Miracle-dz/UniFAR-FTUs huggingface dataset:
Structuring the New Product Development Pipeline

In many new product development NPD situations, the development process is characterized by uncertainty, and no single development approach will necessarily lead to a successful product. To increase the likelihood of having at least one successful product, multiple approaches may be simultaneously funded at the various NPD stages. The managerial challenge is to construct ex ante an appropriate NPD pipeline by choosing the right number of approaches to be funded at each stage. This so-called pipeline problem is also present in, among others, advertising copy selection and new products test markets problems. We describe here a normative model for structuring pipelines for such situations. The optimal structure of the pipeline is driven by the cost of the development approach, its probability of survival, and the expected profitability. We illustrate the workability and implications of the model by applying it to some real-world scenarios in the pharmaceutical industry, and by comparing its normative pipeline recommendations against actual pipelines. Our results suggest that, for the cases we studied, firms tend to use narrower pipelines for their new drug development than they should, and thereby they underspend on research and development. We also present general qualitative insights for one-and two-stage NPD optimal pipeline structures.
Human Immunodeficiency Virus Type 1 Mediates Global Disruption of Innate Antiviral Signaling and Immune Defenses within Infected Cells

ABSTRACT Interferon regulatory factor 3 (IRF-3) is essential for innate intracellular immune defenses that limit virus replication, but these defenses fail to suppress human immunodeficiency virus (HIV) infection, which can ultimately associate with opportunistic coinfections and the progression to AIDS. Here, we examined antiviral defenses in CD4+ cells during virus infection and coinfection, revealing that HIV type 1 (HIV-1) directs a global disruption of innate immune signaling and supports a coinfection model through suppression of IRF-3. T cells responded to paramyxovirus infection to activate IRF-3 and interferon-stimulated gene expression, but they failed to mount a response against HIV-1. The lack of response associated with a marked depletion of IRF-3 but not IRF-7 in HIV-1-infected cells, which supported robust viral replication, whereas ectopic expression of active IRF-3 suppressed HIV-1 infection. IRF-3 depletion was dependent on a productive HIV-1 replication cycle and caused the specific disruption of Toll-like receptor and RIG-I-like receptor innate immune signaling that rendered cells permissive to secondary virus infection. IRF-3 levels were reduced in vivo within CD4+ T cells from patients with acute HIV-1 infection but not from long-term nonprogressors. Our results indicate that viral suppression of IRF-3 promotes HIV-1 infection by disrupting IRF-3-dependent signaling pathways and innate antiviral defenses of the host cell. IRF-3 may direct an innate antiviral response that regulates HIV-1 replication and viral set point while governing susceptibility to opportunistic virus coinfections.
Molecular biomarkers for predicting chemotherapy response in lung cancer.

BACKGROUND Chemotherapy in non-small-cell lung cancer (NSCLC) has reached a plateau, with no evidence of substantial improvement in survival. However, recent advances in the management of lung cancer have paved the way for the optimization of treatment. Several lines of evidence indicate that multiple genetic disturbances found in human cancer cell lines and in the tumors of NSCLC patients have a role as predictive markers for response and survival with chemotherapy regimens now in use. OBJECTIVE This review highlights relevant translational research findings on potential predictive markers in lung cancer with therapeutic impact in both the near and distant future. CONCLUSION The next step is to develop clinical trials that will prospectively validate the benefits of customizing chemotherapy, which should translate into an improvement in outcome in NSCLC patients.
Group-Level Progressive Alterations in Brain Connectivity Patterns Revealed by Diffusion-Tensor Brain Networks across Severity Stages in Alzheimer’s Disease

Alzheimer’s disease (AD) is a chronically progressive neurodegenerative disease highly correlated to aging. Whether AD originates by targeting a localized brain area and propagates to the rest of the brain across disease-severity progression is a question with an unknown answer. Here, we aim to provide an answer to this question at the group-level by looking at differences in diffusion-tensor brain networks. In particular, making use of data from Alzheimer's Disease Neuroimaging Initiative (ADNI), four different groups were defined (all of them matched by age, sex and education level): G1 (N1=36, healthy control subjects, Control), G2 (N2=36, early mild cognitive impairment, EMCI), G3 (N3=36, late mild cognitive impairment, LMCI) and G4 (N4=36, AD). Diffusion-tensor brain networks were compared across three disease stages: stage I 3(Control vs EMCI), stage II (Control vs LMCI) and stage III (Control vs AD). The group comparison was performed using the multivariate distance matrix regression analysis, a technique that was born in genomics and was recently proposed to handle brain functional networks, but here applied to diffusion-tensor data. The results were three-fold: First, no significant differences were found in stage I. Second, significant differences were found in stage II in the connectivity pattern of a subnetwork strongly associated to memory function (including part of the hippocampus, amygdala, entorhinal cortex, fusiform gyrus, inferior and middle temporal gyrus, parahippocampal gyrus and temporal pole). Third, a widespread disconnection across the entire AD brain was found in stage III, affecting more strongly the same memory subnetwork appearing in stage II, plus the other new subnetworks,including the default mode network, medial visual network, frontoparietal regions and striatum. Our results are consistent with a scenario where progressive alterations of connectivity arise as the disease severity increases and provide the brain areas possibly involved in such a degenerative process. Further studies applying the same strategy to longitudinal data are needed to fully confirm this scenario.
The Human Metapneumovirus Fusion Protein Mediates Entry via an Interaction with RGD-Binding Integrins

ABSTRACT Paramyxoviruses use a specialized fusion protein to merge the viral envelope with cell membranes and initiate infection. Most paramyxoviruses require the interaction of two viral proteins to enter cells; an attachment protein binds cell surface receptors, leading to the activation of a fusion (F) protein that fuses the viral envelope and host cell plasma membrane. In contrast, human metapneumovirus (HMPV) expressing only the F protein is replication competent, suggesting a primary role for HMPV F in attachment and fusion. We previously identified an invariant arginine-glycine-aspartate (RGD) motif in the HMPV F protein and showed that the RGD-binding integrin αVβ1-promoted HMPV infection. Here we show that both HMPV F-mediated binding and virus entry depend upon multiple RGD-binding integrins and that HMPV F can mediate binding and fusion in the absence of the viral attachment (G) protein. The invariant F-RGD motif is critical for infection, as an F-RAE virus was profoundly impaired. Further, F-integrin binding is required for productive viral RNA transcription, indicating that RGD-binding integrins serve as receptors for the HMPV fusion protein. Thus, HMPV F is triggered to induce virus-cell fusion by interactions with cellular receptors in a manner that is independent of the viral G protein. These results suggest a stepwise mechanism of HMPV entry mediated by the F protein through its interactions with cellular receptors, including RGD-binding integrins.
Pathogenesis of Autoimmune Arthritis Cells: A Novel Mechanism in the Carbamylation-Dependent Activation of T

The posttranslational modiﬁcation of proteins has the potential to generate neoepitopes that may subsequently trigger immune responses. The carbamylation of lysine residues to form homocitrulline may be a key mechanism triggering inﬂammatory responses. We evaluated the role of carbamylation in triggering immune responses and report a new role for this process in the induction of arthritis. Immunization of mice with homocitrulline-containing peptides induced chemotaxis, T cell activation, and Ab production. The mice also developed erosive arthritis following intra-articular injection of peptides derived from homocitrulline and citrulline. Adoptive transfer of T and B cells from homocitrulline-immunized mice into normal recipients induced arthritis, whereas systemic injection of homocitrulline-speciﬁc Abs or intra-articular injection of homocitrulline-Ab/citrulline-peptide mixture did not. Thus, the T cell response to homocitrulline-derived peptides, as well as the subsequent production of anti-homocitrulline Abs, is critical for the induction of autoimmune reactions against citrulline-derived peptides and provides a novel mechanism for the pathogenesis of arthritis. The Journal of Immunology , 2010, 184: 6882–6890.
Plasticity of Agonist Binding Sites in Hetero‐Oligomers of the Unitary Glutamate Receptor Subunit XenU1

Abstract: Two subunits from Xenopus, XenNR1G and the “short” subunit XenU1, have previously been coexpressed to form a unitary (NMDA/non‐NMDA type) glutamate receptor. We now show that an antibody to XenNR1G or an antibody to XenU1 precipitates the binding sites of both XenNR1G and XenU1, with the recombinant subunits or with solubilised Xenopus brain membranes, i.e., the combination occurs in vivo. The expressed XenU1 subunits are in the cell membrane and oriented correctly. XenU1 binds not only kainate with high affinity (KD 1.2 nM at 25°C), but also the glycine site antagonist 5,7‐dichlorokynurenic acid (DCKA). DCKA, GTP, or GTPγS displaces competitively all of the bound [3H]kainate, but glycine has no effect. The results suggest that a common binding site for kainate, DCKA, and GTP can exist on XenU1. In the XenNR1G/XenU1 complex, the kainate affinity is lowered eightfold, whereas the DCKA affinity is considerably increased (KD 147 nM). Only 18% of the binding to the complex has the properties of the NMDA receptor glycine site, the rest being due to switching of the high‐affinity kainate site of XenU1 (low‐affinity DCKA) to a high‐affinity DCKA (low‐affinity kainate) conformation. Surprisingly, a mammalian NR2 subunit can also combine with XenU1, and this introduces similar reciprocal changes in the binding of kainate and DCKA. The combined evidence suggests a common basic mode of agonist site formation in different subunit types of the ionotropic glutamate receptors.
Robust fractional-order temperature control of a steel slab reheating furnace with large time delay uncertainty

This paper proposes a new strategy to control the temperature of a steel slab reheating furnace based on fractional-order controllers. A second order plus time delay model of the preheating zone of this process is used, which was obtained from an identification procedure applied in an industrial furnace. It is shown that this process experiences very large time delay changes. A fractional-order integral controller (FI) combined with a Smith predictor is designed, which is robust to changes in such time delay. Simulated results of a standard PID controller, PI controller combined with a Smith predictor and the proposed FI controller also combined with a Smith predictor are compared. Seven performance indexes have been used in this comparison: four related to the output performance (settling time, overshoot, ISE and IAE), and three related to the control signal (maximum amplitude, control effort TV and fuel consumption). The analysis of these indexes show that the fractional-order controller exhibits the most robust behaviour (lowest indexes averaged in all the range of time delay variation) for ranges that include large time delays. Then the robustness features of the FI controller combined with a Smith predictor outperform the other integer order controllers both in the time response to a setpoint change and in the control effort aspects.
Cooperative Learning and its Application to Emotion Recognition from Speech

In this paper, we propose a novel method for highly efficient exploitation of unlabeled data-Cooperative Learning. Our approach consists of combining Active Learning and Semi-Supervised Learning techniques, with the aim of reducing the costly effects of human annotation. The core underlying idea of Cooperative Learning is to share the labeling work between human and machine efficiently in such a way that instances predicted with insufficient confidence value are subject to human labeling, and those with high confidence values are machine labeled. We conducted various test runs on two emotion recognition tasks with a variable number of initial supervised training instances and two different feature sets. The results show that Cooperative Learning consistently outperforms individual Active and Semi-Supervised Learning techniques in all test cases. In particular, we show that our method based on the combination of Active Learning and Co-Training leads to the same performance of a model trained on the whole training set, but using 75% fewer labeled instances. Therefore, our method efficiently and robustly reduces the need for human annotations.
Agro-Biodiversity as Natural Insurance and the Development of Financial Insurance Markets

Agro-biodiversity can provide natural insurance to risk averse farmers. We employ a conceptual ecological-economic model to analyze the choice of agrobiodiversity by risk averse farmers who have access to financial insurance. We study the implications for individually and socially optimal agro-ecosystem managementand policy design when on-farm agro-biodiversity, through ecosystem processes at higher hierarchical levels, generates a positive externality on other farmers. We show that for the individual farmer natural insurance from agro-biodiversty and financial insurance are substitutes. While an improved access to financial insurance leads to lower agro-biodiversity, the e ects on the market failure problem (due to the external benefits of on-farm agro-biodiversity) and on welfare are determined by properties of the agro-ecosystem and agro-biodiversity’s external benefits. We derive a specific condition on agro-ecosystem functioning under which, if financial insurance becomes more accessible, welfare in the absence of regulation increases or decreases.
Genetic Algorithms for Multiobjective Optimization: FormulationDiscussion and Generalization

The paper describes a rank-based (cid:12)tness assignment method for Multiple Objective Genetic Algorithms (MOGAs). Conventional niche formationmethods are extended to this class of multimodal problems and theory for setting the niche size is presented. The (cid:12)t-ness assignment method is then modi(cid:12)ed to allow direct intervention of an external decision maker (DM). Finally, the MOGA is generalised further: the genetic algorithmis seen as the optimizing element of a multiobjective optimization loop, which also comprises the DM. It is the interaction between the two that leads to the determination of a satisfactory solution to the problem. Illustrative results of how the DM can interact with the genetic algorithm are presented. They also show the ability of the MOGA to uniformly sample regions of the trade-o(cid:11) surface.
Nonadjacent Dependency Learning Across Domains in Typically Developing Children and Poor Readers

Frequency has been demonstrated to be of great influence in language learning (a.o. Gomez 2002). Language development might be influenced by a deficiency in the ability to derive rules from frequent input. In fact, such a deficiency could even account for certain problems people with dyslexia experience in language. The proposed study set out to provide more insight into children’s sensitivity to frequent patterns in (artificial) language and in the auditory non-linguistic domain. Based on Gomez (2002), Dutch school-aged children were presented with two nonadjacent dependency learning tasks. Neither typically developing children nor poor readers appeared to be sensitive to nonadjacent dependencies of the linguistic or non-linguistic type. Because the findings are likely to be influenced by several methodological factors, no clear conclusions can be drawn about the participants’ capacity to learn nonadjacent dependencies from frequent input.
Platelet response heterogeneity in thrombus formation

Summary Vascular injury leads to formation of a structured thrombus as a consequence of platelet activation and aggregation, thrombin and fibrin formation, and trapping of leukocytes and red cells. This review summarises current evidence for heterogeneity of platelet responses and functions in the thrombus-forming process. Environmental factors contribute to response heterogeneity, as the platelets in a thrombus adhere to different substrates, and sense specific (ant)agonists and rheological conditions. Contraction of platelets and interaction with fibrin and other blood cells cause further response variation. On the other hand, response heterogeneity can also be due to intrinsic differences between platelets in age and in receptor and signalling proteins. As a result, at least three subpopulations of platelets are formed in a thrombus: aggregating platelets with (reversible) integrin activation, procoagulant (coated) platelets exposing phosphatidylserine and binding coagulation factors, and contracting platelets with cell-cell contacts. This recognition of thrombus heterogeneity has implications for the use and development of antiplatelet medication.
Which life course model better explains the association between socioeconomic position and periodontal health?

AIM To assess whether the relationship between socioeconomic position (SEP) and periodontal health fitted the Critical Period or the Social Mobility life course models. METHODS A nationally representative sample of 5570 Korean adults from KNHANES IV study. Log-binomial regression models adjusting for adulthood or childhood socioeconomic (SES) variables was used to assess independent effects of socioeconomic differences for childhood, adulthood and period of transition from child to adult in periodontal health. RESULTS In the Critical Period model, poorer periodontal status was associated with SES disadvantage in adulthood and not predicted by SES disadvantage in childhood. For the intergenerational Social Mobility model, prevalence of current periodontal disease was only different for females aged 30-39 and 40-49 years, after adjustment. Prevalence of periodontal disease in females was highest in the downwardly mobile group. CONCLUSIONS The Critical Period model was better at explaining association between socioeconomic position and periodontal health, such as the adulthood socioeconomic variables (SEP), had a stronger effect than childhood factors on periodontal disease. The Social Mobility model explained more of the variation in the association between SEP and periodontal health among women than among men.
Clarithromycin Resistance and 23S rRNA Mutations in Helicobacter pylori

Helicobacter pylori infects about 50% of the world’s population and is a major cause of chronic gastritis, is strongly associated with the development of gastric and duodenal ulcers and has been linked with gastric adenocarcinoma and B-cell mucosa-associated lymphoid tissue lymphoma [1, 2]. H. pylori Infection results in a sequence of events, ultimately resulting in the development of some gastrointestinal disorders. The sequence was first suggested by Correa et al. in 1975 and has since been supported by many other studies. Colonization of the gastric mucosa by H. pylori first lead to the induction of an inflammatory response, predominantly by Th1 (T helper cells type 1). The initial acute gastritis is followed by active chronic gastritis, which lasts for life if the infection is not treated. Nevertheless, H. pylori-positive subjects are mostly unaware of this inflammation due to the lack of clinical symptoms. The Th1 response results in epithelial cell damage rather than in the removal of H. pylori because H. pylori is not an intracellular pathogen. The ongoing presence of H. pylori thus causes a lifelong proinflammatory response coupled to cellular damage and initiates the histological cascade. The continuous production of reactive oxygen species that results from the ongoing inflammation can result in DNA damage, thus inducing the multiple mutations thought to be required for initiation of the cancer cascade depicted in Figure 1 (3, 4). Among the new methods of magnifying endoscopy, a prototype of endocytoscopy developed by Olympus was used for ex vivo visualization of Helicobacter pylori on experimentally infected gastric biopsies. Moving bacteria were observed at 1100× magnification, giving hope for a possible direct detection during endoscopy. Kim et al. also used magnifying endoscopy on 103 patients to classify the gastric surface according to four patterns: flat, irregular, papillary or nonstructured, which were then compared to the updated Sydney System for histologic gastritis. Histologic gastritis was found in 91% of the biopsy sections with a nonflat type, and among them, 96% were confirmed to harbor H. pylori infection. In another study, the magnified endoscopic findings in the gastric body
The Generative Lexicon

In this paper, I will discuss four major topics relating to current research in lexical semantics: methodology, descriptive coverage, adequacy of the representation, and the computational usefulness of representations. In addressing these issues, I will discuss what I think are some of the central problems facing the lexical semantics community, and suggest ways of best approaching these issues. Then, I will provide a method for the decomposition of lexical categories and outline a theory of lexical semantics embodying a notion of cocompositionality and type coercion, as well as several levels of semantic description, where the semantic load is spread more evenly throughout the lexicon. I argue that lexical decomposition is possible if it is performed generatively. Rather than assuming a fixed set of primitives. I will assume a fixed number of generative devices that can be seen as constructing semantic expressions. I develop a theory of Qualia Structure, a representation language for lexical items, which renders much lexical ambiguity in the lexicon unnecessary, while still explaining the systematic polysemy that words carry. Finally, I discuss how individual lexical structures can be integrated into the larger lexical knowledge base through a theory of lexical inheritance. This provides us with the necessary principles of global organization for the lexicon, enabling us to fully integrate our natural language lexicon into a conceptual whole.