The juxtamembrane and carboxy-terminal domains of Arabidopsis PRK2 are critical for ROP-induced growth in pollen tubes.

Polarized growth of pollen tubes is a critical step for successful reproduction in angiosperms and is controlled by ROP GTPases. Spatiotemporal activation of ROP (Rho GTPases of plants) necessitates a complex and sophisticated regulatory system, in which guanine nucleotide exchange factors (RopGEFs) are key components. It was previously shown that a leucine-rich repeat receptor-like kinase, Arabidopsis pollen receptor kinase 2 (AtPRK2), interacted with RopGEF12 for its membrane recruitment. However, the mechanisms underlying AtPRK2-mediated ROP activation in vivo are yet to be defined. It is reported here that over-expression of AtPRK2 induced tube bulging that was accompanied by the ectopic localization of ROP-GTP and the ectopic distribution of actin microfilaments. Tube depolarization was also induced by a potentially kinase-dead mutant, AtPRK2K366R, suggesting that the over-expression effect of AtPRK2 did not require its kinase activity. By contrast, deletions of non-catalytic domains in AtPRK2, i.e. the juxtamembrane (JM) and carboxy-terminal (CT) domains, abolished its ability to affect tube polarization. Notably, AtPRK2K366R retained the ability to interact with RopGEF12, whereas AtPRK2 truncations of these non-catalytic domains did not. Lastly, it has been shown that the JM and CT domains of AtPRK2 were not only critical for its interaction with RopGEF12 but also critical for its distribution at the plasma membrane. These results thus provide further insight into pollen receptor kinase-mediated ROP activation during pollen tube growth

The Role of Necroptosis in Cardiovascular Disease

A newly discovered mechanism of cell death, programmed necrosis (necroptosis), combines features of both necrosis and apoptosis. Necroptosis is tightly modulated by a series of characteristic signaling pathways. Activating necroptosis by ligands of death receptors requires the kinase activity of receptor-interacting protein 1 (RIP1), which mediates the activation of receptor-interacting protein 3 (RIP3) and mixed lineage kinase domain-like (MLKL) two critical downstream mediators of necroptosis. Recently, different cytokines have been found participating in this mechanism of cell death. Necroptosis has been proposed as an important component to the pathophysiology of heart disease such as vascular atherosclerosis, ischemia-reperfusion injury, myocardial infarction and cardiac remodeling. Targeting necroptosis signaling pathways may provide therapeutic benefit in the treatment of cardiovascular diseases

The Protective Effects of Ivabradine in Preventing Progression from Viral Myocarditis to Dilated Cardiomyopathy

To study the beneficial effects of ivabradine in dilated cardiomyopathy mice, which evolved from coxsackievirus B3-induced chronic viral myocarditis. Four-to-five-week-old male balb/c mice were inoculated intraperitoneally with coxsackievirus B3 (Strain Nancy) on day 1, day 14 and day 28. The day of the first virus inoculation was defined as day 1. Thirty-five days later, the surviving chronic viral myocarditis mice were divided randomly into two groups, a treatment group and an untreated group. Ivabradine was administered by gavage for 30 consecutive days in the treatment group, and the untreated group was administered normal saline. Masson’s trichrome stain was used to evaluate the fibrosis degree in myocardial tissue. The expression levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), Collagen I, Collagen III and p38-MAPK signaling pathway proteins were detected by western blot. Electrocardiogram was used to investigate the heart rate and rhythm. The thickness of the ventricular septum and left ventricular posterior wall, left ventricular end diastolic dimension, left ventricular end systolic dimension, left ventricular ejection fractions and fractional shortening were studied by echocardiography. Compared with the untreated chronic viral myocarditis mice, ivabradine significantly increased the survival rate, attenuated the myocardial lesions and fibrosis, improved the impairment of the left ventricular function, diminished the heart dimension, decreased the production of collagen I and collagen III, reduced the expression of the proinflammatory cytokines TNF-α, IL-1β, and IL-6, and lowered the production of phospho-p38MAPK. The findings indicate the therapeutic effect of ivabradine in preventing the progression from viral myocarditis to dilated cardiomyopathy in mice with chronic viral myocarditis induced by coxsackievirus B3, is associated with inhibition of the p38MAPK pathway, downregulated inflammatory responses and decreased collagen expression. Ivabradine appears a promising approach for the treatment of patients with viral myocarditis

Determination of incommensurate modulated structure in Bi2Sr1.6La0.4CuO6+{\delta} by aberration-corrected transmission electron microscopy

Incommensurate modulated structure (IMS) in Bi2Sr1.6La0.4CuO6+{\delta} (BSLCO) has been studied by aberration corrected transmission electron microscopy in combination with high-dimensional (HD) space description. Two images in the negative Cs imaging (NCSI) and passive Cs imaging (PCSI) modes were deconvoluted, respectively. Similar results as to IMS have been obtained from two corresponding projected potential maps (PPMs), but meanwhile the size of dots representing atoms in the NCSI PPM is found to be smaller than that in PCSI one. Considering that size is one of influencing factors of precision, modulation functions for all unoverlapped atoms in BSLCO were determined based on the PPM obtained from the NCSI image in combination with HD space description

Deficiency of Mkrn2 causes abnormal spermiogenesis and spermiation, and impairs male fertility.

Although recent studies have shed insights on some of the potential causes of male infertility, new underlining molecular mechanisms still remain to be elucidated. Makorin-2 (Mkrn2) is an evolutionarily conserved gene whose biological functions are not fully known. We developed an Mrkn2 knockout mouse model to study the role of this gene, and found that deletion of Mkrn2 in mice led to male infertility. Mkrn2 knockout mice produced abnormal sperms characterized by low number, poor motility, and aberrant morphology. Disruption of Mkrn2 also caused failure of sperm release (spermiation failure) and misarrangement of ectoplasmic specialization (ES) in testes, thus impairing spermiogenesis and spermiation. To understand the molecular mechanism, we found that expression of Odf2, a vital protein in spermatogenesis, was significantly decreased. In addition, we found that expression levels of Odf2 were decreased in Mkrn2 knockout mice. We also found that MKRN2 was prominently expressed in the sperm of normal men, but was significantly reduced in infertile men. This result indicates that our finding is clinically relevant. The results of our study provided insights into a new mechanism of male infertility caused by the MKRN2 downregulation

Detection of rare variant effects in association studies: extreme values, iterative regression, and a hybrid approach

We develop statistical methods for detecting rare variants that are associated with quantitative traits. We propose two strategies and their combination for this purpose: the iterative regression strategy and the extreme values strategy. In the iterative regression strategy, we use iterative regression on residuals and a multimarker association test to identify a group of significant variants. In the extreme values strategy, we use individuals with extreme trait values to select candidate genes and then test only these candidate genes. These two strategies are integrated into a hybrid approach through a weighting technology. We apply the proposed methods to analyze the Genetic Analysis Workshop 17 data set. The results show that the hybrid approach is the most powerful approach. Using the hybrid approach, the average power to detect causal genes for Q1 is about 40% and the powers to detect FLT1 and KDR are 100% and 68% for Q1, respectively. The powers to detect VNN3 and BCHE are 34% and 30% for Q2, respectively

Even high normal blood pressure affects live birth rate in women undergoing fresh embryo transfer

STUDY QUESTION Do differences in blood pressure within the normal range have any impacts on the live birth rate (primary outcome) or biochemical pregnancy rate (beta-hCG positivity), clinical pregnancy rate (heart beating in ultrasound), abortion rate and ectopic pregnancy rate (secondary outcomes) of fresh embryo transfer in women undergoing their IVF/ICSI treatment? SUMMARY ANSWER Even rather small differences in baseline blood pressure in women with normal blood pressure according to current guidelines undergoing fresh embryo transfer after IVF/ICSI affects substantially the live birth rate. WHAT IS KNOWN ALREADY Pre-pregnancy hypertension is a well-known risk factor for adverse pregnancy events such as preeclampsia, fetal growth restriction, placental abruption and adverse neonatal events. It is likewise well known that hypertension during pregnancy in women undergoing ART is associated with adverse pregnancy outcomes. However, whether blood pressure at the high end of the normal range has an impact on ART is unknown. STUDY DESIGN, SIZE, DURATION It is a prospective observational cohort study based on a single IVF center between January 2017 and December 2018. PARTICIPANTS/MATERIALS, SETTING, METHODS Two thousand four hundred and eighteen women with normal blood pressure undergoing fresh embryo transfer after IVF/ICSI at the Reproductive and Genetic Hospital of CITIC-Xiangya were enrolled in this study. MAIN RESULTS AND THE ROLE OF CHANCE Blood pressure was measured at the first visit when women consulted the IVF center due to infertility. In women with a successful pregnancy outcome (1487 live births out of 2418 women undergoing fresh embryo transfer after IVF/ICSI), systolic blood pressure (SBP) (114.1 ± 9.48 mmHg versus 115.4 ± 9.8 mmHg, P = 0.001) and diastolic blood pressure (DBP) (74.5 ± 7.5 mmHg versus 75.3 ± 7.34 mmHg, P = 0.006) were lower than in those who did not achieve live births. Multivariate logistic regression analysis revealed that SBP (OR: 0.987, 95% CI: 0.979–0.996, P = 0.004) and DBP (OR: 0.986, 95% CI: 0.975–0.998, P = 0.016) were negatively associated with live birth. Similarly, SBP was significantly negatively related to clinical pregnancy rate (OR: 0.990, 95% CI: 0.981–0.999, P = 0.033), while for DBP the association was not statistically significant (OR: 0.994, 95% CI: 0.982–1.006, P = 0.343). However, both SBP and DBP were positively associated with miscarriage OR: 1.021 (95% CI: 1.004–1.037, P = 0.013) and OR: 1.027 (95% CI: 1.005–1.049, P = 0.014), respectively. Both SBP and DBP were unrelated to biochemical pregnancy (hCG positivity), implantation and ectopic pregnancy rate. LIMITATIONS, REASONS FOR CAUTION Whether lowering blood pressure before initiating ART treatment in women with SBP or DBP higher than the thresholds defined in our study will confer a benefit is unknown. Also, we cannot exclude bias due to different ethnicities. Moreover, participants in our study only received fresh embryo transfer, whether the results could apply to frozen embryo transfer is unclear. WIDER IMPLICATIONS OF THE FINDINGS Our study challenges the current blood pressure goals in women undergoing fresh embryo transfer after IVF/ICSI. Further studies are needed to figure out the mechanism and effective approach to increase IVF/ICSI pregnancy outcomes. STUDY FUNDING/COMPETING INTEREST(S) Hunan Provincial Grant for Innovative Province Construction (2019SK4012). The authors declare that there were no conflicts of interest in this study. TRIAL REGISTRATION NUMBER N/A