New structures with richer electromagnetic properties are in high demand for developing novel microwave and optic devices aimed at realizing fast light-based information transfer and information processing. Here we show theoretically that a topological photonic state exists in a hexagonal LC circuit with short-range textures in the inductance, which is induced by a band inversion between p- and d-like electromagnetic modes carrying orbital angular momentum, and realize this state experimentally in planar microstrip arrays. Measuring both amplitude and phase of the out-of-plane electric field accurately using microwave near-field techniques, we demonstrate directly that topological interfacial electromagnetic waves launched by a linearly polarized dipole source propagate in opposite directions according to the sign of the orbital angular momentum. The open planar structure adopted in the present approach leaves much room for including other elements useful for advanced information processing, such as electric/mechanical resonators, superconducting Josephson junctions and SQUIDs.
Perovskite solar cells (PSCs) have reached an impressive efficiency over 23%. One of its promising characteristics is the low-cost solution printability, especially for flexible solar cells. However, printing large area uniform electron transport layers on rough and soft plastic substrates without hysteresis is still a great challenge. Herein, we demonstrate slot-die printed high quality tin oxide films for high efficiency flexible PSCs. The inherent hysteresis induced by the tin oxide layer is suppressed using a universal potassium interfacial passivation strategy regardless of fabricating methods. Results show that the potassium cations, not the anions, facilitate the growth of perovskite grains, passivate the interface, and contribute to the enhanced efficiency and stability. The small size flexible PSCs achieve a high efficiency of 17.18% and large size (5 x 6 cm(2)) flexible modules obtain an efficiency over 15%. This passivation strategy has shown great promise for pursuing high performance large area flexible PSCs.
Many patients remain unresponsive to intensive PD-1/PD-L1 blockade therapy despite the presence of tumor-infiltrating lymphocytes. We propose that impaired innate sensing might limit the complete activation of tumor-specific T cells after PD-1/PD-L1 blockade. Local delivery of type I interferons (IFNs) restores antigen presentation, but upregulates PD-L1, dampening subsequent T-cell activation. Therefore, we armed anti-PD-L1 antibody with IFN alpha (IFN alpha-anti-PD-L1) to create feedforward responses. Here, we find that a synergistic effect is achieved to overcome both type I IFN and checkpoint blockade therapy resistance with the least side effects in advanced tumors. Intriguingly, PD-L1 expressed in either tumor cells or tumor-associated host cells is sufficient for fusion protein targeting. IFN alpha-anti-PD-L1 activates IFNAR signaling in host cells, but not in tumor cells to initiate T-cell reactivation. Our data suggest that a next-generation PD-L1 antibody armed with IFNa improves tumor targeting and antigen presentation, while countering innate or T-cell-driven PD-L1 upregulation within tumor.
Aberrant expression of long noncoding RNA H19 has been associated with tumour progression, but the underlying molecular tumourigenesis mechanisms remain largely unknown. Here, we report that H19 expression is frequently downregulated in human primary pituitary adenomas and is negatively correlated with tumour progression. Consistently, upregulation of H19 expression inhibits pituitary tumour cell proliferation in vitro and tumour growth in vivo. Importantly, we uncover a function of H19, which controls cell/tumour growth through inhibiting function of mTORC1 but not mTORC2. Mechanistically, we show that H19 could block mTORC1-mediated 4E-BP1 phosphorylation without affecting S6K1 activation. At the molecular level, H19 interacted with 4E-BP1 at the TOS motif and competitively inhibited 4E-BP1 binding to Raptor. Finally, we demonstrate that H19 is more effective than cabergoline treatment in the suppression of pituitary tumours. Together, our study uncovered the role of H19-mTOR-4E-BP1 axis in pituitary tumour growth regulation that may be a potential therapeutic target for human pituitary tumours.
The manifestation of Weyl fermions in strongly correlated electron systems is of particular interest. We report evidence for Weyl fermions in the heavy fermion semimetal YbPtBi from electronic structure calculations, angle-resolved photoemission spectroscopy, magnetotransport and calorimetric measurements. At elevated temperatures where 4f-electrons are localized, there are triply degenerate points, yielding Weyl nodes in applied magnetic fields. These are revealed by a contribution from the chiral anomaly in the magnetotransport, which at low temperatures becomes negligible due to the influence of electronic correlations. Instead, Weyl fermions are inferred from the topological Hall effect, which provides evidence for a Berry curvature, and a cubic temperature dependence of the specific heat, as expected from the linear dispersion near the Weyl nodes. The results suggest that YbPtBi is a Weyl heavy fermion semimetal, where the Kondo interaction renormalizes the bands hosting Weyl points. These findings open up an opportunity to explore the interplay between topology and strong electronic correlations.
Selective creation of quaternary carbon centers has been a long-standing challenge in synthetic chemistry. We report here the chromium-catalyzed, para-selective formation of arylated quaternary carbon centers by alkylative reactions of benzamide derivatives with tertiary alkylmagnesium bromides at room temperature. The reaction, which was enabled by a low-cost chromium(III) salt combined with trimethylsilyl bromide, introduces a sterically bulky tertiary alkyl scaffold on the para-position of benzamide derivatives in a highly selective fashion without either isomerization of the tertiary alkyl group or formation of ortho-alkylated byproducts. Forming low-valent Cr species in situ by reaction of CrCl3 with t-BuMgBr accompanied by evolution of hydrogen can be considered, which serves as reactive species to promote the reaction. The para-alkylation likely occurs via a radical-type nucleophilic substitution of imino-coordination benzimidate intermediate.
Most of the high-performance organic solar cells are fabricated with the assistance of high-boiling-point solvent additives to optimize their charge transport properties; this has adverse effects on the OSCs' stability and reproducibility in large-scale production. Here, we design volatilizable solid additives by considering the molecular structure feature of an acceptor-donor-acceptor-type non-fullerene acceptor. The application of solid additives can enhance the intermolecular pi-pi stacking of the non-fullerene acceptor and thus facilitate the charge transport properties in the active layers, leading to improved efficiencies of OSCs. Importantly, devices fabricated using volatilizable solid additives exhibit higher stability and reproducibility when compared with the OSCs processed with solvent additives. Our results not only demonstrate an approach of applying volatilizable solid additives to benefit the large-scale production of OSCs but also provide a potential direction for designing specific solid additives for different active layers.
Quantum Griffiths singularity was theoretically proposed to interpret the phenomenon of divergent dynamical exponent in quantum phase transitions. It has been discovered experimentally in three-dimensional (3D) magnetic metal systems and two-dimensional (2D) superconductors. But, whether this state exists in lower dimensional systems remains elusive. Here, we report the signature of quantum Griffiths singularity state in quasi-one-dimensional (1D) Ta2PdS5 nanowires. The superconducting critical field shows a strong anisotropic behavior and a violation of the Pauli limit in a parallel magnetic field configuration. Current-voltage measurements exhibit hysteresis loops and a series of multiple voltage steps in transition to the normal state, indicating a quasi-1D nature of the superconductivity. Surprisingly, the nanowire undergoes a superconductor-metal transition when the magnetic field increases. Upon approaching the zero-temperature quantum critical point, the system uncovers the signature of the quantum Griffiths singularity state arising from enhanced quenched disorders, where the dynamical critical exponent becomes diverging rather than being constant.
The lack of representative nasopharyngeal carcinoma (NPC) models has seriously hampered research on EBV carcinogenesis and preclinical studies in NPC. Here we report the successful growth of five NPC patient-derived xenografts (PDXs) from fifty-eight attempts of transplantation of NPC specimens into NOD/SCID mice. The take rates for primary and recurrent NPC are 4.9% and 17.6%, respectively. Successful establishment of a new EBV-positive NPC cell line, NPC43, is achieved directly from patient NPC tissues by including Rho-associated coiled-coil containing kinases inhibitor (Y-27632) in culture medium. Spontaneous lytic reactivation of EBV can be observed in NPC43 upon withdrawal of Y-27632. Whole-exome sequencing (WES) reveals a close similarity in mutational profiles of these NPC PDXs with their corresponding patient NPC. Whole-genome sequencing (WGS) further delineates the genomic landscape and sequences of EBV genomes in these newly established NPC models, which supports their potential use in future studies of NPC.
Sox2 is a key transcriptional factor for maintaining pluripotency of stem cells. Sox2 deficiency causes neurodegeneration and impairs neurogenesis. Although the transcriptional regulation of Sox2 has been extensively studied, the mechanisms that control Sox2 protein turnover are yet to be clarified. Here we show that the RING-finger ubiquitin ligase complex CUL4A(DET1-COP1) and the deubiquitylase OTUD7B govern Sox2 protein stability during neural progenitor cells (NPCs) differentiation. Sox2 expression declines concordantly with OTUD7B and reciprocally with CUL4A and COP1 levels upon NPCs differentiation. COP1, as the substrate receptor, interacts directly with and ubiquitylates Sox2, while OTUD7B removes polyUb conjugates from Sox2 and increases its stability. COP1 knockdown stabilizes Sox2 and prevents differentiation, while OTUD7B knockdown destabilizes Sox2 and induces differentiation. Thus, CUL4A(DET1-COP1) and OTUD7B exert opposite roles in regulating Sox2 protein stability at the post-translational level, which represents a critical regulatory mechanism involved in the maintenance and differentiation of NPCs.
There have been very few reports on protein domains that specifically recognize sulfur. Here we present the crystal structure of the sulfur-binding domain (SBD) from the DNA phosphorothioation (PT)-dependent restriction endonuclease ScoMcrA. SBD contains a hydrophobic surface cavity that is formed by the aromatic ring of Y164, the pyrolidine ring of P165, and the non-polar side chains of four other residues that serve as lid, base, and wall of the cavity. The SBD and PT-DNA undergo conformational changes upon binding. The S(187)RGRR(191) loop inserts into the DNA major groove to make contacts with the bases of the G(PS)GCC core sequence. Mutating key residues of SBD impairs PT-DNA association. More than 1000 sequenced microbial species from fourteen phyla contain SBD homologs. We show that three of these homologs bind PT-DNA in vitro and restrict PT-DNA gene transfer in vivo. These results show that SBD-like PT-DNA readers exist widely in prokaryotes.
The Warburg effect is a prominent metabolic feature associated with neoplastic diseases; however, the underlying mechanism remains incompletely understood. TAp73, a structural homolog of the tumor suppressor p53, is frequently overexpressed in human tumors, indicating a proliferative advantage that it can confer to tumor cells. Here we show that TAp73 stimulates the expression of phosphofructokinase-1, liver type (PFKL), which catalyzes the committed step in glycolysis. Through this regulation, TAp73 enhances glucose consumption and lactate excretion, promoting the Warburg effect. By activating PFKL, TAp73 also increases ATP production and bolsters anti-oxidant defense. TAp73 deficiency results in a pronounced reduction in tumorigenic potential, which can be rescued by forced PFKL expression. These findings establish TAp73 as a critical regulator of glycolysis and reveal a mechanism by which tumor cells achieve the Warburg effect to enable oncogenic growth.
There is evidence for greater carbon storage in the glacial deep Pacific, but it is uncertain whether it was caused by changes in ventilation, circulation, and biological productivity. The spatial epsilon(Nd) evolution in the deep Pacific provides information on the deepwater transit time. Seven new foraminiferal epsilon(Nd) records are presented to systematically constrain glacial to interglacial changes in deep Pacific overturning and two different epsilon(Nd) evolution regimes occur spatially in the Pacific with reduced meridional epsilon(Nd) gradients in glacials, suggesting a faster deep Pacific overturning circulation. This implies that greater glacial carbon storage due to sluggish circulation, that is believed to have occurred in the deep Atlantic, did not operate in a similar manner in the Pacific Ocean. Other mechanisms such as increased biological pump efficiency and poor high latitude air-sea exchange could be responsible for increased carbon storage in the glacial Pacific.
Many cellular programs of neural development are under combinatorial regulation by different chemoattractive or chemorepulsive factors. Here, we describe a microfluidic platform that utilizes well-controlled three-dimensional (3D) diffusion to generate molecular gradients of varied steepness in a large array of hydrogel cylinders, allowing high-throughput 3D chemotactic assays for mechanistic dissection of steepness-dependent neuronal chemotaxis. Using this platform, we examine neuronal sensitivity to the steepness of gradient composed of netrin-1, nerve growth factor, or semaphorin3A (Sema3A) proteins, and reveal dramatic diversity and complexity in the associated chemotactic regulation of neuronal development. Particularly for Sema3A, we find that serine/threonine kinase-11 and glycogen synthase kinase-3 signaling pathways are differentially involved in steepness-dependent chemotactic regulation of coordinated neurite repellence and neuronal migration. These results provide insights to the critical role of gradient steepness in neuronal chemotaxis, and also prove the technique as an expandable platform for studying other chemoresponsive cellular systems.
It is generally considered that the perennial glaciation of Greenland lasting several orbital cycles began around 2.7 Ma along with the intensification of Northern Hemisphere glaciation (NHG). Both data and model studies have demonstrated that a decline in atmospheric pCO(2) was instrumental in establishing a perennial Greenland ice sheet (GrIS), yet models have generally used simplistic pCO(2) constraints rather than data-inferred pCO(2) evolution. Here, using a method designed for the long-term coupling of climate and cryosphere models and pCO(2) scenarios from different studies, we highlight the pivotal role of pCO(2) on the GrIS expansion across the Plio-Pleistocene Transition (PPT, 3.0-2.5 Ma), in particular in the range between 280 and 320 ppm. Good qualitative agreement is obtained between various IRD reconstructions and some of the possible evolutions of the GrIS simulated by our model. Our results underline the dynamism of the GrIS waxing and waning under pCO(2) levels similar to or lower than today, which supports recent evidence of a dynamic GrIS during the Plio-Pleistocene.