The origin of large molecules in primordial autocatalytic reaction networks

Large molecules such as proteins and nucleic acids are crucial for life, yet their primordial origin remains a major puzzle. The production of large molecules, as we know it today, requires good catalysts, and the only good catalysts we know that can accomplish this task consist of large molecules. Thus the origin of large molecules is a chicken and egg problem in chemistry. Here we present a mechanism, based on autocatalytic sets (ACSs), that is a possible solution to this problem. We discuss a mathematical model describing the population dynamics of molecules in a stylized but prebiotically plausible chemistry. Large molecules can be produced in this chemistry by the coalescing of smaller ones, with the smallest molecules, the `food set', being buffered. Some of the reactions can be catalyzed by molecules within the chemistry with varying catalytic strengths. Normally the concentrations of large molecules in such a scenario are very small, diminishing exponentially with their size. ACSs, if present in the catalytic network, can focus the resources of the system into a sparse set of molecules. ACSs can produce a bistability in the population dynamics and, in particular, steady states wherein the ACS molecules dominate the population. However to reach these steady states from initial conditions that contain only the food set typically requires very large catalytic strengths, growing exponentially with the size of the catalyst molecule. We present a solution to this problem by studying `nested ACSs', a structure in which a small ACS is connected to a larger one and reinforces it. We show that when the network contains a cascade of nested ACSs with the catalytic strengths of molecules increasing gradually with their size (e.g., as a power law), a sparse subset of molecules including some very large molecules can come to dominate the system.Comment: 49 pages, 17 figures including supporting informatio

An ENU-induced mutation of miR-96 associated with progressive hearing loss in mice.

Progressive hearing loss is common in the human population, but little is known about the molecular basis. We report a new N-ethyl-N-nitrosurea (ENU)-induced mouse mutant, diminuendo, with a single base change in the seed region of Mirn96. Heterozygotes show progressive loss of hearing and hair cell anomalies, whereas homozygotes have no cochlear responses. Most microRNAs are believed to downregulate target genes by binding to specific sites on their mRNAs, so mutation of the seed should lead to target gene upregulation. Microarray analysis revealed 96 transcripts with significantly altered expression in homozygotes; notably, Slc26a5, Ocm, Gfi1, Ptprq and Pitpnm1 were downregulated. Hypergeometric P-value analysis showed that hundreds of genes were upregulated in mutants. Different genes, with target sites complementary to the mutant seed, were downregulated. This is the first microRNA found associated with deafness, and diminuendo represents a model for understanding and potentially moderating progressive hair cell degeneration in hearing loss more generally

Socioeconomic differences in cancer survival: The Norwegian Women and Cancer Study

<p>Abstract</p> <p>Background</p> <p>Cancer survival has been observed to be poorer in low socioeconomic groups, but the knowledge about the underlying causal factors is limited. The purpose of this study was to examine how cancer survival varies by socioeconomic status (SES) among women in Norway, and to identify factors that explain this variation. SES was measured by years of education and gross household income, respectively.</p> <p>Methods</p> <p>We used data from The Norwegian Women and Cancer Study, a prospective cohort study including 91 814 women who responded to an extensive questionnaire between 1996 and 1998. A total of 3 899 incident cancer cases were diagnosed during follow-up, of whom 1 089 women died, 919 of them from cancer. Cox Proportional Hazards Model was used to calculate relative risks (RR) of mortality and 95% confidence intervals.</p> <p>Results</p> <p>We observed an overall negative socioeconomic gradient in cancer survival, which was most evident in the site specific analyses for survival of ovarian cancer by years of education. For colorectal cancer, mortality increased with years of education, but not with income. After adjustment for household size, marital status, disease stage, and smoking status the SES variation in cancer survival became non-significant. We found that the unequal socioeconomic distribution of smoking status prior to diagnosis contributed considerably to the poorer survival in low SES groups.</p> <p>Conclusion</p> <p>We found an overall negative socioeconomic gradient in cancer survival when SES is measured as years of education or gross household income. Smoking status prior to diagnosis was an important predictive factor for socioeconomic variation in survival.</p

Effects of rose hip intake on risk markers of type 2 diabetes and cardiovascular disease: a randomized, double-blind, cross-over investigation in obese persons

BACKGROUND/OBJECTIVES:In studies performed in mice, rose hip powder has been shown to both prevent and reverse high-fat diet-induced obesity and glucose intolerance as well as reduce plasma levels of cholesterol. The aim of this study was to investigate whether daily intake of rose hip powder over 6 weeks exerts beneficial metabolic effects in obese individuals.SUBJECTS/METHODS:A total of 31 obese individuals with normal or impaired glucose tolerance were enrolled in a randomized, double-blind, cross-over study in which metabolic effects of daily intake of a rose hip powder drink over 6 weeks was compared with a control drink. Body weight, glucose tolerance, blood pressure, blood lipids and markers of inflammation were assessed in the subjects.RESULTS:In comparison with the control drink, 6 weeks of daily consumption of the rose hip drink resulted in a significant reduction of systolic blood pressure (-3.4%; P=0.021), total plasma cholesterol (-4.9%; P=0.0018), low-density lipoprotein (LDL) cholesterol (-6.0%; P=0.012) and LDL/HDL ratio (-6.5%; P=0.041). The Reynolds risk assessment score for cardiovascular disease was decreased in the rose hip group compared with the control group (-17%; P=0.007). Body weight, diastolic blood pressure, glucose tolerance, and plasma levels of high-density lipoprotein (HDL) cholesterol, triglycerides, incretins and markers of inflammation did not differ between the two groups.CONCLUSIONS:Daily consumption of 40 g of rose hip powder for 6 weeks can significantly reduce cardiovascular risk in obese people through lowering of systolic blood pressure and plasma cholesterol levels.European Journal of Clinical Nutrition advance online publication, 14 December 2011; doi:10.1038/ejcn.2011.203

MyosinVIIa Interacts with Twinfilin-2 at the Tips of Mechanosensory Stereocilia in the Inner Ear

In vertebrates hearing is dependent upon the microvilli-like mechanosensory stereocilia and their length gradation. The staircase-like organization of the stereocilia bundle is dynamically maintained by variable actin turnover rates. Two unconventional myosins were previously implicated in stereocilia length regulation but the mechanisms of their action remain unknown. MyosinXVa is expressed in stereocilia tips at levels proportional to stereocilia length and its absence produces staircase-like bundles of very short stereocilia. MyosinVIIa localizes to the tips of the shorter stereocilia within bundles, and when absent, the stereocilia are abnormally long. We show here that myosinVIIa interacts with twinfilin-2, an actin binding protein, which inhibits actin polymerization at the barbed end of the filament, and that twinfilin localization in stereocilia overlaps with myosinVIIa. Exogenous expression of myosinVIIa in fibroblasts results in a reduced number of filopodia and promotes accumulation of twinfilin-2 at the filopodia tips. We hypothesize that the newly described interaction between myosinVIIa and twinfilin-2 is responsible for the establishment and maintenance of slower rates of actin turnover in shorter stereocilia, and that interplay between complexes of myosinVIIa/twinfilin-2 and myosinXVa/whirlin is responsible for stereocilia length gradation within the bundle staircase

Obstetric fistula in Burundi: a comprehensive approach to managing women with this neglected disease.

BACKGROUND: In Burundi, the annual incidence of obstetric fistula is estimated to be 0.2-0.5% of all deliveries, with 1000-2000 new cases per year. Despite this relatively high incidence, national capacity for identifying and managing obstetric fistula is very limited. Thus, in July 2010, Medecins Sans Frontieres (MSF) set up a specialised Obstetric Fistula Centre in Gitega (Gitega Fistula Centre, GFC), the only permanent referral centre for obstetric fistula in Burundi. A comprehensive model of care is offered including psychosocial support, conservative and surgical management, post-operative care and follow-up. We describe this model of care, patient outcomes and the operational challenges. METHODS: Descriptive study using routine programme data. RESULTS: Between July 2010 and December 2011, 470 women with obstetric fistula presented for the first time at GFC, of whom 458 (98%) received treatment. Early urinary catheterization (conservative management) was successful in four out of 35 (11%) women. Of 454 (99%) women requiring surgical management, 394 (87%) were discharged with a closed fistula, of whom 301 (76%) were continent of urine and/or faeces, while 93 (24%) remained incontinent of urine and/or faeces. In 59 (13%) cases, the fistula was complex and could not be closed. Outcome status was unknown for one woman. Median duration of stay at GFC was 39 days (Interquartile range IQR, 31-51 days). CONCLUSION: In a rural African setting, it is feasible to implement a comprehensive package of fistula care using a dedicated fistula facility, and satisfactory surgical repair outcomes can be achieved. Several operational challenges are discussed

The 3-methylglutaconic acidurias: what’s new?

The heterogeneous group of 3-methylglutaconic aciduria (3-MGA-uria) syndromes includes several inborn errors of metabolism biochemically characterized by increased urinary excretion of 3-methylglutaconic acid. Five distinct types have been recognized: 3-methylglutaconic aciduria type I is an inborn error of leucine catabolism; the additional four types all affect mitochondrial function through different pathomechanisms. We provide an overview of the expanding clinical spectrum of the 3-MGA-uria types and provide the newest insights into the underlying pathomechanisms. A diagnostic approach to the patient with 3-MGA-uria is presented, and we search for the connection between urinary 3-MGA excretion and mitochondrial dysfunction

Cisgenesis and intragenesis as new strategies for crop improvement

Cisgenesis and intragenesis are emerging plant breeding technologies which offer great promise for future acceptance of genetically engineered crops. The techniques employ traditional genetic engineering methods but are confined to transferring of genes and genetic elements between sexually compatible species that can breed naturally. One of the main requirements is the absence of selectable marker genes (such as antibiotic resistance genes) in the genome. Hence the sensitive issues with regard to transfer of foreign genes and antibiotic resistance are overcome. It is a targeted technique involving specific locus; therefore, linkage drag that prolongs the time for crop improvement in traditional breeding does not occur. It has great potential for crop improvement using superior alleles that exist in the untapped germplasm or wild species. Cisgenic and intragenic plants may not face the same stringent regulatory assessment for field release as transgenic plants which is a clear added advantage that would save time. In this chapter, the concepts of cis/intragenesis and the prerequisites for the development of cis/intragenesis plants are elaborated. Strategies for marker gene removal after selection of transformants are discussed based on the few recent reports from various plant species

Physical activity and risk of Metabolic Syndrome in an urban Mexican cohort

Abstract Background In the Mexican population metabolic syndrome (MS) is highly prevalent. It is well documented that regular physical activity (PA) prevents coronary diseases, type 2 diabetes and MS. Most studies of PA have focused on moderate-vigorous leisure-time activity, because it involves higher energy expenditures, increase physical fitness, and decrease the risk of MS. However, for most people it is difficult to get a significant amount of PA from only moderately-vigorous leisure activity, so workplace activity may be an option for working populations, because, although may not be as vigorous in terms of cardio-respiratory efforts, it comprises a considerable proportion of the total daily activity with important energy expenditure. Since studies have also documented that different types and intensity of daily PA, including low-intensity, seem to confer important health benefits such as prevent MS, we sought to assess the impact of different amounts of leisure-time and workplace activities, including low-intensity level on MS prevention, in a sample of urban Mexican adults. Methods The study population consisted of 5118 employees and their relatives, aged 20 to 70 years, who were enrolled in the baseline evaluation of a cohort study. MS was assessed according to the criteria of the National Cholesterol Education Program, ATP III and physical activity with a validated self-administered questionnaire. Associations between physical activity and MS risk were assessed with multivariate logistic regression models. Results The prevalence of the components of MS in the study population were: high glucose levels 14.2%, high triglycerides 40.9%, high blood pressure 20.4%, greater than healthful waist circumference 43.2% and low-high density lipoprotein 76.9%. The prevalence of MS was 24.4%; 25.3% in men and 21.8% in women. MS risk was reduced among men (OR 0.72; 95%CI 0.57–0.95) and women (OR 0.78; 95%CI 0.64–0.94) who reported an amount of ≥30 minutes/day of leisure-time activity, and among women who reported an amount of ≥3 hours/day of workplace activity (OR 0.75; 95%CI 0.59–0.96). Conclusion Our results indicate that both leisure-time and workplace activity at different intensity levels, including low-intensity significantly reduce the risk of MS. This finding highlights the need for more recommendations regarding the specific amount and intensity of leisure-time and workplace activity needed to prevent MS