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Abstract Neovaginas are surgically constructed to correct uterovaginal agenesis in women with Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome or as part of gender-affirming surgery for transfeminine individuals. Understanding the assembly of the neovaginal microbiota is crucial for guiding its management. To address this, we conducted a longitudinal study on MRKH patients following laparoscopic peritoneal vaginoplasty. Our findings reveal that the early microbial assemblage exhibited stochastic characteristics, accompanied with a notable bloom of Enterococcus faecalis and genital Mycoplasmas. While both the pre-surgery dimple microbiota and the fecal microbiota constituted the primary species pool, the neovaginal microbiota developed into a microbiota that resembled that of a normal vagina at 6–12 months post-surgery, albeit with a bacterial vaginosis (BV)-like structure. By 2–4 years post-surgery, the neovaginal microbiota had further evolved into a structure closely resembling with the homeostatic pre-surgery dimple microbiota. This concords with the development of the squamous epithelium in the neovagina and highlights the pivotal roles of progressive selective forces imposed by the evolving neovaginal environment and the colonization tropism of vaginal species. Notably, we observed that strains of Lactobacillus crispatus colonizing the neovagina primarily originated from the dimple. Since L. crispatus is generally associated with vaginal health, this finding suggests potential avenues for future research to promote its colonization.

The interconnectivity of advanced biological systems is essential for their proper functioning. In modern connectomics, biological entities such as proteins, genes, RNA, DNA, and metabolites are often represented as nodes, while the physical, biochemical, or functional interactions between them are represented as edges. Among these entities, metabolites are particularly significant as they exhibit a closer relationship to an organism’s phenotype compared to genes or proteins. Moreover, the metabolome has the ability to amplify small proteomic and transcriptomic changes, even those from minor genomic changes. Metabolic networks, which consist of complex systems comprising hundreds of metabolites and their interactions, play a critical role in biological research by mediating energy conversion and chemical reactions within cells. This review provides an introduction to common metabolic network models and their construction methods. It also explores the diverse applications of metabolic networks in elucidating disease mechanisms, predicting and diagnosing diseases, and facilitating drug development. Additionally, it discusses potential future directions for research in metabolic networks. Ultimately, this review serves as a valuable reference for researchers interested in metabolic network modeling, analysis, and their applications.

RationaleFructose-1,6-bisphosphatase (FBP1) is a tumor suppressor and a key enzyme negatively regulating Warburg effect in cancer. However, regulation of FBP1 protein expression and its exact role in prostate cancer (PCa) is largely unclear. Phosphatase and tensin homolog (PTEN) is one of the most frequently deleted tumor suppressor genes in human PCa. However, the role of PTEN loss in aberrant Warburg effect in cancer remains poorly understood.MethodsExpression of PTEN and FBP1 was analyzed in several PCa cell lines and prostate tumor tissues in mice. Western blot (WB) and RT-PCR approaches were used to examine how PTEN regulates FBP1 expression. Co-immunoprecipitation (co-IP) and in vivo ubiquitination assays were used to define the regulatory mechanisms. A PCa xenograft model was employed to determine the impact of PTEN regulation of FBP1 on PCa growth in vivo.ResultWe demonstrated that in a manner dependent of PI3K/AKT signal pathway PTEN regulated FBP1 expression in various PCa cell lines and tumors in mice. We confirmed that this regulation took place at the protein level and was mediated by SKP2 E3 ubiquitin ligase. Mechanistically, we showed that serine 271 phosphorylation of FBP1 by cyclin-dependent kinases (CDKs) was essential for SKP2-mediated degradation of FBP1 protein induced by PTEN loss. Most importantly, we further showed that loss of PTEN expression enhanced Warburg effect and PCa growth in mice in a manner dependent, at least partially on FBP1 protein degradation.ConclusionsOur results reveal a novel tumor-suppressive feature of PTEN in restraining FBP1 degradation and the Warburg effect. These results also suggest that prohibiting FBP1 protein degradation could be a viable therapeutic strategy for PTEN-deficient PCa.

Brain functional network (BFN) based on electroencephalography (EEG) has been widely used to diagnose brain diseases, such as major depressive disorder (MDD). However, most existing BFNs only consider the correlation between two channels, ignoring the high-level interaction among multiple channels that contain more rich information for diagnosing brain diseases. In such a sense, the BFN is called low-order BFN (LO-BFN). In order to fully explore the high-level interactive information among multiple channels of the EEG signals, a scheme for constructing a high-order BFN (HO-BFN) based on the “correlation’s correlation” strategy is proposed in this paper. Specifically, the entire EEG time series is firstly divided into multiple epochs by sliding window. For each epoch, the short-term correlation between channels is calculated to construct a LO-BFN. The correlation time series of all channel pairs are formulated by these LO-BFNs obtained from all epochs to describe the dynamic change of short-term correlation along the time. To construct HO-BFN, we cluster all correlation time series to avoid the problems caused by high dimensionality, and the correlation of the average correlation time series from different clusters is calculated to reflect the high-order correlation among multiple channels. Experimental results demonstrate the efficiency of the proposed HO-BFN in MDD identification, and its integration with the LO-BFN can further improve the recognition rate.

Functional connectivity (FC) network based on resting-state functional magnetic resonance imaging (rs-fMRI) has become an important tool to explore and understand the brain, which can provide objective basis for the diagnosis of neurodegenerative diseases, such as autism spectrum disorder (ASD). However, most functional connectivity (FC) networks only consider the unilateral features of nodes or edges, and the interaction between them is ignored. In fact, their integration can provide more comprehensive and crucial information in the diagnosis. To address this issue, a new multi-view brain network feature enhancement method based on self-attention mechanism graph convolutional network (SA-GCN) is proposed in this article, which can enhance node features through the connection relationship among different nodes, and then extract deep-seated and more discriminative features. Specifically, we first plug the pooling operation of self-attention mechanism into graph convolutional network (GCN), which can consider the node features and topology of graph network at the same time and then capture more discriminative features. In addition, the sample size is augmented by a “sliding window” strategy, which is beneficial to avoid overfitting and enhance the generalization ability. Furthermore, to fully explore the complex connection relationship among brain regions, we constructed the low-order functional graph network (Lo-FGN) and the high-order functional graph network (Ho-FGN) and enhance the features of the two functional graph networks (FGNs) based on SA-GCN. The experimental results on benchmark datasets show that: (1) SA-GCN can play a role in feature enhancement and can effectively extract more discriminative features, and (2) the integration of Lo-FGN and Ho-FGN can achieve the best ASD classification accuracy (79.9%), which reveals the information complementarity between them.

Abstract Background Cell autophagy has been proposed to be involved in drug resistance therapy. However, how the long non-coding RNA (lncRNA) reduces risks of drug resistance in renal cancer (RC) cells needs a thorough inquiry. This study was assigned to probe the effect and mechanism of HOTAIR on sunitinib resistance of RC. Methods Clinical RC tissues and para-carcinoma tissues were obtained to detect the expressions of miR-17-5p, HOTAIR and Beclin1. Sunitinib-resistant cells (786-O-R and ACHN-R) were constructed using parental RC cells (786-O and ACHN). The resistance of 786-O-R and ACHN-R cells to sunitinib was examined. Western blot and qRT-PCR were assayed to obtain the expressions of miR-17-5p, HOTAIR and Beclin1. The effects of HOTAIR knockdown or miR-17-5p overexpression/knockdown on cell autophagy and sunitinib resistance were measured by MDC staining, immunofluorescence and Western blot. The sensitivity of RC cells to sunitinib and change in cell clone formation after sunitinib treatment were assessed by CCK-8 assay and colony formation assay, respectively. The relationships among HOTAIR, miR-17-5p and Beclin1 were verified by dual-luciferase reporter gene and RIP assay. The role of HOTAIR knockdown in sunitinib resistance was verified in nude mice. Results HOTAIR expression in sunitinib-resistant cells is higher than that in parental cells. Knockdown of HOTAIR in sunitinib-resistant cells lead to refrained sunitinib resistance and cell autophagy both in vivo and in vitro. Activation of autophagy could raise resistance to sunitinib in RC cells, while inhibition of autophagy could improve the sensitivity of sunitinib-resistant cells to sunitinib. HOTAIR could compete with miR-17-5p to regulate Beclin1 expression. Knockdown of miR-17-5p in parental cells increases cell resistant to sunitinib, and overexpression of miR-17-5p in sunitinib-resistant cells increases cell sensitive to sunitinib. Conclusion HOTAIR negatively targets miR-17-5p to activate Beclin1-mediated cell autophagy, thereby enhancing sunitinib resistance in RC cells.

Abstract Background Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is a rare congenital disease characterized by uterovaginal agenesis. The diagnosis of MRKH syndrome generally leads to considerable emotional burdens on patients. However, studies focusing on the psychological influence on patients are limited and of unsatisfactory quality. The aim of this study was to investigate the prevalence of depressive symptoms in Chinese patients with MRKH syndrome and to identify the factors associated with depressive symptoms. We recruited 141 patients with MRKH syndrome and 178 age-matched healthy women as control group in this cross-sectional study. Depressive symptoms were assessed by the Patient Health Questionnaire-9 (PHQ-9). Other parameters such as sociodemographic characteristics, treatment histories, personality traits, and attitudes toward femininity and offspring, were also gathered in the self-administered questionnaire. Results The PHQ-9 score was significantly higher in MRKH patient group than the age-matched control group (7.0 (4.5–11.0) vs. 6.0 (3.0–9.0)), median and IQRs) (P = 0.015). A total of 75.2% of MRKH patients suffered from depressive symptoms, and 34.0% reached a moderate to severe level, while the proportion in the control group was 61.2 and 24.2% respectively. Compared with other age groups, patients in their 20s scored higher on the PHQ-9. Patients with higher neuroticism levels in personality traits (OR 1.19 95% CI 1.11–1.28), negative self-evaluation of femininity (OR 3.964, 95% CI 1.371–11.464) and sexual dysfunction (OR 4.81 95% CI 1.24–18.72) (compared with those having no sexual activity) were more likely to exhibit depressive symptoms. Conclusions Three-quarters of MRKH patients show depressive symptoms, and one-third of these individuals are even at risk for depressive disorders. Therefore, depressive symptom screening and proper psychotherapy in MRKH patients are of great importance.

The pandemic caused by emerging Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) presents a global public health threat. Illustrating human antibody responding to viral antigen could potentially provide valuable information for basic research and clinical diagnosis. The antibody can be used as a complement to the viral detection for the rapid diagnosis of infected patients. Compared with spike protein (SP), nucleocapsid protein (NP) is normally conserved and highly immunogenic in many coronavirus members. As a major antigen, NP is a potential target for the diagnosis of SARS-CoV-2 infection. Here, we constructed a combinatorial fragment of antigen-binding (Fab)antibody phage library based on peripheral blood-derived from five coronavirus disease 2019 (COVID-19) infected donors. From the library, 159 Fab antibodies were obtained and identified by panning with NP. Among them, 16 antibodies were evaluated for their binding properties and epitopes recognition. Among these 16 antibodies, two well-paired antibodies were finally screened out for SARS-CoV-2 diagnosis by double-antibody sandwich enzyme-linked immunosorbent assay (ELISA) method. Our works may provide a potential resource for the clinical diagnosis of SARS-CoV-2 infection.

Background: The ubiquitin-proteasome system (UPS) is thought to be functionally active in atherosclerosis (AS) lesions. Aspirin was found to be a potent inhibitor of the UPS in some tumour studies; however, its effect on AS remains to be demonstrated in vivo. Methods: New Zealand rabbits were placed on a normal diet (N) or on a normal diet with aspirin (NI) or on an atherogenic diet without (H) or with aspirin (HI) for 12 weeks. Proteasome activity, concentrations of plasma lipids and levels of peroxidation were determined. Ubiquitin/ubiquitin-conjugates (Ub), IκBα, phosphorylated IκB (pIκBα) and p65 were investigated by Western blotting or immunochemistry. Results: Concentrations of plasma lipids and peroxidation levels were higher in H or HI vs. N or NI. Histological analysis showed that atheroma was increased in H. Ub and IκBα were mainly localised in subendothelium and media vascular smooth muscle cells. Western blots revealed that Ub, IκBα, and pIκBα were increased, whereas p65 was lower in HI vs. H. The activity of the 20S proteasome was functionally active in H vs. N, NI or HI, while the 26S proteasome was not affected in any of the groups. Conclusions: Aspirin can attenuate the pathogenesis of atheroma formation, the degradation of IκBα and pIκBα, and lower the expression of p65, indicating that its therapeutic effects on AS may be via inhibition of the UPS. Clin Chem Lab Med 2006;44:1218–25. [ABSTRACT FROM AUTHOR]