Operationalizing resilience for conservation objectives: the 4S’s

Although resilience thinking is increasingly popular and attractive among restoration practitioners, it carries an abstract quality that hinders effective application. Because resilience and its components are defined differently in social and ecological contexts, individual managers or stakeholders may disagree on the definition of a system’s state, occurrence of a state change, preferred state characteristics, and appropriate methods to achieve success. Nevertheless, incentives and mandates often force managers to demonstrate how their work enhances resilience. Unclear or conflicting definitions can lead to ineffective or even detrimental decision-making in the name of resilience; essentially, any convenient action can be touted as resilience-enhancing in this case. We contend that any successful resilience management project must clearly identify up-front the stressors of concern, state traits, scales of appropriate management, and success indicators (the 4S’s) relevant to the management targets. We propose a deliberate process for determining these components in advance of resilience management for conservation. Our recommendations were inspired and informed by two case studies wherein different definitions of stressors, state, scales, and success would result in very different management choices, with potentially serious consequences for biodiversity targets

Block of T cell development in P53-deficient mice accelerates development of lymphomas with characteristic RAG-dependent cytogenetic alterations

SummaryMice deficient in the DNA damage sensor P53 display normal T cell development but eventually succumb to thymic lymphomas. Here, we show that inactivation of the TCR β gene enhancer (Eβ) results in a block of T cell development at stages where recombination-activating genes (RAG) are expressed. Introduction of the Eβ mutation into p53−/− mice dramatically accelerates the onset of lethal thymic lymphomas that harbor RAG-dependent aberrant rearrangements, chromosome 14 and 12 translocations, and amplification of the chromosomal region 9A1–A5.3. Phenotypic and genetic analyses suggest that lymphomas emerge through a normal thymocyte development pathway. These findings provide genetic evidence that block of lymphocyte development at stages with RAG endonuclease activity can provoke lymphomagenesis on a background with deficient DNA damage responses

Efficacy and safety of non-steroidal anti-inflammatory drugs (NSAIDs) for the treatment of acute pain after orthopedic trauma: a practice management guideline from the Eastern Association for the Surgery of Trauma and the Orthopedic Trauma Association

OBJECTIVES: Fracture is a common injury after a traumatic event. The efficacy and safety of non-steroidal anti-inflammatory drugs (NSAIDs) to treat acute pain related to fractures is not well established. METHODS: Clinically relevant questions were determined regarding NSAID use in the setting of trauma-induced fractures with clearly defined patient populations, interventions, comparisons and appropriately selected outcomes (PICO). These questions centered around efficacy (pain control, reduction in opioid use) and safety (non-union, kidney injury). A systematic review including literature search and meta-analysis was performed, and the quality of evidence was graded per the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. The working group reached consensus on the final evidence-based recommendations. RESULTS: A total of 19 studies were identified for analysis. Not all outcomes identified as critically important were reported in all studies, and the outcome of pain control was too heterogenous to perform a meta-analysis. Nine studies reported on non-union (three randomized control trials), six of which reported no association with NSAIDs. The overall incidence of non-union in patients receiving NSAIDs compared with patients not receiving NSAIDs was 2.99% and 2.19% (p=0.04), respectively. Of studies reporting on pain control and reduction of opioids, the use of NSAIDs reduced pain and the need for opioids after traumatic fracture. One study reported on the outcome of acute kidney injury and found no association with NSAID use. CONCLUSIONS: In patients with traumatic fractures, NSAIDs appear to reduce post-trauma pain, reduce the need for opioids and have a small effect on non-union. We conditionally recommend the use of NSAIDs in patients suffering from traumatic fractures as the benefit appears to outweigh the small potential risks

Evidence of mTOR Activation by an AKT-Independent Mechanism Provides Support for the Combined Treatment of PTEN-Deficient Prostate Tumors with mTOR and AKT Inhibitors

AbstractActivation of the phosphoinositide 3-kinase pathway is commonly observed in human prostate cancer. Loss of function of phosphatase and tensin homolog (PTEN) is associated with the activation of AKT and mammalian target of rapamycin (mTOR) in many cancer cell lines as well as in other model systems. However, activation of mTOR is also dependent of kinases other than AKT. Here, we show that activation of mTOR is not dependent on AKT in a prostate-specific PTEN-deficient mouse model of prostate cancer. Pathway bifurcation of AKT and mTOR was noted in both mouse and human prostate tumors. We demonstrated for the first time that cotargeting mTOR and AKT with ridaforolimus/MK-8669 and M1K-2206, respectively, delivers additive antitumor effects in vivo when compared to single agents. Our preclinical data suggest that the combination of AKT and mTOR inhibitors might be more effective in treating prostate cancer patients than current treatment regimens or either treatment alone

A genome-wide scan for common alleles affecting risk for autism

Although autism spectrum disorders (ASDs) have a substantial genetic basis, most of the known genetic risk has been traced to rare variants, principally copy number variants (CNVs). To identify common risk variation, the Autism Genome Project (AGP) Consortium genotyped 1558 rigorously defined ASD families for 1 million single-nucleotide polymorphisms (SNPs) and analyzed these SNP genotypes for association with ASD. In one of four primary association analyses, the association signal for marker rs4141463, located within MACROD2, crossed the genome-wide association significance threshold of P < 5 × 10−8. When a smaller replication sample was analyzed, the risk allele at rs4141463 was again over-transmitted; yet, consistent with the winner's curse, its effect size in the replication sample was much smaller; and, for the combined samples, the association signal barely fell below the P < 5 × 10−8 threshold. Exploratory analyses of phenotypic subtypes yielded no significant associations after correction for multiple testing. They did, however, yield strong signals within several genes, KIAA0564, PLD5, POU6F2, ST8SIA2 and TAF1C

Gauging NOTCH1 Activation in Cancer Using Immunohistochemistry

Fixed, paraffin-embedded (FPE) tissues are a potentially rich resource for studying the role of NOTCH1 in cancer and other pathologies, but tests that reliably detect activated NOTCH1 (NICD1) in FPE samples have been lacking. Here, we bridge this gap by developing an immunohistochemical (IHC) stain that detects a neoepitope created by the proteolytic cleavage event that activates NOTCH1. Following validation using xenografted cancers and normal tissues with known patterns of NOTCH1 activation, we applied this test to tumors linked to dysregulated Notch signaling by mutational studies. As expected, frequent NICD1 staining was observed in T lymphoblastic leukemia/lymphoma, a tumor in which activating NOTCH1 mutations are common. However, when IHC was used to gauge NOTCH1 activation in other human cancers, several unexpected findings emerged. Among B cell tumors, NICD1 staining was much more frequent in chronic lymphocytic leukemia than would be predicted based on the frequency of NOTCH1 mutations, while mantle cell lymphoma and diffuse large B cell lymphoma showed no evidence of NOTCH1 activation. NICD1 was also detected in 38% of peripheral T cell lymphomas. Of interest, NICD1 staining in chronic lymphocytic leukemia cells and in angioimmunoblastic lymphoma was consistently more pronounced in lymph nodes than in surrounding soft tissues, implicating factors in the nodal microenvironment in NOTCH1 activation in these diseases. Among carcinomas, diffuse strong NICD1 staining was observed in 3.8% of cases of triple negative breast cancer (3 of 78 tumors), but was absent from 151 non-small cell lung carcinomas and 147 ovarian carcinomas. Frequent staining of normal endothelium was also observed; in line with this observation, strong NICD1 staining was also seen in 77% of angiosarcomas. These findings complement insights from genomic sequencing studies and suggest that IHC staining is a valuable experimental tool that may be useful in selection of patients for clinical trials

Energy gain of wetted-foam implosions with auxiliary heating for inertial fusion studies

Low convergence ratio implosions (where wetted-foam layers are used to limit capsule convergence, achieving improved robustness to instability growth) and auxiliary heating (where electron beams are used to provide collisionless heating of a hotspot) are two promising techniques that are being explored for inertial fusion energy applications. In this paper, a new analytic study is presented to understand and predict the performance of these implosions. Firstly, conventional gain models are adapted to produce gain curves for fixed convergence ratios, which are shown to well-describe previously simulated results. Secondly, auxiliary heating is demonstrated to be well understood and interpreted through the burn-up fraction of the deuterium-tritium fuel, with the gradient of burn-up with respect to burn-averaged temperature shown to provide good qualitative predictions of the effectiveness of this technique for a given implosion. Simulations of auxiliary heating for a range of implosions are presented in support of this and demonstrate that this heating can have significant benefit for high gain implosions, being most effective when the burn-averaged temperature is between 5 and 20 keV

Two Strategies for the Delivery of IPTc in an Area of Seasonal Malaria Transmission in The Gambia: A Randomised Controlled Trial

Bojang and colleagues report a randomized trial showing that delivery of intermittent preventive treatment for malaria in children by village health workers is more effective than delivery by reproductive and child health trekking clinics

Mapping autism risk loci using genetic linkage and chromosomal rearrangements.

International audienceAutism spectrum disorders (ASDs) are common, heritable neurodevelopmental conditions. The genetic architecture of ASDs is complex, requiring large samples to overcome heterogeneity. Here we broaden coverage and sample size relative to other studies of ASDs by using Affymetrix 10K SNP arrays and 1,181 [corrected] families with at least two affected individuals, performing the largest linkage scan to date while also analyzing copy number variation in these families. Linkage and copy number variation analyses implicate chromosome 11p12-p13 and neurexins, respectively, among other candidate loci. Neurexins team with previously implicated neuroligins for glutamatergic synaptogenesis, highlighting glutamate-related genes as promising candidates for contributing to ASDs

Genome sequence of the tsetse fly (Glossina morsitans):Vector of African trypanosomiasis

Tsetse flies are the sole vectors of human African trypanosomiasis throughout sub-Saharan Africa. Both sexes of adult tsetse feed exclusively on blood and contribute to disease transmission. Notable differences between tsetse and other disease vectors include obligate microbial symbioses, viviparous reproduction, and lactation. Here, we describe the sequence and annotation of the 366-megabase Glossina morsitans morsitans genome. Analysis of the genome and the 12,308 predicted protein-encoding genes led to multiple discoveries, including chromosomal integrations of bacterial (Wolbachia) genome sequences, a family of lactation-specific proteins, reduced complement of host pathogen recognition proteins, and reduced olfaction/chemosensory associated genes. These genome data provide a foundation for research into trypanosomiasis prevention and yield important insights with broad implications for multiple aspects of tsetse biology.IS