Arnoldi Stability Analysis of Modulated Tollmien-Schlichting Waves in Shear Flows

The transition of strictly two-dimensional Poiseuille flow from one-frequency amplitude-modulated states to chaotic behaviour is studied through full numerical simulation of spatially periodic channels with large longitudinal aspect ratios. First, time evolution on states at different Reynolds numbers is performed. Then, linear stability techniques, namely Poincaré maps combined with Arnoldi Iteration methods, are used to attain more exact results.2015/201

Signals in a cell uptake of aluminum injection with the as-i bus

Peer Reviewe

The role of idecabtagene vicleucel in patients with heavily pretreated refractory multiple myeloma

The development of several treatment options over the last 2 decades has led to a notable improvement in the survival of patients with multiple myeloma. Despite these advances, the disease remains incurable for most patients. Moreover, standard combinations of alkylating agents, immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies targeting CD38 and corticoids are exhausted relatively fast in a proportion of high-risk patients. Such high-risk patients account for over 20% of cases and currently represent a major unmet medical need. The challenge of drug resistance requires the development of highly active new agents with a radically different mechanism of action. Several immunotherapeutic modalities, including antibody-drug conjugates and T-cell engagers, appear to be promising choices for patients who develop resistance to standard combinations. Chimeric antigen-receptor-modified T cells (CAR-Ts) targeting B-cell maturation antigen have demonstrated encouraging efficacy and an acceptable safety profile compared with alternative options. Multiple CAR-Ts are in early stages of clinical development, but the first phase III trials with CAR-Ts are ongoing for two of them. After the recent publication of the results of a phase II trial confirming a notable efficacy and acceptable safety profile, idecabtagene vicleucel is the first CAR-T to gain regulatory US Food and Drug Administration approval to treat refractory multiple myeloma patients who have already been exposed to antibodies against CD38, proteasome inhibitors, and immunomodulatory agents and who are refractory to the last therapy. Here, we will discuss the preclinical and clinical development of idecabtagene vicleucel and its future role in the changing treatment landscape of relapsed and refractory multiple myeloma

Circulating miRNAs as predictive biomarkers of type 2 diabetes mellitus development in coronary heart disease patients fromt he CORDIOPREV study

Circulating microRNAs (miRNAs) have been proposed as type 2 diabetes biomarkers, and they may be a more sensitive way to predict development of the disease than the currently used tools. Our aim was to identify whether circulating miRNAs, added to clinical and biochemical markers, yielded better potential for predicting type 2 diabetes. The study included 462 non-diabetic patients at baseline in the CORDIOPREV study. After a median follow-up of 60 months, 107 of them developed type 2 diabetes. Plasma levels of 24 miRNAs were measured at baseline by qRT-PCR, and other strong biomarkers to predict diabetes were determined. The ROC analysis identified 9 miRNAs, which, added to HbA1c, have a greater predictive value in early diagnosis of type 2 diabetes (AUC = 0.8342) than HbA1c alone (AUC = 0.6950). The miRNA and HbA1cbased model did not improve when the FINDRISC was included (AUC = 0.8293). Cox regression analyses showed that patients with low miR-103, miR-28-3p, miR-29a, and miR-9 and high miR-30a-5p and miR-150 circulating levels have a higher risk of disease (HR = 11.27; 95% CI = 2.61–48.65). Our results suggest that circulating miRNAs could potentially be used as a new tool for predicting the development of type 2 diabetes in clinical practice

Prior knowledge elicitation: The past, present, and future

Specification of the prior distribution for a Bayesian model is a central part of the Bayesian workflow for data analysis, but it is often difficult even for statistical experts. Prior elicitation transforms domain knowledge of various kinds into well-defined prior distributions, and offers a solution to the prior specification problem, in principle. In practice, however, we are still fairly far from having usable prior elicitation tools that could significantly influence the way we build probabilistic models in academia and industry. We lack elicitation methods that integrate well into the Bayesian workflow and perform elicitation efficiently in terms of costs of time and effort. We even lack a comprehensive theoretical framework for understanding different facets of the prior elicitation problem.Why are we not widely using prior elicitation? We analyze the state of the art by identifying a range of key aspects of prior knowledge elicitation, from properties of the modelling task and the nature of the priors to the form of interaction with the expert. The existing prior elicitation literature is reviewed and categorized in these terms. This allows recognizing under-studied directions in prior elicitation research, finally leading to a proposal of several new avenues to improve prior elicitation methodology.Fil: Mikkola, Petrus. Aalto University; FinlandiaFil: Martín, Osvaldo Antonio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto de Matemática Aplicada de San Luis "Prof. Ezio Marchi". Universidad Nacional de San Luis. Facultad de Ciencias Físico, Matemáticas y Naturales. Instituto de Matemática Aplicada de San Luis "Prof. Ezio Marchi"; Argentina. Aalto University; FinlandiaFil: Chandramoul, Suyog. Aalto University; FinlandiaFil: Hartmann, Marcelo. University of Helsinki; FinlandiaFil: Abril Pla, Oriol. University of Helsinki; FinlandiaFil: Thomas, Owen. University of Oslo; NoruegaFil: Pesonen, Henri. University of Oslo; NoruegaFil: Corander, Jukka. University of Oslo; NoruegaFil: Vehtari, Aki. Aalto University; FinlandiaFil: Kaski, Samuel. Aalto University; FinlandiaFil: Bürkner, Paul Christian. University Of Stuttgart; AlemaniaFil: Klami, Arto. University of Helsinki; Finlandi

Prior knowledge elicitation: The past, present, and future

Specification of the prior distribution for a Bayesian model is a central part of the Bayesian workflow for data analysis, but it is often difficult even for statistical experts. Prior elicitation transforms domain knowledge of various kinds into well-defined prior distributions, and offers a solution to the prior specification problem, in principle. In practice, however, we are still fairly far from having usable prior elicitation tools that could significantly influence the way we build probabilistic models in academia and industry. We lack elicitation methods that integrate well into the Bayesian workflow and perform elicitation efficiently in terms of costs of time and effort. We even lack a comprehensive theoretical framework for understanding different facets of the prior elicitation problem.Why are we not widely using prior elicitation? We analyze the state of the art by identifying a range of key aspects of prior knowledge elicitation, from properties of the modelling task and the nature of the priors to the form of interaction with the expert. The existing prior elicitation literature is reviewed and categorized in these terms. This allows recognizing under-studied directions in prior elicitation research, finally leading to a proposal of several new avenues to improve prior elicitation methodology.Fil: Mikkola, Petrus. Aalto University; FinlandiaFil: Martín, Osvaldo Antonio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto de Matemática Aplicada de San Luis "Prof. Ezio Marchi". Universidad Nacional de San Luis. Facultad de Ciencias Físico, Matemáticas y Naturales. Instituto de Matemática Aplicada de San Luis "Prof. Ezio Marchi"; Argentina. Aalto University; FinlandiaFil: Chandramoul, Suyog. Aalto University; FinlandiaFil: Hartmann, Marcelo. University of Helsinki; FinlandiaFil: Abril Pla, Oriol. University of Helsinki; FinlandiaFil: Thomas, Owen. University of Oslo; NoruegaFil: Pesonen, Henri. University of Oslo; NoruegaFil: Corander, Jukka. University of Oslo; NoruegaFil: Vehtari, Aki. Aalto University; FinlandiaFil: Kaski, Samuel. Aalto University; FinlandiaFil: Bürkner, Paul Christian. University Of Stuttgart; AlemaniaFil: Klami, Arto. University of Helsinki; Finlandi

p27Kip1 and p21Cip1 collaborate in the regulation of transcription by recruiting cyclin-Cdk complexes on the promoters of target genes

Transcriptional repressor complexes containing p130 and E2F4 regulate the expression of genes involved in DNA replication. During the G1 phase of the cell cycle, sequential phosphorylation of p130 by cyclin-dependent kinases (Cdks) disrupts these complexes allowing gene expression. The Cdk inhibitor and tumor suppressor p27(Kip1) associates with p130 and E2F4 by its carboxyl domain on the promoters of target genes but its role in the regulation of transcription remains unclear. We report here that p27(Kip1) recruits cyclin D2/D3-Cdk4 complexes on the promoters by its amino terminal domain in early and mid G1. In cells lacking p27(Kip1), cyclin D2/D3-Cdk4 did not associate to the promoters and phosphorylation of p130 and transcription of target genes was increased. In late G1, these complexes were substituted by p21(Cip1)-cyclin D1-Cdk2. In p21(Cip1) null cells cyclin D1-Cdk2 were not found on the promoters and transcription was elevated. In p21/p27 double null cells transcription was higher than in control cells and single knock out cells. Thus, our results clarify the role of p27(Kip1) and p21(Cip1) in transcriptional regulation of genes repressed by p130/E2F4 complexes in which p27(Kip1) and p21(Cip1) play a sequential role by recruiting and regulating the activity of specific cyclin-Cdk complexes on the promoter

Interplay between gonadal hormones and postnatal overfeeding in defining sex-dependent differences in gut microbiota architecture

Aging is associated with a decline in sex hormones, variable between sexes, that has an impact on many different body systems and might contribute to age-related disease progression. We aimed to characterize the sex differences in gut microbiota; and. to explore the impact of depletion of gonacial hormones, alone or combined with postnatal overfeeding, in rats. Many of the differences in the gut microbiota between sexes persisted after gonadectomy, but removal of gonadal hormones shaped several gut microbiota features towards a more deleterious profile, the effect being greater in females than in males, mainly when animals were concurrently overfed. Moreover, we identified several intestinal miRNAs as potential mediators of the impact of changes in gut microbiota on host organism physiology. Our study points out that gonadal hormones contribute to defining sex-dependent differences of gut microbiota, and discloses a potential role of gonadal hormones in shaping gut microbidta, OS consequence of the interaction between sex and nutrition. Our data suggest that the changes in gut microbion, observed in conditions of sex hormone decline, as those caused by ageing in men and menopause in women, might exert different effects on the host organism, which are putatively mediated by gut microbiota-intestinal miRNA cross-talk

A transcriptomic analysis of Echinococcus granulosus larval stages:implications for parasite biology and host adaptation

The cestode Echinococcus granulosus--the agent of cystic echinococcosis, a zoonosis affecting humans and domestic animals worldwide--is an excellent model for the study of host-parasite cross-talk that interfaces with two mammalian hosts. To develop the molecular analysis of these interactions, we carried out an EST survey of E. granulosus larval stages. We report the salient features of this study with a focus on genes reflecting physiological adaptations of different parasite stages.We generated ~10,000 ESTs from two sets of full-length enriched libraries (derived from oligo-capped and trans-spliced cDNAs) prepared with three parasite materials: hydatid cyst wall, larval worms (protoscoleces), and pepsin/H(+)-activated protoscoleces. The ESTs were clustered into 2700 distinct gene products. In the context of the biology of E. granulosus, our analyses reveal: (i) a diverse group of abundant long non-protein coding transcripts showing homology to a middle repetitive element (EgBRep) that could either be active molecular species or represent precursors of small RNAs (like piRNAs); (ii) an up-regulation of fermentative pathways in the tissue of the cyst wall; (iii) highly expressed thiol- and selenol-dependent antioxidant enzyme targets of thioredoxin glutathione reductase, the functional hub of redox metabolism in parasitic flatworms; (iv) candidate apomucins for the external layer of the tissue-dwelling hydatid cyst, a mucin-rich structure that is critical for survival in the intermediate host; (v) a set of tetraspanins, a protein family that appears to have expanded in the cestode lineage; and (vi) a set of platyhelminth-specific gene products that may offer targets for novel pan-platyhelminth drug development.This survey has greatly increased the quality and the quantity of the molecular information on E. granulosus and constitutes a valuable resource for gene prediction on the parasite genome and for further genomic and proteomic analyses focused on cestodes and platyhelminths

Modelos de novas clásicas con MESA

Classical novae are thermonuclear runaways at the envelope of a WD due to the piling up of H-rich accreted material. They have been observed to produce heavy elements during the explosion, and their role in galactical abundances for some specific elements may not be negligible. MESA (Modules for Experiments in Stellar Astrophysics) code has been thoroughly studied for its application to nova explosions. Detailed know-how of nova simulations with MESA has been achieved, leading the road of future studies using this tool. Its capablities in the field have been tested, demonstrating to reach further than what has been done in previous literature. MESA has been shown to give accurate nucleosynthesis yields for solar-like accreted material without any further postprocessing up to 50 nova bursts. The dependance of the nova outburst properties with the burst number have been anayzed. However, more simulations are needed in order to extract meaningful conclusions about the role of the burst number in the properties of novae outbursts. The key role of the nuclear reaction network has been highlighted, showing that simulations of consecutive novae outbursts require nuclear reactions networks specifically tested for the work. Many nuclear reaction networks that were thoroughly tested in a single nova explosion have not been capable of properly simulating 10 consecutive outbursts. The role of convective overshoot mixing as implemented in MESA has also been tested. It has been found that as shown in previous literature, it does account for dredge up. We plan to extend this work with simulations of consecutive nova outbursts implementing convective overshoot.Les noves clàssiques són explosions nuclears que es duen a terme a l'embolcall d'una nana blanca, degut a l'accreció de matèria rica en hidrogen. S'ha observat la producció d'elements pesats en aquest tipus d'explosions, i podrien tenir un paper important en les abundancies del elements químics a nivell galàctic. S'ha estudiat l'aplicació del codi MESA (Modules for Experiments in Stellar Astrophysics) a la simulació de noves clàssiques, obtenint conèixement detallat sobre com fer aquestes simulacions i demostrant que les possibilitats d'aplicació de MESA van més enllà del que s'ha publicat fins ara. S'ha comprovat que MESA sol, sense cap tipus de postprocessat és capaç d'obtenir factors de produció de nucleosyntesi en noves fins a 50 explosions consecutives. També s'ha estudiat la dependència de varies propietats de les noves en funció del numero d'explosió. Malgrat tot, calen més simulacions per poder extreure conclusions definitives. El paper clau de la xarxa de reaccions nuclears considerada també ha estat posat de manifest, mostrant que cal pensar les xarxes específicament per aquest tipus de problemes, i que comprovar que són adequades per a una sola explosió de nova no és suficient. El paper de la implementació en 1D de les inestabilitats hidrodinamiques degudes a la convecció també s'ha estudiat, comprovant que el model utilitzat en MESA és prou bo per simular la barreja entre les capes esteriors de la nana blanca i el material accretat