MECHANISMS AND ROLES OF DYNAMIC ACTIN ASSEMBLY AROUND DYSFUNCTIONAL MITOCHONDRIA

Possessing the ability to efficiently generate ATP required to sustain cellular functions, mitochondria are often considered the ‘powerhouses of the cell’. However, our understanding of mitochondria in cell biology was further expanded when we recognized that communication between this unique organelle and the rest of the cell regulates cellular bioenergetics, metabolism and signaling processes such as mitophagy and apoptosis. Here, I investigate signaling between mitochondria and the actin cytoskeleton, and how this signaling regulates mitochondrial dynamics and cellular function. Specifically, I find that, upon mitochondrial dysfunction, actin polymerizes rapidly around the dysfunctional organelle, which we term ‘acute damage-induced actin’ (ADA). Hitherto, neither the mechanism of ADA activation nor the cellular role of ADA are well understood. In this dissertation, I show that that two parallel signaling pathways are required for ADA: driven by calcium signaling and ATP depletion, respectively. In the first pathway, mitochondrial calcium efflux through the sodium/calcium exchanger NCLX leads to elevation of cytosolic calcium, activating protein kinase C (PKC)-β. PKC-β activation in turn activates the Rac-GEF Trio, leading to activation of the Rho family GTPase Rac, the WAVE complex, and finally the actin-polymerizing Arp2/3 complex. Simultaneously, ATP depletion caused by mitochondrial dysfunction activates the energy sensor AMPK. AMPK activates in turn the Cdc42 GEF Fgd1, the Rho-family GTPase Cdc42, and finally a specific family of actin-polymerizing formin proteins, FMNL formins. Both FMNL formins and Arp2/3 s are to assemble mitochondrially-associated actin filaments. Next, I elucidated roles for ADA in mitochondrial and cellular dynamics, finding three distinct ADA effects. First, ADA stimulates glycolysis in multiple cell types, including mouse embryonic fibroblasts (MEFs) and cytotoxic T lymphocytes (CTLs). Second, ADA inhibits a specific form of mitochondrial dynamics we term ‘circularization’. Third, ADA delays mitochondrial recruitment of the E3 ubiquitin ligase, Parkin, which delays mitophagy. Taken together, I propose that ADA is an acute mechanism for sensing and responding to mitochondrial damage, by promoting re-establishment of ATP production and giving the cell a ‘pause’ for recovery before the damaged organelle is permanently cleared

A Decomposition Theorem for Maximum Weight Bipartite Matchings

Let G be a bipartite graph with positive integer weights on the edges and without isolated nodes. Let n, N and W be the node count, the largest edge weight and the total weight of G. Let k(x,y) be log(x)/log(x^2/y). We present a new decomposition theorem for maximum weight bipartite matchings and use it to design an O(sqrt(n)W/k(n,W/N))-time algorithm for computing a maximum weight matching of G. This algorithm bridges a long-standing gap between the best known time complexity of computing a maximum weight matching and that of computing a maximum cardinality matching. Given G and a maximum weight matching of G, we can further compute the weight of a maximum weight matching of G-{u} for all nodes u in O(W) time.Comment: The journal version will appear in SIAM Journal on Computing. The conference version appeared in ESA 199

An Even Faster and More Unifying Algorithm for Comparing Trees via Unbalanced Bipartite Matchings

A widely used method for determining the similarity of two labeled trees is to compute a maximum agreement subtree of the two trees. Previous work on this similarity measure is only concerned with the comparison of labeled trees of two special kinds, namely, uniformly labeled trees (i.e., trees with all their nodes labeled by the same symbol) and evolutionary trees (i.e., leaf-labeled trees with distinct symbols for distinct leaves). This paper presents an algorithm for comparing trees that are labeled in an arbitrary manner. In addition to this generality, this algorithm is faster than the previous algorithms. Another contribution of this paper is on maximum weight bipartite matchings. We show how to speed up the best known matching algorithms when the input graphs are node-unbalanced or weight-unbalanced. Based on these enhancements, we obtain an efficient algorithm for a new matching problem called the hierarchical bipartite matching problem, which is at the core of our maximum agreement subtree algorithm.Comment: To appear in Journal of Algorithm

Continuous Monitoring of Distributed Data Streams over a Time-based Sliding Window

The past decade has witnessed many interesting algorithms for maintaining statistics over a data stream. This paper initiates a theoretical study of algorithms for monitoring distributed data streams over a time-based sliding window (which contains a variable number of items and possibly out-of-order items). The concern is how to minimize the communication between individual streams and the root, while allowing the root, at any time, to be able to report the global statistics of all streams within a given error bound. This paper presents communication-efficient algorithms for three classical statistics, namely, basic counting, frequent items and quantiles. The worst-case communication cost over a window is $O(\frac{k} {\epsilon} \log \frac{\epsilon N}{k})$ bits for basic counting and $O(\frac{k}{\epsilon} \log \frac{N}{k})$ words for the remainings, where $k$ is the number of distributed data streams, $N$ is the total number of items in the streams that arrive or expire in the window, and $\epsilon < 1$ is the desired error bound. Matching and nearly matching lower bounds are also obtained.Comment: 12 pages, to appear in the 27th International Symposium on Theoretical Aspects of Computer Science (STACS), 201

Cavity Matchings, Label Compressions, and Unrooted Evolutionary Trees

We present an algorithm for computing a maximum agreement subtree of two unrooted evolutionary trees. It takes O(n^{1.5} log n) time for trees with unbounded degrees, matching the best known time complexity for the rooted case. Our algorithm allows the input trees to be mixed trees, i.e., trees that may contain directed and undirected edges at the same time. Our algorithm adopts a recursive strategy exploiting a technique called label compression. The backbone of this technique is an algorithm that computes the maximum weight matchings over many subgraphs of a bipartite graph as fast as it takes to compute a single matching

Interaction between homophony and semantic transparency of Chinese characters on dictation across primary grades

Also available in print."A dissertation submitted in partial fulfilment of the requirements for the Bachelor of Science (Speech and Hearing Sciences), The University of Hong Kong, June 30, 2006."Thesis (B.Sc)--University of Hong Kong, 2006.published_or_final_versionSpeech and Hearing SciencesBachelorBachelor of Science in Speech and Hearing Science

Intangible project management assets as determinants of competitive advantage

San Jose University, Athabasca University, Social Sciences and Humanities Research Counci

Project management assets and their relationship with the project management capability of the firm

Athabasca University, Social Sciences and Humanities Research Counci

Short-term effects of a gain-focused reappraisal intervention for dementia caregivers: A double-blind cluster-randomized controlled trial

Objectives To examine the effects of a benefit-finding intervention, the key feature being the use of gain-focused reappraisal strategies to find positive meanings and benefits in caring for someone with dementia. Design: Cluster-randomized double-blind controlled trial. Setting: Social centers and clinics. Participants: 129 caregivers. Inclusion criteria were (a) primary caregiver aged 18+ and without cognitive impairment, (b) providing ≥14 care hours per week to a relative with mild-to-moderate Alzheimer's disease, and (c) scoring ≥3 on the Hamilton Depression Rating Scale. Exclusion criterion was care-recipient having parkinsonism or other forms of dementia. Interventions: The benefit-finding intervention was evaluated against two treatment-as-usuals, namely, simplified psychoeducation (lectures only) and standard psychoeducation. Each intervention lasted eight weeks, with a 2-hour session per week. Randomization into these conditions was based on center/clinic membership. Measurements: Primary outcome was depressive symptom. Secondary outcomes were Zarit Burden Interview, role overload, and psychological well-being. Self-efficacy beliefs and positive gains were treated as mediators. Measures were collected at baseline and posttreatment. Results: Regression analyses showed BF treatment effects on all outcomes when compared with SIM-PE, and effects on depressive symptoms and Zarit burden when compared with STD-PE. Effect sizes were medium-to-large for depressive symptoms (d=-0.77– -0.96), and medium for the secondary outcomes (d=|0.42–0.65|). Furthermore, using the bootstrapping method, we found significant mediating effects by self-efficacy in controlling upsetting thoughts and positive gains, with the former being the primary mediator. Conclusions: Finding positive gains reduces depressive symptoms and burden and promotes psychological well-being primarily through enhancing self-efficacy in controlling upsetting thoughts