Reconstructing phylogenies from noisy quartets in polynomial time with a high success probability

<p>Abstract</p> <p>Background</p> <p>In recent years, quartet-based phylogeny reconstruction methods have received considerable attentions in the computational biology community. Traditionally, the accuracy of a phylogeny reconstruction method is measured by simulations on synthetic datasets with known "true" phylogenies, while little theoretical analysis has been done. In this paper, we present a new model-based approach to measuring the accuracy of a quartet-based phylogeny reconstruction method. Under this model, we propose three efficient algorithms to reconstruct the "true" phylogeny with a high success probability.</p> <p>Results</p> <p>The first algorithm can reconstruct the "true" phylogeny from the input quartet topology set without quartet errors in <it>O</it>(<it>n</it>²) time by querying at most (<it>n </it>- 4) log(<it>n </it>- 1) quartet topologies, where <it>n </it>is the number of the taxa. When the input quartet topology set contains errors, the second algorithm can reconstruct the "true" phylogeny with a probability approximately 1 - <it>p </it>in <it>O</it>(<it>n</it>⁴log <it>n</it>) time, where <it>p </it>is the probability for a quartet topology being an error. This probability is improved by the third algorithm to approximately <inline-formula><m:math name="1748-7188-3-1-i1" xmlns:m="http://www.w3.org/1998/Math/MathML"><m:semantics><m:mrow><m:mfrac><m:mn>1</m:mn><m:mrow><m:mn>1</m:mn><m:mo>+</m:mo><m:msup><m:mi>q</m:mi><m:mn>2</m:mn></m:msup><m:mo>+</m:mo><m:mfrac><m:mn>1</m:mn><m:mn>2</m:mn></m:mfrac><m:msup><m:mi>q</m:mi><m:mn>4</m:mn></m:msup><m:mo>+</m:mo><m:mfrac><m:mn>1</m:mn><m:mrow><m:mn>16</m:mn></m:mrow></m:mfrac><m:msup><m:mi>q</m:mi><m:mn>5</m:mn></m:msup></m:mrow></m:mfrac></m:mrow><m:annotation encoding="MathType-MTEF"> MathType@MTEF@5@5@+=feaagaart1ev2aaatCvAUfKttLearuWrP9MDH5MBPbIqV92AaeXatLxBI9gBaebbnrfifHhDYfgasaacPC6xNi=xH8viVGI8Gi=hEeeu0xXdbba9frFj0xb9qqpG0dXdb9aspeI8k8fiI+fsY=rqGqVepae9pg0db9vqaiVgFr0xfr=xfr=xc9adbaqaaeGacaGaaiaabeqaaeqabiWaaaGcbaqcfa4aaSaaaeaacqaIXaqmaeaacqaIXaqmcqGHRaWkcqWGXbqCdaahaaqabeaacqaIYaGmaaGaey4kaSYaaSaaaeaacqaIXaqmaeaacqaIYaGmaaGaemyCae3aaWbaaeqabaGaeGinaqdaaiabgUcaRmaalaaabaGaeGymaedabaGaeGymaeJaeGOnaydaaiabdghaXnaaCaaabeqaaiabiwda1aaaaaaaaa@3D5A@</m:annotation></m:semantics></m:math></inline-formula>, where <inline-formula><m:math name="1748-7188-3-1-i2" xmlns:m="http://www.w3.org/1998/Math/MathML"><m:semantics><m:mrow><m:mi>q</m:mi><m:mo>=</m:mo><m:mfrac><m:mi>p</m:mi><m:mrow><m:mn>1</m:mn><m:mo>−</m:mo><m:mi>p</m:mi></m:mrow></m:mfrac></m:mrow><m:annotation encoding="MathType-MTEF"> MathType@MTEF@5@5@+=feaagaart1ev2aaatCvAUfKttLearuWrP9MDH5MBPbIqV92AaeXatLxBI9gBaebbnrfifHhDYfgasaacPC6xNi=xH8viVGI8Gi=hEeeu0xXdbba9frFj0xb9qqpG0dXdb9aspeI8k8fiI+fsY=rqGqVepae9pg0db9vqaiVgFr0xfr=xfr=xc9adbaqaaeGacaGaaiaabeqaaeqabiWaaaGcbaGaemyCaeNaeyypa0tcfa4aaSaaaeaacqWGWbaCaeaacqaIXaqmcqGHsislcqWGWbaCaaaaaa@3391@</m:annotation></m:semantics></m:math></inline-formula>, with running time of <it>O</it>(<it>n</it>⁵), which is at least 0.984 when <it>p </it>< 0.05.</p> <p>Conclusion</p> <p>The three proposed algorithms are mathematically guaranteed to reconstruct the "true" phylogeny with a high success probability. The experimental results showed that the third algorithm produced phylogenies with a higher probability than its aforementioned theoretical lower bound and outperformed some existing phylogeny reconstruction methods in both speed and accuracy.</p

Short-term locomotor adaptation to a robotic ankle exoskeleton does not alter soleus Hoffmann reflex amplitude

<p>Abstract</p> <p>Background</p> <p>To improve design of robotic lower limb exoskeletons for gait rehabilitation, it is critical to identify neural mechanisms that govern locomotor adaptation to robotic assistance. Previously, we demonstrated soleus muscle recruitment decreased by ~35% when walking with a pneumatically-powered ankle exoskeleton providing plantar flexor torque under soleus proportional myoelectric control. Since a substantial portion of soleus activation during walking results from the stretch reflex, increased reflex inhibition is one potential mechanism for reducing soleus recruitment when walking with exoskeleton assistance. This is clinically relevant because many neurologically impaired populations have hyperactive stretch reflexes and training to reduce the reflexes could lead to substantial improvements in their motor ability. The purpose of this study was to quantify soleus Hoffmann (H-) reflex responses during powered versus unpowered walking.</p> <p>Methods</p> <p>We tested soleus H-reflex responses in neurologically intact subjects (n=8) that had trained walking with the soleus controlled robotic ankle exoskeleton. Soleus H-reflex was tested at the mid and late stance while subjects walked with the exoskeleton on the treadmill at 1.25 m/s, first without power (first unpowered), then with power (powered), and finally without power again (second unpowered). We also collected joint kinematics and electromyography.</p> <p>Results</p> <p>When the robotic plantar flexor torque was provided, subjects walked with lower soleus electromyographic (EMG) activation (27-48%) and had concomitant reductions in H-reflex amplitude (12-24%) compared to the first unpowered condition. The H-reflex amplitude in proportion to the background soleus EMG during powered walking was not significantly different from the two unpowered conditions.</p> <p>Conclusion</p> <p>These findings suggest that the nervous system does not inhibit the soleus H-reflex in response to short-term adaption to exoskeleton assistance. Future studies should determine if the findings also apply to long-term adaption to the exoskeleton.</p

Colorectal cancer screening, perceived discrimination, and low-income and trust in doctors: a survey of minority patients

<p>Abstract</p> <p>Background</p> <p>Completion of colorectal cancer (CRC) screening testing is lower among low-income and minority groups than the population as a whole. Given the multiple cancer screening health disparities known to exist within the U.S., this study investigated the relationship between perceived discrimination, trust in most doctors, and completion of Fecal Occult Blood Testing (FOBT) among a low-income, minority primary care population in an urban setting.</p> <p>Methods</p> <p>We recruited a convenience sample of adults over age 40 (n = 282) from a federally qualified community health center (70% African American). Participants completed a survey which included measures of trust in most doctors, perceived discrimination, demographics and report of cancer screening.</p> <p>Results</p> <p>Participants reported high levels of trust in most doctors, regardless of sex, race, education or income. High trust was associated with low perceived discrimination (p < 0.01). The trend was for older participants to express more trust (p = 0.09) and less perceived discrimination (p < 0.01). Neither trust nor discrimination was associated with race or education. Trust was higher among participants over 50 who were up-to-date on FOBT screening vs. those who were not (31 vs. 29 (median), p < 0.05 by T-test). Among those over 50, up-to-date FOBT screening was nearly associated with high trust (p < 0.06; 95% CI 0.99, 1.28) and low perceived discrimination (p < 0.01; 95% CI 0.76, 0.96). Nevertheless, in multivariate-modeling, age and income explained FOBT completion better than race, trust and discrimination.</p> <p>Conclusion</p> <p>Perceived discrimination was related to income, but not race, suggesting that discrimination is not unique to minorities, but common to those in poverty. Since trust in most doctors trended toward being related to age, FOBT screening could be negatively influenced by low trust and perceived discrimination in health care settings. A failure to address these issues in middle-aged, low income individuals could exacerbate future disparities in CRC screening.</p

Lattice Boltzmann simulations of soft matter systems

This article concerns numerical simulations of the dynamics of particles immersed in a continuum solvent. As prototypical systems, we consider colloidal dispersions of spherical particles and solutions of uncharged polymers. After a brief explanation of the concept of hydrodynamic interactions, we give a general overview over the various simulation methods that have been developed to cope with the resulting computational problems. We then focus on the approach we have developed, which couples a system of particles to a lattice Boltzmann model representing the solvent degrees of freedom. The standard D3Q19 lattice Boltzmann model is derived and explained in depth, followed by a detailed discussion of complementary methods for the coupling of solvent and solute. Colloidal dispersions are best described in terms of extended particles with appropriate boundary conditions at the surfaces, while particles with internal degrees of freedom are easier to simulate as an arrangement of mass points with frictional coupling to the solvent. In both cases, particular care has been taken to simulate thermal fluctuations in a consistent way. The usefulness of this methodology is illustrated by studies from our own research, where the dynamics of colloidal and polymeric systems has been investigated in both equilibrium and nonequilibrium situations.Comment: Review article, submitted to Advances in Polymer Science. 16 figures, 76 page

53BP1 promotes non-homologous end joining of telomeres by increasing chromatin mobility

Double-strand breaks activate the ataxia telangiectasia mutated (ATM) kinase, which promotes the accumulation of DNA damage factors in the chromatin surrounding the break. The functional significance of the resulting DNA damage foci is poorly understood. Here we show that 53BP1 (also known as TRP53BP1), a component of DNA damage foci, changes the dynamic behaviour of chromatin to promote DNA repair. We used conditional deletion of the shelterin component TRF2 (also known as TERF2) from mouse cells (TRF2fl/-) to deprotect telomeres, which, like double-strand breaks, activate the ATM kinase, accumulate 53BP1 and are processed by non-homologous end joining (NHEJ). Deletion of TRF2 from 53BP1-deficient cells established that NHEJ of dysfunctional telomeres is strongly dependent on the binding of 53BP1 to damaged chromosome ends. To address the mechanism by which 53BP1 promotes NHEJ, we used time-lapse microscopy to measure telomere dynamics before and after their deprotection. Imaging showed that deprotected telomeres are more mobile and sample larger territories within the nucleus. This change in chromatin dynamics was dependent on 53BP1 and ATM but did not require a functional NHEJ pathway. We propose that the binding of 53BP1 near DNA breaks changes the dynamic behaviour of the local chromatin, thereby facilitating NHEJ repair reactions that involve distant sites, including joining of dysfunctional telomeres and AID (also known as AICDA)-induced breaks in immunoglobulin class-switch recombination

The oncolytic effect in vivo of reovirus on tumour cells that have survived reovirus cell killing in vitro

The use of oncolytic viruses has received considerable attention in recent years and many viruses have proved to be effective against a variety of cancer models and a few are currently being used in clinical trials. However, the possible emergence and outcome of virus-resistant tumour cells has not been addressed. We previously reported the effective use of reovirus against lymphoid malignancies, including the Burkitt's lymphoma cell line Raji. Here we isolated in vitro persistently infected (PI) Raji cells, and cells ‘cured' of persistent reovirus infection (‘cured' cells). Both PI and cured Raji cells resisted reovirus infection and cell killing in vitro. In vivo, the PI cells were non-tumorigenic in SCID mice, but cured cells regained the parental cells' ability to form tumours. Tumour xenografts from the cured cells, however, were highly susceptible to reovirus oncolysis in vivo. This susceptibility was due to the proteolytic environment within tumours that facilitates reovirus infection and cell killing. Our results show that persistent infection by reovirus impedes tumour development and that although PI cells cleared of reovirus are tumorigenic, they are killed upon rechallenge with reovirus. Both the PI and cured states are therefore not likely to be significant barriers to reovirus oncolytic therapy

A Spoonful of Math Helps the Medicine Go Down: An Illustration of How Healthcare can Benefit from Mathematical Modeling and Analysis

<p>Abstract</p> <p>Objectives</p> <p>A recent joint report from the Institute of Medicine and the National Academy of Engineering, highlights the benefits of--indeed, the need for--mathematical analysis of healthcare delivery. Tools for such analysis have been developed over decades by researchers in Operations Research (OR). An OR perspective typically frames a complex problem in terms of its essential mathematical structure. This article illustrates the use and value of the tools of operations research in healthcare. It reviews one OR tool, queueing theory, and provides an illustration involving a hypothetical drug treatment facility.</p> <p>Method</p> <p>Queueing Theory (QT) is the study of waiting lines. The theory is useful in that it provides solutions to problems of waiting and its relationship to key characteristics of healthcare systems. More generally, it illustrates the strengths of modeling in healthcare and service delivery.</p> <p>Queueing theory offers insights that initially may be hidden. For example, a queueing model allows one to incorporate randomness, which is inherent in the actual system, into the mathematical analysis. As a result of this randomness, these systems often perform much worse than one might have guessed based on deterministic conditions. Poor performance is reflected in longer lines, longer waits, and lower levels of server utilization.</p> <p>As an illustration, we specify a queueing model of a representative drug treatment facility. The analysis of this model provides mathematical expressions for some of the key performance measures, such as average waiting time for admission.</p> <p>Results</p> <p>We calculate average occupancy in the facility and its relationship to system characteristics. For example, when the facility has 28 beds, the average wait for admission is 4 days. We also explore the relationship between arrival rate at the facility, the capacity of the facility, and waiting times.</p> <p>Conclusions</p> <p>One key aspect of the healthcare system is its complexity, and policy makers want to design and reform the system in a way that affects competing goals. OR methodologies, particularly queueing theory, can be very useful in gaining deeper understanding of this complexity and exploring the potential effects of proposed changes on the system without making any actual changes.</p

Response to sunitinib in combination with proton beam radiation in a patient with chondrosarcoma: a case report

<p>Abstract</p> <p>Introduction</p> <p>Chondrosarcoma is well-known to be primarily resistant to conventional radiation and chemotherapy.</p> <p>Case presentation</p> <p>We present the case of a 32-year-old Caucasian man with clear cell chondrosarcoma who presented with symptomatic recurrence in his pelvis and metastases to his skull and lungs. Our patient underwent systemic therapy with sunitinib and then consolidation with proton beam radiation to his symptomatic site. He achieved complete symptomatic relief with a significantly improved performance status and had an almost complete and durable metabolic response on fluorine-18-fluorodeoxyglucose positron emission tomography.</p> <p>Conclusions</p> <p>Our findings have important clinical implications and suggest novel clinical trials for this difficult to treat disease.</p

Activation of synovial fibroblasts from patients at revision of their metal-on-metal total hip arthroplasty

BACKGROUND: The toxicity of released metallic particles generated in metal-on-metal (MoM) total hip arthroplasty (THA) using cobalt chromium (CoCr) has raised concerns regarding their safety amongst both surgeons and the public. Soft tissue changes such as pseudotumours and metallosis have been widely observed following the use of these implants, which release metallic by-products due to both wear and corrosion. Although activated fibroblasts, the dominant cell type in soft tissues, have been linked to many diseases, the role of synovial fibroblasts in the adverse reactions caused by CoCr implants remains unknown. To investigate the influence of implants manufactured from CoCr, the periprosthetic synovial tissues and synovial fibroblasts from patients with failed MoM THA, undergoing a revision operation, were analysed and compared with samples from patients undergoing a primary hip replacement, in order to elucidate histological and cellular changes. RESULTS: Periprosthetic tissue from patients with MoM implants was characterized by marked fibrotic changes, notably an increase in collagen content from less than 20% to 45-55%, an increase in α-smooth muscle actin positive cells from 4 to 9% as well as immune cells infiltration. Primary cell culture results demonstrated that MoM synovial fibroblasts have a decreased apoptosis rate from 14 to 6% compared to control synovial fibroblasts. In addition, synovial fibroblasts from MoM patients retained higher contractility and increased responsiveness to chemotaxis in matrix contraction. Their mechanical properties at a single cell level increased as observed by a 60% increase in contraction force and higher cell stiffness (3.3 kPa in MoM vs 2.18 kPa in control), as measured by traction force microscopy and atomic force microscopy. Further, fibroblasts from MoM patients promoted immune cell invasion by secreting monocyte chemoattractant protein 1 (MCP-1, CCL2) and induced monocyte differentiation, which could also be associated with excess accumulation of synovial macrophages. CONCLUSION: Synovial fibroblasts exposed in vivo to MoM THA implants that release CoCr wear debris displayed dramatic phenotypic alteration and functional changes. These findings unravelled an unexpected effect of the CoCr alloy and demonstrated an important role of synovial fibroblasts in the undesired tissue reactions caused by MoM THAs

Mortality Risk of Hypnotics: Strengths and Limits of Evidence

Sleeping pills, more formally defined as hypnotics, are sedatives used to induce and maintain sleep. In a review of publications for the past 30 years, descriptive epidemiologic studies were identified that examined the mortality risk of hypnotics and related sedative-anxiolytics. Of the 34 studies estimating risk ratios, odds ratios, or hazard ratios, excess mortality associated with hypnotics was significant (p &lt; 0.05) in 24 studies including all 14 of the largest, contrasted with no studies at all suggesting that hypnotics ever prolong life. The studies had many limitations: possibly tending to overestimate risk, such as possible confounding by indication with other risk factors; confusing hypnotics with drugs having other indications; possible genetic confounders; and too much heterogeneity of studies for meta-analyses. There were balancing limitations possibly tending towards underestimates of risk such as limited power, excessive follow-up intervals with possible follow-up mixing of participants taking hypnotics with controls, missing dosage data for most studies, and over-adjustment of confounders. Epidemiologic association in itself is not adequate proof of causality, but there is proof that hypnotics cause death in overdoses; there is thorough understanding of how hypnotics euthanize animals and execute humans; and there is proof that hypnotics cause potentially lethal morbidities such as depression, infection, poor driving, suppressed respiration, and possibly cancer. Combining these proofs with consistent evidence of association, the great weight of evidence is that hypnotics cause huge risks of decreasing a patient's duration of survival