Proliferation regulation of haematopoietic stem cells in normal and leukaemic haematopoiesis

The cellular integrity of the blood is maintained by the cellular output of the haematopoietic stem cell population which produces the specialized precursors and differentiated cells which constitute the blood. The investigation of haematopoietic stem cell behaviour and regulation has been hampered by both the difficulty in their identification and the development of relevant assay systems. The purpose of this investigation was to study the behaviour and regulation of the haematopoietic stem cell population in normal and leukaemic haematopoiesis using an in vitro assay of a primitive haematopoietic precursor. The use of a combination of haematopoietic colony-stimulating factors [interleukin 3 (IL3)/multi-CSF and macrophage colony-stimulating factor (M-CSF/CSF-1)] in semi-solid agar culture of murine haematopoietic tissue, stimulated the proliferation of a haematopoietic colony-forming cell, defined as the "HPP-CFCIL3+CSF-1" population, which was characterized by a high proliferative potential, a multipotency and behavioural and regulatory properties consistent with its being a primitive haematopoietic precursor and possibly a component of the haematopoietic stem cell population. The proportion of the in vitro HPP-CFCIL3+csf-1 population in S-phase in normal murine marrow, was determined to be relatively low at approximately 10%, increasing to approximately 40% in sublethally X-irradiated, regenerating murine marrow and the respective presence of the haematopoietic stem cell proliferation inhibitor and stimulator was demonstrable by the induction of appropriate kinetic changes in the in vitro HPP-CFCIL3+CSF-1 population. In leukaemic haematopoiesis, leukaemic proliferation often occurs at the expense of apparently suppressed normal haematopoiesis. In vitro HPP-CFCIL3+CSF-1 assay of the haematopoietic stem cell proliferation regulators in a number of murine, myeloid leukaemic cell lines, failed to demonstrate either increased levels of the haematopoietic stem cell proliferation inhibitor, or evidence of a direct-acting, leukaemia- associated proliferation inhibitor, however, evidence of a leukaemia- associated impairment of inhibitor and stimulator production was observed and this may be a possible mechanism by which the leukaemic population develops a proliferative advantage over normal haematopoietic tissue. The identification of a possible mechanism of leukaemic progression and suppression of normal haematopoiesis may subsequently allow the development of potentially more effective disease treatment and management regimes. The endogenous haemoregulatory tetrapeptide: Acetyl-N-Ser- Asp-Lys-Pro [AcSDKP, Mr=487 amu] is reported to prevent the G0-G1 transition of haematopoietic stem cells into S-phase. The mechanism of action of AcSDKP and a number of related peptides, was investigated in relation to the stem cell proliferation stimulator and inhibitor. AcSDKP demonstrated no direct haemoregulatory role against the in vitro HPP-CFCIL3+CSF-1 population, which is consistent with reports that AcSDKP is not active against cells already in late G1, or S-phase, rather it appeared to act indirectly by impairing the capacity of the haematopoietic stem cell proliferation stimulator to increase the proportion of the in vitro HPP-CFCIL3+CSF-1 population in S-phase. An apparent impairment of stimulator action may explain the reported AcSDKP-associated 'block' of haematopoietic stem cell recruitment. A putative endogenous AcSDKP precursor and synthetic and degradative enzyme systems have been reported and the possible physiopathological role of AcSDKP in a number of myeloproliferative disorders has been implicated. The potential application of AcSDKP as a 'haemoprotective' agent administered prior to the use of S-phase- specific chemotherapy may be of clinical significance. The in vitro HPP-CFCIL3+CSF-1 assay of a primitive haematopoietic precursor cell population, which may be a component of the haematopoietic stem cell population, should play a significant role in the investigation of haematopoietic stem cell behaviour and regulation in both normal and aberrant haematopoiesis. With the characterization of the mechanism(s) of action of the haematopoietic stem cell proliferation inhibitor and stimulator and the haemoregulatory tetrapeptide AcSDKP, the manipulation of the haematopoietic system to clinical advantage can be envisaged, while the identification of the aberrant regulatory mechanism(s) in haematopoietic dysfunction may allow, the development of more effective disease treatment and management regimes

Disentangling intergalcial sea level and global dynamic topography: analysis of Madagascar

Global inventories of stable sea-level markers for the peak of the last interglacial period, Marine Isotopic Stage (MIS) 5e, play a pivotal role in determining sea-level changes and in testing models of glacial isostatic adjustment. Here, we present surveying and radiometric dating results for emergent terraces from northern Madagascar, which is generally regarded as a stable equatorial site. Fossil coral specimens were dated using conventional and open-system corrected uranium series methods. Elevation of the upper (undated) terrace decreases from 33.8 m to 29.5 m over a distance of 35 km. An intermediate terrace has an average radiometric age of ka (i.e. MIS 5e). Its elevation decreases from 9.3 m to 2.8 m over a distance of 80 km. The record of the lowest terrace is fragmentary and consists of beach rock containing rare corals with ages of 1.6–3.8 ka. The spatial gradient of the MIS 5e marker is inconsistent with glacio-isostatic adjustment calculations. Instead, we propose that variable elevations of this marker around Madagascar, and possibly throughout the Indian Ocean, at least partly reflect spatial patterns of dynamic topography generated by sub-plate mantle convection

Hand-held internet tablets for school-based data collection

<p>Abstract</p> <p>Background</p> <p>In the last 20 years, researchers have been using computer self-administered questionnaires to gather data on a wide range of adolescent health related behaviours. More recently, researchers collecting data in schools have started to use smaller hand-held computers for their ease of use and portability. The aim of this study is to describe a new technology with wi-fi enabled hand-held internet tablets and to compare adolescent preferences of laptop computers or hand-held internet tablets in administering a youth health and well-being questionnaire in a school setting.</p> <p>Methods</p> <p>A total of 177 students took part in a pilot study of a national youth health and wellbeing survey. Students were randomly assigned to internet tablets or laptops at the start of the survey and were changed to the alternate mode of administration about half-way through the questionnaire. Students at the end of the questionnaire were asked which of the two modes of administration (1) they preferred, (2) was easier to use, (3) was more private and confidential, and (4) was easier to answer truthfully.</p> <p>Results</p> <p>Many students expressed no preference between laptop computers or internet tablets. However, among the students who expressed a preference between laptop computers or internet tablets, the majority of students found the internet tablets more private and confidential (p < 0.001) and easier to answer questions truthfully (p < 0.001) compared to laptop computers.</p> <p>Conclusion</p> <p>This study demonstrates that using wi-fi enabled hand-held internet tablets is a feasible methodology for school-based surveys especially when asking about sensitive information.</p

Gentle Perturbations of the Free Bose Gas I

It is demonstrated that the thermal structure of the noncritical free Bose Gas is completely described by certain periodic generalized Gaussian stochastic process or equivalently by certain periodic generalized Gaussian random field. Elementary properties of this Gaussian stochastic thermal structure have been established. Gentle perturbations of several types of the free thermal stochastic structure are studied. In particular new models of non-Gaussian thermal structures have been constructed and a new functional integral representation of the corresponding euclidean-time Green functions have been obtained rigorously.Comment: 51 pages, LaTeX fil

A deformation of AdS_5 x S^5

We analyse a one parameter family of supersymmetric solutions of type IIB supergravity that includes AdS_5 x S^5. For small values of the parameter the solutions are causally well-behaved, but beyond a critical value closed timelike curves (CTC's) appear. The solutions are holographically dual to N=4 supersymmetric Yang-Mills theory on a non-conformally flat background with non-vanishing R-currents. We compute the holographic energy-momentum tensor for the spacetime and show that it remains finite even when the CTC's appear. The solutions, as well as the uplift of some recently discovered AdS_5 black hole solutions, are shown to preserve precisely two supersymmetries.Comment: 16 pages, v2: typos corrected and references adde

Quantum spin systems at positive temperature

We develop a novel approach to phase transitions in quantum spin models based on a relation to their classical counterparts. Explicitly, we show that whenever chessboard estimates can be used to prove a phase transition in the classical model, the corresponding quantum model will have a similar phase transition, provided the inverse temperature $\beta$ and the magnitude of the quantum spins \CalS satisfy \beta\ll\sqrt\CalS. From the quantum system we require that it is reflection positive and that it has a meaningful classical limit; the core technical estimate may be described as an extension of the Berezin-Lieb inequalities down to the level of matrix elements. The general theory is applied to prove phase transitions in various quantum spin systems with \CalS\gg1. The most notable examples are the quantum orbital-compass model on $\Z^2$ and the quantum 120-degree model on $\Z^3$ which are shown to exhibit symmetry breaking at low-temperatures despite the infinite degeneracy of their (classical) ground state.Comment: 47 pages, version to appear in CMP (style files included

THE UNIQUENESS THEOREM FOR ROTATING BLACK HOLE SOLUTIONS OF SELF-GRAVITATING HARMONIC MAPPINGS

We consider rotating black hole configurations of self-gravitating maps from spacetime into arbitrary Riemannian manifolds. We first establish the integrability conditions for the Killing fields generating the stationary and the axisymmetric isometry (circularity theorem). Restricting ourselves to mappings with harmonic action, we subsequently prove that the only stationary and axisymmetric, asymptotically flat black hole solution with regular event horizon is the Kerr metric. Together with the uniqueness result for non-rotating configurations and the strong rigidity theorem, this establishes the uniqueness of the Kerr family amongst all stationary black hole solutions of self-gravitating harmonic mappings.Comment: 18 pages, latex, no figure

Regulation of immune responses in primary biliary cholangitis: a transcriptomic analysis of peripheral immune cells

BACKGROUND AIMS: In patients with primary biliary cholangitis (PBC), the serum liver biochemistry measured during treatment with ursodeoxycholic acid-the UDCA response-accurately predicts long-term outcome. Molecular characterization of patients stratified by UDCA response can improve biological understanding of the high-risk disease, thereby helping to identify alternative approaches to disease-modifying therapy. In this study, we sought to characterize the immunobiology of the UDCA response using transcriptional profiling of peripheral blood mononuclear cell subsets. METHODS: We performed bulk RNA-sequencing of monocytes and TH1, TH17, TREG, and B cells isolated from the peripheral blood of 15 PBC patients with adequate UDCA response ("responders"), 16 PBC patients with inadequate UDCA response ("nonresponders"), and 15 matched controls. We used the Weighted Gene Co-expression Network Analysis to identify networks of co-expressed genes ("modules") associated with response status and the most highly connected genes ("hub genes") within them. Finally, we performed a Multi-Omics Factor Analysis of the Weighted Gene Co-expression Network Analysis modules to identify the principal axes of biological variation ("latent factors") across all peripheral blood mononuclear cell subsets. RESULTS: Using the Weighted Gene Co-expression Network Analysis, we identified modules associated with response and/or disease status (q<0.05) in each peripheral blood mononuclear cell subset. Hub genes and functional annotations suggested that monocytes are proinflammatory in nonresponders, but antiinflammatory in responders; TH1 and TH17 cells are activated in all PBC cases but better regulated in responders; and TREG cells are activated-but also kept in check-in responders. Using the Multi-Omics Factor Analysis, we found that antiinflammatory activity in monocytes, regulation of TH1 cells, and activation of TREG cells are interrelated and more prominent in responders. CONCLUSIONS: We provide evidence that adaptive immune responses are better regulated in patients with PBC with adequate UDCA response

Community-Acquired Pneumonia Due to Pandemic A(H1N1)2009 Influenzavirus and Methicillin Resistant Staphylococcus aureus Co-Infection

BACKGROUND: Bacterial pneumonia is a well described complication of influenza. In recent years, community-onset methicillin-resistant Staphylococcus aureus (cMRSA) infection has emerged as a contributor to morbidity and mortality in patients with influenza. Since the emergence and rapid dissemination of pandemic A(H1N1)2009 influenzavirus in April 2009, initial descriptions of the clinical features of patients hospitalized with pneumonia have contained few details of patients with bacterial co-infection. METHODOLOGY/PRINCIPAL FINDINGS: Patients with community-acquired pneumonia (CAP) caused by co-infection with pandemic A(H1N1)2009 influenzavirus and cMRSA were prospectively identified at two tertiary hospitals in one Australian city during July to September 2009, the period of intense influenza activity in our region. Detailed characterization of the cMRSA isolates was performed. 252 patients with pandemic A(H1N1)2009 influenzavirus infection were admitted at the two sites during the period of study. Three cases of CAP due to pandemic A(H1N1)2009/cMRSA co-infection were identified. The clinical features of these patients were typical of those with S. aureus co-infection or sequential infection following influenza. The 3 patients received appropriate empiric therapy for influenza, but inappropriate empiric therapy for cMRSA infection; all 3 survived. In addition, 2 fatal cases of CAP caused by pandemic A(H1N1)2009/cMRSA co-infection were identified on post-mortem examination. The cMRSA infections were caused by three different cMRSA clones, only one of which contained genes for Panton-Valentine Leukocidin (PVL). CONCLUSIONS/SIGNIFICANCE: Clinicians managing patients with pandemic A(H1N1)2009 influenzavirus infection should be alert to the possibility of co-infection or sequential infection with virulent, antimicrobial-resistant bacterial pathogens such as cMRSA. PVL toxin is not necessary for the development of cMRSA pneumonia in the setting of pandemic A( H1N1) 2009 influenzavirus co-infection