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Myelodysplastic syndromes (MDS) are heterogeneous groups of blood cancers originating from haematopoietic precursors. They are characterized by deregulated haematopoiesis showing a high propensity to acute myeloid leukaemia (AML) (7). Some [...], Acquired uniparental disomy (aUPD) is a common feature of cancer genomes, leading to loss of heterozygosity. aUPD is associated not only with loss-of-function mutations of tumour suppressor genes (1), but also with gain-of-function mutations of proto-oncogenes (2). Here we show unique gain-of-function mutations of the C-CBL (also known as CBL) tumour suppressor that are tightly associated with aUPD of the 11q arm in myeloid neoplasms showing myeloproliferative features. The C-CBL proto-oncogene, a cellular homologue of v-Cbl, encodes an E3 ubiquitin ligase and negatively regulates signal transduction of tyrosine kinases (3-6). Homozygous C-CBL mutations were found in most I1q-aUPD-positive myeloid malignancies. Although the C-CBL mutations were oncogenic in NIH3T3 cells, c-Cbl was shown to functionally and genetically act as a tumour suppressor. C-CBL mutants did not have E3 ubiquitin ligase activity, but inhibited that of wild-type C-CBL and CBL-B (also known as CUB), leading to prolonged activation of tyrosine kinases after cytokine stimulation. [c-Cbl.sup.-/-] haematopoietic stem/progenitor cells (HSPCs) showed enhanced sensitivity to a variety of cytokines compared to [c-Cbl.sup.+/+] HSPCs, and transduction of C-CBL mutants into [c-Cbl.sup.-/-] HSPCs further augmented their sensitivities to a broader spectrum of cytokines, including stem-cell factor (SCF, also known as KITLG), thrombopoietin (TPO, also known as THPO), 10 and FLT3 ligand (FLT3LG), indicating the presence of a gain-of-function that could not be attributed to a simple lossof-function. The gain-of-function effects of C-CBL mutants on cytokine sensitivity of HSPCs largely disappeared in a [c-Cbl.sup.+/+] background or by co-transduction of wild-type C-CBI, which suggests the pathogenic importance of loss of wild-type C-CBL alleles found in most cases of C-CBL-mutated myeloid neoplasms. Our findings provide a new insight into a role of gain-of-function mutations of a tumour suppressor associated with aUPD in the pathogenesis of some myeloid cancer subsets.

Cortical spreading depression as a trigger of migraine pain Written accounts of migraine are nearly as old as writing itself. Descriptions of headaches, dating to roughly 3000 BCE, have been [...], Migraine is an episodic headache disorder affecting as many as 10% of people worldwide. Familial hemiplegic migraine (FHM) is an autosomal dominant subtype of severe migraine accompanied by visual disturbances known as aura. Migrainous aura is caused by cortical spreading depression (CSD)--a slowly advancing wave of tissue depolarization in the cortex. More than half of FHM cases are caused by mutations in the CACNA1A gene, which encodes a neuronal [Ca.sub.v]2.1 [Ca.sup.2+] channel, resulting in increased [Ca.sup.2+] flow into dendrites and excessive release of the excitatory neurotransmitter glutamate. In this issue of the JCI, Eikermann-Haerter et al. show that transgenic mice with FHM-associated mutations in Cacna1a have increased susceptibility to CSD compared with wild-type animals, likely due to augmentation of excitatory neurotransmission (see the related article beginning on page 99). Additional as-yet-undefined channel mutations may similarly render the migraine brain more susceptible to the initiation of CSD, with implications not only for the genesis of migraine but also for the hypoxic injury that accompanies its worst manifestation, complicated migraine.

Introduction Sudden cardiac death (SCD) as a result of cardiac arrhythmias is responsible for 10% of all deaths in the United States (1). The study of monogenetic SCD syndromes has [...], In human cardiomyopathy, anatomical abnormalities such as hypertrophy and fibrosis contribute to the risk of ventricular arrhythmias and sudden death. Here we have shown that increased myofilament [Ca.sup.2+] sensitivity, also a common feature in both inherited and acquired human cardiomyopathies, created arrhythmia susceptibility in mice, even in the absence of anatomical abnormalities. In mice expressing troponin T mutants that cause hypertrophic cardiomyopathy in humans, the risk of developing ventricular tachycardia was directly proportional to the degree of [Ca.sup.2+] sensitization caused by the troponin T mutation. Arrhythmia susceptibility was reproduced with the [Ca.sup.2+]-sensitizing agent EMD 57033 and prevented by myofilament [Ca.sup.2+] desensitization with blebbistatin. [Ca.sup.2+] sensitization markedly changed the shape of ventricular action potentials, resulting in shorter effective refractory periods, greater beat-to-beat variability of action potential durations, and increased dispersion of ventricular conduction velocities at fast heart rates. Together these effects created an arrhythmogenic substrate. Thus, myofilament [Ca.sup.2+] sensitization represents a heretofore unrecognized arrhythmia mechanism. The protective effect of blebbistatin provides what we believe to be the first direct evidence that reduction of [Ca.sup.2+] sensitivity in myofilaments is antiarrhythmic and might be beneficial to individuals with hypertrophic cardiomyopathy.

Since some oxygen defense mutants of Drosophila melanogaster exhibit a crinkled wing phenotype, a screen was performed on strains bearing mutant alleles conferring a visible wing phenotype to determine whether [...]

Abstract: We have produced the largest population of activation-tagged poplar trees to date, approximately 1800 independent lines, and report on phenotypes of interest that have been identified in tissue culture [...]

Alterations in genes involved in the repair of DNA mutations (mut genes) result in an increased mutation frequency and better adaptability of the bacterium to stressful conditions. W-Beijing genotype strains [...]

Summary Sangre de Drago is a red viscous latex extracted from Croton lechleri (Euphorbiaceae) cortex, renowned in South American popular medicine for its wound-healing properties. The in vitro antiproliferative effects [...]

Aim: Paroxysmal nocturnal haemoglobinuria (PNH) is caused by deficient biosynthesis of the glycosylphosphatidylinositol (GPI) anchor in haemopoietic stem cells. Mutation of the phosphatidylinositol glycan class A (PIG-A) gene, an X [...]

Background: Familial adenomatous polyposis (FAP) is a rare autosomal dominantly inherited disease predisposing to colon cancer and caused by germline mutations in the APC (adenomatous polyposis coil) gene. Aims: We [...]

INTRODUCTION Common, multifactorial diseases such as diabetes, hypertension, asthma, and ischemic heart disease are major global health problems. Identifying etiologic alleles at susceptibility loci is an essential step for a [...]

Generations of scientists were taught that 'the' voltage-gated sodium channel serves as a molecular battery, producing electrical impulses in nerve and muscle cells. However, we now know that mammals, including [...]

Finding a mate can be difficult or even dangerous. Moreover, in many organisms one parent--typically the female--makes a much larger energetic contribution to offspring than the other parent, even though [...]