Mechanisms of segmentation in the American cockroach, periplaneta americana

A fully segmented body and jointed legs are defining characteristics of the Arthropoda (Insecta, Crustacea, Myriapoda, and Chelicerata). The underlying mechanisms involved in achieving these features are not well understood outside of the insect Drosophila melanogaster (fruit fly) – a long germ band organism where segmentation occurs all at once in a syncytial blastoderm. In the more common, ancestral mode of development, short germ band, new segments are added sequentially from the cellular environment of a posteriorly extending growth zone. Segmentation in these organisms may not always be comparable to the “Drosophila paradigm” and, therefore, require further analysis. My thesis will explore the conservation and divergence of the molecular mechanisms of segmentation in a phylogenetically basal, short germ band insect, Periplaneta americana (American cockroach). Presented over three results chapters, I will discuss aspects of cockroach segmentation processes, from the establishment of a posterior organiser and growth zone, to subsequent posterior growth and the formation of new segments. In particular, Chapter III describes how interactions between the Cad/Wnt-dependent posterior organiser and the Notch-segmentation clock control posterior growth and segmentation. Chapter IV encompasses the expression patterns and potential roles for Periplaneta homologues of the pair-rule genes: even-skipped, runt, pairberry, and sloppy-paired throughout embryogenesis, identifying deviations in function between anterior and posterior segmentation processes. New functions for the non-canonical, polycistronic small Open Reading Frame (smORF) gene tarsal-less in body patterning are discussed in Chapter V, along with the conserved roles for tarsal-less, nubbin, Notch, and Delta in leg and development. Elucidation of the networks involved in these processes will help establish putative ancestral gene functions allowing us to gain further insights into the evolution of insect (and arthropod) body segmentation and leg joint formation

Functional analysis of Scr during embryonic and post-embryonic development in the cockroach, Periplaneta americana

AbstractThe cockroach, Periplaneta americana represents a basal insect lineage that undergoes the ancestral hemimetabolous mode of development. Here, we examine the embryonic and post-embryonic functions of the hox gene Scr in Periplaneta as a way of better understanding the roles of this gene in the evolution of insect body plans. During embryogenesis, Scr function is strictly limited to the head with no role in the prothorax. This indicates that the ancestral embryonic function of Scr was likely restricted to the head, and that the posterior expansion of expression in the T1 legs may have preceded any apparent gain of function during evolution. In addition, Scr plays a pivotal role in the formation of the dorsal ridge, a structure that separates the head and thorax in all insects. This is evidenced by the presence of a supernumerary segment that occurs between the labial and T1 segments of RNAiScr first nymphs and is attributed to an alteration in engrailed (en) expression. The fact that similar Scr phenotypes are observed in Tribolium but not in Drosophila or Oncopeltus reveals the presence of lineage-specific variation in the genetic architecture that controls the formation of the dorsal ridge. In direct contrast to the embryonic roles, Scr has no function in the head region during post-embryogenesis in Periplaneta, and instead, strictly acts to provide identity to the T1 segment. Furthermore, the strongest Periplaneta RNAiScr phenotypes develop ectopic wing-like tissue that originates from the posterior region of the prothoracic segment. This finding provides a novel insight into the current debate on the morphological origin of insect wings

The PrPC Cl fragment derived from the ovine A(136)R(154)R(171) PRNP allele is highly abundant in sheep brain and inhibits fibrillisation of full-length PrPC protein in vitro

AbstractExpression of the cellular prion protein (PrPC) is crucial for the development of prion diseases. Resistance to prion diseases can result from reduced availability of the prion protein or from amino acid changes in the prion protein sequence. We propose here that increased production of a natural PrP α-cleavage fragment, C1, is also associated with resistance to disease. We show, in brain tissue, that ARR homozygous sheep, associated with resistance to disease, produced PrPC comprised of 25% more C1 fragment than PrPC from the disease-susceptible ARQ homozygous and highly susceptible VRQ homozygous animals. Only the C1 fragment derived from the ARR allele inhibits in-vitro fibrillisation of other allelic PrPC variants. We propose that the increased α-cleavage of ovine ARR PrPC contributes to a dominant negative effect of this polymorphism on disease susceptibility. Furthermore, the significant reduction in PrPC β-cleavage product C2 in sheep of the ARR/ARR genotype compared to ARQ/ARQ and VRQ/VRQ genotypes, may add to the complexity of genetic determinants of prion disease susceptibility

Prion protein amyloidosis with divergent phenotype associated with two novel nonsense mutations in PRNP

Stop codon mutations in the gene encoding the prion protein (PRNP) are very rare and have thus far only been described in two patients with prion protein cerebral amyloid angiopathy (PrP-CAA). In this report, we describe the clinical, histopathological and pathological prion protein (PrPSc) characteristics of two Dutch patients carrying novel adjacent stop codon mutations in the C-terminal part of PRNP, resulting in either case in hereditary prion protein amyloidoses, but with strikingly different clinicopathological phenotypes. The patient with the shortest disease duration (27 months) carried a Y226X mutation and showed PrP-CAA without any neurofibrillary lesions, whereas the patient with the longest disease duration (72 months) had a Q227X mutation and showed an unusual Gerstmann-Sträussler-Scheinker disease phenotype with numerous cerebral multicentric amyloid plaques and severe neurofibrillary lesions without PrP-CAA. Western blot analysis in the patient with the Q227X mutation demonstrated the presence of a 7 kDa unglycosylated PrPSc fragment truncated at both the N- and C-terminal ends. Our observations expand the spectrum of clinicopathological phenotypes associated with PRNP mutations and show that a single tyrosine residue difference in the PrP C-terminus may significantly affect the site of amyloid deposition and the overall phenotypic expression of the prion disease. Furthermore, it confirms that the absence of the glycosylphosphatidylinositol anchor in PrP predisposes to amyloid plaque formation

Preoperative Aspirin Use and Its Effect on Adverse Events in Patients Undergoing Cardiac Operations

BackgroundPreoperative aspirin use within 5 days of cardiac operations is controversial. Aspirin could reduce cardiovascular complications and yet might increase risk of bleeding. Recent reports showed conflicting results, and whether aspirin has variable effects for different cardiac surgical procedures is unclear.MethodsA single-center retrospective cohort analysis was performed. After propensity score matching (PSM) for identified confounders, the relationship between preoperative aspirin use and 30-day all-cause mortality, postoperative renal failure, major adverse cardiocerebral events (MACE), blood transfusion, reoperation for bleeding, and postoperative infection were estimated with separate logistic regression models.ResultsPreoperative aspirin therapy was associated with a 49% (p = 0.04) increased risk of reoperation for bleeding among 868 matched pairs of patients undergoing valve operations. Among 725 matched patients undergoing coronary artery bypass grafting (CABG), preoperative aspirin therapy was not associated with a statistically significant higher risk of reoperation for bleeding. However, preoperative aspirin use, compared with nonuse, was not associated with risks of MACE, 30-day mortality, postoperative renal failure, blood transfusion, or postoperative infection in the entire cohort, in patients undergoing valve operations only, and in patients undergoing CABG only after PSM.ConclusionsPreoperative aspirin use in all patients undergoing cardiac operations was not associated with risks of major cardiac, cerebral, or renal complications and infections and death; however, the risk of reoperation for bleeding was elevated among preoperative aspirin users compared with nonusers in a subpopulation of patients undergoing valve operations only

From Vulnerable Plaque to Vulnerable Patient

Atherosclerotic cardiovascular disease results in >19 million deaths annually, and coronary heart disease accounts for the majority of this toll. Despite major advances in treatment of coronary heart disease patients, a large number of victims of the disease who are apparently healthy die suddenly without prior symptoms. Available screening and diagnostic methods are insufficient to identify the victims before the event occurs. The recognition of the role of the vulnerable plaque has opened new avenues of opportunity in the field of cardiovascular medicine. This consensus document concludes the following. (1) Rupture-prone plaques are not the only vulnerable plaques. All types of atherosclerotic plaques with high likelihood of thrombotic complications and rapid progression should be considered as vulnerable plaques. We propose a classification for clinical as well as pathological evaluation of vulnerable plaques. (2) Vulnerable plaques are not the only culprit factors for the development of acute coronary syndromes, myocardial infarction, and sudden cardiac death. Vulnerable blood (prone to thrombosis) and vulnerable myocardium (prone to fatal arrhythmia) play an important role in the outcome. Therefore, the term "vulnerable patient" may be more appropriate and is proposed now for the identification of subjects with high likelihood of developing cardiac events in the near future. (3) A quantitative method for cumulative risk assessment of vulnerable patients needs to be developed that may include variables based on plaque, blood, and myocardial vulnerability. In Part I of this consensus document, we cover the new definition of vulnerable plaque and its relationship with vulnerable patients. Part II of this consensus document will focus on vulnerable blood and vulnerable myocardium and provide an outline of overall risk assessment of vulnerable patients. Parts I and II are meant to provide a general consensus and overviews the new field of vulnerable patient. Recently developed assays (eg, C-reactive protein), imaging techniques (eg, CT and MRI), noninvasive electrophysiological tests (for vulnerable myocardium), and emerging catheters (to localize and characterize vulnerable plaque) in combination with future genomic and proteomic techniques will guide us in the search for vulnerable patients. It will also lead to the development and deployment of new therapies and ultimately to reduce the incidence of acute coronary syndromes and sudden cardiac death. We encourage healthcare policy makers to promote translational research for screening and treatment of vulnerable patients

Antibody Responses against Xenotropic Murine Leukemia Virus-Related Virus Envelope in a Murine Model

Xenotropic murine leukemia virus-related virus (XMRV) was recently discovered to be the first human gammaretrovirus that is associated with chronic fatigue syndrome and prostate cancer (PC). Although a mechanism for XMRV carcinogenesis is yet to be established, this virus belongs to the family of gammaretroviruses well known for their ability to induce cancer in the infected hosts. Since its original identification XMRV has been detected in several independent investigations; however, at this time significant controversy remains regarding reports of XMRV detection/prevalence in other cohorts and cell type/tissue distribution. The potential risk of human infection, coupled with the lack of knowledge about the basic biology of XMRV, warrants further research, including investigation of adaptive immune responses. To study immunogenicity in vivo, we vaccinated mice with a combination of recombinant vectors expressing codon-optimized sequences of XMRV gag and env genes and virus-like particles (VLP) that had the size and morphology of live infectious XMRV.Immunization elicited Env-specific binding and neutralizing antibodies (NAb) against XMRV in mice. The peak titers for ELISA-binding antibodies and NAb were 1:1024 and 1:464, respectively; however, high ELISA-binding and NAb titers were not sustained and persisted for less than three weeks after immunizations.Vaccine-induced XMRV Env antibody titers were transiently high, but their duration was short. The relatively rapid diminution in antibody levels may in part explain the differing prevalences reported for XMRV in various prostate cancer and chronic fatigue syndrome cohorts. The low level of immunogenicity observed in the present study may be characteristic of a natural XMRV infection in humans

Expression and function of tarsal-less and segmentation genes in the American cockroach, Periplaneta americana

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certifies that this is the approved version of the following dissertation: Undetected boundary slopes and roots of unity for the character variety of a 3-manifold Committee