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Li1.2Ni0.13Co0.13Mn0.54O2 (L2MO) material coated with Li1.3Al0.3Ti1.7(PO4)3(LATP) was synthesized by sol-gel method. The coating amount was 0%, 0.5%, 1%, 1.5%, 2%. It is found that LATP coating improves the cycle stability of the material. After 200 cycles at 0.6 C rate, the cycle retention rate of the uncoated sample is 72.7%, while the retention rate of sample with 1% coating amount reaches 85%. LATP coating improves the rate performance of the material. The sample with 1% coating amount has the best rate performance, and the discharge specific capacity is 71.5 mAh/g at 10 C rate, while the discharge specific capacity of the sample without coating is 60.1 mAh/g. LATP coating alleviates the side reaction between the material surface and the electrolyte. As a solid electrolyte, it promotes the transmission of Li+ and reduces the charge transfer impedance of the material. The thermal stability of these materials was tested by DSC. The results show that LATP coating could improve the thermal stability of the material in charged state.

The Acanthopanax senticosus has been shown to have a wide range of pharmacological activities, which are associated with health benefits, such as antioxidant, anti-inflammatory, and antiapoptotic properties. A previous study has shown that the n-butanol fraction of A. senticosus extract had the strongest antioxidant effect in vitro. This study aimed to investigate the effects that the n-butanol fraction of A. senticosus extract could relieve oxidative stress damage through antioxidant and antiapoptotic in the H2O2-stimulated RAW264.7 macrophages and the CCl4-induced liver injury. The result showed that the n-butanol fraction extract could relieve damage by increasing the intracellular antioxidant enzymes (SOD) level, decreasing intracellular ROS and MDA levels, and regulating antioxidant and antiapoptotic-related gene expression levels. The morphological observation of HE, TUNE, and immunohistochemistry staining of liver tissue verified that the n-butanol fraction extract is though anti-oxidative and antiapoptotic to alleviate cellular oxidative damage. The RT-PCR assay showed that the Keap1-Nrf2-ARE and the Bax/Bcl-2 signaling pathway were related to the molecular mechanism of action. The experimental results show that Acanthopanax senticosus extract has a good effect in treating liver injury and enhancing the antioxidant capacity of the body.

Atherosclerosis is a major risk factor for type 2 diabetes (T2D) mortality. We aim to investigate the changes in miR-21, miR-122, miR-33a and miR-3064-5p in circulation and the liver of ApoE-/- mice with streptozocin (STZ)-induced T2D. Twenty 5-week-old male ApoE-/- mice were randomly assigned to the control (n = 10) and T2D group (n = 10) and intraperitoneally injected with a citrate buffer and streptozotocin (STZ) (40 mg/kg BW) once a day for three consecutive days. The successfully STZ-induced T2D mice (n = 5) and control mice (n = 5) were then fed with a high-fat diet (HFD) for 34 weeks. Compared to the control mice, ApoE-/- mice with STZ-induced T2D had slower (p < 0.05) growth, increased (p < 0.05) total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C), decreased (p < 0.05) high-density lipoprotein cholesterol (HDL-C) in serum, reduced (p < 0.05) TC and sterol regulatory element-binding protein-2 (Srebp-2), elevated (p < 0.05) ATP-binding-cassette-transporter-A1 (Abca1) in the liver, aggravated (p < 0.05) atherosclerotic lesions in the aorta, downregulated (p < 0.05) miR-21 and miR-33a, and upregulated (p < 0.05) miR-122 and miR-3064-5p in serum and the liver. In addition, the aortic lesions showed a positive correlation with miR-122 (r = 1.000, p = 0.001) and a negative correlation with miR-21 (r = −1.000, p = 0.001) in ApoE-/- mice with T2D. In conclusion, T2D-accelerated atherosclerosis correlates with a reduction in miR-21 and miR-33a and an elevation in miR-122 and miR-3064-5p in circulation and the liver of ApoE-/- mice.

A new one-pot preparation of 4-tetrazolyl-3,4-dihydroquinazolines has been reported. The Ugi-azide reactions of 2-azidobenzaldehydes, amines, trimethylsilyl azide, and isocyanides produced azide intermediates without separation, which were treated with isocyanides to give 4-tetrazolyl-3,4-dihydroquinazoline derivatives through a sequential Palladium-catalyzed azide-isocyanide cross-coupling/cyclization reaction in moderate to good yields. The biological evaluation demonstrated that compound

This research aims to study the deformation and fracture behavior of shale by a novel anisotropic regular lattice spring model (ARLSM). The novel ARLSM applies the normal and tangential coupling spring to release the Poisson's ratio limitation in the traditional regular lattice spring model. Meanwhile, a nonlinear strength criterion is introduced into ARLSM to simulate the fracture failure of shale. Two benchmark problems are tested to implement the research. The study shows that ARLSM has larger range of Poisson's ratio and better effects comparing with the existing anisotropic lattice spring model. Moreover, ARLSM can accurately predict the deformation and fracture behavior of shale under different conditions.

The key to increasing shale gas production is to construct fracture networks in shale reservoir to provide channels for shale gas. Understanding the cracking characteristics of shale is necessary for oil and gas exploitation engineering. Given this, uniaxial compression tests were conducted on Longmaxi shale in China to study the mechanical properties and cracking behaviors affected by bedding layers and pre-existing slot. Sandstone specimens with different pre-existing slot angles were also tested as a comparison. A mechanical-optical-acoustical comprehensive data acquisition system consisting of a rigid hydraulic machine, high-speed industrial camera and acoustic emission acquisition instrument was established to monitor the cracking behaviors in real time. The results show that the cracking behaviors of shale specimens are quite different from sandstone specimens in the uniaxial compression tests. Crack initiation is predominantly controlled by the pre-existing slot and is also affected by bedding layers. Crack propagation is mainly controlled by bedding layers and stress field distribution. When the bedding layers are vertical, the cracks are most likely to propagate along the direction of the bedding and tensile cracks are observed. When the bedding is 30°, the shale specimens are most likely to be controlled by the bedding layers, resulting in shear slip failure along the bedding layers. The experimental results contribute to the understanding of cracking properties in layered anisotropic materials.

After the impoundment of a high dam reservoir, the water pressure environment of the rock masses in dam base and reservoir bank changes, which may easily induce engineering problems such as bank slope instability and dam collapse. In order to investigate the differences and mechanisms of different constant water pressures on the rock mass of dam base, triaxial loading tests were conducted on sandstone with initial damage under different high constant porewater pressures, and the multidirectional fracture mechanism was analyzed by combining CT and electron scans. The test results show that:(1) Under the confining pressure of 80 MPa, the greater the pore water pressure, the more brittle the sandstone is, the lower the peak strength, the smaller the volume expansion stress, the pore water pressure increases from 10 MPa to 50 MPa, and the peak strength decreases by 33%. (2) For different pore water pressure, there are significant differences in sandstone internal deterioration range and deterioration effect as the fracture surfaces of sandstone specimens have various forms and directions. Due to CT scaning results, with the pore water pressure increases, the deterioration effect spreads from specimen middle to both ends. When the water pressure-confining pressure ratio is less than 25.0%, the deterioration of pore water pressure is mainly concentrated in the middle 1/3 of the specimen. When the water pressure-confining pressure ratio is bigger than 62.5%, the pore water pressure has obvious deterioration effect on the whole specimen. (3) Electron microscopy scanning reveals that with the increase of pore water pressure: the microgranular structure of sandstone changes from shear slip failure to shear fracture failure, and the microcrystalline structure of sandstone changes from cauliflower to rice granular. The macroscopic failure mode changes from plastic failure to brittle failure, and multidirectional fracture plane is formed, which is related to the migration of fine particles and the fracture of large particles in the meso-particle structure under pore water pressure. The formation of the multidirectional fracture plane is directly related to the shear strength of the microscopic crystal structure.

An inclusion complex formation with cyclodextrin is a promising method to improve the bioavailability of water-insoluble drugs. The pharmacokinetic characteristics of Hyperoside-2-hydroxypropyl-β-cyclodextrin inclusion complex in rats were evaluated. Compared with Hyperoside, the results showed that maximum plasma concentration and AUC0-t indexes of Hyperoside inclusion complex in rat plasma were increased, the value of half-life time was prolonged, and the value of apparent clearance was decreased, which proved that Hyperoside complexed with 2-hydroxypropyl-β-cyclodextrin could improve its bioavailability and increase its blood concentration. Secondly, the therapeutic effect of Hyperoside before and after complexing was further compared through the dextran sodium sulfate-induced colitis in mice. The experimental results showed that under the same dose, the Hyperoside inclusion complex had a better therapeutic effect, which could significantly increase the body weight of mice, improve the disease activity index, alleviate colon shortening, improve pathological colon changes, and have a better protective effect on colitis mice. According to 16S rDNA sequencing analyses, Hyperoside-2-hydroxypropyl-β-cyclodextrin may have an anti-inflammatory effect by increasing the abundance of beneficial bacteria (e.g. Firmicuria) and decreasing the proportion of harmful bacteria (e.g. Bacteroidetes) to balance the colon’s microbiota.

Background Emergence delirium (ED) is a postoperative cognitive dysfunction that not only causes distress to patients and their families in the early post-anesthesia period, but also has long-term adverse effects in children. There are assumptions that non-delirium sedatives reduce adverse outcomes in children admitted to PACU( Post anesthesia care unit )1. Main purpose to verify whether dexmedetomidine can reduce the occurrence of PACU ED in children. To compare the effects of different administration methods of dexmedetomidine on reducing ED. And exploring whether giving dexmedetomidine at different times during the perioperative period affects the incidence of ED. Research type A systematic review and meta-analysis of randomized controlled trials. Data acquisition We searched WOS, WHO Trials, Cochrane Library, Clinical Trials.gov and PubMed for all published studies from the establishment of the library up to 23 Oct.2022. Eligibility criteria If the subjects were actively given dexmedetomidine before entering the PACU, and the occurrence of ED was used as the outcome measure, and the sample mean / median age was no more than 18 years old, they were included in the study. Studies examining the use of dexmedetomidine after surgery were excluded. Results A data analysis from seven studies involving 512 patients showed that prophylactic use of dexmedetomidine reduced the incidence of ED in children(risk ratio[RR] 0.40 ; 95% confidence interval [CI] 0.30–0.55 ; P P = 0.002.), intranasal injection of dexmedetomidine (n = 162, [RR] 0.29, 95%[CI] 0.16–0.52, P P = 0.05.), dexmedetomidine given before and during surgery (n = 162, [RR] 0.29, 95%[CI] 0.16–0.52, P P = 0.02) has a better effect on reducing the incidence of ED. In addition, prophylactic application of dexmedetomidine can reduce the occurrence of PONV (postoperative nausea and vomiting): 7 studies: n = 512 patients; [RR] 0.24; 95%[CI] 0.12–0.49; P = 0.0001. The occurrence of bradycardia was not statistically significant (2 studies: n = 157; [RR] 3.24; 95%[CI] 0.52–20.40; P = 0.21). Otherwise, because there was only one case of hypotension, we did not perform a meta-analysis. Prophylactic application of dexmedetomidine reduced PACU stay time after extubation (n = 446; mean difference [MD] -1.57; 95%[CI] -3.07 to -0.07, P = 0.04). However, sensitivity analysis of PACU stay time after extubation was not statistically significant and stable (n = 296; [MD] -0.55; 95%[CI] -1.30-0.19, P = 0.15) Conclusion Prophylactic use of dexmedetomidine can reduce the occurrence of ED in children and the adverse events no significant increase. In pediatric surgery, the anesthesiologist should consider the use of dexmedetomidine. In the future, we hope to confirm our findings through multi-center trials and clarify and explain the mechanism behind the reduction of ED with dexmedetomidine. TRIAL REGISTRATION PROSPERO: CRD42022371840.

A seepage testing system was designed and a series of seepage experiments on broken rock was conducted using different original porosity conditions and clay contents. The mass-loss process of the broken rock and the change in water flow velocity were investigated. After the mass-loss test, the non-Darcy seepage characteristics of the broken rock were tested through a step-by-step pressure-reduced seepage test. The experimental results show that the mass-loss and water velocity evolution during the water inrush could be divided into four stages: acceleration, stable with slight fluctuations, reacceleration, and stable. The lost-mass and change in water velocity were positively correlated with the clay contents and negatively correlated with the original porosity. By introducing the evolution equation of the Kozeny-Carman equation and the liquid limit index which characterises the effective particle size, the prediction model of the permeability coefficient was built. Six prediction models of the non-Darcy coefficient were verified against the testing results. The prediction model of the critical flow velocity from a Darcy flow to a non-Darcy flow using the Forchheimer number was also established. The results could provide an important reference for understanding water inrush mechanisms, adopting effective control measures for water inrush events, and calculating the water influx of tunnels.

This study sought to address the problem of the insufficient extraction of shallow object information and boundary information when using traditional FPN structures in current object detection algorithms, which degrades object detection accuracy. In this paper, a new FPN structure model, DA-FPN, is proposed. DA-FPN replaces the 1 × 1 convolution used in the conventional FPN structure for lateral connection with a 3 × 3 deformable convolution and adds a feature alignment module after the 2x downsampling operation used for lateral connection. This design allows the detection framework to extract more accurate information about the boundary of the object, particularly the boundary information of small objects. A bottom-up module was also added to incorporate the shallow information of the object more accurately into the high-level feature map, and a feature alignment module was added to the bottom-up module, thereby improving object detection accuracy. The experimental results show that DA-FPN can improve the accuracy of the single-stage object detection algorithms FoveaBox and GFL by 1.7% and 2.4%, respectively, on the MS-COCO dataset. This model was also found to improve the two-stage object detection algorithm SABL by 2.4% and offer higher small object detection accuracy and better robustness.

Fu Xiang, Xuedong Xu Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian City, Liaoning Province, People’s Republic of ChinaCorrespondence: Xuedong Xu, Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, No. 5 Longbin Road, Dalian City, Liaoning Province, 116000, People’s Republic of China, Tel +86-83635963-7098, Email xuedongxudalian@163.comPurpose: CirRNA F-circEA-2a and miR-3613-3p are two recently identified novel cancer-related RNAs. To date, their participation in colorectal cancer (CRC) is unknown. This research was therefore conducted to analyze their participation in CRC.Patients and Methods: Plasma and paired CRC and non-tumor tissues from CRC patients (n=64) and plasma samples from healthy controls (HCs, n=64) were collected. F-circEA-2a and miR-3613-3p levels in these samples were analyzed using RT-qPCR. The 64 CRC patients were followed up for five years to analyze the prognostic value of plasma F-circEA-2a for CRC. The direct interaction between wild type F-circEA-2a (F-circEA-2a-wt) or mutant F-circEA-2a (F-circEA-2a-mut) and miR-3613-3p was analyzed through RNA-RNA pulldown assay. The role of F-circEA-2a and miR-3613-3p in regulating each other’s expression was analyzed through overexpression assay. Their roles in cell proliferation were analyzed using BrdU assay. The role of F-circEA-2a in regulating EZH2 expression was analyzed by RT-qPCR and Western blot.Results: CircEA-2a was overexpressed in CRC, while miR-3613-3p was under-expressed in CRC. Most patients who died during the follow-up had high F-circEA-2a levels. F-circEA-2a-wt, but not F-circEA-2a-mut, directly interacted with miR-3613-3p. F-circEA-2a and miR-3613-3p showed no role in regulating each other’s expression. F-circEA-2a reduced the inhibitory effects of miR-3613-3p on cell proliferation. F-circEA-2a upregulated EZH2 at both mRNA and protein levels.Conclusion: F-circEA-2a may suppress the role of miR-3613-3p in CRC by direct sponging and predicts poor survival.Keywords: F-circEA-2a, miR-3613-3p, colorectal cancer, prognosis

Si-Yi Gong,1,&ast; Yun Shen,1,&ast; Han-Ying Gu,1 Sheng Zhuang,1 Xiang Fu,1,2 Qiao-Jun Wang,1 Cheng-Jie Mao,1 Hua Hu,1 Yong-Ping Dai,1 Chun-Feng Liu1– 3 1Department of Neurology and Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China; 2Institute of Neuroscience, Soochow University, Suzhou, Jiangsu, 215123, People’s Republic of China; 3Department of Neurology, Suqian First Hospital, Suqian, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Chun-Feng Liu; Yong-Ping Dai, Department of Neurology and Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China, Tel +86 512-67783307 ; +86 512-67784179, Fax +86 512-68284303, Email liuchunfeng@suda.edu.cn; dai_yongping@163.comPurpose: Idiopathic rapid eye movement sleep behavior disorder (iRBD) is the prodromal marker of α-synuclein degeneration with markedly high predictive value. We aim to evaluate the value of electroencephalography (EEG) data during rapid eye movement (REM) sleep and subjective RBD severity in predicting the conversion to neurodegenerative diseases in iRBD patients.Methods: At the baseline, iRBD patients underwent clinical assessment and video-polysomnography (PSG). Relative spectral power for nine frequency bands during phasic and tonic REM sleep in three regions of interest, slow-to-fast ratios, clinical and PSG variables were estimated and compared between iRBD patients who converted to neurodegenerative diseases (iRBD-C) and iRBD patients who remained disease-free (iRBD-NC). Receiver operating characteristic (ROC) curves evaluated the predictive performance of slow-to-fast ratios, and subjective RBD severity as assessed with RBD Questionnaire-Hong Kong.Results: Twenty-two (33.8%) patients eventually developed neurodegenerative diseases. The iRBD-C group showed shorter total sleep time (p < 0.001), lower stage 2 sleep percentage (p = 0.044), more periodic leg-movement-related arousal index (p = 0.004), increased tonic chin electromyelographic activity (p = 0.040) and higher REM density in the third REM episode (p = 0.034) than the iRBD-NC group. EEG spectral power analyses revealed that iRBD phenoconverters showed significantly higher delta and lower alpha power, especially in central and occipital regions during the phasic REM state compared to the iRBD-NC group. Significantly higher slow-to-fast ratios were observed in a more generalized way during the phasic state in the iRBD-C group compared to the iRBD-NC group. ROC analyses of the slowing ratio in occipital areas during phasic REM sleep yielded an area under the curve of 0.749 (p = 0.001), while no significant predictive value of subjective RBD severity was observed.Conclusion: Our study shows that EEG slowing, especially in a more generalized manner during the phasic period, may be a promising marker in predicting phenoconversion in iRBD, rather than subjective RBD severity.Keywords: idiopathic rapid eye movement sleep behavior disorder, neurodegenerative diseases, EEG slowing, RBD severity, phenoconversion, neuroprotective therapy

Experimental results indicate that the conventional program suspend scheme in 3D NAND flash memory chip can generate unexpected additional read fail bits and reduce the reliability of 3D NAND flash memory. These extra read fail bits are observed when the program suspend command is issued during the program stage, and particularly, they become more obvious as the delay time between program suspend operation and other following operations exceeds tens of milliseconds. By analyzing the waveform of conventional program suspend scheme, it is suggested that the unexpected extra read fail bits are caused by the different occupancy of grain boundary traps (GBTs) in the polycrystalline silicon (poly-Si) channel during the idle time after the program suspend operation. Accordingly, a novel program suspend scheme is proposed by adding a “stabilizing” pulse immediately after the program stage. Silicon experimental data show that the proposed scheme can effectively limit the read fail bit count (FBC) to a normal range, thus improving the reliability of 3D NAND flash memory significantly.

Mg2BiN3 is a new excellent photovoltaic candidate due to its ideal energy band, high electron mobility, high absorption coefficient and large ferroelectric polarization strength.

CaBiO3 under tensile strain can maintain high ferroelectric polarization strength and strong visible light absorption ability, further promoting photocatalytic hydrogen production.

Li2SbBiO6 slightly improves the ferroelectric polarization of LiSbO3 and significantly reduces the band gap to expand its applications in photovoltaic and photocatalysis under visible light.

In order to quantitatively characterize the pore structure of thermally contacted metamorphic coal by igneous intrusion and investigate the intrinsic connection between the pore and dispersion properties of coal, the samples of metamorphic coal from different locations of Daxing Coal Mine were collected and processed. The correlative analysis on pore characteristics, including pore area, perimeter, shape factor and fractal dimension of pores with different sizes, were carried out by using scanning electron microscopy (SEM) and pore-fracture analysis system (PCAS). The results show that the porosity of macro- and meso-pores and the number of pores in the metamorphic coal are larger than those of the normal coal. The total length of pores per unit area and the average shape factor increase, and the connectivity of pore is raised, resulting in an enhanced gas release capacity (increased V1) within the first one second. The proportion of gas emission in the first one second of metamorphic coal is much higher than that of other coals. The decrease of pore volume and specific surface area of micropores makes the adsorption capacity weaker, which results in a decrease in the total amount of emission - smaller Δp value, and earlier inflection point and faster attenuation on the emission curve, namely an increased α value. In addition, the V1, α value and volatile content satisfy the quadratic nonlinear and linear relationships, respectively. In the prediction of outburst risk of thermally contacted metamorphic coal, it is more reasonable to use the V1 index to characterize the gas release rate.

An X-ray structure of a CLICK chemistry-based BET PROTAC bound to BRD2(BD2) inspired synthesis of JQ1 derived heterocyclic amides. This effort led to the discovery of potent BET inhibitors displaying overall improved profiles when compared to JQ1 and birabresib. A thiadiazole derived 1q (SJ1461) displayed excellent BRD4 and BRD2 affinity and high potency in the panel of acute leukaemia and medulloblastoma cell lines. A structure of 1q co-crystalised with BRD4-BD1 revealed polar interactions with the AZ/BC loops, in particular with Asn140 and Tyr139, rationalising the observed affinity improvements. In addition, exploration of pharmacokinetic properties of this class of compounds suggest that the heterocyclic amide moiety improves drug-like features. Our study led to the discovery of potent and orally bioavailable BET inhibitor 1q (SJ1461) as a promising candidate for further development.

Objectives: Tick-borne rickettsiae are increasingly recognized to cause human infections; however, a complete clinical spectrum is lacking. Thus, surveillance study was conducted among forest rangers with tick bites to describe the clinical manifestations. Methods: One hundred fifty-nine blood samples were obtained from individuals bitten by ticks and 780 tick samples collected in the same endemic region were examined for the presence of Rickettsia. Serum samples were tested for IgM and IgG antibodies against R. heilongjiangensis. Results: Twenty-five (15.7%) individuals were shown to be infected with 5 Rickettsia species, including 14 Candidatus Rickettsia tarasevichiae (CRT), 8 R. raoultii, 1 R. felis, 1 R. heilongjiangensis, and 1 R. massiliae. Five individuals (1 CRT, 1 R. heilongjiangensis, and 3 R. raoultii) had mild illnesses; the other 20 individuals were asymptomatic. CRT was present in 38.4% (274/713) of I. persulcatus and 6.4% (3/47) of Hae. concinna. R. raoultii was demonstrated in 30.0% (6/20) of D. silvarum and 14.9% (7/17) of Hae. concinna. R. heilongjiangensis was detected in 9.5% (2/21) of D. silvarum and 0.3% (2/713) of I. persulcatus. Conclusions: The clinical manifestations of these rickettsioses were non-specific and differed from traditional features, thus supporting the necessity of wider investigations involving individuals with tick bites to develop an early differential diagnosis.

Combinatorial cancer therapies based on nanomedicine have emerged as a promising strategy to achieve potentiated treatment efficiency. Herein, cisplatin (CDDP) prodrug (Pt-CD) and a mitochondria-targeted near-infrared (NIR) photosensitizer IR780 were combined to construct a multifunctional nanomedicine IR780@Pt NPs through a supramolecular self-assembly strategy. Targeted mitochondrial dysfunction of cancer cells was sufficiently induced under NIR laser irradiation through both photothermal and photodynamic effects, inhibiting the overactive mitochondrial energy pathways of cancer cells. The mitochondrial dysfunction significantly attenuated the crosstalk between mitochondria and nucleus

Multicomponent reactions that involve interception of onium ylides through Aldol, Mannich, and Michael addition with corresponding bench-stable acceptors have demonstrated broad applications in synthetic chemistry. However, because of the high reactivity and transient survival of these

Targeting cereblon (CRBN) is currently one of the most frequently reported proteolysis-targeting chimera (PROTAC) approaches, owing to favorable drug-like properties of CRBN ligands, immunomodulatory imide drugs (IMiDs). However, IMiDs are known to be inherently unstable, readily undergoing hydrolysis in body fluids. Here we show that IMiDs and IMiD-based PROTACs rapidly hydrolyze in commonly utilized cell media, which significantly affects their cell efficacy. We designed novel CRBN binders, phenyl glutarimide (PG) analogues, and showed that they retained affinity for CRBN with high ligand efficiency (LE >0.48) and displayed improved chemical stability. Our efforts led to the discovery of PG PROTAC 4c (SJ995973), a uniquely potent degrader of bromodomain and extra-terminal (BET) proteins that inhibited the viability of human acute myeloid leukemia MV4–11 cells at low picomolar concentrations (IC(50) = 3 pM; BRD4 DC(50) = 0.87 nM). These findings strongly support the utility of PG derivatives in the design of CRBN-directed PROTACs.

The high throwing power (TP) value is one of the most important parameters for the Cu electroplating of through-holes in flexible printed circuit (FPC). It was found that an ultra-high TP value could be obtained using a specific suppressor, i.e., iodonitrotetrazolium chloride (INT) in the electrolyte. The ultra-high TP value was attributed to fast-consumption of this suppressor instead of traditional convection-dependence adsorption mechanism. A consumption model was built and simulated to clarify the formation of the ∆θ, i.e., the difference of suppressor fractional coverage between the entrance and center of through-holes sidewalls. It revealed that the TP, proportional to the ∆θ, was determined by the consumption rate of a suppressor. This simulation results were well consistent with the results of electroplating using INT with different concentration. The electrochemical analysis verified the characteristics of fast consumption of INT due to the reduction reaction. The difference of residual INT between the entrance and center of the plated through-holes confirmed the occurrence of ∆θ. These results supported the opinion that the ultra-high TP value was obtained by fast-consumption mechanism of INT suppressor.