Minkowski distances and standardisation for clustering and classification of high dimensional data

There are many distance-based methods for classification and clustering, and for data with a high number of dimensions and a lower number of observations, processing distances is computationally advantageous compared to the raw data matrix. Euclidean distances are used as a default for continuous multivariate data, but there are alternatives. Here the so-called Minkowski distances, $L_1$ (city block)-, $L_2$ (Euclidean)-, $L_3$-, $L_4$-, and maximum distances are combined with different schemes of standardisation of the variables before aggregating them. Boxplot transformation is proposed, a new transformation method for a single variable that standardises the majority of observations but brings outliers closer to the main bulk of the data. Distances are compared in simulations for clustering by partitioning around medoids, complete and average linkage, and classification by nearest neighbours, of data with a low number of observations but high dimensionality. The $L_1$-distance and the boxplot transformation show good results.Comment: Preliminary version; final version to be published by Springer, using Springer's svmult LATEX styl

Accurate reconstruction of insertion-deletion histories by statistical phylogenetics

The Multiple Sequence Alignment (MSA) is a computational abstraction that represents a partial summary either of indel history, or of structural similarity. Taking the former view (indel history), it is possible to use formal automata theory to generalize the phylogenetic likelihood framework for finite substitution models (Dayhoff's probability matrices and Felsenstein's pruning algorithm) to arbitrary-length sequences. In this paper, we report results of a simulation-based benchmark of several methods for reconstruction of indel history. The methods tested include a relatively new algorithm for statistical marginalization of MSAs that sums over a stochastically-sampled ensemble of the most probable evolutionary histories. For mammalian evolutionary parameters on several different trees, the single most likely history sampled by our algorithm appears less biased than histories reconstructed by other MSA methods. The algorithm can also be used for alignment-free inference, where the MSA is explicitly summed out of the analysis. As an illustration of our method, we discuss reconstruction of the evolutionary histories of human protein-coding genes.Comment: 28 pages, 15 figures. arXiv admin note: text overlap with arXiv:1103.434

Provision of antiretroviral treatment in conflict settings: the experience of Médecins Sans Frontières

ABSTRACT: INTRODUCTION: Many countries ravaged by conflict have substantial morbidity and mortality attributed to HIV/AIDS yet HIV treatment is uncommonly available. Universal access to HIV care cannot be achieved unless the needs of populations in conflict-affected areas are addressed. METHODS: From 2003 Médecins Sans Frontières introduced HIV care, including antiretroviral therapy, into 24 programmes in conflict or post-conflict settings, mainly in sub-Saharan Africa. HIV care and treatment activities were usually integrated within other medical activities. Project data collected in the Fuchia software system were analysed and outcomes compared with ART-LINC data. Programme reports and other relevant documents and interviews with local and headquarters staff were used to develop lessons learned. RESULTS: In the 22 programmes where ART was initiated, more than 10,500 people were diagnosed with HIV and received medical care, and 4555 commenced antiretroviral therapy, including 348 children. Complete data were available for adults in 20 programmes (n = 4145). At analysis, 2645 (64%) remained on ART, 422 (10%) had died, 466 (11%) lost to follow-up, 417 (10%) transferred to another programme, and 195 (5%) had an unclear outcome. Median 12-month mortality and loss to follow-up were 9% and 11% respectively, and median 6-month CD4 gain was 129 cells/mm 3.Patient outcomes on treatment were comparable to those in stable resource-limited settings, and individuals and communities obtained significant benefits from access to HIV treatment. Programme disruption through instability was uncommon with only one program experiencing interruption to services, and programs were adapted to allow for disruption and population movements. Integration of HIV activities strengthened other health activities contributing to health benefits for all victims of conflict and increasing the potential sustainability for implemented activities. CONCLUSIONS: With commitment, simplified treatment and monitoring, and adaptations for potential instability, HIV treatment can be feasibly and effectively provided in conflict or post-conflict settings

Immune sensitization of equine bronchus: glutathione, IL-1β expression and tissue responsiveness

BACKGROUND: Increasing clinical epidemiological and experimental evidence indicates that excess of production of reactive oxygen free radicals (ROS) induced by an oxidative stress is involved in the pathogenesis of a number of human airway disorders, as well as equine recurrent airway obstruction. Free-radicals modulate the activation of transcription factors, such as nuclear factor-(NF)-κB and activator protein (AP)-1, in several different cells. This activation leads to expression of many pro-inflammatory cytokines, including interleukin (IL)-1β. We have hypothesized that equine airway sensitization might induce an oxidative stress and increase the ROS production, which in turn might enhance a production of IL-1β and airway hyperresponsiveness. METHODS: We have examined the effect of passive sensitization on IL-1β mRNA expression and electrical field stimulation (EFS)-induced contraction in equine isolated bronchi, and the potential interference of reduced-glutathione (GSH), an antioxidant, with these responses. Bronchi passively sensitized with serum from animals suffering from heaves and having high total level of IgE, and control tissues, either pretreated or not with GSH (100 μM), were used to quantify IL-1β mRNA. Other tissues were used to study the effect of EFS (3–10–25 Hz). RESULTS: Mean IL-1β mRNA expression was higher in passively sensitized than in control rings. GSH significantly (p < 0.05) reduced the IL-1β mRNA expression only in passively sensitized bronchi. ELF induced a frequency-dependent contraction in both non-sensitized and passively sensitized tissues, with a significantly greater response always observed in sensitized tissues. GSH did not modify the EFS-induced contraction in non-sensitized bronchi, but significantly (p < 0.05) decreased it in passively sensitized tissues. CONCLUSION: Our data indicate that the passive sensitization of equine bronchi induces inflammation and hyperresponsiveness. These effects might be due to an oxidative stress because a pretreatment with GSH decreased the increased IL-1β mRNA expression and responsiveness to EFS of passively sensitized bronchi

Classification of HIV-1 Sequences Using Profile Hidden Markov Models

Accurate classification of HIV-1 subtypes is essential for studying the dynamic spatial distribution pattern of HIV-1 subtypes and also for developing effective methods of treatment that can be targeted to attack specific subtypes. We propose a classification method based on profile Hidden Markov Model that can accurately identify an unknown strain. We show that a standard method that relies on the construction of a positive training set only, to capture unique features associated with a particular subtype, can accurately classify sequences belonging to all subtypes except B and D. We point out the drawbacks of the standard method; namely, an arbitrary choice of threshold to distinguish between true positives and true negatives, and the inability to discriminate between closely related subtypes. We then propose an improved classification method based on construction of a positive as well as a negative training set to improve discriminating ability between closely related subtypes like B and D. Finally, we show how the improved method can be used to accurately determine the subtype composition of Common Recombinant Forms of the virus that are made up of two or more subtypes. Our method provides a simple and highly accurate alternative to other classification methods and will be useful in accurately annotating newly sequenced HIV-1 strains

Evolutionary Descent of Prion Genes from the ZIP Family of Metal Ion Transporters

In the more than twenty years since its discovery, both the phylogenetic origin and cellular function of the prion protein (PrP) have remained enigmatic. Insights into a possible function of PrP may be obtained through the characterization of its molecular neighborhood in cells. Quantitative interactome data demonstrated the spatial proximity of two metal ion transporters of the ZIP family, ZIP6 and ZIP10, to mammalian prion proteins in vivo. A subsequent bioinformatic analysis revealed the unexpected presence of a PrP-like amino acid sequence within the N-terminal, extracellular domain of a distinct sub-branch of the ZIP protein family that includes ZIP5, ZIP6 and ZIP10. Additional structural threading and orthologous sequence alignment analyses argued that the prion gene family is phylogenetically derived from a ZIP-like ancestral molecule. The level of sequence homology and the presence of prion protein genes in most chordate species place the split from the ZIP-like ancestor gene at the base of the chordate lineage. This relationship explains structural and functional features found within mammalian prion proteins as elements of an ancient involvement in the transmembrane transport of divalent cations. The phylogenetic and spatial connection to ZIP proteins is expected to open new avenues of research to elucidate the biology of the prion protein in health and disease

Multiple Measures Reveal Antiretroviral Adherence Successes and Challenges in HIV-Infected Ugandan Children

Background: Adherence to HIV antiretroviral therapy (ART) among children in developing settings is poorly understood. Methodology/Principal Findings: To understand the level, distribution, and correlates of ART adherence behavior, we prospectively determined monthly ART adherence through multiple measures and six-monthly HIV RNA levels among 121 Ugandan children aged 2–10 years for one year. Median adherence levels were 100% by three-day recall, 97.4% by 30-day visual analog scale, 97.3% by unannounced pill count/liquid formulation weights, and 96.3% by medication event monitors (MEMS). Interruptions in MEMS adherence of $\geq$48 hours were seen in 57.0% of children; 36.3% had detectable HIV RNA at one year. Only MEMS correlated significantly with HIV RNA levels (r = −0.25, p = 0.04). Multivariable regression found the following to be associated with <90% MEMS adherence: hospitalization of child (adjusted odds ratio [AOR] 3.0, 95% confidence interval [CI] 1.6–5.5; p = 0.001), liquid formulation use (AOR 1.4, 95%CI 1.0–2.0; p = 0.04), and caregiver’s alcohol use (AOR 3.1, 95%CI 1.8–5.2; p<0.0001). Child’s use of co-trimoxazole (AOR 0.5, 95%CI 0.4–0.9; p = 0.009), caregiver’s use of ART (AOR 0.6, 95%CI 0.4–0.9; p = 0.03), possible caregiver depression (AOR 0.6, 95%CI 0.4–0.8; p = 0.001), and caregiver feeling ashamed of child’s HIV status (AOR 0.5, 95%CI 0.3–0.6; p<0.0001) were protective against <90% MEMS adherence. Change in drug manufacturer (AOR 4.1, 95%CI 1.5–11.5; p = 0.009) and caregiver’s alcohol use (AOR 5.5, 95%CI 2.8–10.7; p<0.0001) were associated with $\geq$48-hour interruptions by MEMS, while second-line ART (AOR 0.3, 95%CI 0.1–0.99; p = 0.049) and increasing assets (AOR 0.7, 95%CI 0.6–0.9; p = 0.0007) were protective against these interruptions. Conclusions/Significance: Adherence success depends on a well-established medication taking routine, including caregiver support and adequate education on medication changes. Caregiver-reported depression and shame may reflect fear of poor outcomes, functioning as motivation for the child to adhere. Further research is needed to better understand and build on these key influential factors for adherence intervention development

Contextualizing legal norms: a multi-dimensional view of the 2014 legal capital reform in China

This paper intends to shed light on the contentious theme of the reception of legal transplantation in the host environment, by examining the 2014 legislative reform of legal capital in China, which at least on paper imitates the enabling settings of US Revised Model Business Corporation Act (RMBCA). The paper looks at the interconnections between national-specific contextual elements, the resultant complexities, and the spillover effects of transplanted configurations in the unique Chinese socio-cultural setting, implicating the discrepancy between the ‘law in practice’ and the borrowed words ‘on the books’, and suggesting the importance of gaining a holistic understanding of ‘law’ involving the legal traditions in both the donor country and the recipient nation

Almost a spider: a 305-million-year-old fossil arachnid and spider origins

Spiders are an important animal group, with a long history. Details of their origins remain limited, with little knowledge of their stem group, and no insights into the sequence of character acquisition during spider evolution. We describe a new fossil arachnid, Idmonarachne brasieri gen. et sp. nov. from the Late Carboniferous (Stephanian, ca 305–299 Ma) of Montceau-les-Mines, France. It is three-dimensionally preserved within a siderite concretion, allowing both laboratory- and synchrotron-based phase-contrast computed tomography reconstruction. The latter is a first for siderite-hosted fossils and has allowed us to investigate fine anatomical details. Although distinctly spider-like in habitus, this remarkable fossil lacks a key diagnostic character of Araneae: spinnerets on the underside of the opisthosoma. It also lacks a flagelliform telson found in the recently recognized, spider-related, Devonian–Permian Uraraneida. Cladistic analysis resolves our new fossil as sister group to the spiders: the spider stem-group comprises the uraraneids and I. brasieri. While we are unable to demonstrate the presence of spigots in this fossil, the recovered phylogeny suggests the earliest character to evolve on the spider stem-group is the secretion of silk. This would have been followed by the loss of a flagelliform telson, and then the ability to spin silk using spinnerets. This last innovation defines the true spiders, significantly post-dates the origins of silk, and may be a key to the group's success. The Montceau-les-Mines locality has previously yielded a mesothele spider (with spinnerets). Evidently, Late Palaeozoic spiders lived alongside Palaeozoic arachnid grades which approached the spider condition, but did not express the full suite of crown-group autapomorphies

Minkowski Distances and Standardisation for Clustering and Classification on High-Dimensional Data

There are many distance-based methods for classification and clustering, and for data with a high number of dimensions and a lower number of observations, processing distances is computationally advantageous compared to the raw data matrix. Euclidean distances are used as a default for continuous multivariate data, but there are alternatives. Here the so-called Minkowski distances, L1 (city block)-, L2 (Euclidean)-, L3 , L4 -, and maximum distances are combined with different schemes of standardisation of the variables before aggregating them. Boxplot transformation is proposed, a new transformation method for a single variable that standardises the majority of observations but brings outliers closer to the main bulk of the data. Distances are compared in simulations for clustering by partitioning around medoids, complete and average linkage, and classification by nearest neighbours, of data with a low number of observations but high dimensionality. The L 1 -distance and the boxplot transformation show good results