The role of oxidative stress in the pathogenesis of ocular diseases: an overview.

Dysregulation of oxidative stress serves as a pivotal predisposing or exacerbating factor in the intricate development of numerous pathological processes and diseases. In recent years, substantial evidence has illuminated the crucial role of reactive oxygen species (ROS) in many fundamental cellular functions, including proliferation, inflammation, apoptosis, and gene expression. Notably, producing free radicals within ROS profoundly impacts a wide range of biomolecules, such as proteins and DNA, instigating cellular damage and impairing vital cellular functions. Consequently, oxidative stress emerges as a closely intertwined factor across diverse disease spectra. Remarkably, the pathogenesis of several eye diseases, including age-related macular degeneration, glaucoma, and diabetic retinopathy, manifests an intrinsic association with oxidative stress. In this comprehensive review, we briefly summarize the recent progress in elucidating the intricate role of oxidative stress in the development of ophthalmic diseases, shedding light on potential therapeutic avenues and future research directions.

Spatial skew-normal/independent models for nonrandomly missing clustered data.

Clinical studies on periodontal disease (PD) often lead to data collected which are clustered in nature (viz. clinical attachment level, or CAL, measured at tooth-sites and clustered within subjects) that are routinely analyzed under a linear mixed model framework, with underlying normality assumptions of the random effects and random errors. However, a careful look reveals that these data might exhibit skewness and tail behavior, and hence the usual normality assumptions might be questionable. Besides, PD progression is often hypothesized to be spatially associated, that is, a diseased tooth-site may influence the disease status of a set of neighboring sites. Also, the presence/absence of a tooth is informative, as the number and location of missing teeth informs about the periodontal health in that region. In this paper, we develop a (shared) random effects model for site-level CAL and binary presence/absence status of a tooth under a Bayesian paradigm. The random effects are modeled using a spatial skew-normal/independent (S-SNI) distribution, whose dependence structure is conditionally autoregressive (CAR). Our S-SNI density presents an attractive parametric tool to model spatially referenced asymmetric thick-tailed structures. Both simulation studies and application to a clinical dataset recording PD status reveal the advantages of our proposition in providing a significantly improved fit, over models that do not consider these features in a unified way.

Recent Advances of Molecularly Imprinted Polymers Based on Cyclodextrin.

Molecular imprinting polymers (MIPs), generally considered as artificial mimics that are comparable to natural receptor, are polymers with tailor-made specific recognition sites complementary to the template molecules in shape and size. As a class of supramolecular compounds, cyclodextrins (CDs) are flourishing in the field of molecular imprinting with their unique structural properties. This review presents recent advances in application of MIPs based on CDs during the past five years. The discussion is grouped according to the different role of CDs in MIPs, that is, functional monomer, carrier modifier, etc. Main focus is the application of CD-based MIP on sample preparation, detection, and sensing. Additionally, drug delivery with CD-based MIP is also briefly discussed. Finally, challenges and future prospects of application of CDs in MIP are elaborated.

Cocrystal of Apixaban-Quercetin: Improving Solubility and Bioavailability of Drug Combination of Two Poorly Soluble Drugs.

Drug combinations have been the hotspot of the pharmaceutical industry, but the promising applications are limited by the unmet solubility and low bioavailability. In this work, novel cocrystals, consisting of two antithrombotic drugs with poor solubility and low bioavailability in vivo, namely, apixaban (Apx) and quercetin (Que), were developed to discover a potential method to improve the poor solubility and internal absorption of the drug combination. Compared with Apx, the dissolution behavior of Apx-Que (1:1) and Apx-Que-2ACN (1:1:2) was enhanced significantly, while the physical mixture of the chemicals failed to exhibit the advantages. The dissolution improvements of Apx-Que-2ACN could be explained by the fact that the solid dispersion-like structure and column-shaped cage of Que accelerated the access of the solvent to the inner layer of Apx. The fracture of the hydrogen bonds of Apx, which was the joint of the adjacent Que chains, facilitated the break-up of the structures. Besides, the bioavailability of Apx-Que was increased compared with the physical mixture and Apx, and Apx-Que remained stable in high temperature and illumination conditions. Therefore, a drug-drug cocrystal of two antithrombotic agents with poor solubility was developed, which exhibited greatly improved solubility, bioavailability and superior stability, indicating a novel method to overcome the shortages of drug combination.

Blinatumomab compared with standard of care for the treatment of adult patients with relapsed/refractory Philadelphia chromosome-positive B-precursor acute lymphoblastic leukemia.

BACKGROUND: A single-arm, phase 2 trial demonstrated the efficacy and safety of blinatumomab, a bispecific T-cell-engaging antibody construct, in patients with relapsed/refractory (r/r) Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL), a rare hematologic malignancy with limited treatment options. This study compared outcomes with blinatumomab with those of a historical control treated with the standard of care (SOC). METHODS: The blinatumomab trial enrolled adult patients with Ph+ ALL who were r/r to at least 1 second-generation tyrosine kinase inhibitor (n = 45). Propensity score analysis (PSA) was used to compare outcomes with blinatumomab with those of an external cohort of similar patients receiving SOC chemotherapy (n = 55). The PSA mitigated confounding variables between studies by adjusting for imbalances in the age at diagnosis and start of treatment, sex, duration from diagnosis to most recent treatment, prior allogeneic hematopoietic stem cell transplantation, prior salvage therapy, and number of salvage therapies. Bayesian data augmentation was applied to improve power to 80% with data from a phase 3 blinatumomab study in r/r Philadelphia chromosome-negative ALL. RESULTS: In the PSA, the rate of complete remission or complete remission with partial hematologic recovery was 36% for blinatumomab and 25% for SOC, and this resulted in an odds ratio of 1.54 (95% confidence interval [CI], 0.61-3.89) or 1.70 (95% credible interval [CrI], 0.94-2.94) with Bayesian data augmentation. Overall survival favored blinatumomab over SOC, with a hazard ratio of 0.81 (95% CI, 0.57-1.14) or 0.77 (95% CrI, 0.61-0.96) with Bayesian data augmentation. CONCLUSIONS: These results further support blinatumomab as a treatment option for patients with r/r Ph+ ALL.

Salvianolic Acid D Alleviates Cerebral Ischemia-Reperfusion Injury by Suppressing the Cytoplasmic Translocation and Release of HMGB1-Triggered NF-κB Activation to Inhibit Inflammatory Response.

Inflammatory response participates in the overall pathophysiological process of stroke. It is a promising strategy to develop antistroke drugs targeting inflammation. This study is aimed at investigating the therapeutic effect and anti-inflammatory mechanism of salvianolic acid D (SalD) against cerebral ischemia/reperfusion (I/R) injury. A rat middle cerebral artery occlusion/reperfusion (MCAO/R) injury model was established, and an oxygen-glucose deprivation/reoxygenation (OGD/R) injury model was established in PC12 cells. Neurological deficit score, cerebral infarction, and edema were studied in vivo. Cell viability was achieved using the MTT method in vitro. The Bax, Bcl-2, cytochrome c, HMGB1, TLR4, TRAF6, NF-κB p65, p-NF-κB p65, and cleaved caspase-3 and -9 were tested via the Western blot method. Cytokines and cytokine mRNA, including TNF-α, IL-1ß, and IL-6, were studied via ELISA and PCR methods. The translocation of HMGB1 and NF-κB were studied by immunofluorescence assay. The HMGB1/NeuN, HMGB1/GFAP, and HMGB1/Iba1 double staining was carried out to observe the localization of HMGB1 in different cells. Results showed that SalD alleviated neurological impairment, decreased cerebral infarction, and reduced edema in I/R rats. SalD improved OGD/R-downregulated PC12 cell viability. SalD also promoted Bcl-2 expression and suppressed Bax, cytochrome c, and cleaved caspase-3 and -9 expression. SalD decreased the intensity of TLR4, MyD88, and TRAF6 proteins both in vivo and in vitro, and significantly inhibited the NF-κB nuclear translocation induced by I/R and OGD/R. What's more, SalD inhibited HMGB1 cytoplasmic translocation in neurons, astrocytes, and microglia in both the cortex and hippocampus regions of I/R rats. In conclusion, SalD can alleviate I/R-induced cerebral injury in rats and increase the PC12 cell viability affected by OGD/R. The anti-inflammatory mechanism of SalD might result from the decreased nuclear-to-cytoplasmic translocation of HMGB1 and the inhibition on its downstream TLR4/MyD88/NF-κB signaling.

Functional cerebral asymmetry analyses reveal how the control system implements its flexibility.

The control system in human brain generally exerts the goal-directed regulation on a variety of mental processes. To deal with different control demands, these brain areas of the control system, especially the dorsolateral prefrontal cortex (DLPFC), may be flexibly recruited across different tasks. However, few studies have investigated how the flexibility of the control system is realized during cognitive control. Present study employed functional magnetic resonance imaging to examine the brain responses during two domain distinct conflict tasks (verbal color-word Stroop and visuospatial arrow flanker). The voxel-wise asymmetries in both functional activity and psychophysiological interaction (PPI) between these two tasks were compared. The results showed that the brain areas of control system were consistently activated in these two tasks. When considering functional cerebral asymmetries, the left DLPFC was dominantly activated during the Stroop task, while more symmetric DLPFC activation was found during the flanker task. The left DLPFC rather than the right DLPFC showed greater positive interaction with the visual areas V1 and V2 during the Stroop interference, but interactions of both the left and right DLPFC with the right visual area V5/MT were positively enhanced during the flanker interference. These results suggest that the flexible cognitive control is achieved by the control system's task-specific activity and its top-down interaction with domain-specific brain areas, in implementing flexible representation and modulation of control demands.

Alertness function of thalamus in conflict adaptation.

Conflict adaptation reflects the ability to improve current conflict resolution based on previously experienced conflict, which is crucial for our goal-directed behaviors. In recent years, the roles of alertness are attracting increasing attention when discussing the generation of conflict adaptation. However, due to the difficulty of manipulating alertness, very limited progress has been made in this line. Inspired by that color may affect alertness, we manipulated background color of experimental task and found that conflict adaptation significantly presented in gray and red backgrounds but did not in blue background. Furthermore, behavioral and functional magnetic resonance imaging results revealed that the modulation of color on conflict adaptation was implemented through changing alertness level. In particular, blue background eliminated conflict adaptation by damping the alertness regulating function of thalamus and the functional connectivity between thalamus and inferior frontal gyrus (IFG). In contrast, in gray and red backgrounds where alertness levels are typically high, the thalamus and the right IFG functioned normally and conflict adaptations were significant. Therefore, the alertness function of thalamus is determinant to conflict adaptation, and thalamus and right IFG are crucial nodes of the neural circuit subserving this ability. Present findings provide new insights into the neural mechanisms of conflict adaptation.

Linking inter-individual differences in the conflict adaptation effect to spontaneous brain activity.

Conflict adaptation has been widely researched in normal and clinical populations. There are large individual differences in conflict adaptation, and it has been linked to the schizotypal trait. However, no study to date has examined how individual differences in spontaneous brain activity are related to behavioral conflict adaptation (performance). Resting-state functional magnetic resonance imaging (RS-fMRI) is a promising tool to investigate this issue. The present study evaluated the regional homogeneity (ReHo) of RS-fMRI signals in order to explore the neural basis of individual differences in conflict adaptation across two independent samples comprising a total of 67 normal subjects. A partial correlation analysis was carried out to examine the relationship between ReHo and behavioral conflict adaptation, while controlling for reaction time, standard deviation and flanker interference effects. This analysis was conducted on 39 subjects' data (sample 1); the results showed significant positive correlations in the left dorsolateral prefrontal cortex (DLPFC) and left ventrolateral prefrontal cortex. We then conducted a test-validation procedure on the remaining 28 subjects' data (sample 2) to examine the reliability of the results. Regions of interest were defined based on the correlation results. Regression analysis showed that variability in ReHo values in the DLPFC accounted for 48% of the individual differences in the conflict adaptation effect in sample 2. The present findings provide further support for the importance of the DLPFC in the conflict adaptation process. More importantly, we demonstrated that ReHo of RS-fMRI signals in the DLPFC can predict behavioral performance in conflict adaptation, which provides potential biomarkers for the early detection of cognitive control deterioration.

Curcumin Inhibits the Growth of Hepatocellular Carcinoma via the MARCH1-mediated Modulation of JAK2/STAT3 Signaling.

BACKGROUND: Curcumin has been reported to have anti-hepatocellular carcinoma (HCC) effects, but the underlying mechanism is not well known. OBJECTIVES: To investigate whether membrane-associated RING-CH 1 (MARCH1) is involved in the curcumin-induced growth suppression in HCC and its underlying molecular mechanism. A few recent patents for curcumin for cancer are also reviewed in this article. METHODS: The effect of curcumin on growth inhibition of HCC cells was analyzed through in vitro and in vivo experiments, and the expression levels of MARCH1, Bcl-2, VEGF, cyclin B1, cyclin D1, and JAK2/STAT3 signaling molecules were measured in HCC cells and the xenograft tumors in nude mice. Cell transfection with MARCH1 siRNAs or expression plasmid was used to explore the role of MARCH1 in the curcumin-induced growth inhibition of HCC cells. RESULTS: Curcumin inhibited cell proliferation, promoted apoptosis, and arrested the cell cycle at the G2/M phase in HCC cells with the decrease of Bcl-2, VEGF, cyclin B1, and cyclin D1 expression as well as JAK2 and STAT3 phosphorylation, resulting in the growth suppression of HCC cells. MARCH1 is highly expressed in HCC cells, and its expression was downregulated after curcumin treatment in a dose-dependent manner. The knockdown of MARCH1 by siRNA decreased the phosphorylation levels of JAK2 and STAT3 and inhibited the growth of HCC cells. In contrast, opposite results were observed when HCC cells overexpressed MARCH1. A xenograft tumor model in nude mice also showed that curcumin downregulated MARCH1 expression and decelerated the growth of transplanted HCC with the downregulation of JAK2/STAT3 signaling and functional molecules. The ADC value of MRI analysis showed that curcumin slowed down the progression of HCC. CONCLUSION: Our results demonstrated that curcumin may inhibit the activation of JAK2/STAT3 signaling pathway by downregulating MARCH1 expression, resulting in the growth suppression of HCC. MARCH1 may be a novel target of curcumin in HCC treatment.

Decidual natural killer cells dysfunction is caused by IDO downregulation in dMDSCs with Toxoplasma gondii infection.

Myeloid-derived suppressor cells (MDSCs) play a crucial role in maintaining maternal-fetal tolerance by expressing some immune-suppressive molecules, such as indoleamine 2,3-dioxygenase (IDO). Toxoplasma gondii (T. gondii) infection can break the immune microenvironment of maternal-fetal interface, resulting in adverse pregnancy outcomes. However, whether T. gondii affects IDO expression in dMDSCs and the molecular mechanism of its effect are still unclear. Here we show, the mRNA level of IDO is increased but the protein level decreased in infected dMDSCs. Mechanistically, the upregulation of transcriptional levels of IDO in dMDSCs is regulated through STAT3/p52-RelB pathway and the decrease of IDO expression is due to its degradation caused by increased SOCS3 after T. gondii infection. In vivo, the adverse pregnancy outcomes of IDO-/- infected mice are more severe than those of wide-type infected mice and obviously improved after exogenous kynurenine treatment. Also, the reduction of IDO in dMDSCs induced by T. gondii infection results in the downregulation of TGF-ß and IL-10 expression in dNK cells regulated through Kyn/AhR/SP1 signal pathway, eventually leading to the dysfunction of dNK cells and contributing the occurrence of adverse pregnancy outcomes. This study reveals a novel molecular mechanism in adverse pregnancy outcome induced by T. gondii infection.

Visualization of Microcirculation at Acupoints in vivo of Alzheimer's Disease Animal Model with Photoacoustic Microscope: A Pilot Study.

Background: Alzheimer's disease may be effectively treated with acupoint-based acupuncture, which is acknowledged globally. However, more research is needed to understand the alterations in acupoints that occur throughout the illness and acupuncture treatment. Objective: This research investigated the differences in acupoint microcirculation between normal mice and AD animals in vivo. This research also examined how acupuncture affected AD animal models and acupoint microcirculation. Methods: 6-month-old SAMP8 mice were divided into two groups: the AD group and the acupuncture group. Additionally, SAMR1 mice of the same month were included as the normal group. The study involved subjecting a group of mice to 28 consecutive days of acupuncture at the ST36 (Zusanli) and CV12 (Zhongwan) acupoints. Following this treatment, the Morris water maze test was conducted to assess the mice's learning and memory abilities; the acoustic-resolution photoacoustic microscope (AR-PAM) imaging system was utilized to observe the microcirculation in CV12 acupoint region and head-specific region of each group of mice. Results: In comparison to the control group, the mice in the AD group exhibited a considerable decline in their learning and memory capabilities (p < 0.01). In comparison to the control group, the vascular in the CV12 region and head-specific region in mice from the AD group exhibited a considerable reduction in length, distance, and diameter r (p < 0.01). The implementation of acupuncture treatment had the potential to enhance the aforementioned condition to a certain degree. Conclusions: These findings offered tangible visual evidence that supports the ongoing investigation into the underlying mechanisms of acupuncture's therapeutic effects.

De novo urinary incontinence and lower urinary tract symptoms after colpocleisis: A single-center prospective study.

Background: Colpocleisis is one of traditional surgical procedures for elderly and frail women with advanced pelvic organ prolapse. The occurrence of de novo urinary incontinence following colpocleisis was considered to impair the postoperative quality of life. The incidence of de novo urinary incontinence after colpocleisis has been reported to be ranging from 6.6 % to 27 %. There was an absence of prospective large-sample study to investigate the accurate incidence of de novo urinary incontinence following colpocleisis and the impact on the quality of life till now. Purpose: s The primary objective was to report the incidence of de novo urinary incontinence after colpocleisis. The second objectives were to evaluate the long-term quality of life in patients with de novo urinary incontinence, and to conduct detailed pre- and post-operative evaluations of lower urinary tract symptoms. Methods: This prospective study included 253 patients with symptomatic pelvic organ prolapse who underwent colpocleisis between 2009 and 2021. De novo urinary incontinence was defined as the occurrence of urinary incontinence 3 months postoperatively. All patients were required to complete the Urinary Distress Inventory questionnaire and the Urinary Impact Questionnaire for the evaluation of patients' quality of life, and the Patient Global Impression of Improvement questionnaire for the evaluation of patients' satisfaction. Results: 245 patients (245/253, 96·8 %) completed the 3-month follow-up, and were included in the final analysis. The incidence of de novo urinary incontinence was 5.4 % (10/185). There was no significant difference in the Urinary Distress Inventory -6 scores (22.50 vs. 10.30, P = 0.276) or the subjective satisfaction rate (100 % vs. 98.9 %, P = 0.250) between the patients with or without de novo urinary incontinence at the long-term follow-up. The incidence of voiding difficulty was significantly reduced after colpocleisis (27.8 % vs. 0.0 %, P < 0.001). The patients' quality of life indicated by Urinary Distress Inventory-6 and Urinary Impact Questionnaire-7 scores were significantly improved postoperatively (26.27 vs. 13.39, and 19.13 vs. 6.05, P < 0.05). Conclusion: The incidence of de novo urinary incontinence after colpocleisis was very low. Patients' quality of life, and low urinary tract symptoms were significantly improved after colpocleisis.

Single-cell transcriptomic analysis of decidual immune cell landscape in the occurrence of adverse pregnancy outcomes induced by Toxoplasma gondii infection.

BACKGROUND: Toxoplasma gondii is an obligate intracellular parasite that can lead to adverse pregnancy outcomes, particularly in early pregnancy. Previous studies have illustrated the landscape of decidual immune cells. However, the landscape of decidual immune cells in the maternal-fetal microenvironment during T. gondii infection remains unknown. METHODS: In this study, we employed single-cell RNA sequencing to analyze the changes in human decidual immune cells following T. gondii infection. The results of scRNA-seq were further validated with flow cytometry, reverse transcription-polymerase chain reaction, western blot, and immunofluorescence staining. RESULTS: Our results showed that the proportion of 17 decidual immune cell clusters and the expression levels of 21 genes were changed after T. gondii infection. Differential gene analysis demonstrated that T. gondii infection induced the differential expression of 279, 312, and 380 genes in decidual NK cells (dNK), decidual macrophages (dMφ), and decidual T cells (dT), respectively. Our results revealed for the first time that several previously unknown molecules in decidual immune cells changed following infection. This result revealed that the function of maternal-fetal immune tolerance declined, whereas the killing ability of decidual immune cells enhanced, eventually contributing to the occurrence of adverse pregnancy outcomes. CONCLUSIONS: This study provides valuable resource for uncovering several novel molecules that play an important role in the occurrence of abnormal pregnancy outcomes induced by T. gondii infection.

Disease-associated mutations disrupt functionally important regions of intrinsic protein disorder.

The effects of disease mutations on protein structure and function have been extensively investigated, and many predictors of the functional impact of single amino acid substitutions are publicly available. The majority of these predictors are based on protein structure and evolutionary conservation, following the assumption that disease mutations predominantly affect folded and conserved protein regions. However, the prevalence of the intrinsically disordered proteins (IDPs) and regions (IDRs) in the human proteome together with their lack of fixed structure and low sequence conservation raise a question about the impact of disease mutations in IDRs. Here, we investigate annotated missense disease mutations and show that 21.7% of them are located within such intrinsically disordered regions. We further demonstrate that 20% of disease mutations in IDRs cause local disorder-to-order transitions, which represents a 1.7-2.7 fold increase compared to annotated polymorphisms and neutral evolutionary substitutions, respectively. Secondary structure predictions show elevated rates of transition from helices and strands into loops and vice versa in the disease mutations dataset. Disease disorder-to-order mutations also influence predicted molecular recognition features (MoRFs) more often than the control mutations. The repertoire of disorder-to-order transition mutations is limited, with five most frequent mutations (R→W, R→C, E→K, R→H, R→Q) collectively accounting for 44% of all deleterious disorder-to-order transitions. As a proof of concept, we performed accelerated molecular dynamics simulations on a deleterious disorder-to-order transition mutation of tumor protein p63 and, in agreement with our predictions, observed an increased α-helical propensity of the region harboring the mutation. Our findings highlight the importance of mutations in IDRs and refine the traditional structure-centric view of disease mutations. The results of this study offer a new perspective on the role of mutations in disease, with implications for improving predictors of the functional impact of missense mutations.

Erratum: Author correction to 'Protective effects of VMY-2-95 on corticosterone-induced injuries in mice and cellular models' [Acta Pharmaceutica Sinica B 11(2021) 1903-1913].

[This corrects the article DOI: 10.1016/j.apsb.2021.03.002.].

Erratum: Author correction to 'Protective effects of VMY-2-95 on corticosterone-induced injuries in mice and cellular models' [Acta Pharmaceutica Sinica B 11 (2021) 1903-1913].

[This corrects the article DOI: 10.1016/j.apsb.2021.03.002.].

Cyr61 Mediates Angiotensin II-Induced Podocyte Apoptosis via the Upregulation of TXNIP.

Purpose: It is well documented that angiotensin II (Ang II) elevation promotes apoptosis of podocytes in vivo and vitro, but the potential mechanism is still oscular. The current study is aimed at probing into the assignment of cysteine-rich protein 61 (Cyr61) in Ang II-induced podocyte apoptosis. Methods: Podocytes were treated with Ang II (10-6 mol/L) for 48 hours to establish an injury model in vitro. Western blot assays were detected the expression of Cyr61, Cyt-c, Bax, and Bcl-2. Gene microarray was used to analyze the expression of mRNAs after treatment with Ang II. CRISPR/Cas9 technology was used to knock down Cyr61 and overexpress TXNIP gene, respectively. Results: The expression of Cyr61, TXNIP, Cyt-c, and Bax in podocytes treated with Ang II were upregulated, but the expression and apoptotic rates of Bcl-2 in podocytes were inhibited. The level of the above factors was not significantly different after the knockdown of Cyr61 with Ang II in podocytes. In Ang II group, when knocked down Cyr61, the expressed level of TXNIP, Cyt-c, and Bax was diminished after Ang II treatment; interestingly Bcl-2 expression and podocyte apoptotic rate were reduced. Under the stimulation of Ang II, the expression of Cyt-c and Bax were growing, whereas Bcl-2 was reduced, and the apoptotic rates were higher in the TXNIP overexpression group. Cyt-c and Bax were put on, whereas that of Bcl-2 was to be cut down when the Cyr61 was knockdown, and the apoptotic rates were gained in the TXNIP overexpression+Cyr61 knockdown group. Conclusions: The results of the study extrapolate that Cyr61 plays a dominant role in Ang II-induced podocyte apoptosis. Additionally, Cyr61 may mediate the Ang II-induced podocyte apoptosis by promoting the expression of TNXIP.

Effects of the need fulfillment given by opposite-sex friends on breakup considerations: A moderated mediation model.

The purpose of this study was to investigate the impact of need fulfillment given by opposite-sex friends (NFOF) on breakup considerations, the mediating role of love commitment in this relationship, and the moderating role of need fulfillment given by romantic partners (NFRP). A total of 334 unmarried individuals in romantic relationships from Northwest China were invited to participate in the study. The findings revealed the following: (1) NFOF significantly and positively predicted breakup considerations. (2) This relationship is mediated by love commitment (3) The association between NFOF and breakup considerations was moderated by NFRP (in terms of the first mediation path). Specifically, those who hold higher levels of NFRP are appreciably buffered against the negative impact of NFOF on love commitment. These findings emphasize the crucial role of NFOF and NFRP in shaping love commitment and breakup considerations. Moreover, our research has important realistic implications: NFOF, as a trigger, has a negative effects the quality of romantic relationships and leads to breakup considerations. And, the key to maintaining a romantic relationship is to focus on their partners' need fulfillment as much as possible and increasing the level of their love commitment.

A comprehensive evaluation of spontaneous pelvic organ prolapse in rhesus macaques as an ideal model for the study of human pelvic organ prolapse.

Pelvic organ prolapse (POP) seriously affects a woman's quality of life, and the treatment complications are severe. Although new surgical treatments are being developed, the host tissue responses and safety need to be evaluated in preclinical trials. However, there is a lack of suitable animal models, as most quadrupeds exhibit different structural and pathological changes. In this study, 72 elderly rhesus macaques (Macaca mulatta) were physically examined, and the incidence of spontaneous POP was similar to that in humans. The vaginal wall from five control monkeys and four monkeys with POP were selected for further analysis. Verhoeff-van Gieson staining showed that elastin content decreased significantly in monkeys with POP compared with control samples. Immunohistological staining revealed that the smooth muscle bundles in monkey POP appeared disorganized, and the number of large muscle bundles decreased significantly. The collagen I/III ratio in monkey POP also significantly decreased, as revealed by Sirius Red staining. These histological and biochemical changes in monkeys with POP were similar to those in humans with POP. Moreover, we generated a single-cell transcriptomic atlas of the prolapsed monkey vagina. Cross-species analysis between humans and monkeys revealed a comparable cellular composition. Notably, a differential gene expression analysis determined that dysregulation of the extracellular matrix and an immune disorder were the conserved molecular mechanisms. The interplay between fibroblasts and macrophages contributed to human and monkey POP. Overall, this study represents a comprehensive evaluation of spontaneous POP in rhesus macaques and demonstrates that monkeys are a suitable animal model for POP research.