AIM: To investigate the comorbid disease could be the predictors for the elective colectomy in colonic diverticulitis.
METHODS: A retrospective chart review of 246 patients with colonic diverticulitis admitted between 2000 and 2008 was conducted, and 19 patients received emergent operation were identified and analyzed. Data were collected with regard to age, sex, albumin level on admission, left or right inflammation site, the history of recurrent diverticulitis, preoperative comorbidity, smoking habits, medication, treatment policy, morbidity, and mortality. Preoperative comorbid diseases included cardiovascular disease, diabetes, pulmonary disease, peptic ulcer disease, gouty arthritis, and uremia. Medications in use included non-steroidal anti-inflammatory drugs, acetylsalicylic acid (Aspirin), and corticosteroids. Univariate and multivariate logistic regression analyses were performed to identify the relevant risk factors correlating to colectomy.
RESULTS: The mean age of the 246 patients was 69.5 years (range, 24-94 years). Most diverticulitis could be managed with conservative treatment (n = 227, 92.3%), and urgent colectomy was performed in 19 patients (7.7%). There were three deaths in the surgical group and four deaths in the nonsurgical group. The overall mortality rate in the study was 1.7% among patients with conservative treatment and 15.7% among patients undergoing urgent colectomy. Multiple logistic regression analysis indicated that comorbidities were risk factors for urgent colectomy for diverticulitis.
CONCLUSION: To avoid high mortality and morbidity related to urgent colectomy, we suggest that patients with colonic diverticulitis and comorbid diseases may require elective colectomy.
Colonic diverticulitis; Colectomy; Comorbid disease
Enhanced signaling by the small guanosine triphosphatase Ras is common in T cell acute lymphoblastic leukemia/lymphoma (T-ALL, but the underlying mechanisms are unclear. Here, we identified the guanine nucleotide exchange factor RasGRP1 (Rasgrp1 in mice) as a Ras activator that contributes to leukemogenesis. We found increased RasGRP1 expression in many pediatric T-ALL patients, which we did not observe in rare early T cell precursor (ETP) T-ALL patients with KRAS and NRAS mutations, such as K-RasG12D. Leukemia screens in wild-type mice, but not in mice expressing the mutant K-RasG12D that encodes a constitutively active Ras, yielded frequent retroviral insertions that led to increased Rasgrp1 expression. Rasgrp1 and oncogenic K-RasG12D promoted T-ALL through distinct mechanisms. In K-RasG12D T-ALLs, we found that enhanced Ras activation did not lead to cell cycle arrest. In mouse T-ALL cells with increased Rasgrp1 expression, we found that Rasgrp1 contributed to a previously uncharacterized cytokine receptor–activated Ras pathway that stimulated the proliferation of T-ALL cells in vivo, which was accompanied by dynamic patterns of activation of effector kinases downstream of Ras in individual T-ALLs. Reduction of Rasgrp1 abundance reduced cytokine-stimulated Ras signaling and decreased the proliferation of T-ALL in vivo, suggesting that patients with this cancer should be screened for increased abundance of RasGRP1 to customize treatment.
AIM: To study the diagnostic value of immunoglobulin heavy chain (IgH) and T-cell receptor γ (TCR-γ) gene monoclonal rearrangements in primary gastric lymphoma (PGL).
METHODS: A total of 48 patients with suspected PGL at our hospital were prospectively enrolled in this study from January 2009 to December 2011. The patients were divided into three groups (a PGL group, a gastric linitis plastica group, and a benign gastric ulcer group) based on the pathological results (gastric mucosal specimens obtained by endoscopy or surgery) and follow-up. Endoscopic ultrasonography (EUS) and EUS-guided biopsy were performed in all the patients. The tissue specimens were used for histopathological examination and for IgH and TCR-γ gene rearrangement polymerase chain reaction analyses.
RESULTS: EUS and EUS-guided biopsy were successfully performed in all 48 patients. In the PGL group (n = 21), monoclonal IgH gene rearrangements were detected in 14 (66.7%) patients. A positive result for each set of primers was found in 12 (57.1%), 8 (38.1%), and 4 (19.0%) cases using FR1/JH, FR2/JH, and FR3/JH primers, respectively. Overall, 12 (75%) patients with mucosal-associated lymphoid tissue lymphoma (n = 16) and 2 (40%) patients with diffuse large B-cell lymphoma (n = 5) were positive for monoclonal IgH gene rearrangements. No patients in the gastric linitis plastica group (n = 17) and only one (10%) patient in the benign gastric ulcer group (n = 10) were positive for a monoclonal IgH gene rearrangement. No TCR-γ gene monoclonal rearrangements were detected. The sensitivity of monoclonal IgH gene rearrangements was 66.7% for a PGL diagnosis, and the specificity was 96.4%. In the PGL group, 8 (100%) patients with stage IIE PGL (n = 8) and 6 (46.1%) patients with stage IE PGL (n = 13) were positive for monoclonal IgH gene rearrangements.
CONCLUSION: IgH gene rearrangements may be associated with PGL staging and may be useful for the diagnosis of PGL and for differentiating between PGL and gastric linitis plastica.
Immunoglobulin heavy chain; T-cell receptor γ; Gene rearrangement; Primary gastric lymphoma; Endoscopic biopsy specimen
The purpose of the technical note is to introduce the complex coil assisted coil embolization method in the treatment of intracranial small aneurysm, in order to enhance the safety of the procedure. The first microcatheter was navigated into the aneurysm sac and the ultrasoft coil was used as the embolization coil. If the embolizations coil could not stay within the aneurysm sac smoothly, such as coil herniation into parent artery during the delivery process. The second microcatheter would be navigated to the aneurysm level in the parent artery. Another complex coil was delivered within the parent artery via the second microcatheter to provide the neck bridge effect in order to enhance the stability of embolization coil. Besides, the protection coil will not disturb the parent artery flow. While the embolization coil was put into the aneurysm sac smoothly under the help of complex protective coil, the protective coil was then withdrawn gently. We use the most magnified view, dual-plane approach simultaneously to observe the stability of embolization coil. The embolization coil would be detached without any evidence of coil motion or vibration. The new method could provide the physiological protective method, without leaving any protective device such as stent within the parent artery.
Complex coil; Aneurysm, Ruptured/therapy; Embolization, Therapeutic/methods Intracranial aneurysm
The objective of this study was to prepare baicalin solid nanocrystals (BCN-SNS) to enhance oral bioavailability of baicalin. A Box–Behnken design approach was used for process optimization. The physicochemical properties and pharmacokinetics of the optimal BCN-SNS were investigated. Multiple linear regression analysis for process optimization revealed that the fine BCN-SNS was obtained wherein the optimal values of homogenization pressure (bar), homogenization cycles (cycles), amount of TPGS to drug (w/w), and amount of MCCS to drug (w/w) were 850 bar, 25 cycles, 10%, and 10%, respectively. Transmission electron microscopy and scanning electron microscopy results indicated that no significant aggregation or crystal growth could be observed in the redispersed freeze-dried BCN-SNS. Differential scanning calorimetry and X-ray diffraction results showed that BCN remained in a crystalline state. Dissolution velocity of the freeze-dried BCN-SNS powder was distinctly superior compared to those of the crude powder and physical mixture. The bioavailability of BCN in rats was increased remarkably after oral administration of BCN-SNS (P < 0.05), compared with those of BCN or the physical mixture. The SNS might be a good choice for oral administration of poorly soluble BCN, due to an improvement of the bioavailability and dissolution velocity of BCN-SNS.
baicalin; solid nanocrystals; optimization; in vivo/vitro evaluation
In many medical imaging applications, it is desirable and important to localize and remove the patient table from CT images. However, existing methods often require user interactions to define the table and sometimes make inaccurate assumptions about the table shape. Due to different patient table designs, shapes, and characteristics, these methods are not robust in identifying and removing the patient table. This paper proposes a new automatic approach which first identifies and locates the patient table in the sagittal planes and then removes it from the axial planes. The method has been tested successfully against different tables in different products from multiple vendors, showing it is both a versatile and robust technique for patient table removal.
Computed tomography; Patient table; Hough transform
The concept of “network target” has ushered in a new era in the field of traditional Chinese medicine (TCM). As a new research approach, network pharmacology is based on the analysis of network models and systems biology. Taking advantage of advancements in systems biology, a high degree of integration data analysis strategy and interpretable visualization provides deeper insights into the underlying mechanisms of TCM theories, including the principles of herb combination, biological foundations of herb or herbal formulae action, and molecular basis of TCM syndromes. In this study, we review several recent developments in TCM network pharmacology research and discuss their potential for bridging the gap between traditional and modern medicine. We briefly summarize the two main functional applications of TCM network models: understanding/uncovering and predicting/discovering. In particular, we focus on how TCM network pharmacology research is conducted and highlight different computational tools, such as network-based and machine learning algorithms, and sources that have been proposed and applied to the different steps involved in the research process. To make network pharmacology research commonplace, some basic network definitions and analysis methods are presented.
In the title compound, C8H9N3O4, there are two molecules in the asymmetric unit, one of which is in the zwitterionic form. The zwitterion contains an intramolecular N—H⋯O hydrogen bond and the other molecule contains both an intramolecular N—H⋯O and an intramolecular O—H⋯O hydrogen bond. In the crystal, N—H⋯O and N—H⋯N hydrogen bonds link the molecules, formimg a two-dimensional network parallel to (10-1).
Excessive circular fatty acid, particlarly saturated fatty acid, can result in insulin resistance in skeletal muscle, but other adverse effects of fatty acid accumulation in myocytes remain unclear.
Differentiated C2C12 myotubes were used. The effects of palmitate on cell viability, glucose uptake, gene expression and myotube loss were evaluated by MTT assay, 2NBDG uptake, qRT-PCR, Western Blot and crystal staining-based myotube counting, respectively. In some expreiments, oleate was administrated, or the inhibitors of signaling pathways were applied.
Palmitate-induced cellular insulin resistance was clarified by the reduced Akt phosphorylation, glucose uptake and Glut4 expression. Palmitate-caused myotube loss was clearly observed under microscope and proved by myotube counting and expression analysis of myotube marker genes. Moreover, palmitate-induced transcriptional suppression of three health benefit myokine genes (FNDC5, CTRP15 and FGF21) was found, and the different involvement of p38 and PI3K in the transcription of these genes was noticed.
Palmitate-induced insulin resistance accompanys myotube loss and the impaired expression of FNDC5, CTRP15 and FGF21genes in C2C12 myotubes. These results provide novel evidence indicating the negative role of high concentration of palmitate in myotubes.
Palmitate; Myotube loss; Myokine; Insulin resistance
Membrane potential (Vm), the voltage across the plasma membrane, arises because of the presence of different ion channels/transporters with specific ion selectivity and permeability. Vm is a key biophysical signal in non-excitable cells, modulating important cellular activities, such as proliferation and differentiation. Therefore, the multiplicities of various ion channels/transporters expressed on different cells are finely tuned in order to regulate the Vm. It is well-established that cancer cells possess distinct bioelectrical properties. Notably, electrophysiological analyses in many cancer cell types have revealed a depolarized Vm that favors cell proliferation. Ion channels/transporters control cell volume and migration, and emerging data also suggest that the level of Vm has functional roles in cancer cell migration. In addition, hyperpolarization is necessary for stem cell differentiation. For example, both osteogenesis and adipogenesis are hindered in human mesenchymal stem cells (hMSCs) under depolarizing conditions. Therefore, in the context of cancer, membrane depolarization might be important for the emergence and maintenance of cancer stem cells (CSCs), giving rise to sustained tumor growth. This review aims to provide a broad understanding of the Vm as a bioelectrical signal in cancer cells by examining several key types of ion channels that contribute to its regulation. The mechanisms by which Vm regulates cancer cell proliferation, migration, and differentiation will be discussed. In the long term, Vm might be a valuable clinical marker for tumor detection with prognostic value, and could even be artificially modified in order to inhibit tumor growth and metastasis.
cancer; cell cycle; differentiation; ion channel; membrane potential; migration; proliferation; stem cell
A variety of unfulfilled needs may trigger doctor-shopping behavior (DSB) in patients. In oncology, treatment results usually cause patients the most concern. This study investigated the association of DSB with active treatments received by patients with hepatocellular carcinoma (HCC) and outcomes.
With approval from the institutional review board, all patients registered in the cancer database of a teaching hospital and diagnosed as having HCC by self-referral from outside hospitals or by in-house diagnosis were retrospectively identified. Patient data were then reviewed and analyzed via electronic medical records.
Hepatitis B carriers were significantly more likely than noncarriers to show first-time DSB. Recurrent disease was less likely to result in DSB than predicted. Patients from outside hospitals not receiving upfront first treatment after diagnosis were significantly more likely to show more frequent DSB than those receiving it. Male patients eligible for salvage treatment were less likely to have frequent occurrences of DSB than their female counterparts. Receiving first salvage treatment was not associated with more frequent DSB. Treatment recommendations offered in the study hospital did not influence patients’ decisions to leave or stay. Only elderly patients (>70 years) were less likely to show DSB.
DSB can occur throughout the entire course of treatment for HCC for a variety of reasons. Active treatments, disease status, and patient characteristics all exerted an influence on DSB.
doctor-shopping behavior; second opinion; hepatocellular carcinoma
Although use of the mechanical ventilator is a life-saving intervention, excessive tidal volumes will activate NF-κB in the lung with subsequent induction of lung edema formation, neutrophil infiltration and proinflammatory cytokine/chemokine release. The roles of NF-κB and IL-6 in ventilator-induced lung injury (VILI) remain widely debated.
To study the molecular mechanisms of the pathogenesis of VILI, mice with a deletion of IкB kinase in the myeloid cells (IKKβ△mye), IL-6-/- to WT chimeric mice, and C57BL/6 mice (WT) were placed on a ventilator for 6 hr.
WT mice were also given an IL-6-blocking antibody to examine the role of IL-6 in VILI.
Our results revealed that high tidal volume ventilation induced pulmonary capillary permeability, neutrophil sequestration, macrophage drifting as well as increased protein in bronchoalveolar lavage fluid (BALF). IL-6 production and IL-1β, CXCR2, and MIP2 expression were also increased in WT lungs but not in those pretreated with IL-6-blocking antibodies. Further, ventilator-induced protein concentrations and total cells in BALF, as well as lung permeability, were all significantly decreased in IKKβ△mye mice as well as in IL6-/- to WT chimeric mice.
Given that IKKβ△mye mice demonstrated a significant decrease in ventilator-induced IL-6 production, we conclude that NF-κB–IL-6 signaling pathways induce inflammation, contributing to VILI, and IкB kinase in the myeloid cells mediates ventilator-induced IL-6 production, inflammation, and lung injury.
Mechanical ventilator; Inflammation; IL-6; NF-κB; Alveolar macrophage; Chimeric mice
Acupuncture as an oriental natural healing therapy with prolonged history has been extensively utilized in the management of great numbers of disorders. Deqi, a renowned acupuncture needling sensation, is profoundly regarded as the predictor and also the prerequisite of a preferable acupuncture treatment efficacy. Till now, there is still no consistency being reached towards the mechanism of acupuncture Deqi as a result of the discrepancy for publicly acknowledged evidence. Recent visualized research on Deqi using modern technologies has demonstrated possible central mechanism towards it. However, there is a conspicuous paradox underway in the research of cerebral response to acupuncture Deqi. This paper provided a view of up-to-date studies using visualized tools to characterize the brain response to acupuncture Deqi, such as functional magnetic resonance imaging (fMRI) and positron emission tomography/computed tomography (PET/CT). The paradox was extruded to highlight certain reasons from a TCM view. It is hypothesized that acupoints located at different dermal sites, state of participant, and needling manipulation can all contribute to the current paradox. Hence, further studies on acupuncture Deqi should pay more attention to the strategy of experiment design with generalized measurement, valid sham control methods, and more to subjects in diseased condition.
Objectives. The complement system is a key component of innate immunity and has been implicated in the pathogenesis of diabetic retinopathy (DR). This study aimed at investigating whether polymorphisms of two genes in the complement pathway, complement factor H (CFH) and complement factor B (CFB), are associated with DR. Methods. 552 well-defined subjects with type 2 diabetes, consisting of 277 DR patients and 275 diabetic controls, were recruited. Four Tag-SNPs rs1048709, rs537160, rs4151657, and rs2072633 in CFB and rs800292 (I62V) in CFH were examined using TaqMan Genotyping Assays. Results. There were significant increases in the frequencies of A allele and AA genotype for rs1048709 in DR patients compared with diabetic controls (Pcorr = 0.035, OR = 1.42; Pcorr = 0.02, OR = 2.27, resp.): meanwhile, significant decreases in the frequencies of A allele and AA genotype for rs800292 were observed in DR patients compared with diabetic controls (Pcorr = 0.04, OR = 0.72; Pcorr = 0.015, OR = 0.51, resp.). Joint effect of these two loci was also identified. Moreover, rs800292/AA genotype was found to be related with delayed progression to DR. Conclusions. CFH-rs800292 and CFB-rs1048709 are associated with the presence of DR, which strengthens the concept that complement system plays an important role in the pathogenesis of DR.
Structural microvascular rarefaction, defined by a loss of vessels, is a common characteristic of hypertension and has been associated with elevated microvascular resistance. However, determining the causal relationship between microvascular network structure and resistance requires a consideration of all pattern changes throughout a network. The objectives of this study were to determine whether microvascular rarefaction is associated with other network pattern alterations and to evaluate whether pattern alterations in hypertension necessarily contribute to increased microvascular resistance. Mesenteric tissues from age-matched (15–16 weeks) male spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats were harvested and immunolabeled for PECAM. SHR networks displayed a decreased microvascular area, arteriolar-venular (AV) length, number of AV branches, and number of capillary segments. In addition, SHR networks displayed increased AV connections per network compared to WKY networks. Based on network geometries, resistance per network was calculated using a computational model. For simulations with equal vessel diameter and with relative diameters based on reported intravital measurements, SHR microvascular network resistance was not elevated compared to the WKY level. Our results suggest that microvascular pattern alterations associated with hypertension are more complex than vessel loss, and that these combined alterations do not necessarily lead to elevated resistance.
Microcirculation; Rarefaction; Hypertension; Mesentery; Resistance; SHR
Melatonin receptors are members of the G protein-coupled receptor (GPCR) family. Three genes for melatonin receptors have been cloned. The MT1 (or Mel1a or MTNR1A) and MT2 (or Mel1b or MTNR1B) receptor subtypes are present in humans and other mammals, while an additional melatonin receptor subtype, Mel1c (or MTNR1C), has been identified in fish, amphibians and birds. Another melatonin related orphan receptor, GPR50, which does not bind melatonin, is found exclusively in mammals. The hormone melatonin is secreted primarily by the pineal gland, with highest levels occurring during the dark period of a circadian cycle. This hormone acts systemically in numerous organs. In the brain, it is involved in the regulation of various neural and endocrine processes, and it readjusts the circadian pacemaker, the suprachiasmatic nucleus. This article reviews recent studies of gene organization, expression, evolution and mutations of melatonin receptor genes of vertebrates. Gene polymorphisms reveal that numerous mutations are associated with diseases and disorders. The phylogenetic analysis of receptor genes indicates that GPR50 is an outgroup to all other melatonin receptor sequences. GPR50 may have separated from a melatonin receptor ancestor before the split between MTNR1C and the MTNR1A/B ancestor.
melatonin receptor; evolution; vertebrates
Post-discharge care is challenging due to the high rate of adverse events after discharge. However, details regarding post-discharge care requirements remain unclear. Post-discharge medical counseling (PDMC) by telephone service was set-up to investigate its demand and predictors.
This prospective study was conducted from April 2011 to March 2012 in a tertiary referral center in northern Taiwan. Patients discharged for home care were recruited and educated via telephone hotline counseling when needed. The patient’s characteristics and call-in details were recorded, and predictors of PDMC use and worsening by red-flag sign were analyzed.
During the study period, 224 patients were enrolled. The PDMC was used 121 times by 65 patients in an average of 8.6 days after discharge. The red-flag sign was noted in 17 PDMC from 16 patients. Of the PDMC used, 50% (n = 60) were for symptom change and the rest were for post-discharge care problems and issues regarding other administrative services. Predictors of PDMC were underlying malignancy and lower Barthel index (BI). On the other hand, lower BI, higher adjusted Charlson co-morbidity index (CCI), and longer length of hospital stay were associated with PDMC and red-flag sign.
Demand for PDMC may be as high as 29% in home care patients within 30 days after discharge. PDMC is needed more by patients with malignancy and lower BI. More focus should also be given to those with lower BI, higher CCI, and longer length of hospital stay, as they more frequently have red flag signs.
The identification of mutated metabolic enzymes in hereditary cancer syndromes has established a direct link between metabolic dysregulation and cancer. Mutations in the Krebs cycle enzyme, fumarate hydratase (FH), predispose affected individuals to leiomyomas, renal cysts, and cancers, though the respective pathogenic roles of mitochondrial and cytosolic FH isoforms remain undefined. On the basis of comprehensive metabolomic analyses, we demonstrate that FH1-deficient cells and tissues exhibit defects in the urea cycle/arginine metabolism. Remarkably, transgenic re-expression of cytosolic FH ameliorated both renal cyst development and urea cycle defects associated with renal-specific FH1 deletion in mice. Furthermore, acute arginine depletion significantly reduced the viability of FH1-deficient cells in comparison to controls. Our findings highlight the importance of extramitochondrial metabolic pathways in FH-associated oncogenesis and the urea cycle/arginine metabolism as a potential therapeutic target.
•FH-deficient cells accumulate fumarate and urea cycle metabolites•Cytosolic FH is critical for renal cyst development in FH1-deficient mice•Restoration of cytosolic FH activity restores urea cycle defects•Arginine depletion reduces viability of FH1-deficient cells
In this study, Pollard and colleagues demonstrate the importance of cytosolic fumarate hydratase (FH) in renal cyst development in mice. Metabolite analysis of FH-deficient cysts and tumors identified alterations in urea cycle metabolism. re-expression of extramitochondrial FH in mice with renal-specific FH1 deletion was sufficient to ameliorate cyst development and metabolic alterations in the urea cycle. Significantly, FH-deficient cells exhibit increased sensitivity to arginine depletion. Exploitation of this vulnerability may be a potential route for therapy for FH-mutant tumors.
As an oncoprotein, MDM4 plays a key part in P53 tumor suppressor pathway through negatively regulating P53 function. It has been reported that an rs4245739 A>C polymorphism locating in the MDM4 3′-untranslated region creates a miR-191 target site and results in decreased MDM4 expression. Therefore, we investigated the association between this polymorphism and esophageal squamous cell carcinoma (ESCC) risk as well as its biological function in vivo. Genotypes were determined in two independent case-control sets consisted of 1128 ESCC cases and 1150 controls from two regions of China. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by logistic regression. The impact of the polymorphism on MDM4 expression was examined with esophagus tissues. Our results demonstrated that the MDM4 rs4245739 AC and CC genotypes were significantly associated with decreased ESCC risk compared with the AA genotype in both case-control sets (Jinan set: OR = 0.54, 95% CI = 0.35–0.82, P = 0.004; Huaian set: OR = 0.68, 95% CI = 0.45–0.99, P = 0.049). Stratified analyses revealed that a multiplicative interaction between rs4245739 and smoking or drinking was evident (Gene-smoking: Pinteractioin = 0.022; gene-drinking: Pinteractioin = 0.032). After detecting In vivo MDM4 mRNA expression, we found that the rs4245739 AC and CC genotype carriers had significantly decreased MDM4 expression in normal esophagus tissues compared with AA genotype carriers, indicating a consistent genotype-phenotype correlation. Our results elucidate that the MDM4 rs4245739 polymorphism contributes to susceptibility of ESCC and support the hypothesis that genetic variants, interrupting miRNA-mediated gene regulation, may modify cancer risk.
Peritoneal dialysis (PD) is an increasingly accepted modality of renal replacement therapy. It provides the advantages of having a flexible lifestyle, stable hemodynamics, and better preservation of residual renal function. To enhance our understanding of the peritoneal dialysate of diabetes mellitus (DM), peritoneal dialysate proteins were identified by two-dimensional gel electrophoresis (2DE) combined with reverse-phase nano-ultra performance liquid chromatography electrospray ionization tandem mass spectrometry (RP-nano-UPLC-ESI-MS/MS) followed by peptide fragmentation patterning. To validate the differential proteins, ELISA and Western blotting analyses were applied to detect candidate proteins that may be related to DM. We performed 2DE on the peritoneal dialysate samples, with detection of more than 300 spots. From this, 13 spots were excised, in-gel digested, and identified by RP-nano-UPLC-ESI-MS/MS. Ten of these showed significant differential expression between the DM and chronic glomerulonephritis (CGN) peritoneal dialysate samples. In this study, we conducted a comparative proteomic study on these two groups of dialysate that may provide evidence for understanding the different peritoneal protein changes. These proteins may not be new biomarkers; however, they may indicate a situation for possible drug treatment and can be the predictors of peritonitis for a validation study in the future.
In this paper, a panel of single-stranded DNA aptamers with high affinity and specificity against Salmonella Paratyphi A was selected from an enriched oligonucleotide pool by a whole-cell-Systematic Evolution of Ligands by Exponential Enrichment (SELEX) procedure, during which four other Salmonella serovars were used as counter-selection targets. It was determined through a fluorescence assay that the selected aptamers had high binding ability and specificity to this pathogen. The dissociation constant of these aptamers were up to nanomolar range, and aptamer Apt22 with the lowest Kd (47 ± 3 nM) was used in cell imaging experiments. To detect this bacteria with high specificity and cost-efficiently, a novel useful detection method was also constructed based on the noncovalent self-assembly of single-walled carbon nanotubes (SWNTs) and DNAzyme-labeled aptamer detection probes. The amounts of target bacteria could be quantified by exploiting chemoluminescence intensity changes at 420 nm and the detection limit of the method was 103 cfu/mL. This study demonstrated the applicability of Salmonella specific aptamers and their potential for use in the detection of Salmonella in food, clinical and environmental samples.
Salmonella Paratyphi A; aptamer; single-walled carbon nanotubes; detection
The number of vertebrae is an economically important trait that affects carcass length and meat production in pigs. A major quantitative trait locus (QTL) for thoracic vertebral number has been repeatedly identified on pig chromosome (SSC) 7. To dissect the genetic basis of the major locus, we herein genotyped a large sample of animals from 3 experimental populations of Chinese and Western origins using 60K DNA chips. Genome-wide association studies consistently identified the locus across the 3 populations and mapped the locus to a 947-Kb region on SSC7. An identical-by-descent sharing assay refined the locus to a 100-Kb segment that harbors only two genes including VRTN and SYNDIG1L. Of them, VRNT has been proposed as a strong candidate of the major locus in Western modern breeds. Further, we resequenced the VRTN gene using DNA samples of 35 parental animals with known QTL genotypes by progeny testing. Concordance tests revealed 4 candidate causal variants as their genotypes showed the perfect segregation with QTL genotypes of the tested animals. An integrative analysis of evolutional constraints and functional elements supported two VRTN variants in a complete linkage disequilibrium phase as the most likely causal mutations. The promising variants significantly affect the number of thoracic vertebrae (one vertebra) in large scale outbred animals, and are segregating at rather high frequencies in Western pigs and at relatively low frequencies in a number of Chinese breeds. Altogether, we show that VRTN variants are significantly associated with the number of thoracic vertebrae in both Chinese and Western pigs. The finding advances our understanding of the genetic architecture of the vertebral number in pigs. Furthermore, our finding is of economical importance as it provides a robust breeding tool for the improvement of vertebral number and meat production in both Chinese indigenous pigs and Western present-day commercial pigs.
The gene encoding the Krebs cycle enzyme fumarate hydratase (FH) is mutated in hereditary leiomyomatosis and renal cell cancer (HLRCC). Loss of FH activity causes accumulation of intracellular fumarate, which can directly modify cysteine residues to form 2-succinocysteine through succination. We undertook a proteomic-based screen in cells and renal cysts from Fh1 (murine FH)-deficient mice and identified 94 protein succination targets. Notably, we identified the succination of three cysteine residues in mitochondrial Aconitase2 (ACO2) crucial for iron-sulfur cluster binding. We show that fumarate exerts a dose-dependent inhibition of ACO2 activity, which correlates with increased succination as determined by mass spectrometry, possibly by interfering with iron chelation. Importantly, we show that aconitase activity is impaired in FH-deficient cells. Our data provide evidence that succination, resulting from FH deficiency, targets and potentially alters the function of multiple proteins and may contribute to the dysregulated metabolism observed in HLRCC.
► Fumarate inhibits Aconitase2 activity via succination of critical cysteine residues ► Endogenous Aconitase2 is succinated and inhibited in FH-deficient cells ► Succination occurs in multiple proteins with roles in diverse cellular processes ► Succination can alter metabolism in FH-deficient cells
Loss-of-function mutations in the tumor suppressor gene fumarate hydratase (FH) predispose to an aggressive type of renal cancer. FH inactivation results in accumulation of the Krebs cycle metabolite fumarate, which can irreversibly modify cysteine residues through succination. Yang, Pollard, and colleagues showed that fumarate-mediated succination occurs on three critical cysteine residues in Aconitase2, leading to its inactivation in FH-deficient cells. Succination targets multiple proteins encompassing diverse cellular pathways, potentially contributing to the oncogenesis in FH-deficient tumors.
Granulocyte-colony stimulating factor (G-CSF) has been reported to improve the function of infarcted heart, but its effects on atherosclerosis are unclear. Here we examined the effects and the potential mechanisms in the high-fat diet rabbit model. Six-month-old male New Zealand white rabbits, fed a high-cholesterol diet or a normal diet for 10 weeks, were treated with vehicle or G-CSF. G-CSF increased lesion area in the thoracic aorta and the plasma levels of total cholesterol (TC) and low-density lipoprotein-cholesterol (LDL-C) at the early phase in the high-fat diet group. High-fat diet-induced arterial endothelium damage and apoptosis were greatly aggravated by G-CSF treatment. In vivo, G-CSF impaired apoptosis induced by oxidized low density lipoprotein (OX-LDL) but it had little effect on cultured endothelial cells (ECs) with vehicle treatment. Further research revealed that G-CSF promoted the upregulation of endothelin-1 (ET-1) and the downregulation of endothelial nitric oxide synthase (eNOS) of thoracic aortae induced by a high-fat diet. In vitro, the effects of G-CSF on expression of ET-1 and eNOS in cultured ECs were consistent with those in vivo. Our results suggested that G-CSF exacerbates lipid abnormity and endothelium damage in hyperlipidemia rabbits, thereby resulting in the deterioration of atherosclerosis and that the ET-1/eNOS system may regulate the progression.
atherosclerosis; endothelial cell; ET-1; G-CSF; apoptosis; hyperlipidemia
The study presents an ammonia microsensor integrated with a readout circuit on-a-chip fabricated using the commercial 0.18 μm complementary metal oxide semiconductor (CMOS) process. The integrated sensor chip consists of a heater, an ammonia sensor and a readout circuit. The ammonia sensor is constructed by a sensitive film and the interdigitated electrodes. The sensitive film is zirconium dioxide that is coated on the interdigitated electrodes. The heater is used to provide a working temperature to the sensitive film. A post-process is employed to remove the sacrificial layer and to coat zirconium dioxide on the sensor. When the sensitive film adsorbs or desorbs ammonia gas, the sensor produces a change in resistance. The readout circuit converts the resistance variation of the sensor into the output voltage. The experiments show that the integrated ammonia sensor has a sensitivity of 4.1 mV/ppm.
integrtaed ammonia microsensor; zirconium dioxide; readout circuit; CMOS