Comparing cystatin C and creatinine in the diagnosis of pediatric acute renal allograft dysfunction

Allograft function following renal transplantation is commonly monitored using serum creatinine. Multiple cross-sectional studies have shown that serum cystatin C is superior to creatinine for detection of mild to moderate chronic kidney dysfunction. Recent data in adults indicate that cystatin C might also be a more sensitive marker of acute renal dysfunction. This study aims to compare cystatin C and creatinine for detection of acute allograft dysfunction in children using pediatric RIFLE (risk of renal dysfunction, injury to the kidney, failure or loss of kidney function, end stage renal disease) criteria for acute kidney injury. Retrospective chart review of post-transplant period in 24 patients in whom creatinine and cystatin C were measured every day. Allograft dysfunction was defined as a sustained rise in marker concentration above the mean of the three preceding measurements. In total, there were 13 episodes of allograft dysfunction. Maximum RIFLE stages with creatinine were 'R' in 7, 'I' in 4, and 'F' in 2, with cystatin C 'R' in 6, 'I' in 4 and 'F' in 3, respectively. In 9/13 cases, both markers rose simultaneously, in three, the rise in creatinine preceded cystatin C by 1-5 days (median 4). In one case, the rise in cystatin C preceded creatinine by 1 day. The time lag was not statistically different. The maximum relative rise of creatinine was significantly higher than cystatin C. By multiple linear regression analysis, the maximum rise of cystatin C was related to the maximum rise of creatinine, but independent of patient age, gender, steroid dose, and anthropometric data. In this pediatric population, cystatin C was not superior to creatinine for the detection of acute allograft dysfunctio

Patterning electro-osmotic flow with patterned surface charge

This Letter reports the measurement of electro-osmotic flows (EOF) in microchannels with surface charge patterned on the 200 mu m scale. We have investigated two classes of patterns: (1) Those in which the surface charge varies along a direction perpendicular to the electric field used to drive the EOF; this type of pattern generates multidirectional flow along the direction of the field. (2) Those in which the surface charge pattern varies parallel to the field; this pattern generates recirculating cellular flew, and thus causes motion both parallel and perpendicular to the external field. Measurements of both of these flours agree well with theory in the Limit of thin double layers and low surface potential

Thermal Activation of Valley-Orbit States of Neutral Magnesium in Silicon

Interstitial magnesium acts as a moderately deep double donor in silicon, and is relatively easily introduced by diffusion. Unlike the case of the chalcogen double donors, parameters of the even-parity valley-orbit excited states 1s(T2) and 1s(E) have remained elusive. Here we report on further study of these states in neutral magnesium through temperature dependence absorption measurements. The results demonstrate thermal activation from the ground state 1s(A1) to the valley-orbit states, as observed by transitions from the thermally populated levels to the odd-parity states 2p0 and 2p±. Analysis of the data makes it possible to determine the thermal activation energies of transitions from the donor ground state to 1s(T2) and 1s(E) levels, as well as the binding energies of an electron with the valley-orbit excited states. Keywords: magnesium impurity in silicon, deep center, optical spectroscopy

FeCycle: Attempting an iron biogeochemcial budget from a mesoscale SF 6 tracer experiment in unpertutbed low iron waters

An improved knowledge of iron biogeochemistry is needed to better understand key controls on the functioning of high-nitrate low-chlorophyll (HNLC) oceanic regions. Iron budgets for HNLC waters have been constructed using data from disparate sources ranging from laboratory algal cultures to ocean physics. In summer 2003 we conducted FeCycle, a 10-day mesoscale tracer release in HNLC waters SE of New Zealand, and measured concurrently all sources (with the exception of aerosol deposition) to, sinks of iron from, and rates of iron recycling within, the surface mixed layer. A pelagic iron budget (timescale of days) indicated that oceanic supply terms (lateral advection and vertical diffusion) were relatively small compared to the main sink (downward particulate export). Remote sensing and terrestrial monitoring reveal 13 dust or wildfire events in Australia, prior to and during FeCycle, one of which may have deposited iron at the study location. However, iron deposition rates cannot be derived from such observations, illustrating the difficulties in closing iron budgets without quantification of episodic atmospheric supply. Despite the threefold uncertainties reported for rates of aerosol deposition (Duce et al., 1991), published atmospheric iron supply for the New Zealand region is ∼50-fold (i.e., 7-to 150-fold) greater than the oceanic iron supply measured in our budget, and thus was comparable (i.e., a third to threefold) to our estimates of downward export of particulate iron. During FeCycle, the fluxes due to short term (hours) biological iron uptake and regeneration were indicative of rapid recycling and were tenfold greater than for new iron (i.e. estimated atmospheric and measured oceanic supply), giving an "fe" ratio (uptake of new iron/ uptake of new + regenerated iron) of 0.17 (i.e., a range of 0.06 to 0.51 due to uncertainties on aerosol iron supply), and an "Fe" ratio (biogenic Fe export/uptake of new + regenerated iron) of 0.09 (i.e., 0.03 to 0.24)

TOX Regulates Growth, DNA Repair, and Genomic Instability in T-cell Acute Lymphoblastic Leukemia

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy of thymocytes. Using a transgenic screen in zebrafish, thymocyte selection–associated high mobility group box protein (TOX) was uncovered as a collaborating oncogenic driver that accelerated T-ALL onset by expanding the initiating pool of transformed clones and elevating genomic instability. TOX is highly expressed in a majority of human T-ALL and is required for proliferation and continued xenograft growth in mice. Using a wide array of functional analyses, we uncovered that TOX binds directly to KU70/80 and suppresses recruitment of this complex to DNA breaks to inhibit nonhomologous end joining (NHEJ) repair. Impaired NHEJ is well known to cause genomic instability, including development of T-cell malignancies in KU70- and KU80-deficient mice. Collectively, our work has uncovered important roles for TOX in regulating NHEJ by elevating genomic instability during leukemia initiation and sustaining leukemic cell proliferation following transformation

Recombinant Expression, Purification, and Functional Characterisation of Connective Tissue Growth Factor and Nephroblastoma-Overexpressed Protein

The CCN family of proteins, especially its prominent member, the Connective tissue growth factor (CTGF/CCN2) has been identified as a possible biomarker for the diagnosis of fibrotic diseases. As a downstream mediator of TGF-β1 signalling, it is involved in tissue scarring, stimulates interstitial deposition of extracellular matrix proteins, and promotes proliferation of several cell types. Another member of this family, the Nephroblastoma-Overexpressed protein (NOV/CCN3), has growth-inhibiting properties. First reports further suggest that these two CCN family members act opposite to each other in regulating extracellular matrix protein expression and reciprocally influence their own expression when over-expressed. We have established stable HEK and Flp-In-293 clones as productive sources for recombinant human CCN2/CTGF. In addition, we generated an adenoviral vector for recombinant expression of rat NOV and established protocols to purify large quantities of these CCN proteins. The identity of purified human CCN2/CTGF and rat CCN3/NOV was proven by In-gel digest followed by ESI-TOF/MS mass spectrometry. The biological activity of purified proteins was demonstrated using a Smad3-sensitive reporter gene and BrdU proliferation assay in permanent cell line EA•hy 926 cells. We further demonstrate for the first time that both recombinant CCN proteins are N-glycosylated

Super-enhancer-based identification of a BATF3/IL-2R-module reveals vulnerabilities in anaplastic large cell lymphoma.

Anaplastic large cell lymphoma (ALCL), an aggressive CD30-positive T-cell lymphoma, comprises systemic anaplastic lymphoma kinase (ALK)-positive, and ALK-negative, primary cutaneous and breast implant-associated ALCL. Prognosis of some ALCL subgroups is still unsatisfactory, and already in second line effective treatment options are lacking. To identify genes defining ALCL cell state and dependencies, we here characterize super-enhancer regions by genome-wide H3K27ac ChIP-seq. In addition to known ALCL key regulators, the AP-1-member BATF3 and IL-2 receptor (IL2R)-components are among the top hits. Specific and high-level IL2R expression in ALCL correlates with BATF3 expression. Confirming a regulatory link, IL-2R-expression decreases following BATF3 knockout, and BATF3 is recruited to IL2R regulatory regions. Functionally, IL-2, IL-15 and Neo-2/15, a hyper-stable IL-2/IL-15 mimic, accelerate ALCL growth and activate STAT1, STAT5 and ERK1/2. In line, strong IL-2Rα-expression in ALCL patients is linked to more aggressive clinical presentation. Finally, an IL-2Rα-targeting antibody-drug conjugate efficiently kills ALCL cells in vitro and in vivo. Our results highlight the importance of the BATF3/IL-2R-module for ALCL biology and identify IL-2Rα-targeting as a promising treatment strategy for ALCL