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Gentrification demands updated frameworks to assess the impact of some major global trends on the local populations’ access to housing. Short-term accommodation using digital platforms in previously gentrified central urban areas is playing a significant role in outlining a new wave of ‘transnational gentrification’ in a number of global cities. Having undergone classical patterns of gentrification over the last two decades, the central district of Madrid and its surroundings are showing patterns of a new wave of gentrification in a context of economic crisis, planetary rent gaps, increasing global tourism and an increase in rental prices in central areas that may be related to the emergence of short-term rentals – making Madrid a relevant case for depicting transnational gentrification in the Southern European capitals. Based on empirical data, this work explores the holiday rental supply in Madrid over three years (2015–2018), verifying a strong association between the growth in tourist arrivals, the settlement of new residents from wealthy economic backgrounds and increasing rental prices. Since this process is accompanied by deregulation of local rental contracts and the growth of transnational Real Estate Investment Trusts (REITs), even in some of the most vulnerable areas located beyond the M-30 ring road, this wave of gentrification has the potential to produce displacement and substitution of residents. 绅士化要求更新框架，以评估一些重要的全球趋势对当地居民获得住房的影响。在此前已完成绅士化的中心城市地区，使用数字平台出租的短租房在描绘一些全球城市的新一波“跨国绅士化”方面发挥着重要作用。在过去20年里经历了传统的绅士化模式后，马德里市中心及其周边地区正呈现出新一轮绅士化的模式，其背景是经济危机、全球租金差距、全球旅游业增长以及中心地区租金价格上涨（这些都可能与短租房的出现有关），这使得马德里成为了描绘南欧国家首都跨国绅士化的一个相关案例。基于实证数据，本研究探讨了马德里在三年内（2015-2018年）的假日租赁供应，验证了游客数量的增长、来自富裕经济背景的新居民的定居和租金价格的上涨之间的高相关性。由于这一过程伴随着对当地租赁合同的放松管制和跨国房地产投资信托 (REIT) 的发展，即使在位于M-30环路以外的一些最脆弱的地区，这一绅士化浪潮也有可能造成居民被排挤和取代。

Large-scale microsimulations are increasingly resourceful tools for analysing in detail citywide effects and alternative scenarios of our policy decisions, approximating the ideal of ‘urban digital twins’. Yet, these models are costly and impractical, and there are surprisingly few published examples robustly validated with empirical data. This paper, therefore, presents a new large-scale agent-based traffic microsimulation for the Barcelona urban area using SUMO to show the possibilities and challenges of building these scenarios based on novel fine-grained empirical big data. It combines novel mobility data from real cell phone records with conventional surveys to calibrate the model comparing two different dynamic assignment methods for getting an operationally realistic and efficient simulation. Including through traffic and the use of a stochastic adaptive routing approach results in a larger 24-hour model closer to reality. Based on an extensive multi-scalar evaluation including traffic counts, hourly distribution of trips, and macroscopic metrics, this model expands and outperforms previous large-scale scenarios, which provides new operational opportunities in city co-creation and policy. The novelty of this work relies on the effective modelling approach using newly available data and the realistic robust evaluation. This allows the identification of the fundamental challenges of simulation to accurately capture real-world dynamical systems and to their predictive power at a large scale, even when fed by big data, as envisioned by the digital twin concept applied to smart cities.

Advances in Data Science permeate every field of Transportation Science and Engineering, resulting in developments in the transportation sector that are data-driven. Nowadays, Intelligent Transportation Systems (ITS) could be arguably approached as a “story” intensively producing and consuming large amounts of data. A diversity of sensing devices densely spread over the infrastructure, vehicles or the travelers’ personal devices act as sources of data flows that are eventually fed into software running on automatic devices, actuators or control systems producing, in turn, complex information flows among users, traffic managers, data analysts, traffic modeling scientists, etc. These information flows provide enormous opportunities to improve model development and decision-making. This work aims to describe how data, coming from diverse ITS sources, can be used to learn and adapt data-driven models for efficiently operating ITS assets, systems and processes; in other words, for data-based models to fully become actionable. Grounded in this described data modeling pipeline for ITS, we define the characteristics, engineering requisites and challenges intrinsic to its three compounding stages, namely, data fusion, adaptive learning and model evaluation. We deliberately generalize model learning to be adaptive, since, in the core of our paper is the firm conviction that most learners will have to adapt to the ever-changing phenomenon scenario underlying the majority of ITS applications. Finally, we provide a prospect of current research lines within Data Science that can bring notable advances to data-based ITS modeling, which will eventually bridge the gap towards the practicality and actionability of such models.

Erlotinib has been shown to improve progression-free survival compared with chemotherapy when given as first-line treatment for Asian patients with non-small-cell lung cancer (NSCLC) with activating EGFR mutations. We aimed to assess the safety and efficacy of erlotinib compared with standard chemotherapy for first-line treatment of European patients with advanced EGFR-mutation positive NSCLC. We undertook the open-label, randomised phase 3 EURTAC trial at 42 hospitals in France, Italy, and Spain. Eligible participants were adults (>18 years) with NSCLC and EGFR mutations (exon 19 deletion or L858R mutation in exon 21) with no history of chemotherapy for metastatic disease (neoadjuvant or adjuvant chemotherapy ending ≥6 months before study entry was allowed). We randomly allocated participants (1:1) according to a computer-generated allocation schedule to receive oral erlotinib 150 mg per day or 3 week cycles of standard intravenous chemotherapy of cisplatin 75 mg/m2 on day 1 plus docetaxel (75 mg/m2 on day 1) or gemcitabine (1250 mg/m2 on days 1 and 8). Carboplatin (AUC 6 with docetaxel 75 mg/m2 or AUC 5 with gemcitabine 1000 mg/m2) was allowed in patients unable to have cisplatin. Patients were stratified by EGFR mutation type and Eastern Cooperative Oncology Group performance status (0 vs 1 vs 2). The primary endpoint was progression-free survival (PFS) in the intention-to-treat population. We assessed safety in all patients who received study drug (≥1 dose). This study is registered with ClinicalTrials.gov, number NCT00446225. Between Feb 15, 2007, and Jan 4, 2011, 174 patients with EGFR mutations were enrolled. One patient received treatment before randomisation and was thus withdrawn from the study; of the remaining patients, 86 were randomly assigned to receive erlotinib and 87 to receive standard chemotherapy. The preplanned interim analysis showed that the study met its primary endpoint; enrolment was halted, and full evaluation of the results was recommended. At data cutoff (Jan 26, 2011), median PFS was 9·7 months (95% CI 8·4-12·3) in the erlotinib group, compared with 5·2 months (4·5–5·8) in the standard chemotherapy group (hazard ratio 0·37, 95% CI 0·25–0·54; p<0·0001). Main grade 3 or 4 toxicities were rash (11 [13%] of 84 patients given erlotinib vs none of 82 patients in the chemotherapy group), neutropenia (none vs 18 [22%]), anaemia (one [1%] vs three [4%]), and increased amino-transferase concentrations (two [2%] vs 0). Five (6%) patients on erlotinib had treatment-related severe adverse events compared with 16 patients (20%) on chemotherapy. One patient in the erlotinib group and two in the standard chemotherapy group died from treatment-related causes. Our findings strengthen the rationale for routine baseline tissue-based assessment of EGFR mutations in patients with NSCLC and for treatment of mutation-positive patients with EGFR tyrosine-kinase inhibitors. Spanish Lung Cancer Group, Roche Farma, Hoffmann-La Roche, and Red Temática de Investigacion Cooperativa en Cancer.

There is a large diversity of genetically defined resistance genes in bread wheat against the powdery mildew pathogen Blumeria graminis (B. g.) f. sp. tritici. Many confer race-specific resistance to this pathogen, but until now only the mildew avirulence gene AvrPm3 a2/f2 that is recognized by Pm3a/f was known molecularly. We performed map-based cloning and genome-wide association studies to isolate a candidate for the mildew avirulence gene AvrPm2. We then used transient expression assays in Nicotiana benthamiana to demonstrate specific and strong recognition of AvrPm2 by Pm2. The virulent AvrPm2 allele arose from a conserved 12 kb deletion, while there is no protein sequence diversity in the gene pool of avirulent B. g. tritici isolates. We found one polymorphic AvrPm2 allele in B. g. triticale and one orthologue in B. g. secalis and both are recognized by Pm2. AvrPm2 belongs to a small gene family encoding structurally conserved RNase-like effectors, including Avr a13 from B. g. hordei, the cognate Avr of the barley resistance gene Mla13. These results demonstrate the conservation of functional avirulence genes in two cereal powdery mildews specialized on different hosts, thus providing a possible explanation for successful introgression of resistance genes from rye or other grass relatives to wheat.

We model the distributions of firm sizes and of firms’ total factor productivity (TFP) as outcomes of a market equilibrium from the occupational decisions of individuals with different entrepreneurial skills, of working as employees, employers, or solo entrepreneurs. The model explains empirical regularities such as (i) the positive cross-section correlation between average size of firms and average labor productivity of countries, (ii) the positive association between size and TFP of firms in an economy, and (iii) the power law distribution of firm sizes. Two parameters of the model, one that measures the organizational size diseconomies and other related to the dispersion of the distribution of entrepreneurial skills in the population, appear as main determinants of the differences in firm sizes and in productivity, across economies and among firms within an economy. The results of the paper should be of interest for the design and evaluation of firm-size-dependent policies.

Lung cancers with a mutation in the EGFR gene have heightened sensitivity to tyrosine kinase inhibitors. Asian patients have been the most intensively studied population for such mutations and for responsiveness to tyrosine kinase inhibitors. This study shows that large-scale screening for EGFR mutations in a European population is feasible and can influence decisions about treatment of advanced lung cancer. This study shows that large-scale screening for EGFR mutations in a European population is feasible and can influence decisions about treatment of advanced lung cancer. Molecular-profiling studies indicate that activating mutations in the epidermal growth factor receptor ( EGFR ), PI3K , BRAF, and K-ras genes are generally nonoverlapping and identifiable in approximately 40% of non–small-cell lung cancers. These mutations, plus others that contribute to tumor progression (“driver” mutations), can be found in almost half of all non–small-cell lung cancers. 1 , 2 The two proto-oncogenes that are most commonly mutated in pulmonary adenocarcinomas are K-ras and EGFR . Nearly 90% of lung-cancer–specific EGFR mutations comprise a leucine-to-arginine substitution at position 858 (L858R) and deletion mutants in exon 19 that affect the conserved sequence LREA (delE746-A750). 3 – . . .

Abstract Infectious diseases caused by bacteria, viruses or fungi are among the leading causes of death worldwide. The emergence of drug-resistance mechanisms, especially among bacteria, threatens the efficacy of all current antimicrobial agents, some of them already ineffective. As a result, there is an urgent need for new antimicrobial drugs. Host defense antimicrobial peptides (HDPs) are natural occurring and well-conserved peptides of innate immunity, broadly active against Gram-negative and Gram-positive bacteria, viruses and fungi. They also are able to exert immunomodulatory and adjuvant functions by acting as chemotactic for immune cells, and inducing cytokines and chemokines secretion. Moreover, they show low propensity to elicit microbial adaptation, probably because of their non-specific mechanism of action, and are able to neutralize exotoxins and endotoxins. HDPs have the potential to be a great source of novel antimicrobial agents. The goal of this review is to provide an overview of the advances made in the development of human defensins as well as the cathelicidin LL-37 and their derivatives as antimicrobial agents against bacteria, viruses and fungi for clinical use. Naturally occurring human antimicrobial peptides represent a potential source of new and safe antimicrobial drugs to treat infections with unmet medical needs.

Background PcG complexes are pivotal in orchestrating the transition from embryonic to vegetative development in plants. However, the mechanisms underlying the gene expression reprogramming that takes place during this developmental transition are still not fully understood. Several studies suggest that incorporating PcG modifications into distinct histone variants may play a key role in this process. However, while PRC2-mediated H3K27me3 is essential for gene repression, the timing of PRC2 action on canonical H3.1 or variant H3.3 remains unclear. Furthermore, the exact role of PRC1 in transcriptional regulation is still unresolved, partly owing to limited knowledge of the conditions under which this complex monoubiquitinates canonical H2A or H2A.Z variant. Results Here, we demonstrate that H2A.Z undergoes monoubiquitination during the seed-to-seedling transition. H2A.Zub facilitates the recruitment of PRC2 to mediate H3.3 trimethylation, repressing seed-specific genes; however, H2A.Zub also promotes the activation of vegetative-specific genes by preventing H3K27me1 incorporation into H3.1. Notably, the histone demethylase REF6 initiates this process by removing two methyl groups from stably repressed H3.1K27me3-marked genes, enabling the subsequent H2A.Zub incorporation. This result suggests that REF6 activity is a critical early step in PRC1-mediated transcriptional activation. Conclusions Our findings reveal the long-sought mechanism by which PRC1 participates in transcriptional activation. We demonstrate that PRC1-mediated H2A.Zub, acting as a “switcher”, plays a pivotal role in reprogramming active and repressed genes during the transition from embryonic to vegetative development. Moreover, our results provide new insights into the intricate relationship between histone modifications and histone variants in reprogramming and maintaining gene expression patterns.

This research was funded by the Spanish Ministry of Industry and Competitiveness (DEP2016-78377-R) and by the European Regional Development Fund (ERDF), M.O. is supported by a grant from the Spanish Ministry of Economy and Competitiveness, grant number; BES-2017-080770 and the APC was funded by additional support from the University of Granada, UGR Research and Knowledge Transfer Fund (PPIT) 2016, Excellence Actions Programme, and Excellence Actions Programe. C.M.A. and I.L.G. are part of the 'URG Plan propio de Investigación 2016' and the 'Excellence actions: Unit of Excellence on Exercise and Health (UCEES)', University of Granada.