Agencia Estatal De Research Articles

Comparative Analysis of 2022 Outbreak MPXV and Previous Clade II MPXV.

The 2022-2024 outbreak of MPOX is an important worldwide public health issue that has triggered significant concerns in the scientific community. MPOX is caused by monkeypox virus (MPXV) belonging to the Poxviridae family. The study of MPXV presents a multifaceted challenge due to the diverse viral formThis study was supported by ISIDORe consortium and Agencia Estatal de Investigación.s produced by this pathogen. Notably the intracellular mature viruses (MVs) primarily contribute to localized lesions and host-to-host transmission, while the extracellular enveloped viruses (EVs) are associated with systemic infection. Clinically, MPOX manifests as a vesiculopustular rash that initially emerges on the face and trunk, subsequently spreading throughout the body, with heightened severity observed in immunocompromised individuals. Results obtained in this manuscript indicate that the 2022 outbreak MPXV has a significantly slower viral cycle compared with previous Clade II strains, with WRAIR 7-61 being more intermediate and USA 2003 producing highest viral titers. Additionally, proteomic and phospho-proteomic analysis displays differences in protein expression between these three strains. These findings highlight key differences between the current Lineage B.1 MPXV and previous strains. Further studies will be undertaken to demonstrate if these differences are important for the apparent increased human-to-human transmission mechanisms observed in the Clade IIb MPXV outbreak.

Interim CEO Successions: Implications for CEO Successor Selection and Subsequent Firm Performance

Prior research highlights that interim CEO successions are disruptive for firms. Yet boards appoint interim CEOs in order to focus on finding the right person to take over permanently, suggesting they may offer benefits to CEO selection. Considering these two views, this paper compares the firm performance of CEOs appointed following an interim period with that of CEOs appointed in a direct succession. We argue that, owing to the disruption caused by the interim appointment, firm performance under a CEO appointed following an interim period will be poorer than under a CEO appointed in a direct succession. However, we posit that, in circumstances in which obtaining and processing the information relevant to CEO selection is more difficult, the interim period may be particularly helpful in selecting the most fitting successor and ultimately weakening the associated performance penalty. Using a sample of CEO successions that occurred in S&P 1500 firms between the years 2002 and 2016, we find general support for our hypotheses. This paper, thus, demonstrates that the subsequent performance consequences of appointing an interim CEO depends on the difficulty of selecting the firm’s next permanent CEO. Funding: We gratefully acknowledge financial support from the Spanish FEDER/Ministerio de Ciencia e Innovacion – Agencia Estatal de Investigacion [Grant PID2021-123450OB-I00].

GEMA-Na and MELD 3.0 severity scores to address sex disparities for accessing liver transplantation: a nationwide retrospective cohort study

The Gender-Equity Model for liver Allocation corrected by serum sodium (GEMA-Na) and the Model for End-stage Liver Disease 3.0 (MELD 3.0) could amend sex disparities for accessing liver transplantation (LT). We aimed to assess these inequities in Spain and to compare the performance of GEMA-Na and MELD 3.0. Nationwide cohort study including adult patients listed for a first elective LT (January 2016-December 2021). The primary outcome was mortality or delisting for sickness within the first 90 days. Independent predictors of the primary outcome were evaluated using multivariate Cox's regression with adjusted relative risks (RR) and 95% confidence intervals (95% CI). The discrimination of GEMA-Na and MELD 3.0was assessed using Harrell c-statistics (Hc). The study included 6071 patients (4697 men and 1374 women). Mortality or delisting for clinical deterioration occurred in 286 patients at 90 days (4.7%). Women had reduced access to LT (83.7% vs. 85.9%; p=0.037) and increased risk of mortality or delisting for sickness at 90 days (adjusted RR=1.57 [95% CI 1.09-2.28]; p=0.017). Female sex remained as an independent risk factor when using MELD or MELD-Na but lost its significance in the presence of GEMA-Na or MELD 3.0. Among patients included for reasons other than tumours (n=3606; 59.4%), GEMA-Na had Hc=0.753 (95% CI 0.715-0.792), which was higher than MELD 3.0 (Hc=0.726 [95% CI 0.686-0.767; p=0.001), showing both models adequate calibration. GEMA-Na and MELD 3.0 might correct sex disparities for accessing LT, but GEMA-Na provides more accurate predictions of waiting list outcomes and could be considered the standard of care for waiting list prioritization. Instituto de Salud Carlos III, Agencia Estatal de Investigación (Spain), and European Union.

Iadademstat in combination with azacitidine in patients with newly diagnosed acute myeloid leukaemia (ALICE): an open-label, phase 2a dose-finding study

Iadademstat is a potent, selective, oral inhibitor of both the enzymatic and scaffolding activities of the transcriptional repressor lysine-specific demethylase 1 (LSD1; also known as KDM1A) that showed promising early activity and safety in a phase 1 trial and strong preclinical synergy with azacitidine in acute myeloid leukaemia cell lines. Therefore, we aimed to investigate the combination of iadademstat and azacitidine for the treatment of adult patients with newly diagnosed acute myeloid leukaemia. The open-label, phase 2a, dose-finding ALICE study was conducted at six hospitals in Spain and enrolled patients aged 18 years or older with newly diagnosed acute myeloid leukaemia not eligible for intensive chemotherapy and an ECOG performance status of 0-2. In the dose escalation portion of the trial, patients received a starting dose of iadademstat at 90 μg/m2 per day (with de-escalation to 60 μg/m2 per day and escalation up to 140 μg/m2 per day) orally, for 5 days on, 2 days off weekly, with azacitidine 75 mg/m2 subcutaneously, for seven of 28 days. The primary objectives were safety (analysed in the safety analysis set; all patients who received at least one dose of study treatment) and establishing the recommended phase 2 dose; secondary objectives included response rates in the efficacy analysis set (all patients who had at least one efficacy assessment). This study is registered on EudraCT (EudraCT 2018-000482-36) and has been completed. Between Nov 12, 2018, and Sept 30, 2021, 36 patients with newly diagnosed acute myeloid leukaemia were enrolled; the median age was 76 (IQR 74-79) years, all patients were White, 18 (50%) were male, and 18 (50%) were female, and all had intermediate-risk or adverse-risk acute myeloid leukaemia. The median follow-up was 22 (IQR 16-31) months. The most frequent (≥10%) adverse events considered to be related to treatment were decreases in platelet (25 [69%]) and neutrophil (22 [61%]) counts (all grade 3-4) and anaemia (15 [42%]; of which ten [28%] were grade 3-4). Three patients had treatment-related serious adverse events (one fatal grade 5 intracranial haemorrhage, one grade 3 differentiation syndrome, and one grade 3 febrile neutropenia). Based on safety, pharmacokinetic and pharmacodynamic data, and efficacy, the recommended phase 2 dose of iadademstat was 90 μg/m2 per day with azacitidine. 22 (82%; 95% CI 62-94) of 27 patients in the efficacy analysis set had an objective response. 14 (52%) of 27 patients had complete remission or complete remission with incomplete haematological recovery; of these, ten of 11 evaluable for measurable residual disease achieved negativity. In the safety analysis set, 22 (61%) of 36 patients had an objective response. The combination of iadademstat and azacitidine has a manageable safety profile and shows promising responses in patients with newly diagnosed acute myeloid leukaemia, including those with high-risk prognostic factors. Oryzon Genomics and Spain's Ministerio de Ciencia, Innovacion y Universidades (MICIU)-Agencia Estatal de Investigacion (AEI).

Role of miRNAs regulation of Orai1 and store operated Ca2+ entry in vascular restenosis

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Agencia Estatal de Investigación Background The main cause of restenosis is attributed to the excessive proliferation and migration of vascular smooth muscle cells (VSMCs). Orai1 is one of the main molecular components of Store-Operated Calcium Entry (SOCE), playing a key role in VSMCs proliferation during neointima formation and vascular remodeling. Recent studies have demonstrated the implication of microRNAs (miRNAs) in VSMCs proliferation and migration, however, the role of these miRNAs as regulators of SOCE during vascular remodeling has not been described. Purpose This study aims to determine whether miRNAs regulate the intracellular Ca2+ handling, focusing on SOCE, during neointima formation. Methods Experiments were conducted in an animal rat model following the "Principles of laboratory animal care" and according to the Spanish law. The neointima development was assessed after balloon injury of carotid arteries and confirmed by haematoxylin and eosin staining, and αSMA staining of tissue sections up to 3 weeks after surgery. miRNAs array and RT-qPCR was used to examine the expression of miRNAs. Dual-Luciferase reporter assay was performed in A7R5 VSMCs line. Results Injured arteries showed significant increase in the expression of Orai1, as compared to non-injured arteries, indicating their possible participation in the neointima layer formation. Microarray of miRNAs analysis of the injured carotids compared to control carotids showed significant increase in the expression of miRNAs related to signalling pathways involving cell proliferation and migration, cell differentiation, or VSMCs contraction. Of these, we confirmed the significant increase of miR-18a-5p, miR-20a-5p, miR-20b-5p and miR-17-5p, which belong to widely studied miR-17-92 cluster involved in different cell proliferation. Moreover, we found that mimics of those miRNAs were able to regulate differentially the activity of the Orai1 promotor in A7R5 cell line, indicating that Orai1 can be targeted by miRNAs during in VSMCs. Conclusions In conclusion, our data confirms that Orai1 is upregulated during neointima formation associated with miRNAs dysregulation. Moreover, we found that Orai1-dependent SOCE can be finely regulated by miRNAs during restenosis.

Role of Orai1 and Ca2+-stimulated adenylyl cyclase 8 in the adverse cardiac remodeling after myocardial infarction

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Agencia Estatal de Investigación. Background It is well established that abnormalities in the regulation of the intracellular concentration of Ca2+ ([Ca2+]i) occurs in diseased heart such as under acute myocardial infarction (AMI). Recent studies have demonstrated that proteins related to the Store Operated Calcium Entry (SOCE), such as Orai1/2/3 and TRPC channels, play a role in the adverse cardiac remodelling. Previously, we demonstrated that the expression of Orai1 increased in heart subjected to ischemia and reperfusion (I/R) syndrome. However, the signalling pathway implicated in Orai1 regulation has not been addressed. Objective The aim of this study was to examine the molecular mechanism and signalling pathways involved in the of Orai1 upregulation after I/R in cardiomyocytes. Materials and Methods The experiments were performed in adult (ARVM) and neonatal rat ventricular cardiomyocytes (NRVM), in a rat model of myocardial I/R and in ventricular biopsies of patients with ischemic heart failure. Ca2+ studies were realized using microfluorimetric technique in FURA-2AM loaded cardiomyocytes. Immunofluorescence was used to investigate CREB activation using a specific phospho-CREB antibody and Orai1 and AC8 protein expression were analysed by Western Blot. This study was performed in accordance with the recommendations of the Royal Decree 53/2013 in agreement to the Directive 2010/63/EU of the European Parliament and approved by the local Ethics Committee on human Research and the Animal Research Committee. Results We found that under I/R diastolic level of [Ca2+]i was significantly increased in cardiac myocytes isolated from I/R hearts, which was inhibited by SOCE blockers. Moreover, we found that Orai1 and Ca2+-sensitive adenylyl cyclase 8 (AC8) are overexpressed in the heart isolated from I/R rat model, as compared to sham. Similarly, we found significant increase in the expression of Orai1 and AC8 in ventricle biopsies of post-infarction patients with HF. We also observed that I/R stimulated cAMP production, involving Orai1 and AC8 activation in rats, indicating that Ca2+ entry through Orai1 stimulated AC8. Moreover, I/R phosphorylated cAMP response element-binding protein (CREB) through PKA activation, but not via EPAC2 or ERK1/2. Interestingly, we found that CREB facilitated I/R-induced Orai1 upregulation and related exacerbated SOCE by its activation of Orai1 promoter under I/R. Finally, the intramyocardial administration of AAV9 holding AC8 shRNA decreased the expression of AC8, Orai1 and CREB, which restored diastolic [Ca2+]i. Conclusions Our results show that the activation of Orai1/AC8/CREB axis plays a key role in the I/R-induced Orai1 upregulation, which participated in diastolic [Ca2+]i mishandling related to the adverse cardiac remodelling.

Patents, Freedom to Operate, and Follow-on Innovation: Evidence from Post-Grant Opposition

We study the blocking effect of patents on follow-on innovation by others. We posit that follow-on innovation requires freedom to operate (FTO), which firms typically obtain through a license from the patentee holding the original innovation. Where licensing fails, follow-on innovation is blocked unless firms gain FTO through patent invalidation. Using large-scale data from post-grant oppositions at the European Patent Office, we find that patent invalidation increases follow-on innovation, measured in citations, by 16% on average. This effect exhibits a U-shape in the value of the original innovation. For patents on low-value original innovations, invalidation predominantly increases low-value follow-on innovation outside the patentee’s product market. Here, transaction costs likely exceed the joint surplus of licensing, causing licensing failure. In contrast, for patents on high-value original innovations, invalidation mainly increases high-value follow-on innovation in the patentee’s product market. We attribute this latter result to rent dissipation, which renders patentees unwilling to license out valuable technologies to (potential) competitors. This paper was accepted by Ashish Arora, entrepreneurship and innovation. Funding: This work was supported by the Deutsche Forschungsgemeinschaft [Collaborative Research Center TRR 190]. F. Gaessler acknowledges financial support from the Spanish Agencia Estatal de Investigación through the Severo Ochoa Programme for Centres of Excellence in R&D [Barcelona School of Economics CEX2019-000915-S]. Supplemental Material: The online appendices and data files are available at https://doi.org/10.1287/mnsc.2019.02294 .

Abstract 4483: New drug development opportunities for PARP1

Abstract Personalized therapies allow, not only the increase of its therapeutic efficiency, but also the reduction of the secondary effects associated to the treatment of cancer. Data obtained in our group suggest that PARP1 could play a key role in the cell cycle regulation through its interaction with E2F1 transcription factor. Considering that most oncogenic processes is associated with cell cycle deregulation, the disruption of this interaction would provide a new therapeutic target of great interest and wide spectrum of indications. Therefore, our goal was to find molecules that interfere its role in cell-cycle regulation without affecting its function on DNA repair. The identification of novel compounds disrupting the PARP1/E2F1 interaction was carried out by combining in silico and in vitro screening, using a rational drug design. The virtual screen was performed using a molecular library of several million compounds at the selected target site, using AtomNet® (Atomwise), the first deep learning neural network for structure-based drug design and discovery. Since there is no complete structural information of the PARP-1/E2F1 protein-protein interaction, a homologous structure of BRCT domain of BRCA1 complex with the phospho-peptide (PDBID: 1T2V) was utilized to identify the potential binding interface of BRCT domain of PARP-1 (PDBID: 2COK) and the E2F1 protein. Top scoring compounds were clustered and filtered to arrive at a final subset of 83 compounds, library that were incorporated to our in vitro screening, which included both transcriptional (E2F1 activity) and survival studies. Twelve compounds were finally selected, based upon their higher capacity of inhibiting E2F1 activity.This work was supported by Agencia Estatal de Investigación (AEl/10.13039/501100011033), Xunta de Galicia (GPC GI-1862, ED431B 2020/26; ED431G 2019/02) and European Regional Development Fund-ERDF. AIMS Awards Program - Project A19-513, Atomwise Inc. Citation Format: Pablo Iglesias, David Moreiras, Laura Porres-Ventin, Lara Gonzalez-Rendo, Jose A. Zumalave, Victor M. Arce, Jose A. Costoya. New drug development opportunities for PARP1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4483.

Abstract 5785: Shedding light on PARP1-E2F1 interaction by Cryo-EM

Abstract Cell division is orchestrated by a complex network of interactions between proteins involved in numerous signaling pathways that control cell proliferation. One of these main players is the E2F family of transcription factors. The role of these key players is to regulate the expression of several genes important in cell proliferation, particularly those involved in progression through G1 and into the S-phase of the cell cycle. In fact, cell cycle deregulation is a hallmark of cancer, and multiple studies have highlighted the critical role of E2F hyperactivation in tumor progression, angiogenesis, and metastasis. However, targeting a master regulator of cell growth will also have a pernicious effect on non-cancerous cells, thus limiting its applications. In order to overwhelm these restrictions, we propose a therapeutic approach in which E2F transcriptional activity is specifically reduced in cells with hyperactivation of the pathway, such as cancer cells.We and others have shown that poly (ADP-ribose) polymerase 1 (PARP1) is a transcriptional co-activator of E2F1 and, owing to this, loss of PARP results in cell cycle re-regulation and reduction of tumor growth. Interestingly, this effect of PARP1 does not depend on its enzymatic activity, thus opening a completely new strategic approach. Furthermore, considering that most oncogenic processes are associated with cell cycle deregulation, disruption of PARP1-E2F1 interaction could provide a new therapeutic target with a wide spectrum of indications in cancer. Currently, we lack comprehensive structural details regarding the PARP-1/E2F1 protein-protein interaction. To address this, we used cryo-EM to investigate both the standalone structure of PARP1 (full length) and its interaction with E2F1. This approach yielded high-resolution structural insights into the PARP1-E2F1 complex, enabling precise identification of the protein-protein interaction interface (PPI). Through this exploration of structural and molecular determinants governing this interaction, we aim to develop innovative strategies for designing drugs targeted at disrupting this complex. This work was supported by Agencia Estatal de Investigación (AEl/10.13039/501100011033), Xunta de Galicia (GPC GI-1862, ED431B 2020/26; ED431G 2019/02) and European Regional Development Fund-ERDF. Citation Format: Pablo Iglesias, Ester Casajus-Pelegay, Maria Moreno-Morcillo, Lara González-Rendo, Laura Porres-Ventin, Victor M. Arce, Rafael Fernandez-Leiro, Jose A. Costoya. Shedding light on PARP1-E2F1 interaction by Cryo-EM [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5785.

Global Financial Cycle, Household Credit, and Macroprudential Policies

We show that macroprudential policies dampen the impact of global financial conditions on local bank credit cycles. For identification, we exploit variation in the U.S. volatility index (VIX) and household and business credit registers in an emerging market economy in which banks depend on foreign funding and macroprudential measures vary over the full cycle. Our results suggest that when the VIX is low, tighter macroprudential policies reduce household lending, notably for riskier (foreign currency (FX) and high debt-service-to-income) loans and by banks dependent on foreign funding. Moreover, they increase (less regulated) local currency lending to real estate firms. Such periods are associated with less subsequent total lending to households and firms and with a lower share of FX loans at the local level. Consistently, when the VIX is low, tighter macroprudential policies dampen house prices and economic activity. This paper was accepted by Victoria Ivashina, finance. Funding: M. Epure acknowledges support from the Serra Húnter program. This project received funding from the European Research Council under the European Union’s Horizon 2020 research and innovation program [Grant 648398], from the Agencia Estatal de Investigacion [Grants PID2020-115660GB-I00 and PGC2018-102133-B-I00], and the Severo Ochoa Program for Centers of Excellence in Research and Development [Grant CEX2019-000915-S]. Supplemental Material: The online appendix and data files are available at https://doi.org/10.1287/mnsc.2024.4981 .

Thermodynamic and hydrological drivers of the soil and bedrock thermal regimes in central Spain

Abstract. An assessment of the soil and bedrock thermal structure of the Sierra de Guadarrama, in central Spain, is provided using subsurface and ground surface temperature data coming from four deep (20 m) monitoring profiles belonging to the Guadarrama Monitoring Network (GuMNet) and two shallow profiles (1 m) from the Spanish Meteorology Service (Agencia Estatal de Meteorología, AEMET) covering the time spans of 2015–2021 and 1989–2018, respectively. An evaluation of air and ground surface temperature coupling showed that soil insulation due to snow cover is the main source of seasonal decoupling, being especially relevant in winter at high-altitude sites. Temperature propagation in the subsurface was characterized by assuming a heat conductive regime by considering apparent thermal diffusivity values derived from the amplitude attenuation and phase shift of the annual cycle with depth. This methodology was further extended to consider the attenuation of all harmonics in the spectral domain, which allowed for analysis of thermal diffusivity from high-frequency changes in the soil near the surface at short timescales. For the deep profiles, the apparent thermal diffusivity ranges from 1 to 1.3×10-6 m2 s−1, which is consistent with values for gneiss and granite, the major bedrock components in the Sierra de Guadarrama. However, thermal diffusivity is lower and more heterogeneous in the soil layers close to the surface (0.4–0.8×10-6 m2 s−1). An increase in diffusivity with depth was observed that was generally larger in the soil–bedrock transition at 4–8 m depth. The outcomes are relevant for the understanding of soil thermodynamics in relation to other soil properties. Results with the spectral method suggest that changes in near-surface thermal diffusivity are related to changes in soil moisture content, which makes it a potential tool to gain information about soil drought and water resource availability from soil temperature data.

Corpus de meteo-metáforas y periodismo deportivo en tiempos del COVID-19 De los “aludes de lesiones” al “todo está yendo viento en popa”

This study addresses the analysis of the main lexical patterns, mostly in the form of adverbial locutions and idioms, which could be classified as meteorological metaphors (or meteo-metaphors) used in the Spanish digital sports press and tries to find out if there is a specific sport in which metaphors that use weather phenomena to describe or characterize aspects of sports stand out. From a quasi-experimental approach, a method of content analysis is used on a generated corpus based on the 20 most common meteorological phenomena reported by the Agencia Estatal de Meteorología (AEMET) and the Sistema de Notificación de Observaciones Atmosféricas Singulares (SINOBAS) (System of Notification of Singular Atmospheric Observations); as corpus we analyze the sports section of the digital edition of the Spanish free newspaper 20minutos, the most read newspaper in Spain, in April 2022, according to GfK DAM (the official measure of digital media consumption in Spain). The study is limited in time to one year, between March 14, 2020 (the date of the beginning of the state of alarm for COVID-19 in Spain) and June 21, 2021. After studying the frequency and context of these samples, the data indicate that the four meteorological phenomena that generate the most metaphors are those related to “ola” [wave], huracán [hurricane], calor [heat] and “sequía” [drought]. Moreover, there are no surprises with respect to the sport where such metaphors are used to the greatest extent: soccer. Nevertheless, it will be sociolinguistically justified that other sports connected to those metaphors stand out: “wave” / Tokyo Olympics Games, “hurricane” / F1, “heat” / NFL, and “drought” / tennis. The complete corpus of 273 meteorological metaphors has been publicly hosted at https://t.ly/XPT0V.

Shapley–Scarf Housing Markets: Respecting Improvement, Integer Programming, and Kidney Exchange

In a housing market of Shapley and Scarf, each agent is endowed with one indivisible object and has preferences over all objects. An allocation of the objects is in the (strong) core if there exists no (weakly) blocking coalition. We show that, for strict preferences, the unique strong core allocation “respects improvement”—if an agent’s object becomes more desirable for some other agents, then the agent’s allotment in the unique strong core allocation weakly improves. We extend this result to weak preferences for both the strong core (conditional on nonemptiness) and the set of competitive allocations (using probabilistic allocations and stochastic dominance). There are no counterparts of the latter two results in the two-sided matching literature. We provide examples to show how our results break down when there is a bound on the length of exchange cycles. Respecting improvements is an important property for applications of the housing markets model, such as kidney exchange: it incentivizes each patient to bring the best possible set of donors to the market. We conduct computer simulations using markets that resemble the pools of kidney exchange programs. We compare the game-theoretical solutions with current techniques (maximum size and maximum weight allocations) in terms of violations of the respecting improvement property. We find that game-theoretical solutions fare much better at respecting improvements even when exchange cycles are bounded, and they do so at a low efficiency cost. As a stepping stone for our simulations, we provide novel integer programming formulations for computing core, competitive, and strong core allocations. Funding: P. Biró gratefully acknowledges financial support from the Hungarian Scientific Research Fund, OTKA [Grant K143858] and the Hungarian Academy of Sciences [Grant LP2021-2]. F. Klijn gratefully acknowledges financial support from AGAUR–Generalitat de Catalunya [Grants 2017-SGR-1359 and 2021-SGR-00416] and the Spanish Agencia Estatal de Investigación [Grants ECO2017-88130-P and PID2020-114251GB-I00] (funded by MCIN/AEI/10.13039/501100011033) and the Severo Ochoa Programme for Centres of Excellence in R&D (Barcelona School of Economics) [Grant CEX2019-000915-S]. Research visits related to this work were financed by COST Action [Grant CA15210 ENCKEP], supported by COST (European Cooperation in Science and Technology), http://www.cost.eu/ .

Modelling and Experimental Validation of the Flow and Mixing Processes in a Microfluidic Membraneless X-Cell with Flowing Vanadium Electrolytes

Microfluidic devices are characterized by submillimeter channel cross-sections and tiny flow rates, typically below 100 µL/min. This results in rather small Reynolds numbers that maintain the flow laminar and steady, preventing chaotic mixing from turbulence [1-4]. This orderly flow can be used to remove the ionomeric membrane in redox flow batteries, generating membraneless microfluidic cells with low internal electric resistance. These devices could be manufactured at a lower cost than their macro counterparts. However, without a membrane, the mixing region where the electrolytes come into contact must be accurately controlled to avoid unwanted interface deflections leading to increased cross-contamination of liquid and species.In this work, we compare experimental and CFD realizations of the flow in a membraneless microfluidic flow channel [5], including in the simulations the effect of viscosity variations across the positive and negative vanadium electrolytes. The apparatus includes a microfluidic control system that uses piezoelectric pumps and valves for flow regulation, an X-cell as flow channel, and small tanks with discharged positive (VIV) and negative (VIII) electrolytes. We use a UV/Visible spectrometer to measure the amount of mixing at the outlet of the cell [6]. This allows us to validate the CFD model against the experimentally measured cross-contamination and liquid transfer. To our knowledge, these results are unique in using spectrometry data to quantify the mixing ratio of VIII/VIV, and provide valuable data to validate CFD models that could later be used to engineer the flow in membraneless microfluidic vanadium redox flow batteries. Acknowledgments This work has been partially funded by FEDER/Ministerio de Ciencia, Innovación y Universidades – Agencia Estatal de Investigación Projects PID2019-106740RB-I00 and RTC-2017-5955-3/AEI/10.13039/501100011033, and by Grant IND2019/AMB-17273 of the Comunidad de Madrid.

Optimizing the Electrolyte Mixing in Industrial Tanks of Vanadium Redox Flow Batteries

Redox flow batteries (RFB) are an emerging technology for large-scale grid energy storage. Different approaches have been adopted to investigate the operation of RFBs, such as experimental testing and mathematical modelling of the electrochemical cells [1]. However, the effect of the flow and mixing in the electrolyte tanks on the performance of RFBs has been largely overlooked and only recently has started to receive some attention [2]. In a recent work, the authors used numerical simulations to show how the fluid dynamics of the electrolytes within small lab-scale tanks can lead to different flow behaviors depending on whether forced or natural convection is dominant. The irregular transient mixing of the electrolyte in the tanks modifies both the cell potential and battery capacity with respect to those predicted under the widely used perfect mixing assumption (i.e., continuous stirred-tank reactor) [3]. However, this first attempt relied on several simplifying assumptions, such as two-dimensional geometries under small-cell (i.e., laminar) flow conditions, and thus provided only a qualitatively understanding of the flow in the tanks.This work exploits the idea of using CFD simulations to investigate the effect of operating conditions on the electrolyte flow in the tanks and its impact on battery response, focusing on high capacity industrial tanks with high (i.e., turbulent) flow rates and less restrictive simplifying assumptions. Our numerical simulations show how turbulence improves mixing, but also produces quasi-steady flows where a turbulent jet crosses the tank leaving dead electrolyte regions. Different tank solutions are presented aiming to improve the mixing and increase the capacity of the battery, playing both with the tank geometry and the operating conditions. Results on the charging and discharging operations, cell potential and electrolyte mixing index are presented and discussed. Acknowledgments This work has been partially funded by FEDER/Ministerio de Ciencia, Innovación y Universidades – Agencia Estatal de Investigación Projects PID2019-106740RB-I00 and RTC-2017-5955-3/AEI/10.13039/501100011033, and by Grant IND2019/AMB-17273 of the Comunidad de Madrid.

Monitoring the State of Charge Imbalance of Vanadium Redox Flow Batteries Via Dual Online UV/Visible Spectroscopy

Electrolyte imbalance in Redox Flow Batteries (RFBs) is known to result in significant capacity decay over cycling [1]. This drawback is inherent to the flow battery technology and is caused by unwanted physico-chemical phenomena, such as species and water crossover, hydrogen evolution, air oxidation and precipitation of vanadium ions. The time evolution of electrolyte imbalance is often disregarded or underestimated when measuring the open-circuit voltage (OCV) for keeping track of the battery State of Charge (SOC). In order to correct such asymmetry, in operando real-time monitoring of the SOC of the positive and negative electrolytes would be highly desirable.In this work, we present an experimental test bench for the continuous online monitoring of the anolyte and catholyte SOCs via UV/visible spectroscopy during cycling of an all-vanadium redox flow battery (VRFB). The system notably includes 3D printed microfluidic optical flow cells, an optical switch, and an in-house microfluidic electrochemical cell. Key steps for the calibration of UV/visible spectroscopy with vanadium are presented and applied independently to both electrolytes to accurately estimate the SOC while taking into account the total vanadium concentration [2]. An experimental campaign is then carried out under varying conditions (initial average oxidation state (AOS), air oxidation, crossover, etc.) to illustrate the real-time evolution of electrolyte imbalance during VRFB battery cycling. The results suggest that the imbalance may arise from asymmetric initial Average Oxidation State (AOS ≠ 3.5) [3], vanadium crossover and also hydrogen evolution, which notably reduces the charging speed of the negative electrolyte [4]. The results highlight the benefits of UV/Visible spectroscopy to obtain SOC data for any of the three stable vanadium electrolytes: i) negative, VII/VIII ii) positive VIV/VV and even the iii) VIII/VIV pair. Moreover, the measurements are online, non-invasive and could provide real-time data to a battery management system either in conventional or microfluidic VRFBs to correct the SOC imbalance and maintain the battery capacity and efficiency [1]. Acknowledgments This work has been partially funded by FEDER/Ministerio de Ciencia, Innovación y Universidades – Agencia Estatal de Investigación Project PID2019-106740RB-I00, and by Grant IND2019/AMB-17273 of the Comunidad de Madrid. A. A. Maurice Energy acknowledges the support of an MCSF-Cofund “Energy for Future” (E4F) postdoctoral research fellowship by the Spanish Iberdrola Foundation (GA-101034297).

826-P: Treatment of MODY3 Disease by AAV-Hnf1a-Mediated Gene Therapy

Maturity-onset diabetes of the young (MODY) are a group of monogenic diabetes characterized by onset of hyperglycemia at an early adult age, normally before 25 years. MODY3, the most common type of MODY, is caused by mutations in the gene encoding for the transcription factor hepatocyte nuclear factor 1A (HNF1A). MODY3 patients are usually treated with sulfonylureas, but they tend to become unresponsive to these drugs and adverse effects associated to chronic administration of sulfonylureas have been reported. Presently, there are no current treatments addressing the root cause of MODY3. Here, we have developed a new gene therapy approach to treat this disease. To this end, using the CRISPR/Cas9 technology, we first generated a novel MODY3 mouse model that showed pancreatic down-regulation of HNF1A protein production. These mice developed β-cell dysfunction and hyperglycemia, recapitulating the main alterations observed in human patients. Treatment of MODY3 mice by intra-pancreatic duct administration of adeno-associated viral vectors (AAVs) encoding Hnf1α, under control of β-cell-specific promoter, resulted in HNF1A expression in β-cells, which upregulated the expression of HNF1A main target genes, such as GLUT2 and L-PK. AAV-Hnf1α-mediated gene therapy counteracted hyperglycemia, increased insulinemia, improved glucose tolerance and enhanced insulin secretion by pancreatic β-cells, thus reverting the MODY3 disease. This study represents the first demonstration for the genetic counteraction of a monogenic diabetes and paves the way for the clinical translation of AAV-Hnf1α-based gene therapy to treat MODY 3 patients in the future. Moreover, these results may also contribute to the development of new gene therapy strategies for other monogenic forms of diabetes. Disclosure E.Casana lorente: None. X.Leon: None. S.Franckhauser: None. F.Bosch: None. V.Jimenez: None. M.Garcia: None. A.Casellas: None. M.Morró: None. A.Pujol: None. T.Ferré: None. V.Sacristán: None. C.Jambrina: None. Funding Fundació La Marató de TV3 (201603-31-32-33); Ministerio de Economía, Industria y Competitividad (SAF2017-86266R); Agencia Estatal de Investigación; Fondo Europeo de Desarrollo Regional; Programa Estatal de I+D+i Orientada a los Retos de la Sociedad; MCIN/AEI/10.13039/501100011033 (PID2020-113864RB-I00); Generalitat de Catalunya, Spain 2017 SGR 1508 (to F.B.)

Hub Location with Protection Under Interhub Link Failures

This paper introduces the hub location problem under interhub link failures, a hub location problem in which activated interhub links may fail with a given probability. Two different optimization models are studied, which construct hub backbone networks protected under interhub link disruptions by imposing that, for each commodity, an additional routing path exists besides its original routing path. Both models consider the minimization of the fixed costs of the activated hubs and interhub links plus the expected value of the routing costs of the original and alternative paths. The first model builds explicitly the alternative routing paths, whereas the second model guarantees that, for each commodity, at least one alternative path exists using a large set of connectivity constraints although the alternative paths are not built explicitly. The results of extensive computational testing allow us to analyze the performance of the two proposed models and to evaluate the extra cost required to design a robust backbone network under interhub link failures. The obtained results support the validity of the proposal. History: Accepted by David Alderson, Area Editor for Network Optimization: Algorithms & Application. Funding: The authors of this research acknowledge financial support by the Spanish Ministerio de Ciencia y Tecnología, Agencia Estatal de Investigación and Fondos Europeos de Desarrollo Regional (FEDER) via projects PID2020-114594GB-C21 and MTM2019-105824GB-I00. The authors also acknowledge partial support from projects FEDER-US-1256951, Junta de Andalucía P18-FR-422, P18-FR-2369, B-FQM-322-UGR20 (COXMOS), and NetmeetData: Ayudas Fundación BBVA a equipos de investigación científica 2019. The first author was partially supported by the IMAG-Maria de Maeztu grant [CEX2020-001105-M/AEI/10.13039/501100011033] and UE-NextGenerationEU (ayudas de movilidad para la recualificación del profesorado universitario). Supplemental Material: The online supplement is available at https://doi.org/10.1287/ijoc.2023.1296 .

Plasmodium falciparum sexual conversion rates can be affected by artemisinin-based treatment in naturally infected malaria patients.

SummaryBackgroundArtemisinins (ART) are the key component of the frontline antimalarial treatment, but their impact on Plasmodium falciparum sexual conversion rates in natural malaria infections remains unknown. This is an important knowledge gap because sexual conversion rates determine the relative parasite investment between maintaining infection in the same human host and transmission to mosquitoes.MethodsThe primary outcome of this study was to assess the impact of ART-based treatment on sexual conversion rates by comparing the relative transcript levels of pfap2-g and other sexual ring biomarkers (SRBs) before and after treatment. We analysed samples from previously existing cohorts in Vietnam, Burkina Faso and Mozambique (in total, n=109) collected before treatment and at 12 h intervals after treatment. As a secondary objective, we investigated factors that may influence the effect of treatment on sexual conversion rates.FindingsIn the majority of infections from the African cohorts, but not from Vietnam, we observed increased expression of pfap2-g and other SRBs after treatment. Estimated parasite age at the time of treatment was negatively correlated with the increase in pfap2-g transcript levels, suggesting that younger parasites are less susceptible to stimulation of sexual conversion.InterpretationWe observed enhanced expression of SRBs after ART-based treatment in many patients, which suggests that in natural malaria infections sexual conversion rates can be altered by treatment. ART-based treatment reduces the potential of a treated individual to transmit the disease, but we hypothesise that under some circumstances this reduction may be attenuated by ART-enhanced sexual conversion.FundingSpanish Agencia Estatal de Investigación (AEI), European Regional Development Fund (ERDF, European Union), Belgium Development Cooperation (DGD), Canadian University Health Network (UHN), TransGlobalHealth–Erasmus Mundus (European Union).

Modelling the Electrolyte Flow in the Tanks of Vanadium Redox Flow Batteries: A CFD Perspective

Redox flow batteries are a promising technology for large-scale energy storage. The flow of the electrolyte in the tanks is a relevant factor for battery optimization that has been largely overlooked to date, with departures from perfect mixing associated with an effective capacity loss of the system. The flow in the tanks is driven by the competing effects of inertia and buoyancy, the former associated with the momentum flux of the discharging jet and the latter with the density changes suffered by the electrolyte as it passes through the cell because of the slight changes in temperature and state of charge (SoC). Three different flow regimes may be found in the system, each dominated by one effect or the other, or by both when they are comparable. All these phenomena are governed by the current intensity applied (I), the volumetric flow (q) and the properties of the vanadium electrolyte.In particular, it is seen that an accurate description of the effect of the temperature and state of charge on the density and specific heat of the electrolytes is essential to compute the buoyancy induced flow and heat transfer taking place in the tanks. A parametric sweep is presented to show the impact of these dependences on the mixing process, which calls for the need of accurate experimental measurements of the variation of the physical properties of the electrolytes with their temperature and state of charge.Our numerical simulations show that the electrolytes are never perfectly mixed, and that the homogeneity of the species concentration is strongly dependent on the operation conditions and on the tank design, with details of the inlet and outlet ducts being particularly relevant. Results on the charging and discharging operations, heating process and the rising of the state of charge in the cell are presented and discussed.AcknowledgmentsThis work has been partially funded by the Agencia Estatal de Investigación (PID2019-106740RB-I00 and RTC-2017-5955-3/AEI/10.13039/501100011033), and by Grant IND2019/AMB-17273 of the Comunidad de Madrid. Figure 1