bluuebunny/crossref_metadata_2025_split huggingface dataset:
The RORɣ/SREBP2 pathway is a master regulator of cholesterol metabolism and serves as potential therapeutic target in t(4;11) leukemia
Authors: Erkner Estelle , Hentrich Thomas , Schairer Rebekka , Fitzel Rahel , Secker-Grob Kathy-Ann , Jeong Johan , Keppeler Hildegard , Korkmaz Fulya , Schulze-Hentrich Julia M. , Lengerke Claudia , Schneidawind Dominik , Schneidawind Corina 
Published: November 2023

AbstractDysregulated cholesterol homeostasis promotes tumorigenesis and progression. Therefore, metabolic reprogramming constitutes a new hallmark of cancer. However, until today, only few therapeutic approaches exist to target this pathway due to the often-observed negative feedback induced by agents like statins leading to controversially increased cholesterol synthesis upon inhibition. Sterol regulatory element-binding proteins (SREBPs) are key transcription factors regulating the synthesis of cholesterol and fatty acids. Since SREBP2 is difficult to target, we performed pharmacological inhibition of retinoic acid receptor (RAR)-related orphan receptor gamma (RORγ), which acts upstream of SREBP2 and serves as master regulator of the cholesterol metabolism. This resulted in an inactivated cholesterol-related gene program with significant downregulation of cholesterol biosynthesis. Strikingly, these effects were more pronounced than the effects of fatostatin, a direct SREBP2 inhibitor. Upon RORγ inhibition, RNA sequencing showed strongly increased cholesterol efflux genes leading to leukemic cell death and cell cycle changes in a dose- and time-dependent manner. Combinatorial treatment of t(4;11) cells with the RORγ inhibitor showed additive effects with cytarabine and even strong anti-leukemia synergism with atorvastatin by circumventing the statin-induced feedback. Our results suggest a novel therapeutic strategy to inhibit tumor-specific cholesterol metabolism for the treatment of t(4;11) leukemia.
CASC4/GOLM2 drives high grade serous carcinoma anoikis resistance through the recycling of EGFR
Authors: Bapat Jaidev , Yamamoto Tomomi M. , Woodruff Elizabeth R. , Qamar Lubna , Mikeska Railey G. , Aird Katherine M. , Watson Zachary L. , Brubaker Lindsay W. , Bitler Benjamin G. 
Published: November 2023

AbstractOvarian cancer is the deadliest gynecological malignancy, and accounts for over 150,000 deaths per year worldwide. The high grade serous ovarian carcinoma (HGSC) subtype accounts for almost 70% of ovarian cancers and is the deadliest. HGSC originates in the fimbria of the fallopian tube and disseminates through the peritoneal cavity. HGSC survival in peritoneal fluid requires cells to resist anoikis (anchorage-independent apoptosis). Most anoikis resistant mechanisms are dependent on microenvironment interactions with cell surface-associated proteins, such as integrins and receptor tyrosine kinases (RTKs). We previously identified the gene CASC4 as a driver of anoikis resistance. CASC4 is predicted to be a Golgi-associated protein that may regulate protein trafficking to the plasma membrane, but CASC4 is largely uncharacterized in literature; thus, we sought to determine how CASC4 confers anoikis resistance to HGSC cells. Mining of publicly available ovarian cancer datasets (TCGA) showed that CASC4 is associated with worse overall survival and increased resistance to platinum-based chemotherapies. For experiments, we cultured three human HGSC cell lines (PEO1, CaOV3, OVCAR3), and a murine HGSC cell line, (ID8) with shRNA-mediated CASC4 knockdowns (CASC4 KD) in suspension, to recapitulate the peritoneal fluid environment in vitro. CASC4 KD significantly inhibited cell proliferation and colony formation ability, and increased apoptosis. A Reverse Phase Protein Assay (RPPA) showed that CASC4 KD resulted in a broad re-programming of membrane-associated proteins. Specifically, CASC4 KD led to decreased protein levels of the RTK Epidermal Growth Factor Receptor (EGFR), an initiator of several oncogenic signaling pathways, leading us to hypothesize that CASC4 drives HGSC survival through mediating recycling and trafficking of EGFR. Indeed, loss of CASC4 led to a decrease in both EGFR membrane localization, reduced turnover of EGFR, and increased EGFR ubiquitination. Moreover, a syngeneic ID8 murine model of ovarian cancer showed that knocking down CASC4 leads to decreased tumor burden and dissemination.
Vancomycin tolerance of adherent Staphylococcus aureus is impeded by nanospike-induced physiological changes
Authors: Hayles Andrew , Bright Richard , Nguyen Ngoc Huu , Truong Vi Khanh , Wood Jonathan , Palms Dennis , Vongsvivut Jitraporn , Barker Dan , Vasilev Krasimir 
Published: November 2023

AbstractBacterial colonization of implantable biomaterials is an ever-pervasive threat that causes devastating infections, yet continues to elude resolution. In the present study, we report how a rationally designed antibacterial surface containing sharp nanospikes can enhance the susceptibility of pathogenic bacteria to antibiotics used in prophylactic procedures. We show that Staphylococcus aureus, once adhered to a titanium surface, changes its cell-surface charge to increase its tolerance to vancomycin. However, if the Ti surface is modified to bear sharp nanospikes, the activity of vancomycin is rejuvenated, leading to increased bacterial cell death through synergistic activity. Analysis of differential gene expression provided evidence of a set of genes involved with the modification of cell surface charge. Synchrotron-sourced attenuated Fourier-transform infrared microspectroscopy (ATR-FTIR), together with multivariate analysis, was utilized to further elucidate the biochemical changes of S. aureus adhered to nanospikes. By inhibiting the ability of the pathogen to reduce its net negative charge, the nanoengineered surface renders S. aureus more susceptible to positively charged antimicrobials such as vancomycin. This finding highlights the opportunity to enhance the potency of prophylactic antibiotic treatments during implant placement surgery by employing devices having surfaces modified with spike-like nanostructures.
Compressive strength degradation of engineered bamboo subjected to fungal attack
Authors: Chen C. Q. , Zhang S. J. , Kong Y. B. H. , Ji T. , Huang W. W. , Hu Y. T. , Zhang D. W. , Xiao Y. 
Published: November 2023

AbstractGlue laminated bamboo (glubam) is a type of engineered bamboo material developed for applications in building structures and interiors. This paper focuses on the fungal (Aspergillus niger) colonization from 14 to 56 days in thick- and thin-strip glubam board with the investigation of physical, mechanical (compression), and microcosmic properties. Two-degree of carbonization treatment was employed to improve the antifungal property of the thick-strip glubam. After 56 days of infection, the deep-degree carbonized thick-strip glubam presents better anti-mold properties than medium and non-carbonized specimens. For thin-strip glubam, both parallel and perpendicular to the main bamboo fiber direction were considered. The longitudinal thin-strip glubam retains decent compressive properties, while the transverse specimens stay a stable compressive strength along all fungal tests. The paper reports the experimental values of mass loss, color changes, compressive strengths, modulus of elasticity in compression, and microstructure observations from optical and SEM microscopy at different fungal exposure timespans.
Pesticide use negatively affects bumble bees across European landscapes
Authors: Nicholson Charlie C. , Knapp Jessica , Kiljanek Tomasz , Albrecht Matthias , Chauzat Marie-Pierre , Costa Cecilia , De la Rúa Pilar , Klein Alexandra-Maria , Mänd Marika , Potts Simon G. , Schweiger Oliver , Bottero Irene , Cini Elena , de Miranda Joachim R. , Di Prisco Gennaro , Dominik Christophe , Hodge Simon , Kaunath Vera , Knauer Anina , Laurent Marion , Martínez-López Vicente , Medrzycki Piotr , Pereira-Peixoto Maria Helena , Raimets Risto , Schwarz Janine M. , Senapathi Deepa , Tamburini Giovanni , Brown Mark J. F. , Stout Jane C. , Rundlöf Maj 
Published: November 2023

AbstractSustainable agriculture requires balancing crop yields with the effects of pesticides on non-target organisms, such as bees and other crop pollinators. Field studies demonstrated that agricultural use of neonicotinoid insecticides can negatively affect wild bee species1,2, leading to restrictions on these compounds3. However, besides neonicotinoids, field-based evidence of the effects of landscape pesticide exposure on wild bees is lacking. Bees encounter many pesticides in agricultural landscapes4–9 and the effects of this landscape exposure on colony growth and development of any bee species remains unknown. Here we show that the many pesticides found in bumble bee-collected pollen are associated with reduced colony performance during crop bloom, especially in simplified landscapes with intensive agricultural practices. Our results from 316 Bombus terrestris colonies at 106 agricultural sites across eight European countries confirm that the regulatory system fails to sufficiently prevent pesticide-related impacts on non-target organisms, even for a eusocial pollinator species in which colony size may buffer against such impacts10,11. These findings support the need for postapproval monitoring of both pesticide exposure and effects to confirm that the regulatory process is sufficiently protective in limiting the collateral environmental damage of agricultural pesticide use.
Landscape dynamics and the Phanerozoic diversification of the biosphere
Authors: Salles Tristan , Husson Laurent , Lorcery Manon , Hadler Boggiani Beatriz 
Published: November 2023

AbstractThe long-term diversification of the biosphere responds to changes in the physical environment. Yet, over the continents, the nearly monotonic expansion of life started later in the early part of the Phanerozoic eon1 than the expansion in the marine realm, where instead the number of genera waxed and waned over time2. A comprehensive evaluation of the changes in the geodynamic and climatic forcing fails to provide a unified theory for the long-term pattern of evolution of life on Earth. Here we couple climate and plate tectonics models to numerically reconstruct the evolution of the Earth’s landscape over the entire Phanerozoic eon, which we then compare to palaeo-diversity datasets from marine animal and land plant genera. Our results indicate that biodiversity is strongly reliant on landscape dynamics, which at all times determine the carrying capacity of both the continental domain and the oceanic domain. In the oceans, diversity closely adjusted to the riverine sedimentary flux that provides nutrients for primary production. On land, plant expansion was hampered by poor edaphic conditions until widespread endorheic basins resurfaced continents with a sedimentary cover that facilitated the development of soil-dependent rooted flora, and the increasing variety of the landscape additionally promoted their development.
Gridded livestock density database and spatial trends for Kazakhstan
Authors: Kolluru Venkatesh , John Ranjeet , Saraf Sakshi , Chen Jiquan , Hankerson Brett , Robinson Sarah , Kussainova Maira , Jain Khushboo 
Published: November 2023

AbstractLivestock rearing is a major source of livelihood for food and income in dryland Asia. Increasing livestock density (LSKD) affects ecosystem structure and function, amplifies the effects of climate change, and facilitates disease transmission. Significant knowledge and data gaps regarding their density, spatial distribution, and changes over time exist but have not been explored beyond the county level. This is especially true regarding the unavailability of high-resolution gridded livestock data. Hence, we developed a gridded LSKD database of horses and small ruminants (i.e., sheep & goats) at high-resolution (1 km) for Kazakhstan (KZ) from 2000–2019 using vegetation proxies, climatic, socioeconomic, topographic, and proximity forcing variables through a random forest (RF) regression modeling. We found high-density livestock hotspots in the south-central and southeastern regions, whereas medium-density clusters in the northern and northwestern regions of KZ. Interestingly, population density, proximity to settlements, nighttime lights, and temperature contributed to the efficient downscaling of district-level censuses to gridded estimates. This database will benefit stakeholders, the research community, land managers, and policymakers at regional and national levels.
Lower cardiotoxicity of CPX-351 relative to daunorubicin plus cytarabine free-drug combination in hiPSC-derived cardiomyocytes in vitro
Authors: Fortin Marie C. , LaCroix Andrew S. , Grammatopoulos Tom N. , Tan Lei , Wang Qi , Manca Dino 
Published: November 2023

AbstractLiposomal formulations are hypothesized to alleviate anthracycline cardiotoxicity, although this has only been documented clinically for doxorubicin. We developed an in vitro multiparametric model using human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) to assess the relative toxicity of anthracyclines across formulations. Proof of concept was established by treating hiPSC-CM with equivalent concentrations of free and liposomal doxorubicin. The study was then repeated with free daunorubicin plus cytarabine and CPX-351, a dual-drug liposomal encapsulation of daunorubicin/cytarabine. hiPSC-CM were treated with free-drug or liposomal formulations for 24 h on Days 1, 3, and 5 at equivalent concentrations ranging from 0 to 1000 ng/mL and assessed on subsequent days. Free-drug treatment resulted in concentration-dependent cumulative cytotoxicity (microscopy), more profound decrease in ATP levels, and significant time- and concentration-dependent decreases in oxygen consumption versus liposomal formulations (p < 0.01). Repeated free-drug exposure also resulted in greater release of biomarkers (cardiac troponin I, FABP3) and lactate dehydrogenase, as well as in a biphasic rhythmicity response (initial increase followed by slowing/quiescence of beating) indicating significant injury, which was not observed after repeated exposure to liposomal formulations. Overall, liposomal formulations were considerably less toxic to hiPSC-CM than their free-drug counterparts. Clinical data will be needed to confirm findings for CPX-351.
Assessing the potential of composite confining systems for secure and long-term CO2 retention in geosequestration
Authors: Bakhshian Sahar , Bump Alexander P. , Pandey Shaunak , Ni Hailun , Hovorka Susan D. 
Published: November 2023

AbstractA potential geologic target for CO2 storage should ensure secure containment of injected CO2. Traditionally, this objective has been achieved by targeting reservoirs with overlying seals-regionally extensive, low permeability units that have been proven capable of retaining buoyant fluid accumulations over geologic time. However, considering that the amount of CO2 is limited by a decadal injection period, vertical migration of CO2 can be effectively halted by a composite system of discontinuous shale/silt/mudstone barriers in bedded sedimentary rocks. Here, we studied the impact of depositional architectures in a composite confining system on CO2 migration and confinement at reservoir scale. We stochastically generated lithologically heterogeneous reservoir models containing discontinuous barriers consistent with statistical distributions of net-sand-to-gross-shale ratio (NTG) and horizontal correlation lengths derived from well log data and observations of producing hydrocarbon fields in Southern Louisiana. We then performed an extensive suite of reservoir simulations of CO2 injection and post-injection to evaluate the sensitivity of CO2 plume migration and pressure response of the composite system to a series of geologic and fluid parameters including the lateral continuity of barriers, NTG, permeability anisotropy within the sand body, and capillary pressure contrast between the sand and shale facies. The results indicate that lateral continuity of barriers and NTG are the dominant controls on CO2 plume geometry and pressure build-up in the reservoir, while the impact of NTG is particularly pronounced. The significance of intraformational barriers becomes apparent as they facilitate the local capillary trapping of CO2. Those barriers improve the pore space occupancy by promoting a more dispersed shape of the plume and ultimately retard the buoyancy-driven upward migration of the plume post injection.
Consequences of load distribution in selected vehicles in the context of changing the position of the vehicle’s centre of gravity
Authors: Synák František , Smolková Alexandra , Žúžiová Klára 
Published: November 2023

AbstractThe position of the vehicle’s centre of gravity has an impact on its driving performances, and it also affects the vehicle’s impact on its surroundings. Therefore, the study pays attention to the change in the centre of gravity’s position due to different load distribution. The research was performed by wide-ranging experimental measurements with three different vehicles, i.e. with a passenger car, a van and a truck. The measurement results and their analysis point to the rate of change in the centre of gravity’s position due to different load distribution, and to the fact that a vehicle axle can be overloaded even when the vehicle load capacity is not used completely. In addition, the contribution of the study is a database which can be used for other research via modelling.
On the inadequacy of nominal assortativity for assessing homophily in networks
Authors: Karimi Fariba , Oliveira Marcos 
Published: November 2023

AbstractNominal assortativity (or discrete assortativity) is widely used to characterize group mixing patterns and homophily in networks, enabling researchers to analyze how groups interact with one another. Here we demonstrate that the measure presents severe shortcomings when applied to networks with unequal group sizes and asymmetric mixing. We characterize these shortcomings analytically and use synthetic and empirical networks to show that nominal assortativity fails to account for group imbalance and asymmetric group interactions, thereby producing an inaccurate characterization of mixing patterns. We propose the adjusted nominal assortativity and show that this adjustment recovers the expected assortativity in networks with various level of mixing. Furthermore, we propose an analytical method to assess asymmetric mixing by estimating the tendency of inter- and intra-group connectivities. Finally, we discuss how this approach enables uncovering hidden mixing patterns in real-world networks.
A common timing mechanism across different millisecond domains: evidence from perceptual and motor tasks
Authors: Stanczyk Magdalena , Szelag Elzbieta , Krystecka Klaudia , Szymaszek Aneta 
Published: November 2023

AbstractTemporal information processing (TIP) constitutes a complex construct that underlies many cognitive functions and operates in a few hierarchically ordered time domains. This study aimed to verify the relationship between the tens of milliseconds and hundreds of milliseconds domains, referring to perceptual and motor timing, respectively. Sixty four young healthy individuals participated in this study. They underwent two auditory temporal order judgement tasks to assess their performance in the tens of milliseconds domain; on this basis, groups of high-level performers (HLP) and low-level performers (LLP) were identified. Then, a maximum tapping task was used to evaluate performance in the hundreds of milliseconds domain. The most remarkable result was that HLP achieved a faster tapping rate and synchronised quicker with their “internal clock” during the tapping task than did LLP. This result shows that there is a relationship between accuracy in judging temporally asynchronous stimuli and ability to achieve and maintain the pace of a movement adequate to one’s internal pacemaker. This could indicate the strong contribution of a common timing mechanism, responsible for temporal organisation and coordination of behaviours across different millisecond domains.
An untapped window of opportunity for glioma: targeting therapy-induced senescence prior to recurrence
Authors: Riviere-Cazaux Cecile , Carlstrom Lucas P. , Neth Bryan J. , Olson Ian E. , Rajani Karishma , Rahman Masum , Ikram Samar , Mansour Moustafa A. , Mukherjee Bipasha , Warrington Arthur E. , Short Susan C. , von Zglinicki Thomas , Brown Desmond A. , Burma Sandeep , Tchkonia Tamar , Schafer Marissa J. , Baker Darren J. , Kizilbash Sani H. , Kirkland James L. , Burns Terry C. 
Published: November 2023

AbstractHigh-grade gliomas are primary brain tumors that are incredibly refractory long-term to surgery and chemoradiation, with no proven durable salvage therapies for patients that have failed conventional treatments. Post-treatment, the latent glioma and its microenvironment are characterized by a senescent-like state of mitotic arrest and a senescence-associated secretory phenotype (SASP) induced by prior chemoradiation. Although senescence was once thought to be irreversible, recent evidence has demonstrated that cells may escape this state and re-enter the cell cycle, contributing to tumor recurrence. Moreover, senescent tumor cells could spur the growth of their non-senescent counterparts, thereby accelerating recurrence. In this review, we highlight emerging evidence supporting the use of senolytic agents to ablate latent, senescent-like cells that could contribute to tumor recurrence. We also discuss how senescent cell clearance can decrease the SASP within the tumor microenvironment thereby reducing tumor aggressiveness at recurrence. Finally, senolytics could improve the long-term sequelae of prior therapy on cognition and bone marrow function. We critically review the senolytic drugs currently under preclinical and clinical investigation and the potential challenges that may be associated with deploying senolytics against latent glioma. In conclusion, senescence in glioma and the microenvironment are critical and potential targets for delaying or preventing tumor recurrence and improving patient functional outcomes through senotherapeutics.
Functional analysis of recurrent CDC20 promoter variants in human melanoma
Authors: Godoy Paula M. , Oyedeji Abimbola , Mudd Jacqueline L. , Morikis Vasilios A. , Zarov Anna P. , Longmore Gregory D. , Fields Ryan C. , Kaufman Charles K. 
Published: November 2023

AbstractSmall nucleotide variants in non-coding regions of the genome can alter transcriptional regulation, leading to changes in gene expression which can activate oncogenic gene regulatory networks. Melanoma is heavily burdened by non-coding variants, representing over 99% of total genetic variation, including the well-characterized TERT promoter mutation. However, the compendium of regulatory non-coding variants is likely still functionally under-characterized. We developed a pipeline to identify hotspots, i.e. recurrently mutated regions, in melanoma containing putatively functional non-coding somatic variants that are located within predicted melanoma-specific regulatory regions. We identified hundreds of statistically significant hotspots, including the hotspot containing the TERT promoter variants, and focused on a hotspot in the promoter of CDC20. We found that variants in the promoter of CDC20, which putatively disrupt an ETS motif, lead to lower transcriptional activity in reporter assays. Using CRISPR/Cas9, we generated an indel in the CDC20 promoter in human A375 melanoma cell lines and observed decreased expression ofCDC20, changes in migration capabilities, increased growth of xenografts, and an altered transcriptional state previously associated with a more proliferative and less migratory state. Overall, our analysis prioritized several recurrent functional non-coding variants that, through downregulation ofCDC20, led to perturbation of key melanoma phenotypes.