Automated data integration for developmental biological research

In an era exploding with genome-scale data, a major challenge for developmental biologists is how to extract significant clues from these publicly available data to benefit our studies of individual genes, and how to use them to improve our understanding of development at a systems level. Several studies have successfully demonstrated new approaches to classic developmental questions by computationally integrating various genome-wide data sets. Such computational approaches have shown great potential for facilitating research: instead of testing 20,000 genes, researchers might test 200 to the same effect. We discuss the nature and state of this art as it applies to developmental research

Intervention to Extrasynaptic Gabaa Receptors for Symptom Relief in Mouse Models of Rett Syndrome

Rett Syndrome (RTT) is a neurodevelopmental disorder affecting 1 out of 10,000 females worldwide. Mutations of the X-linked MECP2 gene encoding methyl CpG binding protein 2 (MeCP2) accounts for \u3e90% of RTT cases. People with RTT and mice with Mecp2 disruption show autonomic dysfunction, especially life-threatening breathing disorders, which involves defects in brainstem neurons for breathing controls, including neurons in the locus coeruleus (LC). Accumulating evidence obtained from Mecp2−/Y mice suggests that imbalanced excitation/inhibition or the impaired synaptic communications in central neurons plays a major role. LC neurons in Mecp2−/Ymice are hyperexcited, attributable to the deficiency in GABA synaptic inhibition. Several previous studies indicate that augmenting synaptic GABA receptors (GABARs) leads to a relief of RTT-like symptoms in mice. The extrasynaptic GABARs located outside synaptic cleft, which have the capability to produce sustained inhibition, and may be a potential therapeutic target for the rebalance of excitation/inhibition in RTT. In contrast to the rich information of the synaptic GABARs in RTT research, however, whether Mecp2 gene disruption affects the extrasynaptic GABARs remains unclear. In this study, we show evidence that the extrasynaptic GABAR mediated tonic inhibition of LC neurons was enhanced in Mecp2−/Ymice, which seems attributable to the augmented δ subunit expression. Low-dose THIP exposure, an agonist specific to δ subunit containing extrasynaptic GABARs, extended the lifespan, alleviated breathing abnormalities, enhanced motor function, and improved social behaviors of Mecp2−/Ymice. Such beneficial effects were associated with stabilization of brainstem neuronal hyperexcitability, including neurons in the LC and the mesencephalic trigeminal V nucleus (Me5), and improvement of norepinephrine (NE) biosynthesis. Such phenomena were found in symptomatic Mecp2+/− (sMecp2+/−) female mice model as well, in which the THIP exposure alleviated the hyperexcitability of both LC and Me5 neurons to a similar level as their counterparts in Mecp2−/Y mice, and improved breathing function. In identified LC neurons of sMecp2+/− mice, the hyperexcitability appeared to be determined by both MeCP2 expression and their environmental cues. In conclusion, intervention to extrasynaptic GABAAR by chronic treatment with THIP might be a therapeutic approach to RTT-like symptoms in both Mecp2−/Y and Mecp2+/− mice models and perhaps in people with RTT as well

Genome-Wide Prediction of C. elegans Genetic Interactions

To obtain a global view of functional interactions among genes in a metazoan genome, we computationally integrated interactome data, gene expression data, phenotype data, and functional annotation data from three model organisms—Saccharomyces cerevisiae, Caenorhabditis elegans, and Drosophila melanogaster—and predicted genome-wide genetic interactions in C. elegans. The resulting genetic interaction network (consisting of 18,183 interactions) provides a framework for system-level understanding of gene functions. We experimentally tested the predicted interactions for two human disease-related genes and identified 14 new modifiers

The Differentiation Balance of Bone Marrow Mesenchymal Stem Cells Is Crucial to Hematopoiesis.

Bone marrow mesenchymal stem cells (BMSCs), the important component and regulator of bone marrow microenvironment, give rise to hematopoietic-supporting stromal cells and form hematopoietic niches for hematopoietic stem cells (HSCs). However, how BMSC differentiation affects hematopoiesis is poorly understood. In this review, we focus on the role of BMSC differentiation in hematopoiesis. We discussed the role of BMSCs and their progeny in hematopoiesis. We also examine the mechanisms that cause differentiation bias of BMSCs in stress conditions including aging, irradiation, and chemotherapy. Moreover, the differentiation balance of BMSCs is crucial to hematopoiesis. We highlight the negative effects of differentiation bias of BMSCs on hematopoietic recovery after bone marrow transplantation. Keeping the differentiation balance of BMSCs is critical for hematopoietic recovery. This review summarises current understanding about how BMSC differentiation affects hematopoiesis and its potential application in improving hematopoietic recovery after bone marrow transplantation

An automated system for quantitative analysis of Drosophila larval locomotion

Background: Drosophila larvae have been used as a model to study to genetic and cellular circuitries modulating behaviors. One of the challenges in behavioral study is the quantification of complex phenotypes such as locomotive behaviors. Experimental capability can be greatly enhanced by an automatic single-animal tracker that records an animal at a high resolution for an extended period, and analyzes multiple behavioral parameters. Results: Here we present MaggotTracker, a single-animal tracking system for Drosophila larval locomotion analysis. This system controls the motorized microscope stage while taking a video, so that the animal remains in the viewing center. It then reduces the animal to 13 evenly distributed points along the midline, and computes over 20 parameters evaluating the shape, peristalsis movement, stamina, and track of the animal. To demonstrate its utility, we applied MaggotTracker to analyze both wild-type and mutant animals to identify factors affecting locomotive behaviors. Each animal was tracked for four minutes. Our analysis on Canton-S third-instar larvae revealed that the distance an animal travelled was correlated to its striding speed rather than the percentage of time the animal spent striding, and that the striding speed was correlated to both the distance and the duration of one stride. Sexual dimorphism was observed in body length but not in locomotive parameters such as speed. Locomotive parameters were affected by animal developmental stage and the crawling surface. No significant changes in movement speed were detected in mutants of circadian genes such as period (per), timeout, and timeless (tim). The MaggotTracker analysis showed that ether a go-go (eag), Shaker (Sh), slowpoke (slo), and dunce (dnc) mutant larvae had severe phenotypes in multiple locomotive parameters such as stride distance and speed, consistent with their function in neuromuscular junctions. Further, the phenotypic patterns of the K+ channel genes eag, Sh and slo are highly similar. Conclusions: These results showed that MaggotTracker is an efficient tool for automatic phenotyping. The MaggotTracker software as well as the data presented here can be downloaded from our open-access site www.WormLoco.org/Ma

A strategy to apply quantitative epistasis analysis on developmental traits

Abstract Background Genetic interactions are keys to understand complex traits and evolution. Epistasis analysis is an effective method to map genetic interactions. Large-scale quantitative epistasis analysis has been well established for single cells. However, there is a substantial lack of such studies in multicellular organisms and their complex phenotypes such as development. Here we present a method to extend quantitative epistasis analysis to developmental traits. Methods In the nematode Caenorhabditis elegans, we applied RNA interference on mutants to inactivate two genes, used an imaging system to quantitatively measure phenotypes, and developed a set of statistical methods to extract genetic interactions from phenotypic measurement. Results Using two different C. elegans developmental phenotypes, body length and sex ratio, as examples, we showed that this method could accommodate various metazoan phenotypes with performances comparable to those methods in single cell growth studies. Comparing with qualitative observations, this method of quantitative epistasis enabled detection of new interactions involving subtle phenotypes. For example, several sex-ratio genes were found to interact with brc-1 and brd-1, the orthologs of the human breast cancer genes BRCA1 and BARD1, respectively. We confirmed the brc-1 interactions with the following genes in DNA damage response: C34F6.1, him-3 (ortholog of HORMAD1, HORMAD2), sdc-1, and set-2 (ortholog of SETD1A, SETD1B, KMT2C, KMT2D), validating the effectiveness of our method in detecting genetic interactions. Conclusions We developed a reliable, high-throughput method for quantitative epistasis analysis of developmental phenotypes

Influence of Melatonin on Cerebrovascular Proinflammatory Mediators Expression and Oxidative Stress Following Subarachnoid Hemorrhage in Rabbits

The aim of this study is to analyze whether melatonin administration influenced the nuclear factor-kappa B (NF-κB) activity, proinflammatory cytokines expression, and oxidative response in the basilar artery after SAH. A total of 48 rabbits were randomly divided into four groups: control group, SAH group, SAH + vehicle group, and SAH + melatonin group. All SAH animals were subjected to injection of autologous blood into cisterna magna twice on day 0 and day 2. The melatonin was administered intraperitoneally at a dose of 5 mg/kg/12 h simultaneously with SAH from day 0 to day 5. The basilar arteries were extracted on day 5 after SAH. As a result, we found that vascular inflammation and oxidative stress were induced in all SAH animals. In animals given melatonin, basilar arterial NF-κB and pro-inflammatory cytokines were decreased in comparison to vehicle-treated animals. Measures of oxidative stress also showed significant downregulation after melatonin treatment. Furthermore, administration of melatonin prevented vasospasm on day 5 following SAH. In conclusion, post-SAH melatonin administration may attenuate inflammatory response and oxidative stress in the spasmodic artery, and this may be one mechanism involved in the therapeutic effect of melatonin on the subsequent vasospasm after SAH

Water pollutant fingerprinting tracks recent industrial transfer from coastal to inland China: a case study

In recent years, China’s developed regions have transferred industries to undeveloped regions. Large numbers of unlicensed or unregistered enterprises are widespread in these undeveloped regions and they are subject to minimal regulation. Current methods for tracing industrial transfers in these areas, based on enterprise registration information or economic surveys, do not work. The authors have developed an analytical framework combining water fingerprinting and evolutionary analysis to trace the pollution transfer features between water sources. We collected samples in Eastern China (industrial export) and Central China (industrial acceptance) separately from two water systems. Based on the water pollutant fingerprints and evolutionary trees, we traced the pollution transfer associated with industrial transfer between the two areas. The results are consistent with four episodes of industrial transfers over the past decade. The results also show likely types of the transferred industries - electronics, plastics, and biomedicines - that contribute to the water pollution transfer