Miracle-dz/UniFAR-FTUs huggingface dataset:
The decline of fertility: Innovation or adjustment process.

Abstract In Western society the process of fertility decline is often regarded as an innovation process. The assumptions behind this approach seem rather questionable, and the diffusion lags or gradients of limited importance. Both Swedish and other European data are used as illustrations. It is suggested that the decline be treated within the wider sociological perspective of a time-consuming adjustment or change process, not necessarily starting from a position of completely uncontrolled fertility within marriage. The situation in to-day's high fertility populations is briefly discussed against this background.
KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab.

PURPOSE Cetuximab is efficient in advanced colorectal cancer (CRC). We previously showed that KRAS mutations were associated with resistance to cetuximab in 30 CRC patients. The aim of this study was to validate, in an independent larger series of 89 patients, the prognostic value of KRAS mutations on response to cetuximab and survival. PATIENTS AND METHODS Eighty-nine metastatic CRC patients treated with cetuximab after treatment failure with irinotecan-based chemotherapy were analyzed for KRAS mutation by allelic discrimination on tumor DNA. The association between KRAS mutations and tumor response, skin toxicity, progression-free survival (PFS) and overall survival (OS) was analyzed. RESULTS A KRAS mutation was present in 27% of the patients and was associated with resistance to cetuximab (0% v 40% of responders among the 24 mutated and 65 nonmutated patients, respectively; P < .001) and a poorer survival (median PFS: 10.1 v 31.4 weeks in patients without mutation; P = .0001; median OS: 10.1 v 14.3 months in patients without mutation; P = .026). When we pooled these 89 patients with patients from our previous study, the multivariate analysis showed that KRAS status was an independent prognostic factor associated with OS and PFS, whereas skin toxicity was only associated with OS. In a combined analysis, median OS times of patients with two, one, or no favorable prognostic factors (severe skin toxicity and no KRAS mutation) was of 15.6, 10.7, and 5.6 months, respectively. CONCLUSION These results confirm the high prognostic value of KRAS mutations on response to cetuximab and survival in metastatic CRC patients treated with cetuximab.
Krit 1 interactions with microtubules and membranes are regulated by Rap1 and integrin cytoplasmic domain associated protein‐1

The small G protein Rap1 regulates diverse cellular processes such as integrin activation, cell adhesion, cell–cell junction formation and cell polarity. It is crucial to identify Rap1 effectors to better understand the signalling pathways controlling these processes. Krev interaction trapped 1 (Krit1), a protein with FERM (band four‐point‐one/ezrin/radixin/moesin) domain, was identified as a Rap1 partner in a yeast two‐hybrid screen, but this interaction was not confirmed in subsequent studies. As the evidence suggests a role for Krit1 in Rap1‐dependent pathways, we readdressed this question. In the present study, we demonstrate by biochemical assays that Krit1 interacts with Rap1A, preferentially its GTP‐bound form. We show that, like other FERM proteins, Krit1 adopts two conformations: a closed conformation in which its N‐terminal NPAY motif interacts with its C‐terminus and an opened conformation bound to integrin cytoplasmic domain associated protein (ICAP)‐1, a negative regulator of focal adhesion assembly. We show that a ternary complex can form in vitro between Krit1, Rap1 and ICAP‐1 and that Rap1 binds the Krit1 FERM domain in both closed and opened conformations. Unlike ICAP‐1, Rap1 does not open Krit1. Using sedimentation assays, we show that Krit1 binds in vitro to microtubules through its N‐ and C‐termini and that Rap1 and ICAP‐1 inhibit Krit1 binding to microtubules. Consistently, YFP‐Krit1 localizes on cyan fluorescent protein‐labelled microtubules in baby hamster kidney cells and is delocalized from microtubules upon coexpression with activated Rap1V12. Finally, we show that Krit1 binds to phosphatidylinositol 4,5‐P2‐containing liposomes and that Rap1 enhances this binding. Based on these results, we propose a model in which Krit1 would be delivered by microtubules to the plasma membrane where it would be captured by Rap1 and ICAP‐1.
Topography of Thalamic Projections Requires Attractive and Repulsive Functions of Netrin-1 in the Ventral Telencephalon

Recent studies have demonstrated that the topography of thalamocortical (TC) axon projections is initiated before they reach the cortex, in the ventral telencephalon (VTel). However, at this point, the molecular mechanisms patterning the topography of TC projections in the VTel remains poorly understood. Here, we show that a long-range, high-rostral to low-caudal gradient of Netrin-1 in the VTel is required in vivo for the topographic sorting of TC axons to distinct cortical domains. We demonstrate that Netrin-1 is a chemoattractant for rostral thalamic axons but functions as a chemorepulsive cue for caudal thalamic axons. In accordance with this model, DCC is expressed in a high-rostromedial to low-caudolateral gradient in the dorsal thalamus (DTh), whereas three Unc5 receptors (Unc5A–C) show graded expression in the reverse orientation. Finally, we show that DCC is required for the attraction of rostromedial thalamic axons to the Netrin-1–rich, anterior part of the VTel, whereas DCC and Unc5A/C receptors are required for the repulsion of caudolateral TC axons from the same Netrin-1–rich region of the VTel. Our results demonstrate that a long-range gradient of Netrin-1 acts as a counteracting force from ephrin-A5 to control the topography of TC projections before they enter the cortex.
Sofosbuvir and Simeprevir Therapy for Recurrent Hepatitis C Infection After Liver Transplantation

Introduction Antiviral therapy for recurrent hepatitis C in liver transplant recipients has been associated with low efficacy, poor tolerability, and drug-drug interactions. Recent approval of various hepatitis C direct-acting antivirals has resulted in improvement of these parameters. We evaluated the efficacy and safety of 12 week all-oral interferon- and ribavirin-free therapy with sofosbuvir and simeprevir. Methods Thirty-two genotype 1 liver transplant recipients with recurrent hepatitis C infection were retrospectively analyzed. All patients received 12 weeks of sofosbuvir 400 mg and simeprevir 150 mg orally daily. The primary endpoint was sustained virologic response 12 weeks after treatment. Results Sustained virologic response 12 weeks after treatment was achieved in 30 of 32 (94%; 95% confidence interval, 79-99%) patients. All patients enjoyed on-treatment virological response. Both patients who relapsed were cirrhotic, previously treated with Q80K polymorphism. Significant improvements in alkaline phosphatase, albumin, alanine aminotransferase levels, and platelets were seen at 12-week post therapy. Treatment was well tolerated. No grade 3 or 4 adverse events were noted. Headache and fatigue were the most common complaints. Conclusion Combination of sofosbuvir and simeprevir for 12 weeks resulted in 94% sustained virological response-12 rates in patients with hepatitis C genotype 1 and was well tolerated.
Quantitative immunohistochemistry for evaluating the distribution of Ki67 and other biomarkers in tumor sections and use of the method to study repopulation in xenografts after treatment with paclitaxel.

BACKGROUND Surviving cells may repopulate tumors between courses of chemotherapy, thereby reducing the effectiveness of treatment. Using a novel quantitative method, we characterize the influence of the tumor microenvironment on repopulation of surviving cells in human tumor xenografts after paclitaxel treatment and evaluate the potential of gefitinib, an epidermal growth factor receptor (EGFR) inhibitor, to inhibit repopulation. METHODS High-EGFR-expressing A431 xenografts and low-EGFR-expressing MCF-7 xenografts were treated with paclitaxel or gefitinib. Time-dependent changes in cell proliferation (Ki67) and apoptosis (cleaved caspase 3) in relation to total and functional tumor blood vessels (recognized by CD31 and a flow marker), and regions of hypoxia (recognized by EF5) were quantified using fluorescence microscopy. RESULTS Decrease in functional tumor vasculature and in cell proliferation and increase in apoptosis were observed in A431 xenografts after treatment with either paclitaxel or gefitinib. There was a rebound in functional vasculature and cell proliferation ≈ 12 days after treatment with paclitaxel, and repopulation was observed from tumor cells close to regions of hypoxia. Cell proliferation increased ≈ 5 days after the last dose of gefitinib. There were minimal effects of paclitaxel or gefitinib on cell proliferation, cell death, or tumor vasculature in MCF-7 xenografts. CONCLUSIONS Repopulation in A431 xenografts after treatment with paclitaxel was associated with changes in functional tumor vasculature. Gefitinib decreased cell proliferation in EGFR-overexpressing tumor xenografts, suggesting its potential to inhibit repopulation when used in sequence with chemotherapy.
Copula Distinction and Constrained Variability of Copula Use in Iberian and Mexican Spanish

Spanish has two copulas, ser and estar, which are often translated as English ‘be’. Here, we study their differences by investigating their contrastive distributional patterns in combination with adjectival predicates. Specifically, we test the processing predictions of a presupposition-based analysis (Deo et al. 2016) that accounts for a wide range of distributional patterns of the copulas. This analysis has the advantage that it explains the variable copulas’ uses observed across Spanish varieties. Our focus is on Iberian and Mexican Spanish. The presupposition-based analysis establishes a clear-cut distinction between the two copulas: estar presupposes the contingency of the prejacent, ser does not. Accordingly, the use of estar requires that the common ground contextually entails that its prejacent is contingent. If the common ground does not imply the contingency of the prejacent, this new information would need to be accommodated by the hearer. We hypothesize that estar predications, when presented in isolation with adjectival predicates that show a preference to appear with ser, will engender a processing cost as a result of adding to the common ground the proposition that the prejacent holds contingently. This hypothesis is tested in two studies, an acceptability questionnaire and a self-paced reading. The results show that when the context does not explicitly support estar’s presupposition, sentences are scored lower (study 1, acceptability questionnaire) and read slower (study 2, self-paced reading) by both Iberian and Mexican speakers. In addition, the data provide experimental evidence for the ‘constrained’ variability across Spanish dialects. The results suggest that Mexican speakers are able to accommodate the contingencypresupposition of estar without relying on explicit contextual cues to a larger extent than Iberian speakers. Altogether, the data support an analysis of copula distinction in Spanish that takes into account the contingency-presupposition of estar and the variability in copula use across Spanish dialects. This working paper is available in University of Pennsylvania Working Papers in Linguistics: http://repository.upenn. edu/pwpl/ vol23/iss1/25 Copula Distinction and Constrained Variability of Copula Use in Iberian and Mexican Spanish Sara Sánchez-Alonso, Ashwini Deo and Marı́a Mercedes Piñango
Temporal Cycles in the Archaeology of Maya Residential Groups from Caracol, Belize

Considerations of ancient Maya cycles of time often focus on dated events obtained from texts on carved stone monuments or on Maya prophecies recorded in ethnohistoric documents. However, temporal cycles are also in evidence in the archaeological records of Maya households. Archaeologically recognizable cycles can be seen in the contextual data of Caracol’s residential groups, specifically in terms of timed ritual acts carried out in these locations that are often associated either with cache practices or with human burials. For the Caracol Maya, the dates and sequencing of residential deposits suggests that acts of veneration were linked to overarching temporal cycles rather than to individual history and events relating to household or family – or even to the death of a family member. Taken collectively, these data suggest that the ancient Maya worldview was both focused on and constrained by specific concepts related to time. Commemorating the completion of temporal cycles was important for all levels of Maya society.
Human Robot interaction studies on laban human movement analysis and dynamic background segmentation

Human movement analysis through vision sensing systems is an important subject regarding Human-Robot interaction. This is a growing area of research, with wide range of applications fields. The ability to recognize human actions using passive sensing modalities, is a decisive factor for machine interaction. In mobile platforms, image processing is regarded as a problem, due to constant changes. We propose an approach, based on Horopter technique, to extract Regions Of Interest (ROI) delimiting human contours. This fact will allow tracking algorithms to provide faster and accurate responses to human feature extraction. The key features are head and both hand positions, that will be tracked within image context. Posterior to feature acquisition, they will be contextualized within a technique, Laban Movement Analysis (LMA) and will be used to provide sets of classifiers. The implementation of the LMA technique will be based on Bayesian Networks. We will use these Bayesian classifiers to label/classify human emotion within the context of expressive movements. Compared to full image tracking, results improved with the implemented approach, the horopter and consequently so did classification results.
Antigens derived from melanocyte differentiation proteins: self‐tolerance, autoimmunity, and use for cancer immunotherapy

Summary: A large set of peptide antigens presented by class I major histocompatibility complex (MHC) molecules on human and murine melanomas and recognized by CD8+ T cells have been defined. These peptides represent attractive candidates for the development of therapeutic and/or prophylactic approaches to treat this cancer. However, the majority of the peptides that are presented by multiple tumors and recognized by T cells from multiple patients arise from proteins that are also expressed in normal melanocytes. It is expected that immune responses to such peptides will be compromised by self‐tolerance or, alternatively, that stimulation of effective immune responses will be accompanied by autoimmune vitiligo. In this review, we describe a preclinical model to evaluate these issues and recent data to suggest that tolerance can be overcome to generate effective antitumor responses. This model also allows the rapid and systematic examination of parameters for the effective use of synthetic peptide vaccines.
Transcriptome Sequencing of Gynostemma pentaphyllum to Identify Genes and Enzymes Involved in Triterpenoid Biosynthesis

G. pentaphyllum (Gynostemma pentaphyllum), a creeping herbaceous perennial with many important medicinal properties, is widely distributed in Asia. Gypenosides (triterpenoid saponins), the main effective components of G. pentaphyllum, are well studied. FPS (farnesyl pyrophosphate synthase), SS (squalene synthase), and SE (squalene epoxidase) are the main enzymes involved in the synthesis of triterpenoid saponins. Considering the important medicinal functions of G. pentaphyllum, it is necessary to investigate the transcriptomic information of G. pentaphyllum to facilitate future studies of transcriptional regulation. After sequencing G. pentaphyllum, we obtained 50,654,708 unigenes. Next, we used RPKM (reads per kilobases per million reads) to calculate expression of the unigenes and we performed comparison of our data to that contained in five common databases to annotate different aspects of the unigenes. Finally, we noticed that FPS, SS, and SE showed differential expression of enzymes in DESeq. Leaves showed the highest expression of FPS, SS, and SE relative to the other two tissues. Our research provides transcriptomic information of G. pentaphyllum in its natural environment and we found consistency in unigene expression, enzymes expression (FPS, SS, and SE), and the distribution of gypenosides content in G. pentaphyllum. Our results will enable future related studies of G. pentaphyllum.
Impact of raltegravir on HIV-1 RNA and DNA forms following initiation of antiretroviral therapy in treatment-naive patients.

OBJECTIVES The rapid early-phase decay of plasma HIV-1 RNA during integrase inhibitor-based therapy is not fully understood. The accumulation of biologically active episomal HIV-1 cDNAs, following aborted integration, could contribute to antiviral potency in vivo. METHODS This prospective, controlled clinical observation study explored raltegravir's impact on the dynamics of HIV-1 RNA in plasma, and concentrations of total HIV-1 cDNA, episomal 2-long terminal repeat (LTR) circles and HIV-1 integrants in peripheral blood mononuclear cells (PBMC). Individuals starting therapy with two nucleoside reverse transcriptase inhibitors plus either raltegravir (raltegravir group; n = 10 patients) or boosted protease inhibitor/non-nucleoside reverse transcriptase inhibitor (control group; n = 10 patients) were followed for 48 weeks. RESULTS Suppression of HIV-1 RNA (<50 copies/mL) was reached earlier (5/10 versus 0/10 at week 4; 8/10 versus 4/10 at week 12) on raltegravir. Significant total HIV-1 cDNA reductions in PBMC were reached by day 99 and persisted until day 330, with median factors of decrease of 7.2 and 8.9, respectively. Broad inter-individual variations, yet no treatment-associated differences, were noted for HIV-1 cDNA concentrations. Despite reductions in HIV-1 RNA (∼3 log) and total HIV-1 cDNA (∼1 log), concentrations of integrants and 2-LTR circles remained largely unchanged. CONCLUSIONS These results extend the previously reported early benefit of raltegravir on the decline of plasma viraemia to treatment-naive patients. The modest treatment-associated, yet group-independent, decline in total HIV-1 cDNA load and the lack of significant changes in integrated and episomal HIV-1 cDNA suggest that most integrated DNA is archival and targeting of HIV reservoirs other than PBMC may underlie beneficial effects of raltegravir.
Early Experience with the StopLoss Jones Tube

ABSTRACT Purpose: Extrusion is the most common reason for failure after Jones tube placement. The StopLoss Jones tube (SLJT) is a new innovation in Jones tubes that incorporates a flexible silicone internal flange to resist extrusion. We present our early experience of using this new tube and associated introducer system. Methods: We retrospectively analysed the case notes of a single surgeon consecutive series of patients having SLJT placement from November 2011 to November 2013. Results: 29 SLJTs were placed in 25 eyes of 19 patients. Tube follow-up ranged from 1–25 months (mean 10 months) with a total of 291 tube-months. The indications for SLJT placement were: previous LJT complications (52%), failed canalicular-DCR surgery (31%), primary placement for inoperable canalicular occlusion (14%) and patent non-functioning DCR (3%). Tube length ranged from 10–16 mm. The tube introducer system was simple and effective and there were no intra-operative complications. The tube extrusion rate was 0%. Complications occurred in 5 tubes: 1 was too long, and 4 others (14%) developed conjunctival overgrowth/medial tube migration. Patient satisfaction with the tube was: 86% fully satisfied, 10% was moderately satisfied, 3% not satisfied. The overall final surgical success rate at last follow-up was 92%. Conclusions: In this short follow-up initial study the SLJT is simple to use and has a high rate of success and patient satisfaction. The addition of the internal silicone flange appears to prevent the previously common problem of extrusion.
Inverse FEM for Full-Field Reconstruction of Elastic Deformations in Shear Deformable Plates and Shells

The inverse problem of real-time reconstruction of full-field structural displacements is addressed through the application of a new variational formulation leading to versatile, robust and computationally efficient inverse shell finite element analysis. Utilizing surface strain measurements from strain sensors mounted on the load-carrying structural components, the methodology enables accurate computations of the three-dimensional displacement field. This high fidelity computational technology is essential for providing feedback to the actuation and control systems of the next generation of aerospace vehicles.
Functional gene groups are concentrated within chromosomes, among chromosomes and in the nuclear space of the human genome

Genomes undergo changes in organization as a result of gene duplications, chromosomal rearrangements and local mutations, among other mechanisms. In contrast to prokaryotes, in which genes of a common function are often organized in operons and reside contiguously along the genome, most eukaryotes show much weaker clustering of genes by function, except for few concrete functional groups. We set out to check systematically if there is a relation between gene function and gene organization in the human genome. We test this question for three types of functional groups: pairs of interacting proteins, complexes and pathways. We find a significant concentration of functional groups both in terms of their distance within the same chromosome and in terms of their dispersal over several chromosomes. Moreover, using Hi-C contact map of the tendency of chromosomal segments to appear close in the 3D space of the nucleus, we show that members of the same functional group that reside on distinct chromosomes tend to co-localize in space. The result holds for all three types of functional groups that we tested. Hence, the human genome shows substantial concentration of functional groups within chromosomes and across chromosomes in space.
Co‐clustering numerical data under user‐defined constraints

In the generic setting of objects × attributes matrix data analysis, co‐clustering appears as an interesting unsupervised data mining method. A co‐clustering task provides a bi‐partition made of co‐clusters: each co‐cluster is a group of objects associated to a group of attributes and these associations can support expert interpretations. Many constrained clustering algorithms have been proposed to exploit the domain knowledge and to improve partition relevancy in the mono‐dimensional clustering case (e.g. using the must‐link and cannot‐link constraints on one of the two dimensions). Here, we consider constrained co‐clustering not only for extended must‐link and cannot‐link constraints (i.e. both objects and attributes can be involved), but also for interval constraints that enforce properties of co‐clusters when considering ordered domains. We describe an iterative co‐clustering algorithm which exploits user‐defined constraints while minimizing a given objective function. Thanks to a generic setting, we emphasize that different objective functions can be used. The added value of our approach is demonstrated on both synthetic and real data. Among others, several experiments illustrate the practical impact of this original co‐clustering setting in the context of gene expression data analysis, and in an original application to a protein motif discovery problem. Copyright © 2009 Wiley Periodicals, Inc. Statistical Analysis and Data Mining 3: 38‐55, 2010