Exposure dating of Late Glacial and pre-LGM moraines in the Cordon de Doña Rosa, Northern/Central Chile (~ 31°S)

Despite the important role of the Central Andes (15–30° S) for climate reconstruction, knowledge about the Quaternary glaciation is very limited due to the scarcity of organic material for radiocarbon dating. We applied 10Be surface exposure dating (SED) on 22 boulders from moraines in the Cordon de Doña Rosa, Northern/Central Chile (~31° S). The results show that several glacial advances in the southern Central Andes occurred during the Late Glacial between ~14.7±1.5 and 11.6±1.2 ka. A much more extensive glaciation is dated to ~32±3 ka, predating the temperature minimum of the global LGM (Last Glacial Maximum: ~20 ka). Reviewing these results in the paleoclimatic context, we conclude that the Late Glacial advances were most likely caused by an intensification of the tropical circulation and a corresponding increase in summer precipitation. High-latitude temperatures minima, e.g. the Younger Dryas (YD) and the Antarctic Cold Reversal (ACR) may have triggered individual advances, but current systematic exposure age uncertainties limit precise correlations. The absence of LGM moraines indicates that moisture advection was too limited to allow significant glacial advances at ~20 ka. The tropical circulation was less intensive despite the maximum in austral summer insolation. Winter precipitation was apparently also insufficient, although pollen and marine studies indicate a northward shift of the westerlies at that time. The dominant pre-LGM glacial advances in Northern/Central Chile at ~32 ka required lower temperatures and increased precipitation than today. We conclude that the westerlies were more intense and/or shifted equatorward, possibly due to increased snow and ice cover at higher southern latitudes coinciding with a minimum of insolation.

Update on safety during pregnancy of biological agents and some immunosuppressive anti-rheumatic drugs

A consensus paper concerning the interaction of anti-rheumatic drugs and reproduction was published in 2006, representing data collected during the year 2004 and 2005. Because of an increasing use of biological agents in women of fertile age, the information was updated for the years 2006 and 2007. Experts disagree whether TNF-inhibitors should be stopped as soon as pregnancy is recognized or may be continued throughout pregnancy. Pregnancy experience with abatacept and rituximab is still too limited to prove their safety for the developing fetus. They must be withdrawn before a planned pregnancy. LEF has not been proven to be a human teratogen. Registries of transplant recipients have shown that cyclosporin (CsA) and tacrolimus do not increase the rate of congenital anomalies, whereas mycophenolate mofetil (MMF) clearly carries a risk for congenital anomalies. Prophylactic withdrawal of drugs before pregnancy is mandatory for abatacept, rituximab, LEF and MMF. Data remain insufficient for gonadal toxicity of immunosuppressive drugs in men and for excretion of these drugs in human breast milk.

Mumps

Mumps is a common childhood infection caused by the mumps virus. The hallmark of infection is swelling of the parotid gland. Aseptic meningitis and encephalitis are common complications of mumps together with orchitis and oophoritis, which can arise in adult men and women, respectively; other complications include deafness and pancreatitis. Clinical diagnosis can be based on the classic parotid swelling; however, this feature is not present in all cases of mumps and can also occur in various other disorders. Laboratory diagnosis is based on isolation of virus, detection of viral nucleic acid, or serological confirmation (generally presence of IgM mumps antibodies). Mumps is vaccine-preventable, and one dose of mumps vaccine is about 80% effective against the disease. Routine vaccination has proven highly effective in reducing the incidence of mumps, and is presently used by most developed countries; however, there have been outbreaks of disease in vaccinated populations. In 2005, a large epidemic peaked in the UK, and in 2006 the American midwest had several outbreaks. In both countries, the largest proportion of cases was in young adults. In the UK, susceptible cohorts too old to have been vaccinated and too young to have been exposed to natural infections were the primary cause of the mumps epidemic. In the USA, effectiveness and uptake in combination appear not to have been sufficient to obtain herd immunity for mumps in populations such as college students.

Four thousand years of vegetation and fire history in the spruce forests of northern Kyrgyzstan (Kungey Alatau, Central Asia)

Analyses of pollen, macrofossils and microscopic charcoal in the sediment of a small sub-alpine lake (Karakol, Kyrgyzstan) provide new data to reconstruct the vegetation history of the Kungey Alatau spruce forest during the late-Holocene, i.e. the past 4,000 years. The pollen data suggest that Picea schrenkiana F. and M. was the dominant tree in this region from the beginning of the record. The pollen record of pronounced die-backs of the forests, along with lithostratigraphical evidence, points to possible climatic cooling (and/or drying) around 3,800 cal year B.P., and between 3,350 and 2,520 cal year B.P., with a culmination at 2,800-2,600 cal B.P., although stable climatic conditions are reported for this region for the past 3,000-4,000 years in previous studies. From 2,500 to 190 cal year B.P. high pollen values of P. schrenkiana suggest rather closed and dense forests under the environmental conditions of that time. A marked decline in spruce forests occurred with the onset of modern human activities in the region from 190 cal year B.P. These results show that the present forests are anthropogenically reduced and represent only about half of their potential natural extent. As P. schrenkiana is a species endemic to the western Tien Shan, it is most likely that its refugium was confined to this region. However, our palaeoecological record is too recent to address this hypothesis thoroughly.

Visibility of vascular phenylalanine in dynamic uptake studies in humans using magnetic resonance spectroscopy

In general, vascular contributions to the in vivo magnetic resonance (MR) brain spectrum are too small to be relevant. In cerebral uptake studies, however, vascular contributions may constitute a major confounder. MR visibility of vascular Phe was investigated by recording localized spectra from fully oxygenated and well-mixed whole blood. Blood Phe levels determined by MR spectroscopy (MRS) and ion-exchange chromatography showed excellent correlation. In addition, effects of blood flow were shown to have a small effect on signal amplitude with the MRS methodology used. Hence, blood Phe is almost completely MR visible at 1.5 T, even though it is severely broadened at higher fields. Without appropriate correction, cerebral Phe influx in studies of brain Phe uptake in phenylketonuria patients or healthy subjects would appear to be faster and lead to higher levels. Similar effects are envisaged for studies of ethanol or glucose uptake across the blood-brain barrier.

Transport of anti-IL-6 antigen binding fragments into cartilage and the effects of injury

The efficacy of biological therapeutics against cartilage degradation in osteoarthritis is restricted by the limited transport of macromolecules through the dense, avascular extracellular matrix. The availability of biologics to cell surface and matrix targets is limited by steric hindrance of the matrix, and the microstructure of matrix itself can be dramatically altered by joint injury and the subsequent inflammatory response. We studied the transport into cartilage of a 48 kDa anti-IL-6 antigen binding fragment (Fab) using an in vitro model of joint injury to quantify the transport of Fab fragments into normal and mechanically injured cartilage. The anti-IL-6 Fab was able to diffuse throughout the depth of the tissue, suggesting that Fab fragments can have the desired property of achieving local delivery to targets within cartilage, unlike full-sized antibodies which are too large to penetrate beyond the cartilage surface. Uptake of the anti-IL-6 Fab was significantly increased following mechanical injury, and an additional increase in uptake was observed in response to combined treatment with TNFα and mechanical injury, a model used to mimic the inflammatory response following joint injury. These results suggest that joint trauma leading to cartilage degradation can further alter the transport of such therapeutics and similar-sized macromolecules.

Mitotic figure counts are significantly overestimated in resection specimens of invasive breast carcinomas

Several authors have demonstrated an increased number of mitotic figures in breast cancer resection specimen when compared with biopsy material. This has been ascribed to a sampling artifact where biopsies are (i) either too small to allow formal mitotic figure counting or (ii) not necessarily taken form the proliferating tumor periphery. Herein, we propose a different explanation for this phenomenon. Biopsy and resection material of 52 invasive ductal carcinomas was studied. We counted mitotic figures in 10 representative high power fields and quantified MIB-1 immunohistochemistry by visual estimation, counting and image analysis. We found that mitotic figures were elevated by more than three-fold on average in resection specimen over biopsy material from the same tumors (20±6 vs 6±2 mitoses per 10 high power fields, P=0.008), and that this resulted in a relative diminution of post-metaphase figures (anaphase/telophase), which made up 7% of all mitotic figures in biopsies but only 3% in resection specimen (P<0.005). At the same time, the percentages of MIB-1 immunostained tumor cells among total tumor cells were comparable in biopsy and resection material, irrespective of the mode of MIB-1 quantification. Finally, we found no association between the size of the biopsy material and the relative increase of mitotic figures in resection specimen. We propose that the increase in mitotic figures in resection specimen and the significant shift towards metaphase figures is not due to a sampling artifact, but reflects ongoing cell cycle activity in the resected tumor tissue due to fixation delay. The dwindling energy supply will eventually arrest tumor cells in metaphase, where they are readily identified by the diagnostic pathologist. Taken together, we suggest that the rapidly fixed biopsy material better represents true tumor biology and should be privileged as predictive marker of putative response to cytotoxic chemotherapy.

Two Stable Equilibria of the Atlantic Subpolar Gyre

The cyclonic circulation of the Atlantic subpolar gyre is a key mechanism for North Atlantic climate variability on a wide range of time scales. It is generally accepted that it is driven by both cyclonic winds and buoyancy forcing, yet the individual importance and dynamical interactions of the two contributions remain unclear. The authors propose a simplified four-box model representing the convective basin of the Labrador Sea and its shallow and deep boundary current system, the western subpolar gyre. Convective heat loss drives a baroclinic flow of relatively light water around the dense center. Eddy salt flux from the boundary current to the center increases with a stronger circulation, favors the formation of dense waters, and thereby sustains a strong baroclinic flow, approximately 10%–25% of the total. In contrast, when the baroclinic flow is not active, surface waters may be too fresh to convect, and a buoyancy-driven circulation cannot develop. This situation corresponds to a second stable circulation mode. A hysteresis is found for variations in surface freshwater flux and the salinity of the near-surface boundary current. An analytical solution is presented and analyzed.

Evidence for distinct modes of solar activity

The Sun shows strong variability in its magnetic activity, from Grand minima to Grand maxima, but the nature of the variability is not fully understood, mostly because of the insufficient length of the directly observed solar activity records and of uncertainties related to long-term reconstructions. Here we present a new adjustment-free reconstruction of solar activity over three millennia and study its different modes. Methods. We present a new adjustment-free, physical reconstruction of solar activity over the past three millennia, using the latest verified carbon cycle, 14C production, and archeomagnetic field models. This great improvement allowed us to study different modes of solar activity at an unprecedented level of details. Results. The distribution of solar activity is clearly bi-modal, implying the existence of distinct modes of activity. The main regular activity mode corresponds to moderate activity that varies in a relatively narrow band between sunspot numbers 20 and 67. The existence of a separate Grand minimum mode with reduced solar activity, which cannot be explained by random fluctuations of the regular mode, is confirmed at a high confidence level. The possible existence of a separate Grand maximum mode is also suggested, but the statistics is too low to reach a confident conclusion. Conclusions. The Sun is shown to operate in distinct modes – a main general mode, a Grand minimum mode corresponding to an inactive Sun, and a possible Grand maximum mode corresponding to an unusually active Sun. These results provide important constraints for both dynamo models of Sun-like stars and investigations of possible solar influence on Earth’s climate.

Methane emissions from floodplains in the Amazon Basin: challenges in developing a process-based model for global applications

Tropical wetlands are estimated to represent about 50% of the natural wetland methane (CH4) emissions and explain a large fraction of the observed CH4 variability on timescales ranging from glacial–interglacial cycles to the currently observed year-to-year variability. Despite their importance, however, tropical wetlands are poorly represented in global models aiming to predict global CH4 emissions. This publication documents a first step in the development of a process-based model of CH4 emissions from tropical floodplains for global applications. For this purpose, the LPX-Bern Dynamic Global Vegetation Model (LPX hereafter) was slightly modified to represent floodplain hydrology, vegetation and associated CH4 emissions. The extent of tropical floodplains was prescribed using output from the spatially explicit hydrology model PCR-GLOBWB. We introduced new plant functional types (PFTs) that explicitly represent floodplain vegetation. The PFT parameterizations were evaluated against available remote-sensing data sets (GLC2000 land cover and MODIS Net Primary Productivity). Simulated CH4 flux densities were evaluated against field observations and regional flux inventories. Simulated CH4 emissions at Amazon Basin scale were compared to model simulations performed in the WETCHIMP intercomparison project. We found that LPX reproduces the average magnitude of observed net CH4 flux densities for the Amazon Basin. However, the model does not reproduce the variability between sites or between years within a site. Unfortunately, site information is too limited to attest or disprove some model features. At the Amazon Basin scale, our results underline the large uncertainty in the magnitude of wetland CH4 emissions. Sensitivity analyses gave insights into the main drivers of floodplain CH4 emission and their associated uncertainties. In particular, uncertainties in floodplain extent (i.e., difference between GLC2000 and PCR-GLOBWB output) modulate the simulated emissions by a factor of about 2. Our best estimates, using PCR-GLOBWB in combination with GLC2000, lead to simulated Amazon-integrated emissions of 44.4 ± 4.8 Tg yr−1. Additionally, the LPX emissions are highly sensitive to vegetation distribution. Two simulations with the same mean PFT cover, but different spatial distributions of grasslands within the basin, modulated emissions by about 20%. Correcting the LPX-simulated NPP using MODIS reduces the Amazon emissions by 11.3%. Finally, due to an intrinsic limitation of LPX to account for seasonality in floodplain extent, the model failed to reproduce the full dynamics in CH4 emissions but we proposed solutions to this issue. The interannual variability (IAV) of the emissions increases by 90% if the IAV in floodplain extent is accounted for, but still remains lower than in most of the WETCHIMP models. While our model includes more mechanisms specific to tropical floodplains, we were unable to reduce the uncertainty in the magnitude of wetland CH4 emissions of the Amazon Basin. Our results helped identify and prioritize directions towards more accurate estimates of tropical CH4 emissions, and they stress the need for more research to constrain floodplain CH4 emissions and their temporal variability, even before including other fundamental mechanisms such as floating macrophytes or lateral water fluxes.

Herbivory in Spiders: The Importance of Pollen for Orb-Weavers

Orb-weaving spiders (Araneidae) are commonly regarded as generalist insect predators but resources provided by plants such as pollen may be an important dietary supplementation. Their webs snare insect prey, but can also trap aerial plankton like pollen and fungal spores. When recycling their orb webs, the spiders may therefore also feed on adhering pollen grains or fungal spores via extraoral digestion. In this study we measured stable isotope ratios in the bodies of two araneid species (Aculepeira ceropegia and Araneus diadematus), their potential prey and pollen to determine the relative contribution of pollen to their diet. We found that about 25% of juvenile orb-weaving spiders’ diet consisted of pollen, the other 75% of flying insects, mainly small dipterans and hymenopterans. The pollen grains in our study were too large to be taken up accidentally by the spiders and had first to be digested extraorally by enzymes in an active act of consumption. Therefore, pollen can be seen as a substantial component of the spiders’ diet. This finding suggests that these spiders need to be classified as omnivores rather than pure carnivores.

Influence of the background wind on the local soil moisture-precipitation feedback

The importance of soil moisture anomalies on airmass convection over semiarid regions has been recognized in several studies. The underlying mechanisms remain partly unclear. An open question is why wetter soils can result in either an increase or a decrease of precipitation (positive or negative soil moisture–precipitation feedback, respectively). Here an idealized cloud-resolving modeling framework is used to explore the local soil moisture–precipitation feedback. The approach is able to replicate both positive and negative feedback loops, depending on the environmental parameters. The mechanism relies on horizontal soil moisture variations, which may develop and intensify spontaneously. The positive expression of the feedback is associated with the initiation of convection over dry soil patches, but the convective cells then propagate over wet patches where they strengthen and preferentially precipitate. The negative feedback may occur when the wind profile is too weak to support the propagation of convective features from dry to wet areas. Precipitation is then generally weaker and falls preferentially over dry patches. The results highlight the role of the midtropospheric flow in determining the sign of the feedback. A key element of the positive feedback is the exploitation of both low convective inhibition (CIN) over dry patches (for the initiation of convection) and high CAPE over wet patches (for the generation of precipitation).

Metabolomics and its potential in drug development

Metabolomics is the global and unbiased survey of the complement of small molecules (say, <1 kDa) in a biofluid, tissue, organ or organism and measures the end-products of the cellular metabolism of both endogenous and exogenous substrates. Many drug candidates fail during Phase II and III clinical trials at an enormous cost to the pharmaceutical industry in terms of both time lost and of financial resources. The constantly evolving model of drug development now dictates that biomarkers should be employed in preclinical development for the early detection of likely-to-fail candidates. Biomarkers may also be useful in the preselection of patients and through the subclassification of diseases in clinical drug development. Here we show with examples how metabolomics can assist in the preclinical development phases of discovery, pharmacology, toxicology, and ADME. Although not yet established as a clinical trial patient prescreening procedure, metabolomics shows considerable promise in this regard. We can be certain that metabolomics will join genomics and transcriptomics in lubricating the wheels of clinical drug development in the near future.

Debris discs around M stars: non-existence versus non-detection

Motivated by the reported dearth of debris discs around M stars, we use survival models to study the occurrence of planetesimal discs around them. These survival models describe a planetesimal disc with a small number of parameters, determine if it may survive a series of dynamical processes and compute the associated infrared excess. For the Wide-field Infrared Survey Explorer (WISE) satellite, we demonstrate that the dearth of debris discs around M stars may be attributed to the small semimajor axes generally probed if either: (1) the dust grains behave like blackbodies emitting at a peak wavelength coincident with the observed one; (2) or the grains are hotter than predicted by their blackbody temperatures and emit at peak wavelengths that are shorter than the observed one. At these small distances from the M star, planetesimals are unlikely to survive or persist for time-scales of 300 Myr or longer if the disc is too massive. Conversely, our survival models allow for the existence of a large population of low-mass debris discs that are too faint to be detected with current instruments. We gain further confidence in our interpretation by demonstrating the ability to compute infrared excesses for Sun-like stars that are broadly consistent with reported values in the literature. However, our interpretation becomes less clear and large infrared excesses are allowed if only one of these scenarios holds: (3) the dust grains are hotter than blackbody and predominantly emit at the observed wavelength; (4) or are blackbody in nature and emit at peak wavelengths longer than the observed one. Both scenarios imply that the parent planetesimals reside at larger distances from the star than inferred if the dust grains behaved like blackbodies. In all scenarios, we show that the infrared excesses detected at 22 μm (via WISE) and 70 μm (via Spitzer) from AU Mic are easily reconciled with its young age (12 Myr). Conversely, the existence of the old debris disc (2–8 Gyr) from GJ 581 is due to the large semimajor axes probed by the Herschel PACS instrument. We elucidate the conditions under which stellar wind drag may be neglected when considering dust populations around M stars. The WISE satellite should be capable of detecting debris discs around young M stars with ages ∼10 Myr.

Stability and relapse after orthodontic treatment of deep bite cases-a long-term follow-up study.

The purpose of this long-term follow-up study was twofold-firstly, to assess prevalence of relapse after treatment of deep bite malocclusion and secondly, to identify risk factors that predispose patients with deep bite malocclusion to relapse. Sixty-one former patients with overbite more than 50% incisor overlap before treatment were successfully recalled. Clinical data, morphometrical measurements on plaster casts before treatment, after treatment and at long-term follow-up, as well as cephalometric measurements before and after treatment were collected. The median follow-up period was 11.9 years. Patients were treated by various treatment modalities, and the majority of patients received at least a lower fixed retainer and an upper removable bite plate during retention. Relapse was defined as increase in incisor overlap from below 50% after treatment to equal or more than 50% incisor overlap at long-term follow-up. Ten per cent of the patients showed relapse to equal or larger than 50% incisor overlap, and their amount of overbite increase was low. Among all cases with deep bite at follow-up, gingival contact and palatal impingement were more prevalent in partially corrected noncompliant cases than in relapse cases. In this sample, prevalence and amount of relapse were too low to identify risk factors of relapse.