Multiple Mechanisms Research Articles

Bilateral Direct Investment and Global Value Chain Climbing

According to the spirit of the 20th National Congress report, China should not only adhere to the depth of embedding in the global value chain, but also enhance the height of embedding in the global value chain. Therefore, China should actively explore and develop towards the high-end of the value chain. This article aims to explore the relationship between two-way direct investment and the climb of the global value chain. According to the research results, two-way direct investment can promote economic development through multiple mechanisms and further achieve China's climb in the global value chain. Currently and even in the future, we need to further strengthen policy coordination, optimize the investment environment, improve the efficiency and quality of two-way investment, in order to promote the global value chain to a higher level.

Multiscale microstructure containing nanometer-scale precipitations and stacking faults yields a high-strength Al-5Cu alloy by electron beam freeform fabrication

Electron beam freeform fabrication (EBF3) additive manufacturing technique has been successfully employed to print the non-weldable Al-5Cu thin-walled parts through an optimized set of process parameters. Post-heat treatment is conducted to engineer the desirable microstructure containing multiple nanostructures, i.e., the nanoscale θ" and θ' precipitates, stacking faulted zones and Al-Cu-Cd clusters, leading to a high-strength Al-5Cu alloy with good ductility. The grain formation mechanisms are revealed via a combinatorial simulation and experimentation. It is shown that EBF3 process can produce three different types of grain microstructures: fully equiaxed, fully columnar, and the mixture. In the layerwise melt pool solidification process, wide partially melted zone is observed to favor the formation of equiaxed grains due to its inheritance characteristic. After solution and aging heat treatment, Al-Cu-Cd nanoclusters (∼ 2 nm in Dia.) are generated, which facilitates the formation of nanoscale stacking faulted zones (∼11 nm). Meanwhile, as heterogeneous nucleation sites, Al-Cu-Cd nanoclusters effectively promote θ'-Al2Cu phase (∼ 19 - 114 nm) precipitation to enable the coexistence with fine θ"-Al3Cu precipitates (∼ 7 - 37 nm). The multiscale microstructure, especially incorporating the newly identified nanoscale stacking faulted zones, activates multiple strengthening mechanisms. Consequently, its tensile properties at room temperature reach an ultimate tensile stress of ∼ 496.5 MPa, yield strength of ∼ 435.7 MPa, and elongation of ∼ 9.6%, which are superior to other as-cast and additively manufactured Al-Cu alloys. This work offers a promising processing route to directly fabricate high-strength near-net-shape Al-Cu alloy parts for the aerospace and automotive industries.

Abstract A056: Targeting the mevalonate biosynthesis pathway in gemcitabine resistant pancreatic cancer

Abstract Pancreatic ductal adenocarcinoma (PDA) is a lethal malignancy with a low survival rate. A lack of durable responses to chemotherapy renders its treatment particularly challenging and largely contributes to the devastating prognosis. Gemcitabine, a pyrimidine anti-metabolite, is a cornerstone in PDA therapy, but resistance remains a major hurdle in clinical care. Multiple mechanisms of chemoresistance have been attributed to rewired metabolic pathways in PDA cells. Accordingly, we hypothesized that altered metabolism in gemcitabine resistance represents a therapeutic vulnerability that can be targeted to improve response to treatment. To investigate metabolic vulnerabilities in gemcitabine resistance, we generated gemcitabine resistant murine PDA cell lines and assembled patient-derived gemcitabine high versus low responder organoids. Transcriptomic profiling revealed a downregulation of the mevalonate biosynthesis pathway and its rate-limiting enzyme, HMG-CoA reductase, upon the acquisition of gemcitabine resistance. Upregulation of this pathway has been proposed as a primary resistance mechanism to statins, HMG-CoA reductase inhibitors that are frequently prescribed to treat patients with hyperlipidemia. Accordingly, we postulated that statins would be more potent in gemcitabine resistant PDA cells than in their sensitive counterparts. Indeed, resistant cells were exquisitely susceptible to inhibition of the mevalonate pathway, an observation consistent across multiple clinically available statins. Downstream rescue experiments suggested that the main impact of blocking the mevalonate biosynthesis pathway is through lowered levels of geranylgeranyl pyrophosphate and reduced protein geranylation. To validate our findings in vivo, we implanted gemcitabine resistant murine PDA cells into syngeneic mice that were fed with a modified diet precluding geranylgeraniol. Here, the treatment combination gemcitabine and pitavastatin inhibited tumor growth of resistant allografts. Collectively, these data suggest that targeting the HMG-CoA reductase is a metabolic vulnerability that is gained in PDA cells upon the acquisition of gemcitabine resistance. The combination therapy gemcitabine and pitavastatin, two widely used compounds in patients, has potential to translate into a clinical benefit and improve survival in this deadly disease. Citation Format: Alica K. Beutel, Sabrina Calderon, Ethan Nghiem, Rima Singh, Cecily Anaraki, Kevin Gulay, Herve Tiriac, Alexander Kleger, Thomas Seufferlein, Alexander Muir, Cholsoon Jang, Dennis Juarez, David Fruman, Christopher Halbrook. Targeting the mevalonate biosynthesis pathway in gemcitabine resistant pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A056.

Coronary atherosclerosis and periodontitis have similarities in their clinical presentation.

Periodontitis (PE) and coronary heart disease (CHD) possess multiple mechanisms for a putative association. This case-control study compared the periodontal status among CHD subjects to controls without CHD, while also investigating atheroma invasion by known periodontal pathogens. 161 subjects participated in this study were divided into three CHD groups: No CHD, chronic CHD, acute CHD. Additional analysis involved grouping subjects according to number of atheromas: no atheroma, 1-4 atheromas, 5-18 atheromas. Data were collected from medical records, periodontal examinations, and questionnaires that included demographic, behavioral, and oral health variables. Angiographic catheterizations were analyzed according to the number of atheroma lesions, lesion size, lesion location, and atheroma lesion stability. Lipoprotein profile, inflammatory markers and cells were analyzed. The microbiological branch added 30 individuals who had their atheroma lesion and subgingival plaque analyzed using polymerase chain reaction probes against the 16 s region, red complex and Aggregatibacter actinomycetemcomitans' DNA. Subjects with CHD had high levels of systemic inflammatory markers and low levels of high-density lipoproteins compared to subjects without CHD. Subjects without CHD and clear coronaries had a prevalence of mild CAL, while individuals with more atheroma lesions had advanced CAL and more active PE. Subjects with more advanced CAL were 4 times more likely to have CHD compared to subjects with less, which is comparable to smoking. Only 4 subjects had the screened pathogens detected in atheroma, although these subjects also have the screened pathogens in subgingival plaque. However, 80% of atheromas had bacteria. CHD and PE showed similarities in progression while active PE led to more atheroma lesions that also tended to be larger in size.

The crosstalk of CD8+ T cells and ferroptosis in cancer.

Ferroptosis is an iron-dependent, novel form of programmed cell death characterized by lipid peroxidation and glutathione depletion and is widespread in a variety of diseases. CD8+ T cells are the most important effector cells of cytotoxic T cells, capable of specifically recognizing and killing cancer cells. Traditionally, CD8+ T cells are thought to induce cancer cell death mainly through perforin and granzyme, and Fas-L/Fas binding. In recent years, CD8+ T cell-derived IFN-γ was found to promote cancer cell ferroptosis by multiple mechanisms, including upregulation of IRF1 and IRF8, and downregulation of the system XC-, while cancer cells ferroptosis was shown to enhance the anti-tumor effects of CD8+ T cell by heating the tumor immune microenvironment through the exposure and release of tumor-associated specific antigens, which results in a positive feedback pathway. Unfortunately, the intra-tumoral CD8+ T cells are more sensitive to ferroptosis than cancer cells, which limits the application of ferroptosis inducers in cancer. In addition, CD8+ T cells are susceptible to being regulated by other immune cell ferroptosis in the TME, such as tumor-associated macrophages, dendritic cells, Treg, and bone marrow-derived immunosuppressive cells. Together, these factors build a complex network of CD8+ T cells and ferroptosis in cancer. Therefore, we aim to integrate relevant studies to reveal the potential mechanisms of crosstalk between CD8+ T cells and ferroptosis, and to summarize preclinical models in cancer therapy to find new therapeutic strategies in this review.

Comprehensive analysis of the role of ubiquitin-specific peptidases in colorectal cancer: A systematic review.

Colorectal cancer (CRC) is the third most frequent and the second most fatal cancer. The search for more effective drugs to treat this disease is ongoing. A better understanding of the mechanisms of CRC development and progression may reveal new therapeutic strategies. Ubiquitin-specific peptidases (USPs), the largest group of the deubiquitinase protein family, have long been implicated in various cancers. There have been numerous studies on the role of USPs in CRC; however, a comprehensive view of this role is lacking. To provide a systematic review of the studies investigating the roles and functions of USPs in CRC. We systematically queried the MEDLINE (via PubMed), Scopus, and Web of Science databases. Our study highlights the pivotal role of various USPs in several processes implicated in CRC: Regulation of the cell cycle, apoptosis, cancer stemness, epithelial-mesenchymal transition, metastasis, DNA repair, and drug resistance. The findings of this study suggest that USPs have great potential as drug targets and noninvasive biomarkers in CRC. The dysregulation of USPs in CRC contributes to drug resistance through multiple mechanisms. Targeting specific USPs involved in drug resistance pathways could provide a novel therapeutic strategy for overcoming resistance to current treatment regimens in CRC.

Biological Control Activities of Rhizosphere Fungus Trichoderma virens T1-02 in Suppressing Flower Blight of Flamingo Flower (Anthurium andraeanum Lind.).

Flower blight caused by Neopestalotiopsis clavispora is an emerging disease of flamingo flower (Anthurium andraeanum Lind.) that negatively impacts flower production. The use of rhizosphere fungi as biocontrol agents is an alternative way to control this disease instead of using synthetic fungicides. This research aimed to screen the potential of rhizosphere fungi, Trichoderma spp., with diverse antifungal abilities to control N. clavispora and to reduce flower blight in flamingo flowers. A total of ten isolates were tested against N. clavispora by dual culture assay, and T1-02 was found to be the most effective isolate against N. clavispora, with inhibition of 78.21%. Morphology and molecular phylogeny of multiple DNA sequences of the genes, the internal transcribed spacer (ITS), translation elongation factor 1-α (tef1-α), and RNA polymerase 2 (rpb2) identified isolate T1-02 as Trichoderma virens. Sealed plate method revealed T. virens T1-02 produced volatile antifungal compounds (VOCs) against N. clavispora, with inhibition of 51.28%. Solid-phase microextraction (SPME) was applied to trap volatiles, and GC/MS profiling showed VOCs emitted from T. virens T1-02 contained a sesquiterpene antifungal compound-germacrene D. The pre-colonized plate method showed that T. virens T1-02 aggressively colonized in tested plates with inhibition of 100% against N. clavispora, and microscopy revealed direct parasitism onto fungal hyphae. Furthermore, the application of T. virens T1-02 spore suspension reduced the disease severity index (DSI) of flower blight in flamingo flowers. Based on the results from this study, T. virens T1-02 displays multiple antagonistic mechanisms and has the potential ability to control flower blight of flamingo flowers caused by N. clavispora.

Multiple Immune and Genetic Mechanisms Contribute to Cmv5s-Driven Susceptibility and Tissue Damage during Acute Murine Cytomegalovirus Infection.

The MHC class I molecule H-2Dk conveys resistance to acute murine CMV infection in both C57L (H-2Dk transgenic) and MA/My mice. M.H2k/b mice are on an MA/My background aside from a C57L-derived region spanning the MHC (Cmv5s), which diminishes this resistance and causes significant spleen histopathology. To hone in on the effector elements within the Cmv5s interval, we generated several Cmv5-recombinant congenic mouse strains and screened them invivo, allowing us to narrow the phenotype-associated interval >6-fold and segment the genetic mechanism to at least two independent loci within the MHC region. In addition, we sought to further characterize the Cmv5s-associated phenotypes in their temporal appearance and potential direct relationship to viral load. To this end, we found that Cmv5s histopathology and NK cell activation could not be fully mirrored in the MA/My mice with increased viral dose, and that marginal zone destruction was the first apparent Cmv5s phenotype, being reliably quantified as early as 2 d postinfection in the M.H2k/b mice, prior to divergence in viral load, weight loss, or NK cell phenotype. Finally, we further dissect NK cell involvement, finding no intrinsic differences in NK cell function, despite increased upregulation of activation markers and checkpoint receptors. In conclusion, these data dissect the genetic and immunologic underpinnings of Cmv5 and reveal a model in which polymorphism within the MHC region of the genome leads to the development of tissue damage and corrupts protective NK cell immunity during acute viral infection.

Kinetic and thermodynamic study of composite with jute fiber as reinforcement

In the present work, engineered by compression molding process via a hydraulic press, the A and B composite samples were carried out with 5% and 10% ratio respectively of Ricinodendron heudelotii oil-based alkyd resin in bio-based matrix made of unsaturated polyester using jute fibers as reinforcement material. The samples’ thermal decomposition was performed through thermogravimetry (TG) and derivative thermogravimetry (DTG) analyses. Both composite samples exhibit two stages of decomposition, where the main occurs at 200 - 550°C. Aiming to study and being able to model the thermal degradation of the elaborated composites, finding the kinetic triplets appears the best option to describe the kinetic process undergo by the composites in order to evaluate the performance application of the composites. Two non-isothermal techniques, Flynn-Wall-Ozawa (FWO) and Kissinger have been used to assess the activation energy Ea, and it is found that the apparent activation energy varies with the degree of conversion indicating that both composites decompose with a multiple step mechanism process. The appropriate reaction model for the second stage of decomposition was best suited with Johnson-Mel-Avrami (n<1) model and has been established, allowing us to model thermal degradation behavior of our elaborated composite material and set predictions. The estimated Arrhenius factor values were respectively about A and B composites, 4.12.1015 min-1 and 10.42.1015 min-1, allowing us to set the final equation characterizing the degradation process for the second and main decomposition stage. Finally, as a result of comparison between A and B composites, A appears to be the more thermally stable due to its lower values of Arrhenius pre-exponential factor over the main stage of decomposition and higher calculated the activation energy values.

Biofilm Producing Methicillin-Resistant Staphylococcus aureus (MRSA) Infections in Humans: Clinical Implications and Management.

Since its initial description in the 1960s, methicillin-resistant Staphylococcus aureus (MRSA) has developed multiple mechanisms for antimicrobial resistance and evading the immune system, including biofilm production. MRSA is now a widespread pathogen, causing a spectrum of infections ranging from superficial skin issues to severe conditions like osteoarticular infections and endocarditis, leading to high morbidity and mortality. Biofilm production is a key aspect of MRSA's ability to invade, spread, and resist antimicrobial treatments. Environmental factors, such as suboptimal antibiotics, pH, temperature, and tissue oxygen levels, enhance biofilm formation. Biofilms are intricate bacterial structures with dense organisms embedded in polysaccharides, promoting their resilience. The process involves stages of attachment, expansion, maturation, and eventually disassembly or dispersion. MRSA's biofilm formation has a complex molecular foundation, involving genes like icaADBC, fnbA, fnbB, clfA, clfB, atl, agr, sarA, sarZ, sigB, sarX, psm, icaR, and srtA. Recognizing pivotal genes for biofilm formation has led to potential therapeutic strategies targeting elemental and enzymatic properties to combat MRSA biofilms. This review provides a practical approach for healthcare practitioners, addressing biofilm pathogenesis, disease spectrum, and management guidelines, including advances in treatment. Effective management involves appropriate antimicrobial therapy, surgical interventions, foreign body removal, and robust infection control practices to curtail spread within healthcare environments.

Protein inhibitor of activated STAT1 (PIAS1) alleviates cerebral infarction and inflammation after cerebral ischemia in rats

BackgroundIschemic stroke is a severe disorder with high incidence, disability rate and mortality. Multiple pathogenesis mechanisms are involved in ischemic stroke, such as inflammation and neuronal cell apoptosis. Protein inhibitor of activated signal transducer and activators of transcription 1 (PIAS1) plays a crucial role in various biological processes, including inflammation. PIAS1 is also downregulated in ischemia-reperfusion injury and involved in the disease processes. However, the role of PIAS1 in cerebral ischemia is unclear. MethodsSprague-Dawley (SD) rats were induced with middle cerebral artery occlusion (MCAO). The role and mechanisms of PIAS1 in ischemic cerebral infarction were explored by Longa test, 2,3,5-triphenyltetrazolium chloride (TTC) staining, Morris water maze (MWM) test, hematoxylin-eosin (HE) staining, quantification of brain water content, reverse transcription-quantitative polymerase chain reaction (RT-qPCR), enzyme-linked immunosorbent assay (ELISA), terminal deoxynucleotidyl transferase deoxyuridine triphosphate (dUTP) nick end labeling (TUNEL), Western blot and immunofluorescence assays. ResultsThe expression of PIAS1 in MCAO-induced rat was declined compared to sham rats. Overexpression of PIAS1 reduced the Longa neurological scores, the percent of infarction area, the pathological abnormality, the escape latency of swimming and the percent of brain water content, and increased the number of platform crossings and time in the target quadrant in the MCAO-induced rats. Besides, overexpression of PIAS1 decreased the MCAO-induced the contents of IL-1β, IL-6 and TNF-α, but further elevated the concentrations of IL-10 in both sera and brain tissues. Moreover, overexpression of PIAS1 reversed the MCAO-induced apoptosis rate and the relative protein level of Bax, cleaved caspase3 and Bcl-2. Overexpression of PIAS1 also reversed the level of proteins involved in NF-κB pathway. ConclusionPIAS1 reduced inflammation and apoptosis, thereby alleviating ischemic cerebral infarction in MCAO-induced rats through regulation NF-κB pathway.

Highly permeable nanofibrous polyamide membranes for multi-component wastewater treatment: Exploration of multiple separation mechanism

Multi-component wastewater containing a variety of organic toxins, e.g., dyes and inorganic particulates induces serious environmental concerns, which must be addressed by innovative approaches instead of conventional chemical and physical processes, which are limited by purification efficiency, secondary pollution, and cost-effectiveness. Therefore, it is important to find new avenues of purification methods that are both sustainable and effective. Ultra-fine nanofibrous microfiltration membranes were fabricated by multi-nozzle electrospinning of polyamide-66 (PA-66) and were employed to remove 0.2-μm-nanoparticles and dyes simultaneously from wastewater through filtration and dynamic adsorption performance, in an attempt to discover a one-step filtration system for both dyes and nanoparticles. The fiber diameter and surface morphology of the nanofibrous membranes varied with the concentrations of polyamide solutions, where the ultra-fine nanofibrous membrane exhibited optimum mechanical properties at a specific concentration of PA-66 (11 wt%). The nanofibrous membranes had adsorption capabilities of 133.3 and 204.5 mg/g, respectively, against both anionic dyes (e.g., metanil yellow) and cationic dyes (e.g., chrysoidine), respectively. The membrane also selectively filtrated fine nanoparticles with a nearly 100% rejection ratio. A multiple separation mechanism, including adsorption based on electrostatic interaction, hydrogen bonding interaction, and hydrophobic interaction, as well as depth filtration, was proposed. As an applicable demonstration, the spiral wound cartridge fabricated by PA-66 nanofibrous membrane was used for a simulated multi-component wastewater treatment that contained dyes and nanoparticles of different concentrations. During the multicomponent test at flow rate 1 mL/min, a rejection rate of 97% and greater than 99% were achieved against dyes and nanoparticles, respectively.

From the Colon to the Liver: How Gut Microbiota May Influence Colorectal Cancer Metastatic Potential.

The gut microbiota's influence on human tumorigenesis is a burning topic in medical research. With the new ontological perspective, which considers the human body and its pathophysiological processes as the result of the interaction between its own eukaryotic cells and prokaryotic microorganisms living in different body niches, great interest has arisen in the role of the gut microbiota on carcinogenesis. Indeed, dysbiosis is currently recognized as a cancer-promoting condition, and multiple molecular mechanisms have been described by which the gut microbiota may drive tumor development, especially colorectal cancer (CRC). Metastatic power is undoubtedly one of the most fearsome features of neoplastic tissues. Therefore, understanding the underlying mechanisms is of utmost importance to improve patients' prognosis. The liver is the most frequent target of CRC metastasis, and new evidence reveals that the gut microbiota may yield an effect on CRC diffusion to the liver, thus defining an intriguing new facet of the so-called "gut-liver axis". In this review, we aim to summarize the most recent data about the microbiota's role in promoting or preventing hepatic metastasis from CRC, highlighting some potential future therapeutic targets.

Comparative analysis of mechanical properties in single-phase Ti50-ZrVNbCr medium entropy alloys with different physical parameters

In this study, a series of non-equimolar Ti50-ZrVNbCr medium alloys were designed according to the maximum entropy principle under the valence electron concentration (VEC) constraint. The mechanical properties of the alloys were experimentally investigated and compared, and the effect of the physical parameters on the alloys was extensively discussed. The results showed that in tensile deformation, the multiple slip mechanisms, including {110} 〈111〉, {112}〈111〉 and {123} < 111>, were all activated in the alloys with high VEC. The alloy with the VEC of 4.25 exhibited an optimal combination of strength and elongation. In the strength prediction model, using a weighted-average of the radius differences in the calculation of the atom radius mismatch proved more effective than using a weighted-average of distance differences between the nearest atoms.

Coatings and Surface Modification of Alloys for Tribo-Corrosion Applications

This review of the tribocorrosion of coatings and surface modifications covers nearly 195 papers and reviews that have been published in the past 15 years, as compared to only 37 works published up to 2007, which were the subject of a previous review published in 2007. It shows that the research into the subject area is vibrant and growing, to cover emerging deposition, surface modification and testing techniques as well as environmental influences and modelling developments. This growth reflects the need for machines to operate in harsh environments coupled with requirements for increased service life, lower running costs and improved safety factors. Research has also reacted to the need for multifunctional coating surfaces as well as functionally graded systems with regard to depth. The review covers a range of coating types designed for a wide range of potential applications. The emerging technologies are seen to be molten-, solution-, PVD- and PEO-based coatings, with CVD coatings being a less popular solution. There is a growing research interest in duplex surface engineering and coating systems. Surface performance shows a strong playoff between wear, friction and corrosion rates, often with antagonistic relationships and complicated interactions between multiple mechanisms at different scale lengths within tribocorrosion contacts. The tribologically induced stresses are seen to drive damage propagation and accelerate corrosion either within the coating or at the coating coating–substrate interface. This places a focus on coating defect density. The environment (such as pH, DO2, CO2, salinity and temperature) is also shown to have a strong influence on tribocorrosion performance. Coating and surface modification solutions being developed for tribocorrosion applications include a whole range of electrodeposited coatings, hard and tough coatings and high-impedance coatings such as doped diamond-like carbon. Hybrid and multilayered coatings are also being used to control damage penetration into the coating (to increase toughness) and to manage stresses. A particular focus involves the combination of various treatment techniques. The review also shows the importance of the microstructure, the active phases that are dissolved and the critical role of surface films and their composition (oxide or passive) in tribocorrosion performance which, although discovered for bulk materials, is equally applicable to coating performance. New techniques show methods for revealing the response of surfaces to tribocorrosion (i.e., scanning electrochemical microscopy). Modelling tribocorrosion has yet to embrace the full range of coatings and the fact that some coatings/environments result in reduced wear and thus are antagonistic rather than synergistic. The actual synergistic/antagonistic mechanisms are not well understood, making them difficult to model.

Abh, AbrB3, and Spo0A play distinct regulatory roles during polymyxin synthesis in Paenibacillus polymyxa SC2.

Polymyxins are considered the last line of defense against multidrug-resistant bacteria. The regulatory mechanism of polymyxin synthesis is poorly studied in Paenibacillus polymyxa. In this study, we found that Abh and AbrB3 negatively regulated, whereas Spo0A positively regulated polymyxin synthesis in P. polymyxa SC2. In addition, a regulatory relationship between Abh, AbrB3, and Spo0A was revealed, which regulate polymyxin synthesis via multiple regulatory mechanisms in P. polymyxa.

Experimental Study of Seismic Wave Attenuation in Carbonate Rocks

Summary Seismic wave attenuation has a great potential for studying saturated and fractured media, due to its high sensitivity to the physical properties of geological media. However, accurately estimating this parameter can be challenging due to its sensitivity to signal noise, particularly in heterogeneous media such as carbonate rocks. This explains the paucity of attenuation studies carried out in carbonate rocks compared with sandstones, and the ambiguity around its mechanisms and its relationship with petrophysical properties. To investigate further, we conducted an experimental study of ultrasonic waveform signals (0.5–3 MHz) reordered under dry and fully saturation conditions in 13 samples covering a wide range of petrophysical values and subjected them to differential pressure reaching reservoir pressure. The resulting increase in attenuation magnitudes and their variation with pressure due to brine saturation were more pronounced than in velocity magnitudes, confirming the higher sensitivity of attenuation to fluid content. However, understanding the relationship between attenuation and petrophysical properties required a careful examination of the results and more elucidation about attenuation mechanisms. We suggested that multiple attenuation mechanisms coexist, including scattering, cracks slipping, solid frictional relative motion, and global and squirt flow. This explains the frequency dependence of attenuation, with higher magnitudes at sonic frequencies, where the squirt flow mechanism may be dominant. In contrast to sandstone, the magnitude of compressional to shear attenuation ratio (QP−1/QS−1) was found to be greater than unity in both dry and brine fully saturated carbonate samples at ultrasonic frequencies. This result may be due to the complex porosity structure of carbonate rocks, which makes it not appropriate to the sandstone rock physics models.

Application of the Key Characteristics of Carcinogens to Bisphenol A.

The ten key characteristics (KCs) of carcinogens are based on characteristics of known human carcinogens and encompass many types of endpoints. We propose that an objective review of the large amount of cancer mechanistic evidence for the chemical bisphenol A (BPA) can be achieved through use of these KCs. A search on metabolic and mechanistic data relevant to the carcinogenicity of BPA was conducted and web-based software tools were used to screen and organize the results. We applied the KCs to systematically identify, organize, and summarize mechanistic information for BPA, and to bring relevant carcinogenic mechanisms into focus. For some KCs with very large data sets, we utilized reviews focused on specific endpoints. Over 3000 studies for BPA from various data streams (exposed humans, animals, in vitro and cell-free systems) were identified. Mechanistic data relevant to each of the ten KCs were identified, with receptor-mediated effects, epigenetic alterations, oxidative stress, and cell proliferation being especially data rich. Reactive and bioactive metabolites are also associated with a number of KCs. This review demonstrates how the KCs can be applied to evaluate mechanistic data, especially for data-rich chemicals. While individual entities may have different approaches for the incorporation of mechanistic data in cancer hazard identification, the KCs provide a practical framework for conducting an objective examination of the available mechanistic data without a priori assumptions on mode of action. This analysis of the mechanistic data available for BPA suggests multiple and inter-connected mechanisms through which this chemical can act.

Ultra-strong and ductile precipitation-strengthened high entropy alloy with 0.5 % Nb addition produced by laser additive manufacturing

Achieving a superior strength-ductility combination for fcc single-phase high entropy alloys (HEAs) is challenging. The present work investigates the in-situ synthesis of Fe49.5Mn30Co10Cr10C0.5 interstitial solute-strengthened HEA containing 0.5 wt.% Nb (hereafter referred to as iHEA-Nb) using laser melting deposition (LMD), aiming at simultaneously activating multiple strengthening mechanisms. The effect of Nb addition on the microstructure evolution, mechanical properties, strengthening and deformation mechanisms of the as-deposited iHEA-Nb samples was comprehensively evaluated. Multiple levels of heterogeneity were observed in the LMD-deposited microstructure, including different grain sizes, cellular subgrain structures, various carbide precipitates, as well as elemental segregation. The incorporation of Nb atoms with a large radius leads to lattice distortion, reduces the average grain size, and increases the types and fractions of carbides, aiding in promoting solid solution strengthening, grain boundary strengthening, and precipitation strengthening. Tensile test results show that the Nb addition significantly increases the yield strength and ultimate tensile strength of the iHEA to 1140 and 1450 MPa, respectively, while maintaining the elongation over 30 %. Deformation twins were generated in the tensile deformed samples, contributing to the occurrence of twinning-induced plasticity. This outstanding combination of strength and ductility exceeds that for most additively manufactured HEAs reported to date, demonstrating that the present in situ alloying strategy could provide significant advantages for developing and tailoring microstructures and balancing the mechanical properties of HEAs while avoiding conventional complex thermomechanical treatments. In addition, single-crystal micropillar compression tests revealed that although the twining activity is reduced by the Nb addition to the iHEA, the micromechanical properties of grains with different orientations were significantly enhanced.

Abstract PR006: Elucidating the effect of PARP inhibitors on MMEJ-mediated DNA repair

Abstract First-line maintenance treatment for homologous recombination (HR)-deficient (HRD, e.g., BRCA1/2 mutations) cancers includes poly ADP-ribose inhibitors (PARPi, e.g., olaparib, niraparib). PARPi are lethal through multiple mechanisms, including PARP trapping and PARP activity inhibition, which both destabilize the replication fork machinery in the absence of BRCA1/2. However, only 50% of HRD tumors respond to PARPi treatment due to intrinsic resistance and of those that respond, most tumors eventually relapse due to acquired drug resistance. Because MMEJ is essential in HRD-cancers, it has emerged as a promising target to combat PARPi resistance, with POLQ inhibitors currently in clinical trials. Thus, understanding the interplay between MMEJ and PARP inhibitors is critical. While PARP1 is proposed to promote MMEJ, PARP regulates numerous aspects of DSB repair, and therefore its overall impact on MMEJ levels remains unclear. For instance, the effect of PARP inhibition on DSB end-resection, a critical step of MMEJ, remains controversial. Utilizing a DNA repair reporter, we assessed MMEJ levels following treatment with various PARP inhibitors, including those with minimal PARP trapping activity. Remarkably, we find that PARP inhibition systematically leads to elevated MMEJ levels in a POLQ-dependent fashion. Furthermore, PARP inhibition also induces higher MMEJ levels in cells treated with NHEJ inhibitors as well as in HR-deficient cells, including an HRD ovarian cancer cell line (PEO1, BRCA2mut). Therefore, this MMEJ upregulation cannot be simply attributed to a PARPi-mediated suppression of NHEJ or HR activity. Taken together, our data suggests that the overall effect of PARP inhibitors may lead to upregulation, rather than suppression, of MMEJ activity. We are currently assessing the contribution of PARP1 and PARP2 in MMEJ regulation and are testing whether PARPi also increase MMEJ levels at sites of replication induced DSBs. We hypothesize that PARPi could upregulate MMEJ through modulating DSB end-resection. This insight bears significant implications for the development of combination therapies of MMEJ and PARP inhibitors in treating HRD cancers. Citation Format: Raquel Ortega, Nausica Arnoult, Benjamin G Bitler. Elucidating the effect of PARP inhibitors on MMEJ-mediated DNA repair [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr PR006.