Arctic Science and the Nuclear Submarine

... The entire Arctic Ocean has now ceased to be remote and is open to study on a year-round basis by nuclear submarines (Strong 1961). Admittedly, there are limitations to the use of a nuclear submarine for arctic research, but the advantages heavily out-weigh the disadvantages. First among the advantages to be gained through the use of this type of vehicle is mobility (Lyon and Boyle 1962). The nuclear submarine is a self-contained community capable of operating under all arctic conditions for extended periods of time. Its mobility is not a function of pre-determined drift patterns, for the submarine can be directed to any desired place, at a wide range of speed and depth. With its special equipment, such as underwater television and SONAR, it can "see" and "hear" below the surface (Steele 1962). There is adequate space for modest laboratory facilities, a controlled atmosphere, and accommodation for a scientific staff, who are comfortable and have every incentive for conducting research (Molloy 1961). Another advantage, and an equally important one, is the natural protection that the arctic environment offers to the submarine. The polar ice pack that presents such serious obstacles to the conduct of oceanographic research from the surface can be used to advantage by the nuclear submarine. It provides a nearly homogeneous environment free from disturbances of weather and other factors that the oceanographer encounters in the open ocean. The advantages of submarine research in the Arctic are even more readily apparent after evaluating the accomplishments of the U.S. Navy's arctic submarine cruises during the past few years. The floor of the Arctic Ocean was sounded continuously during each cruise (Lyon and Boyle 1962). As a result of this, there is now more information available on the bathymetry of the Arctic Ocean than had been obtained during the previous 75 years of arctic exploration. We have now more data relating to the ice pack over broad areas and under various seasonal conditions than ever before. Ice and water samples, as well as bathythermograph observations, also have been obtained at various points in the arctic basin (LaFond 1960). In addition the submarine itself has been a prime research tool whose advantages have not been limited to being a vehicle for transportation (Lyon and Boyle 1962). For example, surfacings through the ice have answered some of the questions relating to the ice cover. In many respects the Arctic has been the laboratory and the submarine the instrument with which the research was carried out (Lyon 1961). The arctic cruises of the U.S. Navy submarines have not been conducted as purely oceanographic ventures, but diversified scientific programs have been carried out during each of the cruises (Strong 1961). It is manifest from these modest beginnings that the nuclear submarine is an ideal platform from which to launch a research program of rather large dimensions. ..

Bitopic binding mode of an M1 muscarinic acetylcholine receptor agonist associated with adverse clinical trial outcomes

The realisation of the therapeutic potential of targeting the M1 muscarinic acetylcholine receptor (M1 mAChR) for the treatment of cognitive decline in Alzheimer's disease has prompted the discovery of M1 mAChR ligands showing efficacy in alleviating cognitive dysfunction in both rodents and humans. Among these is GSK1034702, described previously as a potent M1 receptor allosteric agonist, which showed pro-cognitive effects in rodents and improved immediate memory in a clinical nicotine withdrawal test but induced significant side-effects. Here we provide evidence using ligand binding, chemical biology and functional assays to establish that rather than the allosteric mechanism claimed, GSK1034702 interacts in a bitopic manner at the M1 mAChR such that it can concomitantly span both the orthosteric and an allosteric binding site. The bitopic nature of GSK1034702 together with the intrinsic agonist activity and a lack of muscarinic receptor subtype selectivity reported here, all likely contribute to the adverse effects of this molecule in clinical trials. We conclude that these properties, whilst imparting beneficial effects on learning and memory, are undesirable in a clinical candidate due to the likelihood of adverse side effects. Rather, our data supports the notion that "pure" positive allosteric modulators showing selectivity for the M1 mAChR with low levels of intrinsic activity would be preferable to provide clinical efficacy with low adverse responses

Monomeric PcrA helicase processively unwinds plasmid lengths of DNA in the presence of the initiator protein RepD

The helicase PcrA unwinds DNA during asymmetric replication of plasmids, acting with an initiator protein, in our case RepD. Detailed kinetics of PcrA activity were measured using bulk solution and a single-molecule imaging technique to investigate the oligomeric state of the active helicase complex, its processivity and the mechanism of unwinding. By tethering either DNA or PcrA to a microscope coverslip surface, unwinding of both linear and natural circular plasmid DNA by PcrA/RepD was followed in real-time using total internal reflection fluorescence microscopy. Visualization was achieved using a fluorescent single-stranded DNA-binding protein. The single-molecule data show that PcrA, in combination with RepD, can unwind plasmid lengths of DNA in a single run, and that PcrA is active as a monomer. Although the average rate of unwinding was similar in single-molecule and bulk solution assays, the single-molecule experiments revealed a wide distribution of unwinding speeds by different molecules. The average rate of unwinding was several-fold slower than the PcrA translocation rate on single-stranded DNA, suggesting that DNA unwinding may proceed via a partially passive mechanism. However, the fastest dsDNA unwinding rates measured in the single-molecule unwinding assays approached the PcrA translocation speed measured on ssDNA

Models and metaphors: complexity theory and through-life management in the built environment

Complexity thinking may have both modelling and metaphorical applications in the through-life management of the built environment. These two distinct approaches are examined and compared. In the first instance, some of the sources of complexity in the design, construction and maintenance of the built environment are identified. The metaphorical use of complexity in management thinking and its application in the built environment are briefly examined. This is followed by an exploration of modelling techniques relevant to built environment concerns. Non-linear and complex mathematical techniques such as fuzzy logic, cellular automata and attractors, may be applicable to their analysis. Existing software tools are identified and examples of successful built environment applications of complexity modelling are given. Some issues that arise include the definition of phenomena in a mathematically usable way, the functionality of available software and the possibility of going beyond representational modelling. Further questions arising from the application of complexity thinking are discussed, including the possibilities for confusion that arise from the use of metaphor. The metaphor of a 'commentary machine' is suggested as a possible way forward and it is suggested that an appropriate linguistic analysis can in certain situations reduce perceived complexity

Spiritual Well-Being and Depression in Patients with Heart Failure

BACKGROUND: In patients with chronic heart failure, depression is common and associated with poor quality of life, more frequent hospitalizations, and higher mortality. Spiritual well-being is an important, modifiable coping resource in patients with terminal cancer and is associated with less depression, but little is known about the role of spiritual well-being in patients with heart failure. OBJECTIVE: To identify the relationship between spiritual well-being and depression in patients with heart failure. DESIGN: Cross-sectional study. PARTICIPANTS: Sixty patients aged 60 years or older with New York Heart Association class II–IV heart failure. MEASUREMENTS: Spiritual well-being was measured using the total scale and 2 subscales (meaning/peace, faith) of the Functional Assessment of Chronic Illness Therapy—Spiritual Well-being scale, depression using the Geriatric Depression Scale—Short Form (GDS-SF). RESULTS: The median age of participants was 75 years. Nineteen participants (32%) had clinically significant depression (GDS-SF > 4). Greater spiritual well-being was strongly inversely correlated with depression (Spearman’s correlation −0.55, 95% confidence interval −0.70 to −0.35). In particular, greater meaning/peace was strongly associated with less depression (r = −.60, P < .0001), while faith was only modestly associated (r = −.38, P < .01). In a regression analysis accounting for gender, income, and other risk factors for depression (social support, physical symptoms, and health status), greater spiritual well-being continued to be significantly associated with less depression (P = .05). Between the 2 spiritual well-being subscales, only meaning/peace contributed significantly to this effect (P = .02) and accounted for 7% of the variance in depression. CONCLUSIONS: Among outpatients with heart failure, greater spiritual well-being, particularly meaning/peace, was strongly associated with less depression. Enhancement of patients’ sense of spiritual well-being might reduce or prevent depression and thus improve quality of life and other outcomes in this population

Recent advances in organic synthesis using light-mediated n-heterocyclic carbene catalysis

The combination of photocatalysis with other ground state catalytic systems have attracted much attention recently due to the enormous synthetic potential offered by a dual activation mode. The use of N-heterocyclic carbene (NHC) as organocatalysts emerged as an important synthetic tool. Its ability to harness umpolung reactivity by the formation of the Breslow intermediate has been employed in the synthesis of thousands of biologically important compounds. However, the available coupling partners are relatively restricted, and its combination with other catalytic systems might improve its synthetic versatility. Thus, merging photoredox and N-heterocyclic carbene (NHC) catalysis has emerged recently as a powerful strategy to develop new transformations and give access to a whole new branch of synthetic possibilities. This review compiles the NHC catalyzed methods mediated by light, either in the presence or absence of an external photocatalyst, that have been described so far, and aims to give an accurate overview of the potential of this activation modeL.M. acknowledges the Autonomous Community of Madrid (CAM) for the financial support (PEJD-2019-PRE/AMB-16640 and SI1/PJI/ 2019-00237) and for an “Atracción de Talento Investigador” contract (2017-T2/AMB-5037

M1 muscarinic allosteric modulators slow prion neurodegeneration and restore memory loss.

The current frontline symptomatic treatment for Alzheimer's disease (AD) is whole-body upregulation of cholinergic transmission via inhibition of acetylcholinesterase. This approach leads to profound dose-related adverse effects. An alternative strategy is to selectively target muscarinic acetylcholine receptors, particularly the M1 muscarinic acetylcholine receptor (M1 mAChR), which was previously shown to have procognitive activity. However, developing M1 mAChR-selective orthosteric ligands has proven challenging. Here, we have shown that mouse prion disease shows many of the hallmarks of human AD, including progressive terminal neurodegeneration and memory deficits due to a disruption of hippocampal cholinergic innervation. The fact that we also show that muscarinic signaling is maintained in both AD and mouse prion disease points to the latter as an excellent model for testing the efficacy of muscarinic pharmacological entities. The memory deficits we observed in mouse prion disease were completely restored by treatment with benzyl quinolone carboxylic acid (BQCA) and benzoquinazoline-12 (BQZ-12), two highly selective positive allosteric modulators (PAMs) of M1 mAChRs. Furthermore, prolonged exposure to BQCA markedly extended the lifespan of diseased mice. Thus, enhancing hippocampal muscarinic signaling using M1 mAChR PAMs restored memory loss and slowed the progression of mouse prion disease, indicating that this ligand type may have clinical benefit in diseases showing defective cholinergic transmission, such as AD

Case Reports1. A Late Presentation of Loeys-Dietz Syndrome: Beware of TGFβ Receptor Mutations in Benign Joint Hypermobility

Background: Thoracic aortic aneurysms (TAA) and dissections are not uncommon causes of sudden death in young adults. Loeys-Dietz syndrome (LDS) is a rare, recently described, autosomal dominant, connective tissue disease characterized by aggressive arterial aneurysms, resulting from mutations in the transforming growth factor beta (TGFβ) receptor genes TGFBR1 and TGFBR2. Mean age at death is 26.1 years, most often due to aortic dissection. We report an unusually late presentation of LDS, diagnosed following elective surgery in a female with a long history of joint hypermobility. Methods: A 51-year-old Caucasian lady complained of chest pain and headache following a dural leak from spinal anaesthesia for an elective ankle arthroscopy. CT scan and echocardiography demonstrated a dilated aortic root and significant aortic regurgitation. MRA demonstrated aortic tortuosity, an infrarenal aortic aneurysm and aneurysms in the left renal and right internal mammary arteries. She underwent aortic root repair and aortic valve replacement. She had a background of long-standing joint pains secondary to hypermobility, easy bruising, unusual fracture susceptibility and mild bronchiectasis. She had one healthy child age 32, after which she suffered a uterine prolapse. Examination revealed mild Marfanoid features. Uvula, skin and ophthalmological examination was normal. Results: Fibrillin-1 testing for Marfan syndrome (MFS) was negative. Detection of a c.1270G > C (p.Gly424Arg) TGFBR2 mutation confirmed the diagnosis of LDS. Losartan was started for vascular protection. Conclusions: LDS is a severe inherited vasculopathy that usually presents in childhood. It is characterized by aortic root dilatation and ascending aneurysms. There is a higher risk of aortic dissection compared with MFS. Clinical features overlap with MFS and Ehlers Danlos syndrome Type IV, but differentiating dysmorphogenic features include ocular hypertelorism, bifid uvula and cleft palate. Echocardiography and MRA or CT scanning from head to pelvis is recommended to establish the extent of vascular involvement. Management involves early surgical intervention, including early valve-sparing aortic root replacement, genetic counselling and close monitoring in pregnancy. Despite being caused by loss of function mutations in either TGFβ receptor, paradoxical activation of TGFβ signalling is seen, suggesting that TGFβ antagonism may confer disease modifying effects similar to those observed in MFS. TGFβ antagonism can be achieved with angiotensin antagonists, such as Losartan, which is able to delay aortic aneurysm development in preclinical models and in patients with MFS. Our case emphasizes the importance of timely recognition of vasculopathy syndromes in patients with hypermobility and the need for early surgical intervention. It also highlights their heterogeneity and the potential for late presentation. Disclosures: The authors have declared no conflicts of interes

Vampires in the village Žrnovo on the island of Korčula: following an archival document from the 18th century

Središnja tema rada usmjerena je na raščlambu spisa pohranjenog u Državnom arhivu u Mlecima (fond: Capi del Consiglio de’ Dieci: Lettere di Rettori e di altre cariche) koji se odnosi na događaj iz 1748. godine u korčulanskom selu Žrnovo, kada su mještani – vjerujući da su se pojavili vampiri – oskvrnuli nekoliko mjesnih grobova. U radu se podrobno iznose osnovni podaci iz spisa te rečeni događaj analizira u širem društvenom kontekstu i prate se lokalna vjerovanja.The main interest of this essay is the analysis of the document from the State Archive in Venice (file: Capi del Consiglio de’ Dieci: Lettere di Rettori e di altre cariche) which is connected with the episode from 1748 when the inhabitants of the village Žrnove on the island of Korčula in Croatia opened tombs on the local cemetery in the fear of the vampires treating. This essay try to show some social circumstances connected with this event as well as a local vernacular tradition concerning superstitions

Sea Floor Bathymetry near the Clarion and Clipperton Fracture Zones

Three areas of approximately 3 600 square miles each were selected for bathymetric exploration. Surveys were conducted in 1961 aboard IJSNS Richfield and USNS Huntsville. Two of the areas investigated were south of the Clarion Fracture Zone at 13°30' N, and 116°30'W, the third was south of the Clipperton Fracture Zone at 6°00'N and 119°00/ W. A detailed survey of a small seamount was also made. Many small-scale features possibly related to the fracture zones were observed. A correlation may exist between topography and observed heat-flow values in these areas