The human intestinal tract harbors large bacterial community consisting of commensal, symbiotic, and pathogenic strains, which are constantly interacting with the intestinal immune system. This ...interaction elicits a non-pathological basal level of immune responses and contributes to shaping both the intestinal immune system and bacterial community. Recent studies on human microbiota are revealing the critical role of intestinal bacterial community in the pathogenesis of both systemic and intestinal diseases, including Crohn's disease (CD). NOD2 plays a key role in the regulation of microbiota in the small intestine.
is highly expressed in ileal Paneth cells that provide critical mechanism for the regulation of ileal microbiota through the secretion of anti-bacterial compounds. Genome mapping of CD patients revealed that loss of function mutations in
are associated with ileal CD. Genome-wide association studies further demonstrated that
is one of the most critical genetic factor linked to ileal CD. The bacterial community in the ileum is indeed dysregulated in
-deficient mice.
-deficient ileal epithelia exhibit impaired ability of killing bacteria. Thus, altered interactions between ileal microbiota and mucosal immunity through
mutations play significant roles in the disease susceptibility and pathogenesis in CD patients, thereby depicting NOD2 as a critical regulator of ileal microbiota and CD.
Three-dimensional nonlinear finite Larmor radius (FLR)-Landau fluid simulations, which include some small-scale kinetic effects, are performed to explore the nature of the sub-ion scale turbulence in ...the solar wind and to investigate the role of Landau damping and FLR corrections. The resulting steady-state magnetic power spectrum in the dispersive range display exponents that vary within a range of values compatible with statistical results reported from in situ spacecraft measurements of solar wind turbulence as well as from gyrokinetic simulations. The spectral slopes are shown to depend on the strength of the nonlinear effects and on the scale at which turbulent fluctuations are driven in the simulations. The influence of Landau damping is addressed by comparison with simulations where the double-adiabatic closure is imposed. The role of FLR corrections is also analyzed. Comparison with in situ observations in the solar wind are performed to enlighten the influence of the fluctuations power at different scales on the spectral slopes in the sub-ion range. Using diagnosis of both magnetic compressibility and frequency-wavenumber spectra, it is shown that in spite of the evidence of the presence of fast-magnetosonic modes, the magnetic energy is mostly distributed around the kinetic Alfvén waves and the slow modes, in agreement with solar wind measurements. The observed large broadening about the linear dispersion relations may reflect the presence of coherent structures.
To evaluate if gait biomechanics are associated with increased risk of structurally diagnosed disease onset or progression of lower limb osteoarthritis (OA).
A systematic review of Medline and Embase ...was conducted from inception to July 2021. Two reviewers independently screened records, extracted data and assessed risk of bias. Included studies reported gait biomechanics at baseline, and either structural imaging or joint replacement occurrence in the lower limb at follow-up. The primary outcome was the Odds Ratio (OR) (95% confidence interval (CI)) of the association between biomechanics and structural OA outcomes with data pooled for meta-analysis.
Twenty-three studies reporting 25 different biomechanical metrics and 11 OA imaging outcomes were included (quality scores ranged 12–20/21). Twenty studies investigated knee OA progression; three studies investigated knee OA onset. Two studies investigated hip OA progression. 91% of studies reported a significant association between at least one biomechanical variable and OA onset or progression. There was an association between frontal plane biomechanics with medial tibiofemoral and hip OA progression and sagittal plane biomechanics with patellofemoral OA progression. Meta-analyses demonstrated increased odds of medial tibiofemoral OA progression with greater baseline peak knee adduction moment (KAM) (OR: 1.88 95%CI: 1.08, 3.29) and varus thrust presence (OR: 1.97 95%CI: 1.32, 2.96).
Evidence suggests that certain gait biomechanics are associated with an increased odds of OA onset and progression in the knee, and progression in the hip.
PROSPERO CRD42019133920
Amplification and/or overexpression of human epidermal growth factor receptor 2 (HER2) are observed in 15-20% of breast cancers (HER2+ breast cancers), and anti-HER2 therapies have significantly ...improved prognosis of patients with HER2+ breast cancer. One resistance mechanism to anti-HER2 therapies is constitutive activation of the phosphoinositide 3-kinase (PI3K) pathway. Combination therapy with small-molecule inhibitors of AKT and HER2 was conducted in HER2+ breast cancer cell lines with or without PIK3CA mutations, which lead to constitutive activation of the PI3K pathway. PIK3CA mutations played important roles in resistance to single-agent anti-HER2 therapy in breast cancer cell lines. Combination therapy of a HER2 inhibitor and an AKT inhibitor, as well as other PI3K pathway inhibitors, could overcome the therapeutic limitations associated with single-agent anti-HER2 treatment in PIK3CA-mutant HER2+ breast cancer cell lines. Furthermore, expression of phosphorylated 4E-binding protein 1 (p4EBP1) following the treatment correlated with the antiproliferative activities of the combination, suggesting that p4EBP1 may have potential as a prognostic and/or efficacy-linking biomarkers for these combination therapies in patients with HER2+ breast cancer. These findings highlight potential clinical strategies using combination therapy to overcome the limitations associated with single-agent anti-HER2 therapies in patients with HER2+ breast cancer.
The CCAAT enhancer-binding protein α (C/EBPα) plays an important role in myeloid cell differentiation and in the enhancement of C/EBPα expression/activity, which can lead to granulocytic ...differentiation in acute myeloid leukemia (AML) cells. We found that styryl quinazolinones induce upregulation of C/EBPα expression, and thereby induce myeloid differentiation in human myeloid leukemia cell lines. We screened a series of active styryl quinazolinones and evaluated the structure⁻activity relationship (SAR) of these small molecules in inducing C/EBPα expression-thereby prompting the leukemic cells to differentiate. We observed that compound
causes differentiation at 3 μM concentration, while
induces differentiation at 10 μM concentration. We also observed an increase in the expression of neutrophil differentiation marker CD11b upon treatment with
. Both the C/EBPα and C/EBPε levels were found to be upregulated by treatment with
. These SAR findings are inspiration to develop further modified styryl quinazolinones, in the path of this novel differentiation therapy, which can contribute to the care of patients with AML.
ABSTRACT
We report the earliest ever detection of optical polarization from a GRB forward shock (GRB 141220A), measured $129.5{-}204.3\,$s after the burst using the multicolour RINGO3 optical ...polarimeter on the 2-m fully autonomous robotic Liverpool Telescope. The temporal decay gradient of the optical light curves from $86\,$ to $\sim 2200\,$s post-burst is typical of classical forward shocks with α = 1.091 ± 0.008. The low-optical polarization $P_{ BV} = 2.8 _{- 1.6} ^{+ 2.0} \, {{\ \rm per\ cent}}$ (2σ) at mean time $\sim 168\,$s post-burst is compatible with being induced by the host galaxy dust ($A_{V, {\rm HG}}= 0.71 \pm 0.15 \,$mag), leaving low polarization intrinsic to the GRB emission itself – as theoretically predicted for forward shocks and consistent with previous detections of low degrees of optical polarization in GRB afterglows observed hours to days after the burst. The current sample of early-time polarization data from forward shocks suggests polarization from (a) the Galactic and host galaxy dust properties (i.e. $P \sim 1-3{{\ \rm per\ cent}}$), (b) contribution from a polarized reverse shock (GRB deceleration time, jet magnetization) or (c) forward shock intrinsic polarization (i.e. $P \le 2{{\ \rm per\ cent}}$), which depends on the magnetic field coherence length-scale and the size of the observable emitting region (burst energetics, circumburst density).
•Realizing a non-ferromagnetic Sm-rich intergranular phase in equilibrium with Sm(Fe,Co)11Ti.•Development of fine-grain sized Sm(Fe,Co)11Ti magnet with magnetically isolated 1:12 grains.•Discussion ...on possible weak-links to the coercivity of Sm(Fe,Co,Ti)12 magnets.
Realizing a non-ferromagnetic intergranular phase for the ThMn12-type Sm(Fe,Co,Ti)12 compound is a prerequisite for developing high coercive magnets. In this work, we demonstrate that the addition of Ga into the Sm-(Fe,Co)-Ti system results in the formation of non-ferromagnetic Sm–Ga-rich intergranular phases with good wettability on Sm(Fe,Co,Ti)12 grains. In the Sm-(Fe,Co)-Ti system, when the alloy composition was varied to the Sm-rich region as Sm1+w(Fe0.8Co0.2)11Ti (w = 0–0.7), soft ferromagnetic C15-type Sm(Fe,Co)2 intergranular phase and TbCu7-type Sm(Fe,Co,Ti)~7 phase formed along with the ThMn12-type main phase in the as-cast alloy. We demonstrated that by introducing Ga, the formation of these secondary soft ferromagnetic phases can be hindered as the excess Sm and Ga formed non-ferromagnetic Ba5Si3-type Sm5Ga3 and TII-type SmGa intergranular phases with an excellent wettability on Sm(Fe,Co,Ti)12 grains. Fine Sm(Fe,Co,Ti)12 grains of 1–2 µm, well isolated by the Sm–Ga-rich intergranular phase, were realized by melt-spinning the Ga-doped alloy and the maximum coercivity obtained was 0.5 T. According to the detailed microstructure characterizations, the weak-links to the coercivity of this novel microstructure of well-isolated and fine Sm(Fe,Co,Ti)12-based grains is the presence of defects at the interfaces which could lead to a locally reduced magneto-crystalline anisotropy.
ABSTRACT
We report observations and analysis of the nearby gamma-ray burst GRB 161219B (redshift z = 0.1475) and the associated Type Ic supernova (SN) 2016jca. GRB 161219B had an isotropic gamma-ray ...energy of ∼1.6 × 1050 erg. Its afterglow is likely refreshed at an epoch preceding the first photometric points (0.6 d), which slows down the decay rates. Combined analysis of the SN light curve and multiwavelength observations of the afterglow suggest that the GRB jet was broad during the afterglow phase (full opening angle ∼42° ± 3°). Our spectral series shows broad absorption lines typical of GRB supernovae (SNe), which testify to the presence of material with velocities up to ∼0.25c. The spectrum at 3.73 d allows for the very early identification of an SN associated with a GRB. Reproducing it requires a large photospheric velocity ($35\, 000 \pm 7000$ km s−1). The kinetic energy of the SN is estimated through models to be Ekin≈4 × 1052 erg in spherical symmetry. The ejected mass in the explosion was Mej≈6.5 ± 1.5 M⊙, much less than that of other GRB-SNe, demonstrating diversity among these events. The total amount of 56Ni in the explosion was 0.27 ± 0.05 M⊙. The observed spectra require the presence of freshly synthesized 56Ni at the highest velocities, at least three times more than a standard GRB-SN. We also find evidence for a decreasing 56Ni abundance as a function of decreasing velocity. This suggests that SN 2016jca was a highly aspherical explosion viewed close to on-axis, powered by a compact remnant. Applying a typical correction for asymmetry, the energy of SN 2016jca was ∼(1–3) × 1052 erg, confirming that most of the energy produced by GRB-SNe goes into the kinetic energy of the SN ejecta.
We report multicolor optical imaging and polarimetry observations of the afterglow of the first TeV-detected gamma-ray burst (GRB), GRB 190114C, using the RINGO3 and MASTER II polarimeters. ...Observations begin 31 s after the onset of the GRB and continue until ∼7000 s postburst. The light curves reveal a chromatic break at ∼400-500 s, with initial temporal decay = 1.669 0.013 flattening to ∼ 1 postbreak, which we model as a combination of reverse and forward shock components with magnetization parameter RB ∼ 70. The observed polarization degree decreases from 7.7% 1.1% to 2%-4% 52-109 s postburst and remains steady at this level for the subsequent ∼2000 s at a constant position angle. Broadband spectral energy distribution modeling of the afterglow confirms that GRB 190114C is highly obscured (Av,HG = 1.49 0.12 mag; cm−2). We interpret the measured afterglow polarization as intrinsically low and dominated by dust -in contrast to the P > 10% measured previously for other GRB reverse shocks-with a small contribution from polarized prompt photons in the first minute. We test whether first- and higher-order inverse Compton scattering in a magnetized reverse shock can explain the low optical polarization and subteraelectronvolt emission but conclude that neither is explained in the reverse shock inverse Compton model. Instead, the unexpectedly low intrinsic polarization degree in GRB 190114C can be explained if large-scale jet magnetic fields are distorted on timescales prior to reverse shock emission.
Epidermal growth factor receptor (EGFR) gene mutations (G719X, exon 19 deletions/insertions, L858R, and L861Q) predict favorable responses to EGFR tyrosine kinase inhibitors (TKIs) in advanced ...non-small cell lung cancer (NSCLC). However, EGFR exon 20 insertion mutations (~10% of all EGFR mutations) are generally associated with insensitivity to available TKIs (gefitinib, erlotinib, and afatinib). The basis of this primary resistance is poorly understood. We studied a broad subset of exon 20 insertion mutations, comparing in vitro TKI sensitivity with responses to gefitinib and erlotinib in NSCLC patients, and found that most are resistant to EGFR TKIs. The crystal structure of a representative TKI-insensitive mutant (D770_N771insNPG) reveals an unaltered adenosine triphosphate-binding pocket, and the inserted residues form a wedge at the end of the C helix that promotes the active kinase conformation. Unlike EGFR-L858R, D770_N771insNPG activates EGFR without increasing its affinity for EGFR TKIs. Unexpectedly, we find that EGFR-A763_Y764insFQEA is highly sensitive to EGFR TKIs in vitro, and patients whose NSCLCs harbor this mutation respond to erlotinib. Analysis of the A763_Y764insFQEA mutant indicates that the inserted residues shift the register of the C helix in the N-terminal direction, altering the structure in the region that is also affected by the TKI-sensitive EGFR-L858R. Our studies reveal intricate differences between EGFR mutations, their biology, and their response to EGFR TKIs.
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