Abstract
We present a catalog of 315 protostellar outflow candidates detected in SiO
J
= 5 − 4 in the ALMA-IMF Large Program, observed with ∼2000 au spatial resolution, 0.339 km s
−1
velocity ...resolution, and 2–12 mJy beam
−1
(0.18–0.8 K) sensitivity. We find median outflow masses, momenta, and kinetic energies of ∼0.3
M
⊙
, 4
M
⊙
km s
−1
, and 10
45
erg, respectively. Median outflow lifetimes are 6000 yr, yielding median mass, momentum, and energy rates of
M
̇
= 10
−4.4
M
⊙
yr
−1
,
P
̇
= 10
−3.2
M
⊙
km s
−1
yr
−1
, and
E
̇
= 1
L
⊙
. We analyze these outflow properties in the aggregate in each field. We find correlations between field-aggregated SiO outflow properties and total mass in cores (∼3
σ
–5
σ
), and no correlations above 3
σ
with clump mass, clump luminosity, or clump luminosity-to-mass ratio. We perform a linear regression analysis and find that the correlation between field-aggregated outflow mass and total clump mass—which has been previously described in the literature—may actually be mediated by the relationship between outflow mass and total mass in cores. We also find that the most massive SiO outflow in each field is typically responsible for only 15%–30% of the total outflow mass (60% upper limit). Our data agree well with the established mechanical force−bolometric luminosity relationship in the literature, and our data extend this relationship up to
L
≥ 10
6
L
⊙
and
P
̇
≥ 1
M
⊙
km s
−1
yr
−1
. Our lack of correlation with clump
L
/
M
is inconsistent with models of protocluster formation in which all protostars start forming at the same time.
The presence of gas hydrates is well known in the marine realm southwest of Taiwan due to the widespread distribution of bottom simulating reflectors in seismic records. To learn more about gas ...hydrate systems and their dynamics at passive and active margins, we drilled boreholes with MARUM-MeBo200 seafloor drill rig at areas where geophysical indications for gas hydrates have been detected in the past. Several gas hydrate proxies like negative chloride anomalies in the pore water, cold spots detected by infrared thermal scans on cores, increased resistivity, and lithological parameters clearly showed the presence of hydrates in the drilled sections. However, gas hydrate was not recovered by MeBo most likely because of small crystal sizes which dissociated during recovery from the seafloor. Three holes were drilled at southern summit of Formosa Ridge down to 126 m below seafloor (mbsf) and recovered sediments from which in situ hydrate saturation values were estimated between 1 and 10% at 15–42 mbsf and even higher values of up to 38% below 100 mbsf. The latter are probably related to the sealing effect of carbonate precipitation which occur at 85–95 mbsf directly above the hydrate-enriched layer. Four holes were drilled at Four-Way Closure Ridge where a maximum drilling depth of 143.90 mbsf was reached. Hydrate presence starts in 65 mbsf continuing down-core with a range of 1–29% gas hydrate saturation in fine-grained homogenous clay. An abrupt change to higher gas hydrate saturation values of up to 80% occurs below 109 mbsf where silty and sandy turbidite layers are often intercalated. Such high gas hydrate contents only occur in the sand layers and not in the fine-grained sediments intercalated to the sand deposits.
•Drilling in the eastern South China Sea was performed for the first time by using the mobile drilling system MARUM-MeBo.•Several proxies document the presence and the saturation of gas hydrates offshore Southwest off Taiwan.•Higher hydrate saturations were more found in the active margin at 4WC Ridge than in the passive margin at Formosa Ridge.•Drilling revealed the importance of lithological variations for hydrate saturation.•The highest gas hydrate saturations were encountered in sandy turbidites at Four-Way Closure Ridge of the accretionary wedge.
Neoadjuvant chemotherapy (NAC) prior to surgery and immune checkpoint therapy (ICT) have revolutionized bladder cancer management. However, stratification of patients that would benefit most from ...these modalities remains a major clinical challenge. Here, we combine single nuclei RNA sequencing with spatial transcriptomics and single-cell resolution spatial proteomic analysis of human bladder cancer to identify an epithelial subpopulation with therapeutic response prediction ability. These cells express Cadherin 12 (CDH12, N-Cadherin 2), catenins, and other epithelial markers. CDH12-enriched tumors define patients with poor outcome following surgery with or without NAC. In contrast, CDH12-enriched tumors exhibit superior response to ICT. In all settings, patient stratification by tumor CDH12 enrichment offers better prediction of outcome than currently established bladder cancer subtypes. Molecularly, the CDH12 population resembles an undifferentiated state with inherently aggressive biology including chemoresistance, likely mediated through progenitor-like gene expression and fibroblast activation. CDH12-enriched cells express PD-L1 and PD-L2 and co-localize with exhausted T-cells, possibly mediated through CD49a (ITGA1), providing one explanation for ICT efficacy in these tumors. Altogether, this study describes a cancer cell population with an intriguing diametric response to major bladder cancer therapeutics. Importantly, it also provides a compelling framework for designing biomarker-guided clinical trials.
Triglycerides (or triacylglycerols) represent the major form of stored
energy in eukaryotes. Triglyceride synthesis has been assumed to occur primarily
through acyl CoA:diacylglycerol transferase ...(Dgat), a microsomal enzyme that
catalyses the final and only committed step in the glycerol phosphate pathway. Therefore, Dgat has been considered necessary for adipose
tissue formation and essential for survival. Here we show that Dgat-deficient
(Dgat−/−) mice are viable and can still
synthesize triglycerides. Moreover, these mice are lean and resistant to diet-induced
obesity. The obesity resistance involves increased energy expenditure and
increased activity. Dgat deficiency also alters triglyceride metabolism in
other tissues, including the mammary gland, where lactation is defective in
Dgat−/− females. Our findings indicate that
multiple mechanisms exist for triglyceride synthesis and suggest that the
selective inhibition of Dgat-mediated triglyceride synthesis may be useful
for treating obesity.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Hydraulic fracturing has been widely employed to enhance the permeability of tight geological formations including deep geothermal reservoirs. However, due to the complex in-situ stresses, ...high-temperature conditions and heterogeneity of the formations, hydraulic fracturing under deep geothermal conditions is poorly understood to date. The aim of the current study is, therefore, to investigate the effect of reservoir depth, temperature, and sample heterogeneity during hydraulic fracturing and the influences of rock micro-structure on fracture propagation. A series of hydraulic fracturing experiments was conducted on two Australian granite types under a wide range of confining pressures from 0 to 60 MPa and temperatures from room temperature to 300 °C simulating different geothermal environments. The corresponding micro-structural effects on the rock matrix were investigated employing high-resolution CT imaging using the IMBL facility of the Australian Synchrotron. According to the results, the breakdown pressure of reservoir rock linearly increases with reservoir depth (confining pressure). However, with increasing temperature breakdown pressure linearly decreases. This corresponds to the linear reduction of tensile strength measured by high-temperature Brazilian tensile tests. In addition, CT images showed that the injection of cold water into hot rock can result in a porous zone with porosity ranging from 2 to 3% close to the wellbore due to thermally-induced inter- and intra-crystalline cracks. In this condition, fluid leak-off is high and the measured fracture aperture of the main hydraulic fracture is relatively small. Further, fracture propagation paths and apertures are mainly controlled by the stress state and the heterogeneity of the rock matrix. It was found that fractures tend to propagate along preferential paths, mainly along grain boundaries and in large quartz and biotite minerals (grain size > 0.3 mm) and minerals with pre-existing micro-cracks.
ABSTRACT
We report the results of decade-long (2008–2018) γ-ray to 1 GHz radio monitoring of the blazar 3C 279, including GASP/WEBT, Fermi and Swift data, as well as polarimetric and spectroscopic ...data. The X-ray and γ-ray light curves correlate well, with no delay $\gtrsim 3$ h, implying general cospatiality of the emission regions. The γ-ray–optical flux–flux relation changes with activity state, ranging from a linear to a more complex dependence. The behaviour of the Stokes parameters at optical and radio wavelengths, including 43 GHz Very Long Baseline Array images, supports either a predominantly helical magnetic field or motion of the radiating plasma along a spiral path. Apparent speeds of emission knots range from 10 to 37c, with the highest values requiring bulk Lorentz factors close to those needed to explain γ-ray variability on very short time-scales. The Mg ii emission line flux in the ‘blue’ and ‘red’ wings correlates with the optical synchrotron continuum flux density, possibly providing a variable source of seed photons for inverse Compton scattering. In the radio bands, we find progressive delays of the most prominent light-curve maxima with decreasing frequency, as expected from the frequency dependence of the τ = 1 surface of synchrotron self-absorption. The global maximum in the 86 GHz light curve becomes less prominent at lower frequencies, while a local maximum, appearing in 2014, strengthens toward decreasing frequencies, becoming pronounced at ∼5 GHz. These tendencies suggest different Doppler boosting of stratified radio-emitting zones in the jet.
We present a catalog of 315 protostellar outflow candidates detected in SiO J=5-4 in the ALMA-IMF Large Program, observed with ~2000 au spatial resolution, 0.339 km/s velocity resolution, and 2-12 ...mJy/beam (0.18-0.8 K) sensitivity. We find median outflow masses, momenta, and kinetic energies of ~0.3 M\(_{\odot}\), 4 M\(_{\odot}\) km/s, and 10\(^{45}\) erg, respectively. Median outflow lifetimes are 6,000 years, yielding median mass, momentum, and energy rates of \(\dot{M}\) = 10\(^{-4.4}\) M\(_{\odot}\) yr\(^{-1}\), \(\dot{P}\) = 10\(^{-3.2}\) M\(_{\odot}\) km/s yr\(^{-1}\), and \(\dot{E}\) = 1 L\(_{\odot}\). We analyze these outflow properties in the aggregate in each field. We find correlations between field-aggregated SiO outflow properties and total mass in cores (~3\(-\)5\(\sigma\)), and no correlations above 3\(\sigma\) with clump mass, clump luminosity, or clump luminosity-to-mass ratio. We perform a linear regression analysis and find that the correlation between field-aggregated outflow mass and total clump mass - which has been previously described in the literature - may actually be mediated by the relationship between outflow mass and total mass in cores. We also find that the most massive SiO outflow in each field is typically responsible for only 15-30% of the total outflow mass (60% upper limit). Our data agree well with the established mechanical force-bolometric luminosity relationship in the literature, and our data extend this relationship up to L \(\geq\) 10\(^6\) L\(_{\odot}\) and \(\dot{P}\) \(\geq\) 1 M\(_{\odot}\) km/s yr\(^{-1}\). Our lack of correlation with clump L/M is inconsistent with models of protocluster formation in which all protostars start forming at the same time.
Current diagnosis and staging of pancreatic ductal adenocarcinoma (PDAC) has important limitations and better biomarkers are needed to guide initial therapy. We investigated the performance of ...circulating tumour cells (CTCs) as an adjunctive biomarker at the time of disease presentation.
Venous blood (VB) was collected prospectively from 100 consecutive, pre-treatment patients with PDAC. Utilising the microfluidic NanoVelcro CTC chip, samples were evaluated for the presence and number of CTCs. KRAS mutation analysis was used to compare the CTCs with primary tumour tissue. CTC enumeration data was then evaluated as a diagnostic and staging biomarker in the setting of PDAC.
We found 100% concordance for KRAS mutation subtype between primary tumour and CTCs in all five patients tested. Evaluation of CTCs as a diagnostic revealed the presence of CTCs in 54/72 patients with confirmed PDAC (sensitivity=75.0%, specificity=96.4%, area under the curve (AUROC)=0.867, 95% CI=0.798-0.935, and P<0.001). Furthermore, a cut-off of ⩾3 CTCs in 4 ml VB was able to discriminate between local/regional and metastatic disease (AUROC=0.885; 95% CI=0.800-0.969; and P<0.001).
CTCs appear to function well as a biomarker for diagnosis and staging in PDAC.
KRAS, NRAS and BRAF mutations are among the most important oncogenic drivers in many major cancer types, such as melanoma, lung, colorectal and pancreatic cancer. There is currently no effective ...therapy for the treatment of RAS mutant cancers. LY3009120, a pan-RAF and RAF dimer inhibitor advanced to clinical study has been shown to inhibit both RAS and BRAF mutant cell proliferation in vitro and xenograft tumor growth in vivo. Abemaciclib, a CDK4/6-selective inhibitor, is currently in phase III studies for ER-positive breast cancer and KRAS mutant lung cancer. In this study, we found that combinatory treatment with LY3009120 and abemaciclib synergistically inhibited proliferation of tumor cells in vitro and led to tumor growth regression in xenograft models with a KRAS, NRAS or BRAF mutation at the doses of two drugs that were well tolerated in combination. Further in vitro screen in 328 tumor cell lines revealed that tumor cells with KRAS, NRAS or BRAF mutation, or cyclin D activation are more sensitive, whereas tumor cells with PTEN, PIK3CA, PIK3R1 or retinoblastoma (Rb) mutation are more resistant to this combination treatment. Molecular analysis revealed that abemaciclib alone inhibited Rb phosphorylation partially and caused an increase of cyclin D1. The combinatory treatment cooperatively demonstrated more complete inhibition of Rb phosphorylation, and LY3009120 suppressed the cyclin D1 upregulation mediated by abemaciclib. These results were further verified by CDK4/6 siRNA knockdown. Importantly, the more complete phospho-Rb inhibition and cyclin D1 suppression by LY3009120 and abemaciclib combination led to more significant cell cycle G
/G
arrest of tumor cells. These preclinical findings suggest that combined inhibition of RAF and d-cyclin-dependent kinases might provide an effective approach to treat patients with tumors harboring mutations in RAS or RAF genes.
Summary
This study aims to investigate the effects of treatments on the quality of life for patients with esophageal squamous cell carcinoma patients diagnosed at early and late stages. From a ...medical center in central Taiwan, patients who had been diagnosed with esophageal squamous cell carcinoma from February 2007 and March 2011 were recruited. Using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and the Quality of Life Questionnaire Oesophageal 18 (QLQ-OES18), quality of life scores for 105 esophageal squamous cell carcinoma patients were obtained and assessed. Multivariate analysis was performed on the quality of life scores after stratification by cancer stage. Among early-stage esophageal squamous cell carcinoma patients, those received only surgery (S-only) performed better in physical and social functioning compared with patients who underwent surgery and concurrent chemoradiotherapy (S+CCRT) (β = 9.0, P = 0.03; β = 12.1, P = 0.04, respectively). For those that received only concurrent chemoradiotherapy (CCRT-only), they performed worse in role and emotional functioning relative to S+CCRT patients (β = −17.2, P = 0.02; β = −15.7, P = 0.05, respectively). Among late-stage patients, CCRT-only treatment gave insignificantly better global health status and functional scale scores and less severe symptoms compared to the S+CCRT option. Better functional scores and less aggravated symptoms are observed in early-stage esophageal squamous cell carcinoma patients who received surgery-only treatment relative to those that underwent both surgery and chemoradiotherapy. For late-stage esophageal cancer patients, the measured difference of quality of life is not significant between CCRT-only and S+CCRT treatments.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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