Assessing the potential for reopening a building stone quarry : Newbigging Sandstone Quarry, Fife

Newbigging Sandstone Quarry in Fife is one of a number of former quarries in the Burntisland- Aberdour district which exploited the pale-coloured Grange Sandstone from Lower Carboniferous rocks. The quarry supplied building stone from the late 19th century, working intermittently from 1914 until closure in 1937, and again when reopened in the 1970s to the 1990s. The stone was primarily used locally and to supply the nearby markets in the Scottish Central Belt. Historical evidence indicates that prior to sandstone extraction, the area was dominated by largescale quarrying and mining of limestone, and substantial sandstone quarrying is likely to have begun after the arrival of the main railway line in 1890. It is probable that removal of the sandstone was directly associated with limestone exploitation, and that the quarried sandstone was effectively a by-product of limestone production. Sandstone extraction was probably viable due to the existing limestone quarry infrastructure (workforce, equipment, transportation) and the high demand for building stone in Central Scotland in the late 19th century. The geology within Newbigging Sandstone Quarry is dominated by thick-bedded uniform sandstone with a wide joint spacing, well-suited for obtaining large blocks. However, a mudstone (shale) band is likely to be present within a few metres of the principal (north) face of the quarry, around which the sandstone bed thickness and quality is likely to decrease. The mudstone bed forms a plane sloping at a shallow angle to the north, so that expansion of the quarry in this direction is likely to encounter a considerable volume of poor quality stone. Additionally, an east-west trending fault is present approximately 100 metres north of the quarry face, which is also likely to be associated with poor quality (fractured) stone

Neural circuitry and immunity

Research during the last decade has significantly advanced our understanding of the molecular mechanisms at the interface between the nervous system and the immune system. Insight into bidirectional neuroimmune communication has characterized the nervous system as an important partner of the immune system in the regulation of inflammation. Neuronal pathways, including the vagus nerve-based inflammatory reflex are physiological regulators of immune function and inflammation. In parallel, neuronal function is altered in conditions characterized by immune dysregulation and inflammation. Here, we review these regulatory mechanisms and describe the neural circuitry modulating immunity. Understanding these mechanisms reveals possibilities to use targeted neuromodulation as a therapeutic approach for inflammatory and autoimmune disorders. These findings and current clinical exploration of neuromodulation in the treatment of inflammatory diseases defines the emerging field of Bioelectronic Medicine

Making Rasch decisions: the use of Rasch analysis in the construction of preference based health related quality of life instruments

Objective: To set out the methodological process for using Rasch analysis alongside traditional psychometric methods in the development of a health state classification that is amenable to valuation. Methods: The overactive bladder questionnaire is used to illustrate a four step process for deriving a reduced health state classification from an existing nonpreference based health related quality of life instrument. Step I excludes items that do not meet the initial validation process and step II uses criteria based on Rasch analysis and psychometric testing to select the final items for the health state classification. In step III, item levels are examined and Rasch analysis is used to explore the possibility of reducing the number of item levels. Step IV repeats steps I to III on alternative data sets in order to validate the selection of items for the health state classification. Conclusions: The techniques described enable the construction of a health state classification amenable for valuation exercises that will allow the derivation of preference weights. Thus, the health related quality of life of patients with conditions, like overactive bladder, can be valued and quality adjustment weights such as quality adjusted life years derived.Rasch analysis; health related quality of life; condition specific measure; preference-based measures; overactive bladder syndrome

Sepsis: Current Dogma and New Perspectives

Sepsis, a clinical syndrome occurring in patients following infection or injury, is a leading cause of morbidity andmortality worldwide. Current immunological mechanisms do not explain the basis of cellular dysfunction and organ failure, the ultimate cause of death. Here we review current dogma and argue that it is time to delineate novel immunometabolic and neurophysiological mechanisms underlying the altered cellular bioenergetics and failure of epithelial and endothelial barriers that produce organ dysfunction and death. These mechanisms might hold the key to future therapeutic strategies

Generation Of Design Equations In Asynchronous Sequential Circuits

One step in the synthesis procedure for realizing an asynchronous sequential switching circuit is the generation of next-state and output state equations from a simplified and coded flow table description of the circuit. The usual approach for determining these equations is to first construct a state table from the coded flow table, and then construct transition and output tables. For large flow tables this can be quite a lengthy procedure. This note describes an algorithm which simplifies the synthesis procedure for normal fundamental-mode circuits by permitting the determination of these equations without explicit construction of the state table, transition table, or output table. The algorithm has been programmed in PL/1. Copyright © 1969 by The Institute of Electrical and Electronics Engineers, Inc

High-mobility Group Box 1 Protein Initiates Postoperative Cognitive Decline by Engaging Bone Marrow-derived Macrophages

Background: Aseptic trauma engages the innate immune response to trigger a neuroinflammatory reaction that results in postoperative cognitive decline. The authors sought to determine whether high-mobility group box 1 protein (HMGB1), an ubiquitous nucleosomal protein, initiates this process through activation and trafficking of circulating bone marrow-derived macrophages to the brain. Methods: The effects of HMGB1 on memory (using trace fear conditioning) were tested in adult C57BL/6J male mice; separate cohorts were tested after bone marrow-derived macrophages were depleted by clodrolip. The effect of anti-HMGB1 neutralizing antibody on the inflammatory and behavioral responses to tibial surgery were investigated. Results: A single injection of HMGB1 caused memory decline, as evidenced by a decrease in freezing time (52 11% vs. 39 +/- 5%; n = 16-17); memory decline was prevented when bone marrow-derived macrophages were depleted (39 +/- 5% vs. 50 +/- 9%; n = 17). Disabling HMGB1 with a blocking monoclonal antibody, before surgery, reduced postoperative memory decline (52 +/- 11% vs. 29 +/- 5%; n = 15-16); also, hippocampal expression of monocyte chemotactic protein-1 was prevented by the neutralizing antibody (n = 6). Neither the systemic nor the hippocampal inflammatory responses to surgery occurred in mice pretreated with anti-HMGB1 neutralizing antibody (n = 6). Conclusion: Postoperative neuroinflammation and cognitive decline can be prevented by abrogating the effects of HMGB1. Following the earlier characterization of the resolution of surgery-induced memory decline, the mechanisms of its initiation are now described. Together, these data may be used to preoperatively test the risk to surgical patients for the development of exaggerated and prolonged postoperative memory decline that is reflected in delirium and postoperative cognitive dysfunction, respectively

Cortico-brainstem mechanisms of biased perceptual decision-making in the context of pain

Perceptual decision-making is commonly studied using stimuli with different physical properties but of comparable affective value. Here, we investigate neural processes underlying human perceptual decisions in the affectively rich domain of pain using a drift-diffusion model in combination with a probabilistic cueing paradigm. This allowed us to characterize a novel role for the dorsolateral prefrontal cortex (DLPFC), whose anticipatory responses reflecting a decision bias were dependent on the affective value of the stimulus. During intense noxious stimulation, these model-based anticipatory DLPFC responses were linked to an engagement of the periaqueductal gray (PAG), a midbrain region implicated in defensive responses including analgesia. Complementing these findings on biased decision-making, the model parameter reflecting sensory processing predicted subcortical responses (in amygdala and PAG) when expectations were violated. Our findings highlight the importance of taking a broader perspective on perceptual decisions and link decisions about pain with subcortical circuitry implicated in endogenous pain modulation

Monoclonal Antibodies Capable of Binding SARS-CoV-2 Spike Protein Receptor Binding Motif Specifically Prevent GM-CSF Induction.

A severe acute respiratory syndrome (SARS)-like coronavirus (SARS-CoV-2) has recently caused a pandemic COVID-19 disease that infected more than 25.6 million and killed 852,000 people worldwide. Like the SARS-CoV, SARS-CoV-2 also employs a receptor-binding motif (RBM) of its envelope spike protein for binding the host angiotensin-converting enzyme 2 (ACE2) to gain viral entry. Currently, extensive efforts are being made to produce vaccines against a surface fragment of a SARS-CoV-2, such as the spike protein, in order to boost protective antibody responses. It was previously unknown how spike protein-targeting antibodies would affect innate inflammatory responses to SARS-CoV-2 infections. Here we generated a highly purified recombinant protein corresponding to the RBM of SARS-CoV-2, and used it to screen for cross-reactive monoclonal antibodies (mAbs). We found two RBM-binding mAbs that competitively inhibited its interaction with human ACE2, and specifically blocked the RBM-induced GM-CSF secretion in both human monocyte and murine macrophage cultures. Our findings have suggested a possible strategy to prevent SARS-CoV-2-elicited cytokine storm , and provided a potentially useful criteria for future assessment of innate immune-modulating properties of various SARS-CoV-2 vaccines. One Sentence Summary: RBM-binding Antibodies Inhibit GM-CSF Induction