ZNF554 Inhibits Endometrial Cancer Progression via Regulating RBM5 and Inactivating WNT/ß-Catenin Signaling Pathway.

OBJECTIVE: Uterine corpus endometrial carcinoma (UCEC), a kind of gynecologic malignancy, poses a significant risk to women's health. The precise mechanism underlying the development of UCEC remains elusive. Zinc finger protein 554 (ZNF554), a member of the Krüppel-associated box domain zinc finger protein superfamily, was reported to be dysregulated in various illnesses, including malignant tumors. This study aimed to examine the involvement of ZNF554 in the development of UCEC. METHODS: The expression of ZNF554 in UCEC tissues and cell lines were examined by qRT-PCR and Western blot assay. Cells with stably overexpressed or knocked-down ZNF554 were established through lentivirus infection. CCK-8, wound healing, and Transwell invasion assays were employed to assess cell proliferation, migration, and invasion. Propidium iodide (PI) staining combined with fluorescence-activated cell sorting (FACS) flow cytometer was utilized to detect cell cycle distribution. qRT-PCR and Western blotting were conducted to examine relative mRNA and protein levels. Chromatin immunoprecipitation assay and luciferase reporter assay were used to explore the regulatory role of ZNF554 in RNA binding motif 5 (RBM5). RESULTS: The expression of ZNF554 was found to be reduced in both UCEC samples and cell lines. Decreased expression of ZNF554 was associated with higher tumor stage, decreased overall survival, and reduced disease-free survival in UCEC. ZNF554 overexpression suppressed cell proliferation, migration, and invasion, while also inducing cell cycle arrest. In contrast, a decrease in ZNF554 expression resulted in the opposite effect. Mechanistically, ZNF554 transcriptionally regulated RBM5, leading to the deactivation of the Wingless (WNT)/ß-catenin signaling pathway. Moreover, the findings from rescue studies demonstrated that the inhibition of RBM5 negated the impact of ZNF554 overexpression on ß-catenin and p-glycogen synthase kinase-3ß (p-GSK-3ß). Similarly, the deliberate activation of RBM5 reduced the increase in ß-catenin and p-GSK-3ß caused by the suppression of ZNF554. In vitro experiments showed that ZNF554 overexpression-induced decreases in cell proliferation and migration were counteracted by RBM5 knockdown. Additionally, when RBM5 was overexpressed, it hindered the improvements in cell proliferation and migration caused by reducing the ZNF554 levels. CONCLUSION: ZNF554 functions as a tumor suppressor in UCEC. Furthermore, ZNF554 regulates UCEC progression through the RBM5/WNT/ß-catenin signaling pathway. ZNF554 shows a promise as both a prognostic biomarker and a therapeutic target for UCEC.

A Case Report of Three Patients Who Underwent Temporary Peripheral Nerve Stimulation for Treatment of Knee Pain Secondary to Osteoarthritis.

Knee osteoarthritis affects millions of people worldwide. There remains a role for novel therapies to manage pain for patients who are unable or unwilling to undergo knee arthroplasty. A peripheral nerve stimulator (PNS) may be beneficial in this population. We present a case report of three patients who received temporary femoral or saphenous PNS and were either unwilling or unable to undergo knee arthroplasty. Two of the three patients reported significantly reduced pain and improved functioning. Our case report demonstrates that temporary PNS may offer a safe and effective treatment for chronic knee pain secondary to knee osteoarthritis.

The effect of self-limiting on the prevention and control of the diffuse COVID-19 epidemic with delayed and temporal-spatial heterogeneous.

BACKGROUND: The global spread of the novel coronavirus pneumonia is still continuing, and a new round of more serious outbreaks has even begun in some countries. In this context, this paper studies the dynamics of a type of delayed reaction-diffusion novel coronavirus pneumonia model with relapse and self-limiting treatment in a temporal-spatial heterogeneous environment. METHODS: First, focus on the self-limiting characteristics of COVID-19, incorporate the relapse and self-limiting treatment factors into the diffusion model, and study the influence of self-limiting treatment on the diffusion of the epidemic. Second, because the traditional Lyapunov stability method is difficult to determine the spread of the epidemic with relapse and self-limiting treatment, we introduce a completely different method, relying on the existence conditions of the exponential attractor of our newly established in the infinite-dimensional dynamic system to determine the diffusion of novel coronavirus pneumonia. Third, relapse and self-limiting treatment have led to a change in the structure of the delayed diffusion COVID-19 model, and the traditional basic reproduction number [Formula: see text] no longer has threshold characteristics. With the help of the Krein-Rutman theorem and the eigenvalue method, we studied the threshold characteristics of the principal eigenvalue and found that it can be used as a new threshold to describe the diffusion of the epidemic. RESULTS: Our results prove that the principal eigenvalue [Formula: see text] of the delayed reaction-diffusion COVID-19 system with relapse and self-limiting treatment can replace the basic reproduction number [Formula: see text] to describe the threshold effect of disease transmission. Combine with the latest official data and the prevention and control strategies, some numerical simulations on the stability and global exponential attractiveness of the diffusion of the COVID-19 epidemic in China and the USA are given. CONCLUSIONS: Through the comparison of numerical simulations, we find that self-limiting treatment can significantly promote the prevention and control of the epidemic. And if the free activities of asymptomatic infected persons are not restricted, it will seriously hinder the progress of epidemic prevention and control.

Nicotine withdrawal induces hyperalgesia via downregulation of descending serotonergic pathway in the nucleus raphe magnus.

Patients deprived of cigarettes exhibit increased pain sensitivity during perioperative periods, yet the underlying neuroanatomical and molecular bases of this hypersensitivity are unclear. The present study showed that both the mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) were significantly decreased in a rat model of nicotine withdrawal. These rats showed less tryptophan hydroxylase 2 (TPH2) positive neurons and reduced TPH2 expression in the nucleus raphe magnus (NRM), and thus resulted in decreased 5-hydroxytryptamine (5-HT) levels in cerebrospinal fluid. Intrathecal injection of 5-HT or NRM microinjection of TPH-overexpression adeno-associated virus alleviated nicotine withdrawal-induced hyperalgesia, whereas 5-HT receptor pharmacological blockade by methysergide (a 5-HT receptor antagonist) exacerbated hypersensitivity and diminished the difference between the two groups. Together, these data indicate that hyperalgesia after nicotine withdrawal is mediated by declined descending serotonergic pathways in the NRM. This provides a new perspective to improve the postoperative pain management of patients, especially the smokers.

Dynamic analysis of a delayed COVID-19 epidemic with home quarantine in temporal-spatial heterogeneous via global exponential attractor method.

As the COVID-19 epidemic has entered the normalization stage, the task of prevention and control remains very arduous. This paper constructs a time delay reaction-diffusion model that is closer to the actual spread of the COVID-19 epidemic, including relapse, time delay, home quarantine and temporal-spatial heterogeneous environment that affect the spread of COVID-19. These factors increase the number of equations and the coupling between equations in the system, making it difficult to apply the methods commonly used to discuss global dynamics, such as the Lyapunov function method. Therefore, we use the global exponential attractor theory in the infinite-dimensional dynamic system to study the spreading trend of the COVID-9 epidemic with relapse, time delay, home quarantine in a temporal-spatial heterogeneous environment. Using our latest results of global exponential attractor theory, the global asymptotic stability and the persistence of the COVID-19 epidemic are discussed. We find that due to the influence of relapse in the in temporal-spatial heterogeneity environment, the principal eigenvalue λ * can describe the spread of the epidemic more accurately than the usual basic reproduction number R 0 . That is, the non-constant disease-free equilibrium is globally asymptotically stable when λ * < 0 and the COVID-19 epidemic is persisting uniformly when λ * > 0 . Combine with the latest official data of the COVID-19 and the prevention and control strategies of different countries, some numerical simulations on the stability and global exponential attractiveness of the spread of the COVID-19 epidemic in China and the USA are given. The simulation results fully reflect the impact of the temporal-spatial heterogeneous environment, relapse, time delay and home quarantine strategies on the spread of the epidemic, revealing the significant differences in epidemic prevention strategies and control effects between the East and the West. The results of this study provide a theoretical basis for the current epidemic prevention and control.

Single-cell transcriptome analysis reveals that maternal obesity affects DNA repair, histone methylation, and autophagy level in mouse embryos.

Obesity causes many reproductive dysfunctions such as reduced conception, infertility, and early pregnancy loss, and this is largely due to the negative effects of obesity on oocyte and embryo quality. In the present study, we employed single-cell RNA transcriptome sequencing to investigate the potential causes for the maternal obesity effects on mouse embryos. Our results showed that the 4-cell and morula/blastocyst rates were all significantly decreased during embryo development in obese mice. Genome-wide analysis indicated that obesity altered the expression of more than 1100 genes in 2-cell embryos, including the genes which were related to the p53 signaling pathway and apoptosis. Further analysis showed that the expression of 47 genes related to DNA damage was changed, and a positive γH2A signal and the altered expression of Rad51 and Tex15 were observed in the obese embryos. Obesity also affected histone methylation, shown by the decrease of the H3K4-me2 level. Besides this, we observed the occurrence of autophagy and apoptosis in the embryos of obese mice. There were 42 genes that were related to autophagy/apoptosis that showed aberrant expression, and the positive LC3 signal and the decrease of Clec16a, Rraga, and Atg10 level were also observed. In summary, our study suggested that obesity affected early embryonic development by inducing DNA damage, aberrant histone methylation, and autophagy levels in mice.

Spread trend of COVID-19 epidemic outbreak in China: using exponential attractor method in a spatial heterogeneous SEIQR model.

In this paper we introduce a method of global exponential attractor in the reaction-diffusion epidemic model in spatial heterogeneous environment to study the spread trend and long-term dynamic behavior of the COVID-19 epidemic. First, we prove the existence of the global exponential attractor of general dissipative evolution systems. Then, by using the existence theorem, the global asymptotic stability and the persistence of epidemic are discussed. Finally, combine with the official data of the COVID-19 and the national control strategy, some numerical simulations on the stability and global exponential attractiveness of the COVID-19 epidemic are given. Simulations show that the spread trend of the epidemic is in line with our theoretical results, and the preventive measures taken by the Chinese government are effective.

Influence of spatial heterogeneous environment on long-term dynamics of a reaction-diffusion SVIR epidemic model with relaps.

In this paper by adding the factors of disease relapse and vaccination in the space hetero-geneous environment, we establish and discuss a class of reaction-diffusion SVIR model with relapse and a varying external source in spatial heterogeneous environment. By applying a different method than the Lyapunov function, we study the long-term dynamic behavior of this model by means of global exponential attractor theory and gradient flow method. The global asymptotic stability and the persistence of epidemic are proved. To test the validity of our theoretical results, we choose some specific epidemic disease with some more practical and more definitive official data to simulate the global stability and exponential attraction of the model. The simulation results showed that the factors of disease relapse, vaccination and spatial heterogeneity had a great influence on the persists uniformly of the disease.

Effects of obesity and diabetes on the epigenetic modification of mammalian gametes.

Obesity and diabetes are closely associated with numerous reproductive disorders, including termination of ovulation, irregular menstruation, low fertility, abortion, and risky pregnancy, which are now regarded as global health problems. Paternal/maternal obesity and diabetes can also be transmitted to the subsequent generation via gametes, suggesting the association of epigenetic inheritance with obesity and diabetes, particularly for its effects on offspring. Recent studies indicate that both obesity and diabetes change DNA and histone methylation levels, histone acetylation, and noncoding RNAs such as microRNAs (miRNAs) in oocytes and sperm. Several important genes, such as PPAR-α, Igf2, H19, Fyn, Stella, Sirt3, Sirt6, and Peg3 as well as miRNAs, such as let-7c, reportedly participate in the regulation of epigenetic modifications in mammalian gametes. This review summarizes the recent progress that links obesity/diabetes and reproductive disorders from the perspective of gamete epigenetic modifications.

Modelling the effect of immigration on drinking behaviour.

A drinking model with immigration is constructed. For the model with problem drinking immigration, the model admits only one problem drinking equilibrium. For the model without problem drinking immigration, the model has two equilibria, one is problem drinking-free equilibrium and the other is problem drinking equilibrium. By employing the method of Lyapunov function, stability of all kinds of equilibria is obtained. Numerical simulations are also provided to illustrate our analytical results. Our results show that alcohol immigrants increase the difficulty of the temperance work of the region.

Ophthalmological findings in 74 patients with mitochondrial disease.

BACKGROUND: Mitochondrial disease often manifests with ophthalmologic signs and symptoms. Due to the important role of mitochondria in aerobic metabolism, the eyes are among the more preferentially involved organs. The clinical diagnosis of mitochondrial disease can be facilitated by an improved knowledge of the types and magnitude of their various manifestations. The aim of this study was to describe the ophthalmological manifestations of patients with mitochondrial diseases that are currently not well elucidated. METHODS: From a database of patients with verified primary mitochondrial disease (n = 81) who had visited our institution we identified 74 patients who had ophthalmologic examinations. Demographic, clinical, and ophthalmologic data were collected. Institutional review board approval was obtained. RESULTS: A total of 74 patients were identified with Leigh disease, MELAS, MERRF, CPEO, Pearson/Kearns-Sayre syndrome, as well as other mtDNA point mutations, deletions, depletions, and mutations. Overall, 26 of the 74 patients (35%) had one or more ophthalmological abnormalities. Retinal pigmentary changes were present in 12/74 (16%) of patients. Partial or total optic atrophy (OA) was noted in 8/74 (10%) of patients. Decreased extra-ocular movement (EOM) was noted in 6/74 (8%) of patients. Other ophthalmological findings included macular atrophy (2/74), macular dystrophy (1/74), and visual field defects (1/74). CONCLUSIONS: Over one-third of our cohort of patients with mitochondrial disorders had ophthalmological manifestations, some of which affected vision significantly. Eye examinations are critical in patients with mitochondrial disease so that complete assessments of the effects of the underlying mutations are uncovered and the appropriate counseling and care are given.

Altered apoptosis/autophagy and epigenetic modifications cause the impaired postimplantation octaploid embryonic development in mice.

Polyploids are pervasive in plants and have large impacts on crop breeding, but natural polyploids are rare in animals. Mouse diploid embryos can be induced to become tetraploid by blastomere fusion at the 2-cell stage and tetraploid embryos can develop to the blastocyst stage in vitro. However, there is little information regarding mouse octaploid embryonic development and precise mechanisms contributing to octaploid embryonic developmental limitations are unknown. To investigate the genetic and epigenetic mechanisms underlying octaploid embryonic development, we generated mouse octaploid embryos and evaluated the in vitro/in vivo developmental potential. Here we show that octaploid embryos can develop to the blastocyst stage in vitro, but all fetus impaired immediately after implantation. Our results indicate that cell lineage specification of octaploid embryo was disorganized. Furthermore, these octaploid embryos showed increased apoptosis as well as alterations in epigenetic modifications when compared with diploid embryos. Thus, our cumulative data provide cues for why mouse octaploid embryonic development is limited and its failed postimplantation development.

Exposure to HT-2 toxin causes oxidative stress induced apoptosis/autophagy in porcine oocytes.

T-2 toxin is a main type A trichothecene mycotoxin which is the most toxic trichothecence. T-2 toxin has posed various toxic effects on human and animals in vigorous cell proliferation tissues like lymphoid, hematopoietic and gastrointestinal tissues, while HT-2 toxin is the major metabolite which is deacetylated by T-2 toxin. In this study, we focused on the toxic effects of HT-2 on porcine oocyte maturation. We treated the porcine oocyte with HT-2 toxin in vitro, and we first found that HT-2 treatment inhibited porcine oocyte polar body extrusion and cumulus cell expansion. We observed the disrupted meiotic spindle morphology after treatment, which might be due to the reduced p-MAPK protein level. Actin distribution was also disturbed, indicating that HT-2 affects cytoskeleton of porcine oocytes. We next explored the causes for the failure of oocyte maturation after HT-2 treatment. We found that HT-2 treated oocytes showed the increased ROS level, which indicated that oxidative stress had occurred. We also detected autophagy as well as early apoptosis in the treatment oocytes. Due to the fact that oxidative stress could induced apoptosis, our results indicated that HT-2 toxin caused oxidative stress induced apoptosis and autophagy, which further affected porcine oocyte maturation.

Deoxynivalenol exposure induces autophagy/apoptosis and epigenetic modification changes during porcine oocyte maturation.

Deoxynivalenol (DON) is a widespread trichothecene mycotoxin which contaminates agricultural staples and elicits a complex spectrum of toxic effects on humans and animals. It has been shown that DON impairs oocyte maturation, reproductive function and causes abnormal fetal development in mammals; however, the mechanisms remain unclear. In the present study, we investigate the possible reasons of the toxic effects of DON on porcine oocytes. Our results showed that DON significantly inhibited porcine oocyte maturation and disrupted meiotic spindle by reducing p-MAPK protein level, which caused retardation of cell cycle progression. In addition, up-regulated LC3 protein expression and aberrant Lamp2, LC3 and mTOR mRNA levels were observed with DON exposure, together with Annexin V-FITC staining assay analysis, these results indicated that DON treatment induced autophagy/apoptosis in porcine oocytes. We also showed that DON exposure increased DNA methylation level in porcine oocytes through altering DNMT3A mRNA levels. Histone methylation levels were also changed showing with increased H3K27me3 and H3K4me2 protein levels, and mRNA levels of their relative methyltransferase genes, indicating that epigenetic modifications were affected. Taken together, our results suggested that DON exposure reduced porcine oocytes maturation capability through affecting cytoskeletal dynamics, cell cycle, autophagy/apoptosis and epigenetic modifications.

Both diet and gene mutation induced obesity affect oocyte quality in mice.

Obesity was shown to cause reproductive dysfunctions such as reduced conception, infertility and early pregnancy loss. However, the possible effects of obesity on oocyte quality are still not fully understood. In this study we investigated the effects of both diet and gene mutation induced obesity on impairments in mouse oocyte polarization, oxidative stress, and epigenetic modifications. Our results showed that high-fat diet induced obesity (HFD) and gene mutation induced obesity (ob/ob) could both impair oocyte meiotic maturation, disrupt spindle morphology, and reduce oocyte polarity. Oocytes from obese mice underwent oxidative stress, as shown by high DHE and ROS levels. Abnormal mitochondrial distributions and structures were observed in oocytes from obese groups of mice and early apoptosis signals were detected, which suggesting that oxidative stress had impaired mitochondrial function and resulted in oocyte apoptosis. Our results also showed that 5 mC levels and H3K9 and H3K27 methylation levels were altered in oocytes from obese mice, which indicated that DNA methylation and histone methylation had been affected. Our results showed that both HFD and ob/ob induced obesity affected oocyte maturation and that oxidative stress-induced early apoptosis and altered epigenetic modifications may be the reasons for reduced oocyte quality in obese mice.

RhoA-mediated MLC2 regulates actin dynamics for cytokinesis in meiosis.

During oocyte meiosis, the bipolar spindle forms in the central cytoplasm and then migrates to the cortex. Subsequently, the oocyte extrudes the polar body through two successive asymmetric divisions, which are regulated primarily by actin filaments. Myosin light chain2 (MLC2) phosphorylation plays pivotal roles in smooth muscle contraction, stress fiber formation, cell motility and cytokinesis. However, whether MLC2 phosphorylation participates in the oocyte polarization and asymmetric division has not been clarified. The present study investigated the expression and functions of MLC2 during mouse oocyte meiosis. Our result showed that p-MLC2 was localized in the oocyte cortex, with a thickened cap above the chromosomes. Meanwhile, p-MLC2 was also localized in the poles of spindle. Disruption of MLC2 activity by MLC2 knock down (KD) caused the failure of polar body extrusion. Immunofluorescent staining showed that a large proportion of oocytes arrested in telophase stage and failed to undergo cytokinesis after culturing for 12 hours. In the meantime, actin filament staining at oocyte membrane and cytoplasm were reduced in MLC2 KD oocytes. Finally, we found that the phosphorylation of MLC2 protein levels was decreased after disruption of RhoA activity. Above all, our data indicated that the RhoA-mediated MLC2 regulates the actin organization for cytokinesis during mouse oocyte maturation.