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Factor analysis decomposes single-cell gene expression data into a minimal set of gene programs that correspond to processes executed by cells in a sample. However, matrix factorization methods are prone to technical artifacts and poor factor interpretability. We address these concerns with Spectra, an algorithm that combines user-provided gene programs with the detection of novel programs that together best explain expression covariation. Spectra incorporates existing gene sets and cell-type labels as prior biological information, explicitly models cell type and represents input gene sets as a gene–gene knowledge graph using a penalty function to guide factorization toward the input graph. We show that Spectra outperforms existing approaches in challenging tumor immune contexts, as it finds factors that change under immune checkpoint therapy, disentangles the highly correlated features of CD8+ T cell tumor reactivity and exhaustion, finds a program that explains continuous macrophage state changes under therapy and identifies cell-type-specific immune metabolic programs. Spectra decomposes gene expression data into interpretable programs using prior knowledge. [ABSTRACT FROM AUTHOR]

Metacells are cell groupings derived from single-cell sequencing data that represent highly granular, distinct cell states. Here we present single-cell aggregation of cell states (SEACells), an algorithm for identifying metacells that overcome the sparsity of single-cell data while retaining heterogeneity obscured by traditional cell clustering. SEACells outperforms existing algorithms in identifying comprehensive, compact and well-separated metacells in both RNA and assay for transposase-accessible chromatin (ATAC) modalities across datasets with discrete cell types and continuous trajectories. We demonstrate the use of SEACells to improve gene–peak associations, compute ATAC gene scores and infer the activities of critical regulators during differentiation. Metacell-level analysis scales to large datasets and is particularly well suited for patient cohorts, where per-patient aggregation provides more robust units for data integration. We use our metacells to reveal expression dynamics and gradual reconfiguration of the chromatin landscape during hematopoietic differentiation and to uniquely identify CD4 T cell differentiation and activation states associated with disease onset and severity in a Coronavirus Disease 2019 (COVID-19) patient cohort. Single-cell aggregation with archetypes provides intermediate granularity for downstream analyses. [ABSTRACT FROM AUTHOR]

Sequencing-based approaches for the analysis of microbial communities are susceptible to contamination, which could mask biological signals or generate artifactual ones. Methods for in silico decontamination using controls are routinely used, but do not make optimal use of information shared across samples and cannot handle taxa that only partially originate in contamination or leakage of biological material into controls. Here we present Source tracking for Contamination Removal in microBiomes (SCRuB), a probabilistic in silico decontamination method that incorporates shared information across multiple samples and controls to precisely identify and remove contamination. We validate the accuracy of SCRuB in multiple data-driven simulations and experiments, including induced contamination, and demonstrate that it outperforms state-of-the-art methods by an average of 15–20 times. We showcase the robustness of SCRuB across multiple ecosystems, data types and sequencing depths. Demonstrating its applicability to microbiome research, SCRuB facilitates improved predictions of host phenotypes, most notably the prediction of treatment response in melanoma patients using decontaminated tumor microbiome data. Modeling contamination sources over multiple samples enhances the analysis of microbiome data. [ABSTRACT FROM AUTHOR]

Abstract The advent of cost‐effective genotyping and sequencing methods have recently made it possible to ask questions that address the genetic basis of phenotypic diversity and how natural variants interact with the environment. We developed Camelot (CAusal Modelling with Expression Linkage for cOmplex Traits), a statistical method that integrates genotype, gene expression and phenotype data to automatically build models that both predict complex quantitative phenotypes and identify genes that actively influence these traits. Camelot integrates genotype and gene expression data, both generated under a reference condition, to predict the response to entirely different conditions. We systematically applied our algorithm to data generated from a collection of yeast segregants, using genotype and gene expression data generated under drug‐free conditions to predict the response to 94 drugs and experimentally confirmed 14 novel gene–drug interactions. Our approach is robust, applicable to other phenotypes and species, and has potential for applications in personalized medicine, for example, in predicting how an individual will respond to a previously unseen drug.

Metastasis frequently develops from disseminated cancer cells that remain dormant after the apparently successful treatment of a primary tumour. These cells fluctuate between an immune-evasive quiescent state and a proliferative state liable to immune-mediated elimination1–6. Little is known about the clearing of reawakened metastatic cells and how this process could be therapeutically activated to eliminate residual disease in patients. Here we use models of indolent lung adenocarcinoma metastasis to identify cancer cell-intrinsic determinants of immune reactivity during exit from dormancy. Genetic screens of tumour-intrinsic immune regulators identified the stimulator of interferon genes (STING) pathway as a suppressor of metastatic outbreak. STING activity increases in metastatic progenitors that re-enter the cell cycle and is dampened by hypermethylation of the STING promoter and enhancer in breakthrough metastases or by chromatin repression in cells re-entering dormancy in response to TGFβ. STING expression in cancer cells derived from spontaneous metastases suppresses their outgrowth. Systemic treatment of mice with STING agonists eliminates dormant metastasis and prevents spontaneous outbreaks in a T cell- and natural killer cell-dependent manner—these effects require cancer cell STING function. Thus, STING provides a checkpoint against the progression of dormant metastasis and a therapeutically actionable strategy for the prevention of disease relapse.STING signalling is activated in metastatic cancer cells that exit from an immune-evasive dormant state, blocking their progression and cancer relapse. [ABSTRACT FROM AUTHOR]

Defining cellular and subcellular structures in images, referred to as cell segmentation, is an outstanding obstacle to scalable single-cell analysis of multiplex imaging data. While advances in machine learning-based segmentation have led to potentially robust solutions, such algorithms typically rely on large amounts of example annotations, known as training data. Datasets consisting of annotations which are thoroughly assessed for quality are rarely released to the public. As a result, there is a lack of widely available, annotated data suitable for benchmarking and algorithm development. To address this unmet need, we release 105,774 primarily oncological cellular annotations concentrating on tumor and immune cells using over 40 antibody markers spanning three fluorescent imaging platforms, over a dozen tissue types and across various cellular morphologies. We use readily available annotation techniques to provide a modifiable community data set with the goal of advancing cellular segmentation for the greater imaging community. [ABSTRACT FROM AUTHOR]

Dissipative solitons are fundamental wave-pulses that preserve their form in the presence of periodic loss and gain. The canonical realization of dissipative solitons is Kerr-lens mode locking in lasers, which delicately balance nonlinear and linear propagation in both time and space to generate ultrashort optical pulses. This linear-nonlinear balance dictates a unique pulse energy, which cannot be increased (say by elevated pumping), indicating that excess energy is expected to be radiated in the form of dispersive or diffractive waves. Here we show that Kerr-lens mode-locked lasers can overcome this expectation. Specifically, by breaking the spatial symmetry between the forward and backward halves of the round-trip in a linear cavity, the laser can modify the soliton in space to incorporate the excess energy. Increasing the pump power leads therefore to a different soliton solution, rather than to dispersive/diffractive loss. We predict this symmetry breaking by a complete numerical simulation of the spatio-temporal dynamics in the cavity, and confirm it experimentally in a Kerr-lens mode-locked Ti:Sapphire laser with quantitative agreement to the simulation. The simulation opens a window to directly observe the nonlinear space-time dynamics that molds the soliton pulse, and possibly to optimize it. [ABSTRACT FROM AUTHOR]

Tissue damage increases the risk of cancer through poorly understood mechanisms1. In mouse models of pancreatic cancer, pancreatitis associated with tissue injury collaborates with activating mutations in the Kras oncogene to markedly accelerate the formation of early neoplastic lesions and, ultimately, adenocarcinoma2,3. Here, by integrating genomics, single-cell chromatin assays and spatiotemporally controlled functional perturbations in autochthonous mouse models, we show that the combination of Kras mutation and tissue damage promotes a unique chromatin state in the pancreatic epithelium that distinguishes neoplastic transformation from normal regeneration and is selected for throughout malignant evolution. This cancer-associated epigenetic state emerges within 48 hours of pancreatic injury, and involves an ‘acinar-to-neoplasia’ chromatin switch that contributes to the early dysregulation of genes that define human pancreatic cancer. Among the factors that are most rapidly activated after tissue damage in the pre-malignant pancreatic epithelium is the alarmin cytokine interleukin 33, which recapitulates the effects of injury in cooperating with mutant Kras to unleash the epigenetic remodelling program of early neoplasia and neoplastic transformation. Collectively, our study demonstrates how gene–environment interactions can rapidly produce gene-regulatory programs that dictate early neoplastic commitment, and provides a molecular framework for understanding the interplay between genetic and environmental cues in the initiation of cancer.In mouse models of pancreatic cancer, a cooperative interaction between tissue damage and Kras gene mutation rapidly induces cancer-associated chromatin states in pre-malignant tissue, leading to gene dysregulation and neoplastic transformation. [ABSTRACT FROM AUTHOR]

Here we delineate the ontogeny of the mammalian endoderm by generating 112,217 single-cell transcriptomes, which represent all endoderm populations within the mouse embryo until midgestation. We use graph-based approaches to model differentiating cells, which provides a spatio-temporal characterization of developmental trajectories and defines the transcriptional architecture that accompanies the emergence of the first (primitive or extra-embryonic) endodermal population and its sister pluripotent (embryonic) epiblast lineage. We uncover a relationship between descendants of these two lineages, in which epiblast cells differentiate into endoderm at two distinct time points—before and during gastrulation. Trajectories of endoderm cells were mapped as they acquired embryonic versus extra-embryonic fates and as they spatially converged within the nascent gut endoderm, which revealed these cells to be globally similar but retain aspects of their lineage history. We observed the regionalized identity of cells along the anterior–posterior axis of the emergent gut tube, which reflects their embryonic or extra-embryonic origin, and the coordinated patterning of these cells into organ-specific territories. The developing mouse gut endoderm, mapped at single-cell resolution, reveals trajectories of cell differentiation before and during gastrulation and the emergence of regionalized cell identities along the anterior–posterior axis of the gut tube. [ABSTRACT FROM AUTHOR]

Single-cell RNA sequencing studies of differentiating systems have raised fundamental questions regarding the discrete versus continuous nature of both differentiation and cell fate. Here we present Palantir, an algorithm that models trajectories of differentiating cells by treating cell fate as a probabilistic process and leverages entropy to measure cell plasticity along the trajectory. Palantir generates a high-resolution pseudo-time ordering of cells and, for each cell state, assigns a probability of differentiating into each terminal state. We apply our algorithm to human bone marrow single-cell RNA sequencing data and detect important landmarks of hematopoietic differentiation. Palantir's resolution enables the identification of key transcription factors that drive lineage fate choice and closely track when cells lose plasticity. We show that Palantir outperforms existing algorithms in identifying cell lineages and recapitulating gene expression trends during differentiation, is generalizable to diverse tissue types, and is well-suited to resolving less-studied differentiating systems. Palantir uses single-cell RNA-seq data to generate continuous models of differentiation, infer developmental trajectories, and calculate the probabilities of cell fate choices. [ABSTRACT FROM AUTHOR]

While increasingly large reference panels for genome-wide imputation have been recently made available, the degree to which imputation accuracy can be enhanced by population-specific reference panels remains an open question. Here, we sequenced at full-depth (≥ 30×), across two platforms (Illumina X Ten and Complete Genomics, Inc.), a moderately large (n = 738) cohort of samples drawn from the Ashkenazi Jewish population. We developed a series of quality control steps to optimize sensitivity, specificity, and comprehensiveness of variant calls in the reference panel, and then tested the accuracy of imputation against target cohorts drawn from the same population. Quality control (QC) thresholds for the Illumina X Ten platform were identified that permitted highly accurate calling of single nucleotide variants across 94% of the genome. QC procedures also identified numerous regions that are poorly mapped using current reference or alternate assemblies. After stringent QC, the population-specific reference panel produced more accurate and comprehensive imputation results relative to publicly available, large cosmopolitan reference panels, especially in the range of rare variants that may be most critical to further progress in mapping of complex phenotypes. The population-specific reference panel also permitted enhanced filtering of clinically irrelevant variants from personal genomes. [ABSTRACT FROM AUTHOR]

Letter to the Editor [ABSTRACT FROM AUTHOR]

Habitat loss and fragmentation are major drivers of biodiversity loss. A key question, particularly relevant to carnivore conservation, is to which extent species are able to survive in human-modified landscapes. Currently, conservationists are concerned about the impact habitat fragmentation may have on the long-term persistence of the forest-dwelling guiña ( Leopardus guigna), given the increasingly modified landscapes in which they live. Here we evaluate the effect habitat cover, fragmentation and anthropogenic pressure have on the occupancy probability for guiñas in privately-owned forest fragments. We collected camera-trap data from 100 temperate rainforest sites in Chile and used single-season occupancy modeling to evaluate the influence of 13 parameters of landscape structure/anthropogenic pressure and four parameters of detection probability on the ocurrence of guiñas. The camera-trap survey data comprised 4168 camera-trap days and 112 independent records of guiñas. Surprisingly, fragmented (defined as having a high perimeter-to-area ratio) and moderately sized habitat patches best predicted site occupancy. Occupancy also increased where habitat patches were closer to continuous forest and nearer to buildings. Our results imply that guiñas can benefit from a high degree of edge type habitats in fragmented landscapes, capable of adapting to habitat fragmentation in the proximity to large continuous forest patches. This suggests that guiñas have a broader niche than previously believed. Additionally, the guiña is tolerant of human infrastructure. Further research is required to identify potential ecological traps, long-term source-sink dynamics, and the habitat loss/fragmentation threshold beyond which guiña populations are no longer viable. [ABSTRACT FROM AUTHOR]

An accurate dissection of sources of cell-to-cell variability is crucial for quantitative biology at the single-cell level but has been challenging for the cell cycle. We present Cycler, a robust method that constructs a continuous trajectory of cell-cycle progression from images of fixed cells. Cycler handles heterogeneous microenvironments and does not require perturbations or genetic markers, making it generally applicable to quantifying multiple sources of cell-to-cell variability in mammalian cells. [ABSTRACT FROM AUTHOR]

Retinoblastoma (Rb) is a childhood tumor (~1 in 20,000 live births) developing in the retina due to mutations in the RB1 gene. Identification of the oncogenic mutations in the RB1 gene is important for the clinical management and for genetic counseling to families with a child or a parent affected with the tumor. Here we present our experience in detecting the pathogenic mutations in blood samples, from 150 unrelated Rb patients and highlight the relevant counseling issues. Mutation screening in the RB1 gene was based on Sanger sequencing, mosaicism of recurrent CpG transition mutations was detected by allele specific PCR and multiplex ligation dependent probe amplification for detecting of large deletions/duplications. The overall detection rate of mutations in our cohort was 55 % (82/150). In the familial cases it was 100 % (17/17), in bilateral and unilateral-multifocal sporadic cases 91 % (50/55), and in the unilateral sporadic cases 19 % (15/78). Nonsense mutations and small deletions or insertions that results in transcripts with premature termination codons that are subject to nonsense mediated decay were the most frequent, detected in 50/82 (61 %) of the patients. The rest were large deletions detected in 14/82 (17 %), splice site mutations detected in 11/82 (13 %), missense mutations in four patients and mutations in the promoter sequence in three patients. Mutation mosaicism ranging from 10 to 30 % was detected by allele specific PCR in ten patients, 9 % (5/55) of patients with bilateral tumor and 33 % (5/15) of the patients with unilateral tumor. In three patients rare variants were detected as the only finding which was also detected in other healthy family members. Allele specific amplification of recurrent mutations raises in our cohort the identification rate from 82 to 91 % in the sporadic bilateral cases and from 13 to 19 % in the unilateral sporadic cases. Most mosaic cases could not be identified by Sanger sequencing and therefore screening for recurrent CpG transition mutations by allele specific amplification is of utmost importance. Molecular screening is important for the genetic counseling regarding the risk for tumor development and the relevance for prenatal diagnosis but in several families is accompanied by detecting rare variants that might be rare polymorphisms or low penetrant mutations. [ABSTRACT FROM AUTHOR]

The extent of tumor heterogeneity is an emerging theme that researchers are only beginning to understand. How genetic and epigenetic heterogeneity affects tumor evolution and clinical progression is unknown. The precise nature of the environmental factors that influence this heterogeneity is also yet to be characterized. Nature Medicine, Nature Biotechnology and the Volkswagen Foundation organized a meeting focused on identifying the obstacles that need to be overcome to advance translational research in and tumor heterogeneity. Once these key questions were established, the attendees devised potential solutions. Their ideas are presented here. [ABSTRACT FROM AUTHOR]

Emission from astronomical jets extend over the entire spectral band: from radio to the TeV γ-rays. This implies that various radiative processes are taking place in different regions along jets. Understanding the origin of the emission is crucial in understanding the physical conditions inside jets, as well as basic physical questions such as jet launching mechanism, particle acceleration and jet composition. In this chapter I discuss various radiative mechanisms, focusing on jets in active galactic nuclei (AGN) and X-ray binaries (XRB) environment. I discuss various models in use in interpreting the data, and the insights they provide. [ABSTRACT FROM AUTHOR]

p53 loss of heterozygosity (p53LOH) is frequently observed in Li-Fraumeni syndrome (LFS) patients who carry a mutant (Mut) p53 germ-line mutation. Here, we focused on elucidating the link between p53LOH and tumor development in stem cells (SCs). Although adult mesenchymal stem cells (MSCs) robustly underwent p53LOH, p53LOH in induced embryonic pluripotent stem cells (iPSCs) was significantly attenuated. Only SCs that underwent p53LOH induced malignant tumors in mice. These results may explain why LFS patients develop normally, yet acquire tumors in adulthood. Surprisingly, an analysis of single-cell sub-clones of iPSCs, MSCs and ex vivo bone marrow (BM) progenitors revealed that p53LOH is a bi-directional process, which may result in either the loss of wild-type (WT) or Mut p53 allele. Interestingly, most BM progenitors underwent Mutp53LOH. Our results suggest that the bi-directional p53LOH process may function as a cell-fate checkpoint. The loss of Mutp53 may be regarded as a DNA repair event leading to genome stability. Indeed, gene expression analysis of the p53LOH process revealed upregulation of a specific chromatin remodeler and a burst of DNA repair genes. However, in the case of loss of WTp53, cells are endowed with uncontrolled growth that promotes cancer. [ABSTRACT FROM AUTHOR]

The expansion of roads, and the subsequent changes to the surrounding landscape not only lead to landscape fragmentation but also have been shown to be a key driver of biodiversity loss and ecosystem degradation. Local declines of species abundance as well as changes in animal behaviour have drawn attention to wider ecosystem effects including altered species composition and a degradation of ecosystem functioning. However, methods for measuring and quantifying the distribution and environmental impacts of roads are not yet fully developed. We present a new technique for assessing the potential impacts of roads on biodiversity using a spatial road disturbance index (SPROADI). The index is calculated from three sub-indices: traffic intensity as a measure of traffic volume per time and space; vicinity impact, which is the assessment of edge effect of roads on adjacent habitats (the road-effect zone); and fragmentation grade, which provides an indication of the degree to which the landscape is intersected by roads. SPROADI was then tested using data from the Federal State of Brandenburg in north-eastern Germany. A sensitivity analysis was carried out on the results to assess the robustness of the index. The findings revealed expected patterns of high road disturbance in urban and peri-urban landscapes surrounding Berlin. Less obvious were the high levels of road density and impacts in forest plantations across the southern region of Brandenburg, and low levels of road disturbance in agricultural crop lands of the north-western region. Results were variable for areas under some form of protection. The only national park displayed substantially lower SPROADI values in contrast to the surrounding non-protected areas whilst other protected area categories, which were landscape conservation areas and nature parks, revealed SPROADI values that were equally high as those for non-protected areas. The results of this study demonstrate the strengths and potential applications of SPROADI as a quantitative means for identifying low-traffic areas in the context of conservation and sustainable transport planning. [ABSTRACT FROM AUTHOR]

New high-dimensional, single-cell technologies offer unprecedented resolution in the analysis of heterogeneous tissues. However, because these technologies can measure dozens of parameters simultaneously in individual cells, data interpretation can be challenging. Here we present viSNE, a tool that allows one to map high-dimensional cytometry data onto two dimensions, yet conserve the high-dimensional structure of the data. viSNE plots individual cells in a visual similar to a scatter plot, while using all pairwise distances in high dimension to determine each cell's location in the plot. We integrated mass cytometry with viSNE to map healthy and cancerous bone marrow samples. Healthy bone marrow automatically maps into a consistent shape, whereas leukemia samples map into malformed shapes that are distinct from healthy bone marrow and from each other. We also use viSNE and mass cytometry to compare leukemia diagnosis and relapse samples, and to identify a rare leukemia population reminiscent of minimal residual disease. viSNE can be applied to any multi-dimensional single-cell technology. [ABSTRACT FROM AUTHOR]

Various studies have shown that several lethal agents induce cell death via the mitochondrial 18 kDa Translocator Protein (TSPO). In this study we tested the possibility that nitric oxide (NO) is the signaling component inducing the TSPO to initiate cell death process. Cell viability assays included Trypan blue uptake, propidium iodide uptake, lactate dehydrogenase release, and DNA fragmentation. These assays showed that application of the specific TSPO ligand PK 11195 reduced these parameters for the lethal effects of the NO donor sodium nitroprusside (SNP) by 41, 27, 40, and 42 %, respectively. TSPO silencing by siRNA also reduced the measured lethal effects of SNP by 50 % for all of these four assays. With 2,3-bis[2-methoxy-4-nitro-5-sulphophenyl]-2 H-tetrazolium-5-carboxyanilide (XTT) changes in metabolic activity were detected. PK 11195 and TSPO knockdown fully prevented the reductions in XTT signal otherwise induced by SNP. Collapse of the mitochondrial membrane potential was studied with the aid of JC-1 (5,5′,6,6′-tetrachloro-1,1′,3,3′-tetraethyl-benzimidazolylcarbocyanine chloride). PK 11195 and TSPO knockdown reduced, respectively by 36 and 100 %, the incidence of collapse of the mitochondrial membrane potential otherwise induced by SNP. 10- N-Nonyl-Acridine Orange (NAO) was used to detect mitochondrial reactive oxygen species generation due to SNP. PK 11195 and TSPO knockdown reduced this effect of SNP by 65 and 100 %, respectively. SNP did not affect TSPO protein expression and binding characteristics, and also did not cause TSPO S-nitrosylation. However, β-actin and various other proteins (not further defined) were S-nitrosylated. In conclusion, TSPO is required for the lethal and metabolic effects of the NO donor SNP, but TSPO itself is not S-nitrosylated. [ABSTRACT FROM AUTHOR]

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but severe, potentially life threatening adverse drug reactions characterized by skin blistering. Previous studies have identified drug-specific and population-specific genetic risk factors with large effects. In this study, we report the first genome-wide association study (GWAS) of SJS/TEN induced by a variety of drugs. Our aim was to identify common genetic risk factors with large effects on SJS/TEN risk. We conducted a genome-wide analysis of 96 retrospective cases and 198 controls with a panel of over one million single-nucleotide polymorphisms (SNPs). We further improved power with about 4000 additional controls from publicly available datasets. No genome-wide significant associations with SNPs or copy number variants were observed, although several genomic regions were suggested that may have a role in predisposing to drug-induced SJS/TEN. Our GWAS did not find common, highly penetrant genetic risk factors responsible for SJS/TEN events in the cases selected. [ABSTRACT FROM AUTHOR]

Modern day Latin America resulted from the encounter of Europeans with the indigenous peoples of the Americas in 1492, followed by waves of migration from Europe and Africa. As a result, the genomic structure of present day Latin Americans was determined both by the genetic structure of the founding populations and the numbers of migrants from these different populations. Here, we analyzed DNA collected from two well-established communities in Colorado (33 unrelated individuals) and Ecuador (20 unrelated individuals) with a measurable prevalence of the BRCA1 c.185delAG and the GHR c.E180 mutations, respectively, using Affymetrix Genome-wide Human SNP 6.0 arrays to identify their ancestry. These mutations are thought to have been brought to these communities by Sephardic Jewish progenitors. Principal component analysis and clustering methods were employed to determine the genome-wide patterns of continental ancestry within both populations using single nucleotide polymorphisms, complemented by determination of Y-chromosomal and mitochondrial DNA haplotypes. When examining the presumed European component of these two communities, we demonstrate enrichment for Sephardic Jewish ancestry not only for these mutations, but also for other segments as well. Although comparison of both groups to a reference Hispanic/Latino population of Mexicans demonstrated proximity and similarity to other modern day communities derived from a European and Native American two-way admixture, identity-by-descent and Y-chromosome mapping demonstrated signatures of Sephardim in both communities. These findings are consistent with historical accounts of Jewish migration from the realms that comprise modern Spain and Portugal during the Age of Discovery. More importantly, they provide a rationale for the occurrence of mutations typically associated with the Jewish Diaspora in Latin American communities. [ABSTRACT FROM AUTHOR]

Ocular drug delivery has become an increasingly important field of research especially when treating posterior segment diseases of the eye, such as age-related macular degeneration, diabetic retinopathy, posterior uveitis and retinitis. These diseases are the leading causes of vision loss in developed countries which require repeated long-term administration of therapeutic agents. New drugs for the medication of the posterior ocular segment have emerged, but most drugs are delivered by repeated intravitreal injections associated with ocular complications. Advances in ocular drug delivery system research are expected to provide new tools for the treatment of the posterior segment diseases, providing improved drug penetration, prolonged action, higher efficacy, improved safety and less invasive administration, resulting in higher patient compliance. This review provides an insight into the recent progress and trends in ocular drug delivery systems for treating posterior eye segment diseases, with an emphasis on transscleral iontophoresis. [ABSTRACT FROM AUTHOR]

The architecture of natural variation present in a contemporary population is a result of multiple population genetic forces, including population bottleneck and expansion, selection, drift, and admixture. We seek to untangle the contribution of admixture to genetic diversity on the Micronesian island of Kosrae. Toward this goal, we used a complete genetic approach by combining a dense genome-wide map of 100 000 single-nucleotide polymorphisms (SNPs) with data from uniparental markers from the mitochondrial genome and the nonrecombining portion of the Y chromosome. These markers were typed in ∼3200 individuals from Kosrae, representing 80% of the adult population of the island. We developed novel software that uses SNP data to delineate ancestry for individual segments of the genome. Through this analysis, we determined that 39% of Kosraens have some European ancestry. However, the vast majority of admixed individuals (77%) have European alleles spanning less than 10% of their genomes. Data from uniparental markers show most of this admixture to be male, introduced in the late nineteenth century. Furthermore, pedigree analysis shows that the majority of European admixture on Kosrae is because of the contribution of one individual. This approach shows the benefit of combining information from autosomal and uniparental polymorphisms and provides new methodology for determining ancestry in a population. [ABSTRACT FROM AUTHOR]

Schizophrenia, a devastating psychiatric disorder, has a prevalence of 0.5–1%, with high heritability (80–85%) and complex transmission. Recent studies implicate rare, large, high-penetrance copy number variants in some cases, but the genes or biological mechanisms that underlie susceptibility are not known. Here we show that schizophrenia is significantly associated with single nucleotide polymorphisms (SNPs) in the extended major histocompatibility complex region on chromosome 6. We carried out a genome-wide association study of common SNPs in the Molecular Genetics of Schizophrenia (MGS) case-control sample, and then a meta-analysis of data from the MGS, International Schizophrenia Consortium and SGENE data sets. No MGS finding achieved genome-wide statistical significance. In the meta-analysis of European-ancestry subjects (8,008 cases, 19,077 controls), significant association with schizophrenia was observed in a region of linkage disequilibrium on chromosome 6p22.1 (P = 9.54 × 10-9). This region includes a histone gene cluster and several immunity-related genes—possibly implicating aetiological mechanisms involving chromatin modification, transcriptional regulation, autoimmunity and/or infection. These results demonstrate that common schizophrenia susceptibility alleles can be detected. The characterization of these signals will suggest important directions for research on susceptibility mechanisms. [ABSTRACT FROM AUTHOR]

Drug-induced liver injury (DILI) is an important cause of serious liver disease. The antimicrobial agent flucloxacillin is a common cause of DILI, but the genetic basis for susceptibility remains unclear. We conducted a genome-wide association (GWA) study using 866,399 markers in 51 cases of flucloxacillin DILI and 282 controls matched for sex and ancestry. The GWA showed an association peak in the major histocompatibility complex (MHC) region with the strongest association (P = 8.7 × 10−33) seen for rs2395029[G], a marker in complete linkage disequilibrium (LD) with HLA-B*5701. Further MHC genotyping, which included 64 flucloxacillin-tolerant controls, confirmed the association with HLA-B*5701 (OR = 80.6, P = 9.0 × 10−19). The association was replicated in a second cohort of 23 cases. In HLA-B*5701 carrier cases, rs10937275 in ST6GAL1 on chromosome 3 also showed genome-wide significance (OR = 4.1, P = 1.4 × 10−8). These findings provide new insights into the mechanism of flucloxacillin DILI and have the potential to substantially improve diagnosis of this serious disease. [ABSTRACT FROM AUTHOR]

Lesions of the caruncle are uncommon. On account of the histological composition of the caruncle, which includes, in addition to conjunctiva, hair follicles, sebaceous glands, sweat glands, and accessory lacrimal tissue, the caruncle may develop lesions that may be similar to those found in the skin, conjunctiva, or lacrimal gland. Clinical preoperative diagnosis is very difficult and reached only in about half of the cases. The vast majority of lesions of the caruncle are benign, mainly nevi. Reported malignant lesions are very rare but can be potentially fatal. Although malignancy is clinically overestimated, any suspected malignant lesion should be excised and examined histopathologically by an experienced pathologist. This study presents the clinical and histological data of 42 consecutive caruncular lesions processed at our laboratory and reviews previously reported cases of caruncular lesions.Eye (2009) 23, 1004–1018; doi:10.1038/eye.2008.316; published online 17 October 2008 [ABSTRACT FROM AUTHOR]

PurposeA feasibility study comparing retinal nerve fibre layer (RNFL) thickness values obtained with imaging devices against RNFL thickness measurements obtained histologically in a human eye.DesignA single patient scheduled for orbital exenteration, who still possessed a healthy functioning eye.MethodsBefore surgery, the eye was imaged using optical coherence tomography (OCT) and scanning laser polarimetry (SLP). After orbital exenteration, the globe was sectioned, and 100 equidistant RNFL thickness measurements were obtained for each of four concentric rings centred on the optic disc, with diameters of 3.0, 3.5, 4.0, and 4.5 mm.ResultsRNFL thickness was found to be inversely related to the distance from the centre of the optic disc along each radial meridian. Peripapillary RNFL thickness was found comparable for histology, OCT, and SLP. RNFL thickness measured histologically confirmed a ‘double hump’ pattern, peaking at the superior and inferior poles. Histologically derived RNFL thickness (μm), at 3.0 and 3.5 mm diameter ring ranged between 30–135 and 25–115 respectively. In comparison, the 3.0 mm diameter GDx data ranged between 25 and 100, and the 3.4 mm diameter OCT data between 40 and 175.ConclusionsImaging data appear qualitatively similar when compared to the histologically derived data. Quantitative differences may be partly due to scaling differences and histological artefacts. The histological analysis approach demonstrated in this study can potentially serve to validate imaging-derived data, as well as help improve our understanding of RNFL loss in glaucoma.Eye (2009) 23, 171–175; doi:10.1038/sj.eye.6702942; published online 24 August 2007 [ABSTRACT FROM AUTHOR]

Polar molecules have bright prospects for novel quantum gases with long-range and anisotropic interactions, and could find uses in quantum information science and in precision measurements. However, high-density clouds of ultracold polar molecules have so far not been produced. Here, we report a key step towards this goal. We start from an ultracold dense gas of loosely bound 40K87Rb Feshbach molecules with typical binding energies of a few hundred kilohertz, and coherently transfer these molecules in a single transfer step into a vibrational level of the ground-state molecular potential bound by more than 10 GHz. Starting with a single initial state prepared with Feshbach association, we achieve a transfer efficiency of 84%. Given favourable Franck–Condon factors, the presented technique can be extended to access much more deeply bound vibrational levels and those exhibiting a significant dipole moment. [ABSTRACT FROM AUTHOR]