AVOCADO TREE STRUCTURING

Abstract Tree form in Persea americana varies from tall and open to short and compact with varying composites. Tree form is modified in the nursery by grafting, pinching, pruning and nursery spacing. Therefore, the resulting tree is not necessarily in the shape programmed by its genetic information, but has been modified by nursery conditions. The authors point out the problems with the present tree form, and offer an alternative form, the central-leader. Where the centralleader form is most appropriate and how it may enhance orchard productivity is discussed

High Prevalence of Antibiotic-Resistant Mycoplasma genitalium in Nongonococcal Urethritis: The Need for Routine Testing and the Inadequacy of Current Treatment Options.

Background. Empirical antibiotic therapy for nongonococcal urethritis (NGU) and cervicitis is aimed at Chlamydia trachomatis, but Mycoplasma genitalium, which also commonly causes undiagnosed NGU, necessitates treatment with macrolides or fluoroquinolones rather than doxycycline, the preferred chlamydia treatment. Prevalence of M. genitalium and associated genotypic markers of macrolide and fluoroquinolone resistance among men symptomatic of urethritis were investigated. Genetic diversity of M. genitalium populations was determined to infer whether findings were applicable beyond our setting. Methods. Mycoplasma genitalium and other NGU pathogens were detected using nucleic acid amplification methods, and DNA sequencing was used to detect genotypic resistance markers of macrolide and fluoroquinolone antibiotics in 23S ribosomal RNA, gyrA, gyrB, and parC genes. MG191 single-nucleotide polymorphism typing and MG309 variable number tandem analysis were combined to assign a dual locus sequence type (DLST) to each positive sample. Results. Among 217 men, M. genitalium prevalence was 16.7% (95% confidence interval [CI], 9.5%-24.0%) and C. trachomatis prevalence was 14.7% (95% CI, 7.8%-21.6%) in NGU cases. Nine of 22 (41%; 95% CI, 20%-62%) patients with M. genitalium were infected with DLSTs possessing genotypic macrolide resistance and 1 patient was infected with a DLST having genotypic fluoroquinolone resistance. Typing assigned M. genitalium DLSTs to 2 major clusters, broadly distributed among previously typed international strains. Genotypic macrolide resistance was spread within these 2 clusters. Conclusions. Mycoplasma genitalium is a frequent undiagnosed cause of NGU in this population with rates of macrolide resistance higher than those previously documented. Current guidelines for routine testing and empirical treatment of NGU should be modified to reduce treatment failure of NGU and the development of further resistance

Whole-genome sequencing illuminates the evolution and spread of multidrug-resistant tuberculosis in Southwest Nigeria.

Nigeria has an emerging problem with multidrug-resistant tuberculosis (MDR-TB). Whole-genome sequencing was used to understand the epidemiology of tuberculosis and genetics of multi-drug resistance among patients from two tertiary referral centers in Southwest Nigeria. In line with previous molecular epidemiology studies, most isolates of Mycobacterium tuberculosis from this dataset belonged to the Cameroon clade within the Euro-American lineage. Phylogenetic analysis showed this clade was undergoing clonal expansion in this region, and suggests that it was involved in community transmission of sensitive and multidrug-resistant tuberculosis. Five patients enrolled for retreatment were infected with pre-extensively drug resistant (pre-XDR) due to fluoroquinolone resistance in isolates from the Cameroon clade. In all five cases resistance was conferred through a mutation in the gyrA gene. In some patients, genomic changes occurred in bacterial isolates during the course of treatment that potentially led to decreased drug susceptibility. We conclude that inter-patient transmission of resistant isolates, principally from the Cameroon clade, contributes to the spread of MDR-TB in this setting, underscoring the urgent need to curb the spread of multi-drug resistance in this region

Myocilin Predictive Genetic Testing for Primary Open-Angle Glaucoma Leads to Early Identification of At-Risk Individuals.

This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/. Following 12 month embargo from date of publication (16 Dec 2016

mRNA therapy corrects defective glutathione metabolism and restores ureagenesis in preclinical argininosuccinic aciduria

The urea cycle enzyme argininosuccinate lyase (ASL) enables the clearance of neurotoxic ammonia and the biosynthesis of arginine. Patients with ASL deficiency present with argininosuccinic aciduria, an inherited metabolic disease with hyperammonemia and a systemic phenotype coinciding with neurocognitive impairment and chronic liver disease. Here, we describe the dysregulation of glutathione biosynthesis and upstream cysteine utilization in ASL-deficient patients and mice using targeted metabolomics and in vivo positron emission tomography (PET) imaging using ( S)-4-(3-18F-fluoropropyl)-l-glutamate ([18F]FSPG). Up-regulation of cysteine metabolism contrasted with glutathione depletion and down-regulated antioxidant pathways. To assess hepatic glutathione dysregulation and liver disease, we present [18F]FSPG PET as a noninvasive diagnostic tool to monitor therapeutic response in argininosuccinic aciduria. Human hASL mRNA encapsulated in lipid nanoparticles improved glutathione metabolism and chronic liver disease. In addition, hASL mRNA therapy corrected and rescued the neonatal and adult Asl-deficient mouse phenotypes, respectively, enhancing ureagenesis. These findings provide mechanistic insights in liver glutathione metabolism and support clinical translation of mRNA therapy for argininosuccinic aciduria. </p

Antistaphylococcal activity of DNA-interactive pyrrolobenzodiazepine (PBD) dimers and PBD-biaryl conjugates

Objectives: pyrrolobenzodiazepine (PBD) dimers, tethered through inert propyldioxy or pentyldioxy linkers, possess potent bactericidal activity against a range of Gram-positive bacteria by virtue of their capacity to cross-link duplex DNA in sequence-selective fashion. Here we attempt to improve the antibacterial activity and cytotoxicity profile of PBD-containing conjugates by extension of dimer linkers and replacement of one PBD unit with phenyl-substituted or benzo-fused heterocycles that facilitate non-covalent interactions with duplex DNA.Methods: DNase I footprinting was used to identify high-affinity DNA binding sites. A staphylococcal gene microarray was used to assess epidemic methicillin-resistant Staphylococcus aureus 16 phenotypes induced by PBD conjugates. Molecular dynamics simulations were employed to investigate the accommodation of compounds within the DNA helix.Results: increasing the length of the linker in PBD dimers led to a progressive reduction in antibacterial activity, but not in their cytotoxic capacity. Complex patterns of DNA binding were noted for extended PBD dimers. Modelling of DNA strand cross-linking by PBD dimers indicated distortion of the helix. A majority (26 of 43) of PBD-biaryl conjugates possessed potent antibacterial activity with little or no helical distortion and a more favourable cytotoxicity profile. Bactericidal activity of PBD-biaryl conjugates was determined by inability to excise covalently bound drug molecules from bacterial duplex DNA.Conclusions: PBD-biaryl conjugates have a superior antibacterial profile compared with PBD dimers such as ELB-21. We have identified six PBD-biaryl conjugates as potential drug development candidate

Variability in depression prevalence in early rheumatoid arthritis: a comparison of the CES-D and HAD-D Scales

<p>Abstract</p> <p>Background</p> <p>Depression is common in rheumatoid arthritis (RA), however reported prevalence varies considerably. Two frequently used instruments to identify depression are the Center for Epidemiological Studies Depression (CES-D) scale, and the Hospital Anxiety and Depression Scale (HADS). The objectives of this study were to test if the CES-D and HADS-D (a) satisfy current modern psychometric standards for unidimensional measurement in an early RA sample; (b) measure the same construct (i.e. depression); and (c) identify similar levels of depression.</p> <p>Methods</p> <p>Data from the two scales completed by patients with early RA were fitted to the Rasch measurement model to show that (a) each scale satisfies the criteria of fit to the model, including strict unidimensionality; (b) that the scales can be co-calibrated onto a single underlying continuum of depression and to (c) examine the location of the cut points on the underlying continuum as indication of the prevalence of depression.</p> <p>Results</p> <p>Ninety-two patients with early RA (62% female; mean age = 56.3, SD = 13.7) gave 141 sets of paired CES-D and HAD-D data. Fit of the data from the CES-D was found to be poor, and the scale had to be reduced to 13 items to satisfy Rasch measurement criteria whereas the HADS-D met model expectations from the outset. The 20 items combined (CES-D13 and HADS-D) satisfied Rasch model expectations. The CES-D gave a much higher prevalence of depression than the HADS-D.</p> <p>Conclusion</p> <p>The CES-D in its present form is unsuitable for use in patients with early RA, and needs to be reduced to a 13-item scale. The HADS-D is valid for early RA and the two scales measure the same underlying construct but their cut points lead to different estimates of the level of depression. Revised cut points on the CES-D13 provide comparative prevalence rates.</p

Rapid determination of anti-tuberculosis drug resistance from whole-genome sequences

Mycobacterium tuberculosis drug resistance (DR) challenges effective tuberculosis disease control. Current molecular tests examine limited numbers of mutations, and although whole genome sequencing approaches could fully characterise DR, data complexity has restricted their clinical application. A library (1,325 mutations) predictive of DR for 15 anti-tuberculosis drugs was compiled and validated for 11 of them using genomic-phenotypic data from 792 strains. A rapid online ‘TB-Profiler’ tool was developed to report DR and strain-type profiles directly from raw sequences. Using our DR mutation library, in silico diagnostic accuracy was superior to some commercial diagnostics and alternative databases. The library will facilitate sequence-based drug-susceptibility testing

Interpreting whole genome sequencing for investigating tuberculosis transmission: a systematic review

BACKGROUND: Whole genome sequencing (WGS) is becoming an important part of epidemiological investigations of infectious diseases due to greater resolution and cost reductions compared to traditional typing approaches. Many public health and clinical teams will increasingly use WGS to investigate clusters of potential pathogen transmission, making it crucial to understand the benefits and assumptions of the analytical methods for investigating the data. We aimed to understand how different approaches affect inferences of transmission dynamics and outline limitations of the methods. METHODS: We comprehensively searched electronic databases for studies that presented methods used to interpret WGS data for investigating tuberculosis (TB) transmission. Two authors independently selected studies for inclusion and extracted data. Due to considerable methodological heterogeneity between studies, we present summary data with accompanying narrative synthesis rather than pooled analyses. RESULTS: Twenty-five studies met our inclusion criteria. Despite the range of interpretation tools, the usefulness of WGS data in understanding TB transmission often depends on the amount of genetic diversity in the setting. Where diversity is small, distinguishing re-infections from relapses may be impossible; interpretation may be aided by the use of epidemiological data, examining minor variants and deep sequencing. Conversely, when within-host diversity is large, due to genetic hitchhiking or co-infection of two dissimilar strains, it is critical to understand how it arose. Greater understanding of microevolution and mixed infection will enhance interpretation of WGS data. CONCLUSIONS: As sequencing studies have sampled more intensely and integrated multiple sources of information, the understanding of TB transmission and diversity has grown, but there is still much to be learnt about the origins of diversity that will affect inferences from these data. Public health teams and researchers should combine epidemiological, clinical and WGS data to strengthen investigations of transmission