IntCal13 and Marine13 Radiocarbon Age Calibration Curves 0-50,000 Years Cal BP

The IntCal09 and Marine09 radiocarbon calibration curves have been revised utilizing newly available and updated data sets from C measurements on tree rings, plant macrofossils, speleothems, corals, and foraminifera. The calibration curves were derived from the data using the random walk model (RWM) used to generate IntCal09 and Marine09, which has been revised to account for additional uncertainties and error structures. The new curves were ratified at the 21st International Radiocarbon conference in July 2012 and are available as Supplemental Material at www.radiocarbon.org. The database can be accessed at http://intcal.qub.ac.uk/intcal13/.

Pre-clinical development of a combination microbicide vaginal ring containing dapivirine and darunavir

Objectives: Combination microbicide vaginal rings may be more effective than single microbicide rings at reducing/preventing sexual transmission of HIV. Here, we report the preclinical development and macaque pharmacokinetics of matrix-type silicone elastomer vaginal rings containing dapivirine and darunavir.

Methods: Macaque rings containing 25 mg dapivirine, 300 mg darunavir and 100 mg dapivirine, and 300 mg darunavir were manufactured and characterised by differential scanning calorimetry. In vitro release was assessed into isopropanol/water and simulated vaginal fluid. Macaque vaginal fluid and blood serum concentrations for both antiretrovirals were measured during 28-day ring use. Tissue levels were measured on day 28. Ex vivo challenge studies were performed on vaginal fluid samples and IC50 values calculated.

Results: Darunavir caused a concentration-dependent reduction in the dapivirine melting temperature in both solid drug mixes and in the combination ring. In vitro release from rings was dependent on drug loading, the number of drugs present, and the release medium. In macaques, serum concentrations of both microbicides were maintained between 101–102 pg/mL. Vaginal fluid levels ranged between 103–104 ng/g and 104–105 ng/g for dapivirine and darunavir, respectively. Tissue concentrations ranges for each drug were: vagina (1.8×103–3.8×103 ng/g) > cervix (9.4×101–3.9×102 ng/g) > uterus (0–108 ng/g) > rectum (0–40 ng/g). Measured IC50 values were > 2 ng/mL for both compounds.

Conclusions: Based on these results, and in light of recent clinical progress of the 25mg dapivirine ring, a combination vaginal ring containing dapivirine and darunavir is a viable second-generation HIV microbicide candidate.

Dichloridobis(picolinohydrazide)cadmium(II)

The title compound, [CdCl2(C6H7N3O)(2)], was obtained unintentionally as a product of an attempted reaction of CdCl2 center dot 2.5H(2)O and picolinic acid hydrazide, in order to obtain a cadmium(II) complex analogous to a 15-metallacrown-5 complex of the formula [MCu5L5]X-n, with M = a central metal ion, L = picolinic acid hydrazide and X = Cl- , but with cadmium the only metal present. The coordination geometry around the Cd-II atom can be considered as distorted octahedral, with two bidentate picolinic acid hydrazide ligands, each coordinating through their carbonyl O atom and amino N atom, and two chloride anions. In the crystal structure, intermolecular N-H center dot center dot center dot Cl and N-H center dot center dot center dot N hydrogen bonds link the molecules into a two-dimensional network parallel to the ( 100) plane. The pyridine rings of adjacent networks are involved in pi-pi stacking interactions, the minimum distance between the ring centroids being 3.693 (2) angstrom.

Hydroclimatic changes during the 8.2 ka event inferred from Irish subfossil pines

A significant cold event, derived from the Greenland ice cores, took place between 8200 and 8000 cal. BP. Modeling of the event suggests that higher northern latitudes would have experienced considerable decreases in precipitation and that Ireland would have witnessed one of the greatest depressions. However, no well-dated proxy record exists from the British Isles to test the model results. Here we present independent evidence for a phase of major pine recruitment on Irish bogs at around 8150 cal. BP. Dendrochronological dating of subfossil trees from three sites reveal synchronicity in germination across the region, indicative of a regional forcing, and allows for high-precision radiocarbon based dates. The inner-rings of 40% of all samples from the north of Ireland dating to the period 8,500-7,500 cal. BP fall within a 25-year window. The concurrent colonization of pine on peatland is interpreted as drier conditions in the region and provide the first substantive proxy data in support of a significant hydrological change in the north of Ireland accompanying the 8.2 ka event. Our results also indicate that the apparent temporal asynchrony between anomalies in proxy records at the time could be a result of differences in dating methods.

Hydroclimatic changes during the 8.2 ka event revealed by Irish pines

A pivotal cold event, deduced from the Greenland ice cores, took place between 8200 and 8000 cal. BP. Modelling of this climatic episode suggests that higher northern latitudes would have also experienced substantial reduction in rainfall and that Ireland would have observed a notable decline. No well-dated proxy record exists from the British Isles to test the model results. We present significant independent data for a phase of increased Scots pine initiation on Irish bogs at around 8150 cal. BP. Dendrochronological dating of sub-fossil Scots pine trees from three locations reveals synchronicity in germination across the area, indicative of a regional forcing, and allows for high-precision radiocarbon based dates. The starting rings of 40% of all samples from the north of Ireland dating to the period 8500-7500 cal. BP fall within a period of 25 years. The present colonisation model of Scots pine on peatland is interpreted as increasing drier conditions in the region and provides the first meaningful proxy data in support of a significant hydrological change in the north of Ireland accompanying the 8.2 ka event. The dating uncertainties associated with the Irish Scots pine record and the Greenland Ice Core Chronology 2005 (GICC05) do not allow for any overlap between the two. The results indicate that the discrepancy could be a result of dating inaccuracy that could have affected analysis of prior proxy alignments.

Impaired activities of antioxidant enzymes elicit endothelial dysfunction in spontaneous hypertensive rats despite enhanced vascular nitric oxide generation

Objective: Enhanced oxidative stress is involved in mediating the endothelial dysfunction associated with hypertension. The aim of this study was to investigate the relative contributions of pro-oxidant and anti-oxidant enzymes to the pathogenesis of endothelial dysfunction in genetic hypertension. Methods: Dilator responses to endothelium-dependent and endothelium-independent agents such as acetylcholine (ACh) and sodium nitroprusside were measured in the thoracic aortas of 28-week-old spontaneously hypertensive rats (SHR) and their matched normotensive counterparts, Wistar Kyoto rats (WKY). The activity and expression (mRNA and protein levels) of endothelial nitric oxide synthase (eNOS), p22-phox, a membrane-bound component of NAD(P)H oxidase, and antioxidant enzymes, namely, superoxide dismutases (CuZn- and Mn-SOD), catalase and glutathione peroxidase (GPx), were also investigated in aortic rings. Results: Relaxant responses to ACh were attenuated in phenylephrine-precontracted SHR aortic rings, despite a 2-fold increase in eNOS expression and activity. Although the activity and/or expression of SODs, NAD(P)H oxidase (p22-phox) and GPx were elevated in SHR aorta, catalase activity and expression remained unchanged compared to WKY. Pretreatment of SHR aortic rings with the inhibitor of xanthine oxidase, allopurinol, and the inhibitor of cyclooxygenase, indomethacin, significantly potentiated ACh-induced relaxation. Pretreatment of SHR rings with catalase and Tiron, a superoxide anion (O) scavenger, increased the relaxant responses to the levels observed in WKY rings whereas pyrogallol, a O -generator, abolished relaxant responses to ACh. Conclusion: These data demonstrate that dysregulation of several enzymes, resulting in oxidative stress, contributes to the pathogenesis of endothelial dysfunction in SHR and indicate that the antioxidant enzyme catalase is of particular importance in the reversal of this defect. © 2003 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.

Efficacy of Tenofovir 1% Vaginal Gel in Reducing the Risk of HIV-1 and HSV-2 Infection

Human Immunodeficiency Virus (HIV) is a retrovirus that can result in rare opportunistic infections occurring in humans. The onset of these infections is known as Acquired Immune Deficiency Syndrome (AIDS). Sexual transmission is responsible for the majority of infections 1, resulting in transmission of HIV due to infected semen or vaginal and cervical secretions containing infected lymphocytes. HIV microbicides are formulations of chemical or biological agents that can be applied to the vagina or rectum with the intention of reducing the acquisition of HIV. Tenofovir is an NRTI that is phosphorylated by adenylate kinase to tenofovir diphosphate, which in turn competes with deoxyadeosine 5’-triphosphate for incorporation into newly synthesized HIV DNA. Once incorporated, tenofovir diphosphate results in chain termination, thus inhibiting viral replication. Tenofovir has been formulated into a range of vaginal formulations, such as rings, tablets gels and films. It has been shown to safe and effective in numerous animal models, while demonstrating safety and acceptability in numerous human trials. The most encouraging results came from the CAPRISA 004 clinical trial which demonstrated that a 1% Tenofovir vaginal gel reduced HIV infection by approximately 39%.

A Combination Vaginal Ring Releasing Dapivirine and Darunavir

Background: Combination microbicide vaginal rings, containing two or more antiretrovirals targeting different steps in the HIV replicative process, may be more effective than single microbicide products at preventing sexual transmission of HIV. Here, we report the preclinical development, including in vitro release and macaque pharmacokinetics, of matrix-type silicone elastomer rings containing dapivirine (DPV; an experimental non-nucleoside reverse transcriptase inhibitor) and darunavir (DRV; a marketed protease inhibitor). Methods: Macaque rings containing 25 mg DPV, 300 mg DRV and 100 mg DPV, and 300 mg DRV were manufactured and characterised by differential scanning calorimetry. In vitro release was assessed into isopropanol/water and simulated vaginal fluid. Macaque vaginal fluid and blood serum concentrations for both antiretrovirals were measured during 28-day ring use. Tissue levels were measured on day 28. Ex vivo challenge studies were performed on vaginal fluid samples and IC50 values calculated.
Results: DRV caused a concentration-dependent reduction in the DPV melting temperature in both solid drug mixes and in the combination ring. In vitro release from rings was dependent on drug loading, the number of drugs present, and the release medium. In macaques, serum concentrations of both
microbicides were maintained between 101-102 pg/mL. Vaginal fluid levels
ranged between 103-104 ng/g and 104-105 ng/g for DPV and DRV, respectively. Vaginal tissue concentrations decreased in rank order: vagina
(1.8×103-3.8×103 ng/g) > cervix (9.4×101-3.9×102 ng/g) > uterus (0-108 ng/g) > rectum (0-40 ng/g). Measured IC50 values (HIV-1 BaL) determined from macaque vaginal fluid samples were < 2 ng/mL for both compounds. Conclusions: Based on these results, and in light of the ongoing clinical progress of the 25mg DPV ring, a combination vaginal ring containing DPV and DRV is a viable second-generation HIV microbicide candidate.

Lack of in vitro-in vivo correlation for a UC781-releasing vaginal ring in macaques

This study describes the preclinical development of a matrix-type silicone elastomer vaginal ring device designed to provide controlled release of UC781, a non-nucleoside re- verse transcriptase inhibitor. Testing of both human- and macaque-sized rings in a sink condition in vitro release model demonstrated continuous UC781 release in quantities consid- ered sufficient to maintain vaginal fluid concentrations at levels 82–860-fold higher than the in vitro IC50 (2.0 to 10.4 nM) and therefore potentially protect against mucosal trans- mission of HIV. The 100-mg UC781 rings were well tolerated in pig-tailed macaques, did not induce local inflammation as determined by cytokine analysis and maintained median con- centrations in vaginal fluids of UC781 in the range of 0.27 to 5.18 mM during the course of the 28-day study. Analysis of residual UC781 content in rings after completion of both the in vitro release and macaque pharmacokinetic studies revealed that 57 and 5 mg of UC781 was released, respectively. The pharmacokinetic analysis of a 100-mg UC781 vaginal ring in pig-tailed macaques showed poor in vivo–in vitro correlation, attributed to the very poor solubility of UC781 in vaginal fluid and resulting in a dissolution-controlled drug release mecha- nism rather than the expected diffusion-controlled mechanism.

Carreira Alkynylations with Paraformaldehyde. A Mild and Convenient Protocol for the Hydroxymethylation of Complex Base-SensitiveTerminal Acetylenes via Alkynylzinc Triflates

A new synthetic protocol for the hydroxymethylation of terminal acetylenes is described that involves stoichiometric Carreira alkynylation with solid paraformaldehyde (HO[CH₂O]_nH) in PhMe at 60 ^oC. Significantly, the method can be successfully applied on acetylenes that possess base-sensitive ester functionality and heterocyclic rings that readily undergo metallation. While N-methylephedrine (NME) is generally the best Zn(OTf)₂-coordinating ligand for promoting hydroxymethylation, TMEDA can serve as a replacement.

Bis(1,4,7-trithiacyclononane-S,S ',S '')nickel(II) dibromide tetrahydrate

The Ni-II centre in the cation of the title compound, [Ni(C6H12S3)(2)]Br-2. 4H(2)O, occupies a crystallographic inversion centre and is octahedrally coordinated by six S-donors from two [9]aneS(3) ligands. Ni-S distances range from 2.3749 (16) to 2.4077 (15) Angstrom and S-Ni-S angles where both thia donors belong to the same ligand lie in a narrow range between 88.09 (5) and 88.67 (6)degrees. The water molecules participate in extensive hydrogen bonding with each other and with the Br- anions to form double chains with eight- and 12-membered hydrogen-bonded rings running along the crystallographic a direction.

A Temperature-Monitoring Vaginal Ring for Measuring Adherence

Background

Product adherence is a pivotal issue in the development of effective vaginal microbicides to reduce sexual transmission of HIV. To date, the six Phase III studies of vaginal gel products have relied primarily on self-reporting of adherence. Accurate and reliable methods for monitoring user adherence to microbicide-releasing vaginal rings have yet to be established.

Methods

A silicone elastomer vaginal ring prototype containing an embedded, miniature temperature logger has been developed and tested in vitro and in cynomolgus macaques for its potential to continuously monitor environmental temperature and accurately determine episodes of ring insertion and removal.

Results

In vitro studies demonstrated that DST nano-T temperature loggers encapsulated in medical grade silicone elastomer were able to accurately and continuously measure environmental temperature. The devices responded quickly to temperature changes despite being embedded in different thickness of silicone elastomer. Prototype vaginal rings measured higher temperatures compared with a subcutaneously implanted device, showed high sensitivity to diurnal fluctuations in vaginal temperature, and accurately detected periods of ring removal when tested in macaques.

Conclusions

Vaginal rings containing embedded temperature loggers may be useful in the assessment of product adherence in late-stage clinical trials.

A revised age of AD 667-699 for the latest major eruption at Rabaul

The most recent major eruption at Rabaul was one of the largest known events at this complex system, having a VEI rating of 6. The eruption generated widespread airfall pumice lapilli and ash deposits and ignimbrites of different types. The total volume of pyroclastic material produced in the eruption exceeded 11 km3 and led to a new phase of collapse within Rabaul Caldera. Initial 14C dating of the eruptive products yielded an age of about 1400 yrs BP, and the eruption became known as the "1400 BP" eruption. Previous analyses of the timing of the eruption have linked it to events in AD 536 and AD 639. However, we have re-evaluated the age of the eruption using the Bayesian wiggle-match radiocarbon dating method, and the eruption is now thought to
have occurred in the interval AD 667-699. The only significant equatorial eruptions recorded in both Greenland and Antarctic ice during this interval are at AD 681 and AD 684, dates that coincide with frost rings in bristlecone pines of western USA in the same years. Definitively linking the Rabaul eruption to this narrow age range will require identification of Rabaul tephra in the ice records. However, it is proposed that a new working hypothesis for the timing of the most recent major eruption at Rabaul is that it occurred in the interval AD 681-684.

Timing and climate forcing of volcanic eruptions for the past 2,500 years

Volcanic eruptions contribute to climate variability, but quantifying these contributions has been limited by inconsistencies in the timing of atmospheric volcanic aerosol loading determined from ice cores and subsequent cooling from climate proxies such as tree rings. Here we resolve these inconsistencies and show that large eruptions in the tropics and high latitudes were primary drivers of interannual-to-decadal temperature variability in the Northern Hemisphere during the past 2,500 years. Our results are based on new records of atmospheric aerosol loading developed from high-resolution, multi-parameter measurements from an array of Greenland and Antarctic ice cores as well as distinctive age markers to constrain chronologies. Overall, cooling was proportional to the magnitude of volcanic forcing and persisted for up to ten years after some of the largest eruptive episodes. Our revised timescale more firmly implicates volcanic eruptions as catalysts in the major sixth-century pandemics, famines, and socioeconomic disruptions in Eurasia and Mesoamerica while allowing multi-millennium quantification of climate response to volcanic forcing.

Nong Thale Pron - a key site from southern Thailand for studying monsoon variability during the past 15000 years

Studies of marine sediments, cave speleothemes, annually laminated corals, and tree rings from Asian monsoon regions have added knowledge to our understanding of the factors that control inter-annual to millennial monsoon variability in the past and have provided important constraints for climate modeling scenarios. In contrast, the spatial and temporal pattern of sub-millennial scale monsoon variability and its impact on land cover in SE Asia are still unresolved. This shortcoming stems from the fact that temporally well-resolved paleo-environmental studies are missing from large parts of SE Asia, especially from Thailand. Given that global and regional climate models are increasingly using terrestrial paleo- data to test their performance, past changes in land cover are therefore important variables to better understand feedbacks between different Earth systems. We obtained sediments from Lake Nong Thale Pron, in southern Thailand (8º 10`N, 99 º23`E; 380 m.asl). The aim of our study is to reconstruct lake status changes and to evaluate whether the extent of these changes are linked to known shifts in monsoon intensity and variability. Preliminary results show that lake infilling started more than 15,000 years ago and that the sediments cover the last deglaciation and the Holocene. Current analyses include Itrax XRF core scanning, loss-on-ignition (LOI at 950 and 550ºC), CN elemental and isotopic composition. We expect that our results will be able to give a picture of how the lake's status has changed over time and whether the extent of these changes is linked to known shifts in monsoon intensity and variability.