The role of POLG mutations in human disease

PhD ThesisMitochondrial diseases due to mutations in the nuclear Polymerase gamma (POLG) gene, have emerged as a common group of disorders, collectively referred to as POLG-related disorders. POLG is responsible for mitochondrial DNA (mtDNA) replication and repair. Defects in POLG result in secondary mtDNA defects including mtDNA depletion and deletions, which result in respiratory chain deficiency in affected tissues. POLG-related disorders are characterised by phenotypic diversity with common neurological deficits such as epilepsy, which constitutes its predominant manifestation. Alpers’ syndrome is a severe form of POLG-related disorders and it is a rare, early-onset, progressive encephalohepatopathy characterised by: intractable seizures, developmental delay, ataxia, visual loss and liver dysfunction. It is particularly devastating as effective treatments do not currently exist, and little is known about its molecular pathophysiology downstream from POLG mutations. The aim of this work was to gain further insight into the pathogenesis of Alpers, through the characterisation of mitochondrial dysfunction in POLG-mutant fibroblasts, and neuropathological investigation of post-mortem brain tissue from affected patients. Fibroblast characterisation using quantitative methodologies, revealed no evidence of mitochondrial dysfunction in primary POLG-mutant fibroblasts derived from patients with Alpers. Neuropathological assessment of three cortical regions revealed extensive respiratory chain deficiencies in interneurons and to a lesser extent pyramidal neurons in patients with Alpers, which was associated with severe pyramidal neuron loss. A variable degree of astrogliosis, was also observed. Additionally, mtDNA depletion was found in tissue from adult patients with POLG-mutations as well as occasional mtDNA deletions. This study provides evidence that POLG mutations exert a tissue-specific effect in Alpers. Mitochondrial respiratory chain deficiencies in interneurons and pyramidal neurons, combined with extensive pyramidal neuron loss may result in altered neuronal dynamics and contribute to the underlying neuropathology and clinical manifestations of Alpers.The Ryan Stanford Appea

Coral skeleton P/Ca proxy for seawater phosphate: Multi-colony calibration with a contemporaneous seawater phosphate record

A geochemical proxy for surface ocean nutrient concentrations recorded in coral skeleton could provide new insight into the connections between sub-seasonal to centennial scale nutrient dynamics, ocean physics, and primary production in the past. Previous work showed that coralline P/Ca, a novel seawater phosphate proxy, varies synchronously with annual upwelling-driven cycles in surface water phosphate concentration. However, paired contemporaneous seawater phosphate time-series data, needed for rigorous calibration of the new proxy, were lacking. Here we present further development of the P/Ca proxy in Porites lutea and Montastrea sp. corals, showing that skeletal P/Ca in colonies from geographically distinct oceanic nutrient regimes is a linear function of seawater phosphate (PO4 SW) concentration. Further, high-resolution P/Ca records in multiple colonies of Pavona gigantea and Porites lobata corals grown at the same upwelling location in the Gulf of Panama were strongly correlated to a contemporaneous time-series record of surface water PO4 SW at this site (r2 = 0.7–0.9). This study supports application of the following multi-colony calibration equations to down-core records from comparable upwelling sites, resulting in ±0.2 and ±0.1 lmol/kg uncertainties in PO4 SW reconstructions from P. lobata and P. gigantea, respectively.P/Ca Porites lobata (lmol/mol) = (21.1 ? 2.4)PO4 SW (lmol/kg) + (14.3 ? 3.8)P/Ca Pavona gigantea (lmol/mol) = (29.2 ? 1.4)PO4 SW (lmol/kg) + (33.4 ? 2.7)Inter-colony agreement in P/Ca response to PO4 SW was good (±5–12% about mean calibration slope), suggesting that species-specific calibration slopes can be applied to new coral P/Ca records to reconstruct past changes in surface ocean phosphate. However, offsets in the y-intercepts of calibration regressions among co-located individuals and taxa suggest that biologically-regulated “vital effects” and/or skeletal extension rate may also affect skeletal P incorporation. Quantification of the effect of skeletal extension rate on P/Ca could lead to corrected calibration equations and improved inter-colony P/Ca agreement. Nevertheless, the efficacy of the P/Ca proxy is thus supported by both broad scale correlation to mean surface water phosphate and regional calibration against documented local seawater phosphate variations

"hCG priming" effect in controlled ovarian stimulation through a long protocol

<p>Abstract</p> <p>Background</p> <p>Recently, it has been demonstrated that, in patients down-regulated by GnRH analogues (GnRHa), a short-term pre-treatment with recombinant LH (rLH), prior to recombinant FSH (rFSH) administration, increases the number of small antral follicle prior to FSH stimulation and the yield of normally fertilized embryos. However, no data exist in the literature regarding the potential beneficial effect of "hCG priming" in controlled ovarian hyperstimulation (COH) through a long GnRH-a protocol, which binds the same receptor (LH/hCGR), though it is a much more potent compared to LH. The primary aims of this study were to assess the effect of short-term pre-rFSH administration of hCG in women entering an ICSI treatment cycle on follicular development, quality of oocytes and early embryo development. The secondary endpoints were to record the effects on endometrial quality and pregnancy rate.</p> <p>Methods</p> <p>Patients with a history of at least one previous unsuccessful ICSI cycle were randomly assigned into two groups to receive treatment with either a long protocol with rFSH (control group) or a long protocol with rFSH and pre-treatment with hCG (hCG group). In particular, in the latter group, a fixed 7 days course of 200 IU/day hCG was administered as soon as pituitary desensitization was confirmed.</p> <p>Results</p> <p>The mean number of oocytes retrieved was not significantly different between the two treatment groups, although the percentage of mature oocytes tended to be higher but not significantly different in hCG-treated patients. The percentage of patients with more than one grade 3 embryos was higher in the pre-treatment group, which also showed a higher pregnancy rate.</p> <p>Conclusion</p> <p>All the above clinical observations, in conjunction with previous data, suggest a point towards a beneficial "hCG priming" effect in controlled ovarian hyperstimulation through a long GnRH-a down-regulation protocol, particularly in patients with previous ART failures.</p

Testing optically stimulated luminescence dating on sand-sized quartz of deltaic deposits from the Sperchios delta plain, central Greece

This study reports on the first investigation into the potential of luminescence dating to establish a chronological framework for the depositional sequences of the Sperchios delta plain, central Greece. A series of three borehole cores (20 m deep) and two shallow cores (4 m deep), from across the delta plain, were extracted, and samples were collected for luminescence dating. The luminescence ages of sand-sized quartz grains were obtained from small aliquots of quartz, using the Single-Aliquot Regenerative-dose (SAR) protocol. The equivalent dose determination included a series of tests and the selection of the Minimum Age Model (MAM) as the most appropriate statistical model. This made it possible to confirm the applicability of quartz Optically Stimulated Luminescence (OSL) dating to establish absolute chronology for deltaic sediments from the Sperchios delta plain.Testing age results of the five cores showed that the deltaic sediments were deposited during the Holocene. A relatively rapid deposition is implied for the top ∼14 m possibly as a result of the deceleration in the rate of the sea-level rise and the transition to terrestrial conditions, while on the deeper parts, the reduced sedimentation rate may indicate a lagoonal or coastal environment

The role of pH up-regulation in response to nutrient-enriched, low-pH groundwater discharge

Highlights • Dual geochemical approach using δ11B and B/Ca to evaluate coral calcifying fluids from West Maui, Hawai'i. • NMR analysis confirms boron is present as borate with no evidence of boric acid inclusion. • Increased pH up-regulation in corals exposed to high nutrient / low pH submarine groundwater discharge. • Calcifying fluid aragonite saturate state 9 to 10 times higher than ambient seawater. • Up-regulation as an internal coping mechanism to combat multiple stressors from land-based sources of pollution. Coral reefs and their ecosystems are threatened by both global stressors, including increasing sea-surface temperatures and ocean acidification (OA), and local stressors such as land-based sources of pollution that can magnify the effects of OA. Corals can physiologically control the chemistry of their internal calcifying fluids (CF) and can thereby regulate their calcification process. Specifically, increasing aragonite saturation state in the CF (ΩCF) may allow corals to calcify even under external low saturation conditions. Questions remain regarding the physiological processes that govern the CF chemistry and how they change in response to multiple stressors. To address this knowledge gap, the boron systematics (δ11B and B/Ca) were analyzed in tropical corals, Porites lobata, collected at submarine groundwater seeps impacted by the release of treated wastewater in west Maui, Hawai'i, to document the interactions between high nutrient / low pH seep water on CF carbonate chemistry. Results show substantial up-regulation of pH and dissolved inorganic carbon (DIC) with respect to seawater in P. lobata corals collected from within the wastewater impacted area at Kahekili Beach Park compared to the control site at Olowalu Beach. The ΩCF was 9 to 10 times higher than ambient seawater Ω, and 13 to 26% higher than in corals from the control site and from previously observed in tropical Porites spp. corals. Such elevated up-regulation suggests that corals exposed to nutrient-enriched, low pH effluent sustain CF supersaturated with respect to aragonite, possibly as an internal coping mechanism to combat multiple stressors from land-based sources of pollution. This elevated up-regulation has implications to coral vulnerability to future climate- and ocean-change scenarios

Glacial-aged development of the Tunisian Coral Mound Province controlled by glacio-eustatic oscillations and changes in surface productivity

Cold-water corals are key species of benthic ecosystems, sensitive to changes in climate and capable of recording them in the chemical composition of their skeletons. The study of cold-water coral mound development in relation to palaeoceanographic variations during the Pleistocene and Holocene stages in the Mediterranean Sea has mainly been focussed in the Alboran Sea (Western Mediterranean). The present study describes the coral deposits and corresponding ages of 3 gravity cores, acquired from the newly discovered Tunisian Coral Mound Province (Central Mediterranean), which comprises several ridge-like mounds. All the cores acquired displayed dense coral deposits, dominated by Desmophyllum pertusum fragments embedded within a muddy sediment matrix. Overall, 64 coral samples have been dated with the Usingle bondTh laser ablation MC-ICP-MS method, revealing corals of mostly Pleistocene age ranging from ~MIS 11 to 8.4 ka BP. Although coral mound formation was reduced for most of the last 400 kyr, a main stage of pronounced mound formation occurred during the last glacial period, which contrasts to the findings previously published for coral mounds in other regions of the Mediterranean Sea. Coral mound formation during the last glacial was most likely associated with a colder seawater temperature than the one observed in the present-day, an increased surface productivity and an appropriate depth of the interface between Atlantic Waters and Levantine Intermediate Waters. The combination of the data acquired here with that of previous mound formation studies from the Alboran Sea also suggests that cold-water coral mounds located at greater depths develop at slower rates than those found in shallower settings

Global mean surface temperature and climate sensitivity of the early Eocene Climatic Optimum (EECO), Paleocene–Eocene Thermal Maximum (PETM), and latest Paleocene

Accurate estimates of past global mean surface temperature (GMST) help to contextualise future climate change and are required to estimate the sensitivity of the climate system to CO2 forcing through Earth's history. Previous GMST estimates for the latest Paleocene and early Eocene (∼57 to 48 million years ago) span a wide range (∼9 to 23 ∘C higher than pre-industrial) and prevent an accurate assessment of climate sensitivity during this extreme greenhouse climate interval. Using the most recent data compilations, we employ a multi-method experimental framework to calculate GMST during the three DeepMIP target intervals: (1) the latest Paleocene (∼57 Ma), (2) the Paleocene–Eocene Thermal Maximum (PETM; 56 Ma), and (3) the early Eocene Climatic Optimum (EECO; 53.3 to 49.1 Ma). Using six different methodologies, we find that the average GMST estimate (66 % confidence) during the latest Paleocene, PETM, and EECO was 26.3 ∘C (22.3 to 28.3 ∘C), 31.6 ∘C (27.2 to 34.5 ∘C), and 27.0 ∘C (23.2 to 29.7 ∘C), respectively. GMST estimates from the EECO are ∼10 to 16 ∘C warmer than pre-industrial, higher than the estimate given by the Intergovernmental Panel on Climate Change (IPCC) 5th Assessment Report (9 to 14 ∘C higher than pre-industrial). Leveraging the large “signal” associated with these extreme warm climates, we combine estimates of GMST and CO2 from the latest Paleocene, PETM, and EECO to calculate gross estimates of the average climate sensitivity between the early Paleogene and today. We demonstrate that “bulk” equilibrium climate sensitivity (ECS; 66 % confidence) during the latest Paleocene, PETM, and EECO is 4.5 ∘C (2.4 to 6.8 ∘C), 3.6 ∘C (2.3 to 4.7 ∘C), and 3.1 ∘C (1.8 to 4.4 ∘C) per doubling of CO2. These values are generally similar to those assessed by the IPCC (1.5 to 4.5 ∘C per doubling CO2) but appear incompatible with low ECS values (<1.5 per doubling CO2)

An astronomically dated record of Earth's climate and its predictability over the last 66 million years.

Much of our understanding of Earth's past climate comes from the measurement of oxygen and carbon isotope variations in deep-sea benthic foraminifera. Yet, long intervals in existing records lack the temporal resolution and age control needed to thoroughly categorize climate states of the Cenozoic era and to study their dynamics. Here, we present a new, highly resolved, astronomically dated, continuous composite of benthic foraminifer isotope records developed in our laboratories. Four climate states-Hothouse, Warmhouse, Coolhouse, Icehouse-are identified on the basis of their distinctive response to astronomical forcing depending on greenhouse gas concentrations and polar ice sheet volume. Statistical analysis of the nonlinear behavior encoded in our record reveals the key role that polar ice volume plays in the predictability of Cenozoic climate dynamics