Background & AimsThe intestinal immune system is tightly regulated to prevent responses against the many nonpathogenic antigens in the gut. Transforming growth factor (TGF)-β is a cytokine that maintains intestinal homeostasis, in part by inducing Foxp3+ regulatory T cells (Tregs) that suppress immune responses. TGF-β is expressed at high levels in the gastrointestinal tract as a latent complex that must be activated. However, the pathways that control TGF-β activation in the intestine are poorly defined. We investigated the cellular and molecular pathways that control activation of TGF-β and induction of Foxp3+ Tregs in the intestines of mice to maintain immune homeostasis.MethodsSubsets of intestinal dendritic cells (DCs) were examined for their capacity to activate TGF-β and induce Foxp3+ Tregs in vitro. Mice were fed oral antigen, and induction of Foxp3+ Tregs was measured.ResultsA tolerogenic subset of intestinal DCs that express CD103 were specialized to activate latent TGF-β, and induced Foxp3+ Tregs independently of the vitamin A metabolite retinoic acid. The integrin αvβ8, which activates TGF-β, was significantly up-regulated on CD103+ intestinal DCs. DCs that lack expression of integrin αvβ8 had reduced ability to activate latent TGF-β and induce Foxp3+ Tregs in vitro and in vivo.ConclusionsCD103+ intestinal DCs promote a tolerogenic environment in the intestines of mice via integrin αvβ8-mediated activation of TGF-β.

Regulation of an immune response requires complex crosstalk between cells of the innate and adaptive immune systems, via both cell–cell contact and secretion of cytokines. An important cytokine with a broad regulatory role in the immune system is transforming growth factor-β (TGF-β). TGF-β is produced by and has effects on many different cells of the immune system, and plays fundamental roles in the regulation of immune responses during homeostasis, infection and disease. Although many cells can produce TGFβ, it is always produced as an inactive complex that must be activated to bind to the TGFβ receptor complex and promote downstream signalling. Thus, regulation of TGFβ activation is a crucial step in controlling TGFβ function. This review will discuss how TGFβ controls diverse immune responses and how TGFβ function is regulated, with a focus on recent work highlighting a critical role for the integrin αvβ8 expressed by dendritic cells in activating TGFβ.

Nesfatin-1, a newly discovered NUCB2-derived satiety neuropeptide is expressed in several neurons of forebrain, hindbrain, brainstem and spinal cord. This novel anorexigenic substance seems to play an important role in hypothalamic pathways regulating food intake and energy homeostasis. Nesfatin-1 immunoreactive cells are detectable in arcuate (ARC), paraventricular (PVN) and supraoptic nuclei (SON), where the peptide is colocalized with POMC/CART, NPY, oxytocin and vasopressin. The nesfatin-1 molecule interacts with a G-protein coupled receptor and its cytophysiological effect depends on inhibitory hyperpolarization of NPY/AgRP neurons in ARC and melanocortin signaling in PVN. Administration of nesfatin-1 significantly inhibits consumatory behavior and decreases weight gain in experimental animals. These recent findings suggest the evidence for nesfatin-1 involvement in other important brain functions such as reproduction, sleep, cognition and anxiety- or stress-related responses. The neuroprotective and antiapoptotic properties of nesfatin-1 were also reported. From the clinical viewpoint it should be noteworthy, that the serum concentration of nesfatin-1 may be a sensitive marker of epileptic seizures. However, the details of nesfatin-1 physiology ought to be clarified, and it may be considered suitable in the future, as a potential drug in the pharmacotherapy of obesity, especially in patients treated with antipsychotics and antidepressants. On the other hand, some putative nesfatin-1 antagonists may improve eating disorders.

Chronic intestinal parasite infection is a major global health problem, but mechanisms that promote chronicity are poorly understood. Here we describe a novel cellular and molecular pathway involved in the development of chronic intestinal parasite infection. We show that, early during development of chronic infection with the murine intestinal parasite Trichuris muris, TGFβ signalling in CD4+ T-cells is induced and that antibody-mediated inhibition of TGFβ function results in protection from infection. Mechanistically, we find that enhanced TGFβ signalling in CD4+ T-cells during infection involves expression of the TGFβ-activating integrin αvβ8 by dendritic cells (DCs), which we have previously shown is highly expressed by a subset of DCs in the intestine. Importantly, mice lacking integrin αvβ8 on DCs were completely resistant to chronic infection with T. muris, indicating an important functional role for integrin αvβ8-mediated TGFβ activation in promoting chronic infection. Protection from infection was dependent on CD4+ T-cells, but appeared independent of Foxp3+ Tregs. Instead, mice lacking integrin αvβ8 expression on DCs displayed an early increase in production of the protective type 2 cytokine IL-13 by CD4+ T-cells, and inhibition of this increase by crossing mice to IL-4 knockout mice restored parasite infection. Our results therefore provide novel insights into how type 2 immunity is controlled in the intestine, and may help contribute to development of new therapies aimed at promoting expulsion of gut helminths.

We used genotyping-by-sequencing (GBS) to investigate the evolutionary history of domesticated tetraploid wheats. With a panel of 189 wild and domesticated wheats, we identified 1,172,469 single nucleotide polymorphisms (SNPs) with a read depth �3. Principal component analyses (PCAs) separated the Triticum turgidum and Triticum timopheevii accessions, as well as wild T. turgidum from the domesticated emmers and the naked wheats, showing that SNP typing by GBS is capable of providing robust information on the genetic relationships between wheat species and subspecies. The PCAs and a neighbourjoining analysis suggested that domesticated tetraploid wheats have closest affinity with wild emmers from the northern Fertile Crescent, consistent with the results of previous genetic studies on the origins of domesticated wheat. However, a more detailed examination of admixture and allele sharing between domesticates and different wild populations, along with genome-wide association studies (GWAS), showed that the domesticated tetraploid wheats have also received a substantial genetic input from wild emmers from the southern Levant. Taking account of archaeological evidence that tetraploid wheats were first cultivated in the southern Levant, we suggest that a pre-domesticated crop spread from this region to southeast Turkey and became mixed with a wild emmer population from the northern Fertile Crescent. Fixation of the domestication traits in this mixed population would account for the allele sharing and GWAS results that we report. We also propose that feralization of the component of the pre-domesticated population that did not acquire domestication traits has resulted in the modern wild population from southeast Turkey displaying features of both the domesticates and wild emmer from the southern Levant, and hence appearing to be the sole progenitor of domesticated tetraploids when the phylogenetic relationships are studied by methods that assume a treelike pattern of evolution.

Helminths are highly prevalent metazoan parasites that infect over a billion of the world’s population. Hosts have evolved numerous mechanisms to drive the expulsion of these parasites via Th2-driven immunity, but these responses must be tightly controlled to prevent equally devastating immunopathology. However, mechanisms that regulate this balance are still unclear. Here we show that the vigorous Th2 immune response driven by the small intestinal helminth Trichinella spiralis , is associated with increased TGFβ signalling responses in CD4+ T-cells. Mechanistically, enhanced TGFβ signalling in CD4+ T-cells is dependent on dendritic cell-mediated TGFβ activation which requires expression of the integrin αvβ8. Importantly, mice lacking integrin αvβ8 on DCs had a delayed ability to expel a T . spiralis infection, indicating an important functional role for integrin αvβ8-mediated TGFβ activation in promoting parasite expulsion. In addition to maintaining regulatory T-cell responses, the CD4+ T-cell signalling of this pleiotropic cytokine induces a Th17 response which is crucial in promoting the intestinal muscle hypercontractility that drives worm expulsion. Collectively, these results provide novel insights into intestinal helminth expulsion beyond that of classical Th2 driven immunity, and highlight the importance of IL-17 in intestinal contraction which may aid therapeutics to numerous diseases of the intestine.

We used polymerase chain reactions specific for the wheat B and G genomes with nine accessions of the "new" glume wheat (NGW), a type of cultivated wheat that was present across western Asia and Europe during the Neolithic and Bronze Ages but which apparently died out before the end of the 1 st millennium BC. DNA sequences from the G genome were detected in two NGW accessions, the first comprising grain from the mid 7 th millennium BC at Çatalhöyük in Turkey, and the second made up of chaff from the later 5 th millennium BC site of Miechowice 4 in Poland. The Miechowice chaff also yielded a B genome sequence, which we ascribe to an admixture of emmer wheat chaff recorded in the sample from which the NGW material was extracted. Our results therefore provide evidence that NGW is a member of the Triticum timopheevii group of wheats. Triticum timopheevii subsp. timopheevii can therefore no longer be looked upon as a minor crop, restricted to western Georgia, but instead must be viewed as a significant component of prehistoric Eurasian agriculture, with implications for our understanding of the origins of agriculture in southwest Asia.

Insomnia is a serious medical and social problem, its prevalence in the general population ranges from 9 to 35% depending on the country and assessment method. Often, patients are subject to inappropriate and therefore dangerous pharmacotherapies that include prolonged administration of hypnotic drugs, benzodiazepines and other GABAA receptor modulators. This usually does not lead to a satisfactory improvement in patients' clinical states and may cause lifelong drug dependence. Brain state transitions require the coordinated activity of numerous neuronal pathways and brain structures. It is thought that orexin-expressing neurons play a crucial role in this process. Due to their interaction with the sleep-wake-regulating neuronal population, they can activate vigilance-promoting regions and prevent unwanted sleep intrusions. Understanding the multiple orexin modulatory effects is crucial in the context of pathogenesis of insomnia and should lead to the development of novel treatments. An important step in this process was the synthesis of dual antagonists of orexin receptors. Crucially, these drugs, as opposed to benzodiazepines, do not change the sleep architecture and have limited side-effects. This new pharmacological approach might be the most appropriate to treat insomnia.