Phosphorylation Regulation of T-Lymphocyte Migration

Immune surveillance requires efficient trafficking of leukocytes throughout the body. To achieve this, leukocytes have evolved to be highly migratory and responsive to environmental cues, which provide guidance for proper tissue distribution. The translation of external environmental cues to intracellular physical changes in leukocytes requires a cascade of receptors, signal transducers, and mechanical effectors. My doctoral research focused on using T-cells as a model to study the unique cellular process of how signal transducers interact with and regulate mechanical effectors in fast migrating immune cells. Specifically, it is known that the signal transducer Mst1 kinase is required for T-cell polarization, adhesion, and active migration, but the underlying mechanisms remain poorly understood. I have demonstrated that Mst1 regulates two mechanical effectors, the molecular motor Myosin-IIA and the cytoskeleton regulatory protein L-plastin, through the process of phosphorylation. Theregulation of Myosin-IIA enables it to generate contractile force inside a migrating T-cell, maintaining the shape and proper adhesion of the cell to extracellular matrix, both being requirements for successful migration. The regulation of L-plastin enables it to activate integrin adhesion molecules as well as to properly organize lamellipodial actin. In addition, I have identified novel adhesion structures in T-cells called microadhesions, which potentially provide traction force to migrating T-cells. Overall, my research has identified a novel pathway acting between a signal transducer and two mechanical effectors in T-cell migration

Fair value measurements and earnings management: evidence from the banking industry

I examine the association between fair value measurements and bank earnings management using financial data for a sample of U.S. bank holding companies from 2009 to 2012. I follow the methodology in Beatty et al. (2002) and find that banks reporting higher recurring basis fair values, especially level 2 fair values and banks reporting increased fair values are more likely to report small earnings increases both in the current year and one-year ahead after controlling for discretionary loan loss provisions, discretionary security gains and losses, and other bank-specific characteristics. By decomposing the fair values into different types, I find that the positive association between fair value measurements and earnings management is primarily driven by available-for-sale assets. This relation can be found in both public banks and private banks. I also distinguish upward earnings management from downward earnings management and find that level 2 fair values are positively associated with upward earnings management and with downward earnings management via discretionary security gains and losses. By examining the relation between earnings volatility and fair value measurements, I find that banks recognizing more level 2 fair value assets and liabilities report smoother earnings over the tim

Phosphorylation Regulation of T-Lymphocyte Migration

Immune surveillance requires efficient trafficking of leukocytes throughout the body. To achieve this, leukocytes have evolved to be highly migratory and responsive to environmental cues, which provide guidance for proper tissue distribution. The translation of external environmental cues to intracellular physical changes in leukocytes requires a cascade of receptors, signal transducers, and mechanical effectors. My doctoral research focused on using T-cells as a model to study the unique cellular process of how signal transducers interact with and regulate mechanical effectors in fast migrating immune cells. Specifically, it is known that the signal transducer Mst1 kinase is required for T-cell polarization, adhesion, and active migration, but the underlying mechanisms remain poorly understood. I have demonstrated that Mst1 regulates two mechanical effectors, the molecular motor Myosin-IIA and the cytoskeleton regulatory protein L-plastin, through the process of phosphorylation. Theregulation of Myosin-IIA enables it to generate contractile force inside a migrating T-cell, maintaining the shape and proper adhesion of the cell to extracellular matrix, both being requirements for successful migration. The regulation of L-plastin enables it to activate integrin adhesion molecules as well as to properly organize lamellipodial actin. In addition, I have identified novel adhesion structures in T-cells called microadhesions, which potentially provide traction force to migrating T-cells. Overall, my research has identified a novel pathway acting between a signal transducer and two mechanical effectors in T-cell migration

Dual-located kinesin - A class XIV kinesin that can enter the nucleus

Das pflanzliche Zytoskelett besteht aus zwei verschiedenen Arten von Proteinpolymeren: Aktinfilamente und Mikrotubuli. Sie tragen zur zelleigenen Richtung (Zellachse, Zellpolarität) von Pflanzenzellen bei, welche die Morphogenese bis hin zur organismischen Ebene bestimmt. Motoren sind eine Art von Proteinen, die an das Zytoskelett binden und die Energie aus der ATP-Hydrolyse verwenden können, um z.B. Vesikel entlang des Zytoskeletts in eine gewisse Richtung zu bewegen und zu transportieren. Während Myosine Motoren sind, die entlang von Aktinfilamenten laufen, bewegen sich Kinesine und Dyneine entlang von Mikrotubuli. Konventionelle Kinesine bewegen sich in Richtung des Plus-Endes der Mikrotubuli, während Dyneine sich in Richtung des Minus-Endes bewegen. Eine der auffälligsten Besonderheiten der pflanzlichen Motorproteine ist jedoch das Fehlen von in Richtung Minus-Ende laufenden zytoplasmatischen Dyneinmotoren in den meisten Gymnospermen und in allen Angiospermen. Im Gegensatz dazu wurde eine spezifische Klasse von in Richtung Minus-Ende laufenden Kinesinen in Landpflanzen entdeckt, die im Allgemeinen als Klasse-XIV-Kinesine bezeichnet werden. So liegt es nahe, dass einige der Funktionen von Dyneinen von Kinesinen der Klasse- XIV übernommen wurden. In dieser Doktorarbeit wurde die subzelluläre Funktion eines als OsDLK bezeichneten Klasse-XIV-Kinesins untersucht. Die heterozygoten Reismutanten zeigten eine Verzögerung in der Koleoptilenstreckung im Vergleich zu den Keimlingen des Wildtyps. Die homozygoten Mutanten konnten dieses verzögerte Wachstum auch während mehrerer Generationen nicht aufholen. Später zeigte dlk ein relativ hohes Transkriptionsniveau während der ersten 4 Tage nach der Keimung, was auf eine wichtige Rolle von OsDLK während des frühen Stadiums der Reiskeimung hindeutet. Um einen Einblick in die subzelluläre Funktionen zu erhalten, wurde OsDLK, welches mit einem fluoreszierenden Reporter fusioniert wurde, in BY-2 Tabakzellen (Nicotiana tabacum) überexprimiert. Wir zeigten durch ein In-vitro-sliding Assay, dass es die Fähigkeit hat, an Mikrotubuli zu binden und sich in Richtung Minus-Ende zu bewegen. Die Überexpression dieser GFP-Fusion stimulierte die Zellproliferation und verzögerte den Übergang in die Zellexpansion. Durch die Synchronisierung des Zellzyklus konnten wir zeigen, dass der Übergang in die Metaphase in der Überexpressionslinie verzögert wurde, während die späteren Phasen deutlich beschleunigt wurden. Die Lokalisierung von OsDLK während des Zellzyklus ergab, dass das Fusionsprotein neu verteilt wurde und mit den zellwandnahen Bereichen der Mikrotubuli (kortikale Mikrotubuli, Phragmoplast) kolokalisierte. Überraschenderweise stellte sich heraus, dass OsDLK in zwei Populationen in der Interphase auftritt: Eine Subpopulation war mit den kortikalen Mikrotubuli verbunden, was bereits bei anderen Klasse-XIV-Kinesinen beobachtet wurde, die andere Population wurde im Zellkern lokalisiert. Die Verteilung des Proteins auf den Zellkern konnte durch Kältestress oder durch Hemmung des Kernexports durch den Hemmstoff Leptomycin B (200 nM) spezifisch stimuliert werden. Diese Anhäufung von OsDLK im Kern war reversibel. Da dieses Kinesin in der Lage war, sich zwischen zwei Orten in einer bestimmten Weise hin- und herzubewegen, nannten wir dieses besondere Kinesin OsDLK, was für Dual Localisation Kinesin steht

QEBA: Query-Efficient Boundary-Based Blackbox Attack

Machine learning (ML), especially deep neural networks (DNNs) have been widely used in various applications, including several safety-critical ones (e.g. autonomous driving). As a result, recent research about adversarial examples has raised great concerns. Such adversarial attacks can be achieved by adding a small magnitude of perturbation to the input to mislead model prediction. While several whitebox attacks have demonstrated their effectiveness, which assume that the attackers have full access to the machine learning models; blackbox attacks are more realistic in practice. In this paper, we propose a Query-Efficient Boundary-based blackbox Attack (QEBA) based only on model's final prediction labels. We theoretically show why previous boundary-based attack with gradient estimation on the whole gradient space is not efficient in terms of query numbers, and provide optimality analysis for our dimension reduction-based gradient estimation. On the other hand, we conducted extensive experiments on ImageNet and CelebA datasets to evaluate QEBA. We show that compared with the state-of-the-art blackbox attacks, QEBA is able to use a smaller number of queries to achieve a lower magnitude of perturbation with 100% attack success rate. We also show case studies of attacks on real-world APIs including MEGVII Face++ and Microsoft Azure.Comment: Accepted by CVPR 202

The association between XPC Lys939Gln gene polymorphism and urinary bladder cancer susceptibility: a systematic review and meta-analysis

BACKGROUND: Numerous epidemiological studies have been conducted to explore the association between the Lys939Gln polymorphism of Xeroderma pigmentosum group C (XPC) gene and urinary bladder cancer susceptibility. However, the results remain inconclusive. In order to derive a more precise estimation of this relationship, a large and update meta-analysis was performed in this study. METHODS: A comprehensive search was conducted through researching MEDLINE, EMBASE, PubMed, Web of Science, China Biomedical Literature database (CBM) and China National Knowledge Infrastructure (CNKI) databases before June 2013. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to estimate the strength of the association. RESULTS: A total of 12 studies with 4828 cases and 4890 controls for evaluating the XPC Lys939Gln polymorphism and urinary bladder cancer were included. Overall, there was significant associations between the XPC Lys939Gln polymorphism and urinary bladder cancer risk were found for homozygous model (OR = 1.352, 95% CL = 1.088-1.681), heterozygous model (OR = 1.354, 95% CL = 1.085-1.688), and allele comparison (OR = 1.109, 95% CL = 1.013-1.214). In subgroup analysis by ethnicity and source of controls, there were still significant associations detected in some genetic models. CONCLUSION: Our meta-analysis suggested that the XPC Lys939Gln polymorphism contributed to the risk of urinary bladder cancer. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here:

How do auditors perceive and respond to client firms’ technological peer pressure? Evidence from going-concern opinions

We examine how the technological aspect of competition (or technological peer pressure) affects the likelihood that auditors issue going-concern opinions. We find that a client firm’s technological peer pressure increases the likelihood that the firm receives a going-concern opinion. This finding is consistent with the notion that the perceived auditor business risk increases with client technological peer pressure so that auditors are more likely to issue going-concern opinions to such clients. Further evidence shows that this positive effect is more pronounced for client firms with greater innovation originality, that are financially constrained, and for auditors facing higher litigation risk. We also find that technological peer pressure reduces the probability of both Type I and Type II misclassifications when auditors exert more effort. Additional analyses show that client firms’ technological peer pressure positively affects the likelihood of using auditors specialized in auditing R&D. Taken together, our study implies that auditors exert more effort to increase audit quality in response to the higher auditor business risk induced by clients’ technological peer pressure, instead of simply being conservative

Food culture and nostalgia in the Sannong video

This research reviews the rural nature of Chinese society and analyses the elements that engage viewers in the Sannong videos from this perspective. Urban dwellers, rural dwellers and rural migrants have all been greatly affected by rapid urbanisation. The hukou system has led to a dichotomy between urban and rural China and a stigmatised image of peasants and the countryside. In this environment, people lost their sense of belonging and became nostalgic. For the first time since the spread of social media to rural dwellers and rural migrants, peasant groups have had the opportunity to reconstruct the image of peasants and the countryside as the protagonists of a narrative. In this study, 10 videos were selected from each of the two distinctive video accounts to compare and analyse their content. The common features of the two accounts can be considered as the reason for the popularity of the Sannong videos. In addition to the fact that a large number of viewers like the Sannong videos, this phenomenon may reflect the plight of urbanisation in China

Uranium associations and migration behaviour at the Needle’s Eye natural analogue site in SW Scotland

This thesis investigated uranium (U) migration behaviour at the Needle‟s Eye natural analogue site, located close to Southwick Water, South West Scotland. The results of this study are important for the prediction of U behaviour in the far-field environments of nuclear waste repositories over long time-scales. The Needle‟s Eye natural analogue site was selected because the processes involved in U mobilisation, the direction of water flow and the extent of retention of uranium in peaty soils had already been identified. To this end, previous results demonstrated that groundwater passing through the mineralisation oxidized U and transported it to the peaty area, where 80-90% of the released U has been retained. Sequential extraction of the peaty soils indicated that more than 90% of the solid phase U was bound to the organic fraction. However, in-depth characterisation of U associations within the soil porewaters and the peaty soils at this site was lacking. Therefore, the processes controlling the migration of uranium within this organic-rich system were the main focus of this study. There were five sampling trips carried out from 2007-2011, in which cave drip waters, bog waters and surface soil and soil core samples were selectively collected for analysis by a range of methods described below. The cave drip waters emerging from the mineralisation were oxidizing and slightly alkaline (7.6-7.8), U was mainly in truly dissolved (<3 kDa) forms (Ca2UO2(CO3)30, CaUO2(CO3)32- and UO2(CO3)22-). It is known that the formation of the ternary Ca-UVI-CO3 complexes inhibits the reduction of U and so it is likely that it is UVI that is present within the peaty soils and their associated porewaters. Sampling trip 1 quantified the U concentrations in cave waters and soil core porewaters. By 30 m from the cave, U concentrations in the soil porewaters had decreased by a factor of ~10. Ultrafiltration fractionated the colloidal fraction (3 kDa-0.2 μm) into large (100 kDa-0.2 μm), medium (30-100 kDa) and small (3-30 kDa) colloidal fractions. It was found that U was mainly associated with the large colloid (100 kDa-0.2 μm) but, with increasing distance from the mineralisation, the U distribution became bimodal with both large and small fractions being equally important. Iron (Fe) was exclusively associated with the large colloid fraction in the peaty soil porewaters. Gel electrophoresis and gel filtration, applied to study the interactions of U (and other elements) with humic substances (HS), showed that the associations were quite uniform with increasing depth of the cores and increasing distance from the U mineralisation. Uranium (and other elements including Fe) was associated with the largest humic molecules. Sampling trip 2 involved collection of three more soil cores and ultrafiltration again fractionated the total dissolved porewater into large, medium and small colloids. This time, the truly dissolved (<3 kDa) fraction was also analysed. Again, U was mainly associated with the large colloidal (100 kda-0.2 μm) fraction. With increasing distance and increasing depth, U was still predominantly associated with the large colloidal fraction, but the importance of the truly dissolved (<3 kDa) phase could not be neglected. At the same time, Fe was also mainly associated with the large colloidal fraction. The remainder of the experimental work on samples from trip 2 focused on determining the importance of U associations with both Fe and humic components of the solid phase. Sequential extraction of the whole soil mainly targeted different iron phases and found that U was mainly released in the sodium acetate and sodium dithionite solutions, which indicated U was associated with (i) Fe carbonates; and (ii) crystalline Fe oxides (e.g. goethite, hematite, and akaganetite). However, very little Fe was extracted in the “carbonate-bound” fraction and separate experiments showed that U was not associated with Fe carbonates but instead had been released from the surfaces of HS and humic-bound Fe surfaces. XRD spectroscopy showed that mineral compositions were in reasonable agreement with the sequential extraction results and SEM-EDX analysis indicated that U in the soil was generally not present in crystalline form, as only two particles with high U content were found after 4-hour searching. Exhaustive extraction of HS showed that >90% U was associated with organic substances, in agreement with previous work and novel experiments involving gel electrophoresis in conjunction with sequential extraction was used to study the relationships between U, Fe and the HS. It was demonstrated that ~20-25% U was weakly held by the HS or at humic-bound Fe surfaces, ~45% was incorporated into crystalline Fe oxides which were intimately associated with HS and the remainder was in the form of strong U-CO3-humic complexes. In sampling trip 3, U migration behaviour in the soil porewaters was the focus. A 30-m transect line, comprising seven0-5 cm soil samples, starting at the cave and passing through the peaty area towards the Southwick Water, was established. Soil porewaters from these surface soils were fractionated into colloidal (3 kDa-0.2 μm) fraction and truly dissolved (<3 kDa) phase. There was a major change in U speciation, from Ca2UO2(CO3)3 0,CaUO2(CO3)32- and UO2(CO3)22- in the truly dissolved fractions of waters close to the cave to a predominant association with the highly coloured colloidal fractions as soon as the boggy area was reached. With distance through the boggy area, it was clear that the colloidal U was being incorporated into the solid phase since porewater concentrations had decreased ~100-fold by 30 m from the cave. Ultrafiltration in conjunction with acetate extraction was then used to extract U from the porewater colloids isolated from a soil core (20 m from cave). In the organic-rich portion of the core (0-30 cm), ~60-70% U was colloidally associated and ~85-95% of this U was extracted from the colloidal fraction. This indicated that the interactions between U and the porewater colloids were weak. In sampling trip 4, U associations in the porewater colloids were still the main focus. Gel filtration of porewater colloids confirmed that U, Fe and humic colloids were intimately associated. It was concluded that although U in the cave drip water was mainly in truly dissolved forms, weak U----humic/Fe colloids were formed immediately when U entered the peaty area. In sampling trip 5, results for soil core porewaters showed that Fe in the whole core was mainly in the form of FeII. Thus strongly reducing conditions prevailed through the core which was situated within the peaty area. Combining the results from the five sampling trips, three zones within the peaty area were distinguished. Zone I was characterised by extremely high concentrations of dissolved HS and this was where the change in U speciation from dissolved to colloidal forms took place. Zone II contained most of the soil cores collected during this study and was characterised by strongly reducing conditions and moderate concentrations of HS. Colloidal U was removed to the solid phase as waters flow through this area. Zone III marks the transition to the saltmarsh. Focusing on Zone II, a conceptual model of U behaviour was developed: upon entering the peaty area, U is weakly held by very large humic-Fe colloids. These colloids are removed to the solid phase and over time the associations of U are transformed; some becomes incorporated into stable humic-bound crystalline oxides as a result of redox cycling of Fe, some becomes strongly complexed to HS and the remainder is weakly held by the HS and/or humic-bound Fe surfaces. The crystalline Fe oxides were transformed to Fe sulfides below 30 cm depth but the associated U was not transferred to these sulfides. Instead the weak associations became more important. In the wider context, since only UVI forms soluble complexes with acetate, UVI does not appear to be reduced even under the strongly reducing conditions encountered within waterlogged organic-rich soils. Initial interactions between UVI and porewater colloids appear to be weak but stronger interactions such as incorporation into Fe phases and complexation by HS occur once the colloids and associated U are removed to the solid phase. Waterlogged organic-rich soils appear to be a long-term sink for U but changing climatic conditions leading to the drying out of such soils may ultimately release U in association with smaller, more mobile organic-rich colloids

Predicting top performance : a study of sushi chefs

This study investigated the distinction between an employee's typical performance and maximum performance, and tried to explore the link between specific individual characteristics and the discrepancy level between the two types of performances. We expected that personality would affect the level of difference between typical performance and maximum performance. In particular, we believed that Conscientiousness and Emotional Stability from the Big-Five model of Personality would have an impact on the employee's goal setting, goal commitment, performance expectancy, and self-regulation, all of which would further influence the employee's discrepancy level between typical and maximum performance. We also examined the impact of trait affect as well as state affect on the dependent variable, hypothesizing that operating on the cognitive-motivation processes, affect would be related to the discrepancy level between typical performance and maximum performance. The sample of this study was composed of48 sushi chefs in the Canadian food industry. Each participant was observed for typical and maximum performance measurement in working place, and asked to fill out questionnaires. The findings showed a significant performance discrepancy within individuals, and self-regulation, negative trait affect, as well as job tenure contributed to the intra-individual typical/maximum performance discrepancy. Contrary to expectations, personality traits and other affectivity variables were not significant in this study. Possible explanations, contributions and limitations, along with directions for future research, are discussed