Five amino acid mismatches in the zinc-finger domains of Cellulose Synthase 5 and Cellulose Synthase 6 cooperatively modulate their functional properties by controlling homodimerization in Arabidopsis.

Cellulose synthase 5 (CESA5) and CESA6 are known to share substantial functional overlap. In the zinc-finger domain (ZN) of CESA5, there are five amino acid (AA) mismatches when compared to CESA6. These mismatches in CESA5 were replaced with their CESA6 counterparts one by one until all were replaced, generating nine engineered CESA5s. Each N-terminal enhanced yellow fluorescent protein-tagged engineered CESA5 was introduced to prc1-1, a cesa6 null mutant, and resulting mutants were subjected to phenotypic analyses. We found that five single AA-replaced CESA5 proteins partially rescue the prc1-1 mutant phenotypes to different extents. Multi-AA replaced CESA5s further rescued the mutant phenotypes in an additive manner, culminating in full recovery by CESA5G43R + S49T+S54P+S80A+Y88F. Investigations in cellulose content, cellulose synthase complex (CSC) motility, and cellulose microfibril organization in the same mutants support the results of the phenotypic analyses. Bimolecular fluorescence complementation assays demonstrated that the level of homodimerization in every engineered CESA5 is substantially higher than CESA5. The mean fluorescence intensity of CSCs carrying each engineered CESA5 fluctuates with the degree to which the prc1-1 mutant phenotypes are rescued by introducing a corresponding engineered CESA5. Taken together, these five AA mismatches in the ZNs of CESA5 and CESA6 cooperatively modulate the functional properties of these CESAs by controlling their homodimerization capacity, which in turn imposes proportional changes on the incorporation of these CESAs into CSCs.

Unified Strategy Enables the Collective Syntheses of Structurally Diverse Indole Alkaloids.

Natural products and their analogues are significant sources of therapeutic lead compounds. However, synthetic strategies for generating large collections of these molecules remain a significant challenge. The most difficult step in their synthesis is the design of a common intermediate that can be easily transformed into natural products belonging to different families. This study demonstrates the evolution of synthetic tactics designed to assemble the functionalized piperidines present in indole alkaloids from a common intermediate. More importantly, we also report a previously unknown Ir- and Er-catalyzed dehydrogenative spirocyclization reaction that enables direct access to spirocyclic oxindole alkaloids. As a practical application, the asymmetric total syntheses of 29 natural alkaloids belonging to different families were accomplished by following a uniform synthetic route. The proposed methodology extends the capability of the iridium-catalyzed dehydrogenative coupling reaction to the realm of indole-alkaloid synthesis and provides new opportunities for the efficient preparation of natural product-like molecules.

Downregulation of MYBL1 in endothelial cells contributes to atherosclerosis by repressing PLEKHM1-inducing autophagy.

MYBL1 is a strong transcriptional activator involved in the cell signaling. However, there is no systematic study on the role of MYBL1 in atherosclerosis. The aim of this study is to elucidate the role and mechanism of MYBL1 in atherosclerosis. GSE28829, GSE43292 and GSE41571 were downloaded from NCBI for differentially expressed analysis. The expression levels of MYBL1 in atherosclerotic plaque tissue and normal vessels were detected by qRT-PCR, Western blot and Immunohistochemistry. Transwell and CCK-8 were used to detect the migration and proliferation of HUVECs after silencing MYBL1. RNA-seq, Western blot, qRT-PCR, Luciferase reporter system, Immunofluorescence, Flow cytometry, ChIP and CO-IP were used to study the role and mechanism of MYBL1 in atherosclerosis. The microarray data of GSE28829, GSE43292, and GSE41571 were analyzed and intersected, and then MYBL1 were verified. MYBL1 was down-regulated in atherosclerotic plaque tissue. After silencing of MYBL1, HUVECs were damaged, and their migration and proliferation abilities were weakened. Overexpression of MYBL1 significantly enhanced the migration and proliferation of HUVECs. MYBL1 knockdown induced abnormal autophagy in HUVEC cells, suggesting that MYBL1 was involved in the regulation of HUVECs through autophagy. Mechanistic studies showed that MYBL1 knockdown inhibited autophagosome and lysosomal fusion in HUVECs by inhibiting PLEKHM1, thereby exacerbating atherosclerosis. Furthermore, MYBL1 was found to repress lipid accumulation in HUVECs after oxLDL treatment. MYBL1 knockdown in HUVECs was involved in atherosclerosis by inhibiting PLEKHM1-induced autophagy, which provided a novel target of therapy for atherosclerosis.

Planned Hybrid Endoscopic Submucosal Dissection as Alternative for Colorectal Neoplasms: A Propensity Score-Matched Study.

BACKGROUND AND AIMS: Hybrid endoscopic submucosal dissection (H-ESD), a modified ESD with a snare, has become increasingly utilized to overcome the limitations of conventional ESD (C-ESD). This study aimed to compare the efficacy and safety of Planned H-ESD and C-ESD for colorectal lesions. METHODS: Propensity score matching was performed to control for confounding variables in this retrospective study. Outcomes included en bloc resection and complete resection (R0) rates, procedure time, adverse event rates, and local recurrence rate. RESULTS: 1286 lesions were enrolled in the study. After matching, 263 lesions were assigned to each group. The Planned H-ESD group has lower en bloc rate but similar R0 resection rate compared to the C-ESD group (90.9% vs 98.1%, P = 0.001; 77.2% vs 77.9%, P = 0.917). The median procedure time was shorter in the Planned H-ESD group (27.0 min vs 35.0 min, P = 0.001). There were no significant differences in adverse events rates or local recurrence rate. Subgroup analysis based on lesion size revealed that a significantly lower en bloc resection rate in the Planned H-ESD group compared to the C-ESD group for lesions ≥ 40 mm (71.0% vs 94.3%, P = 0.027), but there was no significant difference for lesions < 40 mm. CONCLUSION: The Planned H-ESD has a lower en bloc resection rate but a similar R0 resection rate, adverse event rates, local recurrence rate, and shorter procedure duration. Compared to C-ESD, Planned H-ESD presents advantages for managing colorectal neoplasms below 40 mm.

Performance improvement of Hf0.45Zr0.55Oxferroelectric field effect transistor memory with ultrathin Al-O bonds-modified InOxchannels.

Ferroelectric field effect transistor (FeFET) memories with hafnium zirconium oxide (HZO) ferroelectric gate dielectric and ultrathin InOxchannel exhibit promising applicability in monolithic three-dimensional (M3D) integrated chips. However, the inferior stability of the devices severely limits their applications. In this work, we studied the effect of single cycle of atomic-layer-deposited Al-O bonds repeatedly embedded into an ultrathin InOxchannel (∼2.8 nm) on the Hf0.45Zr0.55OxFeFET memory performance. Compared to the pure InOxchannel, three cycles of Al-O bonds modified InOxchannel (IAO-3) generates a much larger memory window (i.e. drain current ratio between the programmed and erased devices) under the same program conditions (+5.5 V/500 ns), especially after post-annealing at 325 °C for 180 s in O2(1238 versus 317). Meanwhile, the annealed IAO-3 FeFET memory also shows quite stable data retention up to 104s, and much more robust program/erase stabilities till 105cycles. This is because the modification of strong Al-O bonds stabilizes the oxygen vacancies and reduces the bulk trap density in the channel. Furthermore, it is indicated that the program and erase efficiencies increase gradually with reducing the channel length of the memory device. By demonstrating markedly improved performance of the HZO FeFET memory with the ultrathin IAO-3 channel, this work provides a promising device for M3D integratable logic and memory convergent systems.

Associations between the levels of circulating inflammatory adipokines and the risk of type 2 diabetes in Chinese male individuals: A case-control study.

BACKGROUND: Whether the levels of circulating inflammatory adipokines affect the progression of type 2 diabetes (T2D) remains unclear. This study aimed to assess the association between circulating inflammatory adipokine levels and risk of T2D. METHODS: This case-control study involved 130 individuals consisting of 66 healthy controls (Control group) and 64 patients with T2D (T2D group) in Lishui Municipal Central Hospital from January 2017 to June 2017. Multivariate logistic regression analysis was applied to assess the associations between circulating inflammatory adipokine levels and the risk of T2D. RESULTS: There were significant differences in the levels of adiponectin (p = 0.013) and visfatin (p < 0.001) between the T2D and Control groups. In contrast, no significant differences in leptin (p = 0.113), TNF-α (p = 0.632), and IL-6 (p = 0.156) levels were found between the groups. Multivariate logistic regression indicated that elevated visfatin level was associated with an increased risk of T2D (OR: 3.543; 95% CI: 1.771-7.088; p < 0.001), while adiponectin (OR: 1.946; 95% CI: 0.925-4.094; p = 0.079), leptin (OR: 3.723; 95% CI: 0.788-17.583; p = 0.097), TNF-α (OR: 1.081; 95% CI: 0.911-1.281; p = 0.373), and IL-6 (OR: 0.878; 95% CI: 0.657-1.173; p = 0.379) were not associated with the risk of T2D. CONCLUSIONS: This study found elevated visfatin levels are associated with an increased risk of T2D, while adiponectin, leptin, TNF-α, and IL-6 are not. These findings should be further verified by a large-scale prospective study.

Addition of chemoradiotherapy to palliative chemotherapy in de novo metastatic nasopharyngeal carcinoma: a real-world study.

BACKGROUND: To determine whether concurrent chemotherapy is necessary during locoregional radiotherapy (RT) after palliative chemotherapy (PCT) in patients with de novo metastatic nasopharyngeal carcinoma (mNPC). METHODS: A total of 746 patients with mNPC from 2000 to 2017 at our hospital were retrospectively reviewed. Among them, 355 patients received PCT followed by RT. Overall survival (OS) and progression-free survival (PFS), including locoregional progression-free survival (LRPFS) and distant progression-free survival (DPFS) were estimated with the Kaplan-Meier method and log-rank test. Cox proportional-hazards models, landmark analyses, propensity score matching, and subgroup analyses were used to address confounding. RESULTS: Of the patients included in our study, 192 received radiotherapy alone after PCT (PCT + RT), and 163 received concurrent chemoradiotherapy after PCT (PCT + CCRT). The prognosis of PCT + CCRT was significantly better than that of PCT + RT (5 year OS, 53.0 vs 36.2%; P = 0.004). After matching, the 5 year OS rates of the two groups were 55.7 and 39.0%, respectively (P = 0.034) and the median DPFS were 29.4 and 18.7 months, respectively (P = 0.052). Multivariate Cox regression analysis indicated that PCT + CCRT was an independent favorable prognostic factor (P = 0.009). In addition, conducting concurrent chemoradiotherapy after 4-6 cycles of PCT or conducting concurrent chemotherapy with single-agent platinum was associated with significant survival benefit in the matched cohort (5 year OS rate, 60.4 or 57.4%, respectively). The survival difference between groups remained significant when evaluating patients who survived for ≥ 1 year (P = 0.028). CONCLUSIONS: The optimal treatment strategy of mNPC is the combination of PCT followed by concurrent chemoradiotherapy. More specifically, concurrent chemoradiotherapy with single-agent platinum after 4-6 cycles of PCT is suggested.

Design, synthesis and biological evaluation of novel N-(3-amino-4-methoxyphenyl)acrylamide derivatives as selective EGFRL858R/T790M kinase inhibitors.

On the basis of N-(3-amino-4-methoxyphenyl)acrylamide scaffold, a series of novel compounds containing 3-substitutional-1-methyl-1H-indole, 2-substitutional pyrrole or thiophene moieties were synthesized and their in vitro antiproliferation activities against A549 and H1975 cell lines were evaluated. The results indicated that most of the compounds showed moderate to excellent antitumor activities. Especially, compounds 9a (A549 IC50 = 1.96 µM, H1975 IC50 = 0.095 µM), 17i (A549 IC50 = 4.17 µM, H1975 IC50 = 0.052 µM), 17j (A549 IC50 = 1.67 µM, H1975 IC50 = 0.061 µM) exhibited comparable antitumor activities and selectivity ratios compared to the positive control osimertinib (A549 IC50 = 2.91 µM, H1975 IC50 = 0.064 µM). In vitro inhibitory activities against EGFR kinases containing different mutations were also tested. Compound 17i showed remarkable inhibitory activity (with IC50 value of 1.7 nM) to EGFRL858R/T790M kinase and selectivity (22-folds compared to EGFRWT kinase). Furthermore, acridine orange/ethidium bromide (AO/EB) staining assay, cell apoptosis assay, cell cycle distribution assay and wound-healing assay of the compounds 9a and 17i were performed on H1975 cell line. The results showed dose-dependent activities of the induction of apoptosis, G0/G1-phase arrestation and inhibition of migration, which were similar to the positive control osimertinib. Additionally, molecular docking analysis was performed to seek the possible binding mode between the selected compounds (9a, 17i-17j) and EGFRL858R/T790M kinase. The results demonstrated that compound 17i is a promising candidate and worth further study.

Novel 4-phenoxypyridine derivatives bearing imidazole-4-carboxamide and 1,2,4-triazole-3-carboxamide moieties: Design, synthesis and biological evaluation as potent antitumor agents.

Two series of novel 4-phenoxypyridine derivatives containing imidazole-4-carboxamide and 4-methyl-5-oxo-4,5-dihydro-1,2,4-triazole-3-carboxamide moieties were synthesized and evaluated for their in vitro inhibitory activities against c-Met kinase and antiproliferative activities against MKN-45, A549 and H460 cancer cell lines. The results indicated that most of the compounds showed moderate to good antitumor activities. The most promising compound T14 (with c-Met IC50 value of 0.012 µM) showed remarkable antiproliferative activities against MKN-45, A549 and H460 cell lines with IC50 values of 0.64 µM, 1.92 µM and 2.68 µM, respectively. Their preliminary structure-activity relationships (SARs) studies indicate that imidazole-4-carboxamide was more preferred as linker part, and electron-withdrawing groups (especially halogen groups) on the terminal phenyl rings were beneficial for improving the antitumor activities.

Contrast-enhanced ultrasound in the assessment of Crohn's disease activity: comparison with computed tomography enterography.

BACKGROUND AND OBJECTIVE: Continuous assessment of disease activity remains a huge challenge during the follow-ups of patients with Crohn's disease (CD). In this paper, we aimed to evaluate the performance of contrast-enhanced ultrasound (CEUS) by comparing with computed tomography enterography (CTE) in the assessment of disease activity in CD. MATERIALS AND METHODS: Fifty-two patients diagnosed with CD were included in this study, using the CEUS and CTE as imaging methods for comparison. The selected parameters included the location and thickness of the thickest part of the intestinal wall, mesenteric fat proliferation, mesenteric vessels change, enhancement pattern and the presence of complications. Patients were clinically assessed using the Crohn's disease activity index (CDAI), C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). Simple endoscopic score for Crohn's disease (SES-CD) was regarded as the reference standard. RESULTS: The location of the thickest part of the intestinal wall (κ = 0.653), bowel wall thickness (ICC = 0.795), mesenteric vessels change (κ = 0.692) and complications (κ = 0.796) displayed substantial agreement (0.61-0.80) between CEUS and CTE, while the detection of mesenteric fat proliferation (κ = 0.395) and enhancement pattern (κ = 0.288) showed fair consistency (0.21-0.40) for comparison. In CEUS, bowel wall thickness, mesenteric fat proliferation, enhancement pattern and mesenteric vessels change were statistically significant in assessing CD activity, while bowel wall thickness, mesenteric fat proliferation and mesenteric vessels change in CTE. Bowel wall thickness showed the best diagnostic performance in the assessment of CD activity at CEUS and CTE. CONCLUSION: CEUS provides a radiation-free and effective way to assess the CD activity in comparison with CTE, which also avoids frequent colonoscopy examinations, improves tolerance of patients, and reduces the cost of medical care, thereby serving as a useful tool for CD follow-up.

The N-terminal zinc finger of CELLULOSE SYNTHASE6 is critical in defining its functional properties by determining the level of homodimerization in Arabidopsis.

Primary cell wall cellulose is synthesized by the cellulose synthase complex (CSC) containing CELLULOSE SYNTHASE1 (CESA1), CESA3 and one of four CESA6-like proteins in Arabidopsis. It has been proposed that the CESA6-like proteins occupy the same position in the CSC, but their underlying selection mechanism remains unclear. We produced a chimeric CESA5 by replacing its N-terminal zinc finger with its CESA6 counterpart to investigate the consequences for its homodimerization, a crucial step in forming higher-order structures during assembly of the CSC. We found that the mutant phenotypes of prc1-1, a cesa6 null mutant, were rescued by the chimeric CESA5, and became comparable to the wild type (WT) and prc1-1 complemented by WT CESA6 in regard to plant growth, cellulose content, cellulose microfibril organization, CSC dynamics and subcellular localization. Bimolecular fluorescence complementation assays were employed to evaluate pairwise interactions between the N-terminal regions of CESA1, CESA3, CESA5, CESA6 and the chimeric CESA5. We verified that the chimeric CESA5 explicitly interacted with all the other CESA partners, comparable to CESA6, whereas interaction between CESA5 with itself was significantly weaker than that of all other CESA pairs. Our findings suggest that the homodimerization of CESA6 through its N-terminal zinc finger is critical in defining its functional properties, and possibly determines its intrinsic roles in facilitating higher-order structures in CSCs.

Flexible and Filter-Free Color-Imaging Sensors with Multicomponent Perovskites Deposited Using Enhanced Vapor Technology.

Halide perovskites are promising photoactive materials for filter-free color-imaging sensors owing to their outstanding optoelectronic properties, tunable bandgaps, and suitability for large-scale fabrication. However, producing patterned perovskite films of sufficiently high quality for such applications poses a challenge for existing fabrication methods: using solution processes to prepare patterned perovskite films is complicated, while evaporation methods often result in perovskite photodetectors with limited performance. In this paper, the authors report the development of an improved evaporation method in which substrates are treated with a brominated (3-aminopropyl) triethoxysilane self-assembled monolayer to improve the properties of the patterned perovskite films. The resulting perovskite photodetectors exhibit significantly enhanced photosensitivity and long-term stability (exceeding 100 days). Additionally, the polymer substrates facilitate device flexibility. Finally, perovskites comprising three different halide components, each with a different bandgap, are integrated into a device array using the developed evaporation technology, yielding sensors that enable the discrimination of red, green, and blue colors. Thus, the flexible photosensor arrays can generate colorful images closely resembling perceived patterns, demonstrating reliable color imaging. Therefore, this study successfully demonstrates filter-free color-imaging by integrating high-performance patterned and multicomponent perovskite photodetectors, highlighting the potential of such detectors for advanced optoelectronic applications, including hyperspectral imaging.

Pyruvate accelerates palladium reduction by regulating catabolism and electron transfer pathway in Shewanella oneidensis.

Shewanella oneidensis is a model strain of the electrochemical active bacteria (EAB) because of its strong capability of extracellular electron transfer (EET) and genetic tractability. In this study, we investigated the effect of carbon sources on EET in S. oneidensis by using reduction of palladium ions (Pd(II)) as a model and found that pyruvate greatly accelerated the Pd(II) reduction compared with lactate by resting cells. Both Mtr pathway and hydrogenases played a role in Pd(II) reduction when pyruvate was used as a carbon source. Furthermore, in comparison with lactate-feeding S. oneidensis, the transcriptional levels of formate dehydrogenases involving in pyruvate catabolism, Mtr pathway, and hydrogenases in pyruvate-feeding S. oneidensis were up-regulated. Mechanistically, the enhancement of electron generation from pyruvate catabolism and electron transfer to Pd(II) explains the pyruvate effect on Pd(II) reduction. Interestingly, a 2-h time window is required for pyruvate to regulate transcription of these genes and profoundly improve Pd(II) reduction capability, suggesting a hierarchical regulation for pyruvate sensing and response in S. oneidensis IMPORTANCE The unique respiration of EET is crucial for the biogeochemical cycling of metal elements and diverse applications of EAB. Although a carbon source is a determinant factor of bacterial metabolism, the research into the regulation of carbon source on EET is rare. In this work, we reported the pyruvate-specific regulation and improvement of EET in S. oneidensis and revealed the underlying mechanism, which suggests potential targets to engineer and improve the EET efficiency of this bacterium. This study sheds light on the regulatory role of carbon sources in anaerobic respiration in EAB, providing a way to regulate EET for diverse applications from a novel perspective.

The impact of COVID-19 on short-term prognosis of ST-segment elevation myocardial infarction patients receiving primary percutaneous coronary intervention in Wuhan China.

ST-segment elevation myocardial infarction (STEMI) is a common cardiovascular emergency for which timely reperfusion therapies are needed to minimize myocardial necrosis. The aim of this study was to investigate the impact of the COVID-19 pandemic and reorganization of chest pain centers (CPC) on the practice of primary percutaneous coronary intervention (PPCI) and prognosis of STEMI patients. This single-center retrospective survey included all patients with STEMI admitted to our CPC from January 22, 2020 to April 30, 2020 (during COVID-19 pandemic in Wuhan), compared with those admitted during the analogous period in 2019, in respect of important time points of PPCI and clinical outcomes of STEMI patients. In the present article, we observed a descending trend in STEMI hospitalization and a longer time from symptom onset to first medical contact during the COVID-19 pandemic as compared to the control period (4.35 h versus 2.58 h). With a median delay of 17 minutes in the door to balloon time (D2B), the proportion of in-hospital cardiogenic shock was significantly higher in the COVID-19 era group (47.6% versus 19.5%), and major adverse cardiac events (MACE) tend to increase in the 6-month follow-up period (14.3% versus 2.4%). Although the reorganization of CPC may prolong the D2B time, immediate revascularization of the infarct-related artery could be offered to most patients within 90 minutes upon arrival. PPCI remained the preferred treatment for patients with STEMI during COVID-19 pandemic in the context of timely implementation and appropriate protective measures.

High-bandwidth light inputting multilevel photoelectric memory based on thin-film transistor with a floating gate of CsPbBr3/CsPbI3 blend quantum dots.

The electronic-photonic convergent systems can overcome the data transmission bottleneck for microchips by enabling processor and memory chips with high-bandwidth optical input/output. However, current silicon-based electronic-photonic systems require various functional devices/components to convert high-bandwidth optical signals into electrical ones, thus making further integrations of sophisticated systems rather difficult. Here, we demonstrate thin-film transistor-based photoelectric memories employing CsPbBr3/CsPbI3 blend perovskite quantum dots (PQDs) as a floating gate, and multilevel memory cells are achieved under programming and erasing modes, respectively, by imputing high-bandwidth optical signals. For different bandwidth light input (i.e. 500-550, 575-650 and 675-750 nm) with the same intensity, three levels of programming window (i.e. 3.7, 1.9 and 0.8 V) and erasing window (i.e. -1.9, -0.6 and -0.1 V) are obtained under electrical pulses, respectively. This is because the blend PQDs have two different bandgaps, and different amounts of photo-generated carriers can be produced for different wavelength optical inputs. It is noticed that the 675-750 nm light inputs have no effects on both programming and erasing windows because of no photo-carriers generation. Four memory states are demonstrated, showing enough large gaps (1.12-5.61 V) between each other, good data retention and programming/erasing endurance. By inputting different optical signals, different memory states can be switched easily. Therefore, this work directly demonstrates high-bandwidth light inputting multilevel memory cells for novel electronic-photonic systems.

Restoration of forearm supination by combining pronator teres with allogeneic tendon.

BACKGROUND: Many solutions have been proposed in treating of forearm supination. Comparing with other supination function reconstructions, pronator teres rerouting is believed to be less effective due to its insufficient supination strength. The aim of this study is to introduce a modified procedure, and compare its result with two previous approaches. PATIENTS AND METHODS: From 2015 to 2020, 11 patients have restored forearm supination by rerouting of the pronator teres weave sutured with allogeneic tendons. The average follow-up period was 17.5 months (12 to 24). The range of active supination at the final follow-up was recorded. RESULTS: Almost all patients acquired good supination range. The average active post-operative supination was 72.7° (60° to 80°) at the final follow-up. No complication was observed. All patients retained full range of pronation. CONCLUSIONS: This study provides a modified supination function reconstruction with simple operating, fine results, low risks, and no affecting of pronation function. The use of allogeneic tendon makes up for the muscles with insufficient length, making it valuable to reconsider those rebuilding operations that were once considered unpromising by many.

Three-Dimensional Nanoscale Flexible Memristor Networks with Ultralow Power for Information Transmission and Processing Application.

To construct an artificial intelligence system with high efficient information integration and computing capability like the human brain, it is necessary to realize the biological neurotransmission and information processing in artificial neural network (ANN), rather than a single electronic synapse as most reports. Because the power consumption of single synaptic event is ∼10 fJ in biology, designing an intelligent memristors-based 3D ANN with energy consumption lower than femtojoule-level (e.g., attojoule-level) and faster operating speed than millisecond-level makes it possible for constructing a higher energy efficient and higher speed computing system than the human brain. In this paper, a flexible 3D crossbar memristor array is presented, exhibiting the multilevel information transmission functionality with the power consumption of 4.28 aJ and the response speed of 50 ns per synaptic event. This work is a significant step toward the development of an ultrahigh efficient and ultrahigh-speed wearable 3D neuromorphic computing system.

[Platelet function tests and Chinese medicines with antiplatelet function:a review].

Platelet function tests have been increasingly used to assist in the diagnosis of platelet disorders and prethrombotic state, monitoring of the efficacy of antiplatelet therapies, and personalized treatment. On the basis of light transmission aggregometry, new methods for platelet function test have been developed successively. At present, the research and development of platelet function detector is in its infancy in China. The active constituents of antiplatelet Chinese medicines can be classified into terpenoids, flavonoids, saponins, organic acids, lignans, diketones, volatile oils, and stilbenes. The results of dose-antiplatelet effect relationship of Chinese medicines and the active constituents showed that the effective concentration of the extracts or monomers of Chinese medicines was at micromolar level(µmol·L~(-1)), among which salvianolic acid B and ginkgolide K, ginkgolide B, and ginkgolide A had the strongest antiplatelet effect. These results suggest that the antiplatelet effect of Chinese medicine may be weaker than that of chemical drugs and biological products. Therefore, it is necessary to explore the structure-activity relationship of the active constituents in existing Chinese medicines and further improve their efficacy through structure modification. The antiplatelet effect of Chinese medicines and the constituents involves multiple pathways and multiple targets. These research results provide a reference for clinical application of them. However, there is still a lack of large-scale multi-center clinical trials to confirm the efficacy and safety of them. The regularity of the relationship between the structures of various constituents and their corresponding functions is still unknown and the relevant signal transduction pathways and structure-activity relationship need to be further studied. This paper summarized and analyzed the determination methods of platelet functions and the research results of antiplatelet Chinese medicines, which is of reference value for the research of effective and safe antiplatelet Chinese medicines.

Blood biomarker levels of methylation capacity in autism spectrum disorder: a systematic review and meta-analysis.

OBJECTIVE: To compare the peripheral blood levels of methionine (Met), S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), and the SAM/SAH ratio (the most core and predictive indices of cellular methylation ability) between patients with autism spectrum disorder (ASD) and control subjects. METHODS: PubMed, Embase, PsycINFO, Web of Science, and Cochrane Library were searched from inception to August 2, 2019, without language restriction. The random-effects model was used to summarize effect sizes. RESULTS: We retrieved 1,493 records, of which 22 studies met inclusion criteria. Our overall analyses revealed that individuals with ASD had significantly decreased levels of Met (22 studies; Hedges' g = -0.62; 95% confidence interval [CI]: -0.89, -0.35), SAM (8 studies; Hedges' g = -0.60; 95% CI: -0.86, -0.34), and the SAM/SAH ratio (8 studies; Hedges' g = -0.98; 95% CI: -1.30, -0.66) and significantly increased levels of SAH (8 studies; Hedges' g = 0.69; 95% CI: 0.43, 0.94). The findings of the overall analyses were quite stable after being verified by sensitivity analyses and in agreement with the corresponding outcomes of subgroup analyses. Additionally, our results from meta-analytic techniques confirmed that the effect estimates of this meta-analysis did not originate from publication bias. CONCLUSION: Individuals with ASD have substantially aberrant peripheral blood levels of Met, SAM, SAH, and the SAM/SAH ratio, which supports the association between impaired methylation capacity and ASD. Therefore, further investigations into these indices as potential biomarkers for diagnosis and therapeutic targets of ASD are warranted.

Design, synthesis and biological evaluation of novel 4-phenoxypyridine based 3-oxo-3,4-dihydroquinoxaline-2-carboxamide derivatives as potential c-Met kinase inhibitors.

Blocking c-Met kinase activity by small-molecule inhibitors has been identified as a promising approach for the treatment of cancers. Herein, we described the design, synthesis, and biological evaluation of a series of 4-phenoxypyridine-based 3-oxo-3,4-dihydroquinoxaline derivatives as c-Met kinase inhibitors. Inhibitory activitives against c-Met kinase evaluation indicated that most of compounds showed excellent c-Met kinase activity in vitro, and IC50 values of ten compounds (23a, 23e, 23f, 23l, 23r, 23s, 23v, 23w, 23x and 23y) were less than 10.00 nM. Notably, three of them (23v, 23w and 23y) showed remarkable potency with IC50 values of 2.31 nM, 1.91 nM and 2.44 nM, respectively, and thus they were more potent than positive control drug foretinib (c-Met, IC50 = 2.53 nM). Cytotoxic evaluation indicated the most promising compound 23w showed remarkable cytotoxicity against A549, H460 and HT-29 cell lines with IC50 values of 1.57 µM, 0.94 µM and 0.65 µM, respectively. Furthermore, the acridine orange/ethidium bromide (AO/EB) staining, cell apoptosis assays by flow cytometry, wound-healing assays and transwell migration assays on HT-29 and/or A549 cells of 23w were performed. Especially compound 23w, which displayed potent antitumor, apoptosis induction and antimetastatic activity, could be used as a promising lead for further development. Meanwhile, their preliminary structure-activity relationships (SARs) were also discussed.