ProNGF Is a Cell-Type-Specific Mitogen for Adult Hippocampal and for Induced Neural Stem Cells

The role of proNGF, the precursor of Nerve Growth Factor (NGF), on the biology of adult neural stem cells (aNSCs) is still unclear. Here I analyzed adult hippo-campal neurogenesis in AD11 transgenic mice, in which the constitutive expression of anti-NGF antibody leads to an imbalance of proNGF over mature NGF. I found in-creased proliferation of progenitors but a reduced neurogenesis in the AD11 DG- hippocampus (HP-DG). Also in vitro, AD11 hippocampal neural stem cells (NSCs) pro-liferated more but were unable to differentiate into morphologically mature neu-rons. By treating wild-type (WT) hippocampal progenitors with the uncleavable form of proNGF (proNGF-KR) I demonstrated that proNGF acts as mitogen on aNSCs at low concentration. The mitogenic effect of proNGF was specifically addressed to the radial glia-like (RGL) neural stem cells through the induction of cyclin D1 expression. These cells express high level of p75NTR, as demonstrated by immunofluorescence analyses performed ex vivo on RGL cells isolated from freshly-dissociated HP-DG or selected in vitro from NSCs by LIF (leukemia inhibitory factor). Clonogenic assay per-formed in the absence of mitogens showed that RGLs respond to proNGF-KR by re-activating their proliferation and thus leading to neurospheres formation. The mito-genic effect of proNGF was further exploited in the expansion of mouse induced Neural Stem Cells (iNSCs). Chronic exposure of iNSCs to proNGF-KR increased their proliferation. Altogether, I demonstrated that proNGF acts as mitogen on hippo-campal and induced neural stem cells.The role of proNGF, the precursor of nerve growth factor (NGF), in the biology of adult neural stem cells (aNSCs) is still unclear. Here, we analyzed adult hippocampal neurogenesis in AD11 transgenic mice, in which the constitutive expression of anti-NGF antibody leads to an imbalance of proNGF over mature NGF. We found increased proliferation of progenitors but a reduced neurogenesis in the AD11 dentate gyrus (DG)-hippocampus (HP). Also in vitro, AD11 hippocampal neural stem cells (NSCs) proliferated more, but were unable to differentiate into morphologically mature neurons. By treating wild-type hippocampal progenitors with the uncleavable form of proNGF (proNGF-KR), we demonstrated that proNGF acts as mitogen on aNSCs at low concentration. The mitogenic effect of proNGF was specifically addressed to the radial glia-like (RGL) stem cells through the induction of cyclin D1 expression. These cells express high levels of p75NTR, as demonstrated by immunofluorescence analyses performed ex vivo on RGL cells isolated from freshly dissociated HP-DG or selected in vitro from NSCs by leukemia inhibitory factor. Clonogenic assay performed in the absence of mitogens showed that RGLs respond to proNGF-KR by reactivating their proliferation and thus leading to neurospheres formation. The mitogenic effect of proNGF was further exploited in the expansion of mouse-induced neural stem cells (iNSCs). Chronic exposure of iNSCs to proNGF-KR increased their proliferation. Altogether, we demonstrated that proNGF acts as mitogen on hippocampal and iNSCs. Stem Cells 2019;37:1223–1237

Industry dynamics, technological regimes and the role of demand

In this paper, we propose an industrial dynamics model to analyze the interactions between the price-performance sensitivity of demand, the sources of innovation in a sector, and certain features of the corresponding pattern of industrial transformation. More precisely, we study market concentration in different technological regimes and demand conditions. The computational analysis of our model shows that market demand plays a key role in industrial dynamics. Thus, although for intermediate values of the price-performance sensitivity, our results show the well-known relationships in the literature between technological regimes and industry transformation, we find surprising outcomes when demand is strongly biased either towards price or performance. Hence, for different technological regimes, a high performance sensitivity of demand tends to concentrate the market. On the other hand, under conditions of high price sensitivity, the industry generally tends to atomize. That is to say, for extreme values of the price-performance sensitivity of demand, we find concentrated or atomized market structures no matter the technological regime we are in. These results highlight the importance of considering the role of demand in the analysis of industrial dynamics

Hot-electron nanoscopy using adiabatic compression of surface plasmons

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High intake of phytoestrogens and precocious thelarche: case report with a possible correlation

Precocious thelarche is the breast development before 8 years of age with two peaks of incidence during the first two years of life and after 6 years of age. A 4.75-year-old girl presented with thelarche associated to an excessive intake of phytoestrogens (phye). Tanner development B2P1-2, hormonal levels and pelvic US were compatible with peripheral precocious puberty. During follow-up, a daily intake of soy-based foods was observed (> 40 mg phye/day). Soy is rich in phytoestrogens, mainly genistein and daidzein. Although phye are less strong than estradiol, its concentration could be from 13,000 to 22,000 times stronger in children fed only by soy-based formulas. Parents were advised and soy intake was reduced to once a week. Progression of pubertal development ceased at B2-3P1. The patient, now 8.66 years old, keeps growing with similar bone and chronological ages. Some questions related to industrial food security, mainly the soy-based food, remain without precise answer. Although it is well known the entity of non-progressive precocious puberty and premature thelarche, pubertal development in this case was strongly related to excessive daily intake of soy and other phye-rich food that could trigger puberty as endocrine disruptor.Telarca precoce, desenvolvimento mamário antes dos 8 anos de idade, apresenta dois picos de incidência, nos dois primeiros anos de vida e após os 6 anos de idade. Uma menina de 4,75 anos apresentou-se com telarca associada à ingestão excessiva de fitoestrógenos. O desenvolvimento puberal M2P1-2, os níveis hormonais e o US pélvico eram compatíveis com puberdade precoce periférica. Durante o seguimento, observou-se ingestão diária de alimentos baseados em soja (> 40 mg fitoestrógenos/dia). Soja contém fitoestrógenos, principalmente genisteína e daidzeína. Embora menos potentes do que o estradiol, sua concentração pode ser 13.000 a 22.000 vezes maior em crianças alimentadas somente com fórmulas baseadas em soja. Os pais foram aconselhados a reduzir para uma vez na semana o seu fornecimento na dieta. O desenvolvimento puberal cessou em M2-3P1 e a paciente, com 8,66 anos, continua a desenvolver-se com idades óssea e cronológica equivalentes. Questões relacionadas à segurança alimentar, principalmente de alimentos baseados em soja, permanecem sem respostas precisas. Embora sejam conhecidas as etiologias da puberdade precoce não progressiva e da telarca prematura, neste caso esteve fortemente relacionada à ingestão excessiva de soja e de outros alimentos ricos em fitoestrógenos que poderiam ter desencadeado a telarca atuando como desreguladores endócrinos.Universidade Federal de São Paulo (UNIFESP) Escola Paulista de Medicina Departamento de MedicinaUNIFESP, EPM, Depto. de MedicinaSciEL

Pierce the ear and stab the spleen

Splenic abscess is a rare but extremely dangerous condition generally spreading from a local, or systemic, focus of infection. We present the case of a young immunocompetent female admitted with sepsis and multiple splenic abscesses. The patient had a recent left ear piercing on the tragus complicated by an ear infection. The presence of a solitary parotid abscess, the absence of other infectious foci on computed tomography scan, the negativity of blood cultures and the absence of endocarditis vegetations led us to think that the most likely culprit was a hematogenous dissemination from the left tragus. The patient was successfully treated with intravenous antibiotics. There had been no need of splenectomy or any other procedure. This rather unique case underscores that splenic abscess should be suspected when a long-lasting fever and pain in the left hypochondrium are present, even when an apparently innocuous invasive procedure, such as a body piercing, is performed

A Statistical Model for Assessing Genetic Susceptibility as a Risk Factor in Multifactorial Diseases: Lessons from Occupational Asthma

BACKGROUND: Incorporating the influence of genetic variation in the risk assessment process is often considered, but no generalized approach exists. Many common human diseases such as asthma, cancer, and cardiovascular disease are complex in nature, as they are influenced variably by environmental, physiologic, and genetic factors. The genetic components most responsible for differences in individual disease risk are thought to be DNA variants (polymorphisms) that influence the expression or function of mediators involved in the pathological processes. OBJECTIVE: The purpose of this study was to estimate the combinatorial contribution of multiple genetic variants to disease risk. METHODS: We used a logistic regression model to help estimate the joint contribution that multiple genetic variants would have on disease risk. This model was developed using data collected from molecular epidemiology studies of allergic asthma that examined variants in 16 susceptibility genes. RESULTS: Based on the product of single gene variant odds ratios, the risk of developing asthma was assigned to genotype profiles, and the frequency of each profile was estimated for the general population. Our model predicts that multiple disease variants broaden the risk distribution, facilitating the identification of susceptible populations. This model also allows for incorporation of exposure information as an independent variable, which will be important for risk variants associated with specific exposures. CONCLUSION: The present model provided an opportunity to estimate the relative change in risk associated with multiple genetic variants. This will facilitate identification of susceptible populations and help provide a framework to model the genetic contribution in probabilistic risk assessment

Assessing the role of collaboration in the process of museum innovation

The relationship between collaboration and innovation in cultural organisations is an emerging topic that has drawn particular attention from scholars and practitioners. The main aim of this study is to assess the role of collaboration in the process of innovation in museum organisations. To achieve this aim, first, we develop a four-domain analytical framework by matching innovation types to cultural production processes to reflect the peculiarities of museum innovation. By applying this framework to the multiple case studies from four Spanish museums, we identify three main motivations (supplementing manpower, compensating for the scarcity of knowledge, improving demand-driven innovation) and four forms of collaboration (teamwork, outsourcing, consortium and conversation) and summarise the different modes of collaboration involved in various domains of production and innovation. An assessment is conducted subsequently to evaluate the effectiveness of existing collaborations in achieving technological and cultural innovation in museums. Finally, a list of implications for museums' innovation management is presented

Imputation reliability on DNA biallelic markers for drug metabolism studies

Imputation is a statistical process used to predict genotypes of loci not directly assayed in a sample of individuals. Our goal is to measure the performance of imputation in predicting the genotype of the best known gene polymorphisms involved in drug metabolism using a common SNP array genotyping platform generally exploited in genome wide association studies.METHODS:Thirty-nine (39) individuals were genotyped with both Affymetrix Genome Wide Human SNP 6.0 (AFFY) and Affymetrix DMET Plus (DMET) platforms. AFFY and DMET contain nearly 900000 and 1931 markers respectively. We used a 1000 Genomes Pilot + HapMap 3 reference panel. Imputation was performed using the computer program Impute, version 2. SNPs contained in DMET, but not imputed, were analysed studying markers around their chromosome regions. The efficacy of the imputation was measured evaluating the number of successfully imputed SNPs (SSNPs).RESULTS:The imputation predicted the genotypes of 654 SNPs not present in the AFFY array, but contained in the DMET array. Approximately 1000 SNPs were not annotated in the reference panel and therefore they could not be directly imputed. After testing three different imputed genotype calling threshold (IGCT), we observed that imputation performs at its best for IGCT value equal to 50%, with rate of SSNPs (MAF > 0.05) equal to 85%.CONCLUSIONS:Most of the genes involved in drug metabolism can be imputed with high efficacy using standard genome-wide genotyping platforms and imputing procedures

Application of the whole-transcriptome shotgun sequencing approach to the study of Philadelphia-positive acute lymphoblastic leukemia

Although the pathogenesis of BCR–ABL1-positive acute lymphoblastic leukemia (ALL) is mainly related to the expression of the BCR–ABL1 fusion transcript, additional cooperating genetic lesions are supposed to be involved in its development and progression. Therefore, in an attempt to investigate the complex landscape of mutations, changes in expression profiles and alternative splicing (AS) events that can be observed in such disease, the leukemia transcriptome of a BCR–ABL1-positive ALL patient at diagnosis and at relapse was sequenced using a whole-transcriptome shotgun sequencing (RNA-Seq) approach. A total of 13.9 and 15.8 million sequence reads was generated from de novo and relapsed samples, respectively, and aligned to the human genome reference sequence. This led to the identification of five validated missense mutations in genes involved in metabolic processes (DPEP1, TMEM46), transport (MVP), cell cycle regulation (ABL1) and catalytic activity (CTSZ), two of which resulted in acquired relapse variants. In all, 6390 and 4671 putative AS events were also detected, as well as expression levels for 18 315 and 18 795 genes, 28% of which were differentially expressed in the two disease phases. These data demonstrate that RNA-Seq is a suitable approach for identifying a wide spectrum of genetic alterations potentially involved in ALL

Challenges and improvement pathways to develop quasi-1D (Sb1-xBix)2Se3-based materials for optically tuneable photovoltaic applications. Towards chalcogenide narrow-bandgap devices

Quasi-1D chalcogenides have shown great promises in the development of emerging photovoltaic technologies. However, most quasi-1D semiconductors other than Sb2Se3 and Sb2S3 have been seldom investigated for energy generation applications. Indeed, cationic or anionic alloying strategies allow changing the bandgap of these materials, opening the door to the development of an extended range of chalcogenides with tuneable optical and electrical properties. In this work, Bi incorporation into the Sb2Se3 structure has been proved as an effective approach to modulate the bandgap between 0.1. In order to better understand the underlying mechanisms leading to the formation of (Sb1-xBix)2Se3, and thus design specific strategies to enhance its properties, thin films with different annealing time and temperature have been synthesized and characterized. Interestingly, it has been observed that Sb2Se3 and Bi2Se3 are formed first, with Bi melting at 300 ¿C and diffusing rapidly towards the surface of the film. At higher temperature, the binary compounds combine to form the solid solution, however as the dwell time increases, (Sb1-xBix)2Se3 decomposes again into Bi2Se3 and Sb. This study has shown that the material is essentially limited by compositional disorder and recombination via defects. Likewise, routes have been proposed to improve morphology and uniformity of the layer, achieving efficiencies higher than 1% for x > 0.2Postprint (published version