YTHDF2 regulates MSS51 expression contributing to mitochondria dysfunction of granulosa cells in polycystic ovarian syndrome patients.

RESEARCH QUESTION: Granulosa cells (GCs) dysfunction plays a crucial role in the pathogenesis of polycystic ovary syndrome (PCOS). It is reported that YTH domain-containing family protein 2 (YTHDF2) is upregulated in mural GCs of PCOS patients. What effect does the differential expression of YTHDF2 have in PCOS patients? DESIGN: Mural GCs and cumulus GCs from 15 patients with PCOS and 15 ovulatory controls and 4 cases of pathological sections in each group were collected. Real-time PCR, Western Blot, immunohistochemistry, and immunofluorescence experiments were conducted to detect gene and protein expression. RNA immunoprecipitation assay was performed to evaluate the binding relationship between YTHDF2 and MSS51. Mitochondrial morphology, cellular ATP and ROS levels and glycolysis-related gene expression were detected after YTHDF2 overexpression or MSS51 inhibition. RESULTS: In the present study, we found that YTHDF2 was upregulated in GCs of PCOS patients while MSS51 was downregulated. YTHDF2 protein can bind to MSS51 mRNA and affect MSS51 expression. The reduction of MSS51 expression or the increase in YTHDF2 expression can lead to mitochondrial damage, reduced ATP levels, increased ROS levels and reduced expression of LDHA, PFKP and PKM. CONCLUSIONS: YTHDF2 may regulate the expression of MSS51, affecting the structure and function of mitochondria in GCs and interfering with cellular glycolysis, which may disturb the normal biological processes of GCs and follicle development in PCOS patients.

Floquet Engineering Hz-Level Rabi Spectra in Shallow Optical Lattice Clock.

Quantum metrology with ultrahigh precision usually requires atoms prepared in an ultrastable environment with well-defined quantum states. Thus, in optical lattice clock systems deep lattice potentials are used to trap ultracold atoms. However, decoherence, induced by Raman scattering and higher order light shifts, can significantly be reduced if atomic clocks are realized in shallow optical lattices. On the other hand, in such lattices, tunneling among different sites can cause additional dephasing and strongly broadening of the Rabi spectrum. Here, in our experiment, we periodically drive a shallow ^{87}Sr optical lattice clock. Counterintuitively, shaking the system can deform the wide broad spectral line into a sharp peak with 5.4 Hz linewidth. With careful comparison between the theory and experiment, we demonstrate that the Rabi frequency and the Bloch bands can be tuned, simultaneously and independently. Our work not only provides a different idea for quantum metrology, such as building shallow optical lattice clock in outer space, but also paves the way for quantum simulation of new phases of matter by engineering exotic spin orbit couplings.

Interleukin-5-induced eosinophil population improves cardiac function after myocardial infarction.

AIMS: Interleukin (IL)-5 mediates the development of eosinophils (EOS) that are essential for tissue post-injury repair. It remains unknown whether IL-5 plays a role in heart repair after myocardial infarction (MI). This study aims to test whether IL-5-induced EOS population promotes the healing and repair process post-MI and to reveal the underlying mechanisms. METHODS AND RESULTS: MI was induced by permanent ligation of the left anterior descending coronary artery in wild-type C57BL/6 mice. Western blot and real-time polymerase chain reaction revealed elevated expression of IL-5 in the heart at 5 days post-MI. Immunohistostaining indicated that IL-5 was secreted mainly from macrophages and CD127+ cells in the setting of experimental MI. External supply of recombinant mouse IL-5 (20 min, 1 day, and 2 days after MI surgery) reduced the infarct size and increased ejection fraction and angiogenesis in the border zone. A significant expansion of EOS was detected in both the peripheral blood and infarcted myocardium after IL-5 administration. Pharmacological depletion of EOS by TRFK5 pretreatment muted the beneficial effects of IL-5 in MI mice. Mechanistic studies demonstrated that IL-5 increased the accumulation of CD206+ macrophages in infarcted myocardium at 7 days post-MI. In vitro co-culture experiments showed that EOS shifted bone marrow-derived macrophage polarization towards the CD206+ phenotypes. This activity of EOS was abolished by IL-4 neutralizing antibody, but not IL-10 or IL-13 neutralization. Western blot analyses demonstrated that EOS promoted the macrophage downstream signal transducer and activator of transcription 6 (STAT6) phosphorylation. CONCLUSION: IL-5 facilitates the recovery of cardiac dysfunction post-MI by promoting EOS accumulation and subsequent CD206+ macrophage polarization via the IL-4/STAT6 axis.

Doubly Modulated Optical Lattice Clock: Interference and Topology.

The quantum system under periodical modulation is the simplest path to understand the quantum nonequilibrium system because it can be well described by the effective static Floquet Hamiltonian. Under the stroboscopic measurement, the initial phase is usually irrelevant. However, if two uncorrelated parameters are modulated, their relative phase cannot be gauged out so that the physics can be dramatically changed. Here, we simultaneously modulate the frequency of the lattice laser and the Rabi frequency in an optical lattice clock (OLC) system. Thanks to the ultrahigh precision and ultrastability of the OLC, the relative phase could be fine-tuned. As a smoking gun, we observed the interference between two Floquet channels. Finally, by experimentally detecting the eigenenergies, we demonstrate the relation between the effective Floquet Hamiltonian and the one-dimensional topological insulator with a high winding number. Our experiment not only provides a direction for detecting the phase effect but also paves a way in simulating the quantum topological phase in the OLC platform.

Regulation of Type 2 Immunity in Myocardial Infarction.

Type 2 immunity participates in the pathogeneses of helminth infection and allergic diseases. Emerging evidence indicates that the components of type 2 immunity are also involved in maintaining metabolic hemostasis and facilitating the healing process after tissue injury. Numerous preclinical studies have suggested regulation of type 2 immunity-related cytokines, such as interleukin-4, -13, and -33, and cell types, such as M2 macrophages, mast cells, and eosinophils, affects cardiac functions after myocardial infarction (MI), providing new insights into the importance of immune modulation in the infarcted heart. This review provides an overview of the functions of these cytokines and cells in the setting of MI as well as their potential to predict the severity and prognosis of MI.

Protective effects of carnosine on white matter damage induced by chronic cerebral hypoperfusion.

Carnosine is a dipeptide that scavenges free radicals, inhibits inflammation in the central nervous system, and protects against ischemic and hypoxic brain damage through its anti-oxidative and anti-apoptotic actions. Therefore, we hypothesized that carnosine would also protect against white matter damage caused by subcortical ischemic injury. White matter damage was induced by right unilateral common carotid artery occlusion in mice. The animals were treated with 200, 500 or 750 mg/kg carnosine by intraperitoneal injection 30 minutes before injury and every other day after injury. Then, 37 days later, Klüver-Barrera staining, toluidine blue staining and immunofluorescence staining were performed. Carnosine (200, 500 mg/kg) substantially reduced damage to the white matter in the corpus callosum, internal capsule and optic tract, and it rescued expression of myelin basic protein, and alleviated the loss of oligodendrocytes. However, carnosine at the higher dose of 750 mg/kg did not have the same effects as the 200 and 500 mg/kg doses. These findings show that carnosine, at a particular dose range, protects against white matter damage caused by chronic cerebral ischemia in mice, likely by reducing oligodendroglial cell loss.

Retrospective Analysis of Vancomycin Nephrotoxicity in Elderly Chinese Patients.

This study explored nephrotoxicity in elderly Chinese patients after exposure to vancomycin and other nephrotoxic risk factors. This was a single-center retrospective study. The patient population included those who were ≥60 years of age, had normal baseline serum creatinine values, and received vancomycin for ≥48 h between January 1, 2013 and August 30, 2014. Nephrotoxicity occurred in 29% of 124 patients. A baseline creatinine clearance ≥63.5 ml/min was more common in the nephrotoxic group. Patients with high (≥15 mg/l) rather than low (<15 mg/l) average vancomycin troughs had elevated nephrotoxicity (47.2 vs. 27.3%, p = 0.0001). Of the comorbid conditions evaluated, there were more patients with shock (p = 0.001), hypertension (p = 0.020) and congestive heart failure (p = 0.04) in the nephrotoxic group. Drugs frequently given at the same time with vancomycin, such as angiotensin receptor blockers and furosemide, were also associated with increased nephrotoxic risk. In conclusion, nephrotoxicity was frequently observed in patients with concurrent vancomycin trough concentrations ≥15 µg/ml and hypertension, shock, congestive heart failure. In addition, drugs concurrently used with vancomycin may also increase its nephrotoxicity. Therefore, renal function and vancomycin serum troughs should be closely monitored, especially in patients with other renal injury risk factors.

17-Dimethylaminoethylamino-17-demethoxygeldanamycin attenuates inflammatory responses in experimental stroke.

Heat shock protein 90 (HSP90) is a ubiquitous molecular chaperone involved in the proper conformation of many proteins. HSP90 inhibitors (17-dimethyl aminoethylamino-17-demethoxygeldanamycin hydrochloride [17-DMAG]) bind to and inactivate HSP90, suppressing some key signaling pathways involved in the inflammatory process. Since considerable evidence suggests that inflammation accounts for the progression of cerebral ischemic injury, we investigated whether 17-DMAG can modulate inflammatory responses in middle cerebral artery occluded (MCAO) mice. Male C57/BL6 mice were pretreated with 17-DMAG or vehicle for 7 d before being subjected to transient occlusion of middle cerebral artery and reperfusion. Mice were evaluated at 24 h after MCAO for neurological deficit scoring. Moreover, the mechanism of the anti-inflammatory effect of 17-DMAG was investigated with a focus on nuclear factor kappa B (NF-κB) pathway. 17-DMAG significantly reduced cerebral infarction and improved neurological outcome. 17-DMAG suppressed activation of microglia and decreased phosphorylation of inhibitory (I)κB and subsequent nuclear translocation of p65, which eventually downregulated expression of NF-κB-regulated genes. These results suggest that 17-DMAG has a promising therapeutic effect in ischemic stroke treatment through an anti-inflammatory mechanism.

Relationships between PON1 Q192R polymorphism and clinical outcome of antiplatelet treatment after percutaneous coronary intervention: a meta-analysis.

This meta-analysis was performed to assess the relationships between the PON1 Q192R (rs662 T>C) polymorphism and the clinical outcome of antiplatelet treatment after percutaneous coronary intervention (PCI). A range of electronic databases were searched: Web of Science (1945-2013), the Cochrane Library Database (Issue 12, 2013), PubMed (1966-2013), EMBASE (1980-2013), CINAHL (1982-2013) and the Chinese Biomedical Database (CBM) (1982-2013) without language restrictions. Meta-analysis was conducted using the STATA 12.0 software. The crude odds ratio (OR) with their 95 % confidence interval (CI) were calculated. Six clinical cohort studies with a total number of 5,189 patients undergoing PCI for coronary heart disease were included. Our meta-analysis revealed that the PON1 Q192R polymorphism was correlated with an increased risk of major adverse cardiovascular events (MACE) in patients receiving antiplatelet treatment after PCI (C allele vs. T allele: OR = 1.22, 95 % CI 1.04-1.43, P = 0.014; CT+CC vs. TT: OR = 1.38, 95 % CI 1.03-1.86, P = 0.029; CC vs. TT: OR = 1.45, 95 % CI 1.05-1.99, P = 0.024; respectively), especially among Asians. Furthermore, we found significantly positive correlations between the PON1 Q192R polymorphism and the incidence of stent thrombosis in patients receiving antiplatelet treatment after PCI (C allele vs. T allele: OR = 1.42, 95 % CI 1.08-1.87, P = 0.011; CT+CC vs. TT: OR = 1.93, 95 % CI 1.01-3.67, P = 0.046; CC vs. TT: OR = 2.18, 95 % CI 1.09-4.35, P = 0.027; respectively). Our meta-analysis of clinical cohort studies provides evidence that the PON1 Q192R polymorphism may increase the risk of MACE and stent thrombosis in patients receiving antiplatelet treatment after PCI.

FASLG polymorphism is associated with cancer risk.

Many studies have reported the association between the FASLG -844T/C polymorphism and cancer risk, but the data are remaining controversial. A pooled analysis was performed to assess this relationship comprehensively. Medline, PubMed, Embase and Web of Science were searched, and data were extracted and cross-checked independently by three authors. A total of 18 published studies including 22389 subjects were involved in this analysis. Overall, the -844C allele was associated with a significantly increased cancer risk (for CC versus TT: OR=1.23, 95% confidence interval (CI)=1.04-1.45; for CC+TC versus TT: OR=1.15, 95% CI=1.01-1.30; for CC versus TT+TC: OR=1.20, 95% CI=1.05-1.38). In the subgroup analysis by ethnicity, significantly elevated risks were found among Asians (for CC versus TT: OR=1.61, 95% CI=1.37-1.89; for CC+TC versus TT: OR=1.36, 95% CI=1.16-1.60; for CC versus TT+TC: OR=1.44, 95% CI=1.22-1.70). In the subgroup analysis by study design, significantly increased risks were found among population-based case-control studies (for CC versus TT: OR=1.40, 95% CI=1.06-1.84; for CC+TC versus TT: OR=1.25, 95% CI=1.01-1.55; for CC versus TT+TC: OR=1.31, 95% CI=1.06-1.61). These findings indicate that the FASLG -844C allele is emerging as a low-penetrant cancer susceptibility allele for cancer development. However, more comprehensive understanding of the association would certainly have an immense prospect in the promising field of individualised preventive care.