Optimization inWeb Caching: Cache Management, Capacity Planning, and Content Naming

Caching is fundamental to performance in distributed information retrieval systems such as the World Wide Web. This thesis introduces novel techniques for optimizing performance and cost-effectiveness in Web cache hierarchies. When requests are served by nearby caches rather than distant servers, server loads and network traffic decrease and transactions are faster. Cache system design and management, however, face extraordinary challenges in loosely-organized environments like the Web, where the many components involved in content creation, transport, and consumption are owned and administered by different entities. Such environments call for decentralized algorithms in which stakeholders act on local information and private preferences. In this thesis I consider problems of optimally designing new Web cache hierarchies and optimizing existing ones. The methods I introduce span the Web from point of content creation to point of consumption: I quantify the impact of content-naming practices on cache performance; present techniques for variable-quality-of-service cache management; describe how a decentralized algorithm can compute economically-optimal cache sizes in a branching two-level cache hierarchy; and introduce a new protocol extension that eliminates redundant data transfers and allows “dynamic” content to be cached consistently. To evaluate several of my new methods, I conducted trace-driven simulations on an unprecedented scale. This in turn required novel workload measurement methods and efficient new characterization and simulation techniques. The performance benefits of my proposed protocol extension are evaluated using two extraordinarily large and detailed workload traces collected in a traditional corporate network environment and an unconventional thin-client system. My empirical research follows a simple but powerful paradigm: measure on a large scale an important production environment’s exogenous workload; identify performance bounds inherent in the workload, independent of the system currently serving it; identify gaps between actual and potential performance in the environment under study; and finally devise ways to close these gaps through component modifications or through improved inter-component integration. This approach may be applicable to a wide range of Web services as they mature.Ph.D.Computer Science and EngineeringUniversity of Michiganhttp://deepblue.lib.umich.edu/bitstream/2027.42/90029/1/kelly-optimization_web_caching.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/90029/2/kelly-optimization_web_caching.ps.bz

Variable QoS from Shared Web Caches: User-Centered Design and Value-Sensitive Replacement

Due to differences in server capacity, external bandwidth and client demand, some Web servers value cache hits more than others. Assuming that a shared cache knows the extent to which different servers value hits, it may employ a value-sensitive replacement policy in order to generate maximum aggregate value for servers. we consider both the prediction and value aspects of this problem and introduce a novel value-sensitive LFU/LRU hybrid which biases the allocation of cache space toward documents whose origin servers value caching most highly. We compare our algorithm with others from the Web caching literature and discuss from an economic standpoint the problems associated with obtaining servers' private valuation information.http://deepblue.lib.umich.edu/bitstream/2027.42/50430/1/varp.pd

Biased Replacement Policies for Web Caches: Differential Quality-of-Service and Aggregate User Value

Disk space in shared Web caches can be diverted to serve some system users at the expense of others. Cache hits reduce server loads, and if servers desire load reduction to different degrees, a replacement policy which prioritizes cache space across servers can provide differential quality-of-service (QoS). We present a simple generalization of least-frequently-used (LFU) replacement that is sensitive to varying levels of server valuation for cache hits. Through trace-driven simulation we show that under a particular assumption about server valuations our algorithm delivers a reasonable QoS relationship: higher byte hit rates for servers that value hits more. We furthermore adopt the economic perspective that value received by system users is a more appropriate performance metric than hit rate or byte hit rate, and demonstrate that our algorithm delivers higher "social welfare" (aggregate value to servers) than LRU or LFU.http://deepblue.lib.umich.edu/bitstream/2027.42/60420/1/weighted-lfu.pd

Reovirus-Induced Apoptosis in the Intestine Limits Establishment of Enteric Infection

Several viruses induce intestinal epithelial cell death during enteric infection. However, it is unclear whether proapoptotic capacity promotes or inhibits replication in this tissue. We infected mice with two reovirus strains that infect the intestine but differ in the capacity to alter immunological tolerance to new food antigen. Infection with reovirus strain T1L, which induces an inflammatory immune response to fed antigen, is prolonged in the intestine, whereas T3D-RV, which does not induce this response, is rapidly cleared from the intestine. Compared with T1L, T3D-RV infection triggered apoptosis of intestinal epithelial cells and subsequent sloughing of dead cells into the intestinal lumen. We conclude that the infection advantage of T1L derives from its capacity to subvert host restriction by epithelial cell apoptosis, providing a possible mechanism by which T1L enhances inflammatory signals during antigen feeding. Using a panel of T1L × T3D-RV reassortant viruses, we identified the viral M1 and M2 gene segments as determinants of reovirus-induced apoptosis in the intestine. Expression of the T1L M1 and M2 genes in a T3D-RV background was sufficient to limit epithelial cell apoptosis and enhance viral infection to levels displayed by T1L. These findings define additional reovirus gene segments required for enteric infection of mice and illuminate the antiviral effect of intestinal epithelial cell apoptosis in limiting enteric viral infection. Viral strain-specific differences in the capacity to infect the intestine may be useful in identifying viruses capable of ameliorating tolerance to fed antigen in autoimmune conditions like celiac disease

Effects of high-intensity interval training while using a breathing-restrictive mask compared to intermittent hypobaric hypoxia

Background: Previous studies of the Elevation Training Mask (ETM) describe comparisons between groups using the ETM and controls for effects on aerobic performance. However, comparisons have not been made to intermittent hypoxic training (IHT). Further, how the ETM impacts exercise economy is unknown. Therefore, we sought to determine the effects of training with the ETM compared to IHT on aerobic performance and cycling economy. Methods: Thirty participants were randomized into an ETM, IHT, or control group (n = 10 each). Pre- and post-testing occurred using a ramp VO2max test on a cycle ergometer allowing submaximal power output (PO) measures of economy. Economy was measured using POs of 100, 125, and 150W. High-intensity cycling interval training (HIIT) occurred 2x/week for 30 min/session for six weeks. Sessions were 20 min of HIIT (30s at 100% peak power output (PPO) of pre VO2max, 90s active recovery at 25W, 10 bouts) with a 5-minute warm-up and cool-down. Repeated measures ANOVA was used for statistical analyses. RESULTS: All participants improved VO2max, PPO, and PO at ventilatory threshold 2 pre- to post-training (p < 0.05). Interactions between groups showed that the RER for the IHT group increased at 100W and 125W, and decreased at RERmax pre- to post-training while the ETM group showed the opposite response (p < 0.05). Conclusion: The ETM and IHT groups performed similarly to the control at maximal and submaximal effort following six weeks of training. The IHT group, but not the ETM group, experienced an increased glycolytic energy shift during submaximal exercise.This project was funded by the University of the New Mexico Graduate and Professional Student Association grants

Reovirus-Induced Apoptosis in the Intestine Limits Establishment of Enteric Infection

Several viruses induce intestinal epithelial cell death during enteric infection. However, it is unclear whether proapoptotic capacity promotes or inhibits replication in this tissue. We infected mice with two reovirus strains that infect the intestine but differ in the capacity to alter immunological tolerance to new food antigen. Infection with reovirus strain T1L, which induces an inflammatory immune response to fed antigen, is prolonged in the intestine, whereas T3D-RV, which does not induce this response, is rapidly cleared from the intestine. Compared with T1L, T3D-RV infection triggered apoptosis of intestinal epithelial cells and subsequent sloughing of dead cells into the intestinal lumen. We conclude that the infection advantage of T1L derives from its capacity to subvert host restriction by epithelial cell apoptosis, providing a possible mechanism by which T1L enhances inflammatory signals during antigen feeding. Using a panel of T1L × T3D-RV reassortant viruses, we identified the viral M1 and M2 gene segments as determinants of reovirus-induced apoptosis in the intestine. Expression of the T1L M1 and M2 genes in a T3D-RV background was sufficient to limit epithelial cell apoptosis and enhance viral infection to levels displayed by T1L. These findings define additional reovirus gene segments required for enteric infection of mice and illuminate the antiviral effect of intestinal epithelial cell apoptosis in limiting enteric viral infection. Viral strain-specific differences in the capacity to infect the intestine may be useful in identifying viruses capable of ameliorating tolerance to fed antigen in autoimmune conditions like celiac disease

Skeletal muscle stem cells express anti-apoptotic ErbB receptors during activation from quiescence

To be effective for tissue repair, satellite cells (the stem cells of adult muscle) must survive the initial activation from quiescence. Using an in vitro model of satellite cell activation, we show that erbB1, erbB2 and erbB3, members of the EGF receptor tyrosine kinase family, appear on satellite cells within 6 h of activation. We show that signalling via erbB2 provides an anti-apoptotic survival mechanism for satellite cells during the first 24 h, as they progress to a proliferative state. Inhibition of erbB2 signalling with AG825 reduced satellite cell numbers, concomitant with elevated caspase-8 activation and TUNEL labelling of apoptotic satellite cells. In serum-free conditions, satellite cell apoptosis could be largely prevented by a mixture of erbB1, erbB3 and erbB4 ligand growth factors, but not by neuregulin alone (erbB3/erbB4 ligand). Furthermore, using inhibitors specific to discrete intracellular signalling pathways, we identify MEK as a pro-apoptotic mediator, and the erbB-regulated factor STAT3 as an anti-apoptotic mediator during satellite cell activation. These results implicate erbB2 signalling in the preservation of a full compliment of satellite cells as they activate in the context of a damaged muscle

Consensus coding sequence (CCDS) database: a standardized set of human and mouse protein-coding regions supported by expert curation.

The Consensus Coding Sequence (CCDS) project provides a dataset of protein-coding regions that are identically annotated on the human and mouse reference genome assembly in genome annotations produced independently by NCBI and the Ensembl group at EMBL-EBI. This dataset is the product of an international collaboration that includes NCBI, Ensembl, HUGO Gene Nomenclature Committee, Mouse Genome Informatics and University of California, Santa Cruz. Identically annotated coding regions, which are generated using an automated pipeline and pass multiple quality assurance checks, are assigned a stable and tracked identifier (CCDS ID). Additionally, coordinated manual review by expert curators from the CCDS collaboration helps in maintaining the integrity and high quality of the dataset. The CCDS data are available through an interactive web page (https://www.ncbi.nlm.nih.gov/CCDS/CcdsBrowse.cgi) and an FTP site (ftp://ftp.ncbi.nlm.nih.gov/pub/CCDS/). In this paper, we outline the ongoing work, growth and stability of the CCDS dataset and provide updates on new collaboration members and new features added to the CCDS user interface. We also present expert curation scenarios, with specific examples highlighting the importance of an accurate reference genome assembly and the crucial role played by input from the research community. Nucleic Acids Res 2018 Jan 4; 46(D1):D221-D228

Thyroid Hormone Therapy for Older Adults with Subclinical Hypothyroidism.

BACKGROUND: The use of levothyroxine to treat subclinical hypothyroidism is controversial. We aimed to determine whether levothyroxine provided clinical benefits in older persons with this condition. METHODS: We conducted a double-blind, randomized, placebo-controlled, parallel-group trial involving 737 adults who were at least 65 years of age and who had persisting subclinical hypothyroidism (thyrotropin level, 4.60 to 19.99 mIU per liter; free thyroxine level within the reference range). A total of 368 patients were assigned to receive levothyroxine (at a starting dose of 50 μg daily, or 25 μg if the body weight was <50 kg or the patient had coronary heart disease), with dose adjustment according to the thyrotropin level; 369 patients were assigned to receive placebo with mock dose adjustment. The two primary outcomes were the change in the Hypothyroid Symptoms score and Tiredness score on a thyroid-related quality-of-life questionnaire at 1 year (range of each scale is 0 to 100, with higher scores indicating more symptoms or tiredness, respectively; minimum clinically important difference, 9 points). RESULTS: The mean age of the patients was 74.4 years, and 396 patients (53.7%) were women. The mean (±SD) thyrotropin level was 6.40±2.01 mIU per liter at baseline; at 1 year, this level had decreased to 5.48 mIU per liter in the placebo group, as compared with 3.63 mIU per liter in the levothyroxine group (P<0.001), at a median dose of 50 μg. We found no differences in the mean change at 1 year in the Hypothyroid Symptoms score (0.2±15.3 in the placebo group and 0.2±14.4 in the levothyroxine group; between-group difference, 0.0; 95% confidence interval [CI], -2.0 to 2.1) or the Tiredness score (3.2±17.7 and 3.8±18.4, respectively; between-group difference, 0.4; 95% CI, -2.1 to 2.9). No beneficial effects of levothyroxine were seen on secondary-outcome measures. There was no significant excess of serious adverse events prespecified as being of special interest. CONCLUSIONS: Levothyroxine provided no apparent benefits in older persons with subclinical hypothyroidism. (Funded by European Union FP7 and others; TRUST ClinicalTrials.gov number, NCT01660126 .)