Ministry Of Economy , Industry And Competitiveness Research Articles

Human endometrial cell-type-specific RNA sequencing provides new insights into the embryo-endometrium interplay.

Which genes regulate receptivity in the epithelial and stromal cellular compartments of the human endometrium, and which molecules are interacting in the implantation process between the blastocyst and the endometrial cells? A set of receptivity-specific genes in the endometrial epithelial and stromal cells was identified, and the role of galectins (LGALS1 and LGALS3), integrin β1 (ITGB1), basigin (BSG) and osteopontin (SPP1) in embryo-endometrium dialogue among many other protein-protein interactions were highlighted. The molecular dialogue taking place between the human embryo and the endometrium is poorly understood due to ethical and technical reasons, leaving human embryo implantation mostly uncharted. Paired pre-receptive and receptive phase endometrial tissue samples from 16 healthy women were used for RNA sequencing. Trophectoderm RNA sequences were from blastocysts. Cell-type-specific RNA-seq analysis of freshly isolated endometrial epithelial and stromal cells using fluorescence-activated cell sorting (FACS) from 16 paired pre-receptive and receptive tissue samples was performed. Endometrial transcriptome data were further combined in silico with trophectodermal gene expression data from 466 single cells originating from 17 blastocysts to characterize the first steps of embryo implantation. We constructed a protein-protein interaction network between endometrial epithelial and embryonal trophectodermal cells, and between endometrial stromal and trophectodermal cells, thereby focusing on the very first phases of embryo implantation, and highlighting the molecules likely to be involved in the embryo apposition, attachment and invasion. In total, 499 epithelial and 581 stromal genes were up-regulated in the receptive phase endometria when compared to pre-receptive samples. The constructed protein-protein interactions identified a complex network of 558 prioritized protein-protein interactions between trophectodermal, epithelial and stromal cells, which were grouped into clusters based on the function of the involved molecules. The role of galectins (LGALS1 and LGALS3), integrin β1 (ITGB1), basigin (BSG) and osteopontin (SPP1) in the embryo implantation process were highlighted. RNA-seq data are available at www.ncbi.nlm.nih.gov/geo under accession number GSE97929. Providing a static snap-shot of a dynamic process and the nature of prediction analysis is limited to the known interactions available in databases. Furthermore, the cell sorting technique used separated enriched epithelial cells and stromal cells but did not separate luminal from glandular epithelium. Also, the use of biopsies taken from non-pregnant women and using spare IVF embryos (due to ethical considerations) might miss some of the critical interactions characteristic of natural conception only. The findings of our study provide new insights into the molecular embryo-endometrium interplay in the first steps of implantation process in humans. Knowledge about the endometrial cell-type-specific molecules that coordinate successful implantation is vital for understanding human reproduction and the underlying causes of implantation failure and infertility. Our study results provide a useful resource for future reproductive research, allowing the exploration of unknown mechanisms of implantation. We envision that those studies will help to improve the understanding of the complex embryo implantation process, and hopefully generate new prognostic and diagnostic biomarkers and therapeutic approaches to target both infertility and fertility, in the form of new contraceptives. This research was funded by the Estonian Research Council (grant PRG1076); Horizon 2020 innovation grant (ERIN, grant no. EU952516); Enterprise Estonia (grant EU48695); the EU-FP7 Marie Curie Industry-Academia Partnerships and Pathways (IAPP, grant SARM, EU324509); Spanish Ministry of Economy, Industry and Competitiveness (MINECO) and European Regional Development Fund (FEDER) (grants RYC-2016-21199, ENDORE SAF2017-87526-R, and Endo-Map PID2021-127280OB-100); Programa Operativo FEDER Andalucía (B-CTS-500-UGR18; A-CTS-614-UGR20), Junta de Andalucía (PAIDI P20_00158); Margarita Salas program for the Requalification of the Spanish University system (UJAR01MS); the Knut and Alice Wallenberg Foundation (KAW 2015.0096); Swedish Research Council (2012-2844); and Sigrid Jusélius Foundation; Academy of Finland. A.S.-L. is funded by the Spanish Ministry of Science, Innovation and Universities (PRE2018-085440). K.G.-D. has received consulting fees and/or honoraria from RemovAid AS, Norway Bayer, MSD, Gedeon Richter, Mithra, Exeltis, MedinCell, Natural cycles, Exelgyn, Vifor, Organon, Campus Pharma and HRA-Pharma and NIH support to the institution; D.B. is an employee of IGENOMIX. The rest of the authors declare no conflict of interest.

The mid-secretory endometrial transcriptomic landscape in endometriosis: a meta-analysis.

STUDY QUESTIONDo women with endometriosis have a different endometrial gene expression profile at the time of embryo implantation than women without endometriosis?SUMMARY ANSWERThe endometrial gene expression profile of women with endometriosis differs from that of women without endometriosis at the mid-secretory phase, although the differences are small.WHAT IS KNOWN ALREADYAbout 50% of women with endometriosis suffer infertility. Several molecular studies have suggested impaired endometrial receptivity in women with endometriosis, while others have detected no dysregulation of endometrial receptivity. Nevertheless, the previous endometrial transcriptome studies comparing women with and without endometriosis have been performed in small sample size with limited statistical power. We set out to systematically search and compile data of endometrial gene expression signatures at the receptive phase in women with endometriosis versus control women. Based on the obtained data, we conducted a meta-analysis of differentially expressed genes in order to raise the power of the analysis for identifying the molecular profiles of receptive phase endometria in endometriosis.STUDY DESIGN, SIZE, DURATIONA systematic literature search was conducted up to February 2022 following PRISMA criteria and included PubMed, Cochrane and Web of Science databases. For the systematic search, the term ‘endometriosis’ was paired with the terms ‘transcriptomics’, ‘transcriptome’, ‘gene expression’, ‘RNA-seq’, ‘sequencing’ and ‘array’, by using the Boolean operator ‘AND’ to connect them. Articles written in English were screened and interrogated for data extraction.PARTICIPANTS/MATERIALS, SETTING, METHODSA meta-analysis was performed on the selected studies to extract the differentially expressed genes described at the mid-secretory phase in women with endometriosis versus women without endometriosis in natural cycles, using the robust rank aggregation method. In total, transcriptome data of 125 women (78 patients and 47 controls) were meta-analysed, with a special focus on endometrial receptivity-specific genes based on commercial endometrial receptivity tests.MAIN RESULTS AND THE ROLE OF CHANCEIn total, 8 studies were eligible for the quantitative meta-analysis, gathering transcriptome data from the mid-secretory phase endometria of 125 women. A total of 7779 differentially expressed transcripts between the study groups were retrieved (3496 up-regulated and 4283 down-regulated) and were meta-analysed. After stringent multiple correction, there was no differential expression of any single molecule in the endometrium of women with endometriosis versus controls, while enrichment analysis detected that the pathways of chemotaxis and locomotion are dysregulated in endometriosis. Further analysis of endometrial receptivity-specific genes highlighted dysregulation of C4BPA, MAOA and PAEP and enrichment of immune and defence pathways in women with endometriosis.LIMITATIONS, REASONS FOR CAUTIONMost of the studies included into the meta-analysis were relatively small and had different study designs, which might have contributed to a bias.WIDER IMPLICATIONS OF THE FINDINGSThe current meta-analysis supports the hypothesis that endometrial receptivity is altered in women with endometriosis, although the changes are small. The molecules and pathways identified could serve as future biomarkers and therapeutical targets in detecting and treating endometriosis-associated infertility.STUDY FUNDING/COMPETING INTEREST(S)The authors declare no competing interests. This work was supported by the Spanish Ministry of Education, Culture and Sport [grant FPU15/01193] and the Margarita Salas program for the Requalification of the Spanish University system [grant UJAR01MS]; Spanish Ministry of Economy, Industry and Competitiveness (MINECO) and European Regional Development Fund (FEDER): grants RYC-2016-21199 and ENDORE SAF2017-87526-R; Programa Operativo FEDER Andalucía (B-CTS-500-UGR18; A-CTS-614-UGR20); the Junta de Andalucía [BIO-302; and PAIDI P20_00158]; the University of Jaén [PAIUJA-EI_CTS02_2017]; the University of Granada, Plan Propio de Investigación 2016, Excellence actions: Units of Excellence; Unit of Excellence on Exercise and Health (UCEES), and by the Junta de Andalucía, Consejería de Conocimiento, Investigación y Universidades and European Regional Development Fund (ERDF), ref. SOMM17/6107/UGR; the Estonian Research Council (grant PRG1076); Horizon 2020 innovation (ERIN, grant no. EU952516) of the European Commission and Enterprise Estonia (grant EU48695).TRIAL REGISTRATION NUMBERThe systematic review was registered at PROSPERO (identifier: CRD42020122054).

Mapping the entire functionally active endometrial microbiota.

Does endometrium harbour functionally active microorganisms and whether the microbial composition differs between proliferative and mid-secretory phases? Endometrium harbours functionally alive microorganisms including bacteria, viruses, archaea and fungi whose composition and metabolic functions change along the menstrual cycle. Resident microbes in the endometrium have been detected, where microbial dysfunction has been associated with reproductive health and disease. Nevertheless, the core microorganismal composition in healthy endometrium is not determined and whether the identified bacterial DNA sequences refer to alive/functionally active microbes is not clear. Furthermore, whether there are cyclical changes in the microbial composition remains an open issue. RNA sequencing (RNAseq) data from 14 endometrial paired samples from healthy women, 7 samples from the mid-secretory phase and 7 samples from the consecutive proliferative phase were analysed for the microbial RNA sequences. The raw RNAseq data were converted into FASTQ format using SRA Toolkit. The unmapped reads to human sequences were aligned to the reference database Kraken2 and visualised with Krona software. Menstrual phase taxonomic differences were performed by R package metagenomeSeq. The functional analysis of endometrial microbiota was obtained with HUMANn2 and the comparison between menstrual phases was conducted by one-way ANOVA. Human RNAseq analysis was performed using miARma-Seq and the functional enrichment analysis was carried out using gene set enrichment analysis (GSEA; HumanCyc). The integration of metabolic pathways between host and microbes was investigated. The developed method of active microbiota mapping was validated in independent sample set. With the novel metatranscriptomic approach, we mapped the entire alive microbiota composing of >5300 microorganisms within the endometrium of healthy women. Microbes such as bacteria, fungi, viruses and archaea were identified. The validation of three independent endometrial samples from different ethnicity confirmed the findings. Significant differences in the microbial abundances in the mid-secretory vs. proliferative phases were detected with possible metabolic activity in the host-microbiota crosstalk in receptive phase endometrium, specifically in the prostanoid biosynthesis pathway and L-tryptophan metabolism. The raw RNAseq data used in the current study are available at GEO GSE86491 and at BioProject PRJNA379542. These pioneering results should be confirmed in a bigger sample size. Our study confirms the presence of active microbes, bacteria, fungi, viruses and archaea in the healthy human endometrium with implications in receptive phase endometrial functions, meaning that microbial dysfunction could impair the metabolic pathways important for endometrial receptivity. The results of this study contribute to the better understanding of endometrial microbiota composition in healthy women and its possible role in endometrial functions. In addition, our novel methodological pipeline for analysing alive microbes with transcriptional and metabolic activities could serve to inspire new analysis approaches in reproductive medicine. This work is supported by the Spanish Ministry of Economy, Industry and Competitiveness (MINECO) and European Regional Development Fund (FEDER): grants RYC-2016-21199 and ENDORE SAF2017-87526-R; FEDER/Junta de Andalucía-Consejería de Economía y Conocimiento: MENDO (B-CTS-500-UGR18) and by the University of Granada Plan Propio de Investigación 2016 - Excellence actions: Unit of Excellence on Exercise and Health (UCEES) (SOMM17/6107/UGR). A.S.-L. and N.M.M. are funded by the Spanish Ministry of Science, Innovation and Universities (PRE2018-0854409 and FPU19/01638). S.A. has received honoraria for lectures from Merck. The funder had no role in this study.

Hollow Fiber Membrane Contactors in CO2 Desorption: A Review

This work was funded by the Spanish Ministry of Economy, Industry and Competitiveness (MINECO), Project CTQ2016-76231-C2-(AEI/FEDER, UE) and Project PID2019-108136RB-C31). J.M.V. thanks the Concepcion Arenal postgraduate research grant from the University of Cantabria.

1,3,5-Triazine as core for the preparation of dendrons

The work was funded by: Researchers Supporting Project at King Saud University (RSP-2020/50) (Saudi Arabia); National Research Foundation (NRF) and the University of KwaZulu-Natal (South Africa); the Spanish Ministry of Economy, Industry, and Competitiveness (MINECO) (RTI2018-093831-B-100), CIBER-BBN, and the Generalitat de Catalunya (2017 SGR 1439) (Spain). Rotimi Sheyi thanks to MINTEK for a predoctoral fellowship.

(Invited) Efficient Non-Fullerene Polymer Solar Cells

Polymer solar cell (PSCs) haveattracted much interest in the renewable energy field because of their low-cost manufacturing, light weight, flexibility and large-scale production [1, 2]. Conventional PSCs exhibit poor stability and short operational lifetimes under environment conditions, and thus require complex encapsulation process to reduce degradation under oxygen and moisture [3]. To solve those problems, PSCs with an inverted structure (iPSCs) were developed. In iPSCs, transition metal oxides such molybdenum oxide (MoO3) or vanadium oxide (V2O5) are used as the hole transport layer (HTL). On the other hand, titanium oxide (TiOx) and zinc oxide (ZnO) are used as electron transport layer (ETL) [4, 5]. In recent years, iPSCs with power conversion efficiency (PCE) of 11% has been reported [6]. Although fullerene derivatives (e. g PC71BM and PC61BM), have been widely used as acceptor materials, the interest on non-fullerene acceptors have increased because of their high thermal stability, tunable molecular energy levels, excellent optical absorption properties and low-cost synthesis [7, 8]. In this work, we present the fabrication and the analysis of the performance of iPSCs based on the polymer PBDB-T and the non-fullerene acceptor IT-M. All the devices were fabricated on ITO substrate using TiOx as ETL, while the V2O5/Ag bilayer was used as top cathode. The materials PBDB-T:IT-M were dissolved in a mixture of solvents chlorobenzene and 1,8-diiodooctane (99:0.5 v/v) with the total concentration of 20 mg ml-1. The PBDB-T:IT-M blend solution was spin-cast on top of TiOx at two different velocities to analyze the effect of the active layer thickness (100 and 130nm) on the performance parameters of iPSCs. Moreover, the effects of the annealing temperature (0, 100 and 160ºC) on the performance parameters of PBDB-T:IT-M-based devices are also investigated. Current density–voltage (J–V) characteristics were measured under simulated AM1.5G illumination (100mWcm-2) conditions to calculate the performance parameters [open circuit voltage (VOC), short-circuit current density (JSC), fill factor (FF) and power conversion efficiency (PCE)] of all iPSCs. The devices with an active layer with a thickness of 100nm exhibit higher performance parameter than that of devices with an active layer thickness of 130nm. In both type of devices (active layer thickness of 100 and 130 nm), the performance parameter values decrease as the annealing temperature increases. Devices with an active layer thickness of 100nm and without thermal annealing (0ºC) exhibit the highest performance parameters, VOC= 919 mV, JSC= 16.2 mA cm-2, FF = 67% with an a PCE of about 9.9%. The results demonstrated that iPSCs using non-fullerene acceptor allow to reach efficiencies of about 10% after a manufacturing parameters optimization such as thickness of the active layer and annealing temperature.Moreover, we demonstrated that thermal annealing reduces the performance of these devices. Finally, this work shown the fabrication and characterization of high efficiency PSCs using a non-fullerene acceptor material as a promisingalternative to the fabrication of fullerene-based PSC. Acknowledgements This work was supported by the Spanish Ministry of Economy, Industry and Competitiveness (MEIC) for grant numbers, TEC2015-71915-REDT and TEC2015-71324-R (MINECO/FEDER), by the ICREA for the ICREA Academia Award, by the Catalan authority for project AGAUR 2017 SGR 1527. References S. Balderrama, F. Avila-Herrera, J. G. Sanchez, J. Pallares, O. Vigil-Galan, L. F. Marsal, M. Estrada, IEEE J. Photovoltaics, 6, 2, 491–497, 2016.D. Nielsen, C. Cruickshank, S. Foged, J. Thorsen, F. C. Krebs, Sol. Energy Mater. Sol. Cells, 94, 10, 1553–1571, 2010.S. Balderrama, M. Estrada, P. L. Han, P. Granero, J. Pallarés, J. Ferré-Borrull, L. F. Marsal, Sol. Energy Mater. Sol. Cells,125, 155–163, 2014.G. Sánchez, V. S. Balderrama, M. Estrada, E. Osorio, J. Ferré-Borrull, L. F. Marsal, J. Pallarès, Sol. Energy,150, 147–155, 2017.G. Sánchez, V. S. Balderrama, S. I. Garduño, E. Osorio, A. Viterisi, M. Estrada, J. Ferré-Borrull, J. Pallarès, L. F. Marsal, RSC Adv., 8, 24, 13094–13102, 2018.S. Balderrama, J. G. Sánchez, G. Lastra, W. Cambarau, S. Arias, J. Pallarès, E. Palomares, M. Estrada, L. F. Marsal, J. Mater. Chem. A, 6, 45, 2018.Cheng, G. Li, X. Zhan, and Y. Yang, Nat. Photonics, 12, 3, 131–142, 2018.Yan, S. Barlow, Z. Wang, H. Yan, A. K.-Y. Jen, S. R. Marder, and X. Zhan, Nat. Rev. Mater., 3, 3, 18003, 2018. Figure 1

Post-disaster assessment of 2017 catastrophic Xinmo landslide (China) by spaceborne SAR interferometry

This work was funded by Sichuan Science and Technology Plan Key Research and Development Program (Grant No. 2018SZ0339), National Natural Science Foundation of China (Grant No. 41801391), State Key Laboratory of Geodesy and Earth’s Dynamics Open fund (Grant No. SKLGED2018-5-3-E), The Funds for Creative Research Groups of China (Grant No. 41521002) and partially supported by the Spanish Ministry of Economy, Industry and Competitiveness (MINECO), the State Agency of Research (AEI), and European Funds for Regional Development (FEDER), under project TIN2014-55413-C2-2-P and by the Spanish Ministry of Education, Culture and Sport, under project PRX17/00439. This work was also supported by the National Environment Research Council (NERC) through the Centre for the Observation and Modeling of Earthquakes, Volcanoes and Tectonics (COMET, ref.: come30001), the LiCS project (ref. NE/K010794/1), the ESA-MOST DRAGON-4 project (ref. 32244), and the Hunan Province Key Laboratory of Coal Resources Clean-Utilization and Mine Environment Protection, Hunan University of Science and Technology (Ref. E21608).

Unraveling the hidden universe of small proteins in bacterial genomes

Identification of small open reading frames (smORFs) encoding small proteins (≤ 100 amino acids; SEPs) is a challenge in the fields of genome annotation and protein discovery. Here, by combining a novel bioinformatics tool (RanSEPs) with “‐omics” approaches, we were able to describe 109 bacterial small ORFomes. Predictions were first validated by performing an exhaustive search of SEPs present in Mycoplasma pneumoniae proteome via mass spectrometry, which illustrated the limitations of shotgun approaches. Then, RanSEPs predictions were validated and compared with other tools using proteomic datasets from different bacterial species and SEPs from the literature. We found that up to 16 ± 9% of proteins in an organism could be classified as SEPs. Integration of RanSEPs predictions with transcriptomics data showed that some annotated non‐coding RNAs could in fact encode for SEPs. A functional study of SEPs highlighted an enrichment in the membrane, translation, metabolism, and nucleotide‐binding categories. Additionally, 9.7% of the SEPs included a N‐terminus predicted signal peptide. We envision RanSEPs as a tool to unmask the hidden universe of small bacterial proteins.

Endometrial receptivity revisited: endometrial transcriptome adjusted for tissue cellular heterogeneity.

Does cellular composition of the endometrial biopsy affect the gene expression profile of endometrial whole-tissue samples? The differences in epithelial and stromal cell proportions in endometrial biopsies modify the whole-tissue gene expression profiles and affect the results of differential expression analyses. Each cell type has its unique gene expression profile. The proportions of epithelial and stromal cells vary in endometrial tissue during the menstrual cycle, along with individual and technical variation due to the method and tools used to obtain the tissue biopsy. Using cell-population specific transcriptome data and computational deconvolution approach, we estimated the epithelial and stromal cell proportions in whole-tissue biopsies taken during early secretory and mid-secretory phases. The estimated cellular proportions were used as covariates in whole-tissue differential gene expression analysis. Endometrial transcriptomes before and after deconvolution were compared and analysed in biological context. Paired early- and mid-secretory endometrial biopsies were obtained from 35 healthy, regularly cycling, fertile volunteers, aged 23-36 years, and analysed by RNA sequencing. Differential gene expression analysis was performed using two approaches. In one of them, computational deconvolution was applied as an intermediate step to adjust for the proportions of epithelial and stromal cells in the endometrial biopsy. The results were then compared to conventional differential expression analysis. Ten paired endometrial samples were analysed with qPCR to validate the results. The estimated average proportions of stromal and epithelial cells in early secretory phase were 65% and 35%, and during mid-secretory phase, 46% and 54%, respectively, correlating well with the results of histological evaluation (r = 0.88, P = 1.1 × 10-6). Endometrial tissue transcriptomic analysis showed that approximately 26% of transcripts (n = 946) differentially expressed in receptive endometrium in cell-type unadjusted analysis also remain differentially expressed after adjustment for biopsy cellular composition. However, the other 74% (n = 2645) become statistically non-significant after adjustment for biopsy cellular composition, underlining the impact of tissue heterogeneity on differential expression analysis. The results suggest new mechanisms involved in endometrial maturation, involving genes like LINC01320, SLC8A1 and GGTA1P, described for the first time in context of endometrial receptivity. The RNA-seq data presented in this study is deposited in the Gene Expression Omnibus database with accession number GSE98386. Only dominant endometrial cell types were considered in gene expression profile deconvolution; however, other less frequent endometrial cell types also contribute to the whole-tissue gene expression profile. The better understanding of molecular processes during transition from pre-receptive to receptive endometrium serves to improve the effectiveness and personalization of assisted reproduction protocols. Biopsy cellular composition should be taken into account in future endometrial 'omics' studies, where tissue heterogeneity could potentially influence the results. This study was funded by: Estonian Ministry of Education and Research (grant IUT34-16); Enterprise Estonia (EU48695); the EU-FP7 Eurostars program (NOTED, EU41564); the EU-FP7 Marie Curie Industry-Academia Partnerships and Pathways (SARM, EU324509); Horizon 2020 innovation program (WIDENLIFE, EU692065); MSCA-RISE-2015 project MOMENDO (No 691058) and the Miguel Servet Program Type I of Instituto de Salud Carlos III (CP13/00038); Spanish Ministry of Economy, Industry and Competitiveness (MINECO) and European Regional Development Fund (FEDER): grants RYC-2016-21199 and ENDORE SAF2017-87526. Authors confirm no competing interests.

Commentary: Uterine Microbiota: Residents, Tourists, or Invaders?

SA is funded by grants RYC-2016-21199 and ENDORE SAF2017-87526 from the Spanish Ministry of Economy, Industry and Competitiveness (MINECO), and European Regional Development Fund (FEDER).

Arabic Cooperative Answer Generation via Wikipedia Article Infoboxes

The work of the third author was partially funded by the Spanish Ministry of Economy, Industry and Competitiveness (MINECO) under the SomEMBED research project (TIN2015-71147-C2-1-P) and by the Generalitat Valenciana under the grant ALMAMATER (PrometeoII/2014/030).