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MicroRNAs (miRNAs) regulate the expression of multiple proteins in a dose-dependent manner. We hypothesized that increased expression of miRNAs encoded on chromosome 21 (chr 21) contribute to the leukemogenic function of trisomy 21. The levels of chr 21 miRNAs were quantified by qRT–PCR in four types of childhood acute lymphoblastic leukemia (ALL) characterized by either numerical (trisomy or tetrasomy) or structural abnormalities of chr 21. Suprisingly, high expression of the hsa-mir-125b-2 cluster, consisting of three miRNAs, was identified in leukemias with the structural ETV6/RUNX1 abnormality and not in ALLs with trisomy 21. Manipulation of ETV6/RUNX1 expression and chromatin immunoprecipitation studies showed that the high expression of the miRNA cluster is an event independent of the ETV6/RUNX1 fusion protein. Overexpression of hsa-mir-125b-2 conferred a survival advantage to Ba/F3 cells after IL-3 withdrawal or a broad spectrum of apoptotic stimuli through inhibition of caspase 3 activation. Conversely, knockdown of the endogenous miR-125b in the ETV6/RUNX1 leukemia cell line REH increased apoptosis after Doxorubicin and Staurosporine treatments. P53 protein levels were not altered by miR-125b. Together, these results suggest that the expression of hsa-mir-125b-2 in ETV6/RUNX1 ALL provides survival advantage to growth inhibitory signals in a p53-independent manner.

The reciprocal translocation t(12;21)(p13;q22), the most common structural genomic alteration in B-cell precursor acute lymphoblastic leukaemia in children, results in a chimeric transcription factor TEL-AML1 (ETV6-RUNX1). We identified directly and indirectly regulated target genes utilizing an inducible TEL-AML1 system derived from the murine pro B-cell line BA/F3 and a monoclonal antibody directed against TEL-AML1. By integration of promoter binding identified with chromatin immunoprecipitation (ChIP)-on-chip, gene expression and protein output through microarray technology and stable labelling of amino acids in cell culture, we identified 217 directly and 118 indirectly regulated targets of the TEL-AML1 fusion protein. Directly, but not indirectly, regulated promoters were enriched in AML1-binding sites. The majority of promoter regions were specific for the fusion protein and not bound by native AML1 or TEL. Comparison with gene expression profiles from TEL-AML1-positive patients identified 56 concordantly misregulated genes with negative effects on proliferation and cellular transport mechanisms and positive effects on cellular migration, and stress responses including immunological responses. In summary, this work for the first time gives a comprehensive insight into how TEL-AML1 expression may directly and indirectly contribute to alter cells to become prone for leukemic transformation.

The chromosomal translocation t(8;14) is the hallmark of Burkitt's-lymphoma (BL) and fuses the proto-oncogene c-MYC to the IGH locus. We analyzed the genomic structure of MYC/IGH fusions derived from a large series of 78 patients with t(8;14) and asked (i) whether distinct breakpoint clusters exist within the MYC gene and (ii) whether any pairwise association between particular IGH and MYC breakpoints exist. Identification of such associations will help elucidate the etiology of the breaks on the MYC locus. Scan statistic analyses revealed two distinct, but large clusters within c-MYC containing 60/78 (77%) of the breakpoints. Clusters 1 and 2 were 560 and 779 bp in length within a 4555 bp breakpoint cluster region. Breaks within IGH switch mu and joining region did not differ with respect to their corresponding MYC breakpoints. However, there was a highly significant correlation between breakpoints 5' of MYC cluster 1 and fusions to IGH switch gamma region and breakpoints downstream of MYC cluster 2 and fusions to IGH switch alpha region (chi(2)-test: P<0.005). Chromatin changes governing choice of IGH-Fc region recombination may parallel changes in the MYC gene 5' region chromatin leading to some degree of coordinated ontological specificity in breakpoint location.

Large carbonate, bryozoan-serpulid constructions, made by Pentapora fascialis and Salmacina dysteri respectively, were found around karstic freshwater springs, called vruljas, in the Senj Archipelago (Velebit Channel, Croatia). In June 2002, several sites were investigated by SCUBA divers on the rocky cliffs of Grmac and dralova at depths ranging from 19 to 32 m. Mean colony diameter decreased with increasing distance from the vruljas: in the vicinity the mean diameter was 65.8±21 cm, at 2-m distance it was 40.4±8.2. Carbonate contribution was to a great extent due to the bryozoan (5,784±1,186 gm^sup -2^CaCO^sub 3^) rather than to the serpulid (383±218 gm^sup -2^ CaCO^sub 3^). P. fascialis carbonate standing stock was remarkably high if compared with data from literature for shallow carbonate producers. The bryozoan-serpulid constructions can be indicated as important, even if localised, contributions to the carbonate budget in the Adriatic Sea.[PUBLICATION ABSTRACT]

We report a 13-year-old boy with an atypical manifestation of a multilocular paraganglioma. Surgical treatment was not curative despite extirpation of a left-sided abdominal paraganglioma. After surgery, the boy experienced several hypertensive crises. Further investigations including dopamine-positron emission tomography demonstrated bilateral adrenal tumours, a further right-sided paravertebral tumour as well as bilateral cervical glomus tumours. Genetic testing revealed a germline mutation in the succinate dehydrogenase subunit D (SDHD) gene. The final diagnosis was familial pheochromocytoma/paraganglioma type 1 (OMIM 168000). Antihypertensive treatment was succesfull and improved the patient's quality of life.

The chromosomal translocation t(8;14) is the hallmark of Burkitt's-lymphoma (BL) and fuses the proto-oncogene c-MYC to the IGH locus. We analyzed the genomic structure of MYC/IGH fusions derived from a large series of 78 patients with t(8;14) and asked (i) whether distinct breakpoint clusters exist within the MYC gene and (ii) whether any pairwise association between particular IGH and MYC breakpoints exist. Identification of such associations will help elucidate the etiology of the breaks on the MYC locus. Scan statistic analyses revealed two distinct, but large clusters within c - MYC containing 60/78 (77%) of the breakpoints. Clusters 1 and 2 were 560 and 779 bp in length within a 4555 bp breakpoint cluster region. Breaks within IGH switch μ and joining region did not differ with respect to their corresponding MYC breakpoints. However, there was a highly significant correlation between breakpoints 5′ of MYC cluster 1 and fusions to IGH switch γ region and breakpoints downstream of MYC cluster 2 and fusions to IGH switch α region ( χ 2 -test: P <0.005). Chromatin changes governing choice of IGH-Fc region recombination may parallel changes in the MYC gene 5′ region chromatin leading to some degree of coordinated ontological specificity in breakpoint location.

We report on the construction, operation, and performance of the Time-of-Propagation detector with imaging used for the Belle II experiment running at the Super-KEKB \\(e^+e^-\\) collider. This detector is located in the central barrel region and uses Cherenkov light to provide particle identification among hadrons. The Cherenkov light is radiated in highly polished bars of synthetic fused silica (quartz) and transported to the ends of the bars via total internal reflection. One bar end is instrumented with finely segmented micro-channel-plate photomultiplier tubes to record the light, while the other end has a mirror attached to reflect the photons back to the instrumented end. Both the propagation times and hit positions of the Cherenkov photons are measured; these depend on the Cherenkov angle and together provide good discrimination among charged pions, kaons, and protons with momenta up to around 4 GeV/\\(c\\). To date, the detector has been used to record and analyze almost 600 fb\\(^-1\\) of Belle II data.

The Belle II experiment at the SuperKEKB electron-positron collider aims to collect an unprecedented data set of \\(50~{\\rm ab}^{-1}\\) to study \\(CP\\)-violation in the \\(B\\)-meson system and to search for Physics beyond the Standard Model. SuperKEKB is already the world's highest-luminosity collider. In order to collect the planned data set within approximately one decade, the target is to reach a peak luminosity of \\(\\rm 6 \\times 10^{35}~cm^{-2}s^{-1}\\) by further increasing the beam currents and reducing the beam size at the interaction point by squeezing the betatron function down to \\(\\beta^{*}_{\\rm y}=\\rm 0.3~mm\\). To ensure detector longevity and maintain good reconstruction performance, beam backgrounds must remain well controlled. We report on current background rates in Belle II and compare these against simulation. We find that a number of recent refinements have significantly improved the background simulation accuracy. Finally, we estimate the safety margins going forward. We predict that backgrounds should remain high but acceptable until a luminosity of at least \\(\\rm 2.8 \\times 10^{35}~cm^{-2}s^{-1}\\) is reached for \\(\\beta^{*}_{\\rm y}=\\rm 0.6~mm\\). At this point, the most vulnerable Belle II detectors, the Time-of-Propagation (TOP) particle identification system and the Central Drift Chamber (CDC), have predicted background hit rates from single-beam and luminosity backgrounds that add up to approximately half of the maximum acceptable rates.

A sample of 365 fb\\(^{-1}\\) of \\(e^+e^- \\to \\Upsilon(4S) \\to B\\bar{B}\\) data collected by the Belle II experiment is used to measure the partial branching fractions of charmless semileptonic \\(B\\) meson decays and determine the magnitude of the Cabibbo-Kobayashi-Maskawa matrix element \\(V_{ub}\\). Events containing a signal electron or muon \\(\\ell\\) and a fully reconstructed hadronic \\(B\\) decay that constrains the signal kinematics are selected, while the rest of the event defines the hadronic system \\(X_u\\) associated with the signal. To discriminate the signal from the 50-times larger background originating from CKM-favored semileptonic \\(B\\) decays, a template fit is performed in both signal and control regions after applying an optimized selection. The partial branching fraction measured for lepton energies greater than 1 GeV in the signal \\(B\\) meson rest frame is \\(\\Delta\\mathcal{B}(B \\to X_u \\ell \\nu) = (1.54 \\pm 0.08 \\, {\\rm (stat.)} \\pm 0.12 \\, {\\rm (syst.)}) \\times 10^{-3}\\). From this measurement, using the Gambino, Giordano, Ossola, Uraltsev theoretical framework, \\(|V_{ub}| = (4.01 \\pm 0.19 ^{+0.07} _{-0.08}) \\times 10^{-3}\\) is determined, where the uncertainties are experimental and theoretical, respectively. This value is consistent with the world average obtained from previous inclusive measurements. Different theoretical predictions and partial branching fractions measured in other phase-space regions, defined by additional selections on the \\(X_u\\) and leptonic system masses, are also used to determine \\(|V_{ub}|\\).

We report measurements of the ratios of branching fractions \\({\\cal R}(D^{(*)+}) = \\frac{{\\cal B}(\\overline{B}{}^0 \\to D^{(*)+} \\,\\tau^- \\, \\overline{\\nu}_\\tau)}{{\\cal B}(\\overline{B}{}^0 \\to D^{(*)+} \\, \\ell^- \\, \\overline{\\nu}_\\ell)}\\), where \\(\\ell\\) denotes either an electron or a muon. These ratios test the universality of the charged-current weak interaction. The results are based on a \\(365\\, \\mathrm{fb}^{-1}\\) data sample collected with the Belle II detector at the SuperKEKB \\(e^+e^-\\) collider, which operates at a center-of-mass energy corresponding to the \\(\\Upsilon(4S)\\) resonance, just above the threshold for \\(B\\overline{B}{}\\) production. Signal candidates are reconstructed by selecting events in which the companion \\(B\\) meson from the \\(\\Upsilon(4S) \\to B\\overline{B}{}\\) decay is identified in semileptonic modes. The \\(\\tau\\) lepton is reconstructed via its leptonic decays. We obtain \\({\\cal R}(D^+) = 0.418 \\pm 0.074 ~({\\mathrm{stat}}) \\pm 0.051 ~({\\mathrm{syst}})\\) and \\({\\cal R}(D^{*+}) = 0.306 \\pm 0.034 ~({\\mathrm{stat}}) \\pm 0.018 ~({\\mathrm{syst}})\\), which are consistent with world average values. Accounting for the correlation between them, these values differ from the Standard Model expectation by a collective significance of \\(1.7\\) standard deviations.