Conformational and Circular Dichroism Studies on N-Acetyl-L-Prolyl-D-Alanyl-Methylamide

The compact ordered conformations of the molecule N-Acteyl-L-Prolyl-D-Alanyl-Methylamide have been studied by semiempirical energy calculations in vacuum and circular dichroism (CD) in solution. The presence of ordered structure has been observed in hydrogen bond promoting solvents like trifluoroethanol by CD studies. In hydrogen bond breaking solvents, like trifluoroacetic acid (TFA), significant fraction of the ordered conformers probably assume extended conformation without intramolecular hydrogen bonds and perhaps are in equilibrium with the fraction of compact ordered structures. The trend observed in going from nonpolar to polar solvent is also compatible with the previous NMR studies in solution. The semiempirical energy calculations have been carried out in the allowed region for β-bends. The flexibility of pyrrolidine ring has been incorporated into the calculations. Representative puckerings, namely, A-type (Cy-exo) and B-type (Cy-endo) have been considered in this study. The results show the B-type to be slightly preferred over the A-type in this tripeptide moiety. The minimum energy conformation predicted from these studies agree only minimally with that found in crystal structure. A better agreement is found after performing the calculations using the geometrical data as observed in the crystal structure of this molecule. Our studies demonstrate that solvent solute interactions are minimal in nonpolar solvents and the predicted minimum energy conformations are preserved at least in nonpolar solvents

In vivo Spectroscopic and Imaging Studies of Photosensitizer in Photodynamic Therapy

Photodynamic Therapy (PDT) has emerged as a useful cancer treatment modality which utilizes a tumor localizing dye and activating light to selectively destroy neoplastic tissue. In an effort to understand the newly synthesized photosensitizers, we are studying them in a mouse tumor model grown on the dorsal side of the foot by in vivo magnetic resonance techniques. We have synthesized several photosensitizers which are specifically labeled with fluorine. Several coils appropriate for the tumor study by 19F NMR were designed and constructed for this project. The solenoid coil tunable to both 1Hand 19F nuclei was used to monitor the 19F labeled photosensitizer in the mouse foot tumor. An in vivo 19F NMR technique was used to study the retention of the photosensitizer over time in the tumor. We have used 31P NMR to study the outcome of PDT after using the new photosensitizer

Making connections: technological interventions to support students in using, and tutors in creating, assessment feedback

This paper explores the potential of technology to enhance the assessment and feedback process for both staff and students. The ‘Making Connections’ project aimed to better understand the connections that students make between the feedback that they receive and future assignments, and explored whether technology can help them in this activity. The project interviewed 10 tutors and 20 students, using a semi-structured approach. Data were analysed using a thematic approach, and the findings have identified a number of areas in which improvements could be made to the assessment and feedback process through the use of technology. The findings of the study cover each stage of the assessment process from the perspective of both staff and students. The findings are discussed in the context of current literature, and special attention is given to projects from the UK higher education sector intended to address the same issues. Keywords: feed-forward; assessment; practices; technology; technology-enhanced learnin

Plasmodium P-type cyclin CYC3 modulates endomitotic growth during oocyst development in mosquitoes

Cell-cycle progression and cell division in eukaryotes are governed in part by the cyclin family and their regulation of cyclin-dependent kinases (CDKs). Cyclins are very well characterised in model systems such as yeast and human cells, but surprisingly little is known about their number and role in Plasmodium, the unicellular protozoan parasite that causes malaria. Malaria parasite cell division and proliferation differs from that of many eukaryotes. During its life cycle it undergoes two types of mitosis: endomitosis in asexual stages and an extremely rapid mitotic process during male gametogenesis. Both schizogony (producing merozoites) in host liver and red blood cells, and sporogony (producing sporozoites) in the mosquito vector, are endomitotic with repeated nuclear replication, without chromosome condensation, before cell division. The role of specific cyclins during Plasmodium cell proliferation was unknown. We show here that the Plasmodium genome contains only three cyclin genes, representing an unusual repertoire of cyclin classes. Expression and reverse genetic analyses of the single Plant (P)-type cyclin, CYC3, in the rodent malaria parasite, Plasmodium berghei, revealed a cytoplasmic and nuclear location of the GFP-tagged protein throughout the lifecycle. Deletion of cyc3 resulted in defects in size, number and growth of oocysts, with abnormalities in budding and sporozoite formation. Furthermore, global transcript analysis of the cyc3-deleted and wild type parasites at gametocyte and ookinete stages identified differentially expressed genes required for signalling, invasion and oocyst development. Collectively these data suggest that cyc3 modulates oocyst endomitotic development in Plasmodium berghei

Internal water bridge and antiparallel sheet in the structure of benzyloxycarbonyl-L-alanyl-D-phenylalanyl-L-proline monohydrate

Benzyloxycarbonyl-L-alanyl-o-phenylalanyl-L-proline monohydrate, C25H29N3O6.H2O, crystallizes in the orthorhombic space group P212121 with four molecules in a unit cell of dimensions a = 9.594 (9), b = 9.705 (4) and c = 27.9 17 (12) Å. The structure has been refined to an R value of 0.067 for 2046 observed reflections. All the peptide units in the molecule are trans and the prolyl residue is in the conformation. The lone water molecule in the structure is hydrogen bonded to the carbonyl O atom in the C2 - Cγ - exo - Cβ endo conformation. The lone water molecule in the structure is hydrogen bonded to the carbonyl O atom in the benzyloxycarbonyl group and to one of the O atoms in the terminal carboxyl group. This internal water bridge, observed for the first time in a linear peptide, provides a model for water-mediated chain-reversal. An interesting feature of the crystal structure is the presence of an antiparallel sheet involving the alanyl and the phenyl-alanyl residues

Mental healthcare systems research during COVID-19: Lessons for shifting the paradigm post COVID-19

The mental health effects of the Covid-19 pandemic across the globe have been significant, are ongoing, and will persist for a long time. Mental healthcare systems (MHS) to address these effects have been stressed beyond their limit. They have had to: (a) sense the developments and respond to the changing needs quickly, (b) be agile in obtaining feedback and learning from it in very short cycle times, and (c) immediately integrate their personal local experience, the reported global experience and translate the learning to practice. This intense learning cycle has spawned an enormous corpus of research on MHS during COVID-19 and shifted the paradigm of research. Lessons from the paradigm shift should be embraced and normalized in the roadmap for MHS research post COVID-19. This paper presents an ontology of MHS as a framework to systematically: (a) visualize in structured natural-English the dimensions, elements, and narratives of MHS research, (b) map the emphases and gaps in the research during COVID-19, and (c) develop a roadmap to shift the future research paradig

How does exposure to pesticides vary in space and time for residents living near to treated orchards?

This study investigated changes over 25 years (1987-2012) in pesticide usage in orchards in England and Wales and associated changes to exposure and risk for resident pregnant women living 100 and 1000 m downwind of treated areas. A model was developed to estimate aggregated daily exposure to pesticides via inhaled vapour and indirect dermal contact with contaminated ground, whilst risk was expressed as a hazard quotient (HQ) for reproductive and/or developmental endpoints. Results show the largest changes occurred between 1987 and 1996 with total pesticide usage reduced by ca. 25%, exposure per unit of pesticide applied slightly increased, and a reduction in risk per unit exposure by factors of 1.4 to 5. Thereafter, there were no consistent changes in use between 1996 and 2012, with an increase in number of applications to each crop balanced by a decrease in average application rate. Exposure per unit of pesticide applied decreased consistently over this period such that values in 2012 for this metric were 48-65% of those in 1987, and there were further smaller decreases in risk per unit exposure. All aggregated hazard quotients were two to three orders of magnitude smaller than one, despite the inherent simplifications of assuming co-occurrence of exposure to all pesticides and additivity of effects. Hazard quotients at 1000 m were 5 to 30 times smaller than those at 100 m. There were clear signals of the impact of regulatory intervention in improving the fate and hazard profiles of pesticides over the period investigated

Radio Frequency Nonionizing Radiation in a Community Exposed to Radio and Television Broadcasting

Exposure to radio frequency (RF) nonionizing radiation from telecommunications is pervasive in modern society. Elevated disease risks have been observed in some populations exposed to radio and television transmissions, although findings are inconsistent. This study quantified RF exposures among 280 residents living near the broadcasting transmitters for Denver, Colorado. RF power densities outside and inside each residence were obtained, and a global positioning system (GPS) identified geographic coordinates and elevations. A viewshed model within a geographic information system (GIS) characterized the average distance and percentage of transmitters visible from each residence. Data were collected at the beginning and end of a 2.5-day period, and some measurements were repeated 8–29 months later. RF levels logged at 1-min intervals for 2.5 days varied considerably among some homes and were quite similar among others. The greatest differences appeared among homes within 1 km of the transmitters. Overall, there were no differences in mean residential RF levels compared over 2.5 days. However, after a 1- to 2-year follow-up, only 25% of exterior and 38% of interior RF measurements were unchanged. Increasing proximity, elevation, and line-of-sight visibility were each associated with elevated RF exposures. At average distances from > 1–3 km, exterior RF measurements were 13–30 times greater among homes that had > 50% of the transmitters visible compared with homes with ≤ 50% visibility at those distances. This study demonstrated that both spatial and temporal factors contribute to residential RF exposure and that GPS/GIS technologies can improve RF exposure assessment and reduce exposure misclassification

Timing of host feeding drives rhythms in parasite replication

Circadian rhythms enable organisms to synchronise the processes underpinning survival and reproduction to anticipate daily changes in the external environment. Recent work shows that daily (circadian) rhythms also enable parasites to maximise fitness in the context of ecological interactions with their hosts. Because parasite rhythms matter for their fitness, understanding how they are regulated could lead to innovative ways to reduce the severity and spread of diseases. Here, we examine how host circadian rhythms influence rhythms in the asexual replication of malaria parasites. Asexual replication is responsible for the severity of malaria and fuels transmission of the disease, yet, how parasite rhythms are driven remains a mystery. We perturbed feeding rhythms of hosts by 12 hours (i.e. diurnal feeding in nocturnal mice) to desynchronise the hosts' peripheral oscillators from the central, light-entrained oscillator in the brain and their rhythmic outputs. We demonstrate that the rhythms of rodent malaria parasites in day-fed hosts become inverted relative to the rhythms of parasites in night-fed hosts. Our results reveal that the hosts' peripheral rhythms (associated with the timing of feeding and metabolism), but not rhythms driven by the central, light-entrained circadian oscillator in the brain, determine the timing (phase) of parasite rhythms. Further investigation reveals that parasite rhythms correlate closely with blood glucose rhythms. In addition, we show that parasite rhythms resynchronise to the altered host feeding rhythms when food availability is shifted, which is not mediated through rhythms in the host immune system. Our observations suggest that parasites actively control their developmental rhythms. Finally, counter to expectation, the severity of disease symptoms expressed by hosts was not affected by desynchronisation of their central and peripheral rhythms. Our study at the intersection of disease ecology and chronobiology opens up a new arena for studying host-parasite-vector coevolution and has broad implications for applied bioscience