Faculty and Staff

Linnorm is a novel normalization and transformation method for the analysis of single cell RNA sequencing (scRNA-seq) data. Linnorm is developed to remove technical noises and simultaneously preserve biological variations in scRNA-seq data, such that existing statistical methods can be improved. Using real scRNA-seq data, we compared Linnorm with existing normalization methods, including NODES, SAMstrt, SCnorm, scran, DESeq and TMM. Linnorm shows advantages in speed, technical noise removal and preservation of cell heterogeneity, which can improve existing methods in the discovery of novel subtypes, pseudo-temporal ordering of cells, clustering analysis, etc. Linnorm also performs better than existing DEG analysis methods, including BASiCS, NODES, SAMstrt, Seurat and DESeq2, in false positive rate control and accuracy.

Two distinct monocyte (Mo)/macrophage (Mp) subsets (Ly6C^low and Ly6C^hi) orchestrate cardiac recovery process following myocardial infarction (MI). Prostaglandin (PG) E₂ is involved in the Mo/Mp-mediated inflammatory response, however, the role of its receptors in Mos/Mps in cardiac healing remains to be determined. Here we show that pharmacological inhibition or gene ablation of the Ep3 receptor in mice suppresses accumulation of Ly6C^low Mos/Mps in infarcted hearts. Ep3 deletion in Mos/Mps markedly attenuates healing after MI by reducing neovascularization in peri-infarct zones. Ep3 deficiency diminishes CX3C chemokine receptor 1 (CX3CR1) expression and vascular endothelial growth factor (VEGF) secretion in Mos/Mps by suppressing TGFβ1 signaling and subsequently inhibits Ly6C^low Mos/Mps migration and angiogenesis. Targeted overexpression of Ep3 receptors in Mos/Mps improves wound healing by enhancing angiogenesis. Thus, the PGE₂/Ep3 axis promotes cardiac healing after MI by activating reparative Ly6C^low Mos/Mps, indicating that Ep3 receptor activation may be a promising therapeutic target for acute MI.

Modeling of transcriptional regulatory networks (TRNs) has been increasingly used to dissect the nature of gene regulation. Inference of regulatory relationships among transcription factors (TFs) and genes, especially among multiple TFs, is still challenging. In this study, we introduced an integrative method, LogicTRN, to decode TF–TF interactions that form TF logics in regulating target genes. By combining cis-regulatory logics and transcriptional kinetics into one single model framework, LogicTRN can naturally integrate dynamic gene expression data and TF-DNA-binding signals in order to identify the TF logics and to reconstruct the underlying TRNs. We evaluated the newly developed methodology using simulation, comparison and application studies, and the results not only show their consistence with existing knowledge, but also demonstrate its ability to accurately reconstruct TRNs in biological complex systems.

It remains challenging to predict regulatory variants in particular tissues or cell types due to highly context-specific gene regulation. By connecting large-scale epigenomic profiles to expression quantitative trait loci (eQTLs) in a wide range of human tissues/cell types, we identify critical chromatin features that predict variant regulatory potential. We present cepip, a joint likelihood framework, for estimating a variant’s regulatory probability in a context-dependent manner. Our method exhibits significant GWAS signal enrichment and is superior to existing cell type-specific methods. Furthermore, using phenotypically relevant epigenomes to weight the GWAS single-nucleotide polymorphisms, we improve the statistical power of the gene-based association test.

Oppia Quadrangle Av-10 (288–360°E, ±22°) is a junction of key geologic features that preserve a rough history of Asteroid (4) Vesta and serves as a case study of using geologic mapping to define a relative geologic timescale. Clear filter images, stereo-derived topography, slope maps, and multispectral color-ratio images from the Framing Camera on NASA’s Dawn spacecraft served as basemaps to create a geologic map and investigate the spatial and temporal relationships of the local stratigraphy. Geologic mapping reveals the oldest map unit within Av-10 is the cratered highlands terrain which possibly represents original crustal material on Vesta that was then excavated by one or more impacts to form the basin Feralia Planitia. Saturnalia Fossae and Divalia Fossae ridge and trough terrains intersect the wall of Feralia Planitia indicating that this impact basin is older than both the Veneneia and Rheasilvia impact structures, representing Pre-Veneneian crustal material. Two of the youngest geologic features in Av-10 are Lepida (∼45 km diameter) and Oppia (∼40 km diameter) impact craters that formed on the northern and southern wall of Feralia Planitia and each cross-cuts a trough terrain. The ejecta blanket of Oppia is mapped as ‘dark mantle’ material because it appears dark orange in the Framing Camera ‘Clementine-type’ color-ratio image and has a diffuse, gradational contact distributed to the south across the rim of Rheasilvia. Mapping of surface material that appears light orange in color in the Framing Camera ‘Clementine-type’ color-ratio image as ‘light mantle material’ supports previous interpretations of an impact ejecta origin. Some light mantle deposits are easily traced to nearby source craters, but other deposits may represent distal ejecta deposits (emplaced >5 crater radii away) in a microgravity environment.

We produced two 1:250,000 scale geologic maps of the adjacent quadrangles Av-6 Gegania and Av-7 Lucaria, located in the equatorial region of (4) Vesta (0–144°E, 22°S to 22°N). The mapping is based on clear and color filter images of the Framing Camera (FC) onboard the Dawn spacecraft, which has captured the entire illuminated surface of Vesta with high spatial resolution (up to ∼20 m/pixel), and on a digital terrain model derived from FC imagery. Besides the geologic mapping itself, a secondary purpose of this work is to investigate one of the most prominent morphological features on Vesta, namely the aggregation of several giant equatorial troughs termed the Divalia Fossae, most probably formed during the Rheasilvia impact near Vesta’s south pole. The up to 465 km long and 22 km wide troughs show height differences of up to 5 km between adjacent troughs and ridges. Another imprint of the Rheasilvia impact is the >350 km long and ∼250 km wide swath of ejecta crossing quadrangle Av-6 Gegania. This lobe shows a distinct appearance in FC color ratios and a high albedo in FC images, indicating a mineralogical similarity to material typically found within the Rheasilvia basin, in particular composed of diogenite-rich howardites. Almost the entire northern half of the mapping area shows the oldest surface, being dominated by upper crustal basaltic material. To the south, increasingly younger formations related to the Rheasilvia impact occur, either indicated by the troughs formed by Rheasilvia or by the Rheasilvia ejecta itself. Only medium sized impact craters with diameters less than 22 km occur within the two mapped quadrangles. Some of the craters exhibit ejecta blankets and/or distinctly dark or bright ejecta material in ejecta rays outside and exposures within the crater, and mass-wasting deposits down crater slopes, forming the youngest surfaces.

We used Dawn spacecraft data to identify and delineate geological units and landforms in the Marcia quadrangle of Vesta as a means to assess the role of the large, relatively young impact craters Marcia (∼63 km diam.) and Calpurnia (∼53 km diam.) and their surrounding ejecta field on the local geology. We also investigated a local topographic high with a dark-rayed crater named Aricia Tholus, and the impact crater Octavia that is surrounded by a distinctive diffuse mantle. Crater counts and stratigraphic relations suggest that Marcia is the youngest large crater on Vesta, in which a putative impact melt on the crater floor ranges in age between ∼40 and 60 Ma (depending upon choice of chronology system), and Marcia’s ejecta blanket ranges in age between ∼120 and 390 Ma (depending upon choice of chronology system).

We interpret the geologic units in and around Marcia crater to mark a major vestan time-stratigraphic event, and that the Marcia Formation is one of the geologically youngest formations on Vesta. Marcia crater reveals pristine bright and dark material in its walls and smooth and pitted terrains on its floor. The smooth unit we interpret as evidence of flow of impact melts and (for the pitted terrain) release of volatiles during or after the impact process. The distinctive dark ejecta surrounding craters Marcia and Calpurnia is enriched in OH- or H-bearing phases and has a variable morphology, suggestive of a complex mixture of impact ejecta and impact melts including dark materials possibly derived from carbonaceous chondrite-rich material. Aricia Tholus, which was originally interpreted as a putative vestan volcanic edifice based on lower resolution observations, appears to be a fragment of an ancient impact basin rim topped by a dark-rayed impact crater. Octavia crater has a cratering model formation age of ∼280–990 Ma based on counts of its ejecta field (depending upon choice of chronology system), and its ejecta field is the second oldest unit in this quadrangle. The relatively young craters and their related ejecta materials in this quadrangle are in stark contrast to the surrounding heavily cratered units that are related to the billion years old or older Rheasilvia and Veneneia impact basins and Vesta’s ancient crust preserved on Vestalia Terra.

The purpose of this paper is to introduce the Geologic Mapping of Vesta Special Issue/Section of Icarus, which includes several papers containing geologic maps of the surface of Vesta made to support data analysis conducted by the Dawn Science Team during the Vesta Encounter (July 2011–September 2012). In this paper we briefly discuss pre-Dawn knowledge of Vesta, provide the goals of our geologic mapping campaign, discuss the methodologies and materials used for geologic mapping, review the global geologic context of Vesta, discuss the challenges of mapping the geology of Vesta as a small airless body, and describe the content of the papers in this Special Issue/Section. We conclude with a discussion of lessons learned from our quadrangle-based mapping effort and provide recommendations for conducting mapping campaigns as part of planetary spacecraft nominal missions.

Accumulating data from genome-wide association studies (GWAS) have provided a collection of novel candidate genes associated with complex diseases, such as atherosclerosis. We identified an atherosclerosis-associated single-nucleotide polymorphism (SNP) located in the intron of the long noncoding RNA (lncRNA) LINC00305 by searching the GWAS database. Although the function of LINC00305 is unknown, we found that LINC00305 expression is enriched in atherosclerotic plaques and monocytes. Overexpression of LINC00305 promoted the expression of inflammation-associated genes in THP-1 cells and reduced the expression of contractile markers in co-cultured human aortic smooth muscle cells (HASMCs). We showed that overexpression of LINC00305 activated nuclear factor-kappa beta (NF-κB) and that inhibition of NF-κB abolished LINC00305-mediated activation of cytokine expression. Mechanistically, LINC00305 interacted with lipocalin-1 interacting membrane receptor (LIMR), enhanced the interaction of LIMR and aryl-hydrocarbon receptor repressor (AHRR), and promoted protein expression as well as nuclear localization of AHRR. Moreover, LINC00305 activated NF-κB exclusively in the presence of LIMR and AHRR. In light of these findings, we propose that LINC00305 promotes monocyte inflammation by facilitating LIMR and AHRR cooperation and the AHRR activation, which eventually activates NF-κB, thereby inducing HASMC phenotype switching.

Infection after renal transplantation remains a major cause of morbidity and death, especially infection from the extensively drug-resistant bacteria, A. baumannii. A total of fourteen A. baumannii isolates were isolated from the donors’ preserved fluid from DCD (donation after cardiac death) renal transplantation and four isolates in the recipients’ draining liquid at the Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, from March 2013 to November 2014. An outbreak of A. baumannii emerging after DCD renal transplantation was tracked to understand the transmission of the pathogen. PFGE displayed similar DNA patterns between isolates from the same hospital. Antimicrobial susceptibility tests against thirteen antimicrobial agents were determined using the K-B diffusion method and eTest. Whole-genome sequencing was applied to investigate the genetic relationship of the isolates. With the clinical data and research results, we concluded that the A. baumannii isolates 3R1 and 3R2 was probably transmitted from the donor who acquired the bacteria during his stay in the ICU, while isolate 4R1 was transmitted from 3R1 and 3R2 via medical manipulation. This study demonstrated the value of integration of clinical profiles with molecular methods in outbreak investigation and their importance in controlling infection and preventing serious complications after DCD transplantation.