Internal variability and forcing influence model-satellite differences in the rate of tropical tropospheric warming.

Climate-model simulations exhibit approximately two times more tropical tropospheric warming than satellite observations since 1979. The causes of this difference are not fully understood and are poorly quantified. Here, we apply machine learning to relate the patterns of surface-temperature change to the forced and unforced components of tropical tropospheric warming.

Quantification of human contribution to soil moisture-based terrestrial aridity.

Current knowledge of the spatiotemporal patterns of changes in soil moisture-based terrestrial aridity has considerable uncertainty. Using Standardized Soil Moisture Index (SSI) calculated from multi-source merged data sets, we find widespread drying in the global midlatitudes, and wetting in the northern subtropics and in spring between 45°N-65°N, during 1971-2016. Formal detection and attribution analysis shows that human forcings, especially greenhouse gases, contribute significantly to the changes in 0-10 cm SSI during August-November, and 0-100 cm during September-April.

Quantifying stochastic uncertainty in detection time of human-caused climate signals.

Large initial condition ensembles of a climate model simulation provide many different realizations of internal variability noise superimposed on an externally forced signal. They have been used to estimate signal emergence time at individual grid points, but are rarely employed to identify global fingerprints of human influence. Here we analyze 50- and 40-member ensembles performed with 2 climate models; each was run with combined human and natural forcings.

Twentieth-century hydroclimate changes consistent with human influence.

Although anthropogenic climate change is expected to have caused large shifts in temperature and rainfall, the detection of human influence on global drought has been complicated by large internal variability and the brevity of observational records. Here we address these challenges using reconstructions of the Palmer drought severity index obtained with data from tree rings that span the past millennium. We show that three distinct periods are identifiable in climate models, observations and reconstructions during the twentieth century.

Human influence on the seasonal cycle of tropospheric temperature.

We provide scientific evidence that a human-caused signal in the seasonal cycle of tropospheric temperature has emerged from the background noise of natural variability. Satellite data and the anthropogenic "fingerprint" predicted by climate models show common large-scale changes in geographical patterns of seasonal cycle amplitude. These common features include increases in amplitude at mid-latitudes in both hemispheres, amplitude decreases at high latitudes in the Southern Hemisphere, and small changes in the tropics.

Competing influences of anthropogenic warming, ENSO, and plant physiology on future terrestrial aridity.

The 2011-2016 Californian drought illustrates that drought-prone areas do not always experience relief once a favorable phase of El Niño-Southern Oscillation (ENSO) returns. In the 21 century, such an expectation is unrealistic in regions where global warming induces an increase in terrestrial aridity larger than the aridity changes driven by ENSO variability. This premise is also flawed in areas where precipitation supply cannot offset the global warming-induced increased evaporative demand.

Future loss of Arctic sea-ice cover could drive a substantial decrease in California's rainfall.

From 2012 to 2016, California experienced one of the worst droughts since the start of observational records. As in previous dry periods, precipitation-inducing winter storms were steered away from California by a persistent atmospheric ridging system in the North Pacific. Here we identify a new link between Arctic sea-ice loss and the North Pacific geopotential ridge development.

Tropospheric Warming Over The Past Two Decades.

Satellite temperature measurements do not support the recent claim of a "leveling off of warming" over the past two decades. Tropospheric warming trends over recent 20-year periods are always significantly larger (at the 10% level or better) than model estimates of 20-year trends arising from natural internal variability. Over the full 38-year period of the satellite record, the separation between observed warming and internal variability estimates is even clearer.

Identifying external influences on global precipitation.

Changes in global (ocean and land) precipitation are among the most important and least well-understood consequences of climate change. Increasing greenhouse gas concentrations are thought to affect the zonal-mean distribution of precipitation through two basic mechanisms. First, increasing temperatures will lead to an intensification of the hydrological cycle ("thermodynamic" changes).

Human and natural influences on the changing thermal structure of the atmosphere.

Since the late 1970s, satellite-based instruments have monitored global changes in atmospheric temperature. These measurements reveal multidecadal tropospheric warming and stratospheric cooling, punctuated by short-term volcanic signals of reverse sign. Similar long- and short-term temperature signals occur in model simulations driven by human-caused changes in atmospheric composition and natural variations in volcanic aerosols.

Cyclophilin A as negative regulator of apoptosis by sequestering cytochrome c.

The release of cytochrome c from the mitochondrial intermembrane space is a decisive event in programmed cell death. Once in the cytoplasm, cytochrome c is involved in the formation of the macromolecular complex termed apoptosome, which activates procaspase-9 which in turn activates downstream procaspase-3. There are increasing evidence indicating that cyclophilin A is highly expressed in many tumors and cell lines where it exerts an anti-apoptotic function.

Phase II study of the histone deacetylase inhibitor MGCD0103 in patients with previously treated chronic lymphocytic leukaemia.

MGCD0103, an orally available class I histone deacetylase (HDAC) inhibitor, was examined for pre-clinical activity in chronic lymphocytic leukaemia (CLL). A phase II clinical trial was performed, starting at a dose of 85 mg/d, three times per week. Dose escalation to 110 mg or the addition of rituximab was permitted in patients without a response after two or more cycles.

Incorporating model quality information in climate change detection and attribution studies.

In a recent multimodel detection and attribution (D&A) study using the pooled results from 22 different climate models, the simulated "fingerprint" pattern of anthropogenically caused changes in water vapor was identifiable with high statistical confidence in satellite data. Each model received equal weight in the D&A analysis, despite large differences in the skill with which they simulate key aspects of observed climate. Here, we examine whether water vapor D&A results are sensitive to model quality.

Pharmacological inhibition of histone deacetylases for the treatment of cancer, neurodegenerative disorders and inflammatory diseases.

Background: Histone deacetylases (HDACs) constitute a family of enzymes that deacetylate histones and other cellular proteins. They are major regulators of transcription and are also important in other cellular processes.

Objective: The review provides an updated summary of HDAC pharmacological inhibition in clinical oncology, as well as in preclinical studies on inflammation and neurodegenerative diseases.

Evaluation of the pharmacodynamic effects of MGCD0103 from preclinical models to human using a novel HDAC enzyme assay.

Purpose: The pharmacodynamic properties of MGCD0103, an isotype-selective inhibitor of histone deacetylase (HDAC), were evaluated in preclinical models and patients with a novel whole-cell HDAC enzyme assay.

Experimental Design: Boc-Lys(epsilon-Ac)-AMC, a HDAC substrate with fluorescent readout, was found to be cell permeable and was used to monitor MGCD0103-mediated HDAC inhibition in cultured cancer cells in vitro, in peripheral WBC ex vivo, in mice in vivo, and in human patients.

Results: MGCD0103 inhibited HDAC activity in several human cancer cell lines in vitro and in human peripheral WBC ex vivo in a dose-dependent manner.

Phase 1 study of the oral isotype specific histone deacetylase inhibitor MGCD0103 in leukemia.

MGCD0103 is an isotype-selective inhibitor of histone deacetylases (HDACs) targeted to isoforms 1, 2, 3, and 11. In a phase 1 study in patients with leukemia or myelodysplastic syndromes (MDS), MGCD0103 was administered orally 3 times weekly without interruption. Twenty-nine patients with a median age of 62 years (range, 32-84 years) were enrolled at planned dose levels (20, 40, and 80 mg/m(2)).

Identification of apolipoprotein C-III as a potential plasmatic biomarker associated with the resolution of hepatitis C virus infection.

Understanding the virus-host interactions that lead to approximately 20% of patients with acute Hepatitis C Virus (HCV) infection to viral clearance is probably a key towards the development of more effective treatment and prevention strategies. Acute hepatitis C infection is usually asymptomatic and therefore rarely diagnosed. Nevertheless, HCV nucleic acid testing carried out on all blood donations detects donors who have resolved their HCV infection after seroconversion.

MGCD0103, a novel isotype-selective histone deacetylase inhibitor, has broad spectrum antitumor activity in vitro and in vivo.

Nonselective inhibitors of human histone deacetylases (HDAC) are known to have antitumor activity in mice in vivo, and several of them are under clinical investigation. The first of these, Vorinostat (SAHA), has been approved for treatment of cutaneous T-cell lymphoma. Questions remain concerning which HDAC isotype(s) are the best to target for anticancer activity and whether increased efficacy and safety will result with an isotype-selective HDAC inhibitor.

Human-induced changes in the hydrology of the western United States.

Observations have shown that the hydrological cycle of the western United States changed significantly over the last half of the 20th century. We present a regional, multivariable climate change detection and attribution study, using a high-resolution hydrologic model forced by global climate models, focusing on the changes that have already affected this primarily arid region with a large and growing population. The results show that up to 60% of the climate-related trends of river flow, winter air temperature, and snow pack between 1950 and 1999 are human-induced.

Novel aminophenyl benzamide-type histone deacetylase inhibitors with enhanced potency and selectivity.

Significant effort is being made to understand the role of HDAC isotypes in human cancer and to develop antitumor agents with better therapeutic windows. A part of this endeavor was the exploration of the 14 A internal cavity adjacent to the enzyme catalytic site, which led to the design and synthesis of compound 4 with the unusual bis(aryl)-type pharmacophore. SAR studies around this lead resulted in optimization to potent, selective, nonhydroxamic acid HDAC inhibitors.

Empirical evidence for a recent slowdown in irrigation-induced cooling.

Understanding the influence of past land use changes on climate is needed to improve regional projections of future climate change and inform debates about the tradeoffs associated with land use decisions. The effects of rapid expansion of irrigated area in the 20th century has remained unclear relative to other land use changes, such as urbanization, that affected a similar total land area. Using spatial and temporal variations in temperature and irrigation extent observed in California, we show that irrigation expansion has had a large cooling effect on summertime average daily daytime temperatures (-0.

Kinetic analysis of tubulin assembly in the presence of the microtubule-associated protein TOGp.

The microtubule-associated protein TOGp, which belongs to a widely distributed protein family from yeasts to humans, is highly expressed in human tumors and brain tissue. From purified components we have determined the effect of TOGp on thermally induced tubulin association in vitro in the presence of 1 mm GTP and 3.4 m glycerol.

Forced and unforced ocean temperature changes in Atlantic and Pacific tropical cyclogenesis regions.

Previous research has identified links between changes in sea surface temperature (SST) and hurricane intensity. We use climate models to study the possible causes of SST changes in Atlantic and Pacific tropical cyclogenesis regions. The observed SST increases in these regions range from 0.

Simplified stepwise management of primary spontaneous pneumothorax: a pilot study.

In primary spontaneous pneumothorax (PSP) requiring intervention, removal of air from the pleural space can be achieved by manual needle aspiration or by pleural drainage after insertion of a chest tube. This study aimed to evaluate the efficacy and safety of a serial-steps approach with a single system (small-calibre catheter/Heimlich valve) in a homogeneous population of patients with a first episode of PSP. All patients had an 8.

Interactions of Bax and tBid with lipid monolayers.

The release of cytochrome c from mitochondria to the cytosol is a crucial step of apoptosis that involves interactions of Bax and tBid proteins with the mitochondrial membrane. We investigated Bax and tBid interactions with (i) phosphatidylcholine (PC) monolayer as the main component of the outer leaflet of the outer membrane, (ii) with phosphatidylethanolamine (PE) and phosphatidylserine (PS) that are present in the inner leaflet and (iii) with a mixed PC/PE/Cardiolipin (CL) monolayer of the contact sites between the outer and inner membranes. These interactions were studied by measuring the increase of the lipidic monolayer surface pressure induced by the proteins.