Electroosmotic flow of salt-free power-law fluids through planar slit and cylindrical micro and nanochannels with fluid slip is theoretically analyzed. Analytical solutions are obtained to ...investigate the effects of flow behavior index, channel size, applied electric field strength, Gouy-Chapman length (or surface charge density), and fluid slip length on the velocity distribution and volumetric flow rate. The results show that the electroosmotic flow velocity and thereby the flow rate for shear-thinning fluids are many times larger than those for Newtonian and shear-thickening fluids for the ranges of applied electric field strength and surface charge density usually encountered in practice. Such augmentation can be further amplified by increasing the surface charge density, applied electric field strength and fluid slip. Furthermore, the electroosmotic flow velocity profile of shear-thinning fluids becomes more plug-like as the ratio of channel half-width (or radius) to GouyChapman length increases. However, such a profile for shear-thickening fluids always exhibits a parabolic-like flow pattern regardless of the ratios of channel half-width (or radius) to Gouy-Chapman length.
B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor-T cell (CAR-T) therapy is used for refractory or relapsed multiple myeloma (r/r MM). However, CAR-T-related tumor lysis syndrome ...(TLS) has been observed. We aimed to elucidate the incidence, clinical and laboratory characteristics, and prognosis of CAR-T cell-related TLS.
Patients (n=105) with r/r MM treated with BCMA-targeted CAR-T cell therapy were included. Patient characteristics, laboratory parameters, and clinical outcomes were assessed.
Eighteen (17.1%) patients developed TLS after BCMA-targeted CAR-T cell therapy. The median time till TLS onset was 8 days. Patients with TLS had steep rise in uric acid (UA), creatinine, and lactate dehydrogenase (LDH) within 6 days following CAR-T cell infusion and presented earlier and persistent escalation of cytokines (C-reactive protein CRP, interleukin-6 IL-6, interferon-γ IFN-γ, and ferritin levels). All 18 patients had cytokine release syndrome (CRS), of which 13 (72.2%) developed grade 3-4 CRS. Three of 18 patients (16.7%) developed immune effector cell-associated neurotoxicity syndrome (ICANS): two patients with grade 1 ICANS and one with grade 2 ICANS. TLS development had a negative effect on the objective response rate (77.8% in the TLS group vs. 95.4% in the non-TLS group, p<0.01). During the median follow-up of 15.1 months, the median PFS was poorer of patients with TLS (median: 3.4 months in the TLS group vs. 14.7 months in the non-TLS group, p<0.001, hazard ratio HR=3.5 95% confidence interval CI 1.5-8.5). Also, TLS development exhibited significant effects on OS (median: 5.0 months in the TLS group vs. 39.8 months in the non-TLS group, p<0.001, hazard ratio HR=3.7 95% CI 1.3-10.3). TLS was associated with a higher tumor burden, elevated baseline creatinine and UA levels, severe CRS, pronounced CAR-T cell expansion, and corticosteroid use.
TLS is a frequently observed CAR-T therapy complication and negatively influences clinical response and prognosis. Close monitoring for TLS should be implemented during CAR-T cell therapy, especially for those at high TLS risk.
Aim To determine what disease entities show accentuated grey–white differentiation of the cerebral hemisphere on diffusion-weighted images (DWI) or apparent diffusion coefficient (ADC) maps, and ...whether there is a correlation between the different patterns and the cause of the brain injury. Methods and materials The DWI and ADC maps of 19 patients with global brain injury were reviewed and evaluated to investigate whether there was a correlation between the different patterns seen on the DWI and ADC maps and the cause of global brain injury. The ADC values were measured for quantitative analysis. Results There were three different patterns of ADC decrease: a predominant ADC decrease in only the cerebral cortex ( n = 8; pattern I); an ADC decrease in both the cerebral cortex and white matter (WM) and a predominant decrease in the WM ( n = 9; pattern II); and a predominant ADC decrease in only the WM ( n = 3; pattern III). Conclusion Pattern I is cerebral cortical injury, suggesting cortical laminar necrosis in hypoxic brain injury. Pattern II is cerebral cortical and WM injury, frequently seen in brain death, while pattern 3 is mainly WM injury, especially found in hypoglycaemic brain injury. It is likely that pattern I is decorticate injury and pattern II is decerebrate injury in hypoxic ischaemic encephalopathy.Patterns I and II are found in severe hypoxic brain injury, and pattern II is frequently shown in brain death, whereas pattern III was found in severe hypoglycaemic injury.
Abstract Extravillus trophoblast (EVT) invasion plays a critical role in placental development. Integrins bind to extracellular matrix (ECM) proteins to mediate EVT cell adhesion, migration, and ...invasion. Changes in O -glycans on β1-integrin have been found to regulate cancer cell behavior. We hypothesize that O -glycosyltransferases can regulate EVT invasion through modulating the glycosylation and function of β1-integrin. Here, we found that the GALNT1 and GALNT2 mRNA were highly expressed in HTR8/SVneo and first trimester EVT cells. Immunohistochemstry and immunofluorescence staining showed that GALNT2 was expressed in subpopulations of EVT cells in deciduas, but not in syncytiotrophoblasts and cytotrophoblasts of placental villi. The percentage of GALNT2-positive EVT cells increased with gestational ages. Overexpression of GALNT2 in HTR8/SVneo cells significantly enhanced cell-collagen IV adhesion, but suppressed cell migration and invasion. Notably, we found that GALNT2 increased the expression of Tn antigen (GalNAc-Ser/Thr) on β1-integrin as revealed by Vicia Villosa agglutinin (VVA) binding. Furthermore, GALNT2 suppressed the phosphorylation of focal adhesion kinase (FAK), a crucial downstream signaling molecule of β1-integrin. Our findings suggest that GALNT2 is a critical initiating enzyme of O -glycosylation for regulating EVT invasion.
While obesity increases postoperative complications and cardiovascular risks, its effects on long-term kidney transplant outcomes are less clear.
We used data from the Australian and New Zealand ...Dialysis and Transplant (ANZDATA) Registry to examine the relationships between body mass index (BMI, classified according to World Health Organization criteria) at transplant and transplant outcome. Patients starting renal replacement therapy from April 1991 and who received a single-organ, primary kidney transplant (when aged > or =16 years) from April 1991 to December 2004 were included, and followed up to death or December 2005. Survival outcomes adjusted for important covariates were analyzed using Cox models, and cause-specific failures by competing risks analysis. Analysis using BMI at various times posttransplant was also performed. Intermediate outcomes were delayed graft function (DGF) and any acute rejection at 6 months.
In all, 5684 patients were included. Obese patients had worse graft and patient survival only in univariate analyses, not in multivariate analyses (adjusted hazard ratio HR for graft loss: 1.10 0.94-1.259, P=0.25; for patient death: 1.02 0.83-1.25, P=0.87). Underweight patients had greater late (> or =5 years) death-censored graft loss (adjusted HR: 1.70 1.10-2.64, P=0.02), mainly due to chronic allograft nephropathy. Obesity was associated with greater odds for DGF (adjusted OR: 1.56 1.23-1.97, P<0.001) and 6-month risk of acute rejection (adjusted OR: 1.25 1.01-1.54, P=0.04).
Obesity per se was not associated with poorer kidney transplant outcomes, although it was associated with factors that led to poorer graft and patient survival. Underweight was associated with late graft failure, mainly due to chronic allograft nephropathy.
Sepsis is the leading cause of death in hospitalized patients and beyond the hospital stay and these long-term sequelae are due in part to unresolved inflammation. Metabolic shift from oxidative ...phosphorylation to aerobic glycolysis links metabolism to inflammation and such a shift is commonly observed in sepsis under normoxic conditions. By shifting the metabolic state from aerobic glycolysis to oxidative phosphorylation, we hypothesized it would reverse unresolved inflammation and subsequently improve outcome. We propose a shift from aerobic glycolysis to oxidative phosphorylation as a sepsis therapy by targeting the pathways involved in the conversion of pyruvate into acetyl-CoA via pyruvate dehydrogenase (PDH). Chemical manipulation of PDH using dichloroacetic acid (DCA) will promote oxidative phosphorylation over glycolysis and decrease inflammation. We tested our hypothesis in a Drosophila melanogaster model of surviving sepsis infected with Staphylococcus aureus. Drosophila were divided into 3 groups: unmanipulated, sham and sepsis survivors, all treated with linezolid; each group was either treated or not with DCA for one week following sepsis. We followed lifespan, measured gene expression of Toll, defensin, cecropin A, and drosomycin, and levels of lactate, pyruvate, acetyl-CoA as well as TCA metabolites. In our model, metabolic effects of sepsis are modified by DCA with normalized lactate, TCA metabolites, and was associated with improved lifespan of sepsis survivors, yet had no lifespan effects on unmanipulated and sham flies. While Drosomycin and cecropin A expression increased in sepsis survivors, DCA treatment decreased both and selectively increased defensin.
Gene Ontology annotations and resources Blake, J A; Dolan, M; Drabkin, H ...
Nucleic acids research,
01/2013, Volume:
41, Issue:
Database issue
Journal Article
Peer reviewed
Open access
The Gene Ontology (GO) Consortium (GOC, http://www.geneontology.org) is a community-based bioinformatics resource that classifies gene product function through the use of structured, controlled ...vocabularies. Over the past year, the GOC has implemented several processes to increase the quantity, quality and specificity of GO annotations. First, the number of manual, literature-based annotations has grown at an increasing rate. Second, as a result of a new 'phylogenetic annotation' process, manually reviewed, homology-based annotations are becoming available for a broad range of species. Third, the quality of GO annotations has been improved through a streamlined process for, and automated quality checks of, GO annotations deposited by different annotation groups. Fourth, the consistency and correctness of the ontology itself has increased by using automated reasoning tools. Finally, the GO has been expanded not only to cover new areas of biology through focused interaction with experts, but also to capture greater specificity in all areas of the ontology using tools for adding new combinatorial terms. The GOC works closely with other ontology developers to support integrated use of terminologies. The GOC supports its user community through the use of e-mail lists, social media and web-based resources.
H2 permeation in peroxide-crosslinked EPDM blended with carbon black (CB) and silica fillers was studied at pressures ranging from 1.2 MPa to 90 MPa via the volumetric analysis technique. H2 uptake ...in the CB-filled EPDM revealed dual-sorption behaviors via Henry’s law and the Langmuir model, which were attributed to H2 absorption by the polymer chains and H2 adsorption at the filler interfaces, respectively. Additionally, single-sorption mechanisms were observed for neat EPDM and silica-blended EPDM according to Henry’s law, indicating H2 absorption by the polymer chain. The linear decreases in the diffusivity with filler content for the silica-blended EPDMs were attributed to increases in the diffusion paths caused by the filler. Exponential decreases in the diffusivity with increasing filler content and in the permeation with the physical/mechanical properties for CB-filled EPDMs were caused by decreases in the fractional free volume due to increased densities for the EPDM composites. Moreover, good filler-dependent correlations between permeability and density, hardness, and tensile strength were demonstrated for EPDMs used as sealing materials for O-rings. From the resulting equation, we predicted the permeation value without further measurements. Thus, we can select EPDM candidates satisfying the permeation guidelines used in hydrogen infrastructure for the future hydrogen economy.
Summary
Time‐lapse confocal fluorescence microscopy images from mouse embryonic stem cells (ESCs) carrying reporter genes, histone H2B‐mCherry and Mvh‐Venus, have been used to monitor dynamic changes ...in cellular/differentiation characteristics of live ESCs. Accurate cell nucleus segmentation is required to analyse the ESC dynamics and differentiation at a single cell resolution. Several methods used concavities on nucleus contours to segment overlapping cell nuclei. Our proposed method evaluates not only the concavities but also the size and shape of every 2D nucleus region to determine if any of the strait, extrusion, convexity and large diameter criteria is satisfied to segment overlapping nuclei inside the region. We then use a 3D segmentation method to reconstruct simple, convex, and reasonably sized 3D nuclei along the image stacking direction using the radius and centre of every segmented region in respective microscopy images. To avoid false concavities on nucleus boundaries, fluorescence images of the H2B‐mCherry reporter are used for localisation of cell nuclei and Venus fluorescence images are used for determining the cell colony ranges. We use a series of image preprocessing procedures to remove noise outside and inside cell colonies, and in respective nuclei, and to smooth nucleus boundaries based on the colony ranges. We propose dynamic data structures to record every segmented nucleus region and solid in sets (volumes) of 3D confocal images. The experimental results show that the proposed image preprocessing method preserves the areas of mouse ESC nuclei on microscopy images and that the segmentation method effectively segment out every nucleus with a reasonable size and shape. All 3D nuclei in a set (volume) of confocal microscopy images can be accessed by the dynamic data structures for 3D reconstruction. The 3D nuclei in time‐lapse confocal microscopy images can be tracked to calculate cell movement and proliferation in consecutive volumes for understanding the dynamics of the differentiation characteristics about ESCs.
Lay Description
Embryonic stem cells (ESCs) are considered as an ideal source for basic cell biology study and producing medically useful cells in vitro. This study uses time‐lapse confocal fluorescence microscopy images from mouse ESCs carrying reporter gene to monitor dynamic changes in cellular/differentiation characteristics of live ESCs. To automate analyses of ESC differentiation behaviours, accurate cell nucleus segmentation to distinguish respective cells are required. A series of image preprocessing procedures are implemented to remove noise in live‐cell fluorescence images but yield overlapping cell nuclei. A segmentation method that evaluates boundary concavities and the size and shape of every nucleus is then used to determine if any of the strait, extrusion, convexity, large and local minimum diameter criteria satisfied to segment overlapping nuclei. We propose a dynamic data structure to record every newly segmented nucleus. The experimental results show that the proposed image preprocessing method preserves the areas of mouse ESC nuclei and that the segmentation method effectively detects overlapping nuclei. All segmented nuclei in confocal images can be accessed using the dynamic data structures to be visualised and manipulated for quantitative analyses of the ESC differentiation behaviours. The manipulation can be tracking of segmented 3D cell nuclei in time‐lapse images to calculate their dynamics of differentiation characteristics.
Background and Objective
Mechanical stretching modulates extracellular matrix (ECM) protein synthesis by periodontal ligament (PDL) cells. However, the mechanoregulation of lysyl oxidase (LOX), a key ...enzyme for collagen cross‐linking, is not fully understood. In the present study, we hypothesized that low‐level and high‐level mechanical stretching differentially regulates collagen deposition and the expression of LOX and the enzymes responsible for ECM degradation, such as MMP‐2 in PDL cells.
Material and Methods
Human PDL cells were cultured on flexible‐bottom culture plates and subjected to cyclic mechanical stretching (3% and 10% elongation at 0.1 Hz) for 24 and 48 h in a Flexercell FX‐4000 strain unit. The levels of expression of type I collagen alpha 1 (COL1A1), type III collagen alpha 1 (COL3A1), lysyl oxidase (LOX), MMP2 and TIMP2 mRNAs were analyzed using an RT‐PCR technique. The cell layer and the culture medium were separately collected and processed for detection of the following ECM‐related molecules: (i) total collagen content using a Sircol dye‐binding method; (ii) LOX protein expression by western blotting; (iii) LOX activity using a fluorometric assay; and (iv) MMP‐2 enzyme activity by gelatin zymography.
Results
Low‐level (3%) mechanical stretching of PDL cells upregulated the expression of COL1A1, COL3A1 and LOX mRNAs, enhanced the production of collagen and increased the LOX activity but did not change the level of expression of MMP2 or TIMP2 mRNA. The collagen content and LOX activity showed obvious elevation in the medium, but not in the cell layer. High‐level (10%) mechanical stretching downregulated COL1A1 mRNA but upregulated COL3A1 mRNA; however, the effect on COL3A1 was smaller, and occurred earlier, compared with the effect on the COL1A1 gene. High‐level mechanical stretching upregulated the expression of MMP2 and TIMP2 mRNAs but did not change collagen production or LOX activity. Moreover, high‐level mechanical stretching increased the level of pro‐MMP‐2, especially in the cell layer.
Conclusions
This study substantiates the mechanoregulation of the expression of ECM‐related molecules in PDL cells. High‐level mechanical stretching upregulated the expression of MMP2 and TIMP2 mRNAs, but did not affect collagen production or LOX activity. In addition to increasing the transcription of COL1A1, COL3A1 and LOX genes, low‐level mechanical stretching enhanced total collagen production and LOX activity, which should favor ECM stabilization. As an effective regulator of ECM remodeling, mechanical stretching can be exploited in periodontal regeneration and ligament tissue engineering via application of appropriate mechanical stimulation.
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