Miracle-dz/UniFAR-FTUs huggingface dataset:
Increased Frequency of ICOS+ CD4 T Cells as a Pharmacodynamic Biomarker for Anti-CTLA-4 Therapy

In a retrospective study, Tang and colleagues identified an increase in ICOS+ CD4 T cells following anti-CTLA-4 therapy and proposed its use as a pharmacodynamic biomarker for anti-CTLA-4 immunotherapy. Pharmacodynamic biomarkers can play an important role in understanding whether a therapeutic agent has “hit its target” to impact biologic function. A pharmacodynamic biomarker for anti-CTLA-4 therapy remains to be elucidated. We previously reported that anti-CTLA-4 therapy increases the frequency of CD4 T cells expressing the inducible costimulator (ICOS) molecule. To determine whether the frequency of ICOS+ CD4 T cells could be used as a pharmacodynamic biomarker for anti-CTLA-4 therapy, we carried out flow cytometric studies and statistical analyses on data from 56 individuals, which included 10 healthy donors, 36 patients who received anti-CTLA-4 monoclonal antibody (mAb), and 10 patients who received treatment with a different immunomodulatory agent (gp100 DNA vaccine). After treatment with anti-CTLA-4 mAb (ipilimumab; Bristol-Myers Squibb), we detected a statistically significant increase in the frequency of ICOS+ CD4 T-cells. After two doses of anti-CTLA-4 therapy, the assay was found to have an estimated specificity of 96% [95% confidence interval (CI), 88–100] and sensitivity of 71% (95% CI, 54–85), with positive expression defined as a frequency that is more than the upper bound of 95% CI among baseline samples from all subjects. Our data suggest that an increased frequency of ICOS+ CD4 T cells measured by flow cytometry can be used as a reproducible pharmacodynamic biomarker to indicate biologic activity in the setting of anti-CTLA-4 therapy, which should enable appropriate immune monitoring to determine whether patients receiving anti-CTLA-4 monotherapy or combination treatment strategies are having an adequate biologic response. Cancer Immunol Res; 1(4); 229–34. ©2013 AACR.
Ambient temperature correction of photovoltaic system performance data

The performance ratio (PR), which normalizes photovoltaic system energy production in terms of irradiance, is a widely used metric for monitoring, validating, and guaranteeing system performance. To improve the predictability of performance, the PR can be adjusted for additional environmental factors, such as temperature or soiling. This research compares the use of ambient temperature versus module temperature for performing a temperature adjustment of the PR calculation and the ASTM E2848-11 capacity test. Using one year of plant monitoring data for a 500 kWAC system near Las Vegas, Nevada, we applied multiple temperature correction methods to compare PR and ASTM results from measured and modeled values over both annual and monthly timescales. Though an ambient temperature correction increased performance predictability compared to the uncorrected PR, a module temperature adjustment provided the closest match between modeled and measured performance for both the PR and the ASTM methods.
Arrhythmia / Electrophysiology Enhanced Sarcoplasmic Reticulum Ca 2 Leak and Increased Na-Ca 2 Exchanger Function Underlie Delayed Afterdepolarizations in Patients With Chronic Atrial Fibrillation

constitutively phosphorylated RyR2 at Ser2814 showed a higher incidence of Ca sparks and increased susceptibility to pacing-induced AF compared with controls. The relationship between [Ca ]i and INCX density revealed INCX upregulation in cAF. Spontaneous Ca release events accompanied by inward INCX currents and delayed afterdepolarizations/triggered activity occurred more often and the sensitivity of resting membrane voltage to elevated [Ca ]i (diastolic [Ca ]i–voltage coupling gain) was higher in cAF compared with control. Conclusions—Enhanced SR Ca leak through CaMKII-hyperphosphorylated RyR2, in combination with larger INCX for a given SR Ca release and increased diastolic [Ca ]i-voltage coupling gain, causes AF-promoting atrial delayed
Gating Mechanism of BK (Slo1) Channels

Large conductance calcium- and voltage-activated K+ channels (Slo1), also referred to as “BK” or “maxi K” channels because of their high single channel conductance (250–300 pS in symmetrical 150 mM KCl), are widely distributed in many different tissues ([Kaczorowski et al., 1996][1]). A
No Association between Loss-of-Function Mutations in filaggrin and Diabetes, Cardiovascular Disease, and All-Cause Mortality

Background Common loss-of-function mutations in the filaggrin gene (FLG) are a major predisposing risk factor for atopic disease due to reduced epidermal filaggrin protein levels. We previously observed an association between these mutations and type 2 diabetes and hypothesized that an inherited impairment of skin barrier functions could facilitate low-grade inflammation and hence increase the risk of diabetes and cardiovascular disease. We examined the association between loss-of-function mutations in FLG and diabetes, stroke, ischemic heart disease (IHD), and all-cause mortality in the general population. Methods The R501X and 2282del4 loss-of function mutations in FLG were genotyped in four Danish study populations including a total of 13373 adults aged 15-77 years. Two of the studies also genotyped the R2447X mutation. By linkage to Danish national central registers we obtained information for all participants on dates of diagnoses of diabetes, stroke, and IHD, as well as all-cause mortality. Data were analyzed by Cox proportional hazard models and combined by fixed effect meta-analyses. Results In meta-analyses combining the results from the four individual studies, carriage of loss-of-function mutations in FLG was not associated with incident diabetes (hazard ratio (HR) (95% confidence intervals (CI)) = 0.95 (0.73, 1.23), stroke (HR (95% CI) = 1.27 (0.97, 1.65), ischemic heart disease (HR (95%CI) = 0.92 (0.71, 1.19), and all-cause mortality (HR (95%CI) = 1.02 (0.83, 1.25)). Similar results were obtained when including prevalent cases in logistic regression models. Conclusion Our results suggest that loss-of-function mutations in FLG are not associated with type 2 diabetes, cardiovascular disease, and all-cause mortality. However, larger studies with longer follow-up are needed to exclude any associations.
Rethinking serializable multiversion concurrency control

Multi-versioned database systems have the potential to significantly increase the amount of concurrency in transaction processing because they can avoid read-write conflicts. Unfortunately, the increase in concurrency usually comes at the cost of transaction serializability. If a database user requests full serializability, modern multi-versioned systems significantly constrain read-write concurrency among conflicting transactions and employ expensive synchronization patterns in their design. In main-memory multi-core settings, these additional constraints are so burdensome that multi-versioned systems are often significantly outperformed by single-version systems. We propose Bohm, a new concurrency control protocol for main-memory multi-versioned database systems. Bohm guarantees serializable execution while ensuring that reads never block writes. In addition, Bohm does not require reads to perform any bookkeeping whatsoever, thereby avoiding the overhead of tracking reads via contended writes to shared memory. This leads to excellent scalability and performance in multi-core settings. Bohm has all the above characteristics without performing validation based concurrency control. Instead, it is pessimistic, and is therefore not prone to excessive aborts in the presence of contention. An experimental evaluation shows that Bohm performs well in both high contention and low contention settings, and is able to dramatically outperform state-of-the-art multi-versioned systems despite maintaining the full set of serializability guarantees.
18.177 course project: Invariance Principles

We think of this as saying that under some mild conditions on our probability space, the distribution of the linear form Q is roughly the same, regardless of the actual underlying distribution. There are, of course, a family of different central limit theorems, with different “mildness conditions” leading to different notions of the closeness of the resulting distributions. As “central limit theorems,” however, these classical results all aimed to show that a linear form on some (arbitrary) distribution was close to the single Gaussian corresponding to that linear form. When these theorems are stated in the form given here, it is natural to wonder if they hold for a richer class of functions, where although the final distribution may not be Gaussian, it may be close to the distribution produced by a function on Gaussian space. Recently, such generalizations of the Berry-Essen Theorem to multilinear polynomials, i.e., Q of the form
Determination of time delay from the gravitational lens B1422+231

We present the radio light curves of lensed images of the gravitational lens B1422+231. The observations have been carried out using the VLA at 8.4 and 15 GHz over a period of 197 d. We describe a method to estimate the time delay from the observed light curves. Using this method, our cross-correlation analysis shows that the time delay between images B and A is 1.5±1.4 d, that between A and C is 7.6±2.5 d, and that between B and C is 8.2±2.0 d. When applied to other lensed systems with measured time delays our new method gives comparable results.
Language skills of adolescents with Tourette Syndrome

A multiple single‐case study investigated language characteristics of adolescents with Tourette Syndrome (TS). Ten adolescent subjects with diagnosed TS were evaluated on a test battery sensitive to high level language and discourse impairment. Results were compared to established norms or, where no norms have been established, with results obtained by 15 non‐neurologically impaired adolescent subjects. Five subjects were differentiated from normal communicative performance by their test results. Although language profiles were variable, disorganized output, concreteness of language and poor language formulation abilities were apparent in these subjects. This symptomatology may reflect prefrontal disturbance and can possibly be explained by the pathogenesis of the disorder. This finding adds to literature regarding subcortical and frontal cortex language involvement and indicates further research.
Residual Strength Prediction of Fuselage Structures with Multiple Site Damage

This paper summarizes recent results on simulating full-scale pressure tests of wide body, lap-jointed fuselage panels with multiple site damage (MSD). The crack tip opening angle (CTOA) fracture criterion and the FRANC3D/STAGS software program were used to analyze stable crack growth under conditions of general yielding. The link-up of multiple cracks and residual strength of damaged structures were predicted. Elastic-plastic finite element analysis based on the von Mises yield criterion and incremental flow theory with small strain assumption was used. A global-local modeling procedure was employed in the numerical analyses. Stress distributions from the numerical simulations are compared with strain gage measurements. Analysis results show that accurate representation of the load transfer through the rivets is crucial for the model to predict the stress distribution accurately. Predicted crack growth and residual strength are compared with test data. Observed and predicted results both indicate that the occurrence of small MSD cracks substantially reduces the residual strength. Modeling fatigue closure is essential to capture the fracture behavior during the early stable crack growth. Breakage of a tear strap can have a major influence on residual strength prediction.
Cortically-Controlled Population Stochastic Facilitation as a Plausible Substrate for Guiding Sensory Transfer across the Thalamic Gateway

The thalamus is the primary gateway that relays sensory information to the cerebral cortex. While a single recipient cortical cell receives the convergence of many principal relay cells of the thalamus, each thalamic cell in turn integrates a dense and distributed synaptic feedback from the cortex. During sensory processing, the influence of this functional loop remains largely ignored. Using dynamic-clamp techniques in thalamic slices in vitro, we combined theoretical and experimental approaches to implement a realistic hybrid retino-thalamo-cortical pathway mixing biological cells and simulated circuits. The synaptic bombardment of cortical origin was mimicked through the injection of a stochastic mixture of excitatory and inhibitory conductances, resulting in a gradable correlation level of afferent activity shared by thalamic cells. The study of the impact of the simulated cortical input on the global retinocortical signal transfer efficiency revealed a novel control mechanism resulting from the collective resonance of all thalamic relay neurons. We show here that the transfer efficiency of sensory input transmission depends on three key features: i) the number of thalamocortical cells involved in the many-to-one convergence from thalamus to cortex, ii) the statistics of the corticothalamic synaptic bombardment and iii) the level of correlation imposed between converging thalamic relay cells. In particular, our results demonstrate counterintuitively that the retinocortical signal transfer efficiency increases when the level of correlation across thalamic cells decreases. This suggests that the transfer efficiency of relay cells could be selectively amplified when they become simultaneously desynchronized by the cortical feedback. When applied to the intact brain, this network regulation mechanism could direct an attentional focus to specific thalamic subassemblies and select the appropriate input lines to the cortex according to the descending influence of cortically-defined “priors”.
Journal of Neuroscience Methods Automated Tracking and Analysis of Behavior in Restrained Insects

• We present an algorithm for tracking the movement body parts of restrained animals. • The tracking algorithm works with low frame-rate videos. • The tracking algorithm automatically segments and tracks multiple body parts. • We demonstrate the power of the algorithm in analysing insect behaviour. Keywords: Insect Behavior Honey bee Classical conditioning Multi-target tracking Antenna a b s t r a c t Background: Insect behavior is often monitored by human observers and measured in the form of binary responses. This procedure is time costly and does not allow a fine graded measurement of behavioral performance in individual animals. To overcome this limitation, we have developed a computer vision system which allows the automated tracking of body parts of restrained insects. New method: Our system crops a continuous video into separate shots with a static background. It then segments out the insect's head and preprocesses the detected moving objects to exclude detection errors. A Bayesian-based algorithm is proposed to identify the trajectory of each body part. Results: We demonstrate the application of this novel tracking algorithm by monitoring movements of the mouthparts and antennae of honey bees and ants, and demonstrate its suitability for analyzing the behavioral performance of individual bees using a common associative learning paradigm. Comparison with existing methods: Our tracking system differs from existing systems in that it does not require each video to be labeled manually and is capable of tracking insects' body parts even when working with low frame-rate videos. Our system can be generalized for other insect tracking applications. Conclusions: Our system paves the ground for fully automated monitoring of the behavior of restrained insects and accounts for individual variations in graded behavior.
Association of Lipids With Incident Heart Failure Among Adults With and Without Diabetes Mellitus: Multiethnic Study of Atherosclerosis

Background—Dyslipidemia is a known risk factor for coronary disease, but its role in heart failure (HF) development is less well-defined. Methods and Results—We included 5688 participants, aged 45 to 84 years, without clinical cardiovascular disease, and not receiving lipid-lowering medications at baseline, from the Multiethnic Study of Atherosclerosis. Cox-proportional hazards models were used to evaluate associations of triglyceride, total cholesterol/high-density lipoprotein–cholesterol (HDL-C) ratio, HDL-C, and non HDL-C with incident HF. We investigated for effect-modification by diabetes mellitus status and sex. During a median follow-up of 8.5 years, there were 152 incident HF cases. There were no interactions by sex. We observed significant interactions between triglyceride and diabetes mellitus (Pinteraction<0.05). We stratified our analyses by diabetes mellitus status. In participants with diabetes, the hazard ratios were 2.03 (0.97–4.27) and 1.68 (1.18–2.38) for high triglyceride and log of triglyceride, respectively, after adjusting for confounders, comorbidities, and diabetes mellitus severity/treatment. The association of high triglyceride with incident HF was attenuated by interim myocardial infarction. The hazard ratios were greatest in participants with diabetes who also had high triglyceride, low HDL-C, or high total cholesterol/HDL-C ratio (3.59 [2.03–6.33], 3.62 [2.06–6.36], and 3.54 [1.87–6.70], respectively). Lipid measures were not associated with incident HF in individuals without diabetes. Conclusions—The risk of incident HF is greater in individuals with diabetes mellitus who also have high triglyceride, low HDL-C, or high total cholesterol/HDL-C ratio. The association of high triglyceride with incident HF is partly mediated by myocardial infarction.
A General Total Variation Minimization Theorem for Compressed Sensing Based Interior Tomography

Recently, in the compressed sensing framework we found that a two-dimensional interior region-of-interest (ROI) can be exactly reconstructed via the total variation minimization if the ROI is piecewise constant (Yu and Wang, 2009). Here we present a general theorem charactering a minimization property for a piecewise constant function defined on a domain in any dimension. Our major mathematical tool to prove this result is functional analysis without involving the Dirac delta function, which was heuristically used by Yu and Wang (2009).
Emerging applications of read profiles towards the functional annotation of the genome

Functional annotation of the genome is important to understand the phenotypic complexity of various species. The road toward functional annotation involves several challenges ranging from experiments on individual molecules to large-scale analysis of high-throughput sequencing (HTS) data. HTS data is typically a result of the protocol designed to address specific research questions. The sequencing results in reads, which when mapped to a reference genome often leads to the formation of distinct patterns (read profiles). Interpretation of these read profiles is essential for their analysis in relation to the research question addressed. Several strategies have been employed at varying levels of abstraction ranging from a somewhat ad hoc to a more systematic analysis of read profiles. These include methods which can compare read profiles, e.g., from direct (non-sequence based) alignments to classification of patterns into functional groups. In this review, we highlight the emerging applications of read profiles for the annotation of non-coding RNA and cis-regulatory elements (CREs) such as enhancers and promoters. We also discuss the biological rationale behind their formation.
Densification of fused silica: effects on nanoindentation

As compared to other optical glasses, when fused silica (SiO2) is ground or polished, it has some unique features, such as low surface microroughness and subsurface damage, low grinding- induced residual stresses, and low removal rates. It also has higher hardness. On the other hand, fused silica's Young's modulus and fracture toughness are in the middle range of the optical glasses. So, compared to other optical glasses, fused silica behaves differently under compressive loads. When subjected to sufficiently large compressive stresses, fused silica glass will densify permanently. It is also noticed that shear will facilitate densification. We model this behavior by a simple constitutive law including both shear flow and densification. The constitutive model was used to interpret nanoindentation tests on fused silica via 3D finite element simulations of indentations of Berkovich indenter. This work extends our previous work on axisymmetric (2D) indentation.
High efficiency IR supercontinuum generation and applications

In this paper, we have reviewed our recent works on IR supercontinuum generation (SCG) and its applications. First, we provide a brief review on the physical mechanism of the supercontinuum generation. Second, the advance of SCG in single crystal sapphire fibers is reviewed and introduced. In particular, we discussed how to fabricate thinned sapphire fiber and use it for high efficiency SCG. Finally, experimental results of chemical analysis with supercontinuum source are reviewed.
Density Dependence Triggers Runaway Selection of Reduced Senescence

In the presence of exogenous mortality risks, future reproduction by an individual is worth less than present reproduction to its fitness. Senescent aging thus results inevitably from transferring net fertility into younger ages. Some long-lived organisms appear to defy theory, however, presenting negligible senescence (e.g., hydra) and extended lifespans (e.g., Bristlecone Pine). Here, we investigate the possibility that the onset of vitality loss can be delayed indefinitely, even accepting the abundant evidence that reproduction is intrinsically costly to survival. For an environment with constant hazard, we establish that natural selection itself contributes to increasing density-dependent recruitment losses. We then develop a generalized model of accelerating vitality loss for analyzing fitness optima as a tradeoff between compression and spread in the age profile of net fertility. Across a realistic spectrum of senescent age profiles, density regulation of recruitment can trigger runaway selection for ever-reducing senescence. This novel prediction applies without requirement for special life-history characteristics such as indeterminate somatic growth or increasing fecundity with age. The evolution of nonsenescence from senescence is robust to the presence of exogenous adult mortality, which tends instead to increase the age-independent component of vitality loss. We simulate examples of runaway selection leading to negligible senescence and even intrinsic immortality.
Protein secondary structure prediction using periodic-quadratic-logistic models: statistical and theoretical issues

We extend logistic discriminant function methodology to compete effectively with neural networks and "information theory" methods in prediction of protein secondary structure. Unlike "black-box" methods, our model produces 400 pairwise interaction parameters which are interpretable from a molecular standpoint. Under optimal conditions, our model can produce up to 65.9% crossvalidated prediction accuracy on three states. A broad family of models is searched using a semi-parametric (penalized) approach combined with stepwise parameter selection. We show that optimal models have about 800 effective parameters for this data set. The highest prediction accuracy is concentrated in a fraction of the total residues, and the confidence of a prediction can be easily calculated. Such high-confidence predictions may be useful as the basis for prediction of the complete structure of the protein. <<ETX>>