Medium Chain Fatty Acids Are Selective Peroxisome Proliferator Activated Receptor (PPAR) gamma Activators and Pan-PPAR Partial Agonists

Thiazolidinediones (TZDs) act through peroxisome proliferator activated receptor (PPAR) gamma to increase insulin sensitivity in type 2 diabetes (T2DM), but deleterious effects of these ligands mean that selective modulators with improved clinical profiles are needed. We obtained a crystal structure of PPAR gamma ligand binding domain (LBD) and found that the ligand binding pocket (LBP) is occupied by bacterial medium chain fatty acids (MCFAs). We verified that MCFAs (C8-C10) bind the PPAR gamma LBD in vitro and showed that they are low-potency partial agonists that display assay-specific actions relative to TZDs; they act as very weak partial agonists in transfections with PPAR gamma LBD, stronger partial agonists with full length PPAR gamma and exhibit full blockade of PPAR gamma phosphorylation by cyclin-dependent kinase 5 (cdk5), linked to reversal of adipose tissue insulin resistance. MCFAs that bind PPAR gamma also antagonize TZD-dependent adipogenesis in vitro. X-ray structure B-factor analysis and molecular dynamics (MD) simulations suggest that MCFAs weakly stabilize C-terminal activation helix (H) 12 relative to TZDs and this effect is highly dependent on chain length. By contrast, MCFAs preferentially stabilize the H2-H3/beta-sheet region and the helix (H) 11-H12 loop relative to TZDs and we propose that MCFA assay-specific actions are linked to their unique binding mode and suggest that it may be possible to identify selective PPAR gamma modulators with useful clinical profiles among natural products.

Factors Associated with Height Catch-Up and Catch-Down Growth Among Schoolchildren

In developed countries, children with intrauterine growth restriction (IUGR) or born preterm (PT) tend to achieve catch-up growth. There is little information about height catch-up in developing countries and about height catch-down in both developed and developing countries. We studied the effect of IUGR and PT birth on height catch-up and catch-down growth of children from two cohorts of liveborn singletons. Data from 1,463 children was collected at birth and at school age in Ribeirao Preto (RP), a more developed city, and in Sao Luis (SL), a less developed city. A change in z-score between schoolchild height z-score and birth length z-score >= 0.67 was considered catch-up; a change in z-score <=-0.67 indicated catch-down growth. The explanatory variables were: appropriate weight for gestational age/PT birth in four categories: term children without IUGR (normal), IUGR only (term with IUGR), PT only ( preterm without IUGR) and preterm with IUGR; infant's sex; maternal parity, age, schooling and marital status; occupation of family head; family income and neonatal ponderal index (PI). The risk ratio for catch-up and catch-down was estimated by multinomial logistic regression for each city. In RP, preterms without IUGR (RR = 4.13) and thin children (PI<10th percentile, RR = 14.39) had a higher risk of catch-down; catch-up was higher among terms with IUGR (RR = 5.53), preterms with IUGR (RR = 5.36) and children born to primiparous mothers (RR = 1.83). In SL, catch-down was higher among preterms without IUGR (RR = 5.19), girls (RR = 1.52) and children from low-income families ( RR = 2.74); the lowest risk of catch-down (RR = 0.27) and the highest risk of catch-up (RR = 3.77) were observed among terms with IUGR. In both cities, terms with IUGR presented height catch-up growth whereas preterms with IUGR only had height catch-up growth in the more affluent setting. Preterms without IUGR presented height catch-down growth, suggesting that a better socioeconomic situation facilitates height catch-up and prevents height catch-down growth.

Topical Insulin Accelerates Wound Healing in Diabetes by Enhancing the AKT and ERK Pathways: A Double-Blind Placebo-Controlled Clinical Trial

Background: Wound healing is impaired in diabetes mellitus, but the mechanisms involved in this process are virtually unknown. Proteins belonging to the insulin signaling pathway respond to insulin in the skin of rats. Objective: The purpose of this study was to investigate the regulation of the insulin signaling pathway in wound healing and skin repair of normal and diabetic rats, and, in parallel, the effect of a topical insulin cream on wound healing and on the activation of this pathway. Research Design and Methods: We investigated insulin signaling by immunoblotting during wound healing of control and diabetic animals with or without topical insulin. Diabetic patients with ulcers were randomized to receive topical insulin or placebo in a prospective, double-blind and placebo-controlled, randomized clinical trial (NCT 01295177) of wound healing. Results and Conclusions: Expression of IR, IRS-1, IRS-2, SHC, ERK, and AKT are increased in the tissue of healing wounds compared to intact skin, suggesting that the insulin signaling pathway may have an important role in this process. These pathways were attenuated in the wounded skin of diabetic rats, in parallel with an increase in the time of complete wound healing. Upon topical application of insulin cream, the wound healing time of diabetic animals was normalized, followed by a reversal of defective insulin signal transduction. In addition, the treatment also increased expression of other proteins, such as eNOS (also in bone marrow), VEGF, and SDF-1 alpha in wounded skin. In diabetic patients, topical insulin cream markedly improved wound healing, representing an attractive and cost-free method for treating this devastating complication of diabetes.

Rock Art at the Pleistocene/Holocene Boundary in Eastern South America

Background: Most investigations regarding the First Americans have primarily focused on four themes: when the New World was settled by humans; where they came from; how many migrations or colonization pulses from elsewhere were involved in the process; and what kinds of subsistence patterns and material culture they developed during the first millennia of colonization. Little is known, however, about the symbolic world of the first humans who settled the New World, because artistic manifestations either as rock-art, ornaments, and portable art objects dated to the Pleistocene/Holocene transition are exceedingly rare in the Americas. Methodology/Principal Findings: Here we report a pecked anthropomorphic figure engraved in the bedrock of Lapa do Santo, an archaeological site located in Central Brazil. The horizontal projection of the radiocarbon ages obtained at the north profile suggests a minimum age of 9,370640 BP, (cal BP 10,700 to 10,500) for the petroglyph that is further supported by optically stimulated luminescence (OSL) dates from sediment in the same stratigraphic unit, located between two ages from 11.7 +/- 0.8 ka BP to 9.9 +/- 0.7 ka BP. Conclusions: These data allow us to suggest that the anthropomorphic figure is the oldest reliably dated figurative petroglyph ever found in the New World, indicating that cultural variability during the Pleistocene/Holocene boundary in South America was not restricted to stone tools and subsistence, but also encompassed the symbolic dimension.

Serrumab: A human monoclonal antibody that counters the biochemical and immunological effects of Tityus serrulatus venom

In Brazil, the species Tityus serrulatus is responsible for the most severe cases of scorpion envenomation. There is currently a need for new scorpion anti-venoms that are more effective and less harmful. This study attempted to produce human monoclonal antibodies capable of inhibiting the activity of T. serrulatus venom (TsV), using the Griffin.1 library of human single-chain fragment-variable (scFv) phage antibodies. Four rounds of phage antibody selection were performed, and the round with the highest phage antibody titer was chosen for the production of monoclonal phage antibodies and for further analysis. The scFv 2A, designated serrumab, was selected for the production and purification of soluble antibody fragments. In a murine peritoneal macrophage cell line (J774.1), in vitro assays of the cytokines interleukin (IL)-6, tumor necrosis factor (TNF)-alpha, and IL-10 were performed. In male BALB/c mice, in vivo assays of plasma urea, creatinine, aspartate transaminase, and glucose were performed, as well as of neutrophil recruitment and leukocyte counts. It was found that serrumab inhibited the TsV-induced increases in the production of IL-6, TNF alpha, and IL-10 in J774.1 cells. The in vivo inhibition assay showed that serrumab also prevented TsV-induced increases in the plasma levels of urea, creatinine, aspartate transaminase, and glucose, as well as preventing the TsV-induced increase in neutrophil recruitment. The results indicate that the human monoclonal antibody serrumab is a candidate for inclusion in a mixture of specific antibodies to the various toxins present in TsV. Therefore, serrumab shows promise for use in the production of new anti-venom.

Effects of Continuous Erythropoietin Receptor Activator in Sepsis-Induced Acute Kidney Injury and Multi-Organ Dysfunction

Background: Despite advances in supportive care, sepsis-related mortality remains high, especially in patients with acute kidney injury (AKI). Erythropoietin can protect organs against ischemia and sepsis. This effect has been linked to activation of intracellular survival pathways, although the mechanism remains unclear. Continuous erythropoietin receptor activator (CERA) is an erythropoietin with a unique pharmacologic profile and long half-life. We hypothesized that pretreatment with CERA would be renoprotective in the cecal ligation and puncture (CLP) model of sepsis-induced AKI. Methods: Rats were randomized into three groups: control; CLP; and CLP+CERA (5 mu g/kg body weight, i.p. administered 24 h before CLP). At 24 hours after CLP, we measured creatinine clearance, biochemical variables, and hemodynamic parameters. In kidney tissue, we performed immunoblotting-to quantify expression of the Na-K-2Cl cotransporter (NKCC2), aquaporin 2 (AQP2), Toll-like receptor 4 (TLR4), erythropoietin receptor (EpoR), and nuclear factor kappa B (NF-kappa B)-and immunohistochemical staining for CD68 (macrophage infiltration). Plasma interleukin (IL)-2, IL-1 beta, IL-6, IL-10, interferon gamma, and tumor necrosis factor alpha were measured by multiplex detection. Results: Pretreatment with CERA preserved creatinine clearance and tubular function, as well as the expression of NKCC2 and AQP2. In addition, CERA maintained plasma lactate at normal levels, as well as preserving plasma levels of transaminases and lactate dehydrogenase. Renal expression of TLR4 and NF-kappa B was lower in CLP+CERA rats than in CLP rats (p<0.05 and p<0.01, respectively), as were CD68-positive cell counts (p<0.01), whereas renal EpoR expression was higher (p<0.05). Plasma levels of all measured cytokines were lower in CLP+CERA rats than in CLP rats. Conclusion: CERA protects against sepsis-induced AKI. This protective effect is, in part, attributable to suppression of the inflammatory response.

Mental Disorders in Megacities: Findings from the Sao Paulo Megacity Mental Health Survey, Brazil

Background: World population growth is projected to be concentrated in megacities, with increases in social inequality and urbanization-associated stress. Sao Paulo Metropolitan Area (SPMA) provides a forewarning of the burden of mental disorders in urban settings in developing world. The aim of this study is to estimate prevalence, severity, and treatment of recently active DSM-IV mental disorders. We examined socio-demographic correlates, aspects of urban living such as internal migration, exposure to violence, and neighborhood-level social deprivation with 12-month mental disorders. Methods and Results: A representative cross-sectional household sample of 5,037 adults was interviewed face-to-face using the WHO Composite International Diagnostic Interview (CIDI), to generate diagnoses of DSM-IV mental disorders within 12 months of interview, disorder severity, and treatment. Administrative data on neighborhood social deprivation were gathered. Multiple logistic regression was used to evaluate individual and contextual correlates of disorders, severity, and treatment. Around thirty percent of respondents reported a 12-month disorder, with an even distribution across severity levels. Anxiety disorders were the most common disorders (affecting 19.9%), followed by mood (11%), impulse-control (4.3%), and substance use (3.6%) disorders. Exposure to crime was associated with all four types of disorder. Migrants had low prevalence of all four types compared to stable residents. High urbanicity was associated with impulse-control disorders and high social deprivation with substance use disorders. Vulnerable subgroups were observed: women and migrant men living in most deprived areas. Only one-third of serious cases had received treatment in the previous year. Discussion: Adults living in Sao Paulo megacity had prevalence of mental disorders at greater levels than similar surveys conducted in other areas of the world. Integration of mental health promotion and care into the rapidly expanding Brazilian primary health system should be strengthened. This strategy might become a model for poorly resourced and highly populated developing countries.

Natural blood feeding and temperature shift modulate the global transcriptional profile of Rickettsia rickettsii infecting its tick vector

Rickettsia rickettsii is an obligate intracellular tick-borne bacterium that causes Rocky Mountain Spotted Fever (RMSF), the most lethal spotted fever rickettsiosis. When an infected starving tick begins blood feeding from a vertebrate host, R. rickettsii is exposed to a temperature elevation and to components in the blood meal. These two environmental stimuli have been previously associated with the reactivation of rickettsial virulence in ticks, but the factors responsible for this phenotype conversion have not been completely elucidated. Using customized oligonucleotide microarrays and high-throughput microfluidic qRT-PCR, we analyzed the effects of a 10 degrees C temperature elevation and of a blood meal on the transcriptional profile of R. rickettsii infecting the tick Amblyomma aureolatum. This is the first study of the transcriptome of a bacterium in the genus Rickettsia infecting a natural tick vector. Although both stimuli significantly increased bacterial load, blood feeding had a greater effect, modulating five-fold more genes than the temperature upshift. Certain components of the Type IV Secretion System (T4SS) were up-regulated by blood feeding. This suggests that this important bacterial transport system may be utilized to secrete effectors during the tick vector's blood meal. Blood feeding also up-regulated the expression of antioxidant enzymes, which might correspond to an attempt by R. rickettsii to protect itself against the deleterious effects of free radicals produced by fed ticks. The modulated genes identified in this study, including those encoding hypothetical proteins, require further functional analysis and may have potential as future targets for vaccine development.

Oral leucine supplementation is sensed by the brain but neither reduces food intake nor induces an anorectic pattern of gene expression in the hypothalamus

Leucine activates the intracellular mammalian target of the rapamycin (mTOR) pathway, and hypothalamic mTOR signaling regulates food intake. Although central infusion of leucine reduces food intake, it is still uncertain whether oral leucine supplementation is able to affect the hypothalamic circuits that control energy balance. We observed increased phosphorylation of p70s6k in the mouse hypothalamus after an acute oral gavage of leucine. We then assessed whether acute oral gavage of leucine induces the activation of neurons in several hypothalamic nuclei and in the brainstem. Leucine did not induce the expression of Fos in hypothalamic nuclei, but it increased the number of Fos-immunoreactive neurons in the area postrema. In addition, oral gavage of leucine acutely increased the 24 h food intake of mice. Nonetheless, chronic leucine supplementation in the drinking water did not change the food intake and the weight gain of ob/ob mice and of wild-type mice consuming a low- or a high-fat diet. We assessed the hypothalamic gene expression and observed that leucine supplementation increased the expression of enzymes (BCAT1, BCAT2 and BCKDK) that metabolize branched-chain amino acids. Despite these effects, leucine supplementation did not induce an anorectic pattern of gene expression in the hypothalamus. In conclusion, our data show that the brain is able to sense oral leucine intake. However, the food intake is not modified by chronic oral leucine supplementation. These results question the possible efficacy of leucine supplementation as an appetite suppressant to treat obesity

On reproduction in red algae: futher research needed at the molecular level

[EN]Multicellular red algae (Rhodophyta) have some of the most complex life cycles known in living organisms. Economically valuable seaweeds, such as phycocolloid producers, have a triphasic (gametophyte, carposporophyte, and tetrasporophyte) life cycle, not to mention the intricate alternation of generations in the edible “sushi-alga” nori. It is a well-known fact that reproductive processes are controlled by one or more abiotic factor(s), including day length, light quality, temperature, and nutrients. Likewise, endogenous chemical factors such as plant growth regulators have been reported to affect reproductive events in some red seaweeds. Still, in the genomic era and given the high throughput techniques at our disposal, our knowledge about the endogenous molecular machinery lags far behind that of higher plants.

Caring Minds

Honoring a Leader 25th Anniversary Symposium Four Investments in Innovation --Accelerated Ph.D. Campaign --House Bill 4471 Aids Nursing --“Pacesetter” Model --John S. Dunn Research Foundation Gift Fabulous from the Start PARTNERS Luncheon Robert Wood Johnson Foundation Executive Nurse Fellow Alumni News Faculty Scholarship

New Law against an Old State: Land Restitution as a Transition to Justice in Post-Apartheid South Africa?

The research on which this text is based has been financially supported by the Berne University Research Foundation (2009–2011) as well as by an Ambizione Research Fellowship of the Swiss National Science Foundation (2012–2014). During my stays in South Africa, the Departments of Anthropology at the University of the Witwatersrand, Johannesburg, and the University of South Africa (UNISA), Pretoria, provided me with welcoming and inspiring research environments. This article benefitted greatly from engaged discussions around its presentation at various occasions, notably our ECAS 2011 panel Transition and Justice: Negotiating the Terms of New Beginnings in Africa, held in Uppsala. I am particularly grateful to my co-convener and co-editor Gerhard Anders as well as Laurens Bakker, Keebet von Benda-Beckmann, Ben Cousins, Julia Eckert, Marion Fresia, Vinodh Jaichand, Steffen Jensen, Tim Kelsall, Hanri Mostert, Johanna Mugler, David O'Kane, Julia Pauli, Mats Utas, Julia Zenker and the anonymous referees of Development and Change for their critical engagements.

Recommendations for sex/gender neuroimaging research: Key principles and implications for research design, analysis and interpretation

Neuroimaging (NI) technologies are having increasing impact in the study of complex cognitive and social processes. In this emerging field of social cognitive neuroscience, a central goal should be to increase the understanding of the interaction between the neurobiology of the individual and the environment in which humans develop and function. The study of sex/gender is often a focus for NI research, and may be motivated by a desire to better understand general developmental principles, mental health problems that show female-male disparities, and gendered differences in society. In order to ensure the maximum possible contribution of NI research to these goals, we draw attention to four key principles—overlap, mosaicism, contingency and entanglement—that have emerged from sex/gender research and that should inform NI research design, analysis and interpretation. We discuss the implications of these principles in the form of constructive guidelines and suggestions for researchers, editors, reviewers and science communicators.

MS 066 Guide to the Howard B. Hamilton, MD, papers; 1945-1997

The Howard B. Hamilton, MD, papers, MS 66, includes material from 1945-1997 related to the Atomic Bomb Casualty Commission (ABCC) and the Radiation Effects Research Foundation (RERF). Hamilton was the Chief of Clinical Laboratories for the Atomic Bomb Casualty Commission from 1956 until its dissolution in 1975. He served in the same capacity for the Radiation Effects Research Foundation, which succeeded the ABCC, until 1984. This collection encompasses this period of time in Dr. Hamilton's career, as well as his related scholarly work after his retirement from RERF. Dr. Hamilton donated his collection of letters, reprints, newspaper articles, photographs, memos, and ephemera to the John P. McGovern Historical Collections and Research Center between 1985 and 2002. The collection is in good condition and consists of 3.75 cubic feet (10 boxes).

Patenting genes and gene sequences: Analysis of public health implications and the law

At issue is whether or not isolated DNA is patent eligible under the U.S. Patent Law and the implications of that determination on public health. The U.S. Patent and Trademark Office has issued patents on DNA since the 1980s, and scientists and researchers have proceeded under that milieu since that time. Today, genetic research and testing related to the human breast cancer genes BRCA1 and BRCA2 is conducted within the framework of seven patents that were issued to Myriad Genetics and the University of Utah Research Foundation between 1997 and 2000. In 2009, suit was filed on behalf of multiple researchers, professional associations and others to invalidate fifteen of the claims underlying those patents. The Court of Appeals for the Federal Circuit, which hears patent cases, has invalidated claims for analyzing and comparing isolated DNA but has upheld claims to isolated DNA. The specific issue of whether isolated DNA is patent eligible is now before the Supreme Court, which is expected to decide the case by year's end. In this work, a systematic review was performed to determine the effects of DNA patents on various stakeholders and, ultimately, on public health; and to provide a legal analysis of the patent eligibility of isolated DNA and the likely outcome of the Supreme Court's decision. ^ A literature review was conducted to: first, identify principle stakeholders with an interest in patent eligibility of the isolated DNA sequences BRCA1 and BRCA2; and second, determine the effect of the case on those stakeholders. Published reports that addressed gene patents, the Myriad litigation, and implications of gene patents on stakeholders were included. Next, an in-depth legal analysis of the patent eligibility of isolated DNA and methods for analyzing it was performed pursuant to accepted methods of legal research and analysis based on legal briefs, federal law and jurisprudence, scholarly works and standard practice legal analysis. ^ Biotechnology, biomedical and clinical research, access to health care, and personalized medicine were identified as the principle stakeholders and interests herein. Many experts believe that the patent eligibility of isolated DNA will not greatly affect the biotechnology industry insofar as genetic testing is concerned; unlike for therapeutics, genetic testing does not require tremendous resources or lead time. The actual impact on biomedical researchers is uncertain, with greater impact expected for researchers whose work is intended for commercial purposes (versus basic science). The impact on access to health care has been surprisingly difficult to assess; while invalidating gene patents might be expected to decrease the cost of genetic testing and improve access to more laboratories and physicians' offices that provide the test, a 2010 study on the actual impact was inconclusive. As for personalized medicine, many experts believe that the availability of personalized medicine is ultimately a public policy issue for Congress, not the courts. ^ Based on the legal analysis performed in this work, this writer believes the Supreme Court is likely to invalidate patents on isolated DNA whose sequences are found in nature, because these gene sequences are a basic tool of scientific and technologic work and patents on isolated DNA would unduly inhibit their future use. Patents on complementary DNA (cDNA) are expected to stand, however, based on the human intervention required to craft cDNA and the product's distinction from the DNA found in nature. ^ In the end, the solution as to how to address gene patents may lie not in jurisprudence but in a fundamental change in business practices to provide expanded licenses to better address the interests of the several stakeholders. ^