Characterization of the clinically approved MRI tracer resotran for magnetic particle imaging in a comparison study.

The availability of magnetic nanoparticles (MNPs) with medical approval for human intervention is fundamental to the clinical translation of magnetic particle imaging (MPI). In this work, we thoroughly evaluate and compare the magnetic properties of an magnetic resonance imaging (MRI) approved tracer to validate its performance for MPI in future human trials.We analyze whether the recently approved MRI tracer Resotran is suitable for MPI.

Solving the MPI reconstruction problem with automatically tuned regularization parameters.

In the field of medical imaging, magnetic particle imaging (MPI) poses a promising non-ionizing tomographic technique with high spatial and temporal resolution. In MPI, iterative solvers are used to reconstruct the particle distribution out of the measured voltage signal based on a system matrix. The amount of regularization needed to reconstruct an image of good quality differs from measurement to measurement, depending on the MPI system and the measurement settings.

Optimization of magnetic nanoparticles for engineering erythrocytes as theranostic agents.

The application of superparamagnetic iron oxide nanoparticles (SPIONs) in drug delivery, magnetic resonance imaging, cell tracking, and hyperthermia has been long exploited regarding their inducible magnetic properties. Nevertheless, SPIONs remain rapidly cleared from the circulation by the reticuloendothelial system (RES) or mononuclear phagocyte system, with uptake dependent on several factors such as the hydrodynamic diameter, electrical charge and surface coating. This rapid clearance of SPION-based theranostic agents from circulation is one of the main challenges hampering the medical applications that differ from RES targeting.

Extrapolation of System Matrices in Magnetic Particle Imaging.

Magnetic particle imaging exploits the non-linear magnetization of superparamagnetic iron-oxide particles to generate a tomographic image in a defined field-of-view. For reconstruction of the particle distribution, a time-consuming calibration step is required, in which system matrices get measured using a robot. To achieve artifact-free images, system matrices need to cover not only the field-of-view but also a larger area around it.

REViewer: haplotype-resolved visualization of read alignments in and around tandem repeats.

Background: Expansions of short tandem repeats are the cause of many neurogenetic disorders including familial amyotrophic lateral sclerosis, Huntington disease, and many others. Multiple methods have been recently developed that can identify repeat expansions in whole genome or exome sequencing data. Despite the widely recognized need for visual assessment of variant calls in clinical settings, current computational tools lack the ability to produce such visualizations for repeat expansions.

Particle interactions and their effect on magnetic particle spectroscopy and imaging.

Signal stability is crucial for an accurate diagnosis magnetic particle imaging (MPI). However, MPI-tracer nanoparticles frequently agglomerate during their applications leading to particle interactions altering the signal. Here, we investigate the influence of such magnetic coupling phenomena on the MPI signal.

Timing the SARS-CoV-2 index case in Hubei province.

Understanding when severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged is critical to evaluating our current approach to monitoring novel zoonotic pathogens and understanding the failure of early containment and mitigation efforts for COVID-19. We used a coalescent framework to combine retrospective molecular clock inference with forward epidemiological simulations to determine how long SARS-CoV-2 could have circulated before the time of the most recent common ancestor of all sequenced SARS-CoV-2 genomes. Our results define the period between mid-October and mid-November 2019 as the plausible interval when the first case of SARS-CoV-2 emerged in Hubei province, China.

Timing the SARS-CoV-2 Index Case in Hubei Province.

Understanding when SARS-CoV-2 emerged is critical to evaluating our current approach to monitoring novel zoonotic pathogens and understanding the failure of early containment and mitigation efforts for COVID-19. We employed a coalescent framework to combine retrospective molecular clock inference with forward epidemiological simulations to determine how long SARS-CoV-2 could have circulated prior to the time of the most recent common ancestor. Our results define the period between mid-October and mid-November 2019 as the plausible interval when the first case of SARS-CoV-2 emerged in Hubei province.

ExpansionHunter: a sequence-graph-based tool to analyze variation in short tandem repeat regions.

Summary: We describe a novel computational method for genotyping repeats using sequence graphs. This method addresses the long-standing need to accurately genotype medically important loci containing repeats adjacent to other variants or imperfect DNA repeats such as polyalanine repeats. Here we introduce a new version of our repeat genotyping software, ExpansionHunter, that uses this method to perform targeted genotyping of a broad class of such loci.

Strelka2: fast and accurate calling of germline and somatic variants.

We describe Strelka2 ( https://github.com/Illumina/strelka ), an open-source small-variant-calling method for research and clinical germline and somatic sequencing applications. Strelka2 introduces a novel mixture-model-based estimation of insertion/deletion error parameters from each sample, an efficient tiered haplotype-modeling strategy, and a normal sample contamination model to improve liquid tumor analysis.

Social and Genetic Networks of HIV-1 Transmission in New York City.

Background: Sexually transmitted infections spread across contact networks. Partner elicitation and notification are commonly used public health tools to identify, notify, and offer testing to persons linked in these contact networks. For HIV-1, a rapidly evolving pathogen with low per-contact transmission rates, viral genetic sequences are an additional source of data that can be used to infer or refine transmission networks.

A molecular transmission network of recent hepatitis C infection in people with and without HIV: Implications for targeted treatment strategies.

Combining phylogenetic and network methodologies has the potential to better inform targeted interventions to prevent and treat infectious diseases. This study reconstructed a molecular transmission network for people with recent hepatitis C virus (HCV) infection and modelled the impact of targeting directly acting antiviral (DAA) treatment for HCV in the network. Participants were selected from three Australian studies of recent HCV from 2004 to 2014.

Compartmentalized HIV rebound in the central nervous system after interruption of antiretroviral therapy.

To design effective eradication strategies, it may be necessary to target HIV reservoirs in anatomic compartments other than blood. This study examined HIV RNA rebound following interruption of antiretroviral therapy (ART) in blood and cerebrospinal fluid (CSF) to determine whether the central nervous system (CNS) might serve as an independent source of resurgent viral replication. Paired blood and CSF samples were collected longitudinally from 14 chronically HIV-infected individuals undergoing ART interruption.

Standard vaccines increase HIV-1 transcription during antiretroviral therapy.

Objectives: Curative strategies using agents to perturb the HIV reservoir have demonstrated only modest activity, whereas increases in viremia after standard vaccination have been described. We investigated whether vaccination against non-HIV pathogens can induce HIV transcription and thereby play a role in future eradication strategies.

Design: A randomized controlled trial (NCT00329251) was performed to compare the effects of clinical vaccines with placebo on HIV transcription and immune activation.

Using HIV Sequence and Epidemiologic Data to Assess the Effect of Self-referral Testing for Acute HIV Infection on Incident Diagnoses in San Diego, California.

Background: Because recently infected individuals disproportionately contribute to the spread of human immunodeficiency virus (HIV), we evaluated the impact of a primary HIV screening program (the Early Test) implemented in San Diego.

Methods: The Early Test program used combined nucleic acid and serology testing to screen for primary infection targeting local high-risk individuals. Epidemiologic, HIV sequence, and geographic data were obtained from the San Diego County Department of Public Health and the Early Test program.

Comparative Analysis of Cell-Associated HIV DNA Levels in Cerebrospinal Fluid and Peripheral Blood by Droplet Digital PCR.

Background: Measurement of HIV DNA-bearing cells in cerebrospinal fluid (CSF) is challenging because few cells are present. We present a novel application of the sensitive droplet digital (dd)PCR in this context.

Methods: We analyzed CSF cell pellets and paired peripheral blood mononuclear cells (PBMC) from 28 subjects, 19 of whom had undetectable HIV RNA (<48 copies/mL) in both compartments.

Seminal Shedding of CMV and HIV Transmission among Men Who Have Sex with Men.

As in many urban areas in the United States, the largest burden of the HIV epidemic in San Diego is borne by men who have sex with men (MSM). Using data from well-characterized HIV transmitting and non-transmitting partner pairs of MSM in San Diego, we calculated the population attributable risk (PAR) of HIV transmissions for different co-infections common among MSM in this area. We found that over a third of HIV transmissions could be potentially attributed to genital shedding of cytomegalovirus (CMV) (111 transmission events), compared to 21% potentially attributed to bacterial sexually transmitted infections (STI) (62 events) and 17% to herpes simplex virus type-2 (HSV-2) (51 events).

Gene-wide identification of episodic selection.

We present BUSTED, a new approach to identifying gene-wide evidence of episodic positive selection, where the non-synonymous substitution rate is transiently greater than the synonymous rate. BUSTED can be used either on an entire phylogeny (without requiring an a priori hypothesis regarding which branches are under positive selection) or on a pre-specified subset of foreground lineages (if a suitable a priori hypothesis is available). Selection is modeled as varying stochastically over branches and sites, and we propose a computationally inexpensive evidence metric for identifying sites subject to episodic positive selection on any foreground branches.

Less is more: an adaptive branch-site random effects model for efficient detection of episodic diversifying selection.

Over the past two decades, comparative sequence analysis using codon-substitution models has been honed into a powerful and popular approach for detecting signatures of natural selection from molecular data. A substantial body of work has focused on developing a class of "branch-site" models which permit selective pressures on sequences, quantified by the ω ratio, to vary among both codon sites and individual branches in the phylogeny. We develop and present a method in this class, adaptive branch-site random effects likelihood (aBSREL), whose key innovation is variable parametric complexity chosen with an information theoretic criterion.

Comprehensive sieve analysis of breakthrough HIV-1 sequences in the RV144 vaccine efficacy trial.

The RV144 clinical trial showed the partial efficacy of a vaccine regimen with an estimated vaccine efficacy (VE) of 31% for protecting low-risk Thai volunteers against acquisition of HIV-1. The impact of vaccine-induced immune responses can be investigated through sieve analysis of HIV-1 breakthrough infections (infected vaccine and placebo recipients). A V1/V2-targeted comparison of the genomes of HIV-1 breakthrough viruses identified two V2 amino acid sites that differed between the vaccine and placebo groups.

RELAX: detecting relaxed selection in a phylogenetic framework.

Relaxation of selective strength, manifested as a reduction in the efficiency or intensity of natural selection, can drive evolutionary innovation and presage lineage extinction or loss of function. Mechanisms through which selection can be relaxed range from the removal of an existing selective constraint to a reduction in effective population size. Standard methods for estimating the strength and extent of purifying or positive selection from molecular sequence data are not suitable for detecting relaxed selection, because they lack power and can mistake an increase in the intensity of positive selection for relaxation of both purifying and positive selection.

IDEPI: rapid prediction of HIV-1 antibody epitopes and other phenotypic features from sequence data using a flexible machine learning platform.

Since its identification in 1983, HIV-1 has been the focus of a research effort unprecedented in scope and difficulty, whose ultimate goals--a cure and a vaccine--remain elusive. One of the fundamental challenges in accomplishing these goals is the tremendous genetic variability of the virus, with some genes differing at as many as 40% of nucleotide positions among circulating strains. Because of this, the genetic bases of many viral phenotypes, most notably the susceptibility to neutralization by a particular antibody, are difficult to identify computationally.

Evolutionary origins of human herpes simplex viruses 1 and 2.

Herpesviruses have been infecting and codiverging with their vertebrate hosts for hundreds of millions of years. The primate simplex viruses exemplify this pattern of virus-host codivergence, at a minimum, as far back as the most recent common ancestor of New World monkeys, Old World monkeys, and apes. Humans are the only primate species known to be infected with two distinct herpes simplex viruses: HSV-1 and HSV-2.

On the validity of evolutionary models with site-specific parameters.

Evolutionary models that make use of site-specific parameters have recently been criticized on the grounds that parameter estimates obtained under such models can be unreliable and lack theoretical guarantees of convergence. We present a simulation study providing empirical evidence that a simple version of the models in question does exhibit sensible convergence behavior and that additional taxa, despite not being independent of each other, lead to improved parameter estimates. Although it would be desirable to have theoretical guarantees of this, we argue that such guarantees would not be sufficient to justify the use of these models in practice.