Chemoenzymatic Total Syntheses of the Enantiomers of the Protoilludanes 8-Deoxydihydrotsugicoline and Radudiol

Chemoenzymatic and stereoselective total syntheses of the non-natural enantiomeric forms of the recently isolated protoilludane natural products 8-deoxydihydrotsugicoline (1) and radudiol (2) (viz. ent-1 and ent-2, respectively) are reported. The key steps involve the Diels-Alder cycloaddition of cyclopent-2-en-1-one to the acetonide derived from enantiomerically pure and enzymatically derived cis-1,2-dihydrocatechol 3, elaboration of the resulting adduct to the tricyclic ketone 12, and a photochemically promoted rearrangement of this last compound to the octahydro-1H-cyclobuta[e]indenone 13.We thank the Australian Research Council and the Institute of Advanced Studies for financial support. E.L.C. was the grateful recipient of an Australian Postgraduate Award provided by the Australian Government, and P.L. acknowledges receipt of a CSC Ph.D. Scholarship provided by the Government of the People’s Republic of Chin

Affective state influences retrieval-induced forgetting for integrated knowledge

Selectively testing parts of learned materials can impair later memory for nontested materials. Research has shown that such retrieval-induced forgetting occurs for low-integrated materials but may be prevented for high-integrated materials. However, previous research has neglected one factor that is ubiquitous in real-life testing: affective stat

The potential of eye-tracking as a sensitive measure of behavioural change in response to intervention

Abstract One challenge to the development of effective interventions to support learning and behavioural change in neurodevelopmental disorders is a lack of suitable outcome measures. Eye-tracking has been used widely to chart cognitive development and clinically-relevant group differences in many populations. This proof-of-concept study investigates whether it also has the potential to act as a marker of treatment effects, by testing its sensitivity to differential change over a short period of exposure to an iPad app in typically developing children. The app targets a key skill in early social communication development, by rewarding attention to people, operationalised via a finger-tap on screen. We measured attention to images taken from the app, and a selection of matched stimuli to test generalisation of effects, at baseline and two weeks later. Children were assigned to either an app-exposure or no-app condition in the intervening period. The app exposure group showed increases in fixation on people for images from the app, and for distant-generalisation photographs, at high levels of complexity. We conclude that, with careful selection of stimuli, eye-tracking has the potential to make a valuable contribution to the range of outcome measures available for psycho-behavioural interventions in neurodevelopmental disorders

Active Zone Protein Bassoon Co-Localizes with Presynaptic Calcium Channel, Modifies Channel Function, and Recovers from Aging Related Loss by Exercise

The P/Q-type voltage-dependent calcium channels (VDCCs) are essential for synaptic transmission at adult mammalian neuromuscular junctions (NMJs); however, the subsynaptic location of VDCCs relative to active zones in rodent NMJs, and the functional modification of VDCCs by the interaction with active zone protein Bassoon remain unknown. Here, we show that P/Q-type VDCCs distribute in a punctate pattern within the NMJ presynaptic terminals and align in three dimensions with Bassoon. This distribution pattern of P/Q-type VDCCs and Bassoon in NMJs is consistent with our previous study demonstrating the binding of VDCCs and Bassoon. In addition, we now show that the interaction between P/Q-type VDCCs and Bassoon significantly suppressed the inactivation property of P/Q-type VDCCs, suggesting that the Ca2+ influx may be augmented by Bassoon for efficient synaptic transmission at NMJs. However, presynaptic Bassoon level was significantly attenuated in aged rat NMJs, which suggests an attenuation of VDCC function due to a lack of this interaction between VDCC and Bassoon. Importantly, the decreased Bassoon level in aged NMJs was ameliorated by isometric strength training of muscles for two months. The training increased Bassoon immunoreactivity in NMJs without affecting synapse size. These results demonstrated that the P/Q-type VDCCs preferentially accumulate at NMJ active zones and play essential role in synaptic transmission in conjunction with the active zone protein Bassoon. This molecular mechanism becomes impaired by aging, which suggests altered synaptic function in aged NMJs. However, Bassoon level in aged NMJs can be improved by muscle exercise

New live screening of plant-nematode interactions in the rhizosphere

Abstract Free living nematodes (FLN) are microscopic worms found in all soils. While many FLN species are beneficial to crops, some species cause significant damage by feeding on roots and vectoring viruses. With the planned legislative removal of traditionally used chemical treatments, identification of new ways to manage FLN populations has become a high priority. For this, more powerful screening systems are required to rapidly assess threats to crops and identify treatments efficiently. Here, we have developed new live assays for testing nematode responses to treatment by combining transparent soil microcosms, a new light sheet imaging technique termed Biospeckle Selective Plane Illumination Microscopy (BSPIM) for fast nematode detection, and Confocal Laser Scanning Microscopy for high resolution imaging. We show that BSPIM increased signal to noise ratios by up to 60 fold and allowed the automatic detection of FLN in transparent soil samples of 1.5 mL. Growing plant root systems were rapidly scanned for nematode abundance and activity, and FLN feeding behaviour and responses to chemical compounds observed in soil-like conditions. This approach could be used for direct monitoring of FLN activity either to develop new compounds that target economically damaging herbivorous nematodes or ensuring that beneficial species are not negatively impacted

The potential of optical proteomic technologies to individualize prognosis and guide rational treatment for cancer patients

Genomics and proteomics will improve outcome prediction in cancer and have great potential to help in the discovery of unknown mechanisms of metastasis, ripe for therapeutic exploitation. Current methods of prognosis estimation rely on clinical data, anatomical staging and histopathological features. It is hoped that translational genomic and proteomic research will discriminate more accurately than is possible at present between patients with a good prognosis and those who carry a high risk of recurrence. Rational treatments, targeted to the specific molecular pathways of an individual’s high-risk tumor, are at the core of tailored therapy. The aim of targeted oncology is to select the right patient for the right drug at precisely the right point in their cancer journey. Optical proteomics uses advanced optical imaging technologies to quantify the activity states of and associations between signaling proteins by measuring energy transfer between fluorophores attached to specific proteins. Förster resonance energy transfer (FRET) and fluorescence lifetime imaging microscopy (FLIM) assays are suitable for use in cell line models of cancer, fresh human tissues and formalin-fixed paraffin-embedded tissue (FFPE). In animal models, dynamic deep tissue FLIM/FRET imaging of cancer cells in vivo is now also feasible. Analysis of protein expression and post-translational modifications such as phosphorylation and ubiquitination can be performed in cell lines and are remarkably efficiently in cancer tissue samples using tissue microarrays (TMAs). FRET assays can be performed to quantify protein-protein interactions within FFPE tissue, far beyond the spatial resolution conventionally associated with light or confocal laser microscopy. Multivariate optical parameters can be correlated with disease relapse for individual patients. FRET-FLIM assays allow rapid screening of target modifiers using high content drug screens. Specific protein-protein interactions conferring a poor prognosis identified by high content tissue screening will be perturbed with targeted therapeutics. Future targeted drugs will be identified using high content/throughput drug screens that are based on multivariate proteomic assays. Response to therapy at a molecular level can be monitored using these assays while the patient receives treatment: utilizing re-biopsy tumor tissue samples in the neoadjuvant setting or by examining surrogate tissues. These technologies will prove to be both prognostic of risk for individuals when applied to tumor tissue at first diagnosis and predictive of response to specifically selected targeted anticancer drugs. Advanced optical assays have great potential to be translated into real-life benefit for cancer patients

Population genomics of marine zooplankton

Author Posting. © The Author(s), 2017. This is the author's version of the work. It is posted here for personal use, not for redistribution. The definitive version was published in Bucklin, Ann et al. "Population Genomics of Marine Zooplankton." Population Genomics: Marine Organisms. Ed. Om P. Rajora and Marjorie Oleksiak. Springer, 2018. doi:10.1007/13836_2017_9.The exceptionally large population size and cosmopolitan biogeographic distribution that distinguish many – but not all – marine zooplankton species generate similarly exceptional patterns of population genetic and genomic diversity and structure. The phylogenetic diversity of zooplankton has slowed the application of population genomic approaches, due to lack of genomic resources for closelyrelated species and diversity of genomic architecture, including highly-replicated genomes of many crustaceans. Use of numerous genomic markers, especially single nucleotide polymorphisms (SNPs), is transforming our ability to analyze population genetics and connectivity of marine zooplankton, and providing new understanding and different answers than earlier analyses, which typically used mitochondrial DNA and microsatellite markers. Population genomic approaches have confirmed that, despite high dispersal potential, many zooplankton species exhibit genetic structuring among geographic populations, especially at large ocean-basin scales, and have revealed patterns and pathways of population connectivity that do not always track ocean circulation. Genomic and transcriptomic resources are critically needed to allow further examination of micro-evolution and local adaptation, including identification of genes that show evidence of selection. These new tools will also enable further examination of the significance of small-scale genetic heterogeneity of marine zooplankton, to discriminate genetic “noise” in large and patchy populations from local adaptation to environmental conditions and change.Support was provided by the US National Science Foundation to AB and RJO (PLR-1044982) and to RJO (MCB-1613856); support to IS and MC was provided by Nord University (Norway)

Chemoenzymatic Total Syntheses of the Enantiomers of the Protoilludanes 8‑Deoxydihydrotsugicoline and Radudiol

Chemoenzymatic and stereoselective total syntheses of the non-natural enantiomeric forms of the recently isolated protoilludane natural products 8-deoxydihydrotsugicoline (<b>1</b>) and radudiol (<b>2</b>) (viz. <i>ent</i>-<b>1</b> and <i>ent</i>-<b>2</b>, respectively) are reported. The key steps involve the Diels–Alder cycloaddition of cyclopent-2-en-1-one to the acetonide derived from enantiomerically pure and enzymatically derived <i>cis</i>-1,2-dihydrocatechol <b>3</b>, elaboration of the resulting adduct to the tricyclic ketone <b>12</b>, and a photochemically promoted rearrangement of this last compound to the octahydro-1<i>H</i>-cyclobuta­[<i>e</i>]­indenone <b>13</b>