Aminopyridinecarboxamide-based inhibitors: Structure–activity relationship

Series of aminopyridinecarboxamide-based inhibitors were synthesized and tested against human recombinant IKK-2 and in IL-1β stimulated synovial fibroblasts. The 2-amino-5-chloropyridine-4-carboxamides were identified as the most potent inhibitors with improved cellular activity.     

Ghrelin receptors are expressed by distal tubules of the mouse kidney

Ghrelin, a peptide hormone from the stomach, has been recently discovered to reduce sodium excretion from the kidney. Although the effects on the kidney suggest actions in the distal nephron, the sites of expression of ghrelin receptors have not been localised. In the present work we have used a mouse that expresses green fluorescent protein under the control of the ghrelin receptor promoter to locate sites of receptor expression in the kidney. Receptor expression was confined to the straight parts of the distal tubules and the thin limbs of the loops of Henle. No expression was detected in other structures, including the glomeruli, proximal tubules and collecting ducts. Ghrelin receptors were not found in extra-renal or intra-renal arteries, despite observations that ghrelin is a vasodilator. The distribution revealed by in situ hybridisation histochemistry was the same as that revealed by the reporter. In conclusion, ghrelin receptors have a restricted distribution in the kidney. The location in the straight parts of the distal tubules accords with observations that ghrelin promotes sodium retention.     

Water,nutrients and slope position in on-farm pearl millet cultivation in the Sahel

In the Sahel, short periods of intra-seasonal drought, caused by unfavourable rainfall distribution, often have stronger effect on crop growth than fluctuations in annual rainfall. The interactive effects of nutrient deficiency and water shortage (during panicle initiation, flowering and grain filling) on yield and yield components of pearl millet (Pennisetum glaucum (L.) R. Br.), were studied on-farm along a cultivated slope, during three years with close to average annual rainfall. Grain yield was correlated to plant nutrient availability but not to annual rainfall, which was explained by the capacity of the crop to compensate for damage caused by water shortage during early growth phases. The performance of each yield component was positively correlated to cumulative rainfall during the growth phase when it was formed. Leaf area index (LAI) was very low, and leaf development followed rainfall distribution. Water and nutrients interacted during each growth phase for all fertility levels. Fertilised millet suffered less during water shortage at panicle initiation and at grain filling compared to non-fertilised millet. However, compared to favourable soil water conditions yield components were systematically lower for all treatments, indicating the synergistic effect of water and nutrients. The results suggest that water availability plays an exclusive role during flowering. Grain number dropped significantly due to water shortage and was similar for all treatments. Despite extremely high spatial variability in yields (varying with a factor 46 within the field), a significant slope effect was observed, of progressively increasing yields when moving downslope. Spatial redistribution of surface runoff resulting in higher soil water availability on lower slope positions, contributed to the yield gradient, which was reinforced for fertilised millet. For each drought period, yield components suffered systematically more upslope than downslope. This slope effect was smoothed out for manured millet, which indicates that manure increased soil infiltrability on crusted zones upslope. The slope interaction observed here – indicating that downslope (i) the risk for crop failure during droughts is lower and (ii) the response to fertilisers is greater – suggests that farmers can benefit relatively more from fertilisers applied in lower parts of the watershed. Taking advantage of spatial soil and water variability is an interesting system of low technology precision farming, which combined with water harvesting systems to master droughts, can constitute options for increased crop yields in the Sahel.     

Inhibition of IKK-2 by 2-[(aminocarbonyl)amino]-5-acetylenyl-3-thiophenecarboxamides

A series of 21 novel 2-[(aminocarbonyl)amino]-5-acetylenyl-3-thiophenecarboxamides were synthesized and evaluated for the inhibition of IKK-2. In spite of their often modest activity on the enzyme, six selected analogs showed significant inhibition of the production of inflammatory cytokine IL-8 in IL-1beta stimulated rheumatoid arthritis-derived synovial fibroblasts, demonstrating their potential usefulness as NF-kappaB regulators.     

Integrity of developing spinal motor columns is regulated by neural crest derivatives at motor exit points

Spinal motor neurons must extend their axons into the periphery through motor exit points (MEPs), but their cell bodies remain within spinal motor columns. It is not known how this partitioning is established in development. We show here that motor neuron somata are confined to the CNS by interactions with a neural crest subpopulation, boundary cap (BC) cells that prefigure the sites of spinal MEPs. Elimination of BC cells by surgical or targeted genetic ablation does not perturb motor axon outgrowth but results in motor neuron somata migrating out of the spinal cord by translocating along their axons. Heterologous neural crest grafts in crest-ablated embryos stop motor neuron emigration. Thus, before the formation of a mature transitional zone at the MEP, BC cells maintain a cell-tight boundary that allows motor axons to cross but blocks neuron migration.     

Egg discrimination in the Australian reed warbler (Acrocephalus australis): rejection response toward model and conspecific eggs depending on timing and mode of artificial parasitism

In a coevolutionary arms race between an interspecific broodparasite and its host species, both are expected to evolveadaptations and counteradaptations. We studied egg discriminationin the Australian warbler (Acrocephalus australis). This speciesis currently not significantly parasitized by the seven speciesof cuckoo for which it is a suitable host. However, experimentalbrood parasitism in the warbler revealed a fine tuned egg discriminationresponse towards non-mimetic and conspecific eggs, the firstsuch evidence in an Australian passerine: (1) non-mimetic eggswere significantly more often rejected than conspecific eggs;(2) only non-mimetic dummy eggs were rejected selectively,whereas rejection of conspecific eggs entailed a rejectioncost; (3) replacement of a host's egg with a conspecific eggduring egg laying resulted in a significantly higher rejectionrate than after the day of clutch completion; (4) by contrast,rejection rate after addition of a conspecific egg was independentof nest stage; (5) conspecific eggs introduced into a clutchduring the egg laying period led to a significantly highernest desertion rate and a lower egg ejection rate than afterthe day of clutch completion; and (6) addition of a conspecificegg led to egg ejection while egg replacement with a conspecificegg led to nest desertion. The fact that this species respondsdifferentially toward different modes of artificial parasitismsuggests that its egg discrimination has evolved to minimizethe costs of rejection and parasitism. The ability to rejecthighly mimetic conspecific eggs may explain the current paucityof brood parasitism in this species. The significance of thisfor brood parasite-host coevolution is discussed.     

How everyday sounds can trigger strong emotions: ASMR,misophonia and the feeling of wellbeing

We propose that synesthetic cross-activation between the primary auditory cortex and the anatomically adjacent insula may help explain two puzzling conditions—autonomous sensory meridian response (ASMR) and misophonia—in which quotidian sounds involuntarily trigger strong emotional responses. In ASMR the sounds engender relaxation, while in misophonia they trigger an aversive response. The insula both plays an important role in autonomic nervous system control and integrates multiple interoceptive maps representing the physiological state of the body to substantiate a dynamic representation of emotional wellbeing. We propose that in ASMR cross-activation of the map for affective (sensual) touch leads to an increase in subjective wellbeing and parasympathetic activity. Conversely, in misophonia the effect of the cross-activation is to decrease emotional wellbeing and increase sympathetic activity. Our hypothesis also illuminates the connection between hearing and wellbeing more broadly and helps explain why so many people experience decreased wellbeing from modern urban soundscapes.