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The Late Miocene (~11.6-5.3 Ma) palaeorecord provides evidence for a warmer and wetter climate than that of today and there is uncertainty in the palaeo-CO2 record of at least 150 ppmv. We present results from fully coupled atmosphere-ocean-vegetation simulations for the Late Miocene that examine the relative roles of palaeogeography (topography and ice sheet geometry) and CO2 concentration in the determination of Late Miocene climate through comprehensive terrestrial model-data comparisons. Assuming that the data accurately reflects the Late Miocene climate, and that the Late Miocene palaeogeographic reconstruction used in the model is robust, then results indicate that the proxy-derived precipitation differences between the Late Miocene and modern can be largely accounted for by the palaeogeographic changes alone. However, the proxy-derived temperatures differences between the Late Miocene and modern can only begin to be accounted for if we assume a palaeo-CO2 concentration towards the higher end of the range of estimates. [ABSTRACT FROM AUTHOR]

One of Earth's most fundamental climate shifts, the greenhouse-icehouse transition 34 million years ago, initiated Antarctic ice sheet buildup, influencing global climate until today. However, the extent of the ice sheet during the Early Oligocene Glacial Maximum (~33.7 to 33.2 million years ago) that immediately followed this transition-a critical knowledge gap for assessing feedbacks between permanently glaciated areas and early Cenozoic global climate reorganization-is uncertain. In this work, we present shallow-marine drilling data constraining earliest Oligocene environmental conditions on West Antarctica's Pacific margin-a key region for understanding Antarctic ice sheet evolution. These data indicate a cool-temperate environment with mild ocean and air temperatures that prevented West Antarctic Ice Sheet formation. Climate-ice sheet modeling corroborates a highly asymmetric Antarctic ice sheet, thereby revealing its differential regional response to past and future climatic change.

Extensive ice coverage largely prevents investigations of Antarctica's unglaciated past. Knowledge about environmental and tectonic development before large-scale glaciation, however, is important for understanding the transition into the modern icehouse world. We report geochronological and sedimentological data from a drill core from the Amundsen Sea shelf, providing insights into tectonic and topographic conditions during the Eocene (~44 to 34 million years ago), shortly before major ice sheet buildup. Our findings reveal the Eocene as a transition period from >40 million years of relative tectonic quiescence toward reactivation of the West Antarctic Rift System, coinciding with incipient volcanism, rise of the Transantarctic Mountains, and renewed sedimentation under temperate climate conditions. The recovered sediments were deposited in a coastal-estuarine swamp environment at the outlet of a >1500-km-long transcontinental river system, draining from the rising Transantarctic Mountains into the Amundsen Sea. Much of West Antarctica hence lied above sea level, but low topographic relief combined with low elevation inhibited widespread ice sheet formation.

The winter and summer monsoons in Southeast Asia are important but highly variable sources of rainfall. Current understanding of the winter monsoon is limited by conflicting proxy observations, resulting from the decoupling of regional atmospheric circulation patterns and local rainfall dynamics. These signals are difficult to decipher in paleoclimate reconstructions. Here, we present a winter monsoon speleothem record from Southeast Asia covering the Holocene and find that winter and summer rainfall changed synchronously, forced by changes in the Pacific and Indian Oceans. In contrast, regional atmospheric circulation shows an inverse relation between winter and summer controlled by seasonal insolation over the Northern Hemisphere. We show that disentangling the local and regional signal in paleoclimate reconstructions is crucial in understanding and projecting winter and summer monsoon variability in Southeast Asia., (© 2023. Springer Nature Limited.)

Accurate understanding of permafrost dynamics is critical for evaluating and mitigating impacts that may arise as permafrost degrades in the future; however, existing projections have large uncertainties. Studies of how permafrost responded historically during Earth's past warm periods are helpful in exploring potential future permafrost behavior and to evaluate the uncertainty of future permafrost change projections. Here, we combine a surface frost index model with outputs from the second phase of the Pliocene Model Intercomparison Project to simulate the near-surface (~3 to 4 m depth) permafrost state in the Northern Hemisphere during the mid-Pliocene warm period (mPWP, ~3.264 to 3.025 Ma). This period shares similarities with the projected future climate. Constrained by proxy-based surface air temperature records, our simulations demonstrate that near-surface permafrost was highly spatially restricted during the mPWP and was 93 ± 3% smaller than the preindustrial extent. Near-surface permafrost was present only in the eastern Siberian uplands, Canadian high Arctic Archipelago, and northernmost Greenland. The simulations are similar to near-surface permafrost changes projected for the end of this century under the SSP5-8.5 scenario and provide a perspective on the potential permafrost behavior that may be expected in a warmer world.

Wallacea-the meeting point between the Asian and Australian fauna-is one of the world's largest centers of endemism. Twenty-three million years of complex geological history have given rise to a living laboratory for the study of evolution and biodiversity, highly vulnerable to anthropogenic pressures. In the present article, we review the historic and contemporary processes shaping Wallacea's biodiversity and explore ways to conserve its unique ecosystems. Although remoteness has spared many Wallacean islands from the severe overexploitation that characterizes many tropical regions, industrial-scale expansion of agriculture, mining, aquaculture and fisheries is damaging terrestrial and aquatic ecosystems, denuding endemics from communities, and threatening a long-term legacy of impoverished human populations. An impending biodiversity catastrophe demands collaborative actions to improve community-based management, minimize environmental impacts, monitor threatened species, and reduce wildlife trade. Securing a positive future for Wallacea's imperiled ecosystems requires a fundamental shift away from managing marine and terrestrial realms independently., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Institute of Biological Sciences.)

The early Eocene (∼56-48 Myr ago) is characterized by high CO 2 estimates (1,200-2,500 ppmv) and elevated global temperatures (∼10°C-16°C higher than modern). However, the response of the hydrological cycle during the early Eocene is poorly constrained, especially in regions with sparse data coverage (e.g., Africa). Here, we present a study of African hydroclimate during the early Eocene, as simulated by an ensemble of state-of-the-art climate models in the Deep-time Model Intercomparison Project (DeepMIP). A comparison between the DeepMIP pre-industrial simulations and modern observations suggests that model biases are model- and geographically dependent, however, these biases are reduced in the model ensemble mean. A comparison between the Eocene simulations and the pre-industrial suggests that there is no obvious wetting or drying trend as the CO 2 increases. The results suggest that changes to the land sea mask (relative to modern) in the models may be responsible for the simulated increases in precipitation to the north of Eocene Africa. There is an increase in precipitation over equatorial and West Africa and associated drying over northern Africa as CO 2 rises. There are also important dynamical changes, with evidence that anticyclonic low-level circulation is replaced by increased south-westerly flow at high CO 2 levels. Lastly, a model-data comparison using newly compiled quantitative climate estimates from paleobotanical proxy data suggests a marginally better fit with the reconstructions at lower levels of CO 2 ., Competing Interests: The authors declare no conflicts of interest relevant to this study., (© 2022. The Authors.)

Estimates of the permafrost-climate feedback vary in magnitude and sign, partly because permafrost carbon stability in warmer-than-present conditions is not well constrained. Here we use a Plio-Pleistocene lacustrine reconstruction of mean annual air temperature (MAAT) from the Tibetan Plateau, the largest alpine permafrost region on the Earth, to constrain past and future changes in permafrost carbon storage. Clumped isotope-temperatures (Δ 47 -T) indicate warmer MAAT (~1.2 °C) prior to 2.7 Ma, and support a permafrost-free environment on the northern Tibetan Plateau in a warmer-than-present climate. Δ 47 -T indicate ~8.1 °C cooling from 2.7 Ma, coincident with Northern Hemisphere glacial intensification. Combined with climate models and global permafrost distribution, these results indicate, under conditions similar to mid-Pliocene Warm period (3.3-3.0 Ma), ~60% of alpine permafrost containing ~85 petagrams of carbon may be vulnerable to thawing compared to ~20% of circumarctic permafrost. This estimate highlights ~25% of permafrost carbon and the permafrost-climate feedback could originate in alpine areas., (© 2022. The Author(s).)

The mid-Cretaceous period was one of the warmest intervals of the past 140 million years 1-5 , driven by atmospheric carbon dioxide levels of around 1,000 parts per million by volume 6 . In the near absence of proximal geological records from south of the Antarctic Circle, it is disputed whether polar ice could exist under such environmental conditions. Here we use a sedimentary sequence recovered from the West Antarctic shelf-the southernmost Cretaceous record reported so far-and show that a temperate lowland rainforest environment existed at a palaeolatitude of about 82° S during the Turonian-Santonian age (92 to 83 million years ago). This record contains an intact 3-metre-long network of in situ fossil roots embedded in a mudstone matrix containing diverse pollen and spores. A climate model simulation shows that the reconstructed temperate climate at this high latitude requires a combination of both atmospheric carbon dioxide concentrations of 1,120-1,680 parts per million by volume and a vegetated land surface without major Antarctic glaciation, highlighting the important cooling effect exerted by ice albedo under high levels of atmospheric carbon dioxide.

Observations and model experiments highlight the importance of ocean heat in forcing ice sheet retreat during the present and geological past, but past ocean temperature data are virtually missing in ice sheet proximal locations. Here we document paleoceanographic conditions and the (in)stability of the Wilkes Land subglacial basin (East Antarctica) during the mid-Miocene (~17-13.4 million years ago) by studying sediment cores from offshore Adélie Coast. Inland retreat of the ice sheet, temperate vegetation, and warm oligotrophic waters characterise the mid-Miocene Climatic Optimum (MCO; 17-14.8 Ma). After the MCO, expansion of a marine-based ice sheet occurs, but remains sensitive to melting upon episodic warm water incursions. Our results suggest that the mid-Miocene latitudinal temperature gradient across the Southern Ocean never resembled that of the present day. We demonstrate that a strong coupling of oceanic climate and Antarctic continental conditions existed and that the East Antarctic subglacial basins were highly sensitive to ocean warming.

Rapid global cooling at the Eocene - Oligocene Transition (EOT), ~33.9-33.5 Ma, is widely considered to mark the onset of the modern icehouse world. A large and rapid drop in atmospheric pCO 2 has been proposed as the driving force behind extinctions in the marine realm and glaciation on Antarctica. However, the global terrestrial response to this cooling is uncertain. Here we present the first global vegetation and terrestrial temperature reconstructions for the EOT. Using an extensive palynological dataset, that has been statistically grouped into palaeo-biomes, we show a more transitional nature of terrestrial climate change by indicating a spatial and temporal heterogeneity of vegetation change at the EOT in both hemispheres. The reconstructed terrestrial temperatures show for many regions a cooling that started well before the EOT and continued into the Early Oligocene. We conclude that the heterogeneous pattern of global vegetation change has been controlled by a combination of multiple forcings, such as tectonics, sea-level fall and long-term decline in greenhouse gas concentrations during the late Eocene to early Oligocene, and does not represent a single response to a rapid decline in atmospheric pCO 2 at the EOT.

The characteristics of the mid-Pliocene warm period (mPWP: 3.264-3.025 Ma BP) have been examined using geological proxies and climate models. While there is agreement between models and data, details of regional climate differ. Uncertainties in prescribed forcings and in proxy data limit the utility of the interval to understand the dynamics of a warmer than present climate or evaluate models. This uncertainty comes, in part, from the reconstruction of a time slab rather than a time slice, where forcings required by climate models can be more adequately constrained. Here, we describe the rationale and approach for identifying a time slice(s) for Pliocene environmental reconstruction. A time slice centred on 3.205 Ma BP (3.204-3.207 Ma BP) has been identified as a priority for investigation. It is a warm interval characterized by a negative benthic oxygen isotope excursion (0.21-0.23‰) centred on marine isotope stage KM5c (KM5.3). It occurred during a period of orbital forcing that was very similar to present day. Climate model simulations indicate that proxy temperature estimates are unlikely to be significantly affected by orbital forcing for at least a precession cycle centred on the time slice, with the North Atlantic potentially being an important exception.

The circum-Antarctic Southern Ocean is an important region for global marine food webs and carbon cycling because of sea-ice formation and its unique plankton ecosystem. However, the mechanisms underlying the installation of this distinct ecosystem and the geological timing of its development remain unknown. Here, we show, on the basis of fossil marine dinoflagellate cyst records, that a major restructuring of the Southern Ocean plankton ecosystem occurred abruptly and concomitant with the first major Antarctic glaciation in the earliest Oligocene (~33.6 million years ago). This turnover marks a regime shift in zooplankton-phytoplankton interactions and community structure, which indicates the appearance of eutrophic and seasonally productive environments on the Antarctic margin. We conclude that earliest Oligocene cooling, ice-sheet expansion, and subsequent sea-ice formation were important drivers of biotic evolution in the Southern Ocean.

The mid-Piacenzian climate represents the most geologically recent interval of long-term average warmth relative to the last million years, and shares similarities with the climate projected for the end of the 21(st) century. As such, it represents a natural experiment from which we can gain insight into potential climate change impacts, enabling more informed policy decisions for mitigation and adaptation. Here, we present the first systematic comparison of Pliocene sea surface temperature (SST) between an ensemble of eight climate model simulations produced as part of PlioMIP (Pliocene Model Intercomparison Project) with the PRISM (Pliocene Research, Interpretation and Synoptic Mapping) Project mean annual SST field. Our results highlight key regional and dynamic situations where there is discord between the palaeoenvironmental reconstruction and the climate model simulations. These differences have led to improved strategies for both experimental design and temporal refinement of the palaeoenvironmental reconstruction.

It has been suggested that, during the Pliocene (ca 5-1.8Ma), an El Niño state existed as a permanent rather than an intermittent feature; that is, the tropical Pacific Ocean was characterized by a much weaker east-west gradient than today. One line of inquiry used to investigate this idea relates modern El Niño teleconnections to Pliocene proxy data by comparing regional differences in precipitation and surface temperature with climate patterns associated with present-day El Niño events, assuming that agreement between Pliocene data and observations of modern El Niño events supports this interpretation. Here, we examine this assumption by comparing outputs from a suite of Mid-Pliocene climate simulations carried out with the UK Met Office climate model. Regional patterns of climate change associated with changes in model boundary conditions are compared with observed El Niño-Southern Oscillation teleconnection patterns. Our results indicate that many of the proposed 'permanent El Niño' surface temperature and precipitation patterns are observable in Mid-Pliocene climate simulations even when they display variability in tropical Pacific sea surface temperatures (SSTs) or when forced with a modern east-west SST gradient. Our experiments highlight the possibility that the same outcome may be achieved through different initial conditions (equifinality); an important consideration for reconstructed patterns of regional Mid-Pliocene climate.

The majority of MHC class I epitopes is generated through the ubiquitin-proteasome system. In the present study, we have analyzed the proteasome-dependent generation of the IE pp89 MCMV-derived H-2L(d) epitope by both in vitro and in vivo experiments. As revealed by cytotoxic T-cell assays, the pp89 9mer epitope was generated with high fidelity from the recombinant IE pp89 by 20S proteasomes. In vitro processing showed that the recombinant pp89 was rapidly degraded by 20S proteasomes. Analysis of cell lysates under conditions that allowed detection of polyubiquitinated proteins provided no evidence for the presence of ubiquitin-pp89-conjugates in vivo. These findings suggest a ubiquitin-independent mechanism of proteasomal degradation for pp89.

Introduction: Carvedilol is a comprehensive beta(1)-, beta(2)-, and alpha(1)-adrenoreceptor blocker marketed as Dilatrend by F. Hoffmann-La Roche Ltd. (Roche) and as Coreg by GlaxoSmithKline for the treatment of hypertension, stable angina pectoris, post myocardial infarction with left ventricular dysfunction and all degrees of symptomatic chronic heart failure., Objectives: In this report, the pharmaceutical qualities of Dilatrend 6.25 mg, 12.5 mg and 25 mg tablets and 35 randomly selected carvedilol generic products from 20 manufacturers in 19 countries have been assessed according to the European Pharmacopoeia and the Roche specifications., Methods: The generic products were subjected to four key tests: carvedilol content, tablet hardness, tablet dissolution and purity., Results: All three Dilatrend strengths conformed to specifications. At least 17/35 (48.6%) generic products failed the specifications due to: incorrect mean carvedilol content (outside 95-105%) - three products; excess impurities (> 0.3%) - one product; incorrect tablet hardness (outside 30-70 N) - 11 products; inadequate dissolution (< 75% in 30 min) - nine products. Seven products (20%) failed two tests, generally hardness and dissolution., Conclusion: The dose-for-dose substitution of the original formulation of carvedilol (Dilatrend) with a pharmaceutically different, and possibly inferior, generic copy may conceivably result in a change in the efficacy of the treatment, because of an unanticipated change in pharmacokinetics or bioequivalence, and/or in a change in tolerability due to impurities.

The human immunodeficiency virus-1 Tat protein inhibits the peptidase activity of the 20S proteasome and competes with the 11S regulator/PA28 for binding to the 20S proteasome. Structural comparison revealed a common site in the Tat protein and the 11S regulator alpha-subunit (REGalpha) called the REG/Tat-proteasome-binding (RTP) site. Kinetic assays found amino acid residues Lys51, Arg52 and Asp67 forming the RTP site of Tat to be responsible for the effects on proteasomes in vitro. The RTP site identified in REGalpha consists of the residues Glu235, Lys236 and Lys239. Mutation of the REGalpha amino acid residues Glu235 and Lys236 to Ala resulted in an REGalpha mutant that lost the ability to activate the 20S proteasome even though it still forms complexes with REGbeta and binds to the 20S proteasome. The REGalpha RTP site is needed to enhance the presentation of a cytomegalovirus pp89 protein-derived epitope by MHC class I molecules in mouse fibroblasts. Cell experiments demonstrate that the Tat amino acid residues 37-72 are necessary for the interaction of the viral protein with proteasomes in vivo. Full-length Tat and the Tat peptide 37-72 suppressed 11S regulator-mediated presentation of the pp89 epitope. In contrast, the Tat peptide 37-72 with mutations of amino acid residues Lys51, Arg52 and Asp67 to Ala was not able to reduce antigen presentation.

The activation kinetics of constitutive and IFNgamma-stimulated 20S proteasomes obtained with homomeric (recPA28alpha, recPA28beta) and heteromeric (recPA28alphabeta) forms of recombinant 11S regulator PA28 was analysed by means of kinetic modelling. The activation curves obtained with increasing concentrations of the individual PA28 subunits (RecP28alpha/RecP28beta/RecP28alpha + RecP28beta) exhibit biphasic characteristics which can be attributed to a low-level activation by PA28 monomers and full proteasome activation by assembled activator complexes. The dissociation constants do not reveal significant differences between the constitutive and the immunoproteasome. Intriguingly, the affinity of the proteasome towards the recPA28alphabeta complex is about two orders of magnitude higher than towards the homomeric PA28alpha and PA28beta complexes. Striking similarities can been revealed in the way how PA28 mediates the kinetics of latent proteasomes with respect to three different fluorogenic peptides probing the chymotrypsin-like, trypsin-like and peptidylglutamyl-peptide hydrolyzing like activity: (a) positive cooperativity disappears as indicated by a lack of sigmoid initial parts of the kinetic curves, (b) substrate affinity is increased, whereby (c), the maximal activity remains virtually constant. As these kinetic features are independent of the peptide substrates, we conclude that PA28 exerts its activating influence on the proteasome by enhancing the uptake (and release) of shorter peptides.

Proteasomes are the major protein-degrading complexes in the cytosol and regulate many cellular processes. To examine the functional importance of the MC14/MECL-1 proteasome active site subunits, cell lines expressing a catalytically inactive form of MECL-1 were established. Whereas mutant MECL-1 was readily incorporated into cytosolic proteasomes, replacing the constitutive MC14 subunit, removal of the prosequence was incomplete indicating that its processing required autocatalytic cleavage. Functional analyses showed that the absence of the MC14/MECL-1 active sites abrogated proteasomal trypsin-like activity, but did not affect other catalytic activities. Our data demonstrate a conservation of cleavage specificity between mammalian and yeast proteasomes.

The lipoxygenases from reticulocytes, soybeans and green pea seeds produce pentane in an anaerobic assay containing 13Ls-hydroperoxy-9-cis, 11-trans-octadecadienoic acid and 9,12-all-cis-octadecadienoic acid. The presence of oxygen strongly inhibits pentane formation by the three enzymes. Relative to the lipoxygenase activity with linoleic acid as substrate, soybean lipoxygenase is 4-times as effective in pentane formation as the lipoxygenases from reticulocytes or green pea seeds. Pentane formation by the reticulocyte lipoxygenase is completely inhibited by lipoxygenase inhibitors (5,8,11,14-eicosatetraynoic acid, 3-t-butyl-4-hydroxyanisol) but only partially by radical scavengers which do not influence the oxygenase activity (2,6-di-t-butyl-4-hydroxytoluene). From the temperature dependence below 20 degrees C an activation energy of the pentane production by the reticulocyte lipoxygenase of about 28 kJ/mol was calculated, which is somewhat higher than that for the oxygenase activity. During the anaerobic reaction of both reticulocyte and soybean lipoxygenase C18-oxodienes, C13-oxodienes, linoleic acid dimers and a polar compound proposed to be epoxy-hydroxyoctadecenoic acid are produced in a similar pattern. Reticulocyte lipoxygenase produces pentane with submitochondrial particles only under anaerobic conditions after an aerobic preincubation. During the incubation of intact reticulocytes with the calcium ionophore A23187 or arachidonic acid, pentane is released. Preincubation of the cells with lipoxygenase inhibitors completely abolishes the pentane formation. Erythrocytes do not form any pentane under the same experimental conditions.

The endogenous oxygen uptake of rabbit reticulocyte-rich red cell suspensions obtained by bleeding anaemia of rabbits amounted to 7.85 +/- 0.87 mumoles/h . ml of packed cells and was inhibited by antimycin A to 77.2 +/- 1.1%. The antimycin A-resistant oxygen uptake was further inhibited by the lipoxygenase inhibitors salicylhydroxamic acid, 5,8,11,14-eicosatetraynoic acid, nordihydroguaiaretic acid, 4-nitrocatechol or propylgallate by about 20-30% corresponding to 5-7% of the total oxygen uptake. The effects of the lipoxygenase inhibitors were most pronounced during the first period of bleeding anaemia (5th-9th day). 3-amino-1,2,4-triazole inhibited another part of the non-respiratory oxygen uptake and acted additively to 5,8,11,14-eicosatetraynoic acid; the two inhibitors together caused inhibition by one-half. Influx of calcium ions mediated by the ionophore A 23187 led to a two-fold increase in the non-respiratory oxygen uptake which was mainly due to stimulation of the lipoxygenase reaction. The rate of the lipoxygenase-mediated oxygen uptake was sufficient for a complete dioxygenation of the polyenoic fatty acids present in mitochondrial phospholipids during the maturational degradation of mitochondria in reticulocytes.