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Metastasis of the cervical lymph nodes frequently leads to poor survival of patients with oral squamous cell carcinoma (OSCC). The underlying mechanisms of lymph node metastasis are unclear. Wingless-type MMTV integration site family, member 5B (WNT5B), one component of the WNT signal pathway, was markedly up-regulated in OSCC sublines with high potential of lymphatic metastasis compared to that in OSCC cells with low nodal metastasis. Increased WNT5B mRNA was demonstrated in human OSCC tissues in comparison with adjacent non-tumorous tissues. Interestingly, the high level of WNT5B protein in serum was associated with lymph node metastasis in OSCC patients. Knockdown of WNT5B expression in OSCC sublines did not affect tumour growth but impaired lymph node metastasis and tumour lymphangiogenesis of orthotopic transplantation. Conditioned medium from WNT5B knockdown cells reduced the tube formation of lymphatic endothelial cells (LECs). In contrast, recombinant WNT5B enhanced the tube formation, permeability and migration of LECs. In LECs stained with phalloidin, the morphology of those treated with recombinant WNT5B changed from flat to spindle-like. Recombinant WNT5B also increased α-smooth muscle actin and inhibited the expression of vascular endothelial-cadherin but retained characteristics of endothelial cells. The results suggest that WNT5B functions in the partial endothelial-mesenchymal transition (EndoMT). Furthermore, WNT5B-induced tube formation was impaired in the LECs following the knockdown of EndoMT-related transcription factor, SNAIL or SLUG. The WNT5B-induced expression of Snail or Slug was abolished by IWR-1-endo and Rac1 inhibitors, which are involved in the WNT/β-catenin and planar cell polarity pathways, respectively. Collectively, the data suggest that WNT5B induces tube formation by regulating the expression of Snail and Slug proteins through activation of canonical and non-canonical WNT signalling pathways.

Head and neck squamous cell carcinoma is the sixth most common cancer worldwide and has high heterogeneity and unsatisfactory outcomes. To better characterize the tumor progression trajectory, we perform single-cell RNA sequencing of normal tissue, precancerous tissue, early-stage, advanced-stage cancer tissue, lymph node, and recurrent tumors tissue samples. We identify the transcriptional development trajectory of malignant epithelial cells and a tumorigenic epithelial subcluster regulated by TFDP1 . Furthermore, we find that the infiltration of POSTN + fibroblasts and SPP1 + macrophages gradually increases with tumor progression; their interaction or interaction with malignant cells also gradually increase to shape the desmoplastic microenvironment and reprogram malignant cells to promote tumor progression. Additionally, we demonstrate that during lymph node metastasis, exhausted CD8 + T cells with high CXCL13 expression strongly interact with tumor cells to acquire more aggressive phenotypes of extranodal expansion. Finally, we delineate the distinct features of malignant epithelial cells in primary and recurrent tumors, providing a theoretical foundation for the precise selection of targeted therapy for tumors at different stages. In summary, the current study offers a comprehensive landscape and deep insight into epithelial and microenvironmental reprogramming throughout initiation, progression, lymph node metastasis and recurrence of head and neck squamous cell carcinoma. Head and neck squamous cell carcinoma (HNSCC) is characterised with high heterogeneity and unfavourable prognosis. Here, the authors perform single cell transcriptomics to investigate the tumour microenvironment features of HNSCC initiation, progression, lymph node metastasis and recurrence.

Field-tunable bandgap in bilayer graphene The electronic bandgap of a material refers to an energy region where electrons are not 'allowed' to reside because of quantum mechanical considerations related to the symmetries and atomic constituents of the underlying crystal structure. It is a fundamental property of semiconductors and insulators and determines their electrical and optical response, which is why it is a crucial consideration in modern device physics and technologies. Ideally, the bandgap would be tunable by electric fields, which would allow great flexibility in device design and functionality. Until now electrical tunability has proved elusive, but now Zhang et al . demonstrate such a tunable bandgap in a bilayer-graphene-based device, spanning a spectral range from zero to mid-infrared. The ability to electrically control the bandgap, a fundamental property of semiconductors and insulators that determines electrical and optical response, is highly desirable for device design and functionality. Experiments now demonstrate versatile control of the bandgap in bilayer graphene-based devices by use of electric fields. The electronic bandgap is an intrinsic property of semiconductors and insulators that largely determines their transport and optical properties. As such, it has a central role in modern device physics and technology and governs the operation of semiconductor devices such as p–n junctions, transistors, photodiodes and lasers 1 . A tunable bandgap would be highly desirable because it would allow great flexibility in design and optimization of such devices, in particular if it could be tuned by applying a variable external electric field. However, in conventional materials, the bandgap is fixed by their crystalline structure, preventing such bandgap control. Here we demonstrate the realization of a widely tunable electronic bandgap in electrically gated bilayer graphene. Using a dual-gate bilayer graphene field-effect transistor (FET) 2 and infrared microspectroscopy 3 , 4 , 5 , we demonstrate a gate-controlled, continuously tunable bandgap of up to 250 meV. Our technique avoids uncontrolled chemical doping 6 , 7 , 8 and provides direct evidence of a widely tunable bandgap—spanning a spectral range from zero to mid-infrared—that has eluded previous attempts 2 , 9 . Combined with the remarkable electrical transport properties of such systems, this electrostatic bandgap control suggests novel nanoelectronic and nanophotonic device applications based on graphene.

Electrochemical (EC) reactions are crucial in many applications, yet most EC analytical tools lack the sensitivity to access molecular-level information of reactants and products. By combining sum-frequency vibrational spectroscopy and surface plasmon resonance at EC interfaces, we demonstrate the feasibility of measuring in situ and real-time vibrational spectra during EC reactions at noble metal electrodes. Application of the technique to EC reactions at a gold surface helps in understanding how the surface in a basic solution is oxidized and reduced during a cyclic voltammetry cycle. Study of desorption of a thiol self-assembled monolayer from gold through EC reactions in a basic solution shows that the desorbed thiols by reductive reaction remain as an ordered layer near the gold interface, but do diffuse away if they are desorbed oxidatively from gold.

The spatially developing compressible plane mixing layer with a convective Mach number of 0.7 is investigated by direct numerical simulation. A pair of equal and opposite oblique instability waves is introduced to perturb the mixing layer at the inlet. The full evolution process of instability, including formation of $ \\mrm{\\Lambda} $ -vortices and hairpin vortices, breakdown of large structures and establishment of self-similar turbulence, is presented clearly in the simulation. In the transition process, the flow fields are populated sequentially by $ \\mrm{\\Lambda} $ -vortices, hairpin vortices and ‘flower’ structures. This is the first direct evidence showing the dominance of these structures in the spatially developing mixing layer. Hairpin vortices are found to play an important role in the breakdown of the flow. The legs of hairpin vortices first evolve into sheaths with intense vorticity then break up into small slender vortices. The later flower structures are produced by the instability of the heads of the hairpin vortices. They prevail for a long distance in the mixing layer until the flow starts to settle down into its self-similar state. The preponderance of slender inclined streamwise vortices is observed in the transversal middle zone of the transition region after the breakup of the hairpin legs. This predominance of streamwise vortices also persists in the self-similar turbulent region, though the vortices there are found to be relatively very weak. The evolution of both the mean streamwise velocity profile and the Reynolds stresses is found to have close connection to the behaviour of the large vortex structures. High growth rates of the momentum and vorticity thicknesses are observed in the transition region of the flow. The growth rates in the self-similar turbulence region decay to a value that agrees well with previous experimental and numerical studies. Shocklets occur in the simulation, and their formation mechanisms are elaborated and categorized. This is the first three-dimensional simulation that captures shocklets at this low convective Mach number.

Key Points Highlights the importance of irrigation in endodontics. Provides an overview of solutions used in the irrigation of the root canal. Outlines old and new equipment for irrigation. Irrigation is a key part of successful root canal treatment. It has several important functions, which may vary according to the irrigant used: it reduces friction between the instrument and dentine, improves the cutting effectiveness of the files, dissolves tissue, cools the file and tooth, and furthermore, it has a washing effect and an antimicrobial/antibiofilm effect. Irrigation is also the only way to impact those areas of the root canal wall not touched by mechanical instrumentation. Sodium hypochlorite is the main irrigating solution used to dissolve organic matter and kill microbes effectively. High concentration sodium hypochlorite (NaOCl) has a better effect than 1 and 2% solutions. Ethylenediaminetetraacetic acid (EDTA) is needed as a final rinse to remove the smear layer. Sterile water or saline may be used between these two main irrigants, however, they must not be the only solutions used. The apical root canal imposes a special challenge to irrigation as the balance between safety and effectiveness is particularly important in this area. Different means of delivery are used for root canal irrigation, from traditional syringe-needle delivery to various machine-driven systems, including automatic pumps and sonic or ultrasonic energy.

Among natural energy resources, methane clathrate has attracted tremendous attention because of its strong relevance to current energy and environment issues. Yet little is known about how the clathrate starts to nucleate and disintegrate at the molecular level, because such microscopic processes are difficult to probe experimentally. Using surface-specific sum-frequency vibrational spectroscopy, we have studied in situ the nucleation and disintegration of methane clathrate embryos at the methane-gas–water interface under high pressure and different temperatures. Before appearance of macroscopic methane clathrate, the interfacial structure undergoes 3 stages as temperature varies, namely, dissolution of methane molecules into water interface, formation of cage-like methane–water complexes, and appearance of microscopic methane clathrate, while the bulk water structure remains unchanged. We find spectral features associated with methane–water complexes emerging in the induction time. The complexes are present over a wide temperature window and act as nuclei for clathrate growth. Their existence in the melt of clathrates explains why melted clathrates can be more readily recrystallized at higher temperature, the so-called “memory effect.” Our findings here on the nucleation mechanism of clathrates could provide guidance for rational control of formation and disintegration of clathrates.

Magnetic van der Waals (vdW) materials have opened new frontiers for realizing novel many-body phenomena. Recently NiPS 3 has received intense interest since it hosts an excitonic quasiparticle whose properties appear to be intimately linked to the magnetic state of the lattice. Despite extensive studies, the electronic character, mobility, and magnetic interactions of the exciton remain unresolved. Here we address these issues by measuring NiPS 3 with ultra-high energy resolution resonant inelastic x-ray scattering (RIXS). We find that Hund’s exchange interactions are primarily responsible for the energy of formation of the exciton. Measuring the dispersion of the Hund’s exciton reveals that it propagates in a way that is analogous to a double-magnon. We trace this unique behavior to fundamental similarities between the NiPS 3 exciton hopping and spin exchange processes, underlining the unique magnetic characteristics of this novel quasiparticle. Recently, excitons with unconventional properties were reported in a van der Waals antiferromagnet NiPS 3 . Here, using resonant inelastic x-ray scattering, the authors show that the formation of these excitons is primarily driven by Hund’s coupling and that they propagate similarly to two-magnon excitations.

The strong light-matter interaction and the valley selective optical selection rules make monolayer (ML) MoS2 an exciting 2D material for fundamental physics and optoelectronics applications. But, so far, optical transition linewidths even at low temperature are typically as large as a few tens of meV and contain homogeneous and inhomogeneous contributions. This prevented in-depth studies, in contrast to the better-characterized ML materials MoSe2 and WSe2 . In this work, we show that encapsulation of ML MoS2 in hexagonal boron nitride can efficiently suppress the inhomogeneous contribution to the exciton linewidth, as we measure in photoluminescence and reflectivity a FWHM down to 2 meV at T=4K . Narrow optical transition linewidths are also observed in encapsulated WS2 , WSe2 , and MoSe2 MLs. This indicates that surface protection and substrate flatness are key ingredients for obtaining stable, high-quality samples. Among the new possibilities offered by the well-defined optical transitions, we measure the homogeneous broadening induced by the interaction with phonons in temperature-dependent experiments. We uncover new information on spin and valley physics and present the rotation of valley coherence in applied magnetic fields perpendicular to the ML.

Background: Sorafenib is the only drug approved for the treatment of hepatocellular carcinoma (HCC). The bioenergetic propensity of cancer cells has been correlated to anticancer drug resistance, but such correlation is unclear in sorafenib resistance of HCC. Methods: Six sorafenib-naive HCC cell lines and one sorafenib-resistant HCC cell line (Huh-7R; derived from sorafenib-sensitive Huh-7) were used. The bioenergetic propensity was calculated by measurement of lactate in the presence or absence of oligomycin. Dichloroacetate (DCA), a pyruvate dehydrogenase kinase (PDK) inhibitor, and siRNA of hexokinase 2 (HK2) were used to target relevant pathways of cancer metabolism. Cell viability, mitochondrial membrane potential, and sub-G1 fraction were measured for in vitro efficacy. Reactive oxygen species (ROS), adenosine triphosphate (ATP) and glucose uptake were also measured. A subcutaneous xenograft mouse model was used for in vivo efficacy. Results: The bioenergetic propensity for using glycolysis correlated with decreased sorafenib sensitivity ( R 2 =0.9067, among sorafenib-naive cell lines; P =0.003, compared between Huh-7 and Huh-7 R). DCA reduced lactate production and increased ROS and ATP, indicating activation of oxidative phosphorylation (OXPHOS). DCA markedly sensitised sorafenib-resistant HCC cells to sorafenib-induced apoptosis (sub-G1 (combination vs sorafenib): Hep3B, 65.4±8.4% vs 13±2.9%; Huh-7 R, 25.3± 5.7% vs 4.3±1.5%; each P <0.0001), whereas siRNA of HK2 did not. Sorafenib (10 mg kg −1 per day) plus DCA (100 mg kg −1 per day) also resulted in superior tumour regression than sorafenib alone in mice (tumour size: −87% vs −36%, P <0.001). Conclusion: The bioenergetic propensity is a potentially useful predictive biomarker of sorafenib sensitivity, and activation of OXPHOS by PDK inhibitors may overcome sorafenib resistance of HCC.