A Declaration of the State of the Colony: Photographic facsimile edition

Edward Waterhouse’s Declaration of the State of the Colony is the Virginia Company\u27s official response to the Powhatan attack on the plantation in the spring of 1622. The attack, often called the “Jamestown Massacre,” cost the lives of 25% of the population of the colony (individually listed by Waterhouse in a harrowing catalog of the dead). It led to massive retaliation by the English. It also significantly changed the ideological basis of the colonial project in Virginia from one based on naïve hopes that Indians would voluntarily subordinate themselves to the English towards an aggressive colonialism of dispossession. Waterhouse’s text also sought to reassure potential English investors and migrants that the attack would prove a boon to the colony. For this reason, he appended to his account a treatise on the Northwest Passage by Henry Briggs, an account of the charitable donations the colony had secured, and a broadside containing information about the supplies needed by colonists. The British Virginia edition of Waterhouse’s Declaration, edited and introduced by Dylan Ruediger, is the most accessible edition of the text available to students and scholars. It is presented here in two formats, a photographic facsimile of this rare text featuring searchable, full color images of the copy held by the Virginia Historical Society (F229 .W32 1622), and a type facsimile that retains original spelling and layout.https://scholarscompass.vcu.edu/britva/1003/thumbnail.jp

The nucleophillic substitution of various chloroanthraquinones of their possible rearrangement via aryne intermediates

The work in this thesis deals mainly with nucleophilic substitution of chloroanthraquinones as a route to various starting materials which might rearrange, via aryne intermediates to afford fused-ring heterocy1ic carboxylic acids. 1-Amino-5-chloroanthraquinone was successfully prepared by reacting 1,5-dichloroanthraquinone with sodium aZide in ref1uxing dimethylsulfoxide (DMSO). It could also be prepared from the same starting material by reaction with ammonia (gas) in DMSO in the presence of potassium fluoride. Treatment of l-amino-5-chloroanthraquinone with potassium amide in liquid ammonia or with potassium t-butoxide in t-butylbenzene returned mainly starting material, although in the latter case some 1-amino-5-hydroxyanthraquinone was also isolated. 1-Hydroxy-5-chloroanthraquinone was ultimately prepared by diazotization of the amino-analog. It was recovered almost quantitatively after treatmenu'with potassium amide in liquid ammonia. The reaction with potassium t-butoxide in t-buty1benzene was anomalous and gave 1-hydroxyanthraquinone as the only iso1able product. Acridines were successfully prepared by the action of 70% sulfuric acid on 1,5-bis(p-toluidino)-anthraquinone and 1-p-toluidino-5- ch10roanthraquinone, and in the latter case, cleavage to give an acridinecarboxylate was attempted. Substituted anthraquinones reacted with sodium azide in sulfuric acid to give azepindiones by -NH insertion. Methods for separating and identifying isomeric mixtures of these compounds were examined. Attempted decarbonylation of selected azepindiones to give acridones gave mainly what were thought to be amino-benzophenone derivatives. Chloroanthraquinones were found to react with hexamethylphosphoramide (HMPA) to give mixtures of the dimethylamino- and methylaminoderivatives. Under the same conditions halogeno-nitrobenzenes and nitrophenols were substituted to give the appropriate dimethyl aminobenzenes, except in two cases. 3-Chloronitrobenzene reacted anomalously to give a small amount of 3,3'-dichloroazobenzene and a trace of 4-dimethylamino-nitrobenzene. Pentachlorophenol reacted to give a pentachlorophenylphosphorodiamidate in good yield

Generative Active Learning for the Search of Small-molecule Protein Binders

Despite substantial progress in machine learning for scientific discovery in recent years, truly de novo design of small molecules which exhibit a property of interest remains a significant challenge. We introduce LambdaZero, a generative active learning approach to search for synthesizable molecules. Powered by deep reinforcement learning, LambdaZero learns to search over the vast space of molecules to discover candidates with a desired property. We apply LambdaZero with molecular docking to design novel small molecules that inhibit the enzyme soluble Epoxide Hydrolase 2 (sEH), while enforcing constraints on synthesizability and drug-likeliness. LambdaZero provides an exponential speedup in terms of the number of calls to the expensive molecular docking oracle, and LambdaZero de novo designed molecules reach docking scores that would otherwise require the virtual screening of a hundred billion molecules. Importantly, LambdaZero discovers novel scaffolds of synthesizable, drug-like inhibitors for sEH. In in vitro experimental validation, a series of ligands from a generated quinazoline-based scaffold were synthesized, and the lead inhibitor N-(4,6-di(pyrrolidin-1-yl)quinazolin-2-yl)-N-methylbenzamide (UM0152893) displayed sub-micromolar enzyme inhibition of sEH

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

The Changing Landscape for Stroke\ua0Prevention in AF: Findings From the GLORIA-AF Registry Phase 2

Background GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic treatment patterns in patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke. Phase 2 began when dabigatran, the first non\u2013vitamin K antagonist oral anticoagulant (NOAC), became available. Objectives This study sought to describe phase 2 baseline data and compare these with the pre-NOAC era collected during phase 1. Methods During phase 2, 15,641 consenting patients were enrolled (November 2011 to December 2014); 15,092 were eligible. This pre-specified cross-sectional analysis describes eligible patients\u2019 baseline characteristics. Atrial fibrillation disease characteristics, medical outcomes, and concomitant diseases and medications were collected. Data were analyzed using descriptive statistics. Results Of the total patients, 45.5% were female; median age was 71 (interquartile range: 64, 78) years. Patients were from Europe (47.1%), North America (22.5%), Asia (20.3%), Latin America (6.0%), and the Middle East/Africa (4.0%). Most had high stroke risk (CHA2DS2-VASc [Congestive heart failure, Hypertension, Age  6575 years, Diabetes mellitus, previous Stroke, Vascular disease, Age 65 to 74 years, Sex category] score  652; 86.1%); 13.9% had moderate risk (CHA2DS2-VASc = 1). Overall, 79.9% received oral anticoagulants, of whom 47.6% received NOAC and 32.3% vitamin K antagonists (VKA); 12.1% received antiplatelet agents; 7.8% received no antithrombotic treatment. For comparison, the proportion of phase 1 patients (of N = 1,063 all eligible) prescribed VKA was 32.8%, acetylsalicylic acid 41.7%, and no therapy 20.2%. In Europe in phase 2, treatment with NOAC was more common than VKA (52.3% and 37.8%, respectively); 6.0% of patients received antiplatelet treatment; and 3.8% received no antithrombotic treatment. In North America, 52.1%, 26.2%, and 14.0% of patients received NOAC, VKA, and antiplatelet drugs, respectively; 7.5% received no antithrombotic treatment. NOAC use was less common in Asia (27.7%), where 27.5% of patients received VKA, 25.0% antiplatelet drugs, and 19.8% no antithrombotic treatment. Conclusions The baseline data from GLORIA-AF phase 2 demonstrate that in newly diagnosed nonvalvular atrial fibrillation patients, NOAC have been highly adopted into practice, becoming more frequently prescribed than VKA in Europe and North America. Worldwide, however, a large proportion of patients remain undertreated, particularly in Asia and North America. (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation [GLORIA-AF]; NCT01468701

Thermal rearrangement of 1,2-divinylcyclopropanes as applied to the total synthesis of (±)-β-himachalene and the synthesis of bicyclo [3.2.1.] octadienes

The work described in this thesis involves two separate applications of the thermal rearrangement of 1,2-divinylcyclo-propane systems in organic synthesis. In the first case, the thermal rearrangement of the 3-(cyclopropyl)enone (100) to afford the seven-membered ring annelated product (101) comprised the key step in the total synthesis of (±)-β-himachalene (3). Compound (100) was readily prepared in six steps as follows. Treatment of acrolein with 2,2-dimethyl-1,3-propanediol in the presence of p-toluenesul-fonic acid afforded the acetal (117) which reacted with dibromo-carbene under phase transfer conditions to afford the crystalline dibromocyclopropane (116) . The latter material reacted stereoselectively with n-butyllithium and iodomethane at -95°C to give predominantly the cis-methylated cyclopropane (114). Acid hydrolysis of (114) afforded (E)-2-bromo-2-methylcyclo-propanecarboxaldehyde (113) which underwent a Wittig reaction with isopropylidenetriphenylphosphorane to yield the olefin (112). Successive treatment of (112) with t-butyllithium and phenylthiocopper led to the in situ formation of a lithium phenylthiocuprate reagent (111) which reacted with 3-iodo-2-cyclohexen-1-one to give the required β-(cyclopropyl)enone (100). Thermolysis (138°C) of (100) led to the exclusive formation of the bicyclic ketone (101). Methylation of ketone (101) followed by selective catalytic hydrogenation of the disubstituted double bond gave the ketone (127). Preparation of the enol phosphate (128) of the ketone (127) and reduction of the former with lithium in ethylamine completed the successful total synthesis of (±)-β -himachalene. The thermal rearrangements of a number of 6-alkenylbicyclo-[3.1.0]hex-2-enes (221) (R₁-R₄ = Me , H) to afford the corresponding bicyclo[3.2.1]octa-2,6-dienes (222) (R₁-R₄ = Me > H) are also described. The former were readily prepared in four steps from methyl acetoacetate. Thus, the alkylation of the dianion of methyl acetoacetate with (E)-5-bromo-1,3-pentadiene, (E)-5-bromo-2-methyl-1,3-pentadiene, (2E,4E)- and (2E,4Z)-1-bromo-2-methyl-2,4-hexadiene led to a series of β-keto esters. Diazo group transfer reaction of these β-keto esters afforded the corresponding a-diazo esters which underwent a copper-catalyzed intramolecular cyclization to give the appropriate 6-exo-(1-alkenyl)bicyclo[3.1.0]hexan-2-ones. Treatment of these ketones with lithium diisopropylamide followed by trapping of the resultant lithium enolates with tert-butyldimethylsilyl chloride led to the silyl enol ethers (221). Thermolysis (138°C or 165°C) of the latter led cleanly to the desired bicyclo-[3.2.1]octa-2,6-dienes (222). These rearranged silyl enol ethers were readily deprotected to give the corresponding β-keto esters. Similarly , 1-carbornethoxy-6-exo-vinylbicyclo [3 .1. 0] hex-3-en-2-one (237) rearranged thermally to afford 1-carbomethoxy-bicyclo[3.2.1]octa-2,6-dien-8-one (240). [diagrams not included]Science, Faculty ofChemistry, Department ofGraduat

Spectroscopic and biochemical insight into an electron-bifurcating [FeFe] hydrogenase

The heterotrimeric electron-bifurcating [FeFe] hydrogenase (HydABC) from Thermotoga maritima (Tm) couples the endergonic reduction of protons (H+) by dihydronicotinamide adenine dinucleotide (NADH) ( increment G(0) approximate to 18 kJ mol(-1)) to the exergonic reduction of H+ by reduced ferredoxin (Fd(red)) ( increment G(0) approximate to - 16 kJ mol(-1)). The specific mechanism by which HydABC functions is not understood. In the current study, we describe the biochemical and spectroscopic characterization of TmHydABC recombinantly produced in Escherichia coli and artificially maturated with a synthetic diiron cofactor. We found that TmHydABC catalyzed the hydrogen (H-2)-dependent reduction of nicotinamide adenine dinucleotide (NAD(+)) in the presence of oxidized ferredoxin (Fd(ox)) at a rate of approximate to 17 mu mol NADH min(-1) mg(-1). Our data suggest that only one flavin is present in the enzyme and is not likely to be the site of electron bifurcation. FTIR and EPR spectroscopy, as well as FTIR spectroelectrochemistry, demonstrated that the active site for H-2 conversion, the H-cluster, in TmHydABC behaves essentially the same as in prototypical [FeFe] hydrogenases, and is most likely also not the site of electron bifurcation. The implications of these results are discussed with respect to the current hypotheses on the electron bifurcation mechanism of [FeFe] hydrogenases. Overall, the results provide insight into the electron-bifurcating mechanism and present a well-defined system for further investigations of this fascinating class of [FeFe] hydrogenases. Graphic abstrac