AbstractAtherosclerosis is characterized by lipid accumulation, inflammatory response, cell death and fibrosis in the arterial wall, and is a major pathological basis for ischemic coronary heart ...disease (CHD), which is the leading cause of morbidity and mortality in the USA and Europe. Intervention studies with statins have shown to reduce plasma LDL cholesterol concentrations and subsequently the risk of developing CHD. However, not all the aggressive statin therapy could decrease the risk of developing CHD. Many clinical and epidemiological studies have clearly demonstrated that the HDL cholesterol is inversely associated with risk of CHD and is a critical and independent component of predicting this risk. Elucidations of HDL metabolism give rise to therapeutic targets with potential to raising plasma HDL cholesterol levels, thereby reducing the risk of developing CHD. The concept of reverse cholesterol transport is based on the hypothesis that HDL displays an cardioprotective function, which is a process involved in the removal of excess cholesterol that is accumulated in the peripheral tissues (e.g., macrophages in the aortae) by HDL, transporting it to the liver for excretion into the feces via the bile. In this review, we summarize the latest advances in the role of the lymphatic route in reverse cholesterol transport, as well as the biliary and the non-biliary pathways for removal of cholesterol from the body. These studies will greatly increase the likelihood of discovering new lipid-lowering drugs, which are more effective in the prevention and therapeutic intervention of CHD that is the major cause of human death and disability worldwide.
Dapsone is used in the treatment of infections and inflammatory diseases. The dapsone hypersensitivity syndrome, which is associated with a reported mortality of 9.9%, develops in about 0.5 to 3.6% ...of persons treated with the drug. Currently, no tests are available to predict the risk of the dapsone hypersensitivity syndrome.
We performed a genomewide association study involving 872 participants who had received dapsone as part of multidrug therapy for leprosy (39 participants with the dapsone hypersensitivity syndrome and 833 controls), using log-additive tests of single-nucleotide polymorphisms (SNPs) and imputed HLA molecules. For a replication analysis, we genotyped 24 SNPs in an additional 31 participants with the dapsone hypersensitivity syndrome and 1089 controls and performed next-generation sequencing for HLA-B and HLA-C typing at four-digit resolution in an independent series of 37 participants with the dapsone hypersensitivity syndrome and 201 controls.
Genomewide association analysis showed that SNP rs2844573, located between the HLA-B and MICA loci, was significantly associated with the dapsone hypersensitivity syndrome among patients with leprosy (odds ratio, 6.18; P=3.84×10(-13)). HLA-B*13:01 was confirmed to be a risk factor for the dapsone hypersensitivity syndrome (odds ratio, 20.53; P=6.84×10(-25)). The presence of HLA-B*13:01 had a sensitivity of 85.5% and a specificity of 85.7% as a predictor of the dapsone hypersensitivity syndrome, and its absence was associated with a reduction in risk by a factor of 7 (from 1.4% to 0.2%). HLA-B*13:01 is present in about 2 to 20% of Chinese persons, 1.5% of Japanese persons, 1 to 12% of Indians, and 2 to 4% of Southeast Asians but is largely absent in Europeans and Africans.
HLA-B*13:01 was associated with the development of the dapsone hypersensitivity syndrome among patients with leprosy. (Funded by the National Natural Science Foundation of China and others.).
Aims
This study aimed to explore potential drug targets of Streptococcus suis at the system level.
Methods and Results
A homologous protein mapping method was used in the construction of a ...protein–protein interaction (PPI) network of S. suis, which presented 1147 non‐redundant interaction pairs among 286 proteins. The parameters of PPI networks were calculated and showed scale‐free network properties. In all, 41 possibly essential proteins identified from 47 highly connected proteins were selected as potential drug target candidates. Of these proteins, 30 were already regarded as drug targets in other bacterial species. Six transporters with high connections to other functional proteins were identified as probably not essential but important functional proteins. Afterward, the subnetwork centred with cell division protein FtsZ was used in confirming the PPI network through bacterial two‐hybrid analysis.
Conclusions
The predicted PPI network covers 13·04% of the proteome in S. suis. The selected 41 potential drug target candidates are conserved between S. suis and several model bacteria.
Significance and Impact of the Study
The predictions included proteins known to be drug targets, and a verifying experiment confirmed the reliability of predicted interactions. This work is the first to present systematic computational PPI data for S. suis and provides potential drug targets, which are valuable in exploring novel anti‐streptococcus drugs.
Observational properties of throat aurora are investigated in detail by using 7 year continuous auroral observations obtained at Yellow River Station (magnetic latitude 76.24°N). From our inspection, ...throat aurora is often observed under the condition of stripy diffuse aurora contacting with the persistent discrete auroral oval, and the long‐period throat aurora observations generally consist of intermittent subsequences of throat aurora brightening followed by poleward moving auroral form and throat aurora dimming. We also noticed that the orientation of throat aurora is aligned along the ionospheric convection flow, and its local time distribution shows clear dependence on the interplanetary magnetic field (IMF) By component. These observational results indicate that factors inside the magnetosphere may play important role on occurrence of throat aurora. We thus suggest that throat aurora may present the ionospheric signature of redistribution of reconnection rate on the magnetopause by cold magnetospheric plasma flowing into the reconnection site. In addition, we also found that the occurrence rate of throat aurora clearly decreases with increase of the IMF cone angle (arccos(|Bx|/B)), which is very similar with the occurrence rate of high‐speed jet (HSJ) observed in magnetosheath depending on the IMF cone angle. This is suggested as that the HSJs occurred outside the magnetosphere may also play important role for generation of throat aurora by triggering magnetopause reconnection or by direct impacting. Although further studies are needed to clarify how the throat auroras are generated in detail, the relevant observations about throat aurora have presented important implications on a variety open questions, such as distribution and generation of cold plasma structures in the outer magnetosphere, magnetopause deformation, and possible relation between HSJ and reconnection.
Key Points
Throat aurora always observed together with diffuse aurora indicate that the occurrence is affected by factors inside the magnetosphere
Occurrence rate of throat aurora decreasing with increase of the IMF cone angle implies that the occurrence is affected by outside factors
Occurrence of throat aurora is related with factors both inside and outside the magnetosphere
Sex controls have been performed in some farmed fish species because of significant growth differences between females and males. In yellow catfish (Pelteobagrus fulvidraco), adult males are three ...times larger than female adults. In this study, six Y- and X-linked amplified fragment length polymorphism fragments were screened by sex-genotype pool bulked segregant analysis and individual screening. Interestingly, sequence analysis identified two pairs of allelic genes, Pf33 and Pf62. Furthermore, the cloned flanking sequences revealed several Y- and X-specific polymorphisms, and four Y-linked or X-linked sequence characterized amplified region (SCAR) primer pairs were designed and converted into Y- and X-linked SCAR markers. Consequently, these markers were successfully used to identify genetic sex and YY super-males, and applied to all-male population production. Thus, we developed a novel and simple technique to help commercial production of YY super-males and all-male populations in the yellow catfish.
High-mobility semiconducting ultrathin films form the basis of modern electronics, and may lead to the scalable fabrication of highly performing devices. Because the ultrathin limit cannot be reached ...for traditional semiconductors, identifying new two-dimensional materials with both high carrier mobility and a large electronic bandgap is a pivotal goal of fundamental research. However, air-stable ultrathin semiconducting materials with superior performances remain elusive at present. Here, we report ultrathin films of non-encapsulated layered Bi2 O2 Se, grown by chemical vapour deposition, which demonstrate excellent air stability and high-mobility semiconducting behaviour. We observe bandgap values of ∼0.8 eV, which are strongly dependent on the film thickness due to quantum-confinement effects. An ultrahigh Hall mobility value of >20,000 cm2 V-1 s-1 is measured in as-grown Bi2 O2 Se nanoflakes at low temperatures. This value is comparable to what is observed in graphene grown by chemical vapour deposition and at the LaAlO3 -SrTiO3 interface, making the detection of Shubnikov-de Haas quantum oscillations possible. Top-gated field-effect transistors based on Bi2 O2 Se crystals down to the bilayer limit exhibit high Hall mobility values (up to 450 cm2 V-1 s-1 ), large current on/off ratios (>106 ) and near-ideal subthreshold swing values (∼65 mV dec-1 ) at room temperature. Our results make Bi2 O2 Se a promising candidate for future high-speed and low-power electronic applications.
Glucose-6-phosphate dehydrogenase (G6PD) is a key enzyme that generates NADPH to maintain reduced glutathione (GSH), which scavenges reactive oxygen species (ROS) to protect cancer cell from ...oxidative damage. In this study, we mainly investigate the potential roles of G6PD in colorectal cancer (CRC) development and chemoresistance. We discover that G6PD is overexpressed in CRC cells and patient specimens. High expression of G6PD predicts poor prognosis and correlated with poor outcome of oxaliplatin-based first-line chemotherapy in patients with CRC. Suppressing G6PD decreases NADPH production, lowers GSH levels, impairs the ability to scavenge ROS levels, and enhances oxaliplatin-induced apoptosis in CRC via ROS-mediated damage in vitro. In vivo experiments further shows that silencing G6PD with lentivirus or non-viral gene delivery vector enhances oxaliplatin anti-tumor effects in cell based xenografts and PDX models. In summary, our finding indicated that disrupting G6PD-mediated NADPH homeostasis enhances oxaliplatin-induced apoptosis in CRC through redox modulation. Thus, this study indicates that G6PD is a potential prognostic biomarker and a promising target for CRC therapy.
Summary
What is known and objectives
Tacrolimus (TAC) is widely used as part of immunosuppressive regimens. There is great interindividual variation on the disposition of TAC. The aim of this study ...was to develop a population pharmacokinetic (PPK) model for Chinese liver transplant patients and evaluate genetic polymorphism and other possible factors on the PK parameters. The exposure of TAC is to be estimated through Bayesian modelling.
Methods
A total of 47 sets of rich‐time PK and 1234 conventional therapeutic drug monitoring (TDM) data were collected from 125 Chinese liver transplant patients. The pathophysiological data of these patients were recorded. CYP3A5*3 and ABCB1 genotypes were determined for each patient. The PPK model for TAC was established by nonlinear mixed‐effects modelling (nonmem). The impact of pathophysiology and genotype on PPK parameters was evaluated. Bayesian estimators for the area under concentration‐time curve (AUC) of TAC were validated.
Results
A two‐compartment model with lag time was found to be the most suitable model for the pooled full PK and TDM data for Chinese liver transplant patients. The CL/F, V2/F, Q/F, V3/F, Ka and lag time were 17.4±0.81 L/h, 165±44.1 L, 54.9±25.8L/h, 594±87.5 L, 0.51±0.095 L/h and 1.57±0.34 h. Post‐operative day (POD), creatinine clearance (CLcr) and ABCB1 C3435T genotypes were found to have significant influences on CL/F (P<.01). ABCB1 C3435T genotypes showed a significant correlation with V2/F (P<.01). C0–C2 and C0–C2–C4 were shown to be suitable for the estimation of AUC in Chinese liver transplant patients.
What is new and conclusion
A PPK model for TAC was established successfully in Chinese liver transplant patients. POD, CLcr and ABCB1 C3435T genotypes were shown to have significant effects on CL/F. The AUC of TAC in Chinese liver transplant patients could be estimated through Bayesian modelling, based on which individualized immunosuppressive regimens can be designed.
Visual predictive check based on the final model in patients with ABCB1 CC (A), CT (B) and TT (C) genotypes. A population pharmacokinetic (PPK) model for tacrolimus (TAC) was established successfully based on 47 sets of rich time PK and 1234 conventional therapeutic drug monitoring (TDM) data Chinese liver transplant patients. ABCB1 C3435T genotypes were shown to have significant effects on CL/F. The area under concentration‐time curve (AUC) of TAC in Chinese liver‐transplant patients could be estimated through Bayesian modelling, based on which individualized immunosuppressive regimens can be designed.
Hemodynamics have been shown to play an important role in the initiation and progress of intracranial aneurysms, and are considered well-related to vascular configuration. The purpose of this study ...was to quantify the vascular geometry change due to intracranial stent placement and to discuss its potential effects on hemodynamics.
Imaging data of patients with wide-neck AcomA aneurysms, treated with stent-assisted coiling between January 2005 and January 2010, were retrospectively analyzed. The angle between the afferent vessels (A1 segment) and the efferent vessels (ipsilateral or contralateral A2 segment) was calculated to determine the exact change in the angle after stent placement.
In all 20 patients, the stent caused a distinct change in the geometry of the parent vessel. Stent-related vascular angle change ranged from 7.60 to 74.88°, with an average of 29.95°. In 10 cases, the angle changed by >30°. In the 12 patients with the distal segment of the stent placed in the ipsilateral A2 segment, the mean postoperative A1-A2 angle increased by 27.71 ± 13.17° (from 7.60° to 48.29°). In the other 8 patients with the distal segment of the stent placed in the contralateral A2 segment, the mean postoperative A1-AcomA-A2 angle increased by 33.29 ± 21.89°(from 15.49° to 74.88°).
In addition to serving as a scaffold to contain coils, stent placement for AcomA aneurysms has a substantial effect on the vascular geometry, which may result in local hemodynamic changes.
Summary
Dysfunction of the immune regulatory system plays an important role in the pathogenesis of rheumatoid arthritis (RA). Vasoactive intestinal peptide (VIP) has multiple bioactivities. This ...study aims to investigate the role of VIP in the maintenance of the immune regulatory capacity of monocytes (Mos). Human peripheral blood samples were collected from RA patients and healthy control (HC) subjects. Mos and CD14+ CD71–CD73+CD25+ regulatory Mos (RegMos) were isolated from the blood samples and characterized by flow cytometry. A rat RA model was developed to test the role of VIP in the maintenance of the immune regulatory function of Mos. The results showed that RegMos of HC subjects had immune suppressive functions. RegMos of RA patients expressed less interleukin (IL)‐10 and showed an incompetent immune regulatory capacity. Serum levels of VIP were lower in RA patients, which were positively correlated with the expression of IL‐10 in RegMos. In‐vitro experiments showed that the IL‐10 mRNA decayed spontaneously in RegMos, which could be prevented by the presence of VIP in the culture. VIP suppressed the effects of tristetraprolin (TTP) on inducing IL‐10 mRNA decay in RegMos. Administration of VIP inhibited experimental RA in rats through restoring the IL‐10 expression in RegMos. RegMos have immune suppressive functions. VIP is required in maintaining IL‐10 expression in RegMos. The data suggest that VIP has translational potential in the treatment of immune disorders such as RA.
A fraction of peripheral monocyte has immune regulatory function, which is impaired in patients with rheumatoid arthritis.
PDF
