GnRH-driven FTO-mediated RNA m6A modification promotes gonadotropin synthesis and secretion.

BACKGROUND: Gonadotropin precisely controls mammalian reproductive activities. Systematic analysis of the mechanisms by which epigenetic modifications regulate the synthesis and secretion of gonadotropin can be useful for more precise regulation of the animal reproductive process. Previous studies have identified many differential m6A modifications in the GnRH-treated adenohypophysis. However, the molecular mechanism by which m6A modification regulates gonadotropin synthesis and secretion remains unclear. RESULTS: Herein, it was found that GnRH can promote gonadotropin synthesis and secretion by promoting the expression of FTO. Highly expressed FTO binds to Foxp2 mRNA in the nucleus, exerting a demethylation function and reducing m6A modification. After Foxp2 mRNA exits the nucleus, the lack of m6A modification prevents YTHDF3 from binding to it, resulting in increased stability and upregulation of Foxp2 mRNA expression, which activates the cAMP/PKA signaling pathway to promote gonadotropin synthesis and secretion. CONCLUSIONS: Overall, the study reveals the molecular mechanism of GnRH regulating the gonadotropin synthesis and secretion through FTO-mediated m6A modification. The results of this study allow systematic interpretation of the regulatory mechanism of gonadotropin synthesis and secretion in the pituitary at the epigenetic level and provide a theoretical basis for the application of reproductive hormones in the regulation of animal artificial reproduction.

New indole derivatives from endophytic fungus Colletotruchum sp. HK-08 originated from leaves of Nerium indicum.

Objective: To study secondary metabolites from endophytic fungus Colletotruchum sp. HK-08 originated from the leaves of Nerium indicum. Methods: The compounds were isolated by various column chromatographic techniques, and their structures were elucidated by spectroscopic techniques [high resolution electrospray ionization mass spectroscopy (HRESIMS), one-dimensional (1D) and two-dimensional (2D) nuclear magnetic resonance spectroscopy (NMR)], as well as comparison with literature data. The Ellman method was used to determine the acetylcholinesterase (AChE) inhibitory activity. Results: Four indole derivatives were identified from Colletotruchum sp. HK-08, including 6'-hydroxymonaspiloindole (1), 2-(2-oxoindolin-3-yl)ethyl 2-(4-hydroxyphenyl) acetate (2), 2-(2-oxoindolin-3-yl)ethyl 2-(2-hydroxyphenyl)acetate (3), and monaspiloindole (4). Compound 4 presented weak AChE inhibitory activity with IC50 value of (69.30 ± 6.27) µmol/L [tacrine as the positive control, with IC50 value of (0.61 ± 0.07) µmol/L]. Conclusion: Compounds 1-3 were new compounds, and compound 4 had weak AChE inhibitory activity.

Baseline serum testosterone and differential efficacy of bipolar androgen therapy and enzalutamide in the randomized TRANSFORMER trial.

Bipolar androgen therapy (BAT) is effective in a subset of metastatic castration-resistant prostate cancer (mCRPC) patients. Treatment selection biomarkers are needed due to other therapies that can be equally efficacious. We performed post-hoc analysis to determine whether baseline serum testosterone (T) is a treatment selection marker in the TRANSFORMER study, a randomized trial of abiraterone-pretreated mCRPC patients assigned to BAT (n = 94) or enzalutamide (n = 101). The findings suggest that patients with poor outcomes to abiraterone and serum T ≥ 20 ng/dL may benefit preferentially from BAT over enzalutamide. Baseline testosterone could be considered in the treatment selection process when BAT is an option.

A study on pulmonary function in children with obstructive sleep apnea hypopnea syndrome.

OBJECTIVE: To investigate the pulmonary function of children with obstructive sleep apnea syndrome. METHODS: A total of 328 children aged 3 to 12 years old who were evaluated for a sleep disorder from January 2022 to June 2023 were selected as the observation group, classified into mild, moderate, and severe categories based on the apnea hypopnea index. The number of children with mild, moderate, and severe obstructive sleep apnea is 228, 62, and 28 respectively. Additionally, 126 healthy individuals aged 3 to 13 years old undergoing health examinations during the same period were selected as the control group. All subjects underwent sleep respiratory monitoring, pulmonary function tests, and impulse oscillometry. Comparative analysis was performed on pulmonary function indices (forced vital capacity, maximum ventilation, inspiratory capacity, total lung capacity, and inspiratory reserve volume), and respiratory impedance indices (resonant frequency, total respiratory impedance, viscous resistance at 5 Hz, 20 Hz, and 35 Hz). Pulmonary function indices were also compared among patients in the observation group with mild, moderate, and severe conditions. RESULTS: In the observation group, the FVC pre% of patients decreased by 10.5 ± 5.99 compared to the control group. The MVV of the control group decreased by 28.10 ± 2.22 compared to patients in the observation group. The IC of the control group decreased by 0.68 ± 0.44 compared to patients in the observation group. The TLC of the control group decreased by 1.354 ± 0.51 compared to patients in the observation group. The ERV of the control group decreased by 0.53 ± 0.30 compared to patients in the observation group. Additionally, the Fres, Zrs, R5, R20, and R35 of the observation group were higher than those of the control group by 10.73 ± 0.18, 1.78 ± 0.24, 0.11 ± 0.17, 0.86 ± 0.13, and 0.02 ± 0.21, respectively. In sum, the pulmonary function indices of the observation group were significantly lower than those of the control group, while the respiratory impedance indices were higher (P < 0.05). Within the observation group, the pulmonary function indices of severe patients were lower than those of moderate and mild patients, and moderate patients had lower pulmonary function indices than mild patients (P < 0.05). CONCLUSION: The pulmonary function of children with obstructive sleep apnea syndrome is impaired and varies in severity. There are significant differences in pulmonary function, underscoring the importance of monitoring pulmonary function in these children for clinical assessment and treatment prognosis.

Synthesis of N-propanol from CO2 Electroreduction on Bicontinuous Cu2O/Cu Nanodomains.

n-propanol is an important pharmaceutical and pesticide intermediate. To produce n-propanol by electrochemical reduction of CO2 is a promising way, but is largely restricted by the very low selectivity and activity. How to promote the coupling of *C1 and *C2 intermediates to form the *C3 intermediate for n-propanol formation is challenging. Here, we propose the construction of bicontinuous structure of Cu2O/Cu electrocatalyst, which consists of ultra-small Cu2O nanodomains, Cu nanodomains and large amounts of grain boundaries between Cu2O and Cu nanodomains. The n-propanol current density is as high as 101.6 mA cm-2 at the applied potential of -1.1 V vs. reversible hydrogen electrode in flow cell, with the Faradaic efficiency up to 12.1%. Moreover, the catalyst keeps relatively stable during electrochemical CO2 reduction process. Experimental studies and theoretical calculations reveal that the bicontinuous structure of Cu2O/Cu can facilitate the *CO formation, *CO-*CO coupling and *CO-*OCCO coupling for the final generation of n-propanol.

A comprehensive analysis of patients with cerebral arteriovenous malformation with headache: assessment of risk factors and treatment effectiveness.

BACKGROUND: Due to the high mortality and disability rate of intracranial hemorrhage, headache is not the main focus of research on cerebral arteriovenous malformation (AVM), so research on headaches in AVM is still scarce, and the clinical understanding is shallow. This study aims to delineate the risk factors associated with headaches in AVM and to compare the effectiveness of various intervention treatments versus conservative treatment in alleviating headache symptoms. METHODS: This study conducted a retrospective analysis of AVMs who were treated in our institution from August 2011 to December 2021. Multivariable logistic regression analysis was employed to assess the risk factors for headaches in AVMs with unruptured, non-epileptic. Additionally, the effectiveness of different intervention treatments compared to conservative management in alleviating headaches was evaluated through propensity score matching (PSM). RESULTS: A total of 946 patients were included in the analysis of risk factors for headaches. Multivariate logistic regression analysis identified that female (OR 1.532, 95% CI 1.173-2.001, p = 0.002), supply artery dilatation (OR 1.423, 95% CI 1.082-1.872, p = 0.012), and occipital lobe (OR 1.785, 95% CI 1.307-2.439, p < 0.001) as independent risk factors for the occurrence of headaches. There were 443 AVMs with headache symptoms. After propensity score matching, the microsurgery group (OR 7.27, 95% CI 2.82-18.7 p < 0.001), stereotactic radiosurgery group(OR 9.46, 95% CI 2.26-39.6, p = 0.002), and multimodality treatment group (OR 8.34 95% CI 2.87-24.3, p < 0.001) demonstrate significant headache relief compared to the conservative group. However, there was no significant difference between the embolization group (OR 2.24 95% CI 0.88-5.69, p = 0.091) and the conservative group. CONCLUSIONS: This study identified potential risk factors for headaches in AVMs and found that microsurgery, stereotactic radiosurgery, and multimodal therapy had significant benefits in headache relief compared to conservative treatment. These findings provide important guidance for clinicians when developing treatment options that can help improve overall treatment outcomes and quality of life for patients.

[18F] AlF-NOTA-FAPI-04 PET/CT for non-invasive assessment of tubular injury in kidney diseases.

Background: [18F] AlF-NOTA-FAPI-04 is a novel positron emission tomography (PET) ligand, which specifically targets fibroblast activation protein (FAP) expression as a FAP inhibitor (FAPI). We analysed the diagnostic value of [18F] AlF-NOTA-FAPI-04 PET/CT for the non-invasive assessment of kidney interstitial inflammation and fibrosis in different renal pathologies. Methods: Twenty-six patients (14 males and 12 females; mean age, 50.5 ± 16.5 years) with a wide range of kidney diseases and 10 patients (six males and four females; mean age, 55.4 ± 8.6 years) without known evidence of renal disease as disease controls underwent [18F] AlF-NOTA-FAPI-04 PET/CT imaging. Kidney tissues obtained from kidney biopsies were stained with haematoxylin and eosin, periodic acid-Schiff, Masson's trichome, and periodic acid-silver methenamine. Immunohistochemical staining was also performed to assess the expression of α-smooth muscle actin (αSMA) and FAP. Renal parenchymal FAPI uptake reflected by maximum standardized uptake value (SUVmax) and mean standardized uptake value (SUVmean) measurements on PET/CT was analysed against pathohistological findings. Results: We found that renal parenchymal FAPI uptake was significantly higher in patients with various kidney diseases than in control patients in this study (SUVmax = 4.3 ± 1.8 vs 1.9 ± 0.4, SUVmean=3.9 ± 1.7 vs 1.5 ± 0.4, respectively; all P < 0.001). All kidney diseases, both in acute and chronic kidney disease, had increased renal parenchymal uptake to varying degrees. The correlation analysis indicated a positive association between the SUVmax and the tubulointerstitial inflammation (TII), interstitial fibrosis and tubular atrophy (IF/TA), and TII + IF/TA scores (r = 0.612, 0.681, and 0.754, all P < 0.05), and between the SUVmean and the TII, IF/TA, and TII + IF/TA scores (r = 0.603, 0.700, and 0.748, all P < 0.05). Furthermore, we found significant positive correlations between both SUVmax and the SUVmean with SMA and FAP staining scores (r = 0.686 and 0.732, r = 0.667 and 0.739, respectively; both P < 0.001). Conclusions: [18F] AlF-NOTA-FAPI-04 PET/CT is clinically available for the comprehensive and non-invasive assessment of tubular injury in various kidney diseases.

SIRT7 promotes mitochondrial biogenesis to render the adaptive resistance to MAPK inhibition in melanoma.

Melanoma, arising from the malignant transformation of melanocytes, stands as the most lethal type of skin cancer. While significant strides have been made in targeted therapy and immunotherapy, substantially enhancing therapeutic efficacy, the prognosis for melanoma patients remains unoptimistic. SIRT7, a nuclear-localized deacetylase, plays a pivotal role in maintaining cellular homeostasis and adapting to external stressors in melanoma, with its activity closely tied to intracellular nicotinamide adenine dinucleotide (NAD+). However, its involvement in adaptive resistance to targeted therapy remains unclear. Herein, we unveil that up-regulated SIRT7 promotes mitochondrial biogenesis to render the adaptive resistance to MAPK inhibition in melanoma. Initially, we observed a significant increase of SIRT7 expression in publicly available datasets following targeted therapy within a short duration. In consistent, we found elevated SIRT7 expression in melanoma cells subjected to BRAF or MEK inhibitors in vitro. The up-regulation of SIRT7 expression was also confirmed in xenograft tumors in mice after targeted therapy in vivo. Furthermore, we proved that SIRT7 deficiency led to decreased cell viability upon prolonged exposure to BRAF or MEK inhibitors, accompanied by an increase in cell apoptosis. Mechanistically, SIRT7 deficiency restrained the upregulation of genes associated with mitochondrial biogenesis and intracellular ATP levels in response to targeted therapy treatment in melanoma cells. Ultimately, we proved that SIRT7 deficieny could sensitize BRAF-mutant melanoma cells to MAPK inhibition targeted therapy in vivo. In conclusion, our findings underscore the role of SIRT7 in fostering adaptive resistance to targeted therapy through the facilitation of mitochondrial biogenesis. Targeting SIRT7 emerges as a promising strategy to overcome MAPK inhibitor adaptive resistance in melanoma.

Global proteomic analyses of lysine acetylation, malonylation, succinylation, and crotonylation in human sperm reveal their involvement in male fertility.

Protein lysine modifications (PLMs) are hotspots of post-translational modifications and are involved in many diseases; however, their role in human sperm remains obscure. This study examined the presence and functional roles of a classical PLM (lysine acetylation, Kac) and three novel PLMs (lysine malonylation, Kmal; lysine succinylation, Ksucc; lysine crotonylation, Kcr) in human sperm. Immunoblotting and immunofluorescence assays revealed modified proteins (15-150 kDa) in the tails of human sperm. An immunoaffinity approach coupled with liquid chromatography/tandem mass spectrometry revealed 1423 Kac sites in 680 proteins, 196 Kmal sites in 118 proteins, 788 Ksucc sites in 251 proteins, and 1836 Kcr sites in 645 proteins. These modified proteins participate in a variety of biological processes and metabolic pathways. Crosstalk analysis demonstrated that proteins involved in the sperm energy pathways of glycolysis, oxidative phosphorylation, the citrate cycle, fatty acid oxidation, and ketone body metabolism were modified by at least one of these modifications. In addition, these modifications were found in 62 male fertility-related proteins that weave a protein-protein interaction network associated with asthenoteratozoospermia, asthenozoospermia, globozoospermia, spermatogenic failure, hypogonadotropic hypogonadism, and polycystic kidney disease. Our findings shed light on the functional role of PLMs in male reproduction. SIGNIFICANCE: Protein lysine modifications (PLMs) are hotspots of posttranslational modifications and are involved in many diseases. This study revealed the presence of a classical PLM (lysine acetylation) and three novel PLMs (lysine malonylation, lysine succinylation, and lysine crotonylation) in human sperm tails. The modified proteins participate in a variety of biological processes and metabolic pathways. In addition, these modifications were found in 62 male infertility-associated proteins and could serve as potential diagnostic markers and therapeutic targets for male infertility.

Liquid biopsy for human cancer: cancer screening, monitoring, and treatment.

Currently, tumor treatment modalities such as immunotherapy and targeted therapy have more stringent requirements for obtaining tumor growth information and require more accurate and easy-to-operate tumor information detection methods. Compared with traditional tissue biopsy, liquid biopsy is a novel, minimally invasive, real-time detection tool for detecting information directly or indirectly released by tumors in human body fluids, which is more suitable for the requirements of new tumor treatment modalities. Liquid biopsy has not been widely used in clinical practice, and there are fewer reviews of related clinical applications. This review summarizes the clinical applications of liquid biopsy components (e.g., circulating tumor cells, circulating tumor DNA, extracellular vesicles, etc.) in tumorigenesis and progression. This includes the development process and detection techniques of liquid biopsies, early screening of tumors, tumor growth detection, and guiding therapeutic strategies (liquid biopsy-based personalized medicine and prediction of treatment response). Finally, the current challenges and future directions for clinical applications of liquid biopsy are proposed. In sum, this review will inspire more researchers to use liquid biopsy technology to promote the realization of individualized therapy, improve the efficacy of tumor therapy, and provide better therapeutic options for tumor patients.

Readon: a novel algorithm to identify read-through transcripts with long-read sequencing data.

MOTIVATION: There are many clustered transcriptionally active regions in the human genome, in which the transcription complex can not immediately terminate transcription at the upstream gene termination site, but instead continues to transcribe intergenic regions and downstream genes, resulting in read-through transcripts. Several studies have demonstrated the regulatory roles of read-through transcripts in tumorigenesis and development. However, limited by the read length of next-generation sequencing, discovery of read-through transcripts has been slow. For long but also erroneous third-generation sequencing data, this study developed a novel minimizer sketch algorithm to accurately and quickly identify read-through transcripts. RESULTS: Readon initially splits the reference sequence into distinct active regions. It employs a sliding window approach within each region, calculates minimizers, and constructs the specialized structured arrays for query indexing. Following initial alignment anchor screening of candidate read-through transcripts, further confirmation steps are executed. Comparative assessments against existing software reveal Readon's superior performance on both simulated and validated real data. Additionally, two downstream tools are provided: one for predicting whether a read-through transcript is likely to undergo nonsense-mediated decay or encodes a protein, and another for visualizing splicing patterns. AVAILABILITY: Readon is freely available on GitHub (https://github.com/Bulabula45/Readon). SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Unlocking Single Particle Anisotropy in Real-Time for Photoelectrochemistry Processes at the Nanoscale.

The key to rationally and rapidly designing high-performance materials is the monitoring and comprehension of dynamic processes within individual particles in real-time, particularly to gain insight into the anisotropy of nanoparticles. The intrinsic property of nanoparticles typically varies from one crystal facet to the next under realistic working conditions. Here, we introduce the operando collision electrochemistry to resolve the single silver nanoprisms (Ag NPs) anisotropy in photoelectrochemistry. We directly identify the effect of anisotropy on the plasmonic-assisted electrochemistry at the single NP/electrolyte interface. The statistical collision frequency shows that heterogeneous diffusion coefficient among crystal facets facilitates Ag NPs to undergo direction-dependent mass transfer toward the gold ultramicroelectrode. Subsequently, the current amplitudes of transient events indicate that anisotropy enables variations in dynamic interfacial electron transfer behaviors during photothermal processes. The results presented here demonstrate that the measurement precision of collision electrochemistry can be extended to the sub-nanoparticle level, highlighting the potential for high-throughput material screening with comprehensive kinetics information at the nanoscale.

ZnO/g-C3N4 photocatalyst activated by low-pressure ultraviolet for restoring the SWASV signals: A fast pretreatment method for electrochemically detecting Cd2+ and Pb2+ in soil extracts.

Soil organic matter (SOM) significantly impacts the detection accuracy of Cd2+ and Pb2+ using square wave anodic stripping voltammetry (SWASV) due to the complexation of SOM to heavy metal ions (HMIs), thereby attenuating SWASV signals. This study explored an effective pretreatment method that combined low-pressure ultraviolet (LPUV) photolysis with the ZnO/g-C3N4 photocatalyst, activating the photocatalyst to generate highly oxidative •OH radicals and O2•- radicals, which effectively disrupted this complexation, consequently restoring the electroactivity of HMIs and achieving high-fidelity SWASV signals. The parameters of the LPUV-ZnO/g-C3N4 photocatalytic system were meticulously optimized, including the pH of photolysis, duration of photolysis, g-C3N4 mass fraction, and concentration of the photocatalyst. Furthermore, the ZnO/g-C3N4 photocatalyst was thoroughly characterized, with an in-depth investigation on the synergistic interaction between ZnO and g-C3N4 and the mechanisms contributing to the restoration of SWASV signals. This synergistic interaction effectively separated charge carriers and reduced charge transfer resistance, enabling photogenerated electrons (e-) from the conduction band of g-C3N4 to be quickly transferred to the conduction band of ZnO, preventing the recombination of e- and h+ and generating more radicals to disrupt complexation and restore the SWASV signals. Finally, the analysis of HMIs in real soil extracts using the proposed pretreatment method demonstrated high detection accuracy of 94.9% for Cd2+ and 99.8% for Pb2+, which validated the feasibility and effectiveness of the proposed method in environmental applications.

Spatially resolved transcriptomic profiling of placental development in dairy cow.

The placenta plays a crucial role in successful mammalian reproduction. Ruminant animals possess a semi-invasive placenta characterized by a highly vascularized structure formed by maternal endometrial caruncles and fetal placental cotyledons, essential for full-term fetal development. The cow placenta harbors at least two trophoblast cell populations: uninucleate (UNC) and binucleate (BNC) cells. However, the limited capacity to elucidate the transcriptomic dynamics of the placental natural environment has resulted in a poor understanding of both the molecular and cellular interactions between trophoblast cells and niches, and the molecular mechanisms governing trophoblast differentiation and functionalization. To fill this knowledge gap, we employed Stereo-seq to map spatial gene expression patterns at near single-cell resolution in the cow placenta at 90 and 130 days of gestation, attaining high-resolution, spatially resolved gene expression profiles. Based on clustering and cell marker gene expression analyses, key transcription factors, including YBX1 and NPAS2, were shown to regulate the heterogeneity of trophoblast cell subpopulations. Cell communication and trajectory analysis provided a framework for understanding cell-cell interactions and the differentiation of trophoblasts into BNCs in the placental microenvironment. Differential analysis of cell trajectories identified a set of genes involved in regulation of trophoblast differentiation. Additionally, spatial modules and co-variant genes that help shape specific tissue structures were identified. Together, these findings provide foundational insights into important biological pathways critical to the placental development and function in cows.

High-Order line graphs of fMRI data in major depressive disorder.

BACKGROUND: Resting-state functional magnetic resonance imaging (rs-fMRI) technology and the complex network theory can be used to elucidate the underlying mechanisms of brain diseases. The successful application of functional brain hypernetworks provides new perspectives for the diagnosis and evaluation of clinical brain diseases; however, many studies have not assessed the attribute information of hyperedges and could not retain the high-order topology of hypergraphs. In addition, the study of multi-scale and multi-layered organizational properties of the human brain can provide richer and more accurate data features for classification models of depression. PURPOSE: This work aims to establish a more accurate classification framework for the diagnosis of major depressive disorder (MDD) using the high-order line graph algorithm. And accuracy, sensitivity, specificity, precision, F1 score are used to validate its classification performance. METHODS: Based on rs-fMRI data from 38 MDD subjects and 28 controls, we constructed a human brain hypernetwork and introduced a line graph model, followed by the construction of a high-order line graph model. The topological properties under each order line graph were calculated to measure the classification performance of the model. Finally, intergroup features that showed significant differences under each order line graph model were fused, and a support vector machine classifier was constructed using multi-kernel learning. The Kolmogorov-Smirnov nonparametric permutation test was used as the feature selection method and the classification performance was measured with the leave-one-out cross-validation method. RESULTS: The high-order line graph achieved a better classification performance compared with other traditional hypernetworks (accuracy = 92.42%, sensitivity = 92.86%, specificity = 92.11%, precision = 89.66%, F1 = 91.23%). Furthermore, the brain regions found in the present study have been previously shown to be associated with the pathology of depression. CONCLUSIONS: This work validated the classification model based on the high-order line graph, which can better express the topological features of the hypernetwork by comprehensively considering the hyperedge information under different connection strengths, thereby significantly improving the classification accuracy of MDD. Therefore, this method has potential for use in the clinical diagnosis of MDD.

Lab on the Microneedles: A Wearable Metal-organic Frameworks-Based Sensor for Visual Monitoring of Stress Hormone.

Abnormal secretion and dysrhythmias of cortisol (CORT) are associated with various diseases such as sleep disorders, depression, and chronic fatigue. Wearable devices are a cutting-edge technology for point-of-care detection and dynamic monitoring of CORT with inspiring convenience. Herein, we developed a minimally invasive skin-worn device with the advanced integration of both interstitial fluid (ISF) sampling and target molecule sensing for simultaneous detection of CORT via a microneedle-based sensor with high sensitivity, excellent efficiency, and outstanding reproducibility. In the microneedle patch, swellable hydrogel was employed as the adsorption matrix for ISF extraction. Meanwhile, europium metal-organic frameworks (Eu-MOF) wrapped in the matrix played a vital role in CORT recognition and quantitative analysis. The wearable and label-free Eu-MOF-loaded microneedle patch exhibited high sensitivity in CORT detection with the detection limit reaching 10-9 M and excellent selectivity. Molecular dynamics simulation-driven mechanism exploration revealed that the strong interface interaction promoted fluorescence quenching of Eu-MOF. Moreover, in vitro and in vivo investigation confirmed the feasibility and reliability of the sensing method, and excellent biocompatibility was validated. Overall, a sensitive approach based on the wearable Eu-MOF microneedle (MN) patch was established for the simultaneous detection of CORT via visible fluorescence quenching with exciting clinical-translational ability.

Impact of sequential (first- to third-generation) EGFR-TKI treatment on corrected QT interval in NSCLC patients.

Objective: To evaluate the impact of sequential (first- to third-generation) epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) treatment on top-corrected QT interval (top-QTc) in non-small cell lung cancer (NSCLC) patients. Methods: We retrospectively reviewed the medical records of NSCLC patients undergoing sequential EGFR-TKI treatment at Shanghai Chest Hospital between October 2016 and August 2021. The heart rate (HR), top-QT interval, and top-QTc of their ECGs were extracted from the institutional database and analyzed. Logistic regression was performed to identify predictors for top-QTc prolongation. Results: Overall, 228 patients were enrolled. Compared with baseline (median, 368 ms, same below), both first-generation (376 ms vs. 368 ms, p < 0.001) and sequential third-generation EGFR-TKIs (376 ms vs. 368 ms, p = 0.002) prolonged top-QT interval to a similar extent (p = 0.635). Top-QTc (438 ms vs. 423 ms, p < 0.001) and HR (81 bpm vs.79 bpm, p = 0.008) increased after first-generation EGFR-TKI treatment. Further top-QTc prolongation (453 ms vs. 438 ms, p < 0.001) and HR increase (88 bpm vs. 81 bpm, p < 0.001) occurred after treatment advanced. Notably, as HR elevated during treatment, top-QT interval paradoxically increased rather than decreased, and the top-QTc increased rather than slightly fluctuated. Moreover, such phenomena were more significant after treatment advanced. After adjusting for confounding factors, pericardial effusion and lower serum potassium levels were independent predictors of additional QTc prolongation during sequential third-generation EGFR-TKI treatment. Conclusion: First-generation EGFR-TKI could prolong top-QTc, and sequential third-generation EGFR-TKI induced further prolongation. Top-QT interval paradoxically increased and top-QTc significantly increased as HR elevated, which was more significant after sequential EGFR-TKI treatment. Pericardial effusion and lower serum potassium levels were independent predictors of additional QTc prolongation after sequential EGFR-TKI treatment.

The role of small RNAs in resistant melon cultivar against Phelipanche aegyptiaca parasitization.

Bidirectional trans-kingdom RNA silencing, a pivotal factor in plant-pathogen interactions, remains less explored in plant host-parasite dynamics. Here, using small RNA sequencing in melon root systems, we investigated microRNA (miRNA) expression variation in resistant and susceptible cultivars pre-and post-infection by the parasitic plant, broomrape. This approach revealed 979 known miRNAs and 110 novel miRNAs across 110 families. When comparing susceptible (F0) and resistant (R0) melon lines with broomrape infection (F25 and R25), 39 significantly differentially expressed miRNAs were observed in F25 vs. F0, 35 in R25 vs. R0, and 5 in R25 vs. F25. Notably, two miRNAs consistently exhibited differential expression across all comparisons, targeting genes linked to plant disease resistance. This suggests their pivotal role in melon's defense against broomrape. The target genes of these miRNAs were confirmed via degradome sequencing and validated by qRT-PCR, ensuring reliable sequencing outcomes. GO and KEGG analyses shed light on the molecular functions and pathways of these differential miRNAs. Furthermore, our study unveiled four trans-kingdom miRNAs, forming a foundation for exploring melon's resistance to broomrape.