1,724 research outputs found
Dear Old Italy
Illustration of boat with cityscape in backgroundhttps://scholarsjunction.msstate.edu/cht-sheet-music/12679/thumbnail.jp
Tumor-associated stromal cells as key contributors to the tumor microenvironment.
The tumor microenvironment is a heterogeneous population of cells consisting of the tumor bulk plus supporting cells. It is becoming increasingly evident that these supporting cells are recruited by cancer cells from nearby endogenous host stroma and promote events such as tumor angiogenesis, proliferation, invasion, and metastasis, as well as mediate mechanisms of therapeutic resistance. In addition, recruited stromal cells range in type and include vascular endothelial cells, pericytes, adipocytes, fibroblasts, and bone-marrow mesenchymal stromal cells. During normal wound healing and inflammatory processes, local stromal cells change their phenotype to become that of reactive stroma. Under certain conditions, however, tumor cells can co-opt these reactive stromal cells and further transition them into tumor-associated stromal cells (TASCs). These TASCs express higher levels of proteins, including alpha-smooth muscle actin, fibroblast activating protein, and matrix metalloproteinases, compared with their normal, non-reactive counterparts. TASCs are also known to secrete many pro-tumorigenic factors, including IL-6, IL-8, stromal-derived factor-1 alpha, vascular endothelial growth factor, tenascin-C, and matrix metalloproteinases, among others, which recruit additional tumor and pro-tumorigenic cells to the developing microenvironment. Here, we review the current literature pertaining to the origins of recruited host stroma, contributions toward tumor progression, tumor-associated stromal cells, and mechanisms of crosstalk between endogenous host stroma and tumor cells
Ultrafast nonlinear optical response of Dirac fermions in graphene
The speed of solid-state electronic devices, determined by the temporal dynamics of charge
carriers, could potentially reach unprecedented petahertz frequencies through direct
manipulation by optical fields, consisting in a million-fold increase from state-of-the-art
technology. In graphene, charge carrier manipulation is facilitated by exceptionally strong
coupling to optical fields, from which stems an important back-action of photoexcited carriers.
Here we investigate the instantaneous response of graphene to ultrafast optical fields,
elucidating the role of hot carriers on sub-100 fs timescales. The measured nonlinear
response and its dependence on interaction time and field polarization reveal the back-action
of hot carriers over timescales commensurate with the optical field. An intuitive picture is
given for the carrier trajectories in response to the optical-field polarization state. We note
that the peculiar interplay between optical fields and charge carriers in graphene may also
apply to surface states in topological insulators with similar Dirac cone dispersion relations.Peer ReviewedPostprint (published version
Role of Electrostatic Interactions in Calcitonin Prefibrillar Oligomer-Induced Amyloid Neurotoxicity and Protective Effect of Neuraminidase
Salmon calcitonin is a good model for studying amyloid behavior and neurotoxicity. Its slow aggregation rate allows the purification of low molecular weight prefibrillar oligomers, which are the most toxic species. It has been proposed that these species may cause amyloid pore formation in neuronal membranes through contact with negatively charged sialic acid residues of the ganglioside GM1. In particular, it has been proposed that an electrostatic interaction may be responsible for the initial contact between prefibrillar oligomers and GM1 contained in lipid rafts. Based on this evidence, the aim of our work was to investigate whether the neurotoxic action induced by calcitonin prefibrillar oligomers could be counteracted by treatment with neuraminidase, an enzyme that removes sialic acid residues from gangliosides. Therefore, we studied cell viability in HT22 cell lines and evaluated the effects on synaptic transmission and long-term potentiation by in vitro extracellular recordings in mouse hippocampal slices. Our results showed that treatment with neuraminidase alters the surface charges of lipid rafts, preventing interaction between the calcitonin prefibrillar oligomers and GM1, and suggesting that the enzyme, depending on the concentration used, may have a partial or total protective action in terms of cell survival and modulation of synaptic transmission
Petahertz optical response in graphene
The temporal dynamics of charge carriers determines the speed with which
electronics can be realized in condensed matter, and their direct manipulation
with optical fields promises electronic processing at unprecedented petahertz
frequencies, consisting in a million-fold increase from state of the art
technology. Graphene is of particular interest for the implementation of
petahertz optoelectronics due to its unique transport properties, such as high
carrier mobility with near-ballistic transport and exceptionally strong
coupling to optical fields. The back action of carriers in response to an
optical field is therefore of key importance towards applications. Here we
investigate the instantaneous response of graphene to petahertz optical fields
and elucidate the role of hot carriers on a sub-100 fs timescale. Measurements
of the nonlinear response and its dependence on interaction time and field
polarization allow us to identify the back action of hot carriers over
timescales that are commensurate with the optical field. An intuitive picture
is given for the carrier trajectories in response to the optical-field
polarization state. We note that the peculiar interplay between optical fields
and charge carriers in graphene may also apply to surface states in topological
insulators with similar Dirac cone dispersion relations.Comment: 6 pages, 4 figure
Seven unconfirmed ideas to improve future ICU practice
With imprecise definitions, inexact measurement tools, and flawed study execution, our clinical science often lags behind bedside experience and simply documents what appear to be the apparent faults or validity of ongoing practices. These impressions are later confirmed, modified, or overturned by the results of the next trial. On the other hand, insights that stem from the intuitions of experienced clinicians, scientists and educators-while often neglected-help place current thinking into proper perspective and occasionally point the way toward formulating novel hypotheses that direct future research. Both streams of information and opinion contribute to progress. In this paper we present a wide-ranging set of unproven 'out of the mainstream' ideas of our FCCM faculty, each with a defensible rationale and holding clear implications for altering bedside management. Each proposition was designed deliberately to be provocative so as to raise awareness, stimulate new thinking and initiate lively dialog
MiKlip - a National Research Project on Decadal Climate Prediction
A German national project coordinates research on improving a global decadal climate prediction system for future operational use.
MiKlip, an eight-year German national research project on decadal climate prediction, is organized around a global prediction system comprising the climate model MPI-ESM together with an initialization procedure and a model evaluation system. This paper summarizes the lessons learned from MiKlip so far; some are purely scientific, others concern strategies and structures of research that targets future operational use.
Three prediction-system generations have been constructed, characterized by alternative initialization strategies; the later generations show a marked improvement in hindcast skill for surface temperature. Hindcast skill is also identified for multi-year-mean European summer surface temperatures, extra-tropical cyclone tracks, the Quasi-Biennial Oscillation, and ocean carbon uptake, among others. Regionalization maintains or slightly enhances the skill in European surface temperature inherited from the global model and also displays hindcast skill for wind-energy output. A new volcano code package permits rapid modification of the predictions in response to a future eruption.
MiKlip has demonstrated the efficacy of subjecting a single global prediction system to a major research effort. The benefits of this strategy include the rapid cycling through the prediction-system generations, the development of a sophisticated evaluation package usable by all MiKlip researchers, and regional applications of the global predictions. Open research questions include the optimal balance between model resolution and ensemble size, the appropriate method for constructing a prediction ensemble, and the decision between full-field and anomaly initialization.
Operational use of the MiKlip system is targeted for the end of the current decade, with a recommended generational cycle of two to three years
Clinical relevance of postzygotic mosaicism in Cornelia de Lange syndrome and purifying selection of NIPBL variants in blood.
Postzygotic mosaicism (PZM) in NIPBL is a strong source of causality for Cornelia de Lange syndrome
(CdLS) that can have major clinical implications. Here, we further delineate the role of somatic
mosaicism in CdLS by describing a series of 11 unreported patients with mosaic disease-causing
variants in NIPBL and performing a retrospective cohort study from a Spanish CdLS diagnostic
center. By reviewing the literature and combining our findings with previously published data, we
demonstrate a negative selection against somatic deleterious NIPBL variants in blood. Furthermore,
the analysis of all reported cases indicates an unusual high prevalence of mosaicism in CdLS,
occurring in 13.1% of patients with a positive molecular diagnosis. It is worth noting that most of
the affected individuals with mosaicism have a clinical phenotype at least as severe as those with
constitutive pathogenic variants. However, the type of genetic change does not vary between
germline and somatic events and, even in the presence of mosaicism, missense substitutions are
located preferentially within the HEAT repeat domain of NIPBL. In conclusion, the high prevalence
of mosaicism in CdLS as well as the disparity in tissue distribution provide a novel orientation for the
clinical management and genetic counselling of families.post-print3237 K
Near Infrared Fluorescent Nanoparticles Derived from Hyaluronic Acid Improve Tumor Contrast for Image-Guided Surgery.
Tumor tissue that remains undetected at the primary surgical site can cause tumor recurrence, repeat surgery, and treatment strategy alterations that impose a significant patient and healthcare burden. Intraoperative near infrared fluorescence (NIRF) imaging is one potential method to identify remaining tumor by visualization of NIR fluorophores that are preferentially localized to the tumor. This requires development of fluorophores that consistently identify tumor tissue in different patients and tumor types. In this study we examined a panel of NIRF contrast agents consisting of polymeric nanoparticle (NP) formulations derived from hyaluronic acid (HA), with either physically entrapped indocyanine green (ICG) or covalently conjugated Cy7.5. Using orthotopic human breast cancer MDA-MB-231 xenografts in nude mice we identified two lead formulations. One, NanoICGPBA, with physicochemically entrapped ICG, showed 2.3-fold greater tumor contrast than ICG alone at 24 h (p \u3c 0.01), and another, NanoCy7.5100-H, with covalently conjugated Cy7.5, showed 74-fold greater tumor contrast than Cy7.5 alone at 24 h (p \u3c 0.0001). These two lead formulations were then tested in immune competent BALB/c mice bearing orthotopic 4T1 breast cancer tumors. NanoICGPBA showed 2.2-fold greater contrast than ICG alone (p \u3c 0.0001), and NanoCy7.5100-H showed 14.8-fold greater contrast than Cy7.5 alone (p \u3c 0.0001). Furthermore, both NanoICGPBA and NanoCy7.5100-H provided strong tumor enhancement using image-guided surgery in mice bearing 4T1 tumors. These studies demonstrate the efficacy of a panel of HA-derived NPs in delineating tumors in vivo, and identifies promising formulations that can be used for future in vivo tumor removal efficacy studies
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