Identification of constrained sequence elements across 239 primate genomes.

Noncoding DNA is central to our understanding of human gene regulation and complex diseases1,2, and measuring the evolutionary sequence constraint can establish the functional relevance of putative regulatory elements in the human genome3-9. Identifying the genomic elements that have become constrained specifically in primates has been hampered by the faster evolution of noncoding DNA compared to protein-coding DNA10, the relatively short timescales separating primate species11, and the previously limited availability of whole-genome sequences12. Here we construct a whole-genome alignment of 239 species, representing nearly half of all extant species in the primate order. Using this resource, we identified human regulatory elements that are under selective constraint across primates and other mammals at a 5% false discovery rate. We detected 111,318 DNase I hypersensitivity sites and 267,410 transcription factor binding sites that are constrained specifically in primates but not across other placental mammals and validate their cis-regulatory effects on gene expression. These regulatory elements are enriched for human genetic variants that affect gene expression and complex traits and diseases. Our results highlight the important role of recent evolution in regulatory sequence elements differentiating primates, including humans, from other placental mammals.

Dhaka: variational autoencoder for unmasking tumor heterogeneity from single cell genomic data.

MOTIVATION: Intra-tumor heterogeneity is one of the key confounding factors in deciphering tumor evolution. Malignant cells exhibit variations in their gene expression, copy numbers and mutation even when originating from a single progenitor cell. Single cell sequencing of tumor cells has recently emerged as a viable option for unmasking the underlying tumor heterogeneity. However, extracting features from single cell genomic data in order to infer their evolutionary trajectory remains computationally challenging due to the extremely noisy and sparse nature of the data. RESULTS: Here we describe 'Dhaka', a variational autoencoder method which transforms single cell genomic data to a reduced dimension feature space that is more efficient in differentiating between (hidden) tumor subpopulations. Our method is general and can be applied to several different types of genomic data including copy number variation from scDNA-Seq and gene expression from scRNA-Seq experiments. We tested the method on synthetic and six single cell cancer datasets where the number of cells ranges from 250 to 6000 for each sample. Analysis of the resulting feature space revealed subpopulations of cells and their marker genes. The features are also able to infer the lineage and/or differentiation trajectory between cells greatly improving upon prior methods suggested for feature extraction and dimensionality reduction of such data. AVAILABILITY AND IMPLEMENTATION: All the datasets used in the paper are publicly available and developed software package and supporting info is available on Github https://github.com/MicrosoftGenomics/Dhaka. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Adjustment in tumbling rates improves bacterial chemotaxis on obstacle-laden terrains.

The mechanisms of bacterial chemotaxis have been extensively studied for several decades, but how the physical environment influences the collective migration of bacterial cells remains less understood. Previous models of bacterial chemotaxis have suggested that the movement of migrating bacteria across obstacle-laden terrains may be slower compared with terrains without them. Here, we show experimentally that the size or density of evenly spaced obstacles do not alter the average exit rate of Escherichia coli cells from microchambers in response to external attractants, a function that is dependent on intact cell-cell communication. We also show, both by analyzing a revised theoretical model and by experimentally following single cells, that the reduced exit time in the presence of obstacles is a consequence of reduced tumbling frequency that is adjusted by the E. coli cells in response to the topology of their environment. These findings imply operational short-term memory of bacteria while moving through complex environments in response to chemotactic stimuli and motivate improved algorithms for self-autonomous robotic swarms.

TASIC: determining branching models from time series single cell data.

MOTIVATION: Single cell RNA-Seq analysis holds great promise for elucidating the networks and pathways controlling cellular differentiation and disease. However, the analysis of time series single cell RNA-Seq data raises several new computational challenges. Cells at each time point are often sampled from a mixture of cell types, each of which may be a progenitor of one, or several, specific fates making it hard to determine which cells should be used to reconstruct temporal trajectories. In addition, cells, even from the same time point, may be unsynchronized making it hard to rely on the measured time for determining these trajectories. RESULTS: We present TASIC a new method for determining temporal trajectories, branching and cell assignments in single cell time series experiments. Unlike prior approaches TASIC uses on a probabilistic graphical model to integrate expression and time information making it more robust to noise and stochastic variations. Applying TASIC to in vitro myoblast differentiation and in-vivo lung development data we show that it accurately reconstructs developmental trajectories from single cell experiments. The reconstructed models enabled us to identify key genes involved in cell fate determination and to obtain new insights about a specific type of lung cells and its role in development. AVAILABILITY AND IMPLEMENTATION: The TASIC software package is posted in the supporting website. The datasets used in the paper are publicly available. CONTACT: zivbj@cs.cmu.edu. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Applications of intraoperative angiography in head and neck reconstruction.

OBJECTIVE: Laser-assisted angiography with indocyanine green (LAIG) allows objective intraoperative evaluation of tissue vascularity. We endeavored to describe our experience with this technique in the head and neck region. METHODS: A retrospective review from February 2016 till October 2018 was conducted. We included patients who underwent head and neck procedures in which LAIG was employed. The main outcome was postoperative wound complications. We analysed the influence of LAIG results in intraoperative decision-making process. RESULTS: Nineteen patients were included, and follow-up was for at least 6 months. LAIG was employed in 11 local flaps, 9 free flaps and 6 cases of pharyngeal closure during total laryngectomies. Wound complications occurred in two cases with distal tip flap necrosis. LAIG findings resulted in changes in decision making intraoperatively in 84% of procedures, which consisted in trimming poorly perfused tissues. There were no pharyngocutaneous fistulas. CONCLUSIONS: This represents a descriptive report on the use of LAIG on diverse head and neck reconstruction cases, with important impact on the decision-making process. A low number of postoperative wound complications were observed.

A study of fetal anomalies detected by ultrasound in Bangladesh and their relative frequencies.

A total of 5,841 obstetric patients were scanned over a period of 34 months. This study was undertaken to establish the anomalies that can be detected by ultrasound and to find out their relative frequencies in Bangladesh. Of the 41 cases of congenital anomalies, seven cases were of hydrocephalus, seven were of hydronephrosis, five were of mild hydrocele (which could be just a physiological variant), five of anencephalus, five of fetal ascites, three of omphalocele, two of small biparietal diameter (BPD), two of short-limb, and one each of gastroschisis, renal cyst, hepatosplenomegaly, pleural effusion with oedema (hydrops fetalis) and bradycardia with irregular fetal heart beats. The benefits of the procedure are that in some cases like hydronephrosis, early detection can lead to early treatment to save the kidney by removing the congenital obstruction soon after birth, and in hydrocephalus and anencephalus it will help in proper management. The problem was there was a chance of higher detection of hydrocephalus and anencephalus as these were clinically suspected by the obstetrician and referred for a scan.

Separation of benign and malignant glands in prostatic adenocarcinoma.

This paper presents an analysis of the high resolution histopathology images of the prostate with a focus on the evolution of morphological gland features in prostatic adenocarcinoma. Here we propose a novel technique of labeling individual glands as malignant or benign. In the first step, the gland and nuclei objects of the images are automatically segmented. Individual gland units are segmented out by consolidating their lumina with the surrounding layers of epithelium and nuclei. The nuclei objects are segmented by using a marker controlled watershed algorithm. Two new features, Number of Nuclei Layer (N(NL)) and Ratio of Epithelial layer area to Lumen area (R(EL)) have been extracted from the segmented units. The main advantage of this approach is that it can detect individual malignant gland units, irrespective of neighboring histology and/or the spatial extent of the cancer. The proposed algorithm has been tested on 40 histopathology scenes taken from 10 high resolution whole mount images and achieved a sensitivity of 0.83 and specificity of 0.81 in a leave-75%-out cross-validation.