Militarised natural history: tales of the avocet's return to postwar Britain

Absent as a breeding bird from Britain for at least a century, avocets (Recurvirostra avosetta) began nesting on the east coast of Britain, in Suffolk, shortly after the end of the Second World War, having honed in on two spots on Britain's coast that had been flooded for war-related reasons. The avocets' presence was surrounded in secrecy, while a dedicated few kept up a protective watch over them. As the Royal Society for the Protection of Birds (RSPB) took over responsibility for the flourishing colony, they claimed the episode as a symbol of success for British protection, later making the bird their logo. Counter to the RSPB's story of protecting a British bird, I read the narratives of events in terms of making a bird British. I show how, as postwar Britain slumped economically and spiritually and tried to rebuild itself, the birds became a vehicle for formulating national identity: of Britain as a home to which to return and belong. Exploring the themes of returning servicemen and closed territories, the paper also examines the episode in terms of the naturalisation of the military and the militarisation of nature.     

Mapping Fusarium wilt race 1 resistance genes in cotton by inheritance,QTL and sequencing composition

Knowledge of the inheritance of disease resistance and genomic regions housing resistance (R) genes is essential to prevent expanding pathogen threats such as Fusarium wilt [Fusarium oxysporum f.sp. vasinfectum (FOV) Atk. Sny & Hans] in cotton (Gossypium spp.). We conducted a comprehensive study combining conventional inheritance, genetic and quantitative trait loci (QTL) mapping, QTL marker-sequence composition, and genome sequencing to examine the distribution, structure and organization of disease R genes to race 1 of FOV in the cotton genome. Molecular markers were applied to F₂ and recombinant inbred line (RIL) interspecific mapping populations from the crosses Pima-S7 (G. barbadense L.) × ‘Acala NemX’ (G. hirsutum L.) and Upland TM-1 (G. hirsutum) × Pima 3-79 (G. barbadense), respectively. Three greenhouse tests and one field test were used to obtain sequential estimates of severity index (DSI) of leaves, and vascular stem and root staining (VRS). A single resistance gene model was observed for the F₂ population based on inheritance of phenotypes. However, additional inheritance analyses and QTL mapping indicated gene interactions and inheritance from nine cotton chromosomes, with major QTLs detected on five chromosomes [Fov1-C06, Fov1-C08, (Fov1-C11 ₁ and Fov1-C11 ₂₎ , Fov1-C16 and Fov1-C19 loci], explaining 8–31% of the DSI or VRS variation. The Fov1-C16 QTL locus identified in the F₂ and in the RIL populations had a significant role in conferring FOV race 1 resistance in different cotton backgrounds. Identified molecular markers may have important potential for breeding effective FOV race 1 resistance into elite cultivars by marker-assisted selection. Reconciliation between genetic and physical mapping of gene annotations from marker-DNA and new DNA sequences of BAC clones tagged with the resistance-associated QTLs revealed defenses genes induced upon pathogen infection and gene regions rich in disease-response elements, respectively. These offer candidate gene targets for Fusarium wilt resistance response in cotton and other host plants.     

Nucleic acid amplification tests for diagnosis of smear-negative TB in a high HIV-prevalence setting: a prospective cohort study

Background

Nucleic acid amplification tests are sensitive for identifying Mycobacterium tuberculosis in populations with positive sputum smears for acid-fast bacilli, but less sensitive in sputum-smear-negative populations. Few studies have evaluated the clinical impact of these tests in low-income countries with high burdens of TB and HIV.

Methods

We prospectively enrolled 211 consecutive adults with cough ≥2 weeks and negative sputum smears at Mulago Hospital in Kampala, Uganda. We tested a single early-morning sputum specimen for Mycobacterium tuberculosis DNA using two nucleic acid amplification tests: a novel in-house polymerase chain reaction targeting the mycobacterial secA1 gene, and the commercial Amplified® Mycobacterium tuberculosis Direct (MTD) test (Gen-Probe Inc, San Diego, CA). We calculated the diagnostic accuracy of these index tests in reference to a primary microbiologic gold standard (positive mycobacterial culture of sputum or bronchoalveolar lavage fluid), and measured their likely clinical impact on additional tuberculosis cases detected among those not prescribed initial TB treatment.

Results

Of 211 patients enrolled, 170 (81%) were HIV-seropositive, with median CD4+ T-cell count 78 cells/µL (interquartile range 29-203). Among HIV-seropositive patients, 94 (55%) reported taking co-trimoxazole prophylaxis and 29 (17%) reported taking antiretroviral therapy. Seventy-five patients (36%) had culture-confirmed TB. Sensitivity of MTD was 39% (95% CI 28–51) and that of secA1 was 24% (95% CI 15–35). Both tests had specificities of 95% (95% CI 90–98). The MTD test correctly identified 18 (24%) TB patients not treated at discharge and led to a 72% relative increase in the smear-negative case detection rate.

Conclusions

The secA1 and MTD nucleic acid amplification tests had moderate sensitivity and high specificity for TB in a predominantly HIV-seropositive population with negative sputum smears. Although newer, more sensitive nucleic acid assays may enhance detection of Mycobacterium tuberculosis in sputum, even currently available tests can provide substantial clinical impact in smear-negative populations.     

Identification and validation of novel cerebrospinal fluid biomarkers for staging early Alzheimer's disease

Background

Ideally, disease modifying therapies for Alzheimer disease (AD) will be applied during the ‘preclinical’ stage (pathology present with cognition intact) before severe neuronal damage occurs, or upon recognizing very mild cognitive impairment. Developing and judiciously administering such therapies will require biomarker panels to identify early AD pathology, classify disease stage, monitor pathological progression, and predict cognitive decline. To discover such biomarkers, we measured AD-associated changes in the cerebrospinal fluid (CSF) proteome.

Methods and Findings

CSF samples from individuals with mild AD (Clinical Dementia Rating [CDR] 1) (n = 24) and cognitively normal controls (CDR 0) (n = 24) were subjected to two-dimensional difference-in-gel electrophoresis. Within 119 differentially-abundant gel features, mass spectrometry (LC-MS/MS) identified 47 proteins. For validation, eleven proteins were re-evaluated by enzyme-linked immunosorbent assays (ELISA). Six of these assays (NrCAM, YKL-40, chromogranin A, carnosinase I, transthyretin, cystatin C) distinguished CDR 1 and CDR 0 groups and were subsequently applied (with tau, p-tau181 and Aβ42 ELISAs) to a larger independent cohort (n = 292) that included individuals with very mild dementia (CDR 0.5). Receiver-operating characteristic curve analyses using stepwise logistic regression yielded optimal biomarker combinations to distinguish CDR 0 from CDR>0 (tau, YKL-40, NrCAM) and CDR 1 from CDR<1 (tau, chromogranin A, carnosinase I) with areas under the curve of 0.90 (0.85–0.94 95% confidence interval [CI]) and 0.88 (0.81–0.94 CI), respectively.

Conclusions

Four novel CSF biomarkers for AD (NrCAM, YKL-40, chromogranin A, carnosinase I) can improve the diagnostic accuracy of Aβ42 and tau. Together, these six markers describe six clinicopathological stages from cognitive normalcy to mild dementia, including stages defined by increased risk of cognitive decline. Such a panel might improve clinical trial efficiency by guiding subject enrollment and monitoring disease progression. Further studies will be required to validate this panel and evaluate its potential for distinguishing AD from other dementing conditions.     

Identification and Characterization of the Cassava Core-Clock Gene EARLY FLOWERING 4

The angiosperm circadian clock has been well established from molecular-genetic studies in a temperate plant model. Conservation of clock function is less explored in plants from the tropics. Cassava (Manihot esculenta) is a staple crop grown in the tropics that has been of limited research interest, and more generally, research on photoperiod and clock genes has been sparse. EARLY FLOWERING 4 (AtELF4) of the temperate plant Arabidopsis thaliana (Arabidopsis) has been reported to be required for photoperiod perception and circadian function. Here, we describe our start to identify circadian and photoperiod genes in cassava with an account on the characterization of its ELF4 gene (MeELF4). After isolating MeELF4, a phylogenetic study was conducted and it was found to cluster within the ELF4 subclade of the ELF4/EFL super-family. Similar to studies in temperate plants, MeELF4 was shown to be an evening-expressed gene in cassava. This collectively suggested to us that MeELF4 could be a functional ortholog of AtELF4. To test this, complementation studies of MeELF4 were performed in the Arabidopsis elf4 mutant. Hypocotyl-length measurements and flowering-time analysis were performed. MeELF4-complementation transgenics in the elf4 background were restored to the wild-type growth habit, suggesting a total rescue of photoperiodic perception. To expand on the molecular role of MeELF4 in the resulting transgenic-complementation lines, the CCA1 and CCR2 promoter-luciferase markers where respectively introduced and bioluminescence-imaging experiments revealed a restoration of circadian-regulated gene expression. The collective results showed that the cassava gene MeELF4 is a functional clock ortholog of AtELF4.     

Human NK cells differ more in their KIR2DL1-dependent thresholds for HLA-Cw6-mediated inhibition than in their maximal killing capacity

In this study we have addressed the question of how activation and inhibition of human NK cells is regulated by the expression level of MHC class I protein on target cells. Using target cell transfectants sorted to stably express different levels of the MHC class I protein HLA-Cw6, we show that induction of degranulation and that of IFN-γ secretion are not correlated. In contrast, the inhibition of these two processes by MHC class-I occurs at the same level of class I MHC protein. Primary human NK cell clones were found to differ in the amount of target MHC class I protein required for their inhibition, rather than in their maximum killing capacity. Importantly, we show that KIR2DL1 expression determines the thresholds (in terms of MHC I protein levels) required for NK cell inhibition, while the expression of other receptors such as LIR1 is less important. Furthermore, using mathematical models to explore the dynamics of target cell killing, we found that the observed delay in target cell killing is exhibited by a model in which NK cells require some activation or priming, such that each cell can lyse a target cell only after being activated by a first encounter with the same or a different target cell, but not by models which lack this feature.     

Pharmacogenetic associations of MMP9 and MMP12 variants with cardiovascular disease in patients with hypertension

Objectives

MMP-9 and -12 function in tissue remodeling and may play roles in cardiovascular disease (CVD). We assessed associations of four MMP polymorphisms and three antihypertensive drugs with cardiovascular outcomes.

Methods

Hypertensives (n = 42,418) from a double-blind, randomized, clinical trial were randomized to chlorthalidone, amlodipine, lisinopril, or doxazosin treatment (mean follow up, 4.9 years). The primary outcome was coronary heart disease (CHD). Secondary outcomes included combined CHD, all CVD outcomes combined, stroke, heart failure (HF), and mortality. Genotype-treatment interactions were tested.

Results

There were 38,698 participants genotyped for at least one of the polymorphisms included here. For MMP9 R668Q (rs2274756), lower hazard ratios (HRs) were found for AA subjects for most outcomes when treated with chlorthalidone versus amlodipine (eg., CCHD: GG = 1.00, GA = 1.01, AA = 0.64; P = 0.038). For MMP9 R279Q (rs17576), modest pharmacogenetic findings were observed for combined CHD and the composite CVD outcome. For MMP12 N122S (rs652438), lower HRs were observed for CHD in subjects carrying at least one G allele and being treated with chlorthalidone versus lisinopril (CHD: AA = 1.07, AG = 0.80, GG = 0.49; P = 0.005). In the lisinopril-amlodipine comparison, higher HRs were observed for participants having at least one G allele at the MMP12 N122S locus (CHD: AA = 0.94, AG = 1.19, GG = 1.93; P = 0.041). For MMP12 −82A>G (rs2276109), no pharmacogenetic effect was found for the primary outcome, although lower HRs were observed for AA homozygotes in the chlorthalidone-amlodipine comparison for HF (P = 0.015).

Conclusions

We observed interactions between antihypertensive drugs and MMP9 and MMP12 for CHD and composite CVD. The data suggest that these genes may provide useful clinical information with respect to treatment decisions.