Cold exposure may be a potential therapy for diabetes by increasing brown adipose tissue (BAT) mass and activity. Here we report that 10 d of cold acclimation (14-15 °C) increased peripheral insulin sensitivity by ∼43% in eight type 2 diabetes subjects. Basal skeletal muscle GLUT4 translocation markedly increased, without effects on insulin signaling or AMP-activated protein kinase (AMPK) activation and only a minor increase in BAT glucose uptake.

Live vaccines have long been known to trigger far more vigorous immune responses than their killed counterparts1–6. This has been attributed to the ability of live microorganisms to replicate and express specialized virulence factors that facilitate invasion and infection of their hosts7. However, protective immunization can often be achieved with a single injection of live, but not dead, attenuated microorganisms stripped of their virulence factors. Pathogen associated molecular patterns (PAMPs), which serve to alert the immune system8,9, are present in both live and killed vaccines, suggesting that certain poorly characterized aspects of live microorganisms, not incorporated in dead vaccines, are particularly effective at inducing protective immunity. Here we show that the innate immune system can directly sense microbial viability through detection of a special class of viability-associated PAMPs (vita-PAMPs). We identify prokaryotic messenger RNA (mRNA) as a vita-PAMP present only in viable bacteria, recognition of which elicits a unique innate response and a robust adaptive antibody response. Notably, the innate response evoked by viability and prokaryotic mRNA was thus far considered to be reserved for pathogenic bacteria, but we show that even nonpathogenic bacteria in sterile tissues can trigger similar responses, provided they are alive. Thus, the immune system actively gauges the infectious risk by scouring PAMPs for signatures of microbial life and thus infectivity. Detection of vita-PAMPs triggers an alert mode not warranted for dead bacteria. Vaccine formulations that incorporate vita-PAMPs could thus combine the superior protection of live vaccines with the safety of dead vaccines.

Coordination of cell division and pattern formation is central to tissue and organ development, particularly in plants where walls prevent cell migration. Auxin and cytokinin are both critical for division and patterning, but it is unknown how these hormones converge upon tissue development. We identify a genetic network that reinforces an early embryonic bias in auxin distribution to create a local, nonresponding cytokinin source within the root vascular tissue. Experimental and theoretical evidence shows that these cells act as a tissue organizer by positioning the domain of oriented cell divisions. We further demonstrate that the auxin-cytokinin interaction acts as a spatial incoherent feed-forward loop, which is essential to generate distinct hormonal response zones, thus establishing a stable pattern within a growing vascular tissue.

While apical growth in plants initiates upon seed germination, radial growth is only primed during early ontogenesis in procambium cells and activated later by the vascular cambium 1 . Although it is not known how radial growth is organized and regulated in plants, this system resembles the developmental competence observed in some animal systems, in which pre-existing patterns of developmental potential are established early on 2,3 . Here we show that the initiation of radial growth occurs around early protophloem sieve element (PSE) cell files of the root procambial tissue in Arabidopsis. In this domain cytokinin signalling promotes expression of a pair of novel mobile transcription factors, PHLOEM EARLY DOF (PEAR1, PEAR2) and their four homologs (DOF6, TMO6, OBP2 and HCA2), collectively called PEAR proteins. The PEAR proteins form a short-range concentration gradient peaking at PSE and activating gene expression that promotes radial growth. The expression and function of PEAR proteins are antagonized by well-established polarity transcription factors, HD-ZIP III 4 , whose expression is concentrated in the more internal domain of radially non-dividing procambial cells by the function of auxin and mobile miR165/166. The PEAR proteins locally promote transcription of their inhibitory HD-ZIP III genes, thereby establishing a negative feedback loop that forms a robust boundary demarking the zone of cell divisions. Taken together, we have established a network, in which the PEAR -HD-ZIP III module integrates spatial information of the hormonal domains and miRNA gradients during root procambial development, to provide adjacent zones of dividing and more quiescent cells as a foundation for further radial growth. Cambial growth in plants is initiated within the procambial tissues of the apical meristems through periclinal (i.e. longitudinal) divisions associated with formation of the vascular tissues xylem and phloem 1 (Extended Data Fig. 1a). It has been established that during procambial development in Arabidopsis roots there are distinct domains for high auxin and cytokinin signalling, which mark the regions for further development of xylem and phloem/procambium, respectively 5-8 . To accurately map the spatial distribution of the periclinal divisions, we established a new nomenclature for the root procambial cells, including PSE-lateral neighbours (PSE-LN) as cells directly contacting both PSE and the pericycle, the outer procambial cells (OPC) as procambial cells adjacent to the pericycle but not contacting PSE, and SE-internal neighbours (PSE-IN) as cells located internal to and directly contacting PSE (Fig. 1a). Both the PSE cell and PSE-LN showed higher activity of periclinal cell division than the OPC and PSE-IN (Fig. 1b, Extended Data Fig. 1b-d and Supplementary Information).We observed virtually no periclinal divisions in metaxylem (MX) and internal procambial cells (IPC) (Fig. 1b). Furthermore, blocking symplastic transport genetically 9 between the PSE and the surrounding cells results in a dramatic reduct...

Probiotic bacteria, specific representatives of bacterial species that are a common part of the human microbiota, are proposed to deliver health benefits to the consumer by modulation of intestinal function through largely unknown molecular mechanisms. To explore in vivo mucosal responses of healthy adults to probiotics, we obtained transcriptomes in an intervention study after a double-blind placebo-controlled cross-over design. In the mucosa of the proximal small intestine of healthy volunteers, probiotic strains from the species Lactobacillus acidophilus, L. casei, and L. rhamnosus each induced differential gene-regulatory networks and pathways in the human mucosa. Comprehensive analyses revealed that these transcriptional networks regulate major basal mucosal processes and uncovered remarkable similarity to response profiles obtained for specific bioactive molecules and drugs. This study elucidates how intestinal mucosa of healthy humans perceives different probiotics and provides avenues for rationally designed tests of clinical applications.gene regulation | host-microbe interactions | lactobacillus | transcriptomics | gut bacteria