Biomechanical microenvironment regulates fusogenicity of breast cancer cells

Fusion of cancer cells is thought to contribute to tumor development and drug resistance. The low frequency of cell fusion events and the instability of fused cells have hindered our ability to understand the molecular mechanisms that govern cell fusion. We have demonstrated that several breast cancer cell lines can fuse into multinucleated giant cells in vitro, and the initiation and longevity of fused cells can be regulated solely by biophysical factors. Dynamically tuning the adhesive area of the patterned substrates, reducing cytoskeletal tensions pharmacologically, altering matrix stiffness, and modulating pattern curvature all supported the spontaneous fusion and stability of these multinucleated giant cells. These observations highlight that the biomechanical microenvironment of cancer cells, including the matrix rigidity and interfacial curvature, can directly modulate their fusogenicity, an unexplored mechanism through which biophysical cues regulate tumor progression

Rnd3/RhoE Modulates HIF1α/VEGF Signaling by Stabilizing HIF1α and Regulates Responsive Cardiac Angiogenesis

The insufficiency of compensatory angiogenesis in the heart of patients with hypertension contributes to heart failure transition. The hypoxia-inducible factor 1α-vascular endothelial growth factor (HIF1α-VEGF) signaling cascade controls responsive angiogenesis. One of the challenges in reprograming the insufficient angiogenesis is to achieve a sustainable tissue exposure to the proangiogenic factors, such as HIF1α stabilization. In this study, we identified Rnd3, a small Rho GTPase, as a proangiogenic factor participating in the regulation of the HIF1α-VEGF signaling cascade. Rnd3 physically interacted with and stabilized HIF1α, and consequently promoted VEGFA expression and endothelial cell tube formation. To demonstrate this proangiogenic role of Rnd3 in vivo, we generated Rnd3 knockout mice. Rnd3 haploinsufficient (Rnd3(+/-)) mice were viable, yet developed dilated cardiomyopathy with heart failure after transverse aortic constriction stress. The poststress Rnd3(+/-) hearts showed significantly impaired angiogenesis and decreased HIF1α and VEGFA expression. The angiogenesis defect and heart failure phenotype were partially rescued by cobalt chloride treatment, a HIF1α stabilizer, confirming a critical role of Rnd3 in stress-responsive angiogenesis. Furthermore, we generated Rnd3 transgenic mice and demonstrated that Rnd3 overexpression in heart had a cardioprotective effect through reserved cardiac function and preserved responsive angiogenesis after pressure overload. Finally, we assessed the expression levels of Rnd3 in the human heart and detected significant downregulation of Rnd3 in patients with end-stage heart failure. We concluded that Rnd3 acted as a novel proangiogenic factor involved in cardiac responsive angiogenesis through HIF1α-VEGFA signaling promotion. Rnd3 downregulation observed in patients with heart failure may explain the insufficient compensatory angiogenesis involved in the transition to heart failure

Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure < 100 mmHg (n = 1127), estimated glomerular filtration rate < 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation

Global Ionospheric Disturbance Propagation and Vertical Ionospheric Oscillation Triggered by the 2022 Tonga Volcanic Eruption

The Tonga volcano erupted on 15 January 2022, at 04:15:45 UTC, which significantly influenced the atmosphere and space environment, at the same time, an unprecedented opportunity to monitor ionospheric anomalies is provided by its powerful eruption. In current studies of traveling ionospheric disturbance (TID) triggered by the 2022 Tonga volcanic eruption, the particular phenomenon of ionospheric disturbances in various parts of the world has not been reasonably explained, and the vertical ionospheric disturbances are still not effectively detected. In this paper, we calculate the high-precision slant total electron content (STEC) from more than 3000 ground-based GPS stations distributed around the world, then we obtain the radio occultation (RO) data from near-field COSMIC-2 profiles and investigate the horizontal TID and the vertical ionospheric disturbances by the singular spectrum analysis (SSA). Horizontal TID propagation captured by GPS STEC results indicates that acoustic-gravity waves dominate the energy input at the beginning of the ionospheric disturbance with an approximate speed of 1050 m/s initially. With the dissipation of the shock energy, lamb waves become a dominant mode of ionospheric disturbances, moving at a more stable speed of about 326 m/s to a range of 16,000 km beyond the far-field. Local characteristics are evident during the disturbance, such as the ionospheric conjugation in Australia and the rapid decay of TID in Europe. The shock-Lamb-tsunami waves’ multi-fluctuation coupling is recorded successively from the COSMIC-2 RO observation data. The shock and Lamb waves can perturb the whole ionospheric altitude. In contrast, the disturbance caused by tsunami waves is much smaller than that of acoustic-gravity waves and Lamb waves. In addition, influenced by the magnetic field, the propagation speed of TID induced by Lamb waves is higher towards the northern hemisphere than towards the southern hemisphere

Application of high-precision 3D seismic technology to shale gas exploration: A case study of the large Jiaoshiba shale gas field in the Sichuan Basin

The accumulation pattern of the marine shale gas in South China is different from that in North America. The former has generally thin reservoirs and complex preservation conditions, so it is difficult to make a fine description of the structural features of shale formations and to reflect accurately the distribution pattern of high-quality shale by using the conventional 2D and 3D seismic exploration technology, which has an adverse effect on the successful deployment of horizontal wells. In view of this, high-precision 3D seismic prospecting focusing on lithological survey was implemented to make an accurate description of the distribution of shale gas sweet spots so that commercial shale gas production can be obtained. Therefore, due to the complex seismic geological condition of Jiaoshiba area in Fuling, SE Sichuan Basin, the observation system of high-precision 3D seismic acquisition should have such features as wide-azimuth angles, small trace intervals, high folds, uniform vertical and horizontal coverage and long spread to meet the needs of the shale gas exploration in terms of structural interpretation, lithological interpretation and fracture prediction. Based on this idea, the first implemented high-precision 3D seismic exploration project in Jiaoshiba area played an important role in the discovery of the large Jiaoshiba shale gas field. Considering that the high-quality marine shale in the Sichuan Basin shows the characteristics of multi-layer development from the Silurian system to the Cambrian system, the strategy of shale gas stereoscopic exploration should be implemented to fully obtain the oil and gas information of the shallow, medium and deep strata from the high-precision 3D seismic data, and ultimately to expand the prospecting achievements in an all-round way to balance the high upstream exploration cost, and to continue to push the efficient shale gas exploration and development process in China

Analysis of Space-Borne GPS Data Quality and Evaluation of Precise Orbit Determination for COSMIC-2 Mission Based on Reduced Dynamic Method

COSMIC-2 is a remote sensing satellite mission that mainly provides scientific data for weather forecasting, ionosphere, and climate research. High precise orbit is the basis for the application of remote sensing satellite data. In order to realize the precise orbit determination (POD) of COSMIC-2, we have assessed the quality of space-borne GPS observation in detail, including the utilization of GPS observations, cycle slip ratio (o/slps), multipath error, single-noise ratio (SNR) and ionospheric delay rate (IOD) of the data, realized the POD of COSMIC-2 with the reduced dynamic (RD) method, and evaluated the accuracy of the solved orbit by means of the carrier-phase residual, overlapping orbit comparison and the reference orbit comparison. The data quality assessments show that the data is less affected by the multipath effect, the utilization of the data is low, cycle slips occur frequently, and the carrier-phase data is often interrupted. The POD results indicate that the root mean square (RMS) values of the carrier-phase residuals of six COSMIC-2 satellites are between 6.0 mm and 7.5 mm, The mean RMS values of the overlapping orbit are better than 0.92 cm, 1.33 cm and 1.03 cm in the radial (R), tangential (T) and normal (N) directions respectively, and the mean RMS values of the six satellites in the 3D direction are between 1.38 cm and 1.75 cm. The mean RMS values in R, T and N directions orbit determination accuracy of the reference orbit comparison are better than 5.61 cm, 6.59 cm and 2.29 cm respectively, and the mean RMS values of the six satellites in the 3D direction are between 7.35 cm and 8.79 cm

Global Ionospheric Disturbance Propagation and Vertical Ionospheric Oscillation Triggered by the 2022 Tonga Volcanic Eruption

The Tonga volcano erupted on 15 January 2022, at 04:15:45 UTC, which significantly influenced the atmosphere and space environment, at the same time, an unprecedented opportunity to monitor ionospheric anomalies is provided by its powerful eruption. In current studies of traveling ionospheric disturbance (TID) triggered by the 2022 Tonga volcanic eruption, the particular phenomenon of ionospheric disturbances in various parts of the world has not been reasonably explained, and the vertical ionospheric disturbances are still not effectively detected. In this paper, we calculate the high-precision slant total electron content (STEC) from more than 3000 ground-based GPS stations distributed around the world, then we obtain the radio occultation (RO) data from near-field COSMIC-2 profiles and investigate the horizontal TID and the vertical ionospheric disturbances by the singular spectrum analysis (SSA). Horizontal TID propagation captured by GPS STEC results indicates that acoustic-gravity waves dominate the energy input at the beginning of the ionospheric disturbance with an approximate speed of 1050 m/s initially. With the dissipation of the shock energy, lamb waves become a dominant mode of ionospheric disturbances, moving at a more stable speed of about 326 m/s to a range of 16,000 km beyond the far-field. Local characteristics are evident during the disturbance, such as the ionospheric conjugation in Australia and the rapid decay of TID in Europe. The shock-Lamb-tsunami waves’ multi-fluctuation coupling is recorded successively from the COSMIC-2 RO observation data. The shock and Lamb waves can perturb the whole ionospheric altitude. In contrast, the disturbance caused by tsunami waves is much smaller than that of acoustic-gravity waves and Lamb waves. In addition, influenced by the magnetic field, the propagation speed of TID induced by Lamb waves is higher towards the northern hemisphere than towards the southern hemisphere

Analysis of Space-Borne GPS Data Quality and Evaluation of Precise Orbit Determination for COSMIC-2 Mission Based on Reduced Dynamic Method

COSMIC-2 is a remote sensing satellite mission that mainly provides scientific data for weather forecasting, ionosphere, and climate research. High precise orbit is the basis for the application of remote sensing satellite data. In order to realize the precise orbit determination (POD) of COSMIC-2, we have assessed the quality of space-borne GPS observation in detail, including the utilization of GPS observations, cycle slip ratio (o/slps), multipath error, single-noise ratio (SNR) and ionospheric delay rate (IOD) of the data, realized the POD of COSMIC-2 with the reduced dynamic (RD) method, and evaluated the accuracy of the solved orbit by means of the carrier-phase residual, overlapping orbit comparison and the reference orbit comparison. The data quality assessments show that the data is less affected by the multipath effect, the utilization of the data is low, cycle slips occur frequently, and the carrier-phase data is often interrupted. The POD results indicate that the root mean square (RMS) values of the carrier-phase residuals of six COSMIC-2 satellites are between 6.0 mm and 7.5 mm, The mean RMS values of the overlapping orbit are better than 0.92 cm, 1.33 cm and 1.03 cm in the radial (R), tangential (T) and normal (N) directions respectively, and the mean RMS values of the six satellites in the 3D direction are between 1.38 cm and 1.75 cm. The mean RMS values in R, T and N directions orbit determination accuracy of the reference orbit comparison are better than 5.61 cm, 6.59 cm and 2.29 cm respectively, and the mean RMS values of the six satellites in the 3D direction are between 7.35 cm and 8.79 cm

Rnd3/RhoE Modulates HIF1α/VEGF Signaling by Stabilizing HIF1α and Regulates Responsive Cardiac Angiogenesis

The insufficiency of compensatory angiogenesis in the heart of patients with hypertension contributes to heart failure transition. The hypoxia-inducible factor 1α-vascular endothelial growth factor (HIF1α-VEGF) signaling cascade controls responsive angiogenesis. One of the challenges in reprograming the insufficient angiogenesis is to achieve a sustainable tissue exposure to the proangiogenic factors, such as HIF1α stabilization. In this study, we identified Rnd3, a small Rho GTPase, as a proangiogenic factor participating in the regulation of the HIF1α-VEGF signaling cascade. Rnd3 physically interacted with and stabilized HIF1α, and consequently promoted VEGFA expression and endothelial cell tube formation. To demonstrate this proangiogenic role of Rnd3 in vivo, we generated Rnd3 knockout mice. Rnd3 haploinsufficient (Rnd3(+/-)) mice were viable, yet developed dilated cardiomyopathy with heart failure after transverse aortic constriction stress. The poststress Rnd3(+/-) hearts showed significantly impaired angiogenesis and decreased HIF1α and VEGFA expression. The angiogenesis defect and heart failure phenotype were partially rescued by cobalt chloride treatment, a HIF1α stabilizer, confirming a critical role of Rnd3 in stress-responsive angiogenesis. Furthermore, we generated Rnd3 transgenic mice and demonstrated that Rnd3 overexpression in heart had a cardioprotective effect through reserved cardiac function and preserved responsive angiogenesis after pressure overload. Finally, we assessed the expression levels of Rnd3 in the human heart and detected significant downregulation of Rnd3 in patients with end-stage heart failure. We concluded that Rnd3 acted as a novel proangiogenic factor involved in cardiac responsive angiogenesis through HIF1α-VEGFA signaling promotion. Rnd3 downregulation observed in patients with heart failure may explain the insufficient compensatory angiogenesis involved in the transition to heart failure

Table2_Characterization of cardiac involvement in patients with LMNA splice-site mutation–related dilated cardiomyopathy and sudden cardiac death.XLSX

Introduction:LMNA splicing mutations occur in 9.1% of cases with cardiac involvement cases, but the phenotype and severity of disease they cause have not yet been systematically studied. The aim of this study was to understand the clinical and pathogenic characteristics of the LMNA splice-site mutation phenotype in patients with LMNA-related dilated cardiomyopathy (DCM) and sudden cardiac death (SCD).Methods and Results: First, we reported a novel family with LMNA-related DCM and SCD, and the clinical characteristics of all current patients with LMNA splicing mutations were further summarized through the ClinVar database. Seventeen families with a total of 134 individuals, containing a total of 15 LMNA splicing mutation sites, were enrolled. A total of 42 subjects (31.3%) had SCD. Compared without with the non-DCM group (n = 56), the patients within the DCM group (n = 78) presented a lower incidence of atrioventricular block (AVB) (p = 0.015) and a higher incidence rates of non-sustained ventricular tachycardia (p = 0.004),) and implantable cardioverter defibrillator (ICD) implantation (p = 0.005). Kaplan‒Meier survival analysis showed that the patients with pacemaker (PM) implantation had a significantly reduced the occurrence of SCD compared to patientswith those without PM implantation (log-rank p A mutation in the reported family, and pathogenic prediction analysis showed that the mutation site was extremely harmful. Next, we conducted gene expression levels and cardiac pathological biopsy studies on the proband of this family. We found that the expression of normal LMNA mRNA from the proband was significantly downregulated in peripheral blood mononuclear cells than incompared with healthy individuals. Finally, we comprehensively summarized the pathological characteristics of LMNA-related DCM, including hypertrophy, atrophy, fibrosis, white blood cell infiltration, intercalated disc remodeling, and downregulation of desmin and connexin 43 (Cx43) expression.Discussion: Above all, Cardiaccardiac involvement in patients with LMNA splice-site mutation presented with a high rate of SCD. Implanting a pacemaker significantly reduced the SCD rate in non-DCM patients with AVB. The pathogenic characterization was not only haveinvolved suppressed the expression of the healthy LMNA allele, but was also associated with abnormal expression and distribution of desmin and Cx43.</p