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Research advances from the National Institutes of Health (NIH) Intramural Research Program (IRP) are often published in high-impact journals. Read some of our recent articles:

Authors: Scruggs BS, Gilchrist DA, Nechaev S, Muse GW, Burkholder A, Fargo DC, Adelman K

Journal: Mol Cell. 2015 Jun 18;58(6):1101-12. doi: 10.1016/j.molcel.2015.04.006. Epub 2015 May 28.

Anti-sense transcription originating upstream of mammalian protein-coding genes is a well-documented phenomenon, but remarkably little is known about the regulation or function of anti-sense promoters and the non-coding RNAs they generate. Here we define at nucleotide resolution the divergent transcription start sites (TSSs) near mouse mRNA genes. We find that coupled sense and anti-sense TSSs precisely define the boundaries of a nucleosome-depleted region (NDR) that is highly enriched in transcription factor (TF) motifs. Notably, as the distance between sense and anti-sense TSSs increases, so does the size of the NDR, the level of signal-dependent TF binding, and gene activation. We further discover a group of anti-sense TSSs in macrophages with an enhancer-like chromatin signature. Interestingly, this signature identifies divergent promoters that are activated during immune challenge. We propose that anti-sense promoters serve as platforms for TF binding and establishment of active chromatin to further regulate or enhance sense-strand mRNA expression.

Authors: Piaggi P, Thearle MS, Krakoff J, Votruba SB

Journal: J Clin Endocrinol Metab. 2015 Jun 18:jc20152164. [Epub ahead of print]

CONTEXT: Body fat free mass (FFM), energy expenditure (EE) and respiratory quotient (RQ) are known predictors of daily food intake. As FFM largely determines EE, it is unclear whether body composition per se or the underlying metabolism drives dietary intake.

OBJECTIVE: To test whether 24-h measures of EE and RQ and their components influence ad libitum food intake independently of FFM.

DESIGN AND PARTICIPANTS: One-hundred-seven healthy individuals (62M/45F, 84 Native Americans/23 Whites; age: 33±8 yrs.; BMI: 33±8 kg/m2; body fat: 31±8%) had 24-h measures of EE in a whole-room indirect calorimeter during energy balance, followed by three days of ad libitum food intake using computerized vending machine systems. Body composition was estimated by DXA.

MAIN OUTCOME MEASURES: FFM, 24-h EE, RQ, spontaneous physical activity (SPA), sleeping EE (SMR), "awake and fed" thermogenesis (AFT) and ad libitum food intake (INTAKE).

RESULTS: Higher 24-h RQ (P<0.001, partial R2=16%) and EE (P=0.01, partial R2=7%), but not FFM (P=0.65), were independent predictors of INTAKE. Mediation analysis demonstrated that 24-h EE is responsible for 80% of the FFM effect on INTAKE (44.5±16.9 kcal ingested per kg FFM, P=0.01), whereas the unique effect due to solely FFM was negligible (10.6±23.2, P=0.65). SPA (r=0.33, P=0.001), but not SMR (P=0.71), positively predicted INTAKE, while higher AFT determined greater INTAKE only in subjects with a BMI≤29 kg/m2 (r=0.44, P=0.01).

CONCLUSIONS: EE and RQ, rather than FFM, independently determine INTAKE, suggesting that competitive energy-sensing mechanisms driven by the preferential macronutrient oxidation and total energy demands may regulate food intake.

Authors: Xiao Y, Thoresen DT, Williams JS, Wang C, Perna J, Petrova R, Brownell I

Journals: Proc Natl Acad Sci U S A. 2015 Jun 9;112(23):7195-200. doi: 10.1073/pnas.1504177112. Epub 2015 May 26

The touch dome is a highly patterned mechanosensory structure in the epidermis composed of specialized keratinocytes in juxtaposition with innervated Merkel cells. The touch dome epithelium is maintained by tissue-specific stem cells, but the signals that regulate the touch dome are not known. We identify touch dome stem cells that are unique among epidermal cells in their activated Hedgehog signaling and ability to maintain the touch dome as a distinct lineage compartment. Skin denervation reveals that renewal of touch dome stem cells requires a perineural microenvironment, and deleting Sonic hedgehog (Shh) in neurons or Smoothened in the epidermis demonstrates that Shh is an essential niche factor that maintains touch dome stem cells. Up-regulation of Hedgehog signaling results in neoplastic expansion of touch dome keratinocytes but no Merkel cell neoplasia. These findings demonstrate that nerve-derived Shh is a critical regulator of lineage-specific stem cells that maintain specialized sensory compartments in the epidermis.

Authors: Davis FM, Janoshazi A, Janardhan KS, Steinckwich N, D'Agostin DM, Petranka JG, Desai PN, Roberts-Thomson SJ, Bird GS, Tucker DK, Fenton SE, Feske S, Monteith GR, Putney JW Jr

Journal: Proc Natl Acad Sci U S A. 2015 May 5;112(18):5827-32. doi: 10.1073/pnas.1502264112. Epub 2015 Apr 20.

The nourishment of neonates by nursing is the defining characteristic of mammals. However, despite considerable research into the neural control of lactation, an understanding of the signaling mechanisms underlying the production and expulsion of milk by mammary epithelial cells during lactation remains largely unknown. Here we demonstrate that a store-operated Ca(2+) channel subunit, Orai1, is required for both optimal Ca(2+) transport into milk and for milk ejection. Using a novel, 3D imaging strategy, we visualized live oxytocin-induced alveolar unit contractions in the mammary gland, and we demonstrated that in this model milk is ejected by way of pulsatile contractions of these alveolar units. In mammary glands of Orai1 knockout mice, these contractions are infrequent and poorly coordinated. We reveal that oxytocin also induces a large transient release of stored Ca(2+) in mammary myoepithelial cells followed by slow, irregular Ca(2+) oscillations. These oscillations, and not the initial Ca(2+) transient, are mediated exclusively by Orai1 and are absolutely required for milk ejection and pup survival, an observation that redefines the signaling processes responsible for milk ejection. These findings clearly demonstrate that Ca(2+) is not just a substrate for nutritional enrichment in mammals but is also a master regulator of the spatiotemporal signaling events underpinning mammary alveolar unit contraction. Orai1-dependent Ca(2+) oscillations may represent a conserved language in myoepithelial cells of other secretory epithelia, such as sweat glands, potentially shedding light on other Orai1 channelopathies, including anhidrosis (an inability to sweat).

Authors: Alonso A, Huang X, Mosley TH, Heiss G, Chen H.

Journal: Ann Neurol. 2015 May;77(5):877-83. doi: 10.1002/ana.24393. Epub 2015 Mar 27.

OBJECTIVE: Autonomic dysfunction frequently occurs in the context of Parkinson disease (PD) and may precede onset of motor symptoms. Limited data exist on the prospective association of heart rate variability (HRV), a marker of autonomic function, with PD risk.

METHODS: We included 12,162 participants of the Atherosclerosis Risk in Communities study, a community-based cohort, without a diagnosis of PD at baseline (1987-1989) and with available HRV data (mean age = 54 years, 57% women). A 2-minute electrocardiogram was used to measure HRV. Incident PD was identified through 2008 from multiple sources, and adjudicated. Multivariable Cox models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of PD by quartiles of HRV measurements.

RESULTS: During a mean follow-up of 18 years, we identified 78 incident PD cases. Lower values of the root mean square of successive differences in normal-to-normal R-R intervals (rMSSD) and standard deviation of normal-to-normal R-R intervals (SDNN), markers of parasympathetic activity and total variability, respectively, were associated with higher PD risk during follow-up. In multivariate models, the HR (95% CI) of PD in the bottom quartiles of rMSSD and SDNN compared to the top quartiles were 2.1 (1.0-4.3) and 2.9 (1.4-6.1), respectively. Other measures of cardiac autonomic function, including mean R-R interval and frequency-domain measurements, were not associated with PD risk.

INTERPRETATION: In this prospective cohort, decreased HRV was associated with an increased risk of PD. Assessment of cardiac autonomic function may help identify individuals at risk for PD. Ann Neurol 2015;77:877-883.

Authors: Weinberg CR, Zaykin D

Journal: J Natl Cancer Inst. 2015 May 8;107(7). pii: djv125. doi: 10.1093/jnci/djv125. Print 2015 Jul.

A recent study reports that the log lifetime incidence rate across a selection of 31 cancer types is highly correlated with the log of the estimated tissue-specific lifetime number of stem cell divisions. This observation, which underscores the importance of errors in DNA replication, has been viewed as implying that most cancers arise through unavoidable bad luck, leading to the suggestion that research efforts should focus on early detection, rather than etiology or prevention. We argue that three statistical issues can, if ignored, lead analysts to incorrect conclusions. Statistics for traffic fatalities across the United States provide an example to demonstrate those inferential pitfalls. While the contribution of random cellular events to disease is often underappreciated, the role of chance is necessarily difficult to quantify. The conclusion that most cases of cancer are fundamentally unpreventable because they are the result of chance is unwarranted.

Authors: Mueller GA, Pedersen LC, Glesner J, Edwards LL, Zakzuk J, London RE, Arruda LK, Chapman MD, Caraballo L, Pomés A.

Journal: J Allergy Clin Immunol. 2015 Apr 27. pii: S0091-6749(15)00414-5. doi: 10.1016/j.jaci.2015.03.015. [Epub ahead of print]

BACKGROUND: It is not clear whether cross-reactivity or cosensitization to glutathione S-transferases (GSTs) occurs in tropical and subtropical environments. In the United States, Bla g 5 is the most important GST allergen and lack of coexposure to GSTs from certain species allows a better assessment of cross-reactivity.

OBJECTIVES: To examine the molecular structure of GST allergens from cockroach (Bla g 5), dust mites (Der p 8 and Blo t 8), and helminth (Asc s 13) for potential cross-reactive sites, and to assess the IgE cross-reactivity of sensitized patients from a temperate climate for these allergens for molecular diagnostic purposes.

METHODS: Four crystal structures were determined. Sera from patients allergic to cockroach and mite were tested for IgE reactivity to these GSTs. A panel of 6 murine anti-Bla g 5 mAb was assessed for cross-reactivity with the other 3 GSTs using antibody binding assays.

RESULTS: Comparisons of the allergen structures, formed by 2-domain monomers that dimerize, revealed few contiguous regions of similar exposed residues, rendering cross-reactivity unlikely. Accordingly, anti-Bla g 5 or anti-Der p 8 IgE from North American patients did not recognize Der p 8 or Bla g 5, respectively, and neither showed binding to Blo t 8 or Asc s 13. A weaker binding of anti-Bla g 5 IgE to Der p 8 versus Bla g 5 (∼100-fold) was observed by inhibition assays, similar to a weak recognition of Der p 8 by anti-Bla g 5 mAb. Patients from tropical Colombia had IgE to all 4 GSTs.

CONCLUSIONS: The lack of significant IgE cross-reactivity among the 4 GSTs is in agreement with the low shared amino acid identity at the molecular surface. Each GST is needed for accurate molecular diagnosis in different geographic areas.

Authors: Liu C, Peng J, Matzuk MM, Yao HH

Journal: Nat Commun. 2015 Apr 28;6:6934. doi: 10.1038/ncomms7934

Organogenesis of the ovary is a highly orchestrated process involving multiple lineage determination of ovarian surface epithelium, granulosa cells and theca cells. Although the sources of ovarian surface epithelium and granulosa cells are known, the origin(s) of theca progenitor cells have not been definitively identified. Here we show that theca cells derive from two sources: Wt1(+) cells indigenous to the ovary and Gli1(+) mesenchymal cells that migrate from the mesonephros. These progenitors acquire theca lineage marker Gli1 in response to paracrine signals Desert hedgehog (Dhh) and Indian hedgehog (Ihh) from granulosa cells. Ovaries lacking Dhh/Ihh exhibit theca layer loss, blunted steroid production, arrested folliculogenesis and failure to form corpora lutea. Production of Dhh/Ihh in granulosa cells requires growth differentiation factor 9 (GDF9) from the oocyte. Our studies provide the first genetic evidence for the origins of theca cells and reveal a multicellular interaction critical for the formation of a functional theca.

Authors: Hanaoka H, Nakajima T, Sato K, Watanabe R, Phung Y, Gao W, Harada T, Kim I, Paik CH, Choyke PL, Ho M, Kobayashi H

Journal: Nanomedicine (Lond). 2015 Apr;10(7):1139-47. doi: 10.2217/nnm.14.194

AIM: Effectiveness of Glypican-3 (GPC3)-targeted photoimmunotherapy (PIT) combined with the nanoparticle albumin-bound paclitaxel (nab-paclitaxel) for hepatocellular carcinoma was evaluated.

MATERIALS & METHODS: GPC3 expressing A431/G1 cells were incubated with a phthalocyanine-derivative, IRDye700DX (IR700), conjugated to an anti-GPC3 antibody, IR700-YP7 and exposed to near-infrared light. Therapeutic experiments combining GPC3-targeted PIT with nab-paclitaxel were performed in A431/G1 tumor-bearing mice.

RESULTS: IR700-YP7 bound to A431/G1 cells and induced rapid target-specific necrotic cell death by near-infrared light exposure in vitro. IR700-YP7 accumulated in A431/G1 tumors. Tumor growth was inhibited by PIT compared with nontreated control. Additionally, PIT dramatically increased nab-paclitaxel delivery and enhanced the therapeutic effect.

CONCLUSION: PIT targeting GPC3 combined with nab-paclitaxel is a promising method for treating hepatocellular carcinoma.

Authors: Machiela MJ, Zhou W, Sampson JN, Dean MC, Jacobs KB, Black A, Brinton LA, Chang IS, Chen C, Chen C, Chen K, Cook LS, Crous Bou M, De Vivo I, Doherty J, Friedenreich CM, Gaudet MM, Haiman CA, Hankinson SE, Hartge P, Henderson BE, Hong YC, Hosgood HD 3rd, Hsiung CA, Hu W, Hunter DJ, Jessop L, Kim HN, Kim YH, Kim YT, Klein R, Kraft P, Lan Q, Lin D, Liu J, Le Marchand L, Liang X, Lissowska J, Lu L, Magliocco AM, Matsuo K, Olson SH, Orlow I, Park JY, Pooler L, Prescott J, Rastogi R, Risch HA, Schumacher F, Seow A, Setiawan VW, Shen H, Sheng X, Shin MH, Shu XO, VanDen Berg D, Wang JC, Wentzensen N, Wong MP, Wu C, Wu T, Wu YL, Xia L, Yang HP, Yang PC, Zheng W, Zhou B, Abnet CC, Albanes D, Aldrich MC, Amos C, Amundadottir LT, Berndt SI, Blot WJ, Bock CH, Bracci PM, Burdett L, Buring JE, Butler MA, Carreón T, Chatterjee N, Chung CC, Cook MB, Cullen M, Davis FG, Ding T, Duell EJ, Epstein CG, Fan JH, Figueroa JD, Fraumeni JF Jr, Freedman ND, Fuchs CS, Gao YT, Gapstur SM, Patiño-Garcia A, Garcia-Closas M, Gaziano JM, Giles GG, Gillanders EM, Giovannucci EL, Goldin L, Goldstein AM, Greene MH, Hallmans G, Harris CC, Henriksson R, Holly EA, Hoover RN, Hu N, Hutchinson A, Jenab M, Johansen C, Khaw KT, Koh WP, Kolonel LN, Kooperberg C, Krogh V, Kurtz RC, LaCroix A, Landgren A, Landi MT, Li D, Liao LM, Malats N, McGlynn KA, McNeill LH, McWilliams RR, Melin BS, Mirabello L, Peplonska B, Peters U, Petersen GM, Prokunina-Olsson L, Purdue M, Qiao YL, Rabe KG, Rajaraman P, Real FX, Riboli E, Rodríguez-Santiago B, Rothman N, Ruder AM, Savage SA, Schwartz AG, Schwartz KL, Sesso HD, Severi G, Silverman DT, Spitz MR, Stevens VL, Stolzenberg-Solomon R, Stram D, Tang ZZ, Taylor PR, Teras LR, Tobias GS, Viswanathan K, Wacholder S, Wang Z, Weinstein SJ, Wheeler W, White E, Wiencke JK, Wolpin BM, Wu X, Wunder JS, Yu K, Zanetti KA, Zeleniuch-Jacquotte A, Ziegler RG, de Andrade M, Barnes KC, Beaty TH, Bierut LJ, Desch KC, Doheny KF, Feenstra B, Ginsburg D, Heit JA, Kang JH, Laurie CA, Li JZ, Lowe WL, Marazita ML, Melbye M, Mirel DB, Murray JC, Nelson SC, Pasquale LR, Rice K, Wiggs JL, Wise A, Tucker M, Pérez-Jurado LA, Laurie CC, Caporaso NE, Yeager M, Chanock SJ

Journal: Am J Hum Genet. 2015 Mar 5;96(3):487-97. doi: 10.1016/j.ajhg.2015.01.011

Analyses of genome-wide association study (GWAS) data have revealed that detectable genetic mosaicism involving large (>2 Mb) structural autosomal alterations occurs in a fraction of individuals. We present results for a set of 24,849 genotyped individuals (total GWAS set II [TGSII]) in whom 341 large autosomal abnormalities were observed in 168 (0.68%) individuals. Merging data from the new TGSII set with data from two prior reports (the Gene-Environment Association Studies and the total GWAS set I) generated a large dataset of 127,179 individuals; we then conducted a meta-analysis to investigate the patterns of detectable autosomal mosaicism (n = 1,315 events in 925 [0.73%] individuals). Restricting to events >2 Mb in size, we observed an increase in event frequency as event size decreased. The combined results underscore that the rate of detectable mosaicism increases with age (p value = 5.5 × 10(-31)) and is higher in men (p value = 0.002) but lower in participants of African ancestry (p value = 0.003). In a subset of 47 individuals from whom serial samples were collected up to 6 years apart, complex changes were noted over time and showed an overall increase in the proportion of mosaic cells as age increased. Our large combined sample allowed for a unique ability to characterize detectable genetic mosaicism involving large structural events and strengthens the emerging evidence of non-random erosion of the genome in the aging population.

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