Position effect on secretion efficiency v1

A proposed method to evaluate secretion efficiency dependency on relative position inside the expression vector.

Heterogeneity and genomic loci of ubiquitous Cre reporter transgenes in zebrafish

The most-common strategy for zebrafish Cre/lox-mediated lineage labeling experiments combines ubiquitously expressed, lox-based Switch reporter transgenes with tissue-specific Cre or 4-OH-Tamoxifen-inducible CreERT2 driver lines. Although numerous Cre driver lines have been produced, only a few broadly expressed Switch reporters exist in zebrafish and their generation by random transgene integration has been challenging due to position-effect sensitivity of the lox-flanked recombination cassettes. Here, we compare commonly used Switch reporter lines for their recombination efficiency and reporter expression pattern during zebrafish development. Using different experimental setups, we show that ubi:Switch and hsp70l:Switch outperform current generations of two additional Switch reporters due to favorable transgene integration sites. Our comparisons also document preferential Cre-dependent recombination of ubi:Switch and hsp70l:Switch in distinct zebrafish tissues at early developmental stages. To investigate what genomic features may influence Cre accessibility and lox recombination efficiency in highly functional Switch lines, we mapped these transgenes and charted chromatin dynamics at their integration sites. Our data documents the heterogeneity among lox-based Switch transgenes towards informing suitable transgene selection for lineage labeling experiments. Our work further proposes that ubi:Switch and hsp70l:Switch define genomic integration sites suitable for universal transgene or switch reporter knock-in in zebrafish.

Exact breakpoints of In(1)wm4 rearrangement

In(1)wm4 was known for decades as a classic example of position effect variegation-causing rearrangement and was mentioned in hundreds of publications. Nevertheless, the euchromatin breakpoint position of the rearrangement was not precisely localized. We performed nanopore sequencing of DNA from In(1)wm4 homozygous flies and determined the exact position of euchromatic (chrX:2767875) and heterochromatic breakpoints of the rearrangement.

SVInterpreter: A Comprehensive Topologically Associated Domain-Based Clinical Outcome Prediction Tool for Balanced and Unbalanced Structural Variants

With the advent of genomic sequencing, a number of balanced and unbalanced structural variants (SVs) can be detected per individual. Mainly due to incompleteness and the scattered nature of the available annotation data of the human genome, manual interpretation of the SV’s clinical significance is laborious and cumbersome. Since bioinformatic tools developed for this task are limited, a comprehensive tool to assist clinical outcome prediction of SVs is warranted. Herein, we present SVInterpreter, a free Web application, which analyzes both balanced and unbalanced SVs using topologically associated domains (TADs) as genome units. Among others, gene-associated data (as function and dosage sensitivity), phenotype similarity scores, and copy number variants (CNVs) scoring metrics are retrieved for an informed SV interpretation. For evaluation, we retrospectively applied SVInterpreter to 97 balanced (translocations and inversions) and 125 unbalanced (deletions, duplications, and insertions) previously published SVs, and 145 SVs identified from 20 clinical samples. Our results showed the ability of SVInterpreter to support the evaluation of SVs by (1) confirming more than half of the predictions of the original studies, (2) decreasing 40% of the variants of uncertain significance, and (3) indicating several potential position effect events. To our knowledge, SVInterpreter is the most comprehensive TAD-based tool to identify the possible disease-causing candidate genes and to assist prediction of the clinical outcome of SVs. SVInterpreter is available at http://dgrctools-insa.min-saude.pt/cgi-bin/SVInterpreter.py.

Regulation of Gene Expression by Telomere Position Effect

Many diseases that involve malignant tumors in the elderly affect the quality of human life; therefore, the relationship between aging and pathogenesis in geriatric diseases must be under-stood to develop appropriate treatments for these diseases. Recent reports have shown that epigenetic regulation caused by changes in the local chromatin structure plays an essential role in aging. This review provides an overview of the roles of telomere shortening on genomic structural changes during an age-dependent shift in gene expression. Telomere shortening is one of the most prominent events that is involved in cellular aging and it affects global gene expression through genome rearrangement. This review provides novel insights into the roles of telomere shortening in disease-affected cells during pathogenesis and suggests novel therapeutic approaches.

An Adaptive Multi-Modal Control Strategy to Attenuate the Limb Position Effect in Myoelectric Pattern Recognition

Over the last few decades, pattern recognition algorithms have shown promising results in the field of upper limb prostheses myoelectric control and are now gradually being incorporated in commercial devices. A widely used approach is based on a classifier which assigns a specific input value to a selected hand motion. While this method guarantees good performance and robustness within each class, it still shows limitations in adapting to different conditions encountered in real-world applications, such as changes in limb position or external loads. This paper proposes an adaptive method based on a pattern recognition classifier that takes advantage of an augmented dataset—i.e., representing variations in limb position or external loads—to selectively adapt to underrepresented variations. The proposed method was evaluated using a series of target achievement control tests with ten able-bodied volunteers. Results indicated a higher median completion rate >3.33% for the adapted algorithm compared to a classical pattern recognition classifier used as a baseline model. Subject-specific performance showed the potential for improved control after adaptation and a ≤13% completion rate; and in many instances, the adapted points were able to provide new information within classes. These preliminary results show the potential of the proposed method and encourage further development.

Good to Go First? Position Effects in Expert Evaluation of Early-Stage Ventures

There is often considerable anxiety and conflicting advice concerning the benefits of presenting/being evaluated first. We thus investigate how expert evaluators vary in their evaluations of entrepreneurial proposals based upon the order in which they are evaluated. Our research setting is a premiere innovation fund competition in Beijing, China, where the prize money at stake is economically meaningful, and evaluators are quasi-randomly assigned to evaluate written grant proposals without the possibility of peer influence. This enables us to credibly recover a causal position effect. We also theorize and test how heterogeneity in evaluators’ prior (context-specific) judging experience moderates position effects. Overall, we find that a proposal evaluated first requires total assets in the top 10th percentile to merely equal the evaluation of a proposal in the bottom 10th percentile that is not evaluated first. Firm and evaluator fixed-effects models yield consistent findings. We consider evaluation design elements that may mollify these position effects in the discussion section. This paper was accepted by Sridhar Tayur, entrepreneurship and innovation.