Exome sequencing identifies INPPL1 mutations as a cause of opsismodysplasia.

Opsismodysplasia (OPS) is a severe autosomal-recessive chondrodysplasia characterized by pre- and postnatal micromelia with extremely short hands and feet. The main radiological features are severe platyspondyly, squared metacarpals, delayed skeletal ossification, and metaphyseal cupping. In order to identify mutations causing OPS, a total of 16 cases (7 terminated pregnancies and 9 postnatal cases) from 10 unrelated families were included in this study. We performed exome sequencing in three cases from three unrelated families and only one gene was found to harbor mutations in all three cases: inositol polyphosphate phosphatase-like 1 (INPPL1). Screening INPPL1 in the remaining cases identified a total of 12 distinct INPPL1 mutations in the 10 families, present at the homozygote state in 7 consanguinous families and at the compound heterozygote state in the 3 remaining families. Most mutations (6/12) resulted in premature stop codons, 2/12 were splice site, and 4/12 were missense mutations located in the catalytic domain, 5-phosphatase. INPPL1 belongs to the inositol-1,4,5-trisphosphate 5-phosphatase family, a family of signal-modulating enzymes that govern a plethora of cellular functions by regulating the levels of specific phosphoinositides. Our finding of INPPL1 mutations in OPS, a severe spondylodysplastic dysplasia with major growth plate disorganization, supports a key and specific role of this enzyme in endochondral ossification.

Maturation and Functional Integration of New Granule Cells into the Adult Hippocampus.

The adult hippocampus generates functional dentate granule cells (GCs) that release glutamate onto target cells in the hilus and cornus ammonis (CA)3 region, and receive glutamatergic and γ-aminobutyric acid (GABA)ergic inputs that tightly control their spiking activity. The slow and sequential development of their excitatory and inhibitory inputs makes them particularly relevant for information processing. Although they are still immature, new neurons are recruited by afferent activity and display increased excitability, enhanced activity-dependent plasticity of their input and output connections, and a high rate of synaptogenesis. Once fully mature, new GCs show all the hallmarks of neurons generated during development. In this review, we focus on how developing neurons remodel the adult dentate gyrus and discuss key aspects that illustrate the potential of neurogenesis as a mechanism for circuit plasticity and function.

Life without Phd? – Phd Oxygen Sensor Proteins in Hypoxic Carcinoma Cell Survival

The microenvironment within the tumor plays a central role in cellular signaling. Rapidly proliferating cancer cells need building blocks for structures as well as nutrients and oxygen for energy production. In normal tissue, the vasculature effectively transports oxygen, nutrient and waste products, and maintains physiological pH. Within a tumor however, the vasculature is rarely sufficient for the needs of tumor cells. This causes the tumor to suffer from lack of oxygen (hypoxia) and nutrients as well as acidification, as the glycolytic end product lactate is accumulated. Cancer cells harbor mutations enabling survival in the rough microenvironment. One of the best characterized mutations is the inactivation of the von Hippel-Lindau protein (pVHL) in clear cell renal cell carcinoma (ccRCC). Inactivation causes constitutive activation of hypoxia-inducible factor HIF which is an important survival factor regulating glycolysis, neovascularization and apoptosis. HIFs are normally regulated by HIF prolyl hydroxylases (PHDs), which in the presence of oxygen target HIF α-subunit to ubiquitination by pVHL and degradation by proteasomes. In my thesis work, I studied the role of PHDs in the survival of carcinoma cells in hypoxia. My work revealed an essential role of PHD1 and PHD3 in cell cycle regulation through two cyclin-dependent kinase inhibitors (CKIs) p21 and p27. Depletion of PHD1 or PHD3 caused a cell cycle arrest and subjected the carcinoma cells to stress and impaired the survival.

Paul Williams, nephew of C. C. Chapman, Fort Worth, Texas

Studio portrait of Paul Williams, nephew of C. C. Chapman, Fort Worth, Texas. He worked in Chapman's Fullerton office, 5th floor, N. Spadra Street [now Harbor Blvd.], Fullerton, California.

Letter - American soldier's account of battles at Chippewa, Lundy's Lane and Fort Erie, 1814

Transcript (original grammar and spelling retained): My dear wife I take this time to inform you that I am well hoping that these few lines will Reach you and find you the same I shall in form you of all our Battles that we have had sence I left home we crossed in to Canada the 2 day of July and took fort Erie on the 3 day of July without loss of one man. We then marched down to Chipway eighteen miles below the Fort Erie we got there on the forth day and had our first battle on the 5 day our loss was not jistly known But the inemy loss was double to ours. The 6 day we started with the 2 Brigade to make a bridge a crost the crick two miles a bove the fort in Building the Bridge the inemy Brought up their Canon and playd upon us with their artiliery a bout two hours We drove them from the fort our loss was none the inemy loss was nineteen ciled dead on the ground we then marched to Queenston when we got thare our inemy had fledfrom the fort we then remained thair to Queenston ten days then we marched down to Fort George But that caurdly Chaney did not a rive with the fleet so we had to return back to Queenston thare was a bout six hundred militia formed on the heights of land thay fired up on us from their pickets and retreated to the mane body our flankers ciled and wounded and took about twenty before they got to the Maine body we then marched up the hill they gave us two firs but did not damage and then retreated from the field we stayed there one knight and then marched to Chipway and stayed there one night and the next day just as the sun set the first Brigade marched up in order to give them Battle a bout two miles from the Crick and began the Battle the 2 Brigade has to March up to the Niagara path and ingaged them we charged up on their artlery and took all their Canon Miller commanded the four companys that charged....the battles lasted three hours and forty minutes our loss was about 8 hundred cild and wounded our inemies loss was a bout fourteen hundred cild and wounded the next morning we Marched up in order to give them Battle a gin but thay was afraid to ingage us we then marched to Fort Erie and went to fortiffing and made a strong place the inemy folered us up and Began to cananade and held it fifty three days thay a tacked the fort the fifteenth of august thay atacked a bout one hiour be fore day Light we saw them and Blue up our maggerzean & two hundred of our inemy our loss wasa bout forty cild and wounded and our inemy loss was a bout one thousand on the 7 Day of September we atacked them and took their batteries and Broke all their canon and drove them from the field our loss was a Bout two hundred cild and wounded our inemy loss was a Bout 8 hundred cild and wounded...we crossed in to Canada with five thousand and came out with fifteen hundred we then Marched to Sackett’s harbor....am well and harty for the present....a bout comming home it uncarting for there is not any....given this winter as yet But I shall try to Come home if I Can But if I Cant I want you should take good car of the Phiddness[?] I have not Received any Money as yet But soon as I do receive some I send some home. I want you should write to me as soon as you receive this and and how Much Stock you wintor I Received your Letter with Great pleasure I feel uneasy a bout you I am a frade that you are sick or dead this is from your husband Chase Clough

Merrimack Intelligencer Vol. 5 No. 48

This was a weekly paper that was published every Saturday. The motto of the Merrimack was: "Not too rash--Yet not fearful--We aim to be just." It was published from 1808-1817. Topics of interest include: Page 1: State of New York Republicans published a statement arguing against the war and the policies of John Adams and James Madison; account of the capture of York by the Americans, 27 April 1813; Page 2: account of the capture of York by the Americans, 27 April 1813; letter from American Brig. Gen. Henry Miller to Sir John B. Warren warning the British not to execute captured U.S. citizen O'Neal; response from Sir John B. Warren to Brig. Gen. Henry Miller stating that O'Neal had been released; account of Stephen Girard buying back his ransomed ship from the British; Page 3: account of Stephen Girard buying back his ransomed ship from the British; U.S. General Harrison repels British and Indian forces that attack Fort Meigs; account of British forces capturing U.S. privateer ship Alexander; report of British forces near Newport, New York, the Delaware river, and the Potomac River; report of Indian attacks in Kaskaskia, Randolph County; report of a boat load of provisions attacked by Indians near Fort Harrison; Commodore Isaac Chauncey arrived at Sacket's Harbor to unload stores taken from York before leaving for Niagara to commence attack against Fort George; U.S. Army announcement recruiting men 18 to 45 years of age to enlist in the army;

National Intelligencer Vol. XIII, No. 1984- June 8, 1813

The Intelligencer was an American newspaper that was established, in 1800, in Washington by Samuel Harrison Smith, a young Jeffersonian- Republican from Philadelphia. The paper was a supporter of the Jefferson and Madison administrations until 1810 when it was sold to Joseph Gales Jr. from North Carolina. In 1812 William Seaton joined Gales as a publishing partner. This paper made significant contributions to the nation and wielded considerable influence in political circles during its publication. It has been praised for its "high standard of journalistic excellence and high intellectual level of its contents". (William E. Ames , National Intelligencer: Washington's Leading Political Newspaper) The Intelligencer was, until 1810, named the National Intelligencer, and Washington Advertiser. It was a tri-weekly paper and had a peak circulation of 6, 000. Publication was suspended in 1869.

National Intelligencer Vol. XVI, No. 2193- October 15, 1814

The Intelligencer was an American newspaper that was established, in 1800, in Washington by Samuel Harrison Smith, a young Jeffersonian- Republican from Philadelphia. War of 1812 related content includes: Page 1: Major General Winfield Scott's arrival in Washington escorted by Colonel Laval's cavalry; report from Sackett's Harbour on the American and British navies; a debate on a bill to temporarily remove the seat of government from the City of Washington due to the war; the Military Committee wishing to have the President commission gold medals for distinguished service for Major Generals Brown and Scott and silver medals to Brigadier Generals Ripley, Miller and Porter for their efforts at Chippewa, Erie and Niagara as well as gold medals to Brigadier General Gaines for efforts at Erie and Brigadier General Macomb for efforts at Plattsburg; resolutions of the House on the victory of Commodore Thomas Macdonough at the Battle on Lake Champlain; Page 2: more detail on the proposed removal of the seat of government from Washington; Page 3: a letter from Major General Andrew Jackson to the Secretary of War on repelling the British at Fort Bowyer on the Point of Mobile and naval battle reports on the vessels Hermes, Sophie, and Carron; a letter from Major William Lawrence to Andrew Jackson on the battle at Fort Bowyer; military promotions of Alexander Macomb, Roger Jones, J. Hindman; more on the removal of the seat of government; citizens of Washington offering to volunteer in defense of the city; banks willing to loan the government funds to re-build destroyed government buildings; assignments of Major General Scott, General Winder and Major General Gaines; report of 300 British prisoners from Fort Erie passed through Washington; Montreal newspaper report condemning Provost for his actions at the Battle of Lake Champlain; trouble with stage coaches traveling between New Haven and Bridgeport due to cannon fire; report of a British naval squadron appearing off New Port and by Long Island and New Bedford; report of enemy naval movements from Norfolk; announcement of a book entitled "A Narrative of the Battle of Bladensburg" by and officer of General Smith; Page 4: report on the amassing navy at Kingston under Drummond and the defenses at Sackett's Harbor; report of American and British naval news from Nova Scotia and the east coast; actions of the American sloop of war, The Peacock, in international waters; an enlistment announcement by Captain Perrin Willis of the 2nd Regiment Infantry; listing of American officers and privates released from parole on October 13; Other notices report on stray horses, properties for sale, runaway slaves, imprisonments, missing livestock, medical lectures at the University of Maryland, stage lines, auctions, etc. The paper was a supporter of the Jefferson and Madison administrations until 1810 when it was sold to Joseph Gales Jr. from North Carolina. In 1812 William Seaton joined Gales as a publishing partner. This paper made significant contributions to the nation and wielded considerable influence in political circles during its publication. It has been praised for its "high standard of journalistic excellence and high intellectual level of its contents". (William E. Ames , National Intelligencer: Washington's Leading Political Newspaper) The Intelligencer was, until 1810, named the National Intelligencer, and Washington Advertiser. It was a tri-weekly paper and had a peak circulation of 6, 000. Publication was suspended in 1869.

Independent Chronicle Vol. XLVI No. 3477- August 8, 1814

A semi-weekly paper that was published from 1801 to 1817. It was previously called the Independent chronicle and the universal advertiser, and was later the Independent chronicle and Boston patriot (Semiweekly). Publishers were Abijah Adams and Ebenezer Rhoades. Topics of interest in this issue include: Page 1: notice from the U.S. War Department seeking proposals for the supply of rations to troops; account of the battle of Bridgewater; list of important military figures wounded in the battle; news of prisoner exchange; Americans and the British negotiate and new prisoner exchange convention; Page 2: report of more British troops sailing to North America; report of some Indian tribes signing a treaty to fight against the British; report of battle near Detroit; report of militia moving from Fredricksburg, Virginia to Baltimore, Maryland; report of troop numbers and casualties in the battle of Bridgewater; report that Commodore Chauncey has recovered from his illness; news of American Naval forces sailing from Sackett's Harbor; Indian tribes sign peace treaty with U.S.; news of U.S. relations with Indians in the southern U.S.; account of battle of Bridgewater and list of casualties; report of the number of men killed and wounded on both sides in the battle of Chippewa; Page 3: report of surprise attack on the British; news of warship movements in and out of Halifax; frigate Java launched in Baltimore; news of British ship movements; 3 companies of Massachusetts militia arrive at Fort Warren; news of ship movements in and out of the Port of Boston; various Marshal's notices alleging U.S. ships supplying goods to the British;

The Weekly Messenger, Vol.2 No.39- July 16, 1813

A weekly newspaper that was published every Friday from 1811 to 1815.

American Mercury Newspaper, Vol. XXXI, No. 1571. August 9, 1814

A weekly newspaper published in Hartford, Connecticut by Elisha Babcock and Son, "(Printers of the Laws of the Union)". Babcock arrived in Hartford not long after the war in 1784 and created the Mercury. It became the leading Democratic newspaper in Connecticut and ceased not long after his death in 1821.

Sykes Welland Canal Collection

Alexander J. Grant was born in Banffshire Scotland. He joined the Federal Department of Railways and Canals in 1886 and began the job of chief engineer of the Welland Canal in 1919. At one time he was the president of the Engineering Institute of Canada. - Information taken from The Civil Engineer Location: Brock University Archives Source Information:

Charles Larned letter, April 3, 1813.

Charles Larned (1791-1834) was a lawyer and American military officer who served during the War of 1812. He was the son of Simon Larned (1753-1817), who served as a captain in the Revolutionary War and was a member of the United States Congress from Massachusetts from 1804-1805. Charles studied law in the office of Henry Clay in Kentucky, and was dining with a group of prominent citizens when word was received that General William Henry Harrison could soon be overpowered by General Henry Proctor. Colonel Owen, a member of the group, organized a regiment to reinforce Harrison’s troops. Larned became a member and subsequently survived the River Raisin Massacre and was later present at the Battle of the Thames. He was also part of a group of men who learned of General William Hull’s plan to surrender Detroit to the British and planned to overtake him should this occur. However, the plan failed, Hull did surrender and the men became prisoners of the British. After the war, Larned became a lawyer, and served as Attorney General of Michigan Territory during the Black Hawk War. During the cholera epidemic of 1834, he worked tirelessly to assist others, but was stricken with the disease and died. Letter Transcription: Pittsfield, April 8, 1813 I think that by this time my dear Charles you will allow I have some reason to give you a gentle reprimand for breach of duty—but I will not censure you upon suspicion maybe you have substantial reasons—at any rate one cannot very graciously reproach the other for negligence I for one am healthy as ham & that we have so seldom exchanged letters during your absence & on my honor promise to be a better girl in future—but the truth is my Dear Charles I am secretary for the Family—Mama you know never writes & James but seldom & they are all dispersed in different directions, consequently I have many calls upon my time—this to be sure is a pleasant duty & I urge it only as a slight palliation for my remissness if you should consider it as such—now I have finished my preface—I will try to be more interesting & doubtless I succeed. Our dear Father we hope & trust is now in Green Bush, where he will probably remain a month perhaps & from thence he expects to go to Sacket’s harbor—at which place you know our troops are fast collecting-- We shall hope to see him either here or there before he goes. Brother George I believe is [still] at Plattsburgh but expects soon to be removed to some other military part perhaps with Papa (I hope so at least). We have just got letters from Brothers Sylvester & Joseph at Middlebury—they are in good health. Mama has for some weeks been afflicted with an inflammation in her eyes but seems now to be convalescing. Sister Martha has been somewhat unwell for a few weeks but is now tolerably recovered. James & myself are both in our usual good health & at this time seated by the same stand, one reading, the other writing. Thus my Dear Charles have I given you an abstract history of our Family—but here indeed is a wonderful omission; not a word about Miss Harriet Hunt, who in truth ought to have been noted first but the last she’s not the least in my memory. She is much grown since you saw her, but does not speak as fluently as we could wish—a few word she can say. Probably before this you have been informed of the great loss your friend Sherrill has sustained in the death of his mother—also of the revolution that has taken place in Hackbridge as it respects the religion & morality of the place that more than one hundred on the plain have become religious converts & c—indeed I am at a loss what to say that will afford your pleasure—a narrative at this time must be gloomy indeed. The distressing situation of our country at this time would make almost any recital melancholy. The prevailing epidemic has swept off many of your acquaintance no doubt. Mrs. Dewey of Williamstown, the sister of Mrs. Danforth, has left a Husband, Children & many Friends sincerely to lament her loss—some few have died in our village, but we have escaped astonishingly –it has raged in every town about us--If we are unwilling to acknowledge a God in his mercies. I fear she shall be compelled to do it in the awfulness of his judgments.--------I am much [pleased] with our new neighbors the Parsons Wife & a Miss Woodward her cousin is a fine girl, I think, Mrs. Allen has not a handsome face but something in her manner that interests one her person I think the handsomest I ever saw & the Parson seems well pleased with his selection—Mrs. Ripley is with them this winter & will probably remain thro the summer—Her husband at [Sackett’s Harbor] little or no alteration is apparent since her marriage—she seems as gay & fond of company as ever.-------Mrs. [McKnight] it is expected will commence housekeeping in about three weeks in the house formerly occupied by Mr…. [Report] says that Mr. Goodman & Clarissa Weller are soon to be married & many other things that I must omit to mention for Mama wants a… PS reserved--now my Dear Charles remember you are considerably… & I am confident you have as much leisure as I have –… be ceremonious but write whenever I find time not & I beg… the same – I tell James I shall not send his love for he must write himself. I shall anxiously expect you to write & do not disappoint your affectionate, sister--H One word my Dear Charles from your affectionate Mother who longs to see Her Dear son Charles—but being deprived of that rich blessing at present—begs Him so to conduct that she may hope for it ere long—do you search the Scriptures and keep the Sabbath holy unto the Lord—and all the sacred Commandments of God—it is my ardent desire…He would protect, support and provide for your soul and body and believe me your affectionate friend and Mother. R Larned.

The American Mercury, 5 October 1813 (vol. 30, no. 1527) - Newspaper

Volumes of interest were published between 1812 and 1815 with articles about the War of 1812. Issue for Oct. 5, 1813 includes: A report announces the arrival of Commodore Rodgers in the U.S. frigate President, in the harbor from his "brilliant cruise" of five months. There is also a list of the captures Rodgers made during his cruise. The feature item in this issue, however, is the famous dispatch sent by Oliver Hazard Perry at the Battle of Lake Erie to General William Henry Harrison. The dispatch, taken from the Chillicothe Supporter, of Sept. 15, is datelined "U.S. Brig Niagara, off the Western Sister, head of Lake Erie, September 10th, 1813, 4 P.M.", and reads: "Dear General, we have met the enemy; and they are ours! Two ships, two brigs, one schooner and one sloop. Yours with great respect and esteem." The dispatch is signed in type: O. H. Perry.

Port Colborne Canal Entrance - Postcards

Board of six postcards of Port Colborne. First postcard, Port Colborne Harbor, Port Colborne, Ont. Second postcard, Bird's-eye view showing entrance to Welland Canal, Port Colborne, Ont. Third postcard, Harbor, Port Colborne, Ont. Fourth postcard, Harbor Port, Port Colborne, Ont. Fifth postcard, Government elevator, capacity 2,000,000 bushels, Port Colborne, Ontario. Sixth postcard, caption unknown.