A Fuzzy Simheuristic for the Permutation Flow Shop Problem under Stochastic and Fuzzy Uncertainty

[EN] Stochastic, as well as fuzzy uncertainty, can be found in most real-world systems. Considering both types of uncertainties simultaneously makes optimization problems incredibly challenging. In this paper, we analyze the permutation flow shop problem (PFSP) with both stochastic and fuzzy processing times. The main goal is to find the solution (permutation of jobs) that minimizes the expected makespan. However, due to the existence of uncertainty, other characteristics of the solution are also taken into account. In particular, we illustrate how survival analysis can be employed to enrich the probabilistic information given to decision-makers. To solve the aforementioned optimization problem, we extend the concept of a simheuristic framework so it can also include fuzzy elements. Hence, both stochastic and fuzzy uncertainty are simultaneously incorporated in the PFSP. In order to test our approach, classical PFSP instances have been adapted and extended, so that processing times become either stochastic or fuzzy. The experimental results show the effectiveness of the proposed approach when compared with more traditional ones.This work has been partially supported by the Spanish Ministry of Science (PID2019111100RB-C21/AEI/10.13039/501100011033), as well as by the Barcelona Council and the "la Caixa" Foundation under the framework of the Barcelona Science Plan 2020-2023 (grant 21S09355-001).Castaneda, J.; Martín, XA.; Ammouriova, M.; Panadero, J.; Juan-Pérez, ÁA. (2022). A Fuzzy Simheuristic for the Permutation Flow Shop Problem under Stochastic and Fuzzy Uncertainty. Mathematics. 10(10):1-17. https://doi.org/10.3390/math10101760117101

Solving the time capacitated arc routing problem under fuzzy and stochastic travel and service times

[EN] Stochastic, as well as fuzzy uncertainty, can be found in most real-world systems. Considering both types of uncertainties simultaneously makes optimization problems incredibly challenging. In this paper we propose a fuzzy simheuristic to solve the Time Capacitated Arc Routing Problem (TCARP) when the nature of the travel time can either be deterministic, stochastic or fuzzy. The main goal is to find a solution (vehicle routes) that minimizes the total time spent in servicing the required arcs. However, due to uncertainty, other characteristics of the solution are also considered. In particular, we illustrate how reliability concepts can enrich the probabilistic information given to decision-makers. In order to solve the aforementioned optimization problem, we extend the concept of simheuristic framework so it can also include fuzzy elements. Hence, both stochastic and fuzzy uncertainty are simultaneously incorporated into the CARP. In order to test our approach, classical CARP instances have been adapted and extended so that customers' demands become either stochastic or fuzzy. The experimental results show the effectiveness of the proposed approach when compared with more traditional ones. In particular, our fuzzy simheuristic is capable of generating new best-known solutions for the stochastic versions of some instances belonging to the tegl, tcarp, val, and rural benchmarks.Spanish Ministry of Science, Grant/Award Number: PID2019-111100RB-C21/AEI/10.13039/501100011033; Barcelona Council and the "la Caixa" Foundation under the framework of the Barcelona Science Plan 2020-2023, Grant/Award Number: 21S09355-001; Generalitat Valenciana,Grant/Award Number: PROMETEO/2021/065Martín, XA.; Panadero, J.; Peidro Payá, D.; Pérez Bernabeu, E.; Juan-Pérez, ÁA. (2023). Solving the time capacitated arc routing problem under fuzzy and stochastic travel and service times. Networks. 82(4):318-335. https://doi.org/10.1002/net.2215931833582

Tokenized Markets Using Blockchain Technology: Exploring Recent Developments and Opportunities

[EN] The popularity of blockchain technology stems largely from its association with cryptocurrencies, but its potential applications extend beyond this. Fungible tokens, which are interchangeable, can facilitate value transactions, while smart contracts using non-fungible tokens enable the exchange of digital assets. Utilizing blockchain technology, tokenized platforms can create virtual markets that operate without the need for a central authority. In principle, blockchain technology provides these markets with a high degree of security, trustworthiness, and dependability. This article surveys recent developments in these areas, including examples of architectures, designs, challenges, and best practices (case studies) for the design and implementation of tokenized platforms for exchanging digital assets.This work has received financial support from the Horizon Europe Research & amp; Innovation Programme under Grant agreement N. 101092612 (Social and hUman ceNtered XR-SUN project), as well as from the Regional Department of Innovation, Universities, Science and Digital Society of the Generalitat Valenciana "Programa Investigo" (INVEST/2022/342), within the framework of the Plan de Recuperacion, Transformacion y Resiliencia funded by the European Union-NextGenerationEU.Juan-Pérez, ÁA.; Pérez Bernabeu, E.; Li, Y.; Martín, XA.; Ammouriova, M.; Barrios, BB. (2023). Tokenized Markets Using Blockchain Technology: Exploring Recent Developments and Opportunities. Information. 14(6). https://doi.org/10.3390/info1406034714

Maximum aerobic speed, maximum oxygen consumption, and running spatiotemporal parameters during an incremental test among middle- and long-distance runners and endurance non-running athletes

[Abstract] Background. Maximal aerobic speed (MAS) is a useful parameter to assess aerobic capacity and estimate training intensity in middle- and long-distance runners. However, whether middle- and long-distance runners reach different levels of MAS compared to other endurance athletes with similar VO˙ 2max has not been previously studied. Therefore, we aimed to compare VO˙ 2max, MAS and spatiotemporal parameters between sub-elite middle- and long-distance runners (n = 6) and endurance non-runners (n = 6). In addition, we aimed to compare the maximal blood lactate concentration [BLa] experienced by participants after conducting these tests. Methods. Telemetric portable respiratory gas analysis, contact and flight time, and stride length and rate were measured using a 5-m contact platform during an incremental test at a synthetic athletics track. VO˙ 2, heart rate, respiratory quotient values in any 15 s average period during the test were measured. [BLa] was analyzed after the test . Running spatiotemporal parameters were recorded at the last two steps of each 400 m lap. A coefficient of variation (%CV) was calculated for each spatiotemporal variable in each participant from 8 km h−1 onwards. Results. Whereas runners reported faster MAS (21.0 vs. 18.2 km h−1 ) than nonrunners (p = 0.0001, ES = 3.0), no differences were found for VO˙ 2max and maximum blood lactate concentration during the running tests (p > 0.05). While significant increases in flight time and stride length and frequency (p < 0.001, 0.52 ≤ η 2 p ≤ 0.8) were observed throughout the tests, decreases in contact time (p < 0.001, η 2 p = 0.9) were reported. Runners displayed a greater %CV (p = 0.015) in stride length than nonrunners. We conclude that middle- and long-distance runners can achieve a faster MAS compared to non-running endurance athletes despite exhibiting a similar VO˙ 2max. This superior performance may be associated to a greater mechanical efficiency. Overall, runners displayed a greater ability to modify stride length to achieve fast speeds, which may be related to a more mechanically efficient pattern of spatiotemporal parameters than non-runners

High-resolution patterns of palaeoenvironmental changes during the Little Ice Age and the Medieval Climate Anomaly in the northwestern Iberian Peninsula

ABSTRACT: A high resolution core (9.7 yr cm-1 ) from the Chao de Veiga Mol raised bog (NW Iberian Peninsula) was analyzed to identify plant macrofossils, estimate peat humification and calculate hydroclimatic indices based on current bog species, with the overall aim of determining the climate conditions associated with evolution of the bog during the Medieval Climate Anomaly and the Little Ice Age. These proxies, together with historical and climate data, proved to be good indicators of the changes in bog surface wetness. Analysis: of the core led to identification of 9 different periods: two corresponding to the so-called Medieval Climate Anomaly (930 to 1345 AD, 1075–665 calibrated years before present [cal. yr BP]); four corresponding to the Little Ice Age (1345 to 1905 AD; 665–105 cal yr BP); and three corresponding to the last century (1905 to 2000 AD). The findings revealed a generally dry climate that lasted until the 14th century, followed by a transition to a long period with a more humid, but characteristically very variable climate, which ended at the beginning of the 20th century and was followed by a rapid transition to more humid conditions and finally, a change to drier conditions. The Medieval Climate Anomaly was indicated by the abundance of dry-adapted mosses (Leucobryum glaucum, Hypnum cupressiforme) and characterized by warm dry conditions and high levels of peat humification, with alternating wet phases. The LIA period was dated by a large abundance of Sphagnum species (an indicator of wetness) and a gradual increase in the humification index. However, four different climate phases were differentiated in this period. High-resolution reconstruction of the evolution of the CVM bog and the multiproxy approach have together enabled a more detailed identification of climatic variations in this area, which are generally consistent with the global models, as well as better definition of the elusive climatic oscillations in the last millennium and confirmation of the importance of local modulation of global models. The study provides new information and a detailed chronology of climatic events that will help to refine local modulation of the climate evolution model in the still quite unexplored region of the NW Iberian Peninsula, a key area for understanding the paleoclimatic dynamics in SW Europe.This research was funded with the support of the Xunta de Galicia government (Spain) through projects INCITE09-200-019-PR and Consolidacion e Estructuracion 2018 GRC GI- 1243-GEMAP, ED431C 2018/32

An All-Organic Flexible Visible Light Communication System

Visible light communication systems can be used in a wide variety of applications, from driving to home automation. The use of wearables can increase the potential applications in indoor systems to send and receive specific and customized information. We have designed and developed a fully organic and flexible Visible Light Communication system using a flexible OLED, a flexible P3HT:PCBM-based organic photodiode (OPD) and flexible PCBs for the emitter and receiver conditioning circuits. We have fabricated and characterized the I-V curve, modulation response and impedance of the flexible OPD. As emitter we have used a commercial flexible organic luminaire with dimensions 99 × 99 × 0.88 mm, and we have characterized its modulation response. All the devices show frequency responses that allow operation over 40 kHz, thus enabling the transmission of high quality audio. Finally, we integrated the emitter and receiver components and its electronic drivers, to build an all-organic flexible VLC system capable of transmitting an audio file in real-time, as a proof of concept of the indoor capabilities of such a system.This Project was funded by Comunidad de Madrid through the SINFOTON-CM Research Program (S2013/MIT-2790), and the Spanish Ministry of Economy, the Agencia Estatal de Investigación and European Union's FEDER through the TEC2016-77242-C3-(1-R, 2-R and 3-R) AEI/FEDER, UE Projects

Cholangiocarcinoma progression depends on the uptake and metabolization of extracellular lipids

[Background and Aims] Cholangiocarcinoma (CCA) includes a heterogeneous group of biliary cancers with a dismal prognosis. We investigated if lipid metabolism is disrupted in CCA and its role in tumor proliferation.[Approach and Results] The in vitro and in vivo tumorigenic capacity of five human CCA cell lines was analyzed. Proteome, lipid content, and metabolic fluxes were evaluated in CCA cells and compared with normal human cholangiocytes (NHC). The Akt1/NOTCH1 intracellular cytoplasmic domain (Nicd1)-driven CCA mouse model was also evaluated. The proteome of CCA cells was enriched in pathways involved in lipid and lipoprotein metabolism. The EGI1 CCA cell line presented the highest tumorigenic capacity. Metabolic studies in high (EGI1) versus low (HUCCT1) proliferative CCA cells in vitro showed that both EGI1 and HUCCT1 incorporated more fatty acids (FA) than NHC, leading to increased triglyceride storage, also observed in Akt1/Nicd1-driven CCA mouse model. The highly proliferative EGI1 CCA cells showed greater uptake of very-low-density and HDLs than NHC and HUCCT1 CCA cells and increased cholesteryl ester content. The FA oxidation (FAO) and related proteome enrichment were specifically up-regulated in EGI1, and consequently, pharmacological blockade of FAO induced more pronounced inhibition of their tumorigenic capacity compared with HUCCT1. The expression of acyl-CoA dehydrogenase ACADM, the first enzyme involved in FAO, was increased in human CCA tissues and correlated with the proliferation marker PCNA.[Conclusions] Highly proliferative human CCA cells rely on lipid and lipoprotein uptake to fuel FA catabolism, suggesting that inhibition of FAO and/or lipid uptake could represent a therapeutic strategy for this CCA subclass.This work was supported by “Ayudas para apoyar grupos de investigación del sistema Universitario Vasco” (IT971‐16 to PA), MCIU/AEI/FEDER, UE (2018‐095134‐B‐100 to PA and by the University of Basque Country COLAB20/01 to PA; Spanish Carlos III Health Institute (ISCIII) (FIS PI15/01132, PI18/01075, PI21/00922, and Miguel Servet Program CON14/00129 and CPII19/00008 to JMB; FIS PI14/00399, PI17/00022 and PI20/00186 to MJP; Sara Borrell [CD19/00254 to PMR]) cofinanced by “Fondo Europeo de Desarrollo Regional” (FEDER); CIBERehd (ISCIII) to JMB, MJP, PMR, PA and LB); “Diputación Foral Gipuzkoa” (DFG15/010, DFG16/004 to JMB and 2020‐CIEN‐000067‐01 to PMR), Department of Health of the Basque Country (2019111024 to MJP, 2017111010 to JMB, and 2020111077 to JMB and PA), “Euskadi RIS3” (2016222001, 2017222014, 2018222029, 2019222054, 2020333010 to JMB), BIOEF (Basque Foundation for Innovation and Health Research: EiTB Maratoia BIO15/CA/016/BD to JMB) and Department of Industry of the Basque Country (Elkartek: KK‐2020/00008 to JMB); La Caixa Scientific Foundation (HR17‐00601 to JMB). “Fundación Científica de la Asociación Española Contra el Cáncer” (AECC Scientific Foundation, to JMB). AMMF‐The Cholangiocarcinoma Charity (EU/2019/AMMFt/001, to JMB and PMR). MRDG was funded by “Fundación Científica de la Asociación Española Contra el Cáncer” (AECC de Bizkaia), MJP was funded by the Spanish Ministry of Economy and Competitiveness (MINECO: “Ramón y Cajal” Program RYC‐2015‐17755), IL, AL and FG‐R by the Basque Government (PRE_2016_1_0152, PRE_2018_2_0195 and PRE 2020 2 02500, respectively), AN‐Z and BG‐S by the UPV/EHU, AB‐V by “Programa de especialización de Personal Investigador Doctor” at the UPV/EHU (2019‐2020) and MA by the MCIU/AEI/FEDER

Discovery of first-in-class reversible dual small molecule inhibitors against G9a and DNMTs in hematological malignancies

The indisputable role of epigenetics in cancer and the fact that epigenetic alterations can be reversed have favoured development of epigenetic drugs. In this study, we design and synthesize potent novel, selective and reversible chemical probes that simultaneously inhibit the G9a and DNMTs methyltransferase activity. In vitro treatment of haematological neoplasia (acute myeloid leukaemia-AML, acute lymphoblastic leukaemia-ALL and diffuse large B-cell lymphoma-DLBCL) with the lead compound CM-272, inhibits cell proliferation and promotes apoptosis, inducing interferon-stimulated genes and immunogenic cell death. CM-272 significantly prolongs survival of AML, ALL and DLBCL xenogeneic models. Our results represent the discovery of first-in-class dual inhibitors of G9a/DNMTs and establish this chemical series as a promising therapeutic tool for unmet needs in haematological tumours.We particularly acknowledge the Biobank of the University of Navarra for its collaboration. We thank Dr Edorta Martínez de Marigorta and Dr Francisco Palacios from Departamento de Química Orgánica I, Facultad de Farmacia, Universidad del Pais Vasco for 13C NMR determination and Angel Irigoyen Barrio and Dr Ana Romo Hualde, from University of Navarra, for HRMS determination. Dr. Irene de Miguel Turrullols from Small Molecule Discovery Platform, CIMA, University of Navarra is acknowledged for NMR data interpretation. This work was funded by grants from Instituto de Salud Carlos III (ISCIII) PI10/01691, PI13/01469, PI14/01867, PI10/2983, TRASCAN (EPICA), CIBERONC, cofinanciacion FEDER, RTICC RD12/0036/0068, Fundació La Marató de TV3 (20132130-31-32) and ‘Fundación Fuentes Dutor’. B.P. is supported by a Sara Borrell fellowship CD13/00340 and X.A. is a Marie Curie researcher under contract ‘LincMHeM-330598’.S

Epigenetic Activation of SOX11 in Lymphoid Neoplasms by Histone Modifications

Recent studies have shown aberrant expression of SOX11 in various types of aggressive B-cell neoplasms. To elucidate the molecular mechanisms leading to such deregulation, we performed a comprehensive SOX11 gene expression and epigenetic study in stem cells, normal hematopoietic cells and different lymphoid neoplasms. We observed that SOX11 expression is associated with unmethylated DNA and presence of activating histone marks (H3K9/14Ac and H3K4me3) in embryonic stem cells and some aggressive B-cell neoplasms. In contrast, adult stem cells, normal hematopoietic cells and other lymphoid neoplasms do not express SOX11. Such repression was associated with silencing histone marks H3K9me2 and H3K27me3. The SOX11 promoter of non-malignant cells was consistently unmethylated whereas lymphoid neoplasms with silenced SOX11 tended to acquire DNA hypermethylation. SOX11 silencing in cell lines was reversed by the histone deacetylase inhibitor SAHA but not by the DNA methyltransferase inhibitor AZA. These data indicate that, although DNA hypermethylation of SOX11 is frequent in lymphoid neoplasms, it seems to be functionally inert, as SOX11 is already silenced in the hematopoietic system. In contrast, the pathogenic role of SOX11 is associated with its de novo expression in some aggressive lymphoid malignancies, which is mediated by a shift from inactivating to activating histone modifications