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Abstract Histone lysine methyltransferase 2D (KMT2D) is the most frequently mutated epigenetic modifier in head and neck squamous cell carcinoma (HNSCC). However, the role of KMT2D in HNSCC tumorigenesis and whether its mutations confer any therapeutic vulnerabilities remain unknown. Here we show that KMT2D deficiency promotes HNSCC growth through increasing glycolysis. Additionally, KMT2D loss decreases the expression of Fanconi Anemia (FA)/BRCA pathway genes under glycolytic inhibition. Mechanistically, glycolytic inhibition facilitates the occupancy of KMT2D to the promoter/enhancer regions of FA genes. KMT2D loss reprograms the epigenomic landscapes of FA genes by transiting their promoter/enhancer states from active to inactive under glycolytic inhibition. Therefore, combining the glycolysis inhibitor 2-DG with DNA crosslinking agents or poly (ADP-ribose) polymerase (PARP) inhibitors preferentially inhibits tumor growth of KMT2D-deficient mouse HNSCC and patient-derived xenografts (PDXs) harboring KMT2D-inactivating mutations. These findings provide an epigenomic basis for developing targeted therapies for HNSCC patients with KMT2D-inactivating mutations.

Abstract Compressing high-energy laser pulses to a single-cycle and realizing the “λ 3 laser concept”, where λ is the wavelength of the laser, will break the current limitation of super-scale projects and contribute to the future 100-petawatt and even Exawatt lasers. Here, we have realized ultra-broadband gold gratings, core optics in the chirped pulse amplification, in the 750–1150 nm spectral range with a > 90% −1 order diffraction efficiency for near single-cycle pulse stretching and compression. The grating is also compatible with azimuthal angles from −15° to 15°, making it possible to design a three-dimensional compressor. In developing and manufacturing processes, a crucial grating profile with large base width and sharp ridge is carefully optimized and controlled to dramatically broaden the high diffraction efficiency bandwidth from the current 100–200 nm to over 400 nm. This work has removed a key obstacle to achieving the near single-cycle 100-PW lasers in the future.

The large-aperture pulse compression grating (PCG) is a critical component in generating an ultra-high-intensity, ultra-short-pulse laser; however, the size of the PCG manufactured by transmission holographic exposure is limited to large-scale high-quality materials. The reflective method is a potential way for solving the size limitation, but there is still no successful precedent due to the lack of scientific specifications and advanced processing technology of exposure mirrors. In this paper, an analytical model is developed to clarify the specifications of components, and advanced processing technology is adopted to control the spatial frequency errors. Hereafter, we have successfully fabricated a multilayer dielectric grating of 200 mm × 150 mm by using an off-axis reflective exposure system with Φ300 mm. This demonstration proves that PCGs can be manufactured by using the reflection holographic exposure method and shows the potential for manufacturing the meter-level gratings used in 100 petawatt class high-power lasers.

Many aquatic and aerial animals have evolved highly sensitive flow receptors to help them survive in challenging environments. The biological flow receptors, such as filiform hairs, lateral lines, and seal whiskers, are elegantly designed with interesting biomechanical processing principles for extreme sensitivity, exhibiting obvious morphological intelligence. For instance, superficial neuromasts on the surface of fish body have an elongated cupula to enhance flow detection with a magnified drag. The flow‐induced mechanical information is transferred to arrayed hair bundles in the neuromasts, which show spontaneous oscillation and mechanical coupling effects for a high mechanical sensitivity. In this review, the biomechanical principles of morphological intelligence in biological flow field receptors are discussed, with an emphasis on the functions of stimulus enhancement, noise reduction, and nonlinear oscillation. In addition, the recent achievements in flow sensors with morphological intelligence are summarized in this article. Though there is still a big gap in principle discovery and practical application of morphological intelligence in engineered sensors, it can be anticipated that the field of intelligent flow sensing will be significantly promoted by the establishment of morphological intelligence models.

Maximizing the energy-loading performance of gratings is a universal theme in high-energy pulse compression. However, sporadic grating designs strongly restrict the development of high-power laser engineering. This study proposes an all- and mixed-dielectric grating design paradigm for Nd:glass-based pulse compressors. The solution regions are classified according to the line density. High diffraction efficiency solutions are described in more detail based on the dispersion amount and incident angle. Moreover, an energy scaling factor of 7.09 times larger than that of the National Ignition Facility’s Advanced Radiographic Capability (NIF-ARC) is obtained by taking advantage of the low electric field intensity at transverse magnetic polarization and a small incident angle. These results make a pioneering contribution to facilitate future 20–50-petawatt-class ultrafast laser systems.

Obstructive sleep apnea-hypopnea syndrome (OSAHS) is a breathing disorder associated with cognitive impairment. However, the mechanisms leading to cognitive deficits in OSAHS remain uncertain. In this study, a mouse model of chronic intermittent hypoxia (CIH) exposures were applied for simulating the deoxygenation-reoxygenation events occurring in OSAHS. The conventional adenosine A1 receptor gene (A1R) knockout mice and the A1R agonist CCPA- or antagonist DPCPX-administrated mice were utilized to determine the precise function of A1R signaling in the process of OSAHS-relevant cognitive impairment. We demonstrated that CIH induced morphological changes and apoptosis in hippocampal neurons. Further, CIH blunted hippocampal long-term potentiation (LTP) and resulted in learning/memory impairment. Disruption of adenosine A1R exacerbated morphological, cellular, and functional damage induced by CIH. In contrast, activation of adenosine A1R signaling reduced morphological changes and apoptosis of hippocampal neurons, promoted LTP, and enhanced learning and memory. A1Rs may up-regulate protein kinase C (PKC) and its subtype PKC-ζ through the activation of Gα(i) improve spatial learning and memory disorder induced by CIH in mice. Taken together, A1R signaling plays a neuroprotective role in CIH-induced cognitive dysfunction and pathological changes in the hippocampus.

Understanding the fiber-type specification and metabolic switch in skeletal muscle provides insights into energy metabolism in physiology and diseases. Here, we show that miR-182 is highly expressed in fast-twitch muscle and negatively correlates with blood glucose level. miR-182 knockout mice display muscle loss, fast-to-slow fiber-type switching, and impaired glucose metabolism. Mechanistic studies reveal that miR-182 modulates glucose utilization in muscle by targeting FoxO1 and PDK4, which control fuel selection via the pyruvate dehydrogenase complex (PDHC). Short-term high-fat diet (HFD) feeding reduces muscle miR-182 levels by tumor necrosis factor α (TNFα), which contributes to the upregulation of FoxO1/PDK4. Restoration of miR-182 expression in HFD-fed mice induces a faster muscle phenotype, decreases muscle FoxO1/PDK4 levels, and improves glucose metabolism. Together, our work establishes miR-182 as a critical regulator that confers robust and precise controls on fuel usage and glucose homeostasis. Our study suggests that a metabolic shift toward a faster and more glycolytic phenotype is beneficial for glucose control.

p38 has long been known as a central mediator of protein kinase A (PKA) signaling in brown adipocytes, which positively regulate the transcription of uncoupling protein 1 (UCP-1). However, the physiological role of p38 in adipose tissues, especially the white adipose tissue (WAT), is largely unknown. Here, we show that mice lacking p38α in adipose tissues display a lean phenotype, improved metabolism, and resistance to diet-induced obesity. Surprisingly, ablation of p38α causes minimal effects on brown adipose tissue (BAT) in adult mice, as evident from undetectable changes in UCP-1 expression, mitochondrial function, body temperature (BT), and energy expenditure. In contrast, genetic ablation of p38α in adipose tissues not only markedly facilitates the browning in WAT upon cold stress but also prevents diet-induced obesity. Consistently, pharmaceutical inhibition of p38α remarkably enhances the browning of WAT and has metabolic benefits. Furthermore, our data suggest that p38α deficiency promotes white-to-beige adipocyte reprogramming in a cell-autonomous manner. Mechanistically, inhibition of p38α stimulates the UCP-1 transcription through PKA and its downstream cAMP-response element binding protein (CREB), which form a positive feedback loop that functions to reinforce the white-to-beige phenotypic switch during cold exposure. Together, our study reveals that inhibition of p38α is able to promote WAT browning and confer metabolic benefits. Our study also indicates that p38α in WAT represents an exciting pharmacological target to combat obesity and metabolic diseases.

Skeletal muscle has a major role in locomotion and muscle disorders are associated with poor regenerative efficiency. Therefore, a deeper understanding of muscle regeneration is needed to provide a new insight for new therapies. CaMKK2 plays a role in the calcium/calmodulin-dependent kinase cascade; however, its role in skeletal muscle remains unknown. Here, we found that CaMKK2 expression levels were altered under physiological and pathological conditions including postnatal myogensis, freeze or cardiotoxin-induced muscle regeneration, and Duchenne muscular dystrophy. Overexpression of CaMKK2 suppressed C2C12 myoblast proliferation and differentiation, while inhibition of CaMKK2 had opposite effect. We also found that CaMKK2 is able to activate AMPK in C2C12 myocytes. Inhibition of AMPK could attenuate the effect of CaMKK2 overexpression, while AMPK agonist could abrogate the effect of CaMKK2 knockdown on C2C12 cell differentiation and proliferation. These results suggest that CaMKK2 functions as an AMPK kinase in muscle cells and AMPK mediates the effect of CaMKK2 on myoblast proliferation and differentiation. Our data also indicate that CaMKK2 might inhibit myoblast proliferation through AMPK-mediated cell cycle arrest by inducing cdc2-Tyr15 phosphorylation and repress differentiation through affecting PGC1α transcription. Lastly, we show that overexpressing CaMKK2 in the muscle of mice via electroporation impaired the muscle regeneration during freeze-induced injury, indicating that CaMKK2 could serve as a potential target to treat patients with muscle injury or myopathies. Together, our study reveals a new role for CaMKK2 as a negative regulator of myoblast differentiation and proliferation and sheds new light on the molecular regulation of muscle regeneration.

We design and manufacture a fused-silica polarization-independent two-port beam splitter grating. The physical mechanism of this deeply etched grating can be shown clearly by using the simplified modal method with consideration of corresponding accumulated phase difference of two excited propagating grating modes, which illustrates that the binary-phase fused-silica grating structure depends little on the incident wavelength, but mainly on the ratio of groove depth to grating period and the ratio of incident wavelength to grating period. These analytic results would also be very helpful for wavelength bandwidth analysis. The exact grating profile is optimized by using the rigorous coupled-wave analysis. Holographic recording technology and inductively coupled plasma etching are used to manufacture the fused-silica grating. Experimental results agree well with the theoretical values. [c] 2009 Optical Society of America OCIS codes: 050.1950, 230.1360, 050.6624, 060.4510.

Nuclear receptors (NRs) regulate gene transcription by recruiting coregulators, involved in chromatin remodeling and assembly of the basal transcription machinery. The NR-associated protein ligand-dependent corepressor (LCoR) has previously been shown to suppress hepatic lipogenesis by decreasing the binding of steroid receptor coactivators to thyroid hormone receptor. However, the role of LCoR in adipogenesis has not been established. Here, we show that LCoR expression is reduced in the early stage of adipogenesis in vitro. LCoR overexpression inhibited 3T3-L1 adipocyte differentiation, whereas LCoR knockdown promoted it. Using an unbiased affinity purification approach, we identified CCAAT/enhancer-binding protein β (C/EBPβ), a key transcriptional regulator in early adipogenesis, and corepressor C-terminal binding proteins as potential components of an LCoR-containing complex in 3T3-L1 adipocytes. We found that LCoR directly interacts with C/EBPβ through its C-terminal helix-turn-helix domain, required for LCoR's inhibitory effects on adipogenesis. LCoR overexpression also inhibited C/EBPβ transcriptional activity, leading to inhibition of mitotic clonal expansion and transcriptional repression of C/EBPα and peroxisome proliferator-activated receptor γ2 (PPARγ2). However, LCoR overexpression did not affect the recruitment of C/EBPβ to the promoters of C/EBPα and PPARγ2 in 3T3-L1 adipocytes. Of note, restoration of PPAR γ2 or C/EBPα expression attenuated the inhibitory effect of LCoR on adipogenesis. Mechanistically, LCoR suppressed C/EBPβ-mediated transcription by recruiting C-terminal binding proteins to the C/EBPα and PPARγ2 promoters and by modulating histone modifications. Taken together, our results indicate that LCoR negatively regulates early adipogenesis by repressing C/EBPβ transcriptional activity and add LCoR to the growing list of transcriptional corepressors of adipogenesis. [ABSTRACT FROM AUTHOR]

A modal method for designing the one-dimensional (1-D) dielectric multilevel antireflection gratings (ARGs) used for TE polarized waves is proposed based on the effective refractive indices concept of the modal method (MM). In this method, the effective refractive index (ERI) for each level is determined by the effective mode index of the modal method. The refractive indices under and above the grating region are equivalent to their effective refractive indices that is determined by the 0th order propagating wave vector of the Fourier expansion of the electric fields under and above the grating region, which are different from the conventional effective medium theory (EMT), and the relationship between the ERI in MM and that in EMT are also revealed. As an example, we designed and analyzed the fused-silica multilevel ARGs by using the MM and the commonly used second-order effective medium theory (SEMT). The designed results are numerically verified by using the rigorous coupled-wave analysis method (RCWA) and the thin-film theory. [ABSTRACT FROM AUTHOR]

The spectrum selective absorption effect of a vertically cascaded metal-dielectric grating structure is studied. A polarization-independent spectrum selective absorber based on two pairs of stacked metal-dielectric grating structures is presented for the infrared frequencies. The near-unity absorption with polarization independence is observed under normal incidence. The understanding of such a perfect selective absorption mechanism is illustrated by investigating the electric field distributions and power loss density at the resonant wavelength. The angle independence is also studied for this absorber and it is found that the absorber can maintain high absorbance around large incident angle range (0° -33° ), especially for the TM polarization. [ABSTRACT FROM PUBLISHER]

The enhancement of absorption in a thin-film amorphous silicon solar cell based on guided mode resonance is theoretically investigated. This is achieved by patterning a single- or double-groove grating with a waveguide layer as the absorbing layer. The optimized grating parameters are obtained by use of rigorous coupled-wave analysis and the simulated annealing algorithm. The averaged integrated absorptions are weakly dependent on the angle of incidence in both grating structures. It is shown the optimized solar cell with double-groove grating has better optical performance than single-groove grating structures. The qualitative understanding of enhanced absorption based on guided-mode resonance and double-groove grating structure is presented. An antireflective grating structure is proposed and discussed for reducing reflection and enhancing absorption. The solar cell with antireflective grating has much better performance than those without an antireflective grating. The designed solar cells have high integrated absorption and are weakly dependent on the incident angle, which should be highly interesting for practical application. [ABSTRACT FROM AUTHOR]