GNUV201, a novel human/mouse cross-reactive and low pH-selective anti-PD-1 monoclonal antibody for cancer immunotherapy.

BACKGROUND: Several PD-1 antibodies approved as anti-cancer therapies work by blocking the interaction of PD-1 with its ligand PD-L1, thus restoring anti-cancer T cell activities. These PD-1 antibodies lack inter-species cross-reactivity, necessitating surrogate antibodies for preclinical studies, which may limit the predictability and translatability of the studies. RESULTS: To overcome this limitation, we have developed an inter-species cross-reactive PD-1 antibody, GNUV201, by utilizing an enhanced diversity mouse platform (SHINE MOUSE™). GNUV201 equally binds to human PD-1 and mouse PD-1, equally inhibits the binding of human PD-1/PD-L1 and mouse PD-1/PD-L1, and effectively suppresses tumor growth in syngeneic mouse models. The epitope of GNUV201 mapped to the "FG loop" of hPD-1, distinct from those of Keytruda® ("C'D loop") and Opdivo® (N-term). Notably, the structural feature where the protruding epitope loop fits into GNUV201's binding pocket supports the enhanced binding affinity due to slower dissociation (8.7 times slower than Keytruda®). Furthermore, GNUV201 shows a stronger binding affinity at pH 6.0 (5.6 times strong than at pH 7.4), which mimics the hypoxic and acidic tumor microenvironment (TME). This phenomenon is not observed with marketed antibodies (Keytruda®, Opdivo®), implying that GNUV201 achieves more selective binding to and better occupancy on PD-1 in the TME. CONCLUSIONS: In summary, GNUV201 exhibited enhanced affinity for PD-1 with slow dissociation and preferential binding in TME-mimicking low pH. Human/monkey/mouse inter-species cross-reactivity of GNUV201 could enable more predictable and translatable efficacy and toxicity preclinical studies. These results suggest that GNUV201 could be an ideal antibody candidate for anti-cancer drug development.

Effect of 3D-printed polycaprolactone/osteolectin scaffolds on the odontogenic differentiation of human dental pulp cells.

Cell-based tissue engineering often requires the use of scaffolds to provide a 3-dimensional (3D) framework for cell proliferation and tissue formation. Polycaprolactone (PCL), a type of polymer, has good printability, favorable surface modifiability, adaptability, and biodegradability. However, its large-scale applicability is hindered by its hydrophobic nature, which affects biological properties. Composite materials can be created by adding bioactive materials to the polymer to improve the properties of PCL scaffolds (PSs). Osteolectin is an odontogenic factor that promotes the maintenance of the adult skeleton by promoting the differentiation of LepR+ cells into osteoblasts. Therefore, the aim of this study was to evaluate whether 3D-printed PCL/osteolectin scaffolds supply a suitable microenvironment for the odontogenic differentiation of human dental pulp cells (hDPCs). The hDPCs were cultured on 3D-printed PSs with or without pores. Cell attachment and cell proliferation were evaluated using EZ-Cytox. The odontogenic differentiation of hDPCs was evaluated by alizarin red S staining and alkaline phosphatase assays. Western blotting was used to evaluate the expression of the proteins DSPP and DMP-Results: The attachment of hDPCs to PSs with pores was significantly higher than to PSs without pores. The odontogenic differentiation of hDPCs was induced more in PCL/osteolectin scaffolds than in PSs, but there was no statistically significant difference. 3D-printed PSs with pores are suitable for the growth of hDPCs, and the PCL/osteolectin scaffolds can provide a more favorable microenvironment for the odontogenic differentiation of hDPCs. .

Factors influencing baby boomers' intention to choose a dish featuring plant-based meat alternatives (PBMA) at a restaurant: Findings from an online panel study.

The purpose of this study is to examine the psychosocial determinants of baby boomers'-born between 1946 and 1964- intention to choose a menu item featuring plant-based meat alternatives (PBMA) when dining out. The specific objectives are as follows: 1) to identify the baby boomer generation's health-related perceptions about PBMA, and 2) to examine the factors that influence baby boomers' intention to choose a dish featuring PBMA at a restaurant. A total of 174 responses obtained using the Qualtrics panel were analyzed with content analysis and partial least squares structural equation modeling (PLS-SEM). The findings identified various underlying perceptions of baby boomers toward PBMA, such as perceived health outcomes, perceived availability, and willingness to purchase. Furthermore, subjective norm, cues to action, and self-identity were found to be significant predictors of the intention to choose a menu item featuring PBMA when dining out. Theoretical and practical implications are discussed.

Evidence of parental transfer of nanoplastics in pea (Pisum sativum) plants.

The increasing abundance of nanoplastics in the environment is a cause of serious concern and its acute and chronic effects on ecosystems need to be thoroughly investigated. Toward this end, this study investigated the parental transfer of nanoplastics by chronically exposing Pisum sativum (pea) plants to nanoplastics through soil medium. We observed the presence of nanoplastics in harvested fruits and a subsequent generation of plants replanted in uncontaminated soil using confocal laser scanning microscopy. The fluorescence was located in the cell wall of the vascular bundles, but not in the epidermis, indicating the parental transfer of nanoplastics. In addition, we determined the effects of nanoplastics on the health of subsequent plant generations by estimating the reproductive factors and measuring the content of individual nutrients in peas. Decreases in crop yield and fruit biomass, in addition to changes in nutrient content and composition, were noted. The transgenerational effects of nanoplastics on plants can profoundly impact terrestrial ecosystems, including both plant species and their predators, raising critical safety concerns. Our findings highlight the evidence of parental transfer of nanoplastics in the soil through plants and shows that the chronic effects of nanoplastics on plants may pose a threat to the food supply.

Microplastic ingestion in aquatic and soil biota: A comprehensive review of laboratory studies on edible size and intake pattern.

Microplastic contamination is ubiquitous and can be transferred through the food chain to humans. However, studies on microplastic size have mainly focused on large animals with a body length >20 mm. To address this gap, we conducted a comprehensive review of 169 laboratory studies to determine the edible size of microplastics for macrofauna and flora in aquatic and soil biota. Our findings indicate that microplastics with a size of <300 µm and 1 µm, respectively, are edible for these organisms, which are positioned at the base of the food chain. We also analyzed intake and depuration patterns and identified factors affecting microplastic ingestion. Our study fills an important knowledge gap by identifying the range of microplastic sizes that can enter the food chain and be transferred to humans. The study findings have strong implications for the ecological risk assessment of microplastics and suggest a starting point for mitigating this threat.

Chemical toxicity screening of tire particle leachates from vehicles and their effects on organisms across three trophic levels.

Tire particles (TPs) generated on roads are a main contributor to microplastic environmental pollution. In this study, TP leachates from three vehicle types (bicycle, car, and electric scooter) were prepared. TP leachate toxicity impacts on three organisms (Vigna radiata, Daphnia magna, and Danio rerio) were analyzed, in addition to their chemical compositions. Zinc and benzothiazole were the most commonly detected compounds in all three leachate types. Growth inhibition of V. radiata, mortality of D. magna, and abnormality in D. rerio were observed as toxicological impacts. Overall, the lethal effects of TP leachates showed a significant, positive relationship with zinc and benzothiazole concentration. The results confirmed that TPs are complex contaminants, which release chemicals into the environment that affect both soil and aquatic organisms. These findings highlight the need for stricter control measures and environmental regulations to mitigate the ecotoxic effects of TPs and related contaminants across ecosystems and trophic levels.

Microplastics enhance the toxicity and phototoxicity of UV filter avobenzone on Daphnia magna.

Microplastics (MPs) and ultraviolet (UV) filters cause pollution in aquatic ecosystems. Moreover, regulations on the use and discharge of UV filters in personal care products are lacking. Therefore, the combined toxicity of MPs (virgin polystyrene (PS) spheres; size: 200 nm) and avobenzone (AVO; a UV filter) on Daphnia magna were assessed. The exposure groups were AVO, AVO + UV irradiation for 6 h [AVO (UV)], AVO with MPs (Mix), and AVO with MPs + UV irradiation for 6 h [Mix (UV)]. The daphnids were exposed to these treatments for 48 h and observed for an additional 6 h. Energy reserves of all treated groups increased compared to that of the control group. Growth in the Mix group was inhibited despite a high food uptake, and food uptake and growth inhibition were validated in the Mix (UV) group. Additionally, the food uptake of the AVO (UV) and Mix (UV) groups decreased during the recovery period, possibly owing to a decrease in the normal feeding ability resulting from an increase in abnormality. These results indicate that the combined toxicity of MPs+AVO can be exacerbated under natural conditions; the complex toxicity should be considered when assessing aquatic environment pollution.

Species sensitivity distributions of micro- and nanoplastics in soil based on particle characteristics.

Micro- and nanoplastics are released into the soil through various anthropogenic activities; however, research on ecological risk assessment (ERA) of soil microplastics is limited. In this study, the species sensitivity distributions (SSDs) of representative groups of soil biota were analyzed to determine their sensitivity to microplastic properties. A total of 411 datasets from apical endpoint data within 74 studies were classified and utilized in SSD estimation. The hazardous concentrations for 5% of species for microplastics was 88.18 (40.71-191.00) mg/kg soil. It has been established that small-sized microplastics are more toxic to soil organisms than larger microplastics. Most microplastics were spherical and polystyrene, exhibiting the most adverse effects among all the microplastic types assessed herein. The results suggest that physical characteristics of microplastics are important toxicity determinants in soil ecosystems. Given the potential for adverse environmental effects, further effective management strategies should urgently be employed in these areas. This study provided an integrated perspective of microplastic ecotoxicity in soil. In addition, SSDs were estimated using larger datasets and for more species than in previous studies. This is the first study to consider microplastic properties for estimating SSD.

Toxicity assessment of tire particles released from personal mobilities (bicycles, cars, and electric scooters) on soil organisms.

Tire particles are generated by the abrasion of tire treads on roads and are major contributors to microplastics in soil environments. Contamination by tire wear particles worsens annually as the use of personal mobilities increases. Tire particles (112-541 µm) were obtained from three types of personal mobility tires (bicycle, car, and electric scooter) and exposed to plants (Vigna radiata) and springtails (Folsomia candida) for 28 d to assess the toxicity of each tire-particle type. The laboratory-generated tire particles exhibit adverse effects depending on the origin of the tire or test species. Particles from bicycle or electric-scooter tires changed the soil's bulk density and water holding capacity and adversely affected plant growth. Car tire particles had leached various organic compounds and induced detrimental effects on springtails (adult and offspring growth). We concluded that laboratory-generated tire particles (frow new tires) can affect the soil environment by changing soil properties and leaching chemicals; thus, causing adverse effects on soil organisms. Since this study found tire particle toxicity on soil organisms, it would be possible to compare the various contamination levels in areas near road soil and other clean soils.

Earthworm half-pipe assay: A new alternative in vivo skin corrosion test using invertebrates.

As a result of the efforts to introduce the principle of the 3Rs (replacement, reduction, and refinement) into animal testing, alternative in vitro skin corrosion test methods have been developed and standardized globally. However, alternative in vitro skin corrosion test methods have some limitations in terms of the use of humanely killed rats or commercial models and kits. The present study focused on the applicability of invertebrates as alternative in vivo skin models. Even though earthworm skin comprises the same biomolecules as human skin, the possibility of using earthworm skin as an alternative for skin testing remains unexplored. In this study, we developed a half-pipe tool for earthworm skin corrosion testing and optimized the test protocol. Subsequently, the applicability of the earthworm half-pipe assay for corrosion testing with six chemicals, including inorganic acids, organic acids, and alkalis, was investigated using stereomicroscopy and electron microscopy. It was observed that the specific concentrations for earthworm skin corrosion were lower than those for animal or in vitro tests. Therefore, the sensitivity of the earthworm half-pipe assay indicates that it could be useful as a screening tool before conducting in vivo animal tests or in vitro skin tests. This new method can contribute to research on alternative skin corrosion tests by reducing ethical issues, time, and cost while achieving effective results.

Are your shoes safe for the environment? - Toxicity screening of leachates from microplastic fragments of shoe soles using freshwater organisms.

This study investigated the toxic effects of leachates from microplastic fragments of soles from four different types of shoes (slippers, trekking shoes, running shoes, and sneakers) on three aquatic organisms (Chlamydomonas reinhardtii, Daphnia magna, and Danio rerio). The chemical components in each leachate were identified; furthermore, chlorophyll a contents of C. reinhardtii were measured, and immobilization of D. magna and deformities in D. rerio were observed. The abnormalities observed in the test species exposed to the leachates were compared and chemical compounds majorly influencing the species were determined by principal component analysis (PCA). Sneaker leachate showed growth inhibitions in C. reinhardtii, immobility and mortality in D. magna, and severe abnormalities in D. rerio. Consequently, aquatic toxicity was majorly associated with benzothiazole, carbon disulfide, ethyl acetate, and p-xylene. The results showed that toxic chemicals could leach from load-originated microplastics when exposed to aquatic media, and consequently, induce significant negative effects on aquatic organisms. Since microplastics from shoe soles discharge the above-mentioned toxic chemicals, regulating the chemical use during plastic production is critical to prevent severe effects of microplastic toxicity in aquatic organisms, and to maintain the health of aquatic environments.

Effects of synthetic and natural microfibers on Daphnia magna-Are they dependent on microfiber type?

Microfibers, which are sourced from textiles and some products from the fishery industry, are the biggest contributors to microplastic pollution in aquatic ecosystems. In addition to these synthetic microfibers, naturally derived microfibers can also be found in aquatic environments. However, there are limited studies on the ecotoxicity of natural microfibers. To shed light on this topic, this study assessed and compared the toxicity of natural and synthetic microfibers on Daphnia magna, using lyocell, polyester (PET) and polypropylene (PP) microfibers. To evaluate the adverse effect of microfibers on D. magna, after effects including depuration, food intake, growth, mortality, and immobilization rate were continually observed for up to 96 h after the initial 48 h of exposure to the microfibers. Immobilization rate decreased in the following order: PP, PET, and lyocell. However, the depuration of microfibers in the lyocell and PET treatment groups was similar, with higher mortality rates than in the PP treatment group. Furthermore, despite the high rates of food intake following exposure, the lyocell and PET exposed groups exhibited growth inhibition during the same period. This growth inhibition corresponded with, and was likely due to, reductions in the length of gut microvilli, probably an expression of gut damage, which is believed to have reduced nutrient absorption in the affected individuals. Based on the results of this study, it was confirmed that even natural microfibers, and not just synthetic microfibers, can have adverse effects on aquatic organisms. This study confirmed not only the toxicity of microfibers, but also the consequences of their after effects. These results could be the basis for future research on the after effects of microplastics on aquatic organisms and provide directions for further microplastic ecotoxicity studies.

CEO letters: Hospitality corporate narratives during the COVID-19 pandemic.

For hospitality organizations, the need for compelling corporate narratives is particularly acute in dealing with the COVID-19 crisis due to the scope and severity of its threat to employees, customers, the general public, and the fundamental survival of the company itself. Thus, this study aims to identify corporate narrative strategies and examine how hospitality companies deploy such narrative strategies with impression management tactics during the COVID-19 pandemic. Anchored in the Aristotelian concept of persuasive rhetoric and impression management theory, this study content-analyzed 57 CEO letters published by hospitality companies during the COVID-19 outbreak and found the prevalent rhetoric appeals and patterns of rhetoric appeals with impression management tactics embedded in the letters.

Physical Therapy for Chronic Pain Mitigation and Opioid Use Reduction Among People Living with Human Immunodeficiency Virus in Atlanta, GA: A Descriptive Case Series.

People living with HIV (PLH) may be at increased risk of experiencing both chronic pain and opioid dependence. Physical therapy (PT) has been shown to be effective as a nonpharmacological strategy for mitigating chronic pain in the general population, however, there is gap in research investigating PT to reduce chronic pain and opioid use among PLH. This case series describes the feasibility of an innovative PT intervention to decrease chronic pain and opioid use at a multidisciplinary human immunodeficiency virus (HIV) clinic. Participants (n = 4) were evaluated and given an individualized PT "package" consisting of manual therapy, exercise prescription, Transcutaneous Electrical Nerve Stimulation, and pain coping strategies. Pre- and postintervention outcomes were measured for pain reports, opioid use, and quality-of-life measures. After the intervention, all participants reported decrease or total elimination of both pain measured on the 0-10 numerical rating scale and opioid use measured in morphine milligram equivalents (MME). A paired t-test showed a significant difference (<.05) in the preintervention and postintervention pain scores and MME values. Results of this case series suggest in this sample that the described PT intervention is a feasible approach to mitigating chronic pain and opioid use among PLH and should be implemented on a larger scale for maximal effect.

Nuclear Expression of GS28 Protein: A Novel Biomarker that Predicts Worse Prognosis in Cervical Cancers.

OBJECTIVE: The protein GS28 (28-kDa Golgi SNARE protein) has been described as a SNARE (Soluble N-ethylmaleimide-sensitive factor attachment protein receptors) protein family member that plays a critical role in mammalian ER-Golgi or intra-Golgi vesicle transport. Little is known about the possible roles of GS28 in pathological conditions. The purpose of this study was to evaluate GS28 expression in cervical cancer tissues and explore its correlation with clinicopathological features and prognosis. METHODS: We investigated GS28 expression in 177 cervical cancer tissues by using immunohistochemistry and evaluated the correlation of GS28 expression with clinicopathological features, the expression of p53 and Bcl-2, and prognosis of cervical cancer patients. Immunoblotting was performed using six freshly frozen cervical cancer tissues to confirm the subcellular localization of GS28. RESULTS: Immunoreactivity of GS28 was observed in both nuclear and cytoplasmic compartments of cervical cancer cells. High nuclear expression of GS28 was associated with advanced tumor stages (P = 0.036) and negative expression of p53 (P = 0.036). In multivariate analyses, patients with high nuclear expression of GS28 showed significantly worse overall survival (OS) (hazard ratio = 3.785, P = 0.003) and progression-free survival (PFS) (hazard ratio = 3.019, P = 0.008), compared to those with low or no nuclear expression. It was also a reliable, independent prognostic marker in subgroups of patients with early stage T1 and negative lymph node metastasis in OS (P = 0.008 and 0.019, respectively). The nuclear expression of GS28 was confirmed by immunoblotting. CONCLUSION: High nuclear expression of GS28 is associated with poor prognosis in early-stage cervical cancer patients. GS28 might be a novel prognostic marker and a potential therapeutic target in cervical cancer treatment.

Obox4 regulates the expression of histone family genes and promotes differentiation of mouse embryonic stem cells.

Obox genes are preferentially expressed in the ovary, testis and oocyte, and play important roles in many developmental processes. In this study, we report that Obox4 and Obox6 are expressed in mouse embryonic stem cells (mESCs) and that Obox4 regulates histone family gene expression in mESCs. Obox4 protein expressing mESCs formed colonies with a flattened and irregular morphology, and exhibited decreased expression levels of self-renewal related proteins, such as Oct4 and Sox2, as well as reduced alkaline phosphatase activity. The results of microarray analysis and siRNA mediated knockdown experiments suggest that Obox4 is an upstream regulator of the histone gene family.

Structural basis for the specialization of Nur, a nickel-specific Fur homolog, in metal sensing and DNA recognition.

Nur, a member of the Fur family, is a nickel-responsive transcription factor that controls nickel homeostasis and anti-oxidative response in Streptomyces coelicolor. Here we report the 2.4-A resolution crystal structure of Nur. It contains a unique nickel-specific metal site in addition to a nonspecific common metal site. The identification of the 6-5-6 motif of the Nur recognition box and a Nur/DNA complex model reveals that Nur mainly interacts with terminal bases of the palindrome on complex formation. This contrasts with more distributed contacts between Fur and the n-1-n type of the Fur-binding motif. The disparity between Nur and Fur in the conformation of the S1-S2 sheet in the DNA-binding domain can explain their different DNA-recognition patterns. Furthermore, the fact that the specificity of Nur in metal sensing and DNA recognition is conferred by the specific metal site suggests that its introduction drives the evolution of Nur orthologs in the Fur family.