The mass of (1) Ceres from perturbations on (348) May

The most promising ground-based technique for determining the mass of a minor planet is the observation of the perturbations it induces in the motion of another minor planet. This method requires careful observation of both minor planets over extended periods of time. The mass of (1) Ceres has been determined from the perturbations on (348) May, which made three close approaches to Ceres at intervals of 46 years between 1891 and 1984. The motion of May is clearly influenced by Ceres, and by using different test masses for Ceres, a search was made to determine the mass of Ceres that minimizes the residuals in the observations of May

A novel live cell assay to measure diacylglycerol lipase α activity

Diacylglycerol lipase α (DAGLα) hydrolyses DAG to generate the principal endocannabinoid (eCB) 2-arachidonoylglycerol (2-AG) in the central nervous system. DAGLα dependent cannabinoid (CB) signalling has been implicated in numerous processes including axonal growth and guidance, adult neurogenesis and retrograde signalling at the synapse. Recent studies have implicated DAGLα as an emerging drug target for several conditions including pain and obesity. Activity assays are critical to the drug discovery process; however, measurement of diacylglycerol lipase (DAGL) activity using its native substrate generally involves low-throughput MS techniques. Some relatively high-throughput membrane based assays utilizing surrogate substrates have been reported, but these do not take into account the rate-limiting effects often associated with the ability of a drug to cross the cell membrane. In the present study, we report the development of a live cell assay to measure DAGLα activity. Two previously reported DAGLα surrogate substrates, p-nitrophenyl butyrate (PNPB) and 6,8-difluoro-4-methylumbelliferyl octanoate (DiFMUO), were evaluated for their ability to detect DAGLα activity in live cell assays using a human cell line stably expressing the human DAGLα transgene. Following optimization, the small molecule chromogenic substrate PNPB proved to be superior by providing lower background activity along with a larger signal window between transfected and parental cells when compared with the fluorogenic substrate DiFMUO. The assay was further validated using established DAGL inhibitors. In summary, the live cell DAGLα assay reported here offers an economical and convenient format to screen for novel inhibitors as part of drug discovery programmes and compliments previously reported high-throughput membrane based DAGL assays

Amorphous Solid Dispersions of Lidocaine and Lidocaine HCl Produced by Ball Milling with Well-Defined RAFT-Synthesised Methacrylic Acid Polymers

This study focuses on the use of methacrylic acid polymers synthesised via the Reversible Addition Fragmentation chain Transfer (RAFT) polymerisation method for the production of amorphous solid dispersions (ASDs) by ball milling, to kinetically solubilize a poorly water-soluble model drug. The solid-state characteristics and the physical stability of the formulations were investigated using X-ray diffraction, differential scanning calorimetry, and infrared spectroscopy. This was followed by dissolution studies in different media. It was discovered that the acidic polymers of methacrylic acid were capable of interacting with the weakly basic drug lidocaine and its hydrochloride salt form to produce ASDs when a polymer to drug ratio of 70:30 w/w was used. The ASDs remained amorphous following storage under accelerated aging conditions (40 °C and 75% relative humidity) over 8 months. Fast dissolution and increased lidocaine solubility in different media were obtained from the ASDs owing to the reduced microenvironment pH and enhanced solubilization of the drug caused by the presence of the acidic polymer in the formulation. Production of ASDs using well-defined RAFT-synthesised acidic polymers is a promising formulation strategy to enhance the pharmaceutical properties of basic poorly water-soluble drugs

Automated, high accuracy classification of Parkinsonian disorders: a pattern recognition approach

Progressive supranuclear palsy (PSP), multiple system atrophy (MSA) and idiopathic Parkinson’s disease (IPD) can be clinically indistinguishable, especially in the early stages, despite distinct patterns of molecular pathology. Structural neuroimaging holds promise for providing objective biomarkers for discriminating these diseases at the single subject level but all studies to date have reported incomplete separation of disease groups. In this study, we employed multi-class pattern recognition to assess the value of anatomical patterns derived from a widely available structural neuroimaging sequence for automated classification of these disorders. To achieve this, 17 patients with PSP, 14 with IPD and 19 with MSA were scanned using structural MRI along with 19 healthy controls (HCs). An advanced probabilistic pattern recognition approach was employed to evaluate the diagnostic value of several pre-defined anatomical patterns for discriminating the disorders, including: (i) a subcortical motor network; (ii) each of its component regions and (iii) the whole brain. All disease groups could be discriminated simultaneously with high accuracy using the subcortical motor network. The region providing the most accurate predictions overall was the midbrain/brainstem, which discriminated all disease groups from one another and from HCs. The subcortical network also produced more accurate predictions than the whole brain and all of its constituent regions. PSP was accurately predicted from the midbrain/brainstem, cerebellum and all basal ganglia compartments; MSA from the midbrain/brainstem and cerebellum and IPD from the midbrain/brainstem only. This study demonstrates that automated analysis of structural MRI can accurately predict diagnosis in individual patients with Parkinsonian disorders, and identifies distinct patterns of regional atrophy particularly useful for this process

Coral reef ecosystem services in the Anthropocene

Coral reefs underpin a range of ecosystem goods and services that contribute to the well‐being of millions of people. However, tropical coral reefs in the Anthropocene are likely to be functionally different from reefs in the past. In this perspective piece, we ask, what does the Anthropocene mean for the provision of ecosystem services from coral reefs? First, we provide examples of the provisioning, regulating, cultural and supporting services underpinned by coral reef ecosystems. We conclude that coral reef ecosystem service research has lagged behind multidisciplinary advances in broader ecosystem services science, such as an explicit recognition that interactions between social and ecological systems underpin ecosystem services. Second, drawing on tools from functional ecology, we outline how these social–ecological relationships can be incorporated into a mechanistic understanding of service provision and how this might be used to anticipate future changes in coral reef ecosystem services. Finally, we explore the emergence of novel reef ecosystem services, for example from tropicalized coastlines, or through changing technological connections to coral reefs. Indeed, when services are conceived as coming from social–ecological system dynamics, novelty in services can emerge from elements of the interactions between people and the ecosystem. This synthesis of the coral reef ecosystem services literature suggests the field is poorly prepared to understand the changing service provision anticipated in the Anthropocene. A new research agenda is needed that better connects reef functional ecology to ecosystem service provision. This research agenda should embrace more holistic approaches to ecosystem service research, recognizing them as co‐produced by ecosystems and society. Importantly, the likelihood of novel ecosystem service configurations requires further conceptualization and empirical assessment. As with current ecosystem services, the loss or gain of services will not affect all people equally and must be understood in the context in which they occur. With the uncertainty surrounding the future of coral reefs in the Anthropocene, research exploring how the benefits to people change will be of great importance

Guiding coral reef futures in the Anthropocene

Anthropogenic changes to the Earth now rival those caused by the forces of nature and have shepherded us into a new planetary epoch – the Anthropocene. Such changes include profound and often unexpected alterations to coral reef ecosystems and the services they provide to human societies. Ensuring that reefs and their services endure during the Anthropocene will require that key drivers of coral reef change – fishing, water quality, and anthropogenic climate change – stay within acceptable levels or “safe operating spaces”. The capacity to remain within these safe boundaries hinges on understanding the local, but also the increasingly global and cross-scale, socioeconomic causes of these human drivers of change. Consequently, local and regional management efforts that are successful in the short term may ultimately fail if current decision making and institution-building around coral reef systems remains fragmented, poorly coordinated, and unable to keep pace with the escalating speed of social, technological, and ecological change

Long-lived metal complexes open up microsecond lifetime imaging microscopy under multiphoton excitation: from FLIM to PLIM and beyond

Lifetime imaging microscopy with sub-micron resolution provides essential understanding of living systems by allowing both the visualisation of their structure, and the sensing of bio-relevant analytes in vivo using external probes. Chemistry is pivotal for the development of the next generation of bio-tools, where contrast, sensitivity, and molecular specificity facilitate observation of processes fundamental to life. A fundamental limitation at present is the nanosecond lifetime of conventional fluorescent probes which typically confines the sensitivity to sub-nanosecond changes, whilst nanosecond background autofluorescence compromises the contrast. High-resolution visualization with complete background rejection and simultaneous mapping of bio-relevant analytes including oxygen – with sensitivity orders of magnitude higher than that currently attainable – can be achieved using time-resolved emission imaging microscopy (TREM) in conjunction with probes with microsecond (or longer) lifetimes. Yet the microsecond timescale has so far been incompatible with available multiphoton excitation/detection technologies. Here we realize for the first time microsecond-imaging with multiphoton excitation whilst maintaining the essential sub-micron spatial resolution. The new method is background-free and expands available imaging and sensing timescales 1000-fold. Exploiting the first engineered water-soluble member of a family of remarkably emissive platinum-based, microsecond-lived probes amongst others, we demonstrate (i) the first instance of background-free multiphoton-excited microsecond depth imaging of live cells and histological tissues, (ii) over an order-of-magnitude variation in the probe lifetime in vivo in response to the local microenvironment. The concept of two-photon TREM can be seen as “FLIM + PLIM” as it can be used on any timescale, from ultrafast fluorescence of organic molecules to slower emission of transition metal complexes or lanthanides/actinides, and combinations thereof. It brings together transition metal complexes as versatile emissive probes with the new multiphoton-excitation/microsecond-detection approach to create a transformative framework for multiphoton imaging and sensing across biological, medicinal and material sciences