bluuebunny/crossref_metadata_2025 huggingface dataset:
Investigation of preclinical pharmacokinetics of N-demethylsinomenine, a potential novel analgesic candidate, using an UPLC-MS/MS quantification method
Authors: Yu Lulu , Qian Xunjia , Feng Yiheng , Yin Yujian , Zhang Xiao-Dan , Wei Qianqian , Wang Liyun , Rong Weiwei , Li Jie-Jia , Li Jun-Xu , Zhu Qing
Published: July 2023

N- Demethylsinomenine (NDSM), the in vivo demethylated metabolite of sinomenine, has exhibited antinociceptive efficacy against various pain models and may become a novel drug candidate for pain management. However, no reported analytical method for quantification of N- Demethylsinomenine in a biological matrix is currently available, and the pharmacokinetic properties of N- Demethylsinomenine are unknown. In the present study, an ultra-high performance liquid chromatography with tandem mass spectrometry (UPLC-MS/MS) method for quantification of N- Demethylsinomenine in rat plasma was developed and utilized to examine the preclinical pharmacokinetic profiles of N- Demethylsinomenine. The liquid-liquid extraction using ethyl acetate as the extractant was selected to treat rat plasma samples. The mixture of 25% aqueous phase (0.35% acetic acid-10 mM ammonium acetate buffer) and 75% organic phase (acetonitrile) was chosen as the mobile phases flowing on a ZORBAX C18 column to perform the chromatographic separation. After a 6-min rapid elution, NDSM and its internal standard (IS), metronidazole, were separated successfully. The ion pairs of 316/239 and 172/128 were captured for detecting N- Demethylsinomenine and IS, respectively, using multiple reaction monitoring (MRM) under a positive electrospray ionization (ESI) mode in this mass spectrometry analysis. The standard curve met linear requirements within the concentration range from 3 to 1000 ng/mL, and the lower limit of quantification (LLOQ) was 3 ng/mL. The method was evaluated regarding precision, accuracy, recovery, matrix effect, and stability, and all the results met the criteria presented in the guidelines for validation of biological analysis method. Then the pharmacokinetic profiles of N- Demethylsinomenine in rat plasma were characterized using this validated UPLC-MS/MS method. N- Demethylsinomenine exhibited the feature of linear pharmacokinetics after intravenous (i.v.) or intragastric (i.g.) administration in rats. After i. v. bolus at three dosage levels (0.5, 1, and 2 mg/kg), N- Demethylsinomenine showed the profiles of rapid elimination with mean half-life (T1/2Z) of 1.55–1.73 h, and extensive tissue distribution with volume of distribution (VZ) of 5.62–8.07 L/kg. After i. g. administration at three dosage levels (10, 20, and 40 mg/kg), N- Demethylsinomenine showed the consistent peak time (Tmax) of 3 h and the mean absolute bioavailability of N- Demethylsinomenine was 30.46%. These pharmacokinetics findings will aid in future drug development decisions of N- Demethylsinomenine as a potential candidate for pain analgesia.
Predicting the risk of iliofemoral vascular complication in complex transfemoral-TAVR using new generation transcatheter devices
Authors: Koren Ofir , Patel Vivek , Tamir Yuval , Koseki Keita , Kaewkes Danon , Sanders Troy , Naami Robert , Naami Edmund , Cheng Daniel Eugene , Natanzon Sharon Shalom , Shechter Alon , Gornbein Jeffrey , Chakravarty Tarun , Nakamura Mamoo , Cheng Wen , Jilaihawi Hasan , Makkar Raj R.
Published: July 2023

Objective

Design a predictive risk model for minimizing iliofemoral vascular complications (IVC) in a contemporary era of transfemoral-transcatheter aortic valve replacement (TF-TAVR).

Background

IVC remains a common complication of TF-TAVR despite the technological improvement in the new-generation transcatheter systems (NGTS) and enclosed poor outcomes and quality of life. Currently, there is no accepted tool to assess the IVC risk for calcified and tortuous vessels.

Methods

We reconstructed CT images of 516 propensity-matched TF-TAVR patients using the NGTS to design a predictive anatomical model for IVC and validated it on a new cohort of 609 patients. Age, sex, peripheral artery disease, valve size, and type were used to balance the matched cohort.

Results

IVC occurred in 214 (7.2%) patients. Sheath size (p = 0.02), the sum of angles (SOA) (p < .0001), number of curves (NOC) (p < .0001), minimal lumen diameter (MLD) (p < .001), and sheath-to-femoral artery diameter ratio (SFAR) (p = 0.012) were significant predictors for IVC. An indexed risk score (CSI) consisting of multiplying the SOA and NOC divided by the MLD showed 84.3% sensitivity and 96.8% specificity, when set to >100, in predicting IVC (C-stat 0.936, 95% CI 0.911–0.959, p < 0.001). Adding SFAR > 1.00 in a tree model increased the overall accuracy to 97.7%. In the validation cohort, the model predicted 89.5% of the IVC cases with an overall 89.5% sensitivity, 98.9% specificity, and 94.2% accuracy (C-stat 0.842, 95% CI 0.904–0.980, p < .0001).

Conclusion

Our CT-based validated-model is the most accurate and easy-to-use tool assessing IVC risk and should be used for calcified and tortuous vessels in preprocedural planning.
Radiomics and artificial neural networks modelling for identification of high-risk carotid plaques
Authors: Gui Chengzhi , Cao Chen , Zhang Xin , Zhang Jiaxin , Ni Guangjian , Ming Dong
Published: July 2023

Objective

In this study, we aimed to investigate the classification of symptomatic plaques by evaluating the models generated via two different approaches, a radiomics-based machine learning (ML) approach, and an end-to-end learning approach which utilized deep learning (DL) techniques with several representative model frameworks.

Methods

We collected high-resolution magnetic resonance imaging (HRMRI) data from 104 patients with carotid artery stenosis, who were diagnosed with either symptomatic plaques (SPs) or asymptomatic plaques (ASPs), in two medical centers. 74 patients were diagnosed with SPs and 30 patients were ASPs. Sampling Perfection with Application-optimized Contrasts (SPACE) by using different flip angle Evolutions was used for MRI imaging. Repeated stratified five-fold cross-validation was used to evaluate the accuracy and receiver operating characteristic (ROC) of the trained classifier. The two proposed approaches were investigated to train the models separately. The difference in the model performance of the two proposed methods was quantitatively evaluated to find a better model to differentiate between SPs and ASPs.

Results

3D-SE-Densenet-121 model showed the best performance among all prediction models (AUC, accuracy, precision, sensitivity, and F1-score of 0.9300, 0.9308, 0.9008, 0.8588, and 0.8614, respectively), which were 0.0689, 0.1119, 0.1043, 0.0805, and 0.1089 higher than the best radiomics-based ML model (MLP). Decision curve analysis showed that the 3D-SE-Densenet-121 model delivered more net benefit than the best radiomics-based ML model (MLP) with a wider threshold probability.

Conclusion

The DL models were able to accurately differentiate between symptomatic and asymptomatic carotid plaques with limited data, which outperformed radiomics-based ML models in identifying symptomatic plaques.
Application of a new hydrocarbon detection technique with phase decomposition in carbonate reservoir of the Pre-Caspian Basin
Authors: Wang Zhen , Zhang Yiqiong , Ji Zhifeng , Jin Shutang , Jiang Ren , Wang Xueke , Wang Yankun , Sheng Shanbo , Lin Yaping
Published: July 2023

Due to the low porosity and thin thickness of the Carboniferous carbonate reservoir in the Pre-Caspian Basin, the impedance difference between the reservoir and the surrounding rock is not obvious, and the seismic response characteristics are weak. It is ambiguous to detect oil and gas based on the convention attribute amplitude and frequency information. According to the geological characteristics of the Carboniferous Reservoir in the Pre-Caspian Basin, we proposed a new hydrocarbon detection method from the phase decomposition of sensitive frequency in post-stack seismic data, which improves the accuracy of hydrocarbon detection. The forward model that is a method of numerical analysis is utilized to testify the feasibility of hydrocarbon detection with phase decomposition, which showed that the amplitude of oil and gas layers in −90° phase components is stronger than that of water layer. The special frequency band seismic data sensitive to oil and gas is decomposed into 10 Hz, 20 Hz, 30 Hz, 40 Hz, 50 Hz, and 60 Hz single frequency energy body, and then hydrocarbon is detected according to the amplitude anomaly in specific frequency energy body. The application of forward model and filed example demonstrates that the fluid type in the reservoir can be directly identified by the phase decomposition technique, which has higher accuracy than the conventional hydrocarbon detection technology with post-stack data. After the application of this technology, the coincidence between hydrocarbon results and oil test results in the block was increased from 60% to 80%, and the coincidence rate is much higher than the detection results using conventional attributes, more than 90%. All the two exploration wells deployed according to the detection results have obtained higher oil production, new discovered oil geologic reserves have been increased to 5.54 million tons.
The prognosis of patients with postoperative hyperglycemia after Stanford type A aortic dissection surgery and construction of prediction model for postoperative hyperglycemia
Authors: Chen Yubin , Ouyang Tianyu , Yin Yue , Fang Cheng , Tang Can-e , Luo Fanyan , Luo Jingmin
Published: July 2023

Objective

The mortality of type A aortic dissection (TAAD) is extremely high. The effect of postoperative hyperglycemia (PHG) on the prognosis of TAAD surgery is unclear. This study aims to investigate the prognosis of patients with PHG after TAAD surgery and construct prediction model for PHG.

Methods

Patients underwent TAAD surgery from January 2016 to December 2020 in Xiangya Hospital were collected. A total of 203 patients were included and patients were divided into non PHG group and PHG group. The occurrence of postoperative delirium, cardiac complications, spinal cord complication, cerebral complications, acute kidney injury (AKI), hepatic dysfunction, hypoxemia, and in-hospital mortality were compared between two groups. Data from MIMIC-IV database were further applied to validate the relationship between PHG and clinical outcomes. The prediction model for PHG was then constructed using Extreme Gradient Boosting (XGBoost) analysis. The predictive value of selected features was further validated using patient data from MIMIC-IV database. Finally, the 28-days survival rate of patient with PHG was analyzed using data from MIMIC-IV database.

Results

There were 86 patients developed PHG. The incidences of postoperative AKI, hepatic dysfunction, and in-hospital mortality were significant higher in PHG group. The ventilation time after surgery was significant longer in PHG group. Data from MIMIC-IV database validated these results. Neutrophil, platelet, lactic acid, weight, and lymphocyte were selected as features for prediction model. The values of AUC in training and testing set were 0.8697 and 0.8286 respectively. Then, five features were applied to construct another prediction model using data from MIMIC-IV database and the value of AUC in the new model was 0.8185. Finally, 28-days survival rate of patients with PHG was significantly lower and PHG was an independent risk factor for 28-days mortality after TAAD surgery.

Conclusion

PHG was significantly associated with the occurrence of AKI, hepatic dysfunction, increased ventilation time, and in-hospital mortality after TAAD surgery. The feature combination of neutrophil, platelet, lactic acid, weight, and lymphocyte could effectively predict PHG. The 28-days survival rate of patients with PHG was significantly lower. Moreover, PHG was an independent risk factor for 28-days mortality after TAAD surgery.
Dexamethasone affects human fetal adrenal steroidogenesis and subsequent ACTH response in an ex vivo culture model
Authors: Melau Cecilie , Gayete Mor Berta , Lundgaard Riis Malene , Nielsen John E. , Dreisler Eva , Aaboe Kasper , Tutein Brenøe Pia , Langhoff Thuesen Lea , Juul Hare Kristine , Mitchell Rod T. , Frederiksen Hanne , Juul Anders , Jørgensen Anne
Published: July 2023

Introduction

Administration of dexamethasone (DEX) has been used experimentally to suppress androgenization of external genitalia in 46,XX fetuses with congenital adrenal hyperplasia. Despite this, the prenatal biological mechanism-of-action of DEX on fetal development is not known. This study aimed to examine direct effects of DEX on human fetal adrenal (HFA) steroidogenic activity including possible effects on the subsequent response to ACTH-stimulation.

Methods

Human fetal adrenal (HFA) tissue from 30 fetuses (1st trimester) were cultured ex vivo with A) DEX (10 µm) for 14 days, or B) DEX (10 µm) for 10 days followed by ACTH (1 nM) for 4 days. DEX-mediated effects on HFA morphology, viability, and apoptosis (immunohistochemistry), gene expression (quantitative PCR), and steroid hormone secretion (LC-MS/MS) were investigated.

Results

DEX-treatment caused decreased androstenedione (p<0.05) and increased cortisol (p<0.01) secretion suggesting that direct effects on the adrenal gland may contribute to the negative feedback on the hypothalamic-pituitary-adrenal axis in vivo. An altered response to ACTH stimulation in HFA pre-treated with DEX included increased androgen (p<0.05) and reduced cortisol production (p<0.05), supporting clinical observations of a temporary decreased ACTH-response following prenatal DEX-treatment. Additionally, the secretion of corticosterone was decreased (p<0.0001) following ACTH-stimulation in the initially DEX-treated HFAs.

Discussion

The observed effects suggest that prenatal DEX-treatment can cause direct effects on HFA steroidogenesis and in the subsequent response to ACTH-stimulation. This may indicate a requirement for careful monitoring of adrenal function in prenatally DEX-treated neonates, with particular focus on their mineralocorticoid levels.
Identification of tRNA-derived RNAs in adipose tissue from overweight type 2 diabetes mellitus patients and their potential biological functions
Authors: Zhang Jie , Xi Yingfei , Fei Qiuping , Xu Jun , Hu Jinxing
Published: July 2023

Background

Type 2 diabetes mellitus (T2DM)causes a huge public health burden worldwide, especially for those who are overweight or obese, the pain is often greater. And search for effective targets in overweight T2DM could help improve patient quality of life and prognosis. tRNA-derived RNAs (tsRNAs) are multifunctional regulators that are currently receiving much attention, but there is still a lack of knowledge about tsRNAs in overweight T2DM.

Methods

T2DM patients with BMI ≥ 25 (Overweight group) and BMI< 25 (Control group) were subjected to tsRNA sequencing; differentially expressed tsRNAs in the two groups were analyzed and their expression was verified using qRT-PCR. The biological function of downstream target genes was also evaluated by enrichment analysis.

Results

qRT-PCR evaluation identified a tsRNA with up-regulated expression (tRF-1-28-Glu-TTC-3-M2) and a tsRNA with down-regulated expression (tRF-1-31-His-GTG-1), both of which may be involved in metabolic and energy-related processes.

Conclusion

Dysregulation of tsRNA expression in overweight patients with T2DM suggests a potential role for tsRNA in the development of T2DM.
Mesenchymal stem cells therapy improves ovarian function in premature ovarian failure: a systematic review and meta-analysis based on preclinical studies
Authors: Guo Congcong , Ma Yubo , Situ Yanqiu , Liu Li , Luo Guoqun , Li Huan , Ma Wenmin , Sun Li , Wang Wen , Weng Qiuying , Wu Linlin , Fan Dazhi
Published: July 2023

Background

Studies have revealed that the transplantation of mesenchymal stem cells (MSCs) might be a potential star candidate for premature ovarian failure (POF) in animal experiments. However, individual studies with a small sample size cannot be used to draw a clear conclusion. Therefore, we conducted a systematic review and meta-analysis to explore the potential of using MSCs in the treatment of POF in animals.

Methods

Seven databases were searched for studies exploring the effect of the transplantation of MSCs on POF in animal models. The PRISMA guideline was followed, and the methodological quality was ensured using SYRCLE’s risk of bias tool. RevMan 5.4 and STATA 12.0 software was performed to meta-analysis.

Results

In total, 37 studies involving 1,079 animals were included. Significant associations were found for MSCs with the levels of E2 (SMD 2.69 [95% CI 1.97, 3.41]), FSH (-2.02, [-2.74, -1.30]), primary follicles (2.04, [1.17, 2.92]), secondary follicles (1.93, [1.05, 2.81]), and primordial follicles (2.38, [1.19, 3.57]. Other outcomes, such as AMH, LH, INHB, antral follicles, growing follicles, mature follicles, and early antral were also found to be significant. There was no difference in FSH/LH, corpus leteum, follicles, and estruc cycle.

Conclusions

Our meta-analysis result indicated that the transplantation of MSCs might exert therapeutic effects on animal models of POF, and these effects might be associated with improving the disorder of the sexual cycle, modulating serum hormone expressions to a better state, and restoring ovarian function.
Altered glucocorticoid reactivity and behavioral phenotype in rx3-/- larval zebrafish
Authors: Herget Ulrich , Ryu Soojin , De Marco Rodrigo J.
Published: July 2023

Introduction

The transcription factor rx3 is important for the formation of the pituitary and parts of the hypothalamus. Mutant animals lacking rx3 function have been well characterized in developmental studies, but relatively little is known about their behavioral phenotypes.

Methods

We used cell type staining to reveal differences in stress axis architecture, and performed cortisol measurements and behavior analysis to study both hormonal and behavioral stress responses in rx3 mutants.

Results and Discussion

Consistent with the role of rx3 in hypothalamus and pituitary development, we show a distinct loss of corticotrope cells involved in stress regulation, severe reduction of pituitary innervation by hypothalamic cells, and lack of stress-induced cortisol release in rx3 mutants. Interestingly, despite these deficits, we report that rx3-/- larval zebrafish can still display nominal behavioral responses to both stressful and non-stressful stimuli. However, unlike wildtypes, mutants lacking proper pituitary-interrenal function do not show enhanced behavioral performance under moderate stress level, supporting the view that corticotroph cells are not required for behavioral responses to some types of stressful stimuli but modulate subtle behavioral adjustments under moderate stress.
Optimal serving strategy for vehicle-to-grid business: service agreement, energy reserve estimation, and profit maximization
Authors: Peng Chen , Niu Yajie
Published: July 2023

To advocate the adoption of electric vehicle (EV) technologies, this paper studies a practical operating paradigm for running a charge park vehicle-to-grid (V2G) service business. The operating paradigm consists of a service agreement and two consecutive day-ahead analyses. Specifically, i) the service agreement underpins the communication pattern between the EV owners and the V2G service operator, ii) day-ahead analysis-I estimates the V2G energy reserve distribution, and iii) day-ahead analysis-II aims to maximize profit by optimizing decision variables for the scheduled day, such as the output period and sale price of the V2G energy. Correspondingly, the contributions of this paper are three-fold. First, the major principles behind the design of a service agreement are highlighted, and a practical service agreement that abides by the principle is formed. Second, for day-ahead analysis-I, this paper proposes a V2G energy reserve modeling method for the rapid estimation of V2G energy reserve distribution, which is applied to a case study of New York City working and recreational environment charge parks. Third, for day-ahead analysis-II, an evaluation framework is proposed, which provides various metrics for characterizing the V2G output capacity. The metrics evaluation and profit maximization methods are presented with theoretical results and are verified also by computer experiments. For example, we show that for the simulated environment with peak time-of-use hours [13:00, 16:00] and V2G output period [13:00, 14:00], the V2G output power threshold 61 kW selected by our method achieves almost the maximum scheduled day profit (true maximum achieved at 60 kW).
The rights of nature and the human right to nature: an overview of the European legal system and challenges for the ecological transition
Authors: Alves Fátima , Costa Paulo Manuel , Novelli Luca , Vidal Diogo Guedes
Published: July 2023

Introduction: The recognition of the Rights of Nature has been established though several constitutional, legislative, and judicial enactments, which aim to provide legal protection for non-humans’ entities and natural systems. Although some countries have made progress in recognizing the rights of nature, the prevailing assumption remains that nature is a resource to be exploited for human benefit. In the context of ecological transition debates, it is important to understand how the European legal system perceives Nature and its rights. Achieving a significant shift in legal and cultural norms that prioritize nature’s protection may be challenging.

Methods: This paper reports on research conducted in a sample of 6 countries within the PHOENIX consortium, a European H2020 project that aims to develop participatory methodologies and democratic innovations to facilitate the ecological transition as envisioned by the European Green Deal, whose objective was to find out how these countries embodied the Rights of nature into their legal systems, both at constitutional level and at the level of environmental and related laws and policies.

Results: The results indicate that in legislative terms, concepts of nature are absent, and instead, the term environment or natural resources are used. Furthermore, rights of nature are rarely recognized in all countries, with anthropocentric and in instrumental views prevailing. In contrast, the human right to Nature is widely recognized in all countries, referring to the right of all individuals to access to and live in a healthy environment.

Discussion: Despite the importance of the human right to Nature as a matter of equity and justice, failure to recognise the rights of nature and protect/respect its limits may constitute a potential barrier to ecological transition.
The impact of the digital economy on green total factor productivity in Belt and Road countries: the mediating role of energy transition
Authors: Wang Anqi , Ren Junyu
Published: July 2023

Introduction: The prospective Belt and Road (B&R) Initiative by China must be thoroughly examined by the participating nations in all respects. It is now essential to investigate whether the digital economy of the B&R countries can support green total factor productivity (GTFP). This study examines the connection between green total factor productivity (GTFP) and the digital economy in B&R countries with the aim of providing China with practical recommendations for advancing the initiative.

Methods: This study explores 40 B&R countries from 2006 to 2021, calculates the GTFP using the unexpected super-efficient SBM model and the Global Malmquist-Luenberger index method, and constructs the digital economy index using the principal component analysis method. OLS, FMOLS methods, and spatial panel regressions are used to examine the digital economy-GTFP nexus.

Results and Discussion: In the selected 40 B&R countries, there is a non-linear relationship between the digital economy and GTFP, and the overall effect of the digital economy on GTFP is negative, implying that the growth of the digital economy will cause a decline in GTFP. Energy transition has mediation effects that can mitigate the negative impact of digital economic growth on GTFP. The spatial spillover effects of the digital economy on the GTFP of neighboring countries are evident. There is also heterogeneity; the digital economy will reduce GTFP in high- and middle-income countries, but the negative effects are not evident in low-income countries. This paper adds to the discussion of the digital economy and green development by drawing different conclusions from previous studies using a variety of regression models, providing a fresh foundation for policy-making.
First evidence of microplastics and their characterization in bottled drinking water from a developing country
Authors: Hossain M. Belal , Yu Jimmy , Banik Partho , Noman Md. Abu , Nur As-Ad Ujjaman , Haque Md. Rashedul , Rahman Md. Mostafizur , Albeshr Mohammed Fahad , Arai Takaomi
Published: July 2023

Microplastics (MPs) have become pervasive in the environment, posing a threat to the environment, living organisms, and human health. Therefore, MPs have been extensively investigated in bodies of water, soils, and the atmosphere. However, there is limited information about MPs contamination in drinking water sold in plastic packaging from underdeveloped countries. In this study, we analyzed water samples from 10 different common brands of bottled water to detect and characterize MPs using stereomicroscopic and FTIR techniques. Oral consumption of MPs per capita was also estimated. Interestingly, our findings demonstrated that MPs were present in every brand. The average abundance of MPs varied from 14 ± 6.8 particles/L to 56 ± 23 particles/L, with a mean of 35 ± 19 particles/L in all brands. This number of MPs in the studied country was comparatively higher than those found in other countries. MPs were found in four different shapes (fibers, fragments, films, and beads), with fibers dominating the samples (90%). MPs were sorted into eight different colors, with the transparent one accounting for about 66% of the overall count, and 94% of the MPs were <0.5 mm in size. Infrared spectral analysis (FTIR) confirmed four types of polymers, e.g., low-density polyethylene (LDPE), high-density polyethylene (HDPE), ethylene vinyl acetate (EVA), and polyethylene terephthalate (PETE) where LDPE and HDPE were dominant. The estimated daily intake of MPs per person was determined to be 2.63 particles, translating to a yearly intake of 960 particles/person. MPs in bottled drinking water might come from the sources of the raw water and the materials used in the packaging, which warrants additional research. As MPs in drinking water have direct exposure to human health, we should be aware of using plastic packaging for drinking water.
Uncovering ferroptosis in Parkinson’s disease via bioinformatics and machine learning, and reversed deducing potential therapeutic natural products
Authors: Wang Peng , Chen Qi , Tang Zhuqian , Wang Liang , Gong Bizhen , Li Min , Li Shaodan , Yang Minghui
Published: July 2023

Objective: Ferroptosis, a novel form of cell death, is closely associated with excessive iron accumulated within the substantia nigra in Parkinson’s disease (PD). Despite extensive research, the underlying molecular mechanisms driving ferroptosis in PD remain elusive. Here, we employed a bioinformatics and machine learning approach to predict the genes associated with ferroptosis in PD and investigate the interactions between natural products and their active ingredients with these genes.

Methods: We comprehensively analyzed differentially expressed genes (DEGs) for ferroptosis associated with PD (PDFerDEGs) by pairing 3 datasets (GSE7621, GSE20146, and GSE202665) from the NCBI GEO database and the FerrDb V2 database. A machine learning approach was then used to screen PDFerDEGs for signature genes. We mined the interacted natural product components based on screened signature genes. Finally, we mapped a network combined with ingredients and signature genes, then carried out molecular docking validation of core ingredients and targets to uncover potential therapeutic targets and ingredients for PD.

Results: We identified 109 PDFerDEGs that were significantly enriched in biological processes and KEGG pathways associated with ferroptosis (including iron ion homeostasis, iron ion transport and ferroptosis, etc.). We obtained 29 overlapping genes and identified 6 hub genes (TLR4, IL6, ADIPOQ, PTGS2, ATG7, and FADS2) by screening with two machine learning algorithms. Based on this, we screened 263 natural product components and subsequently mapped the “Overlapping Genes-Ingredients” network. According to the network, top 5 core active ingredients (quercetin, 17-beta-estradiol, glycerin, trans-resveratrol, and tocopherol) were molecularly docked to hub genes to reveal their potential role in the treatment of ferroptosis in PD.

Conclusion: Our findings suggested that PDFerDEGs are associated with ferroptosis and play a role in the progression of PD. Taken together, core ingredients (quercetin, 17-beta-estradiol, glycerin, trans-resveratrol, and tocopherol) bind well to hub genes (TLR4, IL6, ADIPOQ, PTGS2, ATG7, and FADS2), highlighting novel biomarkers for PD.
Sequence variants contributing to dysregulated inflammatory responses across keratoconic cone surface in adolescent patients with keratoconus
Authors: Jaskiewicz Katarzyna , Maleszka-Kurpiel Magdalena , Kabza Michał , Karolak Justyna A. , Gajecka Marzena
Published: July 2023

Background

Keratoconus (KTCN) is the most common corneal ectasia resulting in a conical shape of the cornea. Here, genomic variation in the corneal epithelium (CE) across the keratoconic cone surface in patients with KTCN and its relevance in the functioning of the immune system were assessed.

Methods

Samples from four unrelated adolescent patients with KTCN and two control individuals were obtained during the CXL and PRK procedures, respectively. Three topographic regions, central, middle, and peripheral, were separated towards the whole-genome sequencing (WGS) study embracing a total of 18 experimental samples. The coding and non-coding sequence variation, including structural variation, was assessed and then evaluated together with the previously reported transcriptomic outcomes for the same CE samples and full-thickness corneas.

Results

First, pathway enrichment analysis of genes with identified coding variants pointed to “Antigen presentation” and “Interferon alpha/beta signaling” as the most overrepresented pathways, indicating the involvement of inflammatory responses in KTCN. Both coding and non-coding sequence variants were found in genes (or in their close proximity) linked to the previously revealed KTCN-specific cellular components, namely, “Actin cytoskeleton”, “Extracellular matrix”, “Collagen-containing extracellular matrix”, “Focal adhesion”, “Hippo signaling pathway”, and “Wnt signaling” pathways. No genomic heterogeneity across the corneal surface was found comparing the assessed topographic regions. Thirty-five chromosomal regions enriched in both coding and non-coding KTCN-specific sequence variants were revealed, with a most representative 5q locus previously recognized as involved in KTCN.

Conclusion

The identified genomic features indicate the involvement of innate and adaptive immune system responses in KTCN pathogenesis.
Synthesis, antioxidant, and antimicrobial evaluation of novel 2,3-dihydro-1H-pyrazole-4-carbonitrile derivatives using K2CO3/glycerol as a green deep eutectic solvent
Authors: Zwain Ali A. , Ahmad Irfan , Khalaf Jebur Ali Rasha , Kahtan Mustafa , Khdyair Hamad Atheer , Abdulgader Hassan Enas , Asiri Mohammed , Ridha Benien M. , Alsalamy Ali
Published: July 2023

Providing green methods for the synthesis of new heterocyclic compounds with biological properties is interesting for scientists. Through the multi-component reaction of aldehyde derivatives, methyl 2-cyanoacetate, and phenylhydrazine using K2CO3, and glycerol as a deep eutectic solvent, new derivatives of 2,3-dihydro-1H-pyrazole-4-carbonitrile were synthesized. Biological evaluation of the synthesized 2,3-dihydro-1H-pyrazole-4-carbonitrile derivatives, including antioxidant activity on DPPH free radical and antimicrobial activity on a wide range of Gram-negative, Gram-positive bacterial, and fungal species, was done. In the antioxidant activity, IC50 value, and in the antimicrobial activity, IZD, MIC, MFC, and MBC parameters were assessed. The structure of the newly synthesized compounds was confirmed using 1H NMR, 13C NMR, and elemental analysis. 2,3-dihydro-1H-pyrazole-4-carbonitrile derivatives showed significant antioxidant and antibacterial activity and, in examining the results, a good relationship between the structure and biological activity of the 2,3-dihydro-1H-pyrazole-4-carbonitrile derivatives were found.
Predicting characteristics of cracks in concrete structure using convolutional neural network and image processing
Authors: Qayyum Waqas , Ehtisham Rana , Bahrami Alireza , Mir Junaid , Khan Qaiser Uz Zaman , Ahmad Afaq , Özkılıç Yasin Onuralp
Published: July 2023

The degradation of infrastructures such as bridges, highways, buildings, and dams has been accelerated due to environmental and loading consequences. The most popular method for inspecting existing concrete structures has been visual inspection. Inspectors assess defects visually based on their engineering expertise, competence, and experience. This method, however, is subjective, tiresome, inefficient, and constrained by the requirement for access to multiple components of complex structures. The angle, width, and length of the crack allow us to figure out the cause of the propagation and extent of the damage, and rehabilitation can be suggested based on them. This research proposes an algorithm based on a pre-trained convolutional neural network (CNN) and image processing (IP) to obtain the crack angle, width, endpoint length, and actual path length in a concrete structure. The results show low relative errors of 2.19%, 14.88%, and 1.11%, respectively for the crack angle, width, and endpoint length from the CNN and IP methods developed in this research. The actual path length is found to be 14.69% greater than the crack endpoint length. When calculating the crack length, it is crucial to consider its irregular shape and the likelihood that its actual path length will be greater than the direct distance between the endpoints. This study suggests measurement methods that precisely consider the crack shape to estimate its actual path length.
A risk nomogram for predicting prolonged intensive care unit stays in patients with chronic obstructive pulmonary disease
Authors: Cheng Hongtao , Li Jieyao , Wei Fangxin , Yang Xin , Yuan Shiqi , Huang Xiaxuan , Zhou Fuling , Lyu Jun
Published: July 2023

Background

Providing intensive care is increasingly expensive, and the aim of this study was to construct a risk column line graph (nomograms)for prolonged length of stay (LOS) in the intensive care unit (ICU) for patients with chronic obstructive pulmonary disease (COPD).

Methods

This study included 4,940 patients, and the data set was randomly divided into training (n = 3,458) and validation (n = 1,482) sets at a 7:3 ratio. First, least absolute shrinkage and selection operator (LASSO) regression analysis was used to optimize variable selection by running a tenfold k-cyclic coordinate descent. Second, a prediction model was constructed using multifactorial logistic regression analysis. Third, the model was validated using receiver operating characteristic (ROC) curves, Hosmer-Lemeshow tests, calibration plots, and decision-curve analysis (DCA), and was further internally validated.

Results

This study selected 11 predictors: sepsis, renal replacement therapy, cerebrovascular disease, respiratory failure, ventilator associated pneumonia, norepinephrine, bronchodilators, invasive mechanical ventilation, electrolytes disorders, Glasgow Coma Scale score and body temperature. The models constructed using these 11 predictors indicated good predictive power, with the areas under the ROC curves being 0.826 (95%CI, 0.809–0.842) and 0.827 (95%CI, 0.802–0.853) in the training and validation sets, respectively. The Hosmer-Lemeshow test indicated a strong agreement between the predicted and observed probabilities in the training (χ2 = 8.21, p = 0.413) and validation (χ2 = 0.64, p = 0.999) sets. In addition, decision-curve analysis suggested that the model had good clinical validity.

Conclusion

This study has constructed and validated original and dynamic nomograms for prolonged ICU stay in patients with COPD using 11 easily collected parameters. These nomograms can provide useful guidance to medical and nursing practitioners in ICUs and help reduce the disease and economic burdens on patients.
Clinical and biological heterogeneity of multisystem inflammatory syndrome in adults following SARS-CoV-2 infection: a case series
Authors: Barth Kaia E. , Spottiswoode Natasha , Hurabielle Charlotte , Subbaraj Lakshmi ,   COMET Consortium, Calfee Carolyn S. , Matthay Michael A. , French Sarah , Connolly Andrew , Hewitt Stephen M. , Vannella Kevin M. , Barnett Christopher , Langelier Charles R. , Patterson Sarah
Published: July 2023

Importance

Multisystem inflammatory syndrome in adults (MIS-A) is a poorly understood complication of SARS-CoV-2 infection with significant morbidity and mortality.

Objective

Identify clinical, immunological, and histopathologic features of MIS-A to improve understanding of the pathophysiology and approach to treatment.

Design

Three cases of MIS-A following SARS-CoV-2 infection were clinically identified between October 2021 – March 2022 using the U.S. Centers for Disease Control and Prevention diagnostic criteria. Clinical, laboratory, imaging, and tissue data were assessed.

Findings

All three patients developed acute onset cardiogenic shock and demonstrated elevated inflammatory biomarkers at the time of hospital admission that resolved over time. One case co-occurred with new onset Type 1 diabetes and sepsis. Retrospective analysis of myocardial tissue from one case identified SARS-CoV-2 RNA. All three patients fully recovered with standard of care interventions plus immunomodulatory therapy that included intravenous immunoglobulin, corticosteroids, and in two cases, anakinra.

Conclusion

MIS-A is a severe post-acute sequela of COVID-19 characterized by systemic elevation of inflammatory biomarkers. In this series of three cases, we find that although clinical courses and co-existent diseases vary, even severe presentations have potential for full recovery with prompt recognition and treatment. In addition to cardiogenic shock, glucose intolerance, unmasking of autoimmune disease, and sepsis can be features of MIS-A, and SARS-CoV-2 myocarditis can lead to a similar clinical syndrome.
Trends in innovative pediatric drug development in China based on clinical trial registration data
Authors: Wu Wen-Wen , Ji Xing , Mou Xin-Shuang , Ma Xin-Yue , Huang Ya-Ting , Zhang Jie-Ying , Zhang Jing-Xian , Xie Xin-Rong , Mao Ning-Ying , Xu Jing
Published: July 2023

In China, the focus of drug research and development has gradually shifted from generic to innovative drugs. Using the Chinese Clinical Trials Registry and Information Transparency Platform, we retrospectively analyzed clinical trials of innovative pediatric drugs conducted in mainland China over the last decade. The goal of this work was to better understand the characteristics of and historical changes in innovative pediatric drug research and development (R&D) in China and to provide effective data support for policy makers and other stakeholders. This study included 198 innovative pediatric drug clinical trials. The data showed that, although some progress has been made in the R&D of innovative pediatric drugs in China, many factors limiting this progress still exist, such as concentrated R&D areas, inadequate pediatric participants, and unbalanced source distributions. The level of innovative pediatric drug R&D in China currently lags behind the global level and has not kept pace with anti-neoplastic drug R&D in China. To promote the innovative development of pediatric drugs in China, the Chinese government must develop an R&D supervision framework, improve the motivation and innovation capabilities of pharmaceutical companies, and optimize the source distribution between regions.
The impact of the COVID-19 pandemic in diabetes and dyslipidemia management in a Spanish region: a retrospective study of the Aragon population
Authors: Mateo-Gallego Rocio , Gracia-Rubio Irene , Garza María Carmen , Cebollada Alberto , Pérez-Calahorra Sofía , Bayona-Sánchez Ana , Bujeda-Hernández Cristina , Jarauta Estibaliz , Sánchez-Calavera Maria Antonia , Lamiquiz-Moneo Itziar
Published: July 2023

Introduction

Previous research has indicated that the COVID-19 outbreak had a negative impact on the diagnosis and management of cardiometabolic diseases. Our aim was to analyze the impact of the COVID-19 pandemic on the management of dyslipidemia and type 2 diabetes (T2D) in the Aragon region of Spain.

Methods

We conducted an observational retrospective study, which included data from all patients diagnosed with active T2D or dyslipidemia in Aragon during 2019–2021. Data was collected from the BIGAN platform, a big database that includes all healthcare data from the Aragon population. Clinical, biochemical, and pharmacological prescription information was obtained for each patient and for each year.

Results

Out of the total population of 1,330,000 in the Aragon region, 90,000 subjects were diagnosed with T2D each year, resulting in a prevalence of approximately 7%. The COVID-19 pandemic resulted in a decrease in the prevalence of this disease and a lower incidence during the year 2020. In addition, patients with T2D experienced a deterioration of their glucose profile, which led to an increase in the number of patients requiring pharmacological therapy. The prevalence of dyslipidemia was approximately 23.5% in both 2019 and 2020 and increased to 24.5% in 2021. Despite the worsening of the anthropometric profile, the lipid profile improved significantly throughout 2020 and 2021 compared to 2019. Moreover, the number of active pharmacological prescriptions increased significantly in 2021.

Discussion

Our findings suggest that the overload of the health system caused by the COVID-19 pandemic has resulted in an underdiagnosis of T2D. Moreover, patients with T2D experienced a worsening of their glycemic profile, an increase in their pharmacological requirements, and lower performance of their analytical determinations. Dyslipidemic subjects improved their lipid profile although the value of lipid profile determination decreased between 2020 and 2021.
Investigation on sexual function in young breast cancer patients during endocrine therapy: a latent class analysis
Authors: Gan Lu , Miao Yi-Ming , Dong Xiao-Jing , Zhang Qi-Rong , Ren Qing , Zhang Nan
Published: July 2023

Backgrounds

The aim of this study was to investigate the sexual function status of young breast cancer patients during endocrine therapy, identify potential categories of sexual function status, and analyze the factors affecting the potential categories of sexual function status during endocrine therapy.

Methods

A cross-sectional survey was conducted on 189 young breast cancer patients who underwent postoperative adjuvant endocrine therapy in Shanghai Ruijin Hospital. The latent class analysis was used to identify potential categories of patient sexual function characteristics with respect to the FSFI sex health measures. Logistic regression analysis was used to analyze the influencing factors for the high risk latent class groups. A nomogram prognostic model were then established to identify high risk patients for female sexual dysfunction (FSD), and C-index was used to determine the prognostic accuracy.

Results

Patients were divided into a “high dysfunction-low satisfaction” group and a “low dysfunction-high satisfaction” group depending on the latent class analysis, accounting for 69.3% and 30.7%, respectively. Patients who received aromatase inhibitors (AI) combined with ovarian function suppression (OFS) treatment (p = 0.027), had poor body-image after surgery (p = 0.007), beared heavy medical economy burden(p < 0.001), and had a delayed recovery of sexual function after surgery (p = 0.001) were more likely to be classified into the “high dysfunction-low satisfaction” group, and then conducted into the nomogram. The C-index value of the nomogram for predicting FSD was 0.782.

Conclusion

The study revealed the heterogeneity of sexual function status among young breast cancer patients during endocrine therapy, which may help identify high-risk patients and provide early intervention.
Ursolic acid ameliorates obesity of mice fed with high-fat diet via alteration of gut microbiota and amino acid metabolism
Authors: Tian Chunfeng , Li Jie , Bao Yan , Gao Long , Song Lixin , Li Kai , Sun Ming
Published: July 2023

Obesity has been regarded as one of the major health problems worldwide. Studies demonstrated that ursolic acid (UA) can significantly ameliorate the progress of obesity. However, whether the effect of UA on obesity depends on the regulation of gut microbiota and metabolism is uncertain. To investigate the regulatory role of UA in obese mice from the perspective of intestinal microbiome and metabolomics analyses, an obese mice model was established with a high-fat diet, and the effect of UA on obesity was evaluated. The alterations of gut microbiota and metabolism related to obesity were evaluated by bioinformatic analysis. The results of the gut microbiota analysis showed that UA intervention could shift the Firmicutes to Bacteroidetes ratio at the phylum level and increase in the genera of Lactobacillus, Bacteroides, and Akkermansia. Additionally, metabolomics analysis showed that the beneficial influence of UA on obesity partly depended on amino acid metabolism. The current study demonstrated the roles of UA in the anti-obesity process, which depends in part on alterations in the gut microbiota and metabolism. Therefore, our findings highlight the potential therapeutic effect of UA on the improvement of diet-induced obesity in humans.
Probiotics for oral health: do they deliver what they promise?
Authors: Van Holm Wannes , Lauwens Katalina , De Wever Pieter , Schuermans Art , Zayed Naiera , Pamuk Ferda , Saghi Mehraveh , Fardim Pedro , Bernaerts Kristel , Boon Nico , Teughels Wim
Published: July 2023

Probiotics have demonstrated oral health benefits by influencing the microbiome and the host. Although promising, their current use is potentially constrained by several restrictions. One such limiting factor lies in the prevailing preparation of a probiotic product. To commercialize the probiotic, a shelf stable product is achieved by temporarily inactivating the live probiotic through drying or freeze drying. Even though a lyophilized probiotic can be kept dormant for an extended period of time, their viability can be severely compromised, making their designation as probiotics questionable. Additionally, does the application of an inactive probiotic directly into the oral cavity make sense? While the dormancy may allow for survival on its way towards the gut, does it affect their capacity for oral colonisation? To evaluate this, 21 probiotic product for oral health were analysed for the number of viable (probiotic), culturable (CFU) and dead (postbiotic) cells, to verify whether the commercial products indeed contain what they proclaim. After isolating and uniformly lyophilizing three common probiotic species in a simple yet effective lyoprotective medium, the adhesion to saliva covered hydroxyapatite discs of lyophilized probiotics was compared to fresh or reactivated lyophilized probiotics. Unfortunately, many of the examined products failed to contain the claimed amounts of viable cells, but also the strains used were inadequately characterized and lacked clinical evidence for that unknown strain, questioning their label of a ‘probiotic’. Additionally, lyophilized probiotics demonstrated low adhesive capacity compared to their counterparts, prompting the question of why fresh or reactivated probiotics are not currently used.