Mechanistic Study of Rnd3 in Cardiomyopathy

In human end-stage heart failure patients, the activation of Rho kinase 1 (ROCK1) is observed in the heart. ROCK1 activation promotes the activation of caspase 3, which results in a feed-forward loop contributing to myocyte apoptosis. Rnd3, a small GTPase, is an endogenous inhibitor of ROCK1. I observed a decrease in Rnd3 protein levels in human failing hearts, suggesting a pathological significance of Rnd3 alteration in the transition to heart failure. However, the biological function of Rnd3 in the heart remains unexplored. To investigate the functional role of Rnd3 in the heart and the underlying mechanism, the Rnd3 knockout mouse line was generated to mimic the down-regulation of Rnd3 in the diseased human heart. Rnd3 deficiency (Rnd3^-/-) resulted in embryoniclethality. Severe cardiac apoptosis along with elevated ROCK1 activity were observed in the Rnd3^-/- mice at the E10.5 stage. The haploinsufficient (Rnd3^+/-) mice were viable,however, were predisposed to heart failure after transverse aortic constriction (TAC) induced hemodynamic stress. Remarkable cardiomyocyte apoptosis, increased caspase 3 activity, and activation of ROCK1 were detected in the Rnd3^+/- heart compared to the wild-type (WT) control. Pharmacological inhibition of ROCK1 by Fasudil administration partially improved cardiac function and attenuated apoptosis in the Rnd3^+/- mice after TAC. To determine whether ROCK1 contributed to the Rnd3 deficiency-mediated heart failure and cardiac apoptosis, I generated a double knockout (DKO) mouse line with Rnd3^+/- ROCK1-/- background. Again, the genetic deletion of ROCK1 partially rescued the phenotype. My data suggest that Rnd3 is a novel anti- apoptotic factor that protects the heart from cardiac apoptosis partially through the inhibition of the ROCK1 pathway. Determining the ROCK1 independent mechanisms involved in the Rnd3 deficiency-mediated cardiac remodeling is the goal for further investigation. Compensatory angiogenesis is necessary in the cardiac response to the ischemic stimuli. Compared to the wild-type mice, the post-TAC Rnd3^+/- hearts showed significantly smaller capillaryareas, fewer capillary numbers, a 20.8% reduction of coronary flow reserve, and a 5.9-fold increase in the hypoxic myocardial areas. Key pro-angiogenic factors were down-regulated, including hypoxia-inducible factor 1α (HIF1α) and vascular endothelial growth factor A (VEGFA), suggesting a stress-responsive angiogenic defect. Using loss- and gain-of-function approaches, I revealed that Rnd3 physically interacted with and stabilized HIF1α. The deficiency of Rnd3 facilitated the HIF1α protein degradation, reduced the VEGFA expression, and compromised the endothelial cell tube formation. Finally, the angiogenesis defect and the heart failure phenotype in the Rnd3^+/- mice werepartially rescued by cobalt chloride treatment, a HIF1α stabilizer. My data suggests that Rnd3 is a pro-angiogenic factor involved in the responsive angiogenesis in the heart through HIF1α-VEGF signaling promotion. Animals with Rnd3 haploinsufficiency showed cardiac dysfunction with impaired angiogenesis in response to the pressure overload. The down-regulation of Rnd3 observed in the heart failure patients may explain the insufficiency in the compensatory angiogenesis, which contributes to the transition to heart failure

Anisotropically Shaped Magnetic/Plasmonic Nanocomposites for Information Encryption and Magnetic-Field-Direction Sensing.

Instantaneous control over the orientation of anisotropically shaped plasmonic nanostructures allows for selective excitation of plasmon modes and enables dynamic tuning of the plasmonic properties. Herein we report the synthesis of rod-shaped magnetic/plasmonic core-shell nanocomposite particles and demonstrate the active tuning of their optical property by manipulating their orientation using an external magnetic field. We further design and construct an IR-photoelectric coupling system, which generates an output voltage depending on the extinction property of the measured nanocomposite sample. We employ the device to demonstrate that the nanocomposite particles can serve as units for information encryption when immobilized in a polymer film and additionally when dispersed in solution can be employed as a new type of magnetic-field-direction sensor

Kinetic Control on the Depth Distribution of Superdeep Diamonds

Superdeep diamonds contain unique information from the sublithospheric regions of Earth’s interior. Recent studies suggest that reaction between subducted carbonate and iron metal in the mantle plays an important role in the production of superdeep diamonds. It is unknown if this reaction is kinetically feasible in cold slabs subducted into the deep mantle. Here we present experimental data on real‐time tracking of the magnesite‐iron reaction at high pressures and high temperatures to demonstrate the production of diamond at the surface conditions of cold slabs in the transition zone and lower mantle. Our data reveal that the diamond production rate has a positive temperature dependence and a negative pressure dependence, and along a slab geotherm it decreases by a factor of three at pressures from 14.4 to 18.4 GPa. This rate reduction provides an explanation for the rarity of superdeep diamonds from the interior of the mantle transition zone.Plain Language SummarySuperdeep diamonds originate from great depths inside Earth, carrying samples from inaccessible mantle to the surface. The reaction between carbonate and iron may be an important mechanism to form diamond through interactions between subducting slabs and surrounding mantle. Interestingly, most superdeep diamonds formed in two narrow zones, at 250–450 and 600–800 km depths within the ~2,700‐km‐deep mantle. No satisfactory hypothesis explains these preferred depths of diamond formation. We measured the rate of a diamond forming reaction between magnesite and iron. Our data show that high temperature promotes the reaction, while high pressure does the opposite. Particularly, the reaction slows down drastically at about 475(±55) km depth, which may explain the rarity of diamond formation below 450 km depth. The only exception is the second zone at 600–800 km, where carbonate accumulates and warms up due to the stagnation of subducting slabs at the top of lower mantle, providing more reactants and higher temperature for diamond formation. Our study demonstrates that the depth distribution of superdeep diamonds may be controlled by reaction rates.Key PointsReal‐time tracking of diamond production from iron‐magnesite reaction at high pressures and high temperaturesThreefold reduction in the rate of iron‐magnesite reaction from 14.4 to 18.4 GPaDepth distribution of superdeep diamonds may be explained by reaction kineticsPeer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/148362/1/grl58460_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/148362/2/grl58460.pd

Crepe cake structured layered double hydroxide/sulfur/graphene as a positive electrode material for Li-S batteries

This work was financially supported by National Natural Science Foundation of China (Nos. 21975030 and 11674005), and the Ministry of Science and Technology of China (No. 2016YFB0700600 (National Materials Genome Project)).Solving the polysulfide shuttle problem is one of the core challenges for the industrialization of lithium–sulfur batteries. In this work, a triphasic composite of LDH/sulfur/rGO (LDH: layered double hydroxide, rGO: reduced graphene oxide) with a crepe cake like structure is designed and fabricated as a positive electrode material for lithium–sulfur batteries. Sulfur nanoparticles are embedded in the interlayer space of the composite and thus are well protected physically via three-dimensional wrapping and chemically via strong interaction of LDH nanoflakes with lithium polysulfides, such as ionic bonds and S···H hydrogen bonds. In addition, the flexible lamellar structure of the composite with soft graphene layers can tolerate the volume expansion of sulfur during lithiation as well as facilitate ionic permeability and electron transport, which is favorable for the redox reactions of polysulfide. The present work sheds light on the future development and industrialization of lithium–sulfur batteries.PostprintPeer reviewe

ArguGPT: evaluating, understanding and identifying argumentative essays generated by GPT models

AI generated content (AIGC) presents considerable challenge to educators around the world. Instructors need to be able to detect such text generated by large language models, either with the naked eye or with the help of some tools. There is also growing need to understand the lexical, syntactic and stylistic features of AIGC. To address these challenges in English language teaching, we first present ArguGPT, a balanced corpus of 4,038 argumentative essays generated by 7 GPT models in response to essay prompts from three sources: (1) in-class or homework exercises, (2) TOEFL and (3) GRE writing tasks. Machine-generated texts are paired with roughly equal number of human-written essays with three score levels matched in essay prompts. We then hire English instructors to distinguish machine essays from human ones. Results show that when first exposed to machine-generated essays, the instructors only have an accuracy of 61% in detecting them. But the number rises to 67% after one round of minimal self-training. Next, we perform linguistic analyses of these essays, which show that machines produce sentences with more complex syntactic structures while human essays tend to be lexically more complex. Finally, we test existing AIGC detectors and build our own detectors using SVMs and RoBERTa. Results suggest that a RoBERTa fine-tuned with the training set of ArguGPT achieves above 90% accuracy in both essay- and sentence-level classification. To the best of our knowledge, this is the first comprehensive analysis of argumentative essays produced by generative large language models. Machine-authored essays in ArguGPT and our models will be made publicly available at https://github.com/huhailinguist/ArguGP

Financial transfers from adult children and depressive symptoms among mid-aged and elderly residents in China - evidence from the China health and retirement longitudinal study.

Although the awareness of mental health problems in late life is rising, the association between financial transfers to the older generations from children and mental health at older ages in China has received little attention. This study examines the association between financial transfers from children and depressive symptoms among the mid-aged and elderly residents (from 45 years of age and older) in China. We used the data from the China Health and Retirement Longitudinal Study (CHARLS, 2013) (n = 10,935) This included data on financial transfers from all non-co-resident children to their parents, and the individual scores on depressive symptoms as measured by the 10-item Center for Epidemiologic Studies-Depression Scale (CESD-10). A two-level - individual and community levels - mixed linear model was deployed to explore their association. Financial transfers from children to parents was the major component of inter-generational financial transfers in Chinese families. A higher financial support from non-co-resident children was signivicantly and positively related to fewer depressive symptoms (coef. = - 0.195,P-value< 0.001) among both the mid-aged and elderly parents. Financial transfers from non-co-resident children are associated with depressive symptoms among mid-aged and elderly residents in the China situation. Taxation and other policy measures should encourage and facilitate these type of financial transfers and prevent a decrease of support from children to parents

General Epidemiological Parameters of Viral Hepatitis A, B, C, and E in Six Regions of China: A Cross-Sectional Study in 2007

BACKGROUND: Viral hepatitis is a serious health burden worldwide. To date, few reports have addressed the prevalence of hepatitis A, B, C, and E in China. Therefore, the general epidemiological parameters of viral hepatitis remain unknown. PRINCIPAL FINDINGS: In this cross-sectional study, we performed a serological prevalence analysis of viral hepatitis A, B, C, and E in 8,762 randomly selected Chinese subjects, which represented six areas of China. The overall prevalence of anti-Hepatitis C virus antibody (anti-HCV) was 0.58%, which was much lower than was estimated by WHO. The prevalences of Hepatitis B virus surface antigen (HBsAg), anti-Hepatitis B virus surface protein antibody (HBsAb), and anti-Hepatitis B virus core protein antibody (HBcAb) were 5.84%, 41.31%, and 35.92%, respectively, whereas in the group of subjects less than 5 years old, these prevalences were 1.16%, 46.77%, and 8.69% respectively, which suggests that the Hepatitis B virus (HBV)-carrier population is decreasing, and the nationwide HBV vaccine program has contributed to the lowered HBV prevalence in the younger generation in China. Meanwhile, a large deficit remains in coverage provided by the national HBV immune program. In addition, our data suggested the possibility that HBsAb may not last long enough to protect people from HBV infection throughout life. The overall prevalence of anti-Hepatitis A virus antibody (anti-HAV) and anti-Hepatitis E virus antibody (anti-HEV) were as high as 72.87% and 17.66%, respectively. The indices increased with age, which suggests that a large proportion of Chinese adults are protected by latent infection. Furthermore, the pattern of HEV infection was significantly different among ethnic groups in China. CONCLUSIONS: Our study provided much important information concerning hepatitis A, B, C, and E prevalence in China and will contribute to worldwide oversight of viral hepatitis

Genetic deletion of Rnd3 results in aqueductal stenosis leading to hydrocephalus through up-regulation of Notch signaling

Rho family guanosine triphosphatase (GTPase) 3 (Rnd3), a member of the small Rho GTPase family, is involved in the regulation of cell actin cytoskeleton dynamics, cell migration, and proliferation through the Rho kinase-dependent signaling pathway. We report a role of Rnd3 in the pathogenesis of hydrocephalus disorder. Mice with Rnd3 genetic deletion developed severe obstructive hydrocephalus with enlargement of the lateral and third ventricles, but not of the fourth ventricles. The cerebral aqueducts in Rnd3-null mice were partially or completely blocked by the overgrowth of ependymal epithelia. We examined the molecular mechanism contributing to this Rnd3-deficiency–mediated hydrocephalus and found that Rnd3 is a regulator of Notch signaling. Rnd3 deficiency, through either gene deletion or siRNA knockdown, resulted in a decrease in Notch intracellular domain (NICD) protein degradation. However, there was no correlated change in mRNA change, which in turn led to an increase in NICD protein levels. Immunoprecipitation analysis demonstrated that Rnd3 and NICD physically interacted, and that down-regulation of Rnd3 attenuated NICD protein ubiquitination. This eventually enhanced Notch signaling activity and promoted aberrant growth of aqueduct ependymal cells, resulting in aqueduct stenosis and the development of congenital hydrocephalus. Inhibition of Notch activity rescued the hydrocephalus disorder in the mutant animals

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