Predicting phenotype transition probabilities via conditional algorithmic probability approximations.

Unravelling the structure of genotype-phenotype (GP) maps is an important problem in biology. Recently, arguments inspired by algorithmic information theory (AIT) and Kolmogorov complexity have been invoked to uncover simplicity bias in GP maps, an exponentially decaying upper bound in phenotype probability with the increasing phenotype descriptional complexity. This means that phenotypes with many genotypes assigned via the GP map must be simple, while complex phenotypes must have few genotypes assigned. Here, we use similar arguments to bound the probability P(x → y) that phenotype x, upon random genetic mutation, transitions to phenotype y. The bound is [Formula: see text], where [Formula: see text] is the estimated conditional complexity of y given x, quantifying how much extra information is required to make y given access to x. This upper bound is related to the conditional form of algorithmic probability from AIT. We demonstrate the practical applicability of our derived bound by predicting phenotype transition probabilities (and other related quantities) in simulations of RNA and protein secondary structures. Our work contributes to a general mathematical understanding of GP maps and may facilitate the prediction of transition probabilities directly from examining phenotype themselves, without utilizing detailed knowledge of the GP map.

Spatiotemporal model of cellular mechanotransduction via Rho and YAP.

How cells sense and respond to mechanical stimuli remains an open question. Recent advances have identified the translocation of Yes-associated protein (YAP) between nucleus and cytoplasm as a central mechanism for sensing mechanical forces and regulating mechanotransduction. We formulate a spatiotemporal model of the mechanotransduction signalling pathway that includes coupling of YAP with the cell force-generation machinery through the Rho family of GTPases. Considering the active and inactive forms of a single Rho protein (GTP/GDP-bound) and of YAP (non-phosphorylated/phosphorylated), we study the cross-talk between cell polarization due to active Rho and YAP activation through its nuclear localization. For fixed mechanical stimuli, our model predicts stationary nuclear-to-cytoplasmic YAP ratios consistent with experimental data at varying adhesive cell area. We further predict damped and even sustained oscillations in the YAP nuclear-to-cytoplasmic ratio by accounting for recently reported positive and negative YAP-Rho feedback. Extending the framework to time-varying mechanical stimuli that simulate cyclic stretching and compression, we show that the YAP nuclear-to-cytoplasmic ratio's time dependence follows that of the cyclic mechanical stimulus. The model presents one of the first frameworks for understanding spatiotemporal YAP mechanotransduction, providing several predictions of possible YAP localization dynamics, and suggesting new directions for experimental and theoretical studies.

Mesoscale modelling of polymer aggregate digestion.

We use mesoscale simulations to gain insight into the digestion of biopolymers by studying the break-up dynamics of polymer aggregates (boluses) bound by physical cross-links. We investigate aggregate evolution, establishing that the linking bead fraction and the interaction energy are the main parameters controlling stability with respect to diffusion. We show via a simplified model that chemical breakdown of the constituent molecules causes aggregates that would otherwise be stable to disperse. We further investigate breakdown of biopolymer aggregates in the presence of fluid flow. Shear flow in the absence of chemical breakdown induces three different regimes depending on the flow Weissenberg number ( W i ). i) At W i ≪ 1 , shear flow has a negligible effect on the aggregates. ii) At W i ∼ 1 , the aggregates behave approximately as solid bodies and move and rotate with the flow. iii) At W i ≫ 1 , the energy input due to shear overcomes the attractive cross-linking interactions and the boluses are broken up. Finally, we study bolus evolution under the combined action of shear flow and chemical breakdown, demonstrating a synergistic effect between the two at high reaction rates.

Correction: Convective heat transfer in a measurement cell for scanning electrochemical microscopy.

Correction for 'Convective heat transfer in a measurement cell for scanning electrochemical microscopy' by Javor K. Novev et al., Phys. Chem. Chem. Phys., 2016, 18, 29836-29846.

A thermostated cell for electrochemistry: minimising natural convection and investigating the role of evaporation and radiation.

An optimised thermostated electrochemical cell is designed and implemented. This is informed by experimental and computational studies characterizing the extent to which the thermostating of an electrochemical cell via a heated bath can be realised, both with the cell closed and open to the environment. The heat transfer in the system is simulated and probed experimentally; special emphasis is put on heat loss due to radiation and evaporation. Experiments and simulations demonstrate that these two mechanisms of heat transfer lead to a steady temperature in the cell that differs from that of the thermostat by ∼0.1 K. Simulations indicate that spatial inhomogeneities in the stationary temperature drive natural convective flows with a significant velocity. These new physical insights inform the optimization of a new electrochemical cell and its application in measurements of the impact frequency of silver nanoparticles as a function of temperature.

Thermal convection in electrochemical cells. Boundaries with heterogeneous thermal conductivity and implications for scanning electrochemical microscopy.

We investigate the heat transfer in a cylinder-shaped electrochemical cell with solid, thermally insulating walls. The cell is filled with a liquid and a solid substrate that is thermostated from below is situated at its base. The initial temperature of the liquid is different from that of the substrate so as to mimic imperfect thermostating in an electrochemical experiment; as heat transfer acts to diminish the temperature difference between the two, natural convection ensues. The influence of inhomogeneities in the thermal conductivity of the solid is studied - numerical simulations of the heat transfer in the system are conducted for substrates that are comprised of a thermally conductive material, an insulating one or a combination thereof. It is shown that the substrate structure strongly influences the structure and intensity of the natural convective flows emerging in the system. The present work demonstrates that under the idealized conditions under consideration, depending on the substrate structure, natural convection due to imperfect solution thermostating may give rise to flows whose local velocity can reach values as high as 10-3 m s-1. Moreover, as comparison between cells of two different radii shows, both the intensity and the temporal evolution of the flows arising in this system are highly sensitive to the precise geometry of the experimental cell. These results can have far-reaching consequences for the interpretation of results from experimental techniques such as scanning electrochemical microscopy.

Role of the pretreatment 18F-fluorodeoxyglucose positron emission tomography maximal standardized uptake value in predicting outcomes of colon liver metastases and that value's association with Beclin-1 expression.

The current study sought to evaluate the predictive and prognostic performance of the maximum standardized uptake value (SUVmax) prior to treatment in 43 patients with colon cancer and unresectable liver metastases. Patients with colon cancer who underwent 18F-FDG-PET/computed tomography (CT) scans for staging before the start of first-line 5-fluorouracil-based chemotherapy were retrospectively analyzed. Expression of Beclin-1 in cancer cells was evaluated in primary tumors using immunohistochemical staining. The pretreatment SUVmax for liver metastases was not able to predict progression-free survival but was significantly associated with poorer overall survival, with a hazard ratio of 2.05 (95 % CI, 1.016-4.155). Moreover, a negative correlation was noted between SUVmax and expression of a marker of autophagy - Beclin-1 (rho = -0.42, p = 0.006). This suggests that the pretreatment SUVmax in 18F-FDG PET/CT is a useful tool to help predict survival outcome in patients with colon cancer and unresectable liver metastases and may significantly distinguish between patients with low and high levels of Beclin-1 expression (AUC = 0.809, 95% CI: 0.670-0.948, p = 0.001).

Convective heat transfer in a measurement cell for scanning electrochemical microscopy.

Electrochemical experiments, especially those performed with scanning electrochemical microscopy (SECM), are often carried out without taking special care to thermostat the solution; it is usually assumed that its temperature is homogeneous and equal to the ambient. The present study aims to test this assumption via numerical simulations of the heat transfer in a particular system - the typical measurement cell for SECM. It is assumed that the temperature of the solution is initially homogeneous but different from that of its surroundings; convective heat transfer in the solution and the surrounding air is taken into account within the framework of the Boussinesq approximation. The hereby presented theoretical treatment indicates that an initial temperature difference of the order of 1 K dissipates with a characteristic time scale of ∼1000 s; the thermal equilibration is accompanied by convective flows with a maximum velocity of ∼10-4 m s-1; furthermore, the temporal evolution of the temperature profile is influenced by the sign of the initial difference. These results suggest that, unless the temperature of the solution is rigorously controlled, convection may significantly compromise the interpretation of data from SECM and other electrochemical techniques, which is usually done on the basis of diffusion-only models.

Serum levels of RIPK3 and troponin I as potential biomarkers for predicting impaired left ventricular function in patients with myocardial infarction with ST segment elevation and normal troponin I levels prior percutaneous coronary intervention.

The current study examined the serum levels of receptor-interacting protein kinase 3 (RIPK3) in 51 patients with New York Heart Association (NYHA) class III-IV heart failure, 53 patients with myocardial infarction with ST elevation (STEMI), and 19 healthy subjects serving as a control group. An enzyme-linked immunoadsorbent assay (ELISA) was used to measure the levels of RIPK3 expression in serum. The area under the receiver operating characteristic curve (AUC) was then used to evaluate the predictive performance of RIPK3 and troponin I in patients with STEMI. In patients with normal levels of troponin I prior to percutaneous coronary intervention (PCI), serum levels of RIPK3 and troponin I after PCI were sufficient to differentiate patients with a preserved left ventricular ejection fraction (LVEF) from those with impaired left ventricular function after PCI (AUC = 0.780 (95% CI: 0.565-0.995, p = 0.043) with a sensitivity of 76.9% and a specificity of 71.4% vs. AUC = 0.735 (95% CI: 0.530-0.941, p = 0.038) with a sensitivity of 88.2% and a specificity of 63.6% at the optimal cutoff values, respectively). Moreover, elevated levels of troponin I after PCI were associated with an increased risk of an LVEF < 50% prior to discharge (odds ratio, 1.014; 95 % CI, 1.001 to 1.027; p = 0.03), while elevated levels of RIPK3 were not associated with such a risk. The current findings suggest that in patients with normal levels of troponin I prior to PCI, serum levels of RIPK3 and troponin I can serve as a potential marker to identify patients with a decreased LVEF, thus possibly allowing an early shift to more intensive therapy.

Serum expression levels of miR-17, miR-21, and miR-92 as potential biomarkers for recurrence after adjuvant chemotherapy in colon cancer patients.

The present study examined whether miR-17, miR-21, miR-29a, and miR-92 that are dysregulated in colon cancer (CC) can serve as potential predictive markers for relapse of disease after radical surgery and adjuvant chemotherapy. Real-time reverse transcription quantitative polymerase chain reaction was used to measure the expression levels of the miRNAs in serum samples from 37 patients with CC and 7 healthy individuals, tested as a control group. The area under the receiver operating characteristic curve (AUC) was then used to evaluate the predictive performance of the four miRNAs alone or in combination and compare it with carcinoembryonic antigen. The expression of miR-17, miR-21 and miR-92 were significantly higher in serum of patients with disease relapse. The AUCs for miR-17, miR-21, miR-92 for Nx patients were 0.844, 0.948, and 0.935, respectively (p < 0.05). Combining the four miRNAs for stage III patients increased the diagnostic performance, yielding an AUC of 0.881, with a sensitivity of 83.3% and a specificity of 85.7% (p < 0.05). Our study suggests that the expression levels of serum miR-21, miR-17, and miR-92 in patients with CC who underwent radical surgery and adjuvant chemotherapy may have diagnostic value for differentiating between recurred and non-recurred patients.

Surface tension and surface Δχ-potential of concentrated Z+:Z- electrolyte solutions.

Schmutzer's model for the surface of aqueous electrolyte solutions is generalized to Z+:Z- salts. The thickness of the ion-free layer is calculated from the thickness of the "hydrophobic gap" at the water surface (1.38Å) and the radii of the ionic hydration shells. The overlap between the adsorption and the diffuse double layers is accounted for. The proposed model predicts the dependence of the surface tension σ and the surface Δχ-potential on the electrolyte concentration c(el) in agreement with the available data, without adjustable parameters. The Hofmeister effect on σ for salts of the same valence type is explained with their ion-specific activity coefficients. The negative value (toward air) of the Δχ-potential of most 1:1 electrolytes originates from the dipole moment of the water molecules at the surface. The negative χ-potential due to water dipoles is inversely proportional to the dielectric permittivity ε of the solution. Since ε diminishes as c(el) increases, most 1:1 electrolyte solutions exhibit a more negative χ-potential than pure water (Δχ<0). The Hofmeister series of Δχ of 1:1 salts (Δχ(LiCl) ≈ Δχ(NaCl)<Δχ(KCl)<Δχ(KF)) follows the corresponding series of ε (ε(LiCl) ≈ ε(NaCl)<ε(KCl)<ε(KF)). The theory allows the estimation of the surface potential χ0 of pure water from the experimental data for electrolyte solutions; the result, χ0 ≈ -100 mV, confirms the value currently accepted in the literature.

Surface tension of concentrated electrolyte solutions.

The surface tension σ of inorganic electrolyte aqueous solutions at a given concentration c follows the Hofmeister series. The explanation of this phenomenon was sought in the increased adsorption of certain ions due to specific ion-surface interactions. However, the ion-specific dependence of the activity coefficient γ(±) on c also influences σ, and its contribution to the ion-specificity of σ prevails. Thus, the surface tension of potassium salts follows the order σ(KOH)>σ(KCl)>σ(KNO3), which turns out to be a direct corollary of the corresponding activity coefficients series: γ(KOH)>γ(KCl)>γ(KNO3). In fact, the adsorption of NO(3)(-) at the water surface is lower than that of OH(-) and Cl(-)! If the bulk ion-specific effects are correctly evaluated, Schmutzer's classical model predicts accurately the surface tension of a large number of inorganic salt solutions in a wide concentration range, without adjustable parameters. This model accounts for image and hydration forces. Comparison with tensiometric data shows that other ion-surface interactions play a role only in the adsorption of ions of bare radius larger than a threshold value of about 1.95 Å (e.g. HCOO(-), I(-), SCN(-)).

Achieving further glycemic control in type 2 diabetes mellitus.

OBJECTIVES: To identify patients with type 2 diabetes mellitus who were in poor glycemic control and therapeutic adjustments that might improve control. DESIGN: Using electronic pharmacy data, we assigned subjects to 1 of 4 therapeutic categories. We then identified patients within each category who did not meet the recommended standard of glycemic control (glycosylated hemoglobin [Hb A(1c)] <0. 08 [<8.0%]) and studied their therapetic regimens for possible improvements. SUBJECTS: The subjects were 5,061 members of a large group-model health maintenance organization who had type 2 diabetes and 12 months of 1997 health plan eligibility. Main outcome measures The dosage of antihyperglycemic agents (sulfonylureas, metformin, and insulin) in relation to glycemic control as measured by the Hb A(1c). RESULTS: A significant number (n = 1,570 [31.0%]) of persons with type 2 diabetes might improve their glycemic control with simple adjustments to their pharmacologic therapy. CONCLUSION: Busy clinicians with heavy workloads can improve their management of diabetes by identifying patients whose glycemic control could be improved through a change in medication or simple adjustment in dosage.

Predictors of glycemic control in insulin-using adults with type 2 diabetes.

OBJECTIVE: To determine the characteristics that influence glycemic control among insulin-using adults with type 2 diabetes. RESEARCH DESIGN AND METHODS: We studied all 1,333 eligible members of a large not-for-profit health maintenance organization who responded to a 1997 survey. We tested associations among demographic, treatment, and psychometric variables with mean 1997 HbA1c values. The Problem Areas in Diabetes (PAID) instrument was used to assess the emotional effect of living with diabetes, and the Short Form 12 Physical Function Scale was used to assess the effect of physical limitations on daily activities. Based on differences between and within treatment groups, we built models to predict glycemic control for subgroups of subjects who were using insulin alone and those who were using insulin in combination with an oral hypoglycemic agent. RESULTS: Younger age, lower BMI, and increased emotional distress about diabetes (according to the PAID scale) were all significant predictors (P < 0.05) of worse glycemic control. However, except among individuals with an HbA1c level of >8.0 who were receiving combination therapy, only approximately 10% of the variance in glycemic control could be predicted by demographic, treatment, or psychometric characteristics. CONCLUSIONS: Personal characteristics explain little of the variation in glycemic control in insulin-using adults with type 2 diabetes. Possible explanations are that the reduced complexity of control in type 2 diabetes makes the disease less sensitive to personal factors than control in type 1 diabetes, that health-related behavior is less driven by personal and environmental characteristics among older individuals, or that, in populations exposed to aggressive glycemic control with oral hypoglycemic agents and nurse care managers, personal differences become largely irrelevant.

Evaluation of antipsychotic and concomitant medication use patterns in patients with schizophrenia.

OBJECTIVE: To describe antipsychotic medication use patterns in an inner-city, outpatient population of indigent patients with schizophrenia. METHODS: This retrospective cohort study used the Regenstrief Medical Record System to identify schizophrenic patients receiving antipsychotic medication(s). Patients were included and identified as initiating a new treatment episode if they did not receive any antipsychotic prescription for 90 days before their first antipsychotic prescription in 1995. Each patient was followed for 1 year. RESULTS: Three hundred and sixteen patients met study criteria. Typical and atypical (clozapine and risperidone) antipsychotic agents were selected as initial therapy in 88% and 12% patients, respectively. The majority of patients (71.5%) were exposed to only one antipsychotic agent during their treatment year. Approximately 25% of all patients switched from one antipsychotic to a different antipsychotic during 12 months of therapy. Nearly 90% of patients augmented their prescribed antipsychotic with a concomitant medication during the 12-month study period. Approximately 30% of the cohort received treatment with an antipsychotic for 12 continuous months and were, thus, classified as having stable antipsychotic therapy. The majority of patients (67.1%) had periods of interrupted therapy (range, 1-11 months) during the 12 month study period. CONCLUSION: As of 1995 an overwhelming majority of schizophrenic patients in this indigent, inner-city population initiated therapy with a typical antipsychotic. Patients frequently switched antipsychotics and discontinued their therapy during the 1 year study period. Reasons for switching or discontinuing may include the following: ineffective therapy; patient intolerance; change in symptoms; and improved assessment and understanding of the diagnosis or physician preference.

Diabetic ketoacidosis charges relative to medical charges of adult patients with type I diabetes.

OBJECTIVE: To determine the medical charges for treating diabetic ketoacidosis (DKA) episodes relative to direct medical care charges of adult patients with type I diabetes. RESEARCH DESIGN AND METHODS: Using data from an electronic medical record system, we identified adult patients with type I diabetes who had received inpatient or outpatient care on at least two occasions between 1 January 1993 and 30 June 1994. Resources and charges for hospitalizations, emergency room visits, outpatient visits, and pharmaceuticals were recorded during this period. One additional year of information was collected to assess the resources and charges associated with multiple DKA episodes. RESULTS: A total of 200 patients were identified, of whom 72 (36.0%) experienced a total of 161 DKA episodes. The direct medical care charges associated with DKA episodes represented 28.1% of the direct medical care charges for the cohort of patients with type I diabetes. The average charge per DKA episode was $6,444. The estimated annual medical care charge for each patient was $7,855 ($13,096 per patient experiencing a DKA episode versus $4,907 per patient not experiencing an episode). Multiple DKA episodes were experienced by 24 (12.0%) of the study patients and accounted for 55.6% of the direct medical care charges for these patients. CONCLUSIONS: DKA episodes represented more than $1 of every $4 spent on direct medical care for adult patients with type I diabetes and $1 of every $2 in those patients experiencing multiple episodes. Interventions that are capable of even a modest reduction in the number of DKA episodes could produce substantial cost savings in a health care system and could be particularly cost-effective in adult patients with recurrent DKA.