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Carbohydrate Responsive Element-Binding Protein (ChREBP) is a carbohydrate sensing transcription factor that regulates both adaptive and maladaptive genomic responses in coordination of systemic fuel homeostasis. Genetic variants in the ChREBP locus associate with diverse metabolic traits in humans, including circulating lipids. To identify novel ChREBP-regulated hepatokines that contribute to its systemic metabolic effects, we integrated ChREBP ChIP-seq analysis in mouse liver with human genetic and genomic data for lipid traits and identified Hepatocyte Growth Factor Activator (HGFAC) as a promising ChREBP-regulated candidate in mice and humans. HGFAC is a protease that activates the pleiotropic hormone Hepatocyte Growth Factor (HGF). We demonstrate that HGFAC KO mice have phenotypes concordant with putative loss-of-function variants in human HGFAC. Moreover, in gain- and loss-of-function genetic mouse models, we demonstrate that HGFAC enhances lipid and glucose homeostasis, in part, through actions to activate hepatic PPARγ activity. Together, our studies show that ChREBP mediates an adaptive response to overnutrition via activation of an HGFAC-HGF-PPARγ signaling axis in the liver to preserve glucose and lipid homeostasis.

Carbohydrate Responsive Element-Binding Protein (ChREBP) is a carbohydrate sensing transcription factor that regulates metabolic gene programs. Genetic variants in the ChREBP locus associate with diverse metabolic traits in humans, including circulating triglycerides (TG). The transcriptional targets that mediate its pleiotropic physiological effects are poorly understood. To identify novel ChREBP-regulated hepatokines that contribute to its effects on metabolism, we integrated ChIP-seq for ChREBP in mouse liver with human GWAS data for TGs and identified Hepatocyte Growth Factor Activator (HGFAC) as a promising candidate. HGFAC is a circulating zymogen that activates Hepatocyte Growth Factor (HGF), a multifunction cytokine involved in cellular growth, motility, and morphogenesis. High fructose feeding increased circulating HGFAC by 1.8-fold (p Disclosure A. Sargsyan: None. I. Astapova: None. L. T. Tsai: None. M. A. Herman: Research Support; Self; Eli Lilly and Company. L. Doridot: Employee; Spouse/Partner; Eli Lilly and Company. S. A. Hannou: None. W. Tong: None. H. Srinivasan: None. R. Ivison: None. R. Monn: None. H. H. Kou: None. J. Haldeman: None. Funding American Diabetes Association (1-19-PDF-088 to A.S.)

A phylogenetic analysis of combined rDNA LSU and ITS sequence data was carried out to determine the phylogenetic placement of specimens identified as Pseudotryblidium neesii. The species forms a distinct clade within Dermateaceae (Helotiales, Leotiomycetes) with Rhizodermea veluwiensis and two Dermea species. The geographical distribution of this species, previously known only from Europe on Abies alba, is extended to north-western North America where it grows exclusively on A. grandis. The name P. neesii is lectotypified in order to disentangle the complicated nomenclature of the species. A new, detailed description of P. neesii with illustrations is provided after comparison of sequenced specimens with the type material. Furthermore, the new combination Pseudographis rufonigra (basionym Peziza rufonigra) is made for a fungus previously known as Pseudographis pinicola.

Chromogranin B (CgB, also known as CHGB) is abundantly expressed in dense core secretory granules of multiple endocrine tissues and has been suggested to regulate granule biogenesis in some cell types, including the pancreatic islet β-cell, though the mechanisms are poorly understood. Here, we demonstrate a critical role for CgB in regulating secretory granule trafficking in the β-cell. Loss of CgB impairs glucose-stimulated insulin secretion, impedes proinsulin processing to yield increased proinsulin content, and alters the density of insulin-containing granules. Using an in situ fluorescent pulse-chase strategy to track nascent proinsulin, we show that loss of CgB impairs Golgi budding of proinsulin-containing secretory granules, resulting in a substantial delay in trafficking of nascent granules to the plasma membrane with an overall decrease in total plasma membrane-associated granules. These studies demonstrate that CgB is necessary for efficient trafficking of secretory proteins into the budding granule, which impacts the availability of insulin-containing secretory granules for exocytic release. This article has an associated First Person interview with the first author of the paper.

Paracrine interactions between pancreatic islet cells have been proposed as a mechanism to regulate hormone secretion and glucose homeostasis. Here, we demonstrate the importance of proglucagon-derived peptides (PGDPs) for α to β cell communication and control of insulin secretion. Signaling through this system occurs through both the glucagon-like peptide receptor (Glp1r) and glucagon receptor (Gcgr). Loss of PGDPs, or blockade of their receptors, decreases insulin secretion in response to both metabolic and nonmetabolic stimulation of mouse and human islets. This effect is due to reduced β cell cAMP and affects the quantity but not dynamics of insulin release, indicating that PGDPs dictate the magnitude of insulin output in an isolated islet. In healthy mice, additional factors that stimulate cAMP can compensate for loss of PGDP signaling; however, input from α cells is essential to maintain glucose tolerance during the metabolic stress induced by high-fat feeding. These findings demonstrate an essential role for α cell regulation of β cells, raising the possibility that abnormal paracrine signaling contributes to impaired insulin secretion in diabetes. Moreover, these findings support reconsideration of the role for α cells in postprandial glucose control.

Strong associations exist between branched chain amino acids (BCAA) and dysregulated glucose and lipid metabolism, but underlying mechanisms are not well understood. One factor contributing to elevated BCAA in obesity is inhibitory phosphorylation of the branched chain keto-acid dehydrogenase complex (BCKDH) in liver. We studied the impact of modulating the activity of the BCKDH kinase (BDK) and phosphatase (PPM1K) on amino acid, glucose and lipid metabolism in Zucker fatty rats (ZFR). Daily administration of a selective inhibitor of BDK, BT2 (20mg.kg-1, IP), for one week or expression of a recombinant adenovirus overexpressing PPM1K significantly lowered BCAA and branched chain keto acid (BCKA) levels in ZFR. Remarkably, these effects were accompanied by strong lowering of liver triacylglycerides and improved glucose tolerance in the absence of weight loss. Proteomics analysis of liver samples from these studies revealed that both inhibition of BDK with BT2 and adenoviral mediated overexpression of PPM1K results in reduced phosphorylation of the lipogenic enzyme ATP-citrate lyase (ACL) on its regulatory serine 454. Phosphorylation of ACL on this site is activating. Sequence analysis revealed the presence of a canonical BDK phosphorylation motif surrounding ser454 in ACL and incubation of ACL with purified BDK resulted in ACL phosphorylation in vitro. Furthermore, adenovirus-mediated overexpression of BDK increased ACL phosphorylation and activated de novo lipogenesis in liver of lean Wistar rats. Together these studies reveal a novel regulatory function for BDK and PPM1K in integration of BCAA and lipid metabolism. Moreover, we show that modulation of this node provides broad protection against metabolic abnormalities associated with obesity. Disclosure P.J. White: None. R.W. McGarrah: None. P.A. Grimsrud: None. W. Yang: None. G. Zhang: None. J.M. Haldeman: None. M. Arlotto: None. O. Ilkayeva: None. R.M. Wynn: None. D.T. Chuang: None. C.B. Newgard: Advisory Panel; Self; Eli Lilly and Company. Research Support; Self; Eli Lilly and Company.

Current obesity interventions suffer from lack of durable effects and undesirable complications. Fumagillin, an inhibitor of methionine aminopeptidase-2, causes weight loss by reducing food intake, but with effects on weight that are superior to pair-feeding. Here, we show that feeding of rats on a high-fat diet supplemented with fumagillin (HF/FG) suppresses the aggressive feeding observed in pair-fed controls (HF/PF) and alters expression of circadian genes relative to the HF/PF group. Multiple indices of reduced energy expenditure are observed in HF/FG but not HF/PF rats. HF/FG rats also exhibit changes in gut hormones linked to food intake, increased energy harvest by gut microbiota, and caloric spilling in the urine. Studies in gnotobiotic mice reveal that effects of fumagillin on energy expenditure but not feeding behavior may be mediated by the gut microbiota. In sum, fumagillin engages weight loss-inducing behavioral and physiologic circuits distinct from those activated by simple caloric restriction.

In the last two decades, biobanks have become critical components in researchers’ efforts to cure, treat or prevent cancer, diabetes and many other diseases. At the same time, the amassing of specimens has been brought into question by recognition that the lack of standardization across highly diverse collections presents an impediment for future biomedical research. By looking at standardization as a practice of accountability in biobanking, this article examines the relationship between standardization and ethics in the work of six biobanks in the United States. Standards, we argue, are necessary to biobanking, yet there is also an unquestioned faith put into the standardization of biobank practice and products. This, we argue, reveals that beyond their immediate function, standards do other work. Using interview data, we show how standardization can serve as a performance of accountability, which, as we explain using the concept of audit cultures, constitutes biobanks as an ethical subject. We conclude by pointing out that while efforts to standardize are important for making best use of samples and data, when calling for standardization, we should be mindful of the other (ethical) work that standardization does and contemplate its particular consequences.

The leukemogenic CALM-AF10 fusion protein is found in patients with immature acute myeloid and T-lymphoid malignancies. CALM-AF10 leukemias display abnormal H3K79 methylation and increased HOXA cluster gene transcription. Elevated expression of HOXA genes is critical for leukemia maintenance and progression; however, the precise mechanism by which CALM-AF10 alters HOXA gene expression is unclear. We previously determined that CALM contains a CRM1-dependent nuclear export signal (NES), which is both necessary and sufficient for CALM-AF10-mediated leukemogenesis. Here, we find that interaction of CALM-AF10 with the nuclear export receptor CRM1 is necessary for activating HOXA gene expression. We show that CRM1 localizes to HOXA loci where it recruits CALM-AF10, leading to transcriptional and epigenetic activation of HOXA genes. Genetic and pharmacological inhibition of the CALM-CRM1 interaction prevents CALM-AF10 enrichment at HOXA chromatin, resulting in immediate loss of transcription. These results provide a comprehensive mechanism by which the CALM-AF10 translocation activates the critical HOXA cluster genes. Furthermore, this report identifies a novel function of CRM1: the ability to bind chromatin and recruit the NES-containing CALM-AF10 transcription factor.

Comparisons of k independent binomial proportions are studied. Piegorsch (1991) compared the Studentized-range implementation of the Wald interval and the Bonferroni-adjusted interval, both of which performed poorly for small values of the true proportions. Agresti et al. (2008) showed that adding one pseudo observation of each type in forming the Wald interval, along with the Studentized-range implementation, greatly improved the performance. A new two-stage method of multiple comparisons (global test followed by pairwise tests) is proposed. For the pairwise tests, three procedures are proposed, which are the LSD type, modified LSD, and inverse-sine based. Simulation studies show that the new procedures have relatively high power and that the modified LSD and inverse-sine based procedures maintain the familywise error rate near the nominal level.

Genetic manipulation via transgene overexpression, RNAi, or Cas9-based methods is central to biomedical research. Unfortunately, use of these tools is often limited by vector options. We have created a modular platform (pMVP) that allows a gene of interest to be studied in the context of an array of promoters, epitope tags, conditional expression modalities, and fluorescent reporters, packaged in 35 custom destination vectors, including adenovirus, lentivirus, PiggyBac transposon, and Sleeping Beauty transposon, in aggregate >108,000 vector permutations. We also used pMVP to build an epigenetic engineering platform, pMAGIC, that packages multiple gRNAs and either Sa-dCas9 or x-dCas9(3.7) fused to one of five epigenetic modifiers. Importantly, via its compatibility with adenoviral vectors, pMAGIC uniquely enables use of dCas9/LSD1 fusions to interrogate enhancers within primary cells. To demonstrate this, we used pMAGIC to target Sa-dCas9/LSD1 and modify the epigenetic status of a conserved enhancer, resulting in altered expression of the homeobox transcription factor PDX1 and its target genes in pancreatic islets and insulinoma cells. In sum, the pMVP and pMAGIC systems empower researchers to rapidly generate purpose-built, customized vectors for manipulation of gene expression, including via targeted epigenetic modification of regulatory elements in a broad range of disease-relevant cell types.

Recent studies have shown that the pyruvate-isocitrate cycling pathway, involving the mitochondrial citrate/isocitrate carrier and the cytosolic NADP-dependent isocitrate dehydrogenase (ICDc), is involved in control of glucose-stimulated insulin secretion (GSIS). Here we demonstrate that pyruvate-isocitrate cycling regulates expression of the voltage-gated potassium channel family member Kv2.2 in islet β-cells. siRNA-mediated suppression of ICDc, citrate/isocitrate carrier, or Kv2.2 expression impaired GSIS, and the effect of ICDc knockdown was rescued by re-expression of Kv2.2. Moreover, chronic exposure of β-cells to elevated fatty acids, which impairs GSIS, resulted in decreased expression of Kv2.2. Surprisingly, knockdown of ICDc or Kv2.2 increased rather than decreased outward K(+) current in the 832/13 β-cell line. Immunoprecipitation studies demonstrated interaction of Kv2.1 and Kv2.2, and co-overexpression of the two channels reduced outward K(+) current compared with overexpression of Kv2.1 alone. Also, siRNA-mediated knockdown of ICDc enhanced the suppressive effect of the Kv2.1-selective inhibitor stromatoxin1 on K(+) currents. Our data support a model in which a key function of the pyruvate-isocitrate cycle is to maintain levels of Kv2.2 expression sufficient to allow it to serve as a negative regulator of Kv channel activity.

Background With advancements in mobile technology, cellular phone–based store-and-forward teledermatology may be applied to skin cancer screening. Objective We sought to determine diagnostic and management concordance between in-person and teledermatology evaluations for patients at skin cancer screening whose clinical images and history were transmitted through mobile phones. Methods A total of 86 patients with 137 skin lesions presented to a skin cancer screening event in California. These patients' clinical history and skin images were captured by a software-enabled mobile phone. Patients were assessed separately by an in-person dermatologist and a teledermatologist, who evaluated the mobile phone–transmitted history and images. Diagnostic and management concordance was determined between the in-person and teledermatology evaluations. Results The primary categorical diagnostic concordance was 82% between the in-person dermatologist and the teledermatologist (95% confidence interval 0.73-0.89), with a Kappa coefficient of 0.62 indicating good agreement. The aggregated diagnostic concordance between the in-person dermatologist and the teledermatologist was 62% (95% confidence interval 0.51-0.71), with Kappa coefficient of 0.60 indicating good agreement. Management concordance between the in-person dermatologist and the teledermatologist was 81% (95% confidence interval 0.72-0.88), with a Kappa coefficient of 0.57, which indicates moderate agreement between the dermatologists. Multivariate analysis showed that older age and presentation of atypical nevus were significantly associated with disagreement in diagnosis between the teledermatologist and in-person dermatologist, after adjusting for other factors. Limitations Dermatoscopic images were not captured via mobile phones, which might improve diagnostic accuracy. Conclusion Mobile teledermatology using cellular phones is an innovative and convenient modality of providing dermatologic consultations for skin cancer screening.

Summary Branched-chain amino acids (BCAA) are strongly associated with dysregulated glucose and lipid metabolism, but the underlying mechanisms are poorly understood. We report that inhibition of the kinase (BDK) or overexpression of the phosphatase (PPM1K) that regulates branched-chain ketoacid dehydrogenase (BCKDH), the committed step of BCAA catabolism, lowers circulating BCAA, reduces hepatic steatosis, and improves glucose tolerance in the absence of weight loss in Zucker fatty rats. Phosphoproteomics analysis identified ATP-citrate lyase (ACL) as an alternate substrate of BDK and PPM1K. Hepatic overexpression of BDK increased ACL phosphorylation and activated de novo lipogenesis. BDK and PPM1K transcript levels were increased and repressed, respectively, in response to fructose feeding or expression of the ChREBP-β transcription factor. These studies identify BDK and PPM1K as a ChREBP-regulated node that integrates BCAA and lipid metabolism. Moreover, manipulation of the BDK:PPM1K ratio relieves key metabolic disease phenotypes in a genetic model of severe obesity.

Conformational equilibrium within the ubiquitous GNRA tetraloop motif was simulated at the ensemble level, including 10 000 independent all-atom molecular dynamics trajectories totaling over 110 micros of simulation time. This robust sampling reveals a highly dynamic structure comprised of 15 conformational microstates. We assemble a Markov model that includes transitions ranging from the nanosecond to microsecond timescales and is dominated by six key loop conformations that contribute to fluctuations around the native state. Mining of the Protein Data Bank provides an abundance of structures in which GNRA tetraloops participate in tertiary contact formation. Most predominantly observed in the experimental data are interactions of the native loop structure within the minor groove of adjacent helical regions. Additionally, a second trend is observed in which the tetraloop assumes non-native conformations while participating in multiple tertiary contacts, in some cases involving multiple possible loop conformations. This tetraloop flexibility can act to counterbalance the energetic penalty associated with assuming non-native loop structures in forming tertiary contacts. The GNRA motif has thus evolved not only to readily participate in simple tertiary interactions involving native loop structure, but also to easily adapt tetraloop secondary conformation in order to participate in larger, more complex tertiary interactions.

Hospitalizations that require invasive cardiac procedures or support with an intra-aortic balloon pump can be unsettling. This study was undertaken to measure the effect of a music intervention on physiologic and psychological responses of patients on bed rest due to procedural sheaths or an intra-aortic balloon pump. A randomized, two-group, pretest/post-test design was utilized to measure the effect of a 30-minute music intervention on heart rate, blood pressure, respiratory rate, skin temperature, pain perception, and mood states. One hundred forty subjects participated, 65 in the control group and 75 in the treatment group. There were no significant differences between the groups in demographic, clinical, or baseline variables, except for respiratory rate. After the music intervention, there were reductions in blood pressure, respiratory rate, and psychological distress, as measured by the Profile of Mood States (p < 0.05). Music appeared to affect selected physiologic responses and reduce psychological distress in patients on bed rest.

Background Dengue is one of the most aggressively expanding mosquito-transmitted viruses. The human burden approaches 400 million infections annually. Complex transmission dynamics pose challenges for predicting location, timing, and magnitude of risk; thus, models are needed to guide prevention strategies and policy development locally and globally. Weather regulates transmission-potential via its effects on vector dynamics. An important gap in understanding risk and roadblock in model development is an empirical perspective clarifying how weather impacts transmission in diverse ecological settings. We sought to determine if location, timing, and potential-intensity of transmission are systematically defined by weather. Methodology/Principal Findings We developed a high-resolution empirical profile of the local weather-disease connection across Peru, a country with considerable ecological diversity. Applying 2-dimensional weather-space that pairs temperature versus humidity, we mapped local transmission-potential in weather-space by week during 1994-2012. A binary classification-tree was developed to test whether weather data could classify 1828 Peruvian districts as positive/negative for transmission and into ranks of transmission-potential with respect to observed disease. We show that transmission-potential is regulated by temperature-humidity coupling, enabling epidemics in a limited area of weather-space. Duration within a specific temperature range defines transmission-potential that is amplified exponentially in higher humidity. Dengue-positive districts were identified by mean temperature >22°C for 7+ weeks and minimum temperature >14°C for 33+ weeks annually with 95% sensitivity and specificity. In elevated-risk locations, seasonal peak-incidence occurred when mean temperature was 26-29°C, coincident with humidity at its local maximum; highest incidence when humidity >80%. We profile transmission-potential in weather-space for temperature-humidity ranging 0-38°C and 5-100% at 1°C x 2% resolution. Conclusions/Significance Local duration in limited areas of temperature-humidity weather-space identifies potential locations, timing, and magnitude of transmission. The weather-space profile of transmission-potential provides needed data that define a systematic and highly-sensitive weather-disease connection, demonstrating separate but coupled roles of temperature and humidity. New insights regarding natural regulation of human-mosquito transmission across diverse ecological settings advance our understanding of risk locally and globally for dengue and other mosquito-borne diseases and support advances in public health policy/operations, providing an evidence-base for modeling, predicting risk, and surveillance-prevention planning., Author Summary Timing and spatial-extent of diseases such as dengue and malaria that result from transmission between humans and mosquitoes are regulated by weather in complicated ways. For Aedes aegypti mosquitoes, the primary vector of dengue, slight changes in different components of weather have important effects on population dynamics, lifespan, biting-frequency, virus incubation period and capacity to transmit the virus, thus inducing changes in transmission probability. These complicated dynamics produce a weather-disease connection that is not well-defined for different ecological settings. Understanding this connection is important to critical elements of policy development and operational control of dengue such as predicting risk, developing human-vector transmission models, and planning surveillance-intervention strategies locally and globally. The empirical profile of the weather-disease connection for dengue developed in this study provides a needed understanding of how temperature and humidity work together in regulating human-mosquito transmission. The observed likelihood of low to epidemic-level transmission was highly sensitive to local seasonal duration in limited areas of this two-dimensional weather-space. Data presented represent a resource for estimating where and when transmission-potential supports epidemics of varying magnitude. This high-resolution weather-disease profile for dengue reveals systematic relationships that are informative for mosquito-borne diseases in general and discussions of consequences of global warming.

In the past year and a half, the Cryogenic Dark Matter Search (CDMS) collaboration has been active at the Soudan mine in installing a system for running ZIP detectors that will be used to search for dark matter in the form of Weakly Interacting Massive Particles. Presently, there is an operating cryogenic system, working electronics, a functional data acquisition and analysis system, passive shielding, an active muon veto, and 12 ZIP detectors. Six of the 12 ZIP detectors have been tested in situ and are fully operational with acceptable noise profiles. CDMS is in the process of commissioning the experiment and expects to be making a background measurement by the end of summer 2003.

The Sloan Digital Sky Survey (SDSS) is an imaging and spectroscopic survey that will eventually cover approximately one-quarter of the celestial sphere and collect spectra of ≈106 galaxies, 100,000 quasars, 30,000 stars, and 30,000 serendipity targets. In 2001 June, the SDSS released to the general astronomical community its early data release, roughly 462 deg2 of imaging data including almost 14 million detected objects and 54,008 follow-up spectra. The imaging data were collected in drift-scan mode in five bandpasses (u, g, r, i, and z); our 95% completeness limits for stars are 22.0, 22.2, 22.2, 21.3, and 20.5, respectively. The photometric calibration is reproducible to 5%, 3%, 3%, 3%, and 5%, respectively. The spectra are flux- and wavelength-calibrated, with 4096 pixels from 3800 to 9200 A at R ≈ 1800. We present the means by which these data are distributed to the astronomical community, descriptions of the hardware used to obtain the data, the software used for processing the data, the measured quantities for each observed object, and an overview of the properties of this data set.

The empirical literature on the ethical, legal, and social implications (ELSI) of biobanking has almost entirely relied on the perspectives of those outside of biobanks, such as the general public, researchers, and specimen contributors. Little attention has been paid to the perspectives and practices of those who operate biobanks. We conducted a study of U.S. biobanks consisting of six in-depth case studies and a large online survey (N = 456), which was developed from the case study results. The case studies included qualitative interviews with a total of 24 personnel. Both interview and survey questions focused on how biobanks operate, and what policies and practices govern their relationships with specimen contributors and the researchers who use the specimens. Analysis revealed unexpected ethical dilemmas embedded in those policies and practices that highlight a need for practical planning. In this paper, we review three issues seldom explored in the ELSI literature: 1. the discrepancy between biobankers’ hope that the bank will exist “permanently” and the fact that funding is limited; 2. the lack of planning for what will happen to the specimens if the bank closes; and 3. the concern that once collected, specimens may be underutilized. These dilemmas are missing from current public representations of biobanks, which instead focus on the intrinsic value in storing specimens as essential to the advancement of translational research. We argue that attention to these issues is important for biobanking, and that greater transparency of these policies and practices will contribute to promoting public trust in biobanks.

Background/Aims: Efforts to improve individual and population health increasingly rely on large-scale collections of human biological specimens and associated data. Such collections or ‘biobanks' are hailed as valuable resources for facilitating translational biomedical research. However, biobanks also raise important ethical considerations, such as whether, how and why biobanks might engage with those who contributed specimens. This paper examines perceptions and practices of community engagement (CE) among individuals who operate 6 diverse biobanks in the US. Methods: Twenty-four people from a diverse group of 6 biobanks were interviewed in-person or via telephone from March to July 2011. Interview transcripts were coded and analyzed for common themes. Results: Emergent themes include how biobank personnel understand ‘community' and CE as it pertains to biobank operations, information regarding the diversity of practices of CE, and the reasons why biobanks conduct CE. Conclusion: Despite recommendations from federal agencies to conduct CE, the interpretation of CE varies widely among biobank employees, ultimately affecting how CE is practiced and what goals are achieved.

A submerged hydrofoil generated large steady breaking waves of 0.3 m and 0.4 m height in a circulating water channel. We measured water fraction in the breakers with conductivity probes. We observed the radar cross-section of the breakers at X-band with a pulsed step-frequency instrumentation radar with high spatial resolution in the downstream direction. The normalized radar cross-section increases with increasing elevation angle of observation for both vertical and horizontal polarization. This variation is consistent with a simple interpretation of the breaking wave as a diffuse (Lambertian) surface. However, the observed sizes and shapes of fluid elements in the breakers clearly show that construction of a theory for electromagnetic scattering from first principles will be challenging. We also obtained the velocity spectrum of the scattering features within the breakers. This spectrum indicates that slower moving small liquid elements rather than the faster moving large disturbances are responsible for most of the electromagnetic scattering.

Cytokines and insulin-like growth factors (IGFs) are involved in the induction and/or perpetuation of inflammatory bowel disease. The effect of fasting on inflammatory bowel disease was studied in a mouse experimental model of acute colitis caused by adding dextran sulfate sodium (DSS) to drinking water. Animals were either fed ad libitum or fasted (water only) for 2 days before death. Inflammation and tissue damage, measured as a colitis activity score, were markedly reduced in fasted (2.4 +/- 0.1) compared to fed (5.3 +/- 0.1) DSS animals (P < 0.0001). Colon interleukin-1 beta (IL-1 beta), IGF-I, and tumor necrosis factor-alpha messenger RNAs (mRNAs) were quantified by Northern blot hybridization and expressed as a percentage of mRNA abundance in fed controls. In DSS mice, IL-1 beta mRNA was elevated in the fed group (954 +/- 155%; P < 0.001), but was suppressed in fasted animals (71.1 +/- 11%). IGF-I mRNA also was elevated in fed DSS mice (421 +/- 71%; P < 0.01). This increase was attenuated in fasted DSS mice (202 +/- 17%; P < 0.01 compared to fed DSS mice). Tumor necrosis factor-alpha mRNA was increased in fed DSS mice (162 +/- 15%; P < 0.01), but was not significantly lower in fasted animals. By in situ hybridization, IL-1 beta mRNA was localized to the lamina propria of colonic mucosa in fed DSS animals, but was not detectable in other groups. We conclude that fasting has a protective effect on the progression of acute DSS, induced colitis. This is associated with decreased expression of IL-1 beta and IGF-I mRNAs in the colon.

The homeodomain transcription factor Pdx-1 has important roles in pancreatic development and β-cell function and survival. In the present study, we demonstrate that adenovirus-mediated overexpression of Pdx-1 in rat or human islets also stimulates cell replication. Moreover, cooverexpression of Pdx-1 with another homeodomain transcription factor, Nkx6.1, has an additive effect on proliferation compared to either factor alone, implying discrete activating mechanisms. Consistent with this, Nkx6.1 stimulates mainly β-cell proliferation, whereas Pdx-1 stimulates both α- and β-cell proliferation. Furthermore, cyclins D1/D2 are upregulated by Pdx-1 but not by Nkx6.1, and inhibition of cdk4 blocks Pdx-1-stimulated but not Nkx6.1-stimulated islet cell proliferation. Genes regulated by Pdx-1 but not Nkx6.1 were identified by microarray analysis. Two members of the transient receptor potential cation (TRPC) channel family, TRPC3 and TRPC6, are upregulated by Pdx-1 overexpression, and small interfering RNA (siRNA)-mediated knockdown of TRPC3/6 or TRPC6 alone inhibits Pdx-1-induced but not Nkx6.1-induced islet cell proliferation. Pdx-1 also stimulates extracellular signal-regulated kinase 1 and 2 (ERK1/2) phosphorylation, an effect partially blocked by knockdown of TRPC3/6, and blockade of ERK1/2 activation with a MEK1/2 inhibitor partially impairs Pdx-1-stimulated proliferation. These studies define a pathway by which overexpression of Pdx-1 activates islet cell proliferation that is distinct from and additive to a pathway activated by Nkx6.1.

This study aimed to improve dietary compliance, attitudes, morale, and self-efficacy for 58 community-residing women ages 54-83 years regarding heart healthy dietary practices using a randomized control group design in two North Carolina counties. Questionnaires administered prior to Visits 1 (Baseline) and 4 (Day 90) and three 3-day food records were completed within 1 week of Visit 1 and 28-30 days thereafter. Treatment included two individual counseling sessions using pre-tested materials: Controls received corresponding mailings. Data analyses included descriptive statistics, analysis of covariance, correlations, and paired sample t-tests. Collective (total group) and control morale improved (p ≤ 0.01). The efficacy construct "ability to choose healthy foods" improved collectively (p 0.0001). Compliance correlated (p ≤ 0.05) with the ability to follow special dietary regimens collectively and by group. Treatment Compliance correlated (p ≤ 0.03) with the ability to choose healthy foods and morale. No significant between group differences were noted. Tailored nutrition programs empowered older women regarding their nutritional health improve morale and self-efficacy. In-home or mailed education materials with follow-up may be equally effective with similar older women in other locations.

We report the first results from a search for weakly interacting massive particles (WIMPs) in the Cryogenic Dark Matter Search (CDMS) experiment at the Soudan Underground Laboratory. Four Ge and two Si detectors were operated for 52.6 live days, providing 19.4 kg-d of Ge net exposure after cuts for recoil energies between 10--100 keV. A blind analysis was performed using only calibration data to define the energy threshold and selection criteria for nuclear-recoil candidates. Using the standard dark-matter halo and nuclear-physics WIMP model, these data set the world's lowest exclusion limits on the coherent WIMP-nucleon scalar cross-section for all WIMP masses above 15 GeV, ruling out a significant range of neutralino supersymmetric models. The minimum of this limit curve at the 90% C.L. is 4 x 10^{-43} cm^2 at a WIMP mass of 60 GeV., Comment: 4 pages, 5 figures, submitted to Phys. Rev. Lett; minor clarifications in response to referee's comments

Using improved Ge and Si detectors, better neutron shielding, and increased counting time, the Cryogenic Dark Matter Search (CDMS) experiment has obtained stricter limits on the cross section of weakly interacting massive particles (WIMPs) elastically scattering from nuclei. Increased discrimination against electromagnetic backgrounds and reduction of neutron flux confirm WIMP-candidate events previously detected by CDMS were consistent with neutrons and give limits on spin-independent WIMP interactions which are >2X lower than previous CDMS results for high WIMP mass, and which exclude new parameter space for WIMPs with mass between 8-20 GeV/c^2., 4 pages, 4 figures

The Comparative Tracking Index (CTI) and its relation to OEM electrical tapes is discussed. UL 1950 is the UL Standard for Safety titled. Information Technology Including Electrical Business Equipment. The author discusses what equipment is covered by the UL 1950, how CTI is measured, and how CTI is handled in UL 1950. >

A system to collect and process data at high rate, 53 MHz, from a silicon microstrip detector has been developed. The system is implemented using the FASTBUS standard and modularized at the board level in 128 channel increments. The system includes the following features: zero dead time readout for average trigger rate as high as 1 MHz; pipelined triggers and event readout; programmable data delay of up to 4.8 mu s; FASTBUS system readout; histogram readout option; and multiple high-speed bipolar process ASICs (application-specific integrated circuits). A general block diagram of data flow for the SSD (silicon strip detector) readout is provided. All the modules used for the SSD readout were tested individually to satisfy single board test requirements. Attention is given to SSD hardware for E771, a fixed target experiment designed to study the production of B hadrons by an 800 GeV/c proton beam. >

Background & Aims: Growth hormone (GH) is used as therapy for inflammatory bowel disease (IBD), but the specific effects on intestine are unknown. Transgenic mice overexpressing GH (MT1-bGH-TG) were used to test whether increased plasma GH levels alter inflammation or crypt damage during dextran sodium sulfate (DSS)-induced colitis. Methods: MT1-bGH-TG and wild-type (WT) littermates were given 3% DSS for 5 days followed by up to 10 days of recovery. Colitis and epithelial cell proliferation were evaluated histologically. Plasma insulin-like growth factor (IGF)-I and colonic IGF-I, interleukin (IL)-1β, and intestinal trefoil factor (ITF) messenger RNAs (mRNAs) were measured. Results: DSS induced similar disease onset in MT1-bGH-TG and WT. More MT1-bGH-TG survived than WT. By recovery day 7, MT1-bGH-TG had less inflammation and crypt damage, elevated plasma IGF-I, and increased colonic ITF expression relative to WT. Colonic IL-1β was elevated in DSS-treated MT1-bGH-TG and WT, but IL-1β mRNA abundance correlated with disease only in WT. MT1-bGH-TG showed earlier increases in epithelial cell proliferation than WT during recovery but only WT showed atypical repair. Conclusions: GH does not alter susceptibility to acute DSS-induced colitis but enhances survival, remission of inflammation, and mucosal repair during recovery. GH therapy may be beneficial during active IBD by improving mucosal repair. GASTROENTEROLOGY 2001;120:925-937

We have constructed a large format mosaic CCD camera for the Sloan Digital Sky Survey. The camera consists of two arrays, a photometric array which uses 30 2048 x 2048 SITe/Tektronix CCDs (24 micron pixels) with an effective imaging area of 720 square cm, and an astrometric array which uses 24 400 x 2048 CCDs with the same pixel size, which will allow us to tie bright astrometric standard stars to the objects imaged in the photometric camera. The instrument will be used to carry out photometry essentially simultaneously in five color bands spanning the range accessible to silicon detectors on the ground in the time-delay- and-integrate (TDI) scanning mode. The photometric detectors are arrayed in the focal plane in six columns of five chips each such that two scans cover a filled stripe 2.5 degrees wide. This paper presents engineering and technical details of the camera., 67 pages (inc 6 tables), plain TeX, 41 figures (gif), to appear in the Astronomical Journal, December 1998. The figures can be downloaded from http://astro.princeton.edu/~library/prep.html, preprint POPe-774, allfigs.zip, in postscript

Cytokines and insulin-like growth factors (IGFs) are involved in the induction and/or perpetuation of inflammatory bowel disease. The effect of fasting on inflammatory bowel disease was studied in a mouse experimental model of acute colitis caused by adding dextran sulfate sodium (DSS) to drinking water. Animals were either fed ad libitum or fasted (water only) for 2 days before death. Inflammation and tissue damage, measured as a colitis activity score, were markedly reduced in fasted (2.4 +/- 0.1) compared to fed (5.3 +/- 0.1) DSS animals (P0.0001). Colon interleukin-1 beta (IL-1 beta), IGF-I, and tumor necrosis factor-alpha messenger RNAs (mRNAs) were quantified by Northern blot hybridization and expressed as a percentage of mRNA abundance in fed controls. In DSS mice, IL-1 beta mRNA was elevated in the fed group (954 +/- 155%; P0.001), but was suppressed in fasted animals (71.1 +/- 11%). IGF-I mRNA also was elevated in fed DSS mice (421 +/- 71%; P0.01). This increase was attenuated in fasted DSS mice (202 +/- 17%; P0.01 compared to fed DSS mice). Tumor necrosis factor-alpha mRNA was increased in fed DSS mice (162 +/- 15%; P0.01), but was not significantly lower in fasted animals. By in situ hybridization, IL-1 beta mRNA was localized to the lamina propria of colonic mucosa in fed DSS animals, but was not detectable in other groups. We conclude that fasting has a protective effect on the progression of acute DSS, induced colitis. This is associated with decreased expression of IL-1 beta and IGF-I mRNAs in the colon.

A synchronous silicon strip readout system capable of zero dead-time readout at average trigger rates in excess of 1 MHz is described. The system is implemented in Fastbus, uses pipelining techniques, and includes point-to-point fiberoptic data links to transmit detector digital data. Semicustom ASIC (application-specific integrated circuit) chips are used to amplify, discriminate, and logically combine track data before encoding. The overall system, each major Fastbus module, and the functional aspects of the ASIC chips are described. >

We describe a fast trigger processor, developed for and used in Fermilab experiment E-537, for selecting high-mass dimuon events produced by negative pions and anti-protons. The processor finds candidate tracks by matching hit information received from drift chambers and scintillation counters, and determines their momenta. Invariant masses are calculated for all possible pairs of tracks and an event is accepted if any invariant mass is greater than some preselectable minimum mass. The whole process, accomplished within 5 to 10 microseconds, achieves up to a ten-fold reduction in trigger rate.

This paper describes a relatively simply and inexpensive scheme to make phase space measurements of particles with time separations on the order of 130 nsec and greater.

The authors review the design and prototyping of two application specific integrated circuits (ASICs), an amplifier and a discriminator, which are being produced for the Fermilab E771 silicon strip detector readout system. The two bipolar ASICs were designed and prototyped using Tektronix Quickchip 2 linear arrays. Measurements of the performance of the prototype devices are presented that agree very well with the results SPICE simulations. >

A sampling, 96 channel NIM module scanner, which when used in conjunction with Fermilab's conventional 96 wire ionization chambers (WIC's), provides up to ten (96-channel) samples of the charged particle beam profiles during a beam spill. The ability to sample as often as four milliseconds, with minimum sample times of 1 ?second, allows this system to be used at particle rates from 105 to 1014 particles per second per wire, making it useful for beam tuning as well as normal running. The 96 analog channels are digitized after each sample and stored in a 1K × 12 bid RAM. The RAM provides data for local analog output, through a D/A coverter/driver and for block data transfers via a CAMAC controller module to a processor for software data manipulation.

A FASTBUS based data acquisition system is under construction at the Fermi National Accelerator Laboratory for the Collider Detector at FERMILASB (CDF). This system is likely to have in the area 35 to 40 racks, 25 of which may house up to 3, FASTBUS crates, associated power supplies and cooling aparatus. Such a rack may represent as much as $175,000. Th is paper describes a rack protection system, designed to greately reduce the possibility of large scale system damage, which will add an additional cost of approximately 1 to 2 %.

All CDF event data are collected in a multilevel FASTBUS network. At the lowest level of this network, MEP/MX and SSP scanners read and buffer data from RABBIT and FASTBUS front end systems. Operation of these front end scanners is coordinated by the Trigger Supervisor module which initiates parallel readout after receiving Level 1 and Level 2 triggers. Dataflow from scanners to consumer processes on host VAX computers is supervised by the Buffer Manager which directs an Event Builder to collect and format data from a set of scanner modules. This system is designed to allow partitioning into semi-independent sections for parallel development and calibration studies.