Intestinal BMP-9 locally upregulates FGF19 and is down-regulated in obese patients with diabetes

believed to be mainly produced in the liver. The serum levels of BMP-9 were reported to be reduced in newly diagnosed diabetic patients and BMP-9 overexpression ameliorated steatosis in the high fat diet-induced obesity mouse model. Furthermore, injection of BMP-9 in mice enhanced expression of fibroblast growth factor (FGF)21. However, whether BMP-9 also regulates the expression of the related FGF19 is not clear. Because both FGF21 and 19 were described to protect the liver from steatosis, we have further investigated the role of BMP-9 in this context. We first analyzed BMP-9 levels in the serum of streptozotocin (STZ)-induced diabetic rats (a model of type I diabetes) and confirmed that BMP-9 serum levels decrease during diabetes. Microarray analyses of RNA samples from hepatic and intestinal tissue from BMP-9 KO- and wild-type mice (C57/Bl6 background) pointed to basal expression of BMP-9 in both organs and revealed a down-regulation of hepatic Fgf21 and intestinal Fgf19 in the KO mice. Next, we analyzed BMP-9 levels in a cohort of obese patients with or without diabetes. Serum BMP-9 levels did not correlate with diabetes, but hepatic BMP-9 mRNA expression negatively correlated with steatosis in those patients that did not yet develop diabetes. Likewise, hepatic BMP-9 expression also negatively correlated with serum LPS levels. In situ hybridization analyses confirmed intestinal BMP-9 expression. Intestinal (but not hepatic) BMP-9 mRNA levels were decreased with diabetes and positively correlated with intestinal E-Cadherin expression. In vitro studies using organoids demonstrated that BMP-9 directly induces FGF19 in gut but not hepatocyte organoids, whereas no evidence of a direct induction of hepatic FGF21 by BMP-9 was found. Consistent with the in vitro data, a correlation between intestinal BMP-9 and FGF19 mRNA expression was seen in the patients’ samples. In summary, our data confirm that BMP-9 is involved in diabetes development in humans and in the control of the FGF-axis. More importantly, our data imply that not only hepatic but also intestinal BMP-9 associates with diabetes and steatosis development and controls FGF19 expression. The data support the conclusion that increased levels of BMP-9 would most likely be beneficial under pre-steatotic conditions, making supplementation of BMP-9 an interesting new approach for future therapies aiming at prevention of the development of a metabolic syndrome and liver steatosis

B-cell regeneration profile and minimal residual disease status in bone marrow of treated multiple myeloma patients

© 2021 by the authors.B-cell regeneration during therapy has been considered as a strong prognostic factor in multiple myeloma (MM). However, the effects of therapy and hemodilution in bone marrow (BM) B-cell recovery have not been systematically evaluated during follow-up. MM (n = 177) and adult (≥50y) healthy donor (HD; n = 14) BM samples were studied by next-generation flow (NGF) to simultaneously assess measurable residual disease (MRD) and residual normal B-cell populations. BM hemodilution was detected in 41 out of 177 (23%) patient samples, leading to lower total B-cell, B-cell precursor (BCP) and normal plasma cell (nPC) counts. Among MM BM, decreased percentages (vs. HD) of BCP, transitional/naïve B-cell (TBC/NBC) and nPC populations were observed at diagnosis. BM BCP increased after induction therapy, whereas TBC/NBC counts remained abnormally low. At day+100 postautologous stem cell transplantation, a greater increase in BCP with recovered TBC/NBC cell numbers but persistently low memory B-cell and nPC counts were found. At the end of therapy, complete response (CR) BM samples showed higher CD19− nPC counts vs. non-CR specimens. MRD positivity was associated with higher BCP and nPC percentages. Hemodilution showed a negative impact on BM B-cell distribution. Different BM B-cell regeneration profiles are present in MM at diagnosis and after therapy with no significant association with patient outcome.This work has been supported by the International Myeloma Foundation-Black Swan Research Initiative, the EuroFlow Consortium (grant LSHB-CT-2006-018708); Centro de Investigación Biomédica en Red de Cáncer (CIBER-ONC; Instituto de Salud Carlos III, Ministerio de Economía y Competitividad, Madrid, Spain and FONDOS FEDER), numbers: CB16/12/00400, CB16/12/00233, CB16/12/00369, CB16/12/00489 and CB16/12/00480; grant from Bilateral Cooperation Program between Coordenação de Aperfeiçoamento de Pessoal de Nível Superior-CAPES (Brasília/Brazil) and Dirección General de Políticas Universitárias (DGPU)-Ministério de Educación, Cultura y Deportes (Madrid/Spain) number DGPU 311/15; Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro of Brazil (FAPERJ) numbers: E26/110.105/2014 and E26/102.191/2013; grant from Conselho Nacional de Desenvolvimento Científico e Tecnológico of Brazil (CNPQ), number: 400194/2014-7. R.M.d.P. was supported by a grant from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES/DGPU), number: 000281/2016-06 and CAPES/PROEX 641/2018, Brazil; Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro of Brazil (FAPERJ) number: E01/200/537/2018

Armed Rollers: Does Nestling’s Vomit Function as a Defence against Predators?

Chemical defences against predators are widespread in the animal kingdom although have been seldom reported in birds. Here, we investigate the possibility that the orange liquid that nestlings of an insectivorous bird, the Eurasian roller (Coracias garrulus), expel when scared at their nests acts as a chemical defence against predators. We studied the diet of nestling rollers and vomit origin, its chemical composition and deterrent effect on a mammal generalist predator. We also hypothesized that nestling rollers, as their main prey (i.e. grasshoppers) do from plants, could sequester chemicals from their prey for their use. Grasshoppers, that also regurgitate when facing to a threat, store the harmful substances used by plants to defend themselves against herbivores. We found that nestling rollers only vomit after being grasped and moved. The production of vomit depended on food consumption and the vomit contained two deterrent chemicals (hydroxycinnamic and hydroxybenzoic acids) stored by grasshoppers and used by plants to diminish herbivory, suggesting that they originate from the rollers’ prey. Finally, we showed for the first time that the oral secretion of a vertebrate had a deterrent effect on a model predator because vomit of nestling rollers made meat distasteful to dogs. These results support the idea that the vomit of nestling rollers is a chemical defence against predators.Financial support was provided by the Junta de Andalucía (project P06-RNM-02177) and the Spanish Ministry of Science and Education/FEDER (projects CGL2008-00718 and CGL2011-27561)

Usefulness of bone turnover markers as predictors of mortality risk, disease progression and skeletal-related events appearance in patients with prostate cancer with bone metastases following treatment with zoledronic acid: TUGAMO study

Owing to the limited validity of clinical data on the treatment of prostate cancer (PCa) and bone metastases, biochemical markers are a promising tool for predicting survival, disease progression and skeletal-related events (SREs) in these patients. The aim of this study was to evaluate the predictive capacity of biochemical markers of bone turnover for mortality risk, disease progression and SREs in patients with PCa and bone metastases undergoing treatment with zoledronic acid (ZA). Methods: This was an observational, prospective and multicenter study in which ninety-eight patients were included. Patients were treated with ZA (4mg every 4 weeks for 18 months). Data were collected at baseline and 3, 6, 9, 12, 15 and 18 months after the beginning of treatment. Serum levels of bone alkaline phosphtase (BALP), aminoterminal propeptide of procollagen type I (P1NP) and beta-isomer of carboxiterminal telopeptide of collagen I (b-CTX) were analysed at all points in the study. Data on disease progression, SREs development and survival were recorded. Results: Cox regression models with clinical data and bone markers showed that the levels of the three markers studied were predictive of survival time, with b-CTX being especially powerful, in which a lack of normalisation in visit 1 (3 months after the beginning of treatment) showed a 6.3-times more risk for death than in normalised patients. Levels of these markers were also predictive for SREs, although in this case BALP and P1NP proved to be better predictors. We did not find any relationship between bone markers and disease progression. Conclusion: In patients with PCa and bone metastases treated with ZA, b-CTX and P1NP can be considered suitable predictors for mortality risk, while BALP and P1NP are appropriate for SREs. The levels of these biomarkers 3 months after the beginning of treatment are especially importantThis study was supported by Novartis Oncology Spai

Maurey-Rosenthal domination for abstract Banach lattices

We extend the Maurey-Rosenthal theorem on integral domination and factorization of p-concave operators from a p-convex Banach function space through Lp-spaces for the case of operators on abstract p-convex Banach lattices satisfying some essential lattice requirements - mainly order density of its order continuous part - that are shown to be necessary. We prove that these geometric properties can be characterized by means of an integral inequality giving a domination of the pointwise evaluation of the operator for a suitable weight also in the case of abstract Banach lattices. We obtain in this way what in a sense can be considered the most general factorization theorem of operators through Lp-spaces. In order to do this, we prove a new representation theorem for abstract p-convex Banach lattices with the Fatou property as spaces of p-integrable functions with respect to a vector measure.The authors are supported by grants MTM2011-23164 and MTM2012-36740-C02-02 of the Ministerio de Economia y Competitividad (Spain).Juan Blanco, MA.; Sánchez Pérez, EA. (2013). Maurey-Rosenthal domination for abstract Banach lattices. Journal of Inequalities and Applications. (213). https://doi.org/10.1186/1029-242X-2013-213S213Defant A: Variants of the Maurey-Rosenthal theorem for quasi Köthe function spaces. Positivity 2001, 5: 153–175. 10.1023/A:1011466509838Defant A, Sánchez Pérez EA: Maurey-Rosenthal factorization of positive operators and convexity. J. Math. Anal. Appl. 2004, 297: 771–790. 10.1016/j.jmaa.2004.04.047Defant A, Sánchez Pérez EA: Domination of operators on function spaces. Math. Proc. Camb. Philos. Soc. 2009, 146: 57–66. 10.1017/S0305004108001734Fernández A, Mayoral F, Naranjo F, Sáez C, Sánchez-Pérez EA: Vector measure Maurey-Rosenthal type factorizations and l -sums of L 1 -spaces. J. Funct. Anal. 2005, 220: 460–485. 10.1016/j.jfa.2004.06.010Palazuelos C, Sánchez Pérez EA, Tradacete P: Maurey-Rosenthal factorization for p -summing operators and Dodds-Fremlin domination. J. Oper. Theory 2012, 68(1):205–222.Luxemburg WAJ, Zaanen AC: Riesz Spaces I. North-Holland, Amsterdam; 1971.Zaanen AC: Riesz Spaces II. North-Holland, Amsterdam; 1983.Lindenstrauss J, Tzafriri L: Classical Banach Spaces II. Springer, Berlin; 1979.Aliprantis CD, Burkinshaw O: Positive Operators. Academic Press, New York; 1985.Curbera GP, Ricker WJ: Vector measures, integration and applications. Trends Math. In Positivity. Birkhäuser, Basel; 2007:127–160.Okada S, Ricker WJ, Sánchez Pérez EA: Optimal domains and integral extensions of operators acting in function spaces. 180. In Operator Theory Advances and Applications. Birkhäuser, Basel; 2008.Delgado O: L 1 -spaces of vector measures defined on δ -rings. Arch. Math. 2005, 84: 432–443. 10.1007/s00013-005-1128-1Calabuig, JM, Delgado, O, Juan, MA, Sánchez Pérez, EA: On the Banach lattice structure of L w 1 of a vector measure on a δ-ring. Collect. Math. doi:10.1007/s13348–013–0081–8Calabuig JM, Delgado O, Sánchez Pérez EA: Factorizing operators on Banach function spaces through spaces of multiplication operators. J. Math. Anal. Appl. 2010, 364: 88–103. 10.1016/j.jmaa.2009.10.034Delgado O:Optimal domains for kernel operators on [ 0 , ∞ ) × [ 0 , ∞ ) .Stud. Math. 2006, 174: 131–145. 10.4064/sm174-2-2Delgado O, Soria J: Optimal domain for the Hardy operator. J. Funct. Anal. 2007, 244: 119–133. 10.1016/j.jfa.2006.12.011Jiménez Fernández E, Juan MA, Sánchez Pérez EA: A Komlós theorem for abstract Banach lattices of measurable functions. J. Math. Anal. Appl. 2011, 383: 130–136. 10.1016/j.jmaa.2011.05.010Curbera, GP: El espacio de funciones integrables respecto de una medida vectorial. PhD thesis, Univ. of Sevilla (1992)Sánchez Pérez EA: Compactness arguments for spaces of p -integrable functions with respect to a vector measure and factorization of operators through Lebesgue-Bochner spaces. Ill. J. Math. 2001, 45(3):907–923.Fernández A, Mayoral F, Naranjo F, Sáez C, Sánchez-Pérez EA: Spaces of p -integrable functions with respect to a vector measure. Positivity 2006, 10: 1–16. 10.1007/s11117-005-0016-zCalabuig JM, Juan MA, Sánchez Pérez EA: Spaces of p -integrable functions with respect to a vector measure defined on a δ -ring. Oper. Matrices 2012, 6: 241–262.Lewis DR: On integrability and summability in vector spaces. Ill. J. Math. 1972, 16: 294–307.Masani PR, Niemi H: The integration theory of Banach space valued measures and the Tonelli-Fubini theorems. I. Scalar-valued measures on δ -rings. Adv. Math. 1989, 73: 204–241. 10.1016/0001-8708(89)90069-8Masani PR, Niemi H: The integration theory of Banach space valued measures and the Tonelli-Fubini theorems. II. Pettis integration. Adv. Math. 1989, 75: 121–167. 10.1016/0001-8708(89)90035-2Brooks JK, Dinculeanu N: Strong additivity, absolute continuity and compactness in spaces of measures. J. Math. Anal. Appl. 1974, 45: 156–175. 10.1016/0022-247X(74)90130-9Curbera GP:Operators into L 1 of a vector measure and applications to Banach lattices.Math. Ann. 1992, 293: 317–330. 10.1007/BF01444717Delgado O, Juan MA: Representation of Banach lattices as L w 1 spaces of a vector measure defined on a δ -ring. Bull. Belg. Math. Soc. Simon Stevin 2012, 19: 239–256.Curbera GP, Ricker WJ: Banach lattices with the Fatou property and optimal domains of kernel operators. Indag. Math. 2006, 17: 187–204. 10.1016/S0019-3577(06)80015-7Curbera GP, Ricker WJ: The Fatou property in p -convex Banach lattices. J. Math. Anal. Appl. 2007, 328: 287–294. 10.1016/j.jmaa.2006.04.086Aliprantis CD, Border KC: Infinite Dimensional Analysis. Springer, Berlin; 1999.Delgado, O: Optimal extension for positive order continuous operators on Banach function spaces. Glasg. Math. J. (to appear

Next generation flow for minimally-invasive blood characterization of MGUS and multiple myeloma at diagnosis based on circulating tumor plasma cells (CTPC)

© The Author(s) 2018.Here, we investigated for the first time the frequency and number of circulating tumor plasma cells (CTPC) in peripheral blood (PB) of newly diagnosed patients with localized and systemic plasma cell neoplasms (PCN) using next-generation flow cytometry (NGF) and correlated our findings with the distinct diagnostic and prognostic categories of the disease. Overall, 508 samples from 264 newly diagnosed PCN patients, were studied. CTPC were detected in PB of all active multiple myeloma (MM; 100%), and smoldering MM (SMM) patients (100%), and in more than half (59%) monoclonal gammopathy of undetermined significance (MGUS) cases (p <0.0001); in contrast, CTPC were present in a small fraction of solitary plasmacytoma patients (18%). Higher numbers of CTPC in PB were associated with higher levels of BM infiltration and more adverse prognostic features, together with shorter time to progression from MGUS to MM (p <0.0001) and a shorter survival in MM patients with active disease requiring treatment (p ≤ 0.03). In summary, the presence of CTPC in PB as assessed by NGF at diagnosis, emerges as a hallmark of disseminated PCN, higher numbers of PB CTPC being strongly associated with a malignant disease behavior and a poorer outcome of both MGUS and MM.This work has been supported by the International Myeloma Foundation-Black Swan Research Initiative and the EuroFlow Consortium; Centro de Investigación Biomédica en Red de Cáncer (CIBER-ONC; Instituto de Salud Carlos III, Ministerio de Economía y Competitividad, Madrid, Spain and FONDOS FEDER), numbers: CB16/12/00400, CB16/12/00369, CB16/12/00489 and CB16/12/00233; grant SA079U14 from the Consejería de Educación, Junta de Castilla y León, Valladolid, Spain and; grant DTS15/00119 from Instituto de Salud Carlos III, Ministerio de Economía y Competitividad, Madrid, Spain. Acuerdo de colaboración con Fundación de Hemoterapia y Hemodonación de Castilla y León, Valladolid, Spain. This study was also supported by the Qatar National Research Fund (QNRF) Award No. 7-916-3-237, the AACR-Millennium Fellowship in Multiple Myeloma Research (15-40-38-PAIV), ERA-NET TRANSCAN-2 (iMMunocell), by a 2017 Leonardo Grant (BZG10931) for Researchers and Cultural Creators, BBVA Foundation, and the European Research Council (ERC) 2015 Starting Grant (MYELOMANEXT)

Combination of Tocilizumab and Steroids to Improve Mortality in Patients with Severe COVID-19 Infection : A Spanish, Multicenter, Cohort Study

We aimed to determine the impact of tocilizumab use on severe COVID-19 (coronavirus disease 19) pneumonia mortality. We performed a multicentre retrospective cohort study in 18 tertiary hospitals in Spain from March to April 2020. Consecutive patients admitted with severe COVID-19 treated with tocilizumab were compared to patients not treated with tocilizumab, adjusting by inverse probability of the treatment weights (IPTW). Tocilizumab's effect in patients receiving steroids during the 48 h following inclusion was analysed. During the study period, 506 patients with severe COVID-19 fulfilled the inclusion criteria. Among them, 268 were treated with tocilizumab and 238 patients were not. Median time to tocilizumab treatment from onset of symptoms was 11 days [interquartile range (IQR) 8-14]. Global mortality was 23.7%. Mortality was lower in patients treated with tocilizumab than in controls: 16.8% versus 31.5%, hazard ratio (HR) 0.514 [95% confidence interval (95% CI) 0.355-0.744], p < 0.001; weighted HR 0.741 (95% CI 0.619-0.887), p = 0.001. Tocilizumab treatment reduced mortality by 14.7% relative to no tocilizumab treatment [relative risk reduction (RRR) 46.7%]. We calculated a number necessary to treat of 7. Among patients treated with steroids, mortality was lower in those treated with tocilizumab than in those treated with steroids alone [10.9% versus 40.2%, HR 0.511 (95% CI 0.352-0.741), p = 0.036; weighted HR 0.6 (95% CI 0.449-0.804), p < 0.001] (interaction p = 0.094). These results show that survival of patients with severe COVID-19 is higher in those treated with tocilizumab than in those not treated and that tocilizumab's effect adds to that of steroids administered to non-intubated patients with COVID-19 during the first 48 h of presenting with respiratory failure despite oxygen therapy. Randomised controlled studies are needed to confirm these results. European Union electronic Register of Post-Authorization Studies (EU PAS Register) identifier, EUPAS34415 The online version of this article (10.1007/s40121-020-00373-8) contains supplementary material, which is available to authorized users

Good and bad get together: Inactivation of SARS-CoV-2 in particulate matter pollution from different fuels

Air pollution and associated particulate matter (PM) affect environmental and human health worldwide. The intense vehicle usage and the high population density in urban areas are the main causes of this public health impact. Epidemiological studies have provided evidence on the effect of air pollution on airborne SARS-CoV-2 transmission and COVID-19 disease prevalence and symptomatology. However, the causal relationship between air pollution and COVID-19 is still under investigation. Based on these results, the question addressed in this study was how long SARS-CoV-2 survives on the surface of PM from different origin to evaluate the relationship between fuel and atmospheric pollution and virus transmission risk. The persistence and viability of SARS-CoV-2 virus was characterized in 5 engine exhaust PM and 4 samples of atmospheric PM10. The results showed that SARS-CoV-2 remains on the surface of PM10 from air pollutants but interaction with engine exhaust PM inactivates the virus. Consequently, atmospheric PM10 levels may increase SARS-CoV-2 transmission risk thus supporting a causal relationship between these factors. Furthermore, the relationship of pollution PM and particularly engine exhaust PM with virus transmission risk and COVID-19 is also affected by the impact of these pollutants on host oxidative stress and immunity. Therefore, although fuel PM inactivates SARS-CoV-2, the conclusion of the study is that both atmospheric and engine exhaust PM negatively impact human health with implications for COVID-19 and other diseases.We thank Dr. Luis Enjuanes (CNB-CSIC, Spain) for providing the SARS-CoV-2 isolate. The authors would like to thank the fuel supply by REPSOL, SASOL and AMYRIS companies. Ministry of Science and Innovation project RECOVERY (RTI2018-095923-B-C21) ANTICIPA-UCM REACT-UE-Comunidad de Madrid.Peer reviewe

Seed storage conditions change the germination pattern of clonal growth plants in Mediterranean salt marshes.

8 páginas, 4 tablas, 8 figuras.The effect of salinity level and extended exposure to different salinity and flooding conditions on germination patterns of three saltmarsh clonal growth plants (Juncus subulatus, Scirpus litoralis, and S. maritimus) was studied. Seed exposure to extended flooding and saline conditions significantly affected the outcome of the germination process in a different, though predictable, way for each species, after favorable conditions for germination were restored. Tolerance of the germination process was related to the average salinity level measured during the growth/germination season at sites where established individuals of each species dominated the species cover. No relationship was found between salinity tolerance of the germination process and seed response to extended exposure to flooding and salinity conditions. The salinity response was significantly related to the conditions prevailing in the habitats of the respective species during the unfavorable (nongrowth/nongermination) season. Our results indicate that changes in salinity and hydrology while seeds are dormant affect the outcome of the seed-bank response, even when conditions at germination are identical. Because these environmental-history-dependent responses differentially affect seed germination, seedling density, and probably sexual recruitment in the studied and related species, these influences should be considered for wetland restoration and managementFinancial support from the Spanish Ministry of the Environment (MMA, project 05/99) and the Junta de Andalucía (research group 4086)enabled us to carry out the present work.Peer reviewe

Seed storage conditions change the germination pattern of clonal growth plants in Mediterranean salt marshes.

8 páginas, 4 tablas, 8 figuras.The effect of salinity level and extended exposure to different salinity and flooding conditions on germination patterns of three saltmarsh clonal growth plants (Juncus subulatus, Scirpus litoralis, and S. maritimus) was studied. Seed exposure to extended flooding and saline conditions significantly affected the outcome of the germination process in a different, though predictable, way for each species, after favorable conditions for germination were restored. Tolerance of the germination process was related to the average salinity level measured during the growth/germination season at sites where established individuals of each species dominated the species cover. No relationship was found between salinity tolerance of the germination process and seed response to extended exposure to flooding and salinity conditions. The salinity response was significantly related to the conditions prevailing in the habitats of the respective species during the unfavorable (nongrowth/nongermination) season. Our results indicate that changes in salinity and hydrology while seeds are dormant affect the outcome of the seed-bank response, even when conditions at germination are identical. Because these environmental-history-dependent responses differentially affect seed germination, seedling density, and probably sexual recruitment in the studied and related species, these influences should be considered for wetland restoration and managementFinancial support from the Spanish Ministry of the Environment (MMA, project 05/99) and the Junta de Andalucía (research group 4086)enabled us to carry out the present work.Peer reviewe