Slug (SNAI2), a member of the well-conserved Snail family of transcription factors, has multiple developmental roles, including in epithelial-to-mesenchymal transition (EMT). Here, we show that Slug ...is critical for the pathological angiogenesis needed to sustain tumor growth, and transiently necessary for normal developmental angiogenesis. We find that Slug upregulation in angiogenic endothelial cells (EC) regulates an EMT-like suite of target genes, and suppresses Dll4-Notch signaling thereby promoting VEGFR2 expression. Both EC-specific Slug re-expression and reduced Notch signaling, either by γ-secretase inhibition or loss of Dll4, rescue retinal angiogenesis in SlugKO mice. Conversely, inhibition of VEGF signaling prevents excessive angiogenic sprouting of Slug overexpressing EC. Finally, endothelial Slug (but not Snail) is activated by the pro-angiogenic factor SDF1α via its canonical receptor CXCR4 and the MAP kinase ERK5. Altogether, our data support a critical role for Slug in determining the angiogenic response during development and disease.
Atmospheric carbon dioxide (CO 2) mole fractions were continuously measured from January 2009 to Decem-ber 2011 at four atmospheric observatories in China using cavity ring-down spectroscopy ...instruments. The stations are Lin'an (LAN), Longfengshan (LFS), Shangdianzi (SDZ), and Waliguan (WLG), which are regional (LAN, LFS, SDZ) or global (WLG) measurement stations of the World Meteorological Organization's Global Atmosphere Watch program (WMO/GAW). LAN is located near the megacity of Shang-hai, in China's economically most developed region. LFS is in a forest and rice production area, close to the city of Harbin in northeastern China. SDZ is located 150 km northeast of Beijing. WLG, hosting the longest record of measured CO 2 mole fractions in China, is a high-altitude site in northwestern China recording background CO 2 concentration. The CO 2 growth rates are 3.7 ± 1.2 ppm yr −1 for LAN, 2.7 ± 0.8 ppm yr −1 for LFS, 3.5 ± 1.6 ppm yr −1 for SDZ, and 2.2 ± 0.8 ppm yr −1 (1σ) for WLG during the period of 2009 to 2011. The highest annual mean CO 2 mole fraction of 404.2 ± 3.9 ppm was observed at LAN in 2011. A comprehensive analysis of CO 2 variations, their diurnal and seasonal cycles as well as the analysis of the influence of local sources on the CO 2 mole fractions allows a characterization of the sampling sites and of the key processes driving the CO 2 mole fractions. These data form a basis to improve our understanding of atmospheric CO 2 variations in China and the underlying fluxes using atmospheric inversion models.
Activin receptor-like kinase 1 (ALK1) is an endothelial serine-threonine kinase receptor for bone morphogenetic proteins (BMPs) 9 and 10. Inactivating mutations in the ALK1 gene cause hereditary ...haemorrhagic telangiectasia type 2 (HHT2), a disabling disease characterized by excessive angiogenesis with arteriovenous malformations (AVMs). Here we show that inducible, endothelial-specific homozygous Alk1 inactivation and BMP9/10 ligand blockade both lead to AVM formation in postnatal retinal vessels and internal organs including the gastrointestinal (GI) tract in mice. VEGF and PI3K/AKT signalling are increased on Alk1 deletion and BMP9/10 ligand blockade. Genetic deletion of the signal-transducing Vegfr2 receptor prevents excessive angiogenesis but does not fully revert AVM formation. In contrast, pharmacological PI3K inhibition efficiently prevents AVM formation and reverts established AVMs. Thus, Alk1 deletion leads to increased endothelial PI3K pathway activation that may be a novel target for the treatment of vascular lesions in HHT2.
Vesicular trafficking involving SNARE proteins play a crucial role in the delivery of cargo to the target membrane. Arf-like protein 1 (Arl1) is an important regulator of the endosomal trans-Golgi ...network (TGN) and secretory trafficking. In yeast, ER stress-enhances Arl1 activation and Golgin Imh1 recruitment to the late-Golgi. Although Arl1 and Imh1 are critical for GARP-mediated endosomal SNARE-recycling transport in response to ER stress, their downstream effectors are unknown. Here, we report that the SNARE-associated protein Sft2 acts downstream of the Arl1-Imh1 axis to regulate SNARE recycling upon ER stress. We first demonstrated that Sft2 is required for Tlg1/Snc1 SNARE-recycling transport under tunicamycin-induced ER stress. Interestingly, we found that Imh1 regulates Tlg2 retrograde transport to the late-Golgi under ER stress, which in turn is required for Sft2 targeting to the late-Golgi. We further showed that Sft2 with 40 amino acids deleted from the N-terminus exhibits defective mediation of SNARE recycling and decreased association with Tlg1 under ER stress. Finally, we demonstrated that Sft2 is required for GARP-dependent endosome-to-Golgi transport in the absence of Rab protein Ypt6. This study highlights Sft2 as a critical downstream effector of the Arl1-Imh1 axis, mediating the endosome-to-Golgi transport of SNAREs.
ADP-ribosylation factor (Arf)-like 4D (Arl4D), one of the Arf-like small GTPases, functions in the regulation of cell morphology, cell migration, and actin cytoskeleton remodeling. End-binding 1 ...(EB1) is a microtubule (MT) plus-end tracking protein that preferentially localizes at the tips of the plus ends of growing MTs and at the centrosome. EB1 depletion results in many centrosome-related defects. Here, we report that Arl4D promotes the recruitment of EB1 to the centrosome and regulates MT nucleation. We first showed that Arl4D interacts with EB1 in a GTP-dependent manner. This interaction is dependent on the C-terminal EB homology region of EB1 and partially dependent on an SxLP motif of Arl4D. We found that Arl4D colocalized with γ-tubulin in centrosomes and the depletion of Arl4D resulted in a centrosomal MT nucleation defect. We further demonstrated that abolishing Arl4D-EB1 interaction decreased MT nucleation rate and diminished the centrosomal recruitment of EB1 without affecting MT growth rate. In addition, Arl4D binding to EB1 increased the association between the p150 subunit of dynactin and the EB1, which is important for MT stabilization. Together, our results indicate that Arl4D modulates MT nucleation through regulation of the EB1-p150 association at the centrosome.
Abstract Radiation detectors have broad application prospects in environmental radiation monitoring, radiation source identification, biomedical imaging, space exploration, astrophysics, other ...radiation detection and imaging fields. Among the third generation semiconductors, the properties of 4H-SiC are more suitable for making high-temperature and strong radiation neutron detectors. SiC materials have become a current research hotspot. In this paper a special readout integrated circuit is designed for the extremely weak current pulse signal output by SiC trench neutron detector. A leakage current compensation circuit is designed for the influence of leakage current on charge sensitive amplifier(CSA) output baseline. The noise of CSA output is analyzed and the noise minimization is carried out. The circuit can quickly respond to the input signal and extract the energy and time information. The circuit is designed based on the DB Hitek 0.18μm CMOS process model. The layout design is achieved and the post-simulation is completed. Simulated results show that the equivalent input charge range of the system is about 2fC ∼ 20fC. The charge conversion gain is 88mV/fC. The nonlinear error is within 1.6 %. Moreover, the equivalent noise charge is 22e-. The circuit has the advantages of high gain, high linearity and low noise. Therefore, the circuit can effectively adapt to the characteristics of the charge signal output from SiC trench neutron detectors and amplify the output charge signal.
Abstract Hydrophone is an important part of sonar system and convert acoustic signal into electrical signal. However, the electrical signal generated by the hydrophone is relatively weak and cannot ...be directly used for underwater detection and communication. Therefore, it is necessary to preprocess the generated electrical signal. In this paper, a switched capacitor charge-sensitive amplifier for MEMS piezoelectric hydrophone is designed. In the structure, two single-channel charge amplifiers are used for time-division multiplexing. The noise sampling and charge amplification are performed separately in the same half cycle to achieve the effect of alternating output, thereby increasing the sampling rate and solving the problem of discontinuous output of the switched capacitor circuit. In the circuit design, virtual switch and two-phase non-overlapping clock are adopted to reduce the error caused by charge injection and clock feedthrough effect of CMOS switch. What’s more, the correlated double sampling technique is used to reduce the offset and low frequency noise of the circuit. The gain of the charge-sensitive amplifier designed in this study is 26 dB, the bandwidth is 0.8Hz∼17.6kHz, the equivalent input noise power spectral density is 115.6 n V / H z at 0.1Hz, and the charge sensitivity is 2 mV / pC . The fitting line between the input charge and the amplitude of the output curve is similar to the theory. The simulation results show that the charge-sensitive amplifier proposed in this study meets the design requirements of the MEMS piezoelectric hydrophone readout circuit.
Charged particles subjected to magnetic fields form Landau levels (LLs). Originally studied in the context of electrons in metals
, fermionic LLs continue to attract interest as hosts of exotic ...electronic phenomena
. Bosonic LLs are also expected to realize novel quantum phenomena
, but, apart from recent advances in synthetic systems
, they remain relatively unexplored. Cooper pairs in superconductors-composite bosons formed by electrons-represent a potential condensed-matter platform for bosonic LLs. Under certain conditions, an applied magnetic field is expected to stabilize an unusual superconductor with finite-momentum Cooper pairs
and exert control over bosonic LLs
. Here we report thermodynamic signatures, observed by torque magnetometry, of bosonic LL transitions in the layered superconductor Ba
Nb
S
. By applying an in-plane magnetic field, we observe an abrupt, partial suppression of diamagnetism below the upper critical magnetic field, which is suggestive of an emergent phase within the superconducting state. With increasing out-of-plane magnetic field, we observe a series of sharp modulations in the upper critical magnetic field that are indicative of distinct vortex states and with a structure that agrees with predictions for Cooper pair LL transitions in a finite-momentum superconductor
. By applying Onsager's quantization rule
, we extract the momentum. Furthermore, study of the fermionic LLs shows evidence for a non-zero Berry phase. This suggests opportunities to study bosonic LLs, topological superconductivity, and their interplay via transport
, scattering
, scanning probe
and exfoliation techniques
.
Biomass production and carbon storage in short-rotation poplar plantations over 10 years were evaluated at the Hanyuan Forestry Farm, Baoying County, China. Experimental treatments applied in a ...split-plot design included four planting densities (1111, 833, 625 and 500 stems
ha
−1) and three poplar clones (NL-80351, I-69 and I-72). Based on the model of total biomass production developed, total plantation biomass production was significantly different in the plantations. The ranking of the plantation biomass production by planting density was 1111>833⪢625>500 stems
ha
−1, and by components was stem>root⩾branch>leaf for all plantations. At 10 years, the highest total biomass in the plantation of 1111 stems
ha
−1 reached about 146
t
ha
−1, which was 5.3%, 11.6% and 24.2% higher than the plantations of 833, 625 and 500 stems
ha
−1, respectively. The annual increment of biomass production over10 years differed significantly among initial planting densities and stand ages (
p<0.01), but no significant difference was observed from age 7 to 10. Mean carbon concentration among all biomass components ranged from 42–50%, with the highest carbon concentrations in stems and the lowest in leaves. Over the study period, the dynamic pattern of total plantation carbon storage by planting density was similar to that of total biomass production. At age 10, the highest total plantation carbon storage in the plantation of 1111 stems
ha
−1 reached about 72.0
t
ha
−1, which was 5.4%, 11.9% and 24.8% higher than in the plantations of 833, 625 and 500 stems
ha
−1, respectively. The annual carbon storage increment over 10 years differed significantly among initial planting densities and stand ages (
p<0.01), and it showed a pattern similar to the annual biomass production increment of the plantations. The results suggest that biomass production and carbon storage potential were highest for planting densities of 1111 and 833 stems
ha
−1 grown over 5- and 6-year cutting cycles, respectively. If 3- or 4-year cutting cycles are used, the planting density should be higher than 1111 stems
ha
−1 (e.g., 1667 or 2500 stems
ha
−1). Based on the mean annual carbon storage for the plantation of 625 stems
ha
−1, as an estimation, the mean carbon storage in the biomass of poplar plantations (excluding leaves) amounts to 3.75×10
7
t
ha
−1
yr
−1 in China.
Autophagy is the process by which organelles and portions of the cytoplasm are degraded in lysosomes. Several different forms of autophagy are known that are distinguishable chiefly by the mode in ...which cargo is delivered to the lysosome for degradation. Ubiquilin was recently reported to regulate macroautophagy, the form of autophagy in which cytosolic cargo is packaged in a double-membrane structure or autophagosome that fuses with lysosomes for degradation. We confirm here using different morphological and biochemical procedures that ubiquilin is present in autophagosomes in HeLa cells and in brain and liver tissue of mouse. Coimmunoprecipitation studies indicated that ubiquilin binds the autophagosome marker LC3 in a complex and that reduction of ubiquilin expression reduces autophagosome formation, which correlates with a reduction in maturation of LC3-I to the LC3-II form of the protein. We found that ubiquilin is degraded during both macroautophagy and during chaperone-mediated autophagy (CMA), the latter of which involves the active transport of proteins into lysosomes. We discuss the implication of this degradation in mediating cross-talk between macroautophagy and CMA. Finally, we demonstrate that ubiquilin protects cells against starvation-induced cell death propagated by overexpression of mutant Alzheimer's disease PS2N141I protein and green fluorescent protein (GFP)-huntingtin exon-1 fusion protein containing 74 polyglutamines.
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