Centennial relationships between ocean temperature and Atlantic puffin production reveal shifting decennial trends.

The current warming of the oceans has been shown to have detrimental effects for a number of species. An understanding of the underlying mechanisms may be hampered by the non-linearity and non-stationarity of the relationships between temperature and demography, and by the insufficient length of available time series. Most demographic time series are too short to study the effects of climate on wildlife in the classical sense of meteorological patterns over at least 30 years. Here we present a harvest time series of Atlantic puffins (Fratercula arctica) that goes back as far as 1880. It originates in the world's largest puffin colony, in southwest Iceland, which has recently experienced a strong decline. By estimating an annual chick production index for 128 years, we found prolonged periods of strong correlations between local sea surface temperature (SST) and chick production. The sign of decennial correlations switches three times during this period, where the phases of strong negative correlations between puffin productivity and SST correspond to the early 20th century Arctic warming period and to the most recent decades. Most of the variation (72%) in chick production is explained by a model in which productivity peaks at an SST of 7.1°C, clearly rejecting the assumption of a linear relationship. There is also evidence supporting non-stationarity: The SST at which puffins production peaked has increased by 0.24°C during the 20th century, although the increase in average SST during the same period has been more than three times faster. The best supported models indicate that the population's decline is at least partially caused by the increasing SST around Iceland.

Amplified Arctic warming by phytoplankton under greenhouse warming.

Phytoplankton have attracted increasing attention in climate science due to their impacts on climate systems. A new generation of climate models can now provide estimates of future climate change, considering the biological feedbacks through the development of the coupled physical-ecosystem model. Here we present the geophysical impact of phytoplankton, which is often overlooked in future climate projections. A suite of future warming experiments using a fully coupled ocean-atmosphere model that interacts with a marine ecosystem model reveals that the future phytoplankton change influenced by greenhouse warming can amplify Arctic surface warming considerably. The warming-induced sea ice melting and the corresponding increase in shortwave radiation penetrating into the ocean both result in a longer phytoplankton growing season in the Arctic. In turn, the increase in Arctic phytoplankton warms the ocean surface layer through direct biological heating, triggering additional positive feedbacks in the Arctic, and consequently intensifying the Arctic warming further. Our results establish the presence of marine phytoplankton as an important potential driver of the future Arctic climate changes.

Treatment with the HIV protease inhibitor nelfinavir triggers the unfolded protein response and may overcome proteasome inhibitor resistance of multiple myeloma in combination with bortezomib: a phase I trial (SAKK 65/08).

Downregulation of the unfolded protein response mediates proteasome inhibitor resistance in multiple myeloma. The Human Immunodeficieny Virus protease inhibitor nelfinavir activates the unfolded protein response in vitro. We determined dose-limiting toxicity and recommended dose for phase II of nelfinavir in combination with the proteasome inhibitor bortezomib. Twelve patients with advanced hematologic malignancies were treated with nelfinavir (2500-5000 mg/day p.o., days 1-14, 3+3 dose escalation) and bortezomib (1.3 mg/m(2), days 1, 4, 8, 11; 21-day cycles). A run in phase with nelfinavir monotherapy allowed pharmakokinetic/pharmakodynamic assessment of nelfinavir in the presence or absence of concomittant bortezomib. End points included dose-limiting toxicity, activation of the unfolded protein response, proteasome activity, toxicity and response to trial treatment. Nelfinavir 2×2500 mg was the recommended phase II dose identified. Nelfinavir alone significantly up-regulated expression of proteins related to the unfolded protein response in peripheral blood mononuclear cells and inhibited proteasome activity. Of 10 evaluable patients in the dose escalation cohort, 3 achieved a partial response, 4 stable disease for 2 cycles or more, while 3 had progressive disease as best response. In an exploratory extension cohort with 6 relapsed, bortezomib-refractory, lenalidomide-resistant myeloma patients treated at the recommended phase II dose, 3 reached a partial response, 2 a minor response, and one progressive disease. The combination of nelfinavir with bortezomib is safe and shows promising activity in advanced, bortezomib-refractory multiple myeloma. Induction of the unfolded protein response by nelfinavir may overcome the biological features of proteasome inhibitor resistance. (clinicaltrials.gov identifier: 01164709).

Global temperature modes shed light on the Holocene temperature conundrum.

Reconstructions of the global mean annual temperature evolution during the Holocene yield conflicting results. One temperature reconstruction shows global cooling during the late Holocene. The other reconstruction reveals global warming. Here we show that both a global warming mode and a cooling mode emerge when performing a spatio-temporal analysis of annual temperature variability during the Holocene using data from a transient climate model simulation. The warming mode is most pronounced in the tropics. The simulated cooling mode is determined by changes in the seasonal cycle of Arctic sea-ice that are forced by orbital variations and volcanic eruptions. The warming mode dominates in the mid-Holocene, whereas the cooling mode takes over in the late Holocene. The weighted sum of the two modes yields the simulated global temperature trend evolution. Our findings have strong implications for the interpretation of proxy data and the selection of proxy locations to compute global mean temperatures.

Proteasome Inhibition in Multiple Myeloma: Head-to-Head Comparison of Currently Available Proteasome Inhibitors.

Proteasome inhibitors (PIs) are a backbone of multiple myeloma (MM) therapy. The proteasome harbors six proteolytically active subunits (ß1, ß2, ß5), while ß5 was identified as rate-limiting and is a primary target of clinically available PIs. The most effective pattern of subunit inhibition provided by these PIs for cytotoxic activity in MM is unknown. A head-to-head comparison of clinically available PIs shows that in the clinically relevant setting only the co-inhibition of ß1 or ß2 with ß5 activity achieves meaningful functional proteasome inhibition and cytotoxicity, while the selective ß2/ß5 inhibition of both constitutive and immunoproteasome is the most cytotoxic. In the long-term setting, selective inhibition of ß5 subunit is sufficient to induce cytotoxicity in PI-sensitive, but not in PI-resistant MM, and the ß5/ß2 co-inhibition is the most cytotoxic in PI-resistant MM. These results give a rational basis for selecting individual PIs for the treatment of MM.

Developments in the MPI-M Earth System Model version 1.2 (MPI-ESM1.2) and Its Response to Increasing CO2.

A new release of the Max Planck Institute for Meteorology Earth System Model version 1.2 (MPI-ESM1.2) is presented. The development focused on correcting errors in and improving the physical processes representation, as well as improving the computational performance, versatility, and overall user friendliness. In addition to new radiation and aerosol parameterizations of the atmosphere, several relatively large, but partly compensating, coding errors in the model's cloud, convection, and turbulence parameterizations were corrected. The representation of land processes was refined by introducing a multilayer soil hydrology scheme, extending the land biogeochemistry to include the nitrogen cycle, replacing the soil and litter decomposition model and improving the representation of wildfires. The ocean biogeochemistry now represents cyanobacteria prognostically in order to capture the response of nitrogen fixation to changing climate conditions and further includes improved detritus settling and numerous other refinements. As something new, in addition to limiting drift and minimizing certain biases, the instrumental record warming was explicitly taken into account during the tuning process. To this end, a very high climate sensitivity of around 7 K caused by low-level clouds in the tropics as found in an intermediate model version was addressed, as it was not deemed possible to match observed warming otherwise. As a result, the model has a climate sensitivity to a doubling of CO2 over preindustrial conditions of 2.77 K, maintaining the previously identified highly nonlinear global mean response to increasing CO2 forcing, which nonetheless can be represented by a simple two-layer model.

The tropical rain belts with an annual cycle and a continent model intercomparison project: TRACMIP.

This paper introduces the Tropical Rain belts with an Annual cycle and a Continent Model Inter-comparison Project (TRACMIP). TRACMIP studies the dynamics of tropical rain belts and their response to past and future radiative forcings through simulations with 13 comprehensive and one simplified atmosphere models coupled to a slab ocean and driven by seasonally varying insolation. Five idealized experiments, two with an aquaplanet setup and three with a setup with an idealized tropical continent, fill the space between prescribed-SST aquaplanet simulations and realistic simulations provided by CMIP5/6. The simulations reproduce key features of present-day climate and expected future climate change, including an annual-mean intertropical convergence zone (ITCZ) that is located north of the equator and Hadley cells and eddy-driven jets that are similar to present-day climate. Quadrupling CO2 leads to a northward ITCZ shift and preferential warming in Northern high latitudes. The simulations show interesting CO2-induced changes in the seasonal excursion of the ITCZ and indicate a possible state dependence of climate sensitivity. The inclusion of an idealized continent modulates both the control climate and the response to increased CO2; for example, it reduces the northward ITCZ shift associated with warming and, in some models, climate sensitivity. In response to eccentricity-driven seasonal insolation changes, seasonal changes in oceanic rainfall are best characterized as a meridional dipole, while seasonal continental rainfall changes tend to be symmetric about the equator. This survey illustrates TRACMIP's potential to engender a deeper understanding of global and regional climate and to address questions on past and future climate change.

Northern-hemispheric differential warming is the key to understanding the discrepancies in the projected Sahel rainfall.

Future projections of the Sahel rainfall are highly uncertain, with different climate models showing widely differing rainfall trends. Moreover, the twentieth-century cross-model consensus linking Sahel rainfall to tropical sea-surface temperatures (SSTs) is no longer applicable in the twenty-first century. Here we show that the diverse future Northern Hemisphere differential warming between extratropical and tropical SSTs can explain the discrepancy in the projected Sahel rainfall. The relationship between SST and Sahel rainfall that holds for the twentieth-century persists into the twenty-first century when the differential SST warming is taken into account. A suite of SST-sensitivity experiments confirms that strong Northern Hemisphere extratropical warming induces a significant increase in Sahel rainfall, which can predominate over the drying impact of tropical SST warming. These results indicate that a trustworthy projection of Sahel rainfall requires the estimation of the most likely future Northern-hemispheric differential warming.

The novel ß2-selective proteasome inhibitor LU-102 decreases phosphorylation of I kappa B and induces highly synergistic cytotoxicity in combination with ibrutinib in multiple myeloma cells.

PURPOSE: Proteasome-inhibiting drugs (PI) are gaining importance in hematologic oncology. The proteasome carries three proteolytically active subunits (ß1, ß2, ß5). All established PI (bortezomib and carfilzomib), as well as experimental drugs in the field (dalanzomib, oprozomib, and ixazomib), by design target the rate-limiting ß5 subunit. It is unknown whether ß2-selective proteasome inhibition can also be exploited toward anticancer treatment. Combining PI with the pan B-cell-directed Bruton tyrosine kinase inhibitor ibrutinib appears a natural option for future improved treatment of multiple myeloma (MM) and B-cell lymphomas. However, bortezomib induces phosphorylation of IκB and activation of NF-κB in MM cells, while ibrutinib inhibits the IκB/NF-κB axis, suggesting antagonistic signaling. A ß2-selective proteasome inhibitor may lack such antagonistic signaling effects. METHODS: We recently introduced LU-102, the first ß2-selective PI available for preclinical testing. We here compare bortezomib with carfilzomib and LU-102 in MM and MCL in vitro with regard to their effects on pIκB/NF-κB signaling and their cytotoxic activity in combination with ibrutinib. RESULTS: LU-102 reduced phosphorylation of IκB, in contrast to bortezomib and carfilzomib, and was a superior inhibitor of NF-κB activation in MM cells. This translated into highly synergistic cytotoxicity between LU-102 and ibrutinib, which was able to overcome BTZ resistance and CFZ resistance. By contrast, BTZ lacked consistent synergistic cytotoxicity with ibrutinib. CONCLUSION: Ibrutinib is highly synergistic with ß2-selective proteasome inhibition against MM and MCL in vitro. Novel ß2-selective proteasome inhibitors may be exploited to overcome bortezomib/carfilzomib resistance and boost the activity of BTK inhibitors against B-cell-derived malignancies.

Fluorescence resonance energy transfer to study receptor dimerization in living cells.

The versatility, sensitivity, and feasibility of fluorescence methods are very attractive to study protein-protein interaction at low levels of protein expression. However, one of the most severe limits in protein chemistry has been the difficulty of introducing site-specific fluorescent labels. The development of genetically encoded fluorescent probes, that is, green fluorescent protein (GFP) and its variants therefore opened up a broad field of novel applications. To characterize protein-protein interactions and determine detailed spatio-temporal dynamics of partners that are molecularly well characterized, fluorescence energy transfer methods are excellent nondestructive tools in living cells. Cellular responses to external factors are extensively based on direct molecular interaction and especially G-protein-coupled receptors (GPCRs) have been shown to interact with an unexpected level of complexity. Classical models of signal transduction describe GPCRs as monomeric proteins, while recent studies using fluorescence resonance energy transfer (FRET) and other methods show that GPCRs can also function as homo- or heterodimers. Theoretical background information on FRET technology and its diverse applications are summarized here. A detailed description of a spectroscopic method for FRET studies in the field of GPCR interaction is presented to facilitate and propagate studies to increase our understanding of protein-protein interactions involving GPCRs.

Ritonavir, nelfinavir, saquinavir and lopinavir induce proteotoxic stress in acute myeloid leukemia cells and sensitize them for proteasome inhibitor treatment at low micromolar drug concentrations.

BACKGROUND: Protein metabolism is an innovative potential therapeutic target for AML. Proteotoxic stress (PS) sensitizes malignant cells for proteasome inhibitor treatment. Some HIV protease inhibitors (HIV-PI) induce PS and may therefore be combined with proteasome inhibitors to achieve PS-targeted therapy of AML. METHODS: We investigated the effects of all nine approved HIV-PI alone and in combination with proteasome inhibitors on AML cell lines and primary cells in vitro. RESULTS: Ritonavir induced cytotoxicity and PS at clinically achievable concentrations, and induced synergistic PS-triggered apoptosis with bortezomib. Saquinavir, nelfinavir and lopinavir were likewise cytotoxic against primary AML cells, triggered PS-induced apoptosis, inhibited AKT-phosphorylation and showed synergistic cytotoxicity with bortezomib and carfilzomib at low micromolar concentrations. Exclusively nelfinavir inhibited intracellular proteasome activity, including the ß2 proteasome activity that is not targeted by bortezomib/carfilzomib. CONCLUSIONS: Of the nine currently approved HIV-PI, ritonavir, saquinavir, nelfinavir and lopinavir can sensitize AML primary cells for proteasome inhibitor treatment at low micromolar concentrations and may therefore be tested clinically toward a proteotoxic stress targeted therapy of AML.

Homodimerization of neuropeptide y receptors investigated by fluorescence resonance energy transfer in living cells.

Up to now neuropeptide Y (NPY) receptors, which belong to the large family of G-protein-coupled receptors and are involved in a broad range of physiological processes, are believed to act as monomers. Studies with the Y(1)-receptor antagonist and Y(4)-receptor agonist GR231118, which binds with a 250-fold higher affinity than its monomer, led to the first speculation that NPY receptors can form homodimers. In the present work we used the fluorescence resonance energy transfer (FRET) to study homodimerization of the hY(1)-, hY(2)-, and hY(5)-receptors in living cells. For this purpose, we generated fusion proteins of NPY receptors and green fluorescent protein or spectral variants of green fluorescent protein (cyan, yellow, and red fluorescent protein), which can be used as FRET pairs. Two different FRET techniques, fluorescence microscopy and fluorescence spectroscopy, were applied. Both techniques clearly showed that the hY(1)-, hY(2)-, and hY(5)-NPY receptor subtypes are able to form homodimers. By using transiently transfected cells, as well as a stable cell line expressing the hY(2)-GFP fusion protein, we could demonstrate that the Y-GFP fusion proteins are still functional and that dimerization varies from 26 to 44% dependent on the receptor. However, homodimerization is influenced neither by NPY nor by Galpha protein binding.

From transcription profile to expression: the signaling repertoire of the SK-N-MC neuroepithelioma cell-line.

SK-N-MC neuroepithelioma cells are routinely cultured and widely used as a model system in biochemical and pharmacological experiments. To clarify the gene expression patterns of SK-N-MC cells with respect to G protein-coupled receptors and signaling network components, we describe in this report the transcription profile of the cell line. Following the traditional pathway from genome to proteome, selected examples are further examined at the level of protein expression and by functional assays. cRNA targets derived from total RNA extracts were hybridized to Affymetrix Human Genome U133A GeneChip arrays, and the data were analyzed and grouped according to functional aspects. Results obtained for neuropeptide Y (NPY) Y1, Y5, and orexin Ox1 receptors were confirmed by RT-PCR. It is surprising that we found the presence of both NPY receptor subtypes and the absence of the orexin receptor at the mRNA level. Receptor-binding experiments confirmed NPY binding of the Y1 receptor in the nanomolar range but gave no evidence for high expression levels of Y5 receptor subtypes on the cell surface. Protein expression was assayed with immunoblots by using antibodies directed against selected Galpha protein subunits. The presence of at least Galphas, Galphai3, and Galphai2 subunits was indicated.