Kinematics of electrons near a Van Hove singularity

A two dimensional electronic system, where the Fermi surface is close to a Van Hove singularity, shows a variety of weak coupling instabilities, and it is a convenient model to study the interplay between antiferromagnetism and anisotropic superconductivity. We present a detailed analysis of the kinematics of the electron scattering in this model. The similitudes, and differences, between a standard Renormalization Group approach and previous work based on parquet summations of log$^2$ divergences are analyzed, with emphasis on the underlying physical processes. General properties of the phase diagram are discussed.Comment: 5 pages, 3 postscript figure

Zileuton™ loaded in polymer micelles effectively reduce breast cancer circulating tumor cells and intratumoral cancer stem cells

Tumor recurrence, metastatic spread and progressive gain of chemo-resistance of advanced cancers are sustained by the presence of cancer stem cells (CSCs) within the tumor. Targeted therapies with the aim to eradicate these cells are thus highly regarded. However, often the use of new anti-cancer therapies is hampered by pharmacokinetic demands. Drug delivery through nanoparticles has great potential to increase efficacy and reduce toxicity and adverse effects. However, its production has to be based on intelligent design. Likewise, we developed polymeric nanoparticles loaded with Zileuton™, a potent inhibitor of cancer stem cells (CSCs), which was chosen based on high throughput screening. Its great potential for CSCs treatment was subsequently demonstrated in in vitro and in in vivo CSC fluorescent models. Encapsulated Zileuton™ reduces amount of CSCs within the tumor and effectively blocks the circulating tumor cells (CTCs) in the blood stream and metastatic spread

Reiterative infusions of MSCs improve pediatric osteogenesis imperfecta eliciting a pro-osteogenic paracrine response: TERCELOI clinical trial

Background Osteogenesis imperfecta (OI) is a rare genetic disease characterized by bone fragility, with a wide range in the severity of clinical manifestations. The majority of cases are due to mutations in the COL1A1 or COL1A2 genes, which encode type I collagen. Mesenchymal stem cells (MSCs), as the progenitors of the osteoblasts, the main type I collagen secreting cell type in the bone, have been proposed and tested as an innovative therapy for OI with promising but transient outcomes. Methods To overcome the short-term effect of MSCs therapy, we performed a phase I clinical trial based on reiterative infusions of histocompatible MSCs, administered in a 2.5-year period, in two pediatric patients affected by severe and moderate OI. The aim of this study was to assess the safety and effectiveness of this cell therapy in nonimmunosuppressed OI patients. The host response to MSCs was studied by analyzing the sera from OI patients, collected before, during, and after the cell therapy. Results We first demonstrated that the sequential administration of MSCs was safe and improved the bone parameters and quality of life of OI patients along the cell treatment plus 2-year follow-up period. Moreover, the study of the mechanism of action indicated that MSCs therapy elicited a pro-osteogenic paracrine response in patients, especially noticeable in the patient affected by severe OI. Conclusions Our results demonstrate the feasibility and potential of reiterative MSCs infusion for two pediatric OI and highlight the paracrine response shown by patients as a consequence of MSCs treatment.We are grateful to the patients affected by OI and their families, and to the AHUCE Foundation, especially to its director Ms Julia Piniella, for the support during the clinical trial. We also thank Dr ME Fernandez-Santos (GM-Cell Production Unit, IiSGM) for her expertise in the cell production, Jose Ignacio Pijoan Zubizarreta (Clinical Epidemiology Unit of Cruces University Hospital) for the overall support provided to the project, and Natale Imaz (Biocruces Bizkaia Health Research Institute) for providing the data and safety monitoring of the clinical trial. We are indebted to all the health professionals from Cruces University Hospital, especially to the Pediatric Intensive Care Unit for their participation. This study was funded by the Spanish Ministry of Health through the call for independent clinical trials projects "EC10-219," Instituto de Salud Carlos III through the project "PI15/00820" (Co-funded by European Regional Development Fund; "A way to make Europe"), Bioef-EiTB maratoia (BIO14/TP/007), and the AHUCE Foundation

Parental Mosaicism in PAX6 Causes Intra-Familial Variability: Implications for Genetic Counseling of Congenital Aniridia and Microphthalmia

Mutations in PAX6 are involved in several developmental eye disorders. These disorders have considerable phenotypic variability, ranging from panocular forms of congenital aniridia and microphthalmia to isolated anomalies of the anterior or posterior segment. Here, we describe 3 families with variable inter-generational ocular expression of aniridia, iris coloboma, or microphthalmia, and an unusual transmission of PAX6 mutations from an unaffected or mildly affected parent; all of which raised suspicion of gonosomal mosaicism. We first identified two previously known nonsense mutations and one novel likely pathogenic missense variant in PAX6 in probands by means of targeted NGS. The subsequent segregation analysis by Sanger sequencing evidenced the presence of highly probable mosaic events in paternal blood samples. Mosaicism was further confirmed by droplet digital PCR analysis in several somatic tissues of mosaic fathers. Quantification of the mutant allele fraction in parental samples showed a marked deviation from 50%, with a range between 12 and 29% depending on cell type. Gonosomal mosaicsm was definitively confirmed in one of the families thanks to the availability of a sperm sample from the mosaic father. Thus, the recurrence risk in this family was estimated to be about one-third. This is the first report confirming parental PAX6 mosaicism as a cause of disease recurrence in aniridia and other related phenotypes. In addition, we demonstrated that post-zygotic mosaicism is a frequent and underestimated pathogenic mechanism in aniridia, explaining intra-familial phenotypic variability in many cases. Our findings may have substantial implications for genetic counseling in congenital aniridia. Thus, we also highlight the importance of comprehensive genetic screening of parents for new sporadic cases with aniridia or related developmental eye disease to more accurately assess recurrence risk. In conclusion, somatic and/or gonosomal mosaicism should be taken into consideration as a genetic factor to explain not only families with unaffected parents despite multiple affected children but also variable expressivity, apparent de novo cases, and even uncharacterized cases of aniridia and related developmental eye disorders, apparently lacking PAX6 mutations

Array-CGH in patients with Kabuki-like phenotype: Identification of two patients with complex rearrangements including 2q37 deletions and no other recurrent aberration

Background: Kabuki syndrome (KS) is a multiple congenital anomaly syndrome characterized by specific facial features, mild to moderate mental retardation, postnatal growth delay, skeletal abnormalities, and unusual dermatoglyphic patterns with prominent fingertip pads. A 3.5 Mb duplication at 8p23.1-p22 was once reported as a specific alteration in KS but has not been confirmed in other patients. The molecular basis of KS remains unknown. Methods: We have studied 16 Spanish patients with a clinical diagnosis of KS or KS-like to search for genomic imbalances using genome-wide array technologies. All putative rearrangements were confirmed by FISH, microsatellite markers and/or MLPA assays, which also determined whether the imbalance was de novo or inherited. Results: No duplication at 8p23.1-p22 was observed in our patients. We detected complex rearrangements involving 2q in two patients with Kabuki-like features: 1) a de novo inverted duplication of 11 Mb with a 4.5 Mb terminal deletion, and 2) a de novo 7.2 Mb-terminal deletion in a patient with an additional de novo 0.5 Mb interstitial deletion in 16p. Additional copy number variations (CNV), either inherited or reported in normal controls, were identified and interpreted as polymorphic variants. No specific CNV was significantly increased in the KS group. Conclusion: Our results further confirmed that genomic duplications of 8p23 region are not a common cause of KS and failed to detect other recurrent rearrangement causing this disorder. The detection of two patients with 2q37 deletions suggests that there is a phenotypic overlap between the two conditions, and screening this region in the Kabuki-like patients should be considered.This work was funded by grants from the Spanish Ministry of Health (FIS PI042063), Genome Spain and the European Commission (FP6-2005-037627). IC was supported by a Juan de la Cierva Postdoctoral fellowship

Early-Career Coordinated Distributed Experiments: Empowerment Through Collaboration

Este artículo contiene 7 páginas, 1 tabla, 3 figuras.Coordinated distributed experiments (CDEs) enable the study of large-scale ecological patterns in geographically dispersed areas, while simultaneously providing broad academic and personal benefits for the participants. However, the effective involvement of early-career researchers (ECRs) presents major challenges. Here, we analyze the benefits and challenges of the first CDE exclusively led and conducted by ECRs (i.e. ECR-CDE), which sets a baseline for similar CDEs, and we provide recommendations for successful CDE execution. ECR-CDEs achieve most of the outcomes identified in conventional CDEs as well as extensive benefits for the young cohort of researchers, including: (i) receiving scientific credit, (ii) peer-training in new concepts and methods, (iii) developing leadership and communication skills, (iv) promoting a peer network among ECRs, and (v) building on individual engagement and independence. We also discuss the challenges of ECR-CDEs, which are mainly derived from the lack of independence and instability of the participants, and we suggest mechanisms to address them, such as resource re-allocation and communication strategies. We conclude that ECR-CDEs can be a relevant tool to empower ECRs across disciplines by fostering their training, networking and personal well-being.The authors were supported by the following founding: NC the support of the Beatriu de Pinós postdoctoral program of the Government of Catalonia’s Secretariat for Universities and Research of the Ministry of Economy and Knowledge (BP2016- 00215), EE by a predoctoral grant from the Basque Government (2014-2017), AB by a Generalitat de Catalunya—Beatriu de Pinós (BP-00385-2016), AMG-F by a predoctoral research grant (BES-2013-065770) from the Spanish Ministry of Economy and Competitiveness, MAr by a postdoctoral grant from the Basque Government, MIA by a Juan de la Cierva postdoctoral grant (FJCI-2015-26192), PR-L by a Margalida Comas postdoctoral contract (PD/031/2018) funded by the Government of the Balearic Islands and the European Social Fund, AP by a Ramón Areces Foundation Postdoctoral Scholarship, and AL by a Kempe Foundation stipend. DOMIPEX project was founded by the First Call of Collaborative Projects among Young Researchers of the Iberian Association of Limnology (AIL; 2013-2015).Peer reviewe

Oral Ondansetron Administration in Emergency Departments to Children with Gastroenteritis: An Economic Analysis

Stephen Freedman and colleagues performed a cost analysis of the routine administration of ondansetron in both the United States and Canada and show that its routine administration to eligible children in such settings could provide substantial benefit

Primrose syndrome: Characterization of the phenotype in 42 patients

Primrose syndrome (PS; MIM# 259050) is characterized by intellectual disability (ID), macrocephaly, unusual facial features (frontal bossing, deeply set eyes, down-slanting palpebral fissures), calcified external ears, sparse body hair and distal muscle wasting. The syndrome is caused by de novo heterozygous missense variants in ZBTB20. Most of the 29 published patients are adults as characteristics appear more recognizable with age. We present 13 hitherto unpublished individuals and summarize the clinical and molecular findings in all 42 patients. Several signs and symptoms of PS develop during childhood, but the cardinal features, such as calcification of the external ears, cystic bone lesions, muscle wasting, and contractures typically develop between 10 and 16 years of age. Biochemically, anemia and increased alpha-fetoprotein levels are often present. Two adult males with PS developed a testicular tumor. Although PS should be regarded as a progressive entity, there are no indications that cognition becomes more impaired with age. No obvious genotype-phenotype correlation is present. A subgroup of patients with ZBTB20 variants may be associated with mild, nonspecific ID. Metabolic investigations suggest a disturbed mitochondrial fatty acid oxidation. We suggest a regular surveillance in all adult males with PS until it is clear whether or not there is a truly elevated risk of testicular cancer.This article is freely available via Open Access. Click on the Publisher URL to access it via the publisher's site.published version, accepted version (12 month embargo) submitted versio