Fishing-induced life-history changes degrade and destabilize harvested ecosystems

Fishing is widely known to magnify fluctuations in targeted populations. These fluctuations are correlated with population shifts towards young, small, and more quickly maturing individuals. However, the existence and nature of the mechanistic basis for these correlations and their potential ecosystem impacts remain highly uncertain. Here, we elucidate this basis and associated impacts by showing how fishing can increase fluctuations in fishes and their ecosystem, particularly when coupled with decreasing body sizes and advancing maturation characteristic of the life-history changes induced by fishing. More specifically, using an empirically parameterized network model of a well-studied lake ecosystem, we show how fishing may both increase fluctuations in fish abundances and also, when accompanied by decreasing body size of adults, further decrease fish abundance and increase temporal variability of fishes' food resources and their ecosystem. In contrast, advanced maturation has relatively little effect except to increase variability in juvenile populations. Our findings illustrate how different mechanisms underlying life-history changes that may arise as evolutionary responses to intensive, size-selective fishing can rapidly and continuously destabilize and degrade ecosystems even after fishing has ceased. This research helps better predict how life-history changes may reduce fishes' resilience to fishing and ecosystems' resistance to environmental variations.Peer reviewe

Molecular Basis of NDM-1, a New Antibiotic Resistance Determinant

The New Delhi Metallo-β-lactamase (NDM-1) was first reported in 2009 in a Swedish patient. A recent study reported that Klebsiella pneumonia NDM-1 positive strain or Escherichia coli NDM-1 positive strain was highly resistant to all antibiotics tested except tigecycline and colistin. These can no longer be relied on to treat infections and therefore, NDM-1 now becomes potentially a major global health threat

Assisted evolution enables HIV-1 to overcome a high trim5α-imposed genetic barrier to rhesus macaque tropism

Diversification of antiretroviral factors during host evolution has erected formidable barriers to cross-species retrovirus transmission. This phenomenon likely protects humans from infection by many modern retroviruses, but it has also impaired the development of primate models of HIV-1 infection. Indeed, rhesus macaques are resistant to HIV-1, in part due to restriction imposed by the TRIM5α protein (rhTRIM5α). Initially, we attempted to derive rhTRIM5α-resistant HIV-1 strains using two strategies. First, HIV-1 was passaged in engineered human cells expressing rhTRIM5α. Second, a library of randomly mutagenized capsid protein (CA) sequences was screened for mutations that reduced rhTRIM5α sensitivity. Both approaches identified several individual mutations in CA that reduced rhTRIM5α sensitivity. However, neither approach yielded mutants that were fully resistant, perhaps because the locations of the mutations suggested that TRIM5α recognizes multiple determinants on the capsid surface. Moreover, even though additive effects of various CA mutations on HIV-1 resistance to rhTRIM5α were observed, combinations that gave full resistance were highly detrimental to fitness. Therefore, we employed an 'assisted evolution' approach in which individual CA mutations that reduced rhTRIM5α sensitivity without fitness penalties were randomly assorted in a library of viral clones containing synthetic CA sequences. Subsequent passage of the viral library in rhTRIM5α-expressing cells resulted in the selection of individual viral species that were fully fit and resistant to rhTRIM5α. These viruses encoded combinations of five mutations in CA that conferred complete or near complete resistance to the disruptive effects of rhTRIM5α on incoming viral cores, by abolishing recognition of the viral capsid. Importantly, HIV-1 variants encoding these CA substitutions and SIVmac239 Vif replicated efficiently in primary rhesus macaque lymphocytes. These findings demonstrate that rhTRIM5α is difficult to but not impossible to evade, and doing so should facilitate the development of primate models of HIV-1 infection

Evidence for Restriction of Ancient Primate Gammaretroviruses by APOBEC3 but Not TRIM5α Proteins

Because of evolutionary pressures imposed through episodic colonization by retroviruses, many mammals express factors, such as TRIM5α and APOBEC3 proteins, that directly restrict retroviral replication. TRIM5 and APOBEC restriction factors are most often studied in the context of modern primate lentiviruses, but it is likely that ancient retroviruses imposed the selective pressure that is evident in primate TRIM5 and APOBEC3 genes. Moreover, these antiretroviral factors have been shown to act against a variety of retroviruses, including gammaretroviruses. Endogenous retroviruses can provide a ‘fossil record’ of extinct retroviruses and perhaps evidence of ancient TRIM5 and APOBEC3 antiviral activity. Here, we investigate whether TRIM5 and APOBEC3 proteins restricted the replication of two groups of gammaretroviruses that were endogenized in the past few million years. These endogenous retroviruses appear quite widespread in the genomes of old world primates but failed to colonize the human germline. Our analyses suggest that TRIM5α proteins did not pose a major barrier to the cross-species transmission of these two families of gammaretroviruses, and did not contribute to their extinction. However, we uncovered extensive evidence for inactivation of ancient gammaretroviruses through the action of APOBEC3 cytidine deaminases. Interestingly, the identities of the cytidine deaminases responsible for inactivation appear to have varied in both a virus and host species–dependent manner. Overall, sequence analyses and reconstitution of ancient retroviruses from remnants that have been preserved in the genomes of modern organisms offer the opportunity to probe and potentially explain the evolutionary history of host defenses against retroviruses

Adding corticosteroids to the pudendal nerve block for pudendal neuralgia: a randomised, double-blind, controlled trial

International audienceOBJECTIVE:To compare the effect of corticosteroids combined with local anaesthetic versus local anaesthetic alone during infiltrations of the pudendal nerve for pudendal nerve entrapment.DESIGN:Randomised, double-blind, controlled trial.SETTING:Multicentre study.POPULATION:201 patients were included in the study, with a subgroup of 122 women.METHODS:CT-guided pudendal nerve infiltrations were performed in the sacrospinous ligament and Alcock's canal. There were three study arms: patients in Arm A (n = 68) had local anaesthetic alone, those in Arm B (n = 66) had local anaesthetic plus corticosteroid and those in Arm C (n = 67) local anaesthetic plus corticosteroid with a large volume of normal saline.MAIN OUTCOME MEASURES:The primary end-point was the pain intensity score at 3 months. Patients were regarded as responders (at least a 30-point improvement on a 100-point visual analogue scale of mean maximum pain over a 2-week period) or nonresponders.RESULTS:Three months' postinfiltration, 11.8% of patients in the local anaesthetic only arm (Arm A) were responders versus 14.3% in the local anaesthetic plus corticosteroid arms (Arms B and C). This difference was not statistically significant (P = 0.62). No statistically significant difference was observed in the female subgroup between Arm A and Arms B and C (P = 0.09). No significant difference was detected for the various pain assessment procedures, functional criteria or quality-of-life criteria.CONCLUSIONS:Corticosteroids provide no additional therapeutic benefits compared with local anaesthetic and should therefore no longer be used

Infection with Burkholderia pseudomallei - immune correlates of survival in acute melioidosis

Melioidosis, caused by Burkholderia pseudomallei, is a potentially lethal infection with no licensed vaccine. There is little understanding of why some exposed individuals have no symptoms, while others rapidly progress to sepsis and death, or why diabetes confers increased susceptibility. We prospectively recruited a cohort of 183 acute melioidosis patients and 21 control subjects from Northeast Thailand and studied immune parameters in the context of survival status and the presence or absence of diabetes. HLA-B*46 (one of the commonest HLA class I alleles in SE Asia) and HLA-C*01 were associated with an increased risk of death (odds ratio 2.8 and 3.1 respectively). Transcriptomic analysis during acute infection in diabetics indicated the importance of interplay between immune pathways including those involved in antigen presentation, chemotaxis, innate and adaptive immunity and their regulation. Survival was associated with enhanced T cell immunity to nine of fifteen immunodominant antigens analysed including AhpC (BPSL2096), BopE (BPSS1525), PilO (BPSS1599), ATP binding protein (BPSS1385) and an uncharacterised protein (BPSL2520). T cell immunity to GroEL (BPSL2697) was specifically impaired in diabetic individuals. This characterization of immunity associated with survival during acute infection offers insights into correlates of protection and a foundation for design of an effective multivalent vaccine

Inhibitors of VIM-2 by screening pharmacologically active and click-chemistry compound libraries

VIM-2 is an Ambler class B metallo-beta-lactamase (MBL) capable of hydrolyzing a broad-spectrum of beta-lactam antibiotics. Although the discovery and development of MBL inhibitors continue to be an area of active research, an array of potent, small molecule inhibitors is yet to be fully characterized for VIM-2. In the presented research, a compound library screening approach was used to identify and characterize VIM-2 inhibitors from a library of pharmacologically active compounds as well as a focused 'click' chemistry library. The four most potent VIM-2 inhibitors resulting from a VIM-2 screen were characterized by kinetic studies in order to determine K(i) and mechanism of enzyme inhibition. As a result, two previously described pharmacologic agents, mitoxantrone (1,4-dihydroxy-5,8-bis([2-([2-hydroxyethyl]amino)ethyl]amino)-9,10-anthracenedione) and 4-chloromercuribenzoic acid (pCMB) were found to be active, the former as a non-competitive inhibitor (K(i)=K(i)(')=1.5+/-0.2microM) and the latter as a slowly reversible or irreversible inhibitor. Additionally, two novel sulfonyl-triazole analogs from the click library were identified as potent, competitive VIM-2 inhibitors: N-((4-((but-3-ynyloxy)methyl)-1H-1,2,3-triazol-5-yl)methyl)-4-iodobenzenesulfonamide (1, K(i)=0.41+/-0.03microM) and 4-iodo-N-((4-(methoxymethyl)-1H-1,2,3-triazol-5-yl)methyl)benzenesulfonamide (2, K(i)=1.4+/-0.10microM). Mitoxantrone and pCMB were also found to potentiate imipenem efficacy in MIC and synergy assays employing Escherichia coli. Taken together, all four compounds represent useful chemical probes to further investigate mechanisms of VIM-2 inhibition in biochemical and microbiology-based assays