Mitochondrial genome of the dimorphic zygomycete Mucor racemosus

Mitochondria were isolated from the dimorphic zygomycete Mucor racemosus by differential centrifugation. DNA from the organelles was purified by cesium chloride-ethidium bromide isopycnic centrifugation. Examination of the mitochondrial DNA by electron microscopy revealed a circular chromosome approximately 63.8 kbp in circumference. The chromosome was digested with restriction endonucleases and the resulting DNA fragments were separated by agarose-gel electrophoresis. Electrophoretic mobilities and stoichiometry of the fragments indicated a mixed population of mtDNA molecules each with a size of about 63.4 kbp. Physical maps were constructed from analyses of fragments generated in single and double restriction digests and from the hybridization of fragments to probes for the large and small mitochondrial rRNA genes from Saccharomyces cerevisiae. The Mucor mitochondrial chromosome was found to exist in the form of two flip-flop isomers with inverted repeat sequences encoding both rRNA genes.     

Missense mutation in a von Willebrand factor type A domain of the alpha 3(VI) collagen gene (COL6A3) in a family with Bethlem myopathy

The Bethlem myopathy is a rare autosomal dominant proximal myopathy characterized by early childhood onset and joint contractures. Evidence for linkage and genetic heterogeneity has been established, with the majority of families linked to 21q22.3 and one large family linked to 2q37, implicating the three type VI collagen subunit genes, COL6A1 (chromosome 21), COL6A2 (chromosome 21) and COL6A3 (chromosome 2) as candidate genes. Mutations of the invariant glycine residues in the triple-helical domain-coding region of COL6A1 and COL6A2 have been reported previously in the chromosome 21-linked families. We report here the identification of a G-->A mutation in the N-terminal globular domain-coding region of COL6A3 in a large American pedigree (19 affected, 12 unaffected), leading to the substitution of glycine by glutamic acid in the N2 motif, which is homologous to the type A domains of the von Willebrand factor. This mutation segregated to all affected family members, to no unaffected family members, and was not identified in 338 unrelated Caucasian control chromosomes. Thus mutations in either the triple-helical domain or the globular domain of type VI collagen appear to cause Bethlem myopathy.      

Outcome of patients with systemic light chain amyloidosis with concurrent renal and cardiac involvement

Cardiac involvement in systemic light chain amyloidosis (AL) is generally associated with a worse outcome, especially if other organs are also involved. We sought to determine whether concurrent cardiac and renal involvement were associated with a worse outcome than either organ alone. We identified 129 patients with AL, who received high‐dose chemotherapy followed by autologous hematopoietic stem cell transplantation (auto‐HCT) at our institution between 1997 and 2014. Ninety‐nine patients had either renal (group 1: n = 62, 62%), cardiac (group 2: n = 20, 20%), or both cardiac and renal (group 3: n = 17, 17%) involvement. The overall hematological response rate (CR+VGPR+PR) post‐auto‐HCT in groups 1, 2, and 3 was 69%, 74% and 82%, respectively (P = 0.62). Overall, organ response in groups 1, 2, and 3 was 39%, 42%, and 70%, respectively. The median PFS from auto‐HCT in groups 1, 2, and 3 was not reached (NR), 13.3 and 21 months, respectively (P = 0.02). The median OS in groups 1, 2, and 3 was 120, 46, and 60 months, respectively (P = 0.1). In conclusion, median PFS and OS in patients with concurrent cardiac and renal AL were comparable to patients with cardiac AL only, but worse than patients with renal AL.     

Radiationless relaxation in "large" molecules: Experimental evidence for preparation of true molecular eigenstates and Born-Oppenheimer states by a coherent light source

Photon absorption and emission by molecules that undergo radiationless transitions are examined using the single modes of lasers having well-defined coherence properties. Contrary to the usual beliefs, where it is assumed that the molecule is prepared in a Born-Oppenheimer singlet state and then “crosses-over” to other states (vibrationally “hot” singlets and/or triplets), it is shown experimentally that the true eigenstates of the molecule can be prepared, even in “large” molecules, if the laser correlation time is relatively long and the molecular relaxation is made slow. On the other hand, lasers with short (psec) correlation time have yielded effectively the singlet Born-Oppenheimer state, which has a much shorter lifetime than the true eigenstates. Effects of magnetic fields and temperature are also reported. The former changes the amount of mixing amongst the Born-Oppenheimer states. The latter, on the other hand, swings the molecule from being “small” (i.e., sparse vibronic structure with long lifetimes) to being “large” (i.e., dense statistical distribution of levels) since the relaxation between levels is very effective at high temperatures. Finally, the results of this work show that the words fluorescence and phosphorescence in their strict meaning are misleading if the true eigenstates, which may contain both singlet and triplet character, are prepared.     

Risk factors and kinetics of thrombocytopenia associated with bortezomib for relapsed, refractory multiple myeloma

Bortezomib, a proteasome inhibitor with efficacy in multiple myeloma, is associated with thrombocytopenia, the cause and kinetics of which are different from those of standard cytotoxic agents. We assessed the frequency, kinetics, and mechanism of thrombocytopenia following treatment with bortezomib 1.3 mg/m2 in 228 patients with relapsed and/or refractory myeloma in 2 phase 2 trials. The mean platelet count decreased by approximately 60% during treatment but recovered rapidly between treatments in a cyclic fashion. Among responders, the pretreatment platelet count increased significantly during subsequent cycles of therapy. The mean percent reduction in platelets was independent of baseline platelet count, M-protein concentration, and marrow plasmacytosis. Plasma thrombopoietin levels inversely correlated with platelet count. Murine studies demonstrated a reduction in peripheral platelet count following a single bortezomib dose without negative effects on megakaryocytic cellularity, ploidy, or morphology. These data suggest that bortezomib-induced thrombocytopenia is due to a reversible effect on megakaryocytic function rather than a direct cytotoxic effect on megakaryocytes or their progenitors. The exact mechanism underlying bortezomib-induced thrombocytopenia remains unknown but it is unlikely to be related to marrow injury or decreased thrombopoietin production.     

des-Ser2 salmon calcitonin: a biologically potent synthetic analog

We studied the biological activity of a synthetic analog of salmon calcitonin (SCT), from which the serine2 residue within the amino-terminal disulfide ring had been omitted (des-Ser2-SCT). This analog proved to be indistinguishable from SCT with respect to hypocalcemic activity in vivo, displacement of [125I]SCT from rat renal membranes, and accumulation of cAMP in incubated renal cortical slices, des-Ser2SCT was twice as potent as SCT with respect to adenylate cyclase activation in renal membranes. Since the deletion did not impair biological activity, it appears that the function of the intact ring structure does not critically depend on its encompassed peptide chain length.