Exploring the unfolding pathways of protein families using Elastic Network Model.

We explore how a protein's native structure determines its unfolding process. We examine how the local structural features, like shear, and the global structural properties, like the number of soft modes, change during unfolding. Simulations are performed using a Gaussian Network Model (GNM) with bond breaking for both thermal and force-induced unfolding scenarios.

Evaluating the Experience of Teen-to-Teen Crisis Line Volunteers: A Pilot Study.

Teen-to-teen (t2t) crisis lines are a special type of crisis service where youth volunteers help their peers. Although prior research has examined the experience of adult crisis line responders, no research has examined the experience of adolescents who do this work. In collaboration with two of the largest t2t lines in the U.

Machine learning for lumbar and pelvis kinematics clustering.

Clustering algorithms such as k-means and agglomerative hierarchical clustering (HCA) may provide a unique opportunity to analyze time-series kinematic data. Here we present an approach for determining number of clusters and which clustering algorithm to use on time-series lumbar and pelvis kinematic data. Cluster evaluation measures such as silhouette coefficient, elbow method, Dunn Index, and gap statistic were used to evaluate the quality of decision making.

Most probable paths for active Ornstein-Uhlenbeck particles.

Fluctuations play an important role in the dynamics of stochastic systems. In particular, for small systems, the most probable thermodynamic quantities differ from their averages because of the fluctuations. Using the Onsager Machlup variational formalism we analyze the most probable paths for nonequilibrium systems, in particular, active Ornstein-Uhlenbeck particles, and investigate how the entropy production along these paths differs from the average entropy production.

Colossal Power Extraction from Active Cyclic Brownian Information Engines.

Brownian information engines can extract work from thermal fluctuations by utilizing information. To date, the studies on Brownian information engines consider the system in a thermal bath; however, many processes in nature occur in a nonequilibrium setting, such as the suspensions of self-propelled microorganisms or cellular environments called an active bath. Here, we introduce an archetypal model for a Maxwell-demon type cyclic Brownian information engine operating in a Gaussian correlated active bath capable of extracting more work than its thermal counterpart.

A semiparametric modeling approach for analyzing clinical biomarkers restricted to limits of detection.

Before biomarkers can be used in clinical trials or patients' management, the laboratory assays that measure their levels have to go through development and analytical validation. One of the most critical performance metrics for validation of any assay is related to the minimum amount of values that can be detected and any value below this limit is referred to as below the limit of detection (LOD). Most of the existing approaches that model such biomarkers, restricted by LOD, are parametric in nature.

Reaching and violating thermodynamic uncertainty bounds in information engines.

Thermodynamic uncertainty relations (TURs) set fundamental bounds on the fluctuation and dissipation of stochastic systems. Here, we examine these bounds, in experiment and theory, by exploring the entire phase space of a cyclic information engine operating in a nonequilibrium steady state. Close to its maximal efficiency, we find that the engine violates the original TUR.

Score and deviance residuals based on the full likelihood approach in survival analysis.

Assuming the proportional hazards model and non-informative censoring, the full likelihood approach is used to obtain two new residuals. The first residual is based on the ideas used in obtaining score-type residuals similar to the partial likelihood approach. The second type of residual is based on the concept of deviance residuals.

Comparative Survival of Asian and White Metastatic Castration-Resistant Prostate Cancer Men Treated With Docetaxel.

There are few data regarding disparities in overall survival (OS) between Asian and white men with metastatic castration-resistant prostate cancer (mCRPC). We compared OS of Asian and white mCRPC men treated in phase III clinical trials with docetaxel and prednisone (DP) or a DP-containing regimen. Individual participant data from 8820 men with mCRPC randomly assigned on nine phase III trials to receive DP or a DP-containing regimen were combined.

Androgens and Overall Survival in Patients With Metastatic Castration-resistant Prostate Cancer Treated With Docetaxel.

Background: Pre-treatment androgen levels are associated with overall survival (OS) in patients with metastatic castration-resistant prostate cancer (CRPC) treated with androgen synthesis inhibitors. The current study sought to determine whether pre-treatment serum androgens predict clinical outcome among patients with metastatic CRPC treated with docetaxel chemotherapy.

Materials And Methods: Data were obtained from 1050 men who were chemotherapy-naive prior to treatment with docetaxel, prednisone, and either bevacizumab or placebo (CALGB 90401).

Efficiency fluctuations and noise induced refrigerator-to-heater transition in information engines.

Understanding noisy information engines is a fundamental problem of non-equilibrium physics, particularly in biomolecular systems agitated by thermal and active fluctuations in the cell. By the generalized second law of thermodynamics, the efficiency of these engines is bounded by the mutual information passing through their noisy feedback loop. Yet, direct measurement of the interplay between mutual information and energy has so far been elusive.

Statistical ensemble inequivalence for flexible polymers under confinement in various geometries.

The problem of statistical ensemble inequivalence for single polymers has been the subject of intense research. In a recent publication, we show that even though the force-extension relation of a free Gaussian chain exhibits ensemble equivalence, confinement to half-space due to tethering to a planar substrate induces significant inequivalence [S. Dutta and P.

Androgen decline and survival during docetaxel therapy in metastatic castration resistant prostate cancer (mCRPC).

Background: Multiple androgens drive prostate cancer progression and higher pre-treatment levels of androgens, even within the castrate range, have been previously shown to be associated with an improved overall survival (OS) in mCRPC. Docetaxel impairs microtubules, has androgen receptor (AR) inhibitory effects and is used in both the castration resistant and sensitive settings, where androgen dynamics may impact outcome. The present analysis evaluates the association of decline in serum androgen levels (Testosterone (T), Androstenedione (A) and DHEA in docetaxel-treated mCRPC patients with OS.

Overall Survival of Black and White Men With Metastatic Castration-Resistant Prostate Cancer Treated With Docetaxel.

Purpose: Several studies have reported that among patients with localized prostate cancer, black men have a shorter overall survival (OS) time than white men, but few data exist for men with advanced prostate cancer. The primary goal of this analysis was to compare the OS in black and white men with metastatic castration-resistant prostate cancer (mCRPC) who were treated in phase III clinical trials with docetaxel plus prednisone (DP) or a DP-containing regimen.

Methods: Individual participant data from 8,820 men with mCRPC randomly assigned in nine phase III trials to DP or a DP-containing regimen were combined.

Rank-based inference for covariate and group effects in clustered data in presence of informative intra-cluster group size.

There have been numerous attempts to extend the Wilcoxon rank-sum test to clustered data. Recently, one such rank-sum test (Dutta & Datta, 2016, Biometrics 72, 432-440) was developed to compare the group-specific marginal distributions of outcomes in clustered data where the conditional distributions of outcomes depend on the number of observations from that group in a given cluster, a phenomenon referred to as informative intra-cluster group (ICG) size. However, comparison of group-specific marginal distributions may not be sufficient in presence of some potentially useful covariables that are observed in the study.

Inequivalence of fixed-force and fixed-extension statistical ensembles for a flexible polymer tethered to a planar substrate.

Recent advances in single macromolecule experiments have sparked interest in the ensemble dependence of force-extension relations. The thermodynamic limit may not be attainable for such systems, which leads to inequivalence of the fixed-force and the fixed-extension ensembles. We consider an ideal Gaussian chain described by the Edwards Hamiltonian with one end tethered to a rigid planar substrate.

Green function of correlated genes in a minimal mechanical model of protein evolution.

The function of proteins arises from cooperative interactions and rearrangements of their amino acids, which exhibit large-scale dynamical modes. Long-range correlations have also been revealed in protein sequences, and this has motivated the search for physical links between the observed genetic and dynamic cooperativity. We outline here a simplified theory of protein, which relates sequence correlations to physical interactions and to the emergence of mechanical function.

Enzyme leaps fuel antichemotaxis.

There is mounting evidence that enzyme diffusivity is enhanced when the enzyme is catalytically active. Here, using superresolution microscopy [stimulated emission-depletion fluorescence correlation spectroscopy (STED-FCS)], we show that active enzymes migrate spontaneously in the direction of lower substrate concentration ("antichemotaxis") by a process analogous to the run-and-tumble foraging strategy of swimming microorganisms and our theory quantifies the mechanism. The two enzymes studied, urease and acetylcholinesterase, display two families of transit times through subdiffraction-sized focus spots, a diffusive mode and a ballistic mode, and the latter transit time is close to the inverse rate of catalytic turnover.

Temporal Prediction of Future State Occupation in a Multistate Model from High-Dimensional Baseline Covariates via Pseudo-Value Regression.

In many complex diseases such as cancer, a patient undergoes various disease stages before reaching a terminal state (say disease free or death). This fits a multistate model framework where a prognosis may be equivalent to predicting the state occupation at a future time . With the advent of high throughput genomic and proteomic assays, a clinician may intent to use such high dimensional covariates in making better prediction of state occupation.

Finite-temperature quantum effects on confined charges.

A quantum system of N Coulomb charges confined within a harmonic trap is considered over a wide range of densities and temperatures. A recently described construction of an equivalent classical system is applied in order to exploit the rather complete classical description of harmonic confinement via liquid-state theory. Here, the effects of quantum mechanics on that representation are described with attention focused on the origin and nature of shell structure.

Adsorption of highly charged Gaussian polyelectrolytes onto oppositely charged surfaces.

In many biological processes highly charged biopolymers are adsorbed onto oppositely charged surfaces of macroions and membranes. They form strongly correlated structures close to the surface which cannot be explained by the conventional Poisson-Boltzmann theory. In this work strong coupling theory is used to study the adsorption of highly charged Gaussian polyelectrolytes.

Strong-coupling electrostatic theory of polymer counterions close to planar charges.

Strong-coupling phenomena, such as like-charge macroion attraction, opposite-charged macroion repulsion, charge renormalization, and charge inversion, are known to be mediated by multivalent counterions. Most theories treat the counterions as point charges and describe the system by a single coupling parameter that measures the strength of the Coulomb interactions. In many biological systems, the counterions are highly charged and have finite sizes and can be well-described by polyelectrolytes.

Shell formation in short like-charged polyelectrolytes in a harmonic trap.

Inspired by recent experiments and simulations on pattern formation in biomolecules by optical tweezers, a theoretical description based on the reference interaction site model (RISM) is developed to calculate the equilibrium density profiles of small polyelectrolytes in an external potential. The formalism is applied to the specific case of a finite number of Gaussian and rodlike polyelectrolytes trapped in a harmonic potential. The density profiles of the polyelectrolytes are studied over a range of lengths and numbers of polyelectrolytes in the trap, and the strength of the trap potential.

Complexation and coacervation of like-charged polyelectrolytes inspired by mussels.

It is well known that polyelectrolyte complexes and coacervates can form on mixing oppositely charged polyelectrolytes in aqueous solutions, due to mainly electrostatic attraction between the oppositely charged polymers. Here, we report the first (to the best of our knowledge) complexation and coacervation of two positively charged polyelectrolytes, which provides a new paradigm for engineering strong, self-healing interactions between polyelectrolytes underwater and a new marine mussel-inspired underwater adhesion mechanism. Unlike the conventional complex coacervate, the like-charged coacervate is aggregated by strong short-range cation-π interactions by overcoming repulsive electrostatic interactions.

A rank-sum test for clustered data when the number of subjects in a group within a cluster is informative.

The Wilcoxon rank-sum test is a popular nonparametric test for comparing two independent populations (groups). In recent years, there have been renewed attempts in extending the Wilcoxon rank sum test for clustered data, one of which (Datta and Satten, 2005, Journal of the American Statistical Association 100, 908-915) addresses the issue of informative cluster size, i.e.