α-Synuclein Aggregation Inhibitory Prunolides and a Dibrominated β-Carboline Sulfamate from the Ascidian Synoicum prunum

Seven new polyaromatic bis-spiroketal-containing butenolides, the prunolides D–I (4–9) and cis-prunolide C (10), a new dibrominated β-carboline sulfamate named pityriacitrin C (11), alongside the known prunolides A–C (1–3) were isolated from the Australian colonial ascidian Synoicum prunum. The prunolides D–G (4–7) represent the first asymmetrically brominated prunolides, while cis-prunolide C (10) is the first reported with a cis-configuration about the prunolide’s bis-spiroketal core. The prunolides displayed binding activities with the Parkinson’s disease-implicated amyloid protein α-synuclein in a mass spectrometry binding assay, while the prunolides (1–5 and 10) were found to significantly inhibit the aggregation (>89.0%) of α-synuclein in a ThT amyloid dye assay. The prunolides A–C (1–3) were also tested for inhibition of pSyn aggregate formation in a primary embryonic mouse midbrain dopamine neuron model with prunolide B (2) displaying statistically significant inhibitory activity at 0.5 μM. The antiplasmodial and antibacterial activities of the isolates were also examined with prunolide C (3) displaying only weak activity against the 3D7 parasite strain of Plasmodium falciparum. Our findings reported herein suggest that the prunolides could provide a novel scaffold for the exploration of future therapeutics aimed at inhibiting amyloid protein aggregation and the treatment of numerous neurodegenerative diseases.Peer reviewe

Mid- to late Pliocene (3.3-2.6 Ma) global sea-level fluctuations recorded on a continental shelf transect, Whanganui Basin, New Zealand

We present a similar to 900 m-thick, mid- (3.3-3.0 Ma) to late Pliocene (3.0-2.6 Ma), shallow-marine, cyclical sedimentary succession from Whanganui Basin, New Zealand that identifies paleobathymetric changes, during a warmer-than-present interval of Earth history, relevant to future climate change. Our approach applies lithofacies, sequence stratigraphy and benthic foraminiferal analyses to two continuously-cored drillholes integrated with new and existing outcrop studies. We construct a depositional model of orbitally-paced, global sea-level changes on a wave-graded continental shelf. Unlike many previous studies, these shelf sediments were not eroded during sea-level lowstands and thus provide the potential to reconstruct the full amplitude of glacial-interglacial sea-level change. Paleobathymetric interpretations are underpinned by analysis of extant benthic foraminiferal census data and a statistical correlation with the distribution of modern taxa. In general, water depths derived from foraminiferal Modern Analogue Technique (MAT), are consistent with variability recorded by lithofacies. The inferred sea-level cycles co-vary with a qualitative climate record reconstructed from a census of extant pollen and spores, and a modern temperature relationship. A high -resolution age model is established using magnetostratigraphy constrained by biostratigraphy, and the dating and correlation of tephra. This integrated chronostratigraphy allows the recognition of 23 individual sedimentary cycles, that are correlated across the paleo-shelf and a possible "one-to-one" relationship is made to deep-ocean benthic oxygen isotope (delta O-18) records. In general water depth changes were paced by similar to 20 kyr duration between 3.3 and 3.0 Ma, after which cycle duration is similar to 40 kyr during the late Pliocene (3.0-2.6 Ma). This record provides a future opportunity to evaluate the amplitude and frequency of global, Pliocene glacioeustatic sea-level change, independent of the global benthic delta O-18 record. (C) 2018 Elsevier Ltd. All rights reserve

Holocene dynamics of the Southern Hemisphere westerly winds and possible links to CO2 outgassing

The Southern Hemisphere westerly winds (SHW) play an important role in regulating the capacity of the Southern Ocean carbon sink. They modulate upwelling of carbon-rich deep water and, with sea ice, determine the ocean surface area available for air–sea gas exchange. Some models indicate that the current strengthening and poleward shift of these winds will weaken the carbon sink. If correct, centennial- to millennial-scale reconstructions of the SHW intensity should be linked with past changes in atmospheric CO2, temperature and sea ice. Here we present a 12,300-year reconstruction of wind strength based on three independent proxies that track inputs of sea-salt aerosols and minerogenic particles accumulating in lake sediments on sub-Antarctic Macquarie Island. Between about 12.1 thousand years ago (ka) and 11.2 ka, and since about 7 ka, the wind intensities were above their long-term mean and corresponded with increasing atmospheric CO2. Conversely, from about 11.2 to 7.2 ka, the wind intensities were below their long-term mean and corresponded with decreasing atmospheric CO2. These observations are consistent with model inferences of enhanced SHW contributing to the long-term outgassing of CO2 from the Southern Ocean

Molecular Imaging of Pulmonary Tuberculosis in an Ex-Vivo Mouse Model Using Spectral Photon-Counting Computed Tomography and Micro-CT

Assessment of disease burden and drug efficacy is achieved preclinically using high resolution micro computed tomography (CT). However, micro-CT is not applicable to clinical human imaging due to operating at high dose. In addition, the technology differences between micro-CT and standard clinical CT prevent direct translation of preclinical applications. The current proof-of-concept study presents spectral photon-counting CT as a clinically translatable, molecular imaging tool by assessing contrast uptake in an ex-vivo mouse model of pulmonary tuberculosis (TB). Iodine, a common contrast used in clinical CT imaging, was introduced into a murine model of TB. The excised mouse lungs were imaged using a standard micro-CT subsystem (SuperArgus) and the contrast enhanced TB lesions quantified. The same lungs were imaged using a spectral photoncounting CT system (MARS small-bore scanner). Iodine and soft tissues (water and lipid) were materially separated, and iodine uptake quantified. The volume of the TB infection quantified by spectral CT and micro-CT was found to be 2.96 mm(3) and 2.83 mm(3), respectively. This proof-of-concept study showed that spectral photon-counting CT could be used as a predictive preclinical imaging tool for the purpose of facilitating drug discovery and development. Also, as this imaging modality is available for human trials, all applications are translatable to human imaging. In conclusion, spectral photon-counting CT could accelerate a deeper understanding of infectious lung diseases using targeted pharmaceuticals and intrinsic markers, and ultimately improve the efficacy of therapies by measuring drug delivery and response to treatment in animal models and later in humans