We recently used in situ Hi-C to create kilobase-resolution 3D maps of mammalian genomes. Here, we combine these maps with new Hi-C, microscopy, and genome-editing experiments to study the physical ...structure of chromatin fibers, domains, and loops. We find that the observed contact domains are inconsistent with the equilibrium state for an ordinary condensed polymer. Combining Hi-C data and novel mathematical theorems, we show that contact domains are also not consistent with a fractal globule. Instead, we use physical simulations to study two models of genome folding. In one, intermonomer attraction during polymer condensation leads to formation of an anisotropic “tension globule.” In the other, CCCTC-binding factor (CTCF) and cohesin act together to extrude unknotted loops during interphase. Bothmodels are consistent with the observed contact domains and with the observation that contact domains tend to form inside loops. However, the extrusion model explains a far wider array of observations, such as why loops tend not to overlap and why the CTCF-binding motifs at pairs of loop anchors lie in the convergent orientation. Finally, we perform 13 genome-editing experiments examining the effect of altering CTCF-binding sites on chromatin folding. The convergent rule correctly predicts the affected loops in every case. Moreover, the extrusion model accurately predicts in silico the 3D maps resulting from each experiment using only the location of CTCF-binding sites in the WT. Thus, we show that it is possible to disrupt, restore, and move loops and domains using targeted mutations as small as a single base pair.
Glycogen synthase kinase 3 beta (GSK3β) is highly inactivated in epithelial cancers and is known to inhibit tumor migration and invasion. The zinc-finger-containing transcriptional repressor, Slug, ...represses E-cadherin transcription and enhances epithelial-mesenchymal transition (EMT). In this study, we find that the GSK3β-pSer9 level is associated with the expression of Slug in non-small cell lung cancer. GSK3β-mediated phosphorylation of Slug facilitates Slug protein turnover. Proteomic analysis reveals that the carboxyl terminus of Hsc70-interacting protein (CHIP) interacts with wild-type Slug (wtSlug). Knockdown of CHIP stabilizes the wtSlug protein and reduces Slug ubiquitylation and degradation. In contrast, nonphosphorylatable Slug-4SA is not degraded by CHIP. The accumulation of nondegradable Slug may further lead to the repression of E-cadherin expression and promote cancer cell migration, invasion and metastasis. Our findings provide evidence of a de novo GSK3β-CHIP-Slug pathway that may be involved in the progression of metastasis in lung cancer.
Neuronal elements distributed throughout the cardiac nervous system, from the level of the insular cortex to the intrinsic cardiac nervous system, are in constant communication with one another to ...ensure that cardiac output matches the dynamic process of regional blood flow demand. Neural elements in their various ‘levels’ become differentially recruited in the transduction of sensory inputs arising from the heart, major vessels, other visceral organs and somatic structures to optimize neuronal coordination of regional cardiac function. This White Paper will review the relevant aspects of the structural and functional organization for autonomic control of the heart in normal conditions, how these systems remodel/adapt during cardiac disease, and finally how such knowledge can be leveraged in the evolving realm of autonomic regulation therapy for cardiac therapeutics.
We report the discovery of rising X-ray emission from the binary neutron star merger event GW170817. This is the first detection of X-ray emission from a gravitational-wave (GW) source. Observations ...acquired with the Chandra X-ray Observatory (CXO) at t 2.3 days post-merger reveal no significant emission, with L x 3.2 × 10 38 erg s − 1 (isotropic-equivalent). Continued monitoring revealed the presence of an X-ray source that brightened with time, reaching L x 9 × 10 38 erg s − 1 at 15.1 days post-merger. We interpret these findings in the context of isotropic and collimated relativistic outflows (both on- and off-axis). We find that the broadband X-ray to radio observations are consistent with emission from a relativistic jet with kinetic energy E k ∼ 10 49 − 50 erg , viewed off-axis with θ obs ∼ 20 ° - 40 ° . Our models favor a circumbinary density n ∼ 10 − 4 - 10 − 2 cm − 3 , depending on the value of the microphysical parameter ϵ B = 10 − 4 - 10 − 2 . A central-engine origin of the X-ray emission is unlikely. Future X-ray observations at t 100 days, when the target will be observable again with the CXO, will provide additional constraints to solve the model degeneracies and test our predictions. Our inferences on θ obs are testable with GW information on GW170817 from advanced LIGO/Virgo on the binary inclination.
Background and purpose
Statin therapy is beneficial for primary and secondary prevention of ischaemic stroke, but its influence in patients with intracerebral hemorrhage (ICH) is unclear. An ...assessment was made of the effect of early statin therapy on patients with acute ICH.
Methods
Taiwan's National Health Insurance Research Database was screened for patients without prior statin therapy admitted from January to December 2008 for newly diagnosed ICH. Patients taking statins during hospitalization or within 3 months post‐discharge were the early statin group (n = 749); patients who were not were the control group (n = 7583). The study end‐points were recurrent ICH and all‐cause mortality during follow‐up.
Results
All eligible patients were followed up until 31 December 2010. During the follow‐up, 69 (9.2%) patients in the early statin group and 677 (8.9%) control group patients had recurrent ICH. Cox proportional hazards analyses showed that early statin use did not increase the risk of recurrent ICH (adjusted hazard ratio 1.044; 95% confidence interval 0.812–1.341). During the same period, 90 (12.0%) of the early statin group and 1519 (20.0%) control group patients died. All‐cause mortality was lower in the early statin group (adjusted hazard ratio 0.742; 95% confidence interval 0.598–0.919) than in the control group. Matched propensity score analyses were consistent with findings in Cox proportional hazards analyses.
Conclusions
Early statin group patients with acute ICH did not have a higher recurrent risk of ICH and might have lower all‐cause mortality during follow‐up. It is concluded that statin therapy might be beneficial for patients with ICH.
We present the properties of NGC 4993, the host galaxy of GW170817, the first gravitational-wave (GW) event from the merger of a binary neutron star (BNS) system and the first with an electromagnetic ...(EM) counterpart. We use both archival photometry and new optical/near-IR imaging and spectroscopy, together with stellar population synthesis models to infer the global properties of the host galaxy. We infer a star formation history peaked at ago, with subsequent exponential decline leading to a low current star formation rate of 0.01 yr−1, which we convert into a binary merger timescale probability distribution. We find a median merger timescale of Gyr, with a 90% confidence range of . This in turn indicates an initial binary separation of , comparable to the inferred values for Galactic BNS systems. We also use new and archival Hubble Space Telescope images to measure a projected offset of the optical counterpart of 2.1 kpc (0.64re) from the center of NGC 4993 and to place a limit of mag on any pre-existing emission, which rules out the brighter half of the globular cluster luminosity function. Finally, the age and offset of the system indicates it experienced a modest natal kick with an upper limit of ∼200 km s−1. Future GW-EM observations of BNS mergers will enable measurement of their population delay time distribution, which will directly inform their viability as the dominant source of r-process enrichment in the universe.
We present a comprehensive comparison of the properties of the radio through X-ray counterpart of GW170817 and the properties of short-duration gamma-ray bursts (GRBs). For this effort, we utilize a ...sample of 36 short GRBs spanning a redshift range of z 0.12 - 2.6 discovered over 2004-2017. We find that the counterpart to GW170817 has an isotropic-equivalent luminosity that is 3000 times less than the median value of on-axis short GRB X-ray afterglows, and 104 times less than that for detected short GRB radio afterglows. Moreover, the allowed jet energies and particle densities inferred from the radio and X-ray counterparts to GW170817 and on-axis short GRB afterglows are remarkably similar, suggesting that viewing angle effects are the dominant, and perhaps only, difference in their observed radio and X-ray behavior. From comparison to previous claimed kilonovae following short GRBs, we find that the optical and near-infrared (NIR) counterpart to GW170817 is comparatively under-luminous by a factor of 3 - 5 , indicating a range of kilonova luminosities and timescales. A comparison of the optical limits following short GRBs on 1 day timescales also rules out a "blue" kilonova of comparable optical isotropic-equivalent luminosity in one previous short GRB. Finally, we investigate the host galaxy of GW170817, NGC 4993, in the context of short GRB host galaxy stellar population properties. We find that NGC 4993 is superlative in terms of its large luminosity, old stellar population age, and low star formation rate compared to previous short GRB hosts. Additional events within the Advanced Laser Interferometer Gravitational-wave Observatory (LIGO)/Virgo volume will be crucial in delineating the properties of the host galaxies of neutron star-neutron star (NS-NS) mergers, and connecting them to their cosmological counterparts.
Repeated isolation of multidrug-resistant Acinetobacter baumannii (MDRAB) from respiratory secretions poses a great challenge for infection control. We conducted a retrospective case-control study to ...evaluate the efficacy and adverse effect of inhaled colistin methanesulfonate (CMS) in the eradication of MDRAB from the respiratory tract. Patients who were admitted to Taipei Veterans General Hospital between February 2009 and June 2010, had at least two sets of monomicrobial culture of MDRAB from respiratory secretions, and remained in hospital for at least 14 days after the first isolation of MDRAB (index day) were included. Patients who received intravenous CMS were excluded. Patients who received CMS inhalation for ≥3 days were selected as cases whereas the controls were matched for age and Acute Physiology and Chronic Health Evaluation II score. Thirty-nine cases and controls were identified. The duration of CMS inhalation was 10.9 ± 3.6 days. The use of inhaled CMS was the only independent factor associated with the eradication of MDRAB within 14 days after the index day (OR 266.33; 95% CI 11.26–6302.18, p <0.001), and shortened the duration of MDRAB recovery from the respiratory tract by 13.3 ± 1.45 days. The adverse effects were similar for both groups. The increase of colistin minimal inhibitory concentrations in the last isolate compared with the index isolate from the same patient did not differ between the two groups. In conclusion, our study demonstrated that inhaled CMS enhanced the eradication of MDRAB from the respiratory tract without significant clinical adverse effect or impact on colistin resistance.
In understanding the spectral and flavor composition of the astrophysical neutrino flux responsible for the recently observed ultrahigh-energy events at IceCube we see how important both astrophysics ...and particle physics are. Here, we perform a statistical likelihood analysis to the three-year IceCube data and derive the allowed range of the spectral index and flux normalization for various well-motivated physical flavor compositions at the source. While most of the existing analyses so far assume the flavor composition of the neutrinos at an astrophysical source to be (1:2:0), it seems rather unnatural to assume only one type of source, once we recognize the possibility of at least two physical sources. Bearing this in mind, we entertain the possibility of a two-component source for the analysis of IceCube data. It appears that our two-component hypothesis explains some key features of the data better than a single-component scenario; i.e. it addresses the apparent energy gap between 400 TeV and about 1 PeV and easily accommodates the observed track-to-shower ratio. Given the extreme importance of the flavor composition for the correct interpretation of the underlying astrophysical processes as well as for the ramification for particle physics, this two-component flux should be tested as more data is accumulated.
We present optical and ultraviolet spectra of the first electromagnetic counterpart to a gravitational-wave (GW) source, the binary neutron star merger GW170817. Spectra were obtained nightly between ...1.5 and 9.5 days post-merger, using the Southern Astrophysical Research and Magellan telescopes; the UV spectrum was obtained with the Hubble Space Telescope at 5.5 days. Our data reveal a rapidly fading blue component ( T 5500 K at 1.5 days) that quickly reddens; spectra later than 4.5 days peak beyond the optical regime. The spectra are mostly featureless, although we identify a possible weak emission line at ∼7900 at t 4.5 days. The colors, rapid evolution, and featureless spectrum are consistent with a "blue" kilonova from polar ejecta comprised mainly of light r-process nuclei with atomic mass number A 140 . This indicates a sightline within θ obs 45 ° of the orbital axis. Comparison to models suggests ∼0.03 M of blue ejecta, with a velocity of ∼ 0.3 c . The required lanthanide fraction is ∼ 10 − 4 , but this drops to < 10 − 5 in the outermost ejecta. The large velocities point to a dynamical origin, rather than a disk wind, for this blue component, suggesting that both binary constituents are neutron stars (as opposed to a binary consisting of a neutron star and a black hole). For dynamical ejecta, the high mass favors a small neutron star radius of 12 km. This mass also supports the idea that neutron star mergers are a major contributor to r-process nucleosynthesis.
PDF
