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Frew JW
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The Hygiene Hypothesis, Old Friends, and New Genes

FRONTIERS IN IMMUNOLOGY 2019 MAR 6; 10(?):? Article 388
Hosking AM, Coakley BJ, Chang D, Talebi-Liasi F, Lish S, Lee SW, Zong AM, Moore I, Browning J, Jacques SL, Krueger JG, Kelly KM, Linden KG, Gareau DS
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Hyperspectral imaging in automated digital dermoscopy screening for melanoma

LASERS IN SURGERY AND MEDICINE 2019 MAR; 51(3):214-222
ObjectivesEarly melanoma detection decreases morbidity and mortality. Early detection classically involves dermoscopy to identify suspicious lesions for which biopsy is indicated. Biopsy and histological examination then diagnose benign nevi, atypical nevi, or cancerous growths. With current methods, a considerable number of unnecessary biopsies are performed as only 11% of all biopsied, suspicious lesions are actually melanomas. Thus, there is a need for more advanced noninvasive diagnostics to guide the decision of whether or not to biopsy. Artificial intelligence can generate screening algorithms that transform a set of imaging biomarkers into a risk score that can be used to classify a lesion as a melanoma or a nevus by comparing the score to a classification threshold. Melanoma imaging biomarkers have been shown to be spectrally dependent in Red, Green, Blue (RGB) color channels, and hyperspectral imaging may further enhance diagnostic power. The purpose of this study was to use the same melanoma imaging biomarkers previously described, but over a wider range of wavelengths to determine if, in combination with machine learning algorithms, this could result in enhanced melanoma detection. MethodsWe used the melanoma advanced imaging dermatoscope (mAID) to image pigmented lesions assessed by dermatologists as requiring a biopsy. The mAID is a 21-wavelength imaging device in the 350-950nm range. We then generated imaging biomarkers from these hyperspectral dermoscopy images, and, with the help of artificial intelligence algorithms, generated a melanoma Q-score for each lesion (0=nevus, 1=melanoma). The Q-score was then compared to the histopathologic diagnosis. ResultsThe overall sensitivity and specificity of hyperspectral dermoscopy in detecting melanoma when evaluated in a set of lesions selected by dermatologists as requiring biopsy was 100% and 36%, respectively. ConclusionWith widespread application, and if validated in larger clinical trials, this non-invasive methodology could decrease unnecessary biopsies and potentially increase life-saving early detection events. Lasers Surg. Med. 51:214-222, 2019. (c) 2019 The Authors. Lasers in Surgery and Medicine Published by Wiley Periodicals, Inc.
Dominguez S, Flores-Montoya MG, Sobin C
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Early chronic exposure to low-level lead alters total hippocampal microglia in pre-adolescent mice

TOXICOLOGY LETTERS 2019 MAR 1; 302(?):75-82
Developmental lead (Pb) exposure alters brain function through mechanisms that are not yet understood. A previous study showed that early lead exposure reduced microglia number in the dentate gyrus region of the hippocampus. Given the critical role of microglia in brain development, it is important to determine whether these differences are unique to the dentate gyrus, or occur throughout the hippocampus. Unbiased stereology was used to quantify microglia mean cell body number in total hippocampus, and compare the proportion of microglia in the ventral vs. dorsal regions. Total hippocampal volume was also measured and compared. The study included brain tissue from 30 pre-adolescent C57BL/6 J mice, exposed to 30 ppm Pb acetate (n = 10, mean BLL 3.4 mu g/dL at sacrifice), 330 ppm Pb acetate (n = 10, mean BLL 14.1 mu g/dL at sacrifice), or 0 ppm Pb acetate (n = 10, negative controls). In lead exposed animals, microglia mean cell body number was reduced in total hippocampus; total hippocampal volume was reduced. Importantly, effects in low-and high-dose exposure groups did not differ. Contrary to study hypotheses, the distribution of hippocampal microglia in the ventral vs. dorsal hippocampal regions did not differ. Overall, lowest and higher levels of lead exposure during development had strikingly similar disruptive effects in the neuroimmune system. Studies are needed to determine the immune and other mechanisms responsible for these effects. Future studies would benefit from larger samples to determine whether in fact there is a group by sex interaction driving the effects of early lead exposure on microglia.
Birsoy K, Sancak Y
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The role of metabolism in cellular processes

MOLECULAR BIOLOGY OF THE CELL 2019 MAR 15; 30(6):733-733
Mazzu YZ, Hu YL, Shen YW, Tuschl T, Singer S
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miR-193b regulates tumorigenesis in liposarcoma cells via PDGFR, TGF beta, and Wnt signaling

SCIENTIFIC REPORTS 2019 MAR 1; 9(?):? Article 3197
Liposarcoma is the most common soft tissue sarcoma. Molecularly targeted therapeutics have had limited efficacy in liposarcomas, in part because of inadequate knowledge of the complex molecular alterations in these tumors. Our recent study revealed the tumor suppressive function of miR-193b in liposarcoma. Considering the biological and clinical heterogeneity of liposarcoma, here, we confirmed the under-expression of miR-193b in additional patient liposarcoma samples and cell lines. Based on STRING analysis of protein-protein interactions among the reported putative miR-193b targets, we validated three: PDGFR beta, SMAD4, and YAP1, belonging to strongly interacting pathways (focal adhesion, TGF beta, and Hippo, respectively). We show that all three are directly targeted by miR-193b in liposarcoma. Inhibition of PDGFR beta reduces liposarcoma cell viability and increases adipogenesis. Knockdown of SMAD4 promotes adipogenic differentiation. miR-193b targeting of the Hippo signaling effector YAP1 indirectly inhibits Wnt/beta-catenin signaling. Both a PDGFR inhibitor (CP-673451) and a Wnt/beta-catenin inhibitor (ICG-001) had potent inhibitory effects on liposarcoma cells, suggesting their potential application in liposarcoma treatment. In summary, we demonstrate that miR-193b controls cell growth and differentiation in liposarcoma by targeting multiple key components (PDGFR beta, SMAD4, and YAP1) in several oncogenic signaling pathways.
Braun DA, Warejko JK, Ashraf S, Tan WZ, Daga A, Schneider R, Hermle T, Jobst-Schwan T, Widmeier E, Majmundar AJ, Nakayama M, Schapiro D, Rao J, Schmidt JM, Hoogstraten CA, Hugo H, Bakkaloglu SA, Kari JA, El Desoky S, Daouk G, Mane S, Lifton RP, Shril S, Hildebrandt F
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Genetic variants in the LAMA5 gene in pediatric nephrotic syndrome

NEPHROLOGY DIALYSIS TRANSPLANTATION 2019 MAR; 34(3):485-493
Background Nephrotic syndrome (NS), a chronic kidney disease, is characterized by significant loss of protein in the urine causing hypoalbuminemia and edema. In general, approximate to 15% of childhood-onset cases do not respond to steroid therapy and are classified as steroid-resistant NS (SRNS). In approximate to 30% of cases with SRNS, a causative mutation can be detected in one of 44 monogenic SRNS genes. The gene LAMA5 encodes laminin-5, an essential component of the glomerular basement membrane. Mice with a hypomorphic mutation in the orthologous gene Lama5 develop proteinuria and hematuria. Methods To identify additional monogenic causes of NS, we performed whole exome sequencing in 300 families with pediatric NS. In consanguineous families we applied homozygosity mapping to identify genomic candidate loci for the underlying recessive mutation. Results In three families, in whom mutations in known NS genes were excluded, but in whom a recessive, monogenic cause of NS was strongly suspected based on pedigree information, we identified homozygous variants of unknown significance (VUS) in the gene LAMA5. While all affected individuals had nonsyndromic NS with an early onset of disease, their clinical outcome and response to immunosuppressive therapy differed notably. Conclusion We here identify recessive VUS in the gene LAMA5 in patients with partially treatment-responsive NS. More data will be needed to determine the impact of these VUS in disease management. However, familial occurrence of disease, data from genetic mapping and a mouse model that recapitulates the NS phenotypes suggest that these genetic variants may be inherited factors that contribute to the development of NS in pediatric patients.
Farrelly LA, Thompson RE, Zhao S, Lepack AE, Lyu Y, Bhanu NV, Zhang BC, Loh YHE, Ramakrishnan A, Vadodaria KC, Heard KJ, Erikson G, Nakadai T, Bastle RM, Lukasak BJ, Zebroski H, Alenina N, Bader M, Berton O, Roeder RG, Molina H, Gage FH, Shen L, Garcia BA, Li HT, Muir TW, Maze I
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Histone serotonylation is a permissive modification that enhances TFIID binding to H3K4me3

NATURE 2019 MAR 28; 567(7749):535-539
Chemical modifications of histones can mediate diverse DNA-templated processes, including gene transcription(1-3). Here we provide evidence for a class of histone post-translational modification, serotonylation of glutamine, which occurs at position 5 (Q5ser) on histone H3 in organisms that produce serotonin (also known as 5-hydroxytryptamine (5-HT)). We demonstrate that tissue transglutaminase 2 can serotonylate histone H3 tri-methylated lysine 4 (H3K4me3)-marked nucleosomes, resulting in the presence of combinatorial H3K4me3Q5ser in vivo. H3K4me3Q5ser displays a ubiquitous pattern of tissue expression in mammals, with enrichment observed in brain and gut, two organ systems responsible for the bulk of 5-HT production. Genome-wide analyses of human serotonergic neurons, developing mouse brain and cultured serotonergic cells indicate that H3K4me3Q5ser nucleosomes are enriched in euchromatin, are sensitive to cellular differentiation and correlate with permissive gene expression, phenomena that are linked to the potentiation of TFIID4-6 interactions with H3K4me3. Cells that ectopically express a H3 mutant that cannot be serotonylated display significantly altered expression of H3K4me3Q5ser-target loci, which leads to deficits in differentiation. Taken together, these data identify a direct role for 5-HT, independent from its contributions to neurotransmission and cellular signalling, in the mediation of permissive gene expression.
Krause BS, Kaufmann JCD, Kuhne J, Vierock J, Huber T, Sakmar TP, Gerwert K, Bartl FJ, Hegemann P
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Tracking Pore Hydration in Channelrhodopsin by Site-Directed Infrared-Active Azido Probes

BIOCHEMISTRY 2019 MAR 5; 58(9):1275-1286
In recent years, gating and transient ion-pathway formation in the light-gated channelrhodopsins (ChRs) have been intensively studied. Despite these efforts, a profound understanding of the mechanistic details is still lacking. To track structural changes concomitant with the formation and subsequent collapse of the ion-conducting pore, we site-specifically introduced the artificial polarity-sensing probe p-azido-L-phenylalanine (azF) into several ChRs by amber stop codon suppression. The frequently used optogenetic actuator ReaChR (red-activatable ChR) exhibited the best expression properties of the wild type and the azF mutants. By exploiting the unique infrared spectral absorption of azF [nu(as) (N-3) similar to 2100 cm(-1)] and its sensitivity to polarity changes, we monitored hydration changes at various sites of the pore region and the inner gate by stationary and time-resolved infrared spectroscopy. Our data imply that channel closure coincides with a dehydration event occurring between the interface of the central and the inner gate. In contrast, the extracellular ion pathway seems to be hydrated in the open and closed states to similar extents. Mutagenesis of sites in the inner gate suggests that it acts as an intracellular entry funnel, whose architecture and composition modulate water influx and efflux within the channel pore. Our results highlight the potential of genetic code expansion technology combined with biophysical methods to investigate channel gating, particularly hydration dynamics at specific sites, with a so far unprecedented spatial resolution.
Lewy T, Hong BY, Weiser B, Burger H, Tremain A, Weinstock G, Anastos K, George MD
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Oral Microbiome in HIV-Infected Women: Shifts in the Abundance of Pathogenic and Beneficial Bacteria Are Associated with Aging, HIV Load, CD4 Count, and Antiretroviral Therapy

AIDS RESEARCH AND HUMAN RETROVIRUSES 2019 MAR; 35(3):276-286
Human immunodeficiency virus (HIV)-associated nonacquired immunodeficiency syndrome (AIDS) conditions, such as cardiovascular disease, diabetes, osteoporosis, and dementia are more prevalent in older than in young adult HIV-infected subjects. Although the oral microbiome has been studied as a window into pathogenesis in aging populations, its relationship to HIV disease progression, opportunistic infections, and HIV-associated non-AIDS conditions is not well understood. We utilized 16S rDNA-based pyrosequencing to compare the salivary microbiome in three groups: (1) Chronically HIV-infected women >50 years of age (aging); (2) HIV-infected women <35 years of age (young adult); and (3) HIV-uninfected age-matched women. We also examined correlations between salivary dysbiosis, plasma HIV RNA, CD4(+) T cell depletion, and opportunistic oral infections. In both aging and young adult women, HIV infection was associated with salivary dysbiosis characterized by increased abundance of Prevotella melaninogenica and Rothia mucilaginosa. Aging was associated with increased bacterial diversity in both uninfected and HIV-infected women. In HIV-infected women with oral coinfections, aging was also associated with reduced abundance of the common commensal Veillonella parvula. Patients taking antiretroviral therapy showed increased numbers of Neisseria and Haemophilus. High plasma HIV RNA levels correlated positively with the presence of Prevotella and Veillonella, and negatively with the abundance of potentially beneficial Streptococcus and Lactobacillus. Circulating CD4(+) T cell numbers correlated positively with the abundance of Streptococcus and Lactobacillus. Our findings extend previous studies of the role of the microbiome in HIV pathogenesis, providing new evidence that HIV infection is associated with a shift toward an increased pathogenic footprint of the salivary microbiome. Taken together, the data suggest a complex relationship, worthy of additional study, between chronic dysbiosis in the oral cavity, aging, viral burden, CD4(+) T cell depletion, and long-term antiretroviral therapy.
Aaltonen T, Amerio S, Amidei D, Anastassov A, Annovi A, Antos J, Apollinari G, Appel JA, Arisawa T, Artikov A, Asaadi J, Ashmanskas W, Auerbach B, Aurisano A, Azfar F, Badgett W, Bae T, Barbaro-Galtieri A, Barnes VE, Barnett BA, Barria P, Bartos P, Bauce M, Bedeschi F, Behari S, Bellettini G, Bellinger J, Benjamin D, Beretvas A, Bhatti A, Bland KR, Blumenfeld B, Bocci A, Bodek A, Bortoletto D, Boudreau J, Boveia A, Brigliadori L, Bromberg C, Brucken E, Budagov J, Budd HS, Burkett K, Busetto G, Bussey P, Butti P, Buzatu A, Calamba A, Camarda S, Campanelli M, Canelli F, Carls B, Carlsmith D, Carosi R, Carrillo S, Casal B, Casarsa M, Castro A, Catastini P, Cauz D, Cavaliere V, Cerri A, Cerrito L, Chen YC, Chertok M, Chiarelli G, Chlachidze G, Cho K, Chokheli D, Clark A, Clarke C, Convery ME, Conway J, Corbo M, Cordelli M, Cox CA, Cox DJ, Cremonesi M, Cruz D, Cuevas J, Culbertson R, d'Ascenzo N, Datta M, de Barbaro P, Demortier L, Deninno M, D'Errico M, Devoto F, Di Canto A, Di Ruzza B, Dittmann JR, Donati S, D'Onofrio M, Dorigo M, Driutti A, Ebina K, Edgar R, Elagin A, Erbacher R, Errede S, Esham B, Farrington S, Ramos JPF, Field R, Flanagan G, Forrest R, Franklin M, Freeman JC, Frisch H, Funakoshi Y, Galloni C, Garfinkel AF, Garosi P, Gerberich H, Gerchtein E, Giagu S, Giakoumopoulou V, Gibson K, Ginsburg CM, Giokaris N, Giromini P, Glagolev V, Glenzinski D, Gold M, Goldin D, Golossanov A, Gomez G, Gomez-Ceballos G, Goncharov M, Lopez OG, Gorelov I, Goshaw AT, Goulianos K, Gramellini E, Grosso-Pilcher C, da Costa JG, Hahn SR, Han JY, Happacher F, Hara K, Hare M, Harr RF, Harrington-Taber T, Hatakeyama K, Hays C, Heinrich J, Herndon M, Hocker A, Hong Z, Hopkins W, Hou S, Hughes RE, Husemann U, Hussein M, Huston J, Introzzi G, Iori M, Ivanov A, James E, Jang D, Jayatilaka B, Jeon EJ, Jindariani S, Jones M, Joo KK, Jun SY, Junk TR, Kambeitz M, Kamon T, Karchin PE, Kasmi A, Kato Y, Ketchum W, Keung J, Kilminster B, Kim DH, Kim HS, Kim JE, Kim MJ, Kim SH, Kim SB, Kim YJ, Kim YK, Kimura N, Kirby M, Kondo K, Kong DJ, Konigsberg J, Kotwal AV, Kreps M, Kroll J, Kruse M, Kuhr T, Kurata M, Laasanen AT, Lammel S, Lancaster M, Lannon K, Latino G, Lee HS, Lee JS, Leo S, Leone S, Lewis JD, Limosani A, Lipeles E, Lister A, Liu Q, Liu T, Lockwitz S, Loginov A, Lucchesi D, Luca A, Lueck J, Lujan P, Lukens P, Lungu G, Lys J, Lysak R, Madrak R, Maestro P, Malik S, Manca G, Manousakis-Katsikakis A, Marchese L, Margaroli F, Marino P, Matera K, Mattson ME, Mazzacane A, Mazzanti P, McNulty R, Mehta A, Mehtala P, Mesropian C, Miao T, Michielin E, Mietlicki D, Mitra A, Miyake H, Moed S, Moggi N, Moon CS, Moore R, Morello MJ, Mukherjee A, Muller T, Murat P, Mussini M, Nachtman J, Nagai Y, Naganoma J, Nakano I, Napier A, Nett J, Nigmanov T, Nodulman L, Noh SY, Norniella O, Oakes L, Oh SH, Oh YD, Okusawa T, Orava R, Ortolan L, Pagliarone C, Palencia E, Palni P, Papadimitriou V, Parker W, Pauletta G, Paulini M, Paus C, Phillips TJ, Piacentino G, Pianori E, Pilot J, Pitts K, Plager C, Pondrom L, Poprocki S, Potamianos K, Pranko A, Prokoshin F, Ptohos F, Punzi G, Fernandez IR, Renton P, Rescigno M, Rimondi F, Ristori L, Robson A, Rodriguez T, Rolli S, Ronzani M, Roser R, Rosner JL, Ruffini F, Ruiz A, Russ J, Rusu V, Sakumoto WK, Sakurai Y, Santi L, Sato K, Saveliev V, Savoy-Navarro A, Schlabach P, Schmidt EE, Schwarz T, Scodellaro L, Scuri F, Seidel S, Seiya Y, Semenov A, Sforza F, Shalhout SZ, Shears T, Shepard PF, Shimojima M, Shochet M, Shreyber-Tecker I, Simonenko A, Sliwa K, Smith JR, Snider FD, Song H, Sorin V, St Denis R, Stancari M, Stentz D, Strologas J, Sudo Y, Sukhanov A, Suslov I, Takemasa K, Takeuchi Y, Tang J, Tecchio M, Teng PK, Thom J, Thomson E, Thukral V, Toback D, Tokar S, Tollefson K, Tomura T, Tonelli D, Torre S, Torretta D, Totaro P, Trovato M, Ukegawa F, Uozumi S, Vazquez F, Velev G, Vellidis C, Vernieri C, Vidal M, Vilar R, Vizan J, Vogel M, Volpi G, Wagner P, Wallny R, Wang SM, Waters D, Wester WC, Whiteson D, Wicklund AB, Wilbur S, Williams HH, Wilson JS, Wilson P, Winer BL, Wittich P, Wolbers S, Wolfmeister H, Wright T, Wu X, Wu Z, Yamamoto K, Yamato D, Yang T, Yang UK, Yang YC, Yao WM, Yeh GP, Yi K, Yoh J, Yorita K, Yoshida T, Yu GB, Yu I, Zanetti AM, Zeng Y, Zhou C, Zucchelli S
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Search for Higgs-like particles produced in association with bottom quarks in proton-antiproton collisions

PHYSICAL REVIEW D 2019 MAR 12; 99(5):? Article 052001
We report on a search for a spin-zero non-standard model particle in proton-antiproton collisions collected by the Collider Detector at Fermilab at a center-of-mass-energy of 1.96 TeV. This particle, the phi boson, is expected to decay into a bottom-antibottom quark pair and to be produced in association with at least one bottom quark. The data sample consists of events with three jets identified as initiated by bottom quarks and corresponds to 5.4 fb(-1) of integrated luminosity. In each event, the invariant mass of the two most energetic jets is studied by looking for deviations from the multijet background, which is modeled using data. No evidence is found for such a particle. Exclusion upper limits ranging from 20 to 2 pb are set for the product of production cross sections times branching fraction for the hypothetical phi boson with mass between 100 and 300 GeV/c(2). These are the most stringent constraints to date.