Spatial distribution of economic activities in heritage cities: The case of the historic city of Toledo, Spain

[EN] This paper presents the initial results of an ongoing research on the spatial distribution of economic activities in Spanish heritage cities. The study investigate the influence of spatial accessibility and proximity to monuments on the location of businesses in the historic city of Toledo. The research includes two surveys of the entrnaces to monuments and ground florr businesses within the old town, and uses space syntax techniques and tools to determine spatial accessibility. Then, a GIS model of the street segments of the city registers this monuments have a significant impact on the distribution of business in the old town and investigates further to understand and quantify this effect. however, it does not find strong correlations between the considered variables nor a suitable model to explain the differences in business intensity across the street segments within the historic city of Toeldo.This research has been funded by the Spanish Ministry of Economy and Competitiveness through the project Tejidos históricos, paisaje urbanos y movilidad. Análisis y propuestas de regeneración de áreas de borde, espacios públicos y ejes viarios (CSO2015-63815-R).Ruiz-Apilánez, B.; Solís, E.; García-Camacha, I.; Romero De Ávila, V.; Alía, C.; Martín, R. (2018). Spatial distribution of economic activities in heritage cities: The case of the historic city of Toledo, Spain. En 24th ISUF International Conference. Book of Papers. Editorial Universitat Politècnica de València. 221-230. https://doi.org/10.4995/ISUF2017.2017.5164OCS22123

Effect of osteoprotegerin and Dickkopf-related protein 1 on radiological progression in tightly controlled rheumatoid arthritis.

OBJECTIVE: To analyze the association between circulating osteoprotegerin (OPG) and Dickkopf-related protein 1 (DKK-1) and radiological progression in patients with tightly controlled rheumatoid arthritis (RA). METHODS: Serum levels of OPG and DKK-1 were measured in 97 RA patients who were treated according to a treat-to-target strategy (T2T) aimed at remission (DAS28<2.6). Radiologic joint damage progression was assessed by changes in the total Sharp-van der Heijde score (SHS) on serial radiographs of the hands and feet. The independent association between these biomarker levels and the structural damage endpoint was examined using regression analysis. RESULTS: The mean age of the 97 RA patients (68 women) at the time of the study was 54 ± 14 years, and the median disease duration was 1.6 ± 1.5 years. Most patients were seropositive for either RF or ACPA, and the large majority (76%) were in remission or had low disease activity. After a median follow-up time of 3.3 ± 1.5 years (range, 1-7.5 yrs.), the mean total SHS annual progression was 0.88 ± 2.20 units. Fifty-two percent of the patients had no progression (defined as a total SHS of zero). The mean serum OPG level did not change significantly over the study period (from 3.9 ± 1.8 to 4.07 ± 2.23 pmol/L), whereas the mean serum DKK-1 level decreased, although not significantly (from 29.9 ± 10.9 to 23.6 ± 18.8 pmol/L). In the multivariate analysis, the predictive factors increasing the likelihood of total SHS progression were age (OR per year = 1.10; p = 0.003) and a high mean C-reactive protein level over the study period (OR = 1.29; p = 0.005). Circulating OPG showed a protective effect reducing the likelihood of joint space narrowing by 60% (95% CI: 0.38-0.94) and the total SHS progression by 48% (95% CI: 0.28-0.83). The DKK-1 levels were not associated with radiological progression. CONCLUSION: In patients with tightly controlled RA, serum OPG was inversely associated with progression of joint destruction. This biomarker may be useful in combination with other risk factors to improve prediction in patients in clinical remission or low disease activity state

CD45 expression discriminates waves of embryonic megakaryocytes in the mouse

Embryonic megakaryopoiesis starts in the yolk sac on gestational day 7.5 as part of the primitive wave of hematopoiesis, and it continues in the fetal liver when this organ is colonized by hematopoietic progenitors between day 9.5 and 10.5, as the definitive hematopoiesis wave. We characterized the precise phenotype of embryo megakaryocytes in the liver at gestational day 11.5, identifying them as CD41++CD45-CD9++CD61+MPL+CD42c+ tetraploid cells that express megakaryocyte-specific transcripts and display differential traits when compared to those present in the yolk sac at the same age. In contrast to megakaryocytes from adult bone marrow, embryo megakaryocytes are CD45- until day 13.5 of gestation, as are both the megakaryocyte progenitors and megakaryocyte/erythroid-committed progenitors. At gestational day 11.5, liver and yolk sac also contain CD41+CD45+ and CD41+CD45- cells. These populations, and that of CD41++CD45-CD42c+ cells, isolated from liver, differentiate in culture into CD41++CD45-CD42c+ proplatelet-bearing megakaryocytes. Also present at this time are CD41-CD45++CD11b+ cells, which produce low numbers of CD41++CD45-CD42c+ megakaryocytes in vitro, as do fetal liver cells expressing the macrophage-specific Csf receptor-1 (Csf1r/CD115) from MaFIA transgenic mice, which give rise poorly to CD41++CD45-CD42c+ embryo megakaryocytes both in vivo and in vitro In contrast, around 30% of adult megakaryocytes (CD41++CD45++CD9++CD42c+) from C57BL/6 and MaFIA mice express CD115. We propose that differential pathways operating in the mouse embryo liver at gestational day 11.5 beget CD41++CD45-CD42c+ embryo megakaryocytes that can be produced from CD41+CD45- or from CD41+CD45+ cells, at difference from those from bone marrow.This work was supported by grants from the Ministerio de Ciencia e Innovacion (MICINN SAF2009-12596) and from the Ministerio de Economia y Competitividad (MINECO SAF2012-33916 and SAF2015-70880-R MINECO/FEDER). NS was the recipient of a fellowship from the Centro de Biologia Molecular Severo Ochoa (CBMSO) and IC received a fellowship from the MICINN. The CBMSO receives institutional funding from Fundacion Ramon Areces. The CNIC is supported by the MEIC and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (MEIC award SEV-2015-0505).S

Controlled trial of balance training using a video game console in community-dwelling older adults

gamification is a potentially attractive option for improving balance and reducing falls. to assess the effect of balance training using the NintendoTM Wii game console on balance (primary outcome), falls and fear of falling. quasi-randomised, open-label, controlled clinical trial in parallel groups, carried out on community-dwelling patients over 70 years, able to walk independently. Participants were assigned 1:1 to the intervention or control group. Balance training was conducted using the Nintendo WiiFit TM twice a week for 3 months. Balance was assessed using the Tinetti balance test (primary outcome), the unipedal stance and the Wii balance tests at baseline, 3 months and 1 year. Falls were recorded and Fear of falling was assessed by the Falls Efficacy Scale (Short-FES-I). 1,016 subjects were recruited (508 in both the intervention and the control group; of whom 274 and 356 respectively completed the 3-month assessment). There was no between-group difference in the Tinetti balance test score, with a baseline mean of 14.7 (SD 1.8) in both groups, and 15.2 (1.3) at 3 months in the intervention group compared to 15.3 (1.7) in controls; the between-group difference was 0.06 (95% CI 0.30-0.41). No differences were seen in any of the other balance tests, or in incident falls. There was a reduction in the fear of falling at 3 months, but no effect at 1 year. the study found no effect of balance training using the Nintendo TM Wii on balance or falls in older community-dwelling patients. The study protocol is available at clinicaltrials.gov under the code NCT02570178

Postnatal and adult immunoglobulin repertoires of innate-like CD19(+)CD45R(lo) B Cells

The diversity in antibody repertoire relies on different B cell populations working efficiently to fulfil distinct specific functions. We recently described an innate-like CD19(+)CD45R(-/lo) (19(+)45R(lo)) cell population in postnatal unstimulated adult mice, a heterogeneous population containing cells expressing immunoglobulin M (IgM) and others behaving as differentiated mature B lymphocytes (intracytoplasmic IgG1, AID(+), Blimp-1(+)RAG2(-)). In the present study, we characterized the Ig repertoire expressed by splenic 19(+)45R(lo) cells, assuming that they would bear a restricted repertoire biased for germline rearrangements and low mutation rates similar to other innate-like cells. Sequences from 19(+)45R(lo) cells displayed a variety of V, D and J regions, and the analysis of the CDR-H3 region revealed an intermediate overall CDR-H3 length and moderate hydrophobicity. Both IgM and switched sequences of PD15 19(+)45R(lo) cells had shorter CDR-H3 region and fewer non-template N nucleotides than adult sequences, as expected for profiles that correspond to an immature phenotype. Regarding the mutation rate in the VH regions, IgG1 sequences already carried a high rate of replacement mutations at PD15, which increased further in the sequences obtained from adult mice. Moreover, statistical models suggest that a proportion of the switched sequences in adult 19(+)45R(lo) cells had experienced antigen selection, unlike other innate-like B cell compartments.We thank B. Palacios for assisting with the cloning and sequencing, A.G. de la Campa, A. Trento, I. Cuesta and L. Garcia-Albert for their help with the bioinformatics software analyses, and M.A.R. Marcos for his contribution to the original planning of the experiments. This work was supported by grants from the Fondo de Investigaciones Sanitarias (FIS, MPY 1450/11) and from the Ministerio de Ciencia e Innovación (MICINN, SAF2009-12596) and Ministerio de Economia y competitividad (MINECO, SAF2012-33916). I. Cortegano received a postdoctoral fellowship from the MICINN

CD45 expression discriminates waves of embryonic megakaryocytes in the mouse

Embryonic megakaryopoiesis starts in the yolk sac on gestational day 7.5 as part of the primitive wave of hematopoiesis, and it continues in the fetal liver when this organ is colonized by hematopoietic progenitors between day 9.5 and 10.5, as the definitive hematopoiesis wave. We characterized the precise phenotype of embryo megakaryocytes in the liver at gestational day 11.5, identifying them as CD41++CD45-CD9++CD61+MPL+CD42c+ tetraploid cells that express megakaryocyte-specific transcripts and display differential traits when compared to those present in the yolk sac at the same age. In contrast to megakaryocytes from adult bone marrow, embryo megakaryocytes are CD45- until day 13.5 of gestation, as are both the megakaryocyte progenitors and megakaryocyte/erythroid-committed progenitors. At gestational day 11.5, liver and yolk sac also contain CD41+CD45+ and CD41+CD45- cells. These populations, and that of CD41++CD45-CD42c+ cells, isolated from liver, differentiate in culture into CD41++CD45-CD42c+ proplatelet-bearing megakaryocytes. Also present at this time are CD41-CD45++CD11b+ cells, which produce low numbers of CD41++CD45-CD42c+ megakaryocytes in vitro, as do fetal liver cells expressing the macrophage-specific Csf receptor-1 (Csf1r/CD115) from MaFIA transgenic mice, which give rise poorly to CD41++CD45-CD42c+ embryo megakaryocytes both in vivo and in vitro In contrast, around 30% of adult megakaryocytes (CD41++CD45++CD9++CD42c+) from C57BL/6 and MaFIA mice express CD115. We propose that differential pathways operating in the mouse embryo liver at gestational day 11.5 beget CD41++CD45-CD42c+ embryo megakaryocytes that can be produced from CD41+CD45- or from CD41+CD45+ cells, at difference from those from bone marrow.Ministerio de Ciencia e Innovación (MICINN SAF2009-12596) and from the Ministerio de Economía y Competitividad (MINECO SAF2012-33916 and SAF2015-70880-R INECO/FEDER). The CBMSO receives institutional funding from Fundación Ramón Areces. The CNIC is supported by the MEIC and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (MEIC award SEV-2015-0505

The TLR4-MyD88 Signaling Axis Regulates Lung Monocyte Differentiation Pathways in Response to Streptococcus pneumoniae

Streptococcus pneumoniae is the main cause of bacterial pneumonia, a condition that currently produces significant global morbidity and mortality. The initial immune response to this bacterium occurs when the innate system recognizes common motifs expressed by many pathogens, events driven by pattern recognition receptors like the Toll-like family receptors (TLRs). In this study, lung myeloid-cell populations responsible for the innate immune response (IIR) against S. pneumoniae, and their dependence on the TLR4-signaling axis, were analyzed in TLR4–/– and Myeloid-Differentiation factor-88 deficient (MyD88–/–) mice. Neutrophils and monocyte-derived cells were recruited in infected mice 3-days post-infection. Compared to wild-type mice, there was an increased bacterial load in both these deficient mouse strains and an altered IIR, although TLR4–/– mice were more susceptible to bacterial infection. These mice also developed fewer alveolar macrophages, weaker neutrophil infiltration, less Ly6Chigh monocyte differentiation and a disrupted classical and non-classical monocyte profile. The pro-inflammatory cytokine profile (CXCL1, TNF-α, IL-6, and IL-1β) was also severely affected by the lack of TLR4 and no induction of Th1 was observed in these mice. The respiratory burst (ROS production) after infection was profoundly dampened in TLR4–/– and MyD88–/– mice. These data demonstrate the complex dynamics of myeloid populations and a key role of the TLR4-signaling axis in the IIR to S. pneumoniae, which involves both the MyD88 and TRIF (Toll/IL-1R domain-containing adaptor-inducing IFN-β) dependent pathways.This work was supported by grants of Ministerio de Ciencia SAF 2015-70880-R, RTI 2018-099114-B-100, BIO 2017-82951-R, and ISCIII PI14CIII/00049.S

Dynamics of the splenic innate-like CD19 +CD45R lo cell population from adult mice in homeostatic and activated conditions

In the adult spleen, CD19 +CD45R -/lo (19 +45R lo) lymphocytes of embryonic origin exist as a distinct population to that of the conventional B cell lineage. These cells display a plasmablast phenotype, and they spontaneously secrete IgG1 and IgA, whereas the bone marrow population of 19 +45R lo cells contains B1 progenitors. In this study, we show that 19 +45R lo cells are also present in Peyer's patches and in the spleen throughout the life span of wild-type mice, beginning at postnatal day 7. Although this population is heterogeneous, the surface phenotype of most of these cells distinguishes them from follicular, transitional, marginal zone, and B1 cells. In CBA/CaHN mice, few 19 +45R lo cells were detected at postnatal day 7, and none was observed in the adult spleen. Splenic 19 +45R lo cells exhibited homeostatic BrdU uptake in vivo and actively transcribed cell cycle genes. When transferred to immunodeficient RAG2 -/-γchain -/- recipient mice, 19 +45R lo cells survived and differentiated into IgG1- and IgA-plasma cells. Moreover, in vitro stimulation of splenic 19 +45R lo cells with LPS, CpG, BAFF/IL4, and CD40/IL4 induced cell proliferation, IgG1/IgA secretion and the release of IL-10, suggesting a potential immunoregulatory role for this subset of innatelike B cells.Peer Reviewe