The puberty‐ and fertility‐regulating neuropeptide kisspeptin (KISS1) exerts dramatic effects on the physiology of adult gonadotrophin‐releasing hormone (GnRH) neurones as a master regulator of ...mammalian reproduction. Given the action of KISS1 directly on adult GnRH neurones, and that KISS1 activates a signal transduction cascade involved in neurite growth in other neurones, we investigated whether KISS1 may play a role in the normal growth of GnRH neurites to the median eminence. A reverse transcription‐polymerase chain reaction demonstrated the expression of Kiss1 mRNA in the embryonic mediobasal hypothalamus, the target region for GnRH neurite termination, as early as embryonic day 13.5 (E13.5), a time when the first GnRH neurites are arriving. Complementary expression of the mRNA encoding the KISS1 receptor, Kiss1r, in the preoptic area (POA) at E13.5 was also observed, suggesting that POA‐resident GnRH neurones can respond to KISS1 from an early age. To examine the effects of KISS1 on GnRH neurite growth in isolation, E15.5 POA explants, containing GnRH neurones actively extending neurites, were grown in three‐dimensional collagen gels. In the presence of KISS1 (1 μm), both the number and length of GnRH neurites were increased significantly compared to controls without KISS1. The effects of KISS1 on GnRH neurite growth could be inhibited by pretreatment with the phospholipase C inhibitor U73122 (50 μm), indicating that embryonic and adult GnRH neurones respond to KISS1 with the same intracellular signalling pathway. KISS1 provided in a concentration gradient from a fixed source had no effect on GnRH neurite growth, indicating that KISS1 does not function as a long‐range chemoattractant. Taken together, these results identify KISS1 as a stimulator of GnRH neurite growth, and suggest that it influences GnRH neurites at close‐range to innervate the median eminence. These data add a novel developmental role to the repertoire of the functions of KISS1 in mammalian reproduction.
Abstract In this study, we investigated whether the potential positive effects of nicotine in Alzheimer's disease (AD) may involve neurotrophic factors, such as nerve growth factor (NGF), closely ...associated with basal forebrain (BF) cholinergic function and survival. To this aim, we studied the effects of prolonged nicotine treatment on neurotrophin receptors expression and on NGF protein levels in the rat BF cholinergic circuitry. Both in vivo and in vitro experiments were conducted. We found that s.c. nicotine infusion (1.2 mg free base/kg/d delivered by mini-pumps for 7 days) induced in vivo an increase in tyrosine kinase receptor A (TrkA)—but not TrkB, TrkC or low affinity neurotrophin receptor p75 (p75)—expression in BF cholinergic neurons targeting the cerebral cortex. Nicotine did not produce statistically significant long-lasting effects on NGF levels in the cerebral cortex, or in the BF. In vitro experiments performed on primary BF neuronal cultures, showed that 72 h exposure to nicotine increased both TrkA expression, and NGF release in culture medium. Neutralization experiments with an anti-NGF antibody showed that NGF presence was not necessary for nicotine-induced increase of TrkA levels in cultured cholinergic neurons, suggesting that nicotine may act through NGF-independent mechanisms. This study shows that nicotine, independently of its action on NGF levels, may contribute to the restoration of the trophic support to BF cholinergic neurons by increasing TrkA levels.
We proved the ability of Fourier Transform Infrared microspectroscopy (microFTIR) complemented by Principal Component Analysis (PCA) to detect protein phosphorylation/de-phosphorylation in mammalian ...cells. We analyzed by microFTIR human polymorphonuclear neutrophil (PMNs) leukocytes, mouse-derived parental Ba/F3 cells (Ba/F3#PAR), Ba/F3 cells transfected with p210(BCR/ABL) (Ba/F3#WT) and expressing high levels of protein tyrosine kinase (PTK), and human-derived BCR/ABL positive K562 leukemic cell sub-clones engineered to differently express receptor-type tyrosine-protein phosphatase gamma (PTPRG). Synchrotron radiation (SR) and conventional (globar) IR sources were used to perform microFTIR respectively, on single cells and over several cells within the same sample. Ex vivo time-course experiments were run, inducing maximal protein phosphorylation in PMNs by 100 nM N-formylated tripeptide fMLP. Within the specific IR fingerprint 1800-850 cm(-1) frequency domain, PCA identified two regions with maximal signal variance. These were used to model and test the robustness of PCA in representing the dynamics of protein phosphorylation/de-phosphorylation processes. An IR signal ratio marker reflecting the homeostatic control by protein kinases and phosphatases was identified in normal leukocytes. The models identified by microFTIR and PCA in normal leukocytes also distinguished BCR/ABL positive Ba/F3#WT from BCR/ABL negative Ba/F3#PAR cells as well as K562 cells exposed to functionally active protein tyrosine phosphatase recombinant protein ICD-Tat transduced in cells by HIV-1 Tat technology or cells treated with the PTK inhibitor imatinib mesylate (IMA) from cells exposed to phosphatase inactive (D1028A)ICD-Tat recombinant protein and untreated control cells, respectively. The IR signal marker correctly reflected the degrees of protein phosphorylation associated with abnormal PTK activity in BCR/ABL positive leukemic cells and in general was inversely related to the expression/activity of PTPRG in leukemic sub-clones. In conclusion, we have described a new, reliable and simple spectroscopic method to study the ex vivo protein phosphorylation/de-phosphorylation balance in cell models: it is suitable for biomedical and pharmacological research labs but it also needs further optimization and its evaluation on large cohorts of patients to be proposed in the clinical setting of leukemia.
Abstract
The National Center for Biotechnology Information (NCBI) provides a large suite of online resources for biological information and data, including the GenBank® nucleic acid sequence database ...and the PubMed database of citations and abstracts published in life science journals. The Entrez system provides search and retrieval operations for most of these data from 38 distinct databases. The E-utilities serve as the programming interface for the Entrez system. Augmenting many of the web applications are custom implementations of the BLAST program optimized to search specialized data sets. New resources released in the past year include PubMed Labs and a new sequence database search. Resources that were updated in the past year include PubMed, PMC, Bookshelf, genome data viewer, Assembly, prokaryotic genomes, Genome, BioProject, dbSNP, dbVar, BLAST databases, igBLAST, iCn3D and PubChem. All of these resources can be accessed through the NCBI home page at www.ncbi.nlm.nih.gov.
PubMed is a free search engine for biomedical literature accessed by millions of users from around the world each day. With the rapid growth of biomedical literature-about two articles are added ...every minute on average-finding and retrieving the most relevant papers for a given query is increasingly challenging. We present Best Match, a new relevance search algorithm for PubMed that leverages the intelligence of our users and cutting-edge machine-learning technology as an alternative to the traditional date sort order. The Best Match algorithm is trained with past user searches with dozens of relevance-ranking signals (factors), the most important being the past usage of an article, publication date, relevance score, and type of article. This new algorithm demonstrates state-of-the-art retrieval performance in benchmarking experiments as well as an improved user experience in real-world testing (over 20% increase in user click-through rate). Since its deployment in June 2017, we have observed a significant increase (60%) in PubMed searches with relevance sort order: it now assists millions of PubMed searches each week. In this work, we hope to increase the awareness and transparency of this new relevance sort option for PubMed users, enabling them to retrieve information more effectively.
The possibility that neutrinos may be their own antiparticles, unique among the known fundamental particles, arises from the symmetric theory of fermions proposed by Ettore Majorana in 1937
. Given ...the profound consequences of such Majorana neutrinos, among which is a potential explanation for the matter-antimatter asymmetry of the universe via leptogenesis
, the Majorana nature of neutrinos commands intense experimental scrutiny globally; one of the primary experimental probes is neutrinoless double beta (0νββ) decay. Here we show results from the search for 0νββ decay of
Te, using the latest advanced cryogenic calorimeters with the CUORE experiment
. CUORE, operating just 10 millikelvin above absolute zero, has pushed the state of the art on three frontiers: the sheer mass held at such ultralow temperatures, operational longevity, and the low levels of ionizing radiation emanating from the cryogenic infrastructure. We find no evidence for 0νββ decay and set a lower bound of the process half-life as 2.2 × 10
years at a 90 per cent credibility interval. We discuss potential applications of the advances made with CUORE to other fields such as direct dark matter, neutrino and nuclear physics searches and large-scale quantum computing, which can benefit from sustained operation of large payloads in a low-radioactivity, ultralow-temperature cryogenic environment.
Thrombosis of splanchnic or cerebral veins is a typical manifestation of polycythemia vera (PV) or essential thrombocythemia (ET). The recently identified Janus kinase 2 (JAK2) V617F somatic mutation ...is closely related to chronic myeloproliferative disorders (CMD).
To assess the incidence of the JAK2 V617F mutation among patients with splanchnic or cerebral venous thrombosis with or without overt CMD.
We searched for the mutation in 139 adult patients (> 18 years old) with thrombosis of hepatic veins (HVT, n = 15), or extrahepatic portal vein (PVT) and/or mesenteric vein (MVT) (n = 79), or cerebral veins (CVT, n = 45). Only 19 patients fulfilled criteria for diagnosis of PV (n = 8) or ET (n = 11) at the time of thrombosis: four had HVT, 11 PVT and/or MVT, and four CVT.
The JAK2 V617F mutation was found in 94.7% 95% CI 75.3-99.0 of the patients with overt CMD at the time of thrombosis, in 21.5% (95% CI 13.8-31.7) of the patients with abdominal venous thrombosis and without overt CMD, and in 4.8% (95% CI 1.3-16.1) of the patients with CVT and without overt CMD. Among the patients without overt CMD or thrombophilia and with unprovoked thrombosis, 29.4% (95% CI 16.8-46.1) with splanchnic venous thrombosis and 42.8% (95% CI 24.4-63.4) with PVT had the JAK2 V617F mutation.
A substantial proportion of patients with splanchnic venous thrombosis and a small, but significant, number of patients with CVT can be recognized as carriers of the JAK2 V617F mutation in the absence of overt signs of CMD. The clinical significance of such findings deserves further investigation.
Within the vast panorama of multimodal systems for clinical diagnosis, PET/MRI has been receiving significant attention. In parallel, new technological solutions have been paving the way to ...simultaneous SPECT/MRI systems, whose development has been so far delayed due to the challenging compatibility between MRI, gamma-ray detectors, and collimators. This paper presents an silicon photomultiplier (SiPM)-based Anger camera designed for preclinical and clinical SPECT static inserts for standard MR scanners. The gamma-ray detector is based on a continuous CsI(Tl) scintillator readout by arrays of SiPMs and custom ASICs. The design has been adapted to fit with the limited space conditions (23 mm thickness), but also considering mutual compatibility issues. Despite these constraints and thanks to the adoption of an iterative statistical event estimation method simply requiring a flood image, the detector maintains state-of-the-art performance in terms of intrinsic spatial resolution (1.0 mm FWHM within the usable field of view) and an energy resolution below 14% FWHM at 140 keV. The experimental studies here performed show that the camera, designed to operate at 0 °C to reduce the dark current of SiPMs, can operate up to 10 °C without significant worsening of imaging performance.
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