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Precambrian sedimentary successions are difficult to date and correlate. In the Scottish Highlands, potential correlations between the thick, undeformed siliciclastic \"Torridonian\" successions in the foreland of the Caledonian Orogen and the highly deformed and metamorphosed siliciclastic Moine succession within the Caledonian Orogen have long intrigued geologists. New and detailed mapping of the Neoproterozoic Altnaharra Formation (Morar Group, lowest Moine Supergroup) in Sutherland has discovered low-strain zones exhibiting well-preserved sedimentary features. The formation comprises 3-5 km of coarse, thick-bedded psammite with abundant nested trough and planar cross-bedding bedforms, defining metre-scale channels. Palaeocurrent directions are broadly unimodal to the NNE-ENE. We interpret the Altnaharra Formation as high-energy, braided fluvial deposits. The Altnaharra Formation and the unmetamorphosed, Neoproterozoic Applecross-Aultbea formations (Torridon Group) are similar in terms of lithology, stratigraphical thickness, sedimentology, geochemistry, detrital zircon ages and stratigraphical position on Archaean basement. Depositional age constraints for both successions overlap and are coeval with late Grenvillean orogenic activity. Detrital zircons imply similar source regions from the Grenville Orogen. The Morar and Torridon groups can thus be correlated across the Caledonian Moine Thrust and are best explained as parts of a single, large-scale, orogen-parallel foreland basin to the Grenville Orogen.

As computational scientists continue to demand higher performance, the use of parallelism is becoming more pervasive. Workstations with multiple CPU's are no longer unusual. With higher performance networks, clusters of workstations or PCs networked together have become a cost-effective parallel machine for high performance computing. A variety of parallel programming languages and sophisticated compiler technology has been developed for gaining efficient use of the available parallelism. Programmers often have to be concerned with ensuring that communication and synchronization between processes are correctly achieved in addition to programming computational components. For efficiency, most parallel programming paradigms allow for nondeterministic execution, in which processes do not synchronize after every statement. Instead processes execute at different speeds such that different sequences of statements are executed during different runs of the program with the same input data. Parallel programmers find software tools for performance analysis and debugging very valuable, but otherwise there is a lack of software tools for parallel programmers. In particular, little to no support for testing parallel programs exists. Many structural testing methodologies and algorithms for generating test data automatically have been developed and successfully used for testing sequential programs. Some progress has been made in the analysis, testing, and debugging of Ada-like concurrent programs. Also, there has been considerable work in analyzing parallel programs for the detection of deadlock and race conditions, debugging, and optimizing analysis and transformation. The current testing methodologies target concurrent programs with rendezvous communication, hence, do not support the testing of programs using more general synchronization and communication features. Without further consideration, structural testing methodologies used for testing sequential programs cannot be applied to parallel programs. The main objective of this research has been to demonstrate that program-based methodologies can be used to generate test cases automatically for shared memory parallel programs. That is, even when a formal specification is lacking, software testing of shared memory parallel programs can still be performed in a systematic fashion with the aid of software testing tools. The contributions of this research include the following. The framework for testing sequential programs is extended to support parallel program testing, taking into account the nondeterministic nature of parallel programs. A novel algorithm is presented to generate a du-path coverage with respect to a define and use pair, i.e., du-pair, for shared memory parallel programs. Modifications to this algorithm in order to test parallel programs with message passing and rendezvous communication are described. With the goal of exposing synchronization errors, a temporal testing method is presented with the capability of automatically generating temporal test suites. Because the total number of possible temporal test cases is exponential, several approaches to reducing the size of a temporal test suite are presented. The methodologies developed in this dissertation have been implemented and incorporated into a software testing tool, called della pasta, which provides a practical and user-friendly interface for visualizing a du-pair and a path coverage in a shared memory parallel program. (Abstract shortened by UMI.)

Central nervous system neurons communicate via fast synaptic transmission mediated by ligand-gated ion channel (LGIC) receptors and slower neuromodulation mediated by G protein-coupled receptors (GPCRs). These receptors influence many neuronal functions, including presynaptic neurotransmitter release. Presynaptic LGIC and GPCR activation by locally released neurotransmitters influences neuronal communication in ways that modify effects of somatic action potentials. Although much is known about presynaptic receptors and their mechanisms of action, less is known about when and where these receptor actions alter release, especially in vivo. This Review focuses on emerging evidence for important local presynaptic receptor actions and ideas for future studies in this area.Local activation of presynaptic receptors alters neurotransmitter release, modulating effects of somatic action potentials. In this Review, Lovinger et al. discuss the role of presynaptic receptors in regulating synaptic transmission and directions for future research aimed at determining the in vivo roles of presynaptic receptors.

Exposure to psychostimulants results in structural and synaptic plasticity in striatal medium spiny neurons (MSNs). These cellular adaptations arise from alterations in genes that are highly implicated in the rearrangement of the actin-cytoskeleton, such as T-lymphoma invasion and metastasis 1 (Tiam1). Previous studies have demonstrated a crucial role for dopamine receptor 1 (D1)-containing striatal MSNs in mediating psychostimulant induced plasticity changes. These D1-MSNs in the nucleus accumbens (NAc) positively regulate drug seeking, reward, and locomotor behavioral effects as well as the morphological adaptations of psychostimulant drugs. Here, we demonstrate that rats that actively self-administer cocaine display reduced levels of Tiam1 in the NAc. To further examine the cell type-specific contribution to these changes in Tiam1 we used optogenetics to selectively manipulate NAc D1-MSNs or dopamine receptor 2 (D2) expressing MSNs. We find that repeated channelrhodopsin-2 activation of D1-MSNs but not D2-MSNs caused a down-regulation of Tiam1 levels similar to the effects of cocaine. Further, activation of D2-MSNs, which caused a late blunted cocaine-mediated locomotor behavioral response, did not alter Tiam1 levels. We then examined the contribution of D1-MSNs to the cocaine-mediated decrease of Tiam1. Using the light activated chloride pump, eNpHR3.0 (enhanced Natronomonas pharaonis halorhodopsin 3.0), we selectively inhibited D1-MSNs during cocaine exposure, which resulted in a behavioral blockade of cocaine-induced locomotor sensitization. Moreover, inhibiting these NAc D1-MSNs during cocaine exposure reversed the down-regulation of Tiam1 gene expression and protein levels. These data demonstrate that altering activity in specific neural circuits with optogenetics can impact the underlying molecular substrates of psychostimulant-mediated behavior and function.

The World Health Organization (WHO) public health framework for healthy aging advocates for action on the trajectories of intrinsic capacity (IC) across a person's life course to optimize functional ability. While the WHO integrated care for older people (ICOPE) framework provides guidance on a systematic care pathway on IC screening, clinical assessment to clarify IC deficits and person-centered management, its real-world implementation and evaluation remain nascent. The Intrinsic Capacity Promotion in Primary Care for the Frail (IMPACTFrail) program for mildly frail older adults in Singapore's primary care seeks to operationalize WHO ICOPE and national strategies. The objectives of this study are (1) the co-development of IMPACTFrail's core functions and its delivery, as well as selecting, specifying and operationalizing implementation strategies to address anticipated barriers and leverage anticipated facilitators and (2) to conduct a feasibility assessment on the readiness to scale to a main study. For the first objective, the co-development process is guided by the United Kingdom Medical Research Council's (MRC's) framework for developing and evaluating complex interventions and the Framework of Actions for Intervention Development (FAID). The identification of contextual barriers and facilitators will draw on the updated Consolidated Framework for Implementation Research (CFIR) and its Outcomes Addendum. To identify individual-level behavior change barriers, we will extend this framework using the Theoretical Domains Framework (TDF). The Expert Recommendations for Implementing Change (ERIC) taxonomy guided our selection and development of implementation strategies. The collaboration involves implementation researchers, clinic leadership, frontline health care providers, and older adults. A 12-month, single-arm feasibility study will recruit 180 older adults aged 60 years and older with mild frailty (Clinical Frailty Scale score 4-5) across 5 public primary care clinics. Feasibility criteria include implementation, acceptability, practicality, and adaptability. We will narratively triangulate findings across study components to enhance the validity and credibility of the feasibility study, including (1) process evaluation using quantitative process indicators, (2) qualitative study to elicit barriers and facilitators to feasibility, sustainability and scalability, and to assess the attribution of the selected implementation strategies to implementation outcomes, (3) cost analysis, and (4) program description. The study was funded in September 2024. Data collection for the feasibility assessment commenced in April 2025 and will conclude by March 2026. As of manuscript submission, 98 participants have been recruited across 5 sites. Recruitment, data collection, and analysis are ongoing. Publication of results is expected in early 2027. This protocol contributes to the literature by providing a detailed protocol on the co-development and feasibility testing of a complex intervention to enhance transparency, fidelity, and replicability. It disseminates knowledge on the integration of frameworks and methodologies to accelerate the translation of evidence to sustainable and scalable programs in practice. ClinicalTrials.gov NCT06753643; https://clinicaltrials.gov/study/NCT06753643. DERR1-10.2196/84257.

Background: Researchers are increasingly using grounded theory methodologies to study the professional experience of nurses and midwives. Aim: To review common grounded theory characteristics and research design quality as described in grounded theory studies of coping strategies used by nurses and midwives. Methods: A systematic database search for 2005-2015 identified and assessed grounded theory characteristics from 16 studies. Study quality was assessed using a modified Critical Appraisal Skills Programme tool. Findings: Grounded theory was considered a methodology or a set of methods, able to be used within different nursing and midwifery contexts. Specific research requirements determined the common grounded theory characteristics used in different studies. Most researchers did not clarify their epistemological and theoretical perspectives. Conclusion: To improve research design and trustworthiness of grounded theory studies in nursing and midwifery, researchers need to state their theoretical stance and clearly articulate their use of grounded theory methodology and characteristics in research reporting.

Abstract Wound healing is a complex process involving four overlapping phases: haemostasis, inflammation, cell recruitment and matrix remodeling. In mouse models, surgical, pharmacological and genetic approaches targeting androgen actions in skin have shown that androgens increase interleukin-6 and tumor necrosis factor-α production and reduce wound re-epithelization and matrix deposition, retarding cutaneous wound healing. Similarly, clinical studies have shown that cutaneous wound healing is slower in men compared to women. However, in major burn injury, which triggers not only local wound-healing processes but also systemic hypermetabolism, the role of androgens is poorly understood. Recent studies have claimed that a synthetic androgen, oxandrolone, increases protein synthesis, improves lean body mass and shortens length of hospital stay. However, the possible mechanisms by which oxandrolone regulates major burn injury have not been reported. In this review, we summarize the current findings on the roles of androgens in cutaneous and major burn wound healing, as well as androgens as a potential therapeutic treatment option for patients with major burn injuries.

When an organism responds for a reward, its learned behavior can be characterized as goal-directed or habitual based on whether or not it is susceptible to reward devaluation. Here, we evaluated whether instrumental responding for brain stimulation reward (BSR) can be devalued using a paradigm traditionally used for natural rewards. Rats were trained to lever press for BSR; afterward, BSR was paired with either lithium chloride (LiCl, 5 mg/kg, i.p.), a pro-emetic, or AM251, a CB1 receptor antagonist (3 mg/kg, i.p.) or the vehicle of these compounds. Pairings of BSR with these compounds and their vehicles were performed in a novel environment so that only unconditional effects of BSR would be affected by the pharmacological manipulations. Subsequently, in a probe test, all rats were returned in the drug-free state to the boxes where they had received training and instrumental responding was reassessed in the absence of BSR delivery. When compared to control, LiCl produced a significant decrease in the number of responses during the test session, whereas AM251 did not. These results show that instrumental responding for BSR is susceptible to devaluation, in accord with the proposal that this behavior is supported at least in part by associations between the response and the rewarding outcome. Further, they suggest that reward modulation observed in studies involving the use of CB1 receptor antagonists arises from changes in the organism's motivation rather than drug-induced changes in the intrinsic value of reward.

Sign-tracking rats show enhanced cue sensitivity before drug experience that predicts greater discrete cue-induced drug-seeking compared to goal-tracking or intermediate- rats. Cue-evoked dopamine in the nucleus Accumbens (NAc) is a neurobiological signature of sign-tracking behaviors. Here, we examine a critical regulator of the dopamine system; endocannabinoids, which bind the cannabinoid receptor-1 (CB1R) in the Ventral Tegmental Area (VTA) to control cue-evoked striatal dopamine levels. We use cell-type specific optogenetics, intra-VTA pharmacology and fiber photometry to test the hypothesis that VTA CB1R receptor signaling regulates NAc dopamine levels to control sign-tracking. We trained rats in a Pavlovian lever autoshaping task (PLA) to determine their tracking groups before testing the effect of VTA to NAc dopamine inhibition. We found this circuit is critical for mediating the vigor of the ST response. Upstream of this circuit, intra-VTA infusions of rimonabant, a CB1R inverse agonist, during PLA decrease lever and increase foodcup approach in sign-tracking rats. Using fiber photometry to measure fluorescent signals from dopamine sensor, GRABDA, we tested the effects of intra-VTA rimonabant on NAc dopamine dynamics during autoshaping. We found that intra-VTA rimonabant-induced decreases in sign-tracking behaviors are not associated with changes to phasic cue(CS)-evoked NAc dopamine activity. Instead, intra-VTA rimonabant increases NAc shell, but not core, dopamine levels during reward delivery (US). Our results suggest that CB1R signaling in the VTA influences the balance between the CS- and US-evoked dopamine responses in the NAc shell and biases behavioral responding to cues in sign-tracking rats.Competing Interest StatementThe authors have declared no competing interest.Footnotes* This revision contains new analyses and additional text revisions requested in first round of peer review