JOSD2 mediates isoprenaline-induced heart failure by deubiquitinating CaMKIIδ in cardiomyocytes.

Prolonged stimulation of ß-adrenergic receptor (ß-AR) can lead to sympathetic overactivity that causes pathologic cardiac hypertrophy and fibrosis, ultimately resulting in heart failure. Recent studies suggest that abnormal protein ubiquitylation may contribute to the pathogenesis of cardiac hypertrophy and remodeling. In this study, we demonstrated that deficiency of a deubiquitinase, Josephin domain-containing protein 2 (JOSD2), ameliorated isoprenaline (ISO)- and myocardial infarction (MI)-induced cardiac hypertrophy, fibrosis, and dysfunction both in vitro and in vivo. Conversely, JOSD2 overexpression aggravated ISO-induced cardiac pathology. Through comprehensive mass spectrometry analysis, we identified that JOSD2 interacts with Calcium-calmodulin-dependent protein kinase II (CaMKIIδ). JOSD2 directly hydrolyzes the K63-linked polyubiquitin chains on CaMKIIδ, thereby increasing the phosphorylation of CaMKIIδ and resulting in calcium mishandling, hypertrophy, and fibrosis in cardiomyocytes. In vivo experiments showed that the cardiac remodeling induced by JOSD2 overexpression could be reversed by the CaMKIIδ inhibitor KN-93. In conclusion, our study highlights the role of JOSD2 in mediating ISO-induced cardiac remodeling through the regulation of CaMKIIδ ubiquitination, and suggests its potential as a therapeutic target for combating the disease. Please check and confirm that the authors and their respective affiliations have been correctly identified and amend if necessary. All have been checked.

Toll-like receptor-2 in cardiomyocytes and macrophages mediates isoproterenol-induced cardiac inflammation and remodeling.

Heart failure (HF) is the leading cause of morbidity and mortality worldwide. Activation of the innate immune system initiates an inflammatory response during cardiac remodeling induced by isoproterenol (ISO). Here, we investigated whether Toll-like receptor-2 (TLR2) mediates ISO-induced inflammation, hypertrophy, and fibrosis. TLR2 was found to be increased in the heart tissues of mouse with HF under ISO challenge. Further, cardiomyocytes and macrophages were identified as the main cellular sources of the increased TLR2 levels in the model under ISO stimulation. The effect of TLR2 deficiency on ISO-induced cardiac remodeling was determined using TLR2 knockout mice and bone marrow transplantation models. In vitro studies involving ISO-treated cultured cardiomyocytes and macrophages showed that TLR2 knockdown significantly decreased ISO-induced cell inflammation and remodeling via MAPKs/NF-κB signaling. Mechanistically, ISO significantly increased the TLR2-MyD88 interaction in the above cells in a TLR1-dependent manner. Finally, DAMPs, such as HSP70 and fibronectin 1 (FN1), were found to be released from the cells under ISO stimulation, which further activated TLR1/2-Myd88 signaling and subsequently activated pro-inflammatory cytokine expression and cardiac remodeling. In summary, our findings suggest that TLR2 may be a target for the alleviation of chronic adrenergic stimulation-associated HF. In addition, this paper points out the possibility of TLR2 as a new target for heart failure under ISO stimulation.

Isoproterenol induces MD2 activation by ß-AR-cAMP-PKA-ROS signalling axis in cardiomyocytes and macrophages drives inflammatory heart failure.

Cardiac inflammation contributes to heart failure (HF) induced by isoproterenol (ISO) through activating ß-adrenergic receptors (ß-AR). Recent evidence shows that myeloid differentiation factor 2 (MD2), a key protein in endotoxin-induced inflammation, mediates inflammatory heart diseases. In this study, we investigated the role of MD2 in ISO-ß-AR-induced heart injuries and HF. Mice were infused with ISO (30 mg·kg-1·d-1) via osmotic mini-pumps for 2 weeks. We showed that MD2 in cardiomyocytes and cardiac macrophages was significantly increased and activated in the heart tissues of ISO-challenged mice. Either MD2 knockout or administration of MD2 inhibitor L6H21 (10 mg/kg every 2 days, i.g.) could prevent mouse hearts from ISO-induced inflammation, remodelling and dysfunction. Bone marrow transplantation study revealed that both cardiomyocyte MD2 and bone marrow-derived macrophage MD2 contributed to ISO-induced cardiac inflammation and injuries. In ISO-treated H9c2 cardiomyocyte-like cells, neonatal rat primary cardiomyocytes and primary mouse peritoneal macrophages, MD2 knockout or pre-treatment with L6H21 (10 µM) alleviated ISO-induced inflammatory responses, and the conditioned medium from ISO-challenged macrophages promoted the hypertrophy and fibrosis in cardiomyocytes and fibroblasts. We demonstrated that ISO induced MD2 activation in cardiomyocytes via ß1-AR-cAMP-PKA-ROS signalling axis, and induced inflammatory responses in macrophages via ß2-AR-cAMP-PKA-ROS axis. This study identifies MD2 as a key inflammatory mediator and a promising therapeutic target for ISO-induced heart failure.

OTUD1 promotes hypertensive kidney fibrosis and injury by deubiquitinating CDK9 in renal epithelial cells.

Hypertensive renal disease (HRD) contributes to the progression of kidney dysfunction and ultimately leads to end-stage renal disease. Understanding the mechanisms underlying HRD is critical for the development of therapeutic strategies. Deubiquitinating enzymes (DUBs) have been recently highlighted in renal pathophysiology. In this study, we investigated the role of a DUB, OTU Domain-Containing Protein 1 (OTUD1), in HRD models. HRD was induced in wild-type or Otud1 knockout mice by chronic infusion of angiotensin II (Ang II, 1 µg/kg per min) through a micro-osmotic pump for 4 weeks. We found that OTUD1 expression levels were significantly elevated in the kidney tissues of Ang II-treated mice. Otud1 knockout significantly ameliorated Ang II-induced HRD, whereas OTUD1 overexpression exacerbated Ang II-induced kidney damage and fibrosis. Similar results were observed in TCMK-1 cells but not in SV40 MES-13 cells following Ang II (1 µM) treatment. In Ang II-challenged TCMK-1 cells, we demonstrated that OTUD1 bound to CDK9 and induced CDK9 deubiquitination: OTUD1 catalyzed K63 deubiquitination on CDK9 with its Cys320 playing a critical role, promoting CDK9 phosphorylation and activation to induce inflammatory responses and fibrosis in kidney epithelial cells. Administration of a CDK9 inhibitor NVP-2 significantly ameliorated Ang II-induced HRD in mice. This study demonstrates that OTUD1 mediates HRD by targeting CDK9 in kidney epithelial cells, suggesting OTUD1 is a potential target in treating this disease.

Prevalence of Cystic Echinococcosis in Slaughtered Sheep as an Indicator to Assess Control Progress in Emin County, Xinjiang, China.

Hydatid disease imposing serious threat on human health and great loss in live¬stock pastoralism remains a major public health problem in western China. To assess and monitor the effect of control program on transmission dynamics, we used the prevalence of cystic echinococcosis in slaughtered sheep at slaughterhouse as an indicator during the period of 2007 to 2013 in Emin County, Xinjiang Uygur Autonomous Region, China. The results showed a significant decline trend of prevalence in all age groups during the 7 years when the control program was implemented; particularly, the rate was reduced by 72% after first 3 years. Among the sheep slaughtered, the age distribution evidenced that the prevalence increased significantly as the sheep grew older. The baseline data indicated that the rate was 4.5% at the age <1, 6.7% at age 2~, and reached to the highest 17.9% at age ≥ 4 years. Earlier response to the intervention pressure was seen in the sheep at the younger age. Significant decline started from 2008 at the age <1, from 2009 at age of 1~, 2010 at 2~ to 3~, and the latest, in 2012 at age ≥ 4. This study demonstrated that the prevalence of cystic echinococcosis in slaughtered sheep may be used as an indicator to assess and monitor the transmission status during and after control program providing information for betterment of performance to sustain control strength.

Modeling children's moral development in postwar Taiwan through naturalistic observations preserved in historical texts.

A core issue in the interdisciplinary study of human morality is its ontogeny in diverse cultures, but systematic, naturalistic data in specific cultural contexts are rare to find. This study conducts a novel analysis of 213 children's socio-moral behavior in a historical, non-Western, rural setting, based on a unique dataset of naturalistic observations from the first field research on Han Chinese children. Using multilevel multinomial modeling, we examined a range of proactive behaviors in 0-to-12-year-old children's peer cooperation and conflict in an entire community in postwar Taiwan. We modeled the effects of age, sex, kinship, and behavioral roles, and revealed complex interactions between these four variables in shaping children's moral development. We discovered linkages between coercive and non-coercive behaviors as children strategically negotiated leadership dynamics. We identified connections between prosocial and aggressive behaviors, illuminating the nuances of morality in real life. Our analysis also revealed gendered patterns and age-related trends that deviated from cultural norms and contradicted popular assumptions about Chinese family values. These findings highlight the importance of naturalistic observations in cultural contexts for understanding how we become moral persons. This re-analysis of historically significant fieldnotes also enriches the interdisciplinary study of child development across societies.

OTUD1 promotes isoprenaline- and myocardial infarction-induced heart failure by targeting PDE5A in cardiomyocytes.

Heart failure represents a major cause of death worldwide. Recent research has emphasized the potential role of protein ubiquitination/deubiquitination protein modification in cardiac pathology. Here, we investigate the role of the ovarian tumor deubiquitinase 1 (OTUD1) in isoprenaline (ISO)- and myocardial infarction (MI)-induced heart failure and its molecular mechanism. OTUD1 protein levels were raised markedly in murine cardiomyocytes after MI and ISO treatment. OTUD1 deficiency attenuated myocardial hypertrophy and cardiac dysfunction induced by ISO infusion or MI operation. In vitro, OTUD1 knockdown in neonatal rat ventricular myocytes (NRVMs) attenuated ISO-induced injuries, while OTUD1 overexpression aggravated the pathological changes. Mechanistically, LC-MS/MS and Co-IP studies showed that OTUD1 bound directly to the GAF1 and PDEase domains of PDE5A. OTUD1 was found to reverse K48 ubiquitin chain in PDE5A through cysteine at position 320 of OTUD1, preventing its proteasomal degradation. PDE5A could inactivates the cGMP-PKG-SERCA2a signaling axis which dysregulate the calcium handling in cardiomyocytes, and leading to the cardiomyocyte injuries. In conclusion, OTUD1 promotes heart failure by deubiquitinating and stabilizing PDE5A in cardiomyocytes. These findings have identified PDE5A as a new target of OTUD1 and emphasize the potential of OTUD1 as a target for treating heart failure.

Study on the lignin-derived sp2-sp3 hybrid hard carbon materials and the feasibility for industrial production.

Hard carbon has been widely used in anode of lithium/sodium ion battery, electrode of supercapacitor, and carbon molecular sieve for CO2 capture and hydrogen storage. In this study the lignin derived hard carbon products are investigated, and the conclusions are abstracted as follows. (1) The lignin derived hard carbon products consist of microcrystal units of sp2 graphene fragments, jointed by sp3 carbon atoms and forming sp2-sp3 hybrid hard carbon family. (2) From the lignin precursors to the sp2-sp3 hybrid hard carbon products, most carbon atoms retain their original electron configurations (sp2 or sp3) and keep their composition in lignin. (3) The architectures of lignin-derived hard carbon materials are closely dependent on the forms of their lignin precursors, and could be preformed by different pretreatment techniques. (4) The carbonization of lignin precursors follows the mechanism "carbonization in situ and recombination nearby". (5) Due to the high carbon ratio and abundant active functional groups in lignin, new activation techniques could be developed for control of pore size and pore volume. In general lignin is an excellent raw material for sp2-sp3 hybrid hard carbon products, a green and sustainable alternative resource for phenolic resin, and industrial production for lignin derived hard carbon products would be feasible.

Compound SJ-12 attenuates streptozocin-induced diabetic cardiomyopathy by stabilizing SERCA2a.

Heart failure (HF) is one of the major causes of death among diabetic patients. Although studies have shown that curcumin analog C66 can remarkably relieve diabetes-associated cardiovascular and kidney complications, the role of SJ-12, SJ-12, a novel curcumin analog, in diabetic cardiomyopathy and its molecular targets are unknown. 7-week-old male C57BL/6 mice were intraperitoneally injected with single streptozotocin (STZ) (160 mg/kg) to develop diabetic cardiomyopathy (DCM). The diabetic mice were then treated with SJ-12 via gavage for two months. Body weight, fast blood glucose, cardiac utrasonography, myocardial injury markers, pathological morphology of the heart, hypertrophic and fibrotic markers were assessed. The potential target of SJ-12 was evaluated via RNA-sequencing analysis. The O-GlcNAcylation levels of SP1 were detected via immunoprecipitation. SJ-12 effectively suppressed myocardial hypertrophy and fibrosis, thereby preventing heart dysfunction in mice with STZ-induced heart failure. RNA-sequencing analysis revealed that SJ-12 exerted its therapeutic effects through the modulation of the calcium signaling pathway. Furthermore, SJ-12 reduced the O-GlcNAcylation levels of SP1 by inhibiting O-linked N-acetylglucosamine transferase (OGT). Also, SJ-12 stabilized Sarcoplasmic/Endoplasmic Reticulum Calcium ATPase 2a (SERCA2a), a crucial regulator of calcium homeostasis, thus reducing hypertrophy and fibrosis in mouse hearts and cultured cardiomyocytes. However, the anti-fibrotic effects of SJ-12 were not detected in SERCA2a or OGT-silenced cardiomyocytes, indicating that SJ-12 can prevent DCM by targeting OGT-dependent O-GlcNAcylation of SP1.These findings indicate that SJ-12 can exert cardioprotective effects in STZ-induced mice by reducing the O-GlcNAcylation levels of SP1, thus stabilizing SERCA2a and reducing myocardial fibrosis and hypertrophy. Therefore, SJ-12 can be used for the treatment of diabetic cardiomyopathy.

20(S)-ginsenoside Rh2 inhibits angiotensin-2 mediated cardiac remodeling and inflammation associated with suppression of the JNK/AP-1 pathway.

BACKGROUND: Enhanced levels of angiotensin-2 (Ang-II) causes hypertensive heart failure (HHF) through non-hemodynamical and hemodynamical alterations. 20(S)-ginsenoside Rh2 (20(S)-Rh2) is a natural ginseng compound with numerous cardiovascular benefits. This investigation elucidates the influence of 20(S)-Rh2 on Ang-II-induced heart failure and cardiac alterations. METHODS: Ang-II was administered in C57BL/6 mice for 4 weeks to induce HHF. In the last 2 weeks of treatment, 20(S)-Rh2 was orally administered in mice to assess the potential 20(S)-Rh2 mechanism. Subsequently, RNA sequencing was carried out. RESULTS: It was indicated that 20(S)-Rh2 suppresses myocardial fibrosis, hypertrophy, and inflammation, thereby inhibiting cardiac disruption in Ang-II-challenged mice without affecting blood pressure. According to the RNA sequencing data, this cardio-protective effect was linked with the (JNK)/AP 1 pathway. 20(S)-Rh2 alleviated heart tissue and cardiomyocytes inflammation by inhibiting the Ang-II-mediated JNK/AP-1 pathway. Within cardiomyocytes, JNK or AP-1 absence abolished the anti-inflammatory effects of 20(S)-Rh2. CONCLUSION: This study investigation indicated that 20(S)-Rh2 prevents cardiovascular dysfunction induced by Ang-II induced by decreasing JNK-regulated inflammatory responses, providing evidence for its use as an efficient regimen for HHF.

Two Rhabdoviruses, One Novel, Isolated from Armigeres subalbatus in China.

The family Rhabdoviridae contain important human and mammalian pathogens that are vectored by different arthropod species. The ground supernatants of mosquitoes were used to inoculate in BHK-21 and C6/36 cells for virus isolation. Then, the viral complete genome sequence was obtained and used for phylogenetic analysis. In this study, we observed a cytopathic effect (CPE) in mosquito cells (C6/36) and rod-like virion after inoculating a pool of Armigeres subalbatus samples collected in Shanxi Province, China, in 2019 (SX1916). Meta-transcriptomics sequencing revealed the presence of two distinctive rhabdoviruses with similar abundance levels, namely, Shanxi Armigeres subalbatus rhabdovirus (SXARV) and Shanxi Arboretum virus (SXABTV). Despite the fact that the SXARV genome (9590 nt) was much shorter than that of SXABTV (11,480 nt), both belonged to the Almendravirus group within Rhabdoviridae whose genomes encoded five proteins (N, P, M, G, and L) and a small hydrophobin (U1) and the difference in lengths is mainly caused by a substantially shorter N protein encoded by SXARV. On the phylogenetic tree, SXABTV was closely related (90.7% amino acid identity at L protein) with the Arboretum virus isolated from Psorophora albigenu mosquitoes in Peru in 2014, whereas SXARV was distantly related to Rio Chico virus (63.3% amino acid identity), a genetic distance large enough to be defined as a new species within Rhabdoviridae. Collectively, we report a simultaneous isolation of two related rhabdoviruses from Armigeres subalbatus that marked the circulation of almendraviruses in Shanxi, China.

Isolation and Identification of Sandfly-Borne Viruses from Sandflies Collected from June to August, 2019, in Yangquan County, China.

In Yangquan County, the sandfly-transmitted virus (Wuxiang virus) was first isolated from sandflies in 2018. However, relationships between the abundance and seasonal fluctuations of local sandflies and sandfly-transmitted viruses are unknown. Herein, we report that sandfly specimens were collected in three villages in Yangquan County, from June to August, 2019. A total of 8363 sandflies were collected (June, 7927; July, 428; August, 8). Eighteen virus strains (June, 18; July, 0; August, 0) were isolated in pools of Phlebotomus chinensis. The genome sequence of the newly isolated virus strain was highly similar to that of the Wuxiang virus (WUXV), isolated from sandflies in Yangquan County in 2018. Our results suggested that the sandfly-transmitted viruses, and the local sandfly population, are stable in Yangquan County, and that June is the peak period for the virus carried by sandflies in this area.

Wuxiang Virus Is a Virus Circulated Naturally in Wuxiang County, China.

Background: Wuxiang virus was isolated from sandfly specimens collected in Wuxiang County, Shanxi Province, China in 2018, representing the first reported isolation of sandfly-borne virus from sandflies collected in a natural environment in China. The local sandfly density, seasonal fluctuations, and temporal and spatial distributions of the virus in Wuxiang County remain unclear. Materials and Methods: Four fixed sandfly collection sites were set up in Wuxiang County and sandfly specimens were collected continuously from June to August 2019. All sandfly specimens were subjected to viral isolation and molecular biological analysis. Results: The data on sandfly specimens collected in Wuxiang County from June to August 2019 showed a significant difference in the density of sandflies between June 26 and August 16 (p < 0.05). No statistical difference was found in sandfly density among collection sites (p > 0.05). A total of 33 virus isolates causing cytopathic effects in mammalian (BHK-21) cells were obtained from 7466 sandflies (91 pools) collected from June to August 2019. The results of molecular genetic evolution analysis of the nucleotide sequence of these isolates showed that the L and S genes (encoding NS and N proteins) of the 33 viruses isolated in 2019 are in the same evolutionary branch as the previously isolated Wuxiang virus. No significant difference was found in the virus isolation rate (the pool isolation rate of virus) among sandflies collected at different times from June to August (p > 0.05). The virus isolation rate of sandflies collected at different collection sites showed a statistically significant difference (p < 0.05). Conclusions: The results of this study suggest that the Wuxiang virus is a stable viral population in local sandflies. Strengthened research into Wuxiang virus infection of humans and animals and clarification of the public health hazards posed by Wuxiang virus to both humans and animals are urgently needed.

Re-isolation of Wuxiang Virus from Wild Sandflies Collected from Yangquan County, China.

We previously isolated a new species of the genus Phlebovirus from wild sandflies collected from Wuxiang County in central China, which named the Wuxiang virus (WUXV). In this study, we re-isolated the WUXV from wild sandflies collected from two villages in Yangquan County, China in 2019. Four virus isolates that caused cytopathic effects in BHK-21 cells were successfully isolated from sandfly specimens collected from chicken pens and sheep pens. Phylogenetic analyses of the L, M and S gene segments of the viruses revealed that the four virus strains represented the previously isolated WUXV. The minimum infection rate (MIR) of the virus isolated from the sheep pen was 3.21, and the MIR of the virus isolated from the chicken pen was 3.45. The positive rates of Wuxiang virus neutralizing antibodies in serum samples of local healthy people and domestic chickens were 8.7% (4/46) and 100% (4/4), respectively, suggesting that Wuxiang virus can infect human and animal. In view of the fact that Wuxiang virus is infectious to humans and animals and has a relatively wide geographical distribution in China, it is of great public health significance to strengthen the investigation and study on the infection status of Wuxiang virus in humans and animals.

Evaluation of MRI RF electromagnetic field induced heating near leads of cochlear implants.

A typical cochlear implant system under magnetic resonance imaging (MRI) procedures may couple with the radio frequency (RF) electromagnetic field (EMF) and results in an intensified electric field at the lead tip. As a result, the RF energy deposited in human tissues around the lead tip may induce heating and cause tissue damage concerns. The purpose of this work is to evaluate the RF-EMF-induced heating for cochlear implant system in 1.5 T MRI coil and highlight the factors that have significant effects on the heating. The potential factors involved in the RF-EMF-induced heating including the lead type, lead trajectory, human model and MRI landmark. In this paper, the RF-EMF-induced heating for three types of leads is evaluated in two virtual human models. A total of 24 lead trajectories and 23 anatomical landmark positions are studied using the transfer function method. The average temperature rise for all the studied cases in the human models is 0.79 °C, and the maximum value is 2.80 °C for a maximum whole-body average specific absorption rate of 2 W kg-1 in an RF body coil. It is found that the lead trajectory and MRI landmark are two primary influencing factors. The maximum temperature rises for different lead trajectories can vary from 0.82 to 2.80 °C. A difference in heating of 2.80 °C is observed when the landmark changes from -100 to 700 mm. This work demonstrates that it is necessary to take these factors into account when evaluating the RF-EMF-induced heating for implanted medical devices.

Salinomycin, as an autophagy modulator-- a new avenue to anticancer: a review.

Since Salinomycin (Sal) emerged its ability to target breast cancer stem cells in 2009, numerous experiments have been carried out to test Sal's anticancer effects. What deserve to be mentioned is that Sal can efficiently induce proliferation inhibition, cell death and metastasis suppression against human cancers from different origins both in vivo and in vitro without causing serious side effects as the conventional chemotherapeutical drugs on the body. There may be novel cell death pathways involving the anticancer effects of Sal except the conventional pathways, such as autophagic pathway. This review is focused on how autophagy involves the effects of Sal, trying to describe clearly and systematically why autophagy plays a vital role in predominant anticancer effects of Sal, including its distinctive characteristic. Based on recent advances, we present evidence that a dual role of Sal involving in autophagy may account for its unique anticancer effects - the preference for cancer cells. Further researches are required to confirm the authenticity of this suppose in order to develop an ideal anticancer drug.

Bridging the connection between effective viscosity and electrical conductivity through water content in the upper mantle.

Upper mantle viscosity plays a key role in understanding plate tectonics and is usually extrapolated from laboratory-based creep measurements of upper mantle conditions or constrained by modeling geodetic and post-seismic observations. At present, an effective method to obtain a high-resolution viscosity structure is still lacking. Recently, a promising estimation of effective viscosity was obtained from a transform derived from the results of magnetotelluric imaging. Here, we build a relationship between effective viscosity and electrical conductivity in the upper mantle using water content. The contribution of water content to the effective viscosity is isolated in a flow law with reference to relatively dry conditions in the upper mantle. The proposed transform is robust and has been verified by application to data synthesized from an intraoceanic subduction zone model. We then apply the method to transform an electrical conductivity cross-section across the Yangtze block and the North China Craton. The results show that the effective viscosity structure coincides well with that estimated from other independent datasets at depths of 40 to 80 km but differs slightly at depths of 100 to 200 km. We briefly discussed the potentials and associated problems for application.