Bi-directional association of body size and composition with heart failure: A Mendelian randomization study.

PURPOSE: The effect of obesity on the development of heart failure (HF) has received attention, and this study intends to further explore the bidirectional association between body size or composition and HF by using Mendelian Randomization (MR) approach. DESIGN: We performed a two-sample bidirectional MR study to investigate the association between body size or composition and the risk of HF using aggregated data from genome-wide association studies. Univariable MR analysis was used to investigate the causal relationship, and multivariable MR analysis was used to explore the mediating role of general and central obesity in the relationship between body size or composition and HF. RESULTS: This forward MR study found that body mass index (BMI), waist circumference (WC), waist-hip ratio (WHR), fat mass (FM) and fat-free mass (FFM) were risk factors for the development of HF with the strength of causal association BMI > FM > WC > FFM > WHR. After adjusting for BMI, the observed associations between the remaining indicators and heart failure attenuated to null. After adjusting for WC, only BMI (OR = 1.59, 95%CI: 1.32-1.92, P = 9.53E-07) and FM (OR = 1.39, 95%CI: 1.20-1.62, P = 1.35E-0.5) kept significantly related to the risk of HF. Reverse MR analysis showed no association of changes in body size or composition with the onset of HF. CONCLUSION: The two-sample bidirectional MR study found that general obesity, measured by BMI, was an independent indicator of the development of HF, while other related indicators were associated with HF incidence dependent on BMI, besides, no association was observed between HF diagnosis and the body size or composites.

Ethylene enhances MdMAPK3-mediated phosphorylation of MdNAC72 to promote apple fruit softening.

The phytohormone ethylene plays an important role in promoting the softening of climacteric fruits, such as apples (Malus domestica); however, important aspects of the underlying regulatory mechanisms are not well understood. In this study, we identified apple MITOGEN-ACTIVATED PROTEIN KINASE 3 (MdMAPK3) as an important positive regulator of ethylene-induced apple fruit softening during storage. Specifically, we show that MdMAPK3 interacts with and phosphorylates the transcription factor NAM-ATAF1/2-CUC2 72 (MdNAC72), which functions as a transcriptional repressor of the cell wall degradation-related gene POLYGALACTURONASE1 (MdPG1). The increase in MdMAPK3 kinase activity was induced by ethylene, which promoted the phosphorylation of MdNAC72 by MdMAPK3. Additionally, MdPUB24 functions as an E3 ubiquitin ligase to ubiquitinate MdNAC72, resulting in its degradation via the 26S proteasome pathway, which was enhanced by ethylene-induced phosphorylation of MdNAC72 by MdMAPK3. The degradation of MdNAC72 increased the expression of MdPG1, which in turn promoted apple fruit softening. Notably, using variants of MdNAC72 that were mutated at specific phosphorylation sites, we observed that the phosphorylation state of MdNAC72 affected apple fruit softening during storage. This study thus reveals that the ethylene-MdMAPK3-MdNAC72-MdPUB24 module is involved in ethylene-induced apple fruit softening, providing insights into climacteric fruit softening.

Gut dysbiosis-derived ß-glucuronidase promotes the development of endometriosis.

OBJECTIVE: To explore the role of gut dysbiosis-derived ß-glucuronidase (GUSB) in the development of endometriosis (EMs). DESIGN: 16S rRNA sequencing of stool samples from women with (n = 35) or without (n = 30) endometriosis and from a mouse model was conducted to assess gut microbiome changes and identify molecular factors influencing the development of endometriosis. Experiments in vivo in an endometriosis C57BL6 mouse model and in vitro verified the level of GUSB and its role in the development of EMs. SETTING: Department of Obstetrics and Gynecology, The First Affiliated Hospital of Sun Yat-sen University; Guangdong Provincial Clinical Research Center for Obstetrical and Gynecological Diseases. PATIENT(S): Women of reproductive age with a histological diagnosis of endometriosis were enrolled in the endometriosis group (n = 35) and infertile or healthy age-matched women who had undergone a gynecological or radiological examination in the control group (n = 30). Fecal and blood samples were taken the day before surgery. Paraffin-embedded sections from 50 bowel endometriotic lesions, 50 uterosacral lesions, 50 samples without lesions, and 50 normal endometria were collected. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Changes in the gut microbiome of patients with EMs and mice and the effect of ß-glucuronidase on the proliferation and invasion of endometrial stromal cells and the development of endometriotic lesions were assessed. RESULT(S): No difference in α and ß diversity was found between patients with EMs and controls. Immunohistochemistry analysis showed higher ß-glucuronidase expression in bowel lesions and uterosacral ligament lesions than in the normal endometrium (p<0.01). ß-Glucuronidase promoted the proliferation and migration of endometrial stromal cells during cell counting kit-8, Transwell, and wound-healing assays. Macrophage levels, especially M2, were higher in bowel lesions and uterosacral ligament lesions than in controls, and ß-glucuronidase promoted the M0 to M2 transition. Medium conditioned by ß-glucuronidase-treated macrophages promoted endometrial stromal cell proliferation and migration. ß-Glucuronidase increased the number and volume of endometriotic lesions and number of macrophages present in lesions in the mouse EMs model. CONCLUSION(S): This ß-Glucuronidase promoted EMs development directly or indirectly by causing macrophage dysfunction. The characterization of the pathogenic role of ß-glucuronidase in EMs has potential therapeutic implications.

Exogenous Ca2+ promotes transcription factor phosphorylation to suppress ethylene biosynthesis in apple.

Ethylene biosynthesis in apple (Malus domestica) fruit can be suppressed by calcium ions (Ca2+) during storage; however, the underlying mechanisms are unclear. In this study, we identified the apple transcription factor MCM1-AGAMOUS-DEFICIENS-SRF5 (MdMADS5), which functions as a transcriptional activator of the ethylene biosynthesis-related gene 1-AMINOCYCLOPROPANE-1-CARBOXYLIC ACID SYNTHASE1 (MdACS1), a partner of the calcium sensor CALCIUM-DEPENDENT PROTEIN KINASES7 (MdCDPK7). Ca2+ promoted the MdCDPK7-mediated phosphorylation of MdMADS5, which resulted in the degradation of MdMADS5 via the 26S proteasome pathway. MdCDPK7 also phosphorylated 1-AMINOCYCLOPROPANE-1-CARBOXYLIC ACID OXIDASE1 (MdACO1), the key enzyme in ethylene biosynthesis, leading to MdACO1 degradation and inhibition of ethylene biosynthesis. Our results reveal that Ca2+/MdCDPK7-MdMADS5 and Ca2+/MdCDPK7-MdACO1 are involved in Ca2+-suppressed ethylene biosynthesis, which delays apple fruit ripening. These findings provide insights into fruit ripening, which may lead to the development of strategies for extending the shelf life of fruit.

Phosphorylation of MdCYTOKININ RESPONSE FACTOR4 suppresses ethylene biosynthesis during apple fruit ripening.

The plant hormone ethylene plays a central role in the ripening of climacteric fruits, such as apple (Malus domestica). Ethylene biosynthesis in apple fruit can be suppressed by calcium ions (Ca2+); however, the underlying mechanism is largely unknown. In this study, we identified an apple APETALA2/ETHYLENE-RESPONSIVE FACTOR (AP2/ERF) transcription factor, MdCYTOKININ RESPONSE FACTOR4 (MdCRF4), which functions as a transcriptional activator of ethylene biosynthesis- and signaling-related genes, including Md1-AMINOCYCLOPROPANE-1-CARBOXYLIC ACID SYNTHASE1 (MdACS1) and MdETHYLENE-RESPONSIVE FACTOR3 (MdERF3), as a partner of the calcium sensor, calmodulin. Ca2+ promoted the Ca2+/CaM2-mediated phosphorylation of MdCRF4, resulting in MdCRF4 recognition by the E3 ubiquitin ligase MdXB3 ORTHOLOG 1 IN ARABIDOPSIS THALIANA (MdXBAT31), and consequently its ubiquitination and degradation via the 26S proteasome pathway. This in turn resulted in lower expression of MdACS1 and MdERF3 and reduced ethylene biosynthesis. Transiently overexpressing various MdCRF4 proteins with specific mutated phosphorylation sites revealed that the phosphorylation state of MdCRF4 affects the ripening of apple fruit. The results reveal that a Ca2+/CaM-MdCRF4-MdXBAT31 module is involved in Ca2+-suppressed ethylene biosynthesis, which delays apple fruit ripening. This provides insights into fruit ripening that may result in strategies for extending fruit shelf life.

Dynamical behavior of coal shearer under the influence of multiple factors in slant-cutting conditions.

Aiming at the problem of severe vibration and abnormal wear and tear of various components in coal shearer under slant-cutting conditions, a non-linear dynamics model with 13 degrees of freedom for a coal shearer under slant-cutting conditions is developed using vibration mechanics and multi-body dynamics theory, and the characteristics of the slide shoes-middle groove contact, the ranging arm-haulage unit connection with gaps and the guidance sliding boots-pin rail multi-surface contact with gaps are described based on three-dimensional fractal theory and Hertz contact theory. Based on Huco's law, the ranging arm and the hydraulic rod are assumed to be flexible beams, the rigidity characteristics of the ranging arm itself, the connection characteristics of the haulage unit and the fuselage are described, a drum correction load with a traction speed correction factor is proposed as the external excitation of the system, and the model is solved and analyzed. The research results show that the change of traction speed has a greater influence on the vibration swing angle and displacement of the front drum, front ranging arm and front walking unit, and the vibration swing angle and displacement of the three increase with the increase of traction speed, while the change of coalface hardness coefficient has less influence on the vibration displacement of the key components of the coal shearer. Under the working parameters of v = 3 m/min and f = 3, the swing angle and displacement of the front ranging arm and front drum fluctuate in the ranges of - 0.4-0.1 rad and - 15-15 mm respectively; the vibration acceleration is - 300-300 rad/s2 and - 200-200 mm/s2 respectively, the main vibration frequencies are 16.63 Hz and 12.14 Hz respectively, and finally the results are verified by experimental methods.

Analysis on vertical-pitch coupled dynamics characteristics of shearer with corrected load.

With regard to the severe vertical and pitching vibration of shearer in actual working conditions, the vertical-pitch coupled dynamics model of shearer with 13 degrees of freedom was established using multi-body dynamics theory. Based on the elasticity theory, Hertz contact and collision dynamics, the connection stiffness model of shear body and the traction section, the rocker arm with clearance and the traction section, the support stiffness models for the guide shoe and the smooth shoe, and the stiffness characteristics model of the rocker arm were constructed respectively. Taking into account the convergence of solution process and the reliability of results, a modified drum load was proposed as the external excitation of the system and the dynamic characteristics of key parts of shearer under different working conditions were analyzed. The numerical models were validated against the vibration responses of the whole machine and critical components of shearer obtained from mechanical test under different operating conditions. The research results provide theoretical basis for the structure optimization and process parameter optimization of shearer.

Dynamical Behavior of Coal Shearer Traction-swing Coupling under Corrected Loads.

Vibration is a major concern in coal mining with a shearer, and an accurate model that allows complex responses can analyze the overall vibration of the system. The large load impact on and severe vibration of a coal shearer under operating conditions were considered. A numerical model was proposed for characterizing the nonlinear dynamics of the shearer traction-swing coupling in 13 degrees of freedom using vibration mechanics and multibody dynamics. Particularly, the contact between the shearer sliding shoe and scraper conveyor was characterized using three-dimensional fractal theory, the gapped contact between the driving wheel and base plate was characterized using Hertz contact theory, and the rigidity of the lift cylinder, the coupling between the shearer fuselage and haulage unit, and the rigidity of the shearer ranging arm were characterized using Hooke's law. Using experimentally corrected drum loads as the external excitation, the numerical model was resolved to characterize and analyze the dynamical responses of critical shearer components. The numerical model was validated against the vibration responses of a shearer and its critical components under different operating conditions obtained from a mechanical test.The research results provide theoretical basis for the structure optimization and process parameter optimization of the shearer.

Autonomic nervous system and inflammation interaction in endometriosis-associated pain.

Endometriosis is a chronic inflammatory disease. Pain is the most common symptom in endometriosis. Endometriosis-associated pain is caused by inflammation, and is related to aberrant innervation. Although the specific mechanism between endometriosis-associated pain and the interaction of aberrant innervation and inflammation remains unclear, many studies have confirmed certain correlations between them. In addition, we found that some chronic inflammatory autoimmune diseases (AIDs) such as inflammatory bowel disease (IBD) and rheumatoid arthritis (RA) share similar characteristics: the changes in dysregulation of inflammatory factors as well as the function and innervation of the autonomic nervous system (ANS). The mechanisms underlying the interaction between the ANS and inflammation have provided new advances among these disorders. Therefore, the purpose of this review is to compare the changes in inflammation and ANS in endometriosis, IBD, and RA; and to explore the role and possible mechanism of sympathetic and parasympathetic nerves in endometriosis-associated inflammation by referring to IBD and RA studies to provide some reference for further endometriosis research and treatment.

PtCo-excavated rhombic dodecahedral nanocrystals for efficient electrocatalysis.

Platinum (Pt)-based catalysts have shown excellent catalytic performance in many fields, particularly for the oxygen reduction reaction (ORR) and direct oxidation of small fuel molecules. Further development of Pt-based electrocatalysts relies on the morphology design of Pt-based alloy nanocrystals (NCs) with highly accessible and active surface sites to optimize Pt atomic utilization. In this work, we reported PtCo-excavated rhombic dodecahedral (ERD) NCs consisting of the self-assembly of 24 ultrathin nanosheets synthesized by a simple wet chemical method. The morphology can be regulated from convex to excavated polyhedra by controlling the amount of formaldehyde and the molar ratio of the Co/Pt precursor. The as-prepared PtCo ERD NCs/C catalyst exhibits excellent ORR performance, which has about 12 times higher specific activity and 6 times higher mass activity than the commercial Pt/C catalyst. It also displays good electrocatalytic ability towards methanol oxidation, in which the specific activity and mass activity are about 6 times higher and 2 times higher than the commercial Pt/C, respectively. Their enhanced activity is attributed to the excavated structure and alloy feature.

Clinical outcomes in carriers of complex chromosomal rearrangements: a retrospective analysis of comprehensive chromosome screening results in seven cases.

OBJECTIVE: To evaluate the clinical outcomes in carriers of complex chromosomal rearrangements (CCRs). DESIGN: Case series. SETTING: An institute for reproductive and stem cell engineering. PATIENT(S): Seven couples with CCRs. INTERVENTION(S): Assisted reproduction with preimplantation genetic diagnosis (PGD). MAIN OUTCOME MEASURE(S): PGD results, embryo rating, pregnancy outcomes. RESULT(S): In cases 1, 2, 3, 4, 5, and 6, each woman underwent one cycle of PGD. Case 7 underwent two PGD cycles. We obtained 51 blastocysts from seven couples with CCR, of which 47 were eligible for biopsy; only 3 (5.9%) were normal/balanced, and 2 (3.9%) conceptions resulted. One healthy baby girl was born (the other was not yet born at the time of publication). Karyotyping revealed that the healthy baby girl was 46,XX. Although the patient with both a balanced translocation and a CCR (case 7) had 12 embryos available for biopsy, all were chromosomally unbalanced. It is interesting that 22 (57.9%) of the total 38 blastocysts were of high quality for type A CCRs, and 2 (15.4%) of the total 13 blastocysts were of high quality for type B CCR at day 6 after fertilization. CONCLUSION(S): The chances of identifying normal/balanced blastocysts in patients with CCR are <6%; the chances of a pregnancy are <4%. Greater complexity CCRs result in fewer transplantable embryos. Moreover, CCRs of greater complexity have a lower rate of high quality blastocysts than CCRs of less complexity.

Microbiological toxicity of tilmicosin on human colonic microflora in chemostats.

To evaluate the microbiological safety of tilmicosin on human intestinal microflora, four chemostat models of healthy human colonic ecosystems were exposed to tilmicosin (0, 0.436, 4.36, and 43.6 µg/mL) for 7 days. Prior to and during drug exposure, three microbiological endpoints were monitored daily including short-chain fatty acids, bacterial counts and macrolide susceptibility. Colonization resistance of each community was determined by 3 successive daily challenges of Salmonella typhimurium. Genes associated with virulence and macrolide resistance in Enterococcus faecalis were determined by PCR. Transcriptional expression of the virulence gene (gelE) in E. faecalis was determined by real-time RT-PCR. Our results showed that different concentrations of tilmicosin did not disrupt the colonization resistance in each chemostat. During exposure to 4.36 and 43.6 µg/mL tilmicosin, the Bacteroides fragilis population was significantly decreased while the proportion of resistant Enterococci increased. After long-term exposure to the highest concentration (43.6 µg/mL) of tilmicosin, the gelE gene was significantly up-regulated in the high-level macrolide resistant strains that also contained the ermB resistance gene. This study was the first of its kind to evaluate the microbiological toxicity of tilmicosin using a chemostat model. These findings also provide new insight into the co-occurrence of macrolide resistance and virulence in E. faecalis under tilmicosin selective pressure.