And Then There Was One: How the Ruling Styles of Elizabeth I and Mary, Queen of Scots Affected the Outcomes of Their Reigns

In the mid-1500s, England was reeling from its first experience under the rule of a female queen. Mary Tudor had proved to be a ruthless Catholic, a monarch who took every opportunity to persecute Protestants, yet in all other realms of politics, was ineffective. Near the end of her reign, England was torn by religious strife and suffered from a huge government debt.1 England was not to be alleviated of female rule even after Mary died in 1558, as she named her half-sister Elizabeth to succeed her. Not long after, Mary Stuart, the daughter of a French princess, and the heir-apparent to the Scottish throne ascended to the French throne upon marrying the young Dauphin.2 Now, it seemed, the fate of two key players, England and Scotland, lay in the hands of queens. The fate of these women’s monarchies rested not only on how they presented themselves as formidable rulers, but on the reign of the other, as well. Both brought significant strengths to the table, as well as some detrimental weaknesses. The outcome of their reigns would be determined by whether or not the effectiveness of their ruling styles challenged the very nature of the misogynistic society over which they governed. In the end, only one queen, Elizabeth I, would remain standing, showing that her style of rule clearly outweighed that of Mary’s

Quality of life assessment using patient reported outcome (PRO) measures - still a Cinderella outcome?

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Ring chromosome 18 abnormality in acute myelogenous leukemia: the clinical dilemma

The ring chromosome is a circular, structural abnormality composed of either multiple chromosomes or a single chromosome with loss of genetic material at one or both ends. This chromosomal rearrangement is often unstable with frequent recombinations and may be accompanied by either loss or amplification of genetic material[1]. Considering that ring chromosomes are rare in acute myelogenous leukemia (AML), it is difficult to risk stratify patient prognosis, particularly when the ring chromosome occurs as the sole abnormality. Here we report a case of a ring chromosome 18 abnormality in a patient with newly diagnosed AML with monocytic differentiation. Cytogenetic analysis demonstrated 46, XY, r(18)(p11q21) karyotype in 19 of 34 evaluated metaphase cells. The patient received induction chemotherapy and subsequent allogeneic cord blood transplant from a sex-matched donor, and remained in hematologic and cytogenetic remission for 120 days post transplant. Soon after, he developed post transplant lymphoproliferative disorder and died of multi-organ failure. Although r(18) chromosomal abnormalities were not classified in the recent updated evidence-and expert opinion-based recommendations for the diagnosis and management of AML (likely due to the small number of reported cases), the patient was treated as high risk with stem cell transplantation. This was based on the unstable nature of the ring chromosome and the poor outcomes described in the literature of patients with sole ring 18 abnormalities

Two novel mutant human adenylosuccinate lyases (ASLs) associated with autism and characterization of the equivalent mutant Bacillus subtilis ASL

An Australian patient with autism was found to be heterozygous for two mutations in the gene encoding adenylosuccinate lyase (ASL), resulting in the protein mutations E80D and D87E. The patient's mother carried only the E80D mutation. The equivalent positions are 62 and 69 in Bacillus subtilis ASL. Although both human and B. subtilis enzymes normally have Asp at position 87 (or 69), the B. subtilis ASL has Ile and Asp at 62 and 65, respectively, whereas human ASL has Glu and Arg at the equivalent positions. We have constructed, expressed, and purified the double mutant I62E/D65R as a "humanized" normal B. subtilis enzyme to compare with enzymes with a single mutation at position 62 (I62D/D65R), at position 69 (I62E/D65R/D69E), or at both positions (I62D/D65R/D69E). V-max for conversion of adenylosuccinate to AMP and fumarate is 0.57 mumol/min/mg for I62E/D65R, 0.064 mumol/min/mg for I62D/D65R, 0.27 mumol/min/mg for I62E/D65R/D69E, and 0.069 mumol/min/mg for I62D/D65R/D69E. The K-m for adenylosuccinate is elevated in the X62D mutants, and I62D/D65R is the least stable of these ASLs at 37 degreesC. The CD spectra of mutant and wild type enzymes are similar; thus, there are no appreciable structural changes. Clearly the Asp(62) causes the most drastic effect on ASL function, whereas the Glu(69) mutation produces only modest change. These results emphasize the importance of expanding tests for ASL deficiency to individuals with developmental delay of any severity, including individuals with autistic spectrum disorder. This study further demonstrates the usefulness of the B. subtilis ASL as a model to mimic the defective enzyme in ASL deficiency

GacA is essential for Group A <i>Streptococcus </i>and defines a new class of monomeric dTDP-4-dehydrorhamnose reductases (RmlD)

The sugar nucleotide dTDP-L-rhamnose is critical for the biosynthesis of the Group A Carbohydrate, the molecular signature and virulence determinant of the human pathogen Group A Streptococcus (GAS). The final step of the four-step dTDP-L-rhamnose biosynthesis pathway is catalyzed by dTDP-4-dehydrorhamnose reductases (RmlD). RmlD from the Gram-negative bacterium Salmonella is the only structurally characterized family member and requires metal-dependent homo-dimerization for enzymatic activity. Using a biochemical and structural biology approach, we demonstrate that the only RmlD homologue from GAS, previously renamed GacA, functions in a novel monomeric manner. Sequence analysis of 213 Gram-negative and Gram-positive RmlD homologues predicts that enzymes from all Gram-positive species lack a dimerization motif and function as monomers. The enzymatic function of GacA was confirmed through heterologous expression of gacA in a S. mutans rmlD knockout, which restored attenuated growth and aberrant cell division. Finally, analysis of a saturated mutant GAS library using Tn-sequencing and generation of a conditional-expression mutant identified gacA as an essential gene for GAS. In conclusion, GacA is an essential monomeric enzyme in GAS and representative of monomeric RmlD enzymes in Gram-positive bacteria and a subset of Gram-negative bacteria. These results will help future screens for novel inhibitors of dTDP-L-rhamnose biosynthesis