are largely unexplored. Our previous research revealed that epigenetic silencing ofPCDHGC3is linked to decreased survival in neuroendocrine cancer patients. This study investigatesPCDHGC3’s role in clear cell renal cell carcinoma (ccRCC). We found that decreasedPCDHGC3expression is associated with lower survival and advanced disease stage in ccRCC patients. shRNA-mediatedPCDHGC3silencing in renal cancer cell lines significantly increased cell proliferation, invasion, and survival. In orthotopic mouse models,PCDHGC3silencing promoted metastasis. The mTOR and HIF2α pathways were identified as downstream targets activated byPCDHGC3loss. Inhibition of these pathways counteracted the effects ofPCDHGC3silencing, highlighting their importance in tumor progression. Proteomic and metabolomic analyses showed thatPCDHGC3silencing led to overexpression of proteins involved in fatty acid and cholesterol synthesis, increasing lipid droplets and shifting lipid metabolism. This metabolic reprogramming characterizes aggressive ccRCC. Our study emphasizesPCDHGC3’s impact on ccRCC metastasis and suggests mTOR or HIF2α inhibitors as potential therapies forPCDHGC3-deficient patients.
Effects of injury size on local and systemic immune cell dynamics in volumetric muscle loss
Authors: Whitaker Ricardo , Sung Samuel , Tylek Tina , Risser Gregory , O’Brien Erin , Chua Phoebe Ellin , Li Thomas , Petrie Ryan J. , Han Lin , Binder-Markey Benjamin , Spiller Kara L.
Published: August 2024

We took a systems approach to the analysis of macrophage phenotype in regenerative and fibrotic volumetric muscle loss outcomes in mice together with analysis of systemic inflammation and of other leukocytes in the muscle, spleen, and bone marrow. Macrophage dysfunction in the fibrotic group occurred as early as day 1, persisted to at least day 28, and was associated with increased numbers of leukocytes in the muscle and bone marrow, increased pro-inflammatory marker expression in splenic macrophages, and changes in the levels of pro-inflammatory cytokines in the blood. The most prominent differences were in muscle neutrophils, which were much more abundant in fibrotic outcomes compared to regenerative outcomes at day 1 after injury. However, neutrophil depletion had little to no effect on macrophage phenotype or on muscle repair outcomes. Together, these results suggest that the entire system of immune cell interactions must be considered to improve muscle repair outcomes.
Invertebrate species distributions in urban ecosystems are driven by habitat availability, not by anthropogenic drivers
Authors: Morpurgo Joeri , Remme Roy P. , Mudde Quinten , Didaskalou Emilie A. , Serwatowska Kornelia J. , Trimbos Krijn , Hu Mingming , Van Bodegom Peter M.
Published: August 2024

Rapid urbanisation puts pressure on biodiversity by habitat fragmentation and habitat quality among others. These habitat changes are known to affect species dispersal and connectivity and ultimately species distribution in many ecosystems. However, little is known about the changing urban species distributions which in turn influence community assembly. New DNA-based sampling methods combined with species distribution modelling provide a way to quantitatively estimate urban community assembly through assessing many species distributions and their drivers simultaneously.

We investigated species distributions of entire communities in the city of The Hague (the Netherlands) by sampling DNA with two distinct methods: collecting data on invertebrate occurrence with traditional trapping (bulk; n = 205) and a novel Environmental DNA method (eDNA; n = 207). After DNA sequencing, species were identified using Operational Taxonomic Units. Subsequently, individual species presence and absence were used in Species Distribution Models (SDMs), based on spatial information on vegetation and anthropogenic influences.

The results show a difference in coverage of sampling methods (bulk vs. eDNA), indicating their complementary information. The models on species distributions were generally significantly better than random models (59.5%), and performed well during calibration (90.4%, AUC > 0.70). In contrast, during validation very few SDMs (1.3%, AUC > 0.70) performed adequately in predicting species distributions.

Through this novel combination of DNA sampling with SDMs we show that density and structure of vegetation, as well as distance to water are more important for urban invertebrate distribution than direct anthropogenic pressures. This suggests that dispersal is not a limiting factor in The Hague’s urban environment. The availability of a variety of urban green infrastructures seems sufficient to attract many of the species observed. Hence, ensuring sufficient green infrastructure in the urban environment should be the first priority to enhance biodiversity in the urban environment.

Highlights

Vegetation and water indicators are the most important predictors for accurate assessment of species’ distribution

Anthropogenic pressures have lower impact on urban species distributions

DNA-SDM combinations show potential in guiding urban planners in evidence-based decision making
Acetate enhances spatial memory in females via sex- and brain region-specific epigenetic and transcriptional remodeling
Authors: Periandri Erica M. , Dodson Kala M. , Vitorino Francisca N. , Garcia Benjamin A. , Glastad Karl M. , Egervari Gabor
Published: August 2024

Metabolic control of chromatin and gene expression is emerging as a key, but largely unexplored aspect of gene regulation. In the brain, metabolic-epigenetic interactions can influence critical neuronal functions. Here, we use a combination of behavioral, proteomic and genomic approaches to demonstrate that the intermediary metabolite acetate enhances memory in a brain region- and sex-specific manner. We show that acetate facilitates the formation of dorsal hippocampus-dependent spatial memories in female but not in male mice, while having no effect on cortex-dependent non-spatial memories in either sex. Acetate-enhanced spatial memory is driven by increased acetylation of histone variant H2A.Z, and upregulation of genes implicated in spatial learning in the dorsal hippocampus of female mice. In line with the sex-specific behavioral outcomes, the effect of acetate on dorsal hippocampal histone modifications and gene expression shows marked differences between the sexes during critical windows of memory formation (consolidation and recall). Overall, our findings elucidate a novel role for acetate, a ubiquitous and abundant metabolite, in regulating dorsal hippocampal chromatin, gene expression and learning, and outline acetate exposure as a promising new approach to enhance memory formation.
Targeting Liver Epsins Ameliorates Dyslipidemia in Atherosclerosis
Authors: Zhu Bo , Gupta Krishan , Cui Kui , Wang Beibei , Malovichko Marina V. , Han Xiangfei , Li Kathryn , Wu Hao , Arulsamy Kulandai Samy , Singh Bandana , Gao Jianing , Wong Scott , Cowan Douglas B. , Wang Dazhi , Biddinger Sudha , Srivastava Sanjay , Shi Jinjun , Chen Kaifu , Chen Hong
Published: August 2024

Rationale

Low density cholesterol receptor (LDLR) in the liver is critical for the clearance of low-density lipoprotein cholesterol (LDL-C) in the blood. In atherogenic conditions, proprotein convertase subtilisin/kexin 9 (PCSK9) secreted by the liver, in a nonenzymatic fashion, binds to LDLR on the surface of hepatocytes, preventing its recycling and enhancing its degradation in lysosomes, resulting in reduced LDL-C clearance. Our recent studies demonstrate that epsins, a family of ubiquitin-binding endocytic adaptors, are critical regulators of atherogenicity. Given the fundamental contribution of circulating LDL-C to atherosclerosis, we hypothesize that liver epsins promote atherosclerosis by controlling LDLR endocytosis and degradation.

Objective

We will determine the role of liver epsins in promoting PCSK9-mediated LDLR degradation and hindering LDL-C clearance to propel atherosclerosis.

Methods and Results

We generated double knockout mice in which both paralogs of epsins, namely, epsin-1 and epsin-2, are specifically deleted in the liver (Liver-DKO) on an ApoE-/-background. We discovered that western diet (WD)-induced atherogenesis was greatly inhibited, along with diminished blood cholesterol and triglyceride levels. Mechanistically, using scRNA-seq analysis on cells isolated from the livers of ApoE-/-and ApoE-/-/Liver-DKO mice on WD, we found lipogenic Albhihepatocytes to glycogenic HNF4αhihepatocytes transition in ApoE-/-/Liver-DKO. Subsequently, gene ontology analysis of hepatocyte-derived data revealed elevated pathways involved in LDL particle clearance and very-low-density lipoprotein (VLDL) particle clearance under WD treatment in ApoE-/-/Liver-DKO, which was coupled with diminished plasma LDL-C levels. Further analysis using the MEBOCOST algorithm revealed enhanced communication score between LDLR and cholesterol, suggesting elevated LDL-C clearance in the ApoE-/-Liver-DKO mice. In addition, we showed that loss of epsins in the liver upregulates of LDLR protein level. We further showed that epsins bind LDLR via the ubiquitin-interacting motif (UIM), and PCSK9-triggered LDLR degradation was abolished by depletion of epsins, preventing atheroma progression. Finally, our therapeutic strategy, which involved targeting liver epsins with nanoparticle-encapsulated siRNAs, was highly efficacious at inhibiting dyslipidemia and impeding atherosclerosis.

Conclusions

Liver epsins promote atherogenesis by mediating PCSK9-triggered degradation of LDLR, thus raising the circulating LDL-C levels. Targeting epsins in the liver may serve as a novel therapeutic strategy to treat atherosclerosis by suppression of PCSK9-mediated LDLR degradation.
Vapor-based Fixation of Pulmonary Tissue in its Physiological State: A Novel Approach to Histological Validation of Ultra High Resolution Phase Contrast CT in Human Sized Lungs
Authors: Dullin Christian , Reiser Johanna , Wagner Willi , Longo Elena , Prasek Marko , Contillo Adriano , Sodini Nicola , Dreossi Diego , Confalonieri Paola , Salton Francesco , Confalonieri Marco , Baratella Elisa , Cova Maria , Benke Claudia , Sagar Md Motiur Rahman , D'Amico Lorenzo , Albers Jonas , Svetlove Angelika , Flisikowska Tatiana , Flisikowski Krzysztof , Wielpuetz Mark O. , Biederer Juergen , Kauczor Hans-Ulrich , Zanconati Fabrizio , Tromba Giuliana
Published: August 2024

Lung diseases continue to present a major burden on public health. Therefore, improving the process of diagnosis by the development of novel imaging techniques is of great importance. In this perspective, phase sensitive CT imaging techniques such as propagation based imaging (PBI) might play an important role as they allow increasing the spatial resolution at very low x-ray dose levels that are comparable to clinical CT. However, the development of such methods is not only hindered by technological problems but also by the lack of precise validation strategies. We adapted formaldehyde (FA) vapor fixation to demonstrate that fresh porcine lungs that have been investigated by PBI can be fixed in their physiological shape and studied by multi-scale microCT imaging as well as classical histology. In addition, we show that FA vapor fixed pig lungs can be scanned by PBI without visible deterioration of image quality compared to fresh tissue. This opens the possibility of fixing and storing, for instance, human lung tissue before performing a PBI experiment, which in turn allows to study pathological changes in human lungs without questioning the translate-ability of findings in pig lung. The setup can be used by any interested researchers.
Metadichol induces CD14 Glycoprotein Expression in Human Embryonic Stem Cells and Fibroblasts
Authors: Raghavan P. R.
Published: August 2024

CD14, or cluster of differentiation 14, is a glycoprotein essential to the immune system and is found primarily on monocytes, macrophages, and other immune cells. Despite its importance, there are no examples in the literature of small compounds that can induce multifold expression of CD14 in human embryonic stem cells (hESCs) or fibroblasts. This study addresses this gap by exploring the potential of metadichol, a nanoemulsion of long-chain fatty alcohols, to induce CD14 expression in hESCs. Using quantitative real-time PCR (qRT□PCR) and Western blotting techniques, we showed that metadichol significantly upregulated CD14 expression by seventeen -fold in hESCs but downregulated it in fibroblasts. This novel finding indicates that metadichol can modulate CD14 expression in a cell type-specific manner, highlighting its potential for enhancing stem cell-based therapeutics and advancing our understanding of stem cell biology. The implications of these findings are substantial, suggesting new directions for research into the immune modulatory functions of hESCs and their potential applications in regenerative medicine. Our work highlights the potential of metadichol as a powerful tool for modulating CD14 expression in stem as well as somatic cells marking a significant step forward in the field of stem cell research and therapeutic development.
Pericytes orchestrate a tumor-restraining microenvironment in glioblastoma
Authors: Braun Sebastian , Bolivar Paulina , Oudenaarden Clara , Sjölund Jonas , Bocci Matteo , Harbst Katja , Talkhoncheh Mehrnaz Safaee , Phung Bengt , Cordero Eugenia , Rosberg Rebecca , Johansson Elinn , Jönsson Göran B , Pietras Alexander , Pietras Kristian
Published: August 2024

Glioblastoma (GBM) is characterized by fast progression, an infiltrative growth pattern, and a high rate of relapse. A defining feature of GBM is the existence of spatially and functionally distinct cellular niches, i.e. a hypoxic niche, a leading-edge niche, and a perivascular niche, in which malignant cells engage in paracrine crosstalk with cell types comprising the tumor microenvironment. Here, by analysis of single-cell transcriptomic data of human GBM and transgenic mouse models of GBM, we unexpectedly identified pericytes, mural cells intimately associated with the endothelium, as the most active paracrine signaling hub within the tumor parenchyma. Exclusive signaling axes emanating from pericytes were received by endothelial cells, malignant cells, astrocytes, and immune cells. Depletion of pericytes through genetic engineering in several different transgenic and orthotopic mouse models of GBM demonstrated accelerated tumor progression, a disrupted blood-brain-barrier, and premature death of pericyte-poor mice. Mechanistic studies revealed that pericyte deficiency altered the cellular composition of GBM, remodeled the endothelium, and impacted on the immune cell landscape, exacerbating tumor cell invasion and immune suppression. Specifically, endothelial cells deprived of pericyte association altered their signaling programs, which in turn attracted perivascular, tumor-associated macrophages polarized towards an immune-suppressive phenotype. The recruited macrophages expressed Hepatocyte Growth Factor (HGF), which reinforced activation of its receptor tyrosine kinase MET on GBM cells harboring an extreme mesenchymal subtype driven by the key phenotypic regulator Fosl1 within hypoxic regions. Indeed, orthotopic implantation of isolated, MET-expressing GBM cells corroborated their superior tumor-initiating capability and invasive phenotype. In patients, low expression of a pericyte core gene signature was reduced in recurrent GBM, compared to primary tumors. Consistently, gene signatures for transcriptional programs of Fosl1+Met+GBM cells were indicative of poor survival in human tumors, and spatial transcriptomics corroborated their superior invasive capacity. Taken together, we infer that the pericyte represents a critical modulator of GBM development by orchestrating a tumor-suppressive microenvironment; our findings thus highlight the importance of pericyte preservation in the face of current and future GBM therapies.

Abstract Figure
A 3D-printed handheld device for quick citrus tissue lysis and nucleic acid extraction
Authors: Liu Chia-Wei , Kalish Brent , Bodaghi Sohrab , Vidalakis Georgios , Tsutsui Hideaki
Published: August 2024

Abstracts

A 3D-printed handheld device has been developed for rapid and efficient sample preparation from citrus leaves, aimed at streamlining protocols traditionally reliant on mortar and pestle. With its high-speed motor, knurled lysis chamber for rapid sample lysis, and quick nucleic acid extraction using paper disks, this device can yield ready-to-use extracts in just 12 minutes, significantly reducing the time required for sample preparation. The device was optimized for maximum sample lysis by evaluating operation voltages and chamber features. The results showed that the lysis chamber with internal knurling and the motor operated at 7.5 V was sufficient for effective sample lysis in 1 minute, achieving total RNA concentrations up to 87.6% of those obtained with a mortar and pestle. Furthermore, concerns regarding heat generation and resin release during the lysis process were found to not impact sample quality. To further facilitate in-field diagnosis, the capability of in-device sample preparation was verified with citrus sources infected withcitrus tristeza virusandSpiroplasma citriin qPCR-based assays, where low assay variations were demonstrated (< 3.8%). Overall, the in-device sample preparation integrated with the paper disks showed good reliability and compatibility across different pathogens for downstream analysis. An eco-friendly sterilization protocol using household bleach and vitamin C solution was also developed to safely reuse the device for in-field deployment.
Mining Yeast Diversity Unveils Novel Targets for Improved Heterologous Laccase Production inSaccharomyces cerevisiae
Authors: Wong Ryan Wei Kwan , Foo Marissa , Lay Jasmine R. S. , Wai Tiffany L. T. , Moore Jackson , Dutreux Fabien , Molzahn Cristen , Nislow Corey , Measday Vivien , Schacherer Joseph , Mayor Thibault
Published: August 2024

The budding yeastSaccharomyces cerevisiaeis a widely utilized host cell for recombinant protein production due to its well studied and annotated genome, its ability to secrete large and post-translationally modified proteins, fast growth and cost-effective culturing. However, recombinant protein yields fromS. cerevisiaeoften fall behind that of other host systems. To address this, we developed a high throughput screen of wild, industrial and laboratoryS. cerevisiaeisolates to identify strains with a natural propensity for greater recombinant protein production, specifically focussing on laccase multicopper oxidases from the fungiTrametes trogiiandMyceliophthora thermophila. Using this method, we identified 20 non-laboratory strains with higher capacity to produce active laccase. Interestingly, lower levels of laccase mRNA were measured in most cases, indicating that the drivers of elevated protein production capacity lie beyond the regulation of recombinant gene expression. We characterized the identified strains using complementary genomic and proteomic approaches to reveal several potential pathways driving the improved expression phenotype. Gene ontology analysis suggests broad changes in cellular metabolism, specifically in genes/proteins involved in carbohydrate catabolism, thiamine biosynthesis, transmembrane transport and vacuolar degradation. Targeted deletions of the hexose transporterHXT11and the Coat protein complex II interacting paralogsPRM8and9, involved in ER to Golgi transport, resulted in significantly improved laccase production from the S288C laboratory strain. Whereas the deletion of the Hsp110SSE1gene, guided by our proteomic analysis, also led to higher laccase activity, we did not observe major changes of the protein homeostasis network within the strains with higher laccase activity. This study opens new avenues to leverage the vast diversity ofSaccharomyces cerevisiaefor recombinant protein production, as well as offers new strategies and insights to enhance recombinant protein yields of current strains.
Search for charmed baryons in the
Λc+η
system and measurement of the branching fractions of
Λc(2880)+
and
Λc(2940)+
decaying to
Λc+η
and
pD0
relative to
Σc(2455)π
Authors: Li S. X. , Shen C. P. , Adachi I. , Ahn J. K. , Aihara H. , Asner D. M. , Atmacan H. , Aushev T. , Ayad R. , Banerjee Sw. , Belous K. , Bennett J. , Bessner M. , Bilka T. , Biswas D. , Bodrov D. , Bozek A. , Bračko M. , Branchini P. , Browder T. E. , Budano A. , Campajola M. , Chang M.-C. , Cheon B. G. , Chilikin K. , Cho H. E. , Cho K. , Choi S.-K. , Choi Y. , Choudhury S. , Dash N. , De Nardo G. , De Pietro G. , Dhamija R. , Dingfelder J. , Doležal Z. , Dong T. V. , Dubey S. , Ecker P. , Ferber T. , Fulsom B. G. , Gaur V. , Garmash A. , Goldenzweig P. , Graziani E. , Grube B. , Guan Y. , Gudkova K. , Hadjivasiliou C. , Hsu C.-L. , Ipsita N. , Itoh R. , Iwasaki M. , Jacobs W. W. , Ji Q. P. , Jia S. , Jin Y. , Joo K. K. , Kiesling C. , Kim D. Y. , Kim Y. J. , Kinoshita K. , Kodyš P. , Korobov A. , Korpar S. , Kovalenko E. , Križan P. , Krokovny P. , Kuhr T. , Kumar R. , Kumara K. , Kwon Y.-J. , Li L. K. , Li Y. , Li Y. B. , Liventsev D. , Masuda M. , Maurya S. K. , Meier F. , Merola M. , Miyabayashi K. , Mizuk R. , Mussa R. , Nakano T. , Nakao M. , Natochii A. , Nayak M. , Nishida S. , Pakhlov P. , Pakhlova G. , Pardi S. , Park J. , Park S.-H. , Patra S. , Paul S. , Pedlar T. K. , Pestotnik R. , Piilonen L. E. , Podobnik T. , Prencipe E. , Prim M. T. , Russo G. , Sandilya S. , Savinov V. , Schnell G. , Schwanda C. , Seino Y. , Senyo K. , Shiu J.-G. , Solovieva E. , Starič M. , Sumihama M. , Takizawa M. , Tamponi U. , Tanida K. , Tenchini F. , Uchida M. , Uglov T. , Uno S. , Wang E. , Won E. , Yabsley B. D. , Yan W. , Yelton J. , Yin J. H. , Yuan L. , Zhilich V. ,   The Belle Collaboration
Published: August 2024

We search for excited charmed baryons in the Λc+η system using a data sample corresponding to an integrated luminosity of 980  fb−1. The data were collected by the Belle detector at the KEKB e+e− asymmetric-energy collider. No significant signals are found in the Λc+η mass spectrum, including the known Λc(2880)+ and

Λ

c

(

2940

)

+

. Clear Λc(2880)+ and Λc(2940)+ signals are observed in the pD0 mass spectrum. We set upper limits at 90% credibility level on ratios of branching fractions of Λc(2880)+ and Λc(2940)+ decaying to Λc+η relative to Σc(2455)π of <0.13 for the Λc(2880)+ and <1.11 for the Λc(2940)+. We measure ratios of branching fractions of Λc(2880)+ and Λc(2940)+ decaying to pD0 relative to Σc(2455)π of 0.75±0.03(stat)±0.07(syst) for the Λc(2880)+ and 3.59±0.21(stat)±0.56(syst) for the Λc(2940)+.

Published by the American Physical Society
2024
Tcc
in the diabatic diquark model: Effects of
D*D
isospin
Authors: Lebed Richard F. , Martinez Steven R.
Published: August 2024

Tcc+ is an isoscalar 4-quark state with mass lying barely below the D*+D0 threshold, and several times further below the D*0D+ threshold. It allows both dimeson molecular and elementary diquark-antidiquark (cc)(u¯d¯) substructures. The diabatic generalization of the adiabatic approximation within the Born-Oppenheimer formalism rigorously incorporates the mixing of such elementary eigenstates with states corresponding to two-particle thresholds. We examine the separate influence of the two D*D isospin channels and find that the influence of D*+D0 is larger than that of D*0D+ but not overwhelmingly so, and that Tcc+ contains an O(10%) (cc)(u¯d¯) component. We then explore the variation of these results if the isospin breaking between the dimeson thresholds is varied, and also the sensitivity of our results to variation of the mixing-potential parameters.

Published by the American Physical Society
2024
Impact of dark energy on the structure of neutron stars: The vacuum case
Authors: Araújo L. F. , Lima J. A. S. , Lugones G.
Published: August 2024

The potential role of a cosmic vacuum dark component in the properties of neutron stars is investigated. It is assumed that the static, spherically symmetric distribution of matter within neutron stars is supported by two distinct components: ordinary matter and a vacuum fluid. For normal matter we use a set of state-of-the-art nuclear matter equations of state, each grounded in nuclear physics experiments. The vacuum energy component is inhomogeneously distributed within the star and obeys the standard equation of state (pv=−εv). This is characterized by an energy density fraction y=εm/(εm+εv), which we model as either a constant or radius-dependent. Our findings reveal that the inclusion of vacuum energy significantly affects the mass-radius relationships in neutron stars, influencing both the maximum achievable masses and the qualitative form of these relationships. Some constraints from current multimessenger observational data limiting the amount of vacuum energy within neutron stars are also discussed.

Published by the American Physical Society
2024
Experimental realization of supergrowing fields
Authors: K. R. Sethuraj , Karmakar Tathagata , Wadood S. A. , Jordan Andrew N. , Vamivakas A. Nick
Published: August 2024

Supergrowth refers to the local amplitude growth rate of a signal being faster than its fastest Fourier mode. In contrast, superoscillation pertains to the variation of the phase. Compared to the latter, supergrowth can have exponentially higher intensities and promises improvement over superoscillation-based superresolution imaging. Here, we demonstrate the experimental synthesis of controlled supergrowing fields with a maximum growth rate of ∼19.07 times the system bandlimit. Our work is an essential step toward realizing supergrowth-based far-field superresolution imaging.

Published by the American Physical Society
2024
RefXAS: an open access database of X-ray absorption spectra
Authors: Paripsa Sebastian , Gaur Abhijeet , Förste Frank , Doronkin Dmitry E. , Malzer Wolfgang , Schlesiger Christopher , Kanngießer Birgit , Welter Edmund , Grunwaldt Jan-Dierk , Lützenkirchen-Hecht Dirk
Published: August 2024

Under DAPHNE4NFDI, the X-ray absorption spectroscopy (XAS) reference database, RefXAS, has been set up. For this purpose, we developed a method to enable users to submit a raw dataset, with its associated metadata, via a dedicated website for inclusion in the database. Implementation of the database includes an upload of metadata to the scientific catalogue and an upload of files via object storage, with automated query capabilities through a web server and visualization of the data and files. Based on the mode of measurements, quality criteria have been formulated for the automated check of any uploaded data. In the present work, the significant metadata fields for reusability, as well as reproducibility of results (FAIR data principles), are discussed. Quality criteria for the data uploaded to the database have been formulated and assessed. Moreover, the usability and interoperability of available XAS data/file formats have been explored. The first version of the RefXAS database prototype is presented, which features a human verification procedure, currently being tested with a new user interface designed specifically for curators; a user-friendly landing page; a full list of datasets; advanced search capabilities; a streamlined upload process; and, finally, a server-side automatic authentication and (meta-) data storage via MongoDB, PostgreSQL and (data-) files via relevant APIs.