Two-state theory of nonlinear Stochastic Resonance

An amenable, analytical two-state description of the nonlinear population dynamics of a noisy bistable system driven by a rectangular subthreshold signal is put forward. Explicit expressions for the driven population dynamics, the correlation function (its coherent and incoherent part), the signal-to-noise ratio (SNR) and the Stochastic Resonance (SR) gain are obtained. Within a suitably chosen range of parameter values this reduced description yields anomalous SR-gains exceeding unity and, simultaneously, gives rise to a non-monotonic behavior of the SNR vs. the noise strength. The analytical results agree well with those obtained from numerical solutions of the Langevin equation.Comment: 4 pages, 1 figur

Barley-ß-glucans reduce systemic inflammation, renal injury and aortic calcification through ADAM17 and neutral-sphingomyelinase2 inhibition

In chronic kidney disease (CKD), hyperphosphatemia-induced inflammation aggravates vascular calcification (VC) by increasing vascular smooth muscle cell (VSMC) osteogenic differentiation, ADAM17-induced renal and vascular injury, and TNFα-induction of neutral-sphingomyelinase2 (nSMase2) to release pro-calcifying exosomes. This study examined anti-inflammatory β-glucans efficacy at attenuating systemic inflammation in health, and renal and vascular injury favoring VC in hyperphosphatemic CKD. In healthy adults, dietary barley β-glucans (Bβglucans) reduced leukocyte superoxide production, inflammatory ADAM17, TNFα, nSMase2, and pro-aging/pro-inflammatory STING (Stimulator of interferon genes) gene expression without decreasing circulating inflammatory cytokines, except for γ-interferon. In hyperphosphatemic rat CKD, dietary Bβglucans reduced renal and aortic ADAM17-driven inflammation attenuating CKD-progression (higher GFR and lower serum creatinine, proteinuria, kidney inflammatory infiltration and nSMase2), and TNFα-driven increases in aortic nSMase2 and calcium deposition without improving mineral homeostasis. In VSMC, Bβglucans prevented LPS- or uremic serum-induced rapid increases in ADAM17, TNFα and nSMase2, and reduced the 13-fold higher calcium deposition induced by prolonged calcifying conditions by inhibiting osteogenic differentiation and increases in nSMase2 through Dectin1-independent actions involving Bβglucans internalization. Thus, dietary Bβglucans inhibit leukocyte superoxide production and leukocyte, renal and aortic ADAM17- and nSMase2 gene expression attenuating systemic inflammation in health, and renal injury and aortic calcification despite hyperphosphatemia in CKD.A grant to A.S.D. and M.J.M. from IRBLleida and Agrotecnio Research collaborative projects from the Consell Social at Lleida University supported initial work, Instituto de Salud Carlos III and co-funded by European Union (ERDF/FEDER) (FIS PI11/00259, PI14/01452, PI17/02181), Plan de Ciencia, Tecnología e Innovación 2013–2017 y 2018–2022 del Principado de Asturias (GRUPIN14-028, IDI-2018-000152), RedInRen from ISCIII (ISCIII-RETIC REDINREN RD16/0009). Investigator support included: NC-L by GRUPIN14-028 and IDI-2018-000152, LM-A by GRUPIN14-028, SP by FICYT; MVA and PV by Educational Grant 2 A/2015 from ERA-EDTA CKD-MBD Working Group; PV and AC by ERA-EDTA fellowships 2011 and 2012; JR-C by MINECO (“Juan de la Cierva” program, FJCI-2015-23849); A.S.D. by Asociación Investigación de Fisiología Aplicada. A.S.D. and M.J.M. are members of the Campus Iberus (Ebro Valley Campus of International Excellence)

The Ksar Ghilane 002 shergottite-The 100th registered Martian meteorite fragment

We report on the discovery of a new shergottite from Tunisia, Ksar Ghilane (KG) 002. This single stone, weighing 538 g, is a coarse-grained basaltic shergottite, mainly composed of maskelynitized plagioclase (approximately 52 vol%) and pyroxene (approximately 37 vol%). It also contains Fe-rich olivine (approximately 4.5 vol%), large Ca-phosphates, including both merrillites and Cl-apatites (approximately 3.4 vol%), minor amounts of silica or SiO_2-normative K-rich glass, pyrrhotite, Ti-magnetite, ilmenite, and accessory baddeleyite. The largest crystals of pyroxene and plagioclase reach sizes of approximately 4 to 5 mm. Pyroxenes (Fs_(26–96)En_(5–50)Wo_(2–41)). They typically range from cores of about Fs_(29)En_(41)Wo_(30) to rims of about Fs_(68)En_(14)Wo_(17). Maskelynite is Ab_(41–49)An_(39–58)Or_(1–7) in composition, but some can be as anorthitic as An_(93). Olivine (Fa_(91–96)) occurs mainly within symplectitic intergrowths, in paragenesis with ilmenite, or at neighboring areas of symplectites. KG 002 is heavily shocked (S5) as indicated by mosaic extinction of pyroxenes, maskelynitized plagioclase, the occurrence of localized shock melt glass pockets, and low radiogenic He concentration. Oxygen isotopes confirm that it is a normal member of the SNC suite. KG 002 is slightly depleted in LREE and shows a positive Eu anomaly, providing evidence for complex magma genesis and mantle processes on Mars. Noble gases with a composition thought to be characteristic for Martian interior is a dominant component. Measurements of ^(10)Be, ^(26)Al, and ^(53)Mn and comparison with Monte Carlo calculations of production rates indicate that KG 002 has been exposed to cosmic rays most likely as a single meteoroid body of 35–65 cm radius. KG 002 strongly resembles Los Angeles and NWA 2800 basaltic shergottites in element composition, petrography, and mineral chemistry, suggesting a possible launch-pairing. The similar CRE ages of KG 002 and Los Angeles may suggest an ejection event at approximately 3.0 Ma

Safety and Revisit Related to Discharge the Sixty-one Spanish Emergency Department Medical Centers Without Hospitalization in Patients with COVID-19 Pneumonia. A Prospective Cohort Study UMC-Pneumonia COVID-19

Background: Information is needed on the safety and efficacy of direct discharge from the emergency department (ED) of patients with COVID-19 pneumonia. Objectives: The objectives of the study were to study the variables associated with discharge from the ED in patients presenting with COVID-19 pneumonia, and study ED revisits related to COVID-19 at 30 days (EDR30d). Methods: Multicenter study of the SIESTA cohort including 1198 randomly selected COVID patients in 61 EDs of Spanish medical centers from March 1, 2020, to April 30, 2020. We collected baseline and related characteristics of the acute episode and calculated the adjusted odds ratios (aOR) for ED discharge. In addition, we analyzed the variables related to EDR30d in discharged patients. Results: We analyzed 859 patients presenting with COVID-19 pneumonia, 84 (9.8%) of whom were discharged from the ED. The variables independently associated with discharge were being a woman (aOR 1.890; 95%CI 1.176-3.037), age 1200/mm(3) (aOR 4.667; 95%CI 1.045-20.839). The EDR30d of the ED discharged group was 40.0%, being lower in women (aOR 0.368; 95%CI 0.142-0.953). A total of 130 hospitalized patients died (16.8%) as did two in the group discharged from the ED (2.4%) (OR 0.121; 95%CI 0.029-0.498). Conclusion: Discharge from the ED in patients with COVID-19 pneumonia was infrequent and was associated with few variables of the episode. The EDR30d was high, albeit with a low mortality

Prognostic Value of Serum Paraprotein Response Kinetics in Patients With Newly Diagnosed Multiple Myeloma

Response kinetics is not well-established as a prognostic marker in multiple myeloma (MM). We developed a mathematical model to assess the prognostic value of serum monoclonal component (MC) response kinetics during 6 induction cycles in 373 newly diagnosed MM patients. The model calculated a resistance parameter that reflects the stagnation in the response after an initial descent, dividing the patients into two kinetics categories with significantly different progression-free survival (PFS). Introduction: Response kinetics is a well-established prognostic marker in acute lymphoblastic leukemia. The situation is not clear in multiple myeloma (MM) despite having a biomarker for response monitoring (monoclonal component [MC]). Materials and Methods: We developed a mathematical model to assess the prognostic value of serum MC response kinetics during 6 induction cycles, in 373 NDMM transplanted patients treated in the GEM2012Menos65 clinical trial. The model calculated a resistance parameter that reflects the stagnation in the response after an initial descent. Results: Two patient subgroups were defined based on low and high resistance, that respectively captured sensitive and refractory kinetics, with progression-free survival (PFS) at 5 years of 72% and 59% (HR 0.64, 95% CI 0.44-0.93; P =.02). Resistance significantly correlated with depth of response measured after consolidation (80.9% CR and 68.4% minimal residual disease negativity in patients with sensitive vs. 31% and 20% in those with refractory kinetics). Furthermore, it modulated the impact of reaching CR after consolidation; thus, within CR patients those with refractory kinetics had significantly shorter PFS than those with sensitive kinetics (median 54 months vs. NR; P =.02). Minimal residual disease negativity abrogated this effect. Our study also questions the benefit of rapid responders compared to late responders (5-year PFS 59.7% vs. 76.5%, respectively [P <.002]). Of note, 85% of patients considered as late responders were classified as having sensitive kinetics. Conclusion: This semi-mechanistic modeling of M-component kinetics could be of great value to identify patients at risk of early treatment failure, who may benefit from early rescue intervention strategies. (C) 2022 The Authors. Published by Elsevier Inc

Therapeutic effects of hMAPC and hMSC transplantation after stroke in mice

Stroke represents an attractive target for stem cell therapy. Although different types of cells have been employed in animal models, a direct comparison between cell sources has not been performed. The aim of our study was to assess the effect of human multipotent adult progenitor cells (hMAPCs) and human mesenchymal stem cells (hMSCs) on endogenous neurogenesis, angiogenesis and inflammation following stroke. BALB/Ca-RAG 2(-/-) γC(-/-) mice subjected to FeCl(3) thrombosis mediated stroke were intracranially injected with 2 × 10(5) hMAPCs or hMSCs 2 days after stroke and followed for up to 28 days. We could not detect long-term engraftment of either cell population. However, in comparison with PBS-treated animals, hMSC and hMAPC grafted animals demonstrated significantly decreased loss of brain tissue. This was associated with increased angiogenesis, diminished inflammation and a glial-scar inhibitory effect. Moreover, enhanced proliferation of cells in the subventricular zone (SVZ) and survival of newly generated neuroblasts was observed. Interestingly, these neuroprotective effects were more pronounced in the group of animals treated with hMAPCs in comparison with hMSCs. Our results establish cell therapy with hMAPCs and hMSCs as a promising strategy for the treatment of strok

Gene Therapy Corrects Mitochondrial Dysfunction in Hematopoietic Progenitor Cells and Fibroblasts from Coq9R239X Mice

This study has been submitted to the patent's offices at the "University of Granada" and "Fundación Progreso y Salud". Please note that the results of this manuscript have been submitted to patent protection (application number P201630630; title: “Uses of Coenzyme Q biosynthetic proteins”; date:05/16/2016).Recent clinical trials have shown that in vivo and ex vivo gene therapy strategies can be an option for the treatment of several neurological disorders. Both strategies require efficient and safe vectors to 1) deliver the therapeutic gene directly into the CNS or 2) to genetically modify stem cells that will be used as Trojan horses for the systemic delivery of the therapeutic protein. A group of target diseases for these therapeutic strategies are mitochondrial encephalopathies due to mutations in nuclear DNA genes. In this study, we have developed a lentiviral vector (CCoq9WP) able to overexpress Coq9 mRNA and COQ9 protein in mouse embryonic fibroblasts (MEFs) and hematopoietic progenitor cells (HPCs) from Coq9R239X mice, an animal model of mitochondrial encephalopathy due to primary Coenzyme Q (CoQ) deficiency. Ectopic over-expression of Coq9 in both cell types restored the CoQ biosynthetic pathway and mitochondrial function, improving the fitness of the transduced cells. These results show the potential of the CCoq9WP lentiviral vector as a tool for gene therapy to treat mitochondrial encephalopathies.This work was supported by grants from Ministerio de Economía y Competitividad (Spain) and the European Regional Development Fund (ERDF) from the European Union, to LCL through the research grants SAF2013-47761-R and SAF2015-65786-R; by Fondo de Investigaciones Sanitarias ISCIII (Spain) and the European Regional Development Fund (ERDF) from the European Union through the research grants PI12/01097 and ISCIII Red de Terapia Celular TerCel RD12/0019/0006 to FM; by the Consejería de Economía, Innovación, Ciencia y Empleo, Junta de Andalucía-FEDER/Fondo de Cohesion Europeo (FSE) de Andalucía through the research grants P10-CTS-6133 to LCL; P09-CTS-04532, PI-57069, PI-0001/2009 and PAIDI-Bio-326 to F.M.; PI-0160/2012 to KB and PI-0407/2012 to MC; by the NIH through the research P01HD080642 to LCL and by the foundation “todos somos raros, todos somos únicos” to LCL. LCL is supported by the ‘Ramón y Cajal’ National Programme, Ministerio de Economía y Competitividad, Spain (RYC-2011-07643)

Physical Activity Patterns of the Spanish Population Are Mostly Determined by Sex and Age: Findings in the ANIBES Study

Background Representative data for the Spanish population regarding physical activity (PA) behaviors are scarce and seldom comparable due to methodological inconsistencies. Aim Our objectives were to describe the PA behavior by means of the standardized self-reported International Physical Activity Questionnaire (IPAQ) and to know the proportion of the Spanish population meeting and not meeting international PA recommendations. Material and Methods PA was assessed using the IPAQ in a representative sample of 2285 individuals (males, 50.4%) aged 9–75 years and living in municipalities of at least 2,000 inhabitants. Data were analyzed according to: age groups 9–12, 13–17, 18–64, and 65–75 years; sex; geographical distribution; locality size and educational levels. Results Mean total PA was 868.8±660.9 min/wk, mean vigorous PA 146.4±254.1 min/wk, and mean moderate PA 398.1±408.0 min/wk, showing significant differences between sexes (p<0.05). Children performed higher moderate-vigorous PA than adolescents and seniors (p<0.05), and adults than adolescents and seniors (p<0.05). Compared to recommendations, 36.2%of adults performed <150 min/week of moderate PA, 65.4% <75 min/week of vigorous PA and 27.0%did not perform any PA at all, presenting significant differences between sexes (p<0.05). A total of 55.4%of children and adolescents performed less than 420 min/week of MVPA, being higher in the later (62.6%) than in the former (48.4%). Highest non-compliance was observed in adolescent females (86.5%). Conclusion Sex and age are the main influencing factors on PA in the Spanish population. Males engage in more vigorous and light PA overall, whereas females perform more moderate PA. PA behavior differs between age groups and no clear lineal increase with age could be observed. Twenty-seven percent of adults and 55.4% of children and adolescents do not meet international PA recommendations. Identified target groups should be addressed to increase PA in the Spanish populationCoca-Cola Iberia through Spanish Nutrition Foundation (FEN)Coca-Cola Iberi