Evolution of human BCR-ABL1 lymphoblastic leukaemia-initiating cells

Many tumours are composed of genetically diverse cells; however, little is known about how diversity evolves or the impact that diversity has on functional properties. Here, using xenografting and DNA copy number alteration (CNA) profiling of human BCR-ABL1 lymphoblastic leukaemia, we demonstrate that genetic diversity occurs in functionally defined leukaemia-initiating cells and that many diagnostic patient samples contain multiple genetically distinct leukaemia-initiating cell subclones. Reconstructing the subclonal genetic ancestry of several samples by CNA profiling demonstrated a branching multi-clonal evolution model of leukaemogenesis, rather than linear succession. For some patient samples, the predominant diagnostic clone repopulated xenografts, whereas in others it was outcompeted by minor subclones. Reconstitution with the predominant diagnosis clone was associated with more aggressive growth properties in xenografts, deletion of CDKN2A and CDKN2B, and a trend towards poorer patient outcome. Our findings link clonal diversity with leukaemia-initiating-cell function and underscore the importance of developing therapies that eradicate all intratumoral subclones.     

DESIGNING THE OPTIMUM CONFIGURATIONS OF CIRCULAR AND SPHERICAL PRODUCT SPECIFICATIONS FOR MULTIPLE QUALITY CHARACTERISTICS

1. Introduction The problem of determining an optimal tolerance is equivalent to the problem of determining optimal specification limits, since the term tolerance refers to the distance between its lower and upper specification limits. Functional performance and economic considerations are the two primary factors affecting the design of tolerances. A tighttolerance usually implies high manufacturing cost due to additional manufacturing operations, slow processing rates, additional care on part…     

The E. coli ffh gene is necessary for viability and efficient protein export.

Homologues of the gene encoding the 54K (M(r) 54,000) subunit of the mammalian signal recognition particle have been identified in different organisms. The Escherichia coli homologue, termed ffh (for fifty-four homologue), specifies a protein (Ffh) that shares many properties with its eukaryotic counterpart, including association with mammalian 7S RNA and the ability to bind signal sequences specifically. Ffh also associates with E. coli 4.5S RNA, showing that it can form a ribonucleoprotein complex in prokaryotes. These results are intriguing because extensive genetic and biochemical characterization of E. coli failed to identify a signal recognition particle-like mechanism for protein export. Here we address this issue directly by construction of a strain in which ffh expression is arabinose-dependent. Results of depletion experiments indicate that Ffh is important in protein translocation.     

Immunocytochemical localization in rat brain of a prolactin release-inhibiting sequence of gonadotropin-releasing hormone prohormone

The structure of a precursor protein for gonadotropin-releasing hormone (GnRH) of relative molecular mass 10,000 has recently been deduced from cloned complementary DNA sequences derived from human placental messenger RNA. The 56-amino-acid peptide representing residues 14-69 of this prohormone exhibits potent inhibition of prolactin secretion. To investigate whether the same prohormone is synthesized in mammalian brain and describe the anatomical distribution of the prolactin-inhibiting region of this molecule, we have generated antiserum to a synthetic peptide containing residues 40-53 of the human placental precursor. We report here that a substance recognized by this antibody is present in GnRH-containing neurones of the rat brain and appears to coexist with GnRH in secretory granules of nerve terminals in the median eminence. These results indicate homology between hypothalamic and placental prohormones for GnRH and are consistent with the suggestion elsewhere in this issue that a prolactin-inhibiting factor (PIF) is generated from this prohormone and cosecreted with GnRH by nerve terminals in the median eminence.     

Selected mouse lines,alcohol and behavior

Summary The technique of selective breeding has been employed to develop a number of mouse lines differing in genetic sensitivity to specific effects of ethanol. Genetic animal models for sensitivity to the hypnotic, thermoregulatory, excitatory, and dependence-producing effects of alcohol have been developed. These genetic animal models have been utilized in numerous studies to assess the bases for those genetic differences, and to determine the specific neurochemical and neurophysiological bases for ethanol's actions. Work with these lines has challenged some long-held beliefs about ethanol's mechanisms of action. For example, lines genetically sensitive to one effect of ethanol are not necessarily sensitive to others, which demonstrates that no single set of genes modulates all ethanol effects. LS mice, selected for sensitivity to ethanol anesthesia, are not similarly sensitive to all anesthetic drugs, which demonstrates that all such drugs cannot have a common mechanism of action. On the other hand, WSP mice, genetically susceptible to the development of severe ethanol withdrawal, show a similar predisposition to diazepam and phenobarbital withdrawal, which suggests that there may be a common set of genes underlying drug dependentcies. Studies with these models have also revealed important new directions for future mechanism-oriented research. Several studies implicate brain gamma-aminobutyric acid and dopamine systems as potentially important mediators of susceptibility to alcohol intoxication. The stability of the genetic animal models across laboratories and generations will continue to increase their power as analytic tools.     

Consensus supertrees: The synthesis of rooted trees containing overlapping sets of labeled leaves

Given two dendrograms (rooted tree diagrams) which have some but not all of their base points in common, a supertree is a dendrogram from which each of the original trees can be regarded as samples The distinction is made between inconsistent and consistent sample trees, defined by whether or not the samples provide contradictory information about the supertree An algorithm for obtaining the strict consensus supertree of two consistent sample trees is presented, as are procedures for merging two inconsistent sample trees Some suggestions for future work are made     

Crystal structure and molecular interactions of tropomyosin.

The three-dimensional structure of tropomyosin filaments has been determined by X-ray crystallography. The ends of the molecules were located by reference to the single pair of cysteine residues. Departures from the alpha-helical-coiled coil conformation may occur in localised domains along the molecule as well as at the overlapping ends.