CuAAC click chemistry for the enhanced detection of novel alkyne-based natural product toxins

In the context of discovering and quantifying terminal alkyne-based natural products, here we report the combination of CuAAC click chemistry with LC-MS for the detection of polyether toxins (prymnesins) associated with harmful algal blooms. The added-value of the CuAAC-based approach is evident from our ability to detect novel prymnesin-like compounds in algal species with previously uncharacterised toxins

CASPER plus (CollAborative care in Screen-Positive EldeRs with major depressive disorder): study protocol for a randomised controlled trial

Background: Depression accounts for the greatest disease burden of all mental health disorders, contributes heavily to healthcare costs, and by 2020 is set to become the second largest cause of global disability. Although 10% to 16% of people aged 65 years and over are likely to experience depressive symptoms, the condition is under-diagnosed and often inadequately treated in primary care. Later-life depression is associated with chronic illness and disability, cognitive impairment and social isolation. With a progressively ageing population it becomes increasingly important to refine strategies to identity and manage depression in older people. Currently, management may be limited to the prescription of antidepressants where there may be poor concordance; older people may lack awareness of psychosocial interventions and general practitioners may neglect to offer this treatment option. Methods/design: CASPER Plus is a multi-centre, randomised controlled trial of a collaborative care intervention for individuals aged 65 years and over experiencing moderate to severe depression. Selected practices in the North of England identify potentially eligible patients and invite them to participate in the study. A diagnostic interview is carried out and participants with major depressive disorder are randomised to either collaborative care or usual care. The recruitment target is 450 participants. The intervention, behavioural activation and medication management in a collaborative care framework, has been adapted to meet the complex needs of older people. It is delivered over eight to 10 weekly sessions by a case manager liaising with general practitioners. The trial aims to evaluate the clinical and cost effectiveness of collaborative care in addition to usual GP care versus usual GP care alone. The primary clinical outcome, depression severity, will be measured with the Patient Health Questionnaire-9 (PHQ-9) at baseline, 4, 12 and 18 months. Cost effectiveness analysis will assess health-related quality of life using the SF-12 and EQ-5D and will examine cost-consequences of collaborative care. A qualitative process evaluation will be undertaken to explore acceptability, gauge the extent to which the intervention is implemented and to explore sustainability beyond the clinical trial. Discussion: Results will add to existing evidence and a positive outcome may lead to the commissioning of this model of service in primary care. Trial registration: ISRCTN45842879 (24 July 2012)

Insights into toxic prymnesium parvum blooms:The role of sugars and algal viruses

Prymnesium parvum is a toxin-producing microalga that causes harmful algal blooms globally, which often result in large-scale fish kills that have severe ecological and economic implications. Although many toxins have previously been isolated from P. parvum, ambiguity still surrounds the responsible ichthyotoxins in P. parvum blooms and the biotic and abiotic factors that promote bloom toxicity. A major fish kill attributed to P. parvum occurred in Spring 2015 on the Norfolk Broads, a low-lying set of channels and lakes (Broads) found on the East of England. Here, we discuss how water samples taken during this bloom have led to diverse scientific advances ranging from toxin analysis to discovery of a new lytic virus of P. parvum, P. parvum DNA virus (PpDNAV-BW1). Taking recent literature into account, we propose key roles for sialic acids in this type of viral infection. Finally, we discuss recent practical detection and management strategies for controlling these devastating blooms

Molecular and cellular mechanisms underlying the evolution of form and function in the amniote jaw.

The amniote jaw complex is a remarkable amalgamation of derivatives from distinct embryonic cell lineages. During development, the cells in these lineages experience concerted movements, migrations, and signaling interactions that take them from their initial origins to their final destinations and imbue their derivatives with aspects of form including their axial orientation, anatomical identity, size, and shape. Perturbations along the way can produce defects and disease, but also generate the variation necessary for jaw evolution and adaptation. We focus on molecular and cellular mechanisms that regulate form in the amniote jaw complex, and that enable structural and functional integration. Special emphasis is placed on the role of cranial neural crest mesenchyme (NCM) during the species-specific patterning of bone, cartilage, tendon, muscle, and other jaw tissues. We also address the effects of biomechanical forces during jaw development and discuss ways in which certain molecular and cellular responses add adaptive and evolutionary plasticity to jaw morphology. Overall, we highlight how variation in molecular and cellular programs can promote the phenomenal diversity and functional morphology achieved during amniote jaw evolution or lead to the range of jaw defects and disease that affect the human condition

Assessing the toxicity and mitigating the impact of harmful Prymnesium blooms in eutrophic waters of the Norfolk Broads

Prymnesium parvum is a toxin-producing microalga, which causes harmful algal blooms globally, frequently leading to massive fish kills that have adverse ecological and economic implications for natural waterways and aquaculture alike. The dramatic effects observed on fish are thought to be due to algal polyether toxins, known as the prymnesins, but their lack of environmental detection has resulted in an uncertainty about the true ichthyotoxic agents. Using qPCR, we found elevated levels of P. parvum and its lytic virus, PpDNAV-BW1, in a fish-killing bloom on the Norfolk Broads, United Kingdom, in March 2015. We also detected, for the first time, the B-type prymnesin toxins in Broads waterway samples and gill tissue isolated from a dead fish taken from the study site. Furthermore, Norfolk Broads P. parvum isolates unambiguously produced B-type toxins in laboratory-grown cultures. A 2 year longitudinal study of the Broads study site showed P. parvum blooms to be correlated with increased temperature and that PpDNAV plays a significant role in P. parvum bloom demise. Finally, we used a field trial to show that treatment with low doses of hydrogen peroxide represents an effective strategy to mitigate blooms of P. parvum in enclosed water bodies

Expanding Stereochemical and Skeletal Diversity Using Petasis Reactions and 1,3-Dipolar Cycloadditions

A short and modular synthetic pathway using intramolecular 1,3-dipolar cycloaddition reactions and yielding functionalized isoxazoles, isoxazolines, and isoxazolidines is described. The change in shape of previous compounds and those in this study is quantified and compared using principal moment-of-inertia shape analysis.Chemistry and Chemical Biolog