bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lysosomal acid lipase-activity as a novel target to efficiently address triple-negative breast cancer high malignancy
Authors: Steigerwald H. , Bozzetti T. , Tams M. , On J. , Hoffmann G. , Lambertz J. , Weidele K. , Treitschke S. , Reinhard F. , Kulik A. , Krawczyk N. , Niederacher D. , Neubauer H. , Werno C. , Rau T. , Fehm T. , Esser K 
Published: October 2023

AbstractIncreased metabolism of neutral lipids, e.g. triglycerides and cholesterol esters, is a hallmark of malignant cancers such as triple-negative breast cancer (TNBC). Predominantly, cancer cells with a high epigenetic stem cell-associated signature increasingly utilize neutral lipids to maintain their high degree of tumor stemness, linking metabolic aberrations to epigenetically dysregulated differentiation processes. Lysosomal acid lipase (LIPA) is a central enzyme in the cellular utilization of exogenous and endogenous neutral lipids; however, the role of LIPA-activity in TNBC remains unexplored. We here show for the first time that pharmacological inhibition of LIPA, highly expressed in TNBC, reduces the expression markers of breast cancer stemness in cell culture models of TNBC. A role of LIPA in maintaining TNBC high cellular stemness was stressed by specific siRNA knock-down. Furthermore, inhibition of LIPA sensitized TNBC cells to therapy with Paclitaxel and Doxorubicin, two important chemotherapeutics in current TNBC treatment. When LIPA-activity was inhibited in a three-dinensional (3D) patient derived organoid model, we observed a significant reduction in TNBC cellular viability. Importantly, LIPA inhibition prevented tumor metastasis in a TNBC-zebrafish xenograft modelin vivo. These findings introduce LIPA-activity as a novel pharmacological target in TNBC therapy to specifically address its high cancer malignancy with a potential for implementation of LIPA inhibitors into personalized treatment in the future.
Defining melanoma combination therapies that provide senolytic sensitivity in human melanoma cells
Authors: Tchelougou Daméhan , Malaquin Nicolas , Cardin Guillaume , Desmul Jordan , Turcotte Simon , Rodier Francis 
Published: October 2023

AbstractMalignant Melanoma that resists immunotherapy remains the deadliest form of skin cancer owing to poor clinically lasting responses. Alternative like genotoxic or targeted chemotherapy trigger various cancer cell fates after treatment including cell death and senescence. Senescent cells can be eliminated using senolytic drugs and we hypothesize that the targeted elimination of therapy-induced senescent melanoma cells could complement both conventional and immunotherapies.We utilized a panel of cells representing diverse mutational background relevant to melanoma and found that they developed distinct senescence phenotypes in response to treatment. A genotoxic combination therapy of carboplatin-paclitaxel or irradiation triggered a mixed response of cell death and senescence, irrespective of BRAF mutation profiles. DNA damage-induced senescent cells exhibited morphological changes, residual DNA damage, and increased senescence-associated secretory phenotype (SASP). In contrast, dual targeted inhibition of Braf and Mek triggered a partially reversible senescence-like state without DNA damage or SASP.To assess the sensitivity to senolytics we employed a novel real-time imaging-based death assay and observed that Bcl-xl/Bcl-2 inhibitors and piperlongumine were effective in promoting death of carboplatin-paclitaxel and irradiation-induced senescent melanoma cells, while senescent-like cells resulting from Braf-Mek inhibition remained unresponsive. Interestingly, a direct synergy between Bcl-2/Bcl-xl inhibitors and Braf-Mek inhibitors was observed when used out the context of senescence. Overall, we highlight that the hallmarks of melanoma senescence and sensitivity to senolytics are context dependent and provide evidence of effective combinations of senotherapy drugs that could reduce treatment resistance while also discussing the limitations of this strategy in human melanoma cells.
Replicators, genes, and the C-value enigma: High-quality genome assembly of barley provides direct evidence that self-replicating DNA forms ‘cooperative’ associations with genes in arms races
Authors: Rabanus-Wallace M. Timothy , Wicker Thomas , Stein Nils 
Published: October 2023

AbstractThe C-value enigma—the apparent disjunction between the complexity of organisms and the sizes of their genomes—could be in part resolved if it were definitively shown that tolerance of self-copying DNA elements incurred an occasional selective advantage. We leverage the power of the latest genome assembly of the exceptionally repetitive and well-studied cereal crop barley (Hordeum vulgareL.) to explicitly test the hypothesis that the population of genes that have been repeatedly replicated by the action of replication-inducing sequences has undergone selection, favouring genes involved in co-evolutionary arms races (such as genes implicated in pathogen resistance). This was achieved by algorithmically identifying 1,999 genomic stretches that are locally rich in long repeated units. In these loci, we identified 554 geanes, belonging to 42 gene families. These gene families strongly overlap with a test set of pathogen resistance and other likely evolutionary ‘arms-race’ genes compiled independently from the literature. By statistically demonstrating that selection has systematically influenced the composition of replicator-associated genes at a genome-wide scale we provide evidence that tolerance of repeat-inducing DNA sequences is an adaptive strategy that may contribute to enigmatically inflated C-values, and invite more detailed research on how particular genes become prone to duplication, to the organism’s advantage. To this end, we examined the genomic sequences surrounding several of the candidate gene families, and find a repeated pattern of genomic disperse-and-expand dynamics, but where the repeated genomic unit itself varies between sites of expansion. This suggests that genes effectively form opportunistic relationships with replication-inducing DNA elements. We mention implications for agriculture.
Vps18 contributes to phagosome membrane integrity inMycobacterium tuberculosis-infected macrophages
Authors: Jani Charul , Marsh Amanda , Uchil Pooja , Jain Neha , Baskir Zach R. , Glover Owen T. , Root David E. , Doench John G. , Barczak Amy K. 
Published: October 2023

AbstractMycobacterium tuberculosis(Mtb) has evolved to be exquisitely adapted to survive within host macrophages. The capacity to damage the phagosomal membrane has emerged as central to Mtb virulence. While Mtb factors driving membrane damage have been described, host factors that repair that damage to contain the pathogen remain largely unknown. We used a genome-wide CRISPR screen to identify novel host factors required to repair Mtb-damaged phagosomal membranes. Vacuolar protein sorting-associated protein 18 (Vps18), a member of the HOPS and CORVET trafficking complexes, was among the top hits. Vps18 colocalized with Mtb in macrophages beginning shortly after infection, and Vps18-knockout macrophages demonstrated increased damage of Mtb-containing phagosomes without impaired autophagy. Mtb grew more robustly in Vps18-knockout cells, and the first-line anti-tuberculosis antibiotic pyrazinamide was less effective. Our results identify Vps18 as required for phagosomal membrane integrity in Mtb-infected cells and suggest that modulating phagosome integrity may hold promise for improving the efficacy of antibiotic treatment for TB.
A network of transcriptomic signatures identifies novel comorbidity mechanisms between schizophrenia and somatic disorders
Authors: Zhang Youcheng , Bharadhwaj Vinay S. , Kodamullil Alpha T. , Herrmann Carl 
Published: October 2023

AbstractThe clinical burden of mental illness, in particular schizophrenia and bipolar disorder, are driven by frequent chronic courses and increased mortality, as well as the risk for comorbid conditions such as cardiovascular disease and type 2 diabetes. Evidence suggests an overlap of molecular pathways between psychotic disorders and somatic comorbidities. In this study, we developed a computational framework to perform comorbidity modeling via an improved integrative unsupervised machine learning approach based on multi-rank non-negative matrix factorization (mrNMF). Using this procedure, we extracted molecular signatures potentially explaining shared comorbidity mechanisms. For this, 27 case-control microarray transcriptomic datasets across multiple tissues were collected, covering three main categories of conditions including psychotic disorders, cardiovascular diseases and type II diabetes. We addressed the limitation of normal NMF for parameter selection by introducing multi-rank ensembled NMF to identify signatures under various hierarchical levels simultaneously. Analysis of comorbidity signature pairs was performed to identify several potential mechanisms including 1) dysfunction of endothelial systems; 2) induction of hypoxia and oxidative stress; 3) dysregulation of neural transmission GABAergic system associated with neuroendocrine function (e.g. insulin secretion); 4) activation of inflammatory response auxiliarily interconnecting blood-brain systems, oxidative response and GABAergic neuro-action. Overall, we proposed a general cross-cohorts computing workflow for investigating the comorbid pattern across multiple symptoms, applied it to the real-data comorbidity study on schizophrenia, and further discussed the potential for future application of the approach.
Pulsed ultrasound modulates the cytotoxic effect of cisplatin and doxorubicin on cultured human retinal pigment epithelium cells (ARPE-19)
Authors: Mohammadi Seyed Omid , LaRocca Megan C. , Yang Christopher D. , Jessen Jordan , Kenney M. Cristina , Lin Ken Y. 
Published: October 2023

AbstractObjectivePulsed ultrasound has been proposed as a tool to enhance ocular drug delivery, but its effects on drug potency are not well understood. Doxorubicin-HCl and cisplatin are two drugs commonly used to treat ocular melanoma. We report the effects of pulsed ultrasound on the cytotoxicity of doxorubicin-HCl and cisplatinin vitro.MethodsCultured human retinal pigment epithelium cells (ARPE-19) cells were treated with doxorubicin-HCl or cisplatin in the presence or absence of ultrasound. MTT and Trypan blue assays were performed at 24 and 48 hours post-treatment to assess cell metabolism and death.ResultsCells treated with ultrasound plus doxorubicin-HCl demonstrated a significant decrease in metabolism compared to cells treated with doxorubicin-HCl alone. In contrast, cells treated with ultrasound plus cisplatin exhibited a significant increase in metabolism compared to cells treated with cisplatin alone at 48-hours. Cells treated with cisplatin pre-treated with ultrasound (US-Cis) exhibited a significant decrease in metabolism. Cell death was similar in doxorubicin- and cisplatin-treated cells with and without ultrasound.ConclusionPulsed ultrasound enhances the cytotoxicity of doxorubicin-HCl at 24- and 48-hours post-treatment but abrogates cisplatin toxicity 48-hours post-treatment. This suggests ultrasound modulates cell-drug interactions in a drug-specific manner. These findings may influence the future development of ultrasound-assisted ocular drug delivery systems.
Gut metabolite L-lactate supportsCampylobacter jejunipopulation expansion during acute infection
Authors: Sinha Ritam , LeVeque Rhiannon M. , Callahan Sean M. , Chatterjee Shramana , Stopnisek Nejc , Kuipel Matti , Johnson Jeremiah G. , DiRita Victor J. 
Published: October 2023

AbstractHow the microaerobic pathogenCampylobacter jejuniestablishes its niche and expands in the gut lumen during infection is poorly understood. Using six-week-old ferrets as a natural disease model, we examined this aspect ofC. jejunipathogenicity. Unlike mice, which require significant genetic or physiological manipulation to become colonized withC. jejuni, ferrets are readily infected without the need to disarm the immune system or alter the gut microbiota. Disease afterC. jejuniinfection in ferrets reflects closely how humanC. jejuniinfection proceeds. Rapid growth ofC. jejuniand associated intestinal inflammation was observed within two-three days of infection. We observed pathophysiological changes that were noted by cryptic hyperplasia through the induction of tissue repair systems, accumulation of undifferentiated amplifying cells on the colon surface, and instability of HIF-1α in colonocytes, which indicated increased epithelial oxygenation. Metabolomic analysis demonstrated that lactate levels in colon content were elevated in infected animals. AC. jejunimutant lackinglctP, which encodes an L-lactate transporter, was significantly decreased for colonization during infection. Lactate also influences adhesion and invasion byC. jejunito a colon carcinoma cell line (HCT116). The oxygenation required for expression of lactate transporter (lctP) led to discovery of a putative thiol based redox switch regulator (LctR) that may represslctPtranscription under anaerobic conditions. Our work provides new insights into the pathogenicity ofC. jejuni.SignificanceThere is a gap in knowledge about the mechanisms by whichC. jejunipopulations expand during infection. Using an animal model which accurately reflects human infection without the need to alter the host microbiome or the immune system prior to infection, we explored pathophysiological alterations of the gut afterC. jejuniinfection. Our study identified the gut metabolite L-lactate as playing an important role as a growth substrate forC. jejuniduring acute infection. We identified a DNA binding protein, LctR, that binds to thelctPpromoter and may represslctPexpression, resulting in decreased lactate transport under low oxygen levels. This work provides new insights aboutC. jejunipathogenicity.
Sea squirt-inspired bio-derived tissue sealants
Authors: Menon Aishwarya V. , Torres Jessica E. , Cox Abigail D. , Risselada Marije , Schmidt Gudrun , Wilker Jonathan J. , Liu Julie C. 
Published: October 2023

AbstractSea squirts’ or tunicates’ bodies are composed of cellulose nanofibers and gallol- functionalized proteins. These sea creatures are known to heal their injuries under seawater by forming crosslinks between gallols and functional groups from other proteins in their bodies. Inspired by their wound healing mechanism, herein, we have developed a tissue sealant using zein (a plant-based protein) and tannic acid (gallol-containing polyphenol). Except for fibrin- based sealants, most commercial surgical adhesives, and sealants available today are derived from petroleum products that compromise their biodegradability. They often have complicated and multi-step synthesis processes that ultimately affect their affordability. To overcome this challenge, we ensured that these sea squirt-inspired tissue sealants are bio-based, easily synthesized, and low-cost. The sealants were studied on their own and with a food-grade enzyme transglutaminase. The adhesion performances of the sealants were found to be higher than physiological pressures in seven out of nine different tissue substrates studied here. Their performance was also better than or on par with the FDA-approved fibrin sealant Tisseel.Ex vivomodels demonstrate instant sealing of leaking wounds in less than a minute. The sealants were not only cytocompatible but also showed complete wound healing on par with sutures and Tisseel when appliedin vivoon skin incisions in rats. Overall, these sea squirt-inspired bio-based sealants show great potential to replace currently available wound closure methods.
Exploring the role of assurance context in system security assurance evaluation: a conceptual model
Authors: Wen Shao-Fang , Katt Basel 
Published: October 2023

Purpose
Security assurance evaluation (SAE) is a well-established approach for assessing the effectiveness of security measures in systems. However, one aspect that is often overlooked in these evaluations is the assurance context in which they are conducted. This paper aims to explore the role of assurance context in system SAEs and proposes a conceptual model to integrate the assurance context into the evaluation process.

Design/methodology/approach
The conceptual model highlights the interrelationships between the various elements of the assurance context, including system boundaries, stakeholders, security concerns, regulatory compliance and assurance assumptions and regulatory compliance.

Findings
By introducing the proposed conceptual model, this research provides a framework for incorporating the assurance context into SAEs and offers insights into how it can influence the evaluation outcomes.

Originality/value
By delving into the concept of assurance context, this research seeks to shed light on how it influences the scope, methodologies and outcomes of assurance evaluations, ultimately enabling organizations to strengthen their system security postures and mitigate risks effectively.
Analyzing the spatial determinants of housing prices in Dammam, Saudi Arabia: an AHP approach
Authors: Lawal Dano Umar 
Published: October 2023

Purpose
This study aims to examine the determinants that influence housing prices in Dammam metropolitan area (DMA), Saudi Arabia, by using the analytic hierarchy process (AHP) model. The study considers determinants such as building age (BLD AG), building size (BLD SZ), building condition (BLD CN), access to parking (ACC PK), proximity to transport infrastructure (PRX TRS), proximity to green areas (PRX GA) and proximity to amenities (PRX AM).

Design/methodology/approach
The AHP decision model was used to assess the determinants of housing prices in DMA, using a pair-wise comparison matrix to determine the influence of the investigated factors on housing prices.

Findings
The study’s results revealed that building size (BLD SZ) was the most critical determinant affecting housing prices in DMA, with a weight of 0.32, trailed by proximity to transport infrastructure (PRX TRS), with a weight of 0.24 as the second most influential housing price determinant in DMA. The third most important determinant was proximity to amenities (PRX AM), with a weight of 0.18.

Originality/value
This study addresses a research gap by using the AHP model to assess the spatial determinants of housing prices in DMA, Saudi Arabia. Few studies have used this model in examining housing price factors, particularly in the context of Saudi Arabia. Consequently, the findings of this study provide unique insights for policymakers, housing developers and other stakeholders in understanding the importance of building size, proximity to transport infrastructure and proximity to amenities in influencing housing prices in DMA. By considering these determinants, stakeholders can make informed decisions to improve housing quality and prices in the region.
Is voluntary risk disclosure informative? The role of UK firm-level governance
Authors: Elsayed Nader , Hassanein Ahmed 
Published: October 2023

PurposeThe study investigates how firm-level governance (FL_G) affects the disclosure of voluntary risk information. Likewise, it explores the influence of FL_G on the informativeness of voluntary risk disclosure (VRD). Specifically, it examines how FL_G shapes the nexus between VRD and firm value.Design/methodology/approachIt uses a sample of non-financial firms from the FTSE350 index listed on the London Stock Exchange between 2010 and 2018. The authors utilise an automated textual analysis technique to code the VRD in the annual reports of these firms. The firm value, adjusted for the industry median, is a proxy for investor response to VRD.FindingsThe results suggest that UK firms with significant board independence and larger audit committees disclose more risk information voluntarily. Nevertheless, firms with larger boards of directors and higher managerial ownership disseminate less voluntary risk information. Besides, VRD contains relevant information that enhances investors' valuation of UK firms. These results are more pronounced in firms with higher independent directors, lower managerial ownership and large audit committees.Practical implicationsThe study rationalises the ongoing debate on the effect of FL_G on VRD. The findings are helpful to UK policy-setters in reconsidering the guidelines that regulate UK VRD and to the UK investors in considering risk disclosure in their price decisions and thus enhancing their corporate valuations.Originality/valueIt contributes to the risk reporting literature in the UK by presenting the first evidence on the effect of a comprehensive set of FL_G on VRD. Besides, it enriches the existing research by shedding light on the role of FL_G on the informativeness of discretionary risk information in the UK.
Unmasking mobility patterns: international travel behavior and emissions of scientists in a higher research institution
Authors: Hölbling Stefanie , Kirchengast Gottfried , Danzer Julia 
Published: October 2023

Purpose
This study aims to investigate patterns in international travel behavior of scientific staff depending on the categories of gender, scientific field and scientific seniority level. The learning from salient differences possibly revealed may inform measures for reducing travel greenhouse gas (GHG) emissions, especially for high-emitting staff groups, and help strengthen the equality between scientists of different categories concerning their travel behavior.

Design/methodology/approach
The study collected and used novel empirical data on travel GHG emissions from University of Graz scientific staff for five consecutive years (2015–2019) and used statistical analysis and inference to test and answer three distinct research questions on patterns of travel behavior.

Findings
The travel footprint of scientific staff, in terms of annual GHG emissions per scientist, exhibits various highly significant differences across scientific fields, seniority and gender, such as male senior natural scientists showing ten times higher per-person emissions than female junior social scientists.

Originality/value
The five-year travel GHG emissions data set across all fields from natural sciences via social sciences to humanities at a large university (Uni Graz, Austria, about 2,000 scientific staff) and across seniority levels from predocs to professors, both for female and male scientists, enabled a robust empirical study revealing distinct differences in travel GHG footprints of academic staff. In this way, the study adds valuable insights for higher research institutions toward effective GHG reduction policies.