Age-Related Differences in Plasma Proteins: How Plasma Proteins Change from Neonates to Adults

The incidence of major diseases such as cardiovascular disease, thrombosis and cancer increases with age and is the major cause of mortality world-wide, with neonates and children somehow protected from such diseases of ageing. We hypothesized that there are major developmental differences in plasma proteins and that these contribute to age-related changes in the incidence of major diseases. We evaluated the human plasma proteome in healthy neonates, children and adults using the 2D-DIGE approach. We demonstrate significant changes in number and abundance of up to 100 protein spots that have marked differences in during the transition of the plasma proteome from neonate and child through to adult. These proteins are known to be involved in numerous physiological processes such as iron transport and homeostasis, immune response, haemostasis and apoptosis, amongst others. Importantly, we determined that the proteins that are differentially expressed with age are not the same proteins that are differentially expressed with gender and that the degree of phosphorylation of plasma proteins also changes with age. Given the multi-functionality of these proteins in human physiology, understanding the differences in the plasma proteome in neonates and children compared to adults will make a major contribution to our understanding of developmental biology in humans.GE Healthcare Life Sciences Australia funded Sherif Tawfilis' time in the initial laboratory aspects of this project, some aspects of data analysis and preparation of the manuscript. This study was funded by internal Haematology Research Team funds. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Pliocene Te Aute limestones, New Zealand: Expanding concepts for cool-water shelf carbonates

Acceptance of a spectrum of warm- through cold-water shallow-marine carbonate facies has become of fundamental importance for correctly interpreting the origin and significance of all ancient platform limestones. Among other attributes, properties that have become a hallmark for characterising many Cenozoic non-tropical occurrences include: (1) the presence of common bryozoan and epifaunal bivalve skeletons; (2) a calcite-dominated mineralogy; (3) relatively thin deposits exhibiting low rates of sediment accumulation; (4) an overall destructive early diagenetic regime; and (5) that major porosity destruction and lithification occur mainly in response to chemical compaction of calcitic skeletons during moderate to deep burial. The Pliocene Te Aute limestones are non-tropical skeletal carbonates formed at paleolatitudes near 40-42°S under the influence of commonly strong tidal flows along the margins of an actively deforming and differentially uplifting forearc basin seaway, immediately inboard of the convergent Pacific-Australian plate boundary off eastern North Island, New Zealand. This dynamic depositional and tectonic setting strongly influenced both the style and subsequent diagenetic evolution of the limestones. Some of the Te Aute limestones exhibit the above kinds of "normal" non-tropical characteristics, but others do not. For example, many are barnacle and/or bivalve dominated, and several include attributes that at least superficially resemble properties of certain tropical carbonates. In this regard, a number of the limestones are infaunal bivalve rich and dominated by an aragonite over a calcite primary mineralogy, with consequently relatively high diagenetic potential. Individual limestone units are also often rather thick (e.g., up to 50-300 m), with accumulation rates from 0.2 to 0.5 m/ka, and locally as high as 1 m/ka. Moreover, there can be a remarkable array of diagenetic features in the limestones, involving grain alteration and/or cementation to widely varying extents within any, or some combination of, the marine phreatic, burial, and meteoric diagenetic environments, including locally widespread development of meteoric cement sourced from aragonite dissolution. The message is that non-tropical shelf carbonates include a more diverse array of geological settings, of skeletal and mineralogical facies, and of diagenetic features than current sedimentary models mainly advocate. While several attributes positively distinguish tropical from non-tropical limestones, continued detailed documentation of the wide spectrum of shallow-marine carbonate deposits formed outside tropical regions remains an important challenge in carbonate sedimentology

Antarctic climate change and the environment: an update

We present an update of the ‘key points’ from the Antarctic Climate Change and the Environment (ACCE) report that was published by the Scientific Committee on Antarctic Research (SCAR) in 2009. We summarise subsequent advances in knowledge concerning how the climates of the Antarctic and Southern Ocean have changed in the past, how they might change in the future, and examine the associated impacts on the marine and terrestrial biota. We also incorporate relevant material presented by SCAR to the Antarctic Treaty Consultative Meetings, and make use of emerging results that will form part of the Intergovernmental Panel on Climate Change (IPCC) Fifth Assessment Repor

Sources and hydrothermal alteration of organic matter in Quaternary sediments: A synthesis of studies from the Central Gulf of California

Deep sea drilling in the Central Gulf of California, a young and active spreading centre, shows that the high heat flow typical of these regions causes extensive alteration of sediment organic matter, especially near sills and above magma chambers where hydrothermal activity is concentrated. Even on the nearby passive margin, where there are no sills, heat flow is moderately high and hydrocarbon generation has begun in immature sequences. Migrating light hydrocarbons are detected especially where hydrothermal activity is concentrated. Thermogenic methane is more widespread, though not in the passive margin bordering the spreading centre. Despite the incidence of hydrocarbon generation and migration, the amounts of hydrocarbons involved are relatively small and apparently do not lead to commercially significant accumulations of petroleum.The organic matter in these sediments is mostly marine because the Gulf of California generally has low runoff from land and highly productive surface waters. Turbidites rich in terrigenous organic material are locally abundant in the mainly pelagic section in the Guaymas Basin. The highest concentrations of organic matter are found in laminated diatomites deposited on the Guaymas passive margin within the oxygen minimum zone.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/25993/1/0000059.pd

The future extent of the Anthropocene epoch: A synthesis

We synthesize research from complementary scientific fields to address the likely future extent and duration of the proposed Anthropocene epoch. Intensification of human-forced climate change began from about 1970 onwards with steepening increases in greenhouse gases, ocean acidification, global temperature and sea level, along with ice loss. The resulting distinction between relatively stable Holocene climatic conditions and those of the proposed Anthropocene epoch is substantial, with many aspects irreversible. The still-rising trajectory of greenhouse gas emissions is leading to yet greater and more permanent divergence of the Anthropocene from the Holocene Earth System. We focus here on the effects of the ensuing climate transformation and its impact on the likely duration of this novel state of the Earth System. Given the magnitude and rapid rise of atmospheric carbon dioxide (CO2), its long lifetime in the atmosphere, and the present disequilibrium in Earth's energy budget (expressed as the Earth's Energy Imbalance, or EEI), both temperatures and sea level must continue to rise – even with carbon emissions lowered to net zero (where anthropogenic CO2 emissions = anthropogenic CO2 removals) – until the energy budget balance is eventually restored. Even if net zero were achieved immediately, elevated global temperatures would persist for at least several tens of millennia, with expected levels of warmth by the end of this century not seen since the early Late Pliocene. Interglacial conditions are likely to persist for at least 50,000 years under already-accumulated CO2 emissions and Earth's low eccentricity orbit. Continued increases in greenhouse gas emissions are likely to extend that persistence to around 500,000 years, suppressing the pronounced expression of Milankovitch cyclicity typical of the later Pleistocene Epoch. This major perturbation alone is sufficient to justify the Anthropocene as terminating the Holocene Epoch. The wider and mostly irreversible effects of climate change, not least in amplifying reconfiguration of the biosphere, emphasize the scale of this departure from Holocene conditions, justifying the establishment of a new epoch. Given such perspectives, the Anthropocene epoch represents what will become a lasting and substantial change in the Earth System. It is the Holocene Epoch at only 11,700 years duration that will appear as the ‘blip’ in the Geological Time Scale, a brief interval when complex, settled human societies co-existed with, but did not overwhelm, a stable Earth System

From Clinical Trials to Real-life Clinical Practice: The Role of Immunotherapy with PD-1/PD-L1 Inhibitors in Advanced Urothelial Carcinoma

ContextA number of PD-1/PD-L1 inhibitors have recently been approved for use in patients with locally advanced or metastatic urothelial carcinoma (UC) on the basis of results from several clinical trials.ObjectiveTo review the evidence from these trials and consider what it means for the use of these drugs in first-line and post-platinum settings in real-life clinical practice.Evidence acquisitionPubMed was searched for full reports of clinical trials of single-agent PD-1/PD-L1 inhibitors in advanced UC. Twelve publications were included.Evidence synthesisResponses to PD-1/PD-L1 inhibitors appear to be durable but are only achieved in 17–26% of patients. These drugs offer different toxicity and efficacy profiles to standard chemotherapy regimens. This should be considered when choosing a treatment strategy for each patient.ConclusionsPD-1/PD-L1 inhibitors represent a major step forward in the management of advanced UC, although several questions remain regarding their optimal use in routine clinical practice. A validated predictive biomarker of response is yet to be defined, and this is perhaps the most significant unmet need for currently available drugs.Patient summaryWe reviewed the results from clinical trials that investigated how well certain types of anticancer drugs called PD-1/PD-L1 inhibitors worked in patients with bladder cancer. We found that more research is required to identify (1) the factors that might predict which patients with bladder cancer will respond to PD-1/PD-L1 inhibitors and (2) the optimum duration of treatment with these drugs.</p

MicroRNA expression profile identifies high grade, non-muscle-invasive bladder tumors at elevated risk to progress to an invasive phenotype

Abstract: The objective of this study was to identify a panel of microRNAs (miRNAs) differentially expressed in high-grade non-muscle invasive (NMI; TaG3–T1G3) urothelial carcinoma that progress to muscle-invasive disease compared to those that remain non-muscle invasive, whether recurrence happens or not. Eighty-nine high-grade NMI urothelial carcinoma lesions were identified and total RNA was extracted from paraffin-embedded tissue. Patients were categorized as either having a non-muscle invasive lesion with no evidence of progression over a 3-year period or as having a similar lesion showing progression to muscle invasion over the same period. In addition, comparison of miRNA expression levels between patients with and without prior intravesical therapy was performed. Total RNA was pooled for microarray analysis in each group (non-progressors and progressors), and qRT-PCR of individual samples validated differential expression between non-progressive and progressive lesions. MiR-32-5p, -224-5p, and -412-3p were associated with cancer-specific survival. Downregulation of miR-203a-3p and miR-205-5p were significantly linked to progression in non-muscle invasive bladder tumors. These miRNAs include those implicated in epithelial mesenchymal transition, previously identified as members of a panel characterizing transition from the non-invasive to invasive phenotype in bladder tumors. Furthermore, we were able to identify specific miRNAs that are linked to postoperative outcome in patients with high grade NMI urothelial carcinoma of the bladder (UCB) that progressed to muscle-invasive (MI) disease