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Octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine (HMX) is one of the most important energetic materials. Investigations on its phase transitions and chemical reactions under extreme conditions are very important to understand the explosion process and design new energetic materials. By using a diamond anvil cell combined with in situ Raman, IR and X-ray diffraction techniques up to a pressure of ∼40 GPa, we found that β-HMX undergoes four reversible phase transitions without any chemical reaction under external pressure at room temperature. Isostructural phase transitions emerge around 5 GPa (ζ-HMX) and 10–13 GPa (e-HMX), and another two phases emerge at 16 GPa (η-HMX) and 27 GPa (ϕ-HMX). The unit cells of ζ-HMX and e-HMX were determined as a = 6.215 A, b = 10.417 A, c = 8.272 A, β = 124.88°, P21/c at 6.2 GPa and a = 6.130 A, b = 9.846 A, c = 8.258 A, β = 125.06°, P21/c at 12.6 GPa, respectively. The crystal structures of β, ζ, and e-HMX were obtained by Rietveld refinement, based on which the rotations of NO2 groups were found to be related to the phase transition at 5 GPa. Additionally, HMX decomposes at 8.7 GPa and 300 °C. Carbon dioxide, hydroxyl, imino and hydroxyimino groups were detected in the IR spectrum, which indicates that the reaction contains a hydrogen transfer process. Our investigation uncovers the structural variation of β-HMX under external pressure and identifies the decomposition products under extreme conditions, which provides new insight to understand the detonation process of energetic materials.

Efficient electrocatalysts based on abundant transition metals have emerged as important candidates for the oxygen evolution reaction (OER). Herein, significant improvement in OER performance has been achieved by using hierarchical nanostructured Ce–Co3O4 composites derived from Ce-substituted ZIF-67 precursors. Our results show that proper control of the introduced Ce amount and species could precisely tune the Co3+/Co2+ ratio and induce surface oxygen defects, further boosting the OER performance. Especially, the introduction of suitable Ce content (i.e., 6.44 wt% Ce) into the crystal structure and onto the surface of Co3O4 effectively facilitates the formation of Co3+ species and modifies the chemical binding energies, leading to much improved activity for OER with a 369 mV overpotential at 10 mA cm−2, a Tafel slope of 56 mV dec−1 and excellent long-term stability in 1.0 M KOH solution. These results demonstrate the efficient and feasible strategy for tailoring the electrocatalytic properties of metal oxides by Ce-doping and modification.

Pressure is an effective method to modulate the optical properties of organic solid-state light-emitting materials through enhancing intermolecular interactions and/or generating new polymorphs. Herein, we find that the organic molecular crystal of diphenylfluorenone (DPFO) undergoes a large-scale and continuous redshift of the UV-vis absorption and photoluminescence (PL) spectra under high pressure, across the entire visible light region. Remarkably, a redshift of about 300 nm was observed for its PL peak at 13.32 GPa, from greenish-yellow to the near-infrared (NIR) region. The in situ high-pressure IR spectra and synchrotron X-ray diffraction (XRD) analyses suggest a phase transition from the α- to the γ-phase (newly identified) at around 3 GPa, accompanied by the phenyl unit in DPFO converting from perpendicular to parallel packing. Theoretical calculations show that the enhanced π⋯π interactions and the overlap of the molecular orbitals in the γ-phase are responsible for such a tremendous redshift in the PL spectra. Our work highlights the large redshift phenomenon in the DPFO system under high pressure, which may have potential photonic device applications. Furthermore, this work reveals the clear structure-property relation, providing deep insight into the tailoring of the optical characteristics of molecular materials.

We explored an interfacial synthesis of two-dimensional (2D) 2PbCO3·Pb(OH)2 nanosheets with an average thickness of 3.3 nm at the gas/liquid interface. Their morphologies and structures were well characterized by TEM/SAED, SEM, AFM, and PXRD. The single crystal nanosheets are regular hexagons with the edge length ranging from 1 to 10 μm. The as-prepared 2D nanosheets were further used as a catalyst for the oxidation reaction of tetramethylbenzidine (TMB). The experimental results revealed that the 2D nanosheets have an intrinsic enzyme mimetic activity similar to that of peroxidases, which are common in nature. The ultrathin 2D nanosheets prepared via an interfacial synthesis procedure exhibit catalytic activity superior to that of commercial 2PbCO3·Pb(OH)2 powder.

The cross-plane diffusion of Li+ in 2D materials are helpful to improve the Li nucleation and growth in Li-metal batteries, but it is hard to realize the atomic-level in-plane pores for Li + migration near the electrode interface due to the uncontrollable formation of pores on prevailing 2D materials. Herein, a large-scale (13 × 11 cm2 ) ultrathin graphdiyne (GDY) (10 nm) film with naturally atomic-level cavities is first prepared. The ultrathin film is used as co-separator to uniform the interfacial lithium diffusion for lithium plating, and the nucleation overpotential is obviously improved from 115 to 65.4 mV at 0.5 mA cm −2 and 124 to 90 mV at 1.0 mA cm−2, respectively. Associating with the flattening function of this tough 2D film, the lithium dendrites are significantly suppressed, bringing a high Coulombic efficiency (more than 98%) and long lifespan of more than 1200 h at 0.5 mA cm−2 with a high capacity of 2.0 mA h cm−2 on the Cu foil. Theoretical simulation demonstrates that the application of graphdiyne film with atomic-level cavities can produce the single Li+ diffusion near the interface, realizing the highly ordered and uniform migration of Li+, thus effectively increase the anisotropic properties of Li+ diffusion near the electrode, greatly suppressing the lithium dendrites. Beyond, the graphdiyne film shows great promises for accommodating some intractable problems in other alkali metal batteries.

Porphyrias are rare blood disorders caused by genetic defects in the heme biosynthetic pathway and are associated with the accumulation of high levels of porphyrins that become cytotoxic. Porphyrins, due to their amphipathic nature, spontaneously associate into different nanostructures, but very little is known about the cytotoxic effects of these porphyrin nanostructures. Previously, we demonstrated the unique ability of fluorescent biological porphyrins, including protoporphyrin-IX (PP-IX), to cause organelle-selective protein aggregation, which we posited to be a major mechanism by which fluorescent porphyrins exerts their cytotoxic effect. Herein, we tested the hypothesis that PP-IX-mediated protein aggregation is modulated by different PP-IX nanostructures via a mechanism that depends on their oxidizing potential and protein-binding ability. UV–visible spectrophotometry showed pH-mediated reversible transformations of PP-IX nanostructures. Biochemical analysis showed that PP-IX nanostructure size modulated PP-IX-induced protein oxidation and protein aggregation. Furthermore, albumin, the most abundant serum protein, preferentially binds PP-IX dimers and enhances their oxidizing ability. PP-IX binding quenched albumin intrinsic fluorescence and oxidized His-91 residue to Asn/Asp, likely via a previously described photo-oxidation mechanism for other proteins. Extracellular albumin protected from intracellular porphyrinogenic stress and protein aggregation by acting as a PP-IX sponge. This work highlights the importance of PP-IX nanostructures in the context of porphyrias and offers insights into potential novel therapeutic approaches.

Understanding the relationship between water discharge (Q) and suspended sediment concentration (SSC) across the Loess Plateau is a prerequisite for evaluating soil and water conservation measures. Using daily Q and SSC datasets, this study jointly analyzes changes in Q and SSC on the central Loess Plateau, a major sediment producing area of China, during the periods 1971–1987 (P1) and 2008–2016 (P2). The results show that during both P1 and P2, the contribution of the maximum-3-day-per year sediment load to the total annual sediment load (SSL) is almost invariably over 50% (dominant), and in the majority of cases, the size of this contribution increases further between P1 and P2. The contribution of extremely high SSL events plays an overwhelming role in watersheds of area < 10,000 km2 and appears to be almost independent of change in land cover condition. In the Helong section of the Yellow River, there is more evident reduction in SSC than Q between these two periods (streamflow became clearer), while the opposite occurred in the Jing River (streamflow declined). In addition, the range of variation in SSC is large for small Q values, whereas the SSC for flood events tends to be relatively stable in gullied-hilly and flat-surfaced (Yuan) loess areas, which are major sediment producers. Based on scatter plots of SSC versus Q after logarithmic transformation, we find that the lower boundary of the mapped data points for an individual station fits a straight line. This boundary relates to riverbed erosion. Given that soil erosion weakened on gully slopes over time and streamflow in channels during P2 was generally lower, the boundary tended to move downward between P1 and P2 for most watersheds, reflecting a reduction in SSC for a given value of Q in P2 compared to P1.

An end-modified 2′-O-methyl molecular beacon (eMB) with unique nuclease resistance was designed and prepared. The eMB can resist the enzymatic digestion by DNase I, which would otherwise occur upon the hybridization of the eMB with a complementary sequence. As a result, the coupling use of eMBs and DNase I allows highly sensitive detection of miRNA with a limit of detection (LOD) of 2.5 pM. The analytical strategy was further used for detection of tumor exosomal microRNA-21, and down to 0.86 μg mL−1 A375 exosomes were detected. Overall, the present method can effectively quantify tumor-derived exosomes for cancer diagnosis.

The phytohormone auxin controls a myriad of processes in plants, at least in part through its regulation of cell expansion. The "acid growth hypothesis" has been proposed to explain auxin-stimulated cell expansion for five decades, but the mechanism underlying auxin-induced cell wall acidification is poorly characterized. Auxin induces the phosphorylation and activation of the plasma membrane (PM) H+-ATPase that pumps protons into the apoplast, yet how auxin activates its phosphorylation remains elusive. Here, we show that the transmembrane kinase (TMK) auxin signaling proteins interact with PM H+-ATPases and activate their phosphorylation to promote cell wall acidification and hypocotyl cell elongation in Arabidopsis. Auxin induced TMK's interaction with H+-ATPase on the plasma membrane within 1-2 minutes as well as TMK-dependent phosphorylation of the penultimate Thr residue. Genetic, biochemical, and molecular evidence demonstrates that TMKs are required for auxin-induced PM H+-ATPase activation, apoplastic acidification, and cell expansion. Thus, our findings reveal a crucial connection between auxin and PM H+-ATPase activation in regulating apoplastic pH changes and cell expansion via TMK-based cell surface auxin signaling.

The phytohormone auxin controls many processes in plants, at least in part through its regulation of cell expansion1. The acid growth hypothesis has been proposed to explain auxin-stimulated cell expansion for five decades, but the mechanism that underlies auxin-induced cell-wall acidification is poorly characterized. Auxin induces the phosphorylation and activation of the plasma membrane H+-ATPase that pumps protons into the apoplast2, yet how auxin activates its phosphorylation remains unclear. Here we show that the transmembrane kinase (TMK) auxin-signalling proteins interact with plasma membrane H+-ATPases, inducing their phosphorylation, and thereby promoting cell-wall acidification and hypocotyl cell elongation in Arabidopsis. Auxin induced interactions between TMKs and H+-ATPases in the plasma membrane within seconds, as well as TMK-dependent phosphorylation of the penultimate threonine residue on the H+-ATPases. Our genetic, biochemical and molecular evidence demonstrates that TMKs directly phosphorylate plasma membrane H+-ATPase and are required for auxin-induced H+-ATPase activation, apoplastic acidification and cell expansion. Thus, our findings reveal a crucial connection between auxin and plasma membrane H+-ATPase activation in regulating apoplastic pH changes and cell expansion through TMK-based cell surface auxin signalling., Auxin induces transmembrane-kinase-dependent activation of H+-ATPase in the plasma membrane through phosphorylation of its penultimate threonine residue, promoting apoplastic acidification and hypocotyl cell elongation in Arabidopsis.

Umbrella trials are an innovative trial design where different treatments are matched with subtypes of a disease, with the matching typically based on a set of biomarkers. Consequently, when patients can be positive for more than one biomarker, they may be eligible for multiple treatment arms. In practice, different approaches could be applied to allocate patients who are positive for multiple biomarkers to treatments. However, to date there has been little exploration of how these approaches compare statistically. We conduct a simulation study to compare five approaches to handling treatment allocation in the presence of multiple biomarkers - equal randomisation; randomisation with fixed probability of allocation to control; Bayesian adaptive randomisation (BAR); constrained randomisation; and hierarchy of biomarkers. We evaluate these approaches under different scenarios in the context of a hypothetical phase II biomarker-guided umbrella trial. We define the pairings representing the pre-trial expectations on efficacy as linked pairs, and the other biomarker-treatment pairings as unlinked. The hierarchy and BAR approaches have the highest power to detect a treatment-biomarker linked interaction. However, the hierarchy procedure performs poorly if the pre-specified treatment-biomarker pairings are incorrect. The BAR method allocates a higher proportion of patients who are positive for multiple biomarkers to promising treatments when an unlinked interaction is present. In most scenarios, the constrained randomisation approach best balances allocation to all treatment arms. Pre-specification of an approach to deal with treatment allocation in the presence of multiple biomarkers is important, especially when overlapping subgroups are likely.

Bimetallic transition-metal phosphides are gradually evolving as efficient hydrogen evolution catalysts. In this study, graphene-coated MoP and bimetallic phosphide (MoNiP) nanoparticles (MoP/MoNiP@C) were synthesized via one-step straightforward high-temperature calcination and phosphating process. The precursor was obtained from polyaniline, Ni2+ ions, and phosphomolybdic acid hydrate (PMo12) by solvent evaporation. As expected, MoP/MoNiP@C manifests excellent hydrogen evolution activity with a low overpotential of 134 mV at 10 mA cm-2 and a small Tafel slope of 66 mV dec-1. Furthermore, MoP/MoNiP@C exhibits satisfactory stability for 24 h in the acid electrolyte. The outstanding catalytic performance can be attributed to the synergistic effect of MoP and MoNiP nanoparticles, the graphene coating protecting MoP and MoNiP from corrosion, as well as an increase in the number of active sites because of porous structures. This work can provide the experimental foundation for the simple synthesis of bimetallic phosphates with remarkable hydrogen evolution performance.

Porphyrias are caused by genetic defects in the heme biosynthetic pathway and are associated with accumulation of high levels of porphyrins that become cytotoxic. Porphyrins, due to their amphipathic nature, spontaneously associate into different nanostructures but very little is known about the effect of porphyrin speciation on the cytotoxic effects of porphyrins. Previously we demonstrated the unique ability of fluorescent biological porphyrins, including protoporphyrin IX (PP-IX), to cause organelle selective protein aggregation, which we posit to be a major mechanism by which porphyrins exerts their cytotoxic effect. Herein, we tested the hypothesis that PP-IX-mediated protein aggregation is modulated by different PP-IX nanostructures via a mechanism that depends on their oxidizing potential and protein binding ability. We demonstrate that PP-IX nanostructure formation is reversible in nature, and that nanostructure size modulates consequent protein oxidation and aggregation potential. We also show that albumin, the most abundant serum protein, preferentially binds PP-IX dimers and enhances their oxidizing ability. Additionally, extracellular albumin protects from intracellular porphyrinogenic stress and protein aggregation by acting as a PP-IX sponge. This work highlights the importance of PP-IX speciation in the context of the porphyrias, and offers insights into potential novel therapeutic approaches.

The rational design and construction of multifunctional electrocatalysts with high activity, low cost, and outstanding stability are highly desirable for the development of renewable energy but are still a big challenge. Bimetallic catalysts are a kind of promising candidates, like the hybrids of Co and VN nanoparticles (Co/VN). However, the inevitable aggregation during the preparation and electrochemical process lowers their reactivity and durability. Herein, small Co/VN nanoparticles (4-8 nm) embedded in porous graphitic carbon layers (Co/VN NPs@C) were obtained through the pyrolysis of metal-organic frameworks (MOFs). The synergistic effect of in situ generated Co and VN NPs together with fast electron transfer from graphitic carbon layers renders this catalyst to possess excellent trifunctional performance. More attractively, Co/VN NPs@C as both the anode and the cathode shows a low voltage of 1.58 V when the current density is up to 10 mA cm-2, exceeding most electrocatalysts based on non-noble metals. The rechargeable Zn-air batteries constructed by Co/VN NPs@C deliver high round-trip efficiency together with a peak power density of 130 mW cm-2, a specific capacity of 757 mAh g-1, and desirable stability, outperforming the traditional Zn-air batteries based on the Pt/C and RuO2 pair. This work opens a promising avenue toward constructing highly effective multifunctional electrocatalysts by designing small-sized nanoparticles with various active sites derived from MOFs.

Over the past decade, the hydrogels prepared from silk fibroin have received immense research attention due to the advantages of safe nature, biocompatibility, controllable degradation and capability to combine with other materials. They have broad application prospects in biomedicine and other fields. However, the traditional silk protein hydrogels have a simple network structure and single functionality, thus, leading to poor adaptability towards complex application environments. As a result, the application fields and development have been significantly restricted. However, the development of functional silk protein hydrogels has provided the opportunities to overcome the limitations of the silk protein hydrogels. In recent years, the functional design of the silk protein hydrogels and their potential applications have attracted the attention of scholars worldwide. Nevertheless, a comprehensive review on functional silk protein hydrogels is missing so far. In order to gain an in-depth understanding of the development status of the functional silk protein hydrogels, this article reviews the current status of the preparation, properties and application of the functional silk protein hydrogels. The article first briefly introduces the current cross-linking methods (including physical and chemical cross-linking), principles, advantages and limitations of the silk protein hydrogels. Subsequently, the types of functional silk protein hydrogels (e.g., high strength, injectable, self-healing, adhesive, conductive, environmental stimuli-responsive, 3D printable, etc.) and design principles for functional implementation have been introduced. Next, based on the advantages of the various functional aspects of the silk protein hydrogels, the applications of these hydrogels in the biomedical field (tissue engineering, sustained drug release, wound repair, adhesives, etc.) and bioelectronics are reviewed. Finally, the development prospects and challenges associated with silk protein functional hydrogels have been analyzed. It is hoped that this study will contribute towards the future innovation of the silk protein hydrogels by promoting the rational design of new mechanisms and successful realization of the target applications.

Supplemental material, sj-pdf-1-smm-10.1177_0962280220986580 for Bridging across patient subgroups in phase I oncology trials that incorporate animal data by Haiyan Zheng, Lisa V Hampson and Thomas Jaki in Statistical Methods in Medical Research

Immune checkpoint blockade (ICB) is regarded as a promising strategy for cancer therapy. The histone methyltransferase, Enhancer of Zeste Homolog 2 (EZH2), has been implicated in the carcinogenesis of numerous solid tumors. However, the underlying mechanism of EZH2 in cancer immunotherapeutic resistance remains unknown. EZH2 orchestrates the regulation of the innate and adaptive immune systems of the tumor microenvironment (TME). Profound epigenetic and transcriptomic changes induced by EZH2 in tumor cells and immune cells mobilize the elements of the TME, leading to immune-suppressive activity of solid tumors. In this review, we summarized the dynamic functions of EZH2 on the different components of the TME, including tumor cells, T cells, macrophages, natural killer cells, myeloid-derived suppressor cells, dendritic cells, fibroblasts, and mesenchymal stem cells. Several ongoing anti-tumor clinical trials using EZH2 inhibitors have also been included as translational perspectives. In conclusion, based combinational therapy to enable ICB could offer a survival benefit in patients with cancer.

The tumor suppressor Merlin/NF2, a key activator of the Hippo pathway in growth control, is regulated by phosphorylation. However, it is uncertain whether additional post‐translational modifications regulate Merlin. Here, we show that ubiquitination is required to activate Merlin in the Hippo pathway. Ubiquitinated Merlin is mostly conjugated by one or two ubiquitin molecules. Such modification is promoted by serine 518 dephosphorylation in response to Ca(2+) signaling or cell detachment. Merlin ubiquitination is mediated by the E3 ubiquitin ligase, NEDD4L, which requires a scaffold protein, AMOTL1, to approach Merlin. Several NF2‐patient‐derived Merlin mutations disrupt its binding to AMOTL1 and its regulation by the AMOTL1‐NEDD4L apparatus. Lysine (K) 396 is the major ubiquitin conjugation residue. Disruption of Merlin ubiquitination by the K396R mutation or NEDD4L depletion diminishes its binding to Lats1 and inhibits Lats1 activation. These effects are also accompanied by loss of Merlin's anti‐mitogenic and tumor suppressive properties. Thus, we propose that dephosphorylation and ubiquitination compose an intramolecular relay to activate Merlin functions in activating the Hippo pathway during growth control.

Triple-negative breast cancer (TNBC) is highly aggressive, difficult to treat and commonly develops visceral metastasis, including lung metastasis. We observed that High mobility group box 1 protein (HMGB1) was highly expressed in human TNBC and positively correlated with cancer metastasis. The hypoxic tumor environment is known to regulate HMGB1 secretion, but an understanding of the underlying mechanism by which tumor-derived HMGB1 regulates interstitial components and promotes breast cancer lung metastasis has remained elusive. The results of the present study showed that the number of CD62Ldim neutrophils, which have a strong ability to produce neutrophil extracellular traps (NETs), increased significantly in both peripheral blood and lung tissues in a mouse TNBC model and were regulated by tumor-derived HMGB1 through the TLR2 pathway. Furthermore, serum HMGB1 levels were positively correlated with CD62Ldim neutrophils in 86 breast cancer patients. We demonstrated that CD62Ldim neutrophils accelerated lung metastasis and that interventions targeting the “HMGB1-CD62Ldim neutrophil-NETs” axis could inhibit lung metastasis. Our results suggest that the combination of HMGB1 and CD62Ldim neutrophils is a potential marker for breast cancer lung metastasis and is novel target for future prevention and therapy.

Solid-state topochemical polymerization (SSTP) is a promising method to construct functional crystalline polymeric materials, but in contrast to various reactions that happen in solution, only very limited types of SSTP reactions are reported. Diels-Alder (DA) and dehydro-DA (DDA) reactions are textbook reactions for preparing six-membered rings in solution but are scarcely seen in solid-state synthesis. Here, using multiple cutting-edge techniques, we demonstrate that the solid 1,4-diphenylbutadiyne (DPB) undergoes a DDA reaction under 10-20 GPa with the phenyl as the dienophile. The crystal structure at the critical pressure shows that this reaction is "distance-selected". The distance of 3.2 A between the phenyl and the phenylethynyl facilitates the DDA reaction, while the distances for other DDA and 1,4-addition reactions are too large to allow the bonding. The obtained products are crystalline armchair graphitic nanoribbons, and hence our studies open a new route to construct the crystalline carbon materials with atomic-scale control.

Background: Inhalable medication devices on the market deliver aerosolized drugs in a turbulent flow, which creates significant obstacles for reaching the lower lungs. The complexity of the interaction of external turbulent flow from an inhalation device with complex anatomy of the upper airways, including the oropharyngeal cavity, makes the fidelity of aerosolized medication delivery to the lungs extremely low. Unpredictable outcomes, waste, and side effects result from unintended upper airway drug deposition. Methods: Here we compared the efficiency of aerosolized medication (fluticasone) delivery via a novel Flow Modification Device (ModiFlow) to that of a Standard Spacer (SS) device. The ability of ModiFlow to minimize the turbulence in the flow was assessed preliminarily by measuring the length of the Laminar Outflow using video recording. Oral mucosal 3D tissue culture (SkinAxis) was used as a target for delivery, and was placed either “well within” the range of the length of the oro-pharyngeal cavity (5cm) or “well outside” of it (20cm) from exit points of each device. The efficiency of fluticasone delivery to the surface of tissue cultures was quantified by mass spectrometry. Results: The results of the study demonstrated a statistically significant advantage of ModiFlow over a Standard Spacer in delivering aerosolized fluticasone to target tissue at both distances. The difference in the efficiency of delivery between the two spacers was more pronounced at a longer distance.Conclusions: Lamination of the outflow using internal septi helps improve the delivery of aerosolized medication to target tissue despite an increased inner surface area of the spacer device, which also indicates lesser deposition of the medication on the walls of the test tube. This suggests that the use of ModiFlow will potentially result in the more efficient delivery of aerosolized medications to the lungs with lesser deposition in the oral cavity and fewer side effects.

BRCA1 maintains genome integrity and suppresses tumorigenesis by promoting homologous recombination (HR)-mediated repair of DNA double strand breaks (DSB) and DNA damage-induced cell cycle checkpoints. Phosphorylation of BRCA1 by ATM, ATR, CHK2, CDK, and PLK1 kinases has been reported to regulate its functions. Here we show that ATR and ATM-mediated phosphorylation of BRCA1 on T1394, a highly conserved but functionally uncharacterized site, is a key modification for its function in the DNA damage response. Following DNA damage, T1394 phosphorylation ensured faithful repair of DSBs by promoting HR and preventing single strand annealing, a deletion-generating repair process. BRCA1 T1394 phosphorylation further safeguarded chromosomal integrity by maintaining the G2/M checkpoint. Moreover, multiple patient-derived BRCA1 variants of unknown significance were shown to affect T1394 phosphorylation. These results establish an important regulatory mechanism of BRCA1 function in the DNA damage response and may have implications in the development or prognosis of BRCA1-associated cancers.

Background: Circulating adipokines levels have been reported to be associated with the risk of rheumatoid arthritis (RA). However, it is still unclear whether these associations are causal or biased by reverse causation or residual confounding. This study aimed to assess potential causal roles of five adipokines (namely, adiponectin, leptin, resistin, chemerin, and retinol-blinding protein 4 [RBP4]) in the occurrence of RA.Methods: We conducted a two-sample Mendelian randomization analysis to investigate these associations. We used summary-level data from genome-wide association studies (GWASs) for adipokines in individuals of European ancestry as the exposure, and a separate large-scale meta-analysis of a GWAS which included 14,361 RA cases and 43,923 controls of European ancestry as the outcome. Genetic variants were selected as instrumental variables if robustly genome-wide significant in their associations with adipokines. The causal effects were estimated using the inverse-variance weighted method in the primary analysis. Sensitivity analyses were performed to warrant that bias due to genetic pleiotropy was unlikely.Results: The circulating resistin was found to be the only adipokinetic factor having statistical significance, with higher levels causally associated with the risk of RA (odds ratio: 1.28; 95% confidence interval: [1.07, 1.53] per unit increase in the natural log-transformed resistin). In contrast, associations of adiponectin, leptin, chemerin, and RBP4 with risk of RA were not statistically significant. The MR assumptions did not seem to be violated. Sensitivity analyses yielded consistent findings.Conclusions: Genetically predicted circulating resistin levels were positively associated with RA risk. Our analysis suggested that resistin may play a notable causal role in RA pathogenesis. It would be beneficial for the development of clinical as well as public health strategies that target appropriate levels of resistin for future RA intervention.

With the gradual depletion of high-quality iron-ore resources, ironmaking blast furnaces have gradually shifted to using high-content Al2O3 iron ore. Under this condition, the addition of MgO in the slag is adopted to alleviate operation problems caused by the high content of Al2O3. However, the proper value of the MgO/Al2O3 ratio for blast-furnace slag systems (Al2O3 = 8&ndash, 25%) is not systematically studied. In this paper, we discuss the proper MgO/Al2O3 ratio on the basis of blast-furnace slag systems under different Al2O3 contents. On the basis of thermodynamics and phase-diagram analysis, it could be concluded that: (1) the MgO/Al2O3 ratio is not limited when Al2O3 in slag is less than 14%, (2) the MgO/Al2O3 ratio is required to be in the range of 0.40&ndash, 0.50 when Al2O3 in the slag is 15&ndash, 17%, and (3) the MgO/Al2O3 ratio should be 0.45&ndash, 0.55 when Al2O3 in the slag is larger than 18%. The proper MgO/Al2O3 ratio value has been established in various industries, and it has achieved significant economic and social benefits.

Purpose Aging affects a variety of visual functions. In this study, we aim to quantitatively investigate the temporal characteristics of visual processing in aging. Methods Twelve younger (24.1 ± 1.6 years) and 12 older observers (58.4 ± 3.6 years) participated in the study. All participants had normal or corrected-to-normal vision. The contrast thresholds of the participants were measured using an orientation discrimination task with white external noise masks. The target-mask stimulus onset asynchronies were 16.7 ms, 33.4 ms, 50.0 ms, 83.4 ms, and ∞ (no external noise masks) in separate conditions. The signal stimulus was carefully chosen such that it was equally visible for the younger and older participants. An elaborated perceptual template model (ePTM) was fit to the data of each participant. Results Without masks, there was no difference in contrast thresholds between the younger and older groups (P = 0.707). With masks, contrast thresholds in the older group elevated more than those in the younger group, and the pattern of threshold elevation differed in the two groups. The ePTM fitted the data well, with the older observers having lower template gains than the younger observers (P = 3.58 × 10-6). A further analysis of the weight parameters of the temporal window revealed that the older observers had a flatter temporal window than the younger observers (P = 0.025). Conclusions Age-related temporal processing deficits were found in older observers with normal contrast sensitivity to the signal stimuli. The deficits were accounted for by the inferior temporal processing window of the visual system in aging.

AS events affect genes encoding protein domain composition and make the single gene produce more proteins with a certain number of genes to satisfy the establishment of photosynthesis during de-etiolation. The drastic switch from skotomorphogenic to photomorphogenic development is an excellent system to elucidate rapid developmental responses to environmental stimuli in plants. To decipher the effects of different light wavelengths on de-etiolation, we illuminated etiolated maize seedlings with blue, red, blue–red mixed and white light, respectively. We found that blue light alone has the strongest effect on photomorphogenesis and that this effect can be attributed to the higher number and expression levels of photosynthesis and chlorosynthesis proteins. Deep sequencing-based transcriptome analysis revealed gene expression changes under different light treatments and a genome-wide alteration in alternative splicing (AS) profiles. We discovered 41,188 novel transcript isoforms for annotated genes, which increases the percentage of multi-exon genes with AS to 63% in maize. We provide peptide support for all defined types of AS, especially retained introns. Further in silico prediction revealed that 58.2% of retained introns have changes in domains compared with their most similar annotated protein isoform. This suggests that AS acts as a protein function switch allowing rapid light response through the addition or removal of functional domains. The richness of novel transcripts and protein isoforms also demonstrates the potential and importance of integrating proteomics into genome annotation in maize.

With the development of the city, LED street lamps on urban roads gradually come into people's vision. This paper first investigates the lighting situation in some dark places on campus. On the premise of meeting the requirements of campus lighting at night, a new anti-crime method combining crime prevention lighting and optical communication is proposed. Through the transmission of voice signals, pedestrians are reminded to enhance safety and reduce the probability of dangerous events. To solve the question of visible light sound communication based on white LEDs,a 9W white LEDcommunication system is designed which can realize 300~8000Hz sound signal transmission.Firstly,the paper gives the overall design scheme based on UART according to the requirements. Secondly, the hardware equipment is made.Finally,the program of MCU is designed.Tseting and practical application show that the communication distance is 30cm,the baud rate is 227kb/s,the sound power is 0.7w,the system reaches the design requirements

Over the past 50 years, a series of soil and water conservation measures have been implemented on the Loess Plateau, including biological, engineering, and agricultural measures. As a result, water discharge and sediment load on the plateau have undergone significant changes. In this study, we compared the water discharge and sediment load at more than 100 hydrological stations across the Loess Plateau during the period 2008–2016 (P2) with the water discharge and sediment load during the period 1971–1987 (P1), and detected the main sources of sediment in each of the two periods. We then performed an attribution analysis to quantify the influence of different factors on the changes in sediment load. We found the following results: (1) Water discharge was reduced by 22% in P2 compared with P1, whereas the sediment load was reduced by 74%. (2) Sediment resources are mainly concentrated between Toudaoguai and Tongguan stations: this region contributed more than 88% of the total sediment load at the terminal station (Huayuankou station) in both P1 and P2. (3) When considering only the changes in sediment concentration on the Loess Plateau, we conclude that the contribution of human activities was greater than 72%. This study provides a detailed description of the temporal and spatial variations in water and sediment across the Loess Plateau, providing a reliable reference for the future development of ecological soil and water conservation measures on the Loess Plateau.

The issue of how to achieve removal of recently accumulated sediment is one of the largest unresolved puzzles in China's lower Yellow River. In this work, the feasibility and sustainability of achieving full-stream erosion in the lower Yellow River based on a water-sediment regulation scheme (WSRS) have been comprehensively investigated. The results indicate that the erosion–deposition state of the lower Yellow River is controlled by the incoming flow discharge level and the corresponding sediment concentration. The year 1987 is identified as an abrupt change point for streamflow in Xiaolangdi station. The relationships between channel erosion or deposition and the sediment concentration of the incoming discharge are constructed for the periods 1960–1987 and 1988–2017. Based on a constrained optimization approach, a sediment concentration lower than 19.96 kg/m3 in the discharge from Xiaolangdi Reservoir is determined to be the critical controlling condition for achieving full-stream erosion in the lower Yellow River under the average discharge level observed during 1960–1987; however, it is challenging to achieve full-stream erosion under the average discharge level of 1988–2017. Although this erosion status could potentially be achieved through continued implementation of the WSRS, its sustainability is restricted by the declining storage capacity of Xiaolangdi Reservoir, decreasing water discharge levels and riverbed coarsening in the Yellow River. It is necessary to design cross-basin collaboration measures for the upper, middle and lower Yellow River to achieve sustainable sediment reduction and healthy development of the Yellow River basin as a whole.

The research and development of transition metal oxides based electrocatalysts with high activity and stability for both oxygen evolution reaction and hydrogen evolution reaction via a facile design strategy is of critical importance. Herein, we fulfill both significant oxygen evolution reaction and hydrogen evolution reaction improvement in activity by hierarchically nanostructured Ce-MnCo2O4 prepared by an oxalate coprecipitation method and a followed calcination process. X-ray photoelectron spectroscopy and transmission electron microscopy with energy-dispersive X-ray spectroscopy mappings analysis show that the hierarchically nanostructured Ce-MnCo2O4-3% sample is homogeneously modified by 1.49 wt % Ce with increased Co3+ species. We suspect that the introduction of suitable Ce content into MnCo2O4 facilitates the oxygen transfer and the formation of Co3+ species, and modifies the local chemical binding, resulting in active performance for oxygen evolution reaction (390 mV at 10 mA·cm–2 and a Tafel sl...

Autophagy captures intracellular components and delivers them to lysosomes, where they are degraded and recycled to sustain metabolism and to enable survival during starvation1-5. Acute, whole-body deletion of the essential autophagy gene Atg7 in adult mice causes a systemic metabolic defect that manifests as starvation intolerance and gradual loss of white adipose tissue, liver glycogen and muscle mass1. Cancer cells also benefit from autophagy. Deletion of essential autophagy genes impairs the metabolism, proliferation, survival and malignancy of spontaneous tumours in models of autochthonous cancer6,7. Acute, systemic deletion of Atg7 or acute, systemic expression of a dominant-negative ATG4b in mice induces greater regression of KRAS-driven cancers than does tumour-specific autophagy deletion, which suggests that host autophagy promotes tumour growth1,8. Here we show that host-specific deletion of Atg7 impairs the growth of multiple allografted tumours, although not all tumour lines were sensitive to host autophagy status. Loss of autophagy in the host was associated with a reduction in circulating arginine, and the sensitive tumour cell lines were arginine auxotrophs owing to the lack of expression of the enzyme argininosuccinate synthase 1. Serum proteomic analysis identified the arginine-degrading enzyme arginase I (ARG1) in the circulation of Atg7-deficient hosts, and in vivo arginine metabolic tracing demonstrated that serum arginine was degraded to ornithine. ARG1 is predominantly expressed in the liver and can be released from hepatocytes into the circulation. Liver-specific deletion of Atg7 produced circulating ARG1, and reduced both serum arginine and tumour growth. Deletion of Atg5 in the host similarly regulated [corrected] circulating arginine and suppressed tumorigenesis, which demonstrates that this phenotype is specific to autophagy function rather than to deletion of Atg7. Dietary supplementation of Atg7-deficient hosts with arginine partially restored levels of circulating arginine and tumour growth. Thus, defective autophagy in the host leads to the release of ARG1 from the liver and the degradation of circulating arginine, which is essential for tumour growth; this identifies a metabolic vulnerability of cancer.

Lysine acetylation is one of the most important post-translational modifications and is involved in multiple cellular processes in plants. There is evidence that acetylation may play an important role in light-induced de-etiolation, a key developmental switch from skotomorphogenesis to photomorphogenesis. During this transition, establishment of photosynthesis is of great significance. However, studies on acetylome dynamics during de-etiolation are limited. Here, we performed the first global lysine acetylome analysis for Zea mays seedlings undergoing de-etiolation, using nano liquid chromatography coupled to tandem mass spectrometry, and identified 814 lysine-acetylated sites on 462 proteins. Bioinformatics analysis of this acetylome showed that most of the lysine-acetylated proteins are predicted to be located in the cytoplasm, nucleus, chloroplast, and mitochondria. In addition, we detected ten lysine acetylation motifs and found that the accumulation of 482 lysine-acetylated peptides corresponding to 289 proteins changed significantly during de-etiolation. These proteins include transcription factors, histones, and proteins involved in chlorophyll synthesis, photosynthesis light reaction, carbon assimilation, glycolysis, the TCA cycle, amino acid metabolism, lipid metabolism, and nucleotide metabolism. Our study provides an in-depth dataset that extends our knowledge of in vivo acetylome dynamics during de-etiolation in monocots. This dataset promotes our understanding of the functional consequences of lysine acetylation in diverse cellular metabolic regulatory processes, and will be a useful toolkit for further investigations of the lysine acetylome and de-etiolation in plants.

Scientists are searching for the goal-directed methods to synthesize graphene nanoribbons (GNRs) with a particular edge type and width, which determines their electronic transport properties. A series of Li zigzag GNRs (ZGNRs) with different widths were predicted under high pressure with a stoichiometric ratio of Lin+1C2n, which indicates a route to prepare ultranarrow GNRs. Here, with thermodynamics and ab initio Gibbs free-energy calculations by quasi-harmonic approximation, we investigated the phase stabilities of the Li GNR compounds under high pressure and high temperature. We have also identified Li graphenide LiC2 (n = ∞) and Li polyacenide Li3C4 (n = 2) experimentally at the predicted pressure and temperature conditions using in situ X-ray diffraction, which can be recognized as the two end members of Lin+1C2n with the widest and narrowest ZGNR structures. High temperature and the temperature gradient increased the degree of polymerization and facilitated the formation of wider GNR or carbon slice...

A novel and facile post-grafting strategy, via a Schiff base chemical reaction between aldehyde and −NH2 groups within NH2-MIL-125(Ti) has been developed to construct aromatic heterocycle-grafted metal organic frameworks (MOFs) photocatalysts. The improved conjugated system in MOFs showed lower band gaps and their excellent catalytic activities were manifested by selective oxidation of alcohols to corresponding aldehydes under visible light irradiation with high conversion and selectivity. Density functional theory (DFT) was applied for simulating the band gaps and electron orbits of heterocycle-grafted MOFs. The post-synthetic aromatic heterocycles in the MOFs network did not influence the original framework, but effectively expanded its π-delocalized system and promoted the separation and transfer of photo-excited charge carriers. As a result, the aromatic heterocycle-grafted MOFs exhibit significantly enhanced visible-light photo-catalytic activity for selective oxidation of alcohols over pristine NH2-MIL-125(Ti). Especially, the NH2-MIL-125(Ti) grafted by 2-quinolinecarboxaldehyde and 3-thiophenecarboxaldehyde showed better performance (more than 85% conversion of benzyl alcohol) due to the excellent photon adsorption and charge carriers transfer of aromatic heterocycles grafted on MOFs. This general grafting strategy can be utilized to graft large numbers of aromatic rings with different molecular structures onto NH2-MIL-125(Ti).

A novel method is developed for constructing well-defined N-doped graphdiyne (GDY) nanostructures. This method can effectively tune the N-configurations (pyridinic N and triazine-like N cluster), N-content, and porous structures of GDYs, indicating good controllability. The N-configurations and structure of GDYs are well confirmed by the X-ray photoelectron spectrometer measurements, nitrogen absorption measurements and neutron pair distribution function (PDF), respectively. The as-prepared GDYs can be assembled into high-performance two-electrode supercapacitors with specific capacitance high up to 250 F g−1, delivering an energy density of 8.66 Wh kg−1 and power density of 19.3 kW kg−1; the well-defined N-configuration in GDYs offers us an opportunity to understand the controversial nitrogen role in catalyzing the oxygen reduction reaction in sp2 carbons. Importantly, this method for creating well-defined N-doped GDYs may widely extend the GDY materials for new energy fields.

The search for conjugated polymer photocatalysts for H2 production under visible light remains a key challenge. Reported herein is a conjugated polymer (i.e., melamine-terephthalaldehyde polymer (PMTPA)) derived from melamine and terephthalaldehyde precursors without an external solvent through a Schiff-base reaction. By adjusting the polymerization temperature, PMTPA with different sample colors and band gaps was obtained, which was further applied as a photocatalyst to investigate its activity in H2 evolution. A photocatalytic H2 evolution efficiency up to 58.1 μmol h−1 was observed over PMTPA polymerized at 250 °C under visible light (λ > 420 nm), which was about two times as high as that of C3N4. The Schiff-base reaction without external solvent conditions provides a facile strategy for the synthesis of conjugated polymeric semiconductors with better molecular engineering for advanced applications in the fields of catalysis, energy, and environmental remediation.

This paper mainly aims at frequent failures of a certain type aircraft and the shortage of aircraft spare parts, we selected typical data analysis methods and then draw the fault law, The purpose is to improve the application of the quality control fault information system, locate failure trends, types and characteristics Accurately, The purpose is provide accurate theoretical support for decision makers, and improve the applicability of quality control data.

In order to provide a reliable reference for utilizing Indonesia vanadium titano-magnetite (VTM) in blast furnace (BF) economically, metallurgical properties of iron ore sinter with addition of Indonesia VTM in mixed sintering materials were investigated, including low-temperature reduction degradation index (RDI), reducibility index (RI), and softening/melting properties. Additionally, influenced mechanism of Indonesia VTM on metallurgical properties of sinter was studied. It is found that adding Indonesia VTM in sintering process quickly increases the RDI of sinters, and decreases the RI from 78.02% to 68.43%. Moreover, both beginning temperature (T4) and final temperature (TD) of softening/melting increase gradually, and cohesive zone temperature range (TD–T4) enlarges from 219 oC to 315 oC. As a result, the permeability of cohesive zone gets worse, which is proven by the higher maximum pressure drop (δPmax) in softening/melting experiments. It is concluded that, after comprehensively considering all metallurgical properties mentioned above, the proper proportion of Indonesia VTM in sintering process is proposed in the new raw materials conditions.

This paper considers the fast and effective solving method for the unit commitment (UC) problem with wind curtailment and pollutant emission in power systems. Firstly, a suitable mixed-integer quadratic programming (MIQP) model of the corresponding UC problem is presented by some linearization techniques, which is difficult to solve directly. Then, the MIQP model is solved by the outer approximation method (OAM), which decomposes the MIQP into a mixed-integer linear programming (MILP) master problem and a nonlinear programming (NLP) subproblem for alternate iterative solving. Finally, simulation results for six systems with up to 100 thermal units and one wind unit in 24 periods are presented, which show the practicality of MIQP model and the effectiveness of OAM.

Oxytocin and vasopressin are neurohypophyseal hormones with sequence similarity and play a central role in bodily homeostatic regulation. Pain is currently understood to be an important phenotype that those two neurohormones strongly downregulate. Nociceptors, the first component of the ascending neural circuit for pain signals, have constantly been shown to be modulated by those peptides. The nociceptor modulation appears to be critical in pain attenuation, which has led to a gradual increase in scientific interest about their physiological processes and also drawn attention to their translational potentials. This review focused on what are recently understood and stay under investigation in the functional modulation of nociceptors by oxytocin and vasopressin. Effort to produce a nociceptor-specific view could help to construct a more systematic picture of the peripheral pain modulation by oxytocin and vasopressin.

Developing efficient non-noble metal and earth-abundant electrocatalysts with tunable microstructure for overall water-splitting is critical to promote the clean-energy technologies for hydrogen economy. Herein, novel three-dimensional (3D) flower-like Ni2P composed by mesoporous nanoplates with controllable morphology and high surface area was prepared by a hydrothermal method and low-temperature phosphidation as efficient electrocatalysts for hydrogen evolution reaction (HER) and oxygen evolution reaction (OER). Comparing with the scamps-like NixPy, the 3D flower-like Ni2P with a diameter of 5 μm presented efficient and stable catalytic performance in 0.5 M H2SO4, with a small Tefal slope of 79 mV dec-1 and an overpotential of ~ 240 mV at a current density of 10 mA cm-2 with a mass loading density of 0.283 mg cm-2. Besides, the catalyst also exhibited a remarkable performance for OER in 1.0 M KOH electrolyte, with the overpotential of 320 mV to reach current density of 10 mA cm-2 and a small Tafel slope of 72 mV dec-1. The excellent catalytic performance of as-prepared Ni2P may be ascribed to its novel 3D morphology with unique mesoporous structure

Clinical trials have been conducted for the neuronal ceroid lipofuscinoses (NCLs), a group of neurodegenerative lysosomal diseases that primarily affect children. Whereas clinical rating systems will evaluate long-term efficacy, biomarkers to measure short-term response to treatment would be extremely valuable. To identify candidate biomarkers, we analyzed autopsy brain and matching CSF samples from controls and three genetically distinct NCLs due to deficiencies in palmitoyl protein thioesterase 1 (CLN1 disease), tripeptidyl peptidase 1 (CLN2 disease), and CLN3 protein (CLN3 disease). Proteomic and biochemical methods were used to analyze lysosomal proteins, and, in general, we find that changes in protein expression compared with control were most similar between CLN2 disease and CLN3 disease. This is consistent with previous observations of biochemical similarities between these diseases. We also conducted unbiased proteomic analyses of CSF and brain using isobaric labeling/quantitative mass spectrometry. Significant alterations in protein expression were identified in each NCL, including reduced STXBP1 in CLN1 disease brain. Given the confounding variable of post-mortem changes, additional validation is required, but this study provides a useful starting set of candidate NCL biomarkers for further evaluation.

Li2C2 has the highest theoretical capacity (1400 mA·h·g–1) as the electrode material for Li-ion battery, but suffers from low conductivity. Here we found that under external pressure its conductivity was irreversibly enhanced by 109-fold. To explain that, we performed X-ray diffraction, Raman, IR, gas chromatography–mass spectrometry, and theoretical investigations under external pressure. We found that the C22– anions approached to each other and polymerized upon compression, which is responsible for the irreversible enhancement of conductivity. The polymer has a ribbon structure and disproportionates into Li3C4 (Li2–0.5C2) ribbon structure, Li6C3 (Li propenide) and Li4C3 (Li allenide) upon decompression, implying that the carbon skeletal is highly electrochemically active. Our work reported polymerized Li2C2 for the first time, demonstrated that applying pressure is an effective method to prepare novel Li–C frameworks, and hence shed light on the search for novel carbon-based electrode materials.