How well can we quantify dust deposition to the ocean?

Deposition of continental mineral aerosols (dust) in the Eastern Tropical North Atlantic Ocean, between the coast of Africa and the Mid-Atlantic Ridge, was estimated using several strategies based on the measurement of aerosols, trace metals dissolved in seawater, particulate material filtered from the water column, particles collected by sediment traps and sediments. Most of the data used in this synthesis involve samples collected during US GEOTRACES expeditions in 2010 and 2011, although some results from the literature are also used. Dust deposition generated by a global model serves as a reference against which the results from each observational strategy are compared. Observation-based dust fluxes disagree with one another by as much as two orders of magnitude, although most of the methods produce results that are consistent with the reference model to within a factor of 5. The large range of estimates indicates that further work is needed to reduce uncertainties associated with each method before it can be applied routinely to map dust deposition to the ocean. Calculated dust deposition using observational strategies thought to have the smallest uncertainties is lower than the reference model by a factor of 2-5, suggesting that the model may overestimate dust deposition in our study area.This article is part of the themed issue 'Biological and climatic impacts of ocean trace element chemistry'.

Dansgaard-Oeschger cycles of the penultimate and last glacial period recorded in stalagmites from Türkiye.

The last glacial period is characterized by abrupt climate oscillations, also known as Dansgaard-Oeschger (D-O) cycles. However, D-O cycles remain poorly documented in climate proxy records covering the penultimate glacial period. Here we present highly resolved and precisely dated speleothem time series from Sofular Cave in northern Türkiye to provide clear evidence for D-O cycles during Marine Isotope Stage (MIS) 6 as well as MIS 2-4. D-O cycles are most clearly expressed in the Sofular carbon isotope time series, which correlate inversely with regional sea surface temperature (SST) records from the Black Sea. The pacing of D-O cycles is almost twice as long during MIS 6 compared to MIS 2-4, and could be related to a weaker Atlantic Meridional Overturning Circulation (AMOC) and a different mean climate during MIS 6 compared to MIS 2-4, leading most likely to a higher threshold for the occurrence of D-O cycles.

Prodrug activation in malaria parasites mediated by an imported erythrocyte esterase, acylpeptide hydrolase (APEH).

The continued emergence of antimalarial drug resistance highlights the need to develop new antimalarial therapies. Unfortunately, new drug development is often hampered by poor drug-like properties of lead compounds. Prodrugging temporarily masks undesirable compound features, improving bioavailability and target penetration. We have found that lipophilic diester prodrugs of phosphonic acid antibiotics, such as fosmidomycin, exhibit significantly higher antimalarial potency than their parent compounds (1). However, the activating enzymes for these prodrugs were unknown. Here, we show that an erythrocyte enzyme, acylpeptide hydrolase (APEH) is the major activating enzyme of multiple lipophilic ester prodrugs. Surprisingly, this enzyme is taken up by the malaria parasite, Plasmodium falciparum, where it localizes to the parasite cytoplasm and retains enzymatic activity. Using a novel fluorogenic ester library, we characterize the structure activity relationship of APEH, and compare it to that of P. falciparum esterases. We show that parasite-internalized APEH plays an important role in the activation of substrates with branching at the alpha carbon, in keeping with its exopeptidase activity. Our findings highlight a novel mechanism for antimicrobial prodrug activation, relying on a host-derived enzyme to yield activation at a microbial target. Mutations in prodrug activating enzymes are a common mechanism for antimicrobial drug resistance (2-4). Leveraging an internalized host enzyme would circumvent this, enabling the design of prodrugs with higher barriers to drug resistance.

Abrupt change of Antarctic moisture origin at the end of Termination II.

The deuterium excess of polar ice cores documents past changes in evaporation conditions and moisture origin. New data obtained from the European Project for Ice Coring in Antarctica Dome C East Antarctic ice core provide new insights on the sequence of events involved in Termination II, the transition between the penultimate glacial and interglacial periods. This termination is marked by a north-south seesaw behavior, with first a slow methane concentration rise associated with a strong Antarctic temperature warming and a slow deuterium excess rise. This first step is followed by an abrupt north Atlantic warming, an abrupt resumption of the East Asian summer monsoon, a sharp methane rise, and a CO(2) overshoot, which coincide within dating uncertainties with the end of Antarctic optimum. Here, we show that this second phase is marked by a very sharp Dome C centennial deuterium excess rise, revealing abrupt reorganization of atmospheric circulation in the southern Indian Ocean sector.

Speleothem record of mild and wet mid-Pleistocene climate in northeast Greenland.

The five interglacials before the Mid-Brunhes Event (MBE) [c.430 thousand years (ka) ago] are generally considered to be globally cooler than those post-MBE. Inhomogeneities exist regionally, however, which suggest that the Arctic was warmer than present during Marine Isotope Stage (MIS) 15a. Using the first speleothem record for the High Arctic, we investigate the climatic response of northeast Greenland between c.588 and c.549 ka ago. Our results indicate an enhanced warmth of at least +3.5°C relative to the present, leading to permafrost thaw and increased precipitation. We find that δ18O of precipitation was at least 3‰ higher than today and recognize two local cooling events (c.571 and c.594 ka ago) thought to be caused by freshwater forcing. Our results are important for improving understanding of the regional climatic response leading up to the MBE and specifically provide insights into the climatic response of a warmer Arctic.

Delayed hypersensitivity in man: effects of systemic anticoagulation.

Skin test reactivity, lymphocyte transformation, and mononuclear cell tissue factor generation were evaluated both before and during systemic anticoagulation in 24 volunteers. Anticoagulation with warfarin decreased skin test induration and tissue factor generation, but lymphocyte trnasformation remained unchanged. An intact coagulation mechanism, including tissue factor generation, appears to be important for the development of skin test induration in humans.

The timing of high sea levels over the past 200,000 years.

The (230)Th ages and (234)U/(238)U ratios were determined for Barbados corals that grew during periods of high sea level within the last 200,000 years. The similarity of the initial (234)U/(238)U ratios of some of the corals to the modern marine value suggests that these samples are pristine and that the marine (234)U/(238)U ratio 83,000 and 200,000 years ago was within 2 per mil of the modern value. The accuracies of the (230)Th ages are evaluated on the basis of the (234)U/(238)U values and a model of the behavior of uranium and thorium isotopes during diagenesis. For the last three interglacial and two intervening interstadial periods, sea level peaked at or after peaks in summer insolation in the Northern Hemisphere. This overall pattern supports the idea that glacial-interglacial cycles are caused by changes in Earth's orbital geometry. The sea-level drop at the end of the penultimate interglacial, the last interglacial, and a subsequent interstadial period lagged behind the decrease in insolation by 5,000 to 10,000 years.

Precise timing of the last interglacial period from mass spectrometric determination of thorium-230 in corals.

The development of mass spectrometric techniques for determination of (230)Th abundance has made it possible to reduce analytical errors in (238)U-(234)U-(230)Th dating of corals even with very small samples. Samples of 6 x 10(8) atoms of (230)Th can be measured to an accuracy of +/-3 percent (2sigma) and 3 x 10(10) atoms of (230)Th can be measured to an accuracy of +/-0.2 percent. The time range over which useful age data on corals can be obtained now ranges from about 50 to about 500,000 years. For young corals, this approach may be preferable to (14)C dating. The precision with which the age of a coral can now be determined should make it possible to critically test the Milankovitch hypothesis concerning Pleistocene climate fluctuations. Analyses of a number of corals that grew during the last interglacial period yield ages of 122,000 to 130,000 years. The ages coincide with, or slightly postdate, the summer solar insolation high at 65 degrees N latitude which occurred 128,000 years ago. This supports the idea that changes in Pleistocene climate can be the result of variations in the distribution of solar insolation caused by changes in the geometry of the earth's orbit and rotation axis.

A high-resolution absolute-dated late Pleistocene Monsoon record from Hulu Cave, China.

Oxygen isotope records of five stalagmites from Hulu Cave near Nanjing bear a remarkable resemblance to oxygen isotope records from Greenland ice cores, suggesting that East Asian Monsoon intensity changed in concert with Greenland temperature between 11,000 and 75,000 years before the present (yr. B.P.). Between 11,000 and 30,000 yr. B.P., the timing of changes in the monsoon, as established with 230Th dates, generally agrees with the timing of temperature changes from the Greenland Ice Sheet Project Two (GISP2) core, which supports GISP2's chronology in this interval. Our record links North Atlantic climate with the meridional transport of heat and moisture from the warmest part of the ocean where the summer East Asian Monsoon originates.

Sea-surface temperature from coral skeletal strontium/calcium ratios.

Seasonal records of tropical sea-surface temperature (SST) over the past 10(5) years can be recovered from high-precision measurements of coral strontium/calcium ratios with the use of thermal ionization mass spectrometry. The temperature dependence of these ratios was calibrated with corals collected at SST recording stations and by (18)O/(16)O thermometry. The results suggest that mean monthly SST may be determined with an apparent accuracy of better than 0.5 degrees C. Measurements on a fossil coral indicate that 10,200 years ago mean annual SSTs near Vanuatu in the southwestern Pacific Ocean were about 5 degrees C colder than today and that seasonal variations in SST were larger. These data suggest that tropical climate zones were compressed toward the equator during deglaciation.

A Large Drop in Atmospheric 14C/12C and Reduced Melting in the Younger Dryas, Documented with 230Th Ages of Corals.

Paired carbon-14 ((14)C) and thorium-230((230)Th) ages were determined on fossil corals from the Huon Peninsula, Papua New Guinea. The ages were used to calibrate part of the (14)C time scale and to estimate rates of sea-level rise during the last deglaciation. An abrupt offset between the (14)C and (230)Th ages suggests that the atmospheric (14)C/(12)C ratio dropped by 15 percent during the latter part of and after the Younger Dryas (YD). This prominent drop coincides with greatly reduced rates of sea-level rise. Reduction of melting because of cooler conditions during the YD may have caused an increase in the rate of ocean ventilation, which caused the atmospheric (14)C/(12)C ratio to fall. The record of sea-level rise also shows that globally averaged rates of melting were relatively high at the beginning of the YD. Thus, these measurements satisfy one of the conditions required by the hypothesis that the diversion of meltwater from the Mississippi to the St. Lawrence River triggered the YD event.

Extremely large variations of atmospheric 14C concentration during the last glacial period.

A long record of atmospheric 14C concentration, from 45 to 11 thousand years ago (ka), was obtained from a stalagmite with thermal-ionization mass-spectrometric 230Th and accelerator mass-spectrometric 14C measurements. This record reveals highly elevated Delta14C between 45 and 33 ka, portions of which may correlate with peaks in cosmogenic 36Cl and 10Be isotopes observed in polar ice cores. Superimposed on this broad peak of Delta14C are several rapid excursions, the largest of which occurs between 44.3 and 43.3 ka. Between 26 and 11 ka, atmospheric Delta14C decreased from approximately 700 to approximately 100 per mil, modulated by numerous minor excursions. Carbon cycle models suggest that the major features of this record cannot be produced with solar or terrestrial magnetic field modulation alone but also require substantial fluctuations in the carbon cycle.

Long-term neurodevelopmental effects of early detection and treatment in a 6-year-old patient with argininaemia diagnosed by newborn screening.

Newborn screening makes possible the early identification and treatment of asymptomatic ARG1-deficient patients; however, it is unknown whether early intervention prevents neurological insults. We identified a full-term Hispanic male infant with argininaemia by newborn screening with a serum arginine of 327 µmol/L (reference values 0-140); ARG1 was undetectable on enzyme assay. Sequence analysis of ARG1 revealed a heterozygous nonsense mutation, c.223A>T (p.K75X), and a novel heterozygous missense variant, c.425G>A (p.G142E). Dietary protein restriction began from age 3 months, with addition of sodium benzoate at 4 months, and carnitine from 14 months. For the past 6 years, his serum arginine concentrations were maintained between 268 and 763 µmol/L (reference values 10-140). He has normal development without spastic paraplegia, but with mild hepatomegaly and stable hepatic dysfunction. A full neurodevelopmental assessment was conducted at age 5 years. The BASC-2 rated the patient's behaviours as age-appropriate. The Leiter-R assessed his 'Fundamental Visualization', 'Sequential Order', and 'Picture Concept' at 'Average', 'Form Completion' and 'Matching' at 'Low Average', and 'Figure Ground' and 'Repeated Patterns' in the 'Deficit' range. The full-scale IQ and the functioning ability presented in the 'Borderline' range and in the 'Low Average' range, respectively. The VABS/Survey - Spanish Version showed difficulty in receptive and written language and fine and gross motor skills, and his performance to be at younger than his chronological age. The Short Sensory Profile showed some difficulty with taste and smell sensitivity. Long-term observation over 6 years in a patient with early treated argininaemia shows promising neurodevelopmental results.

Evidence of thermophilisation and elevation-dependent warming during the Last Interglacial in the Italian Alps.

Thermophilisation is the response of plants communities in mountainous areas to increasing temperatures, causing an upward migration of warm-adapted (thermophilic) species and consequently, the timberline. This greening, associated with warming, causes enhanced evapotranspiration that leads to intensification of the hydrological cycle, which is recorded by hydroclimate-sensitive archives, such as stalagmites and flowstones formed in caves. Understanding how hydroclimate manifests at high altitudes is important for predicting future water resources of many regions of Europe that rely on glaciers and snow accumulation. Using proxy data from three coeval speleothems (stalagmites and flowstone) from the Italian Alps, we reconstructed both the ecosystem and hydrological setting during the Last Interglacial (LIG); a warm period that may provide an analogue to a near-future climate scenario. Our speleothem proxy data, including calcite fabrics and the stable isotopes of calcite and fluid inclusions, indicate a +4.3 ± 1.6 °C temperature anomaly at ~2000 m a.s.l. for the peak LIG, with respect to present-day values (1961-1990). This anomaly is significantly higher than any low-altitude reconstructions for the LIG in Europe, implying elevation-dependent warming during the LIG. The enhanced warming at high altitudes must be accounted for when considering future climate adaption strategies in sensitive mountainous regions.

Estimating the upper limit of prehistoric peak ground acceleration using an in situ, intact and vulnerable stalagmite from Plavecká priepast cave (Detrekoi-zsomboly), Little Carpathians, Slovakia-first results.

Earthquakes hit urban centres in Europe infrequently, but occasionally with disastrous effects. Obtaining an unbiased view of seismic hazard (and risk) is therefore very important. In principle, the best way to test probabilistic seismic hazard assessments (PSHAs) is to compare them with observations that are entirely independent of the procedure used to produce PSHA models. Arguably, the most valuable information in this context should be information on long-term hazard, namely maximum intensities (or magnitudes) occurring over time intervals that are at least as long as a seismic cycle. The new observations can provide information of maximum intensity (or magnitude) for long timescale as an input data for PSHA studies as well. Long-term information can be gained from intact stalagmites in natural caves. These formations survived all earthquakes that have occurred over thousands of years, depending on the age of the stalagmite. Their 'survival' requires that the horizontal ground acceleration (HGA) has never exceeded a certain critical value within that time period. Here, we present such a stalagmite-based case study from the Little Carpathians of Slovakia. A specially shaped, intact and vulnerable stalagmite in the Plavecká priepast cave was examined in 2013. This stalagmite is suitable for estimating the upper limit of horizontal peak ground acceleration generated by prehistoric earthquakes. The critical HGA values as a function of time going back into the past determined from the stalagmite that we investigated are presented. For example, at the time of Jóko event (1906), the critical HGA value cannot have been higher than 1 and 1.3 m/s2 at the time of the assumed Carnuntum event (∼340 AD), and 3000 years ago, it must have been lower than 1.7 m/s2. We claimed that the effect of Jóko earthquake (1906) on the location of the Plavecká priepast cave is consistent with the critical HGA value provided by the stalagmite we investigated. The approach used in this study yields significant new constraints on the seismic hazard, as tectonic structures close to Plavecká priepast cave did not generate strong earthquakes in the last few thousand years. The results of this study are highly relevant given that the two capitals, Vienna and Bratislava, are located within 40 and 70 km of the cave, respectively.

Effect of mopidamol on survival in carcinoma of the lung and colon: final report of Veterans Administration Cooperative Study No. 188.

Mopidamol (RA-233), a derivative of dipyridamole, is a phosphodiesterase inhibitor that has been shown previously to limit progression of malignancy in certain experimental animal models and in a pilot study in humans. RA-233 plus chemotherapy was compared with chemotherapy alone in a 5-year double-blind trial involving 719 patients with advanced carcinomas of the lung and of the colon. RA-233 treatment was associated with a statistically significant prolongation of survival in patients with non-small cell lung cancer (N-SCLC) limited to one hemithorax and with reduction in mean plasma fibrogen concentration. RA-233 was not toxic. The favorable effects on survival could not be explained by any factor other than the RA-233 treatment. In other tumor categories tested, no differences in survival were observed. These results suggest that RA-233 is useful in the treatment of N-SCLC of limited extent. They also suggest that therapeutic intervention aimed at modified intracellular pathways might constitute a novel investigative approach to the treatment of cancer.

Studies on a circulating anticoagulant in procainamide-induced lupus erythematosus.

Circulating anticoagulant activity that had at least two distinct mechanisms--one directed against factor XII and one directed against blood thromboplastin (prothrombin activator complex)--developed in a patient with clinical and laboratory evidence of procainamide hydrochloride-induced systemic lupus erythematosus. The anticoagulant activity behaved as a gamma-globulin in chromatographic and electrophoretic analyses, with the majority of activity behaving as an IgM immunoglobulin. Despite markedly abnormal coagulation study results, no clinical bleeding occurred. Anticoagulant activity paralleled clinical and laboratory evidence of the inflammatory disease and improved on discontinuance of procainamide therapy.

North Atlantic storm track changes during the Last Glacial Maximum recorded by Alpine speleothems.

The European Alps are an effective barrier for meridional moisture transport and are thus uniquely placed to record shifts in the North Atlantic storm track pattern associated with the waxing and waning of Late-Pleistocene Northern Hemisphere ice sheets. The lack of well-dated terrestrial proxy records spanning this time period, however, renders the reconstruction of past atmospheric patterns difficult. Here we present a precisely dated, continuous terrestrial record of meteoric precipitation in Europe between 30 and 14.7 ka. In contrast to present-day conditions, our speleothem data provide strong evidence for preferential advection of moisture from the South across the Alps supporting a southward shift of the storm track during the local Last Glacial Maximum (that is, 26.5-23.5 ka). Moreover, our age control indicates that this circulation pattern preceded the Northern Hemisphere precession maximum by ~3 ka, suggesting that obliquity may have played a considerable role in the Alpine ice aggradation.

Trends and oscillations in the Indian summer monsoon rainfall over the last two millennia.

Observations show that summer rainfall over large parts of South Asia has declined over the past five to six decades. It remains unclear, however, whether this trend is due to natural variability or increased anthropogenic aerosol loading over South Asia. Here we use stable oxygen isotopes in speleothems from northern India to reconstruct variations in Indian monsoon rainfall over the last two millennia. We find that within the long-term context of our record, the current drying trend is not outside the envelope of monsoon's oscillatory variability, albeit at the lower edge of this variance. Furthermore, the magnitude of multi-decadal oscillatory variability in monsoon rainfall inferred from our proxy record is comparable to model estimates of anthropogenic-forced trends of mean monsoon rainfall in the 21st century under various emission scenarios. Our results suggest that anthropogenic-forced changes in monsoon rainfall will remain difficult to detect against a backdrop of large natural variability.

Alveolar capillary basement membrane lesions in Goodpasture's syndrome and idiopathic pulmonary hemosiderosis.

An ultrastructural study of lung distinguised between lesions of the alveolar capillary basement membrane in a case of Good pasture's syndrome and in three cases of idiopathic pulmonary hemosiderosis. In Goodpasture's syndrome, diffuse vascular injury with wide endothelial gaps, diffusely fragmented basement membranes and an electron dense layer on the basement membrane was found. In idiopathic pulmonary hemosiderosis, focal ruptures of the basement membrane were associated with hydropic changes in pneumocytes and, although fibroblasts were not seen, collagen deposition occurred within the basement membrane. immunofluorescent studies failed to show deposition of immunoglobulins G (IgG), A (IgA), M (IgM) or C3 in the lung in either disease. The ultrastructural lesions appear to separate these clinically similar entities.