Extended system-bath entanglement theorem with multiple baths in the presence of external fields.

The system-bath entanglement theorem (SBET) was established in terms of linear response functions [Du et al., J. Chem. Phys. 152, 034102 (2020)] and generalized to correlation functions [Su et al., J. Chem. Phys. 160, 084104 (2024)] in our previous studies. This theorem connects the entangled system-bath properties to the local system and bare-bath ones. In this work, we extend the SBET to field-dressed conditions with multiple baths at different temperatures. As in reality, the external fields may interact with not only the system but also environments. The extended SBET facilitates, for example, photo-acoustic, photo-thermal, pump-probe related studies. The theorem under the field-free condition (multiple baths) and its counterpart in the classical limit is also presented.

Allosteric Inhibition of the ß2-Adrenergic Receptor: Design and Synthesis of Cmpd-15 Analogs.

We designed and synthesized 27 new amide and dipeptide derivatives containing a substituted phenylalanine as negative allosteric modulators (NAMs) for the beta-2 adrenergic receptor (ß2AR). These analogs aimed to improve the activity of our lead compound, Cmpd-15, by introducing variations in three key regions: the meta-bromobenzyl methylbenzamide (S1), para-formamidophenylalanine (S2), and 1-cyclohexyl-1-phenylacetyl (S3) groups. The synthesis involved the Pd-catalyzed ß-C(sp3)-H arylation of N-acetylglycine with 1-iodo-4-substituent-benzenes as the key step. GloSensor cAMP accumulation assay revealed that six analogs (A1, C5, C6, C13, C15 and C17) surpass Cmpd-15 in ß2AR allosteric function. This highlights the crucial role of the S1 region (meta-bromobenzyl methylbenzamide) in ß2AR allostery while suggesting potential replaceability of the S2 region (para-formamidophenylalanine). These findings serve as a valuable springboard for further optimizing Cmpd-15, potentially leading to smaller, more active, and more stable ß2AR-targeting NAMs.

Impact of gender, posture and phase on back and lower extremity moments and muscle excitation during lifting task: a cross-sectional study.

Purpose: The aim of this work was to investigate and compare back and lower extremity joint moments and muscle excitation during stoop and squat postures by incorporating gender-based differences and analyzing lifting phases. Methods: 18 healthy adults (9 males and 9 females; age: 24.44 ± 4.96 years, body mass: 66.00 ± 12.10 kg, height: 170.11 ± 9.20 cm, lean body mass: 48.46 ± 7.66 kg) lifted an object 30% of their lean body mass using squat and stoop postures. Marker-based motion capture, force plate, and surface electromyography were synchronously used to acquire joint moments and muscle excitation. A 3-way mixed model analysis was performed to determine the effect of gender, posture, and phase on internal joint moments and muscle excitation of the lower back and extremities. Results: Significant differences were observed in the interaction of lifting posture and phase on lower extremity moments and excitation of rectus femoris and medial gastrocnemius. Individual effects of posture were significant for peak internal joint moments of the lower extremities only. Anterior lower extremity muscles showed significantly increased excitation during squat, whereas medial gastrocnemius was higher in stoop. Joint moments and muscle excitations were all higher during the lifting than the bending phase. Gender differences were found only in the peak lumbosacral sagittal plane moment and rectus femoris muscle excitation. Conclusions: The study identified significant variations in the joint moments and muscle excitation in lifting, influenced by gender, posture, and phase, highlighting its complex nature. Overall interactions were lacking, however individual effects were evident, necessitating larger future studies.

In vitro silencing of RIP2 in naive CD4+ T cells from lupus-prone mice promotes pathogenic Th17 cell differentiation.

OBJECTIVE: This work aims to investigate whether RIP2 silencing in naive CD4+ T cells from lupus-prone mice impacts Th17 cell activity or differentiation in vitro. METHODS: Naive CD4+ T cells isolation from MRL/lpr mice's spleens. Three RNA interference target sequences of RIP2 were packaged with lentivirus and transfected into naive CD4+ T cells. The shRIP2 with the highest interference efficiency was selected and transfected into naive CD4+ T cells. Naive CD4+ T cells were cultured under conventional (TGF-ß1 and IL-6) and pathogenic (IL-6, IL-23, IL-1ß) differentiation environments, respectively. Then, RT-qPCR, Western blot or Flow Cytometry were used for measuring the amounts of RIP2 and IL-17 and the differentiation of Th17 cells in two settings. RESULTS: Under the conventional Th17 (cTh17) cell differentiation environment (TGF-ß1 and IL-6), RIP2 deficiency is linked to decreased IL-17A levels (1.00 ± 0.03 vs 0.80 ± 0.03) and attenuated cTh17 cell (2.46 ± 0.08 vs 0.78 ± 0.03) differentiation (all, P < 0.05). Under the pathogenic Th17 (pTh17) cell environment (IL-1ß, IL-23, IL-6), RIP2 deficiency is linked to elevated IL-17A levels (1.03 ± 0.05 vs 1.63 ± 0.07) and enhanced pTh17 cell (3.69 ± 0.19 vs 5.49 ± 0.10) differentiation (all, P < 0.05). CONCLUSION: Our data suggest that RIP2 inhibition induces preferential differentiation of naive CD4+ T cells to pathogenic Th17 cells, while being able to upregulate IL-17A levels in the context of pTh17 cell differentiation. Our study opens up new research areas to reveal the underlying mechanisms and potential therapeutic targets for the prevention and treatment of SLE patients. Key Points • Silencing of RIP2 in naive CD4+ T cells from lupus-prone mice promotes pathogenic Th17 (pTh17) cell differentiation and IL-17A production under pTh17 cell (IL-1ß, IL-23, and IL-6) conditions. • RIP2 deficiency in naive CD4+ T cells reduces conventional Th17 (cTh17) cell differentiation and IL-17A production under cTh17 cell (TGF-ß1 and IL-6) conditions. • RIP2-deficient naive CD4+ T cells preferentially differentiate towards pTh17 cells rather than cTh17 cells in vitro. • Inhibition of RIP2 may be involved in the development of SLE via effects on Th17/IL-17.

Spontaneous separation of attractive chiral mixtures.

The separation of chiral matter has garnered significant attention due to its wide-ranging applications in biological and chemical processes. In prior researches, particle interactions were predominantly repulsive, but the indiscriminate attraction among particles under attractive interactions makes the separation of mixtures more difficult. The question of whether chiral mixed particles, characterized by attractive effects, can undergo spontaneous separation, remains unresolved. We study a binary mixture of chiral (counterclockwise or clockwise) active particles with attractive interactions. It is demonstrated that attractive chiral particles can undergo spontaneous separation without the aid of any specific strategies. The key factor driving the separation is the attractive interactions, enabling the formation of stable clusters of particles with same chirality. There exist optimal parameters (self-propelled velocity, angular velocity, and packing fraction) at which the separation is optimal. Our results may contribute to a deeper understanding of the mechanisms behind chiral matter separation and potentially catalyze further experimental investigations in this field.

Preparation and evaluation of a 1,1'-bi-2-naphthol-based chiral macrocycle bonded silica chiral stationary phase for high performance liquid chromatography.

Macrocycles play vital roles in supramolecular chemistry and chromatography. 1,1'-Bi-2-naphthol (BINOL)-based chiral polyimine macrocycles are an emerging class of chiral macrocycles that can be constructed by one-step aldehyde-amine condensation of BINOL derivatives with other building blocks. These macrocycles exhibit good characteristics, such as facile preparation, rigid cyclic structures, multiple chiral centers, and defined molecular cavities, that make them good candidates as new chiral recognition materials for chromatographic enantioseparations. In this study, a BINOL-based [2+2] chiral polyimine macrocycle was synthesized by one-step condensation of enantiopure (S)-2,2'-dihydroxy-[1,1'-binaphthalene]-3,3'-dicarboxaldehyde with (1R,2R)-1,2-diaminocyclohexane. The product was modified with 5-bromo-1-pentene and then attached to thiolated silica using click chemistry to construct a new chiral stationary phase (CSP). The enantioselectivity of the new CSP was explored by separating various racemates under normal phase (NP) and reversed phase (RP) high performance liquid chromatography (HPLC). Thirteen racemates and eight racemates were enantioseparated under the two separation modes, respectively, including chiral alcohols, phenols, esters, ketones, amines, and organic acids. Among them, nine racemates achieved baseline separation under NP-HPLC and seven racemates achieved baseline separation under RP-HPLC. High resolution separation was observed with benzoin (Rs = 5.10), epinephrine (Rs = 4.98), 3-benzyloxy-1,2-propanediol (Rs = 4.42), and 4,4'-dimethylbenzoin (Rs = 4.52) in NP-HPLC, and with 4-methylbenzhydrol (Rs = 4.72), benzoin ethyl ether (Rs = 3.79), 1-phenyl-1-pentanol (Rs = 3.68), and 1-(3-bromophenyl)ethanol (Rs = 3.60) in RP-HPLC. Interestingly, the CSP complemented Chiralcel OD-H, Chiralpak AD-H, and CYCLOBOND I 2000 RSP columns for resolution of these test racemates, separating several racemic compounds that could not be well separated by the three commercially available columns. The influences of injected sample amount on separation were also evaluated. It was found that the column exhibited excellent stability and reproducibility after hundreds of injections, and the relative standard deviations (n = 5) of the retention time and resolution were less than 0.49% and 0.69%, respectively. This study indicates that the BINOL-based chiral macrocycle has great potential for HPLC enantioseparation.

Choroidal vascular changes in early-stage myopic maculopathy from deep learning choroidal analysis: a hospital-based SS-OCT study.

BACKGROUND: The objective of this study is to illustrate the changes in the choroidal vasculature in individuals with diffuse chorioretinal atrophy (DCA, early-stage myopic maculopathy) and investigate the association between them. METHODS: This study included 1418 highly myopic eyes from 720 participants aged 18 - 60 years from the Wenzhou High Myopia Cohort Study. These participants underwent comprehensive ophthalmic assessments. Myopic maculopathy classification followed the Meta-PM system, with pathological myopia defined as myopic maculopathy of DCA or severer. Eyes with myopic maculopathy categorized as no macular lesions (C0), tessellated fundus (C1), and DCA (C2) were enrolled in the analysis. Choroidal images were obtained from swept-source optical coherence tomography (SS-OCT), and the images were processed with a deep learning-based automatic segmentation algorithm and the Niblack auto-local threshold algorithm. RESULTS: DCA was detected in 247 eyes (17.4%). In comparison to eyes with C0, those with C2 exhibited significant reductions in choroidal thickness (ChT), luminal area (LA), and stromal area (SA) across all evaluated regions (all P < 0.001). An increase in choroidal vascular index (CVI) was observed in all regions, except for the nasal perifoveal (N2) and inferior perifoveal (I2) regions (all P < 0.01). Multivariable logistic regression analysis revealed a negative association between the presence of DCA and increases in choroidal LA and SA (odds ratio ≤ 0.099, P < 0.001). Multivariable linear regression analysis showed that the mean deviation of the visual field test was positively associated with LA and SA at the vertical meridian (B = 1.512, P < 0.001 for LA; B = 1.956, P < 0.001 for SA). Furthermore, the receiver operating characteristic curve analyses showed the optimal ChT to diagnose pathological myopia was 82.4 µm in the N2 region, the LA was 0.076 mm2 and the SA was 0.049 mm2, with area under the curves of 0.916, 0.908, and 0.895, respectively. CONCLUSIONS: The results of this study indicated that both the presence of DCA and visual function impairment were associated with reductions in choroidal perfusion and stromal components. Moreover, we established threshold values for choroidal parameters in diagnosing pathological myopia, offering valuable references for clinical diagnosis and management.

Quantum neural network approach to Markovian dissipative dynamics of many-body open quantum systems.

Numerous variational methods have been proposed for solving quantum many-body systems, but they often face exponentially increasing computational complexity as the Hilbert space dimension grows. To address this, we introduce a novel approach using quantum neural networks to simulate the dissipative dynamics of many-body open quantum systems. This method combines neural-network quantum state representation with the time-dependent variational principle, both implemented via quantum algorithms. This results in accurate open quantum dynamics described by the Lindblad quantum master equation, exemplified by the spin-boson and transverse field Ising models. Our approach avoids the computational expense of classical algorithms and demonstrates the potential advantages of quantum computing for many-body simulations. To reduce measurement errors, we introduce a projection reset procedure, which could benefit other quantum simulations. In addition, our approach can be extended to simulate non-Markovian quantum dynamics.

[Effect of Flow Cytometric MRD Detection at Different Time Points during AML Chemotherapy on Prognosis].

OBJECTIVE: To investigate the effect of flow cytometric minimal residual disease (MRD) detection at different time points during AML chemotherapy on prognosis. METHODS: 130 adult primary AML patients diagnosed and standardized with chemotherapy from March 2018 to March 2022 were retrospectively analyzed, MRD was detected by flow cytometry, Kaplan-Meier curves was used for survival analysis and log-rank test was used for variance analysis, and univariate and multifactor influencing patient survival with COX proportional risk regression model analysis. Cumulative incidence rate (CIR) analysis with competing risk model and variance analysis using Fine-Gray. RESULTS: There were 81 CR1, 26 CR2, 14 PR, and 9 NR patients in 130 patients. OS of the CR1 group was higher than that in the CR2, PR,and NR groups. OS of the CR2 group was higher than that in the PR group, but there was no statistically difference compared to the NR group. There was no statistically difference in OS between the PR and NR groups. 107 patients in CR1 and CR2 were grouped according to MRD detected by flow cytometry, and after the first induction chemotherapy, for patients in the MRD- and MRD+ groups, the 4-year expected RFS rates were 65.3% and 27.9% respectively, the 4-year expected OS rates were 58.7% and 41.4% respectively, and the 4-year expected CIR were 34.7% and 69.7% respectively, with statistically significant differences between 2 groups (χ2=6.639, P =0.010; χ2=6.131, P =0.013 and χ2=6.637， P =0.010). After the second chemotherapy, for patients in the MRD- and MRD+ groups, the 4-year expected RFS rates were 50.8% and 37.9% respectively, the 4-year expected OS rates were 49.2% and 44.5% respectively, and the 4-year expected CIR were 49.2% and 59.5% respectively, with no statistically significant differences between 2 groups (χ2=1.475, P =0.225; χ2=2.432, P =0.119 and χ2=1.416， P =0.234). During consolidation therapy, for patients in the MRD - and MRD+ groups, the 4-year expected RFS rates were 51.9% and 29.6% respectively, the 4-year expected OS rates were 67.5% and 24.6% respectively, and the 4-year expected CIR were 48.1% and 70.4% respectively, with statistically significant differences between 2 groups (χ2=20.982, P < 0.001; χ2=17.794, P < 0.001 and χ2=19.879， P < 0.001). For patients with MRD- at all three time points and positive at either time point, the 4-year expected RFS rates were 69.9% and 33.3% respectively, the 4-year expected OS rates were 59.1% and 44.7% respectively, and the 4-year expected CIR were 30.1% and 65.1% respectively, with statistically significant differences between 2 groups (χ2=7.367, P =0.007; χ2=6.042, P =0.014 and χ2=7.662， P =0.006). Univariate analysis showed that karyotype at high risk of chromosome was an unfavorable factor affecting patients' RFS and OS, while 2 cycles of induction chemotherapy achieved CR, MRD- after the first induction chemotherapy and MRD- after the second induction chemotherapy was a protective factor affecting patients' RFS and OS. MRD- during consolidation therapy and MRD- at all three time points were all protective factors affecting patients' RFS, OS and CIR. Multivariate analysis showed that induction chemotherapy for 2 cycles achieved CR was a protective factor affecting patients' RFS and CIR, and MRD- during consolidation therapy was a protective factor affecting patients' RFS, OS and CIR. CONCLUSION: Early achievement of CR and MRD- in adult AML patients, especially MRD- during consolidation therapy, is a marker of good prognosis, and flow cytometry is the most commonly used method for MRD detection in AML patients.

A new extraction method of underglaze brown decorative pattern based on the coupling of single scale gamma correction and gray sharpening.

In order to solve the problem of image quality and morphological characteristics of primary underglaze brown decorative pattern extraction, this paper proposes a method of primary underglaze brown decorative pattern extraction based on the coupling of single scale gamma correction and gray sharpening. The single-scale gamma correction is combined with the gray sharpening method. The single-scale gamma correction improves the contrast and brightness of the image by nonlinear transformation, but may lead to the loss of image detail. Gray sharpening can enhance the high frequency component and improve the clarity of the image, but it will introduce noise. Combining these two technologies can compensate for their shortcomings. The experimental results show that this method can improve the efficiency of last element underglaze brown decorative pattern extraction by enhancing the image retention detail and reducing the influence of noise. The experimental results showed that F1Score, Miou(%), Recall, Precision and Accuracy(%) were 0.92745, 0.82253, 0.97942, 0.92458 and 0.92745, respectively.

Influence of Ocular Biometric Parameters on Intraocular Lens Position: A Prospective Cohort Study.

PURPOSE: To assess the influence of ocular biometric parameters on intraocular lens (IOL) tilt and decentration after cataract surgery. METHODS: Patients scheduled for cataract surgery were screened for inclusion in this prospective cohort study. Tilt and decentration of the crystalline lens and IOL were measured using the CASIA2 (Tomey). Anterior chamber depth (ACD), lens thickness (LT), and axial length (AL) were preoperatively measured by the IOLMaster 700 (Carl Zeiss Meditec AG). Multivariate regression analysis was performed to assess the influence of ocular biometric parameters on IOL tilt and decentration after cataract surgery. RESULTS: In total, 191 eyes of 120 patients were included. Age was positively correlated with IOL tilt, whereas ACD and AL were negatively correlated with IOL tilt. A strong positive correlation was found between preoperative crystalline lenses and postoperative IOLs in tilt magnitude (r = 0.769, P < .001) and tilt direction (r = 0.688, P < .001). A positive correlation was found between preoperative and postoperative lens decentration magnitude and decentration direction. Greater postoperative IOL tilt and decentration were significantly associated with greater preoperative crystalline lens tilt (P < .001) and decentration (P = .027). CONCLUSIONS: IOL tilt was greater in older patients. Shorter AL and shallower ACD contributed to greater IOL tilt. The tilt and decentration of the IOL will be greater in patients with greater tilt and decentration of the crystalline lens. [J Refract Surg. 2024;40(7):e438-e444.].

Differential responses of soil bacteria, fungi and protists to root exudates and temperature.

The impact of climate warming on soil microbes has been well documented, with studies revealing its effects on diversity, community structure and network dynamics. However, the consistency of soil microbial community assembly, particularly in response to diverse plant root exudates under varying temperature conditions, remains an unresolved issue. To address this issue, we employed a growth chamber to integrate temperature and root exudates in a controlled experiment to examine the response of soil bacteria, fungi, and protists. Our findings revealed that temperature independently regulated microbial diversity, with distinct patterns observed among bacteria, fungi, and protists. Both root exudates and temperature significantly influenced microbial community composition, yet interpretations of these factors varied among prokaryotes and eukaryotes. In addition to phototrophic bacteria and protists, as well as protistan consumers, root exudates determined to varying degrees the enrichment of other microbial functional guilds at specific temperatures. The effects of temperature and root exudates on microbial co-occurrence patterns were interdependent; root exudates primarily simplified the network at low and high temperatures, while responses to temperature varied between single and mixed exudate treatments. Moreover, temperature altered the composition of keystone species within the microbial network, while root exudates led to a decrease in their number. These results emphasize the substantial impact of plant root exudates on soil microbial community responses to temperature, underscoring the necessity for future climate change research to incorporate additional environmental variables.

Rotational inertia-induced glassy transition in chiral particle systems.

The dense active matter exhibits characteristics reminiscent of traditional glassy phenomena, yet the role of rotational inertia in glass dynamics remains elusive. In this study, we investigate the glass dynamics of chiral active particles influenced by rotational inertia. Rotational inertia endows exponential memory to particle orientation, restricting its alteration and amplifying the effective persistence time. At lower spinning frequencies, the diffusion coefficient exhibits a peak function relative to rotational inertia for shorter persistence times, while it steadily increases with rotational inertia for longer persistence times. In the realm of high-frequency spinning, the impact of rotational inertia on diffusion behavior becomes more pronounced, resulting in a nonmonotonic and intricate relationship between the diffusion coefficient and rotational inertia. Consequently, the introduction of rotational inertia significantly alters the glassy dynamics of chiral active particles, allowing for the control over transitions between fluid and glassy states by modulating rotational inertia. Moreover, our findings indicate that at a specific spinning temperature, there exists an optimal spinning frequency at which the diffusion coefficient attains its maximum value.

Plasma lipidomics profiling in predicting the chemo-immunotherapy response in advanced non-small cell lung cancer.

Background: Advanced non-small cell lung cancer (NSCLC) presents significant treatment challenges, with chemo-immunotherapy emerging as a promising approach. This study explores the potential of lipidomic biomarkers to predict responses to chemo-immunotherapy in advanced non-small cell lung cancer (NSCLC) patients. Methods: A prospective analysis was conducted on 68 NSCLC patients undergoing chemo-immunotherapy, divided into disease control (DC) and progressive disease (PD) groups based on treatment response. Pre-treatment serum samples were subjected to lipidomic profiling using liquid chromatography-mass spectrometry (LC-MS). Key predictive lipids (biomarkers) were identified through projection to latent structures discriminant analysis. A biomarker combined model and a clinical combined model were developed to enhance the prediction accuracy. The predictive performances of the clinical combined model in different histological subtypes were also performed. Results: Six lipids were identified as the key lipids. The expression levels of PC(16:0/18:2), PC(16:0/18:1), PC(16:0/18:0), CE(20:1), and PC(14:0/18:1) were significantly up-regulated. While the expression level of TAG56:7-FA18:2 was significantly down-regulated. The biomarker combined model demonstrated a receiver operating characteristic (ROC) curve of 0.85 (95% CI: 0.75-0.95) in differentiating the PD from the DC. The clinical combined model exhibited an AUC of 0.87 (95% CI: 0.79-0.96) in differentiating the PD from the DC. The clinical combined model demonstrated good discriminability in DC and PD patients in different histological subtypes with the AUC of 0.78 (95% CI: 0.62-0.96), 0.79 (95% CI: 0.64-0.94), and 0.86 (95% CI: 0.52-1.00) in squamous cell carcinoma, large cell carcinoma, and adenocarcinoma subtype, respectively. Pathway analysis revealed the metabolisms of linoleic acid, alpha-linolenic acid, glycerolipid, arachidonic acid, glycerophospholipid, and steroid were implicated in the chemo-immunotherapy response in advanced NSCLC. Conclusion: Lipidomic profiling presents a highly accurate method for predicting responses to chemo-immunotherapy in patients with advanced NSCLC, offering a potential avenue for personalized treatment strategies.

Spectral-Sensing System for Distinguishing CH3OH and CD3OD.

Spectrally discriminating CH3OH and CD3OD, and even detecting CH3OH contents in the CD3OD solvent, are important yet have not been achieved so far, likely owing to their very similar chemical/physical properties. Herein, dynamic transesterification reactions, which can be achieved via two-step proton transfers, can be signaled via ultraviolet UV-visible (UV/vis) absorption and fluorescence spectroscopies under mild experimental conditions. Introduction of strong electron-withdrawing groups, such as -NO2, to the aromatic ring (benzoic acid moiety or phenol moiety) of carboxylate esters to activate the esters is important for transesterification reactions and is an intriguing method for modulating the selectivity of the spectral response. The rate constant of the transesterification reaction enhanced with increasing the total number of strong electron-withdrawing groups. Furthermore, the rate constants of esters in which substituent(s) are connected to the phenol moiety are higher than those of corresponding esters in which substituent(s) are connected to the benzoic acid moiety. In transesterification systems, added aliphatic amines mainly play two roles: (i) lowering the energy barrier of the first transesterification step via the formation of intermolecular hydrogen bonding in ternary systems and (ii) deprotonating the released 4-nitrophenol in UV/vis absorption spectral systems to generate an UV/vis absorption spectral signal reporter, i.e., nitrophenolate anions. As a result of the methanol-mediated transesterification reaction, spectral-sensing systems can be established for discriminating CH3OH and CD3OD and even detecting low CH3OH contents in the CD3OD solvent, owing to the kinetic isotope effect. This is the first example of spectral recognition between CD3OD and CH3OH.

FTY720 ameliorates experimental MPO-ANCA-associated vasculitis by regulating fatty acid oxidation via the neutrophil PPARα-CPT1a pathway.

OBJECTIVES: Increasing studies demonstrated the importance of C5a and anti-neutrophil cytoplasmic antibody (ANCA)-induced neutrophil activation in the pathogenesis of ANCA-associated vasculitis (AAV). Sphingosine-1-phosphate (S1P) acts as a downstream effector molecule of C5a and enhances neutrophil activation induced by C5a and ANCA. The current study investigated the role of a S1P receptor modulator, FTY720, in experimental autoimmune vasculitis (EAV) and explored the immunometabolism-related mechanisms of FTY720 in modulating ANCA-induced neutrophil activation. METHODS: The effects of FTY720 in EAV were evaluated by quantifying haematuria, proteinuria, crescent formation, tubulointerstitial injury and pulmonary haemorrhage. RNA sequencing of renal cortex and gene enrichment analysis were performed. The proteins of key identified pathways were analysed in neutrophils isolated from peripheral blood of patients with active AAV and normal controls. We assessed the effects of FTY720 on ANCA-induced neutrophil respiratory burst and neutrophil extracellular traps formation (NETosis). RESULTS: FTY720 treatment significantly attenuated renal injury and pulmonary haemorrhage in EAV. RNA sequencing analyses of renal cortex demonstrated enhanced fatty acid oxidation (FAO) and peroxisome proliferator-activated receptor (PPAR) signalling in FTY720-treated rats. Compared with normal controls, patients with active AAV showed decreased FAO in neutrophils. FTY720-treated differentiated HL-60 cells showed increased expression of carnitine palmitoyltransferase 1a (CPT1a) and PPARα. Blocking or knockdown of CPT1a or PPARα in isolated human neutrophils and HL-60 cells reversed the inhibitory effects of FTY720 on ANCA-induced neutrophil respiratory burst and NETosis. CONCLUSION: FTY720 attenuated renal injury in EAV through upregulating FAO via the PPARα-CPT1a pathway in neutrophils, offering potential immunometabolic targets in AAV treatment.

A PRMT5-ZNF326 axis mediates innate immune activation upon replication stress.

DNA replication stress (RS) is a widespread phenomenon in carcinogenesis, causing genomic instability and extensive chromatin alterations. DNA damage leads to activation of innate immune signaling, but little is known about transcriptional regulators mediating such signaling upon RS. Using a chemical screen, we identified protein arginine methyltransferase 5 (PRMT5) as a key mediator of RS-dependent induction of interferon-stimulated genes (ISGs). This response is also associated with reactivation of endogenous retroviruses (ERVs). Using quantitative mass spectrometry, we identify proteins with PRMT5-dependent symmetric dimethylarginine (SDMA) modification induced upon RS. Among these, we show that PRMT5 targets and modulates the activity of ZNF326, a zinc finger protein essential for ISG response. Our data demonstrate a role for PRMT5-mediated SDMA in the context of RS-induced transcriptional induction, affecting physiological homeostasis and cancer therapy.

Relationship between ultrasound parameters of the umbilical and middle cerebral arteries and intrauterine fetal distress.

BACKGROUND: By comprehensively analyzing the blood flow parameters of the umbilical and middle cerebral arteries, doctors can more accurately identify fetal intrauterine distress, as well as assess its severity, so that timely interventions can be implemented to safeguard the health and safety of the fetus. AIM: To identify the relationship between ultrasound parameters of the umbilical and middle cerebral arteries and intrauterine distress. METHODS: Clinical data of pregnant women admitted between January 2021 and January 2023 were collected and divided into the observation and control groups (n = 50 each), according to the presence or absence of intrauterine distress. The ultrasound hemodynamic parameters of the uterine artery (UtA), fetal middle cerebral artery (MCA), and umbilical artery (UmA) were compared with neonatal outcomes and occurrence of intrauterine distress in the two groups. RESULTS: Comparison of ultrasonic hemodynamic parameters, resistance index (RI), pulsatility index (PI), and systolic maximal blood flow velocity of UmA compared to diastolic blood flow velocity (S/D), revealed higher values of fetal MCA, PI, and S/D of UmA in pregnant women with UtA compared to controls (P < 0.05), while there was no difference between the two groups in terms of RI (P < 0.05) The incidence of a neonatal Apgar score of 8-10 points was lower in the observation group (66.7%) than in the control group (90.0%), and neonatal weight (2675.5 ± 27.6 g) was lower than in the control group (3117.5 ± 31.2 g). Further, cesarean section rate was higher in the observation group (70.0%) than in the control group (11.7%), and preterm labor rate was higher in the observation group (40.0%) than in the control group (10.0%). The incidence of fetal distress, neonatal growth restriction and neonatal asphyxia were also higher in the observation group (all P < 0.05). CONCLUSION: Fetal MCA, UmA, and maternal UtA hemodynamic abnormalities all develop in pregnant women with intrauterine distress during late pregnancy, which suggests that clinical attention should be paid to them, and monitoring should be strengthened to provide guidance for clinical intervention.

Vitamin D supplementation for cardiometabolic risk markers in pregnant women based on the gestational diabetes mellitus or obesity status : a randomized clinical trial.

PURPOSE: Women with gestational diabetes mellitus (GDM) or obesity are vulnerable to impaired gestational cardiovascular health (CVH) and cardiovascular disease (CVD) in the future. It is unclear if prenatal vitamin D supplementation improves gestational CVH, especially in women at high risk for developing CVD. Our goal was to find out if vitamin D supplementation could protect against gestational CVH, including the women with GDM or obesity. DESIGN: We randomly assigned women with a serum 25(OH)D concentration < 75 nmol/L to receive 1600 IU/d (intervention group) or 400 IU/d (control group) of vitamin D3 for two months at 24-28 weeks' gestation. The primary outcome was gestational CVH marks (lipids, inflammatory cytokines, endothelial function). RESULTS: There were 1537 participants divided into the intervention (N = 766) and control groups (N = 771). No baseline differences existed among study groups in CVH markers. At the two-month visit, the intervention group's HDL-C levels (2.01 ± 0.39 VS 1.96 ± 0.39 mmol/L) were significantly higher than those of the control group, while the hs-CRP levels were significantly lower (3.28 ± 2.02 VS 3.64 ± 2.42 mg/L). Subgroup analysis found that HDL-C, TC, hs-CRP, E-Selectin, and SBP were improved in the intervention group among women with GDM or overweight/obesity, and the improvement was not found in women without GDM or overweight/obesity. Vitamin D supplementation significantly decreased the mean triglyceride-glucose index at the two-month visit in women with GDM. CONCLUSIONS: Vitamin D supplementation at mid-gestation might optimize the gestational CVH status for pregnant women, particularly the women with GDM or obesity, which is advantageous for later-life primary prevention of CVD. CLINICAL TRIAL REGISTRATION: The Chinese Clinical Trial Registry (ChiCTR2100051914, 10/9/2021, Prospective registered, https://www.chictr.org.cn/showproj.aspx?proj=134700 ).

Progression of cognitive impairment in Parkinson's disease correlates with uric acid concentration.

Introduction: This study assessed the relationship between the progression of Parkinson's disease (PD) with cognitive impairment and changes in serum uric acid (UA) and homocysteine (Hcy) concentrations and explored the factors influencing PD with cognitive impairment. Methods: The study randomly selected 74 patients with PD and evaluated their cognitive function using the Montreal Cognitive Assessment Scale (MoCA). Patients with PD were divided into two subgroups: those with and without cognitive impairment. PD severity was evaluated and graded using the Hoehn and Yahr (H-Y) scale. Another 60 middle-aged and older individuals without PD during the same period were selected as a control group. Blood UA and Hcy concentrations in each group were measured to assess the relationship between PD, cognitive impairment, and changes in UA and Hcy concentrations. Results: The PD group with cognitive impairment had a lower UA concentration and higher Hcy concentration. The UA concentration was significantly higher in the early PD stages than in the middle and late stages (P<0.05). A significant negative relationship between MoCA scores and serum UA levels was found in patients with PD, whereas a positive relationship existed between MoCA scores and serum Hcy concentrations. Regression analysis showed that a higher UA concentration was an independent protective factor for PD with cognitive impairment, while a higher Hcy concentration was a risk factor (P<0.05). A serum UA concentration of 212.9 mmol/L and Hcy concentration of 13.35 mmol/L could distinguish between patients with PD with or without cognitive impairment with a sensitivity of 93.2% and specificity of 43.3%. Conclusion: PD and cognitive impairment were associated with a decrease in UA concentration; the later the H-Y stage was, the lower the UA concentration was. The increase in Hcy concentration was related to PD and its cognitive impairment, whereas it is not significantly correlated with PD progression.