Early Stages Of Development Research Articles

Loss-of-function mutation in anthocyanidin reductase activates the anthocyanin synthesis pathway in strawberry

Fruit color substantially affects consumer preferences, with darker red strawberries being economically more valuable due to their higher anthocyanin content. However, the molecular basis for the dark red coloration remains unclear. Through screening of an ethyl methanesulfonate mutant library, we identified a rg418 mutant, that demonstrated anthocyanin accumulation during early fruit development stages. Furthermore, the ripening fruits of this mutant had higher anthocyanin content than wild-type (WT) fruits. An analysis of flavonoid content in WT and rg418 mutant fruits revealed substantial changes in metabolic fluxes, with the mutant exhibiting increased levels of anthocyanins and flavonols and decreased levels of proanthocyanidins. Bulked sergeant analysis sequencing indicated that the mutant gene was anthocyanidin reductase (ANR), a key gene in the proanthocyanidin synthesis pathway. Furthermore, transcriptome sequencing revealed the increased expression of MYB105 during the early development stage of mutant fruits, which promoted the expression of UFGT (UDP-glucose flavonoid 3-O-glucosyltransferase), a key gene involved in anthocyanin synthesis, thus substantially enhancing the anthocyanin content in the mutant fruits. Additionally, mutating ANR in a white-fruited strawberry variant (myb10 mutant) resulted in appealing pink-colored fruits, suggesting the diverse roles of ANR in fruit color regulation. Our study provides valuable theoretical insights for improving strawberry fruit color.

169 Vitamin and mineral supplementation to gestating beef heifers: Fetal physiology and metabolic programming

Abstract Vitamins and minerals have key roles in hormone production and action, enzyme activity, tissue synthesis, oxygen transport, and energy production. These micronutrients are efficiently transferred from the dam to the fetus during gestation to be partitioned for metabolic use and stored as postnatal mineral reserves. Maternal nutrient intake is one of the main factors that influence the availability of vitamins and minerals to the fetus. Thus, an inadequate supply of these critical nutrients can have a long-lasting impact on offspring growth and health. Evidence suggests that biological processes regulating normal growth, development, and nutrient utilization are programmed in utero, even during the earliest developmental stages. Therefore, there is a critical need to evaluate the effects of micronutrient supplementation during gestation on fetal physiology and metabolic programming. Our research group has developed research models examining the impact of maternal vitamin and mineral supplementation (VTM, supplemented vs. NoVTM, not supplemented) during the periconceptual period or throughout gestation in beef heifers. A metabolomic analysis revealed that metabolites in the oxidative phosphorylation pathway were more abundant in the liver of fetuses from VTM than NoVTM dams, suggesting that a greater supply of micronutrients during the periconceptual period and first trimester of pregnancy may positively modulate mitochondrial energy metabolism in offspring. These changes in the abundance of metabolites suggested physiological adaptations to meet fetal metabolic needs. Further, high-resolution respirometry analysis revealed greater efficiency of energy utilization in small intestinal samples of neonatal calves from VTM dams. In fact, VTM offspring were heavier from weaning to breeding phase than NoVTM offspring, suggesting that maternal nutrition affects physiological mechanisms in utero that modulate offspring energetics and efficiency of nutrient utilization in the postnatal period. Furthermore, we reported increased concentrations of histidine, aspartate, and 12 out of 14 neutral amino acids in the allantoic fluid of VTM-supplemented dams. Finally, genes involved with amino acid transport in fetal liver were upregulated in response to VTM supplementation, highlighting the intricate relationship between maternal and fetal nutrition. Vitamin and mineral supplementation were also associated with changes in gene expression, biological processes and pathways in placental tissue at d 83 of gestation. We observed an upregulation of genes in the calcium signaling and cyclic guanosine monophosphate (CGMP)-PKG signaling pathways in response to micronutrient supplementation. Calcium-mediated systems may modulate cell proliferation and steroidogenic activity in bovine placentomes, while CGMP-PKG plays a key role in vascular homeostasis. Placental blood vessel vascularity at term was indeed increased in heifers supplemented throughout gestation, emphasizing the importance of micronutrient supplementation beyond early pregnancy. Altogether, our findings suggest that vitamin and mineral supplementation in the periconceptual period and during gestation play a pivotal role in fetal metabolic programming with consequences extending to the postnatal period.

Analysis of the spatio-temporal distribution of Chinese professional football clubs and influential factors based on empirical evidence of clubs

The frequent relocation of professional football clubs is a phenomenon unique to Chinese professional football, which has long attracted extensive attention from policy makers and scholars. Using data on spatial geography and competitive levels between 1994 and 2021, this research explores the spatial distribution and migration characteristics of top professional football clubs in China, in which GIS spatial analysis and exploratory spatial data analysis (ESDA) were used to analyze the influence of the regional economic, demographic, and developmental levels of the sports industry and institutional supply on the distribution and migration of clubs. The results indicate the following: (1) the overall spatial distribution of professional football clubs in China shows the pattern of “more in the east and less in the west”, and the degree of club concentration gradually increases over time; (2) the migration frequency and downward migration of professional football clubs in China gradually decreased during the period of C League and CSL, and the overall situation tends to be stable; and (3) in the early stages of development of professional leagues, changes in ownership and local policy supply had a significant impact on the distribution and migration of professional clubs. As time progressed, the top-down design of institutional arrangements changed, and the regional economic, demographic, and developmental levels of the sports industry gradually became the essential determinants of the distribution and migration of professional football clubs. In the future, Chinese professional football clubs should focus on rationalizing the advantages of the regional economy, demography, and sports industry as well as reducing their reliance on short-term resources, such as corporate investment and policy benefits.

Effects of anti-rainbow trout germ-cell monoclonal antibody on germ cells and gonadal tissues in rainbow trout (Oncorhynchus mykiss)

The development of sterilization technology is important to improve the production efficacy of aquaculture and prevent genetically modified fish from escaping. Immunosterilization is a novel sterilization method that has already been used in mammals. In this study, anti-rainbow trout germ-cell monoclonal antibodies (anti-GC mAbs) were injected into immature rainbow trout Oncorhynchus mykiss, and their effects were analyzed. First, anti-GC mAbs labeled with Alexa Fluor 488 were injected into the body cavity of larvae 20 days (group 1) and 102 days (group 2) after fertilization. Second, anti-GC mAbs were injected into the body cavity of yearling trout (group 3), and their impacts on gonadal tissue were analyzed in terms of histology and gene expression levels. As a result, anti-GC mAbs were observed to bind to some primordial GCs in group 1, whereas there were no obvious positive cells in male testes of group 2. In contrast, green fluorescent signals were observed in an arrangement parallel to the ovarian lamina in female ovaries of group 2, which was similar to the arrangement of positive signals on ovarian tissue sections immunostained with anti-GC mAbs. GCs in group 1 were observed again after 76 days, and double-positive cells remained. In group 3, there were changes in the expression levels of GC-specific genes, but the changes were not seen as biologically meaningful. Moreover, there was no histological abnormality in gonadal tissues after immunization. In conclusion, these results suggested that anti-GC mAbs could only reach GCs in early developmental stages or in the ovary, and injection of anti-GCs mAbs did not have harmful effects on GCs after binding.

Ocean acidification will not affect the shell strength of juveniles of the commercial clam species Chamelea gallina: Implications of the local alkalinization of seawater

Ocean acidification (OA) is expected to decrease the strength of bivalves’ shells, especially during the early stages of development, with negative consequences to the resilience of natural populations and the economy. The objectives of the present study were to assess the long-term effect of increasing pCO2 after 217 days of exposure under controlled conditions of pH of ∼8.2, 8.0, and 7.7 on the strength and integrity of shells of juveniles of the commercial striped venus clam Chamelea gallina. Shell strength was estimated through compression tests and integrity through scanning electron microscopy (SEM) and dispersive X-ray analyses (EDX). The results showed that under increasing pCO2 the shell strength of juveniles is unaffected, which could be related to the locally elevated total alkalinity of seawater with respect to other parts of the coastal lagoon. However, despite this, it was also observed that the juvenile clams exposed to elevated pCO2 decreased their shell thickness and increased the porosity of their prismatic layer. Under future OA conditions, these changes could eventually compromise the integrity of the shells, becoming more vulnerable to the attack of predators and breakable during fishing operations. Future studies should address the plasticity of the organisms and the effect of the alkalinization of seawater on the resilience of shellfish juveniles under global change conditions.

GO promotes detoxification of nicosulfuron in sweet corn by enhancing photosynthesis, chlorophyll fluorescence parameters, and antioxidant enzyme activity

Although graphene oxide (GO) has extensive recognized application prospects in slow-release fertilizer, plant pest control, and plant growth regulation, the incorporation of GO into nano herbicides is still in its early stages of development. This study selected a pair of sweet corn sister lines, nicosulfuron (NIF)-resistant HK301 and NIF-sensitive HK320, and sprayed them both with 80 mg kg–1 of GO-NIF, with clean water as a control, to study the effect of GO-NIF on sweet corn seedling growth, photosynthesis, chlorophyll fluorescence, and antioxidant system enzyme activity. Compared to spraying water and GO alone, spraying GO-NIF was able to effectively reduce the toxic effect of NIF on sweet corn seedlings. Compared with NIF treatment, 10 days after of spraying GO-NIF, the net photosynthetic rate (A), stomatal conductance (Gs), transpiration rate (E), photosystem II photochemical maximum quantum yield (Fv/Fm), photochemical quenching coefficient (qP), and photosynthetic electron transfer rate (ETR) of GO-NIF treatment were significantly increased by 328.31%, 132.44%, 574.39%, 73.53%, 152.41%, and 140.72%, respectively, compared to HK320. Compared to the imbalance of redox reactions continuously induced by NIF in HK320, GO-NIF effectively alleviated the observed oxidative pressure. Furthermore, compared to NIF treatment alone, GO-NIF treatment effectively increased the activities of superoxide dismutase (SOD), guaiacol peroxidase (POD), catalase (CAT), and ascorbate peroxidase (APX) in both lines, indicating GO induced resistance to the damage caused by NIF to sweet corn seedlings. This study will provides an empirical basis for understanding the detoxification promoting effect of GO in NIF and analyzing the mechanism of GO induced allogeneic detoxification in cells.

Human intermediate prostate cancer stem cells contribute to the initiation and development of prostate adenocarcinoma

BackgroundIntermediate cells are present in the early stages of human prostate development and adenocarcinoma. While primary cells isolated from benign human prostate tissues or tumors exhibit an intermediate phenotype in vitro, they cannot form tumors in vivo unless genetically modified. It is unclear about the stem cell properties and tumorigenicity of intermediate cells.MethodsWe developed a customized medium to culture primary human intermediate prostate cells, which were transplanted into male immunodeficient NCG mice to examine tumorigenicity in vivo. We treated the cells with different concentrations of dihydrotestosterone (DHT) and enzalutamide in vitro and surgically castrated the mice after cell transplantation in vivo. Immunostaining, qRT-PCR, RNA sequencing, and western blotting were performed to characterize the cells in tissues and 2D and 3D cultures.ResultsWe found intermediate cells expressing AR+PSA+CK8+CK5+ in the luminal compartment of human prostate adenocarcinoma by immunostaining. We cultured the primary intermediate cells in vitro, which expressed luminal (AR+PSA+CK8+CK18+), basal (CK5+P63+), intermediate (IVL+), and stem cell (CK4+CK13+PSCA+SOX2+) markers. These cells resisted castration in vitro by upregulating the expression of AR, PSA, and proliferation markers KI67 and PCNA. The intermediate cells had high tumorigenicity in vivo, forming tumors in immunodeficient NCG mice in a month without any genetic modification or co-transplantation with embryonic urogenital sinus mesenchyme (UGSM) cells. We named these cells human castration-resistant intermediate prostate cancer stem cells or CriPCSCs and defined the xenograft model as patient primary cell-derived xenograft (PrDX). Human CriPCSCs resisted castration in vitro and in vivo by upregulating AR expression. Furthermore, human CriPCSCs differentiated into amplifying adenocarcinoma cells of luminal phenotype in PrDX tumors in vivo, which can dedifferentiate into CriPCSCs in vitro.ConclusionsOur study identified and established methods for culturing human CriPCSCs, which had high tumorigenicity in vivo without any genetic modification or UGSM co-transplantation. Human CriPCSCs differentiated into amplifying adenocarcinoma cells of luminal phenotype in the fast-growing tumors in vivo, which hold the potential to dedifferentiate into intermediate stem cells. These cells resisted castration by upregulating AR expression. The human CriPCSC and PrDX methods hold significant potential for advancing prostate cancer research and precision medicine.

Las desigualdades y sus consecuencias

In front of economic and social inequalities in our country, a call to arms is urging. Reducing inequality requires transformative change, so it is necessary intensify efforts in the fight against extreme poverty and hunger, especially from the early stages of development, and to work to guarantee a dignified life. This means that economic and social policies must be universal and serve the most disadvantaged and marginalized first.

A Spatiotemporal Transcriptome Reveals Stalk Development in Pearl Millet.

Pearl millet is a major cereal crop that feeds more than 90 million people worldwide in arid and semi-arid regions. The stalk phenotypes of Poaceous grasses are critical for their productivity and stress tolerance; however, the molecular mechanisms governing stalk development in pearl millet remain to be deciphered. In this study, we spatiotemporally measured 19 transcriptomes for stalk internodes of four different early developmental stages. Data analysis of the transcriptomes defined four developmental zones on the stalks and identified 12 specific gene sets with specific expression patterns across the zones. Using weighted gene co-expression network analysis (WGCNA), we found that two co-expression modules together with candidate genes were involved in stalk elongation and the thickening of pearl millet. Among the elongation-related candidate genes, we established by SELEX that a MYB-family transcription factor PMF7G02448 can bind to the promoters of three cell wall synthases genes (CesAs). In summary, these findings provide insights into stalk development and offer potential targets for future genetic improvement in pearl millet.

Endogenous phytohormone analysis during sequential stages of somatic embryogenesis in Musa AAA cv. Grand Naine (subgroup Cavendish)

Abstract This is the first initiative study to provide quantified levels of four endogenous phytohormones during the induction, regeneration, maturation and germination stages of somatic embryogenesis (SE) in banana, using immature male bud explants, in the popular commercial triploid cultivar Grand Naine (AAA). Phytohormones are known to play a major role in the regulation of SE and most protocols have been developed for various cultivars of banana following empirical approaches. Although, several reports are available with regard to the impact of growth regulators exogenously supplemented to the media, the vital role of endogenous growth hormones in various developmental stages of SE remain unclear in banana. Reverse Phase High Performance Liquid Chromatography (RP-HPLC) was used to analyze endogenous status of indole acetic acid (IAA), zeatin, gibberellic acid (GA) and abscisic acid (ABA). Results from this study revealed that endogenous IAA and GA along with exogenous auxin play a major role in the induction of embryogenic competence of male bud explants. The levels of endogenous IAA and zeatin were found to be higher in embryogenic calli than non-embryogenic calli, although three different types of exogenous auxins were supplemented in callogenesis medium, but not cytokinin. Higher level of ABA and GA was observed in early and late developmental stages of somatic embryo, respectively. GA also played a predominant role in germination of somatic embryos. These findings will be applied for improvement of SE protocol in recalcitrant banana cultivars by suitably altering or supplementing exogenous growth hormones.

Financial Sovereignty in the Doctrine of Financial Law of Pre-Revolutionary and Soviet Periods: A Historical and Legal Study

The paper is devoted to the study of the works of leading pre-revolutionary and Soviet period researchers representing the science of financial law in relation to issues related to financial sovereignty. The work analyzes textbooks on financial law written by E. N. Berendts, S. I. Ilovaisky, V. A. Lebedev, D. M. Lvov, I. I. Patlaevsky, I. I. Yanzhul, V. G. Yarotsky, M. A. Gurvich, G. S. Gurevich, S. A. Kotlyarevsky and E. A. Rovinsky. It is noted that at an early stage of development (the end of the 19th — beginning of the 20th century), the science of financial law had not yet formed a unified idea not only about financial sovereignty, but also about the content and system of financial law as a science. At the same time, the authors of this period paid special attention to the problems of financial supremacy (the law of supreme power in the field of public economy). At the initial stage of the formation of Soviet power, researchers do not focus on studying the essence of financial sovereignty. Later, the Soviet authors proceeded from the position based on constitutional provisions, according to which it was the Union republics that possessed sovereignty manifested in the recognition of the fullness of their power on their territory and the right to independently carry out financial activities. It is concluded that granting the status of a sovereign State to individual Union republics, also in the field of financial activity, is inconsistent with the essence of sovereignty and the essence of the federation as a form of government. In the federation, the bearer of sovereignty can only be of the federal level of government common to the whole country.

Physical and practical constraints on atmospheric methane removal technologies

Abstract Despite their apparent utility in mitigating climate change, technologies for removing methane from air are in early stages of development. Here we evaluate the limiting physical constraints, for three types of systems: two- and three-dimensional infrastructure and atmospheric oxidation enhancement, focusing on removing low ( x CH4 < 1000 ppm) and ambient ( x CH4 < 2 ppm) methane from air. With the space velocities and removal efficiencies of current three-dimensional technologies, volumes of 7–350 km3 are required to remove 1 Tg CH4 yr−1. Two-dimensional solutions are limited by the transport rate of methane to a surface. If every molecule of methane that collides with the surface is removed, an area of 1130 km2 is needed to remove 1 Tg CH4 yr−1 at ambient concentration. However, research shows that per-collision reaction probabilities are < 10−8 requiring a surface area of 1010–1015 km2. Finally, we examine atmospheric oxidation enhancement, where 4.8 Tg yr−1 of Cl ⋅ or 8.8 Tg yr−1 of OH ⋅ is required to remove 1 Tg CH4 yr−1, with precursors such as H2O2 or O3. However, limitations arise concerning multiple environmental impacts. We conclude that the physical and practical constraints are considerable, and identify the main barriers that must be addressed.

Embryonic Genome Activation (EGA) Occurred at 1-Cell Stage of Embryonic Development in the Mud Crab, Scylla paramamosain, Revealed by RNA-Seq.

As a prerequisite for the success of embryo development, embryonic genome activation (EGA) is an important biological event in which zygotic gene products in the embryo are activated to replace maternal-derived transcripts. Although EGA has been extensively studied in a large number of vertebrates and invertebrates, there is a lack of information regarding this event in crustacean crab. In this study, the timing of EGA was confirmed by examining a transcriptomic dataset of early embryonic development, including mature oocytes and embryos through six early developmental stages, and signaling pathways associated with EGA were identified in the mud crab, S. paramamosain. The comprehensive transcriptomic data identified a total of 53,915 transcripts from these sequencing samples. Notable transcriptomic change was evident at the 1-cell stage, indicated by a 36% transcript number shift and a reduction in transcript fragment length, compared to those present in the mature oocytes. Concurrently, a substantial increase in the expression of newly transcribed transcripts was observed, with gene counts reaching 3485 at the 1-cell stage, indicative of the onset of EGA. GO functional enrichment revealed key biological processes initiated at the 1-cell stage, such as protein complex formation, protein metabolism, and various biosynthetic processes. KEGG analysis identified several critical signaling pathways activated during EGA, including the "cell cycle," "spliceosome," "RNA degradation", and "RNA polymerase", pathways. Furthermore, transcription factor families, including zinc finger, T-box, Nrf1, and Tub were predominantly enriched at the 1-cell stage, suggesting their pivotal roles in regulating embryonic development through the targeting of specific DNA sequences during the EGA process. This groundbreaking study not only addresses a significant knowledge gap regarding the developmental biology of S. paramamosain, especially for the understanding of the mechanism underlying EGA, but also provides scientific data crucial for the research on the individual synchronization of seed breeding within S. paramamosain aquaculture. Additionally, it serves as a reference basis for the study of early embryonic development in other crustacean species.

Chains of misery: surging invasive group A streptococcal disease.

We describe the epidemiology of the recent global surge in invasive group A streptococcal (GAS) disease and consider its proximate and distal causes. We highlight important knowledge gaps regarding clinical management and discuss potential strategies for prevention. Rates of invasive GAS (iGAS) disease were increasing globally prior to the COVID-19 pandemic. Since mid-2022, following the worst years of the pandemic in 2020 and 2021, many countries with systems to monitor GAS syndromes have reported surges in cases of iGAS concurrent with increased scarlet fever, pharyngitis, and viral co-infections. The emergence of the hypervirulent M1UK strain as a cause of iGAS, particularly in high income countries, is concerning. New data are emerging on the transmission dynamics of GAS. GAS remains universally susceptible to penicillin but there are increasing reports of macrolide and lincosamide resistance, particularly in invasive isolates, with uncertain clinical consequences. Intravenous immunoglobulin is used widely for streptococcal toxic shock syndrome and necrotizing soft tissue infections, although there is limited clinical evidence, and none from a completed randomized controlled trial. Intensive and expensive efforts at population-level control of GAS infections and postinfectious autoimmune complications have been only partially successful. The great hope for control of GAS diseases remains vaccine development. However, all modern vaccine candidates remain in the early development stage. In many countries, iGAS rates surged from mid-2022 in the aftermath of pandemic control measures and physical distancing. The emergence of a dominant hypervirulent strain is an important but incomplete explanation for this phenomenon. Clinical management of iGAS remains highly empirical and new data has not emerged. A vaccine remains the most likely means of achieving a sustainable reduction in the burden of iGAS.

Evolution and Spatiotemporal Expression of ankha and ankhb in Zebrafish.

Craniometaphyseal Dysplasia (CMD) is a rare skeletal disorder that can result from mutations in the ANKH gene. This gene encodes progressive anksylosis (ANK), which is responsible for transporting inorganic pyrophosphate (PPi) and ATP from the intracellular to the extracellular environment, where PPi inhibits bone mineralization. When ANK is dysfunctional, as in patients with CMD, the passage of PPi to the extracellular environment is reduced, leading to excess mineralization, particularly in bones of the skull. Zebrafish may serve as a promising model to study the mechanistic basis of CMD. Here, we provide a detailed analysis of the zebrafish Ankh paralogs, Ankha and Ankhb, in terms of their phylogenic relationship with ANK in other vertebrates as well as their spatiotemporal expression patterns during zebrafish development. We found that a closer evolutionary relationship exists between the zebrafish Ankhb protein and its human and other vertebrate counterparts, and stronger promoter activity was predicted for ankhb compared to ankha. Furthermore, we noted distinct temporal expression patterns, with ankha more prominently expressed in early development stages, and both paralogs also being expressed at larval growth stages. Whole-mount in situ hybridization was used to compare the spatial expression patterns of each paralog during bone development, and both showed strong expression in the craniofacial region as well as the notochord and somites. Given the substantial overlap in spatiotemporal expression but only subtle patterning differences, the exact roles of these genes remain speculative. In silico analyses predicted that Ankha and Ankhb have the same function in transporting PPi across the membrane. Nevertheless, this study lays the groundwork for functional analyses of each ankh paralog and highlights the potential of using zebrafish to find possible targeted therapies for CMD.

Diagnostic value of microRNA-200 expression in peripheral blood-derived extracellular vesicles in early-stage non-small cell lung cancer

ObjectiveThis study assessed the diagnostic value of microRNA-200 (miR-200) expression in peripheral blood-derived extracellular vesicles (EVs) in early-stage non-small cell lung cancer (NSCLC).MethodsThis study retrospectively analyzed 100 healthy volunteers (the control group) receiving physical examinations, 168 early-stage NSCLC patients (the NSCLC group), and 128 patients with benign lung nodules (the benign group). The basic and clinical data of participants were obtained, including age, sex, smoking history, carbohydrate antigen 242 (CA242), carcinoembryonic antigen (CEA), carbohydrate antigen 199 (CA199), forced expiratory volume in 1 s, maximal voluntary ventilation, forced vital capacity, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and miR-200 expression. The correlation of miR-200 expression in peripheral blood-derived EVs with CA242, CEA, and CA199 was analyzed, and the diagnostic value of peripheral blood-derived EV miR-200 for early-stage NSCLC was assessed. The risk factors of early-stage NSCLC development were also determined.ResultsAge, the percentage of patients with smoking history, CA242, CEA, CA199, IL-6, and TNF-α levels, and miR-200 expression in peripheral blood-derived EVs were significantly higher in the NSCLC group than in the benign and control groups. Lung disease patients with high miR-200 expression in peripheral blood-derived EVs comprised a higher percentage of patients with smoking history and mixed lesions and had higher CA242, CEA, CA199, and TNF-α levels than those with low miR-200 expression in peripheral blood-derived EVs. In lung diseases, miR-200 expression in peripheral blood-derived EVs was significantly and positively correlated with CA242, CEA, and CA199. Peripheral blood-derived EV miR-200 combined with CA242, CEA and CA199 had higher diagnostic value (area under the curve = 0.942) than single detection, along with higher specificity, and high expression of peripheral blood-derived EV miR-200 was an independent risk factor for early-stage NSCLC.ConclusionPeripheral blood-derived EV miR-200 expression in patients with lung diseases is closely correlated with CA242, CEA, and CA199, and high expression of peripheral blood-derived EV miR-200 is an independent risk factor for early-stage NSCLC and is of high clinical diagnostic value for early-stage NSCLC.

Modeling the Toxicokinetics of Suspensions of Soluble Metallic Nanomaterials.

Proper risk assessment of the many new nanoforms (NFs) that are currently being developed and marketed is hindered by constraints in time and resources for testing their fate and (eco) toxicity profile. This problem has also been encountered in conventional chemical risk assessments, where the definition of related chemical groups can facilitate risk assessment for all class members. Whereas grouping and read-across methods are well established, such approaches are in the early stages of development for NFs. In this study, a modeling framework was developed for grouping NFs into distinct classes regarding the contribution of released ions to suspension-induced toxicity. The framework is based on combining dissolution rate constants of NFs with information about the toxicokinetics of the NFs and the dissolution products formed. The framework is exemplified for the specific case of suspension toxicity of metallic NFs (silver and copper). To this end, principles of mixture toxicity and dose-response modeling are integrated to derive threshold values for the key NF properties determining suspension toxicity: size, shape, and chemical composition. The threshold values thus derived offer a possible solution for the high-throughput screening of NFs according to their morphological and compositional properties in a regulatory context.

Towards New Delivery Agents for Boron Neutron Capture Therapy: Synthesis and In Vitro Evaluation of a Set of Fluorinated Carbohydrate Derivatives.

Boron Neutron Capture Therapy (BNCT) is a cancer treatment which combines tumor-selective boron delivery agents with thermal neutrons in order to selectively eradicate cancer cells. In this work, we focus on the early-stage development of carbohydrate delivery agents for BNCT. In more detail, we expand upon our previous GLUT-targeting approach by synthesizing and evaluating the potential embedded in a representative set of fluorinated carbohydrates bearing a boron cluster. Our findings indicate that these species may have advantages over the boron delivery agents in current clinical use, e.g., significantly improved boron delivery capacity at the cellular level. Simultaneously, the carbohydrate delivery agents were found to bind strongly to plasma proteins, which may be a concern requiring further action before progression to in vivo studies. Altogether, this work brings new insights into factors which need to be accounted for if attempting to develop theranostic agents for BNCT based on carbohydrates in the future.

A Novelty Model Employing the Quality Life Cycle Assessment (QLCA) Indicator and Frameworks for Selecting Qualitative and Environmental Aspects for Sustainable Product Development

The objective of this investigation was: (i) to develop a model that supports sustainable product development, considering the quality aspect and the environmental impact in the product life cycle, and (ii) to establish a framework to select the proportion of the share of these aspects during product development decisions. This research concentrates on achieving products that meet customer demand and have environmentally friendly life cycles. It also supports the implementation of design activities at an early stage of product development, positioning the share of quality in relation to environmental impact. The model is based on creating hypothetical prototypes of current products, and this approach concentrated on aggregating the quality (customer satisfaction) with life cycle environmental impacts (as in ISO 14040). The model was developed in five main stages, including: (i) defining product prototypes according to the modifications of quality criteria most desired by customers, (ii) assessing the quality of prototypes according to the Q quality index, (iii) prospective assessment of the environmental impacts of the life cycles of prototypes according to the LCA environmental index, (iv) methodical integration of the above-mentioned indicators into one quality and environmental indicator QLCA, and (v) analysis of possible production solutions and setting the direction of product development, taking into account both quality and environmental aspects. This research was extended with a sensitivity analysis of the QLCA indicator, after which a framework for selecting the proportion of the Q and LCA indicator’s share in product development decisions was established. The originality of this research is the ability of the developed model to facilitate eco-innovative product design and improvements while also selecting the share of qualitative and environmental aspects needed to develop sustainable products. The results provide a dynamic and effective tool for manufacturing companies; mainly designers and managers during qualitative and environmental prototyping of products commonly used by customers. The model will provide support in predicting a product that will be manufactured that will be satisfactory for customers and environmentally friendly based on LCA.

Perfluorodecanoic acid induces the increase of innate cells in zebrafish embryos by upregulating oxidative stress levels

Several studies reported that the widespread use of perfluoroalkyl and polyfluoroalkyl substances (PFASs) causes increased environmental pollution, subsequently impacting aquatic organisms. Perfluoroalkyl substances such as perfluorooctane sulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) reportedly cause cardiotoxicity, neurotoxicity, and developmental toxicity in different organisms. However, whether perfluorodecanoic acid (PFDA), a widely used perfluoroalkyl substance, induces animal embryos developmental toxicity remain unknown. Here, we explored the immunotoxicity and associated mechanisms of PFDA in zebrafish embryos via RNA sequencing, morphological assessment and behavioral alteration detection following exposure to 0.5, 1 and 2 mg/L of PFDA. Interestingly, We found that with the increase of PFDA to drug concentration, including neutrophils and macrophages, significantly increased the number of inherent cells, immune related genes expression. Furthermore, oxidative stress increased in the PFDA-treated embryos in a dose-dependent manner and inhibition of oxidative stress levels effectively rescued the number of neutrophils. Changes in embryonic behavior were observed after exposure to PFDA. Overall, our results suggest that PFDA may induce innate immune response by accumulation of oxidative stress in zebrafish at early developmental stages, and concern is needed about its environmental exposure risks for animals embryos development. Environmental implicationPerfluorinated and polyfluorinated alkyl substances (PFASs) are a class of synthetic organic compounds containing fluorine widely used as lubricants, surfactants, insecticides, etc. The PFDA, a typical perfluorinated compound, is often used as a wetting agent and flame retardant in industries.Several studies showed that PFASs can cause serious environmental pollution, leading to developmental toxicity to various animals, including reproductive toxicity, liver toxicity, heart toxicity, neurotoxicity, and immunotoxicity.However, there are still limited studies on the effects and mechanisms of PFDA on aquatic organisms. Therefore, there is a need to evaluate the ecological risks of PFDA in animals.