PYY(3-36) reduces food intake and body weight and improves insulin sensitivity in rodent models of diet-induced obesity

The gut hormone peptide YY (PYY) was recently proposed to comprise an endogenous satiety factor. We have studied acute anorectic functions of PYY(3-36) in mice and rats, as well as metabolic effects of chronic PYY(3-36) administration to diet-induced obese (DIO) mice and rats. A single intraperitoneal injection of PYY(3-36) inhibited food intake in mice, but not in rats. We next investigated the effects of increasing doses (100, 300, and 1,000 microg.kg-1.day-1) of PYY(3-36) administered subcutaneously via osmotic minipumps on food intake and body weight in DIO C57BL/6J mice. Whereas only the highest dose (1,000 microg.kg-1.day-1) of PYY(3-36) significantly reduced food intake over the first 3 days, body weight gain was dose dependently reduced, and on day 28 the group treated with 1,000 microg.kg-1.day-1 PYY(3-36) weighed approximately 10% less than the vehicle-treated group. Mesenteric, epididymal, retroperitoneal, and inguinal fat pad weight was dose dependently reduced. Subcutaneous administration of PYY(3-36) (250 and 1,000 microg.kg-1.day-1) for 28 days reduced body weight and improved glycemic control in glucose-intolerant DIO rats. Neither 250 nor 1,000 microg/kg PYY(3-36) elicited a conditioned taste aversion in male rats.     

Hsp72 is present in plasma from Holstein-Friesian dairy cattle, and the concentration level is repeatable across days and age classes

Although heat shock proteins (Hsps) are primarily considered as being intracellular, this study identified the presence of Hsp72 in plasma from female Holstein-Friesian dairy cattle. Plasma samples were collected from the same animals at different ages and on different days after calving and accordingly divided into 5 age classes. The age classes were calves less than 235 days of age, young heifers between 235 and 305 days of age, older heifers between 305 and 560 days of age, cows early in lactation, and cows later in lactation. For a subsample of animals within each age class, replicate plasma samples were collected from 1 to 7 days apart to test whether the Hsp72 concentration levels are repeatable on this shorter timescale. Hsp72 was observed in plasma samples from animals of all 5 age classes. For animals with blood samples taken a few days apart, the repeatability (within age class) of the Hsp72 concentration was 0.52 +/- 0.06. Age and days from calving significantly affected the Hsp72 concentration level. The highest Hsp72 level was observed in older heifers (305-560 days of age). The repeatability of Hsp72 concentrations across age classes within animal was 0.22 +/- 0.06. High environmental sensitivity and negative genetic associations between production and health traits in this high-producing breed have been documented earlier. Hsp72 is believed to be strictly stress inducible, and the finding of Hsp72 in plasma indicates that even apparently healthy individuals may experience extrinsic or intrinsic stress (or both).     

Membrane-permeable C-terminal Dopamine Transporter Peptides Attenuate Amphetamine-evoked Dopamine Release

The dopamine transporter (DAT) is responsible for sequestration of extracellular dopamine (DA). The psychostimulant amphetamine (AMPH) is a DAT substrate, which is actively transported into the nerve terminal, eliciting vesicular depletion and reversal of DA transport via DAT. Here, we investigate the role of the DAT C terminus in AMPH-evoked DA efflux using cell-permeant dominant-negative peptides. A peptide, which corresponded to the last 24 C-terminal residues of DAT (TAT-C24 DAT) and thereby contained the Ca²⁺-calmodulin-dependent protein kinase IIα (CaMKIIα) binding domain and the PSD-95/Discs-large/ZO-1 (PDZ)-binding sequence of DAT, was made membrane-permeable by fusing it to the cell membrane transduction domain of the HIV-1 Tat protein (TAT-C24WT). The ability of TAT-C24WT but not a scrambled peptide (TAT-C24Scr) to block the CaMKIIα-DAT interaction was supported by co-immunoprecipitation experiments in heterologous cells. In heterologous cells, we also found that TAT-C24WT, but not TAT-C24Scr, decreased AMPH-evoked 1-methyl-4-phenylpyridinium efflux. Moreover, chronoamperometric recordings in striatum revealed diminished AMPH-evoked DA efflux in mice preinjected with TAT-C24WT. Both in heterologous cells and in striatum, the peptide did not further inhibit efflux upon KN-93-mediated inhibition of CaMKIIα activity, consistent with a dominant-negative action preventing binding of CaMKIIα to the DAT C terminus. This was further supported by the ability of a peptide with perturbed PDZ-binding sequence, but preserved CaMKIIα binding (TAT-C24AAA), to diminish AMPH-evoked DA efflux in vivo to the same extent as TAT-C24WT. Finally, AMPH-induced locomotor hyperactivity was attenuated following systemic administration of TAT-C24WT but not TAT-C24Scr. Summarized, our findings substantiate that DAT C-terminal protein-protein interactions are critical for AMPH-evoked DA efflux and suggest that it may be possible to target protein-protein interactions to modulate transporter function and interfere with psychostimulant effects.     

Combining population genomics and ecological niche modeling to assess taxon limits between Carex jemtlandica and C. lepidocarpa

Carex section Ceratocystis (Cyperaceae) is a group of recently evolved plant species, in which hybridization is frequent, introgression is documented, taxonomy is complex, and morphological boundaries are vague. Within this section, a unified taxonomic treatment of the Carex jemtlandica–Carex lepidocarpa species complex does not exist, and Norway may currently be the sole country accepting species rank for both. Carex jemtlandica is mainly confined to Fennoscandia and is thus a Fennoscandian conservation responsibility. This motivated us to test the principal hypothesis that both C. jemtlandica and C. lepidocarpa represent evolutionary significant units, and that both deserve their current recognition at species level. We investigated their evolutionary distinctiveness in Norway,using restriction site-associated DNA sequencing and ecological niche modeling. Our genomic results reveal two genetic clusters, largely corresponding to C. jemtlandica and C. lepidocarpa that also remain distinct in sympatry, despite clear indications of ongoing hybridization and introgression. The ecological niche modeling suggests that they occupy different environmental niches. Jointly, our results clearly show that C. jemtlandica and C. lepidocarpa represent separately evolving entities that should qualify recognition as evolutionary significant units. Given the high level of introgression compared to other hybridizing species pairs in Carex we recommend treating C. jemtlandica as a subspecies of C. lepidocarpa.     

Population bottlenecks constrain host microbiome diversity and genetic variation impeding fitness

It is becoming increasingly clear that microbial symbionts influence key aspects of their host’s fitness, and vice versa. This may fundamentally change our thinking about how microbes and hosts interact in influencing fitness and adaptation to changing environments. Here we explore how reductions in population size commonly experienced by threatened species influence microbiome diversity. Consequences of such reductions are normally interpreted in terms of a loss of genetic variation, increased inbreeding and associated inbreeding depression. However, fitness effects of population bottlenecks might also be mediated through microbiome diversity, such as through loss of functionally important microbes. Here we utilise 50 Drosophila melanogaster lines with different histories of population bottlenecks to explore these questions. The lines were phenotyped for egg-to-adult viability and their genomes sequenced to estimate genetic variation. The bacterial 16S rRNA gene was amplified in these lines to investigate microbial diversity. We found that 1) host population bottlenecks constrained microbiome richness and diversity, 2) core microbiomes of hosts with low genetic variation were constituted from subsets of microbiomes found in flies with higher genetic variation, 3) both microbiome diversity and host genetic variation contributed to host population fitness, 4) connectivity and robustness of bacterial networks was low in the inbred lines regardless of host genetic variation, 5) reduced microbial diversity was associated with weaker evolutionary responses of hosts in stressful environments, and 6) these effects were unrelated to Wolbachia density. These findings suggest that population bottlenecks reduce hologenomic variation (combined host and microbial genetic variation). Thus, while the current biodiversity crisis focuses on population sizes and genetic variation of eukaryotes, an additional focal point should be the microbial diversity carried by the eukaryotes, which in turn may influence host fitness and adaptability with consequences for the persistence of populations.     

Increasing Gap Junctional Coupling: A Tool for Dissecting the Role of Gap Junctions

Much of our current knowledge about the physiological and pathophysiological role of gap junctions is based on experiments where coupling has been reduced by either chemical agents or genetic modification. This has brought evidence that gap junctions are important in many physiological processes. In a number of cases, gap junctions have been implicated in the initiation and progress of disease, and experimental uncoupling has been used to investigate the exact role of coupling. The inverse approach, i.e., to increase coupling, has become possible in recent years and represents a new way of testing the role of gap junctions. The aim of this review is to summarize the current knowledge obtained with agents that selectively increase gap junctional intercellular coupling. Two approaches will be reviewed: increasing coupling by the use of antiarrhythmic peptide and its synthetic analogs and by interfering with the gating of gap junctional channels.     

Impact of host proteases on reovirus infection in the respiratory tract

Virion uncoating is an essential early event in reovirus infection. In natural enteric infections, rapid proteolytic uncoating of virions is mediated by pancreatic serine proteases. The proteases that promote reovirus disassembly and cell entry in the respiratory tract remain unknown. In this report, we show that endogenous respiratory and inflammatory proteases can promote reovirus infection in vitro and that preexisting inflammation augments in vivo infection in the murine respiratory tract.     

Tree diversity drives abundance and spatiotemporal β‐diversity of true bugs (Heteroptera)

1. Spatiotemporal patterns of canopy true bug diversity in forests of different tree species diversity have not yet been disentangled, although plant diversity has been shown to strongly impact the diversity and distribution of many insect communities. 2. Here we compare species richness of canopy true bugs across a tree diversity gradient ranging from simple beech to mixed forest stands. We analyse changes in community composition by additive partitioning of species diversity, for communities on various tree species, as well as for communities dwelling on beech alone. 3. Total species richness (γ‐diversity) and α‐diversity, and abundance of true bugs increased across the tree diversity gradient, while diversity changes were mediated by increased true bug abundance in the highly diverse forest stands. The same pattern was found for γ‐diversity in most functional guilds (e.g. forest specialists, herbivores, predators). Temporal and even more, spatial turnover (β‐diversity) among trees was closely related to tree diversity and accounted for ～90% of total γ‐diversity. 4. Results for beech alone were similar, but species turnover could not be related to the tree diversity gradient, and monthly turnover was higher compared to turnover among trees. 5. Our findings support the hypothesis that with increasing tree diversity and thereby increasing habitat heterogeneity, enhanced resource availability supports a greater number of individuals and species of true bugs. Tree species identity and the dissimilarity of true bug communities from tree to tree determine community patterns. 6. In conclusion, understanding diversity and distribution of insect communities in deciduous forests needs a perspective on patterns of spatiotemporal turnover. Heterogeneity among sites, tree species, as well as tree individuals contributed greatly to overall bug diversity.     

Immunochip analysis identifies association of the RAD50/IL13 region with human longevity

Human longevity is characterized by a remarkable lack of confirmed genetic associations. Here, we report on the identification of a novel locus for longevity in the RAD50/IL13 region on chromosome 5q31.1 using a combined European sample of 3208 long‐lived individuals (LLI) and 8919 younger controls. First, we performed a large‐scale association study on 1458 German LLI (mean age 99.0 years) and 6368 controls (mean age 57.2 years) by targeting known immune‐associated loci covered by the Immunochip. The analysis of 142 136 autosomal single nucleotide polymorphisms (SNPs) revealed an Immunochip‐wide significant signal (P_Immunochip = 7.01 × 10^–9) for the SNP rs2075650 in the TOMM40/APOE region, which has been previously described in the context of human longevity. To identify novel susceptibility loci, we selected 15 markers with P_Immunochip < 5 × 10^–4 for replication in two samples from France (1257 LLI, mean age 102.4 years; 1811 controls, mean age 49.1 years) and Denmark (493 LLI, mean age 96.2 years; 740 controls, mean age 63.1 years). The association at SNP rs2706372 replicated in the French study collection and showed a similar trend in the Danish participants and was also significant in a meta‐analysis of the combined French and Danish data after adjusting for multiple testing. In a meta‐analysis of all three samples, rs2706372 reached a P‐value of P_{Immunochip+Repl} = 5.42 × 10^?7 (OR = 1.20; 95% CI = 1.12–1.28). SNP rs2706372 is located in the extended RAD50/IL13 region. RAD50 seems a plausible longevity candidate due to its involvement in DNA repair and inflammation. Further studies are needed to identify the functional variant(s) that predispose(s) to a long and healthy life.