Miracle-dz/UniFAR-FTUs huggingface dataset:
Cancer-Associated Fibroblasts Derived from EGFR-TKI–Resistant Tumors Reverse EGFR Pathway Inhibition by EGFR-TKIs

Epidermal growth factor receptor (EGFR) plays a critical role in oncogenesis, which makes it an attractive target for pharmacologic inhibition. Yet, EGFR inhibition with tyrosine kinase inhibitors (TKI) does not result in a measurable and sustainable clinical benefit in a vast majority of tumors. This emphasizes the need for further investigations into resistance mechanisms against EGFR-TKIs. We previously reported the generation of an in vivo adenocarcinoma model of EGFR-TKI–acquired resistance that was devoid of the known mechanisms of resistance. Using this same xenograft model, we now show that the tumor stroma plays an important role in limiting responsiveness to EGFR-TKIs. EGFR-TKI–resistant tumors display increased surface expression of CD44hi/CD24lo and markers of epithelial to mesenchymal transition (EMT), SNAI1, and N-cadherin. An in vivo green fluorescent protein–tagging approach reveals that the tumor stroma of the EGFR-TKI–resistant tumors is distinct in that 24% of its cancer-associated fibroblast (CAF) population is composed of EMT-derived tumor cells that represent the in vivo escape from EGFR-TKIs. We further show that EMT subpopulation–harboring CAFs isolated from the EGFR-TKI–resistant tumors are tumorigenic and express the biomarker of gefitinib resistance, epithelial membrane protein-1. Finally, we provide evidence that paracrine factors secreted from the EGFR-TKI–resistant CAFs mitigate the EGFR-TKI–mediated blockade of pEGFR and pMAPK in cocultured tumor cells, regardless of their EGFR mutational status. This is the first demonstration that the tumor stroma is modified with acquisition of EGFR-TKI resistance and that it further contributes in promoting drug resistance. Mol Cancer Res; 8(6); 809–20. ©2010 AACR.
Transforming Growth Factor type b and Smad family signaling in stem cell function

Ligands of the Transforming Growth Factor type b (TGFb) family exert multiple and sometimes opposite effects on most cell types in vivo depending on cellular context, which mainly includes the stage of the target cell, the local environment of this cell or niche, and the identity and the dosage of the ligand. Significant progress has been made in the molecular dissection of the regulation of the activity of the ligands and their intracellular signal transduction pathways, including via the canonical Smad pathway where Smads interact with many transcription factors. This knowledge together with results from functional studies within the embryology and stem cell research fields is giving us insight in the role of individual ligands and other components of this signaling system and where and how it regulates many properties of embryonic and adult stem/progenitor cells, which is anticipated to contribute to successful cell-based therapy in the future. We review and discuss recent progress on the effects of Nodal/Activin and Bone Morphogenetic Proteins (BMPs) and their canonical signaling in cells with stem cell properties. We focus on embryonic stem cells and their maintenance and pluripotency, and conversion into selected cell types of neuroectoderm, mesoderm and endoderm, on induced pluripotent cells and on neurogenic cells in the
Evidence-Based Comprehensive Treatments for Early Autism

Early intervention for children with autism is currently a politically and scientifically complex topic. Randomized controlled trials have demonstrated positive effects in both short-term and longer term studies. The evidence suggests that early intervention programs are indeed beneficial for children with autism, often improving developmental functioning and decreasing maladaptive behaviors and symptom severity at the level of group analysis. Whether such changes lead to significant improvements in terms of greater independence and vocational and social functioning in adulthood is also unknown. Given the few randomized controlled treatment trials that have been carried out, the few models that have been tested, and the large differences in interventions that are being published, it is clear that the field is still very early in the process of determining (a) what kinds of interventions are most efficacious in early autism, (b) what variables moderate and mediate treatment gains and improved outcomes following intervention, and (c) the degree of both short-term and long-term improvements that can reasonably be expected. To examine these current research needs, the empirical studies of comprehensive treatments for young children with autism published since 1998 were reviewed. Lovaas's treatment meet Chambless and colleague's (Chambless et al., 1998; Chambless et al., 1996) criteria for “well-established” and no treatment meets the “probably efficacious” criteria, though three treatments meet criteria for “possibly efficacious” (Chambless & Hollon, 1998). Most studies were either Type 2 or 3 in terms of their methodological rigor based on Nathan and Gorman's (2002) criteria. Implications of these findings are also discussed in relation to practice guidelines as well as critical areas of research that have yet to be answered
Chasing the Hottest IT: Effects of Information Technology Fashion on Organizations

What happens to organizations that chase the hottest information technologies? This study examines some of the important organizational impacts of the fashion phenomenon in IT. An IT fashion is a transitory collective belief that an information technology is new, efficient, and at the forefront of practice. Using data collected from published discourse and annual IT budgets of 109 large companies for a decade, I have found that firms whose names were associated with IT fashions in the press did not have higher performance, but they had better reputation and higher executive compensation in the near term. Companies investing in IT in fashion also had higher reputation and executive pay, but they had lower performance in the short term and then improved performance in the long term. These results support a fashion explanation for the middle phase diffusion of IT innovations, illustrating that following fashion can legitimize organizations and their leaders regardless of performance improvement. The findings also extend institutional theory from its usual focus on taken-for-granted practices to fashion as a novel source of social approval. This study suggests that practitioners balance between performance pressure and social approval when they confront whatever is hottest in IT.
Emerging Infectious Diseases in Free-Ranging Wildlife–Australian Zoo Based Wildlife Hospitals Contribute to National Surveillance

Emerging infectious diseases are increasingly originating from wildlife. Many of these diseases have significant impacts on human health, domestic animal health, and biodiversity. Surveillance is the key to early detection of emerging diseases. A zoo based wildlife disease surveillance program developed in Australia incorporates disease information from free-ranging wildlife into the existing national wildlife health information system. This program uses a collaborative approach and provides a strong model for a disease surveillance program for free-ranging wildlife that enhances the national capacity for early detection of emerging diseases.
The origin and extent of coarse‐grained regularities in protein internal packing

Despite the suitability of various lattice geometries for coarse‐grained modeling of proteins, the actual packing geometry of residues in folded structures has remained largely unexplored. A strong tendency to assume a regular packing geometry is shown here by optimally reorienting and superimposing clusters of neighboring residues from databank structures examined on a coarse‐grained (single‐site‐per‐residue) scale. The orientation function (or order parameter) of the examined coordination clusters with respect to fcc lattice directions is found to be 0.82. The observed geometry, which may be termed an incomplete distorted face‐centered cubic (fcc) packing, is apparently favored by the drive to maximize packing density, in a fashion analogous to the way identical spheres pack densely and follow fcc geometry. About 2/3 of all residues obey this packing geometry, while the remainder occupy other context‐dependent positions. The preferred coordination directions show relatively small variations over the various amino acid types, consistent with uniform residue viewpoint. Both the extremes of solvent‐exposed and completely buried residue neighborhoods approximate the same generic packing, the only difference being in the numbers (and not the orientations) of coordination sites that are occupied (or left void for solvent occupancy). We observe the prevalence of a rather uniform (tight) residue packing density throughout the structure, including even the residues packed near solvent‐exposed regions. The observed orientation distribution reveals an underlying, intrinsic orientation lattice for proteins. Proteins 2003. © 2003 Wiley‐Liss, Inc.
Design, synthesis and characterization of a peptide able to bind proteins of the KCTD family: implications for KCTD—cullin 3 recognition

Pox virus Zinc/Bric‐à‐brac, Tramtrack and Broad (POZ/BTB) is a widespread domain detected in proteins involved in a variety of biological processes. Human genome analyses have unveiled the presence of POZ/BTB domain in a class of proteins (KCTD) whose role as important players in crucial biological processes is emerging. The development of new molecular entities able to interact with these proteins and to modulate their activity is a field of relevant interest. By using molecular modeling and literature mutagenesis analyses, we here designed and characterized a peptide that is able to interact with submicromolar affinities with two different members (KCTD11 and KCTD5) of this family. This finding suggests that the tetrameric KCTD11 and the pentameric KCTD5 are endowed with a similar cavity at the subunit–subunit interface deputed to the Cul3 binding, despite their different oligomeric states. Copyright © 2011 European Peptide Society and John Wiley & Sons, Ltd.
Configurable cache tuning with a victim cache

A victim cache is a small memory block usually connected after the first level cache, and provides recovery of recently evicted cache blocks. This small component can significantly improve the hit rate of the cache hierarchy. However, its effectiveness varies greatly with the application. Thus, tuning the victim cache in combination with its upper cache level to fit the running application can yield important energy savings. In this paper, we propose a tuning cache heuristic that explores the features of a level 1 data cache in combination with the tuning of a victim cache. Experimental results show that this approach generates a significant improvement in energy efficiency, in comparison with a fixed cache hierarchy approach and against a state of the art tuning heuristic.
Dimensionality Reduction for Indexing Time Series Based on the Minimum Distance

We address the problem of efficient similarity search based on the minimum distance in large time series databases. To support minimum distance queries, most of previous work has to take the preprocessing step of vertical shifting. However, the vertical shifting has an additional overhead in building index. In this paper, we propose a novel dimensionality reduction technique for indexing time series based on the minimum distance. We call our approach the SSV-indexing (Segmented Sum of Variation Indexing). The proposed method can match time series of similar shape without vertical shifting and guarantees no false dismissals. Several experiments are performed on real data (stock price movement) to measure the performance of the SSV-indexing.
How do bacteria localize proteins to the cell pole?

ABSTRACT It is now well appreciated that bacterial cells are highly organized, which is far from the initial concept that they are merely bags of randomly distributed macromolecules and chemicals. Central to their spatial organization is the precise positioning of certain proteins in subcellular domains of the cell. In particular, the cell poles – the ends of rod-shaped cells – constitute important platforms for cellular regulation that underlie processes as essential as cell cycle progression, cellular differentiation, virulence, chemotaxis and growth of appendages. Thus, understanding how the polar localization of specific proteins is achieved and regulated is a crucial question in bacterial cell biology. Often, polarly localized proteins are recruited to the poles through their interaction with other proteins or protein complexes that were already located there, in a so-called diffusion-and-capture mechanism. Bacteria are also starting to reveal their secrets on how the initial pole ‘recognition’ can occur and how this event can be regulated to generate dynamic, reproducible patterns in time (for example, during the cell cycle) and space (for example, at a specific cell pole). Here, we review the major mechanisms that have been described in the literature, with an emphasis on the self-organizing principles. We also present regulation strategies adopted by bacterial cells to obtain complex spatiotemporal patterns of protein localization.
Similarity of polygenic profiles limits the potential for elite human physical performance

Human physical capability is influenced by many environmental and genetic factors, and it is generally accepted that physical capability phenotypes are highly polygenic. However, the ways in which relevant polymorphisms combine to influence the physical capability of individuals and populations are unknown. Initially, the literature was searched to identify associations between 23 genetic polymorphisms and human endurance phenotypes. Next, typical genotype frequencies of those polymorphisms in the general population were obtained from suitable literature. Using probability calculations, we found only a 0.0005% chance of a single individual in the world having the ‘preferable’ form of all 23 polymorphisms. As the number of DNA variants shown to be associated with human endurance phenotypes continues to increase, the probability of any single individual possessing the ‘preferable’ form of each polymorphism will become even lower. However, with population turnover, the chance of such genetically gifted individuals existing increases. To examine the polygenic endurance potential of a human population, a ‘total genotype score’ (for the 23 polymorphisms) was calculated for each individual within a hypothetical population of 1000 000. There was considerable homogeneity in terms of genetic predisposition to high endurance potential, with 99% of people differing by no more than seven genotypes from the typical profile. Consequently, with population turnover world and Olympic records should improve even without further enhancement of environmental factors, as more ‘advantageous’ polygenic profiles occasionally, though rarely, emerge. More broadly, human potential appears limited by the similarity of polygenic profiles at both the ‘elite sport’ and ‘chronic disorder’ ends of the performance continuum.
[Guidelines on prevention, diagnosis and treatment of infective endocarditis].

ESC Committee for Practice Guidelines (CPG), Silvia G. Priori (Chairperson) (Italy), Maria Angeles Alonso Garcia (Spain), Jean-Jacques Blanc (France), Andrzej Budaj (Poland), Martin Cowie (UK), Veronica Dean (France), Jaap Deckers (The Netherlands), Enrique Fernández Burgos (Spain), John Lekakis (Greece), Bertil Lindahl (Sweden), Gianfranco Mazzotta (Italy), João Morais (Portugal), Ali Oto (Turkey), Otto A. Smiseth (Norway)
On the geometric aspects of the invariant ellipsoid method: Application to the robust control design

This paper deals with a robust control design for a class of nonlinear affine control systems. The dynamical models under consideration are described by ordinary differential equations in the presence of some additive bounded uncertainties. The design procedure for the robust linear feedback control associated with the linearized dynamic model is based on an extended version of the classical invariant ellipsoid method. The stability/robustness analysis of the resulting closed-loop system involves the celebrated Clarke stability theorem that represents a theoretic extension of the celebrated Lyapunov-type methodology. The obtained analytic results are illustrated by a simple computational example.
The relationship between maternal characteristics and fetal and neonatal anthropometric measurements in women delivering at term: a summary.

BACKGROUND We wanted to determine the relationship between a number of maternal characteristics and various fetal and neonatal anthropometric measurements determined by ultrasound and at birth. METHODS A total of 1205 term singleton maternal-infant pairs were studied. Various ultrasound measurements obtained at 18, 24, 30 and 36 weeks' gestation and neonatal anthropometric measurements obtained at birth were studied in relationship to various maternal characteristics using univariate and multivariate techniques. RESULTS Black race, female sex, cigarette smoking, drug use, having a previous low birthweight infant, maternal hypertension and being short or thin or failing to gain weight each resulted in a birthweight decrease of 100 to 300 g. The effect of each of these characteristics on each ultrasound measurement, the timing of the effect, and its ultimate effect on neonatal anthropometric measurements are described. CONCLUSION The data presented in this paper provide a more complete understanding of the relationship between maternal characteristics, infant sex, and various fetal ultrasound and neonatal measurements.
MOTC with Examples: An Interactive Aid for Multidimensional Hypothesis Generation

This paper reports on conceptual development in the areas of database mining, and knowledge discovery in databases (KDD). Our efforts have also led to a prototype implementation, called MOTC, for exploring hypothesis space in large and complex data sets. Our KDD conceptual development rests on two main principles. First, we use the crosstab representation for working with qualitative data. This is by now standard practice in OLAP (on-line analytical processing) applications and we reaffirm it with additional reasons. Second, and innovatively, we use Prediction Analysis as a measure of goodness for hypotheses. Prediction Analysis is an established statistical technique for analysis of associations among qualitative variables. It generalizes and subsumes a large number of other such measures of association, depending upon specific assumptions the user is willing to make. As such, it provides a very useful framework for exploring hypothesis space in a KDD context. The paper illustrates these points with an extensive discussion of MOTC.
Reasoning about participation constraints and Chen's constraints

Cardinality constraints are often considered as one of the basic constituents of the entity-relationship approach to database design. In his original proposal of this model, Chen [6] defined cardinality constraints as look-across constraints. Alternatively, however, cardinality constraints may also be defined on the basis of the participation or look-here interpretation.While both definitions correspond to each other for binary relationships, they differ for n-ary relationships (with n ≥ 3). Participation constraints restrict the number of relationships a fixed object may participate in. Chen-style constraints limit the number of objects that co-occur with a given tuple comprising instances of the remaining n - 1 components of the relationship type under discussion.In our paper we present a sound and complete system of inference rules for a class of generalized cardinality constraints containing both, participation constraints and Chen-style constraints. It turns out that both constraint classes are almost independent, which justifies their juxtaposition in conceptual database design. Similar results will be presented in the presence of additional functional dependencies. The paper concludes with an axiomatization for the joint class of generalized cardinality constraints and functional dependencies.
Rapid discriminative detection for smart camera applications

Tracking-by-detection is an attractive paradigm for intelligent visual surveillance applications where clutter, lighting variations, target overlap and occlusions hamper conventional background modeling. However, state-of-the-art vehicle and pedestrian detectors based on discriminative classification are too computationally expensive for real-time implementation on embedded smart cameras. This paper presents the Generative Focus of Attention-Discriminative Validation (GFA-DV) detector which uses generative target detection to greatly improve the efficiency of discriminative classification. The proposed method gains further efficiency by using a hierarchical visual codebook to enable each stage of the detector to efficiently utilize the same features within a different quantization of the feature space. This approach reduces the expense of feature matching compared to multiple flat codebooks. The proposed GFA-DV detector is experimentally compared to several state-of-the-art methods, and shown to perform better than other efficient detectors while achieving a 100 times speedup over more accurate detectors.
Kernel data race detection using debug register in Linux

Data races in parallel programs are notoriously difficult to detect and resolve. Existing research has mostly focused on data race detection at the user level and significant progress has been made in this regard. It is difficult to apply detection methods designed for user-level applications to identify OS kernel level races. In this paper, we present a new detection tool that is able to effectively detect race conditions in the Linux kernel environment. We use a dynamic detection approach, employing hardware debug registers available on commodity processors, to catch races on the fly during runtime. Preliminary experimental results show that our tool can effectively identify real data race instances.