Prevalence of Donor-Specific Antibodies After Pediatric Liver Transplantation : A Meta-Analysis

Non peer reviewe

Saliva-based testing for diagnosis of SARS-CoV-2 infection : A meta-analysis

Non peer reviewe

Small But Slow World: How Network Topology and Burstiness Slow Down Spreading

Communication networks show the small-world property of short paths, but the spreading dynamics in them turns out slow. We follow the time evolution of information propagation through communication networks by using the SI model with empirical data on contact sequences. We introduce null models where the sequences are randomly shuffled in different ways, enabling us to distinguish between the contributions of different impeding effects. The slowing down of spreading is found to be caused mostly by weight-topology correlations and the bursty activity patterns of individuals

Control of VEGF-A transcriptional programs by pausing and genomic compartmentalization.

Vascular endothelial growth factor A (VEGF-A) is a master regulator of angiogenesis, vascular development and function. In this study we investigated the transcriptional regulation of VEGF-A-responsive genes in primary human aortic endothelial cells (HAECs) and human umbilical vein endothelial cells (HUVECs) using genome-wide global run-on sequencing (GRO-Seq). We demonstrate that half of VEGF-A-regulated gene promoters are characterized by a transcriptionally competent paused RNA polymerase II (Pol II). We show that transition into productive elongation is a major mechanism of gene activation of virtually all VEGF-regulated genes, whereas only ∼40% of the genes are induced at the level of initiation. In addition, we report a comprehensive chromatin interaction map generated in HUVECs using tethered conformation capture (TCC) and characterize chromatin interactions in relation to transcriptional activity. We demonstrate that sites of active transcription are more likely to engage in chromatin looping and cell type-specific transcriptional activity reflects the boundaries of chromatin interactions. Furthermore, we identify large chromatin compartments with a tendency to be coordinately transcribed upon VEGF-A stimulation. We provide evidence that these compartments are enriched for clusters of regulatory regions such as super-enhancers and for disease-associated single nucleotide polymorphisms (SNPs). Collectively, these findings provide new insights into mechanisms behind VEGF-A-regulated transcriptional programs in endothelial cells

Analysis of ORP2-knockout hepatocytes uncovers a novel function in actin cytoskeletal regulation

ORP2 is implicated in cholesterol transport, triglyceride metabolism, and adrenocortical steroid hormone production. We addressed ORP2 function in hepatocytes by generating ORP2-knockout (KO) HuH7 cells by CRISPR-Cas9 gene editing, followed by analyses of transcriptome, F-actin morphology, migration, adhesion, and proliferation. RNA sequencing of ORP2-KO cells revealed >2-fold changes in 579 mRNAs. The Ingenuity Pathway Analysis (IPA) uncovered alterations in the following functional categories: cellular movement, cell-cell signaling and interaction, cellular development, cellular function and maintenance, cellular growth and proliferation, and cell morphology. Many pathways in these categories involved actin cytoskeleton, cell migration, adhesion, or proliferation. Analysis of the ORP2 interactome uncovered 109 putative new partners. Their IPA analysis revealed Ras homolog A (RhoA) signaling as the most significant pathway. Interactions of ORP2 with SEPT9, MLC12, and ARHGAP12 were validated by independent assays. ORP2-KO resulted in abnormal F-actin morphology characterized by impaired capacity to form lamellipodia, migration defect, and impaired adhesion and proliferation. Rescue of the migration phenotype and generation of typical cell surface morphology required an intact ORP2 phosphoinositide binding site, suggesting that ORP2 function involves phosphoinositide binding and transport. The results point at a novel function of ORP2 as a lipid-sensing regulator of the actin cytoskeleton, with impacts on hepatocellular migration, adhesion, and proliferation.-Kentala, H., Koponen, A., Kivela, A. M., Andrews, R., Li, C., Zhou, Y., Olkkonen, V. M. Analysis of ORP2-knockout hepatocytes uncovers a novel function in actin cytoskeletal regulation.Peer reviewe

Multiscale Analysis of Spreading in a Large Communication Network

In temporal networks, both the topology of the underlying network and the timings of interaction events can be crucial in determining how some dynamic process mediated by the network unfolds. We have explored the limiting case of the speed of spreading in the SI model, set up such that an event between an infectious and susceptible individual always transmits the infection. The speed of this process sets an upper bound for the speed of any dynamic process that is mediated through the interaction events of the network. With the help of temporal networks derived from large scale time-stamped data on mobile phone calls, we extend earlier results that point out the slowing-down effects of burstiness and temporal inhomogeneities. In such networks, links are not permanently active, but dynamic processes are mediated by recurrent events taking place on the links at specific points in time. We perform a multi-scale analysis and pinpoint the importance of the timings of event sequences on individual links, their correlations with neighboring sequences, and the temporal pathways taken by the network-scale spreading process. This is achieved by studying empirically and analytically different characteristic relay times of links, relevant to the respective scales, and a set of temporal reference models that allow for removing selected time-domain correlations one by one

Metastatic uveal melanoma managed with best supportive care

Non peer reviewe

From Relational Data to Graphs: Inferring Significant Links using Generalized Hypergeometric Ensembles

The inference of network topologies from relational data is an important problem in data analysis. Exemplary applications include the reconstruction of social ties from data on human interactions, the inference of gene co-expression networks from DNA microarray data, or the learning of semantic relationships based on co-occurrences of words in documents. Solving these problems requires techniques to infer significant links in noisy relational data. In this short paper, we propose a new statistical modeling framework to address this challenge. It builds on generalized hypergeometric ensembles, a class of generative stochastic models that give rise to analytically tractable probability spaces of directed, multi-edge graphs. We show how this framework can be used to assess the significance of links in noisy relational data. We illustrate our method in two data sets capturing spatio-temporal proximity relations between actors in a social system. The results show that our analytical framework provides a new approach to infer significant links from relational data, with interesting perspectives for the mining of data on social systems.Comment: 10 pages, 8 figures, accepted at SocInfo201

Metastatic uveal melanoma : The final frontier

Publisher Copyright: © 2022Treatment of primary intraocular uveal melanoma has developed considerably, its driver genes are largely unraveled, and the ways to assess its risk for metastases are very precise, being based on an international staging system and genetic data. Unfortunately, the risk of distant metastases, which emerge in approximately one half of all patients, is unaltered. Metastases are the leading single cause of death after uveal melanoma is diagnosed, yet no consensus exists regarding surveillance, staging, and treatment of disseminated disease, and survival has not improved until recently. The final frontier in conquering uveal melanoma lies in solving these issues to cure metastatic disease. Most studies on metastatic uveal melanoma are small, uncontrolled, retrospective, and do not report staging. Meta-analyses confirm a median overall survival of 10–13 months, and a cure rate that approaches nil, although survival exceeding 5 years is possible, estimated 2% either with first-line treatment or with best supportive care. Hepatic ultrasonography and magnetic resonance imaging as surveillance methods have a sensitivity of 95–100% and 83–100%, respectively, to detect metastases without radiation hazard according to prevailing evidence, but computed tomography is necessary for staging. No blood-based tests additional to liver function tests are generally accepted. Three validated staging systems predict, each in defined situations, overall survival after metastasis. Their essential components include measures of tumor burden, liver function, and performance status or metastasis free interval. Age and gender may additionally influence survival. Exceptional mutational events in metastases may make them susceptible to checkpoint inhibitors. In a large meta-analysis, surgical treatment was associated with 6 months longer median overall survival as compared to conventional chemotherapy and, recently, tebentafusp as first-line treatment at the first interim analysis of a randomized phase III trial likewise provided a 6 months longer median overall survival compared to investigator's choice, mostly pembrolizumab; these treatments currently apply to selected patients. Promoting dormancy of micrometastases, harmonizing surveillance protocols, promoting staging, identifying predictive factors, initiating controlled clinical trials, and standardizing reporting will be critical steppingstones in reaching the final frontier of curing metastatic uveal melanoma.Peer reviewe