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Metabolic Synergy between Human Symbionts \u3ci\u3eBacteroides\u3c/i\u3e and \u3ci\u3eMethanobrevibacter\u3c/i\u3e

ABSTRACT Trophic interactions between microbes are postulated to determine whether a host microbiome is healthy or causes predisposition to disease. Two abundant taxa, the Gram-negative heterotrophic bacterium Bacteroides thetaiotaomicron and the methanogenic archaeon Methanobrevibacter smithii, are proposed to have a synergistic metabolic relationship. Both organisms play vital roles in human gut health; B. thetaiotaomicron assists the host by fermenting dietary polysaccharides, whereas M. smithii consumes end-stage fermentation products and is hypothesized to relieve feedback inhibition of upstream microbes such as B. thetaiotaomicron. To study their metabolic interactions, we defined and optimized a coculture system and used software testing techniques to analyze growth under a range of conditions representing the nutrient environment of the host. We verify that B. thetaiotaomicron fermentation products are sufficient for M. smithii growth and that accumulation of fermentation products alters secretion of metabolites by B. thetaiotaomicron to benefit M. smithii. Studies suggest that B. thetaiotaomicron metabolic efficiency is greater in the absence of fermentation products or in the presence of M. smithii. Under certain conditions, B. thetaiotaomicron and M. smithii form interspecies granules consistent with behavior observed for syntrophic partnerships between microbes in soil or sediment enrichments and anaerobic digesters. Furthermore, when vitamin B12, hematin, and hydrogen gas are abundant, coculture growth is greater than the sum of growth observed for monocultures, suggesting that both organisms benefit from a synergistic mutual metabolic relationship. IMPORTANCE The human gut functions through a complex system of interactions between the host human tissue and the microbes which inhabit it. These diverse interactions are difficult to model or examine under controlled laboratory conditions. We studied the interactions between two dominant human gut microbes, B. thetaiotaomicron and M. smithii, using a seven-component culturing approach that allows the systematic examination of the metabolic complexity of this binary microbial system. By combining high-throughput methods with machine learning techniques, we were able to investigate the interactions between two dominant genera of the gut microbiome in a wide variety of environmental conditions. Our approach can be broadly applied to studying microbial interactions and may be extended to evaluate and curate computational metabolic models. The software tools developed for this study are available as user-friendly tutorials in the Department of Energy KBase

High-throughput mutation, selection, and phenotype screening of mutant methanogenic archaea

Bacterial and archaeal genomes can contain 30% or more hypothetical genes with no predicted function. Phylogenetically deep-branching microbes, such as methane-producing archaea (methanogens), contain up to 50% genes with unknown function. In order to formulate hypotheses about the function of hypothetical gene functions in the strict anaerobe, Methanosarcina acetivorans, we have developed high-throughput anaerobic techniques to UV mutagenize, screen, and select for mutant strains in 96-well plates. Using these approaches we have isolated 10 mutant strains that exhibit a variety of physiological changes including increased or decreased growth rate relative to the parent strain when cells use methanol and/or acetate as carbon and energy sources. This method provides an avenue for the first step in identifying new gene functions: associating a genetic mutation with a reproducible phenotype. Mutations in bona fide methanogenesis genes such as corrinoid methyltransferases and proton-translocating F420H2:methanophenazine oxidoreductase (Fpo) were also generated, opening the door to in vivo functional complementation experiments. Irradiation-based mutagenesis such as from ultraviolet (UV) light, combined with modern genome sequencing, is a useful procedure to discern systems- level gene function in prokaryote taxa that can be axenically cultured but which may be resistant to chemical mutagens. Includes supplementary tables & figure

Baytop-Fitzhugh Papers: Letters, 1851-1852

Item 1: John Williams, Philadelphia, Pennsylvania to Rufus King Fitzhugh Esq. Springhill, Stanardsville, Greene Co., Virginia, 25 March 1851 2 pages. Autograph Letter Signed. A "last effort" will be made to earn some profit from the copper mine at Stony Man which has been "condemned...as worthless;" seeks Fitzhughs advice on where Mrs. Williams can board while he is at the mine; and the availability of "Blasting powder" in the area. Including Typewritten Copy. 1 page. Item 2: Mary F. Fitzhugh,Belmont, Hampton, Virginia to Mrs. Rufus Fitzhugh, Stanardsville, Greene County, Virginia, 6 May 1851 2 pages. Autograph Letter Signed. News of family and friends; tells of excitement about making a "missionary quilt for Mr. Payne our African Missionary" with neighborhood women and girls; gladly accepts invitation to visit "next summer" if Ma's health and spirits are good; invites Hettie to visit. Including Typewritten Copy. 1 page. Item 3: James Baytop,Springfield, Gloucester County, Virginia to "My Dr Children," Stanardsville, Greene County, Virginia, 30 July 1851 1 page. Autograph Letter Signed. Family will travel to Gordesville; physical ailments bothering him and his wife. Including Typewritten Copy of Autograph Letter Signed. 1 page. Including Autograph Letter Signed from Lucy Taliaferro Baytop,no place., to Hetty Henrietta Baytop, no place, concerning health of family; travel plans; hot, dry weather, and its effects on their crops. 1 page. Including Typewritten Copy of Autograph Letter Signed. Including Autograph Letter Signed from "Bunn" Baytop, no place, to "Hetty" Baytop, no place, no date, concerning "Kit's" travels to King and Queen, County, Virginia and his efforts to find a wife; went to an Indian concert and saw five Indians who were descendants of the Black Hawk and Oscola tribes; Indians showed them "the manners and customs of the Oregon Indians;" saw the Rocky Mountains, the Columbia River; and a prairie which was on fire; went crabbing; Cousin Sarah T. of Hampton, Virginia has two beaux and dances every night in Old Point, Hampton, Virginia. 1 page. Including Typewritten Copy of Autograph Letter Signed. 1 page. Item 4: Rowena Baytop, Springfield, Gloucester County, Virginia to "Hetty" Fitzhugh, no place 9 December 1851., 9 December 1851 1 page.Including Typewritten Copy of Autograph Letter Signed. Describes parties, with dinner and dancing, of the Christmas season; festivities are over and "we are all at work again;" hopes for an invitation to Miss Ann Martin's wedding; Mr. Sinclair is selling Wilson Creek to pay off his debts; is encouraging "father" to go to Texas. Including Autograph Letter Signed from Lucy Baytop, Springfield, Gloucester, Virginia to "My dear Child," Henrietta Fitzhugh, no place, no date, detailing the food and decorations of the Christmas parties; everyone is sick as a result of the hectic schedule of parties and bad weather; slaughtered 16 hogs and 1 cow; longs for past Christmases when the children were young; related family news; asks if "Mr. Fitzhugh" moves to Texas, "beg him to try to get Mr. Baytop in the notion too." 1 page. Including Typewritten Copy of Autograph Letter Signed. 1 page. Item 5: George Fitzhugh, no place, to Rufus Fitzhugh, no place, 20 December 1851 1 page. Autograph Letter Signed. $80-owed for "interest paid Catlett" is needed; farm is beginning to reap profits; land is expensive and "Belmont" would bring$4500. Including Typewritten Copy of Autographed Letter Signed. 1 page. Item 6: Mary Indiana Winborn Baytop, "Springfield," Gloucester County, Virginia to Hetty Fitzhugh, no place, 28 December 1851 2 pages. Autograph Letter Signed. Christmas has passed and work must resume; "great deal of sickness in the county, colds and pleurisys are very prevalent." Including Autograph Letter Signedfrom Lucy Taliaferro Baytop,no place to Hetty Fitzhugh, 30 December 1851. Concerning division of Concord Negroes which will bring $250. 2 pages. Autograph Letter Signed. Including Typewritten Copy of Autograph Letters Signed. 2 pages. Item 7: Sallie Champe Fitzhugh, Port Royal, Virginia to "my dearest uncle," no place, 30 January 1852 3 pages. Autograph Letter Signed. Hopes to encourage uncle to visit; Papa is expecting him and Aunt Ona to visit in the spring; gossip about weddings. Including Typewritten Copy of Autograph Letter Signed. 1 page. Item 8: Lucy A. Baytop, no place, to Hetty Fitzhugh, Gloucester, Virginia, 7 February 1852 3 pages. Autograph Letter Signed. News of family and friends; the young minister from Bellmeys, preached before a great crowd; Judy had a baby which died a month after birth of unknown causes, is depressed; Mr. Baytop is busy farming and studying to prepare for the ministry. Including Typewritten Copy of Autograph Letter Signed. 1 page. Item 9: Lucy Taliaferro Baytop,Springfield, Gloucester County, Virginia to "my dear child," Hetty Fitzhugh, Standardsville, Greene County, Virginia,, 20 April 1852 3 pages. Autograph Letter Signed. Circuit court is in session and "is summoned as a witness"; father and Mr. Sinclair are going to Washington to see about getting Mr. Sinclair's claim allowed; describes fuss electing persons for different offices as clerk commissioner of the revenue, constable sheriff & c.; "the guinea people have brought out Jefferson Stubbs for clerk and it is thought he will stand a very good chance to be elected. Including Typewritten Copy of Autograph Letter Signed. 2 pages. Item 10: Woodside, to Mrs. Hetty Fitzhugh, Standardsville,Greene County, Virginia, 24 April 1852 2 pages. Autograph Letter. Father and Mr. Sinclair were in Washington; "Father has given up all hope of his military claim." Including Typewritten Copy of Autograph Letter. 1 page. Item 11: Lucy Taliaferro Baytop,Springfield, Gloucester County, Virginia to Hetty Fitzhugh, no place, 5 October 1852 3 pages. Autograph Letter Signed. Reports sicknesses of Rowena, Eugenia, and Lucy Ann; Lucy Ann left to visit Tom Taliaferro and then to travel to Wilson's Creek; reports news about births, visits, farm business of friends; comments on the treatment of "Bob," a slave, who "has a better master this year." Including Typewritten Copy of Autograph Letter Signed. 1 page. Including Autograph Letter Signed from Rowena Baytop, n.p., n.d. to Hetty Fitzhugh, n.p. telling of her sickness and wight loss; "Cousin Lucy and Bun" were travelling to Baltimore and "Eugey is very anxious to go with them"; invites them to visit this winter. 1 page. Including Typewritten Copy of Autograph Letter Signed. 1 page. Item 12: Eugy, Eugenia Baytop, Springfield, Gloucester County, Virginia to Hettie Fitzhugh, Stanardsville, Greene County, Virginia, 4 November 1852 3 pages.Autograph Letter Signed. Hettie's trip to visit should not be postponed until February; had travelled to Baltimore, but cannot describe it adequately "from the pen of so ignorant a creature as myself"; there are many gentlemen available for marriage; Pa has gone to sell a dozen turkeys to Mr. Folk; Lucy's baby is "one of the sweetest babies you ever saw." Including Typewritten Copy of Autograph Letter Signed. 1 page. Item 13: Lucy Ann Baytop, Springfield, Gloucester County, Virginia to Hetty Fitzhugh, Stanardsville, Greene County,Virginia, 10 December 1852 3 pages. Autograph Letter Signed. Pressures of work and business have kept her from writing; reports marriages of "Cousin Tom Field and his bride Miss Davis"; Mr. Shackelfor and Miss Hester Rowe; "Sister" has had another baby boy, as did Aunt Fanny, Martha Waller, and Clara; Clara has a "riseing breast," and "the horses could not go out of a walk for fear of the jar to her breast...Dr. Jones stays with her to attend her"; her brother is in the Sonora mine in California and doing well mining for gold; looks forward to her visit this winter. Including Typewritten Copy of Autograph Letter Signed. 1 page

Baytop-Fitzhugh Papers: Letters, 1853-1861 and undated

Item 1: A. G. G, Christiansburg, Virginia to Rufus K. Fitzhugh, Stanardsville, Greene County,Virginia, 27 August 1853 1 page. Autograph Letter Signed. Has surveyed land tracts of 100,000 acres and 40,000 acres near which there is coal; encourages Fitzhugh to buy land; expects to be in Charlottesville, Virginia by Friday; asks him to send his horse to Charlottesville. Item 2: A. G. G, Madison, Virginia To Rufus K. Fitzhugh, no place, 9 October 1855 2 pages. Autograph Letter Signed. Admonishes Fitzhugh for not keeping his word on a business deal involving the purchase of land. Item 3: A. G. G, Madison, Virginia to Rufus K. Fitzhugh, no place, October 1855 1 page. Autograph Letter Signed. Complains of Fitzhugh not sending a deed on the "Hettick" land which he had promised to do. Item 4: Lucy Ann Baytop, Gloucester County, Virginia to Hetty Fitzhugh, Stanardsville, Greene County, Virginia, 4 April 1857 2 pages. Autograph Letter Signed. Is busy making soap, tending geese and fowl; Mr. Rose and Dr. Williams are going to the Worlds Fair; news about births and deaths and visits of family and friends; a camp meeting is being organized and the date will be announced at the quarterly meeting. Including Typewritten Copy of Autograph Letter Signed. 1 page. Including Autograph Letter Signedfrom T. C. Baytop, no place, no date, to "Hetty" Fitzhugh, no place, telling her that her friends inquire about her well being; has planted corn and will plant marl soon; has planted watermelon for the camp meeting; Brook, a slave?, "is the most industrious fellows we have." 1 page Including Typewritten Copy of Autograph Letter Signed. Item 5: Edgar Macon, Richmond, Virginia to Rufus King Fitzhugh,Stanardsville, Greene County, Virginia, 20 July 1858 1 page. Autograph Letter Signed. Acknowledges receipt of check for $1,000.00; sends deposit slips from the Farmers Bank and the Planters Savings Bank; quotes prices for manufacturing tobacco; "Millers are anxious" to buy wheat stock. Including Typewritten Copy of Autograph Letter Signed. Item 6: George Fitzhugh, Port Royal, Virginia to Rufus K. Fitzhugh, Stanardsville, Greene County, Virginia, 1 October 1858. 1 page. Autograph Letter Signed. Acknowledges receipt for a check of$50.00; is writing for DeBows Review and can "make a fortune by my pen"; planning visit for following year; transfers "title and interest" in estate of Haywood Foote to Rufus K. Fitzhugh. Including Typewritten Copy of Autograph Letter Signed. 1 page. Item 7: James W. Shields, Christiansburg, Virginia to Scott, 15 April 1859 3 pages. Autograph Letter Signed. Letter has caused "no little trouble"; Grayson Estate sale pending; Crocket Farms may be sold and is an "active farm in perfect order in every respect"; description of land. Including Typewritten Copy of Autograph Letter Signed. 1 page. Item 8: Lucy Taliaferro Baytop,Springfield, Gloucester County, Virginia to Hetty Fitzhugh, Stanardsville, Greene County, Virginia, 25 March 1860 2 pages. Autograph Letter Signed. Has been sick with a "congestion of wind"; relates loss of a slave girl who died from burns sustained in a fire; elaborates on struggle between Mr. Booth and Mr. Sinclair establishing ownership and value of the slave girl; comments, "disunion War or abject submission. I am a wonder to myself how I stand so well, once the mere talk of an insurrection would fill me with terror, now we have a white war and a servile one to dread..." Including Typewritten Copy of Autograph Letter Signed. 1 page. Item 9: Lucy Stubbs, Valley Front, Virginia to Hetty Fitzhugh, Stanardsville, Virginia, 19 March 1861 4 pages. Autograph Letter Signed. Unexpected snow storm has killed the fruit; "since Virginia has acted so ridiculously I almost wish that I could forsake her borders..." "The Old Dominion is endeavoring to throw off the galling yoke of Old Lincoln"; secession is impending; "abolitionists certainly can't flourish among us"; Rufus Fitzhugh is considering moving to Arkansas; mother has finished her quilting; cold weather and quilting should never go together; news of family and friends. Including Typewritten Copy of Autograph Letter Signed. 1 page. Item 10: Mary F. Fitzhugh, Fredericksburg, Virginia to Rufus K. Fitzhugh, Stanardsville, Greene County,Virginia, 19 February 1 page. Autograph Letter Signed. Arrival in Fredericksburg has been harried; invites him and family to visit; their mother's health is bad - lists symptoms and treatments by Dr. Wallace. Including Typewritten Copy of Autograph Letter Signed. 1 page. Item 11: Mary F. Fitzhugh, Fredericksburg, Virginia To Hettie Fitzhugh, Standardsville, Greene County, Virginia, 30 December 3 pages. Autograph Letter Signed. Friends and family have made them feel welcome; inquiries about Cousin Mary's "delicate health"; Ma's heath has improved; does not know if their income will support them; lists costs for rent and food. Including Typewritten Copy of Autograph Letter Signed. 1 page. Item 12: "Bun" Baytop, Springfield, Virginia To Mrs. Hetty Fitzhugh, Stanardsville, Greene County, Virginia, December 3 pages. Autograph Letter Signed. Party given in honor of Tom Field and his bride; accident with carriage left them in a muddy ditch; Christmas festivities. Including Typewritten Copy of Autograph Letter Signed. 1 page. Including Autograph Letter Signedfrom James C. Baytop, n.p. to Hetty Fitzhugh, n.p., n.d. thanking her and Rufus Fitzhugh for recommending him to Mr. Taliaferro; will wait to make a decision until Taliaferro sends him an offer. 1 page. Including Typewritten Copy of Autograph Letter Signed

Elevated serum IL-10 levels in diffuse large B-cell lymphoma: a mechanism of aberrant JAK2 activation

Cytokines are deregulated in cancers and can contribute to tumor growth. In patients with diffuse large-cell lymphoma (DLBCL), we observed higher levels of JAK/STAT pathway-related serum cytokines (ie, IL-6, IL-10, epidermal growth factor, and IL-2) compared with controls. Of these, only IL-10 activated the JAK2 pathway in lymphoma cells in vitro. Patients with high serum IL-10 had shorter event-free survival (EFS) than patients with low levels (P > .01) and high IL-10 was correlated with high lactase dehydrogenase (P = .0085) and higher International Prognostic Index scores (P = .01). To explore the mechanism by which IL-10 may contribute to an inferior EFS, we investigated the effect of IL-10 on the JAK2 pathway and found that the IL-10/IL-10 receptor complex up-regulated JAK2 signaling. Neutralizing Ab to IL-10 inhibited constitutive and IL-10–induced JAK2/STAT3 phosphorylation. JAK2 inhibition dephosphorylated JAK2 and STAT3 and caused an inhibitory effect on phospho-JAK2–positive DLBCL cells; there was a minimal effect on phospho-JAK2–negative cells. Apoptosis induced by JAK2 inhibition was dependent on inhibition of autocrine IL-10 and c-myc expression and independent of Bcl-2 family expression. These results provide the rationale for testing JAK2 inhibitors in DLBCL patients, and indicate that serum IL-10 may be a biomarker to identify patients more likely to respond to JAK2-targeted therapy