13C n.m.r. investigation on the nitrogen methylation of some azabenzenes

The 1H and 13C n.m.r. spectra of N-methylated pyridine, pyridazine, pyrimidine and pyrazine and N,N-dimethylated pyrimidine and pyrazine have been recorded and analysed. The change in the 13C chemical shifts under the influence of N-methylation (Δδ) in the diazabenzenes could be predicted by the Δδ values of pyridine. A comparison of the Δδ values of N-methylation with those of N-protonation showed that both reactions have a similar effect

Theoretical study on the protonation of AZA-aromatics

The protonation of azanaphthalenes and azabenzenes has been studied theoretically using CNDO/2 wavefunctions and perturbation theory in order to examine the correlation between pKa values and quantum-mechanical quantities

Diazanaphthalenes: A 13C NMR investigation on the site of protonation and pKa values

The pH dependence of the 13C chemical shifts (δ) of the diazanaphthalenes has been recorded. From this dependence the pKa values have been determined using the Henderson-Hasselbach equation. The change in 13C chemical shifts under the influence of nitrogen protonation (Δδ) has been predicted using the Δδ values of quinoline and isoquinoline. The correlation between observed and expected Δδ values of the symmetric diazanaphthalenes is very good. Assuming these changes in chemical shifts to be of general validity, the site of protonation in the asymmetric diazanaphthalenes has been determined by comparison of the expected Δδ values for α- and ß-nitrogen protonation with the observed ones. The site of protonation for 1,6- and 1,7-naphthyridine is the ß-nitrogen atom, whereas for cinnoline both monoprotonated species are present in a significant amount

Carbon-13 n.m.r. investigation on the nitrogen methylation of the mono- and diazanaphthalenes

The 13C n.m.r. spectra of the N-methylated mono- and diazanaphthalenes have been recorded and analysed. It has been shown that N-methylation as well as N-protonation in cinnoline occur predominantly at the -nitrogen atom. N-methylation and N-protonation show a similar effect on the 13C chemical shift

Fast northward energy transfer in the Atlantic due to Agulhas rings

The adiabatic transit time of wave energy radiated by an Agulhas ring released in the South Atlantic Ocean to the North Atlantic Ocean is investigated in a two-layer ocean model. Of particular interest is the arrival time of baroclinic energy in the northern part of the Atlantic, because it is related to variations in the meridional overturning circulation. The influence of the Mid-Atlantic Ridge is also studied, because it allows for the conversion from barotropic to baroclinic wave energy and the generation of topographic waves. Barotropic energy from the ring is present in the northern part of the model basin within 10 days. From that time, the barotropic energy keeps rising to attain a maximum 500 days after initiation. This is independent of the presence or absence of a ridge in the model basin. Without a ridge in the model, the travel time of the baroclinic signal is 1300 days. This time is similar to the transit time of the ring from the eastern to the western coast of the model basin. In the presence of the ridge, the baroclinic signal arrives in the northern part of the model basin after approximately 10 days, which is the same time scale as that of the barotropic signal. It is apparent that the ridge can facilitate the energy conversion from barotropic to baroclinic waves and the slow baroclinic adjustment can be bypassed. The meridional overturning circulation, parameterized in two ways as either a purely barotropic or a purely baroclinic phenomenon, also responds after 1300 days. The ring temporarily increases the overturning strength. Th presence of the ridge does not alter the time scales

Grand Challenges in Global Health: Community Engagement in Research in Developing Countries

The authors argue that there have been few systematic attempts to determine the effectiveness of community engagement in research

Evidence for a direct effect of the NAD+ precursor acipimox on muscle mitochondrial function in humans.

Recent preclinical studies showed the potential of nicotinamide adenine dinucleotide (NAD(+)) precursors to increase oxidative phosphorylation and improve metabolic health, but human data are lacking. We hypothesize that the nicotinic acid derivative acipimox, an NAD(+) precursor, would directly affect mitochondrial function independent of reductions in nonesterified fatty acid (NEFA) concentrations. In a multicenter randomized crossover trial, 21 patients with type 2 diabetes (age 57.7 +/- 1.1 years, BMI 33.4 +/- 0.8 kg/m(2)) received either placebo or acipimox 250 mg three times daily dosage for 2 weeks. Acipimox treatment increased plasma NEFA levels (759 +/- 44 vs. 1,135 +/- 97 mumol/L for placebo vs. acipimox, P < 0.01) owing to a previously described rebound effect. As a result, skeletal muscle lipid content increased and insulin sensitivity decreased. Despite the elevated plasma NEFA levels, ex vivo mitochondrial respiration in skeletal muscle increased. Subsequently, we showed that acipimox treatment resulted in a robust elevation in expression of nuclear-encoded mitochondrial gene sets and a mitonuclear protein imbalance, which may indicate activation of the mitochondrial unfolded protein response. Further studies in C2C12 myotubes confirmed a direct effect of acipimox on NAD(+) levels, mitonuclear protein imbalance, and mitochondrial oxidative capacity. To the best of our knowledge, this study is the first to demonstrate that NAD(+) boosters can also directly affect skeletal muscle mitochondrial function in humans

Proinsulin degradation and presentation of a proinsulin B-chain autoantigen involves ER-associated protein degradation (ERAD)-enzyme UBE2G2

Type 1 diabetes (T1D) is characterized by HLA class I-mediated presentation of autoantigens on the surface of pancreatic β-cells. Recognition of these autoantigens by CD8+ T cells results in the destruction of pancreatic β-cells and, consequently, insulin deficiency. Most epitopes presented at the surface of β-cells derive from the insulin precursor molecule proinsulin. The intracellular processing pathway(s) involved in the generation of these peptides are poorly defined. In this study, we show that a proinsulin B-chain antigen (PPIB5-14) originates from proinsulin molecules that are processed by ER-associated protein degradation (ERAD) and thus originate from ER-resident proteins. Furthermore, screening genes encoding for E2 ubiquitin conjugating enzymes, we identified UBE2G2 to be involved in proinsulin degradation and subsequent presentation of the PPIB10-18 autoantigen. These insights into the pathway involved in the generation of insulin-derived peptides emphasize the importance of proinsulin processing in the ER to T1D pathogenesis and identify novel targets for future T1D therapies

Human-animal chimeras for vaccine development: an endangered species or opportunity for the developing world?

<p>Abstract</p> <p>Background</p> <p>In recent years, the field of vaccines for diseases such as Human Immunodeficiency Virus (HIV) which take a heavy toll in developing countries has faced major failures. This has led to a call for more basic science research, and development as well as evaluation of new vaccine candidates. Human-animal chimeras, developed with a 'humanized' immune system could be useful to study infectious diseases, including many neglected diseases. These would also serve as an important tool for the efficient testing of new vaccine candidates to streamline promising candidates for further trials in humans. However, developing human-animal chimeras has proved to be controversial.</p> <p>Discussion</p> <p>Development of human-animal chimeras for vaccine development has been slowed down because of opposition by some philosophers, ethicists and policy makers in the west-they question the moral status of such animals, and also express discomfort about transgression of species barriers. Such opposition often uses a contemporary western world view as a reference point. Human-animal chimeras are often being created for diseases which cause significantly higher morbidity and mortality in the developing world as compared to the developed world. We argue in our commentary that given this high disease burden, we should look at socio-cultural perspectives on human-animal chimera like beings in the developing world. On examination, it's clear that such beings have been part of mythology and cultural descriptions in many countries in the developing world.</p> <p>Summary</p> <p>To ensure that important research on diseases afflicting millions like malaria, HIV, Hepatitis-C and dengue continues to progress, we recommend supporting human-animal chimera research for vaccine development in developing countries (especially China and India which have growing technical expertise in the area). The negative perceptions in some parts of the west about human-animal chimeras can be used as an opportunity for nurturing important vaccine development research in the developing world.</p