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1.	Carraminana, Albert, et al. (author) Rationale and Study Design for an Individualized Perioperative Open Lung Ventilatory Strategy in Patients on One-Lung Ventilation (iPROVE-OLV) 2019 In: Journal of Cardiothoracic and Vascular Anesthesia. - : W B SAUNDERS CO-ELSEVIER INC. - 1053-0770 .- 1532-8422. ; 33:9, s. 2492-2502 Journal article (peer-reviewed)abstract Objective: The aim of this clinical trial is to examine whether it is possible to reduce postoperative complications using an individualized perioperative ventilatory strategy versus using a standard lung-protective ventilation strategy in patients scheduled for thoracic surgery requiring one-lung ventilation. Design: International, multicenter, prospective, randomized controlled clinical trial. Setting: A network of university hospitals. Participants: The study comprises 1,380 patients scheduled for thoracic surgery. Interventions: The individualized group will receive intraoperative recruitment maneuvers followed by individualized positive end-expiratory pressure (open lung approach) during the intraoperative period plus postoperative ventilatory support with high-flow nasal cannula, whereas the control group will be managed with conventional lung-protective ventilation. Measurements and Main Results: Individual and total number of postoperative complications, including atelectasis, pneumothorax, pleural effusion, pneumonia, acute lung injury; unplanned readmission and reintubation; length of stay and death in the critical care unit and in the hospital will be analyzed for both groups. The authors hypothesize that the intraoperative application of an open lung approach followed by an individual indication of high-flow nasal cannula in the postoperative period will reduce pulmonary complications and length of hospital stay in high-risk surgical patients. (C) 2019 Published by Elsevier Inc.
2.	Cruz, Raquel, et al. (author) Novel genes and sex differences in COVID-19 severity 2022 In: Human Molecular Genetics. - : Oxford University Press. - 0964-6906 .- 1460-2083. ; 31:22, s. 3789-3806 Journal article (peer-reviewed)abstract Here, we describe the results of a genome-wide study conducted in 11 939 coronavirus disease 2019 (COVID-19) positive cases with an extensive clinical information that were recruited from 34 hospitals across Spain (SCOURGE consortium). In sex-disaggregated genome-wide association studies for COVID-19 hospitalization, genome-wide significance (P < 5 × 10−8) was crossed for variants in 3p21.31 and 21q22.11 loci only among males (P = 1.3 × 10−22 and P = 8.1 × 10−12, respectively), and for variants in 9q21.32 near TLE1 only among females (P = 4.4 × 10−8). In a second phase, results were combined with an independent Spanish cohort (1598 COVID-19 cases and 1068 population controls), revealing in the overall analysis two novel risk loci in 9p13.3 and 19q13.12, with fine-mapping prioritized variants functionally associated with AQP3 (P = 2.7 × 10−8) and ARHGAP33 (P = 1.3 × 10−8), respectively. The meta-analysis of both phases with four European studies stratified by sex from the Host Genetics Initiative (HGI) confirmed the association of the 3p21.31 and 21q22.11 loci predominantly in males and replicated a recently reported variant in 11p13 (ELF5, P = 4.1 × 10−8). Six of the COVID-19 HGI discovered loci were replicated and an HGI-based genetic risk score predicted the severity strata in SCOURGE. We also found more SNP-heritability and larger heritability differences by age (<60 or ≥60 years) among males than among females. Parallel genome-wide screening of inbreeding depression in SCOURGE also showed an effect of homozygosity in COVID-19 hospitalization and severity and this effect was stronger among older males. In summary, new candidate genes for COVID-19 severity and evidence supporting genetic disparities among sexes are provided.
3.	Klionsky, Daniel J, et al. (author) Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). 2016 In: Autophagy. - : Informa UK Limited. - 1554-8635 .- 1554-8627. ; 12:1, s. 1-222 Journal article (peer-reviewed)
4.	Ferrando, Carlos, et al. (author) Effects of oxygen on post-surgical infections during an individualised perioperative open-lung ventilatory strategy : a randomised controlled trial 2020 In: British Journal of Anaesthesia. - : ELSEVIER SCI LTD. - 0007-0912 .- 1471-6771. ; 124:1, s. 110-120 Journal article (peer-reviewed)abstract Background: We aimed to examine whether using a high fraction of inspired oxygen (FIO2) in the context of an individualised intra- and postoperative open-lung ventilation approach could decrease surgical site infection (SSI) in patients scheduled for abdominal surgery. Methods: We performed a multicentre, randomised controlled clinical trial in a network of 21 university hospitals from June 6, 2017 to July 19, 2018. Patients undergoing abdominal surgery were randomly assigned to receive a high (0.80) or conventional (0.3) FIO2 during the intraoperative period and during the first 3 postoperative hours. All patients were mechanically ventilated with an open-lung strategy, which included recruitment manoeuvres and individualised positive end-expiratory pressure for the best respiratory-system compliance, and individualised continuous postoperative airway pressure for adequate peripheral oxyhaemoglobin saturation. The primary outcome was the prevalence of SSI within the first 7 postoperative days. The secondary outcomes were composites of systemic complications, length of intensive care and hospital stay, and 6-month mortality. Results: We enrolled 740 subjects: 371 in the high FIO2 group and 369 in the low FIO2 group. Data from 717 subjects were available for final analysis. The rate of SSI during the first postoperative week did not differ between high (8.9%) and low (9.4%) FIO2 groups (relative risk [RR]: 0.94; 95% confidence interval [CI]: 0.59-1.50; P=0.90]). Secondary outcomes, such as atelectasis (7.7% vs 9.8%; RR: 0.77; 95% CI: 0.48-1.25; P=0.38) and myocardial ischaemia (0.6% [n=2] vs 0% [n=0]; P=0.47) did not differ between groups. Conclusions: An oxygenation strategy using high FIO2 compared with conventional FIO2 did not reduce postoperative SSIs in abdominal surgery. No differences in secondary outcomes or adverse events were found.
5.	2019 Journal article (peer-reviewed)
6.	Olmeda, David, et al. (author) Whole-body imaging of lymphovascular niches identifies pre-metastatic roles of midkine 2017 In: Nature. - : NATURE PUBLISHING GROUP. - 0028-0836 .- 1476-4687. ; 546:7660, s. 676-680 Journal article (peer-reviewed)abstract Cutaneous melanoma is a type of cancer with an inherent potential for lymph node colonization, which is generally preceded by neolymphangiogenesis(1-3). However, sentinel lymph node removal does not necessarily extend the overall survival of patients with melanoma(4,5). Moreover, lymphatic vessels collapse and become dysfunctional as melanomas progress(6,7). Therefore, it is unclear whether (and how) lymphangiogenesis contributes to visceral metastasis. Soluble and vesicle-associated proteins secreted by tumours and/or their stroma have been proposed to condition pre-metastatic sites in patients with melanoma(8-14). Still, the identities and prognostic value of lymphangiogenic mediators remain unclear(2,14). Moreover, our understanding of lymphangiogenesis (in melanomas and other tumour types) is limited by the paucity of mouse models for live imaging of distal pre-metastatic niches(15). Injectable lymphatic tracers have been developed(7), but their limited diffusion precludes whole-body imaging at visceral sites(16). Vascular endothelial growth factor receptor 3 (VEGFR3) is an attractive 'lymphoreporter' 17 because its expression is strongly downregulated in normal adult lymphatic endothelial cells, but is activated in pathological situations such as inflammation and cancer(17,18). Here, we exploit this inducibility of VEGFR3 to engineer mouse melanoma models for whole-body imaging of metastasis generated by human cells, clinical biopsies or endogenously deregulated oncogenic pathways. This strategy revealed early induction of distal pre-metastatic niches uncoupled from lymphangiogenesis at primary lesions. Analyses of the melanoma secretome and validation in clinical specimens showed that the heparin-binding factor midkine is a systemic inducer of neo-lymphangiogenesis that defines patient prognosis. This role of midkine was linked to a paracrine activation of the mTOR pathway in lymphatic endothelial cells. These data support the use of VEGFR3 reporter mice as a 'MetAlert' discovery platform for drivers and inhibitors of metastasis.
7.	Alvarez, Alberto, et al. (author) Tamoxifen-independent recombination of reporter genes limits lineage tracing and mosaic analysis using CreER(T2) lines 2020 In: Transgenic research. - : Springer Nature. - 0962-8819 .- 1573-9368. ; 29:1, s. 53-68 Journal article (peer-reviewed)abstract The CreER(T2)/loxP system is widely used to induce conditional gene deletion in mice. One of the main advantages of the system is that Cre-mediated recombination can be controlled in time through Tamoxifen administration. This has allowed researchers to study the function of embryonic lethal genes at later developmental timepoints. In addition, CreER(T2) mouse lines are commonly used in combination with reporter genes for lineage tracing and mosaic analysis. In order for these experiments to be reliable, it is crucial that the cell labeling approach only marks the desired cell population and their progeny, as unfaithful expression of reporter genes in other cell types or even unintended labeling of the correct cell population at an undesired time point could lead to wrong conclusions. Here we report that all CreER(T2) mouse lines that we have studied exhibit a certain degree of Tamoxifen-independent, basal, Cre activity. Using Ai14 and Ai3, two commonly used fluorescent reporter genes, we show that those basal Cre activity levels are sufficient to label a significant amount of cells in a variety of tissues during embryogenesis, postnatal development and adulthood. This unintended labelling of cells imposes a serious problem for lineage tracing and mosaic analysis experiments. Importantly, however, we find that reporter constructs differ greatly in their susceptibility to basal CreER(T2) activity. While Ai14 and Ai3 easily recombine under basal CreER(T2) activity levels, mTmG and R26R-EYFP rarely become activated under these conditions and are therefore better suited for cell tracking experiments.
8.	Cabeza, Luisa F., et al. (author) CO2 mitigation accounting for Thermal Energy Storage (TES) case studies 2015 In: Applied Energy. - : Pergamon Press. - 0306-2619 .- 1872-9118. ; 155, s. 365-377 Journal article (peer-reviewed)abstract According to the IPCC, societies can respond to climate changes by adapting to its impacts and by mitigation, that is, by reducing GHG emissions. No single technology can provide all of the mitigation potential in any sector, but many technologies have been acknowledged in being able to contribute to such potential. Among the technologies that can contribute in such potential, Thermal Energy Storage (TES) is not included explicitly, but implicitly as part of technologies such as energy supply, buildings, and industry. To enable a more detailed assessment of the CO2 mitigation potential of TES across many sectors, the group Annex 25 "Surplus heat management using advanced TES for CO2 mitigation" of the Energy Conservation through Energy Storage Implementing Agreement (ECES IA) of the International Energy Agency (AEI) present in this article the CO2 mitigation potential of different case studies with integrated TES. This potential is shown using operational and embodied CO2 parameters. Results are difficult to compare since TES is always designed in relation to its application, and each technology impacts the energy system as a whole to different extents. The applications analyzed for operational CO2 are refrigeration, solar power plants, mobile heat storage in industrial waste heat recovery, passive systems in buildings, ATES for a supermarket, greenhouse applications, and dishwasher with zeolite in Germany. The paper shows that the reason for mitigation is different in each application, from energy savings to larger solar share or lowering energy consumption from appliances. The mitigation potential dues to integrated TES is quantified in kg/MW h energy produced or heat delivered. Embodied CO2 in two TES case studies is presented, buildings and solar power plants.
9.	Concepcion Gil-Rodriguez, Maria, et al. (author) De Novo Heterozygous Mutations in SMC3 Cause a Range of Cornelia de Lange Syndrome-Overlapping Phenotypes 2015 In: Human Mutation. - : Wiley: 12 months. - 1059-7794 .- 1098-1004. ; 36:4, s. 454-462 Journal article (peer-reviewed)abstract Cornelia de Lange syndrome (CdLS) is characterized by facial dysmorphism, growth failure, intellectual disability, limb malformations, and multiple organ involvement. Mutations in five genes, encoding subunits of the cohesin complex (SMC1A, SMC3, RAD21) and its regulators (NIPBL, HDAC8), account for at least 70% of patients with CdLS or CdLS-like phenotypes. To date, only the clinical features from a single CdLS patient with SMC3 mutation has been published. Here, we report the efforts of an international research and clinical collaboration to provide clinical comparison of 16 patients with CdLS-like features caused by mutations in SMC3. Modeling of the mutation effects on protein structure suggests a dominant-negative effect on the multimeric cohesin complex. When compared with typical CdLS, many SMC3-associated phenotypes are also characterized by postnatal microcephaly but with a less distinctive craniofacial appearance, a milder prenatal growth retardation that worsens in childhood, few congenital heart defects, and an absence of limb deficiencies. While most mutations are unique, two unrelated affected individuals shared the same mutation but presented with different phenotypes. This work confirms that de novo SMC3 mutations account for approximate to 1%-2% of CdLS-like phenotypes.
10.	Cotte Poveda, Alexander, 1972-, et al. (author) Qualitative comparative analysis (QCA) : An application for the industry 2013 In: Quality and quantity. - : Springer Science and Business Media LLC. - 0033-5177 .- 1573-7845. ; 47:3, s. 1315-1321 Journal article (peer-reviewed)abstract This article examines the management in Colombian industrial sectors using qualitative comparative analysis (QCA). This method conceptualizes cases as combinations of attributes and use Boolean algebra to derive simplified expressions of combinations that lead to a specific outcome. In this analysis, we show the value of this method for studying the management in the industrial from different approaches.
11.	Cotte Poveda, Alexander, et al. (author) Trends in economic growth, poverty and energy in Colombia : long-run and short-run effects 2011 In: Energy Systems, Springer Verlag. - : Springer Science and Business Media LLC. - 1868-3967 .- 1868-3975. ; 2:3-4, s. 281-298 Journal article (peer-reviewed)abstract This research analyses the long run and short run relationships among economic growth, poverty and energy using the Colombian case. In this study, we use the time-series methodologies. The results regarding the relationship among economic growth, poverty and energy show that increases in gross domestic product and energy supply per capita should lead a decrease of poverty, which should demonstrate that access to modern and adequate energy services help to decrease poverty and to increase economic growth. Moreover, the improvements in energy efficiency have contributed to increase economic growth from an approach of sustainable development. These results are important for the adequate design, formulation and application of policies and strategies that encourage a better energy use to improve economic growth and decrease poverty, especially in developing countries.
12.	Dixon-Suen, Suzanne C, et al. (author) Physical activity, sedentary time and breast cancer risk : a Mendelian randomisation study 2022 In: British Journal of Sports Medicine. - : BMJ Publishing Group Ltd. - 0306-3674 .- 1473-0480. ; 56:20, s. 1157-1170 Journal article (peer-reviewed)abstract OBJECTIVES: Physical inactivity and sedentary behaviour are associated with higher breast cancer risk in observational studies, but ascribing causality is difficult. Mendelian randomisation (MR) assesses causality by simulating randomised trial groups using genotype. We assessed whether lifelong physical activity or sedentary time, assessed using genotype, may be causally associated with breast cancer risk overall, pre/post-menopause, and by case-groups defined by tumour characteristics.METHODS: We performed two-sample inverse-variance-weighted MR using individual-level Breast Cancer Association Consortium case-control data from 130 957 European-ancestry women (69 838 invasive cases), and published UK Biobank data (n=91 105-377 234). Genetic instruments were single nucleotide polymorphisms (SNPs) associated in UK Biobank with wrist-worn accelerometer-measured overall physical activity (nsnps=5) or sedentary time (nsnps=6), or accelerometer-measured (nsnps=1) or self-reported (nsnps=5) vigorous physical activity.RESULTS: Greater genetically-predicted overall activity was associated with lower breast cancer overall risk (OR=0.59; 95% confidence interval (CI) 0.42 to 0.83 per-standard deviation (SD;~8 milligravities acceleration)) and for most case-groups. Genetically-predicted vigorous activity was associated with lower risk of pre/perimenopausal breast cancer (OR=0.62; 95% CI 0.45 to 0.87,≥3 vs. 0 self-reported days/week), with consistent estimates for most case-groups. Greater genetically-predicted sedentary time was associated with higher hormone-receptor-negative tumour risk (OR=1.77; 95% CI 1.07 to 2.92 per-SD (~7% time spent sedentary)), with elevated estimates for most case-groups. Results were robust to sensitivity analyses examining pleiotropy (including weighted-median-MR, MR-Egger).CONCLUSION: Our study provides strong evidence that greater overall physical activity, greater vigorous activity, and lower sedentary time are likely to reduce breast cancer risk. More widespread adoption of active lifestyles may reduce the burden from the most common cancer in women.
13.	Fleury, Vanessa, et al. (author) Embarrassment and Shame in People With Parkinson's Disease : A New Tool for Self-Assessment 2020 In: Frontiers in Neurology. - : Frontiers Media S.A.. - 1664-2295. ; 11 Journal article (peer-reviewed)abstract Shame and embarrassment related to Parkinson's disease (PD) are rarely addressed in clinical practice nor studied in neuroscience research, partly because no specific tool exists to detect them in PD.Objective:To develop a self-applied assessment tool of shame and embarrassment specifically related to PD or its treatment, to promptly identify the presence and severity of these two emotions in PD.Methods: Identification and selection of relevant items were obtained from the collection of PD patients' opinions during support groups and interviews. Several further items were added following a literature review. Subsequently, a two-phase pilot study was performed for identification of ambiguous items and omissions, and to obtain preliminary data on acceptability, reliability, validity and relevance of the new scale (SPARK).Results: A total of 105 PD patients were enrolled in the study. Embarrassment was reported in 85% of patients, while shame was present in 26%. Fifteen percent of patients did not describe any shame or embarrassment. On average, the intensity of these two emotions was low with a marked floor effect in SPARK items and subscales. However, SPARK total score inter-individual variability was important (range 1-84 out of 99). Acceptability and quality of data were satisfactory with no floor or ceiling effects (2.9% each) or missing data. Internal consistency (Cronbach's alpha) was 0.94 for total score and 0.73-0.87 for subscales. The scale correlated >= 0.60 with instruments measuring related constructs. Content validity was satisfactory. SPARK total score strongly correlated with impaired health-related quality of life (r(S)= 0.81), the propensity to feel embarrassed or ashamed (r(S)= 0.68 and 0.66, respectively), and anxiety (r(S)= 0.72) and depression (r(S)= 0.63) levels. Moderate to high correlations were observed between SPARK total score and apathy (r(S)= 0.46) and a more pronounced personality trait directed toward harm avoidance (r(S)= 0.46). No significant differences in SPARK scores were found by sex, education level, PD duration, Hoehn and Yahr stages or PD phenotype.Conclusion: Preliminary analysis of psychometric properties suggests that SPARK could be an acceptable and reliable instrument for assessing shame and embarrassment in PD. SPARK could help healthcare professionals to identify and characterize PD-induced shame and embarrassment.
14.	Frye, Maike, et al. (author) Matrix stiffness controls lymphatic vessel formation through regulation of a GATA2-dependent transcriptional program 2018 In: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 9:1 Journal article (peer-reviewed)abstract Tissue and vessel wall stiffening alters endothelial cell properties and contributes to vascular dysfunction. However, whether extracellular matrix (ECM) stiffness impacts vascular development is not known. Here we show that matrix stiffness controls lymphatic vascular morphogenesis. Atomic force microscopy measurements in mouse embryos reveal that venous lymphatic endothelial cell (LEC) progenitors experience a decrease in substrate stiffness upon migration out of the cardinal vein, which induces a GATA2-dependent transcriptional program required to form the first lymphatic vessels. Transcriptome analysis shows that LECs grown on a soft matrix exhibit increased GATA2 expression and a GATA2-dependent upregulation of genes involved in cell migration and lymphangiogenesis, including VEGFR3. Analyses of mouse models demonstrate a cell-autonomous function of GATA2 in regulating LEC responsiveness to VEGF-C and in controlling LEC migration and sprouting in vivo. Our study thus uncovers a mechanism by which ECM stiffness dictates the migratory behavior of LECs during early lymphatic development.
15.	Fullman, Nancy, et al. (author) Measuring performance on the Healthcare Access and Quality Index for 195 countries and territories and selected subnational locations: A systematic analysis from the Global Burden of Disease Study 2016 2018 In: The Lancet. - : Lancet Publishing Group. - 1474-547X .- 0140-6736. ; 391:10136, s. 2236-2271 Journal article (peer-reviewed)
16.	Gallardo Bolanos, Juan M., et al. (author) Phosphorylated AKT preserves stallion sperm viability and motility by inhibiting caspases 3 and 7 2014 In: Reproduction. - : Bioscientifica. - 1470-1626 .- 1476-3990. ; 148:2, s. 221-235 Journal article (peer-reviewed)abstract AKT, also referred to as protein kinase B (PKB or RAC), plays a critical role in controlling cell survival and apoptosis. To gain insights into the mechanisms regulating sperm survival after ejaculation, the role of AKT was investigated in stallion spermatozoa using a specific inhibitor and a phosphoflow approach. Stallion spermatozoa were washed and incubated in Biggers-Whitten-Whittingham medium, supplemented with 1% polyvinyl alcohol (PVA) in the presence of 0 (vehicle), 10, 20 or 30 mu M SH5, an AKT inhibitor. SH5 treatment reduced the percentage of sperm displaying AKT phosphorylation, with inhibition reaching a maximum after 1 h of incubation. This decrease in phosphorylation was attributable to either dephosphorylation or suppression of the active phosphorylation pathway. Stallion spermatozoa spontaneously dephosphorylated during in vitro incubation, resulting in a lack of a difference in AKT phosphorylation between the SH5-treated sperm and the control after 4 h of incubation. AKT inhibition decreased the proportion of motile spermatozoa (total and progressive) and the sperm velocity. Similarly, AKT inhibition reduced membrane integrity, leading to increased membrane permeability and reduced the mitochondrial membrane potential concomitantly with activation of caspases 3 and 7. However, the percentage of spermatozoa exhibiting oxidative stress, the production of mitochondrial superoxide radicals, DNA oxidation and DNA fragmentation were not affected by AKT inhibition. It is concluded that AKT maintains the membrane integrity of ejaculated stallion spermatozoa, presumably by inhibiting caspases 3 and 7, which prevents the progression of spermatozoa to an incomplete form of apoptosis.
17.	Gardenier, Jason C., et al. (author) Diphtheria toxin-mediated ablation of lymphatic endothelial cells results in progressive lymphedema 2016 In: JCI INSIGHT. - : American Society for Clinical Investigation. - 2379-3708. ; 1:15 Journal article (peer-reviewed)abstract Development of novel treatments for lymphedema has been limited by the fact that the pathophysiology of this disease is poorly understood. It remains unknown, for example, why limb swelling resulting from surgical injury resolves initially, but recurs in some cases months or years later. Finding answers for these basic questions has been hampered by the lack of adequate animal models. In the current study, we used Cre-lox mice that expressed the human diphtheria toxin receptor (DTR) driven by a lymphatic-specific promoter in order to noninvasively ablate the lymphatic system of the hind limb. Animals treated in this manner developed lymphedema that was indistinguishable from clinical lymphedema temporally, radiographically, and histologically. Using this model and clinical biopsy specimens, we show that the initial resolution of edema after injury is dependent on the formation of collateral capillary lymphatics and that this process is regulated by M2-polarized macrophages. In addition, we show that despite these initial improvements in lymphatic function, persistent accumulation of CD4(+) cells inhibits lymphangiogenesis and promotes sclerosis of collecting lymphatics, resulting in late onset of edema and fibrosis. Our findings therefore provide strong evidence that inflammatory changes after lymphatic injury play a key role in the pathophysiology of lymphedema.
18.	Gómez-Acosta, Martha Inés, et al. (author) Caracterización de la Logística y las Redes de Valor en empresas cubanas en Perfeccionamiento Empresarial [Characterization of the Logistics and the Value Nets in Cuban Companies in Managerial Improvement] 2013 In: Ingeniería Industrial. - : Facultad de Ingeniería Industrial, Instituto Superior Politécnico José Antonio Echeverría. - 0258-5960 .- 1815-5936. ; 34:2, s. 212-226 Journal article (peer-reviewed)abstract Characterizing the logistic and supply chain level is a fundamental support for strategic development, not only for enterprises but also for the professionals training in these topics. The objective of the present article is to demonstrate that the use of reference models for logistic and supply chain, developed by the authors, is useful to characterize the level of those themes in the companies. The main methods that were used are: surveys, statistics, analysis and summary of data. As a result, a complete diagnosis is obtained with the different levels of logistic and supply chain concept application in a statistically significant sample of firms. The fundamental conclusion is that these models are validated and useful to characterize the aspects of logistic and supply chain in the Cuban enterprises, and constitute a guide to draw up development strategies.
19.	Gramolelli, Silvia, et al. (author) PROX1 is a transcriptional regulator of MMP14 2018 In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8 Journal article (peer-reviewed)abstract The transcription factor PROX1 is essential for development and cell fate specification. Its function in cancer is context-dependent since PROX1 has been shown to play both oncogenic and tumour suppressive roles. Here, we show that PROX1 suppresses the transcription of MMP14, a metalloprotease involved in angiogenesis and cancer invasion, by binding and suppressing the activity of MMP14 promoter. Prox1 deletion in murine dermal lymphatic vessels in vivo and in human LECs increased MMP14 expression. In a hepatocellular carcinoma cell line expressing high endogenous levels of PROX1, its silencing increased both MMP14 expression and MMP14-dependent invasion in 3D. Moreover, PROX1 ectopic expression reduced the MMP14-dependent 3D invasiveness of breast cancer cells and angiogenic sprouting of blood endothelial cells in conjunction with MMP14 suppression. Our study uncovers a new transcriptional regulatory mechanism of cancer cell invasion and endothelial cell specification.
20.	Griswold, Max G., et al. (author) Alcohol use and burden for 195 countries and territories, 1990-2016 : a systematic analysis for the Global Burden of Disease Study 2016 2018 In: The Lancet. - : Elsevier. - 0140-6736 .- 1474-547X. ; 392:10152, s. 1015-1035 Journal article (peer-reviewed)abstract Background: Alcohol use is a leading risk factor for death and disability, but its overall association with health remains complex given the possible protective effects of moderate alcohol consumption on some conditions. With our comprehensive approach to health accounting within the Global Burden of Diseases, Injuries, and Risk Factors Study 2016, we generated improved estimates of alcohol use and alcohol-attributable deaths and disability-adjusted life-years (DALYs) for 195 locations from 1990 to 2016, for both sexes and for 5-year age groups between the ages of 15 years and 95 years and older.Methods: Using 694 data sources of individual and population-level alcohol consumption, along with 592 prospective and retrospective studies on the risk of alcohol use, we produced estimates of the prevalence of current drinking, abstention, the distribution of alcohol consumption among current drinkers in standard drinks daily (defined as 10 g of pure ethyl alcohol), and alcohol-attributable deaths and DALYs. We made several methodological improvements compared with previous estimates: first, we adjusted alcohol sales estimates to take into account tourist and unrecorded consumption; second, we did a new meta-analysis of relative risks for 23 health outcomes associated with alcohol use; and third, we developed a new method to quantify the level of alcohol consumption that minimises the overall risk to individual health.Findings: Globally, alcohol use was the seventh leading risk factor for both deaths and DALYs in 2016, accounting for 2.2% (95% uncertainty interval [UI] 1.5-3.0) of age-standardised female deaths and 6.8% (5.8-8.0) of age-standardised male deaths. Among the population aged 15-49 years, alcohol use was the leading risk factor globally in 2016, with 3.8% (95% UI 3.2-4-3) of female deaths and 12.2% (10.8-13-6) of male deaths attributable to alcohol use. For the population aged 15-49 years, female attributable DALYs were 2.3% (95% UI 2.0-2.6) and male attributable DALYs were 8.9% (7.8-9.9). The three leading causes of attributable deaths in this age group were tuberculosis (1.4% [95% UI 1. 0-1. 7] of total deaths), road injuries (1.2% [0.7-1.9]), and self-harm (1.1% [0.6-1.5]). For populations aged 50 years and older, cancers accounted for a large proportion of total alcohol-attributable deaths in 2016, constituting 27.1% (95% UI 21.2-33.3) of total alcohol-attributable female deaths and 18.9% (15.3-22.6) of male deaths. The level of alcohol consumption that minimised harm across health outcomes was zero (95% UI 0.0-0.8) standard drinks per week.Interpretation: Alcohol use is a leading risk factor for global disease burden and causes substantial health loss. We found that the risk of all-cause mortality, and of cancers specifically, rises with increasing levels of consumption, and the level of consumption that minimises health loss is zero. These results suggest that alcohol control policies might need to be revised worldwide, refocusing on efforts to lower overall population-level consumption.
21.	Gutiérrez-Cueli, Inés, et al. (author) The Housing Struggle of Working-Class Migrant Women in Spain Through a Double Horizon of Political Temporality 2023 In: Housing, Theory and Society. - : Routledge. - 1403-6096 .- 1651-2278. Journal article (peer-reviewed)abstract Impoverished and working-class migrant women have been the hardest hit and most exploited people during both the real estate-financial accumulation cycle and the aftermath of the 2008 crisis in Spain. Since 2009, these women have also been the key actors in outstanding civil disobedience to the neoliberal financial rule through their engagement in housing activism. How has this happened, and with what effects? Our research responds to these questions by focusing on the collective and contextualized strategies of extended struggles for social reproduction. This analytical framework integrates intersectional social structures, spatio-temporal dimensions of social reproduction, and the historical context of real-estate financialisation. Additionally, we argue that the notion of a “double horizon of political temporality” helps explain how the housing struggle evolved and identifies which social and political outcomes were produced. We suggest that this case reveals the mechanisms and impacts of similar grassroots movements challenging the current financialised dynamics of capitalism.
22.	Huang, Jung-Ju, et al. (author) Lymph Node Transplantation Decreases Swelling and Restores Immune Responses in a Transgenic Model of Lymphedema 2016 In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 11:12 Journal article (peer-reviewed)abstract Introduction Secondary lymphedema is a common complication of cancer treatment and recent studies have demonstrated that lymph node transplantation (LNT) can decrease swelling, as well as the incidence of infections. However, although these results are exciting, the mechanisms by which LNT improves these pathologic findings of lymphedema remain unknown. Using a transgenic mouse model of lymphedema, this study sought to analyze the effect of LNT on lymphatic regeneration and T cell-mediated immune responses. Methods We used a mouse model in which the expression of the human diphtheria toxin receptor is driven by the FLT4 promoter to enable the local ablation of the lymphatic system through subdermal hindlimb diphtheria toxin injections. Popliteal lymph node dissection was subsequently performed after a two-week recovery period, followed by either orthotopic LNT or sham surgery after an additional two weeks. Hindlimb swelling, lymphatic vessel regeneration, immune cell trafficking, and T cell-mediated immune responses were analyzed 10 weeks later. Results LNT resulted in a marked decrease in hindlimb swelling, fibroadipose tissue deposition, and decreased accumulation of perilymphatic inflammatory cells, as compared to controls. In addition, LNT induced a marked lymphangiogenic response in both capillary and collecting lymphatic vessels. Interestingly, the resultant regenerated lymphatics were abnormal in appearance on lymphangiography, but LNT also led to a notable increase in dendritic cell trafficking from the periphery to the inguinal lymph nodes and improved adaptive immune responses. Conclusions LNT decreases pathological changes of lymphedema and was shown to potently induce lymphangiogenesis. Lymphatic vessels induced by LNT were abnormal in appearance, but were functional and able to transport antigen-presenting cells. Animals treated with LNT have an increased ability to mount T cell-mediated immune responses when sensitized to antigens in the affected hindlimb.
23.	Humble, Emily, et al. (author) RAD Sequencing and a Hybrid Antarctic Fur Seal Genome Assembly Reveal Rapidly Decaying Linkage Disequilibrium, Global Population Structure and Evidence for Inbreeding 2018 In: G3. - : GENETICS SOCIETY AMERICA. - 2160-1836. ; 8:8, s. 2709-2722 Journal article (peer-reviewed)abstract Recent advances in high throughput sequencing have transformed the study of wild organisms by facilitating the generation of high quality genome assemblies and dense genetic marker datasets. These resources have the potential to significantly advance our understanding of diverse phenomena at the level of species, populations and individuals, ranging from patterns of synteny through rates of linkage disequilibrium (LD) decay and population structure to individual inbreeding. Consequently, we used PacBio sequencing to refine an existing Antarctic fur seal (Arctocephalus gazella) genome assembly and genotyped 83 individuals from six populations using restriction site associated DNA (RAD) sequencing. The resulting hybrid genome comprised 6,169 scaffolds with an N50 of 6.21 Mb and provided clear evidence for the conservation of large chromosomal segments between the fur seal and dog (Canis lupus familiaris). Focusing on the most extensively sampled population of South Georgia, we found that LD decayed rapidly, reaching the background level by around 400 kb, consistent with other vertebrates but at odds with the notion that fur seals experienced a strong historical bottleneck. We also found evidence for population structuring, with four main Antarctic island groups being resolved. Finally, appreciable variance in individual inbreeding could be detected, reflecting the strong polygyny and site fidelity of the species. Overall, our study contributes important resources for future genomic studies of fur seals and other pinnipeds while also providing a clear example of how high throughput sequencing can generate diverse biological insights at multiple levels of organization.
24.	Jansen, Iris E, et al. (author) Genome-wide meta-analysis for Alzheimer's disease cerebrospinal fluid biomarkers. 2022 In: Acta neuropathologica. - : Springer Science and Business Media LLC. - 1432-0533 .- 0001-6322. ; 144:5, s. 821-842 Journal article (peer-reviewed)abstract Amyloid-beta 42 (Aβ42) and phosphorylated tau (pTau) levels in cerebrospinal fluid (CSF) reflect core features of the pathogenesis of Alzheimer's disease (AD) more directly than clinical diagnosis. Initiated by the European Alzheimer & Dementia Biobank (EADB), the largest collaborative effort on genetics underlying CSF biomarkers was established, including 31 cohorts with a total of 13,116 individuals (discovery n=8074; replication n=5042 individuals). Besides the APOE locus, novel associations with two other well-established AD risk loci were observed; CR1 was shown a locus for Aβ42 and BIN1 for pTau. GMNC and C16orf95 were further identified as loci for pTau, of which the latter is novel. Clustering methods exploring the influence of all known AD risk loci on the CSF protein levels, revealed 4 biological categories suggesting multiple Aβ42 and pTau related biological pathways involved in the etiology of AD. In functional follow-up analyses, GMNC and C16orf95 both associated with lateral ventricular volume, implying an overlap in genetic etiology for tau levels and brain ventricular volume.
25.	Jansen, Willemijn J, et al. (author) Prevalence Estimates of Amyloid Abnormality Across the Alzheimer Disease Clinical Spectrum. 2022 In: JAMA neurology. - : American Medical Association (AMA). - 2168-6157 .- 2168-6149. ; 79:3, s. 228-243 Journal article (peer-reviewed)abstract One characteristic histopathological event in Alzheimer disease (AD) is cerebral amyloid aggregation, which can be detected by biomarkers in cerebrospinal fluid (CSF) and on positron emission tomography (PET) scans. Prevalence estimates of amyloid pathology are important for health care planning and clinical trial design.To estimate the prevalence of amyloid abnormality in persons with normal cognition, subjective cognitive decline, mild cognitive impairment, or clinical AD dementia and to examine the potential implications of cutoff methods, biomarker modality (CSF or PET), age, sex, APOE genotype, educational level, geographical region, and dementia severity for these estimates.This cross-sectional, individual-participant pooled study included participants from 85 Amyloid Biomarker Study cohorts. Data collection was performed from January 1, 2013, to December 31, 2020. Participants had normal cognition, subjective cognitive decline, mild cognitive impairment, or clinical AD dementia. Normal cognition and subjective cognitive decline were defined by normal scores on cognitive tests, with the presence of cognitive complaints defining subjective cognitive decline. Mild cognitive impairment and clinical AD dementia were diagnosed according to published criteria.Alzheimer disease biomarkers detected on PET or in CSF.Amyloid measurements were dichotomized as normal or abnormal using cohort-provided cutoffs for CSF or PET or by visual reading for PET. Adjusted data-driven cutoffs for abnormal amyloid were calculated using gaussian mixture modeling. Prevalence of amyloid abnormality was estimated according to age, sex, cognitive status, biomarker modality, APOE carrier status, educational level, geographical location, and dementia severity using generalized estimating equations.Among the 19097 participants (mean [SD] age, 69.1 [9.8] years; 10148 women [53.1%]) included, 10139 (53.1%) underwent an amyloid PET scan and 8958 (46.9%) had an amyloid CSF measurement. Using cohort-provided cutoffs, amyloid abnormality prevalences were similar to 2015 estimates for individuals without dementia and were similar across PET- and CSF-based estimates (24%; 95% CI, 21%-28%) in participants with normal cognition, 27% (95% CI, 21%-33%) in participants with subjective cognitive decline, and 51% (95% CI, 46%-56%) in participants with mild cognitive impairment, whereas for clinical AD dementia the estimates were higher for PET than CSF (87% vs 79%; mean difference, 8%; 95% CI, 0%-16%; P=.04). Gaussian mixture modeling-based cutoffs for amyloid measures on PET scans were similar to cohort-provided cutoffs and were not adjusted. Adjusted CSF cutoffs resulted in a 10% higher amyloid abnormality prevalence than PET-based estimates in persons with normal cognition (mean difference, 9%; 95% CI, 3%-15%; P=.004), subjective cognitive decline (9%; 95% CI, 3%-15%; P=.005), and mild cognitive impairment (10%; 95% CI, 3%-17%; P=.004), whereas the estimates were comparable in persons with clinical AD dementia (mean difference, 4%; 95% CI, -2% to 9%; P=.18).This study found that CSF-based estimates using adjusted data-driven cutoffs were up to 10% higher than PET-based estimates in people without dementia, whereas the results were similar among people with dementia. This finding suggests that preclinical and prodromal AD may be more prevalent than previously estimated, which has important implications for clinical trial recruitment strategies and health care planning policies.
26.	Kassebaum, Nicholas J., et al. (author) Global, regional, and national disability-adjusted life-years (DALYs) for 315 diseases and injuries and healthy life expectancy (HALE), 1990-2015 : a systematic analysis for the Global Burden of Disease Study 2015 2016 In: The Lancet. - 0140-6736 .- 1474-547X. ; 388:10053, s. 1603-1658 Journal article (peer-reviewed)abstract Background Healthy life expectancy (HALE) and disability-adjusted life-years (DALYs) provide summary measures of health across geographies and time that can inform assessments of epidemiological patterns and health system performance, help to prioritise investments in research and development, and monitor progress toward the Sustainable Development Goals (SDGs). We aimed to provide updated HALE and DALYs for geographies worldwide and evaluate how disease burden changes with development. Methods We used results from the Global Burden of Diseases, Injuries, and Risk Factors Study 2015 (GBD 2015) for all-cause mortality, cause-specific mortality, and non-fatal disease burden to derive HALE and DALYs by sex for 195 countries and territories from 1990 to 2015. We calculated DALYs by summing years of life lost (YLLs) and years of life lived with disability (YLDs) for each geography, age group, sex, and year. We estimated HALE using the Sullivan method, which draws from age-specific death rates and YLDs per capita. We then assessed how observed levels of DALYs and HALE differed from expected trends calculated with the Socio-demographic Index (SDI), a composite indicator constructed from measures of income per capita, average years of schooling, and total fertility rate. Findings Total global DALYs remained largely unchanged from 1990 to 2015, with decreases in communicable, neonatal, maternal, and nutritional (Group 1) disease DALYs off set by increased DALYs due to non-communicable diseases (NCDs). Much of this epidemiological transition was caused by changes in population growth and ageing, but it was accelerated by widespread improvements in SDI that also correlated strongly with the increasing importance of NCDs. Both total DALYs and age-standardised DALY rates due to most Group 1 causes significantly decreased by 2015, and although total burden climbed for the majority of NCDs, age-standardised DALY rates due to NCDs declined. Nonetheless, age-standardised DALY rates due to several high-burden NCDs (including osteoarthritis, drug use disorders, depression, diabetes, congenital birth defects, and skin, oral, and sense organ diseases) either increased or remained unchanged, leading to increases in their relative ranking in many geographies. From 2005 to 2015, HALE at birth increased by an average of 2.9 years (95% uncertainty interval 2.9-3.0) for men and 3.5 years (3.4-3.7) for women, while HALE at age 65 years improved by 0.85 years (0.78-0.92) and 1.2 years (1.1-1.3), respectively. Rising SDI was associated with consistently higher HALE and a somewhat smaller proportion of life spent with functional health loss; however, rising SDI was related to increases in total disability. Many countries and territories in central America and eastern sub-Saharan Africa had increasingly lower rates of disease burden than expected given their SDI. At the same time, a subset of geographies recorded a growing gap between observed and expected levels of DALYs, a trend driven mainly by rising burden due to war, interpersonal violence, and various NCDs. Interpretation Health is improving globally, but this means more populations are spending more time with functional health loss, an absolute expansion of morbidity. The proportion of life spent in ill health decreases somewhat with increasing SDI, a relative compression of morbidity, which supports continued efforts to elevate personal income, improve education, and limit fertility. Our analysis of DALYs and HALE and their relationship to SDI represents a robust framework on which to benchmark geography-specific health performance and SDG progress. Country-specific drivers of disease burden, particularly for causes with higher-than-expected DALYs, should inform financial and research investments, prevention efforts, health policies, and health system improvement initiatives for all countries along the development continuum.
27.	Klionsky, Daniel J., et al. (author) Guidelines for the use and interpretation of assays for monitoring autophagy 2012 In: Autophagy. - : Informa UK Limited. - 1554-8635 .- 1554-8627. ; 8:4, s. 445-544 Research review (peer-reviewed)abstract In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
28.	Laurie, Steven, et al. (author) The RD-Connect Genome-Phenome Analysis Platform : Accelerating diagnosis, research, and gene discovery for rare diseases 2022 In: Human Mutation. - : John Wiley & Sons. - 1059-7794 .- 1098-1004. ; 43:6, s. 717-733 Journal article (peer-reviewed)abstract Rare disease patients are more likely to receive a rapid molecular diagnosis nowadays thanks to the wide adoption of next-generation sequencing. However, many cases remain undiagnosed even after exome or genome analysis, because the methods used missed the molecular cause in a known gene, or a novel causative gene could not be identified and/or confirmed. To address these challenges, the RD-Connect Genome-Phenome Analysis Platform (GPAP) facilitates the collation, discovery, sharing, and analysis of standardized genome-phenome data within a collaborative environment. Authorized clinicians and researchers submit pseudonymised phenotypic profiles encoded using the Human Phenotype Ontology, and raw genomic data which is processed through a standardized pipeline. After an optional embargo period, the data are shared with other platform users, with the objective that similar cases in the system and queries from peers may help diagnose the case. Additionally, the platform enables bidirectional discovery of similar cases in other databases from the Matchmaker Exchange network. To facilitate genome-phenome analysis and interpretation by clinical researchers, the RD-Connect GPAP provides a powerful user-friendly interface and leverages tens of information sources. As a result, the resource has already helped diagnose hundreds of rare disease patients and discover new disease causing genes.
29.	Liu, Xiaowan, et al. (author) Measurements and modelling of dynamic stiffness of a railway vehicle primary suspension element and its use in a structure-borne noise transmission model 2021 In: Applied Acoustics. - : Elsevier BV. - 0003-682X .- 1872-910X. ; 182 Journal article (peer-reviewed)abstract The noise inside railway vehicles is transmitted by both structure-borne and airborne paths and, although there are many sources, the rolling noise is often the most important. This paper focuses on the structure-borne transmission of rolling noise in a metro vehicle. Measurements are presented first of the vertical and lateral dynamic stiffness of a primary suspension element consisting of conical rubber/metal elements. Results are presented for various constant preloads over the frequency range 60600 Hz. An analytical model of the suspension element is also developed, based on a mass-spring system and including wave motion within the rubber elements. The dynamic stiffness results are used in a finite element model of the running gear, consisting of the bogie frame, wheelsets and suspension elements. The excitation is provided by the combined wheel/rail roughness at the contact point. This model is used to calculate the blocked forces at the connection points between the secondary suspension elements and the car body. The blocked forces are combined with measured vibro-acoustic transfer functions from these mounting points to the vehicle interior to determine the structure-borne noise inside the vehicle. The proposed methodology is validated against measurements during operation in terms of acceleration levels, blocked forces and structure-borne noise levels inside the vehicle, showing reasonably good agreement. Including the dynamic stiffness for the primary suspension leads to improved agreement between 100 and 500 Hz compared with using a constant stiffness.
30.	Martin-Almedina, Silvia, et al. (author) EPHB4 kinase-inactivating mutations cause autosomal dominant lymphatic-related hydrops fetalis 2016 In: Journal of Clinical Investigation. - 0021-9738 .- 1558-8238. ; 126:8, s. 3080-3088 Journal article (peer-reviewed)abstract Hydrops fetalis describes fluid accumulation in at least 2 fetal compartments, including abdominal cavities, pleura, and pericardium, or in body tissue. The majority of hydrops fetalis cases are nonimmune conditions that present with generalized edema of the fetus, and approximately 15% of these nonimmune cases result from a lymphatic abnormality. Here, we have identified an autosomal dominant, inherited form of lymphatic-related (nonimmune) hydrops fetalis (LRHF). Independent exome sequencing projects on 2 families with a history of in utero and neonatal deaths associated with nonimmune hydrops fetalis uncovered 2 heterozygous missense variants in the gene encoding Eph receptor B4 (EPHB4). Biochemical analysis determined that the mutant EPHB4 proteins are devoid of tyrosine kinase activity, indicating that loss of EPHB4 signaling contributes to LRHF pathogenesis. Further, inactivation of Ephb4 in lymphatic endothelial cells of developing mouse embryos led to defective lymphovenous valve formation and consequent subcutaneous edema. Together, these findings identify EPHB4 as a critical regulator of early lymphatic vascular development and demonstrate that mutations in the gene can cause an autosomal dominant form of LRHF that is associated with a high mortality rate.
31.	Martinez-Corral, Ines, et al. (author) Blockade of VEGF-C signaling inhibits lymphatic malformations driven by oncogenic PIK3CA mutation 2020 In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1 Journal article (peer-reviewed)abstract Lymphatic malformations (LMs) are debilitating vascular anomalies presenting with large cysts (macrocystic) or lesions that infiltrate tissues (microcystic). Cellular mechanisms underlying LM pathology are poorly understood. Here we show that the somatic PIK3CA(H1047R) mutation, resulting in constitutive activation of the p110 alpha PI3K, underlies both macrocystic and microcystic LMs in human. Using a mouse model of PIK3CA(H1047R)-driven LM, we demonstrate that both types of malformations arise due to lymphatic endothelial cell (LEC)-autonomous defects, with the developmental timing of p110 alpha activation determining the LM subtype. In the postnatal vasculature, PIK3CA(H1047R) promotes LEC migration and lymphatic hypersprouting, leading to microcystic LMs that grow progressively in a vascular endothelial growth factor C (VEGF-C)-dependent manner. Combined inhibition of VEGF-C and the PI3K downstream target mTOR using Rapamycin, but neither treatment alone, promotes regression of lesions. The best therapeutic outcome for LM is thus achieved by co-inhibition of the upstream VEGF-C/VEGFR3 and the downstream PI3K/mTOR pathways. Lymphatic malformation (LM) is a debilitating often incurable vascular disease. Using a mouse model of LM driven by a disease-causative PIK3CA mutation, the authors show that vascular growth is dependent on the upstream lymphangiogenic VEGF-C signalling, permitting effective therapeutic intervention.
32.	Martinez-Corral, Ines, et al. (author) Genetic Lineage Tracing of Lymphatic Endothelial Cells in Mice. 2018 In: Methods in Molecular Biology. - New York, NY : Springer New York. - 1064-3745 .- 1940-6029. ; 1846, s. 37-53 Journal article (peer-reviewed)abstract Lineage tracing allows for identification of all progeny produced by a single cell or groups of cells and can thus be used to assess developmental fate of cells. Here we focus on one of the most widely used lineage tracing approaches that utilize the Cre/loxP system for site-specific genetic recombination in studying the developmental origins of lymphatic endothelial cells (LECs) in the mouse embryo. We discuss general considerations for a successful Cre/loxP based lineage tracing experiment and provide information about strains that are available for genetic lineage tracing of LECs. A protocol for lineage tracing analysis of the lymphatic vasculature by whole-mount immunofluorescence in two embryonic tissues, the skin and the mesentery, is also provided.
33.	Martinez-Corral, Ines, et al. (author) Nonvenous Origin of Dermal Lymphatic Vasculature 2015 In: Circulation Research. - 0009-7330 .- 1524-4571. ; 116:10, s. 1649-1654 Journal article (peer-reviewed)abstract Rationale: The formation of the blood vasculature is achieved via 2 fundamentally different mechanisms, de novo formation of vessels from endothelial progenitors (vasculogenesis) and sprouting of vessels from pre-existing ones (angiogenesis). In contrast, mammalian lymphatic vasculature is thought to form exclusively by sprouting from embryonic veins (lymphangiogenesis). Alternative nonvenous sources of lymphatic endothelial cells have been suggested in chicken and Xenopus, but it is unclear whether they exist in mammals. Objective: We aimed to clarify the origin of the murine dermal lymphatic vasculature. Methods and Results: We performed lineage tracing experiments and analyzed mutants lacking the Prox1 transcription factor, a master regulator of lymphatic endothelial cell identity, in Tie2 lineage venous-derived lymphatic endothelial cells. We show that, contrary to current dogma, a significant part of the dermal lymphatic vasculature forms independently of sprouting from veins. Although lymphatic vessels of cervical and thoracic skin develop via sprouting from venous-derived lymph sacs, vessels of lumbar and dorsal midline skin form via assembly of non-Tie2-lineage cells into clusters and vessels through a process defined as lymphvasculogenesis. Conclusions: Our results demonstrate a significant contribution of nonvenous-derived cells to the dermal lymphatic vasculature. Demonstration of a previously unknown lymphatic endothelial cell progenitor population will now allow further characterization of their origin, identity, and functions during normal lymphatic development and in pathology, as well as their potential therapeutic use for lymphatic regeneration.
34.	Martinez-Corral, Ines, et al. (author) Regulation of lymphatic vascular morphogenesis : Implications for pathological (tumor) lymphangiogenesis 2013 In: Experimental Cell Research. - : Elsevier BV. - 0014-4827 .- 1090-2422. ; 319:11, s. 1618-1625 Research review (peer-reviewed)abstract Lymphatic vasculature forms the second part of our circulatory system that plays a critical role in tissue fluid homeostasis. Failure of the lymphatic system can lead to excessive accumulation of fluid within the tissue, a condition called lymphedema. Lymphatic dysfunction has also been implicated in cancer metastasis as well as pathogenesis of obesity, atherosclerosis and cardiovascular disease. Since the identification of the first lymphatic marker VEGFR-3 and growth factor VEGF-C almost 20 years ago, a great progress has been made in understanding the mechanisms of lymphangiogenesis. This has been achieved largely through characterization of animal models with specific lymphatic defects and identification of genes causative of human hereditary lymphedema syndromes. In this review we will summarize the current understanding of the regulation of lymphatic vascular morphogenesis, focusing on mechanisms that have been implicated in both developmental and pathological (tumor) lymphangiogenesis.
35.	Martinez-Corral, Ines, et al. (author) Vegfr3-CreER (T2) mouse, a new genetic tool for targeting the lymphatic system 2016 In: Angiogenesis. - : Springer Science and Business Media LLC. - 0969-6970 .- 1573-7209. ; 19:3, s. 433-445 Journal article (peer-reviewed)abstract The lymphatic system is essential in many physiological and pathological processes. Still, much remains to be known about the molecular mechanisms that control its development and function and how to modulate them therapeutically. The study of these mechanisms will benefit from better controlled genetic mouse models targeting specifically lymphatic endothelial cells. Among the genes expressed predominantly in lymphatic endothelium, Vegfr3 was the first one identified and is still considered to be one of the best lymphatic markers and a key regulator of the lymphatic system. Here, we report the generation of a Vegfr3-CreER (T2) knockin mouse by gene targeting in embryonic stem cells. This mouse expresses the tamoxifen-inducible CreER(T2) recombinase under the endogenous transcriptional control of the Vegfr3 gene without altering its physiological expression or regulation. The Vegfr3-CreER (T2) allele drives efficient recombination of floxed sequences upon tamoxifen administration specifically in Vegfr3-expressing cells, both in vitro, in primary lymphatic endothelial cells, and in vivo, at different stages of mouse embryonic development and postnatal life. Thus, our Vegfr3-CreER (T2) mouse constitutes a new powerful genetic tool for lineage tracing analysis and for conditional gene manipulation in the lymphatic endothelium that will contribute to improve our current understanding of this system.
36.	Ortiz-Rodriguez, Jose Manuel, et al. (author) The incorporation of cystine by the soluble carrier family 7 member 11 (SLC7A11) is a component of the redox regulatory mechanism in stallion spermatozoa 2019 In: Biology of Reproduction. - : OXFORD UNIV PRESS INC. - 0006-3363 .- 1529-7268. ; 101:1, s. 208-222 Journal article (peer-reviewed)abstract Oxidative stress is considered amajor mechanism causing sperm damage during cryopreservation and storage, and underlies male factor infertility. Currently, oxidative stress is no longer believed to be caused only by the overproduction of reactive oxygen species, but rather by the deregulation of redox signaling and control mechanisms. With this concept in mind, here, we describe for the first time the presence of the soluble carrier family 7 member 11 (SLC7A11) antiporter, which exchanges extracellular cystine (Cyss) for intracellular glutamate, in stallion spermatozoa, as well as its impact on sperm function using the specific inhibitor sulfasalazine. Spermatozoa incubated with Cyss exhibited an increased intracellular GSH content compared with controls (P amp;lt; 0.01): 50% in fresh extended stallion spermatozoa and 30% in frozen-thawed spermatozoa. This effect was prevented by the addition of sulfasalazine to the media. Cystine supplementation also reduced the oxidation-reduction potential of spermatozoa, with sulfasalazine only preventing this effect on fresh spermatozoa that were incubated for 3 h at 37 degrees C, but not in frozen-thawed spermatozoa. While sulfasalazine reduced the motility of frozen-thawed spermatozoa, it increased motility in fresh samples. The present findings provide new and relevant data on the mechanism regulating the redox status of spermatozoa and suggest that a different redox regulatory mechanism exists in cryopreserved spermatozoa, thus providing new clues to improve current cryopreservation technologies and treat male factor infertility. Summary Sentence The SLC7A11 antiporter that exchanges cystine by intracellular glutamate is present and functional in stallion spermatozoa, but cryopreserved spermatozoa may present altered functionality.
37.	Ostergaard, Pia, et al. (author) Mutations in GATA2 cause primary lymphedema associated with a predisposition to acute myeloid leukemia (Emberger syndrome). 2011 In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 43:10 Journal article (peer-reviewed)abstract We report an allelic series of eight mutations in GATA2 underlying Emberger syndrome, an autosomal dominant primary lymphedema associated with a predisposition to acute myeloid leukemia. GATA2 is a transcription factor that plays an essential role in gene regulation during vascular development and hematopoietic differentiation. Our findings indicate that haploinsufficiency of GATA2 underlies primary lymphedema and predisposes to acute myeloid leukemia in this syndrome.
38.	Ostergaard, Pia, et al. (author) Mutations in KIF11 cause autosomal-dominant microcephaly variably associated with congenital lymphedema and chorioretinopathy. 2012 In: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 90:2 Journal article (peer-reviewed)abstract We have identified KIF11 mutations in individuals with syndromic autosomal-dominant microcephaly associated with lymphedema and/or chorioretinopathy. Initial whole-exome sequencing revealed heterozygous KIF11 mutations in three individuals with a combination of microcephaly and lymphedema from a microcephaly-lymphedema-chorioretinal-dysplasia cohort. Subsequent Sanger sequencing of KIF11 in a further 15 unrelated microcephalic probands with lymphedema and/or chorioretinopathy identified additional heterozygous mutations in 12 of them. KIF11 encodes EG5, a homotetramer kinesin motor. The variety of mutations we have found (two nonsense, two splice site, four missense, and six indels causing frameshifts) are all predicted to have an impact on protein function. EG5 has previously been shown to play a role in spindle assembly and function, and these findings highlight the critical role of proteins necessary for spindle formation in CNS development. Moreover, identification of KIF11 mutations in patients with chorioretinopathy and lymphedema suggests that EG5 is involved in the development and maintenance of retinal and lymphatic structures.
39.	Palmer, Nicholette D, et al. (author) A genome-wide association search for type 2 diabetes genes in African Americans. 2012 In: PloS one. - San Francisco : Public Library of Science (PLoS). - 1932-6203. ; 7:1, s. e29202- Journal article (peer-reviewed)abstract African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5×10(-8)). SNP rs7560163 (P = 7.0×10(-9), OR (95% CI) = 0.75 (0.67-0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5×10(-5)) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations.
40.	Pardillo-Baez, Yinef, et al. (author) Estudio de disponibilidad de aceite comestible en Cuba para el año 2010 [Study on the availability of edible oil in Cuba in 2010] 2012 In: Ingeniería Industrial. - : Facultad de Ingeniería Industrial, Instituto Superior Politécnico José Antonio Echeverría, Cujae. - 0258-5960 .- 1815-5936. ; 33:1, s. 87-98 Journal article (peer-reviewed)abstract Due to the low presence of edible oil in hard-currency stores in 2006 and the need of knowing their actual demand in the Cuban market, it became necessary to undertake a study of the levels of availability of this product. This study was performed to measure the availability of this product in a phase of implementation of the Model. The study was divided into two stages, a first one that discusses the availability of oil in the country with all the commercial chains and a second one that focuses on Havana and Commercial Chain TRD Caribe. In the first stage the level of availability was high (90,8%), while in the second stage availability levels dropped significantly to 45,84%. The levels of availability are analyzed in various stages of the supply chain, showing that there are large differences in levels of availability in the same period of time for different actors in the supply chain, which leads to the conclusion that there are problems in the organization of the logistics of the edible oil supply chain, which generates low levels of availability meaning low levels at customers service.
41.	Pardo-Camacho, Cristina, et al. (author) Mucosal Plasma Cell Activation and Proximity to Nerve Fibres Are Associated with Glycocalyx Reduction in Diarrhoea-Predominant Irritable Bowel Syndrome : Jejunal Barrier Alterations Underlying Clinical Manifestations 2022 In: Cells. - Basel : MDPI. - 2073-4409. ; 11:13 Journal article (peer-reviewed)abstract Irritable bowel syndrome (IBS) is a disorder of brain-gut interaction characterised by abdominal pain and changes in bowel habits. In the diarrhoea subtype (IBS-D), altered epithelial barrier and mucosal immune activation are associated with clinical manifestations. We aimed to further evaluate plasma cells and epithelial integrity to gain understanding of IBS-D pathophysiology. One mucosal jejunal biopsy and one stool sample were obtained from healthy controls and IBS-D patients. Gastrointestinal symptoms, stress, and depression scores were recorded. In the jejunal mucosa, RNAseq and gene set enrichment analyses were performed. A morphometric analysis by electron microscopy quantified plasma cell activation and proximity to enteric nerves and glycocalyx thickness. Immunoglobulins concentration was assessed in the stool. IBS-D patients showed differential expression of humoral pathways compared to controls. Activation and proximity of plasma cells to nerves and IgG concentration were also higher in IBS-D. Glycocalyx thickness was lower in IBS-D compared to controls, and this reduction correlated with plasma cell activation, proximity to nerves, and clinical symptoms. These results support humoral activity and loss of epithelial integrity as important contributors to gut dysfunction and clinical manifestations in IBS-D. Additional studies are needed to identify the triggers of these alterations to better define IBS-D pathophysiology.
42.	Pardo Martinez, Clara Inés, et al. (author) Analysis of energy use and CO2 emission in service industries : Evidence from Sweden 2012 In: Renewable & sustainable energy reviews. - : Elsevier BV. - 1364-0321 .- 1879-0690. ; 16:7, s. 5285-5294 Journal article (peer-reviewed)abstract This study analyses the trends in energy use and CO2 emissions for 19 sub-sectors in the Swedish service sectors following the classification of the International Standard Industrial Classification of all Economic Activities (ISIC) at the 2-digit level of aggregation over the period 1993-2008. This empirical study intends to examine energy use, energy efficiency and CO2 emissions using data envelopment analysis (DEA) and panel data techniques. DEA is applied to assess energy efficiency within a production framework. Panel data techniques are used to determine which variables influence energy efficiency. The results show that Swedish services industries have increased energy consumption and CO2 emissions in the period 1993-2008. The results from the DEA show significant variation in energy efficiency across service industries. The results also indicate that this sector has increased technical efficiency and energy efficiency while decreasing CO2 emissions, especially in the later years of our sample period. The results of panel data techniques show that higher energy taxes, electricity consumption, investments and labour productivity generate higher energy efficiency, while higher fossil fuel consumption leads to lower energy efficiency. All findings of this study are important for developing effective energy policies that encourage better energy use and energy management in the service industries.
43.	Pardo Martínez, Clara Inés, 1974- (author) Analyzing energy efficiency in german and colombian non-energy intesnive sectors using empirical analysis 2011 In: 34th IAEE International Conference Institutions, Efficiency and Evolving Energy Technologies. - Stockholm : Stockholm School of Economics. Conference paper (peer-reviewed)abstract In this research, data envelopment analysis (DEA) is employed to study the comparative performance of German and Colombian non-energy intensive sectors between 1998 and 2005. The results of the DEA indicate that the great majority of these sectors improved on this index during the sample period, demonstrating that energy input is an important variable within the production structure and a key element in technology development. At a second stage, regression analysis using panel data analysis reveals that several factors, including labour productive, enterprise size, investments and capital input can be considered determinants of differences in energy efficiency among German and Colombian non-eenrgy intensive sectors. Our results also show that different energy policies should apply across non-energy intensive sectors and that they should encourage the importance of energy efficiency in order to improve it, especially in small and medium enterprises and manufacturing industries of developing countries.
44.	Pardo Martínez, Clara Inés, et al. (author) Energy, development, and economic growth in Colombia 2013 In: Global Energy Policy and Security. - London : Springer London. - 9781447152859 - 9781447152866 ; , s. 311-330 Book chapter (peer-reviewed)abstract Purpose: The aim of this study is to describe the causal relationships between energy use, development, and productivity in Colombia. Design/Methodology/Approach: The study was conducted by application of several econometric techniques. The time-series methodology used in this is based on the Granger causality test, which has been found appropriate by using the cointegration technique. Findings: This study shows that economic growth and development drive total energy consumption. The results regarding the relationship among energy, poverty, and inequality indicate that increases in gross domestic product and energy supply per capita contribute to decrease poverty. The results also confirm that access to modern energy services helps to decrease poverty. Moreover, the improvements in energy efficiency and decreases in CO2 emissions have contributed to development and growth. Practical Implications: The results of this study showed the importance of the formulation and adoption of good policies and strategies that encourage sustainable energy use to improve growth and development, especially in developing countries. Originality/Value: This chapter provides an empirical approach for finding the causal relationship between development, productivity, and energy consumption in Colombia. The methodology and the results used in this study could be used for exploring the importance of energy in the productivity and economic development.
45.	Pardo Martínez, Clara Ines, 1974-, et al. (author) Energy efficiency and CO2 emissions in Swedish manufacturing industries 2013 In: Energy Efficiency. - : Springer Science and Business Media LLC. - 1570-646X .- 1570-6478. ; 6:1, s. 117-133 Journal article (peer-reviewed)abstract This paper analyses the trends in energy consumption and CO2 emissions as a result of energy efficiency improvements in Swedish manufacturing industries between 1993 and 2008. Using data at the two-digit level, the performance of this sector is studied in terms of CO2 emissions, energy consumption, energy efficiency measured as energy intensity, value of production, fuel sources, energy prices and energy taxes. It was found that energy consumption, energy intensity and CO2 emission intensity, measured as production values, have decreased significantly in the Swedish manufacturing industries during the period studied. The results of the decomposition analysis show that output growth has not required higher energy consumption, leading to a reduction in both energy and CO2 emission intensities. The role of structural changes has been minor, and the trends of energy efficiency and CO2 emissions have been similar during the sample period. A stochastic frontier model was used to determine possible factors that may have influenced these trends. The results demonstrate that high energy prices, energy taxes, investments and electricity consumption have influenced the reduction of energy and CO2 emission intensities, indicating that Sweden has applied an adequate and effective energy policy. The study confirms that it is possible to achieve economic growth and sustainable development whilst also reducing the pressure on resources and energy consumption and promoting the shift towards a low-carbon economy.
46.	Pardo Martínez, Clara Inés, 1974-, et al. (author) Energy efficiency in Colombian manufacturing industries: An analysis with Data Envelopment Analysis and Panel Data techniques : La eficiencia energética en la industria manufacturera Colombiana:una estimación con Análisis Envolvente de Datos-DEAy Datos de Panel 2011 In: REVISTA ECONOMÍA, GESTIÓN Y DESARROLLO. - Cali, Colombia : Pontificia Universidad Javeriana de Cali. - 1909-4477. ; :11, s. 39-58 Journal article (peer-reviewed)abstract In this study, data envelopment analysis (DEA) is employed to analysis the trendsin energy efficiency in the Colombian manufacturing industries taking as reference energy intensive sectors (EISs).The results of theDEAindicate that the great majority ofEISs improved on this index, demonstrating that energy input is an important variable within the production structure and a key element in technology development.At a second stage, regression analysis using panel data analysis reveals that several factors, including labour productive, enterprise size, investments and capital input can be considered determinants in the trends of energyefficiency. These results indicate that different energy policies should apply in the manufacturing industries to encourage the importance of energy efficiencythrough technology changes and investments in order to improve productivity, decrease energy consumption and pollution.
47.	Pardo Martínez, Clara Inés, 1974- (author) Estimating and Analyzing Energy Efficiency in German and Colombian Manufacturing Industries Using DEA and Data Panel Analysis 2011 In: 17th annual international sustainable development research conference. Moving Towarda Sustainable Future. - New York : The Earth Institute, Columbia University. ; , s. 15-16 Conference paper (peer-reviewed)abstract In this research, data envelopment analysis (DEA) is employed to study the comparative performance of German and Colombian manufacturing industries between 1998 and 2005. The results of the DEA indicate that the great majority of manufacturing industrial sectors improved on this index during the sample period, demonstrating that energy input is an important variable within the production structure and a key element in technology development. At a second stage, regression analysis using panel data analysis reveals that several factors, including labour productive, enterprise size, investments and capital input can be considered determinants of differences in energy efficiency among German and Colombian manufacturing industries. Our results also show that different energy policies should apply across manufacturing industries and that they should encourage the importance of energy efficiency in order to improve it, especially in non-energy-intensive sectors, small and medium enterprises and manufacturing industries of developing countries.
48.	Pardo Martínez, Clara Inés, 1974- (author) Estimating and analyzing energy efficiency in German and Colombian manufacturing industries using DEA and data panel analysis. Part I Energy Intensive Sectors 2011 In: Energy Sources, Part B: Economics, Planning, and Policy. - : Taylor & Francis. - 1556-7257. Journal article (peer-reviewed)abstract In this paper, data envelopment analysis (DEA) is employed to study the comparative performance of German and Colombian energy intensive sectors between 1998 and 2005. The results of the DEA indicate that the great majority of energy intensive sectors improved on this index during the sample period, demonstrating that energy input is an important variable within the production structure and a key element in technology development. At a second stage, regression analysis using panel data analysis reveals that several factors, including labour productive, the share of electricity, investments and enterprise size can be considered determinants of differences in energy efficiency among German and Colombian energy intensive sectors. Our results also show that different energy policies should apply, and that they should encourage the importance of energy efficiency in order to achieve a sustainable economic development and climate stabilization today and in the near future.
49.	Pardo Martínez, Clara Inés, 1974- (author) Estimating and analyzing energy efficiency in German and Colombian manufacturing industries using DEA and data panel analysis. Part II Non-Energy Intensive Sectors 2011 In: Energy Sources, Part B: Economics, Planning, and Policy. - : Taylor & Francis. - 1556-7257. Journal article (peer-reviewed)abstract This study analysis energy efficiency trends in German and Colombian non-energy intensive sectors using data envelopment analysis (DEA) between 1998 and 2005. The results of the DEA show considerable variation in energy efficiency across non-energy intensive sectors during the sample period. At a second stage, regression analysis using panel data analysis reveals that several factors, including labour productive, enterprise size, and capital input can be considered determinants of differences in energy efficiency among German and Colombian non-energy intensive sectors. Our results also show that different energy policies should apply in non-energy intensive sectors and that they should encourage the importance of energy efficiency in order to improve it, especially in small and medium enterprises and industrial sector of developing countries.
50.	Pardo Martínez, Clara Inés, 1974- (author) Investments and Energy Efficiency in Colombian Manufacturing Industries 2011 In: 17th annual international sustainable development research conference Moving Towarda Sustainable Future. - New York : The Earth Institute, Columbia University. ; , s. 169-171 Conference paper (peer-reviewed)abstract This paper investigates the effects of investments on energy efficiency performance using data from Colombian manufacturing industries. These industries were analysed as a whole and as energy intensive sectors(EISs) and nonenergy intensive sectors (NEISs) between 1998 and 2005. Using a simple factor demand model, we estimate the structural parameters of the model using both time-series and cross-sectional dimensions of the data, and we include the effect that investments have on energy efficiency in Colombian manufacturing industries. The results showed that in Colombian manufacturing industries overall, as well as in NEISs, the main variables that determine energy efficiency performance are energy prices, machinery and equipment investments and foreign investments. Whereas electricity prices show lower significance levels, investments in research and development (R&D) are not statistically significant. In contrast, for EISs, only energy prices and foreign investments are statistically significant. Therefore, these results demonstrate the close relationship between energy prices and investments with respect to energy efficiency improvements in Colombian manufacturing industries. These findings have important implications for policy makers aiming to encourage governments to adopt strategies that combine energy prices and technological change, as well as those policy makers wishing to strengthen foreign investment in order to improve technology development, productivity and energy efficiency in manufacturing industries.

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