Biosynthesis and transport of terpenes

Terpenoids are the largest class of natural product that are produced by plants, with functions that range from a role in plant development to direct defence against pathogens and indirect defence against insects through the attraction of natural enemies. While terpene biosynthesis genes have been well studied, there is still only limited knowledge on how terpenes are transported within the cell and from the cell to the apoplast. In this thesis, different aspects of transport of terpenes in plants were addressed. Firstly, the issue of intermediate transport between enzymes was studied, focussing on the regulation of intermediate flux between two different biosynthesis enzymes (CYP71AV1 and DBR2) that determines the resulting Artemisia annua, low or high artemisinin, chemotype. We also investigated the role of Lipid Transfer Proteins and vesicles in the transport of terpenes. Some LTP mutants were indeed shown to emit lower terpene levels, but the exact mechanism could not be resolved. Inhibition of vesicle transport increased terpene levels, most likely due to an effect on protein stability. I conclude that there are multiple transport mechanisms involved in terpene transport which complicates the analysis of a single transport pathway.</p

Quantum Trajectory Approach to Molecular Dynamics Simulation with Surface Hopping

The powerful molecular dynamics (MD) simulation is basically based on a picture that the atoms experience classical-like trajectories under the exertion of classical force field determined by the quantum mechanically solved electronic state. In this work we propose a quantum trajectory approach to the MD simulation with surface hopping, from an insight that an effective "observation" is actually implied in theMDsimulation through tracking the forces experienced, just like checking the meter's result in the quantum measurement process. This treatment can build the nonadiabatic surface hopping on a dynamical foundation, instead of the usual artificial and conceptually inconsistent hopping algorithms. The effects and advantages of the proposed scheme are preliminarily illustrated by a two-surface model system.Comment: 6 pages, 3 figure

Ionizing radiation absorption of vascular surgeons during endovascular procedures

ObjectiveEndovascular procedures have become an integral part of a vascular surgeon’s practice. The exposure of surgeons to ionizing radiation and other safety issues have not been well studied. We investigated the radiation exposure of a team of vascular surgeons in an active endovascular unit and compared yearly dosages absorbed by various body parts among different surgeons. Patients’ radiation exposure was also assessed.MethodsThe radiation absorption of a team of vascular surgeons was prospectively monitored in a 12-month period. During each endovascular procedure, the effective body, eye, and hand radiation doses of all participating surgeons were measured by mini-thermoluminescent dosimeters (TLD) attached at the chest level under a lead apron, at the forehead at eye level, and at the hand. The type of procedure, fluoroscopy machine, fluoroscopy time, and personal and operating theatre radiation protection devices used in each procedure were also recorded. One TLD was attached to the patient’s body near the operative site to measure the patient’s dose. The yearly effective body, eye, and hand dose were compared with the safety limits of radiation for occupational exposure recommended by the International Commission on Radiation Protection (ICRP). The radiation absorption of various body parts per minute of fluoroscopy was compared among different surgeons.ResultsA total of 149 consecutive endovascular procedures were performed, including 30 endovascular aortic repairs (EVAR), 58 arteriograms with and without embolization (AGM), and 61 percutaneous transluminal angioplasty and stent (PTA/S) procedures. The cumulative fluoroscopy time was 1132 minutes. The median yearly effective body, eye, and hand dose for the surgeons were 0.20 mSv (range, 0.13 to 0.27 mSv), 0.19 mSv (range, 0.10 to 0.33 mSv) and 0.99 mSv (0.29 to 1.84 mSv) respectively, which were well below the safety limits of the ICRP. The mean body, eye, and hand dose of the chief surgeon per procedure were highest for EVAR. A significant discrepancy was observed for the average hand dose per minute of fluoroscopy among different surgeons. The mean radiation absorption of patients who underwent EVAR, AGM, and PTA/S was 12.7 mSv, 13.6 mSv, and 3.4 mSv, respectively.ConclusionWith current radiation protection practice, the radiation absorbed by vascular surgeons with a high endovascular workload did not exceed the safety limits recommended by ICRP. Variations in practice, however, can result in significant discrepancy of radiation absorption between surgeons

Worldwide incidence of cervical lesions: a systematic review

We conducted a systematic review summarizing data on incidence of high- and low-grade lesions in women with normal baseline cervical cytology, stratified by age (<30 and ⩾30 years), and baseline human papillomavirus (HPV) infection. Incidence of high- and low-grade lesions in women aged ⩾30 years with a baseline HPV infection increased over follow-up time (5-127 months), although incidence generally remained <10%. Without baseline HPV infection, incidence of high-grade lesions remained low over follow-up time (<5% over 5-122 months). Incidence of high-grade lesions in women aged ⩾30 years with baseline HPV infection appeared similar to that in women aged <30 years. In some women aged <30 years, high-grade lesions can develop relatively shortly after initial HPV infection. We observed an increase in low-grade lesions over time in women aged ⩾30 years with baseline HPV infection, potentially indicative of an HPV infection that is potentially progressing to higher grade lesions

Assessing the appropriateness of the management of upper respiratory tract infection in Australian children: a population-based sample survey

OBJECTIVE:To assess the proportion of Australian children aged 0-15 years that received care in line with clinical practice guidelines (CPGs) for upper respiratory tract infections (URTIs). DESIGN:Retrospective medical record review using a multistage sampling strategy. SETTING:General practices, hospital emergency departments and hospital inpatient service providers in three Australian states. PARTICIPANTS:Children aged up to 15 years who received care for URTI in 2012 and 2013. PRIMARY AND SECONDARY OUTCOME MEASURES:The primary assessment was estimated adherence with 14 indicators of appropriate care as documented in medical records. Indicators were extracted from national and international CPGs and ratified by experts. Secondary assessment was adherence to two bundles of indicators (diagnostic symptoms and medical history taking), where all indicators must be adherent for the bundle to be scored as adherent. RESULTS:There were 1653 children with one or more assessments of URTI care to CPG adherence. Over half of the children were under 3 years of age, with roughly equal numbers of males and females. Three indicators had fewer than 25 visits so were not reported. Overall adherence ranged from 0.5% for 'documented advice around antibiotics' to 88.3% for 'documentation of medical history'. Adherence with Bundle A (documentation of all three definitive symptoms) was 43.1% (95% CI 32.8% to 54.0%) and Bundle B (documentation of all four indicators of medical history) was 30.2% (95% CI 20.9% to 40.9%). CONCLUSIONS:URTIs in children are common, usually self-limiting, conditions that are allocated considerable resources. The results suggest that there may be a need for more thorough holistic assessment of the patient and improved documentation. Since inappropriate prescription of antibiotics for URTIs is still a known problem in Australia, there is a need for consistent, clear communication around antibiotics' lack of impact on symptoms and a high association with undesirable side effects.Janet C Long, Helena M Williams, Shefali Jani, Gaston Arnolda, Hsuen P Ting, Charlotte J Molloy ... et al

Isometric Sliced Inverse Regression for Nonlinear Manifolds Learning

[[abstract]]Sliced inverse regression (SIR) was developed to find effective linear dimension-reduction directions for exploring the intrinsic structure of the high-dimensional data. In this study, we present isometric SIR for nonlinear dimension reduction, which is a hybrid of the SIR method using the geodesic distance approximation. First, the proposed method computes the isometric distance between data points; the resulting distance matrix is then sliced according to K-means clustering results, and the classical SIR algorithm is applied. We show that the isometric SIR (ISOSIR) can reveal the geometric structure of a nonlinear manifold dataset (e.g., the Swiss roll). We report and discuss this novel method in comparison to several existing dimension-reduction techniques for data visualization and classification problems. The results show that ISOSIR is a promising nonlinear feature extractor for classification applications.[[incitationindex]]SCI[[booktype]]紙本[[booktype]]電子

Lymphatic Invasion of Plakoglobin-Dependent Tumor Cell Clusters Drives Formation of Polyclonal Lung Metastases in Colon Cancer

Background & Aims: Patients with colon cancer with liver metastases may be cured with surgery, but the presence of additional lung metastases often precludes curative treatment. Little is known about the processes driving lung metastasis. This study aimed to elucidate the mechanisms governing lung vs liver metastasis formation. Methods: Patient-derived organoid (PDO) cultures were established from colon tumors with distinct patterns of metastasis. Mouse models recapitulating metastatic organotropism were created by implanting PDOs into the cecum wall. Optical barcoding was applied to trace the origin and clonal composition of liver and lung metastases. RNA sequencing and immunohistochemistry were used to identify candidate determinants of metastatic organotropism. Genetic, pharmacologic, in vitro, and in vivo modeling strategies identified essential steps in lung metastasis formation. Validation was performed by analyzing patient-derived tissues. Results: Cecum transplantation of 3 distinct PDOs yielded models with distinct metastatic organotropism: liver only, lung only, and liver and lung. Liver metastases were seeded by single cells derived from select clones. Lung metastases were seeded by polyclonal clusters of tumor cells entering the lymphatic vasculature with very limited clonal selection. Lung-specific metastasis was associated with high expression of desmosome markers, including plakoglobin. Plakoglobin deletion abrogated tumor cell cluster formation, lymphatic invasion, and lung metastasis formation. Pharmacologic inhibition of lymphangiogenesis attenuated lung metastasis formation. Primary human colon, rectum, esophagus, and stomach tumors with lung metastases had a higher N-stage and more plakoglobin-expressing intra-lymphatic tumor cell clusters than those without lung metastases. Conclusions: Lung and liver metastasis formation are fundamentally distinct processes with different evolutionary bottlenecks, seeding entities, and anatomic routing. Polyclonal lung metastases originate from plakoglobin-dependent tumor cell clusters entering the lymphatic vasculature at the primary tumor site