Broadband nonlinear modulation of incoherent light using a transparent optoelectronic neuron array.

Nonlinear optical processing of ambient natural light is highly desired for computational imaging and sensing. Strong optical nonlinear response under weak broadband incoherent light is essential for this purpose. By merging 2D transparent phototransistors (TPTs) with liquid crystal (LC) modulators, we create an optoelectronic neuron array that allows self-amplitude modulation of spatially incoherent light, achieving a large nonlinear contrast over a broad spectrum at orders-of-magnitude lower intensity than achievable in most optical nonlinear materials. We fabricated a 10,000-pixel array of optoelectronic neurons, and experimentally demonstrated an intelligent imaging system that instantly attenuates intense glares while retaining the weaker-intensity objects captured by a cellphone camera. This intelligent glare-reduction is important for various imaging applications, including autonomous driving, machine vision, and security cameras. The rapid nonlinear processing of incoherent broadband light might also find applications in optical computing, where nonlinear activation functions for ambient light conditions are highly sought.

Isolation of Hemiketal and Hydroxy Ketone Tautomers of Synthetic Intermediates Each Affording 18-Hydroxycortisol-1,6,7-d3.

During the synthesis of deuterated 18-hydroxycortisol, two of the synthetic intermediates have been found to exist in tautomeric forms as the acyclic 18-hydroxy 20-ketone and the cyclic 18,20-hemiketal corresponding to the previously identified less polar (L) and more polar (M) forms of C-18 hydroxylated steroids, respectively. Specifically, p-chloranil oxidation of 18-hydroxycortisol-17,21-acetonide afforded two isomers of the 6,7-dehydro analogue; separate catalytic reduction of each isomer under deuterium gave a single isomer of acetonide-protected 18-hydroxycortisol-1,6,7-d3 for each, with the more polar isomer giving a more polar product and the less polar isomer giving a less polar product. The more polar product (corresponding to M) was characterized as 18,20-hemiketal; 18-hydroxycortisol-17,21-acetonide-18,20-hemiketal-1,6,7-d3: in the deuterochloroform solution, it was found to slowly convert to a substance consistent with the hydroxy ketone structure with features resembling those of the isolated less polar isomer (corresponding to L). Deacetonidization of each gave 18-hydroxycortisol as a single product, which was characterized as the 18,20-hemiketal. The issues associated with the existence of 18-hydroxysteroids as hydroxy ketones and hemiketals, both in solution and as isolable solids, are discussed.

4-methylumbelliferone (4-MU) enhances drought tolerance of apple by regulating rhizosphere microbial diversity and root architecture.

The dwarfing rootstocks-mediated high-density apple orchard is becoming the main practice management. Currently, dwarfing rootstocks are widely used worldwide, but their shallow root system and drought sensitivity necessitate high irrigation requirements. Here, the root transcriptome and metabolome of dwarfing (M9-T337, a drought-sensitive rootstock) and vigorous rootstocks (Malus sieversii, a drought-tolerant species, is commonly used as a rootstock) showed that a coumarin derivative, 4-Methylumbelliferon (4-MU), was found to accumulate significantly in the roots of vigorous rootstock under drought condition. When exogenous 4-MU was applied to the roots of dwarfing rootstock under drought treatment, the plants displayed increased root biomass, higher root-to-shoot ratio, greater photosynthesis, and elevated water use efficiency. In addition, diversity and structure analysis of the rhizosphere soil microbial community demonstrated that 4-MU treatment increased the relative abundance of putatively beneficial bacteria and fungi. Of these, Pseudomonas, Bacillus, Streptomyces, and Chryseolinea bacterial strains and Acremonium, Trichoderma, and Phoma fungal strains known for root growth, or systemic resistance against drought stress, were significantly accumulated in the roots of dwarfing rootstock after 4-MU treatment under drought stress condition. Taken together, we identified a promising compound-4-MU, as a useful tool, to strengthen the drought tolerance of apple dwarfing rootstock.

HOTAIR knockdown impairs metastasis of cervical cancer cells by down-regulating metastasis-related genes.

This study investigated the role of LncRNA HOTAIR knockdown in the biological impacts on cervical cancer cells. The HOTAIR gene in two human cervical cancer cell lines was silenced with small interfering (si) RNA siHOTAIR. Proliferation, apoptosis, migration and invasion of cells were assessed following the knockdown. The expressions of Notch1, EpCAM, E-cadherin, vimentin and STAT3 were assessed using qRT-PCR and Western blotting analysis. Compared with controls, HOTAIR levels were reduced significantly, the OD values of cells were significantly decreased in proliferation assays, cell apoptosis was significantly increased, cell migration and invasion were significantly reduced after HOTAIR knockdown. Molecular analysis showed that Notch1, EpCAM, vimentin and STAT3 expressions were decreased significantly, while the expression of E-cadherin was significantly increased after HOTAIR knockdown. Rescue experiments further confirmed that Notch1 and STAT3 were involved in siHOTAIR-mediated reduction of migration and invasion of cervical cancer cells.IMPACT STATEMENTWhat is already known on this subject? Long non-coding RNAs including HOTAIR, is implicated in occurrence and development of cancer and have been explored to develop new therapeutic options for cancer.What do the results of this study add? HOTAIR silencing significantly reduces the viability and migration ability of cells and induces cell apoptosis, adding experimental data supporting the potential use of HOTAIR specific-siRNA as a therapeutic avenue for the cancer.What are the implications of these findings for clinical practice and/or further research? The finding from this study would help develop clinically applicable therapeutic avenues for the cancer and identify new treatment targets in the relevant pathways leading to new drugs or treatments.

Application of γ-aminobutyric acid (GABA) improves fruit quality and rootstock drought tolerance in apple.

GABA (γ-aminobutyric acid) plays a multifaceted role in plant growth, fruit quality, and tolerance to abiotic stresses. However, its physiological roles and mechanisms in the fruit quality and response to long-term drought stress in apple remain unelucidated. To investigate the effect of GABA on apple fruit quality and drought tolerance, we sprayed exogenous GABA on apple cultivar "Cripps Pink" and irrigated rootstock M.9-T337 with GABA, respectively. Results showed that exogenous GABA could effectively improve the fruit quality of "Cripps Pink", including increased sugar-to-acid ratio, flesh firmness, pericarp malleability, and GABA content, as well as reduced fruit acidity. In addition, pretreatment of M.9-T337 plants with GABA improved their tolerance to both long- and short-term drought stress. Specifically, 1 mM exogenous GABA increased the net photosynthetic rate, relative leaf water content, root-to-shoot ratio, and water use efficiency under long-term drought stress, and delayed the increased of the relative electrolyte leakage under short-term drought stress. RNA-seq analysis identified 1271 differentially expressed genes (DEGs) between nontreated and GABA-pretreated plants under short-term drought stress. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis of these DEGs revealed that GABA may enhance plant drought resistance by upregulating the expression of genes related to "Biosynthesis of secondary metabolites", "MAPK signaling pathway", "Glutathione metabolism", and "Carbon fixation in photosynthetic organisms". In conclusion, these results revealed that exogenous GABA can improve fruit quality and enhance drought tolerance in apple.

Strongly enhanced THz generation enabled by a graphene hot-carrier fast lane.

Semiconductor photoconductive switches are useful and versatile emitters of terahertz (THz) radiation with a broad range of applications in THz imaging and time-domain spectroscopy. One fundamental challenge for achieving efficient ultrafast switching, however, is the relatively long carrier lifetime in most common semiconductors. To obtain picosecond ultrafast pulses, especially when coupled with waveguides/transmission lines, semiconductors are typically engineered with high defect density to reduce the carrier lifetimes, which in turn lowers the overall power output of the photoconductive switches. To overcome this fundamental trade-off, here we present a new hybrid photoconductive switch design by engineering a hot-carrier fast lane using graphene on silicon. While photoexcited carriers are generated in the silicon layer, similar to a conventional switch, the hot carriers are transferred to the graphene layer for efficient collection at the contacts. As a result, the graphene-silicon hybrid photoconductive switch emits THz fields with up to 80 times amplitude enhancement compared to its graphene-free counterpart. These results both further the understanding of ultrafast hot carrier transport in such hybrid systems and lay the groundwork toward intrinsically more powerful THz devices based on 2D-3D hybrid heterostructures.

Isoquinolone derivatives as lysophosphatidic acid receptor 5 (LPA5) antagonists: Investigation of structure-activity relationships, ADME properties and analgesic effects.

Blockade of lysophosphatidic acid receptor 5 (LPA5) by a recently reported antagonist AS2717638 (2) attenuated inflammatory and neuropathic pains, although it showed moderate in vivo efficacy and its structure-activity relationships and the ADME properties are little studied. We therefore designed and synthesized a series of isoquinolone derivatives and evaluated their potency in LPA5 calcium mobilization and cAMP assays. Our results show that substituted phenyl groups or bicyclic aromatic rings such as benzothiophenes or benzofurans are tolerated at the 2-position, 4-substituted piperidines are favored at the 4-position, and methoxy groups at the 6- and 7-positions are essential for activity. Compounds 65 and 66 showed comparable in vitro potency, excellent selectivity against LPA1-LPA4 and >50 other GPCRs, moderate metabolic stability, and high aqueous solubility and brain permeability. Both 65 and 66 significantly attenuated nociceptive hypersensitivity at lower doses than 2 and had longer-lasting effects in an inflammatory pain model, and 66 also dose-dependently reduced mechanical allodynia in the chronic constriction injury model and opioid-induced hyperalgesia at doses that had no effect on the locomotion in rats. These results suggest that these isoquinolone derivatives as LPA5 antagonists are of promise as potential analgesics.

MdZAT5 regulates drought tolerance via mediating accumulation of drought-responsive miRNAs and mRNAs in apple.

Drought limits apple yield and fruit quality. However, the molecular mechanism of apple in response to drought is not well known. Here, we report a Cys2/His2 (C2H2)-type zinc-finger protein, MdZAT5, that positively regulates apple drought tolerance by regulating drought-responsive RNAs and microRNAs (miRNAs). DNA affinity purification and sequencing and yeast-one hybrid analysis identified the binding motifs of MdZAT5, T/ACACT/AC/A/G. Chromatin immunoprecipitation quantitative polymerase chain reaction (ChIP-qPCR) and electrophoretic mobility shift assays (EMSAs) showed that MdZAT5 directly binds to the promoters of the drought-responsive genes including MdRHA2a, MdLEA14, MdTPX1, and MdCAT3, and activates their expression under drought stress. MdZAT5 interacts with and directly targets HYPONASTIC LEAVES1 (MdHYL1). MdZAT5 may facilitate the interaction of MdHYL1 with pri-miRNAs or MdDCL1 by activating MdHYL1 expression, thereby regulating the biogenesis of drought-responsive miRNAs. Genetic dissection showed that MdHYL1 is essential for MdZAT5-mediated drought tolerance and miRNA biogenesis. In addition, ChIP-qPCR and EMSA revealed that MdZAT5 binds directly to the promoters of some MIR genes including Mdm-miR171i and Mdm-miR172c, and modulates their transcription. Taken together, our findings improve our understanding of the molecular mechanisms of drought response in apple and provide a candidate gene for the breeding of drought-tolerant cultivars.

Electrically tunable two-dimensional heterojunctions for miniaturized near-infrared spectrometers.

Miniaturized spectrometers are of considerable interest for their portability. Most designs to date employ a photodetector array with distinct spectral responses or require elaborated integration of micro & nano optic modules, typically with a centimeter-scale footprint. Here, we report a design of a micron-sized near-infrared ultra-miniaturized spectrometer based on two-dimensional van der Waals heterostructure (2D-vdWH). By introducing heavy metal atoms with delocalized electronic orbitals between 2D-vdWHs, we greatly enhance the interlayer coupling and realize electrically tunable infrared photoresponse (1.15 to 1.47 µm). Combining the gate-tunable photoresponse and regression algorithm, we achieve spectral reconstruction and spectral imaging in a device with an active footprint < 10 µm. Considering the ultra-small footprint and simple fabrication process, the 2D-vdWHs with designable bandgap energy and enhanced photoresponse offer an attractive solution for on-chip infrared spectroscopy.

MdGH3.6 is targeted by MdMYB94 and plays a negative role in apple water-deficit stress tolerance.

Drought significantly limits apple fruit production and quality. Decoding the key genes involved in drought stress tolerance is important for breeding varieties with improved drought resistance. Here, we identified GRETCHEN HAGEN3.6 (GH3.6), an indole-3-acetic acid (IAA) conjugating enzyme, to be a negative regulator of water-deficit stress tolerance in apple. Overexpressing MdGH3.6 reduced IAA content, adventitious root number, root length and water-deficit stress tolerance, whereas knocking down MdGH3.6 and its close paralogs increased IAA content, adventitious root number, root length and water-deficit stress tolerance. Moreover, MdGH3.6 negatively regulated the expression of wax biosynthetic genes under water-deficit stress and thus negatively regulated cuticular wax content. Additionally, MdGH3.6 negatively regulated reactive oxygen species scavengers, including antioxidant enzymes and metabolites involved in the phenylpropanoid and flavonoid pathway in response to water-deficit stress. Further study revealed that the homolog of transcription factor AtMYB94, rather than AtMYB96, could bind to the MdGH3.6 promoter and negatively regulated its expression under water-deficit stress conditions in apple. Overall, our results identify a candidate gene for the improvement of drought resistance in fruit trees.

Discovery of Arylsulfonamides as Dual Orexin Receptor Agonists.

Loss of orexin-producing neurons results in narcolepsy with cataplexy, and orexin agonists have been shown to increase wakefulness and alleviate narcolepsy symptoms in animal models. Several OX2R agonists have been reported but with little or no activity at OX1R. We conducted structure-activity relationship studies on the OX2R agonist YNT-185 (2) and discovered dual agonists such as RTOXA-43 (40) with EC50's of 24 nM at both OX2R and OX1R. Computational modeling studies based on the agonist-bound OX2R cryogenic electron microscopy structures showed that 40 bound in the same binding pocket and interactions of the pyridylmethyl group of 40 with OX1R may have contributed to its high OX1R potency. Intraperitoneal injection of 40 increased time awake, decreased time asleep, and increased sleep/wake consolidation in 12-month old mice. This work provides a promising dual small molecule agonist and supports development of orexin agonists as potential treatments for orexin-deficient disorders such as narcolepsy.

Insights into the effect of human civilization on Malus evolution and domestication.

The evolutionary history of the Malus genus has not been well studied. In the current study, we presented genetic evidence on the origin of the Malus genus based on genome sequencing of 297 Malus accessions, revealing the genetic relationship between wild species and cultivated apples. Our results demonstrated that North American and East Asian wild species are closer to the outgroup (pear) than Central Asian species, and hybrid species including natural (separated before the Pleistocene, about 2.5 Mya) and artificial hybrids (including ornamental trees and rootstocks) are between East and Central Asian wild species. Introgressions from M. sylvestris in cultivated apples appeared to be more extensive than those from M. sieversii, whose genetic background flowed westward across Eurasia and eastward to wild species including M. prunifolia, M. × asiatica, M. × micromalus, and M. × robust. Our results suggested that the loss of ancestral gene flow from M. sieversii in cultivated apples accompanied the movement of European traders around the world since the Age of Discovery. Natural SNP variations showed that cultivated apples had higher nucleotide diversity than wild species and more unique SNPs than other apple groups. An apple ERECTA-like gene that underwent selection during domestication on 15th chromosome was identified as a likely major determinant of fruit length and diameter, and an NB-ARC domain-containing gene was found to strongly affect anthocyanin accumulation using a genome-wide association approach. Our results provide new insights into the origin and domestication of apples and will be useful in new breeding programmes and efforts to increase fruit crop productivity.

Neural network based 3D tracking with a graphene transparent focal stack imaging system.

Recent years have seen the rapid growth of new approaches to optical imaging, with an emphasis on extracting three-dimensional (3D) information from what is normally a two-dimensional (2D) image capture. Perhaps most importantly, the rise of computational imaging enables both new physical layouts of optical components and new algorithms to be implemented. This paper concerns the convergence of two advances: the development of a transparent focal stack imaging system using graphene photodetector arrays, and the rapid expansion of the capabilities of machine learning including the development of powerful neural networks. This paper demonstrates 3D tracking of point-like objects with multilayer feedforward neural networks and the extension to tracking positions of multi-point objects. Computer simulations further demonstrate how this optical system can track extended objects in 3D, highlighting the promise of combining nanophotonic devices, new optical system designs, and machine learning for new frontiers in 3D imaging.

Genome-wide analysis of SET-domain group histone methyltransferases in apple reveals their role in development and stress responses.

BACKGROUND: Histone lysine methylation plays an important role in plant development and stress responses by activating or repressing gene expression. Histone lysine methylation is catalyzed by a class of SET-domain group proteins (SDGs). Although an increasing number of studies have shown that SDGs play important regulatory roles in development and stress responses, the functions of SDGs in apple remain unclear. RESULTS: A total of 67 SDG members were identified in the Malus×domestica genome. Syntenic analysis revealed that most of the MdSDG duplicated gene pairs were associated with a recent genome-wide duplication event of the apple genome. These 67 MdSDG members were grouped into six classes based on sequence similarity and the findings of previous studies. The domain organization of each MdSDG class was characterized by specific patterns, which was consistent with the classification results. The tissue-specific expression patterns of MdSDGs among the 72 apple tissues in the different apple developmental stages were characterized to provide insight into their potential functions in development. The expression profiles of MdSDGs were also investigated in fruit development, the breaking of bud dormancy, and responses to abiotic and biotic stress; the results indicated that MdSDGs might play a regulatory role in development and stress responses. The subcellular localization and putative interaction network of MdSDG proteins were also analyzed. CONCLUSIONS: This work presents a fundamental comprehensive analysis of SDG histone methyltransferases in apple and provides a basis for future studies of MdSDGs involved in apple development and stress responses.

The regulatory module MdBT2-MdMYB88/MdMYB124-MdNRTs regulates nitrogen usage in apple.

Less than 40% of the nitrogen (N) fertilizer applied to soil is absorbed by crops. Thus, improving the N use efficiency of crops is critical for agricultural development. However, the underlying regulation of these processes remains largely unknown, particularly in woody plants. By conducting yeast two-hybrid assays, we identified one interacting protein of MdMYB88 and MdMYB124 in apple (Malus × domestica), namely BTB and TAZ domain protein 2 (MdBT2). Ubiquitination and protein stabilization analysis revealed that MdBT2 ubiquitinates and degrades MdMYB88 and MdMYB124 via the 26S proteasome pathway. MdBT2 negatively regulates nitrogen usage as revealed by the reduced fresh weight, dry weight, N concentration, and N usage index of MdBT2 overexpression calli under low-N conditions. In contrast, MdMYB88 and MdMYB124 increase nitrate absorption, allocation, and remobilization by regulating expression of MdNRT2.4, MdNRT1.8, MdNRT1.7, and MdNRT1.5 under N limitation, thereby regulating N usage. The results obtained illustrate the mechanism of a regulatory module comprising MdBT2-MdMYB88/MdMYB124-MdNRTs, through which plants modulate N usage. These data contribute to a molecular approach to improve the N usage of fruit crops under limited N acquisition.

Evidence for temporal relationship between the late Mesozoic multistage Qianlishan granite complex and the Shizhuyuan W-Sn-Mo-Bi deposit, SE China.

The world-class Shizhuyuan W-Sn-Mo-Bi deposit is spatially related to the Qianlishan granite complex (QGC) in Hunan Province, China. However, the age and classification of the QGC are still debated, and a better understanding of the temporal genetic relationship between the QGC and the Shizhuyuan deposit is essential. Here, we present chemical compositions the intrusive phases of the QGC and the results of detailed zircon U-Pb dating and muscovite Ar-Ar dating of a mineralized greisen vein. Our new zircon laser ablation inductively coupled plasma mass spectrometry U-Pb age data constrain the emplacement of the QGC to 155-151.7 Ma. According to petrological, geochemical and geochronological data and the inferred redox conditions, the QGC can be classified into four phases: P1, porphyritic biotite granites; P2, porphyritic biotite granites; P3, equigranular biotite granite; and P4, granite porphyry dikes. All phases, and especially P1-P3, have elevated concentrations of ore-forming metals and heat-producing elements (U, Th, K; volume heat-producing rate of 5.89-14.03 µWm-3), supplying the metal and heat for the metalogic process of the Shizhuyuan deposit. The Ar-Ar muscovite age (154.0 ± 1.6 Ma) of the mineralized greisen vein in the Shizhuyuan deposit is consistent with the emplacement time of the QGC, suggesting their temporal genetic relationship.

MerTK activity is not necessary for the proliferation of glioblastoma stem cells.

MerTK has been identified as a promising target for therapeutic intervention in glioblastoma. Genetic studies documented a range of oncogenic processes that MerTK targeting could influence, however robust pharmacological validation has been missing. The aim of this study was to assess therapeutic potential of MerTK inhibitors in glioblastoma therapy. Unlike previous studies, our work provides several lines of evidence that MerTK activity is dispensable for glioblastoma growth. We observed heterogeneous responses to MerTK inhibitors that could not be correlated to MerTK inhibition or MerTK expression in cells. The more selective MerTK inhibitors UNC2250 and UNC2580A lack the anti-proliferative potency of less-selective inhibitors exemplified by UNC2025. Functional assays in MerTK-high and MerTK-deficient cells further demonstrate that the anti-cancer efficacy of UNC2025 is MerTK-independent. However, despite its efficacy in vitro, UNC2025 failed to attenuate glioblastoma growth in vivo. Gene expression analysis from cohorts of glioblastoma patients identified that MerTK expression correlates negatively with proliferation and positively with quiescence genes, suggesting that MerTK regulates dormancy rather than proliferation in glioblastoma. In summary, this study demonstrates the importance of orthogonal inhibitors and disease-relevant models in target validation studies and raises a possibility that MerTK inhibitors could be used to target dormant glioblastoma cells.

Data-Driven Construction of Antitumor Agents with Controlled Polypharmacology.

Controlling which particular members of a large protein family are targeted by a drug is key to achieving a desired therapeutic response. In this study, we report a rational data-driven strategy for achieving restricted polypharmacology in the design of antitumor agents selectively targeting the TYRO3, AXL, and MERTK (TAM) family tyrosine kinases. Our computational approach, based on the concept of fragments in structural environments (FRASE), distills relevant chemical information from structural and chemogenomic databases to assemble a three-dimensional inhibitor structure directly in the protein pocket. Target engagement by the inhibitors designed led to disruption of oncogenic phenotypes as demonstrated in enzymatic assays and in a panel of cancer cell lines, including acute lymphoblastic and myeloid leukemia (ALL/AML) and nonsmall cell lung cancer (NSCLC). Structural rationale underlying the approach was corroborated by X-ray crystallography. The lead compound demonstrated potent target inhibition in a pharmacodynamic study in leukemic mice.

TAM Family Receptor Kinase Inhibition Reverses MDSC-Mediated Suppression and Augments Anti-PD-1 Therapy in Melanoma.

Myeloid cell receptor tyrosine kinases TYRO3, AXL, and MERTK and their ligands, GAS6 and PROTEIN S, physiologically suppress innate immune responses, including in the tumor microenvironment. Here, we showed that myeloid-derived suppressor cells (MDSC) dramatically upregulated TYRO3, AXL, and MERTK and their ligands [monocytic MDSCs (M-MDSC)>20-fold, polymorphonuclear MDSCs (PMN-MDSC)>15-fold] in tumor-bearing mice. MDSCs from tumor-bearing Mertk-/-, Axl-/- , and Tyro3-/- mice exhibited diminished suppressive enzymatic capabilities, displayed deficits in T-cell suppression, and migrated poorly to tumor-draining lymph nodes. In coimplantation experiments using TYRO3-/-, AXL-/-, and MERTK-/- MDSCs, we showed the absence of these RTKs reversed the protumorigenic properties of MDSCs in vivo Consistent with these findings, in vivo pharmacologic TYRO3, AXL, and MERTK inhibition diminished MDSC suppressive capability, slowed tumor growth, increased CD8+ T-cell infiltration, and augmented anti-PD-1 checkpoint inhibitor immunotherapy. Mechanistically, MERTK regulated MDSC suppression and differentiation in part through regulation of STAT3 serine phosphorylation and nuclear localization. Analysis of metastatic melanoma patients demonstrated an enrichment of circulating MERTK+ and TYRO3+ M-MDSCs, PMN-MDSCs, and early-stage MDSCs (e-MDSC) relative to these MDSC populations in healthy controls. These studies demonstrated that TYRO3, AXL, and MERTK control MDSC functionality and serve as promising pharmacologic targets for regulating MDSC-mediated immune suppression in cancer patients.