IL-4 Haplotype -590T, -34T and Intron-3 VNTR R2 Is Associated with Reduced Malaria Risk among Ancestral Indian Tribal Populations

Background

Interleukin 4 (IL-4) is an anti-inflammatory cytokine, which regulates balance between T_H1 and T_H2 immune response, immunoglobulin class switching and humoral immunity. Polymorphisms in this gene have been reported to affect the risk of infectious and autoimmune diseases.

Methods

We have analyzed three regulatory IL-4 polymorphisms; -590C>T, -34C>T and 70 bp intron-3 VNTR, in 4216 individuals; including: (1) 430 ethnically matched case-control groups (173 severe malaria, 101 mild malaria and 156 asymptomatic); (2) 3452 individuals from 76 linguistically and geographically distinct endogamous populations of India, and (3) 334 individuals with different ancestry from outside India (84 Brazilian, 104 Syrian, and 146 Vietnamese).

Results

The -590T, -34T and intron-3 VNTR R2 alleles were found to be associated with reduced malaria risk (P<0.001 for -590C>T and -34C>T, and P = 0.003 for VNTR). These three alleles were in strong LD (r²>0.75) and the TTR2 (-590T, -34T and intron-3 VNTR R2) haplotype appeared to be a susceptibility factor for malaria (P = 0.009, OR = 0.552, 95% CI = 0.356 –0.854). Allele and genotype frequencies differ significantly between caste, nomadic, tribe and ancestral tribal populations (ATP). The distribution of protective haplotype TTR2 was found to be significant (χ² ₃ = 182.95, p-value <0.001), which is highest in ATP (40.5%); intermediate in tribes (33%); and lowest in caste (17.8%) and nomadic (21.6%).

Conclusions

Our study suggests that the IL-4 polymorphisms regulate host susceptibility to malaria and disease progression. TTR2 haplotype, which gives protection against malaria, is high among ATPs. Since they inhabited in isolation and mainly practice hunter-gatherer lifestyles and exposed to various parasites, IL-4 TTR2 haplotype might be under positive selection.     

The isolation and characterization of gibberellin-deficient mutants in tomato

Summary In tomato, nine independent EMS-induced mutants representing recessive mutations at three different loci (gib-1, gib-2, and gib-3) were isolated. Six of these have an almost absolute gibberellin requirement for seed germination and elongation growth. In addition, the leaves are darker green, smaller, and changed in structure as compared to wild type. The three other mutants, which germinate without GA, are allelic to specific, nongerminating mutants and have less severe mutant characteristics. The respective loci are situated on three different chromosomes. The genes identified by these mutants control steps in gibberellin biosynthesis, as endogenous gibberellins are strongly reduced.     

Readiness to lay in the blowfly Lucilia cuprina is unaffected by oviposition site-deprivation or egg-load

Oviposition by Lucilia cuprina Wiedemann (Diptera, Calliphoridae) was examined in relation to period of oviposition site-deprivation and egg-load. Effects of oviposition site-deprivation were examined by comparing oviposition performance of individual females that had matured their batch of oocytes within the previous 24 h with that of females which had reached ovarian maturity 8 days previously. Egg-load was manipulated by causing females of this anautogenous species to consume different amounts of protein-rich material. In no-choice experiments, individual females of the different categories were given access for 4 h to oviposition substrate, soaked with (i) liver exudate, (ii) the exudate diluted 16-fold or (iii) the undilated exudate containing the oviposition deterrent sodium chloride at a concentration of 2 M. These solutions elicited oviposition from different proportions of females, but neither these proportions, nor the interval between introduction of the oviposition site and the initiation of oviposition, was significantly affected by the period of oviposition site-deprivation or the number of eggs matured by the females.

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Résumé L'effet de la privation de lieu de ponte a été étudié en comparant les pontes de femelles isolées ayant formé leurs ufs mûrs dans les 24 heures précédentes, à celles de femelles ayant atteint leur maturité sexuelle 8 jours avant. La rétention ovocytaire est provoquée en faisant consommer aux femelles de cette espèce anautogène différentes quantités d'aliments riches en protéines. La ponte de femelles dont le contingent total de leurs ovocytes s'est développé, — c'est-à-dire 260 —, après consommation ad libitum de foie de mouton pendant 48 heures, a été comparée à celle de femelles ayant formé 190 ovocytes mûrs après ingestion d'une quantité limitée de jus de foie.Dans des expériences sans choix, les femelles isolées de différences catégories ont eu accès pendant 4 heures au substrat de ponte trempé: 1) dans du jus de foie, 2) dans du jus dilué 16 fois, 3) dans du jus de foie non dilué mais contenant NaCl (inhibiteur de la ponte) à la concentration de 2 M. Le jus non dilué a provoqué une forte stimulation, induisant la ponte de 80% des femelles. Le jus dilué et celui contenant NaCl n'ont induit la ponte que de 40% des femelles avec des niveaux de stimulation bien plus faibles. La date d'introduction du lieu de ponte et le taux de rétention des ovocytes mûrs n'ont eu auçun effet sur la proportion de femelles réagissant à ces 3 types de stimulation.

     

Subpicosecond resonance Raman spectra of the early intermediates in the photocycle of bacteriorhodopsin

The resonance Raman spectra are presented for the species formed during the photocycle of bacteriorhodopsin (bR) on a timescale of 800-900 fs. In the ethylenic stretch region two intermediates were found with frequencies of 1,510 and 1,518 cm^-1, corresponding to species with optical absorption maxima at 660 and 625 nm, respectively. This leads to the assignment of the 1,518 cm^-1 band to the J₆₂₅ intermediate. In the fingerprint region, the appearance of a vibration at 1,195 cm^-1 strongly suggests that the isomerization indeed has taken place in a time less than the pulsewidth of our laser. This supports the previous proposals made on the basis of the optical spectra. The spectra are compared with those observed in tens of picoseconds up to nanoseconds.     

Coupling of insulin-responsive glucose transport to receptors for insulin-like growth factor 1 in primary human fibroblasts

We have recently described an insulin-resistant patient with leprechaunism (leprechaun G.) having a homozygous leucine----proline mutation at amino acid position 233 in the alpha-chain of the insulin receptor. The mutation results in a loss of insulin binding to cultured fibroblasts. Fibroblasts from the patient and control individuals were used to quantify the stimulation of 2-deoxyglucose uptake by insulin and insulin-like growth factor 1 (IGF-1). Insulin hardly stimulates basal 2-deoxyglucose uptake in the patient's fibroblasts whereas in control fibroblasts the uptake of 2-deoxyglucose is stimulated by insulin approximately 1.7 times. In contrast, IGF-1 stimulates hexose uptake in the patient's fibroblasts 1.8 times, a similar value to that obtained by stimulation of control fibroblasts with insulin or IGF-1. With both types of fibroblasts, maximal IGF-1 response is reached at about 10 nM IGF-1, the ED50 being approximately 4 nM. The results indicate that the insulin responsive glucose transport in primary fibroblasts is functionally linked to the receptor for IGF-1. Insulin binds with an approximately 200-fold lower affinity to IGF-1 receptors, compared to homologous IGF-1 binding. As an insulin concentration of 10 microM is unable to give maximal stimulation of glucose uptake in the patient's fibroblasts, which is already seen with 10 nM IGF-1, it seems that occupation of IGF-1 receptors by insulin on the patient's cells is less efficient at stimulating hexose uptake compared to homologous activation.     

Shifting daylength regimes associated with range shifts alter aphid‐parasitoid community dynamics

With climate change leading to poleward range expansion of species, populations are exposed to new daylength regimes along latitudinal gradients. Daylength is a major factor affecting insect life cycles and activity patterns, so a range shift leading to new daylength regimes is likely to affect population dynamics and species interactions; however, the impact of daylength in isolation on ecological communities has not been studied so far. Here, we tested for the direct and indirect effects of two different daylengths on the dynamics of experimental multitrophic insect communities. We compared the community dynamics under “southern” summer conditions of 14.5‐hr daylight to “northern” summer conditions of 22‐hr daylight. We show that food web dynamics indeed respond to daylength with one aphid species (Acyrthosiphon pisum) reaching much lower population sizes at the northern daylength regime compared to under southern conditions. In contrast, in the same communities, another aphid species (Megoura viciae) reached higher population densities under northern conditions. This effect at the aphid level was driven by an indirect effect of daylength causing a change in competitive interaction strengths, with the different aphid species being more competitive at different daylength regimes. Additionally, increasing daylength also increased growth rates in M. viciae making it more competitive under summer long days. As such, the shift in daylength affected aphid population sizes by both direct and indirect effects, propagating through species interactions. However, contrary to expectations, parasitoids were not affected by daylength. Our results demonstrate that range expansion of whole communities due to climate change can indeed change interaction strengths between species within ecological communities with consequences for community dynamics. This study provides the first evidence of daylength affecting community dynamics, which could not be predicted from studying single species separately.     

Diverse Brain Myeloid Expression Profiles Reveal Distinct Microglial Activation States and Aspects of Alzheimer’s Disease Not Evident in Mouse Models

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Insights into the evolution of lanthipeptide biosynthesis

Lanthipeptides are a group of posttranslationally modified peptide natural products that contain multiple thioether crosslinks. These crosslinks are formed by dehydration of Ser/Thr residues followed by addition of the thiols of Cys residues to the resulting dehydroamino acids. At least four different pathways to these polycyclic natural products have evolved, reflecting the high efficiency and evolvability of a posttranslational modification route to generate conformationally constrained peptides. The wealth of genomic information that has been made available in recent years has started to provide insights into how these remarkable pathways and their posttranslational modification machineries may have evolved. In this review, we discuss a model for the evolution of the lanthipeptide biosynthetic enzymes that has recently been developed based on the currently available data.     

Substantial Metabolic Activity of Human Brown Adipose Tissue during Warm Conditions and Cold-Induced Lipolysis of Local Triglycerides

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Quantification of the regulation of glycerol and maltose metabolism by IIAGlc of the phosphoenolpyruvate-dependent glucose phosphotransferase system in Salmonella typhimurium.

The amount of IIAGlc, one of the proteins of the phosphoenolpyruvate:glucose phosphotransferase system (PTS), was modulated over a broad range with the help of inducible expression plasmids in Salmonella typhimurium. The in vivo effects of different levels of IIAGlc on glycerol and maltose metabolism were studied. The inhibition of glycerol uptake, by the addition of a PTS sugar, was sigmoidally related to the amount of IIAGlc. For complete inhibition of glycerol uptake, a minimal ratio of about 3.6 mol of IIAGlc to 1 mol of glycerol kinase (tetramer) was required. Varying the level of IIAGlc (from 0 to 1,000% of the wild-type level) did not affect the growth rate on glycerol, the rate of glycerol uptake, or the synthesis of glycerol kinase. In contrast, the growth rate on maltose, the rate of maltose uptake, and the synthesis of the maltose-binding protein increased two- to fivefold with increasing levels of IIAGlc. In the presence of cyclic AMP, the maximal levels were obtained at all IIAGlc concentrations. The synthesis of the MalK protein, the target of IIAGlc, was not affected by varying the levels of IIAGlc. The inhibition of maltose uptake was sigmoidally related to the amount of IIAGlc. For complete inhibition of maltose uptake by a PTS sugar, a ratio of about 18 mol of IIAGlc to 1 mol of MalK protein (taken as a dimer) was required.