Specific Tolerance Research Articles

Sabotaging material extrusion-based 3D printed parts through low-magnitude kinetic manipulation attacks

The increasing ubiquity of material-extrusion-based additive manufacturing is motivating cybersecurity researchers to explore its offensive and defensive landscape. Being a physical system, 3D printers have non-zero tolerance specifications for precision and trueness parameters. While a single-bit change in a digital data file is sufficient to fail its integrity and is easily detected through methods such as hashing, the printing process (and subsequently the printed object) remains compliant within the tolerance zone. This study systematically analyzes the material extrusion process and identifies four attack opportunities where low-magnitude kinetic cyberattacks exploit the physical process compliance zone to sabotage the printed part’s mechanical properties. The attacks are demonstrated on ASTM-compliant tensile and flexure bars through a man-in-the-middle attack scenario by hijacking the network layer communication between the 3D printer and the printer control machine. The physically stealthy attacks did not produce any evident deformation in the parts’ dimensions and mass, while the destructive tests confirm that they are still effective in modifying the tensile and bending strength by up to 25%. The effectiveness of the attacks in bypassing the defenses is assessed by implementing one of the leading detection schemes described in the current literature. The attacks were either not detected at all or detected with a significantly high false negative rate at various attack magnitudes.

The Arabidopsis receptor-like kinase WAKL4 limits cadmium uptake via phosphorylation and degradation of NRAMP1 transporter

Cadmium (Cd) is a detrimental heavy metal propagated from soil to the food chain via plants, posing a great risk to human health upon consumption. Despite the understanding of Cd tolerance mechanisms in plants, whether and how plants actively respond to Cd and in turn restrict its uptake and accumulation remain elusive. Here, we identify a cell wall-associated receptor-like kinase 4 (WAKL4) involved in specific tolerance to Cd stress. We show that Cd rapidly and exclusively induces WAKL4 accumulation by promoting WAKL4 transcription and blocking its vacuole-dependent proteolysis in roots. The accumulated WAKL4 next interacts with and phosphorylates the Cd transporter NRAMP1 at Tyr488, leading to the enhanced ubiquitination and vacuole-dependent degradation of NRAMP1, and consequently reducing Cd uptake. Our findings therefore uncover a mechanism conferred by the WAKL4-NRAMP1 module that enables plants to actively respond to Cd and limit its uptake, informing the future molecular breeding of low Cd accumulated crops or vegetables.

Macroecology of Abiotic Stress Tolerance in Woody Plants of the Northern Hemisphere: Tolerance Biomes and Polytolerance Hotspots.

Understanding the main ecological constraints on plants' adaptive strategies to tolerate multiple abiotic stresses is a central topic in plant ecology. We aimed to uncover such constraints by analysing how the interactions between climate, soil features and species functional traits co-determine the distribution and diversity of stress tolerance strategies to drought, shade, cold and waterlogging in woody plants of the Northern Hemisphere. Functional traits and soil fertility predominantly determined drought and waterlogging/cold tolerance strategies, while climatic factors strongly influenced shade tolerance. We describe the observed patterns by defining 'stress tolerance biomes' and 'polytolerance hotspots', that is, geographic regions where woody plant assemblages have converged to specific tolerance strategies and where the coexistence of multiple tolerance strategies is frequent. The depiction of these regions provides the first macroecological overview of the main environmental and functional requirements underlying the ecological limits to the diversity of abiotic stress tolerance strategies in woody plants.

Letter to the Editor: Misophonia: A Need for Audiological Diagnostic Guidelines.

The goal of this commentary is to present to audiologists the recent consensus definition of misophonia along with current clinical measures useful for audiologists in the diagnosis of misophonia. Up and coming behavioral methods that may be sensitive to misophonia are highlighted. Finally, a call is put out for translational audiologic research with the goal of developing diagnostic criteria for misophonia. The approach to the consensus definition is described, as well as the main characteristics of misophonia agreed upon by the expert panel. Next, available clinical measures that may be useful to audiologists for the diagnosis of misophonia are presented, followed by a brief review of current behavioral assessment methodology that still requires research to determine sensitivity and specificity to misophonia symptomatology. This discussion leads to the need for establishment of audiologic diagnostic criteria in misophonia, especially when differentiating from hyperacusis. While the consensus definition for misophonia is an excellent first step in obtaining expert agreement on the descriptors of misophonic triggers, reactions, and behavior, clinical research is critical in developing criteria for misophonia as a specific sound tolerance disorder.

CAR Treg synergy with anti-CD154 mediates infectious tolerance to dictate heart transplant outcomes.

Successful allograft specific tolerance induction would eliminate the need for daily immunosuppression and improve post-transplant quality of life. Adoptive cell therapy with regulatory T cells expressing donor-specific Chimeric Antigen Receptors (CAR-Tregs) is a promising strategy, but as monotherapy, cannot prolong the survival with allografts with multiple MHC mismatches. Using an HLA-A2-transgenic haplo-mismatched heart transplantation model in immunocompetent C57Bl/6 recipients, we show that HLA-A2-specific (A2) CAR Tregs was able to synergize with low dose of anti-CD154 to enhance graft survival. Using haplo-mismatched grafts expressing the 2W-OVA transgene and tetramer-based tracking of 2W- and OVA-specific T cells, we showed that in mice with accepted grafts, A2.CAR Tregs inhibited endogenous non-A2 donor- specific T cell, B cell and antibody responses, and promoted a significant increase in endogenous FoxP3 + Tregs with indirect donor-specificity. By contrast, in mice where A2.CAR Tregs failed to prolong graft survival, FoxP3 neg A2.CAR T cells preferentially accumulated in rejecting allografts and endogenous donor-specific responses were not controlled. This study therefore provides the first evidence for synergy between A2.CAR Tregs and CD154 blockade to promote infectious tolerance in immunocompetent recipients of haplo-mismatched heart grafts and defines features of A2.CAR Tregs when they fail to reshape host immunity towards allograft tolerance.

Naturally acquired microchimerism: clinical, scientific and ethical issues

Microchimerism (MC) is understood as the presence in the body of cells genetically different from the population of the individual, capable of existence and persistence, that is, reproduction and differentiation. This process is associated with the exchange of cellular material between mother and fetus. The consequences of the intrauterine acquisition of maternal MC (MMC) by the fetus are essentially different from the acquisition by the mother of fetal CM (FMC) in the mature state of the organism. Microchimerism has been implicated in the development of autoimmune diseases, but it also helps the body limit a particular disease. Since all these processes take place during the early development of the fetal immune system, the initial response of the immune system is the development of specific tolerance to maternal antigens. MMС can modify immune functions and reactivity through the nongenetic acquisition of cellular and subcellular material. Both FMС and MMС are quite common phenomena, which affects the body of the child and mother, the differentiation and functionality of the host cells. All this allows us to consider foreign cells as a potential target for drugs in the fight against autoimmune diseases or, conversely, stimulation of regeneration processes of damaged tissues. Issues of evolution and prospects for the prevention of various pathological conditions are considered from the standpoint of taking into account maternal and fetal chimerism syndrome.

Influence of manufacturing errors on the aerodynamic working stability of axial flow compressors

In turbomachinery, manufacturing errors in blades have been found to impact aerodynamic performance. This paper aims to investigate the effect of manufacturing errors on the stability of compressor operation. To this end, a geometric uncertainty reduced-order model is developed to generate the normal profile error of rotor blades based on specific tolerances, considering the simultaneous variation of blade parameters during manufacturing. The stability margin improvement of the compressor is then calculated using computational fluid dynamics (CFD), and a neural network is employed to predict the relationship between the uncertainty input variables and the stability margin improvement. Finally, a large number of samples are generated using the Quasi-Monte Carlo method, and Sobol sensitivity analysis is performed. According to the results, manufacturing errors can reduce the stability margin by an average of 0.9% and up to 3% in the limiting case. The parameters that have the greatest impact on the stability of the compressor are the blade chord length of the hub section and the maximum thickness of the tip section. These two parameters affect blade tip blockage by influencing spanwise secondary flow on the suction surface. Additionally, the decrease in maximum thickness at the tip section affects the separation of the boundary layers on the suction surface, resulting in additional effects.

Form Deviation Uncertainty and Conformity Assessment on a Coordinate Measuring Machine

Coordinate measuring machines are widely used in the industrial field due to their ease of automation. However, estimating the measurement uncertainty is a delicate task, especially when controlling for deviation, given the large number of factors that influence the measurement. A precise estimate of the uncertainty is crucial to avoid incorrect conformity assessments. The purpose of this study is to control geometrical-form tolerance specifications, taking into consideration their associated uncertainty. A surface fitting model based on the least squares criterion is proposed, allowing one to obtain the variance–covariance matrix by iterative calculation according to the Levenberg–Marquard optimization method. The form deviation is then evaluated following the Geometrical Product Specifications (GPS) Standard, and its associated uncertainty is estimated using the guide to the expression of uncertainty in measurement (GUM) propagation of the uncertainty law. Finally, the conformity assessment is performed based on the measured deviation and its associated uncertainty. Different results for the measurement of straightness, flatness, circularity, roundness, and cylindricity are presented and detailed. This model is thereafter validated by a Monte Carlo simulation, and interlaboratory comparisons of the obtained results were performed, which showed satisfactory outcome. This contribution is of great use to manufacturing companies and metrology laboratories, allowing them to meet the normative guidelines, which stipulates that each measurement result must be accompanied by its associated uncertainty.

Numerical investigation on machining of additively manufactured CFRP composite with different build orientations and layer widths

Additive manufacturing (AM) is now a widely researched manufacturing technology in the past two decades to adopt in industry for its added advantage of customization and adopting complex geometries with comparatively low buy-to-fly ratio. Carbon fiber reinforced polymer (CFRP) composite has found applications in different high-performance industries for its greatest benefit of high strength-to-weight ratio. Additive manufacturing of CFRP composite (AM-CFRP) opens up the possibility of enhancing mechanical strength using different printing orientations and enables producing complex shapes maintaining sustainable manufacturing perspective. However, Limitation of AM parts of having surface irregularities and questionable dimensional accuracies. To use AM-CFRP parts in high precision assembly or industrial applications, post processing machining is often required to meet the customers’ specification of geometrical tolerances and acceptable surface finish. In this study, the influence of AM parameters on machinability of AM-CFRP composite has been evaluated using finite element analysis (FEA) based numerical simulation. The slot milling operation was simulated with a tungsten carbide end milling tool and AM-CFRP workpiece with four different printing directions, i.e., 0°-90°, 45°-135°, 0°-90°-45°-135°, two different layer widths, i.e., 50 µm and 100 µm, and two in-fill patterns, i.e., solid and perforated structures. The machinability of the 3D printed CFRP has been analyzed based on cutting forces, stress at first contact and maximum stress generation, and temperature increases at the interface during slot milling of AM-CFRP under different AM parameters. Evolution of failure mechanisms of AM-CFRPs under various machining conditions, such as, delamination, matrix rupture etc., have been discussed and chip and burr formation mechanisms have been analyzed. Finite Element analysis (FEA) package ABAQUS/Explicit was used to model 3D micro slot milling operation of AM-CFRP workpiece with appropriate damage and constitutive models, such as, damage initiation, progression and cohesion in adjacent passes and layers.

Evaluation of diets from various maize hybrids reveals potential tolerance traits against Spodoptera littoralis (Boisd) as measured by developmental and digestive performance.

Spodoptera littoralis (Boisd) (Lepidoptera: Noctuidae) is a highly polyphagous insect that significantly reduces agricultural production of several food staples. We evaluated performance of S. littoralis on several meridic diets based on various maize hybrids, including Oteel, Simon, Valbum, SC703, and SC704. Growth, feeding behaviours, and activity of digestive enzymes of S. littoralis were examined under laboratory conditions. In addition, selected biochemical characteristics of maize hybrid seeds were evaluated, including starch, protein, anthocyanin, as well as phenolic and flavonoid contents, to examine relationships between plant properties and digestive performance of S. littoralis. Performance of S. littoralis on maize hybrids, as measured by nutritional indices, was related to both proteolytic and amylolytic activities quantified using gut extracts. Larval S. littoralis reared on SC703 exhibited the highest efficiency of conversion of digested food, while the lowest was recorded in those fed on the Oteel hybrid. S. littoralis reared on SC703 and Oteel also exhibited the highest and lowest relative growth rates, respectively. The highest levels of proteolytic activity in S. littoralis were measured from larvae reared on the SC703 hybrid, while the lowest levels occurred on the Oteel and Valbum hybrids. Amylolytic activity was lowest in larvae reared on SC703 and Valbum hybrids and highest in larvae reared on the Oteel hybrid. Our results suggest that the SC703 hybrid was the most suitable host for S. littoralis, while the Oteel hybrid demonstrated the greatest level of tolerance against S. littoralis of those evaluated. We discuss the potential utility of maize hybrids exhibiting tolerance traits against this cosmopolitan pest with reference to cultivation of tolerant varieties and identification of specific tolerance traits.

Cancer cell membrane-coated siRNA-Decorated Au/MnO2 nanosensitizers for synergistically enhanced radio-immunotherapy of breast cancer

Radiotherapy plays a critical role in the clinical treatment of breast cancer. However, the efficacy of traditional X-ray radiotherapy is greatly limited by its low tumor specificity and treatment tolerance mediated by the tumor microenvironment. Herein, we proposed a novel nano-radiotherapy sensitization strategy to design and construct a cancer cell membrane-coated siRNA-decorated Au/MnO2 nanosensitizer (R&F@Au/MnO2-CM) to synergistically enhance radio-immunotherapy for breast cancer. In the integrated nanosensitizer, the cancer cell membrane (CM) derived from 4T1 breast cancer cells is utilized for targeted functionality, while Au/MnO2 is designed to improve X-ray absorption and alleviate tumor hypoxia. Additionally, PD-L1 siRNA (R) is used to downregulate PD-L1 expression in tumor cells. In an in situ mouse model of 4T1 breast cancer, R&F@Au/MnO2-CM demonstrated accurate tumor identification via CM-mediated homologous targeting after intravenous injection, which was monitored in real-time through NIR-II fluorescence imaging of NIR-935 (F). Subsequently, the radiotherapy sensitivity was achieved due to the strong radiation absorption properties and oxygen generation through catalysis of Au/MnO2 upon X-ray irradiation. Furthermore, the immunosuppressive microenvironment of the tumor is improved by downregulating PD-L1, enhancing synergistic anti-tumor effect. Our findings demonstrate a promising approach for tumor treatment by combining targeted enhanced radiotherapy with immune activation.

Screening Wheat Genotypes for Specific Genes Linked to Drought Tolerance.

Drought stress, which significantly affects growth and reduces grain yield, is one of the main problems for wheat crops. Producing promising drought-tolerant wheat cultivars with high yields is one of the main targets for wheat breeders. In this study, a total of seven drought-tolerant wheat genotypes were screened for the presence of 19 specific drought tolerance genes. The genotypes were tested under normal and drought conditions for two growing seasons. Four spike traits, namely, spike length (SPL), grain number per spike (GNPS), number of spikelets per spike (NSPS), and grain yield per spike (GYPS), were scored. The results revealed that drought stress decreased the SPL, GNPS, NSPS, and GYPS, with ranges ranging from 2.14 (NSPS) to 13.92% (GNPS) and from 2.40 (NSPS) to 11.09% (GYPS) in the first and second seasons, respectively. ANOVA revealed high genetic variation among the genotypes for each trait under each treatment. According to the drought tolerance indices, Omara 007 presented the highest level of drought tolerance (average of sum ranks = 3), whereas both Giza-36 genotypes presented the lowest level of drought tolerance (average of sum ranks = 4.8) among the genotypes tested. Among the 19 genes tested, 11 were polymorphic among the selected genotypes. Omara 007 and Omara 002 presented the greatest number of specific drought tolerance genes (nine) tested in this study, whereas Sohag-5, Giza-36, and PI469072 presented the lowest number of drought tolerance genes (four). The number of different genes between each pair of genotypes was calculated. Seven different genes were found between Omara 007 and Giza-36, Omara 007 and Sohag-5, and Omara 002 and PI469072. The results of this study may help to identify the best genotypes for crossing candidate genotypes, and not merely to genetically improve drought tolerance in wheat.

Combined transcriptomics and metabolomics analysis reveals salinity stress specific signaling and tolerance responses in the seagrass Zostera japonica.

Multiple regulatory pathways of Zostera japonica to salt stress were identified through growth, physiological, transcriptomic and metabolomic analyses. Seagrasses are marine higher submerged plants that evolved from terrestrial monocotyledons and have fully adapted to the high saline seawater environment during the long evolutionary process. As one of the seagrasses growing in the intertidal zone, Zostera japonica not only has the ability to quickly adapt to short-term salt stress but can also survive at salinities ranging from the lower salinity of the Yellow River estuary to the higher salinity of the bay, making it a good natural model for studying the mechanism underlying the adaptation of plants to salt stress. In this work, we screened the growth, physiological, metabolomic, and transcriptomic changes of Z. japonica after a 5-day exposure to different salinities. We found that high salinity treatment impeded the growth of Z. japonica, hindered its photosynthesis, and elicited oxidative damage, while Z. japonica increased antioxidant enzyme activity. At the transcriptomic level, hypersaline stress greatly reduced the expression levels of photosynthesis-related genes while increasing the expression of genes associated with flavonoid biosynthesis. Meanwhile, the expression of candidate genes involved in ion transport and cell wall remodeling was dramatically changed under hypersaline stress. Moreover, transcription factors signaling pathways such as mitogen-activated protein kinase (MAPK) were also significantly influenced by salt stress. At the metabolomic level, Z. japonica displayed an accumulation of osmolytes and TCA mediators under hypersaline stress. In conclusion, our results revealed a complex regulatory mechanism in Z. japonica under salt stress, and the findings will provide important guidance for improving salt resistance in crops.

Immune modulation permits tolerance and engraftment in a murine model of late-gestation transplantation

AbstractIn utero hematopoietic cell transplantation is an experimental nonmyeloablative therapy with potential applications in hematologic disorders, including sickle cell disease (SCD). Its clinical utility has been limited due to the early acquisition of T-cell immunity beginning at ∼14 weeks gestation, posing significant technical challenges and excluding treatment fetuses evaluated after the first trimester. Using murine neonatal transplantation at 20 days postcoitum (DPC) as a model for late-gestation transplantation (LGT) in humans, we investigated whether immune modulation with anti-CD3 monoclonal antibody (mAb) could achieve donor-specific tolerance and sustained allogeneic engraftment comparable with that of the early-gestation fetal recipient at 14 DPC. In allogeneic wild-type strain combinations, administration of anti-CD3 mAb with transplantation resulted in transient T-cell depletion followed by central tolerance induction confirmed by donor–specific clonal deletion and skin graft tolerance. Normal immune responses to third-party major histocompatibility complex and viral pathogens were preserved, and graft-versus-host disease did not occur. We further demonstrated the successful application of this approach in the Townes mouse model of SCD. These findings confirm the developing fetal T-cell response as a barrier to LGT and support transient T-cell depletion as a safe and effective immunomodulatory strategy to overcome it.

A comparative study on cadmium tolerance and applicability of two Solanum lycopersicum L. cultivars.

Solanum lycopersicum L. can be classified into low Cd-accumulating and high Cd-accumulating types based on their accumulation characteristics of cadmium (Cd). There are many common S. lycopersicum varieties available in the market, but their specific Cd tolerance and enrichment abilities are not well understood. This article uses two S. lycopersicum cultivars, Yellow Cherry and Yellow Pearl, as experimental materials. The experimental method of soil pot planting was adopted, and Cd concentrations in the soil were added at 0, 0.6, 1.5, 2.5, 5, and 10 mg/kg. The changes in Cd content, biomass, photosynthetic pigment content, and photosynthetic parameters of the two S. lycopersicum cultivars were analyzed to screen for low-accumulation S. lycopersicum cultivars. The results showed that S. lycopersicum are Cd-sensitive plants. The Cd accumulation, photosynthetic parameters, and other basic indicators of Yellow Cherry basically showed significant differences when the soil Cd concentration was 0.6 mg/kg, and the biomass showed significant differences when the soil Cd concentration was 1.5 mg/kg. Except for the Cd accumulation in the roots and leaves of Yellow Pearl, which showed significant differences at a soil Cd concentration of 0.6 mg/kg, the other indicators basically showed significant differences when the soil Cd concentration was 1.5 mg/kg. When the soil Cd concentration was 0.6 mg/kg, the Cd accumulation in the fruit of Yellow Pearl was 0.04 mg/kg, making it a low-accumulation S. lycopersicum variety suitable for promoting cultivation in Cd-contaminated soil at 0.6 mg/kg. In conclusion, the Cd accumulation in the fruit of Yellow Pearl is significantly lower than that of Yellow Cherry and even below the Cd limit value for fresh vegetables specified in GB2762-2017. Therefore, Yellow Pearl can be grown as edible crops in soils with Cd concentrations ≤0.6 mg/kg. Furthermore, Yellow Cherry demonstrate strong Cd tolerance and can be used for the remediation of Cd-contaminated soils.

Comparative analysis of <i>cis</i>-regulatory elements associated with salinity and drought tolerance in rice (<i>oryza sativa l.</i>) using <i>in silico</i> analysis

The critical roles of cis-regulatory elements (cREs) in the regulation of gene expression in response to environmental stress were reported in previous studies. Although transcription factor families to regulate gene expression in plants are well documented, there is a limited number of cREs related to salinity and drought tolerance in rice to be identified. Therefore, in this study, a comparative analysis and characterization of cREs associated with specific drought and salinity tolerance genes of rice, namely OsNHX1, OsNHX5, OsHKT1;1, OsHKT2;1, and OsSOS1, was performed using the PLACE and PlantPAN 3.0 databases, along with in silico methods. Several cis-elements within the core promoter region, including TATA-box, CAAT-box, G-box, DPE, and Y-Patch were identified. Additionally, eight other cis elements: ABRE, MYBRS, MYCRS, NAC-binding site, ACGTATERD1, GT1GMSCAM4, W-box, and DRE, were discovered and suggested to be potentially involved in drought and salinity tolerance in rice. Comparative analysis revealed that OsNHX1 and OsHKT1;1 exhibit a higher abundance of cREs compared to the other genes studied. The presence of an increased number of cREs suggests a more complex regulatory network, potentially enhancing the ability of these genes to cope with environmental stressors and fine-tune their responses to changing conditions. Furthermore, understanding the distribution and diversity of cREs across different genes can offer practical implications for genetic engineering and crop improvement strategies. Genes with desirable regulatory profiles, especially those associated with specific stress tolerances, may be prime candidates for genetic manipulation.

The effects of high-intensity physical exercise on the achievement of a 1,500-meter man running competition, maximal heart rate, and the development of personal tolerance

Creating high-density workouts and determining how they affect the development of specific tolerance, maximum heart rate, and success in the 1,500-meter man run competition are the goals of the research. Therefore, the development of high-density physical exercises that arise during the run-off as a consequence of ongoing training and the utilization of exercise quality that satisfies the requirements of the 1,500-meter run-off competition are the primary goals of the research. Research is beset by a shortcoming in the competition's ability to achieve its unique tolerance and accomplishment skills, The 1,500-meter race amongst the elite men of the Iraqi Union of Forces for the Open Ages over 20 years of the 2023 sports season has been designated for the research community. The sample was split up by the 12 players into the six players, the command group, and the two pilot groups. The researchers came to the conclusion that men's 1,500-meter run competition achievement, maximum heart rate, and the development of special tolerance were all positively impacted by high-density physical training. In order to establish a unique tolerance for other competitions, the researchers advised high-density physical training. They also suggested conducting similar experiments and research in various age groups.

Impact of antigen loading in tolerogenic nanoparticles to mitigate Th2-mediated allergic lung inflammation.

Allergic disease is a major global health concern that imposes significant life-altering and economic burdens on affected individuals. However, there is still no cure. Polymer-based nanoparticles (NP) have shown the potential to induce antigen (Ag)-specific immune tolerance in various Th1/17 and Th2-mediated immune disorders including autoimmunity and allergy. Common methods by which Ags are associated with NPs are through surface conjugation or encapsulation. However, these Ag delivery strategies can be associated with several caveats that dampen their effectiveness such as uncontrolled Ag loading, a high Ag burst release, and an increased immune recognition profile. We previously developed Ag-polymer conjugate NPs (acNPs) to overcome those noted limitations, while allowing for controlled delivery of precise quantities of Ag to innate immune cells for Ag-specific CD4 T cell modulation. Here, we utilized ovalbumin (OVA) protein-poly(lactic-co-glycolic acid) (PLGA) conjugate NPs (acNP-OVA) to elucidate the impact of Ag loading on the induction of Th2 tolerance using a prophylactic and therapeutic OVA/ALUM-induced mouse model of allergic lung inflammation (ALI) in comparison to Ag-encapsulated PLGA NPs (NP(Ag)). We demonstrate that acNP-OVA formulations reduced OVA-specific IgE and inhibited Th2 cytokine secretions in an Ag loading-dependent manner when administered prophylactically. Administration of acNP-OVA to pre-sensitized mice did not affect OVA-specific IgE and Th2 cytokines tended to be reduced, however, there was no clear Ag loading dependency. acNP-OVA with medium-to-low Ag loadings were well tolerated, while formulations with high Ag loadings, including NP(Ag) resulted in anaphylaxis. Overall, our results clarify the relationship between Ag loading and Ag-specific IgE and Th2 cytokine responses in a murine model of ALI, which provides insight useful for future design of tolerogenic NP-based immunotherapies.

Perspective on Agricultural Industrialization: Modification Strategies for Enhancing the Catalytic Capacity of Keratinase.

Keratinases is a special hydrolytic enzyme produced by microorganisms, which has the ability to catalyze the degradation of keratin. Currently, keratinases show great potential for application in many agricultural and industrial fields, such as biofermented feed, leather tanning, hair removal, and fertilizer production. However, these potentials have not yet been fully unleashed on an industrial scale. This paper reviews the sources, properties, and catalytic mechanisms of keratinases. Strategies for the molecular modification of keratinases are summarized and discussed in terms of improving the substrate specificity, thermostability, and pH tolerance of keratinases. The modification strategies are also enriched by the introduction of immobilized enzymes and directed evolution. In addition, the selection of modification strategies when facing specific industrial applications is discussed and prospects are provided. We believe that this review serves as a reference for the future quest to extend the application of keratinases from the laboratory to industry.

FOLFOX as a therapeutic option in patients with hepatic failure due to liver metastasis of gastrointestinal (GI) system malignancies: A case series.

e16378 Background: The treatment options for patients with hepatic metastasis presenting with liver dysfunction, particularly those experiencing severe hyperbilirubinemia, are limited. The oxaliplatin and fluorouracil/folinic acid regimen, known as FOLFOX, stands out as a viable option based on its pharmacokinetics. However, clinical data regarding the specific dosage and tolerability of this regimen are limited, and clear recommendations are not currently available. Patients and Methods: Patients who presented with severe hyperbilirubinemia immediately after the diagnosis of GI adeno cancer, and who were not eligible for drainage options, were prospectively observed in our clinic in Turkey throughout the year 2023. Severe hyperbilirubinemia was defined as a bilirubin level > 5mg/dL. The FOLFOX regimen was administered every two weeks, and the fluorouracil dose was initially reduced by 50% for the first two cycles. Subsequently, the dose was increased to the total amount if no toxicity occurred. Results: Six cases of GI cancer patients meeting the criteria were identified. Subsequent laboratory data for these six patients were collected after initiating the FOLFOX regimen. All six patients underwent the FOLFOX regimen with dose reduction for the first two cycles. Following the first cycle of chemotherapy, bilirubin levels dropped and normalized (Table 1), leading to an improvement in the patients' clinical condition. Conclusions: While our series is limited by a small number of patients, treatment with FOLFOX has proven to be feasible and may yield significant benefits in patients with severe liver dysfunction caused by GI cancer, especially when no further drainage options are available. [Table: see text]