Rac1b, an alternative splice form of Rac1, has been previously shown to be upregulated in colon and breast cancer cells, suggesting an oncogenic role for Rac1b in these cancers. Our analysis of NSCLC ...tumor and matched normal tissue samples indicates Rac1b is upregulated in a significant fraction of lung tumors in correlation with mutational status of K-ras. To directly assess the oncogenic potential of Rac1b in vivo, we employed a mouse model of lung adenocarcinoma, in which the expression of Rac1b can be conditionally activated specifically in the lung. Although expression of Rac1b alone is insufficient to drive tumor initiation, the expression of Rac1b synergizes with an oncogenic allele of K-ras resulting in increased cellular proliferation and accelerated tumor growth. Finally, we show that in contrast to our previous findings demonstrating a requirement for Rac1 in K-ras-driven cell proliferation, Rac1b is not required in this context. Given the partially overlapping spectrum of downstream effectors regulated by Rac1 and Rac1b, our findings further delineate the signaling pathways downstream of Rac1 that are required for K-ras driven tumorigenesis.
ABSTRACT
As part of the 100IAS survey, a program aimed to obtain nebular-phase spectra for a volume-limited and homogeneous sample of Type Ia supernovae (SNe Ia), we observed ASASSN-18tb (SN 2018fhw) ...at 139 d past maximum light. ASASSN-18tb was a fast-declining, sub-luminous event that fits well within the observed photometric and spectroscopic distributions of the SN Ia population. We detect a prominent H α emission line (LH α = 2.2 ± 0.2 × 1038 ergs s−1) with FWHM ≈ 1100 km s−1 in the nebular-phase spectrum of this SN Ia. High-luminosity H α emission (LH α ≳ 1040 ergs s−1) has previously been discovered in a rare class of SNe Ia-like objects showing circum-stellar medium (CSM) interactions (SNe Ia–CSM). They predominantly belong to overluminous (Mmax < −19 mag in optical) 1991T-like SNe Ia and are exclusively found in star-forming galaxies. By contrast, ASASSN-18tb is a sub-luminous SN Ia (MB,max ∼ −17.7 mag) found in an early-type galaxy dominated by old stellar populations. We discuss possible origins for the observed hydrogen. Of the 75 SNe Ia for which we have so far obtained nebular spectra in 100IAS, no other SN shows a ${\sim } 1000 \, {\rm km\, s^{-1}}$ H α emission line with comparable line luminosity as ASASSN-18tb, emphasizing the rarity of such emission in the nebular phase. Based on preliminary results from our survey, the rate for ASASSN-18tb-like nebular H α emission could be as high as ${\sim } 10{{\ \rm per\ cent}}$ among sub-luminous SNe Ia.
Cardiac fibrosis is a final common pathology in inherited and acquired heart diseases that causes cardiac electrical and pump failure. Here, we use systems genetics to identify a pro-fibrotic gene ...network in the diseased heart and show that this network is regulated by the E3 ubiquitin ligase WWP2, specifically by the WWP2-N terminal isoform. Importantly, the WWP2-regulated pro-fibrotic gene network is conserved across different cardiac diseases characterized by fibrosis: human and murine dilated cardiomyopathy and repaired tetralogy of Fallot. Transgenic mice lacking the N-terminal region of the WWP2 protein show improved cardiac function and reduced myocardial fibrosis in response to pressure overload or myocardial infarction. In primary cardiac fibroblasts, WWP2 positively regulates the expression of pro-fibrotic markers and extracellular matrix genes. TGFβ1 stimulation promotes nuclear translocation of the WWP2 isoforms containing the N-terminal region and their interaction with SMAD2. WWP2 mediates the TGFβ1-induced nucleocytoplasmic shuttling and transcriptional activity of SMAD2.
A
bstract
Based on 4.5 fb
−
1
data taken at seven center-of-mass energies ranging from 4.600 to 4.699 GeV with the BESIII detector at the BEPCII collider, we measure the branching fractions of
Λ
c
+
...→
Σ
+
+
hadrons
relative to
Λ
c
+
→
Σ
+
π
+
π
−
. Combining with the world average branching fraction of
Λ
c
+
→
Σ
+
π
+
π
−
, their branching fractions are measured to be (0
.
377
±
0
.
042
±
0
.
020
±
0
.
021)% for
Λ
c
+
→
Σ
+
K
+
K
−
, (0
.
200
±
0
.
023
±
0
.
011
±
0
.
011)% for
Λ
c
+
→
Σ
+
K
+
π
−
, (0
.
414
±
0
.
080
±
0
.
030
±
0
.
023)% for
Λ
c
+
→
Σ
+
ϕ
and (0
.
197
±
0
.
036
±
0
.
009
±
0
.
011)% for
Λ
c
+
→ Σ
+
K
+
K
−
(non-
ϕ
). In all the above results, the first uncertainties are statistical, the second are systematic and the third are from external input of the branching fraction of
Λ
c
+
→
Σ
+
π
+
π
−
. Since no signal for
Λ
c
+
→
Σ
+
K
+
π
−
π
0
is observed, the upper limit of its branching fraction is determined to be 0.13% at the 90% confidence level.
Astronomy. ASASSN-15lh: A highly super-luminous supernova Dong, Subo; Shappee, B J; Prieto, J L ...
Science (American Association for the Advancement of Science),
2016-Jan-15, 20160115, Letnik:
351, Številka:
6270
Journal Article
Recenzirano
We report the discovery of ASASSN-15lh (SN 2015L), which we interpret as the most luminous supernova yet found. At redshift z = 0.2326, ASASSN-15lh reached an absolute magnitude of Mu ,AB = -23.5 ± ...0.1 and bolometric luminosity Lbol = (2.2 ± 0.2) × 10(45) ergs s(-1), which is more than twice as luminous as any previously known supernova. It has several major features characteristic of the hydrogen-poor super-luminous supernovae (SLSNe-I), whose energy sources and progenitors are currently poorly understood. In contrast to most previously known SLSNe-I that reside in star-forming dwarf galaxies, ASASSN-15lh appears to be hosted by a luminous galaxy (MK ≈ -25.5) with little star formation. In the 4 months since first detection, ASASSN-15lh radiated (1.1 ± 0.2) × 10(52) ergs, challenging the magnetar model for its engine.
The process e^{+}e^{-}→D_{s}^{*+}D_{s}^{*-} is studied with a semi-inclusive method using data samples at center-of-mass energies from threshold to 4.95 GeV collected with the BESIII detector ...operating at the Beijing Electron Positron Collider. The Born cross sections of the process are measured for the first time with high precision in this energy region. Two resonance structures are observed in the energy-dependent cross sections around 4.2 and 4.4 GeV. By fitting the cross sections with a coherent sum of three Breit-Wigner amplitudes and one phase-space amplitude, the two significant structures are assigned masses of (4186.8±8.7±30) and (4414.6±3.4±6.1) MeV/c^{2}, widths of (55±15±53) and (122.5±7.5±8.1) MeV, where the first errors are statistical and the second ones are systematic. The inclusion of a third Breit-Wigner amplitude is necessary to describe a structure around 4.79 GeV.
Quasi-two-dimensional (quasi-2D) materials hold promise for future electronics because of their unique band structures that result in electronic and mechanical properties sensitive to crystal strains ...in all three dimensions. Quantifying crystal strain is a prerequisite to correlating it with the performance of the device and calls for high resolution but spatially resolved rapid characterization methods. Here, we show that using fly-scan nano X-ray diffraction, we can accomplish a tensile strain sensitivity below 0.001% with a spatial resolution of better than 80 nm over a spatial extent of 100 μm on quasi-2D flakes of 1T-TaS2. Coherent diffraction patterns were collected from a ∼100 nm thick sheet of 1T-TaS2 by scanning a 12 keV focused X-ray beam across and rotating the sample. We demonstrate that the strain distribution around micron- and submicron-sized “bubbles” that are present in the sample may be reconstructed from these images. The experiments use state-of-the-art synchrotron instrumentation and will allow rapid and nonintrusive strain mapping of thin-film samples and electronic devices based on quasi-2D materials.
Context:
Roux-en-Y gastric bypass (RYGB) is one of the most effective long-term therapies for the treatment of severe obesity. Recent evidence indicates that RYGB effects weight loss through multiple ...physiological mechanisms, including changes in energy expenditure, food intake, food preference, and reward pathways.
Objective:
Because central melanocortin signaling plays an important role in the regulation of energy homeostasis, we investigated whether genetic disruption of the melanocortin-4 receptor (MC4R) in rodents and humans affects weight loss after RYGB.
Methods and Results:
Here we report that MC4R−/− mice lost substantially less weight after surgery than wild-type animals, indicating that MC4R signaling is necessary for the weight loss effects of RYGB in this model. Mice heterozygous for MC4R remain fully responsive to gastric bypass. To determine whether mutations affect surgically induced weight loss in humans, we sequenced the MC4R gene in 972 patients undergoing RYGB. Patients heterozygous for MC4R mutations exhibited the same magnitude and distribution of postoperative weight loss as patients without such mutations, suggesting that although two normal copies of the MC4R gene are necessary for normal weight regulation, a single normal copy of the MC4R gene is sufficient to mediate the weight loss effects of RYGB.
Conclusions:
MC4R is the first gene identified that is required for the sustained effects of bariatric surgery. The need for MC4R signaling for the weight loss effects of RYGB in mice underscores the physiological mechanisms of action of this procedure and demonstrates that RYGB both influences and is dependent on the normal pathways that regulate energy balance.
Frequent activation of the co-transcriptional factor YAP is observed in a large number of solid tumors. Activated YAP associates with enhancer loci via TEAD4-DNA-binding protein and stimulates cancer ...aggressiveness. Although thousands of YAP/TEAD4 binding-sites are annotated, their functional importance is unknown. Here, we aim at further identification of enhancer elements that are required for YAP functions.
We first apply genome-wide ChIP profiling of YAP to systematically identify enhancers that are bound by YAP/TEAD4. Next, we implement a genetic approach to uncover functions of YAP/TEAD4-associated enhancers, demonstrate its robustness, and use it to reveal a network of enhancers required for YAP-mediated proliferation. We focus on Enhancer
, as its target gene TRAM2 shows the strongest expression-correlation with YAP activity in nearly all tumor types. Interestingly, TRAM2 phenocopies the YAP-induced cell proliferation, migration, and invasion phenotypes and correlates with poor patient survival. Mechanistically, we identify FSTL-1 as a major direct client of TRAM2 that is involved in these phenotypes. Thus, TRAM2 is a key novel mediator of YAP-induced oncogenic proliferation and cellular invasiveness.
YAP is a transcription co-factor that binds to thousands of enhancer loci and stimulates tumor aggressiveness. Using unbiased functional approaches, we dissect YAP enhancer network and characterize TRAM2 as a novel mediator of cellular proliferation, migration, and invasion. Our findings elucidate how YAP induces cancer aggressiveness and may assist diagnosis of cancer metastasis.
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