A theoretical study on 1,5-diazido-3-nitrazapentane (DANP) and 1,7-diazido-2,4,6-trinitrazaheptane (DATNH): molecular and crystal structures, thermodynamic and detonation properties, and pyrolysis mechanism

1,5-Diazido-3-nitrazapentane (DANP) and 1,7-diazido-2,4,6-trinitrazaheptane (DATNH) are two energetic plasticizers. To better understand them, a detailed theoretical investigation was carried out using density functional theory and molecular mechanics methods. The crystal structures, spectra, thermodynamic properties, heats of formation, detonation velocity, detonation pressure, specific impulse and thermal stability were estimated. Possible initiation steps of pyrolysis were discussed by considering the bond breaking of N–NO₂, C–N₃, and N–N₂ (via hydrogen transfer) for both compounds and the cyclization of the adjacent nitro and azido groups for DATNH. Results show that the rupture of N–NO₂ and N–N₂ (via hydrogen transfer) may happen simultaneously as the initial step of pyrolysis. Both crystals have P-1 symmetry as was observed experimentally. DANP has higher stability than DATNH, while DATNH has better detonation performance than DANP. In addition, DANP has a lower while DATNH has a higher specific impulse than RDX, which shows their prospects as propellant components.     

Effect of superalkali substituents on the strengths and properties of hydrogen and halogen bonds

Quantum chemical calculations have been performed for the complexes Li₃OCCX–Y (X?=?Cl, Br, H; Y?=?NH₃, H₂O, H₂S) and Li₃OCN–X′Y′ (X′Y′?=?ClF, BrCl, BrF, HF) to study the role of superalkalis in hydrogen and halogen bonds. The results show that the presence of an Li₃O cluster in a Lewis acid weakens its acidity, while its presence in a Lewis base enhances its basicity. Furthermore, the latter effect is more prominent than the former one, and the presence of an Na₃O cluster causes an even greater effect than Li₃O. The strengths of hydrogen and halogen bonds were analyzed using molecular electrostatic potentials. The contributions of superalkalis to the strength of hydrogen and halogen bonds were elucidated by analyzing differences in electron density.     

Understanding the Reduced Efficiencies of Organic Solar Cells Employing Fullerene Multiadducts as Acceptors

The use of fullerenes with two or more adducts as acceptors has been recently shown to enhance the performance of bulk‐heterojunction solar cells using poly(3‐hexylthiophene) (P3HT) as the donor. The enhancement is caused by a substantial increase in the open‐circuit voltage due to a rise in the fullerene lowest unoccupied molecular orbital (LUMO) level when going from monoadducts to multiadducts. While the increase in the open‐circuit voltage is obtained with many different polymers, most polymers other than P3HT show a substantially reduced photocurrent when blended with fullerene multiadducts like bis‐PCBM (bis adduct of Phenyl‐C₆₁‐butyric acid methyl ester) or the indene C₆₀ bis‐adduct ICBA. Here we investigate the reasons for this decrease in photocurrent. We find that it can be attributed partly to a loss in charge generation efficiency that may be related to the LUMO‐LUMO and HOMO‐HOMO (highest occupied molecular orbital) offsets at the donor‐acceptor heterojunction, and partly to reduced charge carrier collection efficiencies. We show that the P3HT exhibits efficient collection due to high hole and electron mobilities with mono‐ and multiadduct fullerenes. In contrast the less crystalline polymer Poly[[9‐(1‐octylnonyl)‐9H‐carbazole‐2,7‐diyl]‐2,5‐thiophenediyl‐2,1,3‐benzothiadiazole‐4,7‐diyl‐2,5‐thiophenediyl (PCDTBT) shows inefficient charge carrier collection, assigned to low hole mobility in the polymer and low electron mobility when blended with multiadduct fullerenes.     

SCY1-like 1 binding protein 1 (SCYL1-bp1) interacts with p53-induced RING H2 protein (Pirh2) after traumatic brain injury in rats

Traumatic brain injury (TBI) triggers a complex series of neurochemical and signaling changes that lead to neuronal dysfunction and overreactive astrocytes. In the current study, we showed that interactions between SCYL1-bp1 and Pirh2 are involved in central nervous system (CNS) injury and repair. Western blot and immunohistochemical analysis of an acute traumatic brain injury model in adult rats revealed significantly increased levels of SCYL1-bp1 and Pirh2 in the ipsilateral brain cortex, compared to contralateral cerebral cortex. Immunofluorescence double-labeling analyses further revealed that SCYL1-bp1 is mainly co-expressed with NeuN. Terminal deoxynucleotidyl transferase-mediated biotinylated-dUTP nick-end labeling staining data supported the involvement of SCYL1-bp1 and Pirh2 in neuronal apoptosis after brain injury. We additionally examined the expression profiles of active caspase-3, which were altered in correlation with the levels of SCYL1-bp1 and Pirh2. Notably, both SCYL1-bp1 and Pirh2 were colocalized with active caspase-3, and all three proteins participated in neuronal apoptosis. Immunoprecipitation experiments further revealed interactions of these proteins with each other in the pathophysiology process. To our knowledge, this is the first study to report interactions between SCYL1-bp1 and Pirh2 in traumatic brain. Our data collectively indicate that SCYL1-bp1 and Pirh2 play important roles in CNS pathophysiology after TBI.     

Unfolded Protein Response and Activated Degradative Pathways Regulation in GNE Myopathy

Although intracellular beta amyloid (Aβ) accumulation is known as an early upstream event in the degenerative course of UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) myopathy, the process by which Aβdeposits initiate various degradative pathways, and their relationship have not been fully clarified. We studied the possible secondary responses after amyloid beta precursor protein (AβPP) deposition including unfolded protein response (UPR), ubiquitin proteasome system (UPS) activation and its correlation with autophagy system. Eight GNE myopathy patients and five individuals with normal muscle morphology were included in this study. We performed immunofluorescence and immunoblotting to investigate the expression of AβPP, phosphorylated tau (p-tau) and endoplasmic reticulum molecular chaperones. Proteasome activities were measured by cleavage of fluorogenic substrates. The expression of proteasome subunits and linkers between proteasomal and autophagy systems were also evaluated by immunoblotting and relative quantitative real-time RT-PCR. Four molecular chaperones, glucose-regulated protein 94 (GRP94), glucose-regulated protein 78 (GRP78), calreticulin and calnexin and valosin containing protein (VCP) were highly expressed in GNE myopathy. 20S proteasome subunits, three main proteasome proteolytic activities, and the factors linking UPS and autophagy system were also increased. Our study suggests that AβPP deposition results in endoplasmic reticulum stress (ERS) and highly expressed VCP deliver unfolded proteins from endoplasmic reticulum to proteosomal system which is activated in endoplasmic reticulum associated degradation (ERAD) in GNE myopathy. Excessive ubiquitinated unfolded proteins are exported by proteins that connect UPS and autophagy to autophagy system, which is activated as an alternative pathway for degradation.     

Soluble Guanylate Cyclase α1–Deficient Mice: A Novel Murine Model for Primary Open Angle Glaucoma

Primary open angle glaucoma (POAG) is a leading cause of blindness worldwide. The molecular signaling involved in the pathogenesis of POAG remains unknown. Here, we report that mice lacking the α₁ subunit of the nitric oxide receptor soluble guanylate cyclase represent a novel and translatable animal model of POAG, characterized by thinning of the retinal nerve fiber layer and loss of optic nerve axons in the context of an open iridocorneal angle. The optic neuropathy associated with soluble guanylate cyclase α₁–deficiency was accompanied by modestly increased intraocular pressure and retinal vascular dysfunction. Moreover, data from a candidate gene association study suggests that a variant in the locus containing the genes encoding for the α₁ and β₁ subunits of soluble guanylate cyclase is associated with POAG in patients presenting with initial paracentral vision loss, a disease subtype thought to be associated with vascular dysregulation. These findings provide new insights into the pathogenesis and genetics of POAG and suggest new therapeutic strategies for POAG.     

Engineered External Guide Sequences Are Highly Effective in Inhibiting Gene Expression and Replication of Hepatitis B Virus in Cultured Cells

External guide sequences (EGSs) are RNA molecules that consist of a sequence complementary to a target mRNA and recruit intracellular ribonuclease P (RNase P), a tRNA processing enzyme, for specific degradation of the target mRNA. We have previously used an in vitro selection procedure to generate EGS variants that efficiently induce human RNase P to cleave a target mRNA in vitro. In this study, we constructed EGSs from a variant to target the overlapping region of the S mRNA, pre-S/L mRNA, and pregenomic RNA (pgRNA) of hepatitis B virus (HBV), which are essential for viral replication and infection. The EGS variant was about 50-fold more efficient in inducing human RNase P to cleave the mRNA in vitro than the EGS derived from a natural tRNA. Following Salmonella -mediated gene delivery, the EGSs were expressed in cultured HBV-carrying cells. A reduction of about 97% and 75% in the level of HBV RNAs and proteins and an inhibition of about 6,000- and 130-fold in the levels of capsid-associated HBV DNA were observed in cells treated with Salmonella vectors carrying the expression cassette for the variant and the tRNA-derived EGS, respectively. Our study provides direct evidence that the EGS variant is more effective in blocking HBV gene expression and DNA replication than the tRNA-derived EGS. Furthermore, these results demonstrate the feasibility of developing Salmonella -mediated gene delivery of highly active EGS RNA variants as a novel approach for gene-targeting applications such as anti-HBV therapy.     

Increased Global and Local Efficiency of Human Brain Anatomical Networks Detected with FLAIR-DTI Compared to Non-FLAIR-DTI

Diffusion-weighted MRI (DW-MRI), the only non-invasive technique for probing human brain white matter structures in vivo, has been widely used in both fundamental studies and clinical applications. Many studies have utilized diffusion tensor imaging (DTI) and tractography approaches to explore the topological properties of human brain anatomical networks by using the single tensor model, the basic model to quantify DTI indices and tractography. However, the conventional DTI technique does not take into account contamination by the cerebrospinal fluid (CSF), which has been known to affect the estimated DTI measures and tractography in the single tensor model. Previous studies have shown that the Fluid-Attenuated Inversion Recovery (FLAIR) technique can suppress the contribution of the CSF to the DW-MRI signal. We acquired DTI datasets from twenty-two subjects using both FLAIR-DTI and conventional DTI (non-FLAIR-DTI) techniques, constructed brain anatomical networks using deterministic tractography, and compared the topological properties of the anatomical networks derived from the two types of DTI techniques. Although the brain anatomical networks derived from both types of DTI datasets showed small-world properties, we found that the brain anatomical networks derived from the FLAIR-DTI showed significantly increased global and local network efficiency compared with those derived from the conventional DTI. The increases in the network regional topological properties derived from the FLAIR-DTI technique were observed in CSF-filled regions, including the postcentral gyrus, periventricular regions, inferior frontal and temporal gyri, and regions in the visual cortex. Because brain anatomical networks derived from conventional DTI datasets with tractography have been widely used in many studies, our findings may have important implications for studying human brain anatomical networks derived from DW-MRI data and tractography.     

Whole-Brain Functional Connectivity Identification of Functional Dyspepsia

Recent neuroimaging studies have shown local brain aberrations in functional dyspepsia (FD) patients, yet little attention has been paid to the whole-brain resting-state functional network abnormalities. The purpose of this study was to investigate whether FD disrupts the patterns of whole-brain networks and the abnormal functional connectivity could reflect the severity of the disease. The dysfunctional interactions between brain regions at rest were investigated in FD patients as compared with 40 age- and gender- matched healthy controls. Multivariate pattern analysis was used to evaluate the discriminative power of our results for classifying patients from controls. In our findings, the abnormal brain functional connections were mainly situated within or across the limbic/paralimbic system, the prefrontal cortex, the tempo-parietal areas and the visual cortex. About 96% of the subjects among the original dataset were correctly classified by a leave one-out cross-validation approach, and 88% accuracy was also validated in a replication dataset. The classification features were significantly associated with the patients’ dyspepsia symptoms, the self-rating depression scale and self-rating anxiety scale, but it was not correlated with duration of FD patients (p>0.05). Our results may indicate the effectiveness of the altered brain functional connections reflecting the disease pathophysiology underling FD. These dysfunctional connections may be the epiphenomena or causative agents of FD, which may be affected by clinical severity and its related emotional dimension of the disease rather than the clinical course.     

Regional Brain Structural Abnormality in Meal-Related Functional Dyspepsia Patients: A Voxel-Based Morphometry Study

Background and Aims

Brain dysfunction in functional dyspepsia (FD) has been identified by multiple neuroimaging studies. This study aims to investigate the regional gray matter density (GMD) changes in meal-related FD patients and their correlations with clinical variables, and to explore the possible influence of the emotional state on FD patients’s brain structures.

Methods

Fifty meal-related FD patients and forty healthy subjects (HS) were included and underwent a structural magnetic resonance imaging scan. Voxel-based morphometry analysis was employed to identify the cerebral structure alterations in meal-related FD patients. Regional GMD changes'' correlations with the symptoms and their durations, respectively, have been analyzed.

Results

Compared to the HS, the meal-related FD patients showed a decreased GMD in the bilateral precentral gyrus, medial prefrontal cortex (MPFC), anterior cingulate cortex (ACC) and midcingulate cortex (MCC), left orbitofrontal cortex (OFC) and right insula (p<0.05, FWE Corrected, Cluster size>50). After controlling for anxiety and depression, the meal-related FD patients showed a decreased GMD in the bilateral middle frontal gyrus, left MCC, right precentral gyrus and insula (p<0.05, FWE Corrected, Cluster size>50). Before controlling psychological factors, the GMD decreases in the ACC were negatively associated with the symptom scores of the Nepean Dyspepsia Index (NDI) (r = −0.354, p = 0.048, Bonferroni correction) and the duration of FD (r = −0.398, p = 0.02, Bonferroni correction) respectively.

Conclusions

The regional GMD of meal-related FD patients, especially in the regions of the homeostatic afferent processing network significantly differed from that of the HS, and the psychological factors might be one of the essential factors significantly affecting the regional brain structure of meal-related FD patients.