ERK signaling is triggered by hepatitis C virus E2 protein through DC-SIGN

Dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN) is a binding receptor for hepatitis C virus (HCV). Binding of HCV envelope protein E2 to target cells is a prerequisite to DC-SIGN-mediated signaling. Using cell lines with stable or transient expression of DC-SIGN, we investigated effects of soluble HCV E2 protein on ERK pathway. MEK and ERK are activated by the E2 in NIH3T3 cells stably expressing DC-SIGN. Treatment of the cells with antibody to DC-SIGN results in inhibition of the E2 binding as well as the E2-induced MEK and ERK activation. In HEK293T cells transiently expressing DC-SIGN, activation of MEK and ERK is also induced by the E2. Activation of ERK pathway by HCV E2 through DC-SIGN provides useful information for understanding cellular receptor-mediated signaling.     

Epithelial cell adhesion molecule (EpCAM) is associated with prostate cancer metastasis and chemo/radioresistance via the PI3K/Akt/mTOR signaling pathway

Prostate cancer (CaP) is the second leading malignancy in men. The role of epithelial cell adhesion molecule (EpCAM), also known as CD326, in CaP progression and therapeutic resistance is still uncertain. Here, we aimed to investigate the roles of EpCAM in CaP metastasis and chemo/radioresistance. Expression of EpCAM in CaP cell lines and human CaP tissues was assessed using immunofluorescence and immunohistochemistry, respectively. EpCAM was knocked down (KD) in PC-3, DU145 and LNCaP-C4-2B cells using small interfering RNA (siRNA), and KD results were confirmed by confocal microscope, Western blotting and quantitative real time polymerase chain reaction (qRT-PCR). Cell growth was evaluated by proliferation and colony formation assays. The invasive potential was assessed using a matrigel chamber assay. Tumorigenesis potential was measured by a sphere formation assay. Chemo-/radiosensitivity were measured using a colony formation assay. Over-expression of EpCAM was found in primary CaP tissues and lymph node metastases including cancer cells and surrounding stromal cells. KD of EpCAM suppressed CaP proliferation and invasive ability, reduced sphere formation, enhanced chemo-/radiosensitivity, and down-regulated E-cadherin, p-Akt, p-mTOR, p-4EBP1 and p-S6K expression in CaP cells. Our findings suggest that EpCAM plays an important role in CaP proliferation, invasion, metastasis and chemo-/radioresistance associated with the activation of the PI3K/Akt/mTOR signaling pathway and is a novel therapeutic target to sensitize CaP cells to chemo-/radiotherapy.     

Structure of the Catalytic Domain of EZH2 Reveals Conformational Plasticity in Cofactor and Substrate Binding Sites and Explains Oncogenic Mutations

Polycomb repressive complex 2 (PRC2) is an important regulator of cellular differentiation and cell type identity. Overexpression or activating mutations of EZH2, the catalytic component of the PRC2 complex, are linked to hyper-trimethylation of lysine 27 of histone H3 (H3K27me3) in many cancers. Potent EZH2 inhibitors that reduce levels of H3K27me3 kill mutant lymphoma cells and are efficacious in a mouse xenograft model of malignant rhabdoid tumors. Unlike most SET domain methyltransferases, EZH2 requires PRC2 components, SUZ12 and EED, for activity, but the mechanism by which catalysis is promoted in the PRC2 complex is unknown. We solved the 2.0 Å crystal structure of the EZH2 methyltransferase domain revealing that most of the canonical structural features of SET domain methyltransferase structures are conserved. The site of methyl transfer is in a catalytically competent state, and the structure clarifies the structural mechanism underlying oncogenic hyper-trimethylation of H3K27 in tumors harboring mutations at Y641 or A677. On the other hand, the I-SET and post-SET domains occupy atypical positions relative to the core SET domain resulting in incomplete formation of the cofactor binding site and occlusion of the substrate binding groove. A novel CXC domain N-terminal to the SET domain may contribute to the apparent inactive conformation. We propose that protein interactions within the PRC2 complex modulate the trajectory of the post-SET and I-SET domains of EZH2 in favor of a catalytically competent conformation.     

Diabetic Patients Could Do As Well as Non-Diabetic Patients without Inflammation on Peritoneal Dialysis

Background

Diabetic patients on peritoneal dialysis (PD) have lower survival and are more likely complicated with inflammation than their non-diabetic counterparts. Here, we explored the interaction effects between diabetes and inflammation on the survival of PD patients.

Methods

Overall, 2,264 incident patients were enrolled from a retrospective cohort study in China. Patients were grouped according to the baseline levels of high-sensitive C-reactive protein (hsCRP, ≤3 mg/L or >3 mg/L) or serum albumin (SA, ≥38 g/L or <38 g/L). Then, several multivariable adjusted stratified Cox regression models were constructed for these groups to explore the predicted role of diabetes on all-cause or cardiovascular death under inflammatory or non-inflammatory conditions.

Results

Diabetics on PD were more likely to have inflammation than non-diabetics on PD, and they presented with elevated hsCRP (52.7% vs. 47.3%, P = 0.03) or decreased SA (77.9% vs. 62.7%, P < 0.001) levels. After stratification by size of center and controlling for confounding factors, diabetes was found to predict all-cause death in patients with hsCRP >3 mg/L or SA <38 g/L but not in patients with hsCRP ≤3 mg/L or SA ≥38 g/L. Similarly, the presence of diabetes was an indication of cardiovascular death in patients with hsCRP >3 mg/L or SA <38 g/L. However, if further adjusted by baseline cardiovascular disease, the predicted role of diabetes on death related to cardiovascular disease in patients with SA <38 g/L disappeared.

Conclusion

Diabetic patients could do as well as non-diabetic patients without inflammation on peritoneal dialysis. Active strategies should be implemented to improve inflammation status in diabetic patients on PD.     

Integrated Photoacoustic Ophthalmoscopy and Spectral-domain Optical Coherence Tomography

Both the clinical diagnosis and fundamental investigation of major ocular diseases greatly benefit from various non-invasive ophthalmic imaging technologies. Existing retinal imaging modalities, such as fundus photography¹, confocal scanning laser ophthalmoscopy (cSLO)², and optical coherence tomography (OCT)³, have significant contributions in monitoring disease onsets and progressions, and developing new therapeutic strategies. However, they predominantly rely on the back-reflected photons from the retina. As a consequence, the optical absorption properties of the retina, which are usually strongly associated with retinal pathophysiology status, are inaccessible by the traditional imaging technologies.Photoacoustic ophthalmoscopy (PAOM) is an emerging retinal imaging modality that permits the detection of the optical absorption contrasts in the eye with a high sensitivity^4-7 . In PAOM nanosecond laser pulses are delivered through the pupil and scanned across the posterior eye to induce photoacoustic (PA) signals, which are detected by an unfocused ultrasonic transducer attached to the eyelid. Because of the strong optical absorption of hemoglobin and melanin, PAOM is capable of non-invasively imaging the retinal and choroidal vasculatures, and the retinal pigment epithelium (RPE) melanin at high contrasts ^6,7. More importantly, based on the well-developed spectroscopic photoacoustic imaging^5,8 , PAOM has the potential to map the hemoglobin oxygen saturation in retinal vessels, which can be critical in studying the physiology and pathology of several blinding diseases ⁹ such as diabetic retinopathy and neovascular age-related macular degeneration.Moreover, being the only existing optical-absorption-based ophthalmic imaging modality, PAOM can be integrated with well-established clinical ophthalmic imaging techniques to achieve more comprehensive anatomic and functional evaluations of the eye based on multiple optical contrasts^6,10 . In this work, we integrate PAOM and spectral-domain OCT (SD-OCT) for simultaneously in vivo retinal imaging of rat, where both optical absorption and scattering properties of the retina are revealed. The system configuration, system alignment and imaging acquisition are presented.     

128-Slice Acceletated-Pitch Dual Energy CT Angiography of the Head and Neck: Comparison of Different Low Contrast Medium Volumes

Background

Our study aims to evaluate the image quality and feasibility of 128-slice dual-energy CTA (DE-CTA) for supra-aortic arteries using reduced amounts of contrast medium (CM).

Methods

A prospective study was performed in 54 patients receiving CTA of the head and neck with a 128-slice dual-source CT system. Patients were randomized into two groups with a volume of either 40 mL of CM (Group I) or 50 mL of CM (Group II). Arterial and venous enhancements were recorded for quantitative assessment. Qualitative assessments for images without bone removal (BR) were based on a) the visualization of the circle of Willis and b) streak artifacts due to residual CM in the subclavian or internal jugular veins ipsilateral to injection of CM. Qualitative assessment of dual-energy images using BR was based on the presence of bone remnants and vessel integrity. Quantitative data was compared using the Student t test. The χ² test was used for the qualitative measurements of streak artifacts in veins while the Mann-Whitney U test was used for the qualitative measurements of images with BR.

Results

Arterial and venous attenuation was significantly higher in Group II (P=0.000). Image quality regarding the circle of Willis was excellent in both groups (3.90±0.30 for Group I and 4.00±0 for Group II) . Imaging of the internal jugular veins was scored higher in Group I (1.87±0.72) compared with Group II (1.48±0.51) (P=0.021). Within Group I using BR, mean scores for bone remnants did not differ significantly (P>0.05) but mean scores of vessel integrity (P<0.05) did.

Conclusions

Contrast-enhanced head and neck CTA is feasible using a scan protocol with low amounts of contrast medium (40 mL) on a 128-slice dual-energy CTA. The 40-mL protocol provides satisfactory image quality before and after dual-energy bone-removal post-processing.     

Bis(heptalene) “submarine” metal dimer sandwich compounds (C12H10)2M2 (M = Ti, V, Cr, Mn, Fe, Co, Ni)

The bis(heptalene)dimetal complexes (C₁₂H₁₀)₂M₂ of the first row transition metals from Ti to Ni are predicted by density functional theory to exhibit “submarine” sandwich structures with a pair of metal atoms sandwiched between the two heptalene rings. For the early transition metal derivatives (C₁₂H₁₀)₂M₂ (M = V, Cr) there are two types of such structures. In one structural type the metals are sandwiched between two heptahapto heptalene rings with metal-metal distances (3.5–3.8 Å) too long for direct metal-metal bonding. The other type of (C₁₂H₁₀)₂M₂ (M = V, Cr, Mn) structure has a pair of bonded metal atoms sandwiched between a fully bonded heptalene ligand and a heptalene ligand bonded to the metals only through an eight-carbon heptafulvene subunit, leaving an uncomplexed cis-1,3-diene unit. The formal metal-metal bond orders in these latter structures are 3, 2, and 1 for M = V, Cr, and Mn with predicted bond lengths of 2.5, 2.7, and 2.8 Å, respectively. For (C₁₂H₁₀)₂Fe₂ a singlet structure with each iron atom sandwiched between a hexahapto and a tetrahapto heptalene ring is energetically preferred over an alternate structure with ferrocene-like iron atoms sandwiched between two pentahapto heptalene rings. Partial bonding of each heptalene ring to the metal atoms occurs in the late transition metal derivatives (C₁₂H₁₀)₂M₂ (M = Co, Ni). This leads to an unsymmetrical structure for the cobalt derivative and a structure for the nickel derivative with each nickel atom sandwiched between a trihapto ligand and a tetrahapto ligand.

One‐Step Fabrication of Ultrathin Porous Nickel Hydroxide‐Manganese Dioxide Hybrid Nanosheets for Supercapacitor Electrodes with Excellent Capacitive Performance

A facile one‐step hydrothermal co‐deposition method for growth of ultrathin Ni(OH)₂‐MnO₂ hybrid nanosheet arrays on three dimensional (3D) macroporous nickel foam is presented. Due to the highly hydrophilic and ultrathin nature of hybrid nanosheets, as well as the synergetic effects of Ni(OH)₂ and MnO₂, the as‐fabricated Ni(OH)₂‐MnO₂ hybrid electrode exhibits an ultrahigh specific capacitance of 2628 F g^?1. Moreover, the asymmetric supercapacitor with the as‐obtained Ni(OH)₂‐MnO₂ hybrid film as the positive electrode and the reduced graphene oxide as the negative electrode has a high energy density (186 Wh kg^?1 at 778 W kg^?1), based on the total mass of active materials.