Effect of biodegradable and conventional microplastic exposure in combination with seawater inundation on the coastal terrestrial plant Plantago coronopus.

Coastal ecosystems face a multitude of pressures including plastic pollution and increased flood risk due to sea level rise and the frequency and severity of storms. Experiments seldom examine multiple stressors such as these, but here we quantified the effect of microplastics (polyethylene terephthalate (PET): a durable plastic and polybutylene adipate terephthalate (PBAT): a biodegradable polymer), in combination with simulated seawater inundation on the coastal species Plantago coronopus. After 35-days exposure to plastic (0.02 g.Kg-1, <300µm diameter), P. coronopus were flooded to pot height with artificial seawater for 72-hours, drained and grown for a further 24-days. Plant mortality, necrosis and photosynthetic efficiency (Fv/Fm) were recorded throughout, with root:shoot biomass and scape production (flower stalks) quantified at harvest. There were significant interactions between microplastics and seawater on the root:shoot ratio; a measure of resource allocation. The allocation to belowground biomass increased significantly under the PET + inundation treatment compared to the PBAT + inundation and the no plastic + inundation treatments, with potential consequences on the capture of water, nutrients and sunlight, which can affect plant performance. Plant necrosis significantly increased, and Fv/Fm declined as a result of seawater inundation. While not significant, plant Fv/Fm responses were influenced by microplastics (17% and 7% reduction in PBAT and PET exposure respectively compared to the no plastic control). Plants mediated this stress response with no discernible treatment-specific effects detected in Fv/Fm 14-days after seawater introduction. Plastic exposure significantly influenced potential reproductive output, with lower average scape numbers across PBAT treatments, but higher in PET treatments. This study highlights the complex interactions and potential for microplastics to present an elevated risk when in combination with additional stressors like seawater flooding; establishing the threat presented to ecosystem resilience in a changing world is a priority.

Deterioration of bio-based polylactic acid plastic teabags under environmental conditions and their associated effects on earthworms.

In response to the plastic waste crisis, teabag producers have substituted the petrochemical-plastic content of their products with bio-based, biodegradable polymers such as polylactic acid (PLA). Despite widespread use, the degradation rate of PLA/PLA-blended materials in natural soil and their effects on soil biota are poorly understood. This study examined the percentage mass deterioration of teabags with differing cellulose:PLA compositions following burial (-10 cm depth) in an arable field margin for 7-months, using a suite of analytical techniques, such as size exclusion chromatography, 1H nuclear magnetic resonance, dynamic scanning calorimetry, and scanning electron microscopy. The effect of 28-d exposure to teabag discs at environmentally relevant concentrations (0.02 %, 0.04 % and 0.07 % w/w) on the survival, growth and reproduction (OECD TG 222 protocol) of the key soil detritivore Eisenia fetida was assessed in laboratory trials. After 7-month burial, Tbag-A (2.4:1 blend) and Tbag-B (3.5:1 cellulose:PLA blend) lost 66 ± 5 % and 78 ± 4 % of their total mass, primarily attributed to degradation of cellulose as identified by FTIR spectroscopy and a reduction in the cellulose:PLA mass ratio, while Tbag-C (PLA) remained unchanged. There were clear treatment and dose-specific effects on the growth and reproductive output of E. fetida. At 0.07 % w/w of Tbag-A adult mortality marginally increased (15 %) and both the quantity of egg cocoons and the average mass of juveniles also increased, while at concentrations ≥0.04 % w/w of Tbag-C, the quantity of cocoons was suppressed. Adverse effects are comparable to those reported for non-biodegradable petrochemical-based plastic, demonstrating that bio-based PLA does not offer a more 'environmentally friendly' alternative. Our study emphasises the necessity to better understand the environmental fate and ecotoxicity of PLA/PLA-blends to ensure interventions developed through the UN Plastic Pollution Treaty to use alternatives and substitutes to conventional plastics do not result in unintended negative consequences.

First Evidence of Axial Shape Asymmetry and Configuration Coexistence in

The excited states of N=44 ^{74}Zn were investigated via γ-ray spectroscopy following ^{74}Cu ß decay. By exploiting γ-γ angular correlation analysis, the 2_{2}^{+}, 3_{1}^{+}, 0_{2}^{+}, and 2_{3}^{+} states in ^{74}Zn were firmly established. The γ-ray branching and E2/M1 mixing ratios for transitions deexciting the 2_{2}^{+}, 3_{1}^{+}, and 2_{3}^{+} states were measured, allowing for the extraction of relative B(E2) values. In particular, the 2_{3}^{+}→0_{2}^{+} and 2_{3}^{+}→4_{1}^{+} transitions were observed for the first time. The results show excellent agreement with new microscopic large-scale shell-model calculations, and are discussed in terms of underlying shapes, as well as the role of neutron excitations across the N=40 gap. Enhanced axial shape asymmetry (triaxiality) is suggested to characterize ^{74}Zn in its ground state. Furthermore, an excited K=0 band with a significantly larger softness in its shape is identified. A shore of the N=40 "island of inversion" appears to manifest above Z=26, previously thought as its northern limit in the chart of the nuclides.

Biochemically recurrent prostate cancer: rationalisation of the approach to imaging.

AIM: To assess the utility of magnetic resonance imaging (MRI) in addition to the additive benefit of the conventional imaging techniques, computed tomography (CT) and nuclear medicine (NM) bone scintigraphy, for investigation of biochemical recurrence (BCR) post-prostatectomy where access to prostate specific membrane antigen (PSMA) positron-emission tomography (PET)-CT is challenging. MATERIALS AND METHODS: Relevant imaging over a 5-year period was reviewed. Ethical approval was granted by the internal review board. All patients with suspected BCR, defined as a PSA ≥0.2 ng/ml on two separate occasions, underwent a retrospective imaging review. This was performed on PACS archive search database in a single centre using search terms "PSA" and "prostatectomy" in the three imaging methods; MRI, CT, and NM bone scintigraphy. All PSMA PET CT performed were recorded. RESULTS: One hundred and eighty-five patients were identified. Patients with an MRI pelvis that demonstrated distant metastases (i.e., pelvic bone metastases or lymph node involvement more cranial to the bifurcation of the common iliac arteries) were more likely to have a positive CT and/or NM bone scintigraphy. The Pearson correlation coefficient between the findings of M1 disease at MRI pelvis and the presence of distant metastases at CT thorax, abdomen, pelvis and NM bone scintigraphy was calculated at 0.81 (p<0.01) and 0.91 (p<0.01) respectively. CONCLUSION: An imaging strategy based on risk stratification and technique-specific selection criteria leads to more appropriate use of resources, and in turn, increases the yield of conventional imaging methods. MRI prostate findings can be used to predict the additive value of CT/NM bone scintigraphy allowing a more streamlined approach to their use.

The Impact of COVID-19 on Anxiety and Worries for Families of Individuals with Special Education Needs and Disabilities in the UK.

COVID-19 has affected people across the world. The current study examined anxiety and worries during the first UK national lockdown in March 2020. Parents (n = 402) reported on their own anxiety and worries as well as that of their son/daughter with Special Education Needs and Disabilities (SEND) and typically developing (TD) child (n = 186) at three time points. Although both groups showed increased anxiety across the three time points, levels of anxiety in the SEND group, but not the TD siblings, were predicted by awareness about COVID-19. In addition, worries differed between the groups showing that COVID-19 impacts the wellbeing of those with SEND differently to that of their TD siblings.

Facing up to climate change: Community composition varies with aspect and surface temperature in the rocky intertidal.

Marine rocky intertidal organisms are amongst those most affected by climate change with regional distributional changes observed for many species. Although often ascribed to increased sea surface temperatures, precise assessment of the local habitat conditions underpinning observed and predicted changes in community assembly is lacking. Here we examine how aspect (i.e. north-south orientation) affects intertidal community composition and how rock surface temperatures and stress responses of two dominant grazer species (Patella spp.) elucidate emergent differences. We quantified year-round temperature variation and surveyed intertidal community composition on paired natural rock gullies with Equator- (EF) and Pole-facing (PF) surfaces. We also investigated variation in limpet (Patella spp.) reproductive phenology and osmotic stress. Average annual temperatures were 0.8 °C (1.6 °C at low tide) higher, with six-fold more frequent extremes (i.e. > 30 °C) on EF than PF surfaces. Intertidal community composition varied with aspect across trophic levels with greater overall species richness, abundance of primary producers and grazers on PF-surfaces, and greater barnacle abundance on EF-surfaces. Although species richness of organisms from different biogeographical origins ('Boreal' or 'Lusitanian') did not vary, the Lusitanian limpet Patella depressa exhibited earlier reproductive development on EF-surfaces and both limpet species exhibited greater thermal stress on EF-surfaces. We argue that our study system provides a good model for understanding how temperature variation at local scales can affect community composition, as well as ecophysiological and ecological responses to climate change and so better inform and predict regional range shifts over coming decades.

Estimating six-cycle efficacy of the Dot app for pregnancy prevention.

OBJECTIVE: To assess six-cycle perfect and typical use efficacy of Dynamic Optimal Timing (Dot), an algorithm-based fertility app that identifies the fertile window of the menstrual cycle using a woman's period start date and provides guidance on when to avoid unprotected sex to prevent pregnancy. STUDY DESIGN: We are conducting a prospective efficacy study following a cohort of women using Dot for up to 13 cycles. Study enrollment and data collection are being conducted digitally within the app and include a daily coital diary, prospective pregnancy intentions and sociodemographic information. We used data from the first six cycles to calculate life-table failure rates. RESULTS: We enrolled 718 women age 18-39 years. Of the 629 women 18-35 years old, 15 women became pregnant during the first six cycles for a typical use failure rate of 3.5% [95% CI 1.7-5.2]. All pregnancies occurred with incorrect use, so we did not calculate a perfect use failure rate. CONCLUSIONS: These findings are promising and suggest that the 13-cycle results will demonstrate high efficacy of Dot. IMPLICATIONS: While final 13-cycle efficacy results are forthcoming, 6-cycle results suggest that Dot's guidance provides women with useful information for preventing pregnancy.

Market-testing a smartphone application for family planning: assessing potential of the CycleBeads app in seven countries through digital monitoring.

BACKGROUND: The advent of new technological approaches to family planning has the potential to address unmet need in low- and middle-income countries. Provision of fertility awareness-based apps have the ability to provide accessible, direct-to-user fertility information to help women achieve their reproductive goals. The CycleBeads app, a digital platform for the Standard Days Method (SDM), a modern method of family planning, helps women achieve or prevent pregnancy, or track their cycles using the only their period start dates. METHODS: Brief social marketing campaigns were launched by the app developer to monitor cost and distribution of the CycleBeads app, understand the user profile, and assess user experience. Monitoring and evaluation through in-app micro surveys occurred over a 6-cycle period in seven countries: Egypt, Ghana, India, Jordan, Kenya, Nigeria, and Rwanda. In-app micro-surveys were utilized to collect data around demographics, mode of use of the app, prior experiences with family planning, and satisfaction to better understand women's interactions with the apps, and the possibility for meeting unmet need. Analyzes focused on women who were using the app to prevent pregnancy or track their cycles. RESULTS: Social media campaigns proved to be an easy, low-cost approach to advertising the CycleBeads app. As a result, 356,520 women downloaded the app, and the cost to the advertiser per download ranged from $0.17-0.69. A majority of app users were between 20-29 years old, married or in exclusive relationships. Overall, 39.9% of users were using the app to prevent pregnancy, 38.5% to plan a pregnancy, and 21.6% were tracking their cycles. Among the users preventing pregnancy, 64.1% of women had not used a family planning method 3 months before downloading the CycleBeads app. One-third of users who were using the app to track their cycles, reported that they had not been using any form of family planning. In all seven countries, nearly 60% of women reported that they would definitely recommend the CycleBeads app to a friend, indicating their satisfaction with the app. CONCLUSIONS: Our main findings indicate that a social media campaign is a low-cost approach to making the CycleBeads app accessible to women. The app addresses multiple reproductive intentions and attracts a diverse demographic of users across different life stages. For many women the app was the first modern method they used in the last 3 months, showing that fertility awareness-based apps have the potential to address an unmet need. Future studies should focus on changes in behavior during the fertile window, partner communication, and future family planning intentions.

Atmospheric nitrogen deposition on petals enhances seed quality of the forest herb Anemone nemorosa.

Elevated atmospheric input of nitrogen (N) is currently affecting plant biodiversity and ecosystem functioning. The growth and survival of numerous plant species is known to respond strongly to N fertilisation. Yet, few studies have assessed the effects of N deposition on seed quality and reproductive performance, which is an important life-history stage of plants. Here we address this knowledge gap by assessing the effects of atmospheric N deposition on seed quality of the ancient forest herb Anemone nemorosa using two complementary approaches. By taking advantage of the wide spatiotemporal variation in N deposition rates in pan-European temperate and boreal forests over 2 years, we detected positive effects of N deposition on the N concentration (percentage N per unit seed mass, increased from 2.8% to 4.1%) and N content (total N mass per seed more than doubled) of A. nemorosa seeds. In a complementary experiment, we applied ammonium nitrate to aboveground plant tissues and the soil surface to determine whether dissolved N sources in precipitation could be incorporated into seeds. Although the addition of N to leaves and the soil surface had no effect, a concentrated N solution applied to petals during anthesis resulted in increased seed mass, seed N concentration and N content. Our results demonstrate that N deposition on the petals enhances bioaccumulation of N in the seeds of A. nemorosa. Enhanced atmospheric inputs of N can thus not only affect growth and population dynamics via root or canopy uptake, but can also influence seed quality and reproduction via intake through the inflorescences.

Genome-wide DNA methylation profiling reveals cancer-associated changes within early colonic neoplasia.

Colorectal cancer (CRC) is characterized by genome-wide alterations to DNA methylation that influence gene expression and genomic stability. Less is known about the extent to which methylation is disrupted in the earliest stages of CRC development. In this study, we have combined laser-capture microdissection with reduced representation bisulfite sequencing to identify cancer-associated DNA methylation changes in human aberrant crypt foci (ACF), the earliest putative precursor to CRC. Using this approach, methylation profiles have been generated for 10 KRAS-mutant ACF and 10 CRCs harboring a KRAS mutation, as well as matched samples of normal mucosa. Of 811 differentially methylated regions (DMRs) identified in ACF, 537 (66%) were hypermethylated and 274 (34%) were hypomethylated. DMRs located within intergenic regions were heavily enriched for AP-1 transcription factor binding sites and were frequently hypomethylated. Furthermore, gene ontology analysis demonstrated that DMRs associated with promoters were enriched for genes involved in intestinal development, including homeobox genes and targets of the Polycomb repressive complex 2. Consistent with their role in the earliest stages of colonic neoplasia, 75% of the loci harboring methylation changes in ACF were also altered in CRC samples, though the magnitude of change at these sites was lesser in ACF. Although aberrant promoter methylation was associated with altered gene expression in CRC, this was not the case in ACF, suggesting the insufficiency of methylation changes to modulate gene expression in early colonic neoplasia. Altogether, these data demonstrate that DNA methylation changes, including significant hypermethylation, occur more frequently in early colonic neoplasia than previously believed, and identify epigenomic features of ACF that may provide new targets for cancer chemoprevention or lead to the development of new biomarkers for CRC risk.

Military personnel sustaining Lisfranc injuries have high rates of disability separation.

OBJECTIVES: Lisfranc injuries are relatively uncommon midfoot injuries disproportionately affecting young, active males. Previous studies in civilian populations have reported relatively good results with operative treatment. However, treatment results have not been specifically examined in military personnel, who may have higher physical demands than the general population. The purpose of this study was to examine rates of return to military duty following surgical treatment of isolated Lisfranc injuries. METHODS: Surgical records and radiographic images from all active duty US military personnel treated for an isolated Lisfranc injury between January 2005 and July 2014 were examined. Demographic information, injury data, surgical details and subsequent return to duty information were recorded. The primary outcome was ability to return to unrestricted military duty following treatment. The secondary outcome was secondary conversion to a midfoot arthrodesis following initial open reduction internal fixation. RESULTS: Twenty-one patients meeting inclusion criteria were identified. Median patient age was 23 years, and mean follow-up was 43 months. Within this cohort, 14 patients were able to return to military service, while seven required a disability separation from the armed forces. Of the 18 patients who underwent initial fixation, eight were subsequently revised to midfoot arthrodesis for persistent pain. DISCUSSION: Military personnel sustaining Lisfranc injuries have high rates of persistent pain and disability, even after optimal initial surgical treatment. Military surgeons should counsel patients on the career-threatening nature of this condition and high rates of secondary procedures.

Stranger danger awareness in Williams syndrome.

BACKGROUND: The developmental disorder Williams syndrome (WS) is characterised by a distinctive cognitive profile and an intriguing social phenotype. Individuals with the disorder are often highly social engaging with familiar and unfamiliar people and once in an interaction they often show subtle abnormalities of social behaviour. Atypically increased approach to unfamiliar people is widely reported in the existing literature for both children and adults. Parents frequently report interactions with unfamiliar people as a major concern. METHODS: In this study we aimed to evaluate 'stranger danger' awareness using a video vignette task with individuals who had WS. When linked to other components of the WS phenotype (e.g. reduced intellectual ability, increased social approach) an awareness of stranger danger is particularly important. RESULTS: Qualitative and quantitative data showed that young people with WS have difficulties making judgements about whether or not to trust and engage in conversation with unfamiliar people. Qualitative data showed that individuals with WS often suggested that they would engage in an interaction with an unfamiliar person. CONCLUSIONS: The findings have substantial implications for the safety of young people with the disorder and emphasise the need for intervention regarding this behaviour.

Olfactory selection of Plantago lanceolata by snails declines with seedling age.

BACKGROUND AND AIMS: Despite recent recognition that (1) plant-herbivore interactions during the establishment phase, (2) ontogenetic shifts in resource allocation and (3) herbivore response to plant volatile release are each pivotal to a comprehensive understanding of plant defence, no study has examined how herbivore olfactory response varies during seedling ontogeny. METHODS: Using a Y-tube olfactometer we examined snail (Helix aspersa) olfactory response to pellets derived from macerated Plantago lanceolata plants harvested at 1, 2, 3, 4, 5, 6 and 8 weeks of age to test the hypothesis that olfactory selection of plants by a generalist herbivore varies with plant age. Plant volatiles were collected for 10 min using solid-phase microextraction technique on 1- and 8-week-old P. lanceolata pellets and analysed by gas chromatography coupled with a mass spectrometer. KEY RESULTS: Selection of P. lanceolata was strongly negatively correlated with increasing age; pellets derived from 1-week-old seedlings were three times more likely to be selected as those from 8-week-old plants. Comparison of plant selection experiments with plant volatile profiles from GC/MS suggests that patterns of olfactory selection may be linked to ontogenetic shifts in concentrations of green leaf volatiles and ethanol (and its hydrolysis derivatives). CONCLUSIONS: Although confirmatory of predictions made by contemporary plant defence theory, this is the first study to elucidate a link between seedling age and olfactory selection by herbivores. As a consequence, this study provides a new perspective on the ontogenetic expression of seedling defence, and the role of seedling herbivores, particularly terrestrial molluscs, as selective agents in temperate plant communities.

Targets for antibiotic and healthcare resource stewardship in inpatient community-acquired pneumonia: a comparison of management practices with National Guideline Recommendations.

PURPOSE: Community-acquired pneumonia (CAP) is the most common infection leading to hospitalization in the USA. The objective of this study was to evaluate management practices for inpatient CAP in relation to Infectious Diseases Society of America/American Thoracic Society (IDSA/ATS) guidelines to identify opportunities for antibiotic and health care resource stewardship. METHODS: This was a retrospective cohort study of adults hospitalized for CAP at a single institution from 15 April 2008 to 31 May 2009. RESULTS: Of the 209 patients with CAP who presented to Denver Health Medical Center during the study period and were hospitalized, 166 (79 %) and 43 (21 %) were admitted to a medical ward and the intensive care unit (ICU), respectively. Sixty-one (29 %) patients were candidates for outpatient therapy per IDSA/ATS guidance with a CURB-65 score of 0 or 1 and absence of hypoxemia. Sputum cultures were ordered for 110 specimens; however, an evaluable sample was obtained in only 49 (45 %) cases. Median time from antibiotic initiation to specimen collection was 11 [interquartile range (IQR) 6-19] h, and a potential pathogen was identified in only 18 (16 %) cultures. Blood cultures were routinely obtained for both non-ICU (81 %) and ICU (95 %) cases, but 15 of 36 (42 %) positive cultures were false-positive results. The most common antibiotic regimen was ceftriaxone + azithromycin (182, 87 % cases). Discordant with IDSA/ATS recommendations, oral step-down therapy consisted of a new antibiotic class in 120 (66 %), most commonly levofloxacin (101, 55 %). Treatment durations were typically longer than suggested with a median of 10 (IQR 8-12) days. CONCLUSIONS: In this cohort of patients hospitalized for CAP, management was frequently inconsistent with IDSA/ATS guideline recommendations, revealing potential targets to reduce unnecessary antibiotic and healthcare resource utilization.

Pomegranate juice and pomegranate extract do not impair oral clearance of flurbiprofen in human volunteers: divergence from in vitro results.

Nutrient interactions with prescription drugs are a topic of ongoing basic and clinical research. Pomegranate juice and a 1-g capsule containing pomegranate extract were evaluated in vitro and in vivo as inhibitors of cytochrome P450 2C9 (CYP2C9), with flurbiprofen serving as the index substrate. Fluconazole was the positive control inhibitor. The in vitro 50% inhibitory concentration (IC(50)) values for pomegranate juice and extract were below 1% (vol/vol), with no evidence of mechanism-based (irreversible) inhibition. In clinical studies, flurbiprofen pharmacokinetics were unchanged by pomegranate juice or extract as compared to a low-polyphenol placebo control beverage. However, fluconazole significantly reduced the oral clearance of flurbiprofen. Despite inhibition of CYP2C9 in vitro, pomegranate juice and extract had no effect on CYP2C9 activity in human subjects, and can be consumed by patients taking CYP2C9 substrate drugs with negligible risk of a pharmacokinetic interaction.

Initial experience with a rapid access blackouts triage clinic.

Transient loss of consciousness (T-LOC), or blackout, is common in acute medicine. Clinical skills are not done well, with at least 74,000 patients misdiagnosed and mistreated for epilepsy in England alone. The aim of this study was to provide a rapid, structured assessment and an electrocardiogram (ECG) for patients with blackouts, aiming to identify high risk, reduce misdiagnoses, reduce hospital admission rates for low-risk patients, diagnose and treat where appropriate, and also provide onward specialist referral. The majority of patients had syncope, and very few had epilepsy. A high proportion had an abnormal ECG. A specialist-nurse-led rapid access blackouts triage clinic (RABTC) provided rapid effective triage for risk, a comprehensive assessment format, direct treatment for many patients, and otherwise a prompt appropriate onward referral. Rapid assessment through a RABTC reduced re-admissions with blackouts. Widespread use of the web-based blackouts tool could provide the NHS with a performance map. The U.K. has low rates of pacing compared to Western Europe, which RABTCs might help correct. The RABTC sits between first responders and specialist referral, providing clinical assessment and ECG in all cases, and referral where appropriate.

Grapefruit juice, lyophilized grapefruit juice, and powdered whole grapefruit inhibit cytochrome P450-mediated triazolam hydroxylation by beagle dog liver microsomes.

Coadministration of grapefruit juice (GFJ) has been proposed to enhance the systemic availability and decrease the required dose of drugs such as cyclosporine that are extensively metabolized in the intestine and liver. Although GFJ inhibits human cytochrome P450 (CYP) 3A, effects on dog CYP have not yet been reported. Consequently, we determined whether GFJ inhibits triazolam hydroxylation by Beagle dog liver microsomes (DLM) using human liver microsomes (HLM) as positive control. Results were compared with the effects of lyophilized GFJ and commercially-available powdered grapefruit capsules, which may be more convenient dosage forms. GFJ inhibited alpha-hydroxytriazolam formation in both DLM and HLM with similar IC(50) (inhibitor concentration producing a 50% decrease in reaction velocity) values of 0.56% and 0.52% (v/v), respectively. Lyophilized GFJ and powdered grapefruit also inhibited DLM alpha-hydroxytriazolam formation with IC(50) values of 0.76 and 1.2 mg/mL, respectively. Consistent with mechanism-based enzyme inhibition, preincubation of DLM with any of the grapefruit products for 20 min resulted in significant enhancement of inhibition of triazolam alpha-hydroxylation by 8-20%. The results indicate that 16 g of lyophilized GFJ or 23 g of powdered grapefruit would be equivalent to dosing 100 mL of GFJ. In vivo pharmacokinetic interaction studies are needed to confirm these in vitro findings.

Synthesis of nucleoside 5'-O-alpha,beta-methylene-beta-triphosphates and evaluation of their potency towards inhibition of HIV-1 reverse transcriptase.

A polymer-bound alpha,beta-methylene-beta-triphosphitylating reagent was synthesized and subjected to reactions with unprotected nucleosides, followed by oxidation, deprotection of cyanoethoxy groups, and acidic cleavage to afford nucleoside 5'-O-alpha,beta-methylene-beta-triphosphates. Among all the compounds, cytidine 5'-O-alpha,beta-methylene-beta-triphosphate inhibited RNase H activity of HIV-1 reverse transcriptase with a K(i) value of 225 microM.

Davalintide (AC2307), a novel amylin-mimetic peptide: enhanced pharmacological properties over native amylin to reduce food intake and body weight.

OBJECTIVE: The current set of studies describe the in vivo metabolic actions of the novel amylin-mimetic peptide davalintide (AC2307) in rodents and compares these effects with those of the native peptide. RESEARCH DESIGN AND METHODS: The anti-obesity effects of davalintide were examined after intraperitoneal injection or sustained peripheral infusion through subcutaneously implanted osmotic pumps. The effect of davalintide on food intake after lesioning of the area postrema (AP) and neuronal activation as measured by c-Fos, were also investigated. RESULTS: Similar to amylin, davalintide bound with high affinity to amylin, calcitonin and calcitonin gene-related peptide receptors. Acutely, davalintide displayed greater suppression of dark-cycle feeding and an extended duration of action compared with amylin (23 versus 6 h). Davalintide had no effect on locomotor activity or kaolin consumption at doses that decreased food intake. Davalintide-induced weight loss through infusion was dose dependent, durable up to 8 weeks, fat-specific and lean-sparing, and was associated with a shift in food preference away from high-fat (palatable) chow. Metabolic rate was maintained during active weight loss. Both davalintide and amylin failed to suppress food intake after lesioning of the AP and activated similar brain nuclei, with davalintide displaying an extended duration of c-Fos expression compared with amylin (8 versus 2 h). CONCLUSION: Davalintide displayed enhanced in vivo metabolic activity over amylin while retaining the beneficial properties possessed by the native molecule. In vitro receptor binding, c-Fos expression and AP lesion studies suggest that the metabolic actions of davalintide and amylin occur through activation of similar neuronal pathways.

Impacts of seedling herbivory on plant competition and implications for species coexistence.

BACKGROUND AND AIMS: Although the causes and consequences of seedling herbivory for plant community composition are well understood, the mechanisms by which herbivores influence plant species recruitment to the established phase remain less clear. The aim was to examine how variation in the intensity of seedling herbivory interacts with growth-defence trade-offs and herbivore feeding preferences to affect plant community development. METHODS: Using 14-d-old seedlings of Trifolium pratense and T. repens, relative growth and susceptibility to herbivory by the snail Helix aspersa was quantified to elucidate putative growth-defence trade-offs for these species. Then mixed assemblages of 14-d-old Trifolium seedlings were exposed to herbivory by zero, two, five or ten snails and determined how variation in the intensity of herbivory affected competitive interactions into the mature phase (as measured by total plant biomass at 120 d old). KEY RESULTS: In the absence of herbivory, communities were dominated by T. pratense; a result expected on the basis that it yielded larger and presumably more competitive seedlings. However, when seedlings were exposed to herbivory, the balance of competition shifted. At low levels of herbivory (two snails), both Trifolium species contributed equally to total plant biomass. More intense herbivory (five snails) resulted in almost total mortality of T. pratense and dominance of the mature community by T. repens. The most intense herbivory (ten snails) effectively removed all seedlings from the experimental community. CONCLUSIONS: The study illustrates a mechanism whereby spatio-temporal fluctuations in seedling herbivory, when coupled with species-specific variation in competitive ability and sensitivity to herbivore attack, can differentially influence plant recruitment into the mature phase. This mechanism may be a key element in our attempts to understand plant species coexistence, since fluctuations in plant recruitment are fundamental to the many theories that view coexistence as a consequence of a spatio-temporal lottery for dominance over regeneration micro-sites.