Search

Chronic kidney disease (CKD) is a condition characterized by functional deterioration with sustained inflammation and progressive fibrosis of the kidneys affecting over 800 million people worldwide. The P2X7 receptor (P2X7R) plays a key role in CKD progression. Our previous P2X7R antagonists demonstrated good efficacy for treating kidney injury but were limited by low oral exposure and short half-life, restricting their application. This study reports the optimization of P2X7R antagonists for better oral pharmacokinetics. The candidate compound 13awith the respective IC50of 34.86 and 25.28 nM against human and murine P2X7R, administered orally at 10 mg/kg in mice, exhibits a remarkably long half-life of 161.64 h, with a high exposure of 1,163,980.55 μg·h/L. Oral administration of 13a(0.3 or 1.0 mg/kg, twice weekly) significantly reduced renal injury and fibrosis in unilateral ureteral obstruction and adenine diet-induced mice models, highlighting its potential for delaying the progression of CKD.

Remote sensing images can accurately display the electromagnetic attribute distribution of various ground objects and can be used in many applications. Nevertheless, stripe noise frequently degrades the quality of the captured images. Most current destriping studies are capable of removing the regular stripe noise. However, their outputs often produce a stripe residual or oversmoothing effect when a complex stripe noise exists. To overcome this limitation, in this article, we propose a variational destriping model based on nonconvex regularization and variable weights. First, our model constrains the stripe sparsity using the normalized $\epsilon $ -penalty function and converts it into weighted $\ell _{1}$ norm by $\ell _{1}$ majorization method. Second, unlike previous models that use scalar smoothing weights to control the output smoothness, we propose to design adaptive vector weights to constrain the smoothness. Moreover, the proposed model introduces the region weight to deal with the extreme regions. In view of the region decomposition technique, we transform our optimization model into a series of 1-D weighted $\ell _{1}$ problems in different directions with a linear time solver. Then, an improved alternating direction method is employed to provide fast convergence. The experimental results show that our method achieves a better performance on image detail preservation, complex stripe removal, and a faster convergence than the state-of-the-art methods.

Besides providing energy to sustain life, mitochondria also play crucial roles in stress response and programmed cell death. The mitochondrial hallmark lipid, cardiolipin (CL), is essential to the maintenance of mitochondrial structure and function. However, how mitochondria and CL are involved in stress response is not as well defined in plants as in animal and yeast cells. We previously revealed a role for CL in mitochondrial fission and in heat stress response in Arabidopsis. To further determine the involvement of mitochondria and CL in plant heat response, here we treated Arabidopsisseedlings with varied lengths of acute heat stress. These treatments resulted in decreases in mitochondrial membrane potential, disruption of mitochondrial ultrastructure, accumulation of mitochondrial reactive-oxygen species (ROS), and redistribution of CL to the outer mitochondrial membrane and to a novel type of vesicle. The level of the observed changes correlated with the severeness of the heat stress, indicating the strong relevance of these processes to stress response. Our findings provide the basis for studying mechanisms underpinning the role of mitochondria and CL in plant stress response.

Cotton is a major crop that provides the most important renewable textile fibers in the world. Studies of the taxonomy and evolution of cotton species have received wide attentions, not only due to cotton’s economic value but also due to the fact that Gossypiumis an ideal model system to study the origin, evolution, and cultivation of polyploid species. Previous studies suggested the involvement of mitochondrial genome editing sites and copy number as well as mitochondrial functions in cotton fiber elongation. Whereas, with only a few mitogenomes assembled in the cotton genus Gossypium, our knowledge about their roles in cotton evolution and speciation is still scarce. To close this gap, here we assembled 20 mitogenomes from 15 cotton species spanning all the cotton clades (A–G, K, and AD genomes) and 5 cotton relatives using short and long sequencing reads. Systematic analyses uncovered a high level of mitochondrial gene sequence conservation, abundant sequence repeats and many insertions of foreign sequences, as well as extensive structural variations in cotton mitogenomes. The sequence repeats and foreign sequences caused significant mitogenome size inflation in Gossypiumand its close relative Kokiain general, while there is no significant difference between the lint and fuzz cotton mitogenomes in terms of gene content, RNA editing, and gene expression level. Interestingly, we further revealed the specific presence and expression of two novel mitochondrial open reading frames (ORFs) in lint-fiber cotton species. Finally, these structural features and novel ORFs help us gain valuable insights into the history of cotton evolution and polyploidization and the origin of species producing long lint fibers from a mitogenomic perspective.

The fiber Bragg grating (FBG) temperature measurement technology has advantages, such as high accuracy, small size, anti-interference, and stable performance compared to traditional thermocouple technology in high-speed airflow total temperature testing. However, low recovery factors of FBG total temperature probes at low Mach numbers have been reported, which is very detrimental to improving the accuracy of the total temperature measurement. In this article, a 3-D structure model of FBG total temperature probe is established based on the characteristics of fiber as the temperature sensing element. The temperature distribution under different probe structural parameters, such as the inner diameter of the shield, the position, and length of FBG, is analyzed using conjugate heat transfer (CHT) multiphysics field model. Combined with coupled-mode theory, the spectral characteristics of different FBG parameters and their effects on the recovery factor are analyzed. The structure of FBG total temperature probe with high recovery factor is designed. The comparative experimental results of high-speed airflow show that the improved FBG total temperature probe has a recovery factor exceeding 0.92 from Mach number 0.3–0.8 and up to 0.99 at Mach number greater than 0.4, which has even exceeded the level of most traditional thermocouple total temperature probes.

ABSTRACTThis study aimed to evaluate how the duration of travel affects the behavior of urban and rural residents regarding free COVID-19 vaccination, and provide scientific evidence for promoting free vaccination and building an immune barrier to cope with future epidemics. From August 3, 2022 to February,18,2023, A follow-up survey was conducted in urban and rural adults in four cities in China to collect information on socio-demographic factors, vaccination status and travel time for vaccination. Propensity score matching (PSM) analysis was deployed to measure the net difference of the enhanced vaccination rate between urban and rural residents in different traffic time distribution. A total of 5780 samples were included in the study. The vaccination rate of the booster dose of COVID-19 vaccine among rural residents was higher than that of urban residents with a significant P-value (69.36% VS 64.49%,p < .001). The traffic time had a significant negative impact on the COVID-19 booster vaccination behavior of urban and rural residents. There was a significant interaction between the travel time to the vaccination point and the level of trust in doctors. Travel time had a negative impact on the free vaccination behavior of both urban and rural residents. The government should optimize and expand the number of vaccination sites and enhance residents’ trust in the medical system. This is crucial for promoting free vaccination and effective epidemic management in the future.

ABSTRACTDuring the COVID-19 pandemic, the vaccine hesitancy has significantly affected the vaccination. To evaluate the booster vaccine hesitancy and its influencing factors among urban and rural residents, as well as to estimate the net difference of booster vaccine hesitancy between urban and rural residents. We conducted a nationwide, cross-sectional Internet survey on 1–8 February 2023, and employed stratified random sampling technique to select participants (≥18 years old) from urban and rural areas. Multivariate logistic regression was used to determine the factors impacting booster vaccine hesitancy. Propensity Score Matching was used to estimate the net difference of COVID-19 booster vaccine hesitancy between urban and rural residents. The overall COVID-19 booster vaccine hesitancy rate of residents was 28.43%. The COVID-19 booster vaccine hesitancy rate among urban residents was found to be 34.70%, among rural residents was 20.25%. Chronic diseases, infection status, vaccination benefits, and trust in vaccine developers were associated with booster vaccine hesitancy among urban residents. Barriers of vaccination were associated with booster vaccine hesitancy among rural residents. PSM analysis showed that the urban residents have a higher booster vaccine hesitancy rate than rural residents, with a net difference of 6.20%. The vaccine hesitancy rate increased significantly, and the urban residents have a higher COVID-19 booster vaccine hesitancy than rural residents. It becomes crucial to enhance the dissemination of information regarding the advantages of vaccination and foster greater trust among urban residents toward the healthcare system.

For phosphorescent materials, managing the triplet potential energy surface stands for controlling the phosphorescence quantum yield. However, due to the complexity and variability, the triplet potential energy surface can be managed with difficulty. In this work, a series of bimetallic Pt(II) complexes, namely Pt-1, Pt-1-1, Pt-1-2, Pt-2, Pt-3–5, and Pt-6–7, are employed as models to construct a relationship between the structures and triplet potential energy surfaces, aiming to achieve meaningful information to manage the triplet potential energy surface. On the basis of the results, it is observed that the triplet potential energy surface has an intimate connection with the structures of bimetallic Pt(II) complexes. In the case of the primordial Pt(II) complex, the triplet potential energy surface consists of two minimal points, illustrating various properties, which can largely affect the phosphorescence quantum yield. Once the intramolecular steric hindrance, restriction effect, and metallophilic interaction (Pt–Pd/Pd–Pd) are employed by tailoring the structures of primordial Pt(II) complexes, the triplet potential energy surface can be reconstructed via one minimal point-charactered short metal–metal distance, resulting in different photophysical properties. The relationship between the triplet potential energy surface and structure is essentially unveiled from the structural and electronic viewpoints. The conclusions originated from the structural and electronic investigations can be regarded as indicators to accurately and expediently predict the triplet potential energy surfaces of bimetallic Pt(II) complexes. The results presented here are helpful in addressing the designed strategies as they show that the triplet potential energy surfaces of bimetallic Pt(II) complexes can be properly tuned.

The impact of high-energy electron beam irradiation on silicone rubber composite insulator is investigated in this article. It was discovered that as the irradiation dose increased, the related properties of silicone rubber increased first and then decreased, with the static contact angle increasing to 111.8°, the tensile strength increasing to 4.59 MPa, the tear strength increasing to 26.8 kN/m, and the crosslinking density increasing to $7.09\times 10^{-{4}}$ mol/cm3, but the elongation decreasing. SEM observation revealed that silicone rubber was more compact after irradiation. attenuated total reflection-Fourier transform infrared spectroscopy (ATR-FTIR) and X-ray photoelectron spectroscopy (XPS) studies revealed that when the irradiation dose increased, the irradiation of silicone rubber shifted from crosslinking to degradation, and a new Si(−O)4 structure formed. Considering comprehensive performances, 40–50 kGy is the optimal irradiation dose. This article can provide support for understanding the irradiation modification of silicone rubber materials for composite insulator and also guide the preparation method of new silicone rubber.

Although numerous studies indicate that inhibition of USP7 suppresses tumor growth by activating p53, the precise mechanism by which USP7 contributes to tumor growth through the p53-independent manner is not well understood. p53 is frequently mutated in most triple-negative breast cancers (TNBC), characterized as the very aggressive form of breast cancers with limited treatment options and poor patient outcomes. Here, we found that the oncoprotein Forkhead Box M1 (FOXM1) acts as a potential driver for tumor growth in TNBC and, surprisingly, through a proteomic screen, we identified USP7 as a major regulator of FOXM1 in TNBC cells. USP7 interacts with FOXM1 both in vitro and in vivo. USP7 stabilizes FOXM1 through deubiquitination. Conversely, RNAi-mediated USP7 knockdown in TNBC cells, dramatically reduced the levels of FOXM1. Moreover, based upon the proteolysis targeting chimera (PROTAC) technology, we generated PU7-1 (protein degrader for USP7-1), as a USP7 specific degrader. PU7-1 induces rapid USP7 degradation at low nanomolar concentrations in cells but shows no obvious effect on other USP family proteins. Strikingly, the treatment of TNBC cells with PU7-1 significantly abrogates FOXM1 functions and effectively suppresses cell growth in vitro. By using xenograft mouse models, we found that PU7-1 markedly represses tumor growth in vivo. Notably, ectopic overexpression of FOXM1 can reverse the tumor growth suppressive effects induced by PU7-1, underscored the specific effect on FOXM1 induced by USP7 inactivation. Together, our findings indicate that FOXM1 is a major target of USP7 in modulating tumor growth in a p53-independent manner and reveals the USP7 degrader as a potential therapeutic tool for the treatment of triple-negative breast cancers.

Myopia has become a major public health issue with an increasing prevalence. There are still individuals who experience similar environmental risk factors and, yet, remain non-myopic. Thus, there might be genetic factors protecting people from myopia. Considering the opposite ocular characteristics of primary angle closure glaucoma (PACG) to myopia and possible common pathway between them, we propose that certain risk genes for PACG might act as a protective factor for myopia. In this study, 2,678 young adults were genotyped for 37 targeted single nucleotide polymorphisms. Compared with emmetropia, rs1401999 (allele C: OR=0.795, P=0.03; genotype in dominant model: OR=0.759, P=0.02) and rs1258267 (allele A: OR=0.824, P=0.03; genotype in dominant model: OR=0.603, P=0.01) were associated with low to moderate myopia and high myopia, respectively. Genotype under recessive model of rs11024102 was correlated with myopia (OR=1.456, P=0.01), low to moderate myopia (OR=1.443, P=0.02) and high myopia (OR=1.453, P=0.02). However, these associations did not survive Bonferroni correction. Moreover, rs1401999, rs1258267, and rs11024102 showed associations with certain ocular biometric parameters in different groups. Our study suggests that ABCC5, CHATand PLEKHA7might be associated with refractive errors by contributing to the regulation of ocular biometry, in terms of uncorrected results and their biological functions.

The human equilibrative nucleoside transporter 1 (hENT1) is an effective controller of adenosine signaling by regulating its extracellular and intracellular concentration, and has become a solid drug target of clinical used adenosine reuptake inhibitors (AdoRIs). Currently, the mechanisms of adenosine transport and inhibition for hENT1 remain unclear, which greatly limits the in-depth understanding of its inner workings as well as the development of novel inhibitors. In this work, the dynamic details of hENT1 underlie adenosine transport and the inhibition mechanism of the non-nucleoside AdoRIs dilazep both were investigated by comparative long-time unbiased molecular dynamics simulations. The calculation results show that the conformational transitions of hENT1 from the outward open to metastable occluded state are mainly driven by TM1, TM2, TM7 and TM9. One of the trimethoxyphenyl rings in dilazep serves as the adenosyl moiety of the endogenous adenosine substrate to competitively occupy the orthosteric site of hENT1. Due to extensive and various VDWinteractions with N30, M33, M84, P308 and F334, the other trimethoxyphenyl ring is stuck in the opportunistic site near the extracellular side preventing the complete occlusion of thin gate simultaneously. Obviously, dilazep shows significant inhibitory activity by disrupting the local induce-fit action in substrate binding cavity and blocking the transport cycle of whole protein. This study not only reveals the nucleoside transport mechanism by hENT1 at atomic level, but also provides structural guidance for the subsequent design of novel non-nucleoside AdoRIs with enhanced pharmacologic properties.

This paper proposes a new-designed rim seal configuration with sealing holes based on the conventional radial rim seal, and presents a numerical comparison of the sealing performance between the conventional sealing flow supply configuration and the new sealing flow supply configuration with holes at different sealing flow rates. The sealing effectiveness and unsteady flow yields at the rim seal are numerically simulated by using the URANS method and SST turbulent model from ANSYS CFX. The influence of the new sealing flow supply configuration on the sealing effectiveness at different sealing flow rates is determined. The effectiveness of different sealing flow rates in the conventional rim seal is also studied. As to the conventional rim seal, the increase in the sealing flow rate reduces the degree of gas ingestion induced by the effect of mainstream ingress at the rim clearance, while the unsteady flow characteristics are enhanced, and the number and amplitude of the low-frequency signals increase. The position of the Kelvin-Helmholtz instabilities vortex structures is left by the increased sealing flow rate, and its strength is suppressed. Compared with the conventional rim seal configuration, the new sealing flow supply configuration with holes could reduce the sealing efficiency by 5.06% at most at sealing flow distribution m1:m2=3:1 when Cw=2000, and improve the sealing efficiency by 11.71% at most at sealing flow distribution m1:m2=1:1 when Cw=7500. It shows that the lateral jet from the holes induces a larger-scale Kelvin-Helmholtz vortex structure at Cw=2000, thus the sealing efficiency in the wheel space is also reduced. However, the size of the Kelvin-Helmholtz vortex structures is significantly suppressed by the new sealing flow supply configuration at Cw=7500, which is beneficial to improving the sealing effectiveness of the conventional rim seal.

Let RRbe a unital associative ring. Our motivation is to prove that left derivations in column finite matrix rings over RRare equal to zero and demonstrate that a left derivation d:T→Td:{\mathcal{T}}\to {\mathcal{T}}in the infinite upper triangular matrix ring T{\mathcal{T}}is determined by left derivations dj{d}_{j}in R(j=1,2,…)R\left(j=1,2,\ldots )satisfying d((aij))=(bij)d\left(\left({a}_{ij}))=\left({b}_{ij})for any (aij)∈T\left({a}_{ij})\in {\mathcal{T}}, where bij=dj(a11),i=1,0,i≠1.{b}_{ij}=\left\{\begin{array}{ll}{d}_{j}\left({a}_{11}),& i=1,\\ 0,& i\ne 1.\end{array}\right.The similar results about Jordan left derivations are also obtained when RRis 2-torsion free.

•Low expression of NT5DC2 predicts a favorable prognosis in soft tissue sarcoma.•Downregulated NT5DC2 expression can inhibit soft tissue sarcoma progression.•NT5DC2 acts through the ECM-receptor interaction pathway in soft tissue sarcoma.

Tuberculosis (TB) remains a serious threat to whole human health. In particular, the drug resistance of Mycobacterium tuberculosis (Mtb) has become a huge challenge in clinical medicine, and it is extremely urgent to develop effective inhibitors with novel structures and mechanisms. Belonging to the Resistance, Nodulation and Division (RND) superfamily, Mycobacterial membrane proteins Large 3 (MmpL3) is mainly responsible for transporting mycolic acid outside cell membrane to form cell wall, and plays critical roles in iron acquisition which is vital to the survival of Mtb. As a potential Mtb target in recent years, its inhibitor research has attracted wide attention. A series of inhibitors (such as SQ109, AU1235, BM212, etc.) through experimental screening have been reported in succession, especially SQ109 has entered the clinical stage. In this paper, the structural biology information of target MmpL3 was summarized, and the structure-activity relationship (SAR) of inhibitors reported in recent years and their inhibitory mechanism both were reviewed, aiming to provide help for the rational design of MmpL3 inhibitors in the future.

ABSTRACTIn this work, we reported a facile method to fabricate highly stable superhydrophobic coatings via blending two kinds of nanoparticles and crosslinked fluorosilanes. Simultaneous use of nano-TiO2and hydrophobic nano-SiO2cannot only synergistically construct multi-scale roughness structures on the superhydrophobic surfaces, but also greatly improve the hydrophobic stability of the superhydrophobic coatings. It was found that the water contact angle and contact angle hysteresis of the as-prepared coatings were, respectively, 166.6° and 3.4°. Owing to the excellent properties of crosslinked fluorosilanes, the composite coatings also exhibited good thermal stability, chemical stability and self-cleaning property. Owing to its flexibility and simplicity, the method is a facile and inexpensive way to achieve the lotus effect and exhibits high values in practical application.

ABSTRACTHypoxia, a strong and selective pressure, has been involved in invasion, metastasis, and angiogenesis of tumor cells. Our study performed the transcriptome profiles of 666 non-small-cell lung cancer (NSCLC) patients. Various bioinformatic approaches were combined to evaluate the immune cell infiltration in the high hypoxia risk patients. In addition, in vitro experiments were performed to assess the effects of tumor-associated neutrophils (TANs) on NSCLC cells proliferation, migration and invasion and to reveal the underlying mechanisms. We divided NSCLC into two groups (Cluster1/2) based on the expression profiles of hypoxia-associated genes. Compared with the Cluster1 subgroup, the Cluster2 had a worse prognosis. Significant enrichment analysis revealed that PI3K/AKT/mTOR signaling pathway and TANs were highly related to hypoxia microenvironment. Eleven hypoxia-related genes (FBP1, NDST2, ADM, LDHA, DDIT4, EXT1, BCAN, IGFBP1, PDGFB, AKAP12, and CDKN3) were scored by LASSO COX regression to yield risk scores, and we revealed a significant difference in overall survival (OS) between the low- and high-risk groups. Mechanistically, CXCL6 in hypoxic cancer cells promoted the migration of TANs in vitro, and in turn promote NSCLC cells proliferation, migration and invasion. In summary, this study revealed a 11‐hypoxia gene signature that predicted OS of NSCLC patients, and improved our understanding of the role of TANs in hypoxia microenvironment.

In this study, a computational fluid dynamics approach based on solving the Reynolds-averaged Navier-Stokes equation and shear stress transport (SST) (Menter) k-ω turbulence model is used to solve the rotor in ground effect. A discrete element method based on solving the Hertz-Mindlin (no-slip) contact model and considering the real physical properties and collision is used to solve the motion and distribution of sediment particles in the field. By coupling the two approaches, the dust cloud development in the ground-effect flow field of a helicopter with rectangular-tip and slotted-tip blades is simulated for six seconds. The characteristics of the flow field are analyzed, and the influence of the flow field generated by the two types of blades on the movement and distribution of sediment particles on the ground and the subsequent dust cloud development over time are compared. The relatively long time of numerical results show that the sediment particles initially located on the ground are uplifted by the interaction between the blade tip vortex and the ground. Over time, the particles become more concentrated around the tip vortex core. The sediment particles in the dust cloud move primarily in the radial and axial directions of the rotation center, and the circumferential movement is not significant. The optimized slotted-tip blade provides better dissipation of the tip vortex core intensity near the ground than the rectangular-tip blade, thus weakening the entrainment effect of the sediment particles on the ground and reducing the dust cloud concentration around the disc plane.

Previously, we reported a first-in-class von Hippel–Lindau (VHL)-recruiting mitogen-activated protein kinase kinases 1 and 2 (MEK1/2) degrader, MS432. To date, only two MEK1/2 degrader papers have been published and very limited structure–activity relationships (SAR) have been reported. Here, we describe our extensive SAR studies exploring both von Hippel–Lindau (VHL) and cereblon (CRBN) E3 ligase ligands and a variety of linkers, which resulted in two novel, improved VHL-recruiting MEK1/2 degraders, 24(MS928) and 27(MS934), and the first CRBN-recruiting MEK1/2 degrader 50(MS910). These compounds potently and selectively degraded MEK1/2 by hijacking the ubiquitin-proteasome system, inhibited downstream signaling, and suppressed cancer cell proliferation. Furthermore, concurrent inhibition of BRAF or PI3K significantly potentiated the antitumor activity of degrader 27, suggesting that the combination of MEK1/2 degradation with BRAF or PI3K inhibition may provide potential therapeutic benefits. Finally, besides being more potent, degrader 27displayed improved plasma exposure levels in mice, representing the best MEK1/2 degrader to date for in vivo studies.

An image encryption scheme based on the quick response (QR) code as a data container has aroused wide interest due to the lossless recovery of the decrypted image. In this paper, we apply this method to multi-image encryption. However, since the decrypted image is affected by crosstalk noise, the number of multi-image encryptions is severely limited. To solve this problem, we analyzed the performance of QR code as a data container, and processed the decrypted QR code using the proposed method, so that the number of multi-image encryptions is effectively increased. Finally, we implemented a large image (256 × 256) encryption and decryption.

During the transient state of aero-engine, cavity has evidently transient characteristics in the secondary air system. To investigate transient characteristics, theoretical and experimental studies were implemented for both static and rotating cavities. First of all, the typical transient response phenomena in secondary air system were investigated based on the basic concepts of the dynamic process. According to the basic theory of gas dynamics, the causes of transient phenomena were analyzed in two aspects, external disturbance, and system physical properties. Several dimensionless parameters were introduced to analyze the transient response characteristics of air system. Second, the experimental results of the static cavity indicated that the actual response time increased with the increase of the inlet pressure. The experimental results of the rotor-stator cavity showed that the low rotational speed on the response process had little effect, and the response time gradually increased when the speed continued to increase. Third, the test results of multiple components suggested that when the valve was opening the inlet pressure of the static cavity increased quickly and then reached a stable value, but the pressure of the static cavity, stable pressure cavity and rotor-stator chamber rose gradually. It was also obtained the actual response time of them was increased. The closer the measuring points were to the disturbance source, the shorter the delay time was.

MEK1 and MEK2 (also known as MAP2K1 and MAP2K2) are the “gatekeepers” of the ERK signaling output with redundant roles in controlling ERK activity. Numerous inhibitors targeting MEK1/2 have been developed including three FDA-approved drugs. However, acquired resistance to MEK1/2 inhibitors has been observed in patients, and new therapeutic strategies are needed to overcome the resistance. Here, we report a first-in-class degrader of MEK1/2, MS432 (23), which potently and selectively degraded MEK1 and MEK2 in a VHL E3 ligase- and proteasome-dependent manner and suppressed ERK phosphorylation in cells. It inhibited colorectal cancer and melanoma cell proliferation much more effectively than its negative control MS432N (24), and its effect was phenocopied by MEK1/2 knockdown. Compound 23was highly selective for MEK1/2 in global proteomic profiling studies. It was also bioavailable in mice and can be used for in vivo efficacy studies. We provide two well-characterized chemical tools to the biomedical community.

BRD4 has recently emerged as a promising drug target. Therefore, identifying novel inhibitors with distinct properties could enrich their use in anticancer treatment. Guided by the cocrystal structure of hit compound 4harboring a five-membered-ring linker motif, we quickly identified lead compound 7, which exhibited good antitumor effects in an MM.1S xenograft model by oral administration. Encouraged by its high potency and interesting scaffold, we performed further lead optimization to generate a novel potent series of bromodomain and extra-terminal (BET) inhibitors with a (1,2,4-triazol-5-yl)-3,4-dihydroquinoxalin-2(1H)-one structure. Among them, compound 19was found to have the best balance of activity, stability, and antitumor efficacy. After confirming its low brain penetration, we conducted comprehensive preclinical studies, including a multiple-species pharmacokinetics profile, extensive cellular mechanism studies, hERG assay, and in vivo antitumor growth effect testing, and we found that compound 19is a potential BET protein drug candidate for the treatment of cancer.

We present a novel design of optical nanostructure for efficient light extraction from nitrogen vacancy (NV) center in diamond. Numerical simulations of the optimal structure exhibit significant collection efficiency along with a stable radiation profile. We achieved a photon collection efficiency of 70% even with a lower numerical aperture of 0.5. Two different approaches (simple cone and encapsulated cone) have been adopted to reach a high geometrical tolerance without affecting much to the efficiency and emission profile. Besides that, our structure adds an extra benefit in terms of emission enhancement near zero phonon line (ZPL) region of NV spectra. Overall, this cone shaped diamond structure provides a robust, highly efficient and directional emission which can be integrated with a quantum optical network for various applications.

Testing a seed drill indoors can save a great amount of time and labour force. Conventional seeding-performance test rigs usually need at least two people to operate it. Thus, a small size test rig with an automatic control system need to be developed. In this research, a control system was designed firstly. After that, rotation speed of seed-metering shaft were simulated by Simulink and the parameters of the control algorithm were obtained. Moreover, an experiment were conducted to calibrate the seed mass discharged in per cycle rotated by seed-metering shaft. According to the experimental results, the average seed mass in per cycle was 12.61 g. In each validating experiment, the value that the theoretical seed mass subtracted the actual one and then divided the theoretical seed mass was seen as the error percentage of seed mass. Furthermore, 100% subtracted the error percentage was viewed as the accuracy of seed mass. The results showed that all accuracies of seed mass were higher than 82%, and the average accuracy of total experiments was 89.12%. Furthermore, t-test results showed that there was not significant difference between the actual seed masses and the theoretical ones. According to the statistical results, we can conclude that the control system can be applied on seeding-performance test rigs with an desirable performance.

China is the world's largest consumer of tobacco and has a large smoking-related chronic disease burden. In this nationwide study, we aimed to evaluate smoking prevalence and its implication on chronic diseases in the Chinese population.

Background: We initiated a retrospective study on ankle fractures to assess (1) the time needed for fracture union; (2) the incidence of adverse radiographic outcomes (AROs); (3) factors that might lead to AROs; and (4) whether AROs were associated with worse function and higher incidence of post-trauma osteoarthritis (PTOA).Methods: From 2007 to 2016, a total of 296 patients (169 women, 127 men; average age, 48.6 years; range, 20-84) were diagnosed with a medial malleolar fracture, whether isolated or in the setting of bi- or trimalleolar fractures, and underwent open reduction and internal fixation (ORIF) or percutaneous screw fixation (PSF). The interval to fracture union, radiographic outcomes, American Orthopaedic Foot & Ankle Society (AOFAS) score at 6 months postoperatively, and the incidence of PTOA were recorded. Risk factors were identified both in univariate and multivariate analysis. The average follow-up period was 52.0 months (range, 12-118).Results: The incidence of delayed union, nonunion, and malunion were 20.3%, 3.7%, and 4.4%, respectively. The interval to fracture union was 10.3 ± 6.4 weeks. In the multivariate analysis, the risk factors for AROs were tobacco use, vertical fractures, interposed soft tissue, and fair/poor reduction. Patients with AROs had significantly worse AOFAS score at 6 months postoperatively (P< .001) and higher incidence of PTOA (P< .001).Conclusion: AROs of medial malleolar fractures have an underestimated incidence rate and are associated with worse ankle function and higher incidence of PTOA. Risk factors including tobacco use, vertical fractures, interposed soft tissue, poor/fair reduction should be prudently taken into consideration when treating medial malleolar fractures.Level of Evidence: Level III, retrospective cohort study.

Wildfires near transmission lines are important disasters that affect power transmission. Water mist is a highly efficient method for suppressing wildfires near electrical transmission lines, where it avoids line-tripping to ensure the safety of the grid. However, few studies have investigated the electrical safety during the water mist extinguishing process, including the risk of tripping transmission lines and the shock hazard for users. In this study, we systematically studied the influence of the gap distance and the electric conductivity of the water solution on the insulation characteristics of water mist with a Dv0.99diameter of the droplets of ca. 500 µm, including the breakdown voltage and leakage current. Furthermore, we investigated the effect of water mist on the development of a long-gap discharge, and the insulation mechanism of water mist was also considered. Finally, water mist with multi-component additives was employed for suppressing wildfires near transmission lines in China, and we demonstrated the effectiveness of this method based on the reduction of line-tripping accidents caused by wildfires near transmission lines.

Despite its rapid advancement in the past two decades, bidimensional empirical mode decomposition (BEMD) still has several limitations in multi-scale feature description of input images. To ameliorate this issue, in this paper we present several optimization-based approaches to BEMD. First, we articulate an improved unconstrained optimization approach to BEMD (IUOA-BEMD). The essential idea is to formulate an optimization model to decompose an input image based on the Delaunay triangulation of its local maxima (minima). Second, we design a scale-guided optimization approach to BEMD (SGO-BEMD) so as to arrive at an improved modal image. SGO-BEMD uses the initial modal image (obtained from the aforementioned proposed IUOA-BEMD) as a necessary guide and can capture much clearer features at various spatial scales of the input image. In addition, an additional edge-preserving property can be obtained with the edge-aware decomposition if an edge-aware scale-guided optimization to BEMD (EASGO-BEMD) is used. The visualization and quantitative results for many artificial amplitude-modulated–frequency-modulated (AM-FM) images and real images have shown that the newly-proposed methods are very competitive with state-of-the-art BEMD methods. Moreover, we further evaluate the performance of BEMD methods according to their applications in image detail enhancement and image contrast & brightness enhancement. It may be noted that image contrast & brightness enhancement represents the first attempt to integrate BEMD with Retinex theory. Collectively, both types of enhancement validate the utility of the novel optimization-based approaches to BEMD proposed herein. [ABSTRACT FROM AUTHOR]

With the rapid accumulation of gene expression data, gene functional module identification has become a widely used approach in functional analysis. However, tools to identify organelle functional modules and analyze their relationships are still missing. We present a soft thresholding approach to construct networks of functional modules using gene expression datasets, in which nodes are strongly co-expressed genes that encode proteins residing in the same subcellular localization, and links represent strong inter-module connections. Our algorithm has three steps. First, we identify functional modules by analyzing gene expression data. Next, we use a self-adaptive approach to construct a mixed network of functional modules and genes. Finally, we link functional modules that are tightly connected in the mixed network. Analysis of experimental data from Arabidopsis demonstrates that our approach is effective in improving the interpretability of high-throughput transcriptomic data and inferring function of unknown genes.

Within over 800 members of G-protein-coupled receptors, there are numerous orphan receptors whose endogenous ligands are largely unknown, providing many opportunities for novel drug discovery. However, the lack of an in-depth understanding of the intrinsic working mechanism for orphan receptors severely limits the related rational drug design. The G-protein-coupled receptor 52 (GPR52) is a unique orphan receptor that constitutively increases cellular 5′-cyclic adenosine monophosphate (cAMP) levels without binding any exogenous agonists and has been identified as a promising therapeutic target for central nervous system disorders. Although recent structural biology studies have provided snapshots of both active and inactive states of GPR52, the mechanism of the conformational transition between these states remains unclear. Here, an acceptable self-activation pathway for GPR52 was proposed through 6 μs Gaussian accelerated molecular dynamics (GaMD) simulations, in which the receptor spontaneously transitions from the active state to that matching the inactive crystal structure. According to the three intermediate states of the receptor obtained by constructing a reweighted potential of mean force, how the allosteric regulation occurs between the extracellular orthosteric binding pocket and the intracellular G-protein-binding site is revealed. Combined with the independent gradient model, several important microswitch residues and the allosteric communication pathway that directly links the two regions are both identified. Transfer entropy calculations not only reveal the complex allosteric signaling within GPR52 but also confirm the unique role of ECL2 in allosteric regulation, which is mutually validated with the results of GaMD simulations. Overall, this work elucidates the allosteric mechanism of GPR52 at the atomic level, providing the most detailed information to date on the self-activation of the orphan receptor.

Human decision making can be influenced by presenting different options with positive or negative connotations. This phenomenon is termed the framing effect. Neuroeconomic studies have found that the amygdala plays a significant role in the framing effect, as it incorporates emotional (or intuitive) information into the decision process, which may lead to bias or irrationality. However, previous studies have focused only on the gain domain, in which the initial state is positive (appetitive). The mechanisms underlying the framing effect in the loss (aversive) domain are less well understood, despite their importance for evolution and survival. In this study, we first replicated the findings of De Martino et al. on the framing effect in the gain domain. We then searched for similarities and differences between the gain and loss domains using a similar experimental design combined with functional magnetic resonance imaging. Behaviorally, the participants showed comparable effects for both frame types, suggesting a frame-indiscriminate decision bias. In contrast, at the neuronal level, we found that the amygdala specifically represented the framing effect in the gain domain, and its connectivity to the ventromedial prefrontal cortex was positively modulated by the framing bias, similar to the findings of De Martino et al. However, the striatum was found to represent the framing effect in the loss domain. Striatal connectivity to the dorsomedial prefrontal cortex was similarly affected by the framing bias, suggesting domain-specific neural substrates. Our study emphasizes the importance of distinguishing between gain and loss domains when studying decision making, and highlights the governing role of the cortical–striatal–limbic network in the framing effect.

To obtain motion characteristics of the lubricating oil film on the aero-engine bearing chamber wall, a complete mathematical model based on theoretical study to solve three-dimensional unsteady oil film motion was established. On the basis of verifying the rationality of the computational model, the variations of the oil film thickness, velocity and temperature with the rotation speed and lubricating oil flow were analyzed and studied. The numerical results show that the following: In the stable oil film flow state, the oil film thickness shows a decreasing trend with increase in rotation speed and an increasing trend with increase in the lubricating oil flow. Particularly, comparison with the experimental work shows that the proposed numerical model based on theoretical study to solve unsteady oil film motion is a valuable technical means for the study of oil film movement mechanism and the design of actual bearing chamber.

In this paper, we propose least-squares images (LS-images) as a basis for a novel edge-preserving image smoothing method. The LS-image requires the value of each pixel to be a convex linear combination of its neighbors, i.e., to have zero Laplacian, and to approximate the original image in a least-squares sense. The edge-preserving property inherits from the edge-aware weights for constructing the linear combination. Experimental results demonstrate that the proposed method achieves high quality results compared to previous state-of-the-art works. We also show diverse applications of LS-images, such as detail manipulation, edge enhancement, and clip-art JPEG artifact removal.

Surface-enhanced Raman scattering (SERS) technology coupled with a quick pre-treatment method is used to detect chlorpyriphos (CP) pesticide residue in rice. 72 rice samples containing CP pesticide residue were prepared for SERS spectra acquirement and GC-MS measurement. The lowest detection concentration of CP pesticide in rice is below 0.506 mg L−1by SERS technology. Three methods, i.e.Standard Normal Variate (SNV), Multiple Scattering Correction (MSC) and normalization, were used to preprocess the original SERS spectra, and the prediction models of Partial Least Squares (PLS) were established for detecting CP pesticide residue in rice. The PLS model with normalization is optimal, with correlation coefficient (Rp) of 0.9734, root mean square error of prediction (RMSEP) of 1.76 mg L−1in the prediction, and relative analysis deviation (RPD) of 4.58, which is higher than 3. Six unknown samples were prepared to verify the accuracy of the prediction model. The absolute values of relative deviation were calculated to be between 2.64% and 4.47%, and the predicted recoveries were calculated to be between 96.59% and 104.69%. The value of a Ttest shows that the prediction model is accurate and reliable. This study demonstrates that the method can achieve a rapid detection of CP pesticide residue in rice.

Proteolysis-targeting chimeras (PROTACs) are a promising new class of drugs that selectively degrade cellular proteins of interest. PROTACs that target oncogene products are avidly being explored for cancer therapies, and several are currently in clinical trials. Drug resistance is a substantial challenge in clinical oncology, and resistance to PROTACs has been reported in several cancer cell models. Here, using proteomic analysis, we found intrinsic and acquired resistance mechanisms to PROTACs in cancer cell lines mediated by greater abundance or production of the drug efflux pump MDR1. PROTAC-resistant cells were resensitized to PROTACs by genetic ablation of ABCB1(which encodes MDR1) or by coadministration of MDR1 inhibitors. In MDR1-overexpressing colorectal cancer cells, degraders targeting either the kinases MEK1/2 or the oncogenic mutant GTPase KRASG12Csynergized with the dual epidermal growth factor receptor (EGFR/ErbB)/MDR1 inhibitor lapatinib. Moreover, compared with single-agent therapies, combining MEK1/2 degraders with lapatinib improved growth inhibition of MDR1-overexpressing KRAS-mutant colorectal cancer xenografts in mice. Together, our findings suggest that concurrent blockade of MDR1 will likely be required with PROTACs to achieve durable protein degradation and therapeutic response in cancer.

This paper presents a low power channel-length biasing pulse flip-flop (CLBPFF) aimed at a substantial reduction in leakage power. The proposed CLBPFF has been compared with the transmission gate flip-flop (TGFF) and the hybrid latch flip-flop (HLFF) in term of power dissipation, delay and energy delay product (EDP). Voltage scaling for the proposed CLBPFF has also been carried out. All flip-flops are simulated using a 45nm CMOS technology by varying supply voltage from 1.1V to 0.6V with 0.1V steps. Taken as an example, a practical sequential system realized with the proposed flip-flop is demonstrated using a mode-5 counter. The simulation results demonstrate that the proposed CLBPFF achieves considerable total power and leakage power reductions compared with HLFF and TGFF. Moreover, the results show that lowering supply voltage is advantageous, especially in medium-voltage region (0.8V-0.9V), which yields the best EDP for the proposed CLBPFF.

Case studies are presented for two concrete lined channels shaken by strong ground motions during the 1994 Northridge earthquake, the high speed channel (HSC) and bypass channel (BC), on the Los Angeles Department of Water and Power’s Van Norman Complex. Performances of these two channels as they pass through different subsurface materials identify several important seismic aspects and the critical role of geotechnical earthquake engineering in assessing channel behaviors. Preliminary evaluations using detailed mapping of channel cracks, permanent ground movements, subsurface profiles, and nearby strong ground motion recordings from the 1994 earthquake show that the channel liners may have been damaged from both transient motions and permanent ground movements. Damage from permanent ground deformations is obvious by observation; therefore simplified analyses are presented only for transient movements. Site specific transient response analyses are performed to provide an initial assessment of the differing effects from transient and permanent ground movements on HSC and BC liner damage. These case studies are helpful for introducing the potential for lifeline damage from transient movements within zones of permanent ground movement, a concept not well understood in the earthquake engineering community.

Liquefaction-induced ground deformations are permanent ground displacements resulting from earthquakes, which can extend over areas as large as a few square kilometers and have amplitudes ranging from a few centimeters to few tens of meters. This type of ground deformation caused substantial damage to lifelines and pile-foundations of buildings and bridge piers along the Kobe shoreline during the 1995 Hyogoken-Nanbu, Japan, earthquake. This paper presents a four-parameter multiple-linear-regression model for estimating the amplitude of liquefaction-induced ground displacement for both ground-slope and free-face conditions at a regional scale. The applicability of the model for mapping the amplitude of liquefaction-induced ground deformation is investigated over selected regions. The paper also presents a regional model for estimating the probability for the displacements to exceed some threshold amplitude, and to fall within confidence intervals. Both models are useful for risk assessment to spatially distributed lifeline networks resulting from future earthquakes.

The Rand Bgenes of maize regulate the anthocyanin biosynthetic pathway and constitute a small gene family whose evolution has been shaped by polyploidization and transposable element activity. To compare the evolution of regulatory genes in the distinct but related genomes of rice and maize, we previously isolated two Rhomologues from rice (Oryza sativa). The Ra1gene on chromosome 4 can activate the anthocyanin pathway, whereas the Rbgene, of undetermined function, maps to chromosome 1. In this study, rice Rgenes have been further characterized. First, we found that an RbcDNA can induce pigmentation in maize suspension cells. Second, another rice Rhomologue (Ra2) was identified that is more closely related to Ra1than to Rb. Domesticated rice and its wild relatives harbor multiple Ra-like and Rb-like genes despite the fact that rice is a true diploid with the smallest genome of all the grass species analyzed to date. Finally, several miniature inverted-repeat transposable elements (MITEs) were found in Rfamily members. Their possible role in hastening the divergence of Rgenes is discussed.