Cholinergic Modulation of Locomotion and Striatal Dopamine Release Is Mediated by α6α4* Nicotinic Acetylcholine Receptors

Dopamine (DA) release in striatum is governed by firing rates of midbrain DA neurons, striatal cholinergic tone, and nicotinic ACh receptors (nAChRs) on DA presynaptic terminals. DA neurons selectively express α6* nAChRs, which show high ACh and nicotine sensitivity. To help identify nAChR subtypes that control DA transmission, we studied transgenic mice expressing hypersensitive α6^(L9’S*) receptors. α6^(L9’S) mice are hyperactive, travel greater distance, exhibit increased ambulatory behaviors such as walking, turning, and rearing, and show decreased pausing, hanging, drinking, and grooming. These effects were mediated by α6 α4* pentamers, as α6^(L9’S) mice lacking α4 subunits displayed essentially normal behavior. In α6^(L9’S) mice, receptor numbers are normal, but loss of α4 subunits leads to fewer and less sensitive α6* receptors. Gain-of-function nicotine-stimulated DA release from striatal synaptosomes requires α4 subunits, implicating α6α4β2* nAChRs in α6^(L9’S) mouse behaviors. In brain slices, we applied electrochemical measurements to study control of DA release by α6^(L9’S) nAChRs. Burst stimulation of DA fibers elicited increased DA release relative to single action potentials selectively in α6^(L9’S), but not WT or α4KO/ α6^(L9’S), mice. Thus, increased nAChR activity, like decreased activity, leads to enhanced extracellular DA release during phasic firing. Bursts may directly enhance DA release from α6^(L9’S) presynaptic terminals, as there was no difference in striatal DA receptor numbers or DA transporter levels or function in vitro. These results implicate α6α4β2* nAChRs in cholinergic control of DA transmission, and strongly suggest that these receptors are candidate drug targets for disorders involving the DA system

TRX: A Formally Verified Parser Interpreter

Parsing is an important problem in computer science and yet surprisingly little attention has been devoted to its formal verification. In this paper, we present TRX: a parser interpreter formally developed in the proof assistant Coq, capable of producing formally correct parsers. We are using parsing expression grammars (PEGs), a formalism essentially representing recursive descent parsing, which we consider an attractive alternative to context-free grammars (CFGs). From this formalization we can extract a parser for an arbitrary PEG grammar with the warranty of total correctness, i.e., the resulting parser is terminating and correct with respect to its grammar and the semantics of PEGs; both properties formally proven in Coq.Comment: 26 pages, LMC

Modelling and managing project complexity

The Architecture, Engineering and Construction (AEC) industry, like many others, is increasingly aware of the need to improve efficiency and effectiveness to thrive in an increasingly competitive marketplace. A key discovery in their search for improvements is the benefits of repeatability in both processes and products. However, although the latter has seen significant advances, such as the adoption of pre-assembly and standardised components and systems, the industry has experienced far greater difficulties identifying ways of capturing, understanding, and replicating work processes. The identification and removal of waste from the process can only be achieved once the process has been captured. Their repeated use and development, combined with analysis with the Analytical Design Planning Technique, enable the improvement of work practices and culture in terms of integration, decision-making and reductions in re-work

Association between surgical volume and failure of primary total hip replacement in England and Wales: findings from a prospective national joint replacement register

Objective To investigate the association of volume of total hip arthroplasty (THA) between consultants and within the same consultant in the previous year and the hazard of revision using multilevel survival models. Design Prospective cohort study using data from a national joint replacement register. Setting Elective THA across all private and public centres in England and Wales between April 2003 and February 2017. Participants Patients aged 50 years or more undergoing THA for osteoarthritis. Intervention The volume of THA conducted in the preceding 365 days to the index procedure. Main outcome and measure Revision surgery (excision, addition or replacement) of a primary THA. Results Of the 579 858 patients undergoing primary THA (mean baseline age 69.8 years (SD 10.2)), 61.1% were women. Multilevel survival found differing results for between and within-consultant effects. There was a strong volume–revision association between consultants, with a near-linear 43.3% (95% CI 29.1% to 57.4%) reduction of the risk of revision comparing consultants with volumes between 1 and 200 procedures annually. Changes in individual surgeons (within-consultant) case volume showed no evidence of an association with revision. Conclusion Separation of between-consultant and within- consultant effects of surgical volume reveals how volume contributes to the risk of revision after THA. The lack of association within-consultants suggests that individual changes to consultant volume alone will have little effect on outcomes following THA. These novel findings provide strong evidence supporting the practice of specialisation of hip arthroplasty. It does not support the practice of low-volume consultants increasing their personal volume as it is unlikely their results would improve if this is the only change. Limiting the exposure of patients to consultants with low volumes of THA and greater utilisation of centres with higher volume surgeons with better outcomes may be beneficial to patients

Carbonate-hosted methanotrophy represents an unrecognized methane sink in the deep sea

The atmospheric flux of methane from the oceans is largely mitigated through microbially mediated sulphate-coupled methane oxidation, resulting in the precipitation of authigenic carbonates. Deep-sea carbonates are common around active and palaeo-methane seepage, and have primarily been viewed as passive recorders of methane oxidation; their role as active and unique microbial habitats capable of continued methane consumption has not been examined. Here we show that seep-associated carbonates harbour active microbial communities, serving as dynamic methane sinks. Microbial aggregate abundance within the carbonate interior exceeds that of seep sediments, and molecular diversity surveys reveal methanotrophic communities within protolithic nodules and well-lithified carbonate pavements. Aggregations of microbial cells within the carbonate matrix actively oxidize methane as indicated by stable isotope FISH–nanoSIMS experiments and ^(14)CH_4 radiotracer rate measurements. Carbonate-hosted methanotrophy extends the known ecological niche of these important methane consumers and represents a previously unrecognized methane sink that warrants consideration in global methane budgets

Additive Manufacturing, Modeling and Performance Evaluation of 3D Printed Fins for Surfboards

We demonstrate that Additive Manufacturing (3D printing) is a viable approach to rapidly prototype personalised fins for surfboards. Surfing is an iconic sport that is extremely popular in coastal regions around the world. We use computer aided design and 3D printing of a wide range of composite materials to print fins for surfboards, e.g. ABS, carbon fibre, fibre glass and amorphous thermoplastic poly(etherimide) resins. The mechanical characteristics of our 3D printed fins were found to be comparable to commercial fins. Computational fluid dynamics was employed to calculate longitudinal (drag) and tangential (turning) forces, which are important for surfboard maneuverability, stability and speed. A commercial tracking system was used to evaluate the performance of 3D printed fins under real-world conditions (i.e. surfing waves). These data showed that the surfing performance of surfboards with 3D printed fins is similar to that of surfboards with commercial fins

Evidence for a Heterogeneous Distribution of Water in the Martian Interior

The abundance and distribution of H2O within the terrestrial planets, as well as its timing of delivery, is a topic of vital importance for understanding the chemical and physical evolution of planets and their potential for hosting habitable environments. Analysis of planetary materials from Mars, the Moon, and the eucrite parent body (i.e., asteroid 4Vesta) have confirmed the presence of H2O within their interiors. Moreover, H and N isotopic data from these planetary materials suggests H2O was delivered to the inner solar system very early from a common source, similar in composition to the carbonaceous chondrites. Despite the ubiquity of H2O in the inner Solar System, the only destination with any prospects for past or present habitable environments at this time, outside of the Earth, is Mars. Although the presence of H2O within the martian interior has been confirmed, very little is known regarding its abundance and distribution within the martian interior and how the martian water inventory has changed over time. By combining new analyses of martian apatites within a large number of martian meteorite types with previously published volatile data and recently determined mineral-melt partition coefficients for apatite, we report new insights into the abundance and distribution of volatiles in the martian crust and mantle. Using the subset of samples that did not exhibit crustal contamination, we determined that the enriched shergottite mantle source has 36-73 ppm H2O and the depleted shergottite mantle source has 14-23 ppm H2O. This result is consistent with other observed geochemical differences between enriched and depleted shergottites and supports the idea that there are at least two geochemically distinct reservoirs in the martian mantle. We also estimated the H2O content of the martian crust using the revised mantle H2O abundances and known crust-mantle distributions of incompatible lithophile elements. We determined that the bulk martian crust has approximately 1400 ppm H2O, which is likely distributed toward the martian surface. This crustal water abundance would equate to a global equivalent layer (GEL) of water at a depth of-229 m, which can account for at least some of the surface features on Mars attributed to flowing water and may be sufficient to support the past presence of a shallow sea on Mars' surface

Targeting the LOX/hypoxia axis reverses many of the features that make pancreatic cancer deadly: inhibition of LOX abrogates metastasis and enhances drug efficacy

Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer‐related mortality. Despite significant advances made in the treatment of other cancers, current chemotherapies offer little survival benefit in this disease. Pancreaticoduodenectomy offers patients the possibility of a cure, but most will die of recurrent or metastatic disease. Hence, preventing metastatic disease in these patients would be of significant benefit. Using principal component analysis (PCA), we identified a LOX/hypoxia signature associated with poor patient survival in resectable patients. We found that LOX expression is upregulated in metastatic tumors from Pdx1‐Cre KrasG12D/+ Trp53R172H/+ (KPC) mice and that inhibition of LOX in these mice suppressed metastasis. Mechanistically, LOX inhibition suppressed both migration and invasion of KPC cells. LOX inhibition also synergized with gemcitabine to kill tumors and significantly prolonged tumor‐free survival in KPC mice with early‐stage tumors. This was associated with stromal alterations, including increased vasculature and decreased fibrillar collagen, and increased infiltration of macrophages and neutrophils into tumors. Therefore, LOX inhibition is able to reverse many of the features that make PDAC inherently refractory to conventional therapies and targeting LOX could improve outcome in surgically resectable disease

Food anticipatory activity on a calorie-restricted diet is independent of Sirt1

A number of studies have demonstrated that the Sirtuin family member, Sirt1, is a key integrator of growth, metabolism, and lifespan. Sirt1 directly interacts with and deacetylates key regulators of the circadian clock, positioning it to be an important link between feeding and circadian rhythms. In fact, one study suggests that Sirt1 is necessary for behavioral anticipation of limited daily food availability, a circadian process termed food anticipatory activity (FAA). In their study, mice overexpressing Sirt1 had enhanced FAA, while mice lacking Sirt1 had little to no FAA. Based on the supposition that Sirt1 was indeed required for FAA, we sought to use Sirt1 deletion to map the neural circuitry responsible for FAA. We began by inactivating Sirt1 using the cell-type specific Cre-driver lines proopiomelanocortin, but after observing no effect on body weight loss or FAA we then moved on to more broadly neuronal Cre drivers Ca2+/calmodulin-dependent protein kinase II and nestin. As neither of these neuronal deletions of Sirt1 had impaired FAA, we then tested 1) a broad postnatal tamoxifen-inducible deletion, 2) a complete, developmental knockout of Sirt1, and 3) a gene replacement, catalytically inactive, form of Sirt1; but all of these mice had FAA similar to controls. Therefore, our findings suggest that FAA is completely independent of Sirt1