REDD+, hype, hope and disappointment : The dynamics of expectations in conservation and development pilot projects

We explore the dynamics of expectations in international forest conservation and development programs, and the impacts and implications of (unfulfilled) expectations for actors involved. Early stages of new international conservation and development programs, often involving pilot projects designed to test intervention concepts at village level, are characterized by large amounts of resources and attention, along with high expectations of success. However, evidence shows that these early expectations are rarely fulfilled. Despite this repeated pattern and growing engagement with expectations in critical conservation and development literature, little is known about the dynamics of expectations in conservation and development pilot projects. We address this knowledge gap first by exploring concepts from the sociology of expectations. We then unpack expectations in a case study of REDD+ pilot projects in Tanzania, using extensive qualitative data reflecting the perspectives and experiences of a wide range of actors involved. Our study finds that expectations play a performative role, mobilizing actors and resources, despite uncertainty identified among policy-makers and practitioners. We also find that once raised, expectations are dynamic and continually mediated by actors and social contexts, which conflicts with attempts to ‘manage’ them. We argue therefore that a trade-off exists between fully piloting new initiatives and raising expectations. We also argue that failure to address this trade-off has implications beyond pilot project objectives and timelines, which are experienced most acutely by village communities. We argue for more critical engagement with expectations and the embedding of accountability for expectations in conservation and development practice. Our findings also challenge the discourse of ‘needing’ to pilot, which prioritizes awareness, impact and innovation without fully considering the potential negative impact of unfulfilled expectations

Praziquantel activates a native cation current in Schistosoma mansoni

IntroductionPraziquantel (PZQ), an anthelmintic drug discovered in the 1970s, is still used to treat schistosomiasis and various other infections caused by parasitic flatworms. PZQ causes a triad of phenotypic effects on schistosome worms – rapid depolarization, muscle contraction, and damage throughout the worm tegument. The molecular target mediating these effects has been intimated as a Ca2+-permeable ion channel, but native currents evoked by PZQ have not been reported in any schistosome cell type. The properties of the endogenous PZQ activated conductance therefore remain unknown. MethodsHere, invasive electrophysiology was used to probe for responses to PZQ from different locales in a living schistosome worm.Results and discussionNo direct response was seen in tegument-derived vesicles, or from the sub-tegumental muscle layer despite the presence of voltage-operated currents. However, PZQ rapidly triggered a sustained, non-selective cation current in recordings from neuronal tissue, targeting both the anterior ganglion and the main longitudinal nerve cord. The biophysical signature of this PZQ-evoked current resolved at single channel resolution matched that of a transient receptor potential ion channel named TRPMPZQ, recently proposed as the molecular target of PZQ. The endogenous PZQ-evoked current was also inhibited by a validated TRPMPZQ antagonist. PZQ therefore is a neuroactive anthelmintic, causing a sustained depolarization through ion channels with the characteristics of TRPMPZQ

TRP drop, TRP drop: a steady patter of anti-schistosomal target illumination

Infections caused by parasitic flatworms impart a significant disease burden. This is well exemplified by the neglected tropical disease schistosomiasis, which afflicts millions of people worldwide. The anti-schistosomal activity of various chemotypes has been known for decades, but the parasite targets of many of these remain undefined. Until recently, this included the current clinical therapy, praziquantel (PZQ). However, the tempo of target discovery has recently gathered pace, with discoveries of schistosome targets for praziquantel (PZQ) and the anthelmintic benzodiazepine, meclonazepam (MCLZ). This steady patter of target illumination has also revealed a pattern in that both PZQ and MCLZ target members of the same ion channel subgroup—transient receptor potential ion channels of the melastatin family (TRPM channels). PZQ activates one member of this family (TRPMPZQ) and MCLZ activates a different channel (TRPMMCLZ). Here, similarities and differences between these two new targets are discussed. These data highlight the need for further study of TRPM channels in parasitic flatworms given their vulnerability to chemotherapeutic attack

The anthelmintic praziquantel is a human serotoninergic G-protein-coupled receptor ligand

Schistosomiasis is a debilitating tropical disease caused by infection with parasitic blood flukes. Approximately 260 million people are infected worldwide, underscoring the clinical and socioeconomic impact of this chronic infection. Schistosomiasis is treated with the drug praziquantel (PZQ), which has proved the therapeutic mainstay for over three decades of clinical use. However, the molecular target(s) of PZQ remain undefined. Here we identify a molecular target for the antischistosomal eutomer - (R)-PZQ - which functions as a partial agonist of the human serotoninergic 5HT2B receptor. (R)-PZQ modulation of serotoninergic signaling occurs over a concentration range sufficient to regulate vascular tone of the mesenteric blood vessels where the adult parasites reside within their host. These data establish (R)-PZQ as a G-protein-coupled receptor ligand and suggest that the efficacy of this clinically important anthelmintic is supported by a broad, cross species polypharmacology with PZQ modulating signaling events in both host and parasite

Effects of the pattern of glucocorticoid replacement on neural processing, emotional reactivity and well-being in healthy male individuals:study protocol for a randomised controlled trial

BACKGROUND: Deviation from the physiological glucocorticoid dynamics (circadian and underlying ultradian rhythmicity) is a common characteristic of various neuropsychiatric and endocrine disorders as well as glucocorticoid-based therapeutics. These states may be accompanied by neuropsychiatric symptomatology, suggesting continuous dynamic glucocorticoid equilibrium is essential for brain homeostasis. METHODS/DESIGN: The study consists of two parts. The preliminary stage of the study aims to validate (technically and pharmacologically) and optimise three different patterns of systemic cortisol administration in man. These patterns are based on the combinatory administration of metyrapone, to suppress endogenous cortisol production, and concurrent hydrocortisone replacement. The second, subsequent, core part of the study is a randomised, double-blinded, placebo-controlled, crossover study, where participants (healthy male individuals aged 18–60 years) will undergo all three hydrocortisone replacement schemes. During these infusion regimes, we plan a number of neurobehavioural tests and imaging of the brain to assess neural processing, emotional reactivity and perception, mood and self-perceived well-being. The psychological tests include: ecological momentary assessment, P1vital Oxford Emotional Test Battery and Emotional Potentiated Startle Test, Leeds Sleep Evaluation Questionnaire and the visual working memory task (n-back). The neuroimaging protocol combines magnetic resonance sequences that capture data related to the functional and perfusion status of the brain. DISCUSSION: Results of this clinical trial are designed to evaluate the impact (with possible mechanistic insights) of different patterns of daily glucocorticoid dynamics on neural processing and reactivity related to emotional perception and mood. This evidence should contribute to the optimisation of the clinical application of glucocorticoid-based therapeutics. TRIAL REGISTRATION: UK Clinical Research Network, IRAS Ref: 106181, UKCRN-ID-15236 (23 October 2013

PTF11eon/SN2011dh: Discovery of a Type IIb Supernova From a Compact Progenitor in the Nearby Galaxy M51

On May 31, 2011 UT a supernova (SN) exploded in the nearby galaxy M51 (the Whirlpool Galaxy). We discovered this event using small telescopes equipped with CCD cameras, as well as by the Palomar Transient Factory (PTF) survey, and rapidly confirmed it to be a Type II supernova. Our early light curve and spectroscopy indicates that PTF11eon resulted from the explosion of a relatively compact progenitor star as evidenced by the rapid shock-breakout cooling seen in the light curve, the relatively low temperature in early-time spectra and the prompt appearance of low-ionization spectral features. The spectra of PTF11eon are dominated by H lines out to day 10 after explosion, but initial signs of He appear to be present. Assuming that He lines continue to develop in the near future, this SN is likely a member of the cIIb (compact IIb; Chevalier and Soderberg 2010) class, with progenitor radius larger than that of SN 2008ax and smaller than the eIIb (extended IIb) SN 1993J progenitor. Our data imply that the object identified in pre-explosion Hubble Space Telescope images at the SN location is possibly a companion to the progenitor or a blended source, and not the progenitor star itself, as its radius (~10^13 cm) would be highly inconsistent with constraints from our post-explosion photometric and spectroscopic data

In Situ Monitoring of Intracellular Glucose and Glutamine in CHO Cell Culture

The development of processes to produce biopharmaceuticals industrially is still largely empirical and relies on optimizing both medium formulation and cell line in a product-specific manner. Current small-scale (well plate-based) process development methods cannot provide sufficient sample volume for analysis, to obtain information on nutrient utilization which can be problematic when processes are scaled to industrial fermenters. We envision a platform where essential metabolites can be monitored non-invasively and in real time in an ultra-low volume assay in order to provide additional information on cellular metabolism in high throughput screens. Towards this end, we have developed a model system of Chinese Hamster Ovary cells stably expressing protein-based biosensors for glucose and glutamine. Herein, we demonstrate that these can accurately reflect changing intracellular metabolite concentrations in vivo during batch and fed-batch culture of CHO cells. The ability to monitor intracellular depletion of essential nutrients in high throughput will allow rapid development of improved bioprocesses

Integral Role of Water in the Solid-State Behavior of the Antileishmanial Drug Miltefosine

The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link. Open access articleMiltefosine is a repurposed anticancer drug and currently the only orally administered drug approved to treat the neglected tropical disease leishmaniasis. Miltefosine is hygroscopic and must be stored at sub-zero temperatures. In this work we report the X-ray structures of miltefosine monohydrate and methanol solvate, along with 12- and 14-carbon chain analogue hydrates and a solvate. The three hydrates are all isostructural and are conformational isomorphs with Z' = 2. The water bridges the gap between phosphocholine head groups caused by the interdigitated bilayer structure. The two methanol solvates are also mutually isostructural with the head groups adopting a more extended conformation. Again, the solvent bridges the gap between head groups in the bilayer. No anhydrous form of miltefosine or its analogues were isolated, with dehydration resulting in significantly reduced crystallinity. This arises as a result of the integral role that hydrogen bond donors (in the form of water or solvent molecules) play in the stability of the zwitterionic structures

Mechanisms of SARS-CoV-2 neutralization by shark variable new antigen receptors elucidated through X-ray crystallography

Acknowledgements This work was supported by the Chief Scientist Office, Scottish Government, Grant COV/ABN/20/01 (Elasmogen, Ltd.), a 2018 Prostate Cancer Foundation Challenge Award (AML), a 2013 Prostate Cancer Foundation Young Investigator Award (AML), NCI R01s CA237272, CA233562, and CA245922 (AML). WEM was supported by the NIH T32 HL007741 and JMT by the NIH T32 AI055433. JSM was funded by NIGMS R01 GM088790. HA was funded by NIGMS R35 GM118047 and NCI P01 CA234228. X-ray diffraction data were collected at the Northeastern Collaborative Access Team beamlines, which are funded by the US National Institutes of Health (NIGMS P30 GM124165). The Pilatus 6M detector on 24-ID-C beamline is funded by a NIH-ORIP HEI grant (S10 RR029205). We thank the Marco Pravetoni lab for providing training and access to the OctetRED96e for BLI experiments.Peer reviewedPublisher PD