Acute Kidney Injury Biomarkers for Patients in a Coronary Care Unit: A Prospective Cohort Study

Background: Renal dysfunction is an established predictor of all-cause mortality in intensive care units. This study analyzed the outcomes of coronary care unit (CCU) patients and evaluated several biomarkers of acute kidney injury (AKI), including neutrophil gelatinase-associated lipocalin (NGAL), interleukin-18 (IL-18) and cystatin C (CysC) on the first day of CCU admission. Methodology/Principal Findings: Serum and urinary samples collected from 150 patients in the coronary care unit of a tertiary care university hospital between September 2009 and August 2010 were tested for NGAL, IL-18 and CysC. Prospective demographic, clinical and laboratory data were evaluated as predictors of survival in this patient group. The most common cause of CCU admission was acute myocardial infarction (80%). According to Acute Kidney Injury Network criteria, 28.7 % (43/150) of CCU patients had AKI of varying severity. Cumulative survival rates at 6-month follow-up following hospital discharge differed significantly (p,0.05) between patients with AKI versus those without AKI. For predicting AKI, serum CysC displayed an excellent areas under the receiver operating characteristic curve (AUROC) (0.89560.031, p,0.001). The overall 180-day survival rate was 88.7 % (133/150). Multiple Cox logistic regression hazard analysis revealed that urinary NGAL, serum IL-18, Acute Physiology, Age and Chronic Health Evaluation II (APACHE II) and sodium on CCU admission day one were independent risk factors for 6-month mortality. In terms of 6-month mortality, urinary NGAL had the best discriminatory power, the best Youden index, and the highest overall correctness of prediction

α-Synuclein fibril and synaptic vesicle interactions lead to vesicle destruction and increased lipid-associated fibril uptake into iPSC-derived neurons

Monomeric alpha-synuclein (aSyn) is a well characterised protein that importantly binds to lipids. aSyn monomers assemble into amyloid fibrils which are localised to lipids and organelles in insoluble structures found in Parkinson’s disease patient’s brains. Previous work to address pathological aSyn-lipid interactions has focused on using synthetic lipid membranes, which lack the complexity of physiological lipid membranes. Here, we use physiological membranes in the form of synaptic vesicles (SV) isolated from rodent brain to demonstrate that lipid-associated aSyn fibrils are more easily taken up into iPSC-derived cortical i3Neurons. Lipid-associated aSyn fibril characterisation reveals that SV lipids are an integrated part of the fibrils and while their fibril morphology differs from aSyn fibrils alone, the core fibril structure remains the same, suggesting the lipids lead to the increase in fibril uptake. Furthermore, SV enhance the aggregation rate of aSyn, yet increasing the SV:aSyn ratio causes a reduction in aggregation propensity. We finally show that aSyn fibrils disintegrate SV, whereas aSyn monomers cause clustering of SV using small angle neutron scattering and high-resolution imaging. Disease burden on neurons may be impacted by an increased uptake of lipid-associated aSyn which could enhance stress and pathology, which in turn may have fatal consequences for neurons

The Association Between the Sedative Loads and Clinical Severity Indicators in the First-Onset Major Depressive Disorder

Background: High sedative use in a major depressive episode may imply specific clinical features. This study aims to examine the correlation between sedative use and clinical severity indicators in the initial treatment phase of first-onset major depressive disorder.Methods: A study cohort in the first episode of major depressive disorder was used to conduct pharmacological dissection. All participants had at least a 2-year follow-up period with a complete treatment record. The defined daily dose of antidepressants and augmentation agents were calculated as the antidepressant load and augmentation load, respectively. Sedative use, which was calculated as the equivalent dosage of lorazepam, were defined as the sedative load. These psychotropic loads were measured monthly and the averaged psychotropic loads for each day were obtained.Results: A total of 106 individuals (75.5% female) were included. The mean duration of disease course in participants was 5.5 ± 3.5 years. In the multiple regression analysis, after controlling for other classes of psychotropics and comorbid anxiety disorders, the sedative load independently correlated with higher number of antidepressants used, higher number of antidepressant used with an adequate dose and duration, more psychiatric emergency and outpatient visits within 2 years of disease onset.Conclusion: High loading of sedatives correlated with several indicators of clinical severity in major depressive disorder. The sedative load may be used as a specifier to identify subgroups in patients with major depressive disorder

Elevated Aspartate and Alanine Aminotransferase Levels and Natural Death among Patients with Methamphetamine Dependence

Background: Methamphetamine is one of the fastest growing illicit drugs worldwide, causing multiple organ damage and excessive natural deaths. The authors aimed to identify potential laboratory indices and clinical characteristics associated with natural death through a two-phase study. Methods: Methamphetamine-dependent patients (n = 1,254) admitted to a psychiatric center in Taiwan between 1990 and 2007 were linked with a national mortality database for causes of death. Forty-eight subjects died of natural causes, and were defined as the case subjects. A time-efficient sex-and age-matched nested case-control study derived from the cohort was conducted first to explore the potential factors associated with natural death through a time-consuming standardized review of medical records. Then the identified potential factors were evaluated in the whole cohort to validate the findings. Results: In phase I, several potential factors associated with natural death were identified, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), comorbid alcohol use disorder, and the prescription of antipsychotic drugs. In phase II, these factors were confirmed in the whole cohort using survival analysis. For the characteristics at the latest hospital admission, Cox proportional hazards models showed that the adjusted hazard ratios for natural death were 6.75 (p<0.001) in the group with markedly elevated AST (>80 U/L) and 2.66 (p<0.05) in the group with mildly elevated AST (40-80 U/L), with reference to the control group (>40 U/L). As for ALT, the adjusted hazard ratios were 5.41 (p<0.001), and 1.44 (p>0.05). Comorbid alcohol use disorder was associated with an increased risk of natural death, whereas administration of antipsychotic drugs was not associated with lowered risk. Conclusions: This study highlights the necessity of intensive follow-up for those with elevated AST and ALT levels and comorbid alcohol use disorder for preventing excessive natural deaths

Ναυτικό μουσείο στο δέλτα του Φαλήρου

Σημείωση: το κυρίως κείμενο και το συνοδευτικό υλικό του διατίθεται σε ξεχωριστό ενιαίο αρχείο

Fluorescence lifetime imaging microscopy to study protein aggregation in the context of neurodegenerative diseases

Neurodegenerative diseases are associated with protein misfolding and amyloid aggregation. The work presented in this thesis involves the use of fluorescence lifetime imaging microscopy (FLIM) and other biophysical techniques to elucidate the molecular mechanisms that underlie different amyloid-associated neurodegenerative dis- eases. Currently, there is no prevailing therapeutic option for the latter. Hence, the work presented aims to develop physiologically relevant assays with the potential for diagnostics and drug-screening platforms, as well as to identify different therapeutic targets to alleviate disease progression. In Alzheimer’s disease (AD), there is the characteristic formation of intracellular aggregates of amyloid-β 42 (Aβ42), which have an associated free energy barrier and exothermic elongation kinetics; these aggregates then diffuse out into the extracellular matrix between neuronal cells, triggering neuronal death. By performing intracellular thermometry in live mammalian cells using fluorescent polymeric thermometers (FPT), Aβ42 aggregation is revealed to lead to cellular thermogenesis, which is rescued upon treatment with an amyloid-β (Aβ) elongation-inhibiting, small compound drug. The latter validates the potential use of intracellular thermometry as a diagnostic platform to test inhibitory drugs in live cells. It is further shown that the thermogenesis effect primarily stems from the exothermic elongation of Aβ42, which overrides any contribution from mitochondrial dysfunction. For a better understanding of heat dissipation from Aβ peptides, classical molecular dynamic simulations are performed. It is shown that heat retention by an Aβ peptide is promoted under intracellular-mimicking conditions due to fewer water-protein hydrogen bonding interactions, which highlights the importance of incorporating physiologically relevant parameters for modelling biological and intracellular environments. Fused-in sarcoma (FUS) is a phase-separating, DNA/RNA binding protein that localises to cell nuclei under physiological conditions, where it mediates DNA repair. Mutations to its nuclear localisation signal (NLS) result in cytoplasmic mislocalisation associated with the onset of amyotrophic lateral sclerosis (ALS). Through the combined use of FLIM and single particle tracking (SPT), a tool to infer intracellular FUS viscosity in live cells, without the introduction of an external sensor, is created. Moreover, it is identified that ALS- associated mutants, P525L and R495X exhibit loss of cytoskeletal integrity and enhanced euchromatin expression. Furthermore, they experience greater dysregulation of their autophagy-lysosomal pathway, as modulated by transcription factor EB (TFEB). The latter is triggered by increased de-acidification of lysosomes, which also leads to a collapse in tubular endoplasmic reticulum (ER) and mitochondrial fission. Macroautophagy needed for degradation and clearance of aberrant FUS aggregates is inhibited despite an up-regulation of TFEB and increased lysosomal biogenesis. Although the sequence of events leading to macroautophagy inhibition which perpetuates aberrant FUS aggregation remains unknown, it is believed that regulating TFEB and lysosomal function could be a potential therapeutic option for ALS/FTD. The rich β-sheets that comprise an amyloid result in electron delocalisation leading to intrinsic amyloid fluorescence in the visible range, upon ultraviolet (UV) excitation. This phenomenon is independent of intrinsic aromatic fluorescence, the excitation and emission of which occur solely in the UV range. A two-photon (2P) titanium sapphire (Ti:S) laser is used to achieve UV excitation to characterise different amyloids by their unique intrinsic fluorescence lifetimes in a label-free manner. It is further shown that intrinsic amyloid fluorescence lifetime can be used to distinguish between different polymorphic populations of alpha-synuclein (αS) (known to influence disease pathology) formed under intracellular- and extracellular-mimicking buffers, as well as disaggregated fibrils. 2P-FLIM gives a medium-throughput assay which avoids the use of extrinsic fluorescent markers that may otherwise affect aggregation behaviour and the polymorphic species formed.Vice Chancellor's Award (Cambridge Trust); Wolfson College Scholarshi

A dynamic general equilibrium model for public R&D investment in Taiwan

In terms of economic development policies, public research and development (R&D) investment may be one of the most critical and useful tools in Taiwan, having frequently played a role in leading related overall investment in Taiwan. Although the impact channels of R&D investment are varied and complex, its benefits in terms of the development of human capital, industrial productivity, and basic research are clear. With the rapid growth of the private sector in the Taiwan economy, it is, however, debatable whether the government should continue to use the public financial budget to invest in R&D. By using a computable general equilibrium (CGE) model to simulate the impact of public R&D investment on the economy in Taiwan, the empirical evidence of the present paper is that public R&D investment gives rise to different short-term and medium-term impacts on real GDP that are mostly felt in the third or fourth years of their implementation among different industries. These impacts then gradually converge back to equilibrium in the long run. Public R&D investment boosts the technology of high-tech industries and increases exports, but it also crowds out the output of primary industries. Although the public R&D investment has a positive effect on the real wage, its effect on inflation should not be overlooked. Because of the pros and cons surrounding the impact of public R&D investment on industries and the economy, the study provided by the present paper can serve as valuable reference not only to decision-makers in government agencies but also to academic researchers.Public R&D investment CGE model Economic development policy Input-output analysis

Raw Data: Intracellular Aβ42 aggregation leads to cellular thermogenesis

Raw data (.xlsx) for 'Intracellular Aβ42 aggregation leads to cellular thermogenesis' manuscript. Includes data for (i) FLIM measurements, (ii) ThT assay, (iii) dSTORM quantification, (iv) Seahorse assay, (v) molecular dynamics simulations

Effect of Scour on the Natural Frequency Responses of the Meteorological Mast in the Taiwan Strait

The meteorological mast (met mast) for the Taiwan Power Company’s offshore wind farm is located in Taiwan Strait near Changhua County. The p–y curve method recommended in the current offshore foundation design codes does not account for the local scour around the pile foundation; it overestimates the lateral pile deformation and underestimates the foundation stiffness. This paper presents a method to correct the initial modulus of subgrade reaction and modify the ultimate lateral resistance caused by the local scour. The natural frequency of the met mast structure is also determined by a numerical model and verified with the measured data in situ. A comprehensive parameter study is performed to analyze the effect of scour on the dynamic responses of the met mast. Two types of foundation model, a coupled-springs foundation model and a distributed-springs foundation model, are considered in the dynamic analysis of the met mast. The results demonstrate that using a distributed-springs foundation model provides a relatively accurate estimate of the natural frequencies of the met mast structure. Furthermore, the scour exerted significant effects on certain modes of the vibration responses. The natural frequencies of the met mast structure can be reduced by approximately 14% due to scour, particularly in the horizontal bending modes. This paper also provides a preliminary strategy for structural monitoring and analysis to detect scour damage on offshore wind turbines with monopile foundations