Miracle-dz/UniFAR-FTUs huggingface dataset:
Drug-drug interactions involving lysosomes: mechanisms and potential clinical implications

Introduction: Many commercially available, weakly basic drugs have been shown to be lysosomotropic, meaning they are subject to extensive sequestration in lysosomes through an ion trapping-type mechanism. The extent of lysosomal trapping of a drug is an important therapeutic consideration because it can influence both activity and pharmacokinetic disposition. The administration of certain drugs can alter lysosomes such that their accumulation capacity for co-administered and/or secondarily administered drugs is altered. Areas covered: In this review the authors explore what is known regarding the mechanistic basis for drug-drug interactions involving lysosomes. Specifically, the authors address the influence of drugs on lysosomal pH, volume and lipid processing. Expert opinion: Many drugs are known to extensively accumulate in lysosomes and significantly alter their structure and function; however, the therapeutic and toxicological implications of this remain controversial. The authors propose that drug-drug interactions involving lysosomes represent an important potential source of variability in drug activity and pharmacokinetics. Most evaluations of drug-drug interactions involving lysosomes have been performed in cultured cells and isolated tissues. More comprehensive in vivo evaluations are needed to fully explore the impact of this drug-drug interaction pathway on therapeutic outcomes.
MorphoGraphX: A platform for quantifying morphogenesis in 4D

Morphogenesis emerges from complex multiscale interactions between genetic and mechanical processes. To understand these processes, the evolution of cell shape, proliferation and gene expression must be quantified. This quantification is usually performed either in full 3D, which is computationally expensive and technically challenging, or on 2D planar projections, which introduces geometrical artifacts on highly curved organs. Here we present MorphoGraphX (www.MorphoGraphX.org), a software that bridges this gap by working directly with curved surface images extracted from 3D data. In addition to traditional 3D image analysis, we have developed algorithms to operate on curved surfaces, such as cell segmentation, lineage tracking and fluorescence signal quantification. The software's modular design makes it easy to include existing libraries, or to implement new algorithms. Cell geometries extracted with MorphoGraphX can be exported and used as templates for simulation models, providing a powerful platform to investigate the interactions between shape, genes and growth. DOI: http://dx.doi. org/10.7554/eLife.05864. 001
Small wind turbine generic model design for BTS radio interaction studies

Because radar systems and TV reception are affected by wind turbines, the important development of hybrid-powered BTS (fuel, solar and wind energy) raises questions about possible radio impact between cellular radio signals and the small wind turbines (SWTs) that contribute to BTS supply. SWTs come in a wider variety of designs than bigger wind turbines. In the context of the OPERA-Net2 European project, a new generic parameterized model is developed to support electromagnetic interaction studies. It is notably scalable depending on the SWT nominal power to be considered. Monostatic Radar Cross Section (RCS) calculation in the wind turbine principal planes is done to select among different possible shapes and dimensions. Then an original study of the near field coupling between SWT and BTS panel antenna is carried out.
High Blood Pressure as Risk Factor in Diabetic Retinopathy Development in NIDDM Patients

The correlation between diabetic retinopathy and blood pressure was analyzed in 742 type II diabetic patients. Systolic and pulse blood pressures were significantly higher in the patients with retinopathy than in those without (mean systolic pressure 142 vs. 139 mmHg, P < .01; mean pulse pressure 60.5 vs. 56.4 mmHg, P < .001). There was no difference in the diastolic blood pressure between these two groups. The correlation between blood pressure and the components of retinopathy (including microaneurysms, hemorrhages, and exudates) was also analyzed. Even when the patient with microaneurysms or dot hemorrhages, blot hemorrhages, or hard or soft exudates were separately evaluated, systolic and pulse blood pressures were higher in those with one of these diabetic changes than in patients without them. To avoid the influence of nephropathy, the patients were divided into nonproteinuric or proteinuric groups. In the nonproteinuric group, pulse blood pressure was higher in patients with retinopathy than in those without. In the proteinuric group, systolic blood pressure was also higher in patients with retinopathy than in those without. However, these observed differences in blood pressure were slight after the division of the patients. With respect to the components of retinopathy, systolic and pulse blood pressures were significantly higher in the patient with blot hemorrhages than in those without in both nonproteinuric and proteinuric groups (nonproteinuric: systolic pressure 142 vs. 137 mmHg, P < .005, and pulse pressure 60.4 vs. 55.5 mmHg, P < .001; proteinuric: systolic pressure 155 vs. 146 mmHg, P < 0.01, and pulse pressure 69.0 vs. 63.5 mmHg, P < .05) In regard to other components (microaneurysms, dot hemorrhages, or hard or soft exudates), no significant difference was found in blood pressure when analyzed in both nonproteinuric and proteinuric patients. Systolic, diastolic, and pulse blood pressures did not correlate with blood glucose level in any of our patients. These data revealed that systolic hypertension is a risk for diabetic retinopathy, especially for blot hemorrhage.
Bolt-on causal consistency

We consider the problem of separating consistency-related safety properties from availability and durability in distributed data stores via the application of a "bolt-on" shim layer that upgrades the safety of an underlying general-purpose data store. This shim provides the same consistency guarantees atop a wide range of widely deployed but often inflexible stores. As causal consistency is one of the strongest consistency models that remain available during system partitions, we develop a shim layer that upgrades eventually consistent stores to provide convergent causal consistency. Accordingly, we leverage widely deployed eventually consistent infrastructure as a common substrate for providing causal guarantees. We describe algorithms and shim implementations that are suitable for a large class of application-level causality relationships and evaluate our techniques using an existing, production-ready data store and with real-world explicit causality relationships.
Tangent-Free Property for Periodic Cells Generated by Some General Piecewise Isometries

Iterating an orientation-preserving piecewise isometry of -dimensional Euclidean space, the phase space can be partitioned with full measure into the union of the rational set consisting of periodically coded points, and the complement of the rational set is usually called the exceptional set. The tangencies between the periodic cells have been studied in some previous papers, and the results showed that almost all disk packings for certain families of planar piecewise isometries have no tangencies. In this paper, the authors further investigate the structure of any periodic cells for a general piecewise isometry of even dimensional Euclidean space and the tangencies between the periodic cells. First, we show that each periodic cell is a symmetrical body to a center if the piecewise isometry is irrational; this result is a generalization of the results in some previously published papers. Second, we show that the periodic cell packing induced by an invertible irrational planar piecewise rotation, such as the Sigma-Delta map and the overflow map, has no tangencies. And furthermore, we generalize the result to general even dimensional Euclidean spaces. Our results generalize and strengthen former research results on this topic.
Global existence and asymptotic behavior of solutions for a system of higher-order Kirchhoff-type equations

This paper deals with the global existence and energy decay of solutions for some coupled system of higher-order Kirchhoff-type equations with nonlinear dissipative and source terms in a bounded domain. We prove the existence of global solutions for this problem by constructing a stable set in H1 0 (Ω)× H m2 0 (Ω) and give the decay estimate of global solutions by applying a lemma of V. Komornik.
Client Side Cloud Computing Security: a mixed Market Analysis

Could computing service providers have to ensure that the service applications, cloud software, and the physical location of the cloud are secure. Furthermore, providers need to ensure that the service is secure on the client’s side of the system. To examine the client side security level we build economic models that consider the tradeoffs between system usability and client side security restrictions. Our mixed market model is based on firms with different objectives (i.e., social welfare maximizing vs. profit maximizing). Under the mixed market model, we show that it is desirable to maintain adequate client side security differentiation. The equilibrium price charged by the welfare maximizing firm for its cloud computing service is always equal to that charged by the profit maximizing firm. The result shows that socially optimal solution is achieved when the welfare maximizing firm is the market leader.
Growth Modeling of the Maternal Cytokine Milieu throughout Normal Pregnancy: Macrophage-Derived Chemokine Decreases as Inflammation/Counterregulation Increases

Several recent studies have shown differences in the maternal immune milieu at different phases of pregnancy, but most studies have been cross-sectional or of relatively few time points. Levels of 42 cytokines were determined using a multiplex bead-based assay on archived serum from a cohort of pregnant women (N = 16) at median of 18 time points tested, from the first trimester through to parturition, per woman. Unconditional growth modeling was then used to determine time-dependent changes in levels of these cytokines. Macrophage-derived chemokine (MDC, aka CCL22) decreases as pregnancy progresses. IL-1β, IL-6, IL-8, IL-12p70, IL-13, IL-15, IP-10, and FLT3-ligand increase as a function of gestational weeks, and IFNα2, IL-1ra, IL-3, IL-9, IL-12p40, and soluble CD40 ligand increase as a function of trimester. As pregnancy normally progresses, a maternal shift away from a type 2-biased immune response and toward an inflammatory/counterregulatory response is observed.
Design and evaluation of a compiler algorithm for prefetching

Software-controlled data prefetching is a promising technique for improving the performance of the memory subsystem to match today’s high-performance processors. While prefctching is useful in hiding the latency, issuing prefetches incurs an instruction overhead and can increase the load on the memory subsystem. As a resu 1~ care must be taken to ensure that such overheads do not exceed the benefits. This paper proposes a compiler algorithm to insert prefetch instructions into code that operates on dense matrices. Our algorithm identiEes those references that are likely to be cache misses, and issues prefetches only for them. We have implemented our algorithm in the SUfF (Stanford University Intermediate Form) optimizing compiler. By generating fully functional code, we have been able to measure not only the improvements in cache miss rates, but also the oversdl performance of a simulated system. We show that our algorithm significantly improves the execution speed of our benchmark programs-some of the programs improve by as much as a factor of two. When compared to an algorithm that indiscriminately prefetches alf array accesses, our algorithm can eliminate many of the unnecessary prefetches without any significant decrease in the coverage of the cache misses.
Static and vibration control of composite laminates integrated with piezoelectric sensors and actuators using the radial point interpolation method

A meshfree model based on the first-order shear deformation theory is presented for the shape and vibration control of laminated composite plates with integrated piezoelectric sensors and actuators. A point interpolation method using radial basis functions (RPIM) is employed to construct shape functions for mechanical and electrical variables, which possess the delta function property and show linear reproduction behavior. The method shows a high convergence rate equivalent to that of the second-order finite elements approach. Comparing, one sees that a very simple nodal topology can be used for the field representation and no element continuity is required. A constant displacement and velocity feedback control algorithm is used for the active control of the static deflection as well as the dynamic response of plates through closed loop control. Numerical results for the static deformation, vibration modes and dynamic responses are in good agreement with those from the finite element method.
Supportive Family Environments Ameliorate the Link Between Racial Discrimination and Epigenetic Aging

This study tested the hypothesis that supportive family environments during adolescence buffer exposure to racial discrimination, reducing its impact on biological weathering and its manifestation in cellular aging. Perceived racial discrimination, support in the family environment, and confounder variables were assessed for 3 consecutive years across adolescence in two independent cohorts of African American youth from rural Georgia. DNA was extracted from peripheral blood mononuclear cells collected during young adulthood. Patterns of methylation were used to index the epigenetic ages of these cells and the extent to which they differed from participants’ chronological ages. Among youth in supportive family environments, exposure to higher levels of racial discrimination did not forecast greater epigenetic aging. Among youth in less supportive family environments, exposure to higher levels of racial discrimination did forecast greater epigenetic aging. The associations emerged independently of confounder variables, and the results were replicated across the two cohorts.
The Balance of Protein Kinase C and Calcium Signaling Directs T Cell Subset Development1

Development of naive T cells into type 1 (Th1, Tc1) or type 2 (Th2, Tc2) effector cells is thought to be under the control of cytokines. In this study, we show that when both IL-12 and IL-4 are present, murine and human T cell differentiation is regulated by the balance of protein kinase C (PKC) and calcium signaling within T cells. Although both biochemical signals were required for T cell activation via the TCR, altering the balance between them redirected type 1 cells to type 2 and vice versa. Stimulation of calcium signaling or inhibition of PKC favored type 1 differentiation, whereas stimulation of PKC or inhibition of calcineurin resulted in type 2 effectors. Altered peptide ligands induced distinct balances of PKC/calcium signaling and altered Tc1/Tc2 development in TCR-transgenic CD8 T cells. The data suggest novel strategies for manipulation of the immune response in vivo.
The Two-Person Construction of Defenses: Disorganized Attachment Strategies, Unintegrated Mental States, and Hostile/Helpless Relational Processes

Since the initial identification of disorganized and controlling forms of attachment behavior 15 years ago, the accumulated findings of attachment research have also contributed to the paradigm shift in psychoanalytic thinking toward a more fully relational theory and model of treatment. This research report will provide an overview of recent work charting the developmental pathways and family processes associated with disorganized forms of attachment behaviors in infancy. These research findings both converge with and expand on earlier less systematic analytic clinical observations which have variously described inconsistency or role reversal or coercive discipline in the parenting behaviors of parents of clinically referred children. Attachment research provides one scientific foundation for positing relational as well as biological contributions to many forms of psychopathology. However, attachment theory also advances a more specific model within the broader relational framework. I will describe some of the more specific tenets of attachment theory of the development of psychopathology, and then present a brief overview of recent findings regarding the development of disorganized and controlling forms of attachment behavior.
In Silico Detection of Sequence Variations Modifying Transcriptional Regulation

Identification of functional genetic variation associated with increased susceptibility to complex diseases can elucidate genes and underlying biochemical mechanisms linked to disease onset and progression. For genes linked to genetic diseases, most identified causal mutations alter an encoded protein sequence. Technological advances for measuring RNA abundance suggest that a significant number of undiscovered causal mutations may alter the regulation of gene transcription. However, it remains a challenge to separate causal genetic variations from linked neutral variations. Here we present an in silico driven approach to identify possible genetic variation in regulatory sequences. The approach combines phylogenetic footprinting and transcription factor binding site prediction to identify variation in candidate cis-regulatory elements. The bioinformatics approach has been tested on a set of SNPs that are reported to have a regulatory function, as well as background SNPs. In the absence of additional information about an analyzed gene, the poor specificity of binding site prediction is prohibitive to its application. However, when additional data is available that can give guidance on which transcription factor is involved in the regulation of the gene, the in silico binding site prediction improves the selection of candidate regulatory polymorphisms for further analyses. The bioinformatics software generated for the analysis has been implemented as a Web-based application system entitled RAVEN (regulatory analysis of variation in enhancers). The RAVEN system is available at http://www.cisreg. ca for all researchers interested in the detection and characterization of regulatory sequence variation.
Error bars in experimental biology

Error bars commonly appear in figures in publications, but experimental biologists are often unsure how they should be used and interpreted. In this article we illustrate some basic features of error bars and explain how they can help communicate data and assist correct interpretation. Error bars may show confidence intervals, standard errors, standard deviations, or other quantities. Different types of error bars give quite different information, and so figure legends must make clear what error bars represent. We suggest eight simple rules to assist with effective use and interpretation of error bars.
Particulate matter characteristics of a light-duty diesel engine with alternative fuel blends

The non-volatile particle emission characteristics of alternative (rapeseed methyl ester and gas-to-liquid) diesel fuel blends were studied through an experimental investigation carried out on a light-duty common-rail diesel engine. A blend ratio of 10 vol % was chosen as the practical limit for biodiesels in this study, and the research focus was on the particle number concentration and size distribution with various injection strategies, in which the non-volatile emissions were measured using thermodilution. The particle morphology and mass, together with the related gaseous emissions, were measured and analysed. The results indicate that, without any engine modification, adding selected alternative fuels even at a low percentage could result in a favourable reduction in the number of particles and in a significant reduction in the total particle concentration in both the nucleation mode and the accumulation mode. The particle emissions of the three fuels demonstrated monomodal size distributions under most engine conditions tested, except for the engine idling case, which produced a bimodal size distribution. The influence of 10 vol % rapeseed methyl ester or gas-to-liquid diesel blends on the carbon monoxide and nitrogen oxide emissions is not significant. Nevertheless, using these diesel fuel blends may increase the total hydrocarbon emissions and may lead to high particulate matter emissions.
Randomized multicenter phase 2 study of pomalidomide, cyclophosphamide, and dexamethasone in relapsed refractory myeloma.

Pomalidomide and low-dose dexamethasone (PomDex) is standard treatment of lenalidomide refractory myeloma patients who have received >2 prior therapies. We aimed to assess the safety and efficacy of the addition of oral weekly cyclophosphamide to standard PomDex. We first performed a dose escalation phase 1 study to determine the recommended phase 2 dose of cyclophosphamide in combination with PomDex (arm A). A randomized, multicenter phase 2 study followed, enrolling patients with lenalidomide refractory myeloma. Patients were randomized (1:1) to receive pomalidomide 4 mg on days 1 to 21 of a 28-day cycle in combination with weekly dexamethasone (arm B) or pomalidomide, dexamethasone, and cyclophosphamide (PomCyDex) 400 mg orally on days 1, 8, and 15 (arm C). The primary end point was overall response rate (ORR). Eighty patients were enrolled (10 in phase 1 and 70 randomized in phase 2: 36 to arm B and 34 to arm C). The ORR was 38.9% (95% confidence interval [CI], 23-54.8%) and 64.7% (95% CI, 48.6-80.8%) for arms B and C, respectively (P = .035). As of June 2015, 62 of the 70 randomized patients had progressed. The median progression-free survival (PFS) was 4.4 (95% CI, 2.3-5.7) and 9.5 months (95% CI, 4.6-14) for arms B and C, respectively (P = .106). Toxicity was predominantly hematologic in nature but was not statistically higher in arm C. The combination of PomCyDex results in a superior ORR and PFS compared with PomDex in patients with lenalidomide refractory multiple myeloma. The trial was registered at www.clinicaltrials. gov as #NCT01432600.