Drug Susceptibility Patterns in MDR-TB Patients: Challenges for Future Regimen Design. A Cross-Sectional Study

Globally, there is substantial concern regarding the challenges of treating complex drug resistance patterns in multidrug resistant tuberculosis cases. Utilising data from three different settings (Estonia, Latvia, Romania) we sought to contrast drug susceptibility profiles for multidrug resistant tuberculosis cases, highlight the difficulties in designing universal regimen, and inform future regimen selection. Demographic and microbiological surveillance data for multidrug resistant tuberculosis cases from 2004–13 were analysed. High levels of additional resistance to currently recommended second line drugs were seen in all settings, with extensive variability between countries. Accurate drug susceptibility testing and drug susceptibility testing data are vital to inform the development of comprehensive, flexible, multidrug resistant tuberculosis guidance.     

Time-Course Association Mapping of the Grain-Filling Rate in Rice (Oryza sativa L.)

Detecting quantity trait locus (QTLs) and elite alleles that are associated with grain-filling rate (GFR) in rice is essential for promoting the utilization of hybrid japonica rice and improving rice yield. Ninety-five varieties including 58 landraces and 37 elite varieties from the core germplasm collection were genotyped with 263 simple sequence repeat (SSR) markers. The GFR of the 95 varieties was evaluated at five stages, 7, 14, 21, 28 and 35 days after flowering (DAF) both in 2011 and 2012. We found abundant phenotypic and genetic diversity in the studied population. A population structure analysis identified seven subpopulations. A linkage disequilibrium (LD) analysis indicated that the levels of LD ranged from 60.3 cM to 84.8 cM and artificial selection had enhanced the LD. A time-course association analysis detected 31 marker-GFR associations involving 24 SSR markers located on chromosomes 1, 2, 3, 4, 5, 6, 8, 9, 11 and 12 of rice at five stages. The elite alleles for high GFR at each stage were detected. Fifteen excellent parental combinations were predicted, and the best parental combination ‘Nannongjing62401×Laolaihong’ could theoretically increase 4.086 mg grain^-1 d^-1 at the five stages. Our results demonstrate that the time-course association mapping for GFR in rice could detect elite alleles at different filling stages and that these elite alleles could be used to improve the GFR via pyramiding breeding.     

Tuberculosis Prevention in South Africa

Background

South Africa has one of the highest per capita rates of tuberculosis (TB) incidence in the world. In 2012, the South African government produced a National Strategic Plan (NSP) to control the spread of TB with the ambitious aim of zero new TB infections and deaths by 2032, and a halving of the 2012 rates by 2016.

Methods

We used a transmission model to investigate whether the NSP targets could be reached if immediate scale up of control methods had happened in 2014. We explored the potential impact of four intervention portfolios; 1) “NSP” represents the NSP strategy, 2) “WHO” investigates increasing antiretroviral therapy eligibility, 3) “Novel Strategies” considers new isoniazid preventive therapy strategies and HIV “Universal Test and Treat” and 4) “Optimised” contains the most effective interventions.

Findings

We find that even with this scale-up, the NSP targets are unlikely to be achieved. The portfolio that achieved the greatest impact was “Optimised”, followed closely by “NSP”. The “WHO” and “Novel Strategies” had little impact on TB incidence by 2050. Of the individual interventions explored, the most effective were active case finding and reductions in pre-treatment loss to follow up which would have a large impact on TB burden.

Conclusion

Use of existing control strategies has the potential to have a large impact on TB disease burden in South Africa. However, our results suggest that the South African TB targets are unlikely to be reached without new technologies. Despite this, TB incidence could be dramatically reduced by finding and starting more TB cases on treatment.     

Intraskeletal isotopic compositions (δ13C, δ15N) of bone collagen: Nonpathological and pathological variation

Paleodiet research traditionally interprets differences in collagen isotopic compositions (δ¹³C, δ¹⁵N) as indicators of dietary distinction even though physiological processes likely play some role in creating variation. This research investigates the degree to which bone collagen δ¹³C and δ¹⁵N values normally vary within the skeleton and examines the influence of several diseases common to ancient populations on these isotopic compositions. The samples derive from two medieval German cemeteries and one Swiss reference collection and include examples of metabolic disease (rickets/osteomalacia), degenerative joint disease (osteoarthritis), trauma (fracture), infection (osteomyelitis), and inflammation (periostitis). A separate subset of visibly nonpathological skeletal elements from the German collections established normal intraindividual variation. For each disease type, tests compared bone lesion samples to those near and distant to the lesions sites. Results show that normal (nonpathological) skeletons exhibit limited intraskeletal variation in carbon‐ and nitrogen‐isotope ratios, suggesting that sampling of distinct elements is appropriate for paleodiet studies. In contrast, individuals with osteomyelitis, healed fractures, and osteoarthritis exhibit significant intraskeletal differences in isotope values, depending on whether one is comparing lesions to near or to distant sites. Skeletons with periostitis result in significant intraskeletal differences in nitrogen isotope values only, while those with rickets/osteomalacia do not exhibit significant intraskeletal differences. Based on these results, we suggest that paleodiet researchers avoid sampling collagen at or close to lesion sites because the isotope values may be reflecting both altered metabolic processes and differences in diet relative to others in the population. Am J Phys Anthropol 153:598–604, 2014. © 2013 Wiley Periodicals, Inc.     

Climate change increases risk of fusarium ear blight on wheat in central China

To estimate potential impact of climate change on wheat fusarium ear blight (FEB), simulated weather for the A1B climate change scenario was input into a model for estimating FEB in central China. In this article, a logistic weather‐based regression model for estimating incidence of wheat FEB in central China was developed, using up to 10 years (2001–2010) of disease, anthesis date and weather data available for 10 locations in Anhui and Hubei provinces. In the model, the weather variables were defined with respect to the anthesis date for each location in each year. The model suggested that incidence of FEB is related to number of days of rainfall in a 30‐day period after anthesis and that high temperatures before anthesis increase the incidence of disease. Validation was done to test whether this relationship was satisfied for another five locations in Anhui province with FEB data for 4–5 years but no nearby weather data, using simulated weather data obtained employing the regional climate modelling system PRECIS. How climate change may affect wheat anthesis date and FEB in central China was investigated for period 2020–2050 using wheat growth model Sirius and climate data simulated using PRECIS. The projection suggested that wheat anthesis dates will generally be earlier and FEB incidence will increase substantially for most locations.     

THE COEVOLUTIONARY IMPLICATIONS OF HOST TOLERANCE

Host tolerance to infectious disease, whereby hosts do not directly “fight” parasites but instead ameliorate the damage caused, is an important defense mechanism in both plants and animals. Because tolerance to parasite virulence may lead to higher prevalence of disease in a population, evolutionary theory tells us that while the spread of resistance genes will result in negative frequency dependence and the potential for diversification, the evolution of tolerance is instead likely to result in fixation. However, our understanding of the broader implications of tolerance is limited by a lack of fully coevolutionary theory. Here we examine the coevolution of tolerance across a comprehensive range of classic coevolutionary host–parasite frameworks, including equivalents of gene‐for‐gene and matching allele and evolutionary invasion models. Our models show that the coevolution of host tolerance and parasite virulence does not lead to the generation and maintenance of diversity through either static polymorphisms or through “Red‐queen” cycles. Coevolution of tolerance may however lead to multiple stable states leading to sudden shifts in parasite impacts on host health. More broadly, we emphasize that tolerance may change host–parasite interactions from antagonistic to a form of “apparent commensalism,” but may also lead to the evolution of parasites that are highly virulent in nontolerant hosts.     

IRS1 phosphorylation does not mediate mTORC1-induced insulin resistance

Increased mammalian target of rapamycin complex 1 (mTORC1) activity has been suggested to play important roles in development of insulin resistance in obesity. mTORC1 hyperactivity also increases endoplasmic reticulum (ER) stress, which in turn contributes to development of insulin resistance and glucose intolerance. Increased IRS1 phosphorylation at Ser307 in vitro is correlated with mTORC1- and ER stress-induced insulin resistance. This phosphorylation site correlates strongly with impaired insulin receptor signaling in diabetic mice and humans. In contrast, evidence from knock-in mice suggests that phosphorylation of IRS1 at Ser307 is actually required to maintain insulin sensitivity. To study the involvement of IRS1^Ser307 phosphorylation in mTORC1-mediated glucose intolerance and insulin sensitivity in vivo, we investigated the effects of liver specific TSC1 depletion in IRS1^Ser307Ala mice and controls. Our results demonstrate that blockade of IRS1^Ser307 phosphorylation in vivo does not prevent mTORC1-mediated glucose intolerance and insulin resistance.     

Three-Dimensional Organization of Troponin on Cardiac Muscle Thin Filaments in the Relaxed State

Muscle contraction is regulated by troponin-tropomyosin, which blocks and unblocks myosin binding sites on actin. To elucidate this regulatory mechanism, the three-dimensional organization of troponin and tropomyosin on the thin filament must be determined. Although tropomyosin is well defined in electron microscopy helical reconstructions of thin filaments, troponin density is mostly lost. Here, we determined troponin organization on native relaxed cardiac muscle thin filaments by applying single particle reconstruction procedures to negatively stained specimens. Multiple reference models led to the same final structure, indicating absence of model bias in the procedure. The new reconstructions clearly showed F-actin, tropomyosin, and troponin densities. At the 25 Å resolution achieved, troponin was considerably better defined than in previous reconstructions. The troponin density closely resembled the shape of troponin crystallographic structures, facilitating detailed interpretation of the electron microscopy density map. The orientation of troponin-T and the troponin core domain established troponin polarity. Density attributable to the troponin-I mobile regulatory domain was positioned where it could hold tropomyosin in its blocking position on actin, thus suggesting the underlying structural basis of thin filament regulation. Our previous understanding of thin filament regulation had been limited to known movements of tropomyosin that sterically block and unblock myosin binding sites on actin. We now show how troponin, the Ca²⁺ sensor, may control these movements, ultimately determining whether muscle contracts or relaxes.     

Temperature and Electrolyte Optimization of the α-Hemolysin Latch Sensing Zone for Detection of Base Modification in Double-Stranded DNA

The latch region of the wild-type protein pore α-hemolysin (α-HL) constitutes a sensing zone for individual abasic sites (and furan analogs) in double-stranded DNA (dsDNA). The presence of an abasic site or furan within a DNA duplex, electrophoretically captured in the α-HL vestibule and positioned at the latch region, can be detected based on the current blockage prior to duplex unzipping. We investigated variations in blockage current as a function of temperature (12–35°C) and KCl concentration (0.15–1.0 M) to understand the origin of the current signature and to optimize conditions for identifying the base modification. In 1 M KCl solution, substitution of a furan for a cytosine base in the latch region results in an ∼8 kJ mol⁻¹ decrease in the activation energy for ion transport through the protein pore. This corresponds to a readily measured ∼2 pA increase in current at room temperature. Optimal resolution for detecting the presence of a furan in the latch region is achieved at lower KCl concentrations, where the noise in the measured blockage current is significantly lower. The noise associated with the blockage current also depends on the stability of the duplex (as measured from the melting temperature), where a greater noise in the measured blockage current is observed for less stable duplexes.