Genetic Polymorphism in Evolving Population

We present a model for evolving population which maintains genetic polymorphism. By introducing random mutation in the model population at a constant rate, we observe that the population does not become extinct but survives, keeping diversity in the gene pool under abrupt environmental changes. The model provides reasonable estimates for the proportions of polymorphic and heterozygous loci and for the mutation rate, as observed in nature

Historic genetic structuring and paraphyly within the Great-tailed Grackle

The Great-tailed Grackle (Quiscalus mexicanus) and Boat-tailed Grackle (Q. major) are sister species that have expanded their ranges during historical times. This expansion has created an area of sympatry between these species in Texas and Louisiana, and between distinctive Great-tailed Grackle subspecies in the southwestern United States and northern Mexico. We investigated the evolutionary histories of both species using mitochondrial DNA sequence data and modern phylogenetic methods. Our results reveal genetic structure within Great-tailed, but not Boat-tailed Grackles. Great-tailed Grackles are separated into two clades, but range expansion in the north has led to secondary contact between them. Boat-tailed Grackles are monophyletic and are embedded within the Great-tailed Grackle assemblage, rendering the latter paraphyletic. These results reveal a complex phylogeographic pattern caused by recent range expansion and secondary contact of once allopatric units

Co-Transport of Polycyclic Aromatic Hydrocarbons by Motile Microorganisms Leads to Enhanced Mass Transfer under Diffusive Conditions.

The environmental chemodynamics of hydrophobic organic chemicals (HOCs) are often rate-limited by diffusion in stagnant boundary layers. This study investigated whether motile microorganisms can act as microbial carriers that enhance mass transfer of HOCs through diffusive boundary layers. A new experimental system was developed that allows (1) generation of concentration gradients of HOCs under the microscope, (2) exposure and direct observation of microorganisms in such gradients, and (3) quantification of HOC mass transfer. Silicone O-rings were integrated into a Dunn chemotaxis chamber to serve as sink and source for polycyclic aromatic hydrocarbons (PAHs). This resulted in stable concentration gradients in water (>24 h). Adding the model organism <i>Tetrahymena pyriformis</i> to the experimental system enhanced PAH mass transfer up to hundred-fold (benzo­[a]­pyrene). Increasing mass transfer enhancement with hydrophobicity indicated PAH co-transport with the motile organisms. Fluorescence microscopy confirmed such transport. The effective diffusivity of <i>T. pyriformis</i>, determined by video imaging microscopy, was found to exceed molecular diffusivities of the PAHs up to four-fold. Cell-bound PAH fractions were determined to range from 28% (naphthalene) to 92% (pyrene). Motile microorganisms can therefore function as effective carriers for HOCs under diffusive conditions and might significantly enhance mobility and availability of HOCs

Perioperative changes in hemoglobin levels during major hepatopancreatic surgery in transfused and non-transfused patients

AbstractBackground: Several studies have shown that restrictive transfusion policies are safe. However, in clinical practice, transfusion policies seem to be inappropriate. In order to assist in decision-making concerning red blood cell transfusions, we determined perioperative hemoglobin (Hb) levels during major pancreatic and hepatic operations.Methods: Patients who underwent major pancreatic or hepatic resections between 2002 and 2011 were classified into the transfused (TF+) and non-transfused (TF) groups. The perioperative Hb values of these patients were evaluated at six points in time.Results: The study included 1596 patients, of which 785 underwent pancreatoduodenectomy, 79 total pancreatectomy, and 732 partial hepatectomy. Similar perioperative changes in Hb levels were seen in all patients regardless of whether they received a blood transfusion. In patients undergoing pancreatoduodenectomy and total pancreatectomy, the median of the lowest measured hemoglobin values was 89.2 g/L and in partial hepatectomy patients 92.6 g/L, and these were assumed to be the trigger points for red blood cell transfusion.Conclusions: Despite guidelines on blood transfusion thresholds, restrictive blood transfusion policies were not observed during our study period. After major pancreatic and hepatic surgery, Hb levels recovered without transfusions. This should encourage clinicians to obey the restrictive blood transfusion policies after major hepatopancreatic surgery.Abstract Background: Several studies have shown that restrictive transfusion policies are safe. However, in clinical practice, transfusion policies seem to be inappropriate. In order to assist in decision-making concerning red blood cell transfusions, we determined perioperative hemoglobin (Hb) levels during major pancreatic and hepatic operations. Methods: Patients who underwent major pancreatic or hepatic resections between 2002 and 2011 were classified into the transfused (TF+) and non-transfused (TF) groups. The perioperative Hb values of these patients were evaluated at six points in time. Results: The study included 1596 patients, of which 785 underwent pancreatoduodenectomy, 79 total pancreatectomy, and 732 partial hepatectomy. Similar perioperative changes in Hb levels were seen in all patients regardless of whether they received a blood transfusion. In patients undergoing pancreatoduodenectomy and total pancreatectomy, the median of the lowest measured hemoglobin values was 89.2 g/L and in partial hepatectomy patients 92.6 g/L, and these were assumed to be the trigger points for red blood cell transfusion. Conclusions: Despite guidelines on blood transfusion thresholds, restrictive blood transfusion policies were not observed during our study period. After major pancreatic and hepatic surgery, Hb levels recovered without transfusions. This should encourage clinicians to obey the restrictive blood transfusion policies after major hepatopancreatic surgery

Multiple psychological factors predict pain and disability among community-dwelling knee osteoarthritis patients : a five-year prospective study

Objective: To identify predictors of long-term pain and disability in knee osteoarthritis. Design: A longitudinal cohort study of five years. Setting: Primary care providers. Subjects: In all, 108 patients (mean age = 63.6 years, standard deviation (SD) = 7.2 years) with knee pain (> 40 mm on a 100 mm visual analogue scale in the Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index pain scale) and radiographic grading (Kellgren-Lawrence: 2-4) of knee osteoarthritis who participated in a randomized controlled trial. Main measures: Disease-specific pain and functioning were assessed using the corresponding WOMAC subscales. Generic functioning was assessed by the RAND-36 subscales for function and physical and mental component summary scores. Possible baseline predictors for these outcomes were (1) demographic and disease-related variables and (2) psychological variables of mood (anxiety, depression), pain-related cognitions (pain self-efficacy, pain catastrophizing, kinesiophobia), and positive resource factors (life satisfaction, sense of coherence). Results: Multivariate linear mixed model analyses revealed that minimal anxiety at baseline predicted significantly better results for pain (WOMAC, P = 0.019) and function (WOMAC, P = 0.001, RAND-36 function P = 0.001). High pain self-efficacy predicted significantly better scores in RAND-36 function (P = 0.006), physical (P = 0.004) and mental (P = 0.001) component summaries. Pain catastrophizing predicted higher pain (P = 0.015), whereas fear of movement predicted poorer functioning in RAND-36 physical (P = 0.016) and mental (P = 0.009) component summaries. Those satisfied with life reported higher scores in RAND-36 function (P = 0.002) and mental component summary (P = 0.041). A low number of comorbidities predicted significantly better results in pain (WOMAC P = 0.019) and function (WOMAC P = 0.033, RAND-36 P = 0.009). Conclusion: Anxiety, pain-related cognitions, and psychological resources predict symptoms in knee osteoarthritis in the long term.Peer reviewe

Long-term clinical and economic outcomes in previously untreated paediatric patients with severe haemophilia A : A nationwide real-world study with 700 person-years

AimFor previously untreated patients (PUPs) with severe haemophilia A in Finland for the past 2 decades, the standard practice has been to start early primary prophylaxis. We evaluated the long-term clinical outcomes and costs of treatment with high-dose prophylaxis in PUPs from birth to adolescence, including immune tolerance induction (ITI). MethodsFrom the medical records of all PUPs born between June 1994 and May 2013 in Finland, we retrospectively extracted data on clinical outcomes and healthcare use. Using linear mixed models, we analysed longitudinal clinical outcome data. To analyse skewed cost data, including zero costs, we applied hurdle regression. ResultsAll 62 patients received early regular prophylaxis; totally, they have had treatment for nearly 700 patient-years. The median age of starting home treatment was 1.1years. The mean (SD) annual treatment costs (Europerkg) were 4391Euro (3852). For ages 1-3, ITI comprised over half of the costs; in other groups, prophylactic FVIII treatment dominated. With these high costs, however, clinical outcomes were desirable; median (IQR) ABR was low at 0.19 (0.07-0.46) and so was AJBR at 0.06 (0-0.24). Thirteen (21%) patients developed a clinically significant inhibitor, 10 (16%) with a high titre. All ITIs were successful. The mean costs for ITI were 383448Euro (259085). The expected ITI payback period was 1.81 (95% CI 0.62-12.12) years. ConclusionsEarly high-dose prophylaxis leads to excellent long-term clinical outcomes, and early childhood ITI therapy seems to turn cost-neutral generally already in 2years.Peer reviewe

Fine-Scale Mapping of the 4q24 Locus Identifies Two Independent Loci Associated with Breast Cancer Risk

Background: A recent association study identified a common variant (rs9790517) at 4q24 to be associated with breast cancer risk. Independent association signals and potential functional variants in this locus have not been explored. Methods: We conducted a fine-mapping analysis in 55,540 breast cancer cases and 51,168 controls from the Breast Cancer Association Consortium. Results: Conditional analyses identified two independent association signals among women of European ancestry, represented by rs9790517 [conditional P = 2.51 × 10−4; OR, 1.04; 95% confidence interval (CI), 1.02–1.07] and rs77928427 (P = 1.86 × 10−4; OR, 1.04; 95% CI, 1.02–1.07). Functional annotation using data from the Encyclopedia of DNA Elements (ENCODE) project revealed two putative functional variants, rs62331150 and rs73838678 in linkage disequilibrium (LD) with rs9790517 (r2 ≥ 0.90) residing in the active promoter or enhancer, respectively, of the nearest gene, TET2. Both variants are located in DNase I hypersensitivity and transcription factor–binding sites. Using data from both The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), we showed that rs62331150 was associated with level of expression of TET2 in breast normal and tumor tissue. Conclusion: Our study identified two independent association signals at 4q24 in relation to breast cancer risk and suggested that observed association in this locus may be mediated through the regulation of TET2. Impact: Fine-mapping study with large sample size warranted for identification of independent loci for breast cancer risk

A Computational and Experimental Study of the Regulatory Mechanisms of the Complement System

The complement system is key to innate immunity and its activation is necessary for the clearance of bacteria and apoptotic cells. However, insufficient or excessive complement activation will lead to immune-related diseases. It is so far unknown how the complement activity is up- or down- regulated and what the associated pathophysiological mechanisms are. To quantitatively understand the modulatory mechanisms of the complement system, we built a computational model involving the enhancement and suppression mechanisms that regulate complement activity. Our model consists of a large system of Ordinary Differential Equations (ODEs) accompanied by a dynamic Bayesian network as a probabilistic approximation of the ODE dynamics. Applying Bayesian inference techniques, this approximation was used to perform parameter estimation and sensitivity analysis. Our combined computational and experimental study showed that the antimicrobial response is sensitive to changes in pH and calcium levels, which determines the strength of the crosstalk between CRP and L-ficolin. Our study also revealed differential regulatory effects of C4BP. While C4BP delays but does not decrease the classical complement activation, it attenuates but does not significantly delay the lectin pathway activation. We also found that the major inhibitory role of C4BP is to facilitate the decay of C3 convertase. In summary, the present work elucidates the regulatory mechanisms of the complement system and demonstrates how the bio-pathway machinery maintains the balance between activation and inhibition. The insights we have gained could contribute to the development of therapies targeting the complement system.Singapore. Ministry of Education (Grant T208B3109)Singapore. Agency for Science, Technology and Research (BMRC 08/1/21/19/574)Singapore-MIT Alliance (Computational and Systems Biology Flagship Project)Swedish Research Counci

Maternal Transmission of Resistance to Development of Allergic Airway Disease

Parental phenotype is known to influence the inheritance of atopic diseases, such as allergic asthma, with a maternal history being a more significant risk factor for progeny than paternal history. We hypothesized that recall Th1- or Th2-type immune responses during pregnancy would result in transfer of maternal factors that would differentially impact development of immune responsiveness in offspring. Following weaning, susceptibility and severity of allergic airway disease (a murine model of human asthma) was evaluated in progeny, disease being elicited by immunization with OVA-Al(OH)3 and challenge with aerosolized OVA. We found that progeny of mothers with Th1-biased immunity to OVA subjected to recall aerosol challenge during pregnancy had reduced levels of Ag-specific IgE and airway eosinophilia compared with progeny of mothers with Th2-biased immunity to OVA or naive mothers. Interestingly, progeny of mothers with Th1-type immunity to a heterologous albumin, BSA, were not protected from developing OVA-induced allergic airway disease. These findings demonstrated that maternal transfer of protection from development of allergic airway disease to offspring in this model of maternal Th1-type immunity was Ag specific