Abstract
Stimuli‐responsive hydrogels are intriguing biomimetic materials. Previous efforts to develop mechano‐responsive hydrogels have mostly relied on chemical modifications of the hydrogel ...structures. Here, we present a simple, generalizable strategy that confers mechano‐responsive behavior on hydrogels. Our approach involves embedding hybrid vesicles, composed of phospholipids and amphiphilic block copolymers, within the hydrogel matrix to act as signal transducers. Under mechanical stress, these vesicles undergo deformation and rupture, releasing encapsulated compounds that can control the hydrogel network. To demonstrate this concept, we embedded vesicles containing ethylene glycol tetraacetic acid (EGTA), a calcium chelator, into a calcium‐crosslinked alginate hydrogel. When compressed, the released EGTA sequesters calcium ions and degrades the hydrogel. This study provides a novel method for engineering mechano‐responsive hydrogels that may be useful in various biomedical applications.
Plasma and wave measurements from the NASA Magnetospheric Multiscale mission are presented for magnetotail reconnection events on 3 July and 11 July 2017. Linear dispersion analyses were performed ...using distribution functions comprising up to six drifting bi‐Maxwellian distributions. In both events electron crescent‐shaped distributions are shown to be responsible for upper hybrid waves near the X‐line. In an adjacent location within the 3 July event a monodirectional field‐aligned electron beam drove parallel‐propagating beam‐mode waves. In the 11 July event an electron distribution consisting of a drifting core and two crescents was shown to generate upper‐hybrid and beam‐mode waves at three different frequencies, explaining the observed broadband waves. Multiple harmonics of the upper hybrid waves were observed but cannot be explained by the linear dispersion analysis since they result from nonlinear beam interactions.
Plain Language Summary
Magnetic reconnection is a process that occurs throughout the universe in ionized gases (plasmas) containing embedded magnetic fields. This process converts magnetic energy to electron and ion energy, causing phenomena such as solar flares and auroras. The NASA Magnetospheric Multiscale mission has shown that in magnetic reconnection regions there are intense electric field oscillations or waves and that electrons form crescent and beam‐like populations propagating both along and perpendicular to the magnetic field. This study shows that the observed electron populations are responsible for high‐frequency waves including their propagation directions and frequency ranges.
Key Points
Electron crescent‐shaped distributions produce upper hybrid waves in magnetotail reconnection events
Field‐aligned electron beams generate parallel electrostatic waves through the beam‐mode
Multiple crescent and convecting core distributions act together to produce broad frequency spectra as observed by MMS
The separation of sarcomatous and desmoplastic mesotheliomas from benign organizing pleuritis can be morphologically very difficult. Deletion of p16 (CDKN2A) by fluorescence in situ hybridization ...(FISH) testing appears to be a reliable marker of malignancy in mesothelial proliferations, and more recently it has been reported that, in this setting, loss of BAP1 by immunohistochemistry is only seen in malignant mesotheliomas. To determine how useful these tests are with sarcomatous and desmoplastic mesotheliomas, we examined 20 such tumors. Loss of BAP1 was seen in 3/20 (15%) and deletion of p16 by FISH was seen in 16/20 (80%) cases. Loss of one or the other marker was observed in 17/20 (85%). We also examined 13 sarcomatoid carcinomas, an important differential diagnosis of sarcomatoid mesotheliomas, and found that BAP1 was never lost, but p16 was deleted in 3/11 (27%). We conclude that(1) BAP1 immunohistochemistry is relatively insensitive in the context of sarcomatous and desmoplastic mesotheliomas, but as a matter of time and cost efficiency may nonetheless be a useful first approach to the problem; (2) deletion of p16 by FISH is considerably more sensitive, but there remain a proportion of cases in which p16 is not deleted; (3) a small improvement in sensitivity can be achieved by using both markers; (4) in the context of a spindle cell malignant tumor in the pleura or peritoneum, which morphologically might be a metastatic sarcomatoid carcinoma or a mesothelioma, the finding of BAP1 loss favors mesothelioma, but p16 FISH cannot be used to separate sarcomatous mesotheliomas from sarcomatoid carcinomas.
Abstract
Each neurodegenerative syndrome reflects a stereotyped pattern of cellular, regional, and large-scale brain network degeneration. In behavioral variant of frontotemporal dementia (bvFTD), a ...disorder of social-emotional function, von Economo neurons (VENs), and fork cells are among the initial neuronal targets. These large layer 5 projection neurons are concentrated in the anterior cingulate and frontoinsular (FI) cortices, regions that anchor the salience network, a large-scale system linked to social-emotional function. Here, we studied patients with bvFTD, amyotrophic lateral sclerosis (ALS), or both, given that these syndromes share common pathobiological and genetic factors. Our goal was to determine how neuron type-specific TAR DNA-binding protein of 43 kDa (TDP-43) pathobiology relates to atrophy in specific brain structures and to loss of emotional empathy, a cardinal feature of bvFTD. We combined questionnaire-based empathy assessments, in vivo structural MR imaging, and quantitative histopathological data from 16 patients across the bvFTD/ALS spectrum. We show that TDP-43 pathobiology within right FI VENs and fork cells is associated with salience network atrophy spanning insular, medial frontal, and thalamic regions. Gray matter degeneration within these structures mediated loss of emotional empathy, suggesting a chain of influence linking the cellular, regional/network, and behavioral levels in producing signature bvFTD clinical features.
The question of how Zika virus (ZIKV) changed from a seemingly mild virus to a human pathogen capable of microcephaly and sexual transmission remains unanswered. The unexpected emergence of ZIKV's ...pathogenicity and capacity for sexual transmission may be due to genetic changes, and future changes in phenotype may continue to occur as the virus expands its geographic range. Alternatively, the sheer size of the 2015-16 epidemic may have brought attention to a pre-existing virulent ZIKV phenotype in a highly susceptible population. Thus, it is important to identify patterns of genetic change that may yield a better understanding of ZIKV emergence and evolution. However, because ZIKV has an RNA genome and a polymerase incapable of proofreading, it undergoes rapid mutation which makes it difficult to identify combinations of mutations associated with viral emergence. As next generation sequencing technology has allowed whole genome consensus and variant sequence data to be generated for numerous virus samples, the task of analyzing these genomes for patterns of mutation has become more complex. However, understanding which combinations of mutations spread widely and become established in new geographic regions versus those that disappear relatively quickly is essential for defining the trajectory of an ongoing epidemic. In this study, multiscale analysis of the wealth of genomic data generated over the course of the epidemic combined with in vivo laboratory data allowed trends in mutations and outbreak trajectory to be assessed. Mutations were detected throughout the genome via deep sequencing, and many variants appeared in multiple samples and in some cases become consensus. Similarly, amino acids that were previously consensus in pre-outbreak samples were detected as low frequency variants in epidemic strains. Protein structural models indicate that most of the mutations associated with the epidemic transmission occur on the exposed surface of viral proteins. At the macroscale level, consensus data was organized into large and interactive databases to allow the spread of individual mutations and combinations of mutations to be visualized and assessed for temporal and geographical patterns. Thus, the use of multiscale modeling for identifying mutations or combinations of mutations that impact epidemic transmission and phenotypic impact can aid the formation of hypotheses which can then be tested using reverse genetics.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The determination of molecular features that mediate clinically aggressive phenotypes in prostate cancer remains a major biological and clinical challenge
. Recent advances in interpretability of ...machine learning models as applied to biomedical problems may enable discovery and prediction in clinical cancer genomics
. Here we developed P-NET-a biologically informed deep learning model-to stratify patients with prostate cancer by treatment-resistance state and evaluate molecular drivers of treatment resistance for therapeutic targeting through complete model interpretability. We demonstrate that P-NET can predict cancer state using molecular data with a performance that is superior to other modelling approaches. Moreover, the biological interpretability within P-NET revealed established and novel molecularly altered candidates, such as MDM4 and FGFR1, which were implicated in predicting advanced disease and validated in vitro. Broadly, biologically informed fully interpretable neural networks enable preclinical discovery and clinical prediction in prostate cancer and may have general applicability across cancer types.
Data from the NASA Magnetospheric Multiscale mission are used to investigate asymmetric magnetic reconnection at the dayside boundary between the Earth's magnetosphere and the solar wind. ...High‐resolution measurements of plasmas and fields are used to identify highly localized (~15 electron Debye lengths) standing wave structures with large electric field amplitudes (up to 100 mV/m). These wave structures are associated with spatially oscillatory energy conversion, which appears as alternatingly positive and negative values of J · E. For small guide magnetic fields the wave structures occur in the electron stagnation region at the magnetosphere edge of the electron diffusion region. For larger guide fields the structures also occur near the reconnection X‐line. This difference is explained in terms of channels for the out‐of‐plane current (agyrotropic electrons at the stagnation point and guide field‐aligned electrons at the X‐line).
Key Points
Energy conversion is highly localized within asymmetric reconnection electron diffusion regions
Oscillatory reconnection electric fields show characteristics of both spatial structures and propagating waves that are consistent with standing oblique quasi‐electrostatic whistlers
Both positive and negative values of J · E result from uniform current and oscillating electric fields
Breast cancer patients with BRCA1/2‐driven tumors may benefit from targeted therapy. It is not clear whether current BRCA screening guidelines are effective at identifying these patients. The purpose ...of our study was to evaluate the prevalence of inherited BRCA1/2 pathogenic variants in a large, clinically representative breast cancer cohort and to estimate the proportion of BRCA1/2 carriers not detected by selectively screening individuals with the highest probability of being carriers according to current clinical guidelines. The study included 5,122 unselected Swedish breast cancer patients diagnosed from 2001 to 2008. Target sequence enrichment (48.48 Fluidigm Access Arrays) and sequencing were performed (Illumina Hi‐Seq 2,500 instrument, v4 chemistry). Differences in patient and tumor characteristics of BRCA1/2 carriers who were already identified as part of clinical BRCA1/2 testing routines and additional BRCA1/2 carriers found by sequencing the entire study population were compared using logistic regression models. Ninety‐two of 5,099 patients with valid variant calls were identified as BRCA1/2 carriers by screening all study participants (1.8%). Only 416 study participants (8.2%) were screened as part of clinical practice, but this identified 35 out of 92 carriers (38.0%). Clinically identified carriers were younger, less likely postmenopausal and more likely to be associated with familiar ovarian cancer compared to the additional carriers identified by screening all patients. More BRCA2 (34/42, 81.0%) than BRCA1 carriers (23/50, 46%) were missed by clinical screening. In conclusion, BRCA1/2 mutation prevalence in unselected breast cancer patients was 1.8%. Six in ten BRCA carriers were not detected by selective clinical screening of individuals.
What's new?
In order to provide personalized therapy to patients with pathogenic BRCA1/2 variants, it's necessary to find them. Currently, patients are screened based on risk factors, such as family history. How many BRCA1/2 carriers are missed? What if everyone were screened? Here, the authors sequenced DNA from more than 5,000 Swedish breast cancer patients looking for pathogenic BRCA1/2 variants, and they found 92 carriers. Of these, only 35 had been identified by clinical screening. 60% of cancer‐causing BRCA variants had not been detected. This is one of the largest population‐based studies to date examining BRCA1/2 prevalence.
We report strong THz-induced transparency in CVD-grown graphene where 92–96% of the peak-field is transmitted compared to 74% at lower field strength. Time-resolved THz pump/THz probe studies reveal ...that the absorption recovers in 2–3 ps. The induced transparency is believed to arise from nonlinear pumping of carriers in graphene which suppresses the mobility and consequently the conductivity in a spectral region where the light–matter interaction is particularly strong.
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