Environmental enrichment during development may reduce drug abuse liability by modulating dopamine transporter (DAT) function. Nucleus accumbens (NAc) shell and core respond differentially to regulate the rewarding properties and locomotor stimulant effects of psychostimulants. The current study evaluated dopamine (DA) clearance (CLDA) in the NAc shell and core using in vivo voltammetry in rats raised in an enriched condition (EC) or an impoverished condition (IC) and determined the effect of nicotine (0.4 mg/kg) on CLDA. Baseline CLDA in NAc shell and core was not different between EC and IC rats. In the saline control group, CLDA in NAc shell was greater across time in IC when compared with EC rats, whereas CLDA in NAc core was greater in EC rats when compared with IC rats. Consistent with these findings, opposite effects of enrichment on DA clearance in shell and core were obtained following acute nicotine administration. In NAc shell, nicotine increased CLDA in EC rats, but not in IC rats. Conversely, in NAc core, nicotine increased CLDA in IC rats, but not in EC rats. The current results demonstrate that environmental enrichment differentially regulates the response to nicotine in NAc shell and core via alterations in DAT function, which may explain how environmental enrichment reduces the behavioral response to nicotine.
dopamine transporter; nicotine; nucleus accumbens; environmental enrichment; dopamine clearance; in vivo voltammetry
The Sun’s procedure is a surgical technique proposed by Dr. Li-Zhong Sun in 2002 that integrates total aortic arch replacement using a tetrafurcated graft with implantation of a specially designed frozen elephant trunk (Cronus®) in the descending aorta. It is used as a treatment option for extensive aortic dissections or aneurysms involving the ascending aorta, aortic arch and the descending aorta. The technical essentials of Sun’s procedure include implantation of the special open stented graft into the descending aorta, total arch replacement with a 4-branched vascular graft, right axillary artery cannulation, selective antegrade cerebral perfusion for brain protection, moderate hypothermic circulatory arrest at 25 °C, a special anastomotic sequence for aortic reconstruction (i.e., proximal descending aorta → left carotid artery → ascending aorta → left subclavian artery → innominate artery), and early rewarming and reperfusion after distal anastomosis to minimize cerebral and cardiac ischemia. The core advantage of Sun’s procedure lies in the use of a unique stented graft, which has superior technical simplicity, flexibility, inherent mechanical durability and an extra centimeter of attached regular vascular graft at both ends. Since its introduction in 2003, the Sun’s procedure has produced satisfactory early and long-term results in over 8,000 patients in China and more than 200 patients in South American countries. In a series of 1,092 patients, the authors have achieved an in-hospital mortality rate of 6.27% (7.98% in emergent or urgent vs. 3.98% in elective cases). Given the accumulating clinical experience and the consequent, continual evolution of surgical indications, the Sun’s procedure is becoming increasingly applied/used worldwide as an innovative and imaginative enhancement of surgical options for the dissected (or aneurysmal) ascending aorta, aortic arch and proximal descending aorta, and may become the next standard treatment for type A aortic dissections requiring repair of the aortic arch.
Sun’s procedure; frozen elephant trunk; aortic arch surgery; aortic dissection; aortic aneurysm
Acute type A aortic dissection (AAAD) remains one of the most lethal conditions requiring surgical repair, and is associated with a high rate of postoperative mortality and morbidity. Despite the satisfactory clinical outcomes achieved with the frozen elephant trunk technique so far, controversies still exist regarding the use of this aggressive approach in patients with AAAD. In this study, we seek to analyze the early outcomes of the Sun’s procedure, which is an approach integrating total arch replacement using a 4-branched graft with implantation of a special stented graft in the descending aorta, and identify the risk factors for postoperative mortality and morbidity of the Sun’s procedure in patients with AAAD.
Clinical data of 398 consecutive AAAD patients undergoing the Sun’s procedure were analyzed. The associations between 20 preoperative and intraoperative variables and early mortality were assessed by univariate and multivariate analysis.
Early mortality occurred in 31 patients (7.8%, 31/398), with leading causes including multi-organ failure in 16 patients (51.6%), permanent neurologic deficit in 6 (19.4%), and low cardiac output syndrome in 4 (12.9%). Permanent neurologic deficit and spinal cord injury occurred, each in 10 patients (2.5%, 10/398). Five significant risk factors for early mortality were identified with multivariate analysis: preexisting cerebrovascular disease [relative risk (RR) 14.76; P<0.001], acute heart failure (RR 18.18; P=0.001), spinal cord malperfusion (RR 60.13; P<0.002), visceral malperfusion (RR 30.25; P<0.001) and cardiopulmonary bypass time >190 minutes (RR 3.62; P=0.007).
The Sun’s procedure has generated a relatively lower mortality rate in 398 patients with AAAD. Patients with preexisting cerebrovascular disease, acute heart failure, spinal cord malperfusion, visceral malperfusion and long cardiopulmonary bypass time are at a higher risk of early mortality.
Aortic dissection; stented graft; surgery; outcome; mortality; complication
Elevated lipoprotein(a) [Lp(a)] levels predict cardiovascular events incidence in patients with coronary artery disease (CAD). Genetic variants in the rs3798220, rs10455872 and rs6415084 single-nucleotide polymorphisms (SNPs) in the Lp(a) gene (LPA) correlate with elevated Lp(a) levels, but whether these SNPs have prognostic value for CAD patients is unknown. The present study evaluated the association of LPA SNPs with incidence of subsequent cardiovascular events in CAD patients after percutaneous coronary intervention (PCI).
TaqMan SNP genotyping assays were performed to detect the rs6415084, rs3798220 and rs10455872 genotypes in 517 Chinese Han patients with CAD after PCI. We later assessed whether there was an association of these SNPs with incidence of major adverse cardiovascular events (MACE: cardiac death, nonfatal myocardial infarction, ischemic stroke and coronary revascularization). Serum lipid profiles were also determined using biochemical methods.
Only the rs6415084 variant allele was associated with higher Lp(a) levels [41.3 (20.8, 74.6) vs. 18.6 (10.3, 40.9) mg/dl, p < 0.001]. During a 2-year follow-up period, 102 patients suffered MACE, and Cox regression analysis demonstrated that elevated Lp(a) (≥30 mg/dl) levels correlated with increased MACE (adjusted HR, 1.69; 95% CI 1.13-2.53), but there was no association between LPA genetic variants (rs6415084 and rs3798220) and MACE incidence (p > 0.05).
Our data did not support a relationship between genetic LPA variants (rs6415084 and rs3798220) and subsequent cardiovascular events after PCI in Chinese Han CAD patients.
Coronary artery disease; Lipoprotein(a); Major adverse cardiovascular events; Percutaneous coronary intervention; Single-nucleotide polymorphism
Androgenetic alopecia (AGA) is a well-characterized type of progressive hair loss commonly seen in men, with different prevalences in different ethnic populations. It is generally considered to be a polygenic heritable trait. Several susceptibility genes/loci, such as AR/EDA2R, HDAC9 and 20p11, have been identified as being involved in its development in European populations. In this study, we aim to validate whether these loci are also associated with AGA in the Chinese Han population.
We genotyped 16 previously reported single nucleotide polymorphisms (SNPs) with 445 AGA cases and 546 healthy controls using the Sequenom iPlex platform. The trend test was used to evaluate the association between these loci and AGA in the Chinese Han population. Conservatively accounting for multiple testing by the Bonferroni correction, the threshold for statistical significance was P ≤3.13×10−3.
We identified that 5 SNPs at 20p11 were significantly associated with AGA in the Chinese Han population (1.84×10−11≤P≤2.10×10−6).
This study validated, for the first time, that 20p11 also confers risk for AGA in the Chinese Han population and implicated the potential common genetic factors for AGA shared by both Chinese and European populations.
Plant disease resistance genes are a key component of defending plants from a range of pathogens. The majority of these resistance genes belong to the super-family that harbors a Nucleotide-binding site (NBS). A number of studies have focused on NBS-encoding genes in disease resistant breeding programs for diverse plants. However, little information has been reported with an emphasis on systematic analysis and comparison of NBS-encoding genes in cotton. To fill this gap of knowledge, in this study, we identified and investigated the NBS-encoding resistance genes in cotton using the whole genome sequence information of Gossypium raimondii. Totally, 355 NBS-encoding resistance genes were identified. Analyses of the conserved motifs and structural diversity showed that the most two distinct features for these genes are the high proportion of non-regular NBS genes and the high diversity of N-termini domains. Analyses of the physical locations and duplications of NBS-encoding genes showed that gene duplication of disease resistance genes could play an important role in cotton by leading to an increase in the functional diversity of the cotton NBS-encoding genes. Analyses of phylogenetic comparisons indicated that, in cotton, the NBS-encoding genes with TIR domain not only have their own evolution pattern different from those of genes without TIR domain, but also have their own species-specific pattern that differs from those of TIR genes in other plants. Analyses of the correlation between disease resistance QTL and NBS-encoding resistance genes showed that there could be more than half of the disease resistance QTL associated to the NBS-encoding genes in cotton, which agrees with previous studies establishing that more than half of plant resistance genes are NBS-encoding genes.
AIM: To assess whole-body fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) in the management of small bowel obstructions (SBOs) secondary to gastric cancer and its role in treatment strategies.
METHODS: The medical records of all of the patients who were admitted for an intestinal obstruction after curative resection for gastric cancer were retrospectively reviewed. PET/CT was performed before a clinical treatment strategy was established for each patient. The patients were divided into 2 groups: patients with no evidence of a tumor recurrence and patients with evidence of a tumor recurrence. Tumor recurrences included a local recurrence, peritoneal carcinomatosis or distant metastases. The primary endpoint was the 1-year survival rate, and other variables included patient demographics, the length of hospital stay, complications, and mortality.
RESULTS: The median time between a diagnosis of gastric cancer and the detection of a SBO was 1.4 years. Overall, 31 of 65 patients (47.7%) had evidence of a tumor recurrence on the PET/CT scan, which was the only factor that was associated with poor survival. Open and close surgery was the main type of surgical procedure reported for the patients with tumor recurrences. R0 resections were performed in 2 patients, including 1 who underwent combined adjacent organ resection. In the group with no evidence of a tumor recurrence on PET/CT, bowel resections were performed in 7 patients, adhesiolysis was performed in 7 patients, and a bypass was performed in 1 patient. The 1-year survival curves according to PET/CT evidence of a tumor recurrence vs no PET/CT evidence of a tumor recurrence were significantly different, and the 1-year survival rates were 8.8% vs 93.5%, respectively. There were no significant differences (P = 0.71) in the 1-year survival rates based on surgical vs nonsurgical management (0% with nonoperative treatment vs 20% after exploratory laparotomy).
CONCLUSION: 18F-FDG PET/CT can be used to identify the causes of bowel obstructions in patients with a history of gastric cancer, and this method is useful for planning the surgical management of these patients.
Positron emission tomography/computed tomography; Small bowel obstructions; Gastric cancer; Clinical treatment strategy
Mutualisms are common in nature, though these symbioses can be quite permeable to cheaters in situations where one individual parasitizes the other by discontinuing cooperation yet still exploits the benefits of the partnership. In the Rhizobium-legume system, there are two separate contexts, namely nodulation and nitrogen fixation processes, by which resident Rhizobium individuals can benefit by cheating. Here, we constructed reversible and irreversible mutations in key nodulation and nitrogen-fixation pathways of Rhizobium etli and compared their interaction with plant hosts Phaseolus vulgaris to that of wild type. We show that R. etli reversible mutants deficient in nodulation factor production are capable of intra-specific cheating, wherein mutants exploit other Rhizobium individuals capable of producing these factors. Similarly, we show that R. etli mutants are also capable of cheating inter-specifically, colonizing the host legume yet contributing nothing to the partnership in terms of nitrogen fixation. Our findings indicate that cheating is possible in both of these frameworks, seemingly without damaging the stability of the mutualism itself. These results may potentially help explain observations suggesting that legume plants are commonly infected by multiple bacterial lineages during the nodulation process.
Delphinidin-3-glucoside (Dp) is a member of a family of bioactive compounds known as anthocyanins that occur naturally in pigmented plants and are known to ameliorate oxidative stress. Previous studies have showed that Dp decreased oxidative stress in vascular endothelial cells, however, the underlying mechanisms remain largely unknown. In the present study, we showed that pretreatment with Dp significantly suppressed oxidized low-density lipoprotein (oxLDL)-induced cell proliferation inhibition and apoptosis in primary human umbilical vein endothelial cells (HUVECs). Also, Dp pretreatment attenuated oxLDL-induced mitochondrial dysfunction via decreased reactive oxygen species (ROS) and superoxide anion generation, thereby repressing mitochondrial membrane potential and closing mitochondrial permeability transition pore. Furthermore, in vitro and in vivo data showed that Dp was transported into endothelial cells in a temperature, concentration, and time-dependent manner via the sodium-dependent glucose transporter (SGLT1). Suppression of SGLT1 by its substrate glucose, its inhibitor phlorizin or SGLT1 siRNA blocked Dp transportation. Repression of SGLT1 significantly inhibited Dp function of ameliorating mitochondrial dysfunction induced by pro-apoptotic factors (Apoptosis-inducing factor, Cytochrome c, Caspase-3 and Bax/Bcl-2 ratio). Taken together, our data indicate that Dp protects VECs via the SGLT1-ROS-mitochodria pathway. This new insight may help to elucidate the molecular mechanisms underlying the vascular protection afforded by Dp, and anthocyanins in general, in the context of prevention of endothelial dysfunction and atherosclerosis.
To explore the efficacy and safety of L-asparaginase in newly-diagnosed extranodal nature killer (NK)/T –cell lymphoma (ENKTL), we conducted a prospective phase II study of L-asparaginase, cyclophosphamide, vincristine, doxorubicin and dexamethasone (CHOP-L) regimen in combination with radiotherapy.
Patients and methods
Patients with newly diagnosed ENKTL and an ECOG performance status of 0 to 2 were eligible for enrollment. Treatment included 6–8 cycles of CHOP-L (cyclophosphamide, 750 mg/m2 day 1; vincristine, 1.4 mg/m2 day 1 (maximal dose 2 mg), doxorubicin 50 mg/m2 day 1; dexamethasone 10 mg days 1–8; L-asparaginase 6000 u/m2 days 2–8). Radiotherapy was scheduled after 4–6 cycles of CHOP-L regimen, depending on stage and primary anatomic site. The primary endpoint was complete response (CR) rate.
A total of 38 eligible patients were enrolled. The median age was 40.5 years (range, 15 to 71 years). Their clinical characteristics were male to female ratio, 24:14; Ann Arbor stage I, 20; II, 11; III, 3; IV, 4. CR and overall response rates were 81.6% (95% CI, 69.3% to 93.9%) and 84.2%, respectively. With a median follow-up of 25 months, the 2-year overall survival, progression-free survival and disease-free survival rates were 80.1% (95%CI, 73.3% to 86.9%), 81% (95%CI, 74.5% to 87.5%) and 93.6% (95%CI, 89.3% to 97.9%), respectively. The major adverse events were myelosuppression, liver dysfunction, and digestive tract toxicities. Grade 3 to 4 leukopenia and neutropenia were 76.3% and 84.2%, respectively. No treatment-related death was observed.
CHOP-L chemotherapy in combination with radiotherapy is a safe and highly effective treatment for newly diagnosed ENKTL.
Gallbladder carcinoma is a malignant tumor with a very low 5-year survival rate because of the difficulty with its early diagnosis and the very poor prognosis of the advanced cancer state. The aims of this study were to determine whether curcumin could induce the apoptosis of a gallbladder carcinoma cell line, GBC-SD, and to clarify its related mechanism.
First, the anti-proliferative activities of curcumin-treated and untreated GBC-SD cells were determined using the MTT and colony formation assays. Then, the early apoptosis of cells was detected by the annexin V/propidium iodide double-staining assay and Hoechst 33342 staining assay. Detection of mitochondrial membrane potential was used to validate the ability of curcumin on inducing apoptosis in GBC-SD cells. Cell cycle changes were detected by flow cytometric analysis. Finally, the expressions of the apoptosis-related proteins or genes caspase-3, PARP, Bcl-2, and Bax were analyzed by western blot and quantitative real time PCR assay. Statistical analyses were performed using the Student’s t-test for comparison of the results obtained from cells with or without curcumin treatment.
The MTT assay revealed that curcumin had induced a dose- and a time-dependent decrease in cell viability. Colony counting indicated that curcumin had induced a dose-dependent decrease in the colony formation ability in GBC-SD cells. Cells treated with curcumin were arrested at the S phase, according to the flow cytometric analysis. A significant induction of both the early and late phases of apoptosis was shown by the annexin V-FITC and PI staining. Morphological changes in apoptotic cells were also found by the Hoechst 33342 staining. After treatment with curcumin fluorescence shifted from red to green as ΔΨm decreased. Furthermore, western blot and quantitative real time PCR assays demonstrated that the curcumin induced apoptosis in GBC-SD cells by regulating the ratio of Bcl-2/Bax and activating the expression of cleaved caspase-3.
Taken together, the results indicate that curcumin may be a potential agent for the treatment of gallbladder cancer.
Curcumin; Gallbladder carcinoma GBC-SD cell; Proliferation; Apoptosis
The dopamine (DA) transporter (DAT) and vesicular monoamine transporter (VMAT2) proteins interact as a biochemical complex to regulate dopaminergic neurotransmission. We have reported that HIV-1Tat1–86 decreases the specific [3H]DA uptake and [3H]WIN 35,428 binding sites without a change in total DAT immunoreactivity in rat striatum (Zhu et al., 2009b). The present study determined the effects of Tat on DAT phosphorylation and trafficking, and vesicular [3H]DA uptake. Pre-incubation of rat striatal synaptosomes with the protein kinase C (PKC) inhibitor bisindolylmaleimide I (1 µM) completely blocked Tat1–86 -induced reduction of [3H]DA uptake, indicating that Tat regulates DAT function through a PKC-dependent mechanism. After exposure of synaptosomes to Tat1–86 (1 µM), DAT immunoreactivity was decreased in plasma membrane enriched fractions (P3) and increased in vesicle-enriched fractions (P4) relative to controls without change in total synaptosomal fractions (P2), suggesting that Tat-induced inhibition of DA uptake is attributable to DAT internalization. Although both DAT and VMAT2 proteins are essential for the regulation of DA disposition in synapse and cytosol, Tat inhibited the specific [3H]DA uptake into vesicles (P4) and synaptosomes (P2) by 35% and 26%, respectively, inferring that the inhibitory effect of Tat was more profound in VMAT2 protein than in DAT protein. Taken together, the current study reveals that Tat inhibits DAT function through a PKC and trafficking-dependent mechanism and that Tat impacts the dopaminergic tone by regulating both DAT and VMAT2 proteins. These findings provide new insight into understanding the pharmacological mechanisms of HIV-1 viral protein-induced dysfunction of DA neurotransmission in HIV-infected patients.
dopamine transporter; vesicular monoamine transporter; HIV-1 Tat; protein kinase C; uptake; trafficking
Motivation: Pre-mRNA cleavage and polyadenylation are essential steps for 3′-end maturation and subsequent stability and degradation of mRNAs. This process is highly controlled by cis-regulatory elements surrounding the cleavage/polyadenylation sites (polyA sites), which are frequently constrained by sequence content and position. More than 50% of human transcripts have multiple functional polyA sites, and the specific use of alternative polyA sites (APA) results in isoforms with variable 3′-untranslated regions, thus potentially affecting gene regulation. Elucidating the regulatory mechanisms underlying differential polyA preferences in multiple cell types has been hindered both by the lack of suitable data on the precise location of cleavage sites, as well as of appropriate tests for determining APAs with significant differences across multiple libraries.
Results: We applied a tailored paired-end RNA-seq protocol to specifically probe the position of polyA sites in three human adult tissue types. We specified a linear-effects regression model to identify tissue-specific biases indicating regulated APA; the significance of differences between tissue types was assessed by an appropriately designed permutation test. This combination allowed to identify highly specific subsets of APA events in the individual tissue types. Predictive models successfully classified constitutive polyA sites from a biologically relevant background (auROC = 99.6%), as well as tissue-specific regulated sets from each other. We found that the main cis-regulatory elements described for polyadenylation are a strong, and highly informative, hallmark for constitutive sites only. Tissue-specific regulated sites were found to contain other regulatory motifs, with the canonical polyadenylation signal being nearly absent at brain-specific polyA sites. Together, our results contribute to the understanding of the diversity of post-transcriptional gene regulation.
Availability: Raw data are deposited on SRA, accession numbers: brain SRX208132, kidney SRX208087 and liver SRX208134. Processed datasets as well as model code are published on our website: http://www.genome.duke.edu/labs/ohler/research/UTR/
R-CHOP has significantly improved survival rates of patients with diffuse large B cell lymphoma (DLBCL) by ~20% as compared to CHOP. CD20 antigen, highly expressed on more than 80% of B-cell lymphomas, is the target for rituximab. The goal of our study was to examine polymorphism in the CD20 gene in Chinese DLBCL population and whether CD20 gene polymorphism is associated with clinical response to R-CHOP.
CD20 gene polymorphism was detected in the entire coding regions including 6 exons by polymerase chain reaction (PCR)-sequencing assay in 164 patients with DLBCL. Among them, 129 patients treated with R-CHOP as frontline therapy (R ≥ 4 cycles) were assessable for the efficacy.
Polymorphisms at three single nucleotides (SNP) were identified in the entire coding regions of the CD20 gene in the 164 patients. One of them, CD20 Exon2  was found to be highly correlated with response to R-CHOP. Patients with homozygous C genotype showed a trend toward higher overall response rate than others with CT plus TT genotype (90.6% vs. 79.5%; P =0.166). A trend toward higher complete remission (CR) rate was observed in patients with homozygous C genotype (67.4%) compared with CT plus TT genotype (47.1%) (P = 0.091).
These results suggest that there are 3 SNPs in CDS of the CD20 gene in Chinese DLBCL population. The CC genotype at Exon2  appears to be associated with favourable response to R-CHOP.
dopamine transporter; HIV-1 tat; allosteric modulation; uptake; cocaine
High-voltage spindles (HVSs) have been reported to appear spontaneously and widely in the cortical–basal ganglia networks of rats. Our previous study showed that dopamine depletion can significantly increase the power and coherence of HVSs in the globus pallidus (GP) and motor cortex of freely moving rats. However, it is unclear whether dopamine regulates HVS activity by acting on dopamine D1-like receptors or D2-like receptors. We employed local-field potential and electrocorticogram methods to simultaneously record the oscillatory activities in the GP and primary motor cortex (M1) in freely moving rats following systemic administration of dopamine receptor antagonists or saline. The results showed that the dopamine D2-like receptor antagonists, raclopride and haloperidol, significantly increased the number and duration of HVSs, and the relative power associated with HVS activity in the GP and M1 cortex. Coherence values for HVS activity between the GP and M1 cortex area were also significantly increased by dopamine D2-like receptor antagonists. On the contrary, the selective dopamine D1-like receptor antagonist, SCH23390, had no significant effect on the number, duration, or relative power of HVSs, or HVS-related coherence between M1 and GP. In conclusion, dopamine D2-like receptors, but not D1-like receptors, were involved in HVS regulation. This supports the important role of dopamine D2-like receptors in the regulation of HVSs. An siRNA knock-down experiment on the striatum confirmed our conclusion.
Bacillus thuringiensis is an important microbial insecticide used in the control of agricultural pests. Here we report the finished, annotated genome sequence of Bacillus thuringiensis serovar Sichuansis strain MC28, which can form parasporal crystals consisting of Cry4Cc1, Cry30Fa1, Cry53Ab1, Cry54Aa1, Cry54Ab1, Cry68Aa1, Cry69Aa1, Cry69Aa2, Cry70Ba1, Cyt1Da1, and Cyt2Aa3. It is also highly toxic to lepidopterous and dipterous insects.
Although genome-wide association studies (GWAS) have identified a significant number of single-nucleotide polymorphisms (SNPs) associated with many complex human traits, the susceptibility loci identified so far can explain only a small fraction of the genetic risk. Among other possible explanations, the lack of a comprehensive examination of gene–gene interaction (G×G) is often considered a source of the missing heritability. Previously, we reported a model-free Generalized Multifactor Dimensionality Reduction (GMDR) approach for detecting G×G in both dichotomous and quantitative phenotypes. However, the computational burden and less efficient implementation of the original programs make them impossible to use for GWAS. In this study, we developed a graphics processing unit (GPU)-based GMDR program (named GWAS-GPU), which is able not only to analyze GWAS data but also to run much faster than the earlier version of the GMDR program. As a demonstration of the program, we used the GMDR-GPU software to analyze a publicly available GWAS dataset on type 2 diabetes (T2D) from the Wellcome Trust Case Control Consortium. Through an exhaustive search of pair-wise interactions and a selected search of three- to five-way interactions conditioned on significant pair-wise results, we identified 24 core SNPs in six genes (FTO: rs9939973, rs9940128, rs9922047, rs1121980, rs9939609, rs9930506; TSPAN8: rs1495377; TCF7L2: rs4074720, rs7901695, rs4506565, rs4132670, rs10787472, rs11196205, rs10885409, rs11196208; L3MBTL3: rs10485400, rs4897366; CELF4: rs2852373, rs608489; RUNX1: rs445984, rs1040328, rs990074, rs2223046, rs2834970) that appear to be important for T2D. Of these core SNPs, 11 in FTO, TSPAN8, and TCF7L2 have been reported to be associated with T2D, obesity, or both, providing an independent replication of previously reported SNPs. Importantly, we identified three new susceptibility genes; i.e., L3MBTL3, CELF4, and RUNX1, for T2D, a finding that warrants further investigation with independent samples.
Glucosinolates (GSs) play an important role in plant defense systems and human nutrition. We investigated the content and composition of GSs in the shoots and roots of seven cultivars of pak choi. We found that ‘Si Yue Man’ had the highest total and aliphatic GS contents in the shoots and the highest benzenic GS content in the roots, ‘Shanghai Qing’ contained the highest amounts of benzenic and total GS contents in the roots, while ‘Nanjing Zhong Gan Bai’ had the lowest benzenic, indole, and total GS contents in both the shoots and roots. Therefore, the ‘Si Yue Man’ cultivar appears to be a good candidate for future breeding. Variation between the shoots and roots was also examined, and a significant correlation among the total, aliphatic, and some individual GSs was found, which is of value in agricultural breeding. GS concentrations of the leaf, petiole, and root increased dramatically during the period of rapid growth of the dry matter of the plant 10 to 20 d after transplantation, reaching peak values on Day 20 and decreasing on Day 25. We conclude that the pak choi should be harvested and consumed from 20 to 25 d after transplantation to take advantages of the high GS content in the plant.
Glucosinolate; Pak choi; Cultivar; Organ; Growth stage
The incidence of primary gastrointestinal lymphomas (PGILs) has been increasing. The clinical presentation and treatment of PGIL are distinct from those of nodular lymphomas. Symptoms include abdominal pain, abdominal mass, changes in bowel habits, obstruction, and bleeding. Less life-threatening gastrointestinal bleeding occurs after chemotherapy and few reports have focused on the bleeding of PGILs. We report a case of severe gastrointestinal bleeding caused by low-dose chemotherapy, which was dramatically improved by rituximab monotherapy treatment. The prevention and treatment of gastrointestinal bleeding in PGIL should be given much attention.
Gastrointestinal tract; mantle lymphoma; bleeding
Uptake through the Dopamine Transporter (DAT) is the primary mechanism of terminating dopamine signaling within the brain, thus playing an essential role in neuronal homeostasis. Deregulation of DAT function has been linked to several neurological and psychiatric disorders including ADHD, schizophrenia, Parkinson’s disease, and drug addiction. Over the last 15 years, several studies have revealed a plethora of mechanisms influencing the activity and cellular distribution of DAT; suggesting that fine-tuning of dopamine homeostasis occurs via an elaborate interplay of multiple pathways. Here, we show for the first time that the βγ subunits of G proteins regulate DAT activity. In heterologous cells and brain tissue, a physical association between Gβγ subunits and DAT was demonstrated by co-immunoprecipitation. Furthermore, in vitro pull-down assays using purified proteins established that this association occurs via a direct interaction between the intracellular carboxy-terminus of DAT and Gβγ. Functional assays performed in the presence of the non-hydrolyzable GTP analog GTP-γ-S, Gβγ subunit overexpression, or the Gβγ activator mSIRK all resulted in rapid inhibition of DAT activity in heterologous systems. Gβγ activation by mSIRK also inhibited dopamine uptake in brain synaptosomes and dopamine clearance from mouse striatum as measured by high-speed chronoamperometry in vivo. Gβγ subunits are intracellular signaling molecules that regulate a multitude of physiological processes through interactions with enzymes and ion channels. Our findings add neurotransmitter transporters to the growing list of molecules regulated by G-proteins and suggest a novel role for Gβγ signaling in the control of dopamine homeostasis.
The marriage of energy transfer with electrochemiluminescence has produced a new technology named electrochemiluminescence energy transfer (ECL-ET), which can realize effective and sensitive detection of biomolecules. To obtain optimal ECL-ET efficiency, perfect energy overlapped donor/acceptor pair is of great importance. Herein, we present a sensitive ECL-ET based immunosensor for the detection of tumor markers, using energy tunable CdSeTe/CdS/ZnS double shell quantum dots (QDs) and gold nanorods (GNRs) as the donor and acceptor, respectively. Firstly a facile microwave-assisted strategy for the synthesis of green- to near-infrared-emitting CdSeTe/CdS/ZnS QDs with time- and component-tunable photoluminescence was proposed. And, on the basis of the adjustable optical properties of both CdSeTe/CdS/ZnS QDs and GNRs, excellent overlap between donor emission and acceptor absorption can be obtained to ensure effective ECL-ET quenching, thus improving the sensing sensitivity. This method represents a novel approach for versatile detection of biomolecules at low concentrations.
A series of lobelane analogues has been synthesized and their structure–activity relationships at the vesicular monoamine transporter-2 (VMAT2) have been evaluated. The most potent analogues in this series were the cis-2,6-piperidino analogues, 25b, 27b, 28b, and 30b, with Ki values ranging from 430 to 580 nM.
Lobeline; Methamphetamine; Vesicular monoamine transporter; Structure–activity relationships