Evolutionary rescue by compensatory mutations is constrained by genomic and environmental backgrounds

Since deleterious mutations may be rescued by secondary mutations during evolution, compensatory evolution could identify genetic solutions leading to therapeutic targets. Here, we tested this hypothesis and examined whether these solutions would be universal or would need to be adapted to one's genetic and environmental makeups. We performed experimental evolutionary rescue in a yeast disease model for the Wiskott–Aldrich syndrome in two genetic backgrounds and carbon sources. We found that multiple aspects of the evolutionary rescue outcome depend on the genotype, the environment, or a combination thereof. Specifically, the compensatory mutation rate and type, the molecular rescue mechanism, the genetic target, and the associated fitness cost varied across contexts. The course of compensatory evolution is therefore highly contingent on the initial conditions in which the deleterious mutation occurs. In addition, these results reveal biologically favored therapeutic targets for the Wiskott–Aldrich syndrome, including the target of an unrelated clinically approved drug. Our results experimentally illustrate the importance of epistasis and environmental evolutionary constraints that shape the adaptive landscape and evolutionary rate of molecular networks.     

Systematic Literature Review and Meta-Analysis of Renal Function in Human Immunodeficiency Virus (HIV)-Infected Patients Treated with Atazanavir (ATV)-Based Regimens

Some HIV antiretroviral therapies (ART) have been associated with renal toxicities, which become of increasing concern as HIV-infected patients age and develop comorbidities. The objective of this study was to evaluate the relative impact of atazanavir (ATV)-based regimens on the renal function of adult patients with HIV. We conducted a systematic literature review by searching PubMed, EMBASE, Cochrane library, and the CRD from 2000 until March 2013. Major HIV-related conferences occurring in the past two years were also searched. All randomized clinical trials and large cohort studies assessing renal function in treatment-naïve and/or treatment-experienced HIV patients on ATV-based regimens were included. Fixed-effect mixed-treatment network analyses were carried out on the most frequently reported renal outcomes. 23 studies met the inclusion criteria, and change in estimated glomerular filtration rate (eGFR) from baseline to 48 weeks was identified as the main outcome. Two networks including, respectively, six studies (using the Cockcroft-Gault method) and four studies (using MDRD and CKD-EPI) were analysed. With CG network, ATV/r + TDF/FTC was associated with lower impact on the decline of eGFR than ATV/cobicistat + TDF/FTC but with higher decrease in eGFR than ATV/r + ABC/3TC (difference in mean change from baseline in eGFR repectively +3.67 and –3.89). The use of ATV/cobicistat + TDF/FTC led to a similar decline in eGFR as EVG/cobicistat/TDF/FTC. With respect to third agents combined with TDF/FTC, ATV/r had a lower increase in eGFR in comparison to EFV, and no difference was shown when compared to SQV/r and DRV/r. The effect of ATV-based regimens on renal function at 48 weeks appears similar to other ART regimens and appears to be modest regardless of boosting agent or backbone, although TDF containing backbones consistently leads to greater decline in eGFR.     

Edge effects across boundaries between natural and restored jarrah (Eucalyptus marginata) forests in south‐western Australia

Edge effects are a widespread and ubiquitous ecological phenomenon, yet they remain poorly studied across edges between restored and natural forests. To address this lack of knowledge, we studied vertebrate communities across edges between 3‐year old restored mine‐pits and adjacent unmined forest in the jarrah (Eucalyptus marginata) forest of south‐western Australia. We found that mammal communities showed no edge response but reptile communities did. Overall reptile abundance and Morethia obscura abundance were higher in unmined forest along edges, Egernia napoleonis abundance was lower in unmined forest along edges, while Pogona minor abundance was lower in restored mine‐pits along edges. Predictive models were unable to predict species edge responses, due to the lack of knowledge of the ecology of jarrah forest reptiles, but proved useful in identifying potential ecological mechanisms behind observed edge responses and suggested that potential mechanisms were likely different for each species. Our study is the first to show edge responses in both habitats forming the edge between restored and natural forests, emphasizing the importance of studying both habitats forming the edge. Our results also suggest that, despite being poorly studied, edge responses are common across edges between restored and natural forest and result from a variety of ecological mechanisms. An increased understanding of the ecological mechanisms driving edge responses across edges between restored and natural forests will improve our ability to integrate restored areas into cross‐landscape management and, ultimately, improve our ability to manage landscapes for biodiversity conservation.     

Acceleration of cyanobacterial dominance in north temperate‐subarctic lakes during the Anthropocene

Increases in atmospheric temperature and nutrients from land are thought to be promoting the expansion of harmful cyanobacteria in lakes worldwide, yet to date there has been no quantitative synthesis of long‐term trends. To test whether cyanobacteria have increased in abundance over the past ~ 200 years and evaluate the relative influence of potential causal mechanisms, we synthesised 108 highly resolved sedimentary time series and 18 decadal‐scale monitoring records from north temperate‐subarctic lakes. We demonstrate that: (1) cyanobacteria have increased significantly since c. 1800 ce , (2) they have increased disproportionately relative to other phytoplankton, and (3) cyanobacteria increased more rapidly post c. 1945 ce . Variation among lakes in the rates of increase was explained best by nutrient concentration (phosphorus and nitrogen), and temperature was of secondary importance. Although cyanobacterial biomass has declined in some managed lakes with reduced nutrient influx, the larger spatio‐temporal scale of sedimentary records show continued increases in cyanobacteria throughout the north temperate‐subarctic regions.     

Chlamydiae interaction with the endoplasmic reticulum: contact,function and consequences

Chlamydiae and chlamydiae‐related organisms are obligate intracellular bacterial pathogens. They reside in a membrane‐bound compartment termed the inclusion and have evolved sophisticated mechanisms to interact with cellular organelles. This review focuses on the nature, the function(s) and the consequences of chlamydiae–inclusion interaction with the endoplasmic reticulum (ER). The inclusion membrane establishes very close contact with the ER at specific sites termed ER–inclusion membrane contact sites (MCSs). These MCSs are constituted of a specific set of factors, including the C. trachomatis effector protein IncD and the host cell proteins CERT and VAPA/B. Because CERT and VAPA/B have a demonstrated role in the non‐vesicular trafficking of lipids between the ER and the Golgi, it was proposed that Chlamydia establish MCSs with the ER to acquire host lipids. However, the recruitment of additional factors to ER–inclusion MCSs, such as the ER calcium sensor STIM1, may suggest additional functions unrelated to lipid acquisition. Finally, chlamydiae interaction with the ER appears to induce the ER stress response, but this response is quickly dampened by chlamydiae to promote host cell survival.     

Neural stem and progenitor cell fate transition requires regulation of Musashi1 function

Background

There is increasing evidence of a pivotal role for regulated mRNA translation in control of developmental cell fate transitions. Physiological and pathological stem and progenitor cell self-renewal is maintained by the mRNA-binding protein, Musashi1 through repression of translation of key mRNAs encoding cell cycle inhibitory proteins. The mechanism by which Musashi1 function is modified to allow translation of these target mRNAs under conditions that require inhibition of cell cycle progression, is unknown.

Results

In this study, we demonstrate that differentiation of primary embryonic rat neural stem/progenitor cells (NSPCs) or human neuroblastoma SH-SY5Y cells results in the rapid phosphorylation of Musashi1 on the evolutionarily conserved site serine 337 (S337). Phosphorylation of this site has been shown to be required for cell cycle control during the maturation of Xenopus oocytes. S337 phosphorylation in mammalian NSPCs and human SH-SY5Y cells correlates with the de-repression and translation of a Musashi reporter mRNA and with accumulation of protein from the endogenous Musashi target mRNA, p21^WAF1/CIP1. Inhibition of Musashi regulatory phosphorylation, through expression of a phospho-inhibitory mutant Musashi1 S337A or over-expression of the wild-type Musashi, blocked differentiation of both NSPCs and SH-SY5Y cells. Musashi1 was similarly phosphorylated in NSPCs and SH-SY5Y cells under conditions of nutrient deprivation-induced cell cycle arrest. Expression of the Musashi1 S337A mutant protein attenuated nutrient deprivation-induced NSPC and SH-SY5Y cell death.

Conclusions

Our data suggest that in response to environmental cues that oppose cell cycle progression, regulation of Musashi function is required to promote target mRNA translation and cell fate transition. Forced modulation of Musashi1 function may present a novel therapeutic strategy to oppose pathological stem cell self-renewal.

     

Prediction of Recurrence and Survival for Triple-Negative Breast Cancer (TNBC) by a Protein Signature in Tissue Samples

To date, there is no available targeted therapy for patients who are diagnosed with triple-negative breast cancers (TNBC). The aim of this study was to identify a new specific target for specific treatments. Frozen primary tumors were collected from 83 adjuvant therapy-naive TNBC patients. These samples were used for global proteome profiling by iTRAQ-OFFGEL-LC-MS/MS approach in two series: a training cohort (n = 42) and a test set (n = 41). Patients who remains free of local or distant metastasis for a minimum of 5 years after surgery were classified in the no-relapse group; the others were in the relapse group. OPLS and Kaplan–Meier analyses were performed to select candidate markers, which were validated by immunohistochemistry. Three proteins were identified in the training set and validated in the test set by Kaplan–Meier method and immunohistochemistry (IHC): TrpRS as a good prognostic markers and DP and TSP1 as bad prognostic markers. We propose the establishment of an IHC test to calculate the score of TrpRS, DP, and TSP1 in TNBC tumors to evaluate the degree of aggressiveness of the tumors. Finally, we propose that DP and TSP1 could provide therapeutic targets for specific treatments.Triple-negative breast cancers (TNBC)¹ are defined by a lack of expression of estrogen (ER), progesterone (PR), and HER2/neu receptors and account for about 15% of all breast cancers. This subtype is associated with poor prognosis (1) in terms of distant free survival (DFS) and overall survival (OS), and to date, there is no clinically available targeted therapy for patients diagnosed with TNBC. Because of the absence of specific treatment guidelines for this group of patients, TNBC are managed with standard adjuvant chemotherapy (2), which, however, seems to be less effective in those cancers. In order to improve survival, it is important to determine new specific-targeted treatment.A proteomic analysis has several inherent advantages over a genomic approach in that measured mRNA levels do not necessarily correlate to corresponding protein levels. In addition, protein detection is probably also more reflective of the tumor microenvironment. Several proteomic studies have been conducted on TNBC (3–5), but no proteomic study was conducted on large cohorts including the clinical outcome of the patients, except a recent comparative proteome analysis that identified a 11-protein signature for aggressive TNBC in a large cohort of 93 microdissected tumors (6). Although microdissection was necessary to elucidate the contribution of TNBC cells, it did not reflect the tumor with its microenvironment that is increasingly described as fundamental to explain the tumor outcome. Thus, it is now recognized that carcinomas derive from phenomena that occur in tissues, not in individual cancer cells. From this perspective, the microenvironment becomes an integral, essential part of the tumor (7, 8). In this context, taking into account the tumor microenvironment, we investigated a cohort of 83 TNBC samples without microdissection by a quantitative proteomic approach using iTRAQ labeling. Based on clinical data, we established a protein signature of the most aggressive tumors. From these differentially expressed proteins, some of them appeared to be potential therapeutic targets.     

Differential Gene Expression Profiling of Dystrophic Dog Muscle after MuStem Cell Transplantation

BackgroundSeveral adult stem cell populations exhibit myogenic regenerative potential, thus representing attractive candidates for therapeutic approaches of neuromuscular diseases such as Duchenne Muscular Dystrophy (DMD). We have recently shown that systemic delivery of MuStem cells, skeletal muscle-resident stem cells isolated in healthy dog, generates the remodelling of muscle tissue and gives rise to striking clinical benefits in Golden Retriever Muscular Dystrophy (GRMD) dog. This global effect, which is observed in the clinically relevant DMD animal model, leads us to question here the molecular pathways that are impacted by MuStem cell transplantation. To address this issue, we compare the global gene expression profile between healthy, GRMD and MuStem cell treated GRMD dog muscle, four months after allogenic MuStem cell transplantation.ResultsIn the dystrophic context of the GRMD dog, disease-related deregulation is observed in the case of 282 genes related to various processes such as inflammatory response, regeneration, calcium ion binding, extracellular matrix organization, metabolism and apoptosis regulation. Importantly, we reveal the impact of MuStem cell transplantation on several molecular and cellular pathways based on a selection of 31 genes displaying signals specifically modulated by the treatment. Concomitant with a diffuse dystrophin expression, a histological remodelling and a stabilization of GRMD dog clinical status, we show that cell delivery is associated with an up-regulation of genes reflecting a sustained enhancement of muscle regeneration. We also identify a decreased mRNA expression of a set of genes having metabolic functions associated with lipid homeostasis and energy. Interestingly, ubiquitin-mediated protein degradation is highly enhanced in GRMD dog muscle after systemic delivery of MuStem cells.ConclusionsOverall, our results provide the first high-throughput characterization of GRMD dog muscle and throw new light on the complex molecular/cellular effects associated with muscle repair and the clinical efficacy of MuStem cell-based therapy.