The role of PLK1 in Hepatitis B Virus (HBV) infection of the liver

With 250 million reported chronic infections globally, Hepatitis B Virus (HBV) is a major human health issue, linked to increased risk for development of hepatocellular carcinoma (HCC). Current treatments to control chronic HBV infection remain ineffective. New and effective therapies that target the persisting viral molecules are needed in order to clear infection. My research aims to understand the role of hepatitis B virus (HBV) in inducing HCC and identify novel host molecules that are targeted by HBV. Understanding how HBV modifies and manipulates host cellular pathways is critical for the development of mechanism based therapeutics. Here, I provide a review for the HBV core protein (HBc), its function and the host molecules it usurps during infection and pathogenesis. I also identify Polo-like-kinase 1 (PLK1) as a proviral factor in HBV pathogenesis. I demonstrate by loss of function as well as gain of function approaches that PLK1 inhibition suppresses viral replication both in vitro and in vivo. I also show that HBc is a phosphorylation substrate for PLK1 in vitro and I mapped the PLK1 phosphorylation sites to HBc residues S168, S176 and S178. Finally, I used a global proteomics approach to study human HBc interactome identifying potential interacting partners with interesting links to viral pathogenesis. Collectively, my research expands our understanding of the role of HBc in HBV pathogenesis and the ensuing transformation of the liver

Alendronate treatment results in similar levels of trabecular bone remodeling in the femoral neck and vertebra

Introduction Bone turnover suppression in sites that already have a low surface-based remodeling rate may lead to oversuppression that could have negative effects on the biomechanical properties of bone. The goal was to determine how alendronate suppresses bone turnover at sites with different surface-based remodeling rates. Methods Dynamic histomorphometric parameters were assessed in trabecular bone of the femoral neck and lumbar vertebrae obtained from skeletally mature beagles treated with saline (1 ml/kg/day) or alendronate (ALN 0.2 or 1.0 mg/kg/day). The ALN0.2 and ALN1.0 doses approximate, on a milligram per kilogram basis, the clinical doses used for the treatment of postmenopausal osteoporosis and Paget’s disease, respectively. Results Alendronate treatment resulted in similar absolute levels of bone turnover in the femoral neck and vertebrae, although the femoral neck had 33% lower pre-treatment surface-based remodeling rate than the vertebra (p < 0.05). Additionally, the high dose of alendronate (ALN 1.0) suppressed bone turnover to similar absolute levels as the low dose of alendronate (ALN 0.2) in both sites. Conclusions Alendronate treatment may result in a lower limit of trabecular bone turnover suppression, suggesting that sites of low pre-treatment remodeling rate are not more susceptible to oversuppression than those of high pre-treatment remodeling rate

Pramlintide, the synthetic analogue of amylin: physiology, pathophysiology, and effects on glycemic control, body weight, and selected biomarkers of vascular risk

Pramlintide is a synthetic version of the naturally occurring pancreatic peptide called amylin. Amylin and pramlintide have similar effects on lowering postprandial glucose, lowering postprandial glucagon and delaying gastric emptying. Pramlintide use in type 1 and insulin requiring type 2 diabetes mellitus (DM) is associated with modest reductions in HbA1c often accompanied by weight loss. Limited data show a neutral effect on blood pressure. Small studies suggest small reductions in LDL-cholesterol in type 2 DM and modest reductions in triglycerides in type 1 DM. Markers of oxidation are also reduced in conjunction with reductions in postprandial glucose. Nausea is the most common side effect. These data indicate that pramlintide has a role in glycemic control of both type 1 and type 2 DM. Pramlintide use is associated with favorable effects on weight, lipids and other biomarkers for atherosclerotic disease

Nonlinear estimation of coupling and directionality between signals: Application to uterine EMG propagation.

International audienceUnderstanding the direction and quantity of information flowing in a complex system is a fundamental task in signal processing. Several measures have been proposed to detect the quantity of synchronization and the directionality between time series and in physiological data. In this paper we use two methods that are widely used in synchronization and directionality analysis: Nonlinear correlation coefficient (h(2)) and the general synchronization (H). The performances of both methods were tested on four dimensional coupled synthetic nonlinear Rössler models. They were then applied to a single real labor contraction uterine EMG burst with the aim of using them to detect synchronization and to plot the map of direction of information flow between the whole signal channels. The results on synthetic signal show a slight superiority of H over h(2). The results obtained on a single contraction are encouraging for the future use of these tools for resolving the open question of the directionality of uterine contractions and may provide a way of finding their source loci

Cross-cultural medical education: Using narratives to reflect on experience

Introduction. Educating students in a multi-cultural society is a challenge as teachers, students and the community they serve all tend to representvarious social groups. Skills alone are not adequate for competency in understanding cultural aspects of consultations. A combination of knowledge, skills and attitude is the most widely accepted current approach to teaching culturally competent communication to medical students. Collaborative reflection on narratives of experienced clinicians’ cultural encounters served to construct an understanding of how to develop these attributes.Process. An interest group of medical teachers met to address the specific needs of teaching a relevant cross-cultural curriculum. Participants offerednarratives from their professional life and reflected on these encounters to understand how to improve the current curriculum to better address theneeds of the students and patients they serve.Results. Through narratives, participants were able to reflect on how their experience had allowed them to develop cultural awareness. All storiesrepresented how attitudes of respect, curiosity and unconditional positive regard were held above all else. The process of collaborative reflection withpeers unpacked the complexity and potential in the stories and different learning opportunities were discovered. Learning was personalised becausethe stories were based on real experiences.Conclusion. The use of collaborative reflection on narratives of clinical encounters could facilitate insights about cultural aspects of medical practice. Elements such as curiosity, respect and unconditional positive regard are illustrated in a unique way that allows students to appreciate the real-life aspects of cross-cultural clinical encounters

Effects of 1 to 3 years' treatment with alendronate on mechanical properties of the femoral shaft in a canine model: implications for subtrochanteric femoral fracture risk

Bisphosphonate (BP) treatment used to prevent bone loss in postmenopausal osteoporosis has recently been implicated in an apparent increase in subtrochanteric femoral fractures. Previous work showed that BPs can reduce the energy to fracture of cancellous bone, but limited data exist on material-level mechanical properties of compact bone from the long bones. This study examined intrinsic mechanical properties of the femoral diaphysis of a canine model treated for 1 or 3 years with alendronate at two different doses. Seventy-two dogs were treated orally with 0.2 mg/kg/day alendronate or 1.0 mg/kg/day alendronate; a control group was administered saline. Prismatic beam specimens were tested in four-point bending under displacement control, and the intrinsic mechanical properties were calculated. No significant differences were found among groups in any mechanical property at either 1 or 3 years of treatment. We conclude that the material properties of the femoral diaphysis are not degraded following 1 to 3 years treatment with alendronate, even at high doses. Longer periods of treatment have not been studied using clinical doses of alendronate, but such studies need to be carried out to confirm a lack of effect of alendronate on mechanical properties of cortical bone in the subtrochanteric region of the femur

Work-related airway symptoms, nasal reactivity and health-related quality of life in female hairdressers: a follow-up study during exposure.

OBJECTIVES: Hairdressers often complain of work-related rhinitis (WR). They are infrequently sensitized to persulphates. The cause and mechanism of the symptoms and the effects on their health-related quality of life (HRQoL) remains unclear. The objectives were to follow female hairdressers with WR mainly from bleaching powder regarding nasal reactivity to persulphate and to evaluate symptoms, HRQoL and inflammatory markers in nasal lavage during a working period after vacation and compared with hairdressers without symptoms and pollen allergic women. METHODS: Skin prick tests to persulphate were performed in the hairdressers. Participants kept a diary of symptoms and of work tasks (hairdressers only). They completed HRQoL questionnaires. Eosinophil cationic protein (ECP) in nasal lavage fluid was examined. The symptomatic hairdressers performed nasal challenges with persulphate before and after the exposure. RESULTS: Skin prick tests were negative. Although the nasal reactivity to persulphate did not change a steady increase in nasal symptoms, especially blockage, and in ECP was noticed in the symptomatic hairdressers. The HRQoL deteriorated in the symptomatic hairdressers indicating an effect on their working situation and daily life. The atopics had more, but varying symptoms (itching, sneezing and secretion). CONCLUSIONS: The difference in the clinical picture between the symptomatic hairdressers and the pollen allergic women, the increase in symptoms and ECP in the nasal lavage support the view that a sensitization to hairdresser chemicals by a mechanism not yet understood is operating. The deterioration of the HRQoL in the symptomatic hairdressers indicates a considerable effect on their life

Quasi two-level PWM operation of a nine-arm modular multilevel converter for six-phase medium-voltage motor drives

This paper proposes a hybrid converter for medium-voltage six-phase machine drive systems that mixes the operation of a traditional two-level voltage-source inverter and the modular multilevel converter (MMC) to enable operation over a wide frequency range. Topologically, the proposed converter consists of nine arms resembling two sets of three-phase MMCs with three common arms, yielding a nine-arm MMC with a 25% reduction in the number of employed arms compared to a traditional dual three-phase MMC. The multilevel property of a standard MMC is emulated in the proposed converter, however on a two-level basis, resulting in a stepped two-level output voltage waveform. The proposed converter has a reduced footprint with advantages of small voltage steps, modular structure, and ease of scalability. Further, it is able to drive high-power six-phase machines within low operating frequencies at the rated torque. The operating principle of the converter is elaborated, and its modulation scheme is discussed. The features of the proposed converter are verified through simulations and experimentally

One Year of Alendronate Treatment Lowers Microstructural Stresses Associated with Trabecular Microdamage Initiation

Alendronate, an anti-remodeling agent, is commonly used to treat patients suffering from osteoporosis by increasing bone mineral density. Though fracture risk is lowered, an increase in microdamage accumulation has been documented in patients receiving alendronate, leading to questions about the potentially detrimental effects of remodeling suppression on the local tissue (material) properties. In this study, trabecular bone cores from the distal femur of beagle dogs treated for one year with alendronate, at doses scaled by weight to approximate osteoporotic and Paget's disease treatment doses in humans, were subjected to uniaxial compression to induce microdamage. Tissue level von Mises stresses were computed for alendronate-treated and non-treated controls using finite element analysis and correlated to microdamage morphology. Using a modified version of the Moore and Gibson classification for damage morphology, we determined that the von Mises stress for trabeculae exhibiting severe and linear microcrack patterns was decreased by approximately 25% in samples treated with alendronate compared with non-treated controls (p<0.01), whereas there was no reduction in the von Mises stress state for diffuse microdamage formation. Furthermore, an examination of the architectural and structural characteristics of damaged trabeculae demonstrated that severely damaged trabeculae were thinner, more aligned with the loading axis, and less mineralized than undamaged trabeculae in alendronate-treated samples (p<0.01). Similar relationships with damage morphology were found only with trabecular orientation in vehicle-treated control dogs. These results indicate that changes in bone's architecture and matrix properties associated with one year of alendronate administration reduce trabecular bone's ability to resist the formation of loading-induced severe and linear microcracks, both of which dissipate less energy prior to fracture than does diffuse damage

Design, synthesis, characterization and toxicity studies of Poly (N-Iso-Propylacrylamide-co-Lucifer Yellow) particles for drug delivery applications

A novel fluorescent temperature/pH responsive particle was designed, synthesized, characterised and tested for toxicity. Poly ( N-iso- propylacrylamide -co- 5%-lucifer yellow) (p(NIPAM -co- 5% LY)) was prepared using a surfactant free emulsion polymerisation technique. The particles were negatively charged and were approximately 250 nm at 15°C. When the particles de-swell following an increase in temperature, a particle size around 100 nm is obtained. The toxicity of different concentrations of the new particles (p(NIPAM) -co- 5% LY, as well as the 100% p(NIPAM) and the main monomer NIPAM was tested on two cell lines (Hela and Vero). The toxicity was tested in comparison to a positive control (dextran sugar) and a negative one (poly(ethylenimine)) (PEI). The results show that the two particles show cell viability over 80% (for both cell lines Hela and Vero) up to a concentration of 3 mg/mL while NIPAM monomer showed cell viability over 80% at a concentration equal to or less than 0.3 mg/mL. The fluorescence property of the novel particles make them traceable. Combining this property (tracing) to the ability of the particles to release their content in response to temperature and pH change can be a potential drug delivery system for cancer treatment