Cancer cell molecular mimicry of stem cells (SC) imbues neoplastic cells with enhanced proliferative and renewal capacities. In support, numerous mediators of SC self-renewal have been evinced to ...show oncogenic potential. We have recently reported that short-hairpin RNA-mediated knockdown of the embryonic stem cell (ESC) self-renewal gene NANOG significantly reduced the clonogenic and tumorigenic capabilities of various cancer cells. In this study, we sought to test the potential pro-tumorigenic functions of NANOG, particularly, in prostate cancer (PCa). Using qRT-PCR, we first confirmed that PCa cells expressed NANOG mRNA primarily from the NANOGP8 locus on chromosome 15q14. We then constructed a lentiviral promoter reporter in which the -3.8-kb NANOGP8 genomic fragment was used to drive the expression of green fluorescence protein (GFP). We observed that NANOGP8-GFP(+) PCa cells showed cancer stem cell (CSC) characteristics such as enhanced clonal growth and tumor regenerative capacity. To further investigate the functions and mechanisms of NANOG in tumorigenesis, we established tetracycline-inducible NANOG-overexpressing cancer cell lines, including both PCa (Du145 and LNCaP) and breast (MCF-7) cancer cells. NANOG induction promoted drug resistance in MCF-7 cells, tumor regeneration in Du145 cells and, most importantly, castration-resistant tumor development in LNCaP cells. These pro-tumorigenic effects of NANOG were associated with key molecular changes, including an upregulation of molecules such as CXCR4, IGFBP5, CD133 and ALDH1. The present gain-of-function studies, coupled with our recent loss-of-function work, establish the integral role for NANOG in neoplastic processes and shed light on its mechanisms of action.
Immune checkpoint inhibitors in combination with tyrosine kinase inhibitors are standard treatments for advanced clear cell renal cell carcinoma (RCC). This phase III RENOTORCH study compared the ...efficacy and safety of toripalimab plus axitinib versus sunitinib for the first-line treatment of patients with intermediate-/poor-risk advanced RCC.
Patients with intermediate-/poor-risk unresectable or metastatic RCC were randomized in a ratio of 1 : 1 to receive toripalimab (240 mg intravenously once every 3 weeks) plus axitinib (5 mg orally twice daily) or sunitinib 50 mg orally once daily for 4 weeks (6-week cycle) or 2 weeks (3-week cycle). The primary endpoint was progression-free survival (PFS) assessed by an independent review committee (IRC). The secondary endpoints were investigator-assessed PFS, overall response rate (ORR), overall survival (OS), and safety.
A total of 421 patients were randomized to receive toripalimab plus axitinib (n = 210) or sunitinib (n = 211). With a median follow-up of 14.6 months, toripalimab plus axitinib significantly reduced the risk of disease progression or death by 35% compared with sunitinib as assessed by an IRC hazard ratio (HR) 0.65, 95% confidence interval (CI) 0.49-0.86; P = 0.0028. The median PFS was 18.0 months in the toripalimab–axitinib group, whereas it was 9.8 months in the sunitinib group. The IRC-assessed ORR was significantly higher in the toripalimab–axitinib group compared with the sunitinib group (56.7% versus 30.8%; P < 0.0001). An OS trend favoring toripalimab plus axitinib was also observed (HR 0.61, 95% CI 0.40-0.92). Treatment-related grade ≥3 adverse events occurred in 61.5% of patients in the toripalimab–axitinib group and 58.6% of patients in the sunitinib group.
In patients with previously untreated intermediate-/poor-risk advanced RCC, toripalimab plus axitinib provided significantly longer PFS and higher ORR than sunitinib and had a manageable safety profile
ClinicalTrials.gov NCT04394975
•Toripalimab plus axitinib provided significantly better PFS than sunitinib as a first-line treatment for advanced RCC.•A significantly higher ORR was found in patients who received toripalimab plus axitinib than those who received sunitinib.•The combination of toripalimab plus axitinib was generally well tolerated.•No new safety signals were identified in the combination outside the known safety profile of toripalimab or axitinib.
The technological appeal of multiferroics is the ability to control magnetism with electric field. For devices to be useful, such control must be achieved at room temperature. The only single-phase ...multiferroic material exhibiting unambiguous magnetoelectric coupling at room temperature is BiFeO3 (refs 4 and 5). Its weak ferromagnetism arises from the canting of the antiferromagnetically aligned spins by the Dzyaloshinskii-Moriya (DM) interaction. Prior theory considered the symmetry of the thermodynamic ground state and concluded that direct 180-degree switching of the DM vector by the ferroelectric polarization was forbidden. Instead, we examined the kinetics of the switching process, something not considered previously in theoretical work. Here we show a deterministic reversal of the DM vector and canted moment using an electric field at room temperature. First-principles calculations reveal that the switching kinetics favours a two-step switching process. In each step the DM vector and polarization are coupled and 180-degree deterministic switching of magnetization hence becomes possible, in agreement with experimental observation. We exploit this switching to demonstrate energy-efficient control of a spin-valve device at room temperature. The energy per unit area required is approximately an order of magnitude less than that needed for spin-transfer torque switching. Given that the DM interaction is fundamental to single-phase multiferroics and magnetoelectrics, our results suggest ways to engineer magnetoelectric switching and tailor technologically pertinent functionality for nanometre-scale, low-energy-consumption, non-volatile magnetoelectronics.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Agnathan fish hold a key position in vertebrate evolution, especially regarding the origin of the head and neural-crest-derived tissue. In contrast to amphioxus, lampreys and other vertebrates ...possess a complex brain and placodes that contribute to well-developed eyes, as well as auditory and olfactory systems. These sensory sytems were arguably a trigger to subsequent vertebrate diversifications. However, although they are known from skeletal impressions in younger Palaeozoic agnathans, information about the earliest records of these systems has been largely wanting. Here we report numerous specimens of the Lower Cambrian vertebrate Haikouichthys ercaicunensis, until now only known from the holotype. Haikouichthys shows significant differences from other fossil agnathans: key features include a small lobate extension to the head, with eyes and possible nasal sacs, as well as what may be otic capsules. A notochord with separate vertebral elements is also identifiable. Phylogenetic analysis indicates that this fish lies within the stem-group craniates. Although Haikouichthys somewhat resembles the ammocoete larva of modern lampreys, this is because of shared general craniate characters; adult lampreys and hagfishes (the cyclostomes if monophyletic) are probably derived in many respects.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
We report experimental observation of large anomalous Hall effect exhibited in non-collinear triangular antiferromagnet D0
19
-type Mn
3
Ga with coplanar spin structure at temperatures ...higher than 100 K. The value of anomalous Hall resistivity increases with increasing temperature, which reaches 1.25 μΩ · cm at a low field of ~300 Oe at room temperature. The corresponding room-temperature anomalous Hall conductivity is about 17 (Ω · cm)
−1
. Most interestingly, as temperature falls below 100 K, a temperature-independent topological-like Hall effect was observed. The maximum peak value of topological Hall resistivity is about 0.255 μΩ · cm. The appearance of the topological Hall effect is attributed to the change of spin texture as a result of weak structural distortion from hexagonal to orthorhombic symmetry in Mn
3
Ga. Present study suggests that Mn
3
Ga shows promising possibility to be antiferromagnetic spintronics or topological Hall effect-based data storage devices.
The optical design and performance of the recently opened 13A biological small‐angle X‐ray scattering (SAXS) beamline at the 3.0 GeV Taiwan Photon Source of the National Synchrotron Radiation ...Research Center are reported. The beamline is designed for studies of biological structures and kinetics in a wide range of length and time scales, from angstrom to micrometre and from microsecond to minutes. A 4 m IU24 undulator of the beamline provides high‐flux X‐rays in the energy range 4.0–23.0 keV. MoB4C double‐multilayer and Si(111) double‐crystal monochromators (DMM/DCM) are combined on the same rotating platform for a smooth rotation transition from a high‐flux beam of ∼4 × 1014 photons s−1 to a high‐energy‐resolution beam of ΔE/E ≃ 1.5 × 10−4; both modes share a constant beam exit. With a set of Kirkpatrick–Baez (KB) mirrors, the X‐ray beam is focused to the farthest SAXS detector position, 52 m from the source. A downstream four‐bounce crystal collimator, comprising two sets of Si(311) double crystals arranged in a dispersive configuration, optionally collimate the DCM (vertically diffracted) beam in the horizontal direction for ultra‐SAXS with a minimum scattering vector q down to 0.0004 Å−1, which allows resolving ordered d‐spacing up to 1 µm. A microbeam, of 10–50 µm beam size, is tailored by a combined set of high‐heat‐load slits followed by micrometre‐precision slits situated at the front‐end 15.5 m position. The second set of KB mirrors then focus the beam to the 40 m sample position, with a demagnification ratio of ∼1.5. A detecting system comprising two in‐vacuum X‐ray pixel detectors is installed to perform synchronized small‐ and wide‐angle X‐ray scattering data collections. The observed beamline performance proves the feasibility of having compound features of high flux, microbeam and ultra‐SAXS in one beamline.
The optical design and performance of the BioSAXS beamline at the Taiwan Photon Source are reported
Complex topological configurations are fertile ground for exploring emergent phenomena and exotic phases in condensed-matter physics. For example, the recent discovery of polarization vortices and ...their associated complex-phase coexistence and response under applied electric fields in superlattices of (PbTiO
)
/(SrTiO
)
suggests the presence of a complex, multi-dimensional system capable of interesting physical responses, such as chirality, negative capacitance and large piezo-electric responses
. Here, by varying epitaxial constraints, we discover room-temperature polar-skyrmion bubbles in a lead titanate layer confined by strontium titanate layers, which are imaged by atomic-resolution scanning transmission electron microscopy. Phase-field modelling and second-principles calculations reveal that the polar-skyrmion bubbles have a skyrmion number of +1, and resonant soft-X-ray diffraction experiments show circular dichroism, confirming chirality. Such nanometre-scale polar-skyrmion bubbles are the electric analogues of magnetic skyrmions, and could contribute to the advancement of ferroelectrics towards functionalities incorporating emergent chirality and electrically controllable negative capacitance.
Aim
This study investigated the effects of environmental variables on the bacterial and fungal communities of the Beilu River (on the Tibetan Plateau) permafrost soils with different vegetation ...types.
Methods and Results
Microbial communities were sampled from meadow, steppe and desert steppe permafrost soils during May, June, August and November, and they were analysed by both pyrosequencing and the use of Biolog EcoPlates. The dominant bacterial and fungal phyla in meadow and steppe soils were Proteobacteria and Ascomycota, whereas Actinobacteria and Basidiomycota predominated in desert steppe soils. The bacterial communities in meadow soils degraded amines and amino acids very rapidly, while polymers were degraded rapidly by steppe communities. The RDA patterns showed that the microbial communities differed greatly between meadow, steppe and desert steppe, and they were related to variations in the soil moisture, C/N ratio and pH. A UniFrac analysis detected clear differences between the desert steppe bacterial community and others, and seasonal shifts were observed. The fungal UniFrac patterns differed significantly between meadow and steppe soils. There were significant correlations between the bacterial diversity (H′) and soil moisture (r = 0·506) and C/N (r = 0·527). The fungal diversity (Hf′) was significantly correlated with the soil pH (r = 0·541).
Conclusion
The soil moisture, C/N ratio and pH were important determinants of the microbial community structure in Beilu River permafrost soils.
Significance and Impact of the Study
These results may provide a useful baseline for predicting the variation in microbial communities in response to climate changes.
A grand challenge underlies the entire field of topology-enabled quantum logic and information science: how to establish topological control principles driven by quantum coherence and understand the ...time dependence of such periodic driving. Here we demonstrate a few-cycle THz-pulse-induced phase transition in a Dirac semimetalZrTe5that is periodically driven by vibrational coherence due to excitation of the lowest Raman active mode. Above a critical THz-pump field threshold, there emerges a long-lived metastable phase, approximately 100 ps, with unique Raman phonon-assisted topological switching dynamics absent for optical pumping. The switching also manifests itself by distinct features: nonthermal spectral shape, relaxation slowing near the Lifshitz transition where the critical Dirac point occurs, and diminishing signals at the same temperature that the Berry-curvature-induced anomalous Hall effect magnetoresistance vanishes. These results, together with first-principles modeling, identify a mode-selective Raman coupling that drives the system from strong to weak topological insulators with a Dirac semimetal phase established at a critical atomic displacement controlled by the phonon coherent pumping. Harnessing of vibrational coherence can be extended to steer symmetry-breaking transitions, i.e., Dirac to Weyl ones, with implications for THz topological quantum gate and error correction applications.
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