Simulation of weather-driven deterioration of clay embankments

Clay embankments used for road, rail, and flood defense infrastructure experience several weather-driven deterioration processes that lead to a progressive degradation in their hydromechanical performance. This paper presents a numerical modeling approach that accounts for the development of desiccation cracking in clay embankments. Specifically, a bimodal soil water retentivity model was adopted to capture the long-term hydraulic behavior of clay embankments prone to weather-driven desiccation cracking. A numerical model was developed for a heavily instrumented and monitored full-scale research embankment with long-term field data. The model was able to capture the variation of near-surface soil moisture and matric suction over a monitored period of nine years in response to weather cycles. The developed and validated numerical modeling approach enables forecasting of the long-term performance of clay embankments under a range of future climate scenarios

ACHILLES Reading Guide 3: Asset scale deterioration

The deterioration of earthworks reduces theirserviceable performance and increases thelikelihood of instability. This can havesignificant impacts on the safe and reliableoperation of the transportation networks thatthey support. These deterioration processesare weather-driven and may lead to failuremany years after construction even in theabsence of increased mechanical loads.Evidence also indicates that climate changewill increase rates of asset deterioration andreduce time to failure. This documentsummarises the key conclusions on assetdeterioration drawn from the ACHILLES bodyof work. A more detailed overview of theACHILLES concept can be found in ReadingGuide 1 [1], the project website (achilles-grant.org.uk), and the following papers: [2,3]

Emulating long-term weather-driven transportation earthworks deterioration models to support asset management

The deterioration of transport infrastructure earthworks is a global problem, with negative impacts for infrastructure resilience, becoming of increasing significance as existing infrastructure ages. Key mechanisms which affect this deterioration include seasonal pore pressure cycling driven by changing weather and climate, and the long-term dissipation of construction induced excess pore pressures. These complex processes lead to significant uncertainty in rates of deterioration and the current state of existing earthworks assets. The objective in this work was to establish a framework to emulate deterministic numerical models of slope deterioration over time using statistical (Gaussian process) emulation. A validated, physically based, deterministic modeling capability has been developed that can replicate the hydro-mechanically coupled behavior of cut and embankment slopes and their deterioration as driven by weather and climate. In parallel, a statistical (Gaussian process) emulator model was developed, and then trained with data from a deterministic modeling parametric study, using a formal experimental design approach, making use of Latin hypercube sampling. Exemplar forecasting outputs are presented to demonstrate application of the approach for use in decision-making. This information can be used in the design of new earthworks and the management of existing earthwork portfolio

Factors associated with low cure rate of tuberculosis in remote poor areas of Shaanxi Province, China: a case control study

<p>Abstract</p> <p>Background</p> <p>The directly observed therapy-short course (DOTS) strategy was introduced in Shaanxi province, China to improve tuberculosis (TB) control by means of improved case detection (target: > = 70%) and treatment success rates (target: > = 85%) in new smear positive (SS+) TB patients. At a provincial level the targets were both reached in 2005. However in 30 (28%) out of 107 counties of Shaanxi province the cure rate was below 85%. This study aimed to investigate patient and treatment characteristics associated with non-cure after tuberculosis (TB) treatment in these counties.</p> <p>Methods</p> <p>In this case-control study, new smear positive TB cases in 30 counties with a cure rate <85% were included. Cured patients were compared to non-cured patients using logistic regression analysis to assess determinants for non-cure.</p> <p>Results</p> <p>Of the 659 patients included, 153 (23.2%) did not have cure as treatment outcome. Interruption of treatment was most strongly associated with non-cure (OR = 8.7, 95% CI 3.9-18.4). Other independent risk factors were co-morbidity, low education level, lack of appetite as an initial symptom of TB disease, diagnosis of TB outside of the government TB control institutes, missing sputum re-examinations during treatment, and not having a treatment observer. Twenty-six percent of patients did not have a treatment observer. The non-cure rate was better for those with a doctor (odds ratio (OR) 0.38, 95% confidence interval (CI) 0.17-0.88) as treatment observer than for those with a family member (OR 0.62, 95%CI 0.37-1.03). The main reason for interrupted treatment mentioned by patients was presence of adverse effects during treatment (46.5%).</p> <p>Conclusions</p> <p>Interruption of treatment was most strongly associated with non-cure. Although treatment observation by medical staff is preferred, in order to diminish the proportion of patients who do not have a treatment observer and thereby reduce the proportion of patients who interrupt treatment, we suggest making it possible for family members, after sufficient training, to be treatment observers in remote areas where it is logistically difficult to have village doctors observe treatment for all patients.</p

Homozygous Resistance to Thyroid Hormone β: Can combined anti-thyroid drug and triiodothyroacetic acid treatment prevent cardiac failure?

Resistance to Thyroid Hormone beta (RTHβ) due to homozygous THRB defects is exceptionally rare, with only five cases reported worldwide; cardiac dysfunction, which can be life-threatening, is recognised in the disorder. Here we describe the clinical, metabolic, ophthalmic and cardiac findings in a nine-year old boy harbouring a biallelic THRB mutation (R243Q), along with biochemical, physiological and cardiac responses to carbimazole and triiodothyroacetic acid (TRIAC) therapy. The patient exhibits recognised features (goitre, non-suppressed TSH levels, upper respiratory tract infections, hyperactivity, low body mass index) of heterozygous RTHβ, with additional characteristics (dysmorphic facies, winging of scapulae) and more markedly elevated thyroid hormone levels, associated with the homozygous form of the disorder. Notably, an older sibling with similar clinical features and probable homozygous RTHβ, had died of cardiac failure at age 13 yrs. Features of early dilated cardiomyopathy in our patient prompted combination treatment with carbimazole and TRIAC. Careful titration of therapy limited elevation in TSH levels and associated increase in thyroid volume. Subsequently, sustained reduction in thyroid hormones with normal TSH levels was reflected in lower basal metabolic rate, gain of lean body mass and improved growth and cardiac function. A combination of anti-thyroid drug and TRIAC therapy may prevent hyrotoxic cardiomyopathy and its decompensation in homozygous or even heterozygous RTHβ in which life-threatening hyperthyroid features predominate.Our research is supported by funding from the Wellcome Trust (095564/Z/11/Z to K.C.), National Institute for Health Research Cambridge Biomedical Research Centre (C.M., K.C.), the Great Ormond Street Hospital Children’s Charity (F.V.K., M.D.), and Medical Research Council (MRC Programme no. U105960371 to K.W.). G.E.H. receives research funding from the National Institute for Health Research (United Kingdom) and the Foundation Fighting Blindness (United States)

Identification of a Novel Calotropis procera Protein That Can Suppress Tumor Growth in Breast Cancer through the Suppression of NF-κB Pathway

10.1371/journal.pone.0048514PLoS ONE712

Characterizing the morbid genome of ciliopathies

Background Ciliopathies are clinically diverse disorders of the primary cilium. Remarkable progress has been made in understanding the molecular basis of these genetically heterogeneous conditions; however, our knowledge of their morbid genome, pleiotropy, and variable expressivity remains incomplete. Results We applied genomic approaches on a large patient cohort of 371 affected individuals from 265 families, with phenotypes that span the entire ciliopathy spectrum. Likely causal mutations in previously described ciliopathy genes were identified in 85% (225/265) of the families, adding 32 novel alleles. Consistent with a fully penetrant model for these genes, we found no significant difference in their “mutation load” beyond the causal variants between our ciliopathy cohort and a control non-ciliopathy cohort. Genomic analysis of our cohort further identified mutations in a novel morbid gene TXNDC15, encoding a thiol isomerase, based on independent loss of function mutations in individuals with a consistent ciliopathy phenotype (Meckel-Gruber syndrome) and a functional effect of its deficiency on ciliary signaling. Our study also highlighted seven novel candidate genes (TRAPPC3, EXOC3L2, FAM98C, C17orf61, LRRCC1, NEK4, and CELSR2) some of which have established links to ciliogenesis. Finally, we show that the morbid genome of ciliopathies encompasses many founder mutations, the combined carrier frequency of which accounts for a high disease burden in the study population. Conclusions Our study increases our understanding of the morbid genome of ciliopathies. We also provide the strongest evidence, to date, in support of the classical Mendelian inheritance of Bardet-Biedl syndrome and other ciliopathies

Diagnostic implications of pitfalls in causal variant identification based on 4577 molecularly characterized families

Despite large sequencing and data sharing efforts, previously characterized pathogenic variants only account for a fraction of Mendelian disease patients, which highlights the need for accurate identification and interpretation of novel variants. In a large Mendelian cohort of 4577 molecularly characterized families, numerous scenarios in which variant identification and interpretation can be challenging are encountered. We describe categories of challenges that cover the phenotype (e.g. novel allelic disorders), pedigree structure (e.g. imprinting disorders masquerading as autosomal recessive phenotypes), positional mapping (e.g. double recombination events abrogating candidate autozygous intervals), gene (e.g. novel gene-disease assertion) and variant (e.g. complex compound inheritance). Overall, we estimate a probability of 34.3% for encountering at least one of these challenges. Importantly, our data show that by only addressing non-sequencing-based challenges, around 71% increase in the diagnostic yield can be expected. Indeed, by applying these lessons to a cohort of 314 cases with negative clinical exome or genome reports, we could identify the likely causal variant in 54.5%. Our work highlights the need to have a thorough approach to undiagnosed diseases by considering a wide range of challenges rather than a narrow focus on sequencing technologies. It is hoped that by sharing this experience, the yield of undiagnosed disease programs globally can be improved

Light Plays an Essential Role in Intracellular Distribution of Auxin Efflux Carrier PIN2 in Arabidopsis thaliana

BACKGROUND: Light plays a key role in multiple plant developmental processes. It has been shown that root development is modulated by shoot-localized light signaling and requires shoot-derived transport of the plant hormone, auxin. However, the mechanism by which light regulates root development is not largely understood. In plants, the endogenous auxin, indole-3-acetic acid, is directionally transported by plasma-membrane (PM)-localized auxin influx and efflux carriers in transporting cells. Remarkably, the auxin efflux carrier PIN proteins exhibit asymmetric PM localization, determining the polarity of auxin transport. Similar to PM-resident receptors and transporters in animal and yeast cells, PIN proteins undergo constitutive cycling between the PM and endosomal compartments. Auxin plays multiple roles in PIN protein intracellular trafficking, inhibiting PIN2 endocytosis at some concentrations and promoting PIN2 degradation at others. However, how PIN proteins are turned over in plant cells is yet to be addressed. METHODOLOGY AND PRINCIPLE FINDINGS: Using laser confocal scanning microscopy, and physiological and molecular genetic approaches, here, we show that in dark-grown seedlings, the PM localization of auxin efflux carrier PIN2 was largely reduced, and, in addition, PIN2 signal was detected in vacuolar compartments. This is in contrast to light-grown seedlings where PIN2 was predominantly PM-localized. In light-grown plants after shift to dark or to continuous red or far-red light, PIN2 also accumulated in vacuolar compartments. We show that PIN2 vacuolar targeting was derived from the PM via endocytic trafficking and inhibited by HY5-dependent light signaling. In addition, the ubiquitin 26S proteasome is involved in the process, since its inhibition by mutations in COP9 and a proteasome inhibitor MG132 impaired the process. CONCLUSIONS AND SIGNIFICANCE: Collectively, our data indicate that light plays an essential role in PIN2 intracellular trafficking, promoting PM-localization in the presence of light and, on the other hand, vacuolar targeting for protein degradation in the absence of light. Based on these results, we postulate that light regulation of root development is mediated at least in part by changes in the intracellular distribution of auxin efflux carriers, PIN proteins, in response to the light environment