Fatty acid synthesis and pyruvate metabolism pathways remain active in dihydroartemisinin induced dormant ring stages of Plasmodium falciparum

Artemisinin (ART) based combination therapy (ACT) is used as the first line treatment of uncomplicated falciparum malaria worldwide. However, despite high potency and rapid action there is a high rate of recrudescence associated with ART monotherapy or ACT long before the recent emergence of ART resistance. ART induced ring stage dormancy and recovery has been implicated as possible cause of recrudescence; however, little is known about the characteristics of dormant parasites including whether dormant parasites are metabolically active. We investigated the transcription of 12 genes encoding key enzymes in various metabolic pathways in P. falciparum during dihydroartemisinin (DHA) induced dormancy and recovery. Transcription analysis showed an immediate down regulation for 10 genes following exposure to DHA, but continued transcription of 2 genes encoding apicoplast and mitochondrial proteins. Transcription of several additional genes encoding apicoplast and mitochondrial proteins, particularly genes encoding enzymes in pyruvate metabolism and fatty acid synthesis pathways, were also maintained. Additions of inhibitors for biotin acetyl CoA carbozylase and enoyl-acyl carrier reductase of the fatty acid synthesis pathways delayed the recovery of dormant parasites by 6 and 4 days, respectively following DHA treatment. Our results demonstrate most metabolic pathways are down regulated in DHA induced dormant parasites. In contrast fatty acid and pyruvate metabolic pathways remain active. These findings highlight new targets to interrupt recovery of parasites from ART-induced dormancy and to reduce the rate of recrudescence following ART treatment.

Surface fluxes of Si and C adatoms at initial growth stages of SiC quantum dots

Self-assembly of highly stoichiometric SiC quantum dots still remains a major challenge for the gas/plasma-based nanodot synthesis. By means of a multiscale hybrid numerical simulation of the initial stage (0.1-2.5 s into the process) of deposition of SiCSi (100) quantum dot nuclei, it is shown that equal Si and kst atom deposition fluxes result in strong nonstoichiometric nanodot composition due to very different surface fluxes of Si and C adatoms to the quantum dots. At this stage, the surface fluxes of Si and C adatoms to SiC nanodots can be effectively controlled by manipulating the SiC atom influx ratio and the Si (100) surface temperature. It is demonstrated that at a surface temperature of 800 K the surface fluxes can be equalized after only 0.05 s into the process; however, it takes more then 1 s at a surface temperature of 600 K. Based on the results of this study, effective strategies to maintain a stoichiometric ([Si] [C] =1:1) elemental ratio during the initial stages of deposition of SiCSi (100) quantum dot nuclei in a neutral/ionized gas-based process are proposed.

Self-management programs in stage 1-4 chronic kidney disease : a literature review.

Background Chronic kidney disease (CKD) is a complex health problem, which requires individuals to invest considerable time and energy in managing their health and adhering to multifaceted treatment regimens. Objectives To review studies delivering self-management interventions to people with CKD (Stages 1–4) and assess whether these interventions improve patient outcomes. Design: Systematic review. Methods Nine electronic databases (MedLine, CINAHL, EMBASE, ProQuest Health & Medical Complete, ProQuest Nursing & Allied Health, The Cochrane Library, The Joanna Briggs Institute EBP Database, Web of Science and PsycINFO) were searched using relevant terms for papers published between January 2003 and February 2013. Results The search strategy identified 2,051 papers, of which 34 were retrieved in full with only 5 studies involving 274 patients meeting the inclusion criteria. Three studies were randomised controlled trials, a variety of methods were used to measure outcomes, and four studies included a nurse on the self-management intervention team. There was little consistency in the delivery, intensity, duration and format of the self-management programmes. There is some evidence that knowledge- and health-related quality of life improved. Generally, small effects were observed for levels of adherence and progression of CKD according to physiologic measures. Conclusion The effectiveness of self-management programmes in CKD (Stages 1–4) cannot be conclusively ascertained, and further research is required. It is desirable that individuals with CKD are supported to effectively self-manage day-to-day aspects of their health.

Arabic translation, adaptation and modification of the dialysis symptom index for chronic kidney disease stages four and five

Background Symptom burden in chronic kidney disease (CKD) is poorly understood. To date, the majority of research focuses on single symptoms and there is a lack of suitable multidimensional symptom measures. The purpose of this study was to modify, translate, cross-culturally adapt and psychometrically analyse the Dialysis Symptom Index (DSI). Methods The study methods involved four phases: modification, translation, pilot-testing with a bilingual non-CKD sample and then psychometric testing with the target population. Content validity was assessed using an expert panel. Inter-rater agreement, test-retest reliability and Cronbach’s alpha coefficient were calculated to demonstrate reliability of the modified DSI. Discriminative and convergent validity were assessed to demonstrate construct validity. Results Content validity index during translation was 0.98. In the pilot study with 25 bilingual students a moderate to perfect agreement (Kappa statistic = 0.60-1.00) was found between English and Arabic versions of the modified DSI. The main study recruited 433 patients CKD with stages 4 and 5. The modified DSI was able to discriminate between non-dialysis and dialysis groups (p < 0.001) and demonstrated convergent validity with domains of the Kidney Disease Quality of Life short form. Excellent test-retest and internal consistency (Cronbach’s α = 0.91) reliability were also demonstrated. Conclusion The Arabic version of the modified DSI demonstrated good psychometric properties, measures the multidimensional nature of symptoms and can be used to assess symptom burden at different stages of CKD. The modified instrument, renamed the CKD Symptom Burden Index (CKD-SBI), should encourage greater clinical and research attention to symptom burden in CKD.

Multiple stages classification of Alzheimer’s disease based on structural brain networks using generalized low rank approximations (GLRAM)

To classify each stage for a progressing disease such as Alzheimer’s disease is a key issue for the disease prevention and treatment. In this study, we derived structural brain networks from diffusion-weighted MRI using whole-brain tractography since there is growing interest in relating connectivity measures to clinical, cognitive, and genetic data. Relatively little work has usedmachine learning to make inferences about variations in brain networks in the progression of the Alzheimer’s disease. Here we developed a framework to utilize generalized low rank approximations of matrices (GLRAM) and modified linear discrimination analysis for unsupervised feature learning and classification of connectivity matrices. We apply the methods to brain networks derived from DWI scans of 41 people with Alzheimer’s disease, 73 people with EMCI, 38 people with LMCI, 47 elderly healthy controls and 221 young healthy controls. Our results show that this new framework can significantly improve classification accuracy when combining multiple datasets; this suggests the value of using data beyond the classification task at hand to model variations in brain connectivity.

The impact of international potentials, entrepreneurial motivations and firm stages on new venture internationalisation

Past research on early internationalising firms often examined factors and motivations potentially influencing internationalisation activities separately. The purpose of this paper was to investigate a set of indicators and their interplay with each other. Firstly, the impact of (a) international potential in the form of the depth and diversity of international experience and network contacts was investigated. Secondly, it was examined to what extent (b) motivational factors and (c) firm stages affect the relationship between international potential and internationalisation activities. This paper used longitudinal data from the Comprehensive Australian Study of Entrepreneurial Emergence (CAUSEE). Results suggest that the international potential of a new venture as a whole is a significant determinant of subsequent internationalisation activities. However, having a diverse international experience from a variety of foreign countries appears to be more beneficial than a long-lasting experience from only a limited number of foreign countries. Furthermore, analyses showed that the interplay of high growth ambitions and the depth of international experience positively affect internationalisation activities. Opportunity or necessity driven entrepreneurship, however, neither exaggerate nor weaken the positive relationship between international potentials and internationalisation activities. Similarly, no moderation by firm stages was found.

Flow of metal into the flash gap in the last stages of a plane-strain closed-die forging operation

In closed-die forging the flash geometry should be such as to ensure that the cavity is completely filled just as the two dies come into contact at the parting plane. If metal is caused to extrude through the flash gap as the dies approach the point of contact — a practice generally resorted to as a means of ensuring complete filling — dies are unnecessarily stressed in a high-stress regime (as the flash is quite thin and possibly cooled by then), which reduces the die life and unnecessarily increases the energy requirement of the operation. It is therefore necessary to carefully determine the dimensions of the flash land and flash thickness — the two parameters, apart from friction at the land, which control the lateral flow. The dimensions should be such that the flow into the longitudinal cavity is controlled throughout the operation, ensuring complete filling just as the dies touch at the parting plane. The design of the flash must be related to the shape and size of the forging cavity as the control of flow has to be exercised throughout the operation: it is possible to do this if the mechanics of how the lateral extrusion into the flash takes place is understood for specific cavity shapes and sizes. The work reported here is part of an ongoing programme investigating flow in closed-die forging. A simple closed shape (no longitudinal flow) which may correspond to the last stages of a real forging operation is analysed using the stress equilibrium approach. Metal from the cavity (flange) flows into the flash by shearing in the cavity in one of the three modes considered here: for a given cavity the mode with the least energy requirement is assumed to be the most realistic. On this basis a map has been developed which, given the depth and width of the cavity as well as the flash thickness, will tell the designer of the most likely mode (of the three modes considered) in which metal in the cavity will shear and then flow into the flash gap. The results of limited set of experiments, reported herein, validate this method of selecting the optimum model of flow into the flash gap.

Recruitment and loss of juvenile stages of Helicoverpa spp. (Lepidoptera: Noctuidae) on contaminant plants in chickpea crops

The hypothesis that contaminant plants growing amongst chickpea serve as Helicoverpa sinks by diverting oviposition pressure away from the main crop was tested under field conditions. Gain (recruitment) and loss (presumed mortality) of juvenile stages of Helicoverpa spp. on contaminant faba bean and wheat plants growing in chickpea plots were quantified on a daily basis over a 12-d period. The possibility of posteclosion movement of larvae from the contaminants to the surrounding chickpea crop was examined. Estimated total loss of the census population varied from 80 to 84% across plots and rows. The loss of brown eggs (40–47%) contributed most to the overall loss estimate, followed by loss of white eggs (27–35%) and larvae (6–9%). The cumulative number of individuals entering the white and brown egg and larval stages over the census period ranged from 15 to 58, 10–48 and 1–6 per m row, respectively. The corresponding estimates of mean stage-specific loss, expressed as a percentage of individuals entering the stage, ranged from 52 to 57% for white eggs, 87–108% for brown eggs and 71–87% for first-instar larvae. Mean larval density on chickpea plants in close proximity to the contaminant plants did not exceed the baseline larval density on chickpea further away from the contaminants across rows and plots. The results support the hypothesis that contaminant plants in chickpea plots serve as Helicoverpa sinks by diverting egg pressure from the main crop and elevating mortality of juvenile stages. Deliberate contamination of chickpea crops with other plant species merits further investigation as a cultural pest management strategy for Helicoverpa spp.

Antibody response against endogenous stages of an attenuated strain of Eimeria tenella

The application of attenuated vaccines for the prevention of chicken coccidiosis has increased exponentially in recent years. In Eimeria infections, protective immunity is thought to rely on a strong cell mediated response with antibodies supposedly playing a minor role. However, under certain conditions antibodies seem to be significant in protection. Furthermore, antibodies could be useful for monitoring natural exposure of flocks to Eimeria spp. and for monitoring the infectivity of live vaccines. Our objective was to investigate the chicken antibody response to the different parasite lifecycle stages following infection with an attenuated strain of Eimeria tenella. Western blotting analysis of parasite antigens prepared from the lining of caeca infected with the attenuated strain of E. tenella revealed two dominant antigens of 32 and 34 kDa, apparently associated with trophozoites and merozoites that were present at high concentrations between 84 and 132 h post-infection. When cryosections of caeca infected with E. tenella were probed with IgY purified from immune birds the most intense reaction was observed with the asexual stages. Western blotting analysis of proteins of purified sporozoites and third generation merozoites and absorption of stage-specific antibodies from sera suggested that a large proportion of antigens is shared by the two stages. The time-courses of the antibody response to sporozoite and merozoite antigens were similar but varied depending on the inoculation regime and the degree of oocyst recirculation.

Side Chain Structure Determines Unique Physiologic and Therapeutic Properties of norUrsodeoxycholic Acid in Mdr2(-/-) Mice

24-norursodeoxycholic acid (norUDCA), a side chain-modified ursodeoxycholic acid derivative, has dramatic therapeutic effects in experimental cholestasis and may be a promising agent for the treatment of cholestatic liver diseases. We aimed to better understand the physiologic and therapeutic properties of norUDCA and to test if they are related to its side chain length and/or relative resistance to amidation. For this purpose, Mdr2-/- mice, a model for sclerosing cholangitis, received either a standard diet or a norUDCA-, tauro norursodeoxycholic acid (tauro- norUDCA)-, or di norursodeoxycholic acid (di norUDCA)-enriched diet. Bile composition, serum biochemistry, liver histology, fibrosis, and expression of key detoxification and transport systems were investigated. Direct choleretic effects were addressed in isolated bile duct units. The role of Cftr for norUDCA-induced choleresis was explored in Cftr-/- mice. norUDCA had pharmacologic features that were not shared by its derivatives, including the increase in hepatic and serum bile acid levels and a strong stimulation of biliary HCO3- -output. norUDCA directly stimulated fluid secretion in isolated bile duct units in a HCO3- -dependent fashion to a higher extent than the other bile acids. Notably, the norUDCA significantly stimulated HCO 3- -output also in Cftr-/- mice. In Mdr2-/- mice, cholangitis and fibrosis strongly improved with norUDCA, remained unchanged with tauro- norUDCA, and worsened with di norUDCA. Expression of Mrp4, Cyp2b10, and Sult2a1 was increased by norUDCA and di norUDCA, but was unaffected by tauro- norUDCA. Conclusion:The relative resistance of norUDCA to amidation may explain its unique physiologic and pharmacologic properties. These include the ability to undergo cholehepatic shunting and to directly stimulate cholangiocyte secretion, both resulting in a HCO3- -rich hypercholeresis that protects the liver from cholestatic injury.

Cellular stages of root formation, root system quality and survival of Pinus elliottii var. elliottii x P. caribaea var. hondurensis cuttings in different temperature environments.

Time to first root in cuttings varies under different environmental conditions and understanding these differences is critical for optimizing propagation of commercial forestry species. Temperature environment (15, 25, 30 or 35 +/- A 2A degrees C) had no effect on the cellular stages in root formation of the Slash x Caribbean Pine hybrid over 16 weeks as determined by histology. Initially callus cells formed in the cortex, then tracheids developed and formed primordia leading to external roots. However, speed of development followed a growth curve with the fastest development occurring at 25A degrees C and slowest at 15A degrees C with rooting percentages at week 12 of 80 and 0% respectively. Cutting survival was good in the three cooler temperature regimes (> 80%) but reduced to 59% at 35A degrees C. Root formation appeared to be dependant on the initiation of tracheids because all un-rooted cuttings had callus tissue but no tracheids, irrespective of temperature treatment and clone.

Cellular stages of root formation, root system quality and survival of Pinuselliottii var. elliottii x P. caribaea var. hondurensis cuttings in different temperature environments.

Time to first root in cuttings varies under different environmental conditions and understanding these differences is critical for optimizing propagation of commercial forestry species. Temperature environment (15, 25, 30 or 352C) had no effect on the cellular stages in root formation of the Slash * Caribbean Pine hybrid over 16 weeks as determined by histology. Initially callus cells formed in the cortex, then tracheids developed and formed primordia leading to external roots. However, speed of development followed a growth curve with the fastest development occurring at 25C and slowest at 15C with rooting percentages at week 12 of 80 and 0% respectively. Cutting survival was good in the three cooler temperature regimes (>80%) but reduced to 59% at 35C. Root formation appeared to be dependant on the initiation of tracheids because all un-rooted cuttings had callus tissue but no tracheids, irrespective of temperature treatment and clone.

Ageing delays the cellular stages of adventitious root formation in pine.

Vegetative propagation programs internationally are affected by the significant decline of rooting success as trees mature. This study compared the cellular stages of root formation in stem cuttings from 15-week-old (juvenile) and 9-y-old (mature) stock plants of the slash x Caribbean pine hybrid (Pinus elliottii var. elliottii x P. caribaea van hondurensis). The cellular stages of root formation were the same in both juvenile and mature cuttings, beginning with cell divisions of the vascular cambium forming callus tissue. Within the callus, tracheids differentiated and elongated to form root primordia. Roots in juvenile cuttings developed faster than those in mature cuttings and the juvenile cuttings had a much higher rooting percent at the end of the study (92% and 26% respectively). Cuttings of the two juvenile genotypes had more primary roots (5.5 and 3.3) than the three mature genotypes (0.96, 0.18 and 0.07). The roots of juvenile cuttings were more evenly distributed around the basal circumference when compared with those on cuttings from the mature genotypes. Further work is needed to improve understanding of physiological changes with maturation so that the rooting success and the speed of development in cuttings from mature stock plants can be optimised, hence improving genetic gain.