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Refereed/Peer-reviewed We present a highly fluorescent, solvatochromic, 1,8-naphthalimide for simultaneous imaging of lipid droplets and endoplasmic reticulum, with distinguishable emission maxima. By delineating organelles based on their emission profiles, lipid droplet biogenesis and intercellular trafficking events are visualised. The probe also stains myelin lipids in ex vivo brain tissue, indicating histochemical applications.

Diagnosis and assessment of patients with prostate cancer is dependent on accurate interpretation and grading of histopathology. However, morphology does not necessarily reflect the complex biological changes occurring in prostate cancer disease progression, and current biomarkers have demonstrated limited clinical utility in patient assessment. This study aimed to develop biomarkers that accurately define prostate cancer biology by distinguishing specific pathological features that enable reliable interpretation of pathology for accurate Gleason grading of patients. Online gene expression databases were interrogated and a pathogenic pathway for prostate cancer was identified. The protein expression of key genes in the pathway, including adaptor protein containing a pleckstrin homology (PH) domain, phosphotyrosine-binding (PTB) domain, and leucine zipper motif 1 (Appl1), Sortilin and Syndecan-1, was examined by immunohistochemistry (IHC) in a pilot study of 29 patients with prostate cancer, using monoclonal antibodies designed against unique epitopes. Appl1, Sortilin, and Syndecan-1 expression was first assessed in a tissue microarray cohort of 112 patient samples, demonstrating that the monoclonal antibodies clearly illustrate gland morphologies. To determine the impact of a novel IHC-assisted interpretation (the utility of Appl1, Sortilin, and Syndecan-1 labelling as a panel) of Gleason grading, versus standard haematoxylin and eosin (H&E) Gleason grade assignment, a radical prostatectomy sample cohort comprising 114 patients was assessed. In comparison to H&E, the utility of the biomarker panel reduced subjectivity in interpretation of prostate cancer tissue morphology and improved the reliability of pathology assessment, resulting in Gleason grade redistribution for 41% of patient samples. Importantly, for equivocal IHC-assisted labelling and H&E staining results, the cancer morphology interpretation could be more accurately applied upon re-review of the H&E tissue sections. This study addresses a key issue in the field of prostate cancer pathology by presenting a novel combination of three biomarkers and has the potential to transform clinical pathology practice by standardising the interpretation of the tissue morphology. Refereed/Peer-reviewed

Dipeptidyl peptidase-4 inhibitors (DPP4i) are a class of orally available, small molecule inhibitors for the management of Type-II diabetes. A rapid, real-time, functional breath test for DPP4 enzyme activity could help to define DPP4i efficacy in patients that are refractory to treatment. We aimed to develop a selective, non-invasive, stable-isotope 13C-breath test for DPP4. In vitro experiments were performed using high (Caco-2) and low (HeLa) DPP4 expressing cells. DPP gene expression was determined in cell lines by qRT-PCR. A DPP4 selective 13C-tripeptide was added to cells in the presence and absence of the DPP4 inhibitor Sitagliptin. Gas samples were collected from the cell headspace and 13CO2 content quantified by isotope ratio mass spectrometry (IRMS). DPP4 was highly expressed in Caco-2 cells compared to HeLa cells and using the 13C-tripeptide, we detected a high 13CO2 signal from Caco2 cells. Addition of Sitaglitpin to Caco2 cells significantly inhibited this 13CO2 signal. 13C-assay DPP4 activity correlated positively with the enzyme activity detected using a colorimetric substrate. We have developed a selective, non-invasive, 13C-assay for DPP4 that could have broad translational applications in diabetes and gastrointestinal disease.

Lipid droplets (LDs) are found in most eukaryotic cells and in addition to serving as lipid reservoirs, these highly dynamic organelles play fundamental roles in cell metabolism and growth. The study of LDs and their interactions with other cellular compartments provides new insights into normal cell biology and disease processes such as virus packaging, metabolic disorders, and cancer progression. Here we report the synthesis and comprehensive evaluation of two readily prepared, low molecular weight 3,4-dimethoxy-1,8-naphthalimides, as selective LD stains. The newly synthesised 1,8-naphthalimide derivative (DMN-LD), demonstrated impressive versatility compared to currently available options, by staining LDs in both live and fixed cells, as well as a three-dimensional spheroid, using both single and two-photon excitation. This new imaging agent has the potential to further unravel the complex biology of LDs, which are essential to cell survival, and when altered, underpin many disease states. Refereed/Peer-reviewed

The design, synthesis and evaluation of a small series of potent amphiphilic norbornane antibacterial agents has been performed (compound 10 MIC = 0.25 μg/mL against MRSA). Molecular modelling indicates rapid aggregation of this class of antibacterial agent prior to membrane association and insertion. Two fluorescent analogues (compound 29 with 4-amino-naphthalimide and 34 with 4-nitrobenz-2-oxa-1,3-diazole fluorophores) with good activity (MIC = 0.5 μg/mL against MRSA) were also constructed and confocal microscopy studies indicate that the primary site of interaction for this family of compounds is the bacterial membrane. Refereed/Peer-reviewed

Re(I) complexes have potential in biomedical sciences as imaging agents, diagnostics and therapeutics. Thus, it is crucial to understand how Re(I) complexes interact with carrier proteins, like serum albumins. Here, we used two neutral Re(I) complexes ( fac ‐[Re(CO) 3 (1,10‐phenanthroline)L], where L is either 4‐cyanophenyltetrazolate (1) or 4‐methoxycarbonylphenyltetrazole ester (2) , to study the interactions with bovine serum albumin (BSA). Spectroscopic measurements, calculations of thermodynamic and Förster resonance energy transfer parameters, as well as molecular modelling were performed to study differential binding between BSA and complex 1 and 2 . Induced‐fit docking combined with quantum‐polarised ligand docking were employed in what is believed to be a first for a Re(I) complex as a ligand for BSA. Our findings provide a basis for other molecular interaction studies and suggest that subtle functional group alterations at the terminal region of the Re(I) complex have a significant impact on the ability of this class of compounds to interact with BSA; which is important for the functional design of Re(I) complexes in biomedical applications. Refereed/Peer-reviewed

The Buchwald–Hartwig cross-coupling reaction between 4-methylumbelliferone-derived nonaflates with amides, carbamates, and sulfonamides is described. A wide variety of N-substituted 7-amino coumarin analogues was prepared in good to excellent yields. The photophysical properties of aqueous-soluble derivatives were determined, and they displayed auxochrome-based variations. Gram-scale synthesis provided an acrylamide analogue, which was used to fabricate a fluorescent poly(2-hydroxylethyl methacrylate) (pHEMA) hydrogel that was resistant to leaching in ultrapure H2O. We envisage that our reported protocol to access 7-amino-4-methylcoumarin derivatives will find use toward the development of new fluorescent coumarin-based probes by researchers in the field. usc Refereed/Peer-reviewed

Five cyclometalated Ir(III) tetrazolato complexes functionalised with fatty acid chains (octanoic, palmitic, stearic, palmitoleic, and oleic) have been synthesised. The fatty acids were chosen to evaluate the potential effect of the length and degree of unsaturation on the biological properties of the complexes for use as cellular imaging agents. The complexes were analysed in both organic and aqueous media to determine if the presence and nature of the fatty acid chains had a significant effect on their photophysical properties. The complexes display green&ndash, yellow emission in dichloromethane solutions with relatively long excited state decays, within the range 360&ndash, 393 ns, and quantum yields between 5.4% and 6.7% (from degassed solutions). Temperature-dependent photophysical studies suggest that the emitting excited states of the complexes might be quenched by the thermal population of dark states. In water, the quantum yields drop within the range of 0.5%&ndash, 2.4%, and the photophysical measurements are influenced by the variable degrees of aggregation. In general, the entire series displayed low cytotoxicity and relatively high photostability, which are favourable attributes in the design of cellular imaging agents. Images of live HeLa cells were obtained for all the complexes, but those functionalised with palmitic and stearic acids had limitations due the lower solubility conferred by the saturated aliphatic chains. The complexes were mainly detected within the endoplasmic reticulum.

Innate immunity is critical for host defence against pathogen and environmental challenge and this involves the production and secretion of immune mediators, such as antimicrobial peptides and pro-inflammatory cytokines. However, when dysregulated, innate immunity can contribute to multifactorial diseases, including inflammatory rheumatic disorders, type 2 diabetes, cancer, neurodegenerative and cardiovascular diseases and even septic shock. During an innate immune response, antimicrobial peptides and cytokines are trafficked via Rab11 multivesicular endosomes, and then sorted into Rab11 vesicles for traffic to the plasma membrane and secretion. In this study, a cyclin-dependent kinase inhibitor CDKI-73 was used to determine its effect on the innate immune response, based on previously identified targets for this compound. Our results showed that CDKI-73 inhibited the delivery of Rab11 vesicles to the plasma membrane, resulting in the accumulation of large multivesicular Rab11 endosomes near the cell periphery. In addition to the effect on endosome delivery, CDKI-73 down-regulated the amount of innate immune cargo, including the antimicrobial peptide Drosomycin and pro-inflammatory cytokines interleukin-6 (IL-6) and tumour necrosis factor alpha (TNF&alpha, ). We concluded that CDKI-73 has the potential to regulate the delivery and secretion of certain innate immune cargo, which could be used to control inflammation.

Lipids are important cellular components which can be significantly altered in a range of disease states including prostate cancer. Here, a unique systematic approach has been used to define lipid profiles of prostate cancer cell lines, using quantitative mass spectrometry (LC-ESI-MS/MS), FTIR spectroscopy and fluorescent microscopy. All three approaches identified significant difference in the lipid profiles of the three prostate cancer cell lines (DU145, LNCaP and 22RV1) and one non-malignant cell line (PNT1a). Specific lipid classes and species, such as phospholipids (e.g., phosphatidylethanolamine 18:1/16:0 and 18:1/18:1) and cholesteryl esters, detected by LC-ESI-MS/MS, allowed statistical separation of all four prostate cell lines. Lipid mapping by FTIR revealed that variations in these lipid classes could also be detected at a single cell level, however further investigation into this approach would be needed to generate large enough data sets for quantitation. Visualisation by fluorescence microscopy showed striking variations that could be observed in lipid staining patterns between cell lines allowing visual separation of cell lines. In particular, polar lipid staining by a fluorescent marker was observed to increase significantly in prostate cancer lines cells, when compared to PNT1a cells, which was consistent with lipid quantitation by LC-ESI-MS/MS and FTIR spectroscopy. Thus, multiple technologies can be employed to either quantify or visualise changes in lipid composition, and moreover specific lipid profiles could be used to detect and phenotype prostate cancer cells Refereed/Peer-reviewed

The primary metabolic pathway required to produce ATP differs as a result of tissue type, developmental stage and substrate availability.We utilized molecular and histological techniques to define the metabolic status in foetal and adult, adipose and skeletal muscle tissues. Redox ratios of these tissues were also determined optically by two-photon microscopy.Adult perirenal adipose tissue had a higher optical redox ratio than fetal perirenal adipose tissue, which aligned with glycolysis being used for ATP production;whereas adult skeletal muscle had a lower optical redox ratio than fetal skeletal muscle, which aligned with oxygen demanding oxidative phosphorylation activity being utilized for ATP production. We have compared traditional molecular and microscopy techniques of metabolic tissue characterization with optical redox ratios to provide a more comprehensive report on the dynamics of tissue metabolism. Refereed/Peer-reviewed

The molecular chaperone Hsp90 is overexpressed in prostate cancer (PCa) and is responsible for the folding, stabilization and maturation of multiple oncoproteins, which are implicated in PCa progression. Compared to first-in-class Hsp90 inhibitors such as 17-allylamino-demethoxygeldanamycin (17-AAG) that were clinically ineffective, second generation inhibitor AUY922 has greater solubility and efficacy. Here, transcriptomic and proteomic analyses of patient-derived PCa explants identified cytoskeletal organization as highly enriched with AUY922 treatment. Validation in PCa cell lines revealed that AUY922 caused marked alterations to cell morphology, and suppressed cell motility and invasion compared to vehicle or 17-AAG, concomitant with dysregulation of key extracellular matrix proteins such as fibronectin (FN1). Interestingly, while the expression of FN1 was increased by AUY922, FN1 secretion was significantly decreased. This resulted in cytosolic accumulation of FN1 protein within late endosomes, suggesting that AUY922 disrupts vesicular secretory trafficking pathways. Depletion of FN1 by siRNA knockdown markedly reduced the invasive capacity of PCa cells, phenocopying AUY922. These results highlight a novel mechanism of action for AUY922 beyond its established effects on cellular mitosis and survival and, furthermore, identifies extracellular matrix cargo delivery as a potential therapeutic target for the treatment of aggressive PCa.

Two Pavlovian appetitive conditioning experiments with rats demonstrated that spontaneous recovery can be strongly reduced (prevented). The experiments also investigated potential common factors associated with that prevention of spontaneous recovery after extinction. After pairings of a conditioned stimulus (CS) with a food unconditioned stimulus (US), an extinction cue (EC) was presented during extinction and spontaneous recovery testing with the CS. Replicating Brooks and Bowker (2001), EC–US pairings in the CS extinction–test interval subsequently resulted in the EC strongly reducing (preventing) spontaneous recovery to the CS (Experiment 1). Experiment 1 also assessed an “erasure” hypothesis of how the EC may reduce spontaneous recovery. Experiment 2 assessed EC– or US–alone presentations, or unpairings of EC and US, in the CS extinction–test interval. Spontaneous recovery was also prevented when the EC was presented alone or unpaired with the US, but USs alone interfered with the EC’s spontaneous recovery–preventing effect. No evidence was found for the EC operating by erasure, conditioned inhibition, generalized extinction, or generalized extinction. Together the results suggest that after CS extinction additional EC presentations are sufficient to prevent spontaneous recovery.

The design, synthesis and characterisation of a luminescent probe based on the ‘click’ conjugation between a Eu(III) complex and an anthracene moiety, Eu-A, is reported. Eu-A is demonstrated to be able to colourimetrically detect singlet oxygen (1O2) in aqueous media at neutral pH with a clear ‘off-on’ rapid response time of two minutes. Refereed/Peer-reviewed

A Pavlovian appetitive conditioning preparation with rats was used to assess the effect of an extinction cue on reinstatement after extinction. Reinstatement provides an animal analog to relapses following treatment in humans; it occurs when a conditioned stimulus elicits strong conditioned responding following extinction and presentation of the unconditioned stimulus. An extinction cue is a stimulus presented during extinction of behavior controlled by the conditioned stimulus and is also presented later when the behavior would be expected to return/relapse following extinction (i.e., when reinstatement occurs). An extinction cue has been shown previously to reduce and prevent other instances of relapse analogs (spontaneous recovery and renewal). The authors tested whether an extinction cue would also reduce reinstatement, and included controls for reinstatement and for potential alternative accounts of an extinction cue’s effect on reinstatement. The extinction cue reduced reinstatement, but a cue not presented during extinction did not affect reinstatement, bearing on several alternative explanations of the reduction effect. The authors suggest the extinction cue reduces reinstatement by helping to retrieve a memory encoded during extinction, and that reinstatement is due at least in part to a failure to retrieve that extinction memory.

Patient-derived explant (PDE) culture of solid tumors is increasingly being applied to preclinical evaluation of novel therapeutics and for biomarker discovery. In this technique, treatments are added to culture medium and penetrate the tissue via a gelatin sponge scaffold. However, the penetration profile and final concentrations of small molecule drugs achieved have not been determined to date. Here, we determined the extent of absorption of the clinical androgen receptor antagonist, enzalutamide, into prostate PDEs, using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and matrix-assisted laser/desorption ionisation (MALDI) mass spectrometry imaging (MSI). In a cohort of 11 PDE tissues from eight individual patients, LC-MS/MS quantification of PDE homogenates confirmed enzalutamide (10 µM) uptake by all PDEs, which reached maximal average tissue concentration of 0.24–0.50 ng/µg protein after 48 h culture. Time dependent uptake of enzalutamide (50 µM) in PDEs was visualized using MALDI MSI over 24–48 h, with complete penetration throughout tissues evident by 6 h of culture. Drug signal intensity was not homogeneous throughout the tissues but had areas of markedly high signal that corresponded to drug target (androgen receptor)-rich epithelial regions of tissue. In conclusion, application of MS-based drug quantification and visualization in PDEs, and potentially other 3-dimensional model systems, can provide a more robust basis for experimental study design and interpretation of pharmacodynamic data.

Two Pavlovian appetitive conditioning experiments with rats assessed extinction cue (EC) transfer using spontaneous recovery tests. In each experiment, after conditioned stimulus (CS) A-US pairings, an EC (X) was presented during A-extinction, followed by spontaneous recovery testing with A. Experiment 1 tested for transfer between ECs; the additional CS (B) was conditioned and then was extinguished with a second EC (Y). CS A was tested with X and with Y (the possible transfer EC). Experiment 2 tested for transfer between an EC and an explicitly trained serial negative occasion setter (OS). Prior to testing with A, Y was trained in a serial Y→C-, C + discrimination; a Z→B-, B + discrimination was also trained. A was tested with X and with Y (with Y as the possible transfer OS). X and Y were also tested with B (where X with B tests possible EC-OS transfer). In each experiment Y did not reduce spontaneous recovery to A, showing no transfer of one EC to another (Experiment 1) and no transfer of a serial negative OS to a CS (A) extinguished with an EC (X; Experiment 2). X did not reduce responding to B, showing no transfer of an EC to the target CS of a serial negative OS discrimination, although Y did transfer to B (Experiment 2) showing transfer between serial OSs. X did reduce responding to the CS (A) it had occurred with during extinction (Experiments 1 and 2). The results are discussed in terms of EC characteristics and regarding theories of an EC's possible mechanisms.

Live cell imaging can provide important information on cellular dynamics; however, the full utilisation of this technology has been hampered by the limitations of imaging reagents. Metal-based complexes have the potential to overcome many of the issues common to many current imaging agents. The rhenium (I)-based complex fac-[Re(CO)(3)(1,10-phenanthroline)(4-pyridyltetrazolate)], herein referred to as ReZolve-ER, shows promise as a live cell imaging agent with rapid cell uptake, low cytotoxicity, resistance to photobleaching and compatibility with multicolour imaging. ReZolve-ER localised to the nuclear membrane/endoplasmic reticulum (ER) and allowed the detection of exocytotic events at the plasma membrane. Thus, we present a new imaging agent for monitoring live cell events in real time, which is ideal for imaging either short- or long-time courses. Refereed/Peer-reviewed

As Asian economies have become more connected through physical and institutional infrastructure, the region's trade has grown and changed. Intraregional trade has increased its share, in large part through the expansion of trade in intermediates in connection with development of global value chains. At the same time, as part of the same process and as part of the structural transformation that underlies most economic development, the share of services in Asia's trade has risen. Policies that support the development of regional infrastructure and the flow of goods and services, as well as factors of production, can increase the benefits from connectivity. Meanwhile, regional cooperation has a key role to play in mitigating negative impacts that may arise from the vulnerabilities that accompany greater connectivity.

Dipeptidyl peptidase-4 inhibitors (DPP4i) are a class of orally available, small molecule inhibitors for the management of Type-II diabetes. A rapid, real-time, functional breath test for DPP4 enzyme activity could help to define DPP4i efficacy in patients that are refractory to treatment. We aimed to develop a selective, non-invasive, stable-isotope 13C-breath test for DPP4. In vitro experiments were performed using high (Caco-2) and low (HeLa) DPP4 expressing cells. DPP gene expression was determined in cell lines by qRT-PCR. A DPP4 selective 13C-tripeptide was added to cells in the presence and absence of the DPP4 inhibitor Sitagliptin. Gas samples were collected from the cell headspace and 13CO2 content quantified by isotope ratio mass spectrometry (IRMS). DPP4 was highly expressed in Caco-2 cells compared to HeLa cells and using the 13C-tripeptide, we detected a high 13CO2 signal from Caco2 cells. Addition of Sitaglitpin to Caco2 cells significantly inhibited this 13CO2 signal. 13C-assay DPP4 activity correlated positively with the enzyme activity detected using a colorimetric substrate. We have developed a selective, non-invasive, 13C-assay for DPP4 that could have broad translational applications in diabetes and gastrointestinal disease.

Coronary heart disease is one of the largest causes of death worldwide, making this a significant health care issue. A critical problem for the adult human heart is that it does not undergo effective repair in response to damage, leaving patients with a poor prognosis. Unlike the adult, fetal hearts have the ability to repair after myocardial damage. Using two-photon microscopy, we have visualised the morphological and metabolic changes following myocardial infarction in sheep fetuses, to characterise response to cardiac injury in a mammalian model. Following myocardial infarction, fetal hearts showed no significant increase in collagen deposition in the region of the infarction, when compared to either the surrounding tissue or shams. In contrast, metabolic activity (i.e. NAD(P)H and FAD) was significantly reduced in the region of myocardial infarction, when compared to either the surrounding tissue or sham hearts. For comparison, we also imaged two hearts from preadolescent sheep (sham and myocardial infarction) and showed highly ordered collagen deposition with decreased metabolic activity within the infarcted area. Therefore, two-photon imaging had the capacity to image both morphological and metabolic changes in response to myocardial infarction and showed differences in the response with age. Picture: Two-photon imaging of myocardial infarction (b and d) enabled the visualisation of increased collagen (blue; Em=431nm) and changes in other tissue autofluorescence (green; Em=489-606nm) in fetal (a and b) and preadolescent (c and d) hearts, compared to shams (a and c). The excitation wavelength was 840nm. Scale bars: 10μm. Refereed/Peer-reviewed

Mitochondrial morphology is important for the function of this critical organelle and, accordingly, altered mitochondrial structure is exhibited in many pathologies. Imaging of mitochondria can therefore provide important information about disease presence and progression. However, mitochondrial imaging is currently limited by the availability of agents that have the capacity to image mitochondrial morphology in both live and fixed samples. This can be particularly problematic in clinical studies or large, multi-centre cohort studies, where tissue archiving by fixation is often more practical. We previously reported the synthesis of an iridium coordination complex [Ir(ppy)2(MeTzPyPhCN)]+; where ppy is a cyclometalated 2-phenylpyridine and TzPyPhCN is the 5-(5-(4-cyanophen-1-yl)pyrid-2-yl)tetrazolate ligand; and showed that this complex (herein referred to as IraZolve-Mito) has a high specificity for mitochondria in live cells. Here we demonstrate that IraZolve-Mito can also effectively stain mitochondria in both live and fixed tissue samples. The staining protocol proposed is versatile, providing a universal procedure for cell biologists and pathologists to visualise mitochondria.

The heart has high metabolic demand to maintain function. The primary source of energy supply to support correct contractile muscle function differs between a fetus and an adult. In fetal life, ATP is primarily generated by glycolysis and lactate oxidation, whereas following birth, there is a shift towards a reliance on mitochondrial metabolism and fatty acid oxidation. This change in metabolic status is an adaptation to different fuel availability, oxygenation and growth patterns. In this study, we have employed 2-photon excitation fluorescence microscopy to define the relationship between two critical metabolic cofactors nicotinamide adenine dinucleotide(P)H and flavin adenine dinucleotide, effectively utilizing a redox ratio to differentiate between the metabolic status in fetal (proliferative) and adult (quiescent/hypertrophic) hearts. Two-photon imaging was also used to visually confirm the known increase in collagen deposition in the adult heart. The changes observed were consistent with a hypertrophic growth profile and greater availability of fatty acids in the adult heart, compared to the proliferative fetal heart. Two-photon excitation fluorescence microscopy is therefore a convenient imaging technology that enables the monitoring of striated muscle architecture and the metabolic status of heart tissue. This imaging technology can potentially be employed to visualize cardiac and other muscle pathologies. Refereed/Peer-reviewed

The evolutionary conserved family of 14-3-3 proteins appears to have a role in integrating numerous intracellular pathways, including signal transduction, intracellular trafficking, and metabolism. However, little is known about how this interactive network might be affected by the direct abrogation of 14-3-3 function. The loss of Drosophila 14-3-3ϵ resulted in reduced survival of mutants during larval-to-adult transition, which is known to depend on an energy supply coming from the histolysis of fat body tissue. Here we report a differential proteomic analysis of larval fat body tissue at the onset of larval-to-adult transition, with the loss of 14-3-3ϵ resulting in the altered abundance of 16 proteins. These included proteins linked to protein biosynthesis, glycolysis, tricarboxylic acid cycle, and lipid metabolic pathways. The ecdysone receptor (EcR), which is responsible for initiating the larval-to-adult transition, colocalized with 14-3-3ϵ in wild-type fat body tissues. The altered protein abundance in 14-3-3ϵ mutant fat body tissue was associated with transcriptional deregulation of alcohol dehydrogenase, fat body protein 1, and lamin genes, which are known targets of the EcR. This study indicates that 14-3-3ϵ has a critical role in cellular metabolism involving either molecular crosstalk with the EcR or direct interaction with metabolic proteins. Refereed/Peer-reviewed

Foreign direct investment (FDI) plays an important role in achieving economic growth in developing economies, especially in economies with insufficient domestic capital. FDI acts as a potential source of capital, foreign exchange, skills, market access, employment, and linkages for growth in other areas of the host (and possibly source) economy.

The Asia-Pacific region includes a majority of the world's population and many of its most rapidly growing economies. It is also home to the world's largest number of extremely poor people, many fragile states, and unsustainable environmental practices. The region has increased its influence in the world economy but is still grappling to overcome complex interrelated challenges of poverty, inequality and sustainable development. Its priorities must be addressed as a central element of any post-2015 global development goal framework. Drawing from lessons of the Millennium Development Goals, this paper suggests a conceptual framework to guide a new generation of goals, along with an intergovernmental approach to implementation. The “ZEN” framework stresses the distinct challenges of achieving zero extreme poverty (Z), setting country-specific “Epsilon” benchmarks for broader development challenges (E), and promoting environmental sustainability both within and across borders (N).

Optical epifluorescence microscopy was used in conjunction with X-ray fluorescence imaging to monitor the stability and intracellular distribution of the luminescent rhenium(I) complex fac-[Re(CO)3(phen)L], where phen = 1,10-phenathroline and L = 5-(4-iodophenyl)tetrazolato, in 22Rv1 cells. The rhenium complex showed no signs of ancillary ligand dissociation, a conclusion based on data obtained via X-ray fluorescence imaging aligning iodine and rhenium distributions. A diffuse reticular localisation was detected for the complex in the nuclear/perinuclear region of cells, by either optical or X-ray fluorescence imaging techniques. X-ray fluorescence also showed that the rhenium complex disrupted the homeostasis of some biologically relevant elements, such as chlorine, potassium and zinc. Refereed/Peer-reviewed

Syntenin-1 is an essential multi-functional adaptor protein, which has multiple roles in membrane trafficking and exosome biogenesis, as well as scaffolding interactions with either the actin cytoskeleton or focal adhesions. However, how this functional multiplicity relates to syntenin-1 distribution in different endosome compartments or other intracellular locations and its underlying involvement in cancer pathogenesis have yet to be fully defined. To help facilitate the investigation of syntenin-1 biology, we developed two specific monoclonal antibodies (Synt-2C6 and Synt-3A11) to spatially distinct linear sequence epitopes on syntenin-1, which were each designed to be unique at the six-amino acid level. These antibodies produced very different intracellular staining patterns, with Synt-2C6 detecting endosomes and Synt-3A11 producing a fibrillar staining pattern suggesting a cytoskeletal localisation. Treatment of cells with Nocodazole altered the intracellular localisation of Synt-3A11, which was consistent with the syntenin-1 protein interacting with microtubules. In prostate tissue biopsies, Synt-3A11 defined atrophy and early-stage prostate cancer, whereas Synt-2C6 only showed minimal interaction with atrophic tissue. This highlights a critical need for site-specific antibodies and a knowledge of their reactivity to define differential protein distributions, interactions and functions, which may differ between normal and malignant cells. Refereed/Peer-reviewed

With the aim of directing lanthanide complex uptake via the mannose receptor, a first generation of luminescent lanthanide complexes has been developed with an α-D-mannose targeting motif. Four complexes were produced to investigate photophysical properties and determine the effect of the coordinated mannose residue on emission intensity. The free hydroxyls of the α-D-mannose residue quenched lanthanide phosphorescence due to their close proximity, though they did not bind the lanthanide centre as observed by q-values ≈1.0 for all complexes between pH 3 and 10. Fluorescent emission was found to vary significantly with pH, though phosphorescent emission was relatively insensitive to pH. This lack of pH sensitivity has the potential to provide stable emission for the visualisation of the endosome-lysosome system where acidic pH is often encountered.

This paper examines the relationship between cross-border mergers and acquisitions (M&A) and financial development in emerging Asian economies. Bilateral cross-border M&A data for nine emerging Asian economies covering 2000–2009 are analyzed with a sample selection model and a panel data model. The estimation results show that although the banking sector still plays a crucial role in facilitating cross-border M&A, the role of equity markets has increased in importance because, in addition to cash, the issuance of common stock and the exchange of stocks have become popular forms of payment for M&A deals. Because of the relatively thin market, the primary corporate bond market plays a limited role in supporting cross-border M&A, which is in contrast to the primary public bond market. However, for the secondary market, the corporate bond market is more effective in facilitating cross-border M&A. The results also show that financial development in terms of stock and bond markets in their home countries tends to become more important when the target firms reside in more developed countries. In addition to financial development, the paper shows that most cross-border M&A are invested in technology-related and resource-based industries while cheap labor industries are relatively less attractive.

(ProQuest: ... denotes formulae omitted.)I. INTRODUCTIONBased mainly on experience gained in Asia and elsewhere, there is a need to improve the stability and security of sources of trade finance, especially to help deal with periods of financial crisis.WTO Document WT/WGTDF/M/2 (2002)The global crisis in 2008 contributed to the steepest fall of world trade recorded since the Great Depression. In the first quarter of 2009, nominal trade value fell 30% on average compared to 2008. The global trade volume also dropped by 18.5% year on year during this period (World trade monitor, 2012). Figure 1 indicates the drop in world trade and output from the recent crisis. If merchandise trade stops, causing containers to stall at ports, global supply chains are affected, multiplying the influence on output.The question is why the recent crisis brought about such an abrupt and deep collapse in world trade, while other world-wide recessions had more moderate effects on world trade, and why the decrease in world trade is much greater than the decrease in income. Some argue that the global demand shock was a driving factor for the 2008 abrupt collapse in trade. Freund (2009) asserts that the income elasticity of trade has been increasing over time, that during recessions, trade is especially responsive to income, and that the significant increase in the income elasticity of trade may be attributed to the fragmentation of production and lean retailing.1 Newbery and Stiglitz (1984) argue that trade can potentially increase uncertainty and income volatility by affecting price elasticities. Financial development could then be fostered by increased demand for trade insurance. Baldwin (2009) argues that the compositional and synchronicity effects exaggerate movement of the trade to GDP ratio. The compositional effect argument is based on the fact that postponeable goods consist of a small portion of the GDP, but the trade and demand shocks disproportionately affect the production of postponeable goods such as consumer durables and investment goods. The synchronicity effect is attributed to the increasing in-time delivery nature of vertically integrated production networks as well as the spatial synchronization of the global income drop. One potential source of supply shocks for explaining the recent abrupt and synchronized trade decrease on a global scale is internationalized supply chains. Since most trading activities are closely interconnected with each other, bankruptcies among trading companies due to deteriorating credit conditions suppress trade along the whole chain.However, the abrupt and deep decrease in trade in a global scale in 2008 cannot be explained by the previous arguments. This paper focuses on the relationship between trade and financial factors. We believe that a lack of trade-credit financing in particular is a contributing factor to decrease in global trade in 2008 which is differ from other recessions. Beginning in 2008, financial turmoil in global markets led to the collapse of some banks engaged in trade finance. The credit squeeze in international financial markets began to seriously impinge on world trade, where roughly 90% of all merchandise trade is reliant upon some form of short-term credit, insurance, or guarantee. Evidence of a slowdown in trade finance was also seen in declining growth of the foreign liabilities of commercial banks. The cost of short-term credit for trade finance also rose, contributing to the slowdown in trading activities. The WTO estimated that a gap of as much as $25 billion opened between global demand and supply for trade credit.The combination of the global inter-bank lending freeze and collapse of the speculative, leveraged commodity price bubble undermined both the confidence of banks in the ability of peer banks to pay obligations when due, and confidence in the value of cargo as security for trade credit if liquidated on default. The credit crunch in banks that were leading trade finance providers, concerns about traders' access to credit and creditworthiness, higher cost of letters of credit, and more stringent lending standards and guarantee requirements especially impacted short-term financing for exporters, importers, and shipping firms, and for smaller firms (who are more dependent on letters of credit). …

This study calculates the decline in costs involving merchandise trade between the People’s Republic of China (PRC) and India during the period 1980–2008. Drawing from the recent literature, a comprehensive measure of trade costs is derived from a theory-founded gravity model of international trade, which can be computed based on the observed bilateral trade flows and GDP data. The analysis reveals that trade costs have declined sharply since the 1980s, accounting for a large and increasing portion of growth in total trade between the two countries. Whereas the reduction in trade costs accounted for less than one-third of the increase in trade between PRC and India during the 1980s, lower costs seem to explain about three-quarters of trade expansion during the 1990s and up to nearly 85 per cent in 2001–08.