John R. Stevens

Plant-soil feedbacks: a meta-analytical review.

Plants can change soil biology, chemistry and structure in ways that alter subsequent plant growth. This process, referred to as plant-soil feedback (PSF), has been suggested to provide mechanisms for plant diversity, succession and invasion. Here we use three meta-analytical models: a mixed model and two Bayes models, one correcting for sampling dependence and one correcting for sampling and hierarchical dependence (delta-splitting model) to test these hypotheses. All three models showed that PSFs have medium to large negative effects on plant growth, and especially grass growth, the life form for which we had the most data. This supports the hypothesis that PSFs, through negative frequency dependence, maintain plant diversity, especially in grasslands. PSFs were also large and negative for annuals and natives, but the delta-splitting model indicated that more studies are needed for these results to be conclusive. Our results support the hypotheses that PSFs encourage successional replacements and plant invasions. Most studies were performed using monocultures of grassland species in greenhouse conditions. Future research should examine PSFs in plant communities, non-grassland systems and field conditions.

A Meta-Analytic Review of Corridor Effectiveness

Using corridors for conservation is increasing despite a lack of consensus on their efficacy. Specifically, whether corridors increase movement of plants and animals between habitat fragments has been addressed on a case-by-case basis with mixed results. Because of the growing number of well-designed experiments that have addressed this question, we conducted a meta-analysis to determine whether corridors increase movement; whether corridor effectiveness differs among taxa; how recent changes in experimental design have influenced findings; and whether corridor effectiveness differs between manipulative and natural experiments. To conduct our meta-analysis, we analyzed 78 experiments from 35 studies using a conservative hierarchical Bayesian model that accounts for hierarchical and sampling dependence. We found a highly significant result that corridors increase movement between habitat patches by approximately 50% compared to patches that are not connected with corridors. We found that corridors were more important for the movement of invertebrates, nonavian vertebrates, and plants than they were for birds. Recent methodological advances in corridor experiments, such as controlling for the area added by corridors, did not influence whether corridors increased movement, whereas controlling for the distance between source and connected or unconnected recipient patches decreased movement through corridors. After controlling for taxa differences and whether studies controlled for distance in experimental design, we found that natural corridors (those existing in landscapes prior to the study) showed more movement than manipulated corridors (those created and maintained for the study). Our results suggest that existing corridors increase species movement in fragmented landscapes and that efforts spent on maintaining and creating corridors are worthwhile.

Treatment of Late Stage Disease in a Model of Arenaviral Hemorrhagic Fever: T-705 Efficacy and Reduced Toxicity Suggests an Alternative to Ribavirin

A growing number of arenaviruses are known to cause viral hemorrhagic fever (HF), a severe and life-threatening syndrome characterized by fever, malaise, and increased vascular permeability. Ribavirin, the only licensed antiviral indicated for the treatment of certain arenaviral HFs, has had mixed success and significant toxicity. Since severe arenaviral infections initially do not present with distinguishing symptoms and are difficult to clinically diagnose at early stages, it is of utmost importance to identify antiviral therapies effective at later stages of infection. We have previously reported that T-705, a substituted pyrazine derivative currently under development as an anti-influenza drug, is highly active in hamsters infected with Pichinde virus when the drug is administered orally early during the course of infection. Here we demonstrate that T-705 offers significant protection against this lethal arenaviral infection in hamsters when treatment is begun after the animals are ill and the day before the animals begin to succumb to disease. Importantly, this coincides with the time when peak viral loads are present in most organs and considerable tissue damage is evident. We also show that T-705 is as effective as, and less toxic than, ribavirin, as infected T-705-treated hamsters on average maintain their weight better and recover more rapidly than animals treated with ribavirin. Further, there was no added benefit to combination therapy with T-705 and ribavirin. Finally, pharmacokinetic data indicate that plasma T-705 levels following oral administration are markedly reduced during the latter stages of disease, and may contribute to the reduced efficacy seen when treatment is withheld until day 7 of infection. Our findings support further pre-clinical development of T-705 for the treatment of severe arenaviral infections.

An evaluation and replication of miRNAs with disease stage and colorectal cancer‐specific mortality

MicroRNAs (miRNAs) have been implicated in colorectal cancer (CRC) development and associated with prognostic indicators such as disease stage and survival. Prognostic associations are often based on few individuals and imprecise. In this study, we utilize population‐based data from 1,141 CRC cases to replicate previously reported associations between 121 miRNAs and disease stage and survival. The Agilent Human miRNA Microarray V19.0 was used to generate miRNA data following a stringent quality control protocol. Assessment of survival was done using Cox Proportional Hazard models adjusting for age, disease stage and tumor molecular phenotype. Five miRNAs were associated with more advanced disease stage; hsa‐miR‐145‐5p and hsa‐miR‐31‐5p showed increased expression with more advanced tumor stage, while hsa‐miR‐200b‐3p, hsa‐miR‐215 and hsa‐miR‐451a had decreased expression with more advanced tumors. Thirteen miRNAs were associated with CRC mortality among individuals diagnosed with colon cancer while 14 were associated with CRC mortality after a diagnosis with rectal cancer. Strongest associations were observed for those miRNAs that were expressed in a small subset of tumors. Most notable associations were for hsa‐miR‐145‐3p [hazard ratio (HR) 2.94, 95% confidence interval (CI) 1.54, 5.61], and hsa‐miR‐9‐3p (HR 10.28, 95% CI 1.31, 80.84) with colon cancer and hsa‐miR‐335‐5p (HR 0.17, 95% CI 0.05, 0.54) for rectal cancer. hsa‐miR‐374a‐5p, hsa‐miR‐570‐3p and hsa‐miR‐18a‐5p significantly reduced the hazard of dying for all cases, regardless of tumor site. Our findings illustrate the need for a large sample to evaluate the association of miRNAs with survival and disease stage in order to determine associations by tumor site.

Hierarchical Dependence in Meta-Analysis

Meta-analysis is a frequent tool among education and behavioral researchers to combine results from multiple experiments to arrive at a clear understanding of some effect of interest. One of the traditional assumptions in a meta-analysis is the independence of the effect sizes from the studies under consideration. This article presents a meta-analytic review of 13 experiments with 18 study reports all involving the effect of native-language (L1) vocabulary aids on second-language (L2) reading comprehension. Some experiments produced multiple study reports, creating a dependence structure among the resulting effect size estimates. The covariance among these effect size estimates is estimated and incorporated into a proposed meta-analysis model that accounts for the dependence at a hierarchical level. The overall effect size estimate (g =.63) indicates that L1 vocabulary aids can be an effective L2 reading comprehension aid in the short term. An interpretation of the hierarchical components is discussed.

Random forests for microarrays.

Random Forests is a powerful multipurpose tool for predicting and understanding data. If gene expression data come from known groups or classes (e.g., tumor patients and controls), Random Forests can rank the genes in terms of their usefulness in separating the groups. When the groups are unknown, Random Forests uses an intrinsic measure of the similarity of the genes to extract useful multivariate structure, including clusters. This chapter summarizes the Random Forests methodology and illustrates its use on freely available data sets.

MicroRNA profiles in colorectal carcinomas, adenomas and normal colonic mucosa: variations in miRNA expression and disease progression

Summary Roughly 27% of miRNAs are commonly expressed in colonic tissue; of these, over 86% are dysregulated between carcinoma and normal tissue when applying a false discovery rate of 0.05. MiRNA expression from normal to adenoma to carcinoma varied by miRNA and its frequency of expression in the population.

Expression Profiles of miRNA Subsets Distinguish Human Colorectal Carcinoma and Normal Colonic Mucosa.

OBJECTIVES:MicroRNAs (miRNAs) are small, non-protein-coding RNA molecules that are commonly dysregulated in colorectal tumors. The objective of this study was to identify smaller subsets of highly predictive miRNAs.METHODS:Data come from population-based studies of colorectal cancer conducted in Utah and the Kaiser Permanente Medical Care Program. Tissue samples were available for 1,953 individuals, of which 1,894 had carcinoma tissue and 1,599 had normal mucosa available for statistical analysis. Agilent Human miRNA Microarray V.19.0 was used to generate miRNA expression profiles; validation of expression levels was carried out using quantitative PCR. We used random forest analysis and verified findings with logistic modeling in separate data sets. Important microRNAs are identified and bioinformatics tools are used to identify target genes and related biological pathways.RESULTS:We identified 16 miRNAs for colon and 17 miRNAs for rectal carcinoma that appear to differentiate between carcinoma and normal mucosa; of these, 12 were important for both colon and rectal cancer, hsa-miR-663b, hsa-miR-4539, hsa-miR-17-5p, hsa-miR-20a-5p, hsa-miR-21-5p, hsa-miR-4506, hsa-miR-92a-3p, hsa-miR-93-5p, hsa-miR-145-5p, hsa-miR-3651, hsa-miR-378a-3p, and hsa-miR-378i. Estimated misclassification rates were low at 4.83% and 2.5% among colon and rectal observations, respectively. Among independent observations, logistic modeling reinforced the importance of these miRNAs, finding the primary principal components of their variation statistically significant (P<0.001 among both colon and rectal observations) and again producing low misclassification rates. Repeating our analysis without those miRNAs initially identified as important identified other important miRNAs; however, misclassification rates increased and distinctions between remaining miRNAs in terms of classification importance were reduced.CONCLUSIONS:Our data support the hypothesis that while many miRNAs are dysregulated between carcinoma and normal mucosa, smaller subsets of these miRNAs are useful and informative in discriminating between these tissues.

Preadaptation to cold stress in Salmonella enterica serovar Typhimurium increases survival during subsequent acid stress exposure.

ABSTRACT Salmonella is an important cause of bacterial food-borne gastroenteritis. Salmonella encounters multiple abiotic stresses during pathogen elimination methods used in food processing, and these stresses may influence its subsequent survivability within the host or in the environment. Upon ingestion, Salmonella is exposed to gastrointestinal acidity, a first line of the host innate defense system. This study tested the hypothesis that abiotic stresses encountered during food processing alter the metabolic mechanisms in Salmonella that enable survival and persistence during subsequent exposure to the host gastrointestinal acidic environment. Out of the four different abiotic stresses tested, viz., cold, peroxide, osmotic, and acid, preadaptation of the log-phase culture to cold stress (5°C for 5 h) significantly enhanced survival during subsequent acid stress (pH 4.0 for 90 min). The gene expression profile of Salmonella preadapted to cold stress revealed induction of multiple genes associated with amino acid metabolism, oxidative stress, and DNA repair, while only a few of the genes in the above-mentioned stress response and repair pathways were induced upon exposure to acid stress alone. Preadaptation to cold stress decreased the NAD+/NADH ratio and hydroxyl (OH·) radical formation compared with those achieved with the exposure to acid stress alone, indicating alteration of aerobic respiration and the oxidative state of the bacteria. The results from this study suggest that preadaptation to cold stress rescues Salmonella from the deleterious effect of subsequent acid stress exposure by induction of genes involved in stress response and repair pathways, by modification of aerobic respiration, and by redox modulation.

Disruption of epidermal specific gene expression and delayed skin development in AP-2γ mutant mice

Summary Sentence: Conditional ablation of AP-2 gamma results in a delay in skin development and abnormal expression of p63, K14, K1, filaggrin, repetin and secreted Ly6/Plaur domain containing 1, key genes required for epidermal development and differentiation. The development of the epidermis, a stratified squamous epithelium, is dependent on the regulated differentiation of keratinocytes. Differentiation begins with the initiation of stratification, a process tightly controlled through proper gene expression. AP-2 gamma is expressed in skin and previous research suggested a pathway where p63 gene induction results in increased expression of AP-2 gamma, which in turn is responsible for induction of K14. This study uses a conditional gene ablation model to further explore the role of AP-2 gamma in skin development. Mice deficient for AP-2 gamma exhibited delayed expression of p63, K14, and K1, key genes required for development and differentiation of the epidermis. In addition, microarray analysis of E16.5 skin revealed delayed expression of additional late epidermal differentiation genes: filaggrin, repetin and secreted Ly6/Plaur domain containing 1, in mutant mice. The genetic delay in skin development was further confirmed by a functional delay in the formation of an epidermal barrier. These results document an important role for AP-2 gamma in skin development, and reveal the existence of regulatory factors that can compensate for AP-2 gamma in its absence.