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In this paper, we propose a software correction technique to eliminate the misalignment errors in the measurement of antenna radiated fields for frequency-diverse imaging. It is shown that by using RF fiducials integrated into the antennas, the effect of rotation (range and cross-range) and offset misalignment errors can be corrected to a good accuracy, holding significant potential for applications where precise alignment is required for antenna field measurements.

We demonstrate the design of a frequency-diverse aperture for imaging of human size objects. Frequency-diversity is an all-electronic technique, allowing the imaging to be performed without any mechanical moving parts or active circuit components. Leveraging computational imaging algorithms, the concept of frequency-diverse imaging offers a simplified alternative to conventional techniques limited in key metrics, such as data acquisition speed, system complexity and cost. It is shown that the synthesized-frequency diverse aperture can reconstruct good quality images of a human-size target by means of a simple frequency sweep over the K-band frequency regime.

Computational imaging is a proven strategy for obtaining high-quality images with fast acquisition rates and simpler hardware. Metasurfaces provide exquisite control over electromagnetic fields, enabling the radiated field to be molded into unique patterns. The fusion of these two concepts can bring about revolutionary advances in the design of imaging systems for security screening. In the context of computational imaging, each field pattern serves as a single measurement of a scene; imaging a scene can then be interpreted as estimating the reflectivity distribution of a target from a set of measurements. As with any computational imaging system, the key challenge is to arrive at a minimal set of measurements from which a diffraction-limited image can be resolved. Here, we show that the information content of a frequency-diverse metasurface aperture can be maximized by design, and used to construct a complete millimeter-wave imaging system spanning a 2 m by 2 m area, consisting of 96 metasurfaces, capable of producing diffraction-limited images of human-scale targets. The metasurfacebased frequency-diverse system presented in this work represents an inexpensive, but tremendously flexible alternative to traditional hardware paradigms, offering the possibility of low-cost, real-time, and ubiquitous screening platforms.

Background The physiological and behavioral symptoms of sickness, including fever, anorexia, behavioral depression, and weight loss can be both beneficial and detrimental. These sickness responses are triggered by pro-inflammatory cytokines acting on cells within the brain. Previous research demonstrates that the febrile response to peripheral insults depends upon prostaglandin production by vascular endothelial cells, but the mechanisms and specific cell type(s) responsible for other sickness responses remain unknown. The purpose of the present study was to identify which cells within the brain are required for sickness responses triggered by central nervous system inflammation. Methods Intracerebroventricular (ICV) administration of 10 ng of the potent pro-inflammatory cytokine interleukin-1β (IL-1β) was used as an experimental model of central nervous system cytokine production. We examined which cells respond to IL-1β in vivo via fluorescent immunohistochemistry. Using multiple transgenic mouse lines expressing Cre recombinase under the control of cell-specific promoters, we eliminated IL-1β signaling from different populations of cells. Food consumption, body weight, movement, and temperature were recorded in adult male mice and analyzed by two-factor ANOVA to determine where IL-1β signaling is essential for sickness responses. Results Endothelial cells, microglia, ependymal cells, and astrocytes exhibit nuclear translocation of NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) in response to IL-1β. Interfering with IL-1β signaling in microglia, endothelial cells within the parenchyma of the brain, or both did not affect sickness responses. Only mice that lacked IL-1β signaling in all endothelium including fenestrated capillaries lacked sickness responses. Conclusions These experiments show that IL-1β-induced sickness responses depend on intact IL-1β signaling in blood vessels and suggest that fenestrated capillaries act as a critical signaling relay between the immune and nervous systems. Trial registration Not applicable. Electronic supplementary material The online version of this article (10.1186/s12974-017-0990-7) contains supplementary material, which is available to authorized users.

Frequency-diverse imaging is an all-electronic method, capable of sampling the scene to be imaged without the need for a mechanical scan or active circuit components. In order to optimize the imaging characteristics, such as imaging resolution and fidelity of the reconstructed images, the antennas used within this scheme need to be optimized. It is demonstrated that using a Mills-Cross iris distribution, superior sampling of the Fourier components (wide support extent and minimum sampling redundancy) can be achieved. Using the optimized antennas, an experimental imaging system is built, reconstructing a good quality image of a cross-shaped target in less than 0.1 seconds.

We demonstrate a frequency-diverse imaging system using an air-filled cavity-backed antenna as a transceiver (cavity-to-cavity system layout) for the K-band (17.5–26.5 GHz) frequency regime. Leveraging the computational imaging concept, the frequency-diversity enables imaging in an all-electronic manner, without the need for mechanical raster scanning or active circuit components, minimizing the data acquisition time and simplifying the system architecture. It is shown that the proposed system is capable of reconstructing good fidelity images in a sub-second time frame, holding significant potential for real-time imaging applications.

Melanocortin neurons conserve body mass in hyper- or hypo-caloric conditions by conveying signals from nutrient sensors into areas of the brain governing appetite and metabolism. In mice, melanocortin-3 receptor (MC3R) deletion alters nutrient partitioning independently of hyperphagia, promoting accumulation of fat over muscle mass. Enhanced rhythms in insulin and insulin-responsive metabolic genes during hypocaloric feeding suggest partial insulin resistance and enhanced lipogenesis. However, exactly where and how MC3Rs affect metabolic control to alter nutrient partitioning is not known. The behavioral phenotypes exhibited by MC3R-deficient mice suggest a contextual role in appetite control. Homeostatic responses to hypocaloric conditioning involving increased expression of appetite-stimulating (orexigenic) neuropeptides, binge-feeding, food anticipatory activity, entrainment to nutrient availability and enhanced feeding-related motivational responses are compromised with MC3R-deficiency. Rescuing Mc3r transcription in hypothalamic and limbic neurons improves appetitive responses during hypocaloric conditioning, suggesting orexigenic functions. Rescuing hypothalamic MC3Rs also restores responses of fasting-responsive hypothalamic orexigenic neurons in hypocaloric conditions, suggesting actions that sensitize fasting-responsive neurons to signals from nutrient sensors. MC3R signaling in ventromedial hypothalamic SF1(+ve) neurons improves metabolic control, but does not restore appetitive responses or nutrient partitioning. In summary, desensitization of fasting-responsive orexigenic neurons may underlie attenuated appetitive responses of MC3R-deficient mice in hypocaloric situations. The orexigenic actions of hypothalamic and limbic MC3Rs are contextual, and do not affect feeding behavior in ad libitum conditions or nutrient partitioning. Further studies are needed to identify the specific location(s) of MC3Rs controlling appetitive responses and partitioning of nutrients between fat and lean tissues.

This paper summarizes the recent advances in using frequency-diverse metasurfaces for computational imaging in the microwave and millimeter wave regimes. Frequency-diverse apertures are defined as structures that can generate distinct radiation patterns as a function of frequency. Such waveforms can multiplex a scene information into a set of backscattered measurements, which can be decoded using computational algorithms. In this manner, these apertures can retrieve a scene's reflectivity map using a fast frequency sweep (all-electronic operation), circumventing the requirement for a mechanical scan or active circuit components. We review recent advances in developing these apertures and examine their performance in both simulation and experimental settings. Finally, efforts to build large apertures, which can image at the diffraction limit, are discussed.

Background Cachexia is a complex metabolic and behavioural syndrome lacking effective therapies. Pancreatic ductal adenocarcinoma (PDAC) is one of the most important conditions associated with cachexia, with >80% of PDAC patients suffering from the condition. To establish the cardinal features of a murine model of PDAC‐associated cachexia, we characterized the effects of implanting a pancreatic tumour cell line from a syngeneic C57BL/6 KRASG12D P53R172H Pdx‐Cre+/+ (KPC) mouse. Methods Male and female C57BL/6 mice were inoculated subcutaneously, intraperitoneally, or orthotopically with KPC tumour cells. We performed rigorous phenotypic, metabolic, and behavioural analysis of animals over the course of tumour development. Results All routes of administration produced rapidly growing tumours histologically consistent with moderate to poorly differentiated PDAC. The phenotype of this model was dependent on route of administration, with orthotopic and intraperitoneal implantation inducing more severe cachexia than subcutaneous implantation. KPC tumour growth decreased food intake, decreased adiposity and lean body mass, and decreased locomotor activity. Muscle catabolism was observed in both skeletal and cardiac muscles, but the dominant catabolic pathway differed between these tissues. The wasting syndrome in this model was accompanied by hypothalamic inflammation, progressively decreasing brown and white adipose tissue uncoupling protein 1 (Ucp1) expression, and increased peripheral inflammation. Haematological and endocrine abnormalities included neutrophil‐dominant leukocytosis and anaemia, and decreased serum testosterone. Conclusions Syngeneic KPC allografts are a robust model for studying cachexia, which recapitulate key features of the PDAC disease process and induce a wide array of cachexia manifestations. This model is therefore ideally suited for future studies exploring the physiological systems involved in cachexia and for preclinical studies of novel therapies.

We demonstrate a low-profile holographic imaging system at millimeter wavelengths based on an aperture composed of frequency-diverse metasurfaces. Utilizing measurements of spatially-diverse field patterns, diffraction-limited images of human-sized subjects are reconstructed. The system is driven by a single microwave source swept over a band of frequencies (17.5–26.5 GHz) and switched between a collection of transmit and receive metasurface panels. High fidelity image reconstruction requires a precise model for each field pattern generated by the aperture, as well as the manner in which the field scatters from objects in the scene. This constraint makes scaling of computational imaging systems inherently challenging for electrically large, coherent apertures. To meet the demanding requirements, we introduce computational methods and calibration approaches that enable rapid and accurate imaging performance.

Objective Recent evidence indicates that the adult hematopoietic system is susceptible to diet-induced lineage skewing. It is not known whether the developing hematopoietic system is subject to metabolic programming via in utero high-fat diet (HFD) exposure, an established mechanism of adult disease in several organ systems. We previously reported substantial losses in offspring liver size with prenatal HFD. As the liver is the main hematopoietic organ in the fetus, we asked whether the developmental expansion of the hematopoietic stem and progenitor cell (HSPC) pool is compromised by prenatal HFD and/or maternal obesity. Methods We used quantitative assays, progenitor colony formation, flow cytometry, transplantation, and gene expression assays with a series of dietary manipulations to test the effects of gestational high-fat diet and maternal obesity on the day 14.5 fetal liver hematopoietic system. Results Maternal obesity, particularly when paired with gestational HFD, restricts physiological expansion of fetal HSPCs while promoting the opposing cell fate of differentiation. Importantly, these effects are only partially ameliorated by gestational dietary adjustments for obese dams. Competitive transplantation reveals compromised repopulation and myeloid-biased differentiation of HFD-programmed HSPCs to be a niche-dependent defect, apparent in HFD-conditioned male recipients. Fetal HSPC deficiencies coincide with perturbations in genes regulating metabolism, immune and inflammatory processes, and stress response, along with downregulation of genes critical for hematopoietic stem cell self-renewal and activation of pathways regulating cell migration. Conclusions Our data reveal a previously unrecognized susceptibility to nutritional and metabolic developmental programming in the fetal HSPC compartment, which is a partially reversible and microenvironment-dependent defect perturbing stem and progenitor cell expansion and hematopoietic lineage commitment.

Fatigue is the most common symptom related to cytotoxic chemotherapeutic treatment of cancer. Peripheral inflammation associated with cytotoxic chemotherapy is likely a causal factor of fatigue. The neural mechanisms by which cytotoxic chemotherapy associated inflammation induces fatigue behavior are not known. This lack of knowledge hinders development of interventions to reduce or prevent this disabling symptom. Infection induced fatigue/lethargy in rodents is mediated by suppression of hypothalamic orexin activity. Orexin is critical for maintaining wakefulness and motivated behavior. Though there are differences between infection and cytotoxic chemotherapy in some symptoms, both induce peripheral inflammation and fatigue. Based on these similarities we hypothesized that cytotoxic chemotherapy induces fatigue by disrupting orexin neuron activity. We found that a single dose of a cytotoxic chemotherapy cocktail (cyclophosphamide, adriamycin, 5-fluorouracil—CAF) induced fatigue/lethargy in mice and rats as evidenced by a significant decline in voluntary locomotor activity measured by telemetry. CAF induced inflammatory gene expression—IL-1R1 (p

Purpose/Objectives: The disease-associated wasting condition cachexia is a common complication of pancreatic ductal adenocarcinoma (PDAC) that impacts quality of life and portends poor survival. Undernutrition is a major driver of wasting in PDAC, yet cachexia remains refractory to nutritional supplementation. By modifying nutritional challenges at different stages of cachexia development, we sought to understand the relative contributions of undernutrition and metabolic reprogramming on adipose and skeletal muscle wasting. Materials/Methods: Adult mice received orthotopic PDAC tumor injections (KrasG12D; p53R172H/+; Pdx1-cre) or sham injections. Mice were fasted or food restricted at different times during tumor growth in a series of 2x2 factorial studies. Anthropometrics, voluntary wheel running activity, and body composition were measured throughout study. Blood glucose and ketones were measured by glucometer and ketometer. Ketogenic potential was assessed using octanoate challenge after fasting. Liver mRNA levels were measured using qPCR. Hepatic IL-6 signaling was assessed using qPCR and ELISA for plasma IL-6. Results: PDAC mice maintained food intake and wheel running for 8 days after tumor injection, before progressive decline. Loss of adipose mass in PDAC mice occurred only in the context of decreased nutrition, whereas loss of lean mass preceded decreases in food intake. Overnight fasting mitigated differences in fat mass between groups, whereas the effect of fasting on skeletal muscle loss was similar in PDAC and control mice. Fasting blood glucose and ketogenic potential were lower in PDAC mice, suggesting impaired hepatic response to metabolic stress. In the liver, glycolytic genes were increased, whereas gluconeogenic and ketogenic genes were decreased in PDAC mice. Wasting and hepatic reprogramming occurred independently of hepatic IL-6 signaling. Conclusions: Undernutrition drives PDAC-associated adipose wasting, yet muscle wasting occurs prior to changes in food intake and in the absence of systemic inflammation. Hepatic macronutrient partitioning and metabolic gene expression are altered in PDAC, implicating impaired adaptive responses to negative energy balance in PDAC-associated cachexia. Citation Format: Heike Mendez, Xinxia Zhu, Brennan Olsen, Daniel L. Marks, Aaron J. Grossberg. Impaired adaptation to negative energy balance in pancreatic cancer-associated wasting [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr C19.

Magnetomotive ultrasound (MMUS) contrasts superparamagnetic iron-oxide nanoparticles (SPIOs) that undergo submicrometer-scale displacements in response to a magnetic gradient force applied to an imaging sample. Typically, MMUS signals are defined in a way that is proportional to the medium displacement, rendering an indirect measure of the density distribution of SPIOs embedded within. Displacement-based MMUS, however, suffers from 'halo effects' that extend into regions without SPIOs due to their inherent mechanical coupling with the medium. To reduce such effects and to provide a more accurate representation of the SPIO density distribution, we propose a model-based inversion of MMUS displacement fields by reconstructing the body force distribution. Displacement fields are modelled using the static Navier-Cauchy equation for linear, homogeneous, and isotropic media, and the body force fields are, in turn, reconstructed by minimizing a regularized least-squares error functional between the modelled and the measured displacement fields. This reconstruction, when performed on displacement fields of two tissue-mimicking phantoms with cuboidal SPIO-laden inclusions, improved the range of errors in measured heights and widths of the inclusions from 54%-282% pre-inversion to-15%-20%. Likewise, the post-inversion contrast to noise ratios (CNRs) of the images were significantly larger than displacement-derived CNRs alone (p = 0.0078, Wilcoxon signed rank test). Qualitatively, it was found that inversion ameliorates halo effects and increases overall detectability of the inclusion. These findings highlight the utility of model-based inversion as a tool for both signal processing and accurate characterization of the number density distribution of SPIOs in magnetomotive imaging.

We show that Holevo's inequality upper-bounds the information capacity of a volume hologram without requiring a specification of the implementation of the hologram or the measurements to be made on the field scattered by the hologram. We find that, in the weakly scattering limit, the information capacity is not determined by the number of possible configurations of the holographic medium but only by the specification of the incident fields in the medium volume, which are determined at the volume boundary. By treating a volume hologram as a quantum communication channel, we establish a correspondence between the reconstruction of a hologram with multiple incident and scattered waves and the measurement of a quantum state with an operator-valued measure. We determine a bound on the probability of communications error, which describes the degree to which the incident fields may be distinguished by measurements of the scattered waves or, in other words, the crosstalk between the incident fields.

A fundamental challenge has plagued computer-generated volumetric holography since its inception: design methods are available only in the perturbative limit, but this poses serious limitations on efficiency and the amount of multiplexing achievable. Given the recent progress in highly tailorable artificial media, such as metamaterials, the need for general and robust design techniques grows. We present a method based on the electromagnetic variational principle that applies to media that can be described as collections of point dipoles, as most metamaterials are. We demonstrate its efficacy by designing highly efficient, non-perturbative, multiplexing devices.

Adipose tissue inflammation is a cause of obesity-related metabolic disease. Natural killer (NK) cells are an understudied cell type in the context of obesity. The goal of this study was to determine the phenotype of human adipose tissue NK cells.We used flow cytometry phenotyping to study adipose tissue and peripheral blood NK cells from obese and lean humans.Human adipose tissue NK cells, relative to peripheral blood NK cells, express increased levels of activation markers. Adipose tissue NK cells also demonstrate an activated phenotype in obese relative to lean subjects, with increased expression of the activating receptor NKG2D.These data are the first detailed phenotypic characterization of human adipose tissue NK cells, and suggest a role for NK cells in adipose tissue inflammation in obesity.

Hyperglycemia worsens stroke, yet rigorous glycemic control does not improve neurologic outcome. An alternative is to target downstream molecular mediator(s) triggered by hyperglycemia but independent of prevailing glycemia. Soluble epoxide hydrolase (sEH) is a potential mediator of injury via its metabolism of neuroprotective epoxyeicosatrienoic acids (EETs). We tested whether hyperglycemia exacerbates cerebral injury by upregulating sEH and decreasing brain EET levels. Type 1 diabetes mellitus was modeled by streptozotocin (STZ;50 mg/kg per day intraperitoneally, 5 days) in male mice. At 4 weeks, STZ-treated and control mice underwent 45-minute middle cerebral artery occlusion (MCAO) with or without sEH blockade by trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (t-AUCB;1 mg/kg intraperitoneally daily for 6 days before MCAO). The STZ-treated mice had increased sEH mRNA expression in cerebral vessels and decreased EET concentrations in brain. There was no difference in cortical perfusion between groups. The STZ-treated mice sustained larger brain infarct than controls. Pretreatment with t-AUCB eliminated the difference in infarct size and EETs concentration between STZ-treated mice and controls, without altering glycemia. We conclude that type 1 diabetes mellitus upregulates sEH mRNA and decreases concentrations of neuroprotective EETs within the brain, leading to worse stroke outcome. The data indicate that sEH antagonism may be beneficial in the setting of hyperglycemic stroke.

Cachexia is a wasting condition defined by skeletal muscle atrophy in the setting of systemic inflammation. To explore the site at which inflammatory mediators act to produce atrophy in vivo, we utilized mice with a conditional deletion of the inflammatory adaptor protein myeloid differentiation factor 88 (MyD88). Although whole-body MyD88-knockout (wbMyD88KO) mice resist skeletal muscle atrophy in response to LPS, muscle-specific deletion of MyD88 is not protective. Furthermore, selective reexpression of MyD88 in the muscle of wbMyD88KO mice via electroporation fails to restore atrophy gene induction by LPS. To evaluate the role of glucocorticoids as the inflammation-induced mediator of atrophy in vivo, we generated mice with targeted deletion of the glucocorticoid receptor in muscle (mGRKO mice). Muscle-specific deletion of the glucocorticoid receptor affords a 71% protection against LPS-induced atrophy compared to control animals. Furthermore, mGRKO mice exhibit 77% less skeletal muscle atrophy than control animals in response to tumor growth. These data demonstrate that glucocorticoids are a major determinant of inflammation-induced atrophy in vivo and play a critical role in the pathogenesis of endotoxemic and cancer cachexia.—Braun, T. P., Grossberg, A. J., Krasnow, S. M., Levasseur, P. R., Szumowski, M., Zhu, X. X., Maxson, J. E., Knoll, J. G., Barnes, A. P., and Marks, D. L. Cancer- and endotoxin-induced cachexia require intact glucocorticoid signaling in skeletal muscle.

We propose a polarimetric microwave imaging technique that exploits recent advances in computational imaging. We utilize a frequency-diverse cavity-backed metasurface, allowing us to demonstrate high-resolution polarimetric imaging using a single transceiver and frequency sweep over the operational microwave bandwidth. The frequency-diverse metasurface imager greatly simplifies the system architecture compared with active arrays and other conventional microwave imaging approaches. We further develop the theoretical framework for computational polarimetric imaging and validate the approach experimentally using a multi-modal leaky cavity. The scalar approximation for the interaction between the radiated waves and the target---often applied in microwave computational imaging schemes---is thus extended to retrieve the susceptibility tensors, and hence providing additional information about the targets. Computational polarimetry has relevance for existing systems in the field that extract polarimetric imagery, and particular for ground observation. A growing number of short-range microwave imaging applications can also notably benefit from computational polarimetry, particularly for imaging objects that are difficult to reconstruct when assuming scalar estimations., Comment: 17 pages, 15 figures

Computational imaging systems leverage generalized measurements to produce high-fidelity images, enabling novel and often lower cost hardware platforms at the expense of increased processing. However, obtaining full resolution images across a large field-of-view (FOV) can lead to slow reconstruction times, limiting system performance where faster frame rates are desired. In many imaging scenarios, the highest resolution is needed only in smaller subdomains of interest within a scene, suggesting an aperture supporting multiple modalities of image capture with different resolutions can provide a path to system optimization. We explore this concept in the context of millimeter-wave imaging, presenting the design and simulation of a single frequency (75 GHz), multistatic, holographic spotlight aperture integrated into a K-band (17.5–26.5 GHz), frequency-diverse imager. The spotlight aperture – synthesized using an array of dynamically tuned, holographic, metasurface antennas – illuminates a constrained region-of-interest (ROI) identified from a low-resolution image, extracting a high-fidelity image of the constrained-ROI with a minimum number of measurement modes. The designs of both the static, frequency-diverse sub-aperture and the integrated dynamic spotlight aperture are evaluated using simulation techniques developed for large-scale synthetic apertures.

Melanocortin-3 receptors (MC3R) have a contextual role in appetite control that is amplified with hypocaloric conditioning. C57BL/6J (B6) mice subjected to hypocaloric feeding schedules (HFS) exhibit compulsive behavioral responses involving food anticipatory activity (FAA) and caloric loading following food access. These homeostatic responses to calorie-poor environs are attenuated in B6 mice in which Mc3r transcription is suppressed by a lox-stop-lox sequence in the 5’UTR (Mc3rTB/TB ). Here, we report that optimization of caloric loading in B6 mice subject to HFS, characterized by increased meal size and duration, is not observed in Mc3rTB/TB mice. Analysis of hypothalamic and neuroendocrine responses to HFS throughout the light-dark cycle suggests uncoupling of hypothalamic responses involving appetite-stimulating fasting-responsive hypothalamic neurons expressing agouti-related peptide (AgRP) and neuropeptide Y (Npy). Rescuing Mc3rs expression in Nkx2.1(+ve) neurons is sufficient to restore normal hypothalamic responses to negative energy balance. In addition, Mc3rs expressed in Nkx2.1(+ve) neurons are also sufficient to restore FAA and caloric loading of B6 mice subjected to HFS. In summary, MC3Rs expressed in Nkx2.1(+ve) neurons are sufficient to coordinate hypothalamic response and expression of compulsive behavioral responses involving meal anticipation and consumption of large meals during situations of prolonged negative energy balance.

Mesenchymal stromal cells (MSCs) present in the bone marrow microenvironment secrete cytokines and angiogenic factors that support the maintenance and regenerative expansion of hematopoietic stem and progenitor cells (HSPCs). Here, we tested the hypothesis that extracellular vesicles (EVs) released by MSCs contribute to the paracrine crosstalk that shapes hematopoietic function. We systematically characterized EV release by murine stromal cells and demonstrate that MSC-derived EVs prompt a loss of HSPC quiescence with concomitant expansion of murine myeloid progenitors. Our studies reveal that HSPC expansion by MSC EVs is mediated via the MyD88 adapter protein and is partially blocked by treatment with a TLR4 inhibitor. Imaging of fluorescence protein-tagged MSC EVs corroborated their cellular co-localization with TLR4 and endosomal Rab5 compartments in HSPCs. The dissection of downstream responses to TLR4 activation reveals that the mechanism by which MSC EVs impact HSPCs involves canonical NF-κB signaling and downstream activation of Hif-1α and CCL2 target genes. Our aggregate data identify a previously unknown role for MSC-derived EVs in the regulation of hematopoiesis through innate immune mechanisms and illustrate the expansive cell-cell crosstalk in the bone marrow microenvironment.

Signs and symptoms of multiple sclerosis are usually attributed to demyelinating lesions in the spinal cord or cerebral cortex. The hypothalamus is a region that is often overlooked yet controls many important homeostatic functions, including those that are perturbed in multiple sclerosis. In this review we discuss how hypothalamic dysfunction may contribute to signs and symptoms in people with multiple sclerosis. While dysfunction of the hypothalamic-pituitary-adrenal axis is common in multiple sclerosis, the effects and mechanisms of this dysfunction are not well understood. We discuss three hypothalamic mechanisms of fatigue in multiple sclerosis: (1) general hypothalamic-pituitary-adrenal axis hyperactivity, (2) disordered orexin neurotransmission, (3) abnormal cortisol secretion. We then review potential mechanisms of weight dysregulation caused by hypothalamic dysfunction. Lastly, we propose future studies and therapeutics to better understand and treat hypothalamic dysfunction in multiple sclerosis. Hypothalamic dysfunction appears to be common in multiple sclerosis, yet current studies are underpowered and contradictory. Future studies should contain larger sample sizes and standardize hormone and neuropeptide measurements.

In this article we introduce a new type of frequency diverse antenna based on a leaky waveguide. We have shown with simulated experiment that the antenna can achieve 2cm spatial resolution at K-band frequencies.

Leukemia inhibitory factor (LIF) has been suggested to function as a potent inhibitor of feed intake in rodents. In sheep, intravenous injection of lipopolysaccharide (LPS) resulted in an increase in gene expression for LIF in the arcuate nucleus ( < 0.01). In the same experiment, agouti related protein (AgRP) expression was elevated ( < 0.05) but there were no effects on proopiomelanocortin expression. Another group of sheep were provided intracerebroventricular (ICV) injections of LIF at 250, 500, 1,000, and 2,500 ng per sheep. Cumulative feed intake was inhibited by the 1,000- and 2,500-ng doses at 8 and 10 h after ICV injection ( < 0.03). All doses of LIF elevated temperature above 40°C, indicating a fever. When AgRP was intracerebroventricularly injected before LIF, there was no effect of LIF to reduce feed intake, suggesting the LIF inhibition of feed intake is consistent with the concept that the effect is mediated by the melanocortin-4 receptor. In an experiment to determine whether endocrine and metabolic effects of LIF were similar to reported effects of LPS, sheep were intracerebroventricularly injected with 2,500 ng LIF, and blood samples were collected at 10-min intervals for 6 h for assay of LH, samples from the first 3 h were assayed for GH, and samples at 30-min intervals were assayed for glucose and free fatty acids. The effect of treatment and treatment × time interaction was significant, indicating elevated plasma free fatty acids ( < 0.03 and < 0.001, respectively) and glucose ( < 0.01 and < 0.0001, respectively). There was also a treatment × time interaction on circulating concentrations of LH such that LIF caused LH to decrease ( < 0.0001). Additionally, there was a tendency for LIF treatment to increase circulating concentrations of GH (P = 0.0874). The effects of LIF on feed intake and other parameters was similar to the effects of LPS and leads to a hypothesis that LIF expression in response to LPS may be a component of the mechanism for feed intake inhibition and perhaps for changes in selected hormone and metabolites in disease models.

In this paper, we propose a metallized 3D printed cavity for K-band imaging and investigate the effect of metallization type on mode diversity and image reconstruction. The 3D printed cavity acts as a frequency-diverse aperture and is capable of imaging objects in an all-electronic manner utilizing computational imaging techniques. We demonstrate that metallization material choice can increase the mode diversity by 90.8%, significantly improving imaging.

We consider multi-static imaging systems composed of frequency-diverse transmitting antenna arrays (or apertures). In these frequency diverse imaging modalities, accurate near-field characterization of the antennas is vital to achieving imaging. It is shown that considerable simplification in system characterization can be achieved without compromising the image quality when planar cavity antennas are used, because their radiation characteristics can be manufacture repeatable. In contrast, it is also demonstrated that the increased complexity of antennas utilizing sub-wavelength elements significantly reduces fabrication tolerances, making it necessary to characterize the metamaterial apertures individually.

Radio imaging devices and synthetic aperture radar typically use either mechanical scanning or phased arrays to illuminate a target with spatially varying radiation patterns. Mechanical scanning is unsuitable for many high-speed imaging applications, and phased arrays contain many active components and are technologically and cost prohibitive at millimeter and terahertz frequencies. We show that antennas deliberately designed to produce many different radiation patterns as the frequency is varied can reduce the number of active components necessary while still capturing high-quality images. This approach, called frequency-diversity imaging, can capture an entire two-dimensional image using only a single transmit and receive antenna with broadband illumination. We provide simple principles that ascertain whether a design is likely to achieve particular resolution specifications, and illustrate these principles with simulations.

We demonstrate a frequency diverse, multistatic microwave imaging system based on a set of transmit and receive, radiating, planar cavity apertures. The cavities consist of double-sided, copper-clad circuit boards, with a series of circular radiating irises patterned into the upper conducting plate. The iris arrangement is such that for any given transmitting and receiving aperture pair, a Mills-Cross pattern is formed from the overlapped patterns. The Mills-Cross distribution provides optimum coverage of the imaging scene in the spatial Fourier domain (k-space). The Mills-Cross configuration of the apertures produces measurement modes that are diverse and consistent with the computational imaging approach used for frequency-diverse apertures, yet significantly minimizes the redundancy of information received from the scene. We present a detailed analysis of the Mills-Cross aperture design, with numerical simulations that predict the performance of the apertures as part of an imaging system. Images reconstructed using fabricated apertures are presented, confirming the anticipated performance.

Sickness behaviors and metabolic responses to invading pathogens are common to nearly all types of infection. These responses evolved to provide short-term benefit to the host to ward off infection, but impact on quality of life and when prolonged lead to neurodegeneration, depression and cachexia. Among the major infectious agents, viruses most frequently enter the brain, resulting in profound neuroinflammation. We sought to define the unique features of the inflammatory response in the brain to these infections. We demonstrate that the molecular pathway defining the central response to dsRNA is distinct from that found in the periphery. The behavioral and physical response to the dsRNA mimetic poly I:C is dependent on signaling via MyD88 when it is delivered centrally, whereas this response is mediated via the TRIF pathway when delivered peripherally. We also define the likely cellular candidates for this MyD88-dependent step. These findings suggest that symptom management is possible without ameliorating protective antiviral immune responses.

Animals exhibit a rapid and sustained anorexia when fed a diet that is deficient in a single indispensable amino acid (IAA). The chemosensor for IAA deficiency resides within the anterior piriform cortex (APC). Although the cellular and molecular mechanisms by which the APC detects IAA deficiency are well established, the efferent neural pathways that reduce feeding in response to an IAA-deficient diet remain to be fully characterized. In the present work, we investigated whether 1) central melanocortin signaling is involved in IAA deficiency-induced anorexia (IAADA) and 2) IAADA engages other key appetite-regulating neuronal populations in the hypothalamus. Rats and mice that consumed a valine-deficient diet (VDD) for 2–3 wk exhibited marked reductions in food intake, body weight, fat and lean body mass, body temperature, and white adipose tissue leptin gene expression, as well as a paradoxical increase in brown adipose tissue uncoupling protein-1 mRNA. Animals consuming the VDD had altered hypothalamic gene expression, typical of starvation. Pharmacological and genetic blockade of central melanocortin signaling failed to increase long-term food intake in this model. Chronic IAA deficiency was associated with a marked upregulation of corticotropin-releasing hormone expression in the lateral hypothalamus, particularly in the parasubthalamic nucleus, an area heavily innervated by efferent projections from the APC. Our observations indicate that the hypothalamic melanocortin system plays a minor role in acute, but not chronic, IAADA and suggest that the restraint on feeding is analogous to that observed after chronic dehydration.

Adipose tissue macrophages are important mediators of inflammation and insulin resistance in obesity. IFN-γ is a central regulator of macrophage function. The role of IFN-γ in regulating systemic inflammation and insulin resistance in obesity is unknown. We studied obese IFN-γ knockout mice to identify the role of IFN-γ in regulating inflammation and insulin sensitivity in obesity. IFN-γ-knockout C57Bl/6 mice and wild-type control litter mates were maintained on normal chow or a high fat diet for 13 weeks and then underwent insulin sensitivity testing then sacrifice and tissue collection. Flow cytometry, intracellular cytokine staining, and QRTPCR were used to define tissue lymphocyte phenotype and cytokine expression profiles. Adipocyte size was determined from whole adipose tissue explants examined under immunofluorescence microscopy. Diet-induced obesity induced systemic inflammation and insulin resistance, along with a pan-leukocyte adipose tissue infiltrate that includes macrophages, T-cells, and NK cells. Obese IFN-γ-knockout animals, compared with obese wild-type control animals, demonstrate modest improvements in insulin sensitivity, decreased adipocyte size, and an M2-shift in ATM phenotype and cytokine expression. These data suggest a role for IFN-γ in the regulation of inflammation and glucose homeostasis in obesity though multiple potential mechanisms, including effects on adipogenesis, cytokine expression, and macrophage phenotype.

In this paper we derive a general analytical solution for a monocentric lens system and present a global optimization method combining sequential design for global optimization and an expected improvement algorithm for global optimization for the design and analysis of a layered monocentric lens system, which provides an “intelligent” way to search the optimization space based on accumulated experience. We then apply these methods to an example of monocentric lens design, and explore the improvement in system performance obtained through increasing the system volume.

Systemic and CNS-delimited inflammation triggers skeletal muscle catabolism in a manner dependent on glucocorticoid signaling., Skeletal muscle catabolism is a co-morbidity of many chronic diseases and is the result of systemic inflammation. Although direct inflammatory cytokine action on muscle promotes atrophy, nonmuscle sites of action for inflammatory mediators are less well described. We demonstrate that central nervous system (CNS)–delimited interleukin 1β (IL-1β) signaling alone can evoke a catabolic program in muscle, rapidly inducing atrophy. This effect is dependent on hypothalamic–pituitary–adrenal (HPA) axis activation, as CNS IL-1β–induced atrophy is abrogated by adrenalectomy. Furthermore, we identified a glucocorticoid-responsive gene expression pattern conserved in models of acute and chronic inflammatory muscle atrophy. In contrast with studies suggesting that the direct action of inflammatory cytokines on muscle is sufficient to induce catabolism, adrenalectomy also blocks the atrophy program in response to systemic inflammation, demonstrating that glucocorticoids are requisite for this process. Additionally, circulating levels of glucocorticoids equivalent to those produced under inflammatory conditions are sufficient to cause profound muscle wasting. Together, these data suggest that a significant component of inflammation-induced muscle catabolism occurs indirectly via a relay in the CNS.

The melanocortin-3 receptor (MC3R) gene is pleiotropic, influencing body composition, natriuresis, immune function, and entrainment of circadian rhythms to nutrient intake. MC3Rs are expressed in hypothalamic and limbic regions of the brain and in peripheral tissues. To investigate the roles of central MC3Rs, we inserted a "lox-stop-lox" (LoxTB) 5' of the translation initiation codon of the mouse Mc3r gene and reactivated transcription using neuron-specific Cre transgenic mice. As predicted based on earlier observations of Mc3r knock-out mice, Mc3r(TB/TB) mice displayed reduced lean mass, increased fat mass, and accelerated diet-induced obesity. Surprisingly, rescuing Mc3r expression in the nervous system using the Nestin-Cre transgene only partially rescued obesity in chow-fed conditions and had no impact on the accelerated diet-induced obesity phenotype. The ventromedial hypothalamus (VMH), a critical node in the neural networks regulating feeding-related behaviors and metabolic homeostasis, exhibits dense Mc3r expression relative to other brain regions. To target VMH MC3R expression, we used the steroidogenic factor-1 Cre transgenic mouse. Although restoring VMH MC3R signaling also had a modest impact on obesity, marked improvements in metabolic homeostasis were observed. VMH MC3R signaling was not sufficient to rescue the lean mass phenotype or the regulation of behaviors anticipating food anticipation. These results suggest that actions of MC3Rs impacting on energy homeostasis involve both central and peripheral sites of action. The impact of central MC3Rs on behavior and metabolism involves divergent pathways; VMH MC3R signaling improves metabolic homeostasis but does not significantly impact on the expression of behaviors anticipating nutrient availability.

BACKGROUND: Under physiological conditions, the melanocortin system is a crucial part of the complex network regulating food intake and energy expenditure. In pathological states, like cachexia, these two parameters are deregulated, i.e., food intake is decreased and energy expenditure is increased-a vicious combination leading to catabolism. Agouti-related protein (AgRP), the endogenous antagonist at the melanocortin-4 receptor (MC-4R), was found to increase food intake and to reduce energy expenditure. This qualifies MC-4R blockade as an attractive mode of action for the treatment of cachexia. Based on this rationale, a novel series of small-molecule MC-4R antagonists was designed, from which the orally active compound BL-6020/979 (formerly known as SNT207979) emerged as the first promising development candidate showing encouraging pre-clinical efficacy and safety properties which are presented here. METHODS AND RESULTS: BL-6020/979 is an orally available, selective and potent MC-4R antagonist with a drug-like profile. It increased food intake and decreased energy expenditure in healthy wild-type but not in MC-4R deficient mice. More importantly, it ameliorated cachexia-like symptoms in the murine C26 adenocarcinoma model; with an effect on body mass and body composition and on the expression of catabolic genes. Moreover, BL-6020/979 showed antidepressant-like properties in the chronic mild stress model in rats and exhibits a favorable safety profile. CONCLUSION: The properties of BL-6020/979 demonstrated in animal models and presented here make it a promising candidate suitable for further development towards a first-in-class treatment option for cachexia that potentially opens up the opportunity to treat two hallmarks of the disease, i.e., decreased food intake and increased energy expenditure, with one drug.

Exposure to chronic and acute oxidative stress is correlated with many human diseases, including, but not limited to, cancer, heart disease, diabetes, and obesity. In addition to cellular lipids and proteins, cellular oxidative stress can result in damage to DNA bases, especially in mitochondrial DNA. We previously described the development of spontaneous late-onset obesity, hepatic steatosis, hyperinsulinemia, and hyperleptinemia in mice that are deficient in the DNA glycosylase nei-like 1 (NEIL1), which initiates base excision repair of several oxidatively damaged bases. In the current study, we report that exposure to a chronic oxidative stress in the form of a high-fat diet greatly accelerates the development of obesity in neil1−/−mice. Following a 5-wk high-fat diet challenge, neil1−/−mice gained significantly more body weight than neil1+/+littermates and had increased body fat accumulation and moderate to severe hepatic steatosis. Analysis of oxygen consumption by indirect calorimetry indicated a modest reduction in total oxygen consumption in neil1−/−mice that was abolished upon correction for lean body mass. Additionally, hepatic expression of several inflammatory genes was significantly upregulated in neil1−/−mice following high-fat diet challenge compared with chow-fed or neil1+/+counterparts. A long-term high-fat diet also induced glucose intolerance as well as a significant reduction in mitochondrial DNA and protein content in neil1−/−mice. Collectively, these data indicate that NEIL1 deficiency results in an increased susceptibility to obesity and related complications potentially by lowering the threshold for tolerance of cellular oxidative stress in neil1−/−mice.

Various examples of out-of-plane multicolor waveguide holography systems, methods of manufacture, and methods of use are described herein. In some examples, a multicolor waveguide holography system includes a planar waveguide to convey optical radiation between a grating coupler and a metasurface hologram. The grating coupler may be configured to couple out-of-plane optical radiation of three different color incident at three different angles into the planar waveguide. The combined multicolor optical radiation may be conveyed by the waveguide to the metasurface hologram. The metasurface hologram may diffractively decouple the three colors of optical radiation for off-plane propagation to form a multicolor holographic image in free space.

Current models of SIRT1 enzymatic regulation primarily consider the effects of fluctuating levels of its co-substrate NAD+, which binds to the stably folded catalytic domain. By contrast, the roles of the sizeable disordered N- and C-terminal regions of SIRT1 are largely unexplored. Here we identify an insulin-responsive sensor in the SIRT1 N-terminal region (NTR), comprising an acidic cluster (AC) and a 3-helix bundle (3HB), controlling deacetylase activity. The allosteric assistor DBC1 removes a distal N-terminal shield from the 3-helix bundle, permitting PACS-2 to engage the acidic cluster and the transiently exposed helix 3 of the 3-helix bundle, disrupting its structure and inhibiting catalysis. The SIRT1 activator (STAC) SRT1720 binds and stabilizes the 3-helix bundle, protecting SIRT1 from inhibition by PACS-2. Identification of the SIRT1 insulin-responsive sensor and its engagement by the DBC1 and PACS-2 regulatory hub provides important insight into the roles of disordered regions in enzyme regulation and the mode by which STACs promote metabolic fitness.

Decreased appetite and involuntary weight loss are common occurrences in chronic disease and have a negative impact on both quality of life and eventual mortality. Weight loss in chronic disease comes from both fat and lean mass, and is known as cachexia. Both alterations in appetite and body weight loss occur in a wide variety of diseases, including cancer, heart failure, renal failure, chronic obstructive pulmonary disease and HIV. An increase in circulating inflammatory cytokines has been implicated as a uniting pathogenic mechanism of cachexia and associated anorexia. One of the targets of inflammatory mediators is the central nervous system, and in particular feeding centers in the hypothalamus located in the ventral diencephalon. Current research has begun to elucidate the mechanisms by which inflammation reaches the hypothalamus, and the neural substrates underlying inflammatory anorexia. Research into these neural mechanisms has suggested new therapeutic possibilities, which have produced promising results in preclinical and clinical trials. This review will discuss inflammatory signaling in the hypothalamus that mediates anorexia, and the opportunities for therapeutic intervention that these mechanisms present.

Sensitive assays for rapid quantitative analysis of histologic sections, resected tissue specimens, or in situ tissue are highly desired for early disease diagnosis. Stained histopathology is the gold standard but remains a subjective practice on processed tissue taking from hours to days. We describe a microscopy technique that obtains a sensitive and accurate color-coded image from intrinsic molecular markers. Spectrally reconstructed nonlinear interferometric vibrational imaging can differentiate cancer versus normal tissue sections with greater than 99% confidence interval in a preclinical rat breast cancer model and define cancer boundaries to ±100 μm with greater than 99% confidence interval, using fresh unstained tissue sections imaged in less than 5 minutes. By optimizing optical sources and beam delivery, this technique can potentially enable real-time point-of-care optical molecular imaging and diagnosis. Cancer Res; 70(23); 9562–9. ©2010 AACR.

PURPOSE: With recent advances in immunotherapy, many novel cancer treatments are rapidly entering the clinical arena. However, immunotherapies may differ from traditional chemotherapies in their effects on cachexia and treatment-associated sickness. Cachexia is a common comorbidity of cancer that limits therapeutic options, decreases quality of life, and increases mortality risk. Many chemotherapy agents induce or worsen cachexia by independently causing anorexia, weight loss, muscle wasting, and fatigue. Acute systemic inflammation, an effect of many immunotherapies, results in sickness responses that are typically self-limited in healthy individuals. Whether immunotherapy-associated sickness is self-limited or chronic in the context of cancer, and how cachexia is impacted by immunotherapy, remains unknown. METHODS: We recently found that the TLR7/8 agonist R848 reduces tumor size in mice implanted with epithelial cells from a syngeneic KRASG12D/+ P53R172H/+ Pdx-Cre (KPC) pancreatic tumor. To assess cachexia outcomes and R848-induced sickness, mice were orthotopically implanted with KPC cells or saline, and 2 days later were randomized to daily IP R848 (10µg) or vehicle until sacrifice (n=5-7/group/experiment, 3 experiments). Mice were tracked for weight, food intake, body composition, and locomotor activity (LMA), with end-stage analysis of tissue mass and gene expression. RESULTS: Initially, KPC-bearing mice treated with R848 developed significant weight gain and ascites, but had a similar degree of anorexia and decreased LMA as vehicle-treated KPC-bearing mice. However, ongoing R848 resulted in subsequent tumor regression, decreased ascites, increased appetite, and increased LMA. At necropsy, KPC-bearing mice treated with R848 had a 50-70% reduction in tumor mass, histologically characterized by lymphocytic infiltrate and germinal centers. Furthermore, R848-treated KPC-bearing mice had improved total lean mass and heart mass; decreased expression of genes related to skeletal and cardiac muscle catabolism (Mafbx, Murf1, Foxo1, Bnip3, Gabarapl, Ctsl) and hepatic acute phase reactants (Orm1, Apcs); a trend toward decreased CNS inflammatory gene expression (Selp, Il1r1); and unchanged brown adipose tissue thermogenic gene expression (Ucp1). In sham-operated mice, R848 resulted in self-limited anorexia and weight loss, without muscle wasting or decreased LMA. Current work is underway to elucidate tumor intrinsic and tumor extrinsic mechanisms of R848 in this model. SUMMARY: These studies show that R848 does not independently cause sustained sickness, and in a murine model of pancreatic cancer, can induce antitumor responses and improve cachexia outcomes. This represents a key difference from many cytotoxic chemotherapies and suggests immunotherapy approaches may be useful in the treatment of cachexia-associated malignancies. Citation Format: Katherine A. Michaelis, Mason A. Norgard, Xinxia Zhu, Peter R. Levasseur, Katherine R. Pelz, Kevin G. Burfeind, Terry K. Morgan, Daniel L. Marks. The TLR7/8 agonist R848 induces antitumor responses and attenuates cachexia in a murine model of pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3779.

Vibrational contrast imaging of the distribution of complex biological molecules requires the use of techniques that provide broadband spectra with sufficient resolution. Coherent anti-Stokes Raman scattering (CARS) microscopy is currently limited in meeting these requirements due to the presence of a nonresonant background and its inability to target multiple resonances simultaneously. We present nonlinear interferometric vibrational imaging (NIVI), a technique based on CARS that uses femtosecond pump and Stokes pulses to retrieve broadband vibrational spectra over 200 cm(-1) (full-width at half maximum). By chirping the pump and performing spectral interferometric detection, the anti-Stokes pulses are resolved in time. This phase-sensitive detection allows suppression of not only the nonresonant background, but also of the real part of the nonlinear susceptibility χ((3)), improving the spectral resolution and features to make them comparable to those acquired with spontaneous Raman microscopy, as shown for a material sample and mammary tissue.

The central melanocortin system plays a key role in the regulation of food intake and energy homeostasis. We investigated whether genetic or pharmacologic blockade of central melanocortin signaling attenuates cardiac cachexia in mice and rats with heart failure. Permanent ligation of the left coronary artery (myocardial infarction (MI)) or sham operation was performed in wild-type (WT) or melanocortin-4 receptor (MC4R) knockout mice. Eight weeks after surgery, WT-Sham mice had significant increases in lean body mass (LBM; PPPPPPP

Multiplex volume holograms are conventionally constructed by the repeated exposure of a photosensitive medium to a sequence of external fields, each field typically being the superposition of a reference wave that reconstructs the hologram and the other being a desired signal wave. Because there are no sources of radiation internal to the hologram, the pattern of material modulation is limited to the solutions to Helmholtz's equation in the medium. If the three-dimensional structure of the medium could be engineered at each point rather than limited to the patterns produced by standing waves, more versatile structures may result that can overcome the typical limitations to hologram dynamic range imposed by sequentially superimposing holograms. Metamaterial structures and other synthetic electromagnetic materials offer the possibility of achieving high medium contrast engineered at the subwavelength scale. By posing the multiplex volume holography problem as a linear medium design problem, we explore the potential improvements that such engineered synthetic media may provide over conventional multiplex volume holograms.

We present a reconfigurable, dynamic beam steering holographic metasurface aperture to synthesize a microwave camera at K-band frequencies. The aperture consists of a 1D printed microstrip transmission line with the front surface patterned into an array of slot-shaped subwavelength metamaterial elements (or meta-elements) dynamically tuned between "ON" and "OFF" states using PIN diodes. The proposed aperture synthesizes a desired radiation pattern by converting the waveguide-mode to a free space radiation by means of a binary modulation scheme. This is achieved in a holographic manner; by interacting the waveguide-mode (reference-wave) with the metasurface layer (hologram layer). It is shown by means of full-wave simulations that using the developed metasurface aperture, the radiated wavefronts can be engineered in an all-electronic manner without the need for complex phase-shifting circuits or mechanical scanning apparatus. Using the dynamic beam steering capability of the developed antenna, we synthesize a Mills-Cross composite aperture, forming a single-frequency all-electronic microwave camera.

The hypothalamic melanocortin system, which controls appetite and energy expenditure, develops during the third trimester in primates. Thus, maternal nutrition and health may have a profound influence on the development of this system. To study the effects of chronic maternal high-fat diet (HFD) on the development of the melanocortin system in the fetal nonhuman primate, we placed adult female macaques on either a control (CTR) diet or a HFD for up to 4 yr. A subgroup of adult female HFD animals was also switched to CTR diet during the fifth year of the study (diet reversal). Third-trimester fetuses from mothers on HFD showed increases in proopiomelanocortin mRNA expression, whereas agouti-related protein mRNA and peptide levels were decreased in comparison with CTR fetuses. Proinflammatory cytokines, including IL-1β and IL-1 type 1 receptor, and markers of activated microglia were elevated in the hypothalamus, suggesting an activation of the local inflammatory response. Fetuses of diet-reversal mothers had normal melanocortin levels. These results raise the concern that chronic consumption of a HFD during pregnancy, independent of maternal obesity and diabetes, can lead to widespread activation of proinflammatory cytokines that may alter the development of the melanocortin system. The abnormalities in the fetal POMC system, if maintained into the postnatal period, could impact several systems, including body weight homeostasis, stress responses, and cardiovascular function. Indeed, the HFD offspring develop early-onset excess weight gain. These abnormalities may be prevented by healthful nutrient consumption during pregnancy even in obese and severely insulin-resistant individuals.

Background Pediatric acute lymphoblastic leukemia (ALL) therapies have been associated with many late effects, including obesity, hyperglycemia, and insulin resistance. Few data are available linking these abnormalities to specific risk factors present during ALL treatment. Methods Retrospective cohort study with prospective follow-up. Subjects had been diagnosed with ALL at ages 1–18 years and had been off chemotherapy for >9 months. Oral glucose tolerance testing (OGTT) was performed and these results compared to demographic, treatment, and anthropomorphic data from medical records. Results Twenty-seven subjects (11 female) were evaluated. Mean (±SD) diagnosis age 5.7 ± 3.5 years, mean study age 11.3 ± 3.7 years, mean time off therapy 2.8 ± 1.5 years. Six subjects had transient hyperglycemia during ALL treatment. At study time, one subject had prediabetes; eight (29.6%) had insulin resistance. Insulin resistance was not predicted by glucose levels during treatment, cumulative steroid or asparaginase dose, or type of steroid received. Body mass index (BMI) for age correlated significantly with several measures of insulin resistance, including fasting insulin, HOMA index, Matsuda index and insulin AUC (P = 0.001–0.009). Waist/hip ratio and BMI at ALL diagnosis also correlated with insulin resistance, but these factors' effects could not be separated from BMI at study time. Conclusions Variations in ALL therapy and presence of transient hyperglycemia do not appear to increase risk of glucose intolerance or insulin resistance in the first few years after completion of therapy. Elevated BMI strongly predicted insulin resistance in this study, as it does in the general population. Pediatr Blood Cancer 2009;53:58–63. © 2009 Wiley-Liss, Inc.