Algebraic Systems Biology: A Case Study for the Wnt Pathway

Steady state analysis of dynamical systems for biological networks give rise to algebraic varieties in high-dimensional spaces whose study is of interest in their own right. We demonstrate this for the shuttle model of the Wnt signaling pathway. Here the variety is described by a polynomial system in 19 unknowns and 36 parameters. Current methods from computational algebraic geometry and combinatorics are applied to analyze this model.Comment: 24 pages, 2 figure

Natural Progression of Biochemical Markers of Biliary Tract Obstruction in Patients with Gallstone Pancreatitis

The presenting pattern and natural progression of biochemical markers of biliary tract obstruction in patients with gallstone pancreatitis have not been elucidated. We analyzed serial values of bilirubin levels following admission to discharge in 143 patients. Ninety-four of patients demonstrated a Decrescendo (falling) pattern of bilirubin levels from admission until normalization at 21 hours (median). Forty-nine patients demonstrated a Crescendo-Decrescendo (initially rising) pattern with peak levels of bilirubin occurring at 39 hours after admission followed by a subsequent normalization after a median of 119 hours. Patients in the Decrescendo group were significantly younger (33 versus 41 years, P = .02) and more patients had experienced symptoms for greater than 48 hours (65% versus 47%, P = .05). Ten percent of patients in the Decrescendo group and 29% of patients in the Crescendo-Decrescendo group underwent ERCP (P = .02). Normalization of biochemical markers after ERCP was significantly delayed in both groups compared to no ERCP. Older patients present earlier, with higher bilirubin levels and normalize slower than younger patients, perhaps due to fibrosis of the ampulla and decreased compliance of the common bile duct. Patients who disobstruct spontaneously (90%) normalize quicker than patients undergoing ERCP

Increased Cell–Cell Coupling Increases Infarct Size and Does not Decrease Incidence of Ventricular Tachycardia in Mice

Increasing connexin43 (Cx43) gap junctional conductance as a means to improve cardiac conduction has been proposed as a novel antiarrhythmic modality. Yet, transmission of molecules via gap junctions may be associated with increased infarct size. To determine whether maintaining open gap junction channels impacts on infarct size and induction of ventricular tachycardia (VT) following coronary occlusion, we expressed the pH- and voltage-independent connexin isoform connexin32 (Cx32) in ventricle and confirmed Cx32 expression. Wild-type (WT) mice injected with adenovirus-Cx32 (Cx32inj) were examined following coronary occlusion to determine infarct size and inducibility of VT. There was an increased infarct size in Cx32inj hearts as compared to WT (WT 22.9 ± 4%; Cx32inj 44.3 ± 5%; p < 0.05). Programmed electrical stimulation showed no difference in VT inducibility in WT and Cx32inj mice (VT was reproducibly inducible in 55% of shams and 50% of Cx32inj mice (p > 0.05). Following coronary occlusion, improving cell–cell communication increased infarct size, and conferred no antiarrhythmic benefit

Estimates of burden and consequences of infants born small for gestational age in low and middle income countries with INTERGROWTH-21st standard: analysis of CHERG datasets

Objectives: To estimate small for gestational age birth prevalence and attributable neonatal mortality in low and middle income countries with the INTERGROWTH-21st birth weight standard.Design: Secondary analysis of data from the Child Health Epidemiology Reference Group (CHERG), including 14 birth cohorts with gestational age, birth weight, and neonatal follow-up. Small for gestational age was defined as infants weighing less than the 10th centile birth weight for gestational age and sex with the multiethnic, INTERGROWTH-21st birth weight standard. Prevalence of small for gestational age and neonatal mortality risk ratios were calculated and pooled among these datasets at the regional level. With available national level data, prevalence of small for gestational age and population attributable fractions of neonatal mortality attributable to small for gestational age were estimated.Setting: CHERG birth cohorts from 14 population based sites in low and middle income countries.Main outcome measures: In low and middle income countries in the year 2012, the number and proportion of infants born small for gestational age; number and proportion of neonatal deaths attributable to small for gestational age; the number and proportion of neonatal deaths that could be prevented by reducing the prevalence of small for gestational age to 10%.Results: In 2012, an estimated 23.3 million infants (uncertainty range 17.6 to 31.9; 19.3% of live births) were born small for gestational age in low and middle income countries. Among these, 11.2 million (0.8 to 15.8) were term and not low birth weight (≥2500 g), 10.7 million (7.6 to 15.0) were term and low birth weight (\u3c2500 \u3eg) and 1.5 million (0.9 to 2.6) were preterm. In low and middle income countries, an estimated 606 500 (495 000 to 773 000) neonatal deaths were attributable to infants born small for gestational age, 21.9% of all neonatal deaths. The largest burden was in South Asia, where the prevalence was the highest (34%); about 26% of neonatal deaths were attributable to infants born small for gestational age. Reduction of the prevalence of small for gestational age from 19.3% to 10.0% in these countries could reduce neonatal deaths by 9.2% (254 600 neonatal deaths; 164 800 to 449 700).Conclusions: In low and middle income countries, about one in five infants are born small for gestational age, and one in four neonatal deaths are among such infants. Increased efforts are required to improve the quality of care for and survival of these high risk infants in low and middle income countries

Message in a Bottle -- An Update to the Golden Record

Communication is an essential asset enabling humankind to forge an advanced civilization. Using approximately 31,000 languages from the Stone Age to our present digital information society, humans have connected and collaborated to accomplish remarkable feats. As the newly dawned Space Age progresses, we are attempting to communicate with intelligent species beyond our world, on distant planets and in Earth's far future. Absent mutually understood signs, symbols, and semiotic conventions, this study, the "Message in a Bottle", uses scientific methods to assess and design a means of communication encapsulating the story of humanity, conveying our thoughts, emotions, ingenuity, and aspirations. The message will be structured to provide a universal yet contextual understanding of modern human society, evolution of life on Earth, and challenges for the future. In assembling this space and time capsule, we aim to energize and unite current generations to celebrate and preserve humanity

Estrogen regulation of mammary gland development and breast cancer: amphiregulin takes center stage

Estrogen-mediated proliferation is fundamental to normal mammary gland development. Recent studies have demonstrated that amphiregulin is a critical paracrine regulator of estrogen action during ductal morphogenesis. These studies implicate a critical role for amphiregulin in mammary stem cell differentiation as well as breast cancer initiation and progression

Diffusive gradient thin-films in seawater: time integrated technique for aqueous trace metal monitoring in impacted waterways

As part of an ambient monitoring program being conducted for the Puget Sound Naval Shipyard & Intermediate Maintenance Facility in Sinclair and Dyes Inlets of the Puget Sound, receiving waters of the Inlets are routinely monitored for trace metals and toxicity to assess water quality status, track progress in achieving water quality goals, and demonstrate protection of aquatic life. Recently, aqueous metal bioavailability using diffusive gradient thin-film (DGT) passive samplers has been incorporated into the monitoring program. The DGT samplers allow for the measurement of trace metal concentrations integrated over time via in situ chelation of labile metals. The DGT samplers are selective for free and weakly complexed metal species, allowing uptake to mimic diffusion limited bioavailability. This provides a monitoring solution by which episodic events are captured that provides a better representation of the potential for biological effects. A combination of laboratory performance tests and field deployed DGTs have been used to assess the reliability of the method to accurately measure labile concentrations Cu, Pb, and Zn under baseline and episodic storm events. Based on the results from DGTs deployed over different intervals spanning continuous deployments of 1-56 days and rainfall events of 0.4 – 3.2 inches/24 hr, reproducibility was affected by the presence of partially labile complexes, mass loading rate (time to equilibrium) which is proportional to free ion concentration, and variation in resin blank values. Best results were obtained for 3-7 day DGT deployments which showed high resolution of labile metal concentrations over varying spatial and temporal scales. The ability to conduct constant surveillance of metal bioavailable for a variety of freshwater and nearshore marine environments under varying environmental conditions greatly improves the assessment of potential ecological effects from exposure to metals

Assessing 21st century contaminants of concern using integrative passive sampling devices to obtain more meaningful and cost effective data on impacts from stormwater runoff

In many cases stormwater compliance monitoring is labor intensive, expensive, and largely unsuccessful in providing the data needed to support stormwater management goals. In addition, data from manual grab sampling and automated composite sampling are rarely collected in a manner that provides the information required to identify sources of contamination, evaluate the effectiveness of Best Management Practices, and inform effective decision making. Furthermore, monitoring is often driven by the need to meet low concentration benchmarks for metals and other constituents that do not take into account loading into the receiving waters, resulting in arbitrary monitoring requirements (monthly or seasonally) that are not tied to the driving forces within the watershed such as hydrology (flow regime), weather (storm events and antecedent dry periods), and upland land use and cover. To help address these issues, passive sampling devices including Diffusive Gradients in Thin films (DGT) for metals and Polar Organic Chemical Integrative Samples (POCIS) for a wide range of household, personal care, pharmaceutical, and endocrine disrupting compounds are being used to monitor stormwater runoff. In the Puget Sound a network of monitoring stations was established in Sinclair and Dyes Inlets to assess runoff from industrial areas of Naval Base Kitsap as well as commercial, residential, and rural areas within the watershed. Passive samplers were co-located with autosamplers to provide a direct comparison with grab and composite sampling. Preliminary results from multiple DGT deployments showed that time-dependent variability in stormwater impacts on ambient metal concentrations could be detected on small time scales, as well as over multiple days of rainfall. The POCIS samplers showed that a wide range of organic compounds could be reliably detected from the surveillance monitoring which should prove very useful for finger printing likely sources of contamination in stormwater runoff in the areas monitored