Peptide nucleic acid–DNA duplexes: Long range hole migration from an internally linked anthraquinone

The discovery that peptide nucleic acids (PNA) mimic DNA and RNA by forming complementary duplex structures following Watson–Crick base pairing rules opens fields in biochemistry, diagnostics, and medicine for exploration. Progress requires the development of modified PNA duplexes having unique and well defined properties. We find that anthraquinone groups bound to internal positions of a PNA oligomer intercalate in the PNA–DNA hybrid. Their irradiation with near-UV light leads to electron transfer and oxidative damage at remote GG doublets on the complementary DNA strand. This behavior mimics that observed in related DNA duplexes and provides the first evidence for long range electron (hole) transport in PNA–DNA hybrid. Analysis of the mechanism for electron transport supports hole hopping.

Fatal embryonic bleeding events in mice lacking tissue factor, the cell-associated initiator of blood coagulation.

Tissue factor (TF) is the cellular receptor for coagulation factor VI/VIIa and is the membrane-bound glycoprotein that is generally viewed as the primary physiological initiator of blood coagulation. To define in greater detail the physiological role of TF in development and hemostasis, the TF gene was disrupted in mice. Mice heterozygous for the inactivated TF allele expressed approximately half the TF activity of wild-type mice but were phenotypically normal. However, homozygous TF-/- pups were never born in crosses between heterozygous mice. Analysis of mid-gestation embryos showed that TF-/- embryos die in utero between days 8.5 and 10.5. TF-/- embryos were morphologically distinct from their TF+/+ and TF+/- littermates after day 9.5 in that they were pale, edematous, and growth retarded. Histological studies showed that early organogenesis was normal. The initial failure in TF-/- embryos appeared to be hemorrhaging, leading to the leakage of embryonic red cells from both extraembryonic and embryonic vessels. These studies indicate that TF plays an indispensable role in establishing and/or maintaining vascular integrity in the developing embryo at a time when embryonic and extraembryonic vasculatures are fusing and blood circulation begins.

Urokinase-type plasminogen activator is effective in fibrin clearance in the absence of its receptor or tissue-type plasminogen activator.

The availability of gene-targeted mice deficient in the urokinase-type plasminogen activator (uPA), urokinase receptor (uPAR), tissue-type plasminogen activator (tPA), and plasminogen permits a critical, genetic-based analysis of the physiological and pathological roles of the two mammalian plasminogen activators. We report a comparative study of animals with individual and combined deficits in uPAR and tPA and show that these proteins are complementary fibrinolytic factors in mice. Sinusoidal fibrin deposits are found within the livers of nearly all adult mice examined with a dual deficiency in uPAR and tPA, whereas fibrin deposits are never found in livers collected from animals lacking uPAR and rarely detected in animals lacking tPA alone. This is the first demonstration that uPAR has a physiological role in fibrinolysis. However, uPAR-/-/tPA-/- mice do not develop the pervasive, multi-organ fibrin deposits, severe tissue damage, reduced fertility, and high morbidity and mortality observed in mice with a combined deficiency in tPA and the uPAR ligand, uPA. Furthermore, uPAR-/-/tPA-/- mice do not exhibit the profound impairment in wound repair seen in uPA-/-/tPA-/- mice when they are challenged with a full-thickness skin incision. These results indicate that plasminogen activation focused at the cell surface by uPAR is important in fibrin surveillance in the liver, but that uPA supplies sufficient fibrinolytic potential to clear fibrin deposits from most tissues and support wound healing without the benefit of either uPAR or tPA.

Ultra-low concentrations of naloxone selectively antagonize excitatory effects of morphine on sensory neurons, thereby increasing its antinociceptive potency and attenuating tolerance/dependence during chronic cotreatment.

Ultra-low picomolar concentrations of the opioid antagonists naloxone (NLX) and naltrexone (NTX) have remarkably potent antagonist actions on excitatory opioid receptor functions in mouse dorsal root ganglion (DRG) neurons, whereas higher nanomolar concentrations antagonize excitatory and inhibitory opioid functions. Pretreatment of naive nociceptive types of DRG neurons with picomolar concentrations of either antagonist blocks excitatory prolongation of the Ca(2+)-dependent component of the action potential duration (APD) elicited by picomolar-nanomolar morphine and unmasks inhibitory APD shortening. The present study provides a cellular mechanism to account for previous reports that low doses of NLX and NTX paradoxically enhance, instead of attenuate, the analgesic effects of morphine and other opioid agonists. Furthermore, chronic cotreatment of DRG neurons with micromolar morphine plus picomolar NLX or NTX prevents the development of (i) tolerance to the inhibitory APD-shortening effects of high concentrations of morphine and (ii) supersensitivity to the excitatory APD-prolonging effects of nanomolar NLX as well as of ultra-low (femtomolar-picomolar) concentrations of morphine and other opioid agonists. These in vitro studies suggested that ultra-low doses of NLX or NTX that selectively block the excitatory effects of morphine may not only enhance the analgesic potency of morphine and other bimodally acting opioid agonists but also markedly attenuate their dependence liability. Subsequent correlative studies have now demonstrated that cotreatment of mice with morphine plus ultra-low-dose NTX does, in fact, enhance the antinociceptive potency of morphine in tail-flick assays and attenuate development of withdrawal symptoms in chronic, as well as acute, physical dependence assays.

Costa Blanca: Public Space And Perceived Image as Key to Tourism Competitiveness

Los destinos turísticos tradicionales del litoral español se enfrentan a profundas transformaciones debidas a varios factores, entre los que se encuentran cambios notables en el comportamiento de la demanda y un intenso crecimiento de la competencia a todos los niveles, que puede poner en duda la pervivencia del modelo de desarrollo de estas áreas maduras. Lejos de ser una excepción, la situación que se describe para la Costa Blanca es extrapolable a otros destinos turísticos en otras regiones y en ámbitos urbanos, que se enfrentan al reto de incorporar nuevas estrategias de renovación, diversificación y reestructuración de su tejido urbano y turístico, como clave de reorientación de su ciclo de vida. A partir del estudio del caso de la Costa Blanca, pero con una vocación globalizadora, se tratan a continuación argumentos referidos a los cambios en la demanda turística y de ocio cotidiano, y cómo ello afecta a la necesidad de intervenir de un modo distinto en el diseño y gestión del tejido urbano que perciben los visitantes y residentes. Se percibe de forma clara que se ha de trabajar de un modo distinto tanto la escena urbana como el territorio turístico a partir de la potenciación de valores diferenciadores: por una adecuada intervención urbanística en los espacios públicos con acciones capaces de distinguir al destino de sus competidores, por la incorporación de nuevos elementos de atracción e innovación urbana, o por una gestión más eficiente de los servicios y las funciones urbanas de los destinos turísticos. A partir de varios indicadores se demuestra que la competitividad de los destinos tradicionales, sean áreas costeras o ciudades, ya no sólo reside en sus recursos patrimoniales, litorales o climáticos, sino que su valor diferenciador se vincula también a la calidad urbana percibida y a la capacidad de incorporar en las acciones de futuro las nuevas necesidades de residentes y visitantes, cada vez más exigentes e impredecibles.

Bill of disbursments [for the] sch[oone]r Lydia : manuscript, 1790

List of ship's expenses between Feb. 7 and May 25; dated at Aux Cayes, (Haiti) May 27, 1790; includes money paid to an interpreter at Tobago, workers for ship maintenance, and various harbor officials; and notation of purchases for goods such as sugar, coffee, rice, tar, food, and rum.

Account book of Andrew Croswell, 1794-1802

Andrew Croswell kept this account book while an undergraduate at Harvard College. It contains entries from 1794, the year he entered, until his graduation in 1798. There is also one entry on the back cover apparently made in 1802. The entries, divided by school term, are very detailed. Croswell indicates the cost of the following, among many other expenses and purchases: transportation, most often to Hingham and Plymouth; payment for "passing the bridge"; candles; hiring a horse; wood and having it cut; laundry; quills and pencils; paper and ink; razors, haircuts, hair ribbons; a trunk; clothing and cloth for trousers; furniture; tickets to the theater; door locks; a bowl and spoon; "batts and balls" and "other necessaries"; tobacco; toothbrushes; shoe and boot repair; fruit; wine, brandy and rum; cheese; coffee and tea; butter; lemons; sugar; and wafers. There are also entries for college-related costs, including the payment of quarter bills, buttery bills, Hasty Pudding Club dues, and a fee to the President of Harvard College related to Croswell's graduation. There are also entries pertaining to the cost of celebrating various special occasions, including Election Day, Christmas Eve, "Independent Day," and George Washington's birthday.

William Blair Townsend letter and receipt books, 1743-1805, bulk 1744-1777

The collection consists of two volumes, which date from 1743 to 1805, spanning his whole career as a merchant. Volume one is a letter book containing Townsend's business correspondence from November 23, 1743 to December 12, 1774. Most of the letters were written to American (many in North Carolina) and British (predominately in London) merchants. His earliest letters document his efforts to establish himself as a trader. Over time his letters turn to illustrate the common problems faced by many merchants: damaged goods, overpriced goods, embargos, and high freight costs. Particularly enlightening are his comments on the challenges of doing business throughout the French and Indian War and the years leading up to the American Revolution. He most frequently corresponded with London merchants Champion & Hayley, Lane & Booth, Lane Son & Fraser, Harrison & Ansley, and Leeds merchant Samuel Elam. In addition he frequently corresponded with Eliakim Palmer, colonial agent and merchant in London, as well as Dr. Walley Chauncy of North Carolina. He dealt in a wide variety of goods including molasses, rum, tar, medicines, pitch, saddles, tallow, hides, skins, pickled beef and pork, and wine. The letters also document Townsend's involvement in the slave trade through his occasional purchases of slaves.

Receipt book of Francis Kittredge, 1780

Contains instructions for preparing and administering medicine for adults and children, and generalized uses for certain ingredients, written by Dr. Francis Kittredge. Preparations include ointment for scurvy, bone ointment, nerve ointments, procedures to soothe a sore mouth and to stop excessive bleeding, and treatment to kill worms. The materials used to prepare bone ointment include fresh butter, hog fat, chamomile, garlic, and night shade, among other ingredients. The recipe for “simple nerve ointment” instructs the preparer to simmer half a pint of neet foot oil, a pint of rum, and one jell of oil of turpentine over a “gentle fire.” Kittredge writes that oil of St. John’s Wort is effective in treating swelling of the legs, for cold and aches, and for burning and scalds, while oil of Elderflower is indicated for belly aches. The manuscript is housed in a binding created by the Harvard Medical School library. Tipped into the binding is one letter from Frederick O. West, M.D., Harvard Medical School, Boston, Massachusetts, that accompanied his donation of the Kittredge receipt book to the library in 1919. There is also one letter of unknown provenance enclosed with the receipt book, which contains an inventory of the estate of Antipas Brigham, of Grafton, Massachusetts, signed by Worcester County Judge Joseph Wilder on 7 November 1749. It is unclear if this letter has any connection to Frederick O. West or Francis Kittredge.

Pollen record and age determiation of sediments from the Labaz Lake area

Pollen records from perennially frozen sequences provide vegetation and climate reconstruction for the last 48,000 14C years in the central part of Taymyr Peninsula. Open larch forest with Alnus fruticosa and Betula nana grew during the Kargin (Middle Weichselian) Interstade, ca. 48,000-25,000 14C yr B.P. The climate was generally warmer and wetter than today. Open steppe-like communities with Artemisia, Poaceae, Asteraceae, and herb tundralike communities with dwarf Betula and Salix dominated during the Sartan (Late Weichselian) Stade, ca. 24,000-10,300 14C yr B.P. The statistical information method used for climate reconstruction shows that the coldest climate was ca. 20,000-17,000 14C yr B.P. A warming (Allerød Interstade?) with mean July temperature ca. 1.5°C warmer than today occurred ca. 12,000 14C yr B.P. The following cooling with temperatures about 3°-4°C cooler than present and precipitation about 100 mm lower corresponds well with the Younger Dryas Stade. Tundra-steppe vegetation changed to Betula nana-Alnus fruticosa shrub tundra ca. 10,000 14C yr B.P. Larch appeared in the area ca. 9400 14C yr B.P. and disappeared after 2900 14C yr B.P. Cooling events ca. 10,500, 9600, and 8200 14C yr B.P. characterized the first half of the Holocene. A significant warming occurred ca. 8500 14C yr B.P., but the Holocene temperature maximum was at about 6000-4500 14C yr B.P. The vegetation cover approximated modern conditions ca. 2800 14C yr B.P. Late Holocene warming events occurred at ca. 3500, 2000, and 1000 14C yr B.P. A cooling (Little Ice Age?) took place between 500 and 200 14C yr ago.

The late Pliocene pollen record of ODP Site 108-658 off Cape Blanc, Atlantic Ocean

A 200 m long marine pollen record from ODP Site 658 (21°N, 19°W) reveals cyclic fluctuations in vegetation and continental climate in northwestern Africa from 3.7 to 1.7 Ma. These cycles parallel oxygen isotope stages. Prior to 3.5 Ma, the distribution of tropical forests and mangrove swamps reached Cape Blanc, 5°N of the present distribution. Between 3.5 and 2.6 Ma, forests occurred at this latitude during irregular intervals and nearly disappeared afterwards. Likewise, a Saharan paleoriver flowed continuously until isotope Stage 134 (3.35 Ma). When river discharge ceased, wind transport of pollen grains prevailed over fluvial transport. Pollen indicators of trade winds gradually increased between 3.3 and 2.5 Ma. A strong aridification of the climate of northwestern Africa occurred during isotope Stage 130 (3.26 Ma). Afterwards, humid conditions reestablised followed by another aridification around 2.7 Ma. Repetitive latitudinal shifts of vegetation zones ranging from wooded savanna to desert flora dominated for the first time between between 2.6 and 2.4 Ma as a response to the glacial stages 104, 100 and 98. Although climatic conditions, recorded in the Pliocene, were not as dry as those of the middle and Late Pleistocene, latitudinal vegetation shifts near the end of the Pliocene resembled those of the interglacial-glacial cycles of the Brunhes chron.

Pollen content and radiocarbon ages of profile Delorett, Austria

A pollen profile from the highest known peatbog in the Alps is presented. The peatbog started to grow about 8000 years ago and over the last 5000 years. The influence of man on the vegetation is documented. Before the beginning of the bronze age pasturing started.

Pollen, DNA and Vegetation records from surface sediments of lacustrine lakes along a forest tundra - tundra transect at the Taymyr peninsula, northern Siberia

Reliable information of past vegetation changes are important to project future changes, especially for areas undergoing rapid transitioning such as the boreal treeline. The application of detailed sedDNA records has the potential to enhance our understanding of vegetation changes gained mainly from pollen studies of lake sediments. This study investigates sedDNA and pollen records from 31 lakes along a gradient of increasing larch forest cover in northern Siberia (Taymyr Peninsula) and compares them with vegetation field surveys within the lake's catchment. With respect to vegetation richness, sedDNA recorded 114 taxa, about half of them to species level, while pollen analyses identified 43 pollen taxa. Both approaches exceed the 31 taxa revealed by vegetation field surveys of 400 m**2 plots. From north to south, Larix percentages increase, as is consistently recorded by all three methods. Furthermore, tundra sites are separated from forested sites in the plots of the principal component analyses. Comparison of ordination results by Procrustes and Protest analyses yields a significant fit among all compared pairs of records. Despite the overall comparability of sedDNA and pollen analyses certain idiosyncrasies in the compositional signal are observed, such as high percentages of Alnus and Betula in all pollen spectra and high percentages of Salix in all sedDNA spectra. In conclusion, our results from the treeline show that sedDNA analyses perform better than pollen in recording site-specific richness (i.e. presence/absence of certain vegetation taxa in the direct vicinity of the lake) and perform as good as pollen in tracing regional vegetation composition.

Results of a sediment profile and water analyses from Lake Hancza in northeastern Poland

We investigated the sedimentary record of Lake Hancza (northeastern Poland) using a multi-proxy approach, focusing on early to mid-Holocene climatic and environmental changes. AMS 14C dating of terrestrial macrofossils and sedimentation rate estimates from occasional varve thickness measurements were used to establish a chronology. The onset of the Holocene at c. 11600 cal. a BP is marked by the decline of Lateglacial shrub vegetation and a shift from clastic-detrital deposition to an autochthonous sedimentation dominated by biochemical calcite precipitation. Between 10000 and 9000 cal. a BP, a further environmental and climatic improvement is indicated by the spread of deciduous forests, an increase in lake organic matter and a 1.7% rise in the oxygen isotope ratios of both endogenic calcite and ostracod valves. Rising d18O values were probably caused by a combination of hydrological and climatic factors. The persistence of relatively cold and dry climate conditions in northeastern Poland during the first one and a half millennia of the Holocene could be related to a regional eastern European atmospheric circulation pattern. Prevailing anticyclonic circulation linked to a high-pressure cell above the retreating Scandinavian Ice Sheet might have blocked the influence of warm and moist Westerlies and attenuated the early Holocene climatic amelioration in the Lake Hancza region until the final decay of the ice sheet.

Changes in the vegetation and trade winds in equatorial Northwest Africa 140,000-70,000 yr B.P., as deduced from two marine pollen records

The deep-sea cores M 16415-2 and M 16416-2 at about 9°N off Sierra Leone were analysed palynologically for the time interval 140,000-70,000 yr B.P. Results were presented in absolute (pollen concentration and pollen influx) and relative diagrams (pollen percentage). In a previous study it was evidenced that in northwest Africa pollen is mainly transported to the Atlantic by wind, so that the efficiency of aeolian pollen transport (pollen flux) could be used to evaluate changes in the intensity of the northeast trade winds. The glacial episodes (represented by the oxygen isotope stages 6 and 4) are characterized by strong northeast trade winds, whereas the last interglacial (stage 5) is characterized by weak trade winds. The pollen influx diagram shows that the intensity of the trade winds increased slightly during the relatively cool intervals of stage 5 (viz. 5.4 and 5.2). Tropical forest had maximally expanded around 124,000 yr B.P. (stage 5.5), around 98,000 yr B.P. (transition of stage 5.3 to 5.2), and around 70,000 yr B.P. (first part of stage 4): an increasing delay of the response of tropical forest to global intervals with maximum temperature is apparent during the last interglacial. As tropical forests need continuous humidity, the record of tropical forest monitors changes in climatic humidity south of the Sahara. During the last interglacial, the southern boundary of the Sahara shifted only little: expansions and contractions of the tropical forest area are correlated with contra-oscillations of the grass-dominated savanna zone. Great latitudinal shifts of the desert savanna boundary, on the contrary, occurred during the penultimate glacial interglacial transition (around 128,000 yr B.P.) to the north, and during the last interglacial-glacial transition (around 65,000 yr B.P.) to the south.