1,519 research outputs found
A global transcriptional network connecting noncoding mutations to changes in tumor gene expression.
Although cancer genomes are replete with noncoding mutations, the effects of these mutations remain poorly characterized. Here we perform an integrative analysis of 930 tumor whole genomes and matched transcriptomes, identifying a network of 193 noncoding loci in which mutations disrupt target gene expression. These 'somatic eQTLs' (expression quantitative trait loci) are frequently mutated in specific cancer tissues, and the majority can be validated in an independent cohort of 3,382 tumors. Among these, we find that the effects of noncoding mutations on DAAM1, MTG2 and HYI transcription are recapitulated in multiple cancer cell lines and that increasing DAAM1 expression leads to invasive cell migration. Collectively, the noncoding loci converge on a set of core pathways, permitting a classification of tumors into pathway-based subtypes. The somatic eQTL network is disrupted in 88% of tumors, suggesting widespread impact of noncoding mutations in cancer
Plane waves with weak singularities
We study a class of time dependent solutions of the vacuum Einstein equations
which are plane waves with weak null singularities. This singularity is weak in
the sense that though the tidal forces diverge at the singularity, the rate of
divergence is such that the distortion suffered by a freely falling observer
remains finite. Among such weak singular plane waves there is a sub-class which
do not exhibit large back reaction in the presence of test scalar probes.
String propagation in these backgrounds is smooth and there is a natural way to
continue the metric beyond the singularity. This continued metric admits string
propagation without the string becoming infinitely excited. We construct a one
parameter family of smooth metrics which are at a finite distance in the space
of metrics from the extended metric and a well defined operator in the string
sigma model which resolves the singularity.Comment: 22 pages, Added references and clarifying comment
In vivo rate-determining steps of tau seed accumulation in Alzheimer's disease.
[Figure: see text].We acknowledge funding
from Sidney Sussex College Cambridge (GM) and the European Research Council Grant Number
669237 (to D.K.) and the Royal Society (to D.K.). The Cambridge Brain Bank is supported
by the NIHR Cambridge Biomedical Research Centre
Commensal Microbes and Hair Follicle Morphogenesis Coordinately Drive Treg Migration into Neonatal Skin
Regulatory T cells (Tregs) are required to establish immune tolerance to commensal microbes. Tregs accumulate abruptly in the skin during a defined window of postnatal tissue development. However, the mechanisms mediating Treg migration to neonatal skin are unknown. Here we show that hair follicle (HF) development facilitates the accumulation of Tregs in neonatal skin and that upon skin entry these cells localize to HFs, a primary reservoir for skin commensals. Further, germ-free neonates had reduced skin Tregs indicating that commensal microbes augment Treg accumulation. We identified Ccl20 as a HF-derived, microbiota-dependent chemokine and found its receptor, Ccr6, to be preferentially expressed by Tregs in neonatal skin. The Ccl20-Ccr6 pathway mediated Treg migration in vitro and in vivo. Thus, HF morphogenesis, commensal microbe colonization, and local chemokine production work in concert to recruit Tregs into neonatal skin, thereby establishing this tissue Treg niche early in life
A Symbiotic Brain-Machine Interface through Value-Based Decision Making
BACKGROUND: In the development of Brain Machine Interfaces (BMIs), there is a great need to enable users to interact with changing environments during the activities of daily life. It is expected that the number and scope of the learning tasks encountered during interaction with the environment as well as the pattern of brain activity will vary over time. These conditions, in addition to neural reorganization, pose a challenge to decoding neural commands for BMIs. We have developed a new BMI framework in which a computational agent symbiotically decoded users' intended actions by utilizing both motor commands and goal information directly from the brain through a continuous Perception-Action-Reward Cycle (PARC). METHODOLOGY: The control architecture designed was based on Actor-Critic learning, which is a PARC-based reinforcement learning method. Our neurophysiology studies in rat models suggested that Nucleus Accumbens (NAcc) contained a rich representation of goal information in terms of predicting the probability of earning reward and it could be translated into an evaluative feedback for adaptation of the decoder with high precision. Simulated neural control experiments showed that the system was able to maintain high performance in decoding neural motor commands during novel tasks or in the presence of reorganization in the neural input. We then implanted a dual micro-wire array in the primary motor cortex (M1) and the NAcc of rat brain and implemented a full closed-loop system in which robot actions were decoded from the single unit activity in M1 based on an evaluative feedback that was estimated from NAcc. CONCLUSIONS: Our results suggest that adapting the BMI decoder with an evaluative feedback that is directly extracted from the brain is a possible solution to the problem of operating BMIs in changing environments with dynamic neural signals. During closed-loop control, the agent was able to solve a reaching task by capturing the action and reward interdependency in the brain
Resistance to autosomal dominant Alzheimer's disease in an APOE3 Christchurch homozygote: a case report.
We identified a PSEN1 (presenilin 1) mutation carrier from the world's largest autosomal dominant Alzheimer's disease kindred, who did not develop mild cognitive impairment until her seventies, three decades after the expected age of clinical onset. The individual had two copies of the APOE3 Christchurch (R136S) mutation, unusually high brain amyloid levels and limited tau and neurodegenerative measurements. Our findings have implications for the role of APOE in the pathogenesis, treatment and prevention of Alzheimer's disease
Electron quantum metamaterials in van der Waals heterostructures
In recent decades, scientists have developed the means to engineer synthetic
periodic arrays with feature sizes below the wavelength of light. When such
features are appropriately structured, electromagnetic radiation can be
manipulated in unusual ways, resulting in optical metamaterials whose function
is directly controlled through nanoscale structure. Nature, too, has adopted
such techniques -- for example in the unique coloring of butterfly wings -- to
manipulate photons as they propagate through nanoscale periodic assemblies. In
this Perspective, we highlight the intriguing potential of designer
sub-electron wavelength (as well as wavelength-scale) structuring of electronic
matter, which affords a new range of synthetic quantum metamaterials with
unconventional responses. Driven by experimental developments in stacking
atomically layered heterostructures -- e.g., mechanical pick-up/transfer
assembly -- atomic scale registrations and structures can be readily tuned over
distances smaller than characteristic electronic length-scales (such as
electron wavelength, screening length, and electron mean free path). Yet
electronic metamaterials promise far richer categories of behavior than those
found in conventional optical metamaterial technologies. This is because unlike
photons that scarcely interact with each other, electrons in subwavelength
structured metamaterials are charged, and strongly interact. As a result, an
enormous variety of emergent phenomena can be expected, and radically new
classes of interacting quantum metamaterials designed
Pre-hospital management protocols and perceived difficulty in diagnosing acute heart failure
Aim To illustrate the pre-hospital management arsenals and protocols in different EMS units, and to estimate the perceived difficulty of diagnosing suspected acute heart failure (AHF) compared with other common pre-hospital conditions. Methods and results A multinational survey included 104 emergency medical service (EMS) regions from 18 countries. Diagnostic and therapeutic arsenals related to AHF management were reported for each type of EMS unit. The prevalence and contents of management protocols for common medical conditions treated pre-hospitally was collected. The perceived difficulty of diagnosing AHF and other medical conditions by emergency medical dispatchers and EMS personnel was interrogated. Ultrasound devices and point-of-care testing were available in advanced life support and helicopter EMS units in fewer than 25% of EMS regions. AHF protocols were present in 80.8% of regions. Protocols for ST-elevation myocardial infarction, chest pain, and dyspnoea were present in 95.2, 80.8, and 76.0% of EMS regions, respectively. Protocolized diagnostic actions for AHF management included 12-lead electrocardiogram (92.1% of regions), ultrasound examination (16.0%), and point-of-care testings for troponin and BNP (6.0 and 3.5%). Therapeutic actions included supplementary oxygen (93.2%), non-invasive ventilation (80.7%), intravenous furosemide, opiates, nitroglycerine (69.0, 68.6, and 57.0%), and intubation 71.5%. Diagnosing suspected AHF was considered easy to moderate by EMS personnel and moderate to difficult by emergency medical dispatchers (without significant differences between de novo and decompensated heart failure). In both settings, diagnosis of suspected AHF was considered easier than pulmonary embolism and more difficult than ST-elevation myocardial infarction, asthma, and stroke. Conclusions The prevalence of AHF protocols is rather high but the contents seem to vary. Difficulty of diagnosing suspected AHF seems to be moderate compared with other pre-hospital conditions
GOALS-JWST: Small neutral grains and enhanced 3.3 micron PAH emission in the Seyfert galaxy NGC 7469
We present James Webb Space Telescope (JWST) Near Infrared Spectrograph
(NIRSpec) integral-field spectroscopy of the nearby luminous infrared galaxy,
NGC 7469. We take advantage of the high spatial/spectral resolution and
wavelength coverage of JWST /NIRSpec to study the 3.3 um neutral polycyclic
aromatic hydrocarbon (PAH) grain emission on ~60 pc scales. We find a clear
change in the average grain properties between the star-forming ring and the
central AGN. Regions in the vicinity of the AGN, with [NeIII]/[NeII]>0.25, tend
to have larger grain sizes and lower aliphatic-to-aromatic (3.4/3.3) ratios
indicating that smaller grains are preferentially removed by photo-destruction
in the vicinity of the AGN. We find an overall suppression of the total PAH
emission relative to the ionized gas in the central 1 kpc region of the AGN in
NGC 7469 compared to what has been observed with Spitzer on 3 kpc scales.
However, the fractional 3.3 um to total PAH power is enhanced in the starburst
ring, possibly due to a variety of physical effects on sub-kpc scales,
including recurrent fluorescence of small grains or multiple photon absorption
by large grains. Finally, the IFU data show that while the 3.3 um PAH-derived
star formation rate (SFR) in the ring is 8% higher than that inferred from the
[NeII] and [NeIII] emission lines, the integrated SFR derived from the 3.3 um
feature would be underestimated by a factor of two due to the deficit of PAHs
around the AGN, as might occur if a composite system like NGC 7469 were to be
observed at high-redshift.Comment: 14 pages, 5 figures, 2 tables, Submitted to ApJ
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