HDAC6 mediates tumorigenesis during mitosis and the development of targeted deactivating agents.

Epigenetics, particularly deacetylation, plays a critical role in tumorigenesis as many carcinogens are under tight control by post-translational modification. HDAC6, an important and special histone deacetylase (HDAC) family member, has been indicated to increase carcinogenesis through various functions. Recent studies demonstrated the effects of HDAC6 inhibitors in mitotic arrest, however, detailed mechanisms still remain unknown. Herein, we review and summarize HDAC6-associated proteins that have been implicated in important roles in mitosis. We also discuss the development of medicinal agents targeting HDAC6.

Recent development of selective inhibitors targeting the HDAC6 as anti-cancer drugs: Structure, function and design.

HDAC6, a member of the histone deacetylase family, mainly is a cytosolic protein and regulates cell growth by acting on non-histone substrates, such as α -tubulin, cortactin, heat shock protein HSP90, programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1), that are closely related to the proliferation, invasion, immune escape and angiogenesis of cancer tissues. The approved drugs targeting the HDACs are all pan-inhibitors and have many side effects due to their lack of selectivity. Therefore, development of selective inhibitors of HDAC6 has attracted much attention in the field of cancer therapy. In this review, we will summarize the relationship between HDAC6 and cancer, and discuss the design strategies of HDAC6 inhibitors for cancer treatment in recent years.

A New Memristor with 2D Ti3 C2 Tx MXene Flakes as an Artificial Bio-Synapse.

Two-dimensional (2D) materials have attracted extensive research interest in academia due to their excellent electrochemical properties and broad application prospects. Among them, 2D transition metal carbides (Ti3 C2 Tx ) show semiconductor characteristics and are studied widely. However, there are few academic reports on the use of 2D MXene materials as memristors. In this work, reported is a memristor based on MXene Ti3 C2 Tx flakes. After electroforming, Al/Ti3 C2 Tx /Pt devices exhibit repeatable resistive switching (RS) behavior. More interestingly, the resistance of this device can be continuously modulated under the pulse sequence with 10 ns pulse width, and the pulse width of 10 ns is much lower than that in other reported work. Moreover, on the nanosecond scale, the transition from short-term plasticity to long-term plasticity is achieved. These two properties indicate that this device is favorable for ultrafast biological synapse applications and high-efficiency training of neural networks. Through the exploration of the microstructure, Ti vacancies and partial oxidation are proposed as the origins of the physical mechanism of RS behavior. This work reveals that 2D MXene Ti3 C2 Tx flakes have excellent potential for use in memristor devices, which may open the door for more functions and applications.

Vacancy-Induced Synaptic Behavior in 2D WS2 Nanosheet-Based Memristor for Low-Power Neuromorphic Computing.

Memristors with nonvolatile memory characteristics have been expected to open a new era for neuromorphic computing and digital logic. However, existing memristor devices based on oxygen vacancy or metal-ion conductive filament mechanisms generally have large operating currents, which are difficult to meet low-power consumption requirements. Therefore, it is very necessary to develop new materials to realize memristor devices that are different from the mechanisms of oxygen vacancy or metal-ion conductive filaments to realize low-power operation. Herein, high-performance and low-power consumption memristors based on 2D WS2 with 2H phase are demonstrated, which show fast ON (OFF) switching times of 13 ns (14 ns), low program current of 1 µA in the ON state, and SET (RESET) energy reaching the level of femtojoules. Moreover, the memristor can mimic basic biological synaptic functions. Importantly, it is proposed that the generation of sulfur and tungsten vacancies and electron hopping between vacancies are dominantly responsible for the resistance switching performance. Density functional theory calculations show that the defect states formed by sulfur and tungsten vacancies are at deep levels, which prevent charge leakage and facilitate the realization of low-power consumption for neuromorphic computing application.

Sulforaphane Attenuates Muscle Inflammation in Dystrophin-deficient mdx Mice via NF-E2-related Factor 2 (Nrf2)-mediated Inhibition of NF-κB Signaling Pathway.

Inflammation is widely distributed in patients with Duchenne muscular dystrophy and ultimately leads to progressive deterioration of muscle function with chronic muscle damage, oxidative stress, and reduced oxidative capacity. NF-E2-related factor 2 (Nrf2) plays a critical role in defending against inflammation in different tissues via activation of phase II enzyme heme oxygenase-1 and inhibition of the NF-κB signaling pathway. However, the role of Nrf2 in the inflammation of dystrophic muscle remains unknown. To determine whether Nrf2 may counteract inflammation in dystrophic muscle, we treated 4-week-old male mdx mice with the Nrf2 activator sulforaphane (SFN) by gavage (2 mg/kg of body weight/day) for 4 weeks. The experimental results demonstrated that SFN treatment increased the expression of muscle phase II enzyme heme oxygenase-1 in an Nrf2-dependent manner. Inflammation in mice was reduced by SFN treatment as indicated by decreased infiltration of immune cells and expression of the inflammatory cytokine CD45 and proinflammatory cytokines tumor necrosis factor-α, interleukin-1ß, and interleukin-6 in the skeletal muscles of mdx mice. In addition, SFN treatment also decreased the expression of NF-κB(p65) and phosphorylated IκB kinase-α as well as increased inhibitor of κB-α expression in mdx mice in an Nrf2-dependent manner. Collectively, these results show that SFN-induced Nrf2 can alleviate muscle inflammation in mdx mice by inhibiting the NF-κB signaling pathway.

Ferroptosis: A Novel Therapeutic Direction of Spinal Cord Injury.

An injury to the spinal cord results in a crucial central nervous system event that further causes irreversible impairment or loss of motor, autonomic, and sensory functions. A progressive pathophysiological cascade following spinal cord injury (SCI) includes ischemia/reperfusion injury, oxidative stress, proapoptotic signaling, peripheral inflammatory cell infiltration, and glutamate-mediated excitotoxicity, and regulated cell death. These complex pathological and physiological changes continue to cause cell injury over the long-term and severely limit the efficacy of clinical treatment strategies in restoring the injured nervous system. Ferroptosis is a nonapoptotic, iron-regulated kind of cell death that has recently been discovered. It is distinguished by iron overload-induced toxic lipid peroxidation associated with mitochondrial morphological changes during the cell death process. For example, after SCI, iron overload activates the reactive oxygen species generation, dysregulation of glutathione/glutathione peroxidase 4 (GSH/GPX4) metabolism, and accumulation of lipid peroxides, which cause lipid membrane deterioration and ferroptosis. Conversely, knockout or differential expression of key genes and application of lipid peroxidation inhibitors and iron chelators (e.g., deferoxamine) (e.g., SRS-16-86) can block ferroptosis and promote neuronal repair for functional recovery after SCI. Although the findings of numerous investigations have been confirmed the importance of ferroptosis in several human neurologic sicknesses and its potential in SCI, the mechanism of ferroptosis and its application in SCI has not been elucidated. This review highlights current ferroptosis research and its impact on SCI, as well as the key molecular mechanism of ferroptosis in promoting the recovery from SCI. Understanding ferroptosis' process and function in SCI could provide useful insight into the treatment and avoidance of such a destructive injury.

An integrated model for evaluation of maternal health care in China.

In recent years, in the context of China's continuous medical and health reforms, the health status of Chinese women and children has been significantly improved through the continuous efforts of staff at all levels of maternal and child health care institutions. Many indicators in maternal health care have improved significantly, but the speed and magnitude of changes have varied. The purpose of this study is to evaluate the dynamic changes in China's maternal health status from 2004 to 2018, in order to determine whether China's medical and health reform measures in recent years have improved maternal health. A total of 6 evaluation indicators from the data of China Health Statistics Yearbook 2019 were selected. Then, based on the multi-criteria decision-making (MCDA) methodology, the entropy weighted technique for order preference by similarity to an ideal solution (TOPSIS), entropy weighted rank-sum ratio (RSR) method and the fuzzy comprehensive evaluation were employed in this study. In addition, sensitivity analysis was engaged to validate the stability and accuracy of the achieved results. The study results shows the ranking values of various methods were not exactly the same, but the overall trend was consistent. Overall, the maternal health care in China improved from 2004 to 2018 year by year, of which the top four were ranked from 2015 to 2018, and relatively poor from 2004 to 2006. This means that the policies and measures implemented in China's medical and health reform in the past few decades have effectively promoted China's maternal health care, and this will also provide a theoretical basis for future decisions to promote maternal health care.

Prevalence of short stature among children in China: A systematic review.

IMPORTANCE: The prevalence and characteristics of short stature (SS) among children in China should be assessed to provide guidance for planning and implementation of nationwide public health policies. Thus far, there have been no accurate estimates of the prevalence of SS in China. OBJECTIVE: To analyze the prevalence of SS among children in China and to explore the influences of sex, area, age, study year, and study site on prevalence rates. METHODS: Relevant literature was identified by searching the following databases: PubMed, Embase, The Cochrane Library, Chinese Biomedical Literature, China Knowledge Resource Integrated, WeiPu, and WanFang databases. Meta-analysis was carried out using STATA 11.2. RESULTS: This meta-analysis included 39 studies with 348 326 Chinese participants; the studies covered 20 provinces, municipalities, and autonomous regions. The pooled prevalence of SS was 3.2% (95% confidence interval [CI], 2.6%-3.7%; I 2 = 99.8%). The prevalence of SS in boys and girls were 3.1% (95% CI, 2.5%-3.7%) and 3.2% (95% CI, 2.6%-3.9%), respectively. The sex difference was not statistically significant (P > 0.05). The prevalence of SS was higher in rural areas than in urban areas (4.7% [95% CI, 3.6%-5.8%] vs. 2.8% [95% CI, 2.2%-3.4%]; P < 0.001). The prevalence of SS was higher in West China (5.2%; 95% CI, 4.4%-6.0%) than in Northeast China (0.6%; 95% CI, 0.3%-0.8%), East China (2.3%; 95% CI, 1.9%-2.8%), or Central China (2.9%; 95% CI, 1.9%-3.9%). INTERPRETATION: The prevalence of SS among children was higher in western and rural areas of China. Close attention to children's growth and development is needed to prevent the occurrence of SS.

CLEAR: Comprehensive Learning Enabled Adversarial Reconstruction for Subtle Structure Enhanced Low-Dose CT Imaging.

X-ray computed tomography (CT) is of great clinical significance in medical practice because it can provide anatomical information about the human body without invasion, while its radiation risk has continued to attract public concerns. Reducing the radiation dose may induce noise and artifacts to the reconstructed images, which will interfere with the judgments of radiologists. Previous studies have confirmed that deep learning (DL) is promising for improving low-dose CT imaging. However, almost all the DL-based methods suffer from subtle structure degeneration and blurring effect after aggressive denoising, which has become the general challenging issue. This paper develops the Comprehensive Learning Enabled Adversarial Reconstruction (CLEAR) method to tackle the above problems. CLEAR achieves subtle structure enhanced low-dose CT imaging through a progressive improvement strategy. First, the generator established on the comprehensive domain can extract more features than the one built on degraded CT images and directly map raw projections to high-quality CT images, which is significantly different from the routine GAN practice. Second, a multi-level loss is assigned to the generator to push all the network components to be updated towards high-quality reconstruction, preserving the consistency between generated images and gold-standard images. Finally, following the WGAN-GP modality, CLEAR can migrate the real statistical properties to the generated images to alleviate over-smoothing. Qualitative and quantitative analyses have demonstrated the competitive performance of CLEAR in terms of noise suppression, structural fidelity and visual perception improvement.

Domain Progressive 3D Residual Convolution Network to Improve Low-Dose CT Imaging.

The wide applications of X-ray computed tomography (CT) bring low-dose CT (LDCT) into a clinical prerequisite, but reducing the radiation exposure in CT often leads to significantly increased noise and artifacts, which might lower the judgment accuracy of radiologists. In this paper, we put forward a domain progressive 3D residual convolution network (DP-ResNet) for the LDCT imaging procedure that contains three stages: sinogram domain network (SD-net), filtered back projection (FBP), and image domain network (ID-net). Though both are based on the residual network structure, the SD-net and ID-net provide complementary effect on improving the final LDCT quality. The experimental results with both simulated and real projection data show that this domain progressive deep-learning network achieves significantly improved performance by combing the network processing in the two domains.

Deep iterative reconstruction estimation (DIRE): approximate iterative reconstruction estimation for low dose CT imaging.

The image quality in low dose computed tomography (LDCT) can be severely degraded by amplified mottle noise and streak artifacts. Although the iterative reconstruction (IR) algorithms bring sound improvements, their high computation cost remains a major inconvenient. In this work, a deep iterative reconstruction estimation (DIRE) strategy is developed to estimate IR images from LDCT analytic reconstructions images. Within this DIRE strategy, a 3D residual convolutional network (3D ResNet) architecture is proposed. Experiments on several simulated and real datasets as well as comparisons with state-of-the-art methods demonstrate that the proposed approach is effective in providing improved LDCT images.

Robust Ag/ZrO2/WS2/Pt Memristor for Neuromorphic Computing.

The development of the information age has made resistive random access memory (RRAM) a critical nanoscale memristor device (MD). However, due to the randomness of the area formed by the conductive filaments (CFs), the RRAM MD still suffers from a problem of insufficient reliability. In this study, the memristor of Ag/ZrO2/WS2/Pt structure is proposed for the first time, and a layer of two-dimensional (2D) WS2 nanosheets was inserted into the MD to form 2D material and oxide double-layer MD (2DOMD) to improve the reliability of single-layer devices. The results indicate that the electrochemical metallization memory cell exhibits a highly stable memristive switching and concentrated ON- and OFF-state voltage distribution, high speed (∼10 ns), and robust endurance (>109 cycles). This result is superior to MDs with a single-layer ZrO2 or WS2 film because two layers have different ion transport rates, thereby limiting the rupture/rejuvenation of CFs to the bilayer interface region, which can greatly reduce the randomness of CFs in MDs. Moreover, we used the handwritten recognition dataset (i.e., the Modified National Institute of Standards and Technology (MNIST) database) for neuromorphic simulations. Furthermore, biosynaptic functions and plasticity, including spike-timing-dependent plasticity and paired-pulse facilitation, have been successfully achieved. By incorporating 2D materials and oxides into a double-layer MD, the practical application of RRAM MD can be significantly enhanced to facilitate the development of artificial synapses for brain-enhanced computing systems in the future.

Self-Assembled Networked PbS Distribution Quantum Dots for Resistive Switching and Artificial Synapse Performance Boost of Memristors.

With the advent of the era of big data, resistive random access memory (RRAM) has become one of the most promising nanoscale memristor devices (MDs) for storing huge amounts of information. However, the switching voltage of the RRAM MDs shows a very broad distribution due to the random formation of the conductive filaments. Here, self-assembled lead sulfide (PbS) quantum dots (QDs) are used to improve the uniformity of switching parameters of RRAM, which is very simple comparing with other methods. The resistive switching (RS) properties of the MD with the self-assembled PbS QDs exhibit better performance than those of MDs with pure-Ga2 O3 and randomly distributed PbS QDs, such as a reduced threshold voltage, uniformly distributed SET and RESET voltages, robust retention, fast response time, and low power consumption. This enhanced performance may be attributed to the ordered arrangement of the PbS QDs in the self-assembled PbS QDs which can efficiently guide the growth direction for the conducting filaments. Moreover, biosynaptic functions and plasticity, are implemented successfully in the MD with the self-assembled PbS QDs. This work offers a new method of improving memristor performance, which can significantly expand existing applications and facilitate the development of artificial neural systems.

Effects of acrylonitrile-induced oxidative stress on testicular apoptosis through activation of NF-κB signaling pathway in male sprague dawley rats.

Acrylonitrile (ACN) treatment can induce testicular toxicity in Sprague-Dawley (SD) rats, with the toxicity potentially related to apoptosis, mediated by nuclear factor-κB (NF-κB). The present study investigated the potential role of NF-κB in the induction of apoptosis and testicular toxicity in ACN-treated rats. Adult male SD rats were randomly divided into 3 treatment groups: a control group (corn oil), an ACN group (50 mg/kg) in which ACN was administered by gavage, and an ACN and N-acetylcysteine (ACN+NAC) group. The rats were given NAC (300 mg/kg) 30 min prior to the administration of ACN, and ACN was administered by gavage for 90 days. The ACN treatment markedly increased malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) activity in the testis. Glutathione (GSH) was significantly depleted in the ACN groups, and the effects of ACN were blocked by the anti-oxidant NAC. The ACN treatment also increased the expression of NF-κB (p65) and phosphorylated-IκB kinase (IKK)-α/ß and decreased the expression of an inhibitor of NF-κB (IκB-α). The pretreatment with NAC significantly inhibited the activation of NF-κB. In addition, the expression of Bax increased after the ACN treatment, and the induction of Bax was abolished by NAC. Taken together, the data suggested that ACN-induced oxidative stress activated the NF-κB signaling pathway, which modulated the expression of Bax and contributed to testicular apoptosis.

[Effects of pretreatment of electroacupuncture on bupivacaine poisoning in rats].

OBJECTIVE: To observe the effects of electroacupuncture (EA) pretreatment at different times for heart arrest induced by bupivacaine poisoning in rats. METHODS: With a randomized, blind, control study, 24 SD rats were divided into a control group, a EA for 60 min (EA 60) group and a EA for 30 min (EA 30) group, 8 cases in each one. Rats in the EA 60 group and EA 30 groups were treated with EA at bilateral "Neiguan" (PC 6), "Zusanli" (ST 36) and "Fenglong" (ST 40) for 60 min and 30 min respectively. While no treatment was given in the control group. Then rats were monitored by leadⅡelectrocardiograph; catheters were inserted into the femoral vein to open the vein access and into the carotis to monitor the arterial pressure. Three hours after EA, 10 mg/kg bupivacaine was injected through femoral vein. The mean arterial pressure (MAP) and heart rate (HR) were automatically recorded by PowerLab system. The time points when QRS widened by 20 percent and cardiac arrest and the survival rates were observed. RESULTS: After the injection of bupivacaine, five rats in the EA 60 group caught cardiac arrest,while all the rats in the other two groups caught it. The survival rates were not statistically significant among the three groups (P>0.05). The time of QRS widening by 20 percent in the EA 60 group was (87.4±14.8) s,which was longer than (63.6±14.2) s in the EA 30 group and (51.2±12.4) s in the control group (both P<0.05). From injection of bupivacaine to cardiac arrest, the time of (375.3±23.7) s in the EA 60 group and that of (328.3±47.7)s in the EA 30 group were more than (235.5±91.5) s in the control group (both P<0.05). After the injection, MAP and HR in the EA 60 group were higher than those in the EA 30 group and control group at most time points (all P<0.05). CONCLUSIONS: EA pretreatment apparently decreases the vulnerability of bupivacaine-induced heart arrest, with better protective effect of 60 min pretreatment than that of 30 min.

Superhydrophobic Surface With Shape Memory Micro/Nanostructure and Its Application in Rewritable Chip for Droplet Storage.

Recently, superhydrophobic surfaces with tunable wettability have aroused much attention. Noticeably, almost all present smart performances rely on the variation of surface chemistry on static micro/nanostructure, to obtain a surface with dynamically tunable micro/nanostructure, especially that can memorize and keep different micro/nanostructures and related wettabilities, is still a challenge. Herein, by creating micro/nanostructured arrays on shape memory polymer, a superhydrophobic surface that has shape memory ability in changing and recovering its hierarchical structures and related wettabilities was reported. Meanwhile, the surface was successfully used in the rewritable functional chip for droplet storage by designing microstructure-dependent patterns, which breaks through current research that structure patterns cannot be reprogrammed. This article advances a superhydrophobic surface with shape memory hierarchical structure and the application in rewritable functional chip, which could start some fresh ideas for the development of smart superhydrophobic surface.

Electroacupuncture pretreatment induces rapid tolerance to bupivacaine cardiotoxicity in rats.

BACKGROUND: Evidence suggests that electroacupuncture (EA) protects against arrhythmia and myocardial injury induced by myocardial ischaemia-reperfusion. However, to our knowledge, it remains unknown whether EA could alleviate bupivacaine-induced cardiotoxicity. Therefore, we aimed to explore the effect of EA pretreatment on bupivacaine-induced cardiac arrest and outcomes of cardiopulmonary resuscitation (CPR) in rats. METHODS: 24 adult male Sprague-Dawley rats were randomly divided into two groups: EA (n=12), and minimal acupuncture (MA) (n=12). Rats in both groups were needled at bilateral PC6, ST36, and ST40. Needles in the EA group were electrically stimulated for 60 min. ECG and invasive arterial blood pressure measurements were recorded. Two hours after EA or MA, 10 mg/kg bupivacaine was infused intravenously at a rate of 5 mg/kg/min in all rats. Rats suffering cardiac arrest were immediately subjected to CPR. At the end of the experiment, arterial blood samples were taken from surviving rats for blood gas analysis. RESULTS: The time from bupivacaine infusion until 20% prolongation of the QRS and QT interval, and the time to cardiac arrest, were notably increased among the rats pretreated with EA. Moreover, EA pretreatment significantly improved mean arterial pressure and heart rate at all monitored points after bupivacaine infusion. The proportion of animals surviving was higher in the EA group (9/12) than the MA group (3/12) at the end of experiment (p=0.039). CONCLUSIONS: Tolerance to bupivacaine-induced cardiotoxicity appeared to be increased following EA pre-treatment. The mechanism of action underlying the effects of EA on bupivacaine-induced cardiotoxicity requires further investigation.