A Fluoride-Rich Solid-Like Electrolyte Stabilizing Lithium Metal Batteries.

To address the problems associated with Li metal anodes, a fluoride-rich solid-like electrolyte (SLE) that combines the benefits of solid-state and liquid electrolytes is presented. Its unique triflate-group-enhanced frame channels facilitate the formation of a functional inorganic-rich solid electrolyte interphase (SEI), which not only improves the reversibility and interfacial charge transfer of Li anodes but also ensures uniform and compact Li deposition. Furthermore, these triflate groups contribute to the decoupling of Li+ and provide hopping sites for rapid Li+ transport, enabling a high room-temperature ionic conductivity of 1.1 mS cm-1 and a low activation energy of 0.17 eV, making it comparable to conventional liquid electrolytes. Consequently, Li symmetric cells using such SLE achieve extremely stable plating/stripping cycling over 3500 h at 0.5 mA cm-2 and support a high critical current up to 2 mA cm-2. The assembled Li||LiFePO4 solid-like batteries exhibit exceptional cyclability for over 1 year and a half, even outperforming liquid cells. Additionally, high-voltage cylindrical cells and high-capacity pouch cells are demonstrated, corroborating much simpler processibility in battery assembly compared to all-solid-state batteries.

Nicotinamide restores tissue NAD+ and improves survival in rodent models of cardiac arrest.

Metabolic suppression in the ischemic heart is characterized by reduced levels of NAD+ and ATP. Since NAD+ is required for most metabolic processes that generate ATP, we hypothesized that nicotinamide restores ischemic tissue NAD+ and improves cardiac function in cardiomyocytes and isolated hearts, and enhances survival in a mouse model of cardiac arrest. Mouse cardiomyocytes were exposed to 30 min simulated ischemia and 90 min reperfusion. NAD+ content dropped 40% by the end of ischemia compared to pre-ischemia. Treatment with 100 µM nicotinamide (NAM) at the start of reperfusion completely restored the cellular level of NAD+ at 15 min of reperfusion. This rescue of NAD+ depletion was associated with improved contractile recovery as early as 10 min post-reperfusion. In a mouse model of cardiac arrest, 100 mg/kg NAM administered IV immediately after cardiopulmonary resuscitation resulted in 100% survival at 4 h as compared to 50% in the saline group. In an isolated rat heart model, the effect of NAM on cardiac function was measured for 20 min following 18 min global ischemia. Rate pressure product was reduced by 26% in the control group following arrest. Cardiac contractile function was completely recovered with NAM treatment given at the start of reperfusion. NAM restored tissue NAD+ and enhanced production of lactate and ATP, while reducing glucose diversion to sorbitol in the heart. We conclude that NAM can rapidly restore cardiac NAD+ following ischemia and enhance glycolysis and contractile recovery, with improved survival in a mouse model of cardiac arrest.

Reducing the Surface Tension of Zn Anodes by an Abietic Acid Layer for High Redox Kinetics and Reversibility.

Aqueous zinc batteries are appealing devices for cost-effective and environmentally sustainable energy storage. However, the critical issues of uncontrolled dendrite propagation and side reactions with Zn anodes have hindered their practical applications. Inspired by the functions of the rosin flux in soldering, an abietic acid (ABA) layer is fabricated on the surface of Zn anodes (ABA@Zn). The ABA layer protects the Zn anode from corrosion and the concomitant hydrogen evolution reaction. It also facilitates fast interfacial charge transfer and horizontal growth of the deposited Zn by reducing the surface tension of the Zn anode. Consequently, promoted redox kinetics and reversibility are simultaneously achieved by the ABA@Zn. It demonstrates stable Zn plating/stripping cycling over 5100 h and a high critical current of 8.0 mA cm-2. Moreover, the assembled ABA@Zn|(NH4)2V6O16 full cell delivers outstanding long-term cycling stability with an 89% capacity retention after 3000 cycles. This work provides a straightforward yet effective solution to the key issues of aqueous zinc batteries.

Recent advances of antibacterial starch-based materials.

Starch has attracted a lot of attention because it is biodegradable, renewable, nontoxic and low cost. By adding antibacterial substances to starch, starch-based materials have antibacterial properties. The composite with other materials can improve the comprehensive performance of starch-based materials, thus broadening the application field of the material. In this paper, we focus on antibacterial starch-based materials and review their preparation and applications. It was found that antibacterial starch-based materials were most widely used in packaging, followed by medicine, and the research on smart starch-based materials was relatively less. This review may provide some reference value for subsequent studies of starch-based materials.

Preparation and Properties of Photoresponsive Pendimethalin@Silica-cinnamamide/γ-CD Microspheres for Pesticide Controlled Release.

Photocontrolled pesticide delivery systems have broad prospects for application in agriculture. Here, a novel photoresponsive herbicide delivery system was fabricated by functionalizing silica microsphere surfaces with cinnamamide and encapsulating the silica-cinnamamide with γ-cyclodextrin (γ-CD) to form a double-layered microsphere shell loaded with pendimethalin (pendimethalin@silica-cinnamamide/γ-CD). The microspheres showed remarkable loading capacity for pendimethalin (approximately 30.25% w/w) and displayed excellent photoresponsiveness and controlled release. The cumulative drug release rate exceeded 80% over 72 h under UV or sunlight irradiation. The herbicidal activity of the microspheres against Echinochloa crusgalli (L.) Beauv. was almost the same as that of pendimethalin under UV or sunlight. A bioactivity survey confirmed that the pendimethalin@silica-cinnamamide/γ-CD microspheres exhibited longer duration weed control than commercial pendimethalin. Allium cepa chromosomal aberration assays demonstrated that the microspheres showed lower genotoxicity than pendimethalin. These advantages indicate that pendimethalin@silica-cinnamamide/γ-CD microspheres constitute an environmentally friendly herbicidal formulation.

Miz1 promotes KRAS-driven lung tumorigenesis by repressing the protocadherin Pcdh10.

Targeting KRAS-mutated non-small-cell lung cancer (NSCLC) remains clinically challenging. Here we show that loss of function of Miz1 inhibits lung tumorigenesis in a mouse model of oncogenic KRAS-driven lung cancer. In vitro, knockout or silencing of Miz1 decreases cell proliferation, clonogenicity, migration, invasion, or anchorage-independent growth in mutant (MT) KRAS murine or human NSCLC cells but has unremarkable impact on non-tumorigenic cells or wild-type (WT) KRAS human NSCLC cells. RNA-sequencing reveals Protocadherin-10 (Pcdh10) as the top upregulated gene by Miz1 knockout in MT KRAS murine lung tumor cells. Chromatin immunoprecipitation shows Miz1 binding on the Pcdh10 promoter in MT KRAS lung tumor cells but not non-tumorigenic cells. Importantly, silencing of Pcdh10 rescues cell proliferation and clonogenicity in Miz1 knockout/knockdown MT KRAS murine or human tumor cells, and rescues allograft tumor growth of Miz1 knockout tumor cells in vivo. Miz1 is upregulated in MT KRAS lung tumor tissues compared with adjacent non-involved tissues in mice. Consistent with this, Miz1 is upregulated while Pcdh10 is downregulated in human lung adenocarcinomas (LUAD) compared with normal tissues, and high Miz1 levels or low Pcdh10 levels are associated with poor survival in lung cancer patients. Furthermore, the Miz1 signature is associated with worse survival in MT but not WT KRAS LUAD, and Pcdh10 is downregulated in MT compared to WT KRAS LUAD. Taken together, our studies implicate the Miz1/Pcdh10 axis in oncogenic KRAS-driven lung tumorigenesis.

Cortactin loss protects against hemin-induced acute lung injury in sickle cell disease.

In patients with sickle cell disease (SCD), acute chest syndrome (ACS) is a common form of acute lung injury and a major cause of morbidity and mortality. The pathophysiology of ACS is complex, and hemin, the prosthetic moiety of hemoglobin, has been implicated in endothelial cell (EC) activation and subsequent acute lung injury (ALI) and ACS in vitro and in animal studies. Here, we examined the role of cortactin (CTTN), a cytoskeletal protein that regulates EC function, in response to hemin-induced ALI and ACS. Cortactin heterozygous (Cttn+/-) mice (n = 8) and their wild-type siblings (n = 8) were irradiated and subsequently received bone marrow cells (BMCs) extruded from the femurs of SCD mice (SS) to generate SS Cttn+/- and SS CttnWT chimeras. Following hemoglobin electrophoretic proof of BMC transplantation, the mice received 35 µmol/kg of hemin. Within 24 h, surviving mice were euthanized, and bronchoalveolar fluid (BAL) and lung samples were analyzed. For in vitro studies, human lung microvascular endothelial cells (HLMVECs) were used to determine hemin-induced changes in gene expression and reactive oxygen species (ROS) generation in cortactin deficiency and control conditions. When compared with wild-type littermates, the mortality for SS Cttn+/- mice trended to be lower after hemin infusion and these mice exhibited less severe lung injury and less necroptotic cell death. In vitro studies confirmed that cortactin deficiency is protective against hemin-induced injury in HMLVECs, by decreasing protein expression of p38/HSP27, improving cell barrier function, and decreasing the production of ROS. Further studies examining the role of CTTN in ACS are warranted and may open a new avenue of potential treatment for this devastating disease.

MRSA-induced endothelial permeability and acute lung injury are attenuated by FTY720 S-phosphonate.

Disruption of the lung endothelial barrier is a hallmark of acute respiratory distress syndrome (ARDS), for which no effective pharmacologic treatments exist. Prior work has demonstrated that FTY720 S-phosphonate (Tys), an analog of sphingosine-1-phosphate (S1P) and FTY720, exhibits potent endothelial cell (EC) barrier protective properties. In this study, we investigated the in vitro and in vivo efficacy of Tys against methicillin-resistant Staphylococcus aureus (MRSA), a frequent bacterial cause of ARDS. Tys-protected human lung EC from barrier disruption induced by heat-killed MRSA (HK-MRSA) or staphylococcal α-toxin and attenuated MRSA-induced cytoskeletal changes associated with barrier disruption, including actin stress fiber formation and loss of peripheral VE-cadherin and cortactin. Tys-inhibited Rho and myosin light chain (MLC) activation after MRSA and blocked MRSA-induced NF-κB activation and release of the proinflammatory cytokines, IL-6 and IL-8. In vivo, intratracheal administration of live MRSA in mice caused significant vascular leakage and leukocyte infiltration into the alveolar space. Pre- or posttreatment with Tys attenuated MRSA-induced lung permeability and levels of alveolar neutrophils. Posttreatment with Tys significantly reduced levels of bronchoalveolar lavage (BAL) VCAM-1 and plasma IL-6 and KC induced by MRSA. Dynamic intravital imaging of mouse lungs demonstrated Tys attenuation of HK-MRSA-induced interstitial edema and neutrophil infiltration into lung tissue. Tys did not directly inhibit MRSA growth or viability in vitro. In conclusion, Tys inhibits lung EC barrier disruption and proinflammatory signaling induced by MRSA in vitro and attenuates acute lung injury induced by MRSA in vivo. These results support the potential utility of Tys as a novel ARDS therapeutic strategy.

miR-221-5p-Mediated Downregulation of JNK2 Aggravates Acute Lung Injury.

Sepsis and acute lung injury (ALI) are linked to mitochondrial dysfunction; however, the underlying mechanism remains elusive. We previously reported that c-Jun N-terminal protein kinase 2 (JNK2) promotes stress-induced mitophagy by targeting small mitochondrial alternative reading frame (smARF) for ubiquitin-mediated proteasomal degradation, thereby preventing mitochondrial dysfunction and restraining inflammasome activation. Here we report that loss of JNK2 exacerbates lung inflammation and injury during sepsis and ALI in mice. JNK2 is downregulated in mice with endotoxic shock or ALI, concomitantly correlated inversely with disease severity. Small RNA sequencing revealed that miR-221-5p, which contains seed sequence matching to JNK2 mRNA 3' untranslated region (3'UTR), is upregulated in response to lipopolysaccharide, with dynamically inverse correlation with JNK2 mRNA levels. miR-221-5p targets the 3'UTR of JNK2 mRNA leading to its downregulation. Accordingly, miR-221-5p exacerbates lung inflammation and injury during sepsis in mice by targeting JNK2. Importantly, in patients with pneumonia in medical intensive care unit, JNK2 mRNA levels in alveolar macrophages flow sorted from non-bronchoscopic broncholaveolar lavage (BAL) fluid were inversely correlated strongly and significantly with the percentage of neutrophils, neutrophil and white blood cell counts in BAL fluid. Our data suggest that miR-221-5p targets JNK2 and thereby aggravates lung inflammation and injury during sepsis.

Group V Phospholipase A2 Mediates Endothelial Dysfunction and Acute Lung Injury Caused by Methicillin-Resistant Staphylococcus Aureus.

Lung endothelial dysfunction is a key feature of acute lung injury (ALI) and clinical acute respiratory distress syndrome (ARDS). Previous studies have identified the lipid-generating enzyme, group V phospholipase A2 (gVPLA2), as a mediator of lung endothelial barrier disruption and inflammation. The current study aimed to determine the role of gVPLA2 in mediating lung endothelial responses to methicillin-resistant Staphylococcus aureus (MRSA, USA300 strain), a major cause of ALI/ARDS. In vitro studies assessed the effects of gVPLA2 inhibition on lung endothelial cell (EC) permeability after exposure to heat-killed (HK) MRSA. In vivo studies assessed the effects of intratracheal live or HK-MRSA on multiple indices of ALI in wild-type (WT) and gVPLA2-deficient (KO) mice. In vitro, HK-MRSA increased gVPLA2 expression and permeability in human lung EC. Inhibition of gVPLA2 with either the PLA2 inhibitor, LY311727, or with a specific monoclonal antibody, attenuated the barrier disruption caused by HK-MRSA. LY311727 also reduced HK-MRSA-induced permeability in mouse lung EC isolated from WT but not gVPLA2-KO mice. In vivo, live MRSA caused significantly less ALI in gVPLA2 KO mice compared to WT, findings confirmed by intravital microscopy assessment in HK-MRSA-treated mice. After targeted delivery of gVPLA2 plasmid to lung endothelium using ACE antibody-conjugated liposomes, MRSA-induced ALI was significantly increased in gVPLA2-KO mice, indicating that lung endothelial expression of gVPLA2 is critical in vivo. In summary, these results demonstrate an important role for gVPLA2 in mediating MRSA-induced lung EC permeability and ALI. Thus, gVPLA2 may represent a novel therapeutic target in ALI/ARDS caused by bacterial infection.

TAT delivery of a PTEN peptide inhibitor has direct cardioprotective effects and improves outcomes in rodent models of cardiac arrest.

We have recently shown that pharmacologic inhibition of PTEN significantly increases cardiac arrest survival in a mouse model, however, this protection required pretreatment 30 min before the arrest. To improve the onset of PTEN inhibition during cardiac arrest treatment, we have designed a TAT fused cell-permeable peptide (TAT-PTEN9c) based on the C-terminal PDZ binding motif of PTEN for rapid tissue delivery and protection. Western blot analysis demonstrated that TAT-PTEN9c peptide significantly enhanced Akt activation in mouse cardiomyocytes in a concentration- and time-dependent manner. Mice were subjected to 8 min asystolic arrest followed by CPR, and 30 mice with successful CPR were then randomly assigned to receive either saline or TAT-PTEN9c treatment. Survival was significantly increased in TAT-PTEN9c-treated mice compared with that of saline control at 4 h after CPR. The treated mice had increased Akt phosphorylation at 30 min resuscitation with significantly decreased sorbitol content in heart or brain tissues and reduced release of taurine and glutamate in blood, suggesting improved glucose metabolism. In an isolated rat heart Langendorff model, direct effects of TAT-PTEN9c on cardiac function were measured for 20 min following 20 min global ischemia. Rate pressure product was reduced by >20% for both TAT vehicle and nontreatment groups following arrest. Cardiac contractile function was completely recovered with TAT-PTEN9c treatment given at the start of reperfusion. We conclude that TAT-PTEN9c enhances Akt activation and decreases glucose shunting to the polyol pathway in critical organs, thereby preventing osmotic injury and early cardiovascular collapse and death.NEW & NOTEWORTHY We have designed a cell-permeable peptide, TAT-PTEN9c, to improve cardiac arrest survival. It blocked endogenous PTEN binding to its adaptor and enhanced Akt signaling in mouse cardiomyocytes. It improved mouse survival after cardiac arrest, which is related to improved glucose metabolism and reduced glucose shunting to sorbitol in critical organs.

Thermal properties and enzymatic degradation of PBS copolyesters containing dl-malic acid units.

A series of biodegradable copolyester of poly (butylene succinate-co-butylene malate) (P (BS-co-BM)) bearing hydroxyl groups were prepared by one-pot synthetic strategy without hydroxy-protection. The structure and properties of the P (BS-co-BM) were characterized by nuclear magnetic resonance (1H NMR), thermogravimetry analysis (TGA), differential scanning calorimetry (DSC), polarized optical microscope (POM), contact angle tester and enzymatic degradation. The results showed that the P (BS-co-BM) manifested excellent thermal properties. The glass transition temperature (Tg) of the P (BS-co-BM) increased with malic acid units added, the crystallizability temperature (Tc) decreased from 72.6 °C to 21.7 °C, and the melting point temperature (Tm) decreased from 117.9 °C to 82.4 °C. The crystallization rate of poly(butylene succinate) (PBS) segment within P (BS-co-BM) was improved by the introduction of malic acid. The enzymatic degradation rate increased with hydrophilicity of the copolyester improving.

Correction: Poly(adenine)-mediated DNA-functionalized gold nanoparticles for sensitive detection of mercury ions in aqueous media.

[This corrects the article DOI: 10.1039/C9RA03041G.].

Akt1-mediated CPR cooling protection targets regulators of metabolism, inflammation and contractile function in mouse cardiac arrest.

Therapeutic hypothermia initiated during cardiopulmonary resuscitation (CPR) in pre-clinical studies appears to be highly protective against sudden cardiac arrest injury. Given the challenges to implementing CPR cooling clinically, insights into its critical mechanisms of protection could guide development of new CPR drugs that mimic hypothermia effects without the need for physical cooling. Here, we used Akt1-deficient mice that lose CPR hypothermia protection to identify hypothermia targets. Adult female C57BL/6 mice (Akt1+/+ and Akt1+/-) underwent 8 min of KCl-induced asystolic arrest and were randomized to receive hypothermia (30 ± 0.5°C) or normothermia. Hypothermia was initiated during CPR and extended for 1 h after resuscitation. Neurologically scored survival was measured at 72 h. Other outcomes included mean arterial pressure and target measures in heart and brain related to contractile function, glucose utilization and inflammation. Compared to northothermia, hypothermia improved both 2h mean arterial pressure and 72h neurologically intact survival in Akt1+/+ mice but not in Akt1+/- mice. In Akt1+/+ mice, hypothermia increased Akt and GSK3ß phosphorylation, pyruvate dehydrogenase activation, and NAD+ and ATP production while decreasing IκBα degradation and NF-κB activity in both heart and brain at 30 min after CPR. It also increased phospholamban phosphorylation in heart tissue. Further, hypothermia reduced metabolic and inflammatory blood markers lactate and Pre-B cell Colony Enhancing Factor. Despite hypothermia treatment, all these effects were reversed in Akt1+/- mice. Taken together, drugs that target Akt1 and its effectors may have the potential to mimic hypothermia-like protection to improve sudden cardiac arrest survival when administered during CPR.

Poly(adenine)-mediated DNA-functionalized gold nanoparticles for sensitive detection of mercury ions in aqueous media.

In this work, a facile and sensitive colorimetric sensor for Hg2+ ions based on poly (adenine)-mediated DNA-functionalized gold nanoparticles (Au NPs) is reported. One DNA sequence consisting of poly-A and T-rich DNA was designed rationally. Poly-A was used as an anchoring block to bind tightly to Au NPs, and T-rich DNA was utilized for specific recognition of Hg2+ ions. With the assistance of poly-A, T-rich DNA was easily introduced onto the surface of Au NPs and kept an upright orientation. In the presence of Hg2+ ions, T base binding with Hg2+ ions results in the formation of "T-Hg2+-T" among the Au NPs, which caused aggregation of the Au NPs and a subsequent change in the color of the solution, from wine red to grayish blue. On this occasion, the limit of detection (LOD) was 3.75 nM Hg2+ ions with a linear range from 5 nM to 200 nM, as measured by UV-Vis spectroscopy. Moreover, successful application of this method for the detection of Hg2+ ions in real samples was demonstrated.

Attenuation of murine acute lung injury by PF-573,228, an inhibitor of focal adhesion kinase.

Acute lung injury (ALI) is characterized by endothelial barrier disruption resulting in increased vascular permeability. As focal adhesion kinase (FAK), a non-receptor protein tyrosine kinase, is involved in endothelial cell (EC) barrier regulation, we hypothesized that FAK inhibition could attenuate agonist-induced EC barrier disruption relevant to ALI. Human lung EC were pretreated with one of three pharmacologic FAK inhibitors, PF-573,228 (PF-228, 10 µM), PF-562,271 (PF-271, 5 µM) or NVP-TAE226 (TAE226, 5 µM) for 30 min prior to treatment with thrombin (1 U/ml, 30 min). Western blotting confirmed attenuated thrombin-induced FAK phosphorylation associated with all three inhibitors. Subsequently, EC were pretreated with either PF-228 (10 µM), TAE226 (5 µM) or PF-271 (5 µM) for 30 min prior to thrombin stimulation (1 U/ml) followed by measurements of barrier integrity by transendothelial electrical resistance (TER). Separately, EC grown in transwell inserts prior to thrombin (1 U/ml) with measurements of FITC-dextran flux after 30 min confirmed a significant attenuation of thrombin-induced EC barrier disruption by PF-228 alone. Finally, in a murine ALI model induced by LPS (1.25 mg/ml, IT), rescue treatment with PF-228 was associated with significantly reduced lung injury. Our findings PF-228, currently being studied in clinical trials, may serve as a novel and effective therapeutic agent for ALI.

Surface modification of PS microtiter plate with chitosan oligosaccharides by 60Co irradiation.

By 60Co-γ irradiation method, the Chitosan-oligosaccharide (COS) was grafted onto the inner surface of the polystyrene (PS) microtiter, which was soaked with COS solution before the irradiation. To evaluated the effect of COS concentration on the properties of the PS microtiter, FTIR, XPS, AFM, Contact angle tester and enzyme-linked analyser was used to measure the surface properties and BSA adsorption of PS-COS plates. The results shows that, with the increase of COS concentration, the contact angle clearly decreased at the dose of 12kGy. The absorbance variances of the COS modified plate is less than 5% while the BSA adsorption is higher than the PS plates. The COS-modified microtiter has the potential applications in biochemical analysis.

Preparation of green and gelatin-free nanocrystalline cellulose capsules.

The ambiguous source and uncontrolled solubility of gelatin make it crucial to develop gelatin capsule substitutes. Nanocrystalline cellulose (NCC) of excellent mechanical performance, good biocompatibility and green origin has drawn many attentions as a new class of biomaterials. In this work, NCC capsule was prepared by dipping method with PEG and glycerol as plasticizer. The effect of PEG and glycerol on the rheological property of NCC gel and the surface morphology of NCC capsule was evaluated. The disintegration time of NCC capsule meet the criteria in United States Pharmacopoeia (USP32-701).There is no significant difference in the release of sulfuric acid between gelatin capsule and NCC capsule. NCC capsule thus has the potential as a green platform for biomedical applications in drug delivery.

Parkin regulates lipopolysaccharide-induced proinflammatory responses in acute lung injury.

The acute respiratory distress syndrome (ARDS) is a serious condition resulting from direct or indirect lung injury that is associated with high mortality and morbidity. A key biological event in the pathogenesis of the acute lung injury (ALI) that causes acute respiratory distress syndrome is activation of the lung endothelium cells (ECs), which is triggered by a variety of inflammatory insults leading to barrier disruption and excessive accumulation of neutrophils. Recently, we demonstrated that imatinib protects against lipopolysaccharide (LPS)-induced EC activation by inhibiting c-Abl kinase. In the present study, we explored the role of parkin, a novel c-Abl substrate, in ALI. Parkin is an E3 ubiquitin ligase originally characterized in the pathogenesis of Parkinson disease; however, its potential role in acute inflammatory processes and lung EC function remains largely unknown. Using parkin deficient (PARK2-/-) mice, we now demonstrate that parkin mediates LPS-induced ALI. After LPS, PARK2-/- mice have reduced total protein and cell levels in bronchoalveolar lavage (BAL) compared to wild type. Moreover, in LPS-treated PARK2-/- lungs, the sequestration and activation of neutrophils and release of inflammatory cytokines (interleukin 6 [IL-6], tumor necrosis factor alpha [TNF-α]) are significantly reduced. The BAL levels of soluble VCAM-1 and ICAM-1 are also decreased in LPS-treated PARK2-/- mice compared to wild type. In cultured human lung endothelial cells, downregulation of parkin by small interfering RNA decreases LPS-induced VCAM-1 expression, IL-8 and IL-6 secretion, and NF-kB phosphorylation. These results suggest a previously unidentified role of parkin in mediating endotoxin-induced endothelial proinflammatory signaling and indicate that it may play a critical role in acute inflammation.

FUS-linked essential tremor associated with motor dysfunction in Drosophila.

Essential tremor (ET) is one of the most common adult-onset neurological disorders which produce motor and non-motor symptoms. To date, there are no gold standard pathological hallmarks of ET, and despite a strong genetic contribution toward ET development, only a few pathogenic mutations have been identified. Recently, a pathogenic FUS-Q290X mutation has been reported in a large ET-affected family; however, the pathophysiologic mechanism underlying FUS-linked ET is unknown. Here, we generated transgenic Drosophila expressing hFUS-WT and hFUS-Q290X and targeted their expression in different tissues. We found that the targeted expression of hFUS-Q290X in the dopaminergic and the serotonergic neurons did not cause obvious neuronal degeneration, but it resulted in motor dysfunction which was accompanied by impairment in the GABAergic pathway. The involvement of the GABAergic pathway was supported by rescue of motor symptoms with gabapentin. Interestingly, we observed gender specific downregulation of GABA-R and NMDA-R expression and reduction in serotonin level. Overexpression of hFUS-Q290X also caused an increase in longevity and this was accompanied by downregulation of the IIS/TOR signalling pathway. Our in vivo studies of the hFUS-Q290X mutation in Drosophila link motor dysfunction to impairment in the GABAergic pathway. Our findings would facilitate further efforts in unravelling the pathophysiology of ET.