Model System Research Articles

Optimising Malaysia’s power mix for a sustainable future: a multi-scenario modelling approach

PurposeThis study employs advanced modelling to assess the effectiveness of Malaysia’s current energy policies in achieving a low-carbon future. By optimising a 100% renewable energy mix, including energy storage, the research identifies pathways to decarbonise the power sector while minimising costs. These findings will inform the development of future policies.Design/methodology/approachThis study employs the Stockholm Environment Institute-developed Low Emissions Analysis Platform (LEAP) and Next Energy Modeling system for Optimization (NEMO) to construct and optimise a comprehensive Malaysian power sector model. The model encompasses both electricity supply, including diverse electricity generation sources and demand across key sectors. Three scenarios – existing policy, optimised existing policy and more ambitious policy (near-zero emissions) – are analysed.FindingsSolar photovoltaic (PV) is the dominant technology, but realising its full potential requires significant grid upgrades. While natural gas expansion underpins Malaysia’s decarbonisation strategy, solar and storage offer a cleaner and potentially cost-effective alternative. Rapid technological advancements in clean energy increase stranded asset risk for new gas power plants. Malaysia’s abundant bioenergy resources need more tapping. This can contribute to decarbonisation and rural development. Transitioning to a fully renewable grid necessitates substantial investments in energy storage and grid infrastructure. While falling battery costs and regional interconnection can mitigate costs, careful consideration of potential disruptions and cost fluctuations is essential for resilience.Research limitations/implicationsEnergy sector modelling results are inherently dependent on input assumptions, such as future technology costs, resource availability and fossil fuel prices. These factors can be highly uncertain. While this study did not conduct sensitivity analyses to explore how variations in these assumptions might affect the results (e.g. cost variations across scenarios, technology mix fluctuations), the core findings provide valuable insights into potential decarbonisation pathways for Malaysia’s power sector. Future studies could build upon this work by incorporating sensitivity analyses to provide a more comprehensive understanding of how key results might change under a wider range of future possibilities.Originality/valueThis study co-optimises a 100% renewable energy mix for Malaysia, incorporating a comprehensive range of renewable resources, battery and pumped hydro storage. The research also provides a unique perspective on the interplay of philosophical underpinnings, psychological maturity and energy policy.

Formation of Chlorinated Carbohydrate Degradation Products and Amino Acids during Heating of Sucralose in Model Systems and Food

Formation of Chlorinated Carbohydrate Degradation Products and Amino Acids during Heating of Sucralose in Model Systems and Food

Selenium alters the gene content but not the taxonomic composition of the soil microbiome

Abstract Background Microbiomes, essential to ecosystem processes, face strong selective forces that can drive rapid evolutionary adaptation. However, our understanding of evolutionary processes within natural systems remains limited. We investigated evolution in response to naturally occurring selenium in soils of different geological parental materials on the Western Slope of Colorado. Our study focused on examining changes in gene frequencies within microbial communities in response to selenium exposure. Results Despite expectations of taxonomic composition shifts and increased gene content changes at high-selenium sites, we found no significant alterations in microbial diversity or community composition. Surprisingly, we observed a significant increase in differentially abundant genes within high-selenium sites. Conclusions These findings are suggestive that selection within microbiomes primarily drives the accumulation of genes among existing microbial taxa, rather than microbial species turnover, in response to strong stressors like selenium. Our study highlights an unusual system that allows us to examine evolution in response to the same stressor annually in a non-model system, contributing to understanding microbiome evolution beyond model systems.

Plumage polymorphism in the black sparrowhawk (Accipiter melanoleucus) is strongly associated with expression level of agouti signalling protein

Abstract Melanin-based plumage polymorphisms in birds are often associated with mutations in the melanogenesis genes, notably the melanocortin-1 receptor (MC1R), but may also arise through changes in the expression of these genes. Here we investigate the molecular basis of plumage polymorphism in both adult and juvenile black sparrowhawks (Accipiter melanoleucus), an African raptor that occurs in two adult colour morphs, light and dark, and also exhibits variation in juvenile plumage colouration. Our results confirmed that plumage differences in adult morphs were a result of differential deposition of eumelanin in their ventral contour feathers. No polymorphisms in the coding regions of the MC1R or the agouti signalling protein (ASIP) genes associated with adult colour morph were identified. However, lack of pigmentation in the developing breast feathers of light morph birds was strongly associated with elevated ASIP expression, and concomitant down-regulation of the downstream melanogenesis genes microphthalmia-associated transcription factor (MITF), tyrosinase (TYR) and tyrosinase-related protein 1 (TYRP1). Variation in the rufous coloured plumage of juveniles was found to be due to covariation in eumelanin and pheomelanin levels in dorsal and ventral contour feathers. As in adult birds, an inverse relationship between melanin pigmentation and ASIP expression was observed. This covariation between eumelanin and pheomelanin levels is not consistent with the pigment type-switching model of melanogenesis, where increased ASIP expression results in a switch from eumelanin to pheomelanin production. This highlights the need for caution when extrapolating results from model systems to other animals and the value of conducting research in wild species.

The Rhesus Macaque as an Animal Model for Human Nutrition: An Ecological-Evolutionary Perspective

Nutrition is a complex and contested area in biomedicine, which requires diverse evidence sources. Nonhuman primate models are considered an important biomedical research tool because of their biological similarities to humans, but they are typically used with little explicit consideration of their ecology and evolution. Using the rhesus macaque (RM), we consider the potential of nutritional ecology for enriching the use of primates as models for human nutrition. We introduce some relevant aspects of RM evolutionary and social ecology and discuss two examples where they have been used in biomedical research: obesity and aging. We next consider how insights from nutritional ecology can help inform and direct the use of RM as a biomedical model. We conclude by illustrating how conceptual tools might inform the use of RM as a model for human nutrition and extracting insights from RM that might be relevant to broader theoretical considerations around animal model systems.

Forest Breeze - Cold Pool Interactions Drive Convective Organization over Heterogeneous Vegetation

Abstract Heterogeneous landscapes can influence the development of convection through the generation of thermally-driven mesoscale circulations. To assess the impacts of these circulations and their interaction with sea breezes, we simulated convection in an idealized coastal environment using the Regional Atmospheric Modeling System (RAMS). We compared simulations with striped patterns of surface vegetation to those of uniform vegetation to identify the importance of vegetation heterogeneity in impacting convective development. Under dry soil conditions representative of those during the TRACER and ESCAPE campaigns in June 2022, we found that these vegetation-induced circulations, referred to in literature as “forest breezes,” are more important than the sea breeze in determining the location of convection initiation. Convection and precipitation are also found to be favored over forests and suppressed over pasture and suburban landscapes as a result of greater surface sensible heat flux over the forest. Our findings also indicate that forest breezes are important for initiating convection along the boundaries of the forest, but that cold pools may play a key role in propagating the forest breezes toward the center of the forest stripe. In our simulations, the collisions of these breezes in the center of the forest stripe leads to uplift and strong convection there; however, a different width of the forest stripe would alter when the forest breezes collide, or whether they collide at all. The presence of these cold pools may therefore impact the “ideal stripe width”, the width of each vegetation stripe which maximizes domain-wide precipitation.

A biomimetic phosphor that can build a rigid microenvironment for its long-lived afterglow in aqueous medium.

Organic phosphorescent materials have great prospects for application, whose performance particularly depends on the preparation method. Inspired by nature's wisdom, we report a phosphor that can utilize monomers in its environment by polymerization to construct a rigid microenvironment under light illumination, leading to a glow-in-the-dark emulsion with a phosphorescence lifetime of 1 s in water. This phosphor can achieve active growth of the aqueous emulsion with the introduction of more monomers. In the presence of trace amounts of oxygen (which has adverse effects on both polymerization and afterglow), this phosphor can still undergo photo-induced polymerization, removing the influence of oxygen and obtaining afterglow emulsion, demonstrating its adaptability to the environment. This phosphor can also catalyze the polymerization of monomers containing yellow fluorophore, obtaining long-lifetime yellow afterglow emulsion through excited state energy transfer. We have also conducted in-depth studies on the photo-catalytic and phosphorescent properties of this phosphor in model systems. This biomimetic intelligent manufacturing provides a new approach for organic phosphorescent materials and is significant for future applications.

Abstract A009: PIEZO1 driven tumor aggressiveness in an organ-on-chip model of colorectal cancer

Abstract Mechanical forces have long been known to affect the progression of cancer, however exact study of the specific consequences of these forces has been hampered by currently available model systems. Traditional cell culture models often lack the ability to incorporate physiologically relevant mechanical forces, and animal models offer too much complexity to be able to effectively isolate and study the mechanical forces. Organ-on-chip (OOC) technology allows for the integration of human relevant physiological forces in a setting conducive to their study. Here, we explore how the early metastatic spread of colorectal cancer (CRC) can be influenced by physiological mechanical forces. Specifically, we investigated the ability of peristaltic motions, responsible for natural bowel motility, to enhance the invasive capability of colon tumor cells. Our microfluidic OOC model comprises of an epithelial channel and endothelial channel separated by a porous membrane allowing for biological and chemical crosstalk between them. Vacuum channels spanning the length of the structure allow force to applied in a cyclic manner mimicking peristaltic contraction and relaxation. Our OOC model supports the addition of tumor microenvironment (TME) components in a piece-wise manner to better understand how specific factors influence the behavior of tumor cells. Analyzing gene and protein expression levels, we have found that peristaltic-like motions induce changes in the Hippo signaling and epithelial-to-mesenchymal (EMT) pathways resulting in greater invasion of tumor cells into the endothelial compartment as observed by on-chip confocal imaging. Moreover, knock down studies have demonstrated that the response to peristaltic-like stretch is driven through a PIEZO1-mediated mechanism. Furthermore, to increase the physiological relevance of our model, we administered peripheral blood mononuclear cells (PBMCs) to the endothelial channel to simulate aspects of the immune TME. Preliminary studies revealed that the recruitment of PBMCs can be altered by the presence of peristaltic-like stretch. Our findings demonstrate that mechanical forces in the CRC TME can dramatically alter tumor behavior as shown in our CRC-OOC model. Citation Format: Curran A. Shah, Carly R. Strelez, Aaron Schatz, Hannah Jiang, Rachel Perez, Shannon M. Mumenthaler. PIEZO1 driven tumor aggressiveness in an organ-on-chip model of colorectal cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr A009.

Abstract PR016: Early changes to the colon tumor microenvironment during benign-to- malignant transition

Abstract Colorectal cancer (CRC) is now the first and second leading cause of cancer-related deaths in men and women under 50, respectively, upending prior predictions. While many risk factors have been identified, the etiology of early onset disease is poorly understood, and it is unclear why some benign polyps progress to CRC while most do not. The genetic drivers of colon tumor initiation and progression to malignancy are not sufficient to drive disease on their own, as evidenced by the near ubiquitous presence of oncogenic mutations within morphologically “normal” adult tissues like the colon. This raises several fundamental questions: 1) what are the pioneering molecular and cellular events underlying benign-to-malignant transition following oncogenic mutation? 2) Is this sequence of events predetermined by cancer genetics or are additional (micro)environmental stimuli necessary? 3) How does the benign-to-malignant transition reshape tumor clonal architecture and is this immunogenic? We have begun to address these questions using a combination of rare human colon polyps with evidence of early malignant transition and innovative new mouse models that enable control of stepwise colon cancer progression. These autochthonous models combine in vivo CRISPR-Cas9 and an inducible “split-Cre” system to decouple focal tumor initiation in the distal colon (via Apc knockout) from spatiotemporal control of secondary driver events of malignant progression (e.g., Kras G12D, Trp53 knockout) in rare cells of benign adenomas. We have validated the in vivo functionality of these models, generating early “intramucosal carcinoma” and “adenocarcinoma-in-adenoma”—physiologically relevant and elusive stages of human colon cancer development that have never been reliably captured in model systems to date. Comparing these tumors with spatial transcriptomic data from human specimens, we report distinct transcriptional programs of early progression, a unique stromal reaction associated with early progression, and restructuring of glandular architecture and the stem cell niche in early carcinoma. By delineating the earliest events underlying cancer progression, this work promises to inform new strategies for early detection and prevention. We anticipate that the models will also be particularly valuable in functionally interrogating host and environmental factors that impact risk of early onset cancer. Citation Format: Peter M.K. Westcott, Yihan Qin, Daniel Zhang, Nikita Persaud, Zakeria Aminzada, Nischal Bhandari, Colin McLaughlin, William Rideout III, Santiago Naranjo, Song Han, Rodrigo Romero, Claire Regan, Jonathan Preall, Semir Beyaz, Tyler Jacks, Zhen Zhao, Sepideh Gholami. Early changes to the colon tumor microenvironment during benign-to- malignant transition [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr PR016.

Abstract B009: Characterization and CRISPR perturbation of cancer-associated fibroblast heterogeneity in vitro models

Abstract Cancer-associated fibroblasts (CAFs) are attractive therapeutic targets for cancer due to their abundance in the tumor microenvironment (TME) and extensive pro- and antitumorigenic functions. However, formulating CAF-targeting strategies remains challenging due to the complexity of CAF biology. CAFs specialize into phenotypically and functionally distinct subtypes that may respond differently to specific treatments. Thus, designing CAF-targeting therapies necessitates a thorough understanding of CAF heterogeneity and preclinical model systems that can reliably prototype CAF biology observed in tumors. However, CAF heterogeneity is still not well-understood for many solid tumors, including the stroma-rich pancreatic ductal adenocarcinoma (PDAC), and the translatability of stroma models has not been comprehensively evaluated. In this work, we developed in vitro cell lines of tumor-CAF cocultures using primary CAFs derived from PDAC and used single-cell transcriptomics and CRISPR perturbation to investigate CAF heterogeneity and subtype-specific responses. We found that coculturing primary CAFs with the BxPC3 PDAC cell line could capture the tumor-CAF crosstalks underlying CAF activation. We characterized eight subtypes, including myofibroblastic, inflammatory, extracellular matrix (ECM)-like, and interferon CAFs, which could be preserved with immortalization. We also delineated the trajectories of CAF subtype interconvertibility, highlighting inflammatory CAFs as the likely initial diseased state and ECM CAFs as a “reservoir” that seeded the later states. By correlating the in vitro subtypes with clinical data of immunotherapy responses, we established that the in vitro cell lines could model the immuno-modulatory and immunoresistant phenotypes of CAFs. Finally, using an immortalized tumor-CAF coculture line, we performed Perturb-seq single-cell perturbation to perturb several stroma genes of interest, including TGFBR1, SPATS2L, AEBP1, and PTGS1, and evaluated the subtype-specific effects of the perturbations. We found that perturbing TGFBR1 resulted in the expected eradication of myofibroblastic CAFs, while the other perturbations resulted in subtype-specific modulations of metabolic and extracellular matrix related pathways. Overall, our findings underscored that in vitro tumor-CAF coculture models could serve as a translatable system that effectively captured CAF biology and heterogeneity observed in tumors and highlighted some similarities between PDAC CAFs and previously characterized breast cancer CAFs. We also demonstrated that single-cell perturbation could be a useful approach for interrogating the distinct responses of different CAF subtypes to perturbations. Citation Format: Elysia Saputra, Shamsudheen Karuthedath Vellarikkal, Lixia Li, Hong Sun, Suchitra Natarajan, Federica Piccioni, Alex M. Tamburino, Xin Yu, Aleksandra K. Olow. Characterization and CRISPR perturbation of cancer-associated fibroblast heterogeneity in vitro models [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr B009.

Abstract A008: Microenvironmentally released cytokines mediate organ specific transcriptional profiles for metastatic colorectal cancer

Abstract Metastatic disease represents a complex series of interaction between tumors and their surrounding microenvironment. Here we utilize model systems to define organ specific transcriptional signatures present in metastatic seeding. We have identified unique epigenetic programing necessary for the colonization of the liver or the lung by colorectal cancer. We have shown that manipulation of master regulators of these signatures in vitro and in vivo changes the metastatic potential of the tumor. In specific, we have found that native cytokines within the liver and lung are engaged by the metastatic tumor cells to promote this reprograming. In the case of the liver, we have identified hepatocyte released CCL2 acts on metastasizing tumors to promote colonization. Through in vitro and in vivo models, we showed that CCL2 engagement drives upregulation of the transcription factor TCF7 and subsequent enhancer reprograming to promote survival of the metastatic cells in the liver. In the lung, we have identified additional, unique secreted cytokines which lead to the upregulation of other TCF family members. Together this data identifies an important signaling nodes in colorectal cancer. Here we propose a model in which secreted factors by the host organ, such as CCL2, reprogram genes within the tumor cell to promote growth and survival of the metastatic cell in foreign microenvironments such as the lung or liver. Targeting these proteins may kill existing metastatic lesions as well as block new metastases from forming which will be essential in improving the outcomes of patients with oligometastatic and premetastatic disease. Citation Format: Charlie Niesen, Nathan Wu, Jonathan Rennhack. Microenvironmentally released cytokines mediate organ specific transcriptional profiles for metastatic colorectal cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr A008.

α-Tocopherol Long-Chain Metabolite α-T-13'-COOH Exhibits Biphasic Effects on Cell Viability, Induces ROS-Dependent DNA Damage, and Modulates Redox Status in Murine RAW264.7 Macrophages.

The α-tocopherol long-chain metabolite α-tocopherol-13'-hydroxy-chromanol (α-T-13'-COOH) is a proposed regulatory intermediate of endogenous vitamin E metabolism. Effects of α-T-13'-COOH on cell viability and adaptive stress response are not well understood. The present study aims to investigate the concentration-dependent effects of α-T-13'-COOH on cellular redox homeostasis, genotoxicity, and cytotoxicity in murine RAW264.7 macrophages as a model system. Murine RAW264.7 macrophages are exposed to various dosages of α-T-13'-COOH to determine its regulatory effects on reactive oxygen species (ROS) production, DNA damage, expression of stress-related markers, and the activity of ROS scavenging enzymes including superoxide dismutases, catalase, and glutathione-S-transferases. The impact on cell viability is assessed by analyzing cell proliferation, cell cycle arrest, and cell apoptosis. α-T-13'-COOH influences ROS production and induces DNA damage in a dose-dependent manner. The metabolite modulates the activity of ROS-scavenging enzymes, with significant changes observed in the activities of antioxidant enzymes. A biphasic response affecting cell viability is noted: sub-micromolar doses of α-T-13'-COOH promote cell proliferation and enhance DNA synthesis, whereas supraphysiological doses lead to DNA damage and cytotoxicity. It hypothesizes an adaptive stress response, characterized by upregulation of ROS detoxification mechanisms, enhanced cell cycle arrest, and increased apoptosis, indicating a correlation with oxidative stress and subsequent cellular damage.

Maximizing Oxygen Evolution Performance of NiFeOx Semitransparent Electrocatalysts Applicable to Photoelectrochemical Water Splitting Device

In photoelectrochemical (PEC) water splitting, semiconductor‐based photoelectrodes can improve reaction rates and durability by incorporating cocatalysts that serve as active sites for the water splitting process. However, achieving both high light transmittance and efficient catalytic activity is essential for these cocatalysts. This study aimed to optimize the surface loading of semitransparent NiFeOx thin‐film electrocatalysts to enhance the oxygen evolution reaction (OER) rates while maintaining high light transmittance. NiFeOx thin films were deposited on fluorine‐doped SnO2 (FTO) transparent conductive substrates, and the relationship between the NiFeOx loading amount (Γ) and the OER rate was examined using electrochemical techniques. The OER rate of NiFeOx on FTO (NiFeOx/FTO) was the highest at a Γ value of 0.20 μmol cm‐2. To further explore the connection between this optimized Γ and PEC activity, the impact of Γ on the PEC OER performance of visible‐light‐absorbing α‐Fe2O3 semitransparent photoanodes was evaluated as a model system. Applying the optimized Γ of NiFeOx to modify the α‐Fe2O3 surface also led to enhanced PEC OER performance. These findings highlight the critical role of surface design, specifically the optimization of cocatalyst loading and electrocatalytic activity, in improving PEC water splitting efficiency, providing valuable guidelines for future semitransparent photoelectrode development.

Modeling extrahepatic hepatitis E virus infection in induced human primary neurons

Hepatitis E virus (HEV) infections are one of the most common causes of acute viral hepatitis, annually causing over 3 million symptomatic cases and 70,000 deaths worldwide. Historically, HEV was described as a hepatotropic virus, but has recently been associated with various extrahepatic manifestations including neurological disorders such as Guillain-Barré syndrome and neuralgic amyotrophy. However, the underlying pathogenesis of these neurological diseases remains largely unknown. The aim of this study was to investigate extrahepatic HEV manifestations in a neuronal model system using human-induced primary neurons (iPNs). Renal epithelial cells from human urine were reprogrammed to induced pluripotent stem cells to generate neuronal progenitor cells, which were subsequently differentiated into iPNs over 21 d. These iPNs supported HEV infection preferentially in neurite-bearing cells. Transcriptional profiling of the neuronal development process as well as viral infection dynamics in iPNs uncovered a lack of antiviral innate immune responses to HEV infection with only an intrinsic expression of distinct interferon-regulated genes and signaling molecules. Viral open reading frame 2 encoded capsid protein could be visualized by volumetric three-dimensional reconstitution within the neurites, which were reduced in length in an HEV inoculation-dependent manner. In conclusion, this neuron-derived human model system provides a powerful tool for studying extrahepatic manifestations of HEV infection. It further indicates a potential mechanism of pathogenesis driven by the interaction between host and viral factors.

Harnessing AI for advancing pathogenic microbiology: a bibliometric and topic modeling approach

IntroductionThe integration of artificial intelligence (AI) in pathogenic microbiology has accelerated research and innovation. This study aims to explore the evolution and trends of AI applications in this domain, providing insights into how AI is transforming research and practice in pathogenic microbiology.MethodsWe employed bibliometric analysis and topic modeling to examine 27,420 publications from the Web of Science Core Collection, covering the period from 2010 to 2024. These methods enabled us to identify key trends, research areas, and the geographical distribution of research efforts.ResultsSince 2016, there has been an exponential increase in AI-related publications, with significant contributions from China and the USA. Our analysis identified eight major AI application areas: pathogen detection, antibiotic resistance prediction, transmission modeling, genomic analysis, therapeutic optimization, ecological profiling, vaccine development, and data management systems. Notably, we found significant lexical overlaps between these areas, especially between drug resistance and vaccine development, suggesting an interconnected research landscape.DiscussionAI is increasingly moving from laboratory research to clinical applications, enhancing hospital operations and public health strategies. It plays a vital role in optimizing pathogen detection, improving diagnostic speed, treatment efficacy, and disease control, particularly through advancements in rapid antibiotic susceptibility testing and COVID-19 vaccine development. This study highlights the current status, progress, and challenges of AI in pathogenic microbiology, guiding future research directions, resource allocation, and policy-making.

The Application of Virtual Reality Technology in Clothing Product Development

With the rapid development of modern technology, virtual reality technology is gradually emerging in the clothing industry, which has a profound impact on key aspects such as product design, sample clothing production, production management, and supply chain management. This study delves into the specific application status, efficiency advantages, and complex challenges faced by virtual reality technology in clothing product development. Through system analysis, this article provides a detailed explanation of the technology's implementation of digital clothing design, virtual fitting, and efficient integration of 3D modeling and simulation systems. Meanwhile, this article provides a detailed and in-depth discussion on the application details of virtual reality technology in areas such as sample clothing production, production process management, and supply chain operations. The research results show that virtual reality technology has brought new design and management tools to the clothing industry, effectively improving design efficiency, reducing cost expenditures, enhancing user experience, and driving the entire industry towards more efficient, intelligent, and sustainable development.

PARG inhibitor sensitivity correlates with accumulation of single-stranded DNA gaps in preclinical models of ovarian cancer

Poly (ADP-ribose) glycohydrolase (PARG) is a dePARylating enzyme which promotes DNA repair by removal of poly (ADP-ribose) (PAR) from PARylated proteins. Loss or inhibition of PARG results in replication stress and sensitizes cancer cells to DNA-damaging agents. PARG inhibitors are now undergoing clinical development for patients having tumors with homologous recombination deficiency (HRD), such as cancer patients with germline or somatic BRCA1/2-mutations. PARP inhibitors kill BRCA-deficient cancer cells by increasing single-stranded DNA gaps (ssGAPs) during replication. Here, we report that, like PARP inhibitor (PARPi), PARG inhibitor (PARGi) treatment also causes an accumulation of ssGAPs in sensitive cells. PARGi exposure increased accumulation of S-phase-specific PAR, a marker for Okazaki fragment processing (OFP) defects on lagging strands and induced ssGAPs, in sensitive cells but not in resistant cells. PARGi also caused accumulation of PAR at the replication forks and at the ssDNA sites in sensitive cells. Additionally, PARGi exhibited monotherapy activity in specific HR-deficient, as well as HR-proficient, patient-derived, or patient-derived xenograft (PDX)-derived organoids of ovarian cancer, and drug sensitivity directly correlated with the accumulation of ssGAPs. Taken together, PARGi treatment results in toxic accumulation of PAR at replication forks resulting in ssGAPs due to OFP defects during replication. Regardless of the BRCA/HRD-status, the induction of ssGAPs in preclinical models of ovarian cancer cells correlates with PARGi sensitivity. Patient-derived organoids (PDOs) may be a useful model system for testing PARGi sensitivity and functional biomarkers.

Biochemical characterization of the human ubiquitous glucose-6-phosphatase in neutrophil granulocytes.

Glucose-6-phosphatase-β (G6PC3) is a ubiquitous phosphatase present in the endoplasmic reticulum, which, unlike G6PC1, is not responsible for maintaining blood glucose level under starvation. Recently, G6PC3 has been shown to play an important role in neutrophil granulocytes, eliminating the toxic metabolite 1,5-anhydroglucitol-6-phosphate. The present study aimed to look for alternative substrates for the enzyme and outline the expression changes in the parts of this multicomponent system during neutrophil granulocyte differentiation. We determined the kinetic characteristics of recombinant human G6PC3 towards different sugar phosphates, and the transport of these compounds was also measured in rat liver microsomes. We found that all investigated sugar phosphates are substrates for G6PC3, although their microsomal transport is much slower than that of glucose-6-phosphate. Using the HL-60 promyelocytic leukemia cell line as an in vitro model system for myeloid differentiation, we found no significant differences in enzyme expression and phosphatase activity latency between undifferentiated and differentiated cells. Our results provide novel insights into the possible role of G6PC3 in the dephosphorylation of alternative sugar phosphates or their metabolites synthesized in the endoplasmic reticulum and confirm the potential feature of the enzyme in the promyelocytic stage as well. These findings contribute to our knowledge of intracellular carbohydrate metabolism of neutrophil granulocytes, which facilitates further research directions to better understand the underlying mechanisms of neutropenias.

Influence of Process Conditions During Aqueous and Direct Recycling of NMC811 Cathodes.

This study investigated the impact of various process conditions on the aqueous, direct recycling of LiNi0.8Mn0.1Co0.1O2 (NMC811) cathodes. Three model systems were used. The first system assumes that the current collector delamination is performed in a dry environment without the use of water as a process medium. Consequently, the NMC811 is only exposed to water during classification, where no aluminum foil is present. The second model system assumes that the current collector delamination occurs in water. Therefore, the NMC811 is exposed to water in the presence of aluminum foil. Due to the pH increase caused by the Li+/H+ exchange reaction, the pH value surpasses the stability window of the aluminum-oxide passivation layer (pH 4.5-8.5), resulting in the deposition of aluminum-containing species on the NMC811 surface. The third model system is identical to the second, with the exception that H3PO4 is added. This causes the pH to decrease and prevents corrosion of the aluminum foil. The findings reveal that process conditions significantly affect the surface chemistry on NMC811, influencing electrochemical performance. Notably, aluminum-containing species increase polarization. Heat treatment simulating regeneration led to cation mixing as surface species diffused into the NMC811 bulk structure, highlighting the need to control recycling process conditions.

Big fish can't jump? Allometry of terrestrial jumping in cyprinodontiform fishes.

Teleost fishes that emerge onto land must produce effective terrestrial movements to return to the water. Using the Cyprinodontiformes as a model system, we examined a terrestrial behavior termed the tail-flip jump across a size range of individuals representing three species of aquatic killifishes (Gambusia affinis, Poecilia mexicana, and Jordanella floridae) and two species of amphibious killifishes (Kryptolebias marmoratus and Fundulus heteroclitus) to identify potential effects of size (mass) on jumping performance. The ballistic trajectory equation was used to partition the contributions of velocity (determined by acceleration and contact time) and takeoff angle to jump distance. Despite differences in size (over an order of magnitude) all fishes took off from the ground at ∼45°. However, in terms of total displacement, aquatic and amphibious killifish species scaled differently in their ability to perform the tail-flip jump. Aquatic killifishes decrease in total jump distance as mass increases; however, amphibious killifishes increase in total jump distance as mass increases. Aquatic killifishes cannot produce adequate accelerations at larger sizes, but amphibious killifishes produce similar accelerations despite over an order of magnitude size difference. Because of this, amphibious killifish species are able to maintain fast takeoff velocities at large body sizes. Distinct scaling patterns may be generated by differences in body shape. Aquatic killifishes have a fusiform body shape, with most of their body mass in the anterior of the body, while amphibious killifishes have a more uniform body shape that reduces their overall mass present in the anterior body. We hypothesize that reduced mass in the anterior body facilitates raising the head over the tail to prepare for takeoff. In contrast with amphibious species, the negative scaling relationship seen in body size vs. displacement in aquatic killifishes implies an upper size limit to producing the tail-flip jump for fish species that infrequently encounter the terrestrial environment.