Subsequent Development Research Articles

Structural Optimization and Structure-Activity Relationship of 1H-Pyrazole-4-carboxylic Acid Derivatives as DNA 6mA Demethylase ALKBH1 Inhibitors and Their Antigastric Cancer Activity.

DNA N6-methyladenine (6mA) demethylase ALKBH1 plays an important role in various cellular processes. Dysregulation of ALKBH1 is associated with the development of some cancer types, including gastric cancer, implicating a potential therapeutic target. However, there is still a lack of potent ALKBH1 inhibitors. Herein, we report the discovery of a highly potent ALKBH1 inhibitor, 1H-pyrazole-4-carboxylic acid derivative 29. The structure-activity relationship of this series of compounds was also discussed. Because of the poor cell membrane permeability of 29, we prepared a prodrug of 29 (29E), which showed excellent cellular activities. In gastric cancer cell lines HGC27 and AGS, 29E treatment significantly increased the abundance of 6mA, inhibited cell viability, and upregulated the AMP-activated protein kinase (AMPK) signaling pathway. In addition, the hydrolysis product 29 showed high exposure in mice after administration of 29E. Collectively, this research provides a new potent ALKBH1 inhibitor, which could serve as a lead compound for subsequent drug development.

Генетический потенциал токсигенных Escherichia coli, выделенных от телят и поросят

Abstract. The study aims to genetically characterize diarrhoeagenic Escherichia coli isolated from cattle and pigs. The main propose is genetic potential responsible for the production of exotoxins in pathogenic E. coli, the causative agents of escherichiosis in calves and piglets. The scientific novelty of the work consists in deciphering the genomes of diarrheogenic E. coli with the presence of nucleotide sequences of several exotoxins, including thermolabile, thermostable and shigap-like, as well as colicins, hemolysins and cyclomodulins, which have pathogenetic significance in the development of escherichia infection in calves and piglets. The study was carried out using microbiological and molecular genetic methods of research and mass spectrometric analysis. As a result, 135 E. coli isolates were subjected to genetic screening by polymerase chain reaction in agarose gel. It was found that 68 (50.36 %) escherichia had toxigenicity markers, while the thermolabile exotoxin gene was recorded more often than others (48.5 %), and the majority was recorded in E. coli isolated from piglets (29.4 %). In 19 (27.9 %) isolates, the presence of genes encoding the production of several exotoxins was established. According to the results of the polymerase-chain reaction, 4 E. coli isolates with a different set of nucleotide sequences responsible for the production of two or more exotoxins at the same time were subjected to genome-wide sequencing. The Escherichia genomes were assembled and annotated and deposited in the NCBI Prokaryotic Genome Annotation Pipeline database under the general number BioProject PRJNA887444. Further studies of E. coli genes and their role in the pathogenic potential of escherichiosis pathogens are needed for the subsequent development of effective means of preventing and controlling infection.

Changes in Prevalence of IgE Sensitization and Allergenic Exposition over a 10-Year Period in a Tropical Region.

Multiple antigen environmental sources have been identified as possible causes of allergies, but few studies have evaluated changes in the sensitization profiles over time. The aim of this study was to evaluate the changes in IgE sensitization and exposure to dust mites, cats, dogs, and cockroaches over a 10-year period. During a period of 10 years among patients with asthma, rhinitis and/or atopic dermatitis, we evaluated the annual frequency of atopy to Dermatophagoides farinae, Dermatophagoides pteronyssinus, Blomia tropicalis, Canis familiaris, Felis domesticus and cockroaches (Periplaneta americana and Blatella germanica). Exposure to sources was also assessed using questionnaires (Pets) or direct counts (House dust mites and cockroaches). The association between some risk factors and the prevalence of atopy was explored. A total of 6,000 records were included. Among the patients, 82% had IgE sensitization to at least one of the six allergenic sources. Sensitization to Dermatophagoides spp. was the most frequent (>78%). Exposure and sensitization in the first decade of life to Dermatophagoides spp. seem to determine the molecular spreading to other allergenic sources. Exposure to Blomia tropical increases significantly over time (year 2015; 38% vs. year 2022; 51%, p 0.03). Exposure to dogs was higher than with cats but association between atopy and exposure was stronger with cats (OR 27.4, 95% CI: 22.3-33.6, p < 0.01). Exposure and sensitization in the first decade of life to Dermatophagoides spp. determine the molecular spreading of IgE antibodies to other allergenic sources. Household exposure to dogs and cats seems to be important for the subsequent development of atopy. Sensitization to B. tropicalis and cockroach appears to be mostly from cross-reactivity rather than direct exposure.

Application study of apnea-hypopnea duration for assessing adult obstructive sleep apnea.

Obstructive sleep apnea (OSA) is a common sleep disordered breathing disorder, which can cause serious damage to multiple human systems. Although polysomnography (PSG) is the current gold standard for diagnosis, it is complex and expensive. Therefore, it is of great significance to find a simple, economical and rapid primary screening and diagnosis method to replace PSG for the diagnosis of OSA. The purpose of this study is to propose a new method for the diagnosis and classification of OSA, which is used to automatically detect the duration of sleep apnea hypopnea events (AHE), so as to estimate the ratio(S) of the total duration of all-night AHE to the total sleep time only based on the sound signal of sleep respiration, and to identify OSA. We performed PSG tests on participants and extracted relevant sleep breathing sound signal data. This study is carried out in two stages. In the first stage, the relevant PSG report data of eligible subjects were recorded, the total duration of AHE in each subject's data was extracted, and the S value was calculated to evaluate the severity of OSA. In the second stage, only the sleep breath sound signal data of the same batch of subjects were used for automatic detection, and the S value in the sleep breath sound signal was extracted, and the S value was compared with the PSG diagnosis results to calculate the accuracy of the experimental method. Among 225 subjects. Using PSG as the reference standard, the S value extracted from the PSG diagnostic data report can accurately diagnose OSA(accuracy rate 99.56%) and distinguish its severity (accuracy rate 95.11%). The accuracy of the S value detected in the sleep breathing sound signal in the diagnosis of severe OSA reached 100%. The results show that the experimental parameter S value is feasible in OSA diagnosis and classification. OSA can be identified and evaluated only by sleep breathing sounds. This method helps to simplify the diagnostic grading of traditional OSA and lays a foundation for the subsequent development of simple diagnostic grading equipment.

Designing a Creative Heritage for a Deep-Tech Start-Up in the Scale-Up Phase

The prospect of solving ‘grand challenges’ through technological innovation justifies the interest shown in deep-tech start-ups. These companies develop technological solutions, which they then seek to implement on a massive scale during their scale-up phase. They nevertheless encounter difficulties at this stage, which starts with the validation of their business model. This research supplements the results reported in the literature on business models in the scale-up phase, with a design-oriented approach, which is better suited to the case of technology companies. Based on intervention research carried out in an urban agriculture deep-tech start-up, an axiomatic design tool is used to highlight the importance of distinguishing between the validation of elements of the business model and their preservation. This ensures that the deep-tech start-up’s subsequent developments are aligned with the goals of resolving major challenges.

The Association between Preserved Ratio Impaired Spirometry and Depression: Results from a Prospective Population-Based Study

Introduction: The relationship between preserved ratio impaired spirometry (PRISm) and depression remains unclear. This study aimed to assess the bidirectional relationship between PRISm and depression using data from a national cohort. Methods: Data from wave 2 (2004–2005) to wave 4 (2008–2009) of the English Longitudinal Study of Ageing (ELSA) were analyzed. Lung function and depressive symptoms were measured at baseline and follow-up. Cox proportional hazard models were used to calculate the hazard ratio (HR) of PRISm with depression (study 1) and depression with PRISm (study 2). Results: Studies 1 and 2 included 2,934 and 2,277 participants, respectively. The follow-up period extended from wave 2 to wave 4. In univariate analyses, a bidirectional association between PRISm and depression was observed, with unadjusted HRs of 1.49 (95% confidence interval [CI], 1.12–1.99; p = 0.007) in study 1 and 1.69 (95% CI, 1.13–2.52; p = 0.010) in study 2. However, in multivariable Cox models, baseline PRISm was not associated with subsequent depression development (adjusted HR 1.26; 95% CI, 0.94–1.69; p = 0.128). Conversely, participants with depression had a significantly higher risk of developing PRISm compared to those without depression (adjusted HR 1.54; 95% CI, 1.03–2.32; p = 0.038). These findings were consistent with z-score-based interpretive strategies, with an adjusted HR of 1.30 (95% CI, 0.95–1.77; p = 0.105) in study 1 and 1.59 (95% CI, 1.03–2.47; p = 0.038) in study 2. Conclusions: Depression was associated with an increased risk of developing PRISm, whereas PRISm did not increase the risk of developing depression. Physicians should be vigilant for potential PRISm development in patients with depression.

Genome Sequencing of Lentinula edodes Revealed a Genomic Variant Block Associated with a Thermo-Tolerant Trait in Fruit Body Formation.

The formation of multicellular fruiting bodies in basidiomycete mushrooms is a crucial developmental process for sexual reproduction and subsequent spore development. Temperature is one of the most critical factors influencing the phase transition for mushroom reproduction. During the domestication of mushrooms, traits related to fruiting bodies have significantly impacted agricultural adaptation and human preferences. Recent research has demonstrated that chromosomal variations, such as structural variants (SVs) and variant blocks (VBs), play crucial roles in agronomic traits and evolutionary processes. However, the lack of high-quality genomic information and important trait data have hindered comprehensive identification and characterization in Lentinula edodes breeding processes. In this study, the genomes of two monokaryotic L. edodes strains, characterized by thermo-tolerance and thermo-sensitivity during fruiting body formation, were reassembled at the chromosomal level. Comparative genomic studies of four thermo-tolerant and thermo-sensitive monokaryotic L. edodes strains identified a 0.56 Mbp variant block on chromosome 9. Genes associated with DNA repair or cellular response to DNA damage stimulus were enriched in this variant block. Finally, we developed eight CAPS markers from the variant block to discriminate the thermo-tolerant traits in L. edodes cultivars. Our findings show that the identified variant block is highly correlated with the thermo-tolerant trait for fruiting body formation and that alleles present in this block may have been artificially selected during L. edodes domestication.

DMDA-PatA mediates RNA sequence-selective translation repression by anchoring eIF4A and DDX3 to GNG motifs

Small-molecule compounds that elicit mRNA-selective translation repression have attracted interest due to their potential for expansion of druggable space. However, only a limited number of examples have been reported to date. Here, we show that desmethyl desamino pateamine A (DMDA-PatA) represses translation in an mRNA-selective manner by clamping eIF4A, a DEAD-box RNA-binding protein, onto GNG motifs. By systematically comparing multiple eIF4A inhibitors by ribosome profiling, we found that DMDA-PatA has unique mRNA selectivity for translation repression. Unbiased Bind-n-Seq reveals that DMDA-PatA-targeted eIF4A exhibits a preference for GNG motifs in an ATP-independent manner. This unusual RNA binding sterically hinders scanning by 40S ribosomes. A combination of classical molecular dynamics simulations and quantum chemical calculations, and the subsequent development of an inactive DMDA-PatA derivative reveals that the positive charge of the tertiary amine on the trienyl arm induces G selectivity. Moreover, we identified that DDX3, another DEAD-box protein, is an alternative DMDA-PatA target with the same effects on eIF4A. Our results provide an example of the sequence-selective anchoring of RNA-binding proteins and the mRNA-selective inhibition of protein synthesis by small-molecule compounds.

Ancient Greek laws of nature

The prevailing narrative in the history of science maintains that the ancient Greeks did not have a concept of a ‘law of nature’. This paper overturns that narrative and shows that some ancient Greek philosophers did have an idea of laws of nature and, moreover, they referred to them as ‘laws of nature’. This paper analyzes specific examples of laws of nature in texts by Plato, Aristotle, Philo of Alexandria, Nicomachus of Gerasa, and Galen. These examples emerged out of the closely intertwined Platonic and Pythagorean traditions, and these philosophers' texts make reference to laws of nature when describing arithmetical methods, arithmological doctrines, or medical theories. Nicomachus' laws of nature are especially noteworthy, because they have features that historians look for in the search for the origin of the modern concept of laws of nature. Nicomachus' laws of nature are mathematical, universal, and necessary. This paper raises the possibility that the ancient Platonic and Pythagorean traditions influenced the subsequent development of the idea of laws of nature in medieval and early modern Europe, including the conception of laws of nature deployed by Johannes Kepler and Isaac Newton.

Pastoral Care for Christian and Muslim Women Regarding Radicalism in Indonesia

Women are known as those who give birth to life and maintain life. However, the conflict that occurred in Indonesia has destroyed lives and made many women victims. In subsequent developments, women are not only victims but also perpetrators or victimizers, particularly in religious-based conflicts because of their involvement in radicalism movements. This happens a lot among Muslim women to defend their religion. The question that arises is whether the same thing also happens among Christian women as a result of the pressure and oppression they experience from the majority group, namely Muslims. Research on this topic was carried out using a mixed method between quantitative and qualitative research. This topic is reviewed from a feminist perspective. This research will be carried out in pastoral care to prevent women from being involved in radical movements and encourage them to become agents of peace who seek positive radicalism or peaceful radicalism.

Comparative proteomics analysis reveals the domesticated Lepista sordida primordium differentiation regulation mechanism and the subsequent different development patterns in the pileus and stipe

Comparative proteomics analysis reveals the domesticated Lepista sordida primordium differentiation regulation mechanism and the subsequent different development patterns in the pileus and stipe

Detecting Age Prone to Growth Retardation in Children Through a Bi-Response Nonparametric Regression Model with a Penalized Spline Estimator.

The growth of children aged 0-60 months can impact their subsequent growth and development. This study aims to identify the vulnerable age for boys and girls, who experience growth retardation within this age range. The study design used was a cross-sectional approach in which each child's measurement data was only taken once. The data were obtained from weighing results at the Health Integrated Service Post in South Sulawesi Province in 2022. The number of data analyzed was 698 children, namely 369 boys and 329 girls by considering the factors of age, weight, and height. We used a nonparametric bi-response regression model estimated using a penalized spline. The knots used are 12, 24, 36, and 48 on each model. The value of the penalized spline regression coefficient in the model indicates that the child's growth is slowed down and is not within normal limits. This can be seen in the weight and height of boys from the age of reaching 12 months to 24 months, only increasing by about 0.3 kg and 0.3 cm. For girls, the problem occurs from the age of 24 to 36 months, namely their weight increases by about 0.6 kg, and their height increases by about 1 cm. The analysis results show that boys' growth slows down at 2 years of age and continues until 5 years of age. In the case of girls, their growth begins to slow when they are 3 years old until they reach 5 years old.

1377P Association of anatomic proximity of brain parenchymal metastasis to the CSF space and upfront stereotactic radiosurgery to subsequent leptomeningeal metastasis development in brain metastatic NSCLC

1377P Association of anatomic proximity of brain parenchymal metastasis to the CSF space and upfront stereotactic radiosurgery to subsequent leptomeningeal metastasis development in brain metastatic NSCLC

Evaluation of conical 9 well dish on bovine oocyte maturation and subsequent embryonic development.

The Conical 9 well dish (C9 well dish) is characterized by a decreasing cross-sectional area towards the base. This design was hypothesized to enhance embryonic development by emulating the in vivo physical environment through density modulation. Comparative analyses revealed no significant difference in nuclear maturation rates between the C9 well dish and the 5-well dish. Reactive oxygen species (ROS) generation was lower in the C9 well dish compared to the 5-well dish; however, this difference was not statistically significant. On the second day of in vitro culture, the cleavage rate in the C9 well dish was 4.66% higher, although not statistically significant, and the rates of blastocyst development were similar across both dishes. No significant differences were observed in the intracellular levels of glutathione (GSH) and ROS, as well as in the total cell number within the blastocysts between the dish types. The expression of mitogen-related factors, TGFα and IGF-1, in the blastocysts was consistent between the dishes. However, PDGFβ expression was significantly lower in the C9 well dish compared to the 35 mm petri dish. Similarly, the expression of the apoptosis factor Bax/Bcl2l2 showed no significant differences between the two dishes. Despite the marked difference in PDGFβ expression, its impact on blastocyst formation appeared negligible. The study also confirmed the feasibility of culturing a small number of oocytes per donor, collected via Ovum Pick-Up (OPU), with reduced volumes of culture medium and mineral oil, thus offering economic advantages. In conclusion, the present study indicates that the C9 well dish is effective for in vitro development of a small quantity of oocytes and embryos, presenting it as a viable alternative to traditional cell culture dishes.

Do early midlife work characteristics predict 20-year change in control beliefs?

Previous research showed the importance of control beliefs for many life outcomes. The present study examines associations between subjectively perceived work environment and objectively measured work activities at the beginning of midlife as a central developmental phase in the context of work, with control beliefs across the subsequent 20 years. We analyzed four-wave longitudinal data from N = 374 participants (born 1950-1952; Mage baseline = 44 years, SD = 1; 44% women) from the Interdisciplinary Longitudinal Study of Adult Development and Aging within a structural equation modeling framework. Over 20 years and overall, internal control beliefs were stable, while external control beliefs decreased. Individuals who reported higher task variety and better social integration at work at baseline also reported higher levels of control beliefs for positive life outcomes. In addition, higher social integration at work at baseline was related to lower levels of external control beliefs. Work characteristics at baseline were not associated with individual differences in change in control beliefs across the 20-year observational interval. In summary, our findings suggest that work experiences at the prime of job-related development around the midst of the fifth decade of life do not play a major role in subsequent control beliefs development across 20 years. However, investigations measuring control beliefs as well as work characteristics continuously over a long period of time are necessary to shed light on reciprocal influences between work and personality. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Progress on SOX9 and its enhancers in mammalian sex determination.

The sex determination in mammals refers to the development of an initial bipotential organ, termed the bipotential gonad/genital ridge, into either a testis or an ovary at the early stages of embryonic development, under the precise regulation of transcription factors. SOX9 (SRY-box transcription factor 9) is a multifunctional transcription factor in mammalian development and plays a critical role in sex determination and subsequent male reproductive organs development. Recent studies have shown that several enhancers upstream of SOX9 also play an important role in the process of sex determination. In this review, we summarize the progress on the role of SOX9 and its gonadal enhancers in sex determination. This review will facilitate to understand the regulatory mechanism of sex determination of SOX9 and provides a theoretical basis for the further development of animal sex manipulation technologies.

Metabolic theory of preeclampsia: implications for maternal cardiovascular health.

Preeclampsia (PE) is a multisystemic disorder of pregnancy that not only causes perinatal mortality and morbidity but also has a long-term toll on the maternal and fetal cardiovascular system. Women diagnosed with PE are at greater risk for the subsequent development of hypertension, ischemic heart disease, cardiomyopathy, cerebral edema, seizures, and end-stage renal disease. Although PE is considered heterogeneous, inefficient extravillous trophoblast (EVT) migration leading to deficient spiral artery remodeling and increased uteroplacental vascular resistance is the likely initiation of the disease. The principal pathophysiology is placental hypoxia, causing subsequent oxidative stress, leading to mitochondrial dysfunction, mitophagy, and immunological imbalance. The damage imposed on the placenta in turn results in the "stress response" categorized by the dysfunctional release of vasoactive components including oxidative stressors, proinflammatory factors, and cytokines into the maternal circulation. These bioactive factors have deleterious effects on systemic endothelial cells and coagulation leading to generalized vascular dysfunction and hypercoagulability. A better understanding of these metabolic factors may lead to novel therapeutic approaches to prevent and treat this multisystemic disorder. In this review, we connect the hypoxic-oxidative stress and inflammation involved in the pathophysiology of PE to the resulting persistent cardiovascular complications in patients with preeclampsia.

Urethroplasty and the Subsequent Development of SCC Urethra – An Emerging Clinical Entity?

Urethroplasty and the Subsequent Development of SCC Urethra – An Emerging Clinical Entity?

Pipette-tip solid-phase extraction coupled with matrix-assisted laser desorption/ionization mass spectrometry enables rapid and high-throughput analysis of antidepressants in rat serum.

Therapeutic drug monitoring is essential for ensuring the efficacy and safety of medications. This study introduces a streamlined approach that combines pipette-tip solid-phase extraction (PT-SPE) with matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS), facilitating rapid and high-throughput monitoring of drug concentrations. As a demonstration, this method was applied to the extraction and quantification of antidepressants in serum. Utilizing Zip-Tip C18, the method enabled the extraction of antidepressants from complex biological matrices in less than 2min, with the subsequent MALDI-MS analysis yielding results in just 1min. Optimal extraction recoveries were achieved using a sampling solution at pH 9.0 and a 10 μL ethanol desorption solution containing 0.1% phosphoric acid. For MALDI analysis, 2,5-dihydroxybenzoic acid was identified as the most effective matrix for producing the highest signal intensity. The quantification strategy exhibited robust linearities (R2 ≥ 0.997) and satisfactory limits of quantification, ranging from 0.05 to 0.5 μg/mL for a suite of antidepressants. The application for monitoring dynamic concentration changes of antidepressants in rat serum emphasized the method's efficacy. This strategy offers the advantages of high throughput, minimal sample usage, environmental sustainability, and simplicity, providing ideas and a reference basis for the subsequent development of methods for therapeutic drug monitoring.

Appendicitis links to the afterward subsequent psoriatic disease occurrence in Taiwan national health insurance research database: A population-based cohort study: Appendicitis links to psoriatic diseases.

To investigate the psoriatic disease risk among patients with previous appendicitis. This study was a nationwide population-based case-control study about the association between the psoriatic disease risk among patients with a history of appendicitis in Taiwan. The study population consisted of newly diagnosed psoriatic disease with at least two outpatient visits, and the control group included those patients without psoriatic disease at the same index date. Patients with a previous diagnosis of appendicitis or who underwent appendectomy surgery prior to their psoriatic disease diagnosis were recorded. The odds ratio of psoriatic disease diagnosis in the two groups with and without a history of appendicitis were analyzed and compared. A total of 48 894 individuals diagnosed with psoriatic disease were matched with 292 656 controls by age and gender. Notably, the proportion of patients with a history of appendicitis or primary appendectomy was significantly elevated among those with psoriatic disease compared with the control cohort (both p < .05). On average, the occurrence of appendicitis preceded the index date by 3.3 ± 2.3 years. Multivariate analysis revealed a heightened incidence rate of psoriatic disease in patients previously diagnosed with appendicitis, periodontal disease, Charlson comorbidity index score (CCIS) ≧1, and ill-defined intestinal infections. This association persisted after adjusting for confounding factors, such as periodontal disease, CCIS, Salmonella, and ill-defined intestinal infections. The odds ratios for psoriatic disease in individuals with a history of appendicitis, periodontal disease, CCIS ≧1, and ill-defined intestinal infections were 1.16, 1.008, 1.69, and 1.23, respectively, with corresponding 95% confidence intervals of 1.03-1.31, 1.05-1.11, 1.65-1.74, and 1.20-1.26. These findings underscore the independent association between appendicitis and subsequent development of psoriatic disease, even after adjusting for relevant comorbidities and potential confounders. Our research illustrates that appendicitis is associated with an increased likelihood of developing a psoriatic disease, despite several limitations. These limitations encompass variables such as dietary and smoking habits, alongside other potential confounding factors that were not fully considered. Moreover, inherent biases in utilizing national health insurance data, such as the absence of laboratory information, as well as the constraints inherent in a retrospective study design, should be acknowledged.