Ring Closures and the Hammond Postulate

This work reports an investigation of ring closure processes in relation to the Hammond postulate. Calculations favor the importance of thermodynamics, not kinetics, as the basis for the Hammond postulate. A kinetically rapid, but thermodynamically unfavorable reaction is shown to resemble product. The ease of ring closure to three-membered rings, compared to four-membered rings, is thought to be associated with conformational mobility and perhaps vibrations coupled to the reaction coordinate motion in the case of four-membered rings

Ring Closures and the Hammond Postulate

This work reports an investigation of ring closure processes in relation to the Hammond postulate. Calculations favor the importance of thermodynamics, not kinetics, as the basis for the Hammond postulate. A kinetically rapid, but thermodynamically unfavorable reaction is shown to resemble product. The ease of ring closure to three-membered rings, compared to four-membered rings, is thought to be associated with conformational mobility and perhaps vibrations coupled to the reaction coordinate motion in the case of four-membered rings

D/H Exchange in Nitro Diastereomers

The two diastereomers of 4-nitro-1,3-diphenylpentan-1-one behave differently in deuterium for hydrogen exchange in DMSO-d6/D2O solutions using various bases as catalyst. Reaction of the erythro diastereomer gives largely the same diastereomer upon D/H exchange (retention), i.e., exchange exceeds epimerization. Pyridine and acetonitrile as solvents lead to faster epimerization than exchange. In the threo diastereomer (DMSO-d6 solution), epimerization exceeds exchange, and the anion to some extent regains the same hydrogen originally removed by the base on the opposite face. 2-Bromo-4-nitro-1,3-diphenylbutan-1-one undergoes ring closure to the cyclopropane faster than exchange (within seconds). The cyclopropane shows faster exchange than equilibration, i.e., retention of configuration, although it is the hydrogen α to carbonyl that is involved

Why are the Nitro and Sulfone Groups Poor Hydrogen Bonders?

The interactions of water or methanol with nitromethane and dimethyl sulfone vs. comparison molecules, e.g. dimethylsulfoxide (DMSO), are reported. For nitromethane with water, the classical (edgewise) hydrogen bonded configuration is modestly stabilizing. However, the approach of water over the face of the nitro group is preferred in AM1 calculations. Generally, molecules such as sulfones and nitro compounds have lower energy bonding orbitals than sulfoxides. The energy of the n δ σ* interaction (e.g. nitro lone pair to O-H of water) thus is larger for the nitro and sulfone cases, and this interaction is less prevalent than other cases. Since the interaction of the nitro group with water is somewhat favorable, the reason for the insolubility of nitromethane is water was investigated. It was found that the energy of segregated sets of nitromethane and of water molecules was lower than the mixed nitromethane - water state. In contrast, the energy of the mixed DMSO-water hydrogen bonded mixed state is lower than segregated molecules

Thinking critically about beliefs it\u27s hard to think critically about

There are some beliefs that are difficult to think critically about, even for those who have critical thinking skills and are committed to applying them to their own beliefs. These resistant beliefs are not all of a kind, and so a range of different strategies may be needed to get ourselves and others (in particular our students) to think critically about them. In this paper we suggest some such strategies

Open Mindedness

Dewey defines open-mindedness as “freedom from prejudice, partisanship, and other such habits as close the mind and make it unwilling to consider new problems and entertain new ideas (1910, p. 30). It is commonly included in lists of epistemic and argumentative virtues. We begin this paper with brief discussion of various accounts of open-mindedness. Our principle interest is in what it is to behave as an open-minded enquirer. Drawing on two cases, we consider whether open-minded behaviour varies between the contexts of solitary and community enquiry and whether inquirers face different challenges to behaving open-mindedly in each of these contexts. We conclude that although group deliberation introduces some extra barriers to open-mindedness, it can also make it easier to achieve by providing an external check that is absent in solitary inquiry

Glucagon-like peptide 1 receptor stimulation reverses key deficits in distinct rodent models of Parkinson's disease

<p>Abstract</p> <p>Background</p> <p>It has recently become apparent that neuroinflammation may play a significant role in Parkinson's disease (PD). This is also the case in animal paradigms of the disease. The potential neuroprotective action of the glucagon-like peptide 1 receptor (GLP-1R) agonist exendin-4 (EX-4), which is protective against cytokine mediated apoptosis and may stimulate neurogenesis, was investigated In paradigms of PD.</p> <p>Methods</p> <p>Two rodent 'models' of PD, 6-hydroxydopamine (6-OHDA) and lipopolysaccaride (LPS), were used to test the effects of EX-4. Rats were then investigated <it>in vivo </it>and <it>ex vivo </it>with a wide range of behavioural, neurochemical and histological tests to measure integrity of the nigrostriatal system.</p> <p>Results</p> <p>EX-4 (0.1 and 0.5 μg/kg) was given seven days after intracerebral toxin injection. Seven days later circling behaviour was measured following apomorphine challenge. Circling was significantly lower in rats given EX-4 at both doses compared to animals given 6-OHDA/LPS and vehicle. Consistent with these observations, striatal tissue DA concentrations were markedly higher in 6-OHDA/LPS + EX-4 treated rats versus 6-OHDA/LPS + vehicle groups, whilst assay of L-DOPA production by tyrosine hydroxylase was greatly reduced in the striata of 6-OHDA/LPS + vehicle rats, but this was not the case in rats co-administered EX-4. Furthermore nigral TH staining recorded in 6-OHDA/LPS + vehicle treated animals was markedly lower than in sham-operated or EX-4 treated rats. Finally, EX-4 clearly reversed the loss of extracellular DA in the striata of toxin lesioned freely moving rats.</p> <p>Conclusion</p> <p>The apparent ability of EX-4 to arrest progression of, or even reverse nigral lesions once established, suggests that pharmacological manipulation of the GLP-1 receptor system could have substantial therapeutic utility in PD. Critically, in contrast to other peptide agents that have been demonstrated to possess neuroprotective properties in pre-clinical models of PD, EX-4 is in current clinical use in the management of type-II diabetes and freely crosses the blood brain barrier; hence, assessment of the clinical efficacy of EX-4 in patients with PD could be pursued without delay.</p

What is known about the effects of medical tourism in destination and departure countries? A scoping review

<p>Abstract</p> <p>Background</p> <p>Medical tourism involves patients intentionally leaving their home country to access non-emergency health care services abroad. Growth in the popularity of this practice has resulted in a significant amount of attention being given to it from researchers, policy-makers, and the media. Yet, there has been little effort to systematically synthesize what is known about the effects of this phenomenon. This article presents the findings of a scoping review examining what is known about the effects of medical tourism in destination and departure countries.</p> <p>Methods</p> <p>Drawing on academic articles, grey literature, and media sources extracted from18 databases, we follow a widely used scoping review protocol to synthesize what is known about the effects of medical tourism in destination and departure countries. The review design has three main stages: (1) identifying the question and relevant literature; (2) selecting the literature; and (3) charting, collating, and summarizing the data.</p> <p>Results</p> <p>The large majority of the 203 sources accepted into the review offer a perspective of medical tourism from the Global North, focusing on the flow of patients from high income nations to lower and middle income countries. This greatly shapes any discussion of the effects of medical tourism on destination and departure countries. Five interrelated themes that characterize existing discussion of the effects of this practice were extracted from the reviewed sources. These themes frame medical tourism as a: (1) user of public resources; (2) solution to health system problems; (3) revenue generating industry; (4) standard of care; and (5) source of inequity. It is observed that what is currently known about the effects of medical tourism is minimal, unreliable, geographically restricted and mostly based on speculation.</p> <p>Conclusions</p> <p>Given its positive and negative effects on the health care systems of departure and destination countries, medical tourism is a highly significant and contested phenomenon. This is especially true given its potential to serve as a powerful force for the inequitable delivery of health care services globally. It is recommended that empirical evidence and other data associated with medical tourism be subjected to clear and coherent definitions, including reports focused on the flows of medical tourists and surgery success rates. Additional primary research on the effects of medical tourism is needed if the industry is to develop in a manner that is beneficial to citizens of both departure and destination countries.</p

Streptomycin-induced inflammation enhances Escherichia coli gut colonization through nitrate respiration.

UnlabelledTreatment with streptomycin enhances the growth of human commensal Escherichia coli isolates in the mouse intestine, suggesting that the resident microbial community (microbiota) can inhibit the growth of invading microbes, a phenomenon known as "colonization resistance." However, the precise mechanisms by which streptomycin treatment lowers colonization resistance remain obscure. Here we show that streptomycin treatment rendered mice more susceptible to the development of chemically induced colitis, raising the possibility that the antibiotic might lower colonization resistance by changing mucosal immune responses rather than by preventing microbe-microbe interactions. Investigation of the underlying mechanism revealed a mild inflammatory infiltrate in the cecal mucosa of streptomycin-treated mice, which was accompanied by elevated expression of Nos2, the gene that encodes inducible nitric oxide synthase. In turn, this inflammatory response enhanced the luminal growth of E. coli by nitrate respiration in a Nos2-dependent fashion. These data identify low-level intestinal inflammation as one of the factors responsible for the loss of resistance to E. coli colonization after streptomycin treatment.ImportanceOur intestine is host to a complex microbial community that confers benefits by educating the immune system and providing niche protection. Perturbation of intestinal communities by streptomycin treatment lowers "colonization resistance" through unknown mechanisms. Here we show that streptomycin increases the inflammatory tone of the intestinal mucosa, thereby making the bowel more susceptible to dextran sulfate sodium treatment and boosting the Nos2-dependent growth of commensal Escherichia coli by nitrate respiration. These data point to the generation of alternative electron acceptors as a by-product of the inflammatory host response as an important factor responsible for lowering resistance to colonization by facultative anaerobic bacteria such as E. coli