Reciprocal t(9;22) ABL/BCR fusion proteins: leukemogenic potential and effects on B cell commitment

Background: t(9;22) is a balanced translocation, and the chromosome 22 breakpoints (Philadelphia chromosome – Ph+) determine formation of different fusion genes that are associated with either Ph+ acute lymphatic leukemia (Ph+ ALL) or chronic myeloid leukemia (CML). The "minor" breakpoint in Ph+ ALL encodes p185BCR/ABL from der22 and p96ABL/BCR from der9. The "major" breakpoint in CML encodes p210BCR/ABL and p40ABL/BCR. Herein, we investigated the leukemogenic potential of the der9-associated p96ABL/BCR and p40ABL/BCR fusion proteins and their roles in the lineage commitment of hematopoietic stem cells in comparison to BCR/ABL. Methodology: All t(9;22) derived proteins were retrovirally expressed in murine hematopoietic stem cells (SL cells) and human umbilical cord blood cells (UCBC). Stem cell potential was determined by replating efficiency, colony forming - spleen and competitive repopulating assays. The leukemic potential of the ABL/BCR fusion proteins was assessed by in a transduction/transplantation model. Effects on the lineage commitment and differentiation were investigated by culturing the cells under conditions driving either myeloid or lymphoid commitment. Expression of key factors of the B-cell differentiation and components of the preB-cell receptor were determined by qRT-PCR. Principal Findings: Both p96ABL/BCR and p40ABL/BCR increased proliferation of early progenitors and the short term stem cell capacity of SL-cells and exhibited own leukemogenic potential. Interestingly, BCR/ABL gave origin exclusively to a myeloid phenotype independently from the culture conditions whereas p96ABL/BCR and to a minor extent p40ABL/BCR forced the B-cell commitment of SL-cells and UCBC. Conclusions/Significance: Our here presented data establish the reciprocal ABL/BCR fusion proteins as second oncogenes encoded by the t(9;22) in addition to BCR/ABL and suggest that ABL/BCR contribute to the determination of the leukemic phenotype through their influence on the lineage commitment

Sulfur metabolism in <i>Allium cepa</i> is hardly affected by chloride and sulfate salinity

Salinity as a major agricultural problem can affect crop growth and quality. Onion (Allium cepa L.) plant contains a wide variety of sulfur-containing compounds which may be involved in plant protection against salt stress. In the current study, a similar reduction in growth caused by chloride and sulfate salts was observed when onion was exposed to equimolar concentrations of Na+. Also, no difference was observed for shoot/root ratio and dry matter content of roots and shoots. Plants accumulated Na+ and the respective anions (chloride and sulfate) which in turn caused changes in the content of other nutrients. The content of potassium and calcium was decreased more than the other elements by both sodium salts. Sulfate salinity resulted in substantial increase in total sulfur and sulfate content but chloride salinity affected neither the total sulfur nor sulfate content of the roots and shoots, only in onion exposed to 200 mM chloride salt, those of roots and shoots were reduced. Furthermore, the water-soluble non-protein thiol content as well as the content of alliin remained rather unaffected. In conclusion, either salts affected the uptake and distribution of sulfate in onion, but had no or only a minor effect on the plant sulfur metabolism

TarO : a target optimisation system for structural biology

This work was funded by the UK Biotechnology and Biological Sciences Research Council (BBSRC) Structural Proteomics of Rational Targets (SPoRT) initiative, (Grant BBS/B/14434). Funding to pay the Open Access publication charges for this article was provided by BBSRC.TarO (http://www.compbio.dundee.ac.uk/taro) offers a single point of reference for key bioinformatics analyses relevant to selecting proteins or domains for study by structural biology techniques. The protein sequence is analysed by 17 algorithms and compared to 8 databases. TarO gathers putative homologues, including orthologues, and then obtains predictions of properties for these sequences including crystallisation propensity, protein disorder and post-translational modifications. Analyses are run on a high-performance computing cluster, the results integrated, stored in a database and accessed through a web-based user interface. Output is in tabulated format and in the form of an annotated multiple sequence alignment (MSA) that may be edited interactively in the program Jalview. TarO also simplifies the gathering of additional annotations via the Distributed Annotation System, both from the MSA in Jalview and through links to Dasty2. Routes to other information gateways are included, for example to relevant pages from UniProt, COG and the Conserved Domains Database. Open access to TarO is available from a guest account with private accounts for academic use available on request. Future development of TarO will include further analysis steps and integration with the Protein Information Management System (PIMS), a sister project in the BBSRC Structural Proteomics of Rational Targets initiative.Publisher PDFPeer reviewe

The Simian Immunodeficiency Virus Targets Central Cell Cycle Functions through Transcriptional Repression In vivo

A massive and selective loss of CD4+ memory T cells occurs during the acute phase of immunodeficiency virus infections. The mechanism of this depletion is poorly understood but constitutes a key event with implications for progression. We assessed gene expression of purified T cells in Rhesus Macaques during acute SIVmac239 infection in order to define mechanisms of pathogenesis. We observe a general transcriptional program of over 1,600 interferon-stimulated genes induced in all T cells by the infection. Furthermore, we identify 113 transcriptional changes that are specific to virally infected cells. A striking downregulation of several key cell cycle regulator genes was observed and shared promotor-region E2F binding sites in downregulated genes suggested a targeted transcriptional control of an E2F regulated cell cycle program. In addition, the upregulation of the gene for the fundamental regulator of RNA polymerase II, TAF7, demonstrates that viral interference with the cell cycle and transcriptional regulation programs may be critical components during the establishment of a pathogenic infection in vivo

Spatial variation in the composition of motile macroinvertebrate assemblages associated with two bed types of the seagrass Posidonia oceanica

The influence of continuous (non-fragmented) and reticulate (fragmented) bed type and plant architecture on the species richness, abundance and assemblage composition of motile macroinvertebrates associated with the seagrass Posidonia oceanica was investigated at 3 different spatial scales (10s of metres [‘small’], 100s of metres [‘medium’] and kilometres [‘large’]). Univariate and multivariate analyses did not identify significant differences in the attributes of macroinverte- brate assemblages between the 2 P. oceanica bed types over the 3 spatial scales considered. On the other hand, significant spatial variation in macroinvertebrate attributes was detected at the large spa- tial scale. Results of univariate regression and multivariate correlation analysis consistently indicated significant relationships between attributes of the macroinvertebrate assemblages and epiphyte bio- mass at the large spatial scale. Although less consistent, significant relationships were also detected between attributes of the macroinvertebrate assemblages, and mean sediment grain size, total organic carbon in sediment and shoot biomass at the large and medium spatial scales. The findings indicate that naturally fragmented and non-fragmented P. oceanica beds have similar habitat charac- teristics for the associated macroinvertebrates and that local factors, which influence seagrass bed architecture and particularly epiphyte load, have greater influence on the seagrass fauna. Data from the present study support the notion that fragmented seagrass beds should receive the same attention as non-fragmented ones with regard to habitat conservation and protection.peer-reviewe

Occurrence and distribution of different bed types of seagrass Posidonia oceanica around the Maltese Islands

The small-scale distribution of Posidonia oceanica bed types were mapped at four locations off the northern coast of the Maltese Islands, using aerial photography supplemented by surveys using SCUBA diving. Results showed a similar pattern of occurrence of the seagrass at all locations surveyed. In shallow waters (2 m – 4 m), P. oceanicaoccurred as patches of variable size on a rocky and/or sandy substratum. In deeper waters (5 m – 10 m), the patches of seagrass were often replaced by reticulate beds consisting of P. oceanicainterspersed with areas of bare sand. Deeper still (11 m – 13 m), a transition from reticulate to continuous beds occurred. Continuous beds extended to depths of around 25 - 30 m and eventually became reticulate or patchy in deeper waters (>25 m). Values of total seagrass percentage cover increased, while the ratio of fragmented:continuous bed cover decreased for the four study locations on moving southwards (Ramla Bay to St Thomas Bay), indicating that P. oceanica habitat was more abundant and less fragmented in the south-eastern parts of the Maltese Islands. However, values calculated using an exposure index did not did indicate a relationship between exposure and the observed decease in fragmentation of seagrass beds on moving northwest to southwest along the north-eastern coast. Data from the four sites surveyed, together with data from other surveys, were used to show the large-scale distribution of P. oceanica beds around the Maltese Islands. The implications of the study findings for the conservation and management of P. oceanica habitat around the Maltese Islands are discussed.peer-reviewe

Interventions for post-stroke fatigue

BACKGROUND: Post-stroke fatigue (PSF) is a common and distressing problem after stroke. The best ways to prevent or treat PSF are uncertain. Several different interventions can be argued to have a rational basis. OBJECTIVES: To determine whether, among people with stroke, any intervention reduces the proportion of people with fatigue, fatigue severity, or both; and to determine the effect of intervention on health-related quality of life, disability, dependency and death, and whether such intervention is cost effective. SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register (last searched May 2014), Cochrane Central Register of Controlled Trials (The Cochrane Library, 2014, Issue 4), MEDLINE (1950 to May 2014), EMBASE (1980 to May 2014), CINAHL (1982 to May 2014), AMED (1985 to May 2014), PsycINFO (1967 to May 2014), Digital Dissertations (1861 to May 2014), British Nursing Index (1985 to May 2014), PEDro (searched May 2014) and PsycBITE (searched May 2014). We also searched four ongoing trials registries, scanned reference lists, performed citation tracking of included trials and contacted experts. SELECTION CRITERIA: Two review authors independently scrutinised all titles and abstracts and excluded obviously irrelevant studies. We obtained the full texts for potentially relevant studies and three review authors independently applied the inclusion criteria. We included randomised controlled trials (RCTs) that compared an intervention with a control, or compared different interventions for PSF. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed risk of bias for each included trial. The primary outcomes were severity of fatigue, or proportion of people with fatigue after treatment. We performed separate analyses for trials investigating efficacy in treating PSF, trials investigating efficacy in preventing PSF and trials not primarily investigating efficacy in PSF but which reported fatigue as an outcome. We pooled results from trials that had a control arm. For trials that compared different potentially active interventions without a control arm, we performed analyses for individual trials without pooling.We calculated standardised mean difference (SMD) as the effect size for continuous outcomes and risk ratio (RR) for dichotomous outcomes. We pooled the results using a random-effects model and assessed heterogeneity using the I(2) statistic. We performed separate subgroup analyses for pharmacological and non-pharmacological interventions. We also performed sensitivity analyses to assess the influence of methodological quality. MAIN RESULTS: We retrieved 12,490 citations, obtained full texts for 58 studies and included 12 trials (three from the 2008 search and nine from the 2014 search) with 703 participants. Eight trials primarily investigated the efficacy in treating PSF, of which six trials with seven comparisons provided data suitable for meta-analysis (five pharmacological interventions: fluoxetine, enerion, (-)-OSU6162, citicoline and a combination of Chinese herbs; and two non-pharmacological interventions: a fatigue education programme and a mindfulness-based stress reduction programme). The fatigue severity was lower in the intervention groups than in the control groups (244 participants, pooled SMD -1.07, 95% confidence interval (CI) -1.93 to -0.21), with significant heterogeneity between trials (I(2) = 87%, degrees of freedom (df) = 6, P value &#60; 0.00001). The beneficial effect was not seen in trials that had used adequate allocation concealment (two trials, 89 participants, SMD -0.38, 95% CI -0.80 to 0.04) or trials that had used adequate blinding of outcome assessors (four trials, 198 participants, SMD -1.10, 95% CI -2.31 to 0.11).No trial primarily investigated the efficacy in preventing PSF.Four trials (248 participants) did not primarily investigate the efficacy on fatigue but other symptoms after stroke. None of these interventions showed any benefit on reducing PSF, which included tirilazad mesylate, continuous positive airway pressure for sleep apnoea, antidepressants and a self management programme for recovery from chronic diseases. AUTHORS' CONCLUSIONS: There was insufficient evidence on the efficacy of any intervention to treat or prevent fatigue after stroke. Trials to date have been small and heterogeneous, and some have had a high risk of bias. Some of the interventions described were feasible in people with stroke, but their efficacy should be investigated in RCTs with a more robust study design and adequate sample sizes

High-fidelity single-shot readout for a spin qubit via an enhanced latching mechanism

The readout of semiconductor spin qubits based on spin blockade is fast but suffers from a small charge signal. Previous work suggested large benefits from additional charge mapping processes, however uncertainties remain about the underlying mechanisms and achievable fidelity. In this work, we study the single-shot fidelity and limiting mechanisms for two variations of an enhanced latching readout. We achieve average single-shot readout fidelities > 99.3% and > 99.86% for the conventional and enhanced readout respectively, the latter being the highest to date for spin blockade. The signal amplitude is enhanced to a full one-electron signal while preserving the readout speed. Furthermore, layout constraints are relaxed because the charge sensor signal is no longer dependent on being aligned with the conventional (2, 0) - (1, 1) charge dipole. Silicon donor-quantum-dot qubits are used for this study, for which the dipole insensitivity substantially relaxes donor placement requirements. One of the readout variations also benefits from a parametric lifetime enhancement by replacing the spin-relaxation process with a charge-metastable one. This provides opportunities to further increase the fidelity. The relaxation mechanisms in the different regimes are investigated. This work demonstrates a readout that is fast, has one-electron signal and results in higher fidelity. It further predicts that going beyond 99.9% fidelity in a few microseconds of measurement time is within reach.Comment: Supplementary information is included with the pape

Cd/Pt Precursor Solution for Solar H-2 Production and in situ Photochemical Synthesis of Pt Single-atom Decorated CdS Nanoparticles

Despite extensive efforts to develop high-performance H2 evolution catalysts, this remains a major challenge. Here, we demonstrate the use of Cd/Pt precursor solutions for significant photocatalytic H2 production (154.7 mmol g−1 h−1), removing the need for a pre-synthesized photocatalyst. In addition, we also report simultaneous in situ synthesis of Pt single-atoms anchored CdS nanoparticles (PtSA-CdSIS) during photoirradiation. The highly dispersed in situ incorporation of extensive Pt single atoms on CdSIS enables the enhancement of active sites and suppresses charge recombination, which results in exceptionally high solar-to-hydrogen conversion efficiency of ≈1 % and an apparent quantum yield of over 91 % (365 nm) for H2 production. Our work not only provides a promising strategy for maximising H2 production efficiency but also provides a green process for H2 production and the synthesis of highly photoactive PtSA-CdSIS nanoparticles