Texas A&M University System

categorical data analysis , categorical data analysis , کتابخانه مرکزی دانشگاه علوم پزشکی تهران

AUTORES: Daniel J Klionsky1745,1749*, Kotb Abdelmohsen840, Akihisa Abe1237, Md Joynal Abedin1762, Hagai Abeliovich425,
\nAbraham Acevedo Arozena789, Hiroaki Adachi1800, Christopher M Adams1669, Peter D Adams57, Khosrow Adeli1981,
\nPeter J Adhihetty1625, Sharon G Adler700, Galila Agam67, Rajesh Agarwal1587, Manish K Aghi1537, Maria Agnello1826,
\nPatrizia Agostinis664, Patricia V Aguilar1960, Julio Aguirre-Ghiso784,786, Edoardo M Airoldi89,422, Slimane Ait-Si-Ali1376,
\nTakahiko Akematsu2010, Emmanuel T Akporiaye1097, Mohamed Al-Rubeai1394, Guillermo M Albaiceta1294,
\nChris Albanese363, Diego Albani561, Matthew L Albert517, Jesus Aldudo128, Hana Alg€ul1164, Mehrdad Alirezaei1198,
\nIraide Alloza642,888, Alexandru Almasan206, Maylin Almonte-Beceril524, Emad S Alnemri1212, Covadonga Alonso544,
\nNihal Altan-Bonnet848, Dario C Altieri1205, Silvia Alvarez1497, Lydia Alvarez-Erviti1395, Sandro Alves107,
\nGiuseppina Amadoro860, Atsuo Amano930, Consuelo Amantini1554, Santiago Ambrosio1458, Ivano Amelio756,
\nAmal O Amer918, Mohamed Amessou2089, Angelika Amon726, Zhenyi An1538, Frank A Anania291, Stig U Andersen6,
\nUsha P Andley2079, Catherine K Andreadi1690, Nathalie Andrieu-Abadie502, Alberto Anel2027, David K Ann58,
\nShailendra Anoopkumar-Dukie388, Manuela Antonioli832,858, Hiroshi Aoki1791, Nadezda Apostolova2007,
\nSaveria Aquila1500, Katia Aquilano1876, Koichi Araki292, Eli Arama2098, Agustin Aranda456, Jun Araya591,
\nAlexandre Arcaro1472, Esperanza Arias26, Hirokazu Arimoto1225, Aileen R Ariosa1749, Jane L Armstrong1930,
\nThierry Arnould1773, Ivica Arsov2120, Katsuhiko Asanuma675, Valerie Askanas1924, Eric Asselin1867, Ryuichiro Atarashi794,
\nSally S Atherton369, Julie D Atkin713, Laura D Attardi1131, Patrick Auberger1787, Georg Auburger379, Laure Aurelian1727,
\nRiccardo Autelli1992, Laura Avagliano1029,1755, Maria Laura Avantaggiati364, Limor Avrahami1166, Suresh Awale1986,
\nNeelam Azad404, Tiziana Bachetti568, Jonathan M Backer28, Dong-Hun Bae1933, Jae-sung Bae677, Ok-Nam Bae409,
\nSoo Han Bae2117, Eric H Baehrecke1729, Seung-Hoon Baek17, Stephen Baghdiguian1368,
\nAgnieszka Bagniewska-Zadworna2, Hua Bai90, Jie Bai667, Xue-Yuan Bai1133, Yannick Bailly884,
\nKithiganahalli Narayanaswamy Balaji473, Walter Balduini2002, Andrea Ballabio316, Rena Balzan1711, Rajkumar Banerjee239,
\nG abor B anhegyi1052, Haijun Bao2109, Benoit Barbeau1363, Maria D Barrachina2007, Esther Barreiro467, Bonnie Bartel997,
\nAlberto Bartolom e222, Diane C Bassham550, Maria Teresa Bassi1046, Robert C Bast Jr1273, Alakananda Basu1798,
\nMaria Teresa Batista1578, Henri Batoko1336, Maurizio Battino970, Kyle Bauckman2085, Bradley L Baumgarner1909,
\nK Ulrich Bayer1594, Rupert Beale1553, Jean-Fran¸cois Beaulieu1360, George R. Beck Jr48,294, Christoph Becker336,
\nJ David Beckham1595, Pierre-Andr e B edard749, Patrick J Bednarski301, Thomas J Begley1135, Christian Behl1419,
\nChristian Behrends757, Georg MN Behrens406, Kevin E Behrns1627, Eloy Bejarano26, Amine Belaid490,
\nFrancesca Belleudi1041, Giovanni B enard497, Guy Berchem706, Daniele Bergamaschi983, Matteo Bergami1401,
\nBen Berkhout1441, Laura Berliocchi714, Am elie Bernard1749, Monique Bernard1354, Francesca Bernassola1880,
\nAnne Bertolotti791, Amanda S Bess272, S ebastien Besteiro1351, Saverio Bettuzzi1828, Savita Bhalla913,
\nShalmoli Bhattacharyya973, Sujit K Bhutia838, Caroline Biagosch1159, Michele Wolfe Bianchi520,1378,1381,
\nMartine Biard-Piechaczyk210, Viktor Billes298, Claudia Bincoletto1314, Baris Bingol350, Sara W Bird1128, Marc Bitoun1112,
\nIvana Bjedov1258, Craig Blackstone843, Lionel Blanc1183, Guillermo A Blanco1496, Heidi Kiil Blomhoff1812,
\nEmilio Boada-Romero1297, Stefan B€ockler1464, Marianne Boes1423, Kathleen Boesze-Battaglia1835, Lawrence H Boise286,287,
\nAlessandra Bolino2063, Andrea Boman693, Paolo Bonaldo1823, Matteo Bordi897, J€urgen Bosch608, Luis M Botana1308,
\nJoelle Botti1375, German Bou1405, Marina Bouch e1038, Marion Bouchecareilh1331, Marie-Jos ee Boucher1901,
\nMichael E Boulton481, Sebastien G Bouret1926, Patricia Boya133, Micha€el Boyer-Guittaut1345, Peter V Bozhkov1141,
\nNathan Brady374, Vania MM Braga469, Claudio Brancolini1997, Gerhard H Braus353, Jos e M Bravo-San Pedro299,393,508,1374,
\nLisa A Brennan322, Emery H Bresnick2022, Patrick Brest490, Dave Bridges1939, Marie-Agn es Bringer124, Marisa Brini1822,
\nGlauber C Brito1311, Bertha Brodin631, Paul S Brookes1872, Eric J Brown352, Karen Brown1690, Hal E Broxmeyer480,
\nAlain Bruhat486,1339, Patricia Chakur Brum1893, John H Brumell446, Nicola Brunetti-Pierri315,1171,
\nRobert J Bryson-Richardson781, Shilpa Buch1777, Alastair M Buchan1819, Hikmet Budak1022, Dmitry V Bulavin118,505,1789,
\nScott J Bultman1792, Geert Bultynck665, Vladimir Bumbasirevic1470, Yan Burelle1356, Robert E Burke216,217,
\nMargit Burmeister1750, Peter B€utikofer1473, Laura Caberlotto1987, Ken Cadwell896, Monika Cahova112, Dongsheng Cai24,
\nJingjing Cai2099, Qian Cai1018, Sara Calatayud2007, Nadine Camougrand1343, Michelangelo Campanella1700,
\nGrant R Campbell1525, Matthew Campbell1249, Silvia Campello556,1876, Robin Candau1769, Isabella Caniggia1983,
\nLavinia Cantoni560, Lizhi Cao116, Allan B Caplan1656, Michele Caraglia1051, Claudio Cardinali1043, Sandra Morais Cardoso1579, Jennifer S Carew208, Laura A Carleton874, Cathleen R Carlin101, Silvia Carloni2002,
\nSven R Carlsson1267, Didac Carmona-Gutierrez1643, Leticia AM Carneiro312, Oliana Carnevali971, Serena Carra1318,
\nAlice Carrier120, Bernadette Carroll900, Caty Casas1324, Josefina Casas1116, Giuliana Cassinelli324, Perrine Castets1462,
\nSusana Castro-Obregon214, Gabriella Cavallini1841, Isabella Ceccherini568, Francesco Cecconi253,555,1884,
\nArthur I Cederbaum459, Valent ın Ce~na199,1281, Simone Cenci1323,2064, Claudia Cerella444, Davide Cervia1996,
\nSilvia Cetrullo1478, Hassan Chaachouay2028, Han-Jung Chae187, Andrei S Chagin634, Chee-Yin Chai626,628,
\nGopal Chakrabarti1502, Georgios Chamilos1601, Edmond YW Chan1142, Matthew TV Chan181, Dhyan Chandra1003,
\nPallavi Chandra548, Chih-Peng Chang818, Raymond Chuen-Chung Chang1653, Ta Yuan Chang345, John C Chatham1434,
\nSaurabh Chatterjee1910, Santosh Chauhan527, Yongsheng Che62, Michael E Cheetham1263, Rajkumar Cheluvappa1783,
\nChun-Jung Chen1153, Gang Chen598,1676, Guang-Chao Chen9, Guoqiang Chen1078, Hongzhuan Chen1077, Jeff W Chen1514,
\nJian-Kang Chen370,371, Min Chen249, Mingzhou Chen2104, Peiwen Chen1823, Qi Chen1674, Quan Chen172,
\nShang-Der Chen138, Si Chen325, Steve S-L Chen10, Wei Chen2125, Wei-Jung Chen829, Wen Qiang Chen979, Wenli Chen1113,
\nXiangmei Chen1133, Yau-Hung Chen1157, Ye-Guang Chen1250, Yin Chen1447, Yingyu Chen953,955, Yongshun Chen2135,
\nYu-Jen Chen712, Yue-Qin Chen1145, Yujie Chen1208, Zhen Chen339, Zhong Chen2123, Alan Cheng1702,
\nChristopher HK Cheng184, Hua Cheng1728, Heesun Cheong814, Sara Cherry1836, Jason Chesney1703,
\nChun Hei Antonio Cheung817, Eric Chevet1359, Hsiang Cheng Chi140, Sung-Gil Chi656, Fulvio Chiacchiera308,
\nHui-Ling Chiang958, Roberto Chiarelli1826, Mario Chiariello235,567,577, Marcello Chieppa835, Lih-Shen Chin290,
\nMario Chiong1285, Gigi NC Chiu878, Dong-Hyung Cho676, Ssang-Goo Cho650, William C Cho982, Yong-Yeon Cho105,
\nYoung-Seok Cho1064, Augustine MK Choi2095, Eui-Ju Choi656, Eun-Kyoung Choi387,400,685, Jayoung Choi1563,
\nMary E Choi2093, Seung-Il Choi2116, Tsui-Fen Chou412, Salem Chouaib395, Divaker Choubey1574, Vinay Choubey1936,
\nKuan-Chih Chow822, Kamal Chowdhury730, Charleen T Chu1856, Tsung-Hsien Chuang827, Taehoon Chun657,
\nHyewon Chung652, Taijoon Chung978, Yuen-Li Chung1194, Yong-Joon Chwae18, Valentina Cianfanelli254,
\nRoberto Ciarcia1775, Iwona A Ciechomska886, Maria Rosa Ciriolo1876, Mara Cirone1042, Sofie Claerhout1694,
\nMichael J Clague1698, Joan Cl aria1457, Peter GH Clarke1687, Robert Clarke361, Emilio Clementi1045,1398, C edric Cleyrat1781,
\nMiriam Cnop1366, Eliana M Coccia574, Tiziana Cocco1459, Patrice Codogno1375, J€orn Coers271, Ezra EW Cohen1533,
\nDavid Colecchia235,567,577, Luisa Coletto25, N uria S Coll123, Emma Colucci-Guyon516, Sergio Comincini1829,
\nMaria Condello578, Katherine L Cook2073, Graham H Coombs1929, Cynthia D Cooper2076, J Mark Cooper1395,
\nIsabelle Coppens601, Maria Tiziana Corasaniti1387, Marco Corazzari485,1884, Ramon Corbalan1566,
\nElisabeth Corcelle-Termeau251, Mario D Cordero1899, Cristina Corral-Ramos1289, Olga Corti507,1109, Andrea Cossarizza1767,
\nPaola Costelli1993, Safia Costes1518, Susan L Cotman721, Ana Coto-Montes946, Sandra Cottet566,1688, Eduardo Couve1301,
\nLori R Covey1015, L Ashley Cowart762, Jeffery S Cox1536, Fraser P Coxon1427, Carolyn B Coyne1846, Mark S Cragg1919,
\nRolf J Craven1679, Tiziana Crepaldi1995, Jose L Crespo1300, Alfredo Criollo1285, Valeria Crippa558, Maria Teresa Cruz1576,
\nAna Maria Cuervo26, Jose M Cuezva1277, Taixing Cui1907, Pedro R Cutillas987, Mark J Czaja27, Maria F Czyzyk-Krzeska1572,
\nRuben K Dagda2068, Uta Dahmen1404, Chunsun Dai800, Wenjie Dai1187, Yun Dai2059, Kevin N Dalby1940,
\nLuisa Dalla Valle1822, Guillaume Dalmasso1340, Marcello D’Amelio557, Markus Damme188, Arlette Darfeuille-Michaud1340,
\nCatherine Dargemont950, Victor M Darley-Usmar1433, Srinivasan Dasarathy205, Biplab Dasgupta202, Srikanta Dash1254,
\nCrispin R Dass242, Hazel Marie Davey8, Lester M Davids1560, David D avila227, Roger J Davis1731, Ted M Dawson604,
\nValina L Dawson606, Paula Daza1898, Jackie de Belleroche470, Paul de Figueiredo1180,1182,
\nRegina Celia Bressan Queiroz de Figueiredo135, Jos e de la Fuente1023, Luisa De Martino1775,
\nAntonella De Matteis1171, Guido RY De Meyer1443, Angelo De Milito631, Mauro De Santi2002,

Continued growth and intensification of aquaculture production depends upon the development of sustainable protein sources to replace fish meal in aquafeeds. This document reviews various plant feedstuffs, which currently are or potentially may be incorporated into aquafeeds to support the sustainable production of various fish species in aquaculture. The plant feedstuffs considered include oilseeds, legumes and cereal grains, which traditionally have been used as protein or energy concentrates as well as novel products developed through various processing technologies. The nutritional composition of these various feedstuffs are considered along with the presence of any bioactive compounds that may positively or negatively affect the target organism. Lipid composition of these feedstuffs is not specifically considered although it is recognized that incorporating lipid supplements in aquafeeds to achieve proper fatty acid profiles to meet the metabolic requirements of fish and maximize human health benefits are important aspects. Specific strategies and techniques to optimize the nutritional composition of plant feedstuffs and limit potentially adverse effects of bioactive compounds are also described. Such information will provide a foundation for developing strategic research plans for increasing the use of plant feedstuffs in aquaculture to reduce dependence of animal feedstuffs and thereby enhance the sustainability of aquaculture.

BACKGROUND: Severe coronavirus disease 2019 (Covid-19) is associated with dysregulated inflammation. The effects of combination treatment with baricitinib, a Janus kinase inhibitor, plus remdesivir are not known. METHODS: We conducted a double-blind, randomized, placebo-controlled trial evaluating baricitinib plus remdesivir in hospitalized adults with Covid-19. All the patients received remdesivir (≤10 days) and either baricitinib (≤14 days) or placebo (control). The primary outcome was the time to recovery. The key secondary outcome was clinical status at day 15. RESULTS: A total of 1033 patients underwent randomization (with 515 assigned to combination treatment and 518 to control). Patients receiving baricitinib had a median time to recovery of 7 days (95% confidence interval [CI], 6 to 8), as compared with 8 days (95% CI, 7 to 9) with control (rate ratio for recovery, 1.16; 95% CI, 1.01 to 1.32; P = 0.03), and a 30% higher odds of improvement in clinical status at day 15 (odds ratio, 1.3; 95% CI, 1.0 to 1.6). Patients receiving high-flow oxygen or noninvasive ventilation at enrollment had a time to recovery of 10 days with combination treatment and 18 days with control (rate ratio for recovery, 1.51; 95% CI, 1.10 to 2.08). The 28-day mortality was 5.1% in the combination group and 7.8% in the control group (hazard ratio for death, 0.65; 95% CI, 0.39 to 1.09). Serious adverse events were less frequent in the combination group than in the control group (16.0% vs. 21.0%; difference, -5.0 percentage points; 95% CI, -9.8 to -0.3; P = 0.03), as were new infections (5.9% vs. 11.2%; difference, -5.3 percentage points; 95% CI, -8.7 to -1.9; P = 0.003). CONCLUSIONS: Baricitinib plus remdesivir was superior to remdesivir alone in reducing recovery time and accelerating improvement in clinical status among patients with Covid-19, notably among those receiving high-flow oxygen or noninvasive ventilation. The combination was associated with fewer serious adverse events. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT04401579.).

The electrocatalysis of the oxygen reduction reaction (ORR) on five binary Pi alloys (PtCr/C, P tMn/C, PtFe/C, PtCo/C, and PtNi/C) supported on high surface area carbon in a proton exchange membrane fuel cell was investigated. All the alloy electrocatalysts exhibited a high degree of crystallinity with the pr imary phase of the type P t3M (LI2 structure with fcc type lattice) and a secondary phase (only minor contribution f rom this phase) being of the type P tM (LIo structure with tetragonal lattice) as evidenced f rom x-ray powder diffraction (XRD) analysis. The electrode kinetic studies on the Pt alloys at 95 ~ and 5 a tm pressure showed a two- to threefold increase in the exchange current densities and the current density at 900 mV as well as a decrease in the overvoltage at i0 mA em-2 relative to Pt/C eleetrocatalyst. The P tCr /C alloy exhibited the best performance. I n s i tu EXAFS and XANES analysis at potentials in the double-layer region [0.54 V vs. reversible hydrogen electrode (RHE)] revealed (i) all the alloys possess higher Pt d-band vacancies per a tom (with the exception of P tMn/C alloy) relative to Pt/C electrocatalyst and (it) contractions in the Pt-Pt bond distances wh ich con-f i rmed the results f rom ex s i tu XRD analysis. A potential excursion to 0.84 V vs. RHE showed that, in contrast to the Pt alloys, the Pt/C electrocatalyst exhibits a significant increase in the Pt d-band vacancies per atom. This increase, in Pt/C has been rationalized as being due to adsorption of OH species f rom the electrolyte following a Temkin isotherm behavior, wh ich does not occur on the Pt alloys. Correlation of the electronic (Pt d-band vacancies) and geometric (Pt-Pt bond

Genetic regulation of mammalian heart size is poorly understood. Hippo signaling represents an organ-size control pathway in Drosophila, where it also inhibits cell proliferation and promotes apoptosis in imaginal discs. To determine whether Hippo signaling controls mammalian heart size, we inactivated Hippo pathway components in the developing mouse heart. Hippo-deficient embryos had overgrown hearts with elevated cardiomyocyte proliferation. Gene expression profiling and chromatin immunoprecipitation revealed that Hippo signaling negatively regulates a subset of Wnt target genes. Genetic interaction studies indicated that β-catenin heterozygosity suppressed the Hippo cardiomyocyte overgrowth phenotype. Furthermore, the Hippo effector Yap interacts with β-catenin on Sox2 and Snai2 genes. These data uncover a nuclear interaction between Hippo and Wnt signaling that restricts cardiomyocyte proliferation and controls heart size.

Neutrophil extracellular traps (NETs) are webs of DNA covered with antimicrobial molecules that constitute a newly described killing mechanism in innate immune defense. Previous publications reported that NETs take up to 3-4 h to form via an oxidant-dependent event that requires lytic death of neutrophils. In this study, we describe neutrophils responding uniquely to Staphylococcus aureus via a novel process of NET formation that did not require neutrophil lysis or even breach of the plasma membrane. The multilobular nucleus rapidly became rounded and condensed. During this process, we observed the separation of the inner and outer nuclear membranes and budding of vesicles, and the separated membranes and vesicles were filled with nuclear DNA. The vesicles were extruded intact into the extracellular space where they ruptured, and the chromatin was released. This entire process occurred via a unique, very rapid (5-60 min), oxidant-independent mechanism. Mitochondrial DNA constituted very little if any of these NETs. They did have a limited amount of proteolytic activity and were able to kill S. aureus. With time, the nuclear envelope ruptured, and DNA filled the cytoplasm presumably for later lytic NET production, but this was distinct from the vesicular release mechanism. Panton-Valentine leukocidin, autolysin, and a lipase were identified in supernatants with NET-inducing activity, but Panton-Valentine leukocidin was the dominant NET inducer. We describe a new mechanism of NET release that is very rapid and contributes to trapping and killing of S. aureus.

BACKGROUND: Delphi surveys with panels of experts in a particular area of interest have been widely utilized in the fields of clinical medicine, nursing practice, medical education and healthcare services. Despite this wide applicability of the Delphi methodology, there is no clear identification of what constitutes a sufficient number of Delphi survey participants to ensure stability of results. METHODS: The study analyzed the response characteristics from the first round of a Delphi survey conducted with 23 experts in healthcare quality and patient safety. The panel members had similar training and subject matter understanding of the Malcolm Baldrige Criteria for Performance Excellence in Healthcare. The raw data from the first round sampling, which usually contains the largest diversity of responses, were augmented via bootstrap sampling to obtain computer-generated results for two larger samples obtained by sampling with replacement. Response characteristics (mean, trimmed mean, standard deviation and 95% confidence intervals) for 54 survey items were compared for the responses of the 23 actual study participants and two computer-generated samples of 1000 and 2000 resampling iterations. RESULTS: The results from this study indicate that the response characteristics of a small expert panel in a well-defined knowledge area are stable in light of augmented sampling. CONCLUSION: Panels of similarly trained experts (who possess a general understanding in the field of interest) provide effective and reliable utilization of a small sample from a limited number of experts in a field of study to develop reliable criteria that inform judgment and support effective decision-making.

Clinical observations suggest a recent increase in intrahepatic biliary tract malignancies. Thus, our aim was to determine recent trends in the epidemiology of intrahepatic cholangiocarcinoma in the United States. Reported data from the Surveillance, Epidemiology, and End Results (SEER) program and the United States Vital Statistics databases were analyzed to determine the incidence, mortality, and survival rates of primary intrahepatic cholangiocarcinoma. Between 1973 and 1997, the incidence and mortality rates from intrahepatic cholangiocarcinoma markedly increased, with an estimated annual percent change (EAPC) of 9.11% (95% CI, 7.46 to 10.78) and 9.44% (95%, CI 8.46 to 10.41), respectively. The age-adjusted mortality rate per 100,000 persons for whites increased from 0.14 for the period 1975-1979 to 0.65 for the period 1993-1997, and that for blacks increased from 0.15 to 0.58 over the same period. The increase in mortality was similar across all age groups above age 45. The relative 1- and 2-year survival rates following diagnosis from 1989 to 1996 were 24.5% and 12.8%, respectively. In conclusion, there has been a marked increase in the incidence and mortality from intrahepatic cholangiocarcinoma in the United States in recent years. This tumor continues to be associated with a poor prognosis.

IMPLICATIONS: We present evidence-based guidelines developed by an international panel of experts for the management of postoperative nausea and vomiting.

Immune checkpoint blockade produces clinical benefit in many patients. However, better biomarkers of response are still needed, and mechanisms of resistance remain incompletely understood. To address this, we recently studied a cohort of melanoma patients treated with sequential checkpoint blockade against cytotoxic T lymphocyte antigen-4 (CTLA-4) followed by programmed death receptor-1 (PD-1) and identified immune markers of response and resistance. Building on these studies, we performed deep molecular profiling including T cell receptor sequencing and whole-exome sequencing within the same cohort and demonstrated that a more clonal T cell repertoire was predictive of response to PD-1 but not CTLA-4 blockade. Analysis of CNAs identified a higher burden of copy number loss in nonresponders to CTLA-4 and PD-1 blockade and found that it was associated with decreased expression of genes in immune-related pathways. The effect of mutational load and burden of copy number loss on response was nonredundant, suggesting the potential utility of a combinatorial biomarker to optimize patient care with checkpoint blockade therapy.

Interkingdom signaling is established in the gastrointestinal tract in that human hormones trigger responses in bacteria; here, we show that the corollary is true, that a specific bacterial signal, indole, is recognized as a beneficial signal in intestinal epithelial cells. Our prior work has shown that indole, secreted by commensal Escherichia coli and detected in human feces, reduces pathogenic E. coli chemotaxis, motility, and attachment to epithelial cells. However, the effect of indole on intestinal epithelial cells is not known. Because intestinal epithelial cells are likely to be exposed continuously to indole, we hypothesized that indole may be beneficial for these cells, and investigated changes in gene expression with the human enterocyte cell line HCT-8 upon exposure to indole. Exposure to physiologically relevant amounts of indole increased expression of genes involved in strengthening the mucosal barrier and mucin production, which were consistent with an increase in the transepithelial resistance of HCT-8 cells. Indole also decreased TNF-alpha-mediated activation of NF-kappaB, expression of the proinflammatory chemokine IL-8, and the attachment of pathogenic E. coli to HCT-8 cells, as well as increased expression of the antiinflammatory cytokine IL-10. The changes in transepithelial resistance and NF-kappaB activation were specific to indole: other indole-like molecules did not elicit a similar response. Our results are similar to those observed with probiotic strains and suggest that indole could be important in the intestinal epithelial cells response to gastrointestinal tract pathogens.

Recent observations have demonstrated that one of the functions of mesenchymal stem/stromal cells (MSCs) is to serve as guardians against excessive inflammatory responses. One mode of action of the cells is that they are activated to express the interleukin (IL)-1 receptor antagonist. A second mode of action is to create a negative feedback loop in which tumor necrosis factor-α (TNF-α) and other proinflammatory cytokines from resident macrophages activate MSCs to secrete the multifunctional anti-inflammatory protein TNF-α stimulated gene/protein 6 (TSG-6). The TSG-6 then reduces nuclear factor-κB (NF-κB) signaling in the resident macrophages and thereby modulates the cascade of proinflammatory cytokines. A third mode of action is to create a second negative feedback loop whereby lipopolysaccharide, TNF-α, nitric oxide, and perhaps other damage-associated molecular patterns (DAMPs) from injured tissues and macrophages activate MSCs to secrete prostaglandin E2 (PGE2). The PGE2 converts macrophages to the phenotype that secretes IL-10. There are also suggestions that MSCs may produce anti-inflammatory effects through additional modes of action including activation to express the antireactive oxygen species protein stanniocalcin-1. Recent observations have demonstrated that one of the functions of mesenchymal stem/stromal cells (MSCs) is to serve as guardians against excessive inflammatory responses. One mode of action of the cells is that they are activated to express the interleukin (IL)-1 receptor antagonist. A second mode of action is to create a negative feedback loop in which tumor necrosis factor-α (TNF-α) and other proinflammatory cytokines from resident macrophages activate MSCs to secrete the multifunctional anti-inflammatory protein TNF-α stimulated gene/protein 6 (TSG-6). The TSG-6 then reduces nuclear factor-κB (NF-κB) signaling in the resident macrophages and thereby modulates the cascade of proinflammatory cytokines. A third mode of action is to create a second negative feedback loop whereby lipopolysaccharide, TNF-α, nitric oxide, and perhaps other damage-associated molecular patterns (DAMPs) from injured tissues and macrophages activate MSCs to secrete prostaglandin E2 (PGE2). The PGE2 converts macrophages to the phenotype that secretes IL-10. There are also suggestions that MSCs may produce anti-inflammatory effects through additional modes of action including activation to express the antireactive oxygen species protein stanniocalcin-1. We and other vertebrates are equipped to live in a sea of microorganisms. The reason we survive is because we have formidable inflammatory and immune response systems to protect us against both external confrontations with microorganisms and internal confrontations with the bacteria in our intestinal flora that outnumber the cells in our bodies.1Berg RD The indigenous gastrointestinal microflora.Trends Microbiol. 1996; 4: 430-435Abstract Full Text PDF PubMed Scopus (853) Google Scholar,2Savage DC Microbial ecology of the gastrointestinal tract.Annu Rev Microbiol. 1977; 31: 107-133Crossref PubMed Scopus (1667) Google Scholar However, the same systems need multiple checks to protect us against excessive inflammatory and immune responses. In fact, there is an increasing realization that excessive or nonresolving inflammation makes a major contribution to the damage wrought by diseases such as obesity, diabetes, myocardial infarction (MI), stroke, parkinsonism, and Alzheimer's disease.3Nathan C Ding A Nonresolving inflammation.Cell. 2010; 140: 871-882Abstract Full Text Full Text PDF PubMed Scopus (1416) Google Scholar,4Chen GY Nuñez G Sterile inflammation: sensing and reacting to damage.Nat Rev Immunol. 2010; 10: 826-837Crossref PubMed Scopus (2045) Google Scholar Fortunately, we have multiple systems for resolving and modulating inflammation. The systems include small molecules such as prostaglandins, lipoxins, protectins, and resolvins.5Serhan CN Chiang N Van Dyke TE Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators.Nat Rev Immunol. 2008; 8: 349-361Crossref PubMed Scopus (2200) Google Scholar They also include cellular phenotypes such as alternatively activated M2 macrophages6Gordon S Martinez FO Alternative activation of macrophages: mechanism and functions.Immunity. 2010; 32: 593-604Abstract Full Text Full Text PDF PubMed Scopus (2799) Google Scholar and regulatory T cells.7Izcue A Coombes JL Powrie F Regulatory lymphocytes and intestinal inflammation.Annu Rev Immunol. 2009; 27: 313-338Crossref PubMed Scopus (408) Google Scholar,8Wan YY Regulatory T cells: immune suppression and beyond.Cell Mol Immunol. 2010; 7: 204-210Crossref PubMed Scopus (60) Google Scholar Recent reports indicate that additional important guardian cells for modulating inflammation are mesenchymal stem/stromal cells (MSCs). The interest in the guardian role of MSCs is in part related to their presence as adventitial reticular cells9Bianco P Sacchetti B Riminucci M Osteoprogenitors and the hematopoietic microenvironment.Best Pract Res Clin Haematol. 2011; 24: 37-47Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar that participate in normal wound repair and in regulation of hematopoietic cells in bone marrow.10Méndez-Ferrer S Michurina TV Ferraro F Mazloom AR Macarthur BD Lira SA et al.Mesenchymal and haematopoietic stem cells form a unique bone marrow niche.Nature. 2010; 466: 829-834Crossref PubMed Scopus (2468) Google Scholar The interest in MSCs has been further enhanced by their potential use for therapies of various diseases, because the cells can be readily obtained from patients, they are easily expanded in culture, and they are generally not tumorigenic. Recent reports have demonstrated that many, but not all, of the therapeutic effects of the cells seen in animal models are explained by MSCs being activated by signals from injured tissues to secrete anti-inflammatory factors. In some instances, direct administration of the same factors replicates the anti-inflammatory effects of the MSCs. Therefore, the factors secreted by activated MSCs may replace the use of the cells for some therapeutic applications. The role of MSCs as guardians of inflammation has gradually emerged from research on the cells over the past several decades. The evolving data have prompted dramatic shifts in the hypotheses or paradigms for the research.11Prockop DJ Kota DJ Bazhanov N Reger RL Evolving paradigms for repair of tissues by adult stem/progenitor cells (MSCs).J Cell Mol Med. 2010; 14: 2190-2199Crossref PubMed Scopus (216) Google Scholar Initially, the cells were explored as feeder layers that provided a niche for culture of hematopoietic cells (paradigm I). Then the cells were explored as reparative cells that can engraft in injured tissues and differentiate to replace damaged cells (paradigm II). More recently, the data demonstrate that the cells only transiently appear in injured tissues under most conditions, but during their brief appearance they respond to crosstalk with injured cells to limit tissue destruction or enhance repair by a variety of mechanisms (paradigm III). The mechanisms include (a) upregulation of genes that modulate excessive inflammatory and immune reactions; (b) providing a niche to enhance proliferation and differentiation of tissue-endogenous stem/progenitor cells (as in paradigm I); and (c) transfer of vesicular components that contain mitochondria and microRNAs. The role of MSCs as guardians of inflammation became more apparent as the events initiating inflammation have been defined in greater detail.4Chen GY Nuñez G Sterile inflammation: sensing and reacting to damage.Nat Rev Immunol. 2010; 10: 826-837Crossref PubMed Scopus (2045) Google Scholar,12Rock KL Latz E Ontiveros F Kono H The sterile inflammatory response.Annu Rev Immunol. 2010; 28: 321-342Crossref PubMed Scopus (613) Google Scholar,13Eigenbrod T Park JH Harder J Iwakura Y Núñez G Cutting edge: critical role for mesothelial cells in necrosis-induced inflammation through the recognition of IL-1α released from dying cells.J Immunol. 2008; 181: 8194-8198Crossref PubMed Scopus (187) Google Scholar,14Soehnlein O Lindbom L Phagocyte partnership during the onset and resolution of inflammation.Nat Rev Immunol. 2010; 10: 427-439Crossref PubMed Scopus (720) Google Scholar The events include (a) both passive and active release from injured cells or macrophages of intracellular cytokines such as interleukin (IL)-1α that stimulate parenchymal cells to produce chemokines that recruit neutrophils; (b) classical activation of resident macrophages by damage-associated molecular patterns (DAMPs) or pathogen-associated molecular patterns (PAMPs) that interact with pattern recognition receptors to produce high levels of proinflammatory cytokines as well as reactive nitrogen and reactive oxygen species that induce the acute phase response of inflammation. The literature on the anti-inflammatory effects of MSCs is continuing to expand at a rapid rate with over 500 entries in PubMed under “MSCs and inflammation.” We are unable to review all the entries in detail, and therefore we elected to focus here on several examples in which the anti-inflammatory effects of MSCs appear to be best explained at the cellular and molecular levels. The examples deal with inflammation of tissues as a discrete process and not as a component of adaptive immunity, a topic that has been covered in other recent reviews.15Uccelli A Prockop DJ Why should mesenchymal stem cells (MSCs) cure autoimmune diseases?.Curr Opin Immunol. 2010; 22: 768-774Crossref PubMed Scopus (121) Google Scholar,16Tolar J Villeneuve P Keating A Mesenchymal stromal cells for graft-versus-host disease.Hum Gene Ther. 2011; 22: 257-262Crossref PubMed Scopus (48) Google Scholar,17English K Mahon BP Allogeneic mesenchymal stem cells: agents of immune modulation.J Cell Biochem. 2011; 112: 1963-1968Crossref PubMed Scopus (111) Google Scholar,18Singer NG Caplan AI Mesenchymal stem cells: mechanisms of inflammation.Annu Rev Pathol. 2011; 6: 457-478Crossref PubMed Scopus (641) Google Scholar One series of experiments were with a model of bleomycin-induced lung injury.19Ortiz LA Dutreil M Fattman C Pandey AC Torres G Go K et al.Interleukin 1 receptor antagonist mediates the antiinflammatory and antifibrotic effect of mesenchymal stem cells during lung injury.Proc Natl Acad Sci USA. 2007; 104: 11002-11007Crossref PubMed Scopus (841) Google Scholar,20Ortiz LA Gambelli F McBride C Gaupp D Baddoo M Kaminski N et al.Mesenchymal stem cell engraftment in lung is enhanced in response to bleomycin exposure and ameliorates its fibrotic effects.Proc Natl Acad Sci USA. 2003; 100: 8407-8411Crossref PubMed Scopus (1200) Google Scholar In the model, intravenous (i.v.) infusion of minimally expanded murine bone marrow-derived MSCs (500,000 cells per mouse) decreased the inflammatory response to bleomycin and prevented the lungs from developing fibrosis.19Ortiz LA Dutreil M Fattman C Pandey AC Torres G Go K et al.Interleukin 1 receptor antagonist mediates the antiinflammatory and antifibrotic effect of mesenchymal stem cells during lung injury.Proc Natl Acad Sci USA. 2007; 104: 11002-11007Crossref PubMed Scopus (841) Google Scholar,20Ortiz LA Gambelli F McBride C Gaupp D Baddoo M Kaminski N et al.Mesenchymal stem cell engraftment in lung is enhanced in response to bleomycin exposure and ameliorates its fibrotic effects.Proc Natl Acad Sci USA. 2003; 100: 8407-8411Crossref PubMed Scopus (1200) Google Scholar The beneficial effects of the MSCs were largely explained by the cells being activated to secrete IL-1 receptor antagonist (IL-1ra). The MSCs were effective only when administered at the same time as the bleomycin and not at later time points. This observation suggests that the action of MSCs in this model was exerted in the initial phases of the injury in which there is extensive apoptosis of macrophages.21Ortiz LA Moroz K Liu JY Hoyle GW Hammond T Hamilton RF et al.Alveolar macrophage apoptosis and TNF-α, but not p53, expression correlate with murine response to bleomycin.Am J Physiol. 1998; 275: L1208-L1218PubMed Google Scholar The observations were consistent with demonstrations that the IL-1 pathway plays a role in the of sterile T Park JH Harder J Iwakura Y Núñez G Cutting edge: critical role for mesothelial cells in necrosis-induced inflammation through the recognition of IL-1α released from dying cells.J Immunol. 2008; 181: 8194-8198Crossref PubMed Scopus (187) Google Kono H D G S KL of a pathway for the sterile inflammatory response by dying Med. 2007; PubMed Scopus Google Scholar and its effects are to the effects of tumor necrosis factor-α (TNF-α) in GY Nuñez G Sterile inflammation: sensing and reacting to damage.Nat Rev Immunol. 2010; 10: 826-837Crossref PubMed Scopus (2045) Google Scholar,12Rock KL Latz E Ontiveros F Kono H The sterile inflammatory response.Annu Rev Immunol. 2010; 28: 321-342Crossref PubMed Scopus (613) Google and of 2008; PubMed Scopus Google Scholar and MSCs from the bone marrow express high levels of LA Dutreil M Fattman C Pandey AC Torres G Go K et al.Interleukin 1 receptor antagonist mediates the antiinflammatory and antifibrotic effect of mesenchymal stem cells during lung injury.Proc Natl Acad Sci USA. 2007; 104: 11002-11007Crossref PubMed Scopus (841) Google Scholar and experiments in culture demonstrated that secreted from MSCs the of TNF-α by macrophages However, infusion of MSCs in the model of bleomycin-induced lung injury was more effective or The that one in which MSCs can modulate the phases of inflammation is to secrete and thereby the effects of IL-1 and TNF-α in both sterile and and of 2008; PubMed Scopus Google Scholar mechanism was provided by the H A N Y Y Y et bone marrow stromal cells inflammation Ther. 2010; Full Text Full Text PDF PubMed Scopus Google Scholar that MSCs inflammation in of by for which to TNF-α and the of the One of the observations with MSCs is that of MSCs beneficial effects in tissues in such as and most MSCs are in the DJ Kota DJ Bazhanov N Reger RL Evolving paradigms for repair of tissues by adult stem/progenitor cells (MSCs).J Cell Mol Med. 2010; 14: 2190-2199Crossref PubMed Scopus (216) Google Scholar The was at in part by experiments with were in a model for Kota DJ J et myocardial infarction in because cells in lung are activated to secrete the anti-inflammatory protein 2009; Full Text Full Text PDF PubMed Scopus Google Scholar The of cells per mouse) the inflammatory response to of the and the of the myocardial was in the of the as by However, for and for as a for live that only a small of the MSCs were in the the appearance of the in the was of the were at and they by of the cells were in the lungs as Kota DJ J et myocardial infarction in because cells in lung are activated to secrete the anti-inflammatory protein 2009; Full Text Full Text PDF PubMed Scopus Google J Prockop DJ The protein and MSCs with and to in 2009; PubMed Scopus Google Scholar and they with a of In an to the beneficial effects of the was from lungs of the infusion of the and was on for with the data that the in the lungs as were activated to the expression of over the the most was the for the anti-inflammatory protein to as TNF-α stimulated gene/protein 6 (TSG-6). The with an of the TSG-6 or effect in the the administration of TSG-6 the same beneficial effect as The were explained by a in which the were activated by being as to secrete and the TSG-6 decreased the and excessive inflammatory response in the that destruction of tissue In by being activated to secrete the MSCs at a to injury to the administration of was also to at a to inflammation in a model of sterile injury to the in The were injured by brief exposure to by of the and that the stem cells in the cells per decreased of proinflammatory and of the in the GW JY JH K et at a administered adult stem/progenitor cells (MSCs) inflammatory damage to the engraftment and by of 2011; PubMed Scopus Google Scholar infusion of the was also effective in inflammation and the in the A for for demonstrated that were in the of 1 and or administration of 1 However, the with an of the TSG-6 were not the beneficial effects of were largely by administration of Therefore, the data demonstrated that administered inflammatory damage to the engraftment in the tissue and that the anti-inflammatory effects of the cells were explained by their of A related series of experiments demonstrated that direct of the of the also decreased excessive inflammation in injured The anti-inflammatory effects of the were JY GW H JH et protein TSG-6 reduces inflammatory damage to the and injury.Proc Natl Acad Sci USA. 2010; PubMed Scopus Google Scholar The effective suppression of excessive inflammation in the phase of injury to a in of and of the at of data indicate that MSCs protect the or from injury and tissue by modulating acute excessive inflammation by The anti-inflammatory action of MSCs through of TSG-6 was further demonstrated in a model in which was in by of a from the cell of H Bazhanov N JY Prockop DJ protein TSG-6 secreted by activated MSCs by signaling in resident 2011; PubMed Scopus Google Scholar cells per mouse) were there was a in and in the in the with the TSG-6 were not and infusion of largely the anti-inflammatory effects of The anti-inflammatory effects of the were explained by their effects on resident the cell for inflammatory in most GY Nuñez G Sterile inflammation: sensing and reacting to damage.Nat Rev Immunol. 2010; 10: 826-837Crossref PubMed Scopus (2045) Google Scholar,12Rock KL Latz E Ontiveros F Kono H The sterile inflammatory response.Annu Rev Immunol. 2010; 28: 321-342Crossref PubMed Scopus (613) Google Scholar,14Soehnlein O Lindbom L Phagocyte partnership during the onset and resolution of inflammation.Nat Rev Immunol. 2010; 10: 427-439Crossref PubMed Scopus (720) Google Scholar In of murine macrophages that were stimulated with both and decreased the of the proinflammatory TNF-α and They also the activation and of the nuclear factor-κB (NF-κB) to the effect the TSG-6 was with an The effects of and TSG-6 were on the expression of because they not signaling in cells or in that not express signaling through the receptor The action of TSG-6 was on the of with and not on the of TSG-6 not the pathway in cells of and that interact with the of The effect was that the a negative feedback loop the inflammatory response in which MSCs and TSG-6 the initial of proinflammatory cytokines from They thereby the of the proinflammatory signals by mesothelial cells that produce high levels of and to recruit H Bazhanov N JY Prockop DJ protein TSG-6 secreted by activated MSCs by signaling in resident 2011; PubMed Scopus Google Scholar on resident macrophage critical in initiating inflammation in most GY Nuñez G Sterile inflammation: sensing and reacting to damage.Nat Rev Immunol. 2010; 10: 826-837Crossref PubMed Scopus (2045) Google Scholar,14Soehnlein O Lindbom L Phagocyte partnership during the onset and resolution of inflammation.Nat Rev Immunol. 2010; 10: 427-439Crossref PubMed Scopus (720) Google P an damage-associated molecular pattern that immune Rev Immunol. 4: PubMed Scopus Google G A K D et edge: pattern recognition and receptors activation by Immunol. 2009; PubMed Scopus Google Scholar The negative feedback loop by MSCs and TSG-6 on the pathway in macrophages may therefore largely for the beneficial effects of MSCs in other models in which excessive inflammatory to tissue A for the anti-inflammatory effects of MSCs was demonstrated in a model of by and K A B A K et marrow stromal cells prostaglandin of macrophages to their Med. 2009; PubMed Scopus Google Scholar et that there was a in the of that 1 MSCs at the time of or 1 the levels of TNF-α and proinflammatory cytokines that have a role in L The a for Mol Med. Full Text Full Text PDF PubMed Scopus Google Scholar were by administration of the most of the were in the and they over time but were the of an anti-inflammatory secreted by was at 6 and in MSCs. of macrophages or administration of to beneficial effects of MSCs in with MSCs from were effective in the of with the data that MSCs were not the of but they by in The MSCs the of in the macrophages by nitric oxide, but some of the data that the macrophages also nitric A series of in and in experiments demonstrated that and activation of in the expression of and thereby of prostaglandin E2 (PGE2). PGE2 in to and receptors on macrophages and macrophages to the phenotype that secretes IL-10. 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There are several for the including in when the MSCs were in when the was and in the of cells et that were and obtained from an Therefore, they the of that are easily by in DJ Kota DJ Bazhanov N Reger RL Evolving paradigms for repair of tissues by adult stem/progenitor cells (MSCs).J Cell Mol Med. 2010; 14: 2190-2199Crossref PubMed Scopus (216) Google DJ M E K et the of mesenchymal stromal cell 2010; Full Text Full Text PDF PubMed Scopus Google Scholar The by et K A B A K et marrow stromal cells prostaglandin of macrophages to their Med. 2009; PubMed Scopus Google Scholar that MSCs can macrophages from a proinflammatory phenotype to the alternatively activated or anti-inflammatory M2 phenotype was by several other et J P Mesenchymal stem macrophages: a of alternatively activated 2009; Full Text Full Text PDF PubMed Scopus Google Scholar that macrophages with bone marrow-derived MSCs high levels of a of alternatively activated M2 macrophages a high levels of and and levels of and They In observations with et J G J et bone marrow-derived mesenchymal stromal cells activated macrophages a 2010; PubMed Scopus Google Scholar also that bone marrow-derived MSCs macrophages to a regulatory phenotype by decreased expression of inflammatory of and to by intracellular The effects were by of PGE2 by the MSCs a the of MSCs to the phenotype of the In experiments with et P A et mesenchymal stem cells of macrophages and enhance wound 2010; 28: PubMed Scopus Google Scholar also that the MSCs or from the MSCs macrophages to the M2 and because of the they enhanced wound repair in In they that the MSCs TNF-α by macrophages in a that with activation of Therefore, there is a of that MSCs inflammation and enhance tissue repair by modulating the phenotype of The observations that of the anti-inflammatory effects of MSCs can be by factors the cells produce an can therapies with the factors replace therapies with of the factors are not with has been to have because were seen in a small of with A T S J A of IL-1 by in acute Res Ther. 2007; PubMed Scopus Google Scholar but there was in with and C C G IL-1 in inflammation and Rev 2010; 6: PubMed Scopus Google Scholar factors by such as nitric oxide, or PGE2 are not because they have or they have effects when administered However, there appear to be for the protein TSG-6 for therapeutic The protein was to have multiple anti-inflammatory effects in to its of signaling in H Bazhanov N JY Prockop DJ protein TSG-6 secreted by activated MSCs by signaling in resident 2011; PubMed Scopus Google Scholar apparent in the J expression at the of immunity, inflammation and TSG-6 and Full Text Full Text PDF PubMed Scopus Google a inflammatory PubMed Scopus Google Scholar of the beneficial effects of MSCs in models may additional factors that can be the factors of therapeutic interest is that is secreted by MSCs in response to signals from S F J C et stromal cells are activated to apoptosis in part by upregulation and of 2009; 27: PubMed Scopus Google Scholar and that reduces reactive oxygen species by the expression of of Y L M A et in macrophages through of 2009; PubMed Scopus Google Scholar levels of reactive oxygen species are proinflammatory and high levels are may be both anti-inflammatory and The role of MSCs as guardians against excessive inflammation of the beneficial effects with administration of the cells in animal models for a of diseases, including models for lung diabetes, sterile injury to the and The recent that has defined the anti-inflammatory factors by the cells in the of one or more of the factors to therapies that may be and more therapies with the cells However, MSCs modulate their anti-inflammatory effects in multiple that appear to be to the by tissue Therefore, MSCs may be the of for some

Delivering consistently good service quality is difficult but profitable for service organizations. Understanding why it is so difficult and how it might be facilitated is the purpose of the article. The authors' intent is to identify a reasonably exhaustive set of factors potentially affecting the magnitude and direction of four gaps on the marketer's side of their service quality model. Most factors involve (1) communication and control processes implemented in service organizations to manage employees and (2) consequences of these processes, such as role clarity and role conflict of contact personnel. Literature from the marketing and organizational behavior fields on these topics is reviewed and integrated with qualitative data from an exploratory study. Discussion centers on insights that can be obtained from empirical testing of the extended model.

Modern sugarcanes are polyploid interspecific hybrids, combining high sugar content from Saccharum officinarum with hardiness, disease resistance and ratooning of Saccharum spontaneum. Sequencing of a haploid S. spontaneum, AP85-441, facilitated the assembly of 32 pseudo-chromosomes comprising 8 homologous groups of 4 members each, bearing 35,525 genes with alleles defined. The reduction of basic chromosome number from 10 to 8 in S. spontaneum was caused by fissions of 2 ancestral chromosomes followed by translocations to 4 chromosomes. Surprisingly, 80% of nucleotide binding site-encoding genes associated with disease resistance are located in 4 rearranged chromosomes and 51% of those in rearranged regions. Resequencing of 64 S. spontaneum genomes identified balancing selection in rearranged regions, maintaining their diversity. Introgressed S. spontaneum chromosomes in modern sugarcanes are randomly distributed in AP85-441 genome, indicating random recombination among homologs in different S. spontaneum accessions. The allele-defined Saccharum genome offers new knowledge and resources to accelerate sugarcane improvement.

Phase and antigenic variation result in a heterogenic phenotype of a clonal bacterial population, in which individual cells either express the phase-variable protein(s) or not, or express one of multiple antigenic forms of the protein, respectively. This form of regulation has been identified mainly, but by no means exclusively, for a wide variety of surface structures in animal pathogens and is implicated as a virulence strategy. This review provides an overview of the many bacterial proteins and structures that are under the control of phase or antigenic variation. The context is mainly within the role of the proteins and variation for pathogenesis, which reflects the main body of literature. The occurrence of phase variation in expression of genes not readily recognizable as virulence factors is highlighted as well, to illustrate that our current knowledge is incomplete. From recent genome sequence analysis, it has become clear that phase variation may be more widespread than is currently recognized, and a brief discussion is included to show how genome sequence analysis can provide novel information, as well as its limitations. The current state of knowledge of the molecular mechanisms leading to phase variation and antigenic variation are reviewed, and the way in which these mechanisms form part of the general regulatory network of the cell is addressed. Arguments both for and against a role of phase and antigenic variation in immune evasion are presented and put into new perspective by distinguishing between a role in bacterial persistence in a host and a role in facilitating evasion of cross-immunity. Finally, examples are presented to illustrate that phase-variable gene expression should be taken into account in the development of diagnostic assays and in the interpretation of experimental results and epidemiological studies.

The growth factor progranulin (PGRN) has been implicated in embryonic development, tissue repair, tumorigenesis, and inflammation, but its receptors remain unidentified. We report that PGRN bound directly to tumor necrosis factor receptors (TNFRs) and disturbed the TNFα-TNFR interaction. PGRN-deficient mice were susceptible to collagen-induced arthritis, and administration of PGRN reversed inflammatory arthritis. Atsttrin, an engineered protein composed of three PGRN fragments, exhibited selective TNFR binding. PGRN and Atsttrin prevented inflammation in multiple arthritis mouse models and inhibited TNFα-activated intracellular signaling. Collectively, these findings demonstrate that PGRN is a ligand of TNFR, an antagonist of TNFα signaling, and plays a critical role in the pathogenesis of inflammatory arthritis in mice. They also suggest new potential therapeutic interventions for various TNFα-mediated pathologies and conditions, including rheumatoid arthritis.

Ray Ming, Robert Paull, Qingyi Yu and colleagues report the genome sequences of two cultivated pineapple varieties and one wild pineapple relative. Their analysis supports the use of the pineapple as a reference genome for monocot comparative genomics and provides insight into the evolution of crassulacean acid metabolism photosynthesis. Pineapple (Ananas comosus (L.) Merr.) is the most economically valuable crop possessing crassulacean acid metabolism (CAM), a photosynthetic carbon assimilation pathway with high water-use efficiency, and the second most important tropical fruit. We sequenced the genomes of pineapple varieties F153 and MD2 and a wild pineapple relative, Ananas bracteatus accession CB5. The pineapple genome has one fewer ancient whole-genome duplication event than sequenced grass genomes and a conserved karyotype with seven chromosomes from before the ρ duplication event. The pineapple lineage has transitioned from C3 photosynthesis to CAM, with CAM-related genes exhibiting a diel expression pattern in photosynthetic tissues. CAM pathway genes were enriched with cis-regulatory elements associated with the regulation of circadian clock genes, providing the first cis-regulatory link between CAM and circadian clock regulation. Pineapple CAM photosynthesis evolved by the reconfiguration of pathways in C3 plants, through the regulatory neofunctionalization of preexisting genes and not through the acquisition of neofunctionalized genes via whole-genome or tandem gene duplication.

BACKGROUND: Obesity increases the risk of heart failure with preserved ejection fraction. Tirzepatide, a long-acting agonist of glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, causes considerable weight loss, but data are lacking with respect to its effects on cardiovascular outcomes. METHODS: In this international, double-blind, randomized, placebo-controlled trial, we randomly assigned, in a 1:1 ratio, 731 patients with heart failure, an ejection fraction of at least 50%, and a body-mass index (the weight in kilograms divided by the square of the height in meters) of at least 30 to receive tirzepatide (up to 15 mg subcutaneously once per week) or placebo for at least 52 weeks. The two primary end points were a composite of adjudicated death from cardiovascular causes or a worsening heart-failure event (assessed in a time-to-first-event analysis) and the change from baseline to 52 weeks in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS; scores range from 0 to 100, with higher scores indicating better quality of life). RESULTS: A total of 364 patients were assigned to the tirzepatide group and 367 to the placebo group; the median duration of follow-up was 104 weeks. Adjudicated death from cardiovascular causes or a worsening heart-failure event occurred in 36 patients (9.9%) in the tirzepatide group and in 56 patients (15.3%) in the placebo group (hazard ratio, 0.62; 95% confidence interval [CI], 0.41 to 0.95; P = 0.026). Worsening heart-failure events occurred in 29 patients (8.0%) in the tirzepatide group and in 52 patients (14.2%) in the placebo group (hazard ratio, 0.54; 95% CI, 0.34 to 0.85), and adjudicated death from cardiovascular causes occurred in 8 patients (2.2%) and 5 patients (1.4%), respectively (hazard ratio, 1.58; 95% CI, 0.52 to 4.83). At 52 weeks, the mean (±SD) change in the KCCQ-CSS was 19.5±1.2 in the tirzepatide group as compared with 12.7±1.3 in the placebo group (between-group difference, 6.9; 95% CI, 3.3 to 10.6; P<0.001). Adverse events (mainly gastrointestinal) leading to discontinuation of the trial drug occurred in 23 patients (6.3%) in the tirzepatide group and in 5 patients (1.4%) in the placebo group. CONCLUSIONS: Treatment with tirzepatide led to a lower risk of a composite of death from cardiovascular causes or worsening heart failure than placebo and improved health status in patients with heart failure with preserved ejection fraction and obesity. (Funded by Eli Lilly; SUMMIT ClinicalTrials.gov number, NCT04847557.).

The Staphylococcus aureus Panton-Valentine leukocidin (PVL) is a pore-forming toxin secreted by strains epidemiologically associated with the current outbreak of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) and with the often-lethal necrotizing pneumonia. To investigate the role of PVL in pulmonary disease, we tested the pathogenicity of clinical isolates, isogenic PVL-negative and PVL-positive S. aureus strains, as well as purified PVL, in a mouse acute pneumonia model. Here we show that PVL is sufficient to cause pneumonia and that the expression of this leukotoxin induces global changes in transcriptional levels of genes encoding secreted and cell wall-anchored staphylococcal proteins, including the lung inflammatory factor staphylococcal protein A (Spa).