Mitochondrial tRNA pseudouridylation governs erythropoiesis.

Pseudouridine is the most prevalent RNA modification, and its aberrant function is implicated in various human diseases. However, the specific impact of pseudouridylation on hematopoiesis remains poorly understood. In this study, we investigated the role of tRNA pseudouridylation in erythropoiesis and its association with mitochondrial myopathy, lactic acidosis, and sideroblastic anemia syndrome (MLASA) pathogenesis. By utilizing patient-specific induced pluripotent stem cells (iPSCs) carrying a genetic PUS1 mutation and a corresponding mutant mouse model, we demonstrated impaired erythropoiesis in MLASA iPSCs and anemia in the MLASA mouse model. Both MLASA iPSCs and mouse erythroblasts exhibited compromised mitochondrial function and impaired protein synthesis. Mechanistically, we revealed that PUS1 deficiency resulted in reduced mitochondrial tRNA levels due to pseudouridylation loss, leading to aberrant mitochondrial translation. Screening of mitochondrial supplements aimed at enhancing respiration or heme synthesis showed limited effect in promoting erythroid differentiation. Interestingly, the mTOR inhibitor rapamycin facilitated erythroid differentiation in MLASA-iPSCs by suppressing mTOR signaling and protein synthesis, and consistent results were observed in the MLASA mouse model. Importantly, rapamycin treatment effectively ameliorated anemia phenotypes in the MLASA patient. Our findings provide novel insights into the crucial role of mitochondrial tRNA pseudouridylation in governing erythropoiesis and present potential therapeutic strategies for anemia patients facing challenges related to protein translation.

Application of Electro-Activated Dissociation Fragmentation Technique to Identifying Glucuronidation and Oxidative Metabolism Sites of Vepdegestrant by Liquid Chromatography-High Resolution Mass Spectrometry.

Drug metabolite identification is an integrated part of drug metabolism and pharmacokinetics studies in drug discovery and development. Definitive identification of metabolic modification sides of test compounds such as screening metabolic soft spots and supporting metabolite synthesis are often required. Currently, liquid chromatography-high resolution mass spectrometry is the dominant analytical platform for metabolite identification. However, the interpretation of product ion spectra generated by commonly used collision-induced disassociation (CID) and higher-energy collisional dissociation (HCD) often fails to identify locations of metabolic modifications, especially glucuronidation. Recently, a ZenoTOF 7600 mass spectrometer equipped with electron-activated dissociation (EAD-HRMS) was introduced. The primary objective of this study was to apply EAD-HRMS to identify metabolism sites of vepdegestrant (ARV-471), a model compound that consists of multiple functional groups. ARV-471 was incubated in dog liver microsomes and 12 phase I metabolites and glucuronides were detected. EAD generated unique product ions via orthogonal fragmentation, which allowed for accurately determining the metabolism sites of ARV-471, including phenol glucuronidation, piperazine N-dealkylation, glutarimide hydrolysis, piperidine oxidation, and piperidine lactam formation. In contrast, CID and HCD spectral interpretation failed to identify modification sites of three O-glucuronides and three phase I metabolites. The results demonstrated that EAD has significant advantages over CID and HCD in definitive structural elucidation of glucuronides and phase I metabolites although the utility of EAD-HRMS in identifying various types of drug metabolites remains to be further evaluated. SIGNIFICANCE STATEMENT: Definitive identification of metabolic modification sites by liquid chromatography-high resolution mass spectrometry is highly needed in drug metabolism research, such as screening metabolic soft spots and supporting metabolite synthesis. However, commonly used collision-induced dissociation (CID) and higher-energy collisional dissociation (HCD) fragmentation techniques often fail to provide critical information for definitive structural elucidation. In this study, the electron-activated dissociation (EAD) was applied to identifying glucuronidation and oxidative metabolism sites of vepdegestrant, which generated significantly better results than CID and HCD.

Multivariate pattern analysis of EEG reveals nuanced impact of negation on sentence processing in the N400 and later time windows.

The neurocognitive mechanism underlying negation processing remains controversial. While negation is suggested to modulate the access of word meaning, no such evidence has been observed in the event-related potential (ERP) literature on sentence processing. In the current study, we applied both univariate ERP and multivariate pattern analysis (MVPA) methods to examine the processing of sentence negation. We investigated two types of negative congruent/incongruent sentence pairs with truth-value evaluation (e.g., "A robin is a/not a bird") and without (e.g., "The woman reads a/no book"). In the N400 time window, ERPs consistently showed increased negativity for negative and incongruent conditions. MVPA, on the other hand, revealed nuanced interactions between polarity and congruency. In the later P600 time window, MVPA but not the ERPs revealed an effect of congruency, which may be functionally distinct from the N400 window. We further used cross-decoding to show that the cognitive processes underlying the N400 window for both affirmative and negative sentences are comparable, whereas in the P600 window, only for the truth sentences, negative sentences showed a distinct pattern from their affirmative counterparts. Our results thus speak for a more interactive, but nevertheless serial and biphasic, and potentially construction-specific processing account of negation. We also discuss the advantage of applying MVPA in addition to the classical univariate methods for a better understanding of the neurobiology of negation processing and language comprehension alike.

Pre-movement event-related potentials and multivariate pattern of EEG encode action outcome prediction.

Self-initiated movements are accompanied by an efference copy, a motor command sent from motor regions to the sensory cortices, containing a prediction of the movement's sensory outcome. Previous studies have proposed pre-motor event-related potentials (ERPs), including the readiness potential (RP) and its lateralized sub-component (LRP), as potential neural markers of action feedback prediction. However, it is not known how specific these neural markers are for voluntary (active) movements as compared to involuntary (passive) movements, which produce much of the same sensory feedback (tactile, proprioceptive) but are not accompanied by an efference copy. The goal of the current study was to investigate how active and passive movements are distinguishable from premotor electroencephalography (EEG), and to examine if this change of neural activity differs when participants engage in tasks that differ in their expectation of sensory outcomes. Participants made active (self-initiated) or passive (finger moved by device) finger movements that led to either visual or auditory stimuli (100 ms delay), or to no immediate contingency effects (control). We investigated the time window before the movement onset by measuring pre-movement ERPs time-locked to the button press. For RP, we observed an interaction between task and movement. This was driven by movement differences in the visual and auditory but not the control conditions. LRP conversely only showed a main effect of movement. We then used multivariate pattern analysis to decode movements (active vs. passive). The results revealed ramping decoding for all tasks from around -800 ms onwards up to an accuracy of approximately 85% at the movement. Importantly, similar to RP, we observed lower decoding accuracies for the control condition than the visual and auditory conditions, but only shortly (from -200 ms) before the button press. We also decoded visual vs. auditory conditions. Here, task is decodable for both active and passive conditions, but the active condition showed increased decoding shortly before the button press. Taken together, our results provide robust evidence that pre-movement EEG activity may represent action-feedback prediction in which information about the subsequent sensory outcome is encoded.

Pharmacokinetics, mass balance, and metabolism of [14C]TPN171, a novel PDE5 inhibitor, in humans for the treatment of pulmonary arterial hypertension.

TPN171 is a novel phosphodiesterase-5 (PDE5) inhibitor used to treat pulmonary arterial hypertension (PAH) and erectile dysfunction (ED), which currently is undergoing phase II clinical trials in China. In this single-center, single-dose, nonrandomized, and open design study, radiolabeled [14C]TPN171 was used to investigate the metabolic mechanism, pharmacokinetic characteristics, and clearance pathways of TPN171 in 6 healthy Chinese male volunteers. Each volunteer was administered a single oral suspension of 10 mg (100 µCi) of [14C]TPN171. We found that TPN171 was absorbed rapidly in humans with a peak time (Tmax) of 0.667 h and a half-life (t1/2) of approximately 9.89 h in plasma. Excretion of radiopharmaceutical-related components was collected 216 h after administration, accounting for 95.21% of the dose (46.61% in urine and 48.60% in feces). TPN171 underwent extensive metabolism in humans. Twenty-two metabolites were detected in human plasma, urine, and feces using a radioactive detector combined with a high-resolution mass spectrometer. According to radiochromatograms, a glucuronide metabolite of O-dealkylated TPN171 exceeded 10% of the total drug-related components in human plasma. However, according to the Food and Drug Administration (FDA) guidelines, no further tests are needed to evaluate the safety of this metabolite because it is a phase II metabolite, but the compound is still worthy of attention. The main metabolic biotransformation of TPN171 was mono-oxidation (hydroxylation and N-oxidation), dehydrogenation, N-dealkylation, O-dealkylation, amide hydrolysis, glucuronidation, and acetylation. Cytochrome P450 3A4 (CYP3A4) mainly catalyzed the formation of metabolites, and CYP2E1 and CYP2D6 were involved in the oxidative metabolism of TPN171 to a lesser extent. According to the incubation data, M1 was mainly metabolized to M1G by UDP-glucuronosyltransferase 1A9 (UGT1A9), followed by UGT1A7 and UGT1A10.

Comparison of clinical characteristics and disease burden between early- and late-onset type 2 diabetes patients: a population-based cohort study.

BACKGROUND: The clinical characteristics of early-onset type 2 diabetes (T2D) patients are not fully understood. To address this gap, we conducted a cohort study to evaluate clinical characteristics and disease burden in the new-onset T2D population, especially regarding the progression of diseases. METHODS: This cohort study was conducted using a population-based database. Patients who were diagnosed with T2D were identified from the database and were classified into early- (age < 40) and late-onset (age ≥ 40) groups. A descriptive analysis was performed to compare clinical characteristics and disease burden between early- and late-onset T2D patients. The progression of disease was compared using Kaplan‒Meier analysis. RESULTS: A total of 652,290 type 2 diabetic patients were included. Of those, 21,347 were early-onset patients, and 300,676 were late-onset patients. Early-onset T2D patients had poorer glycemic control than late-onset T2D patients, especially at the onset of T2D (HbA1c: 9.3 [7.5, 10.9] for early-onset vs. 7.7 [6.8, 9.2] for late-onset, P < 0.001; random blood glucose: 10.9 [8.0, 14.3] for early-onset vs. 8.8 [6.9, 11.8] for late-onset, P < 0.001). Insulin was more often prescribed for early-onset patients (15.2%) than for late-onset patients (14.8%). Hypertension (163.0 [28.0, 611.0] days) and hyperlipidemia (114.0 [19.0, 537.0] days) progressed more rapidly among early-onset patients, while more late-onset patients developed hypertension (72.7% vs. 60.1%, P < 0.001), hyperlipidemia (65.4% vs. 51.0%, P < 0.001), cardiovascular diseases (66.0% vs. 26.7%, P < 0.001) and chronic kidney diseases (5.5% vs. 2.1%, P < 0.001) than early-onset patients. CONCLUSIONS: Our study results indicate that patients with newly diagnosed early-onset T2D had earlier comorbidities of hypertension and hyperlipidemia. Both clinical characteristics and treatment patterns suggest that the degree of metabolic disturbance is more severe in patients with early-onset type 2 diabetes. This highlights the importance of promoting healthy diets or lifestyles to prevent T2D onset in young adults.

Antibacterial Mechanism of Shikonin Against Vibrio vulnificus and Its Healing Potential on Infected Mice with Full-Thickness Excised Skin.

Shikonin has anticancer, anti-inflammatory, and wound healing activities. Vibrio vulnificus is an important marine foodborne pathogen with a high fatality rate and rapid pathogenesis that can infect humans through ingestion and wounds. In this study, the antibacterial activity and possible antibacterial mechanism of shikonin against V. vulnificus were investigated. In addition, the ability of shikonin to control V. vulnificus infection in both pathways was assessed by artificially contaminated oysters and full-thickness excised skin-infected mice. Shikonin treatment can cause abnormal cell membrane function, as evidenced by hyperpolarization of the cell membrane, significant decreased intracellular ATP concentration (p < 0.05), significant increased intracellular reactive oxygen species and malondialdehyde content (p < 0.05), decreased cell membrane integrity, and changes in cell morphology. Shikonin at 40 and 80 µg/mL reduced bacterial numbers in shikonin-contaminated oysters by 3.58 and 2.18 log colony-forming unit (CFU)/mL. Shikonin can promote wound healing in mice infected with V. vulnificus by promoting the formation of granulation tissue, hair follicles, and sebaceous glands, promoting epithelial cell regeneration and epidermal growth factor production. These findings suggest that shikonin has a strong inactivation effect on V. vulnificus and can be used in food production and wound healing to effectively control V. vulnificus and reduce the number of diseases associated with it.

Molecular imprinting electrochemiluminescence sensor based on nitrogen-doped carbon quantum dots /Ru(bpy)3@SiO2 for the determination of citrinin.

An electrochemiluminescence (ECL) sensor based on molecular imprinting polymer and SiO2 nanoparticles loaded Ru(bpy)3 and nitrogen-doped carbon quantum dots (NCQDs) is constructed for citrinin detection. The Ru(bpy)3 acts as ECL emitter, and the NCQDs cooperate with tri-n-propylamine (TPA) in solution as a coreactant to facilitate the luminescence. The citrinin imprinted poly(p-aminothiophenol) film is deposited on the surface of the luminophore by electrochemical method, which can immobilize the luminophore besides recognizing the target. The obtained ECL sensor exhibits high sensitivity, stability, and reproducibility. The change of ECL intensity and the logarithm of citrinin concentration display a good linear relationship in the range 1.0 to 100 pg mL-1, and the detection limit is 5 fg mL-1. When it is applied to the detection of citrinin contents in food sample (i.e., rice and millet) solutions, the RSD is less than 6.1%, and the recoveries for spiked standards range from 95.5 to 102.0%. Hence, this work provides a promising alternative for citrinin detection.

Monensin Enhanced Generation of Extracellular Vesicles as Transfersomes for Promoting Tumor Penetration of Pyropheophorbide-a from Fusogenic Liposome.

The current state of antitumor nanomedicines is severely restricted by poor penetration in solid tumors. It is indicated that extracellular vesicles (EVs) secreted by tumor cells can mediate the intercellular transport of antitumor drug molecules in the tumor microenvironment. However, the inefficient generation of EVs inhibits the application of this approach. Herein, we construct an EV-mediated self-propelled liposome containing monensin as the EV secretion stimulant and photosensitizer pyropheophorbide-a (PPa) as a therapeutic agent. Monensin and PPa are first transferred to the tumor plasma membrane with the help of membrane fusogenic liposomes. By hitchhiking EVs secreted by the outer tumor cells, both drugs are layer-by-layer transferred into the deep region of a solid tumor. Particularly, monensin, serving as a sustainable booster, significantly amplifies the EV-mediated PPa penetration by stimulating EV production. Our results show that this endogenous EV-driven nanoplatform leads to deep tumor penetration and enhanced phototherapeutic efficacy.

Absorption, Distribution, Metabolism, and Excretion of [14C]BS1801, a Selenium-Containing Drug Candidate, in Rats.

BS1801 is a selenium-containing drug candidate with potential for treating liver and lung fibrosis. To fully elucidate the biotransformation of BS1801 in animals and provide sufficient preclinical drug metabolism data for human mass balance study, the metabolism of BS1801 in rats was investigated. We used radiolabeling techniques to investigate the mass balance, tissue distribution, and metabolite identification of BS1801 in Sprague-Dawley/Long-Evans rats after a single oral dose of 100 mg/kg (100 µCi/kg) [14C]BS1801: 1. The mean recovery of radioactive substances in urine and feces was 93.39% within 168 h postdose, and feces were the main excretion route. 2. Additionally, less than 1.00% of the dose was recovered from either urine or bile. 3. BS1801-related components were widely distributed throughout the body. 4. Fifteen metabolites were identified in rat plasma, urine, feces, and bile, and BS1801 was detected only in feces. 5. BS1801-M484, the methylation product obtained via a N-Se bond reduction in BS1801, was the most abundant drug-related component in plasma. The main metabolic pathways of BS1801 were reduction, amide hydrolysis, oxidation, and methylation. Overall, BS1801 was distributed throughout the body, and excreted mainly as an intact BS1801 form through feces. No differences were observed between male and female rats in distribution, metabolism, and excretion of BS1801.

Conformer-RL: A deep reinforcement learning library for conformer generation.

Conformer-RL is an open-source Python package for applying deep reinforcement learning (RL) to the task of generating a diverse set of low-energy conformations for a single molecule. The library features a simple interface to train a deep RL conformer generation model on any covalently bonded molecule or polymer, including most drug-like molecules. Under the hood, it implements state-of-the-art RL algorithms and graph neural network architectures tuned specifically for molecular structures. Conformer-RL is also a platform for researching new algorithms and neural network architectures for conformer generation, as the library contains modular class interfaces for RL environments and agents, allowing users to easily swap components with their own implementations. Additionally, it comes with tools to visualize and save generated conformers for further analysis. Conformer-RL is well-tested and thoroughly documented with tutorials for each of the functionalities mentioned above, and is available on PyPi and Github: https://github.com/ZimmermanGroup/conformer-rl.

Inactivation of Shigella flexneri by 405-nm Light-Emitting Diode Treatment and Possible Mechanism of Action.

Shigella flexneri, a common Gram-negative foodborne pathogen, is widely distributed in fresh-cut fruits and vegetables, unpasteurized milk, and food processing environments. The aims of this study were to evaluate the antibacterial effects of 405-nm light-emitting diode (LED) treatment on S. flexneri and to investigate the possible mechanism. The results showed that LED irradiation (360 min) reduced the number of S. flexneri in phosphate-buffered saline by 3.29 log colony-forming unit (CFU)/mL (initial bacterial count: 6.81 log CFU/mL). The cells in reconstituted infant formula, cells on fresh-cut carrot slices, and biofilm-associated cells on stainless steel surfaces were reduced by 1.83 log CFU/mL, 7.00 log CFU/cm2, and 4.35 log CFU/cm2 following LED treatment for 360, 120, and 120 min, respectively. LED treatment damaged both DNA and cell wall of S. flexneri and changed cell morphology and cell membrane permeability. In addition, LED treatment decreased total cell protein concentration of S. flexneri. These results indicated that 405-nm LED treatment effectively controlled S. flexneri contamination of foods and food contact surfaces and that the bacterial inactivation may be the result of damage to multiple cellular components. These findings highlight the potential of LED technology in controlling S. flexneri during food processing, storage, and preparation.

Gesture's body orientation modulates the N400 for visual sentences primed by gestures.

Body orientation of gesture entails social-communicative intention, and may thus influence how gestures are perceived and comprehended together with auditory speech during face-to-face communication. To date, despite the emergence of neuroscientific literature on the role of body orientation on hand action perception, limited studies have directly investigated the role of body orientation in the interaction between gesture and language. To address this research question, we carried out an electroencephalography (EEG) experiment presenting to participants (n = 21) videos of frontal and lateral communicative hand gestures of 5 s (e.g., raising a hand), followed by visually presented sentences that are either congruent or incongruent with the gesture (e.g., "the mountain is high/low…"). Participants underwent a semantic probe task, judging whether a target word is related or unrelated to the gesture-sentence event. EEG results suggest that, during the perception phase of handgestures, while both frontal and lateral gestures elicited a power decrease in both the alpha (8-12 Hz) and the beta (16-24 Hz) bands, lateral versus frontal gestures elicited reduced power decrease in the beta band, source-located to the medial prefrontal cortex. For sentence comprehension, at the critical word whose meaning is congruent/incongruent with the gesture prime, frontal gestures elicited an N400 effect for gesture-sentence incongruency. More importantly, this incongruency effect was significantly reduced for lateral gestures. These findings suggest that body orientation plays an important role in gesture perception, and that its inferred social-communicative intention may influence gesture-language interaction at semantic level.

The effects of job satisfaction and psychological resilience on job performance among residents of the standardized residency training: a nationwide study in China.

High resident job performance is essential for effective medical professionalism. To date, few studies have investigated the potential predictors of job performance among residents in standardized residency training (SRT) program in China. Therefore, a nationwide survey among Chinese residents in SRT program was conducted to evaluate the impact of job satisfaction and psychological resilience on job performance. A total of 1146 residents from 9 hospitals were recruited in this study. Demographic and work-related information, job satisfaction, psychological resilience and job performance were collected through questionnaires. Hierarchical regression analyses indicated that, "work pressure", "doctor-patient conflict", "intrinsic job satisfaction" and "psychological resilience" were significant predictors of job performance for residents in SRT programs and explained 61.3% of variance, while the three dimensions of psychological resilience (tenacity, strength and optimism) accounted for 27.2% of variance. The area under curve (AUC) of the receiver operating characteristic (ROC) curve showed that resilience had the highest predictive accuracy than another three subscales. This study indicated that intrinsic job satisfaction and psychological resilience had a significant influence on job performance. Strategies and measures to improve residents' intrinsic job satisfaction and psychological resilience may be efficacious ways to enhance their job performance.

The facilitative effect of gestures on the neural processing of semantic complexity in a continuous narrative.

Gestures are elemental components of social communication and aid comprehension of verbal messages; however, little is known about the potential role of gestures in facilitating processing of semantic complexity in an ecologically valid setting. The goal of this study was to investigate whether cognitive load, as indexed by semantic complexity, is modulated by the presentation of gestures accompanying speech. Twenty healthy participants watched 16 video clips of a short narrative while instructed to carefully listen to and watch the narrator while functional magnetic resonance imaging (fMRI) data were acquired. The videos contained passages with and without various co-speech gestures, as well as passages where the semantic complexity was either low or high, as measured by the metric of idea density. Increasing semantic complexity led to reduced activation within the default mode network (DMN); whereas, presents of gestures decreased activation in language-related regions (left middle temporal gyrus and left inferior frontal gyrus) and increased activation in high-level visual and multimodal regions of occipitotemporal cortex. Most interestingly, an interaction between semantic complexity and gestures was observed in a language-related area in left anterior temporal cortex; specifically, increasing gestures led to a greater drop in activation with high vs. Low semantic complexity. These results provide evidence that the facilitation of gestures on semantic processing, particularly for complex narratives, is reflected in the neural substrates of language processing.

The connectivity signature of co-speech gesture integration: The superior temporal sulcus modulates connectivity between areas related to visual gesture and auditory speech processing.

Humans integrate information communicated by speech and gestures. Functional magnetic resonance imaging (fMRI) studies suggest that the posterior superior temporal sulcus (STS) and adjacent gyri are relevant for multisensory integration. However, a connectivity model representing this essential combinatory process is still missing. Here, we used dynamic causal modeling for fMRI to analyze the effective connectivity pattern between middle temporal gyrus (MTG), occipital cortex (OC) and STS associated with auditory verbal, visual gesture-related, and integrative processing, respectively, to unveil the neural mechanisms underlying integration of intrinsically meaningful gestures (e.g., "Thumbs-up gesture") and corresponding speech. 20 participants were presented videos of an actor either performing intrinsic meaningful gestures in the context of German or Russian sentences, or speaking a German sentence without gesture, while performing a content judgment task. The connectivity analyses resulted in a winning model that included bidirectional intrinsic connectivity between all areas. Furthermore, the model included modulations of both connections to the STS (OC→STS; MTG→STS), and non-linear modulatory effects of the STS on bidirectional connections between MTG and OC. Coupling strength in the occipital pathway (OC→STS) correlated with gesture related advantages in task performance, whereas the temporal pathway (MTG→STS) correlated with performance in the speech only condition. Coupling between MTG and OC correlated negatively with subsequent memory performance for sentences of the Gesture-German condition. Our model provides a first step towards a better understanding of speech-gesture integration on network level. It corroborates the importance of the STS during audio-visual integration by showing that this region inhibits direct auditory-visual coupling.

Action-Related Speech Modulates Beta Oscillations During Observation of Tool-Use Gestures.

Language and action have been thought of as closely related. Comprehending words or phrases that are related to actions commonly activates motor and premotor areas, and this comprehension process interacts with action preparation and/or execution. However, it remains unclear whether comprehending action-related language interacts with action observation. In the current study, we examined whether the observation of tool-use gesture subjects to interaction with language. In an electroencephalography (EEG) study (n = 20), participants were presented with video clips of an actor performing tool-use (TU, e.g., hammering with a fist) and emblematic (EM, e.g., the thumb up sign for 'good job') gestures accompanied by either comprehensible German (G) or incomprehensible Russian sentences (R). Participants performed a semantic judging task, evaluating whether the co-speech gestures were object- or socially-related. Behavioral results from the semantic task showed faster response for the TU versus EM gestures only in the German condition. For EEG, we found that TU elicited beta power decrease (~ 20 Hz) when compared to EM gestures, however this effect was reduced when gestures were accompanied by German instead of Russian sentences. We concluded that the processing of action-related sentences might facilitate gesture observation, in the sense that motor simulation required for TU gestures, as indexed by reduced beta power, was modulated when accompanied by comprehensible German speech. Our results corroborate the functional role of the beta oscillations during perception of hand gestures, and provide novel evidence concerning language-motor interaction.

Quantitative comparison of the copolymerisation kinetics in catalyst-transfer copolymerisation to synthesise polythiophenes.

Polythiophenes are one of the most widely studied conjugated polymers. With the discovery of the chain mechanism of Kumada catalyst-transfer polymerisation (KCTP), various polythiophene copolymer structures, such as random, block, and gradient copolymers, have been synthesized via batch or semi-batch (sequential addition) methods. However, the lack of quantitative kinetic data for thiophene monomers brings challenges to experimental design and structure prediction when synthesizing the copolymers. In this study, the reactivity ratios and the polymerisation rate constants of 3-hexylthiophene with 4 thiophene comonomers in KCTP are measured by adapting the Mayo-Lewis equation and the first-order kinetic behaviour of chain polymerisation. The obtained kinetic information highlights the impact of the monomer structure on the reactivity in the copolymerisations. The kinetic data are used to predict the copolymer structure of equimolar batch copolymerisations of the 4 thiophene derivatives with 3-hexylthiophene, with the experimental data agreeing well with the predictions. 3-Dodecylthiophene and 3-(6-bromo)hexylthiophene, which have higher structural similarity to 3-hexylthiophene, show nearly equivalent reactivity to 3-hexylthiophene and give random copolymers in the batch copolymerisation. 3-(2-Ethylhexyl)thiophene with a branched side chain is less reactive compared to 3-hexylthiophene and failed to homopolymerize at room temperature, but produced gradient copolymers with 3-hexylthiophene. Finally, the bulkiest 3-(4-octylphenyl)thiophene, despite its ability to homopolymerize, failed to maintain chain polymerisation in the copolymerisation with 3-hexylthiophene, possibly due to the large steric hindrance caused by the phenyl ring directly attached to the thiophene center. This study highlights the importance of monomer structures in copolymerisations and the need for accurate kinetic data.

Construction and Application of a Traditional Chinese Medicine Syndrome Differentiation Model for Dysmenorrhea Based on Machine Learning.

BACKGROUND: Dysmenorrhea is one of the most common ailments affecting young and middle-aged women, significantly impacting their quality of life. Traditional Chinese Medicine (TCM) offers unique advantages in treating dysmenorrhea. However, an accurate diagnosis is essential to ensure correct treatment. This research integrates the age-old wisdom of TCM with modern Machine Learning (ML) techniques to enhance the precision and efficiency of dysmenorrhea syndrome differentiation, a pivotal process in TCM diagnostics and treatment planning. METHODS: A total of 853 effective cases of dysmenorrhea were retrieved from the CNKI database, including patients' syndrome types, symptoms, and features, to establish the TCM information database of dysmenorrhea. Subsequently, 42 critical features were isolated from a potential set of 86 using a selection procedure augmented by Python's Scikit-Learn Library. Various machine learning models were employed, including Logistic Regression, Random Forest Classifier, Support Vector Machine (SVM), K-Nearest Neighbors (KNN), and Artificial Neural Networks (ANN), each chosen for their potential to unearth complex patterns within the data. RESULTS: Based on accuracy, precision, recall, and F1-score metrics, SVM emerged as the most effective model, showcasing an impressive precision of 98.29% and an accuracy of 98.24%. This model's analytical prowess not only highlighted the critical features pivotal to the syndrome differentiation process but also stands to significantly aid clinicians in formulating personalized treatment strategies by pinpointing nuanced symptoms with high precision. CONCLUSION: The study paves the way for a synergistic approach in TCM diagnostics, merging ancient wisdom with computational acuity, potentially innovating the diagnosis and treatment mode of TCM. Despite the promising outcomes, further research is needed to validate these models in real-world settings and extend this approach to other diseases addressed by TCM.

The PP2A inhibitor LB-100 mitigates lupus nephritis by suppressing tertiary lymphoid structure formation.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by multi-organ involvement and autoantibody production. Patients with SLE face a substantial risk of developing lupus nephritis (LN), which imposes a substantial burden on both patients and their families. Protein phosphatase 2A (PP2A) is a widely distributed serine/threonine phosphatase that participates in regulating multiple signaling pathways. Inhibition of PP2A has been implicated in the treatment of various diseases. LB-100, a small molecule inhibitor of PP2A, has demonstrated anti-tumor therapeutic effects and high safety profile in preclinical experiments. However, the role of PP2A and its inhibitor has been insufficiently studied in LN. In this study, we assessed the potential effects of LB-100 in both MRL/lpr mice and R848-induced BALB/c mice. Our findings indicated that LB-100 administration led to reduced spleen enlargement, decreased deposition of immune complexes, ameliorated renal damage, and improved kidney function in both spontaneous and R848-induced lupus mouse models. Importantly, we observed the formation of tertiary lymphoid structures (TLSs) in the kidneys of two distinct lupus mouse models. The levels of signature genes of TLS were elevated in the kidneys of lupus mice, whereas LB-100 mitigated chemokine production and inhibited TLS formation. In addition, we confirmed that inhibition or knockdown of PP2A reduced the production of T cell-related chemokines by renal tubular epithelial cells (RTEC). In summary, our study highlighted the renal protective potential of the PP2A inhibitor LB-100 in two distinct lupus mouse models, suggesting its potential as a novel strategy for treating LN and other autoimmune diseases.