Likelihood-based inference of B-cell clonal families

The human immune system depends on a highly diverse collection of antibody-making B cells. B cell receptor sequence diversity is generated by a random recombination process called "rearrangement" forming progenitor B cells, then a Darwinian process of lineage diversification and selection called "affinity maturation." The resulting receptors can be sequenced in high throughput for research and diagnostics. Such a collection of sequences contains a mixture of various lineages, each of which may be quite numerous, or may consist of only a single member. As a step to understanding the process and result of this diversification, one may wish to reconstruct lineage membership, i.e. to cluster sampled sequences according to which came from the same rearrangement events. We call this clustering problem "clonal family inference." In this paper we describe and validate a likelihood-based framework for clonal family inference based on a multi-hidden Markov Model (multi-HMM) framework for B cell receptor sequences. We describe an agglomerative algorithm to find a maximum likelihood clustering, two approximate algorithms with various trade-offs of speed versus accuracy, and a third, fast algorithm for finding specific lineages. We show that under simulation these algorithms greatly improve upon existing clonal family inference methods, and that they also give significantly different clusters than previous methods when applied to two real data sets

A Bayesian phylogenetic hidden Markov model for B cell receptor sequence analysis.

The human body generates a diverse set of high affinity antibodies, the soluble form of B cell receptors (BCRs), that bind to and neutralize invading pathogens. The natural development of BCRs must be understood in order to design vaccines for highly mutable pathogens such as influenza and HIV. BCR diversity is induced by naturally occurring combinatorial "V(D)J" rearrangement, mutation, and selection processes. Most current methods for BCR sequence analysis focus on separately modeling the above processes. Statistical phylogenetic methods are often used to model the mutational dynamics of BCR sequence data, but these techniques do not consider all the complexities associated with B cell diversification such as the V(D)J rearrangement process. In particular, standard phylogenetic approaches assume the DNA bases of the progenitor (or "naive") sequence arise independently and according to the same distribution, ignoring the complexities of V(D)J rearrangement. In this paper, we introduce a novel approach to Bayesian phylogenetic inference for BCR sequences that is based on a phylogenetic hidden Markov model (phylo-HMM). This technique not only integrates a naive rearrangement model with a phylogenetic model for BCR sequence evolution but also naturally accounts for uncertainty in all unobserved variables, including the phylogenetic tree, via posterior distribution sampling

Toward Mechanical Systems Biology in Bone

Cyclic mechanical loading is perhaps the most important physiological factor regulating bone mass and shape in a way which balances optimal strength with minimal weight. This bone adaptation process spans multiple length and time scales. Forces resulting from physiological exercise at the organ scale are sensed at the cellular scale by osteocytes, which reside inside the bone matrix. Via biochemical pathways, osteocytes orchestrate the local remodeling action of osteoblasts (bone formation) and osteoclasts (bone resorption). Together these local adaptive remodeling activities sum up to strengthen bone globally at the organ scale. To resolve the underlying mechanisms it is required to identify and quantify both cause and effect across the different scales. Progress has been made at the different scales experimentally. Computational models of bone adaptation have been developed to piece together various experimental observations at the different scales into coherent and plausible mechanisms. However additional quantitative experimental validation is still required to build upon the insights which have already been achieved. In this review we discuss emerging as well as state of the art experimental and computational techniques and how they might be used in a mechanical systems biology approach to further our understanding of the mechanisms governing load induced bone adaptation, i.e., ways are outlined in which experimental and computational approaches could be coupled, in a quantitative manner to create more reliable multiscale models of bon

Comparison of the physical acoustic channel response of a line array of thin rectangular bars to an equivalent model of thin vibrating rectangular pistons.

The resolution of an array is determined by the number and spatial distance of apertures (channels) within the array and the geometry of each aperture. The accurate design of acoustic sensing arrays relies on an a prioiri estimate of the expected far field radiation pattern of reciprocally behaved elements chosen for each aperture which is difficult to calculate under damped and loaded conditions. The estimated response of one channel of a vertical line array, when modeled as a series of rectangular vibrating pistons on a rigid baffle, is compared to the measured response of one channel of a line array comprised of a series of thin rectangular bars under load and operating off resonance. Although simple modeling can predict the 3dB main lobe width of the channel with some accuracy, loading and damping effects will alter the individual element response and hence the sensitivity of the array and side lobe magnitudes when off axis steering. This is important to note when estimating array gain and noise contributions from sidelobes under steered conditions

Communication channel analysis and real time compressed sensing for high density neural recording devices

Next generation neural recording and Brain- Machine Interface (BMI) devices call for high density or distributed systems with more than 1000 recording sites. As the recording site density grows, the device generates data on the scale of several hundred megabits per second (Mbps). Transmitting such large amounts of data induces significant power consumption and heat dissipation for the implanted electronics. Facing these constraints, efficient on-chip compression techniques become essential to the reduction of implanted systems power consumption. This paper analyzes the communication channel constraints for high density neural recording devices. This paper then quantifies the improvement on communication channel using efficient on-chip compression methods. Finally, This paper describes a Compressed Sensing (CS) based system that can reduce the data rate by > 10x times while using power on the order of a few hundred nW per recording channel

Responding to ash dieback (Hymenoscyphus fraxineus) in the UK: woodland composition and replacement tree species

Common ash (Fraxinus excelsior L.) is an important timber species that is widespread in broadleaved woodlands across Europe, where it is currently declining due to the fungal pathogen (Hymenoscyphus fraxineus (T. Kowal) Baral et al., 2014) causing ash dieback. Using the UK as our case study, we assess: (1) likely woodland composition following ash dieback and (2) choice of replacement species for production planting. The greatest impacts on woodland composition will occur where ash forms a larger proportion of the canopy. In such woodlands, larger gaps formed from the loss of ash, are likely to be filled by sycamore (Acer pseudoplatanus L.) and beech (Fagus sylvatica L.) under current climatic conditions and where there is little management intervention. Native woodland policy regarding sycamore and beech may need to be reviewed in UK-designated woodlands where these species are considered non-native. For actively managed production woodlands, 27 replacement tree species for ash are considered, some of these are non-native and present options for continuing production forestry objectives on former ash sites. An assessment of replacement species shows there is no single species that can substitute for the wide range of site conditions associated with the good growth of ash. In deciding to replace ash with another tree species, the decision on selection should be made based on particular site conditions and woodland objectives

Trouble at Work

This book is available as open access through the Bloomsbury Open Access programme and is available on www.bloomsburycollections.com. Trouble in the workplace - whether it is bullying, harassment or stress - is always in the headlines. Yet, in many discussions, the research and statistics that are cited prove unreliable. This book summarizes the largest specialist research programme on ill-treatment in the workplace so far undertaken. It provides a powerful antidote to half-truths and misinformation and offers a new way of conceptualizing trouble at work, moving the discussion away from individualized explanations - and talk of 'bullies' and 'victims' - towards the workplace characteristics that cause trouble at work. The biggest problems arise where organisations fail to create a workplace culture in which individuals really matter. Paradoxically, these are often the organizations which are well-versed in modern management practices

Low-range airspeed sensors

The work reported herein is comprised of two parts: a critical assessment of the existing low airspeed sensors for helicopters and V/STOL aircraft and the development of two-dimensional jet interaction velocity sensors. The theory of operation, system description, associated electronics, advantages and disadvantages, and the development stage of the existing sensors (pilot-static system, optical convolution velocimeter, low-range orthogonal airspeed system, omnidirectional low-range airspeed sensor, swiveling probe air data system, and the fluid velocity sensor) have been critically discussed. The need to develop a low-airspeed sensor with no moving parts and a relatively linear sensitivity through the operating range and without excessive electronic amplification of the pressure signal led to the exploration of the jet-interaction. principle. This culminated in the development of a two-dimensional sensor with extremely encouraging results. Continued design and development will be required to bring the jet-interaction sensor to the point of field tests with helicopters and V-STOL aircraft.http://archive.org/details/lowrangeairspeed00duncLieutenant, United States NavyApproved for public release; distribution is unlimited

Trouble at Work

This book is available as open access through the Bloomsbury Open Access programme and is available on www.bloomsburycollections.com. Trouble in the workplace - whether it is bullying, harassment or stress - is always in the headlines. Yet, in many discussions, the research and statistics that are cited prove unreliable. This book summarizes the largest specialist research programme on ill-treatment in the workplace so far undertaken. It provides a powerful antidote to half-truths and misinformation and offers a new way of conceptualizing trouble at work, moving the discussion away from individualized explanations - and talk of 'bullies' and 'victims' - towards the workplace characteristics that cause trouble at work. The biggest problems arise where organisations fail to create a workplace culture in which individuals really matter. Paradoxically, these are often the organizations which are well-versed in modern management practices