Abstract-Excess weight is established as a major risk factor for cardiovascular diseases, particularly in young individuals.To get a better understanding of the pathophysiology underlying increased cardiovascular disease risk, we evaluated early signs of organ damage and their possible relationship to sympathetic nervous activity. Eighteen lean (body mass index Ͻ25 kg/m 2 ) and 25 overweight or obese (body mass index Ͼ25 kg/m 2 ) healthy university students were included in the study. We comprehensively assessed subclinical target organ damage, including the following: (1) assessment of renal function; (2) left ventricular structure and systolic and diastolic function; and (3) O besity is an established risk factor for cardiovascular disease (CVD) development. 1 Although excess adiposity is frequently linked with metabolic abnormalities such as elevated triglycerides, low levels of high-density lipoprotein (HDL), elevated glucose, elevated blood pressure (BP), insulin resistance, and a proinflammatory state, most likely contributing to excess CVD, 2 large scale epidemiological studies have shown that the CVD risk associated with obesity remains appreciable even after correction for these factors. 1,3 Perhaps surprising is the finding that the obesity-related relative risk of death from stroke and all of the CVDs combined is higher in younger than in older subjects, 4,5 indicating that excess adiposity is likely to have deleterious effects on the cardiovascular system already at an early age, well before clinical manifestations of CVD become apparent. In agreement with this view, recent studies have demonstrated that the presence of obesity since childhood was the only consistent and significant determinant of adverse cardiac remodeling 6 and that being overweight at age 20 years or obese at any time in life was linked with a 3-fold increased risk of developing chronic renal failure. 7 Moreover, functional and structural abnormalities of the endothelium are already evident in obese children aged 9 to 12 years. 8 Given that the sympathetic nervous system (SNS) is an important regulatory mechanism of both metabolic and cardiovascular functions, altered SNS may likely play a role in the etiology and complications of obesity. 9 It is now well established that obesity is associated with elevated SNS Continuing medical education (CME) credit is available for this article. Go to http://cme.ahajournals.org to take the quiz.

Although glucose uniquely stimulates proinsulin biosynthesis in β cells, surprisingly little is known of the underlying mechanism(s). Here, we demonstrate that glucose activates the unfolded protein response transducer inositol-requiring enzyme 1 alpha (IRE1α) to initiate X-box-binding protein 1 (Xbp1) mRNA splicing in adult primary β cells. Using mRNA sequencing (mRNA-Seq), we show that unconventional Xbp1 mRNA splicing is required to increase and decrease the expression of several hundred mRNAs encoding functions that expand the protein secretory capacity for increased insulin production and protect from oxidative damage, respectively. At 2 wk after tamoxifen-mediated Ire1α deletion, mice develop hyperglycemia and hypoinsulinemia, due to defective β cell function that was exacerbated upon feeding and glucose stimulation. Although previous reports suggest IRE1α degrades insulin mRNAs, Ire1α deletion did not alter insulin mRNA expression either in the presence or absence of glucose stimulation. Instead, β cell failure upon Ire1α deletion was primarily due to reduced proinsulin mRNA translation primarily because of defective glucose-stimulated induction of a dozen genes required for the signal recognition particle (SRP), SRP receptors, the translocon, the signal peptidase complex, and over 100 other genes with many other intracellular functions. In contrast, Ire1α deletion in β cells increased the expression of over 300 mRNAs encoding functions that cause inflammation and oxidative stress, yet only a few of these accumulated during high glucose. Antioxidant treatment significantly reduced glucose intolerance and markers of inflammation and oxidative stress in mice with β cell-specific Ire1α deletion. The results demonstrate that glucose activates IRE1α-mediated Xbp1 splicing to expand the secretory capacity of the β cell for increased proinsulin synthesis and to limit oxidative stress that leads to β cell failure.

Due to their relative synthetic and chemical simplicity compared to antibodies, aptamers afford enhanced stability and functionality for the detection of environmental contaminants and for use in environmental monitoring. Furthermore, nucleic acid aptamers can be selected for toxic targets which may prove difficult for antibody development. Of particular relevance, aptamers have been selected and used to develop biosensors for environmental contaminants such as heavy metals, small-molecule agricultural toxins, and water-borne bacterial pathogens. This review will focus on recent aptamer-based developments for the detection of diverse environmental contaminants. Within this domain, aptamers have been combined with other technologies to develop biosensors with various signal outputs. The goal of much of this work is to develop cost-effective, user-friendly detection methods that can complement or replace traditional environmental monitoring strategies. This review will highlight recent examples in this area. Additionally, with innovative developments such as wearable devices, sentinel materials, and lab-on-a-chip designs, there exists significant potential for the development of multifunctional aptamer-based biosensors for environmental monitoring. Examples of these technologies will also be highlighted. Finally, a critical perspective on the field, and thoughts on future research directions will be offered.

The yeast Candida albicans causes human infections that have mortality rates approaching 50%. The key to developing improved therapeutics is to understand the host-pathogen interface. A critical interaction is that with macrophages: intracellular Candida triggers the NLRP3/caspase-1 inflammasome for escape through lytic host cell death, but this also activates antifungal responses. To better understand how the inflammasome response to Candida is fine-tuned, we established live-cell imaging of inflammasome activation at single-cell resolution, coupled with analysis of the fungal ERMES complex, a mitochondrial regulator that lacks human homologs. We show that ERMES mediates Candida escape via inflammasome-dependent processes, and our data suggest that inflammasome activation is controlled by the level of hyphal growth and exposure of cell wall components as a proxy for severity of danger. Our study provides the most detailed dynamic analysis of inflammasome responses to a fungal pathogen so far and establishes promising pathogen- and host-derived therapeutic strategies.

Biocompatible fluorescent reporters with spectral properties spanning the entire visible spectrum are indispensable tools for imaging the biochemistry of living cells and organisms in real time. Here, we report the engineering of a fluorescent chemogenetic reporter with tunable optical and spectral properties. A collection of fluorogenic chromophores with various electronic properties enables to generate bimolecular fluorescent assemblies that cover the visible spectrum from blue to red using a single protein tag engineered and optimized by directed evolution and rational design. The ability to tune the fluorescence color and properties through simple molecular modulation provides a broad experimental versatility for imaging proteins in live cells, including neurons, and in multicellular organisms, and opens avenues for optimizing Förster resonance energy transfer (FRET) biosensors in live cells. The ability to tune the spectral properties and fluorescence performance enables furthermore to match the specifications and requirements of advanced super-resolution imaging techniques.

Using a mouse model harboring a naturally occurring WHIM syndrome–linked gain-of-function Cxcr4 mutation, Freitas et al. show that Cxcr4 desensitization is critical for quiescence/cycling balance of murine short-term hematopoietic stem cells and their differentiation into multipotent and downstream lymphoid-biased progenitors.

Highlights d Nutrient restriction and autophagy regulate axonal growth and neuronal polarity d VAMP7 mediates nutrient restriction/autophagy-dependent neurite growth d VAMP7 mediates the secretion of ER-phagy factor Reticulon 3

The extrafollicular immune response is essential to generate a rapid but transient wave of protective antibodies upon infection. Despite its importance, the molecular mechanisms controlling this first response are poorly understood. Here, we demonstrate that enhanced Cxcr4 signaling due to defective receptor desensitization leads to exacerbated extrafollicular B cell response. Using a mouse model bearing a gain of function mutation of Cxcr4 described in two human hematological disorders, WHIM syndrome and Waldenström's Macroglobulinemia, we demonstrated that mutant B cells exhibited enhanced mTOR signaling, cycled more and differentiated more potently into plasma cells than wild-type B cells upon TLR stimulation. Moreover, Cxcr4 gain-of-function promoted enhanced homing and persistence of immature plasma cells in the bone marrow, a phenomenon recapitulated in WHIM syndrome patient samples. This translated in increased and more sustained production of antibodies upon T-independent immunization in Cxcr4 mutant mice. Thus, our results establish that fine-tuning of Cxcr4 signaling is essential to limit the strength and length of the extrafollicular immune response.