219 research outputs found
Novel functions of Tribbles 1 in macrophages
Tribbles (Trib) protein was first described in Drosophila as a regulator of
proliferation, later being implicated as a G2/M modulator. In mammalian systems,
three Trib gene family members have been identified, which share a conserved motif
similar to the catalytic domain of serine/threonine kinases. However, they lack
several conserved residues in the ATP-binding pocket and the core motif of the
catalytic domain necessary for catalytic function. Tribbles 1 (Trib1) is involved in
inflammation through its ability to regulate MAPK, NF-ÎşB and the CCAAT
Enhancer Binding Protein (C/EBP). Moreover, Trib1 is associated with human
disease, such as atherosclerosis and acute myeloid leukaemia. In this thesis, I
investigated the functional role of Trib1 in Toll-like Receptor (TLR)-induced
inflammatory responses together with pro- or anti-inflammatory cytokines. The
RAW264.7 myeloid cell line was stimulated with TLR2/9 ligands in the presence or
absence of IFN-Îł or IL-10. I observed a high level of Trib1 expression in the
presence of IFN-Îł and TLR2 ligands, but weak Trib1 expression following treatment
with IL-10 and TLR9 ligands. In gene knock-down experiments using small
interfering RNAs (siRNA) to reduce Trib1 expression, C/EBPβ was up-regulated in
both stimulated (by IFN-Îł and TLR2 ligands) and resting macrophage populations.
TNF-Îą production was increased following Trib1 knockdown after treatment with
IFN-Îł and/or TLR2 ligands but IL-6 secretion remained unchanged. Furthermore,
ERK1/2 expression was reduced in Trib1 siRNA-treated cells and failed to induce
chemokinesis in macrophages. Finally, Trib1 was demonstrated to act as a modulator
of cell cycle (G2/M) transition and displays a delayed apoptotic phenotype. The work in this thesis demonstrates that mammalian Trib1 contributes to the
pro-inflammatory response and functions as a regulator of the ERK1/2 and C/EBPβ
pathways following TLR ligand-mediated activation. Its novel functions include
acting as a modulator of G2/M arrest and suppressing macrophage migration
Transmission Electron Microscopy Data on drusen-like deposits in the retinal degeneration sTg-IRBP : HEL mouse model
We are grateful to the Microscopy and Histology Core Facility of the University of Aberdeen for their assistance with sample processing. This work was generously funded by the charity Saving Sight in Grampian of the University of Aberdeen Development Trust.Peer reviewedPublisher PD
Direct Determination of ECD in ECD Kit: A Solid Sample Quantitation Method for Active Pharmaceutical Ingredient in Drug Product
Technetium-99m ethyl
cysteinate dimer (Tc-99m-ECD) is an essential
imaging agent used in evaluating the regional
cerebral blood flow in patients with
cerebrovascular diseases. Determination of
active pharmaceutical ingredient, that is,
L-Cysteine, N, Nâ˛-1,2-ethanediylbis-, diethyl ester, dihydrochloride (ECD) in ECD Kit is a relevant requirement for the pharmaceutical
quality control in processes of mass fabrication. We here
presented a direct solid sample determination method of ECD in ECD
Kit without sample dissolution to avoid the rapid degradation of
ECD. An elemental analyzer equipped with a nondispersive infrared
detector and a calibration curve of coal standard was used for the
quantitation of sulfur in ECD Kit. No significant matrix effect
was found. The peak area of coal standard against the amount of
sulfur was linear over the range of 0.03â0.10âmg,
with a correlation coefficient (r) of 0.9993. Method validation
parameters were achieved to demonstrate the potential of this
method
Using nomogram of the Barcelona Clinic Liver Cancer system for treatment selection in patients with stage C hepatocellular carcinoma
Abstract
Background
The nomogram of the Barcelona Clinic Liver Cancer (BCLC) for hepatocellular carcinoma (HCC) has been used for outcome prediction. Patients with BCLC stage C HCC often undergo anti-cancer therapy against current treatment guidelines in real world practice. We aimed to use the nomogram to provide guidance on treatment selection for BCLC stage C patients.
Methods
A total of 1317 patients with stage C HCC were retrospectively analyzed and divided into four groups by nomogram points. One-to-one matched pairs between patients receiving different treatments were generated by the propensity score with matching model within these groups. Survival analysis was performed by Kaplan-Meier method with log-rank test.
Results
Patients with higher nomogram points were more often treated with targeted or supportive therapies (pââ15, there was no significant difference in survival between patients receiving two different treatment strategies.
Conclusions
The nomogram of BCLC system is a feasible tool to help stage C HCC patients to select primary anti-cancer treatment in pursuance of better overall survival.https://deepblue.lib.umich.edu/bitstream/2027.42/142787/1/12885_2018_Article_4202.pd
Treatment with FoxP3+ Antigen-Experienced T Regulatory Cells Arrests Progressive Retinal Damage in a Spontaneous Model of Uveitis
FUNDING: This work was funded by Fight for Sight, The Eye Charity (CSO project grant award: 3031-3032), and The Development Trust of the University of Aberdeen (Saving Sight in Grampian) (Grant codes: RG-12663 and RG-14251). ACKNOWLEDGMENTS: We thank the Iain Fraser Flow Cytometry core facility, and the Microscopy and Histology core facility of the University of Aberdeen.Peer reviewedPublisher PD
The B73 Maize Genome: Complexity, Diversity, and Dynamics
We report an improved draft nucleotide sequence of the 2.3-gigabase genome of maize, an important crop plant and model for biological research. Over 32,000 genes were predicted, of which 99.8% were placed on reference chromosomes. Nearly 85% of the genome is composed of hundreds of families of transposable elements, dispersed nonuniformly across the genome. These were responsible for the capture and amplification of numerous gene fragments and affect the composition, sizes, and positions of centromeres. We also report on the correlation of methylation-poor regions with Mu transposon insertions and recombination, and copy number variants with insertions and/or deletions, as well as how uneven gene losses between duplicated regions were involved in returning an ancient allotetraploid to a genetically diploid state. These analyses inform and set the stage for further investigations to improve our understanding of the domestication and agricultural improvements of maize
Albuminâ bilirubin gradeâ based nomogram of the BCLC system for personalized prognostic prediction in hepatocellular carcinoma
Background & AimsThe prognostic accuracy of individual hepatocellular carcinoma (HCC) patient in each Barcelona Clinic Liver Cancer (BCLC) stage is unclear. We aimed to develop and validate an albuminâ bilirubin (ALBI) gradeâ based nomogram of BCLC to estimate survival for individual HCC patient.MethodsBetween 2002 and 2016, 3690 patients with newly diagnosed HCC were prospectively enrolled and retrospectively analysed. Patients were randomly split into derivation and validation cohort by 1:1 ratio. Multivariate Cox proportional hazards model was used to generate the nomogram from tumour burden, ALBI grade and performance status (PS). The concordance index and calibration plot were determined to evaluate the performance of this nomogram.ResultsBeta coefficients from the Cox model were used to assign nomogram points to different degrees of tumour burden, ALBI grade and PS. The scores of the nomogram ranged from 0 to 24, and were used to predict 3â and 5â year patient survival. The concordance index of this nomogram was 0.77 (95% confidence interval [CI]: 0.71â 0.81) in the derivation cohort and 0.76 (95% CI: 0.71â 0.81) in the validation cohort. The calibration plots to predict both 3â and 5â year survival rate well matched with the 45â degree ideal line for both cohorts, except for ALBIâ based BCLC stage 0 in the validation cohort.ConclusionsThe proposed ALBIâ based nomogram of BCLC system is a simple and feasible strategy in the precision medicine era. Our data indicate it is a straightforward and userâ friendly prognostic tool to estimate the survival of individual HCC patient except for very early stage patients.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/153250/1/liv14249_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/153250/2/liv14249.pd
A Post-hoc Study of D-Amino Acid Oxidase in Blood as an Indicator of Post-stroke Dementia
Stroke is an important risk factor for dementia. Epidemiological studies have indicated a high incidence of dementia in stroke patients. There is currently no effective biomarker for the diagnosis of post-stroke dementia (PSD). D-amino acid oxidase (DAO) is a flavin-dependent enzyme widely distributed in the central nervous system. DAO oxidizes D-amino acids, a process which generates neurotoxic hydrogen peroxide and leads to neurodegeneration. This study aimed to examine post-stroke plasma DAO levels as a biomarker for PSD. In total, 53 patients with PSD, 20 post-stroke patients without dementia (PSNoD), and 71 age- and gender-matched normal controls were recruited. Cognitive function was evaluated at more than 30 days post-stroke. Plasma DAO was measured using the enzyme-linked immunosorbent assay. White matter hyperintensity (WMH), a neuroimaging biomarker of cerebral small vessel diseases, was determined by magnetic resonance imaging. We found that plasma DAO levels were independently higher in PSD subjects than in PSNoD subjects or the controls and were correlated with the WMH load in stroke patients. Using an area under the curve (AUC)/receiver operating characteristic analysis, plasma DAO levels were significantly reliable for the diagnosis of PSD. The sensitivity and specificity of the optimal cut-off value of 321 ng/ml of plasma DAO for the diagnosis of PSD were 75 and 88.7%, respectively. In conclusion, our data support that plasma DAO levels were increased in PSD patients and correlated with brain WMH, independent of age, gender, hypertension, and renal function. Plasma DAO levels may therefore aid in PSD diagnosis
Patient-derived iPSCs link elevated mitochondrial respiratory complex I function to osteosarcoma in Rothmund-Thomson syndrome
Rothmund-Thomson syndrome (RTS) is an autosomal recessive genetic disorder characterized by poikiloderma, small stature, skeletal anomalies, sparse brows/lashes, cataracts, and predisposition to cancer. Type 2 RTS patients with biallelic RECQL4 pathogenic variants have multiple skeletal anomalies and a significantly increased incidence of osteosarcoma. Here, we generated RTS patient-derived induced pluripotent stem cells (iPSCs) to dissect the pathological signaling leading to RTS patient-associated osteosarcoma. RTS iPSC-derived osteoblasts showed defective osteogenic differentiation and gain of in vitro tumorigenic ability. Transcriptome analysis of RTS osteoblasts validated decreased bone morphogenesis while revealing aberrantly upregulated mitochondrial respiratory complex I gene expression. RTS osteoblast metabolic assays demonstrated elevated mitochondrial respiratory complex I function, increased oxidative phosphorylation (OXPHOS), and increased ATP production. Inhibition of mitochondrial respiratory complex I activity by IACS-010759 selectively suppressed cellular respiration and cell proliferation of RTS osteoblasts. Furthermore, systems analysis of IACS-010759-induced changes in RTS osteoblasts revealed that chemical inhibition of mitochondrial respiratory complex I impaired cell proliferation, induced senescence, and decreased MAPK signaling and cell cycle associated genes, but increased H19 and ribosomal protein genes. In summary, our study suggests that mitochondrial respiratory complex I is a potential therapeutic target for RTS-associated osteosarcoma and provides future insights for clinical treatment strategies
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