Mitochondrial One-Carbon Pathway Supports Cytosolic Folate Integrity in Cancer Cells.

Mammalian folate metabolism is comprised of cytosolic and mitochondrial pathways with nearly identical core reactions, yet the functional advantages of such an organization are not well understood. Using genome-editing and biochemical approaches, we find that ablating folate metabolism in the mitochondria of mammalian cell lines results in folate degradation in the cytosol. Mechanistically, we show that QDPR, an enzyme in tetrahydrobiopterin metabolism, moonlights to repair oxidative damage to tetrahydrofolate (THF). This repair capacity is overwhelmed when cytosolic THF hyperaccumulates in the absence of mitochondrially produced formate, leading to THF degradation. Unexpectedly, we also find that the classic antifolate methotrexate, by inhibiting its well-known target DHFR, causes even more extensive folate degradation in nearly all tested cancer cell lines. These findings shed light on design features of folate metabolism, provide a biochemical basis for clinically observed folate deficiency in QDPR-deficient patients, and reveal a hitherto unknown and unexplored cellular effect of methotrexate.

Post-transcriptional Regulation of De Novo Lipogenesis by mTORC1-S6K1-SRPK2 Signaling.

mTORC1 is a signal integrator and master regulator of cellular anabolic processes linked to cell growth and survival. Here, we demonstrate that mTORC1 promotes lipid biogenesis via SRPK2, a key regulator of RNA-binding SR proteins. mTORC1-activated S6K1 phosphorylates SRPK2 at Ser494, which primes Ser497 phosphorylation by CK1. These phosphorylation events promote SRPK2 nuclear translocation and phosphorylation of SR proteins. Genome-wide transcriptome analysis reveals that lipid biosynthetic enzymes are among the downstream targets of mTORC1-SRPK2 signaling. Mechanistically, SRPK2 promotes SR protein binding to U1-70K to induce splicing of lipogenic pre-mRNAs. Inhibition of this signaling pathway leads to intron retention of lipogenic genes, which triggers nonsense-mediated mRNA decay. Genetic or pharmacological inhibition of SRPK2 blunts de novo lipid synthesis, thereby suppressing cell growth. These results thus reveal a novel role of mTORC1-SRPK2 signaling in post-transcriptional regulation of lipid metabolism and demonstrate that SRPK2 is a potential therapeutic target for mTORC1-driven metabolic disorders.

Genome-wide CRISPR screens in spheroid culture reveal that the tumor suppressor LKB1 inhibits growth via the PIKFYVE lipid kinase.

The tumor suppressor LKB1 is a serine/threonine protein kinase that is frequently mutated in human lung adenocarcinoma (LUAD). LKB1 regulates a complex signaling network that is known to control cell polarity and metabolism; however, the pathways that mediate the tumor-suppressive activity of LKB1 are incompletely defined. To identify mechanisms of LKB1-mediated growth suppression, we developed a spheroid-based cell culture assay to study LKB1-dependent growth. We then performed genome-wide CRISPR screens in spheroidal culture and found that LKB1 suppresses growth, in part, by activating the PIKFYVE lipid kinase. Finally, we used chemical inhibitors and a pH-sensitive reporter to determine that LKB1 impairs growth by promoting the internalization of wild-type EGFR in a PIKFYVE-dependent manner.

Membrane Lipids Speak to Histones.

In this issue of Molecular Cell, Ye et al. (2017) use a combination of genetic, metabolomic, and transcriptomic approaches to explore the potential for methionine metabolism to influence signal transduction and gene expression in budding yeast.

PARK2 Depletion Connects Energy and Oxidative Stress to PI3K/Akt Activation via PTEN S-Nitrosylation.

PARK2 is a gene implicated in disease states with opposing responses in cell fate determination, yet its contribution in pro-survival signaling is largely unknown. Here we show that PARK2 is altered in over a third of all human cancers, and its depletion results in enhanced phosphatidylinositol 3-kinase/Akt (PI3K/Akt) activation and increased vulnerability to PI3K/Akt/mTOR inhibitors. PARK2 depletion contributes to AMPK-mediated activation of endothelial nitric oxide synthase (eNOS), enhanced levels of reactive oxygen species, and a concomitant increase in oxidized nitric oxide levels, thereby promoting the inhibition of PTEN by S-nitrosylation and ubiquitination. Notably, AMPK activation alone is sufficient to induce PTEN S-nitrosylation in the absence of PARK2 depletion. Park2 loss and Pten loss also display striking cooperativity to promote tumorigenesis in vivo. Together, our findings reveal an important missing mechanism that might account for PTEN suppression in PARK2-deficient tumors, and they highlight the importance of PTEN S-nitrosylation in supporting cell survival and proliferation under conditions of energy deprivation.

Tunable Single-Photon Emission with Wafer-Scale Plasmonic Array.

Bright, scalable, and deterministic single-photon emission (SPE) is essential for quantum optics, nanophotonics, and optical information systems. Recently, SPE from hexagonal boron nitride (h-BN) has attracted intense interest because it is optically active and stable at room temperature. Here, we demonstrate a tunable quantum emitter array in h-BN at room temperature by integrating a wafer-scale plasmonic array. The transient voltage electrophoretic deposition (EPD) reaction is developed to effectively enhance the filling of single-crystal nanometals in the designed patterns without aggregation, which ensures the fabricated array for tunable performances of these single-photon emitters. An enhancement of ∼500% of the SPE intensity of the h-BN emitter array is observed with a radiative quantum efficiency of up to 20% and a saturated count rate of more than 4.5 × 106 counts/s. These results suggest the integrated h-BN-plasmonic array as a promising platform for scalable and controllable SPE photonics at room temperature.

Development and validation of a simple and practical model for early detection of diabetic macular edema in patients with type 2 diabetes mellitus using easily accessible systemic variables.

OBJECTIVE: Diabetic macular edema (DME) is the leading cause of visual impairment in patients with diabetes mellitus (DM). The goal of early detection has not yet achieved due to a lack of fast and convenient methods. Therefore, we aim to develop and validate a prediction model to identify DME in patients with type 2 diabetes mellitus (T2DM) using easily accessible systemic variables, which can be applied to an ophthalmologist-independent scenario. METHODS: In this four-center, observational study, a total of 1994 T2DM patients who underwent routine diabetic retinopathy screening were enrolled, and their information on ophthalmic and systemic conditions was collected. Forward stepwise multivariable logistic regression was performed to identify risk factors of DME. Machine learning and MLR (multivariable logistic regression) were both used to establish prediction models. The prediction models were trained with 1300 patients and prospectively validated with 104 patients from Guangdong Provincial People's Hospital (GDPH). A total of 175 patients from Zhujiang Hospital (ZJH), 115 patients from the First Affiliated Hospital of Kunming Medical University (FAHKMU), and 100 patients from People's Hospital of JiangMen (PHJM) were used as external validation sets. Area under the receiver operating characteristic curve (AUC), accuracy (ACC), sensitivity, and specificity were used to evaluate the performance in DME prediction. RESULTS: The risk of DME was significantly associated with duration of DM, diastolic blood pressure, hematocrit, glycosylated hemoglobin, and urine albumin-to-creatinine ratio stage. The MLR model using these five risk factors was selected as the final prediction model due to its better performance than the machine learning models using all variables. The AUC, ACC, sensitivity, and specificity were 0.80, 0.69, 0.80, and 0.67 in the internal validation, and 0.82, 0.54, 1.00, and 0.48 in prospective validation, respectively. In external validation, the AUC, ACC, sensitivity and specificity were 0.84, 0.68, 0.90 and 0.60 in ZJH, 0.89, 0.77, 1.00 and 0.72 in FAHKMU, and 0.80, 0.67, 0.75, and 0.65 in PHJM, respectively. CONCLUSION: The MLR model is a simple, rapid, and reliable tool for early detection of DME in individuals with T2DM without the needs of specialized ophthalmologic examinations.

High-reliability infrared broadband thin-film polarizing beam splitter with ZnSe compensation layers.

Thin-film polarizing beam splitters (PBSs) fulfill a pivotal role in laser beam splitting, modulation, shaping and isolation. In this study, a high-reliability infrared broadband thin-film PBS was developed. To correct for tensile stress in Ge/YbF3 multilayer coatings, ZnSe compensation layers were incorporated in the multilayer design. The effects of different symmetrical periods on the spectral properties of the infrared PBS were systematically discussed. The infrared PBS operated at 45° and in the long-wave infrared (LWIR) band. Using the percent of optical extrema monitoring (POEM) strategy combined with the high-temperature optical constants (HTOC) of Ge film, the infrared PBS was precisely fabricated on ZnSe substrates. Subsequently, the spectral performance and film reliability of the infrared PBS were carefully characterized. Specifically, the transmittance of p-polarization surpassed 96%, while the extinction ratio exceeded 100:1 within the 10.6 ± 0.15 µm band. The infrared PBS demonstrated commendable environmental reliability, in addition to exhibiting excellent spectral characteristics.

The Lipid Kinase PI5P4Kß Is an Intracellular GTP Sensor for Metabolism and Tumorigenesis.

While cellular GTP concentration dramatically changes in response to an organism's cellular status, whether it serves as a metabolic cue for biological signaling remains elusive due to the lack of molecular identification of GTP sensors. Here we report that PI5P4Kß, a phosphoinositide kinase that regulates PI(5)P levels, detects GTP concentration and converts them into lipid second messenger signaling. Biochemical analyses show that PI5P4Kß preferentially utilizes GTP, rather than ATP, for PI(5)P phosphorylation, and its activity reflects changes in direct proportion to the physiological GTP concentration. Structural and biological analyses reveal that the GTP-sensing activity of PI5P4Kß is critical for metabolic adaptation and tumorigenesis. These results demonstrate that PI5P4Kß is the missing GTP sensor and that GTP concentration functions as a metabolic cue via PI5P4Kß. The critical role of the GTP-sensing activity of PI5P4Kß in cancer signifies this lipid kinase as a cancer therapeutic target.

Multimodal action of KRP203 on phosphoinositide kinases in vitro and in cells.

Increased phosphoinositide signaling is commonly associated with cancers. While "one-drug one-target" has been a major drug discovery strategy for cancer therapy, a "one-drug multi-targets" approach for phosphoinositide enzymes has the potential to offer a new therapeutic approach. In this study, we sought a new way to target phosphoinositides metabolism. Using a high-throughput phosphatidylinositol 5-phosphate 4-kinase-alpha (PI5P4Kα) assay, we have identified that the immunosuppressor KRP203/Mocravimod induces a significant perturbation in phosphoinositide metabolism in U87MG glioblastoma cells. Despite high sequence similarity of PI5P4K and PI4K isozymes, in vitro kinase assays showed that KRP203 activates some (e.g., PI5P4Kα, PI4KIIß) while inhibiting other phosphoinositide kinases (e.g., PI5P4Kß, γ, PI4KIIα, class I PI3K-p110α, δ, γ). Furthermore, KRP203 enhances PI3P5K/PIKFYVE's substrate selectivity for phosphatidylinositol (PI) while preserving its selectivity for PI(3)P. At cellular levels, 3 h of KRP203 treatment induces a prominent increase of PI(3)P and moderate increase of PI(5)P, PI(3,5)P2, and PI(3,4,5)P3 levels in U87MG cells. Collectively, the finding of multimodal activity of KRP203 towards multi-phosphoinositide kinases may open a novel basis to modulate cellular processes, potentially leading to more effective treatments for diseases associated with phosphoinositide signaling pathways.

Performance of finite-size metal-dielectric nanoslits metasurface optical filters.

In this work, we analyze the performance of finite-size metal-dielectric nanoslits guided mode resonance metasurface optical filters by using finite-difference time-domain simulations and spatial Fourier transform analysis. It is shown that in the direction of the nanoslits period, the critical size required to maintain the performance of the corresponding infinite size filter is the product of the nanoslits period and the quality factor of the infinite size filter. Size reduction in this dimension below the critical dimension reduces the peak transmittance and broadens the spectral linewidth of the filter. In the dimension orthogonal to the nanoslits period direction, the critical dimension size required is not related to the quality factor of the corresponding infinite size filter. Our analysis shows that the critical size is 12 times the filter peak wavelength in the orthogonal dimension for maintaining the filter performance. The 12 times filter wavelength requirement corresponds to the second zero of the Fourier transform of the aperture function.

Low polarization-sensitive ultra-broadband anti-reflection coatings with improved reliability.

Broader spectra, lower reflectivity and higher reliability are the performance requirements for broadband antireflective (BBAR) films. In this work, a BBAR film structure was proposed, which maintains extremely low reflectivity, ultra-wide spectra, low polarization sensitivity and practical reliability. The BBAR film consists of a dense multilayer interference stack on the bottom and a nano-grass-like alumina (NGLA) layer with a gradient low refractive index distribution on the top. The film was deposited by atomic layer deposition, while the NGLA layer was formed by means of a hot water bath on Al2O3 layer. The top NGLA layer has extremely high porosity and ultra-low refractive index, along with extremely fragile structure. To surmount the fragility of NGLA layer, a sub-nano layer of SiO2 was grown by atomic layer deposition to solidify its structure and also to adjust the refractive index with different thicknesses of SiO2. Finally, in the wide wavelength range of 400-1100 nm, the average transmittance of the double-sided coated fused quartz reaches 99.2%. The absorption, light scattering, reliability and polarization characteristics of BBAR films were investigated. An optimized BBAR film with low polarization-sensitivity and improved reliability was realized, which should be potentially promising for application in optical systems.

Structural, mechanical, electronic and optical properties of biphenylene hydrogenation: a first-principles study.

Biphenylene networks typically exhibit a metallic electronic nature, while hydrogenation can open the band gap changing it to a semiconductor. This property makes hydrogenated biphenylene a promising candidate for use in semiconductor optoelectronic materials and devices. In this work, three representative configurations of hydrogenated biphenylene, denoted by α, ß and γ, were investigated. The structural, mechanical, electronic, and optical properties of these hydrogenated biphenylene configurations were calculated by first-principles calculations. Band gaps with HSE correction were 4.69, 4.42 and 4.39 eV for α, ß, and γ configurations, respectively. Among these three configurations, ß presents the best electronic performance and special elastic properties (negative Poisson's ratio), while γ exhibits the best elastic properties. In addition, we comprehensively analyze the mechanical properties of these configurations and provide evidence that hydrogenated biphenylene possibly exhibits a negative-Poisson's-ratio along the zigzag and armchair directions when hydrogen atoms are added to biphenylene in certain ways. Furthermore, although the electronic properties of γ are weaker than those of ß, they are also excellent. In addition, the binding energies of ß and γ are relatively lower, which indicates that ß and γ are more stable. Our findings demonstrate that the hydrogenated biphenylene is a promising material with significant application potential in optoelectronic devices.

Leveraging Protein Dynamics to Identify Functional Phosphorylation Sites using Deep Learning Models.

Accurate prediction of post-translational modifications (PTMs) is of great significance in understanding cellular processes, by modulating protein structure and dynamics. Nowadays, with the rapid growth of protein data at different "omics" levels, machine learning models largely enriched the prediction of PTMs. However, most machine learning models only rely on protein sequence and little structural information. The lack of the systematic dynamics analysis underlying PTMs largely limits the PTM functional predictions. In this research, we present two dynamics-centric deep learning models, namely, cDL-PAU and cDL-FuncPhos, by incorporating sequence, structure, and dynamics-based features to elucidate the molecular basis and underlying functional landscape of PTMs. cDL-PAU achieved satisfactory area under the curve (AUC) scores of 0.804-0.888 for predicting phosphorylation, acetylation, and ubiquitination (PAU) sites, while cDL-FuncPhos achieved an AUC value of 0.771 for predicting functional phosphorylation (FuncPhos) sites, displaying reliable improvements. Through a feature selection, the dynamics-based coupling and commute ability show large contributions in discovering PAU sites and FuncPhos sites, suggesting the allosteric propensity for important PTMs. The application of cDL-FuncPhos in three oncoproteins not only corroborates its strong performance in FuncPhos prioritization but also gains insight into the physical basis for the functions. The source code and data set of cDL-PAU and cDL-FuncPhos are available at https://github.com/ComputeSuda/PTM_ML.

A new direct band gap Si-Ge allotrope with advanced electronic and optical properties.

Direct-band silicon materials have been a sought-after material for potential applications in silicon photonics and solar cells. Accordingly, methodologies like nanostructure engineering, alloy engineering and strain engineering have been developed. In this work, the particle swarm optimization (PSO) algorithm is used to design direct-band Si-Ge alloys. The findings of phonon computations demonstrate that all these structures are dynamically stable. In addition, ab initio molecular dynamics and elastic constant calculations are carried out, with results indicating these structures are thermodynamically stable at 300 K, as well as being mechanically stable. All of these materials exhibit semiconductor behavior with band gaps of 1.03, 0.68 and 1.37 eV for α, ß and γ phases, respectively, at the HSE06 level. The results of effective mass and mobility of carriers that are important in applications show that holes are more easily transported in all structures, with higher concentration of holes accompanied by lower carrier mobility. Different concentrations of holes nh lead to different limits in the scattering process. When nh is lower than the value of around 1016 cm-3, deformation potential scattering is dominant, while the ionized impurity scattering process limits overall mobility when nh is higher than such a value. Finally, the absorption spectra shows that both α and ß phases have isotropic optical properties in the X- and Y-directions while strong anisotropy can be seen in the Z-direction. However, the γ phase exhibits no notable isotropy. This investigation finds three direct-band and potentially CMOS compatible materials, a finding which will benefit the development of high efficiency emitters or solar cells.

Double-sided optical coating of strongly curved glass by atomic layer deposition.

A reaction chamber of atomic layer deposition (ALD) was developed for simultaneous coating on the inner and outer surfaces of a large-size and strongly curved glass bowl. The inner surface ALD process was in a showerhead reaction mode and the outer surface ALD process was in a cross-flow reaction mode. Blue reflection (BR) film of 400 nm wavelength and broadband antireflection (BBAR) film of 400-700 nm wavelength were coated on different glass bowls by ALD. The spectral uniformity of both coated bowls was studied. The measured spectra at multiple positions of the glass bowl with the BBAR coating show better spectral uniformity along the circumference than the depth. The spectral deviation is mainly caused by the non-uniformity of the film on the outer surface (<±3%), and the film on the inner surface has good uniformity along both the circumference and the depth (<±0.7%). The growth rate of the outer film was reduced by 10% on average compared to that of the inner film due to the different gas flow mode.

Electronic and optical properties of hydrogen-terminated biphenylene nanoribbons: a first-principles study.

The electronic structures and optical properties of novel 2D biphenylene and hydrogen-terminated nanoribbons of different widths which are cut from a layer of biphenylene were explored via first-principles calculations. The findings of phonon computations demonstrate that such a biphenylene is dynamically stable and shows metallic properties. The crystal orbital Hamilton population analysis indicates that the tetra-ring local structure results in anisotropic mechanical properties. For 1D nanoribbons, their band gaps shrink, and a direct-indirect transition occurs in the band gap as the width increases, transforming the nanoribbon to endow them with metallic characteristics at a certain width. This is attributed to the weak coupling between the tetra-ring atoms, shrinking the direct band gap at the Y point in the Brillouin zone. Finally, the contribution of interband transitions to the dielectric function in 6-, 9-, and 12-armchair biphenylene nanoribbons (ABNRs) was identified. The lowest peak in the imaginary part of the dielectric function ε2 spectrum was mainly a contribution of a Γ-Γ transition. As the width of ABNR increases, the transitions in the x direction become stronger while the transition strength in the y direction is not significantly altered. This investigation extends the understanding of the electronic and optical properties of 2D biphenylene and 1D nanoribbons, which will benefit the practical applications of these materials in optoelectronics and electronics.

High-accuracy and rapid azimuth calibration for polarizing elements in ellipsometry by differential spectral analysis on the ellipse azimuth.

We propose an accurate and rapid azimuth calibration method for polarizing elements in ellipsometry. Over 200 calibrations were achieved simultaneously at different wavelength points in a spectral range of 550-650 nm without any calibrated element. The azimuth of the polarizer was determined from the differential spectral analysis on the ellipse azimuth of reflected light. The information of the ellipse azimuth is experimentally acquired in the spectral range by a rotating polarizing element and a spectrometer. The presented method was performed and verified with Si and Au bulk, respectively, showing reliability and feasibility for efficient and reliable calibration in ellipsometry.

Optical properties of thickness-controlled PtSe2 thin films studied via spectroscopic ellipsometry.

Platinum diselenide (PtSe2) has attracted huge attention due to its intriguing physical properties for both fundamental research and promising applications in electronics and optoelectronics. Here, we explored the optical properties of chemical vapor deposition-grown PtSe2 thin films with varied thicknesses via spectroscopic ellipsometry. The dielectric function was extracted by using a Lorentz model over the spectral range of 1.25-6.0 eV. We firstly ascribed the resonant energies, extracted from the Lorentz model, to different interband electronic transitions between valence bands and conduction bands in the Brillouin zone. A predicted exciton is observed at 2.18 eV for the monolayer and the corresponding exciton binding energy is 0.65 eV, in line with previous theoretical calculation and the measured absorption spectra. Additionally, the exciton peak shows a red shift with the increase of thickness, which is the consequence of strong interlayer interaction. These results enrich the fundamental understanding of PtSe2 and are conducive to its potential applications.

A Double-Edged Sword: Complement Component 3 in Toxoplasma gondii Infection.

Sprague Dawley rats and Kunming (KM) mice are artificially infected with type II Toxoplasma gondii strain Prugniaud (Pru) to generate toxoplasmosis, which is a fatal disease mediated by T. gondii invasion of the central nervous system (CNS) by unknown mechanisms. The aim is to explore the mechanism of differential susceptibility of mice and rats to T. gondii infection. Therefore, a strategy of isobaric tags for relative and absolute quantitation (iTRAQ) is established to identify differentially expressed proteins (DEPs) in the rats' and the mice's brains compared to the healthy groups. In KM mice, which is susceptible to T. gondii infection, complement component 3 (C3) is upregulated and the tight junction (TJ) pathway shows a disorder. It is presumed that T. gondii-stimulated C3 disrupts the TJ of the blood-brain barrier in the CNS. This effect allows more T. gondii passing to the brain through the intercellular space.