BCR-ABL activity and its response to drugs can be determined in CD34+ CML stem cells by CrkL phosphorylation status using flow cytometry.

In chronic myeloid leukaemia, CD34(+) stem/progenitor cells appear resistant to imatinib mesylate (IM) in vitro and in vivo. To investigate the underlying mechanism(s) of IM resistance, it is essential to quantify Bcr-Abl kinase status at the stem cell level. We developed a flow cytometry method to measure CrkL phosphorylation (P-CrkL) in samples with <10(4) cells. The method was first validated in wild-type (K562) and mutant (BAF3) BCR-ABL(+) as well as BCR-ABL(-) (HL60) cell lines. In response to increasing IM concentration, there was a linear reduction in P-CrkL, which was Bcr-Abl specific and correlated with known resistance. The results were comparable to those from Western blotting. The method also proved to be reproducible with small samples of normal and Ph(+) CD34(+) cells and was able to discriminate between Ph(-), sensitive and resistant Ph(+) cells. This assay should now enable investigators to unravel the mechanism(s) of IM resistance in stem cells

Single-hole properties in the tt-JJ and strong-coupling models

We report numerical results for the single-hole properties in the $t$-$J$ model and the strong-coupling approximation to the Hubbard model in two dimensions. Using the hopping basis with over $10^6$ states we discuss (for an infinite system) the bandwidth, the leading Fourier coefficients in the dispersion, the band masses, and the spin-spin correlations near the hole. We compare our results with those obtained by other methods. The band minimum is found to be at ($\pi/2,\pi/2$) for the $t$-$J$ model for $0.1 \leq t/J \leq 10$, and for the strong-coupling model for $1 \leq t/J \leq 10$. The bandwidth in both models is approximately $2J$ at large $t/J$, in rough agreement with loop-expansion results but in disagreement with other results. The strong-coupling bandwidth for t/J\agt6 can be obtained from the $t$-$J$ model by treating the three-site terms in first-order perturbation theory. The dispersion along the magnetic zone face is flat, giving a large parallel/perpendicular band mass ratio.Comment: 1 RevTeX file with epsf directives to include 8 .eps figures 8 figure files encoded using uufile

Self-diffusion in dense granular shear flows

Diffusivity is a key quantity in describing velocity fluctuations in granular materials. These fluctuations are the basis of many thermodynamic and hydrodynamic models which aim to provide a statistical description of granular systems. We present experimental results on diffusivity in dense, granular shear in a 2D Couette geometry. We find that self-diffusivities are proportional to the local shear rate with diffusivities along the mean flow approximately twice as large as those in the perpendicular direction. The magnitude of the diffusivity is D \approx \dot\gamma a^2 where a is the particle radius. However, the gradient in shear rate, coupling to the mean flow, and drag at the moving boundary lead to particle displacements that can appear sub- or super-diffusive. In particular, diffusion appears superdiffusive along the mean flow direction due to Taylor dispersion effects and subdiffusive along the perpendicular direction due to the gradient in shear rate. The anisotropic force network leads to an additional anisotropy in the diffusivity that is a property of dense systems with no obvious analog in rapid flows. Specifically, the diffusivity is supressed along the direction of the strong force network. A simple random walk simulation reproduces the key features of the data, such as the apparent superdiffusive and subdiffusive behavior arising from the mean flow, confirming the underlying diffusive motion. The additional anisotropy is not observed in the simulation since the strong force network is not included. Examples of correlated motion, such as transient vortices, and Levy flights are also observed. Although correlated motion creates velocity fields qualitatively different from Brownian motion and can introduce non-diffusive effects, on average the system appears simply diffusive.Comment: 13 pages, 20 figures (accepted to Phys. Rev. E

Transformations in network governance: the case of migration intermediaries

types: Article"This is an Accepted Manuscript of an article published by Taylor & Francis in Journal of Ethnic and Migration Studies on 3 February 2015 available online: http://wwww.tandfonline.com/10.1080/1369183X.2014.1003803Market liberalisation has fundamentally changed state interventions in the supply of services and supportive infrastructure across a range of public services. While this trend has been relatively well documented, there has been a dearth of research into the changing nature of state interventions in migration and mobility. Indeed the increasing presence of migration intermediaries to service the many and varied needs of migrant workers, particularly skilled migrants, remains significantly under-researched both theoretically and empirically. In providing an analysis of the location, role and changing nature of migration intermediaries, we highlight the implications of commercially-driven governance structures. In particular we suggest that the shift from government to network governance has important implications for skilled migration including: inequities in access to information regarding the process of migration and labour market integration; and, greater dependence on (largely unregulated) private intermediaries. Accordingly, we present empirical examples of migration intermediaries to illustrate their role and the relationship with and implications of their exchange with migrants

Pancreatic β-cell signaling: toward better understanding of diabetes and its treatment

Pancreatic β-cells play a central role in the maintenance glucose homeostasis by secreting insulin, a key hormone that regulates blood glucose levels. Dysfunction of the β-cells and/or a decrease in the β-cell mass are associated closely with the pathogenesis and pathophysiology of diabetes mellitus, a major metabolic disease that is rapidly increasing worldwide. Clarification of the mechanisms of insulin secretion and β-cell fate provides a basis for the understanding of diabetes and its better treatment. In this review, we discuss cell signaling critical for the insulin secretory function based on our recent studies

Scaling properties of the ferromagnetic state in the Hubbard model

A numerical scaling analysis is used to show that Nagaoka's ferromagnetic state in two-dimensional Hubbard model with one hole is supersede by an antiferromagnetic (AF) state with a discontinuous jump in the total spin due to the AF coupling as the Hubbard $U$ is made finite. The same applies to the two-hole system, which has a spiral spin structure. We can show, via the scaling, that the crossover to an AF state is a precursor of a pathological coalescence of states having the minimum spin and Nagaoka's state at $U=\infty$ in the thermodynamic limit.Comment: 10 pages, typeset in LATEX, KA-94-01, 3 figures available upon request at [email protected]

Bi-allelic Variants in the GPI Transamidase Subunit PIGK Cause a Neurodevelopmental Syndrome with Hypotonia, Cerebellar Atrophy, and Epilepsy

Glycosylphosphatidylinositol (GPI)-anchored proteins are critical for embryogenesis, neurogenesis, and cell signaling. Variants in several genes participating in GPI biosynthesis and processing lead to decreased cell surface presence of GPI-anchored proteins (GPI-APs) and cause inherited GPI deficiency disorders (IGDs). In this report, we describe 12 individuals from nine unrelated families with 10 different bi-allelic PIGK variants. PIGK encodes a component of the GPI transamidase complex, which attaches the GPI anchor to proteins. Clinical features found in most individuals include global developmental delay and/or intellectual disability, hypotonia, cerebellar ataxia, cerebellar atrophy, and facial dysmorphisms. The majority of the individuals have epilepsy. Two individuals have slightly decreased levels of serum alkaline phosphatase, while eight do not. Flow cytometric analysis of blood and fibroblasts from affected individuals showed decreased cell surface presence of GPI-APs. The overexpression of wild-type (WT) PIGK in fibroblasts rescued the levels of cell surface GPI-APs. In a knockout cell line, transfection with WT PIGK also rescued the GPI-AP levels, but transfection with the two tested mutant variants did not. Our study not only expands the clinical and known genetic spectrum of IGDs, but it also expands the genetic differential diagnosis for cerebellar atrophy. Given the fact that cerebellar atrophy is seen in other IGDs, flow cytometry for GPI-APs should be considered in the work-ups of individuals presenting this feature

Acute flaccid myelitis:cause, diagnosis, and management

Acute flaccid myelitis (AFM) is a disabling, polio-like illness mainly affecting children. Outbreaks of MM have occurred across multiple global regions since 2012, and the disease appears to be caused by non-polio enterovirus infection, posing a major public health challenge. The clinical presentation of flaccid and often profound muscle weakness (which can invoke respiratory failure and other critical complications) can mimic several other acute neurological illnesses. There is no single sensitive and specific test for MM, and the diagnosis relies on identification of several important clinical, neuroimaging, and cerebrospinal fluid characteristics. Following the acute phase of AFM, patients typically have substantial residual disability and unique long-term rehabilitation needs. In this Review we describe the epidemiology, clinical features, course, and outcomes of AFM to help to guide diagnosis, management, and rehabilitation. Future research directions include further studies evaluating host and pathogen factors, including investigations into genetic, viral, and immunological features of affected patients, host-virus interactions, and investigations of targeted therapeutic approaches to improve the long-term outcomes in this population

A case-control analysis of common variants in GIP with type 2 diabetes and related biochemical parameters in a South Indian population

<p>Abstract</p> <p>Background</p> <p>Glucose-dependent insulinotropic polypeptide (GIP) is one of the incretins, which plays a crucial role in the secretion of insulin upon food stimulus and in the regulation of postprandial glucose level. It also exerts an effect on the synthesis and secretion of lipoprotein lipase, from adipocytes, important for lipid metabolism. The aim of our study was to do a case-control association analysis of common variants in <it>GIP </it>in association with type 2 diabetes and related biochemical parameters.</p> <p>Method</p> <p>A total of 2000 subjects which includes 1000 (584M/416F) cases with type 2 diabetes and 1000 (470M/530F) normoglycemic control subjects belonging to Dravidian ethnicity from South India were recruited to assess the effect of single nucleotide polymorphisms (SNPs) in <it>GIP </it>(rs2291725, rs2291726, rs937301) on type 2 diabetes in a case-control manner. The SNPs were genotyped by using tetra primer amplification refractory mutation system-PCR (ARMS PCR). For statistical analysis, our study population was divided into sub-groups based on gender (male and female). Association analysis was carried out using chi-squared test and the comparison of biochemical parameters among the three genotypes were performed using analysis of covariance (ANCOVA).</p> <p>Result</p> <p>Initial analysis revealed that, out of the total three SNPs selected for the present study, two SNPs namely rs2291726 and rs937301 were in complete linkage disequilibrium (LD) with each other. Therefore, only two SNPs, rs2291725 and rs2291726, were genotyped for the association studies. No significant difference in the allele frequency and genotype distribution of any of the SNPs in <it>GIP </it>were observed between cases and controls (<it>P </it>> 0.05). Analysis of biochemical parameters among the three genotypes showed a significant association of total cholesterol (<it>P </it>= 0.042) and low density lipoprotein (LDL) with the G allele of the SNP rs2291726 in <it>GIP </it>(<it>P </it>= 0.004), but this was observed only in the case of female subjects. However this association does not remain significant after correction for multiple testing by Bonferroni's inequality method.</p> <p>Conclusion</p> <p>No statistically significant association was observed between any of the SNPs analysed and type 2 diabetes in our population. But the analysis of biochemical parameters indicates that the G allele in rs2291726 may be a putative risk allele for increased LDL cholesterol and further studies in other population needs to be carried out for ascertaining its role in cholesterol metabolism and subsequent cardiovascular risk.</p