The BK polyoma virus is a leading cause of chronic post kidney transplantation rejection. One target for therapeutic intervention is the initial association of the BK virus with the host cell. We hypothesize that the rate of BKV infection can be curbed by competitively preventing viral binding to cells. The x-ray structures of homologous viruses complexed with N-terminal glycoproteins suggest that the BC and HI loops of the viral coat are determinant for binding and thereby, infection of the host cell. The large size of the viral coat precludes it from common biophysical and small molecule screening studies. Hence, we sought to develop a smaller protein template incorporating the identified binding loops of the BK viral coat in a manner that adequately mimics the binding activity of the BK virus coat protein to cells. Such a mimic may serve as a tool for the identification of inhibitors of BK viral progression. Herein, we report the design and characterization of a reduced-size and soluble template derived from a four helix protein—TM1526 of Thermatoga maritima archaea bacteria—which maintains the topological display of the BC and HI loops as found in the viral coat protein, VP1, of BKV. We demonstrate that the GT1b and GD1b sialogangliosides, which bind to the VP1 of BKV, also associate with our BKV-template. Employing a GFP-tagged template, we show host cell association that is dose dependent and that can be reduced by neuraminidase treatment. These data demonstrate that the BKV-template mimics the host-cell binding observed for the wild-type virus coat protein, VP1.
BK virus; viral coat protein; sialoganglioside receptors; polyoma viruses
Cadmium has been widely used in industry and is known to be carcinogenic to humans. Although it is widely accepted that chronic exposure to cadmium increases the incidence of cancer, the mechanisms underlying cadmium-induced carcinogenesis are unclear. The main aim of this study was to investigate the role of reactive oxygen species (ROS) in cadmium-induced carcinogenesis and the signal transduction pathways involved. Chronic exposure of human bronchial epithelial BEAS-2B cells to cadmium induced cell transformation, as evidenced by anchorage-independent growth in soft agar and clonogenic assays. Chronic cadmium treatment also increased the potential of these cells to invade and migrate. Injection of cadmium-stimulated cells into nude mice resulted in the formation of tumors. In contrast, the cadmium-mediated increases in colony formation, cell invasion and migration were prevented by transfection with catalase, superoxide dismutase-1 (SOD1), or SOD2. In particular, chronic cadmium exposure led to activation of signaling cascades involving PI3K, AKT, GSK-3β, and β-catenin and transfection with each of the above antioxidant enzymes markedly inhibited cadmium-mediated activation of these signaling proteins. Inhibitors specific for AKT or β-catenin almost completely suppressed the cadmium-mediated increase in total and active β-catenin proteins and colony formation. Moreover, there was a marked induction of AKT, GSK-3β, β-catenin, and carcinogenic markers in tumor tissues formed in mice after injection with cadmium-stimulated cells. Collectively, our findings suggest a direct involvement of ROS in cadmium-induced carcinogenesis and implicate a role of AKT/GSK-3β/β-catenin signaling in this process.
cadmium; carcinogenesis; ROS; GSK-3β; β-catenin
A new class of nitric oxide (NO•)-releasing nonsteroidal anti-inflammatory drugs (NONO-NSAIDs) were developed in recent years and have shown promising potential as NSAID substitutes due to their gentle nature on cardiovascular and gastrointestinal systems. Since nitric oxide plays a role in regulation of cell adhesion, we assessed the potential use of NONO-NSAIDs as anti-metastasis drugs. In this regard, we compared the effects of NONO-aspirin and a novel NONO-naproxen, to those exerted by their respective parent NSAIDs on avidities of human melanoma M624 cells. Both NONO-NSAIDs, but not the corresponding parent NSAIDs, reduced M624 adhesion on vascular cellular adhesion molecule-1 (VCAM-1) by 20-30% and fibronectin by 25-44% under fluid flow conditions and static conditions, respectively. Only NONO-naproxen reduced (~56%) the activity of β1 integrin, which binds to α4 integrin to form very late antigen-4 (VLA-4), the ligand of VCAM-1. These results indicate that the diazeniumdiolate (NO•)-donor moiety is critical for reducing the adhesion between VLA-4 and its ligands, while the NSAID moiety can impact the regulation mechanism of melanoma cell adhesion.
NONO-NASAIDs; melanoma; cell adhesion; integrin
Depression is a common non-motor symptom in patients with Parkinson's disease (PD). There are many kinds of antidepressants being used, such as tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), and Dopamine agonists which are suggested as alternative antidepressants for the treatment of depression in PD. Which one should we choose first? Literatures have shown inconsistent results.
We conducted a network meta-analysis of randomized controlled trials to compare the efficacy and acceptability of therapeutic methods for the treatment of depression in Parkinson's disease.
We used the odds ratios (OR) as effect size firstly and the results indicated no statistical significance between each compared intervention. Then we used the logarithm of the individual odds ratios as effect size. With efficacy of TCAs as the standard of comparison, the degree of incoherence (a measure of how closely the entire network fits together) was small (ω = 4.824827e-05). The logor were: SSRIs −0.69 (95% CI −1.28– −0.10); Pramipexole −0.73 (−1.71– −0.26); Pergolide −1.97 (−3.67– 0.27); SNRIs −0.86 (−1.86– 0.15); Placebo −1.24 (−1.99– −0.50). With Placebo as the standard of comparison, the logor were: TCAs 1.24 (0.50– 1.99); SSRIs 0.55 (−0.03– 1.13); Pramipexole 0.51 (−0.12– 1.15); Pergolide −0.73 (−2.25– 0.80); SNRIs 0.38 (−0.42– 1.19); TCAs, pramipexole, pergolide and SNRIs showed better profile of acceptability, leading to significant fewer discontinuations than that of SSRIs.
There is insufficient evidence to support antidepressant efficacy for SSRIs, pramipexole, pergolide and SNRIs. TCAs might be the best choice when starting antidepressant treatment in patients of Parkinson's disease because it has the most favorable balance between benefits and acceptability, followed by pramipexole and SNRIs, SSRIs might be the last choice.
In this article, we use longitudinal morphometry (shape and size) measures of hippocampus in subjects with mild dementia of Alzheimer type (DAT) and nondemented controls in logistic discrimination. The morphometric measures we use are volume and metric distance measures at baseline and follow-up (two years apart from baseline). Morphometric differences with respect to a template hippocampus were measured by the metric distance obtained from the large deformation diffeomorphic metric mapping (LDDMM) algorithm. LDDMM assigns metric distances on the space of anatomical images, thereby allowing for the direct comparison and quantization of morphometric changes. We also apply principal component analysis (PCA) on volume and metric distance measures to obtain principal components that capture some salient aspect of morphometry. We construct classifiers based on logistic regression to distinguish diseased and healthy hippocampi (hence potentially diagnose the mild form of DAT). We consider logistic classifiers based on volume and metric distance change over time (from baseline to follow-up), on the raw volumes and metric distances, and on principal components from various types of PCA analysis. We provide a detailed comparison of the performance of these classifiers and guidelines for their practical use. Moreover, combining the information conveyed by volume and metric distance measures by PCA can provide a better biomarker for detection of dementia compared to volume, metric distance, or both.
computational anatomy; dementia of Alzheimer Type; hippocampus; large deformation diffeomorphic metric mapping (LDDMM); logistic discrimination; morphometry; principal component analysis
Biomarkers are needed to improve the sensitivity and accuracy of diagnosis as well as prognosis in individuals with early Alzheimer disease (AD). Measures of brain structure and disease-related proteins in the cerebrospinal fluid (CSF) have been proposed as biomarkers, yet relatively little is known about the relationships between such measures. The present study was conducted to assess the relationship between CSF Aβ and tau protein levels and longitudinal measures of hippocampal structure in individuals with and without very mild dementia of the Alzheimer type.
A single CSF sample and longitudinal MR scans were collected. The CSF samples were assayed for tau, p-tau181, Aβ1–42 and Aβ1–40 by ELISA. Large-deformation diffeomorphic metric mapping was used to generate hippocampal surfaces, and a composite hippocampal surface (previously constructed from 86 healthy participants) was used as a structural reference.
Patients or Other Participants
13 participants with very mild AD (Clinical Dementia Rating, CDR 0.5) and 11 cognitively normal participants (CDR 0).
Main Outcome Measures
Initial and rate-of-change measures of total hippocampal volume and displacement of the hippocampal surface within zones overlying the CA1, subiculum and CA2-4+DG cellular subfields. Their correlations with initial CSF measures.
Lower CSF Aβ1–42 levels and higher tau/Aβ1–42 and p-tau181/Aβ1–42 ratios were strongly correlated with decreases in hippocampal volume and measure of progressive inward deformations of the CA1 subfield in participants with early AD, but not cognitively normal participants.
Despite small sample size, we found that Aβ1–42 and tau-related CSF measures were related to hippocampal degeneration in individuals with clinically diagnosed early AD, and may reflect an association with a common underlying disease mechanism.
Magnetic Resonance Imaging (MRI); Hippocampal subfields; β-Amyloid; Tau; P-Tau; biomarkers
In eukaryotes, 5S rRNA is transcribed in the nucleoplasm and requires the ribosomal protein L5 to deliver it to the nucleolus for ribosomal assembly. The trypanosome-specific proteins P34 and P37 form a novel preribosomal complex with the eukaryotic conserved L5-5S rRNA complex in the nucleoplasm. Previous results suggested that P34 acts together with L5 to bridge the interaction with 5S rRNA and thus to stabilize 5S rRNA, an important role in the early steps of ribosomal biogenesis. Here, we have delineated the domains of the two protein components, L5 and P34, and regions of the RNA partner, 5S rRNA, that are critical for protein-RNA interactions within the complex. We found that the L18 domain of L5 and the N terminus and RNA recognition motif of P34 bind 5S rRNA. We showed that Trypanosoma brucei L5 binds the β arm of 5S rRNA, while P34 binds loop A/stem V of 5S rRNA. We demonstrated that 5S rRNA is able to enhance the association between the protein components of the complex, L5 and P34. Both loop A/stem V and the β arm of 5S rRNA can separately enhance the protein-protein association, but their effects are neither additive nor synergistic. Domains in the two proteins for protein-protein and protein-RNA interactions overlap or are close to each other. This suggests that 5S rRNA binding might cause conformational changes in L5 and P34 and might also bridge the interactions, thus enhancing binding between the protein partners of this novel complex.
The Mount Jinggangshan region is located between Jiangxi and Hunan provinces in southeastern China in the central section of the Luoxiao Mountains. A detailed investigation of Mount Jinggangshan region shows that the seed plant flora comprises 2,958 species in 1,003 genera and 210 families (Engler’s system adjusted according to Zhengyi Wu’s concept). Among them, 23 species of gymnospermae belong to 17 genera and 9 families, and 2,935 species of angiosperms are in 986 genera and 201 families. Moreover, they can also be sorted into woody plants (350 genera and 1,295 species) and herbaceous plants (653 genera and 1,663 species). The dominant families are mainly Fagaceae, Lauraceae, Theaceae, Hamamelidaceae, Magnoliaceae, Ericaceae, Styracaceae, Aquifoliaceae, Elaeocarpaceae, Aceraceae, Rosaceae, Corylaceae, Daphniphyllaceae, Symplocaceae, Euphorbiaceae, Pinaceae, Taxodiaceae, Cupressaceae and Taxaceae. Ancient and relic taxa include Ginkgo biloba, Fokieniahodginsii, Amentotaxusargotaenia, Disanthuscercidifolia subsp. longipes, Hamamelismollis, Manglietiafordiana, Magnoliaofficinalis, Tsoongiodendronodorum, Fortuneariasinensis, Cyclocaryapaliurus, Eucommiaulmoides, Sargentodoxacuneata, Bretschneiderasinensis, Camptothecaacuminata, Tapisciasinensis, etc. The flora of Mount Jinggangshan region includes 79 cosmopolitan genera and 924 non-cosmopolitan genera, which are 7.88% and 92.12% of all genera. The latter includes 452 tropical genera (48.92%) and 472 temperate genera (51.08%). The temperate elements include 44 genera endemic to China, accounting for 4.76% of all genera. Among 1,003 genera, 465 have only a single species and 401 are oligotypic genera (with 2-5 species). These genera account for 86.34% of all genera. The floristic analysis indicates that the flora of Mount Jinggangshan region is closely related to the flora of Mount Wuyishan region in southeastern China. The flora of Mount Jinggangshan region also contains many elements of central and southern China. Mount Jinggangshan region is an important north-south floristic passageway and is also a boundary between the floras of eastern, central and south China.
Factor in the germline alpha (FIGLA) is an oocyte-specific basic helix-loop-helix transcription factor essential for primordial follicle formation and expression of many genes required for folliculogenesis, fertilization and early embryonic survival. Here we report the characterization of bovine FIGLA gene and its regulation during early embryogenesis. Bovine FIGLA mRNA expression is restricted to gonads and is detected in fetal ovaries harvested as early as 90 days of gestation. FIGLA mRNA and protein are abundant in germinal vesicle and metaphase II stage oocytes, as well as in embryos from pronuclear to eight-cell stage but barely detectable at morula and blastocyst stages, suggesting that FIGLA might be a maternal effect gene. Recent studies in zebrafish and mice have highlighted the importance of non-coding small RNAs (microRNAs) as key regulatory molecules targeting maternal mRNAs for degradation during embryonic development. We hypothesized that FIGLA, as a maternal transcript, is regulated by microRNAs during early embryogenesis. Computational predictions identified a potential microRNA recognition element (MRE) for miR-212 in the 3’ UTR of the bovine FIGLA mRNA. Bovine miR-212 is expressed in oocytes and tends to increase in four-cell and eight-cell stage embryos followed by a decline at morula and blastocyst stages. Transient transfection and reporter assays revealed that miR-212 represses the expression of FIGLA in a MRE dependent manner. In addition, ectopic expression of miR-212 mimic in bovine early embryos dramatically reduced the expression of FIGLA protein. Collectively, our results demonstrate that FIGLA is temporally regulated during bovine early embryogenesis and miR-212 is an important negative regulator of FIGLA during the maternal to zygotic transition in bovine embryos.
In the HPTN 052 study, transmission between HIV-discordant couples was reduced by 96% when the HIV-infected partner received suppressive antiretroviral therapy (ART). We examined two transmission events where the newly infected partner was diagnosed after the HIV-infected partner (index) initiated therapy. We evaluated the sequence complexity of the viral populations and antibody reactivity in the newly infected partner to estimate the dates of transmission to the newly infected partners. In both cases, transmission most likely occurred significantly before HIV-1 diagnosis of the newly infected partner, and either just before the initiation of therapy or before viral replication was adequately suppressed by therapy of the index. This study further strengthens the conclusion about the efficacy of blocking transmission by treating the infected partner of discordant couples. However, this study does not rule out the potential for HIV-1 transmission to occur shortly after initiation of ART, and this should be recognized when antiretroviral therapy is used for HIV-1 prevention.
To exploit the biological and pharmacological properties of immunoglobulin constant domain Fc fragment and increase the killing efficacy of T cells, a single chain variable fragment specific to CD3 was fused with Fcab (Fc antigen binding), a mutant Fc fragment with specificity against Human epidermal growth factor receptor 2 (HER2) developed by F-star. The bispecific fusion named as FcabCD3 was expressed by transient transfection in HEK-293T cells and purified by affinity chromatography. Specific cytolytic activity of retargeted T cells to kill HER2 positive SKBR3 cell line was evaluated in vitro. FcabCD3 was able to retarget T cells to kill both Herceptin insensitive Colo205-luc cell line and HER2 low expression MDA-MB-231-luc cell line. Furthermore, FcabCD3 was effective in eliminating the Colo205 tumor established on BALB/c nu/nu mice.
Obesity is associated with increased levels of angiotensin-II (Ang-II), which activates angiotensin type-1a receptors (AT1a) to influence cardiovascular function and energy homeostasis. To test the hypothesis that specific AT1a within the brain control these processes, we utilized the Cre/lox system to delete AT1a from the paraventricular nucleus of the hypothalamus (PVN) of mice. PVN AT1a deletion did not affect body mass or adiposity when mice were maintained on standard chow. However, maintenance on a high-fat diet revealed a gene by environment interaction whereby mice lacking AT1a in the PVN had increased food intake and decreased energy expenditure that augmented body mass and adiposity relative to controls. Despite this increased adiposity, PVN AT1a deletion reduced systolic blood pressure, suggesting that this receptor population mediates the positive correlation between adiposity and blood pressure. Gene expression studies revealed that PVN AT1a deletion decreased hypothalamic expression of corticotrophin-releasing hormone and oxytocin, neuropeptides known to control food intake and sympathetic nervous system activity. Whole cell patch clamp recordings confirmed that PVN AT1a deletion eliminates responsiveness of PVN parvocellular neurons to Ang-II, and suggest that Ang-II responsiveness is increased in obese wild-type mice. Central inflammation is associated with metabolic and cardiovascular disorders and PVN AT1a deletion reduced indices of hypothalamic inflammation. Collectively, these studies demonstrate that PVN AT1a regulate energy balance during environmental challenges that promote metabolic and cardiovascular pathologies. The implication is that the elevated Ang-II that accompanies obesity serves as a negative feedback signal that activates PVN neurons to alleviate weight gain.
The 5-substituted pyrrolo[2,3-d]pyrimidine antifolate pemetrexed (Pmx) is an active agent for malignant pleural mesothelioma (MPM). Pmx is transported into MPM cells by the reduced folate carrier (RFC) and proton-coupled folate transporter (PCFT). We tested the notion that a novel 6-substituted pyrrolo[2,3-d]pyrimidine thienoyl antifolate (compound 2) might be an effective treatment for MPM, reflecting its highly selective membrane transport by PCFT over RFC. Compound 2 selectively inhibited proliferation of a HeLa subline expressing exclusively PCFT (R1-11-PCFT4) over an isogenic subline expressing only RFC (R1-11-RFC6). By outgrowth, H2452 human MPM cells were highly sensitive to the inhibitory effects of compound 2. By colony-forming assays, following an intermittent (24 h) drug exposure, 2 was cytotoxic. Cytotoxic activity by 2 was due to potent inhibition of glycinamide ribonucleotide formyltransferase (GARFTase) in de novo purine biosynthesis, as confirmed by nucleoside protection and in situ GARFTase assays with [14C]glycine. Assays with [3H]compound 2 and R1-11-PCFT4 or R1-11-RFC6 cells directly confirmed selective membrane transport by PCFT over RFC. PCFT transport was also confirmed for H2452 cells. In R1-11-PCFT4 and H2452 cells, [3H]compound 2 was metabolized to polyglutamates. Potent in vivo efficacy was confirmed toward early- and upstage H2452 xenografts in severe combined immunodeficient mice administered intravenous compound 2. Our results demonstrate potent antitumor efficacy of compound 2 toward H2452 MPM in vitro and in vivo, reflecting its efficient membrane transport by PCFT over RFC, synthesis of polyglutamates, and inhibition of GARFTase. Selectivity for non-RFC cellular uptake processes by novel tumor-targeted antifolates such as compound 2 presents an exciting new opportunity for treating solid tumors.
proton-coupled folate transporter; mesothelioma; folate; antifolate; pemetrexed
The photomutagenicity of the popular skin conditioning agents azulene and guaiazulene were tested in Salmonella typhimurium TA98, TA100 and TA102. Following irradiation with UVA and/or visible light, both azulene and guaiazulene exhibited mutagenicity 4–5-fold higher than the spontaneous background mutation. In contrary, naphthalene, a structural isomer of azulene, was not photomutagenic under the same conditions. Azulene was photomutagenic when irradiated with UVA light alone, visible light alone, or a combination of UVA and visible light. Azulene and guaiazulene are not mutagenic when the experiment is conducted with the exclusion of light. Therefore, extreme care must be taken when using cosmetic products with azulene/guaiazulene as ingredients since after applying these products on the skin, exposure to sunlight is inevitable.
Azulene; Guaiazulene; Photomutagenicity; Light irradiation; Ames test; TA102
The photocytotoxicity of 16 polycyclic aromatic hydrocarbons (PAHs) on the priority pollutant list of the United States Environmental Protection Agency (US EPA) were tested in human skin HaCaT keratinocytes. A selected PAH was mixed with HaCaT cells and irradiated with a solar simulator lamp for a dose equivalent to 5 min of outdoor sunlight and the cell viability was determined immediately and also after 24 h of incubation. For the cells without incubation after the treatments, it is found that all PAHs with three rings or less, except anthracene, are not photocytotoxic, while the four or five-ring PAHs (except chrysene), benz[a]anthracene, dibenzo[a,h]anthracene, benzo[ghi]perylene, benzo[a]pyrene, indeno[1,2,3-cd]pyrene, benzo[b]fluorenthene, fluorenthene, and pyrene, are photocytotoxic to the human skin HaCaT keratinocytes. If the cells were incubated for 24 h after the treatments, the photocytotoxic effect of the PAHs was greatly amplified in comparison to the nonincubated cells. For the 24 h incubated cells, all PAHs except naphthalene exhibit photocytotoxicity to some extent. Exposure to 5 μM of the 4- and 5-ring PAHs (except chrysene) and 3-ring anthracene more than 80% of the cells lose viability. The photocytotoxicity of the PAHs correlates well with several of their excited state properties: light absorption, excited singlet-state energy, excited triplet-state energy, and HOMO-LUMO energy gap. All the photocytotoxic PAHs absorb light at >300 nm, in the solar UVB and UVA region. There is a threshold for each of the three excited state descriptors of a photocytotoxic PAH: singlet energy <355 kJ/mol (corresponding to 337 nm light), triplet energy <230 kJ/mol (corresponding to 520 nm light), HOMO-LUMO gap <3.6 eV (corresponding to 344 nm light) obtained at the Density Functional Theory B3LYP/6-31G(d) level.
polycyclic aromatic hydrocarbons (PAHs); phototoxicity; human skin keratinocytes; light absorption; excited state energy; HOMO–LUMO gap; DFT
3,3’-Dichlorobenzidine (DCB) is used primarily as an intermediate in the manufacture of diarylide yellow or azo red pigments for printing inks, textiles, paints, and plastics. It is also used in tattoo inks. In this article, we investigate light-induced toxicity of DCB in both bacteria and human Jurkat T-cells. DCB itself is not toxic or mutagenic to Salmonella typhimurium TA102, but is photomutagenic at concentrations as low as 2 µM and phototoxic at concentrations >100 µM when the bacteria is exposed to DCB and light at the same time (1.2 J/cm2 of UVA and 2.1 J/cm2 of visible light). Furthermore, DCB is both photocytotoxic and photogenotoxic to human Jurkat T-cells. Under a constant light irradiation dose of 2.3 J/cm2 of UVA and 4.2 J/cm2 of visible light, it causes the Jurkat T-cells to become non-viable in a DCB dose-dependent manner and only 40% viable cells remaining at DCB concentrations higher than 50 µM. At the same time, DNA fragmentation is observed for the cells exposed to both DCB and light, determined by single cell gel electrophoresis (Comet assay). As much as 8 % of the cellular DNA is fragmented when exposed to 200 µM DCB and light irradiation. This suggests that DCB can penetrate the cell membrane and enter the cell. Upon light activation, DCB in the cells can cause various cellular damages, including DNA fragmentation, leading to non-viable Jurkat T-cells. It appears, though, non-viable cells may not be caused solely by fragmentation of cellular DNA, but other damages such as to proteins and cell membranes, or other forms of DNA damage such as alkylation that does not cause DNA to fragment, may also be involved. Therefore, persons exposed to DCB through environmental contamination or through tattoo piercing using DCB-contaminated inks must not only concern about its toxicity without exposing to light, but also about its phototoxicity.
3,3’-Dichlorobenzidine; Salmonella typhimurium TA102; Phototoxicity; Photomutagenicity; Jurkat T-cell; Single cell gel electrophoresis (Comet assay)
Qiliqiangxin capsule (QL) was developed under the guidance of TCM theory of collateral disease and had been shown to be effective and safe for the treatment of heart failure. The present study explored the role of and mechanism by which the herbal compounds QL act on energy metabolism, in vivo, in pressure overload heart failure. SD rats received ascending aorta constriction (TAC) to establish a model of myocardial hypertrophy. The animals were treated orally for a period of six weeks. QL significantly inhibited cardiac hypertrophy due to ascending aortic constriction and improved hemodynamics. This effect was linked to the expression levels of the signaling factors in connection with upregulated energy and the regulation of glucose and lipid substrate metabolism and with a decrease in metabolic intermediate products and the protection of mitochondrial function. It is concluded that QL may regulate the glycolipid substrate metabolism by activating AMPK/PGC-1α axis and reduce the accumulation of free fatty acids and lactic acid, to protect cardiac myocytes and mitochondrial function.
Myocardial ischemia/reperfusion (I/R) can induce lethal ventricular arrhythmia and myocardial infarction. One of the clinical strategies for managing patients with high risk of myocardial I/R is to prevent the occurrence of arrhythmias and limit the size of infarction following a coronary episode. Tongguan Capsule (TGC) is one of the popular herbal remedies in treating coronary artery disease in the clinics of Chinese medicine. However, the potential roles and mechanisms of TGC in reducing I/R injury are still unclear. The present study statistically assessed the effectiveness of TGC in reducing I/R injury by comparing the infarct size (IS), risk region (RR), and arrhythmia (in electrocardiogram) among four groups of surgically created mice models of myocardial I/R: SHAM, I/R, VER (I/R with verapamil 20 mg/kg pretreatment), and TGC (I/R with TGC 5 g/kg/d pretreatment). We found that IS was significantly smaller in the TGC and VER groups than I/R group, and the incidence of arrhythmias was reduced in the TGC group compared with I/R group, although there were no differences in RR among the four groups. We conclude that TGC is effective in reducing I/R injury in mice. These results provided an experimental basis for clinical application of TGC in reducing I/R injury.
The adsorption of Cu(II) on oxidized multi-walled carbon nanotubes (oMWCNTs) as a function of contact time, pH, ionic strength, temperature, and hydroxylated fullerene (C60(OH)n) and carboxylated fullerene (C60(C(COOH)2)n) were studied under ambient conditions using batch techniques. The results showed that the adsorption of Cu(II) had rapidly reached equilibrium and the kinetic process was well described by a pseudo-second-order rate model. Cu(II) adsorption on oMWCNTs was dependent on pH but independent of ionic strength. Compared with the Freundlich model, the Langmuir model was more suitable for analyzing the adsorption isotherms. The thermodynamic parameters calculated from temperature-dependent adsorption isotherms suggested that Cu(II) adsorption on oMWCNTs was spontaneous and endothermic. The effect of C60(OH)n on Cu(II) adsorption of oMWCNTs was not significant at low C60(OH)n concentration, whereas a negative effect was observed at higher concentration. The adsorption of Cu(II) on oMWCNTs was enhanced with increasing pH values at pH < 5, but decreased at pH ≥ 5. The presence of C60(C(COOH)2)n inhibited the adsorption of Cu(II) onto oMWCNTs at pH 4–6. The double sorption site model was applied to simulate the adsorption isotherms of Cu(II) in the presence of C60(OH)n and fitted the experimental data well.
Most hemiplegic patients have difficulties in their balance and posture control while walking because of the asymmetrical posture and the abnormal body balance. The assessment of rehabilitation of hemiplegic gait is usually made by doctors using clinical scale, but it is difficult and could not be used frequently. It is therefore needed to quantitatively analyze the characteristics of hemiplegic gait. Thus the assessment would be simple, and real-time evaluation of rehabilitation could be carried out.
Twenty subjects (ten hemiplegic patients, ten normal subjects) were recruited. The subjects walked straight for five meters at their self-selected comfortable speed towards a target line on the floor.
Xsens MTx motion trackers were used for acquiring gestures of body segments to estimate knee joint angles and identify gait cycles. A practical method for data acquisition that does not need to obtain accurate distances between a knee joint and its corresponding sensors is presented.
The results showed that there were significant differences between the two groups in the three nominated angle amplitudes. The mean values of balance level of each parameter in hemiplegic gait and normal gait were: 0.21 versus 0.01, 0.18 versus 0.03, and 0.92 versus 0.03, respectively. The mean values of added angles of each parameter in hemiplegic gait and normal gait were: 74.64 versus 91.31, -76.48 versus −132.4, and 6.77 versus 35.74.
It was concluded that the wearable bio-motion acquisition platform provided a practical approach that was effective in discriminating gait symptoms between hemiplegic and asymptomatic subjects. The extensibility of hemiplegic patients’ lower limbs was significantly lower than that of normal subjects, and the hemiplegic gait had worse balance level compared with normal gait. The effect of rehabilitation training of hemiplegic gait could be quantitatively analyzed.
Gait analysis; Body Sensor Network; Hemiplegic gait; Biomechanics
As a by product of higher value cotton fibre, cotton seed has been increasingly recognised to have excellent potential as a source of additional food, feed, biofuel stock and even a renewable platform for the production of many diverse biological molecules for agriculture and industrial enterprises. The large size difference between cotyledon and embryo axis that make up a cotton seed results in the under-representation of embryo axis gene transcript levels in whole seed embryo samples. Therefore, the determination of gene transcript levels in the cotyledons and embryo axes separately should lead to a better understanding of metabolism in these two developmentally diverse tissues.
A comparative study of transcriptome changes between cotton developing cotyledon and embryo axis has been carried out. 17,384 unigenes (20.74% of all the unigenes) were differentially expressed in the two adjacent embryo tissues, and among them, 7,727 unigenes (44.45%) were down-regulated and 9,657 unigenes (55.55%) were up-regulated in cotyledon.
Our study has provided a comprehensive dataset that documents the dynamics of the transcriptome at the mid-maturity of cotton seed development and in discrete seed tissues, including embryo axis and cotyledon tissues. The results showed that cotton seed is subject to many transcriptome variations in these two tissue types and the differential gene expression between cotton embryo axis and cotyledon uncovered in our study should provide an important starting point for understanding how gene activity is coordinated during seed development to make a seed. Further, the identification of genes involved in rapid metabolite accumulation stage of seed development will extend our understanding of the complex molecular and cellular events in these developmental processes and provide a foundation for future studies on the metabolism, embryo differentiation of cotton and other dicot oilseed crops.
Background and aim
Limitations of the currently recommended stepwise treatment pathway for type 2 diabetes mellitus (T2DM), especially the failure of monotherapies to maintain good glycemic control, have prompted use of early, more aggressive combination therapies.
The VISION study is designed to explore the efficacy and safety of vildagliptin as an add-on to metformin therapy compared with up-titration of metformin monotherapy in Chinese patients with T2DM.
VISION, a 24-week, phase 4, prospective, randomized, multicenter, open-label, parallel-group study, will include 3312 Chinese T2DM patients aged ≥18 years who are inadequately controlled (6.5% >HbA1c ≤9%) by metformin (750–1000 mg/day). Eligible patients will be randomized to receive either vildagliptin plus metformin or up-titration of metformin monotherapy (5:1). Patients will also be subgrouped (1:1:1:1) based on their age and body mass index (BMI): <60 years and <24 kg/m2; <60 years and ≥24 kg/m2; ≥60 years and <24 kg/m2; and ≥60 years and ≥24 kg/m2.
The VISION study will test the hypothesis that early use of combination therapy with vildagliptin and metformin will provide good glycemic control and will be better tolerated than up-titration of metformin monotherapy. The study will also correlate these benefits with age and BMI.
VISION study; Vildagliptin; Type 2 diabetes; Study design; DPP-IV inhibitors
China has seen the largest human migration in history, and the country's rapid urbanisation has important consequences for public health. A provincial analysis of its urbanisation trends shows shifting and accelerating rural-to-urban migration across the country and accompanying rapid increases in city size and population. The growing disease burden in urban areas attributable to nutrition and lifestyle choices is a major public health challenge, as are troubling disparities in health-care access, vaccination coverage, and accidents and injuries in China's rural-to-urban migrant population. Urban environmental quality, including air and water pollution, contributes to disease both in urban and in rural areas, and traffic-related accidents pose a major public health threat as the country becomes increasingly motorised. To address the health challenges and maximise the benefits that accompany this rapid urbanisation, innovative health policies focused on the needs of migrants and research that could close knowledge gaps on urban population exposures are needed.
The rhizobium-legume symbiosis is a model system for studying mutualistic interactions between bacteria and eukaryotes. Sinorhizobium sp. NGR234 is distinguished by its ability to form either indeterminate nodules or determinate nodules with diverse legumes. Here, we presented a high-resolution RNA-seq transcriptomic analysis of NGR234 bacteroids in indeterminate nodules of Leucaena leucocephala and determinate nodules of Vigna unguiculata. In contrast to exponentially growing free-living bacteria, non-growing bacteroids from both legumes recruited several common cellular functions such as cbb3 oxidase, thiamine biosynthesis, nitrate reduction pathway (NO-producing), succinate metabolism, PHB (poly-3-hydroxybutyrate) biosynthesis and phosphate/phosphonate transporters. However, different transcription profiles between bacteroids from two legumes were also uncovered for genes involved in the biosynthesis of exopolysaccharides, lipopolysaccharides, T3SS (type three secretion system) and effector proteins, cytochrome bd ubiquinol oxidase, PQQ (pyrroloquinoline quinone), cytochrome c550, pseudoazurin, biotin, phasins and glycolate oxidase, and in the metabolism of glutamate and phenylalanine. Noteworthy were the distinct expression patterns of genes encoding phasins, which are thought to be involved in regulating the surface/volume ratio of PHB granules. These patterns are in good agreement with the observed granule size difference between bacteroids from L. leucocephala and V. unguiculata.
Cortical abnormalities are considered a neurobiological characteristic of schizophrenia. However, the pattern of such deficits as they progress over the illness remains poorly understood. The goal of this project was to assess the progression of cortical thinning in frontal and temporal cortical regions in schizophrenia, and determine whether relationships exist between them and neuropsychological and clinical symptom profiles. As part of a larger longitudinal 2-year follow-up study, schizophrenia (n=20) and healthy participants (n=20) group-matched for age, gender, and recent-alcohol use, were selected. Using MRI, estimates of gray matter thickness were derived from primary anatomical gyri of the frontal and temporal lobes using surface-based algorithms. These values were entered into repeated-measures analysis of variance models to determine group status and time effects. Change values in cortical regions were correlated with changes in neuropsychological functioning and clinical symptomatology. Results revealed exaggerated cortical thinning of the middle frontal, superior temporal, and middle temporal gyri in schizophrenia participants. These thickness changes strongly influenced volumetric reductions, but were not related to shrinking surface area. Neuropsychological and clinical symptom profiles were stable in the schizophrenia participants despite these neuroanatomic changes. Overall it appears ongoing abnormalities in the cerebral cortex continue after initial onset of schizophrenia, particularly the lateral aspects of frontal and temporal regions, and do not relate to neuropsychological or clinical measures over time. Maintenance of neuropsychological performance and clinical stability in the face of changing neuroanatomical structure suggests the involvement of alternative compensatory mechanisms.
schizophrenia; longitudinal; neuroimaging; frontal lobes; temporal lobes; neuropsychology; clinical symptoms