Combination of Shengji ointment and bromelain in the treatment of exposed tendons in diabetic foot ulcers: study protocol for a non-blind, randomized, positive control clinical trial.

BACKGROUND: Diabetic foot ulcers often affect tendon tissue. Consequently, the infection may spread proximally along the tendon, leading to amputation or even the death of patients. Exposed, degenerated, and necrotic tendons are key factors affecting the healing of diabetic foot ulcers. The effective treatment of the tendon involvement may positively affect the prognosis. In clinical practice, treatment with Shengji ointment and bromelain induces islands of granulation tissue on the denatured tendon surface, which gradually grows and merges. Ideally, the exposed tendon is covered entirely by granulation tissue. This trial aims to assess the effect of a combined treatment regime of Shengji ointment, which has been shown to regenerate muscle tissue and pineapple protease in preventing the loss of function and amputation caused by tendon necrosis. This trial will provide high-quality evidence for the effectiveness of this combination in healing diabetic ulcers with tendon necrosis. METHODS: The sample size will be 180 patients who will be randomly assigned 1:1 to a treatment group (90 patients) using Shengji ointment combined with bromelain and a control group (90 patients) using hydrocolloid dressing. Both groups will continue their conventional treatments, such as blood glucose and blood pressure medication, lipid regulation, antiplatelets, and others. The primary outcome will be the wound coverage with granulation tissue. Secondary outcomes will be the wound healing rate, amputation extent (where needed), time to granulation, and the Maryland Foot Score. Other efficacy outcomes will be the time to debridement of necrotic tendon tissue and granulation tissue score. DISCUSSION: This study will treat patients with diabetic foot ulcers with exposed, degenerated, and necrotic tendons with Shengji ointment and bromelain. The trial aims to promote regeneration and healing, to preserve the limb and its function, and to develop a comprehensive and effective protocol that can be applied to promote the healing of exposed tendons in diabetic foot wounds. TRIAL REGISTRATION: ChiCTR2000039327 ; date of registration: 2020-10-23.

Predictive factors and clinical efficacy of Chinese medicine Shengji ointment in the treatment of diabetic foot ulcers in the elderly: a prospective study.

Objective: This study aims to investigate the predictive factors and efficacy of traditional Chinese medicine Shengji Ointment in the treatment of diabetic foot ulcers in the elderly population, with the intent of formulating an effective predictive model for deep diabetic foot ulcer healing. The importance of this research lies in its provision of new perspectives and tools for addressing the severe health impact of diabetic foot ulcers in the elderly population, considering the complexity and diversity of its treatment methods. Methods: The study includes 180 elderly patients with Wagner grade 3-4 diabetic foot ulcers that involve the tendon or fascia. The dependent variable is the initiation time of granulation tissue development. Independent variables encompass demographic information, a treatment strategy including Shengji Ointment, pre-treatment trauma assessment data, routine blood count, and biochemical index test results. Lasso regression is employed for variable selection, and Cox regression is utilized for the construction of a prediction model. A nomogram is generated to authenticate the model. Results: The Chinese Medicine treatment approach, ulcer location, creatinine levels, BMI, and haemoglobin levels are identified as independent predictors of granulation tissue development in diabetic foot ulcers. The combined treatment of Chinese herbal Shengji ointment and bromelain positively influenced granulation tissue development. The location of plantar ulcers, impaired renal functionality, obesity, and anaemia are established as independent risk factors that might influence the speed and probability of ulcer healing. The area under the time-dependent ROC curve fluctuates between 0.7 and 0.8, demonstrating substantial discrimination and calibration of the model. Conclusion: The study ascertains that a combined treatment strategy incorporating Shengji Ointment demonstrates greater effectiveness than the use of cleansing gel debridement alone in facilitating the healing of Wagner grade 3 or higher diabetic foot ulcers. Furthermore, the predictive model developed in this research serves as a valuable tool in evaluating the efficacy of Chinese Medicine treatments like Shengji Ointment for diabetic foot ulcers in the elderly. It aids clinicians in effectively assessing and adjusting treatment strategies, thereby proving its significant application value in clinical practice. Clinical Trial Registration: (https://www.chictr.org.cn/hvshowproject.html?id=73862&v=1.5&u_atoken=b403af53-d3b9-41ae-a7e2-db5498609b0c&u_asession=01tNh69p235bMUO4CmHIXcv8Hxirl5-557Duue9QB5lGfl3mf8IvPlcs2kN2zC30voX0KNBwm7Lovlpxjd_P_q4JsKWYrT3W_NKPr8w6oU7K_AyPrQhedMUWBMR2-ZDL_KO0uwDPR9XlF566xraDvT9mBkFo3NEHBv0PZUm6pbxQU&u_asig=05Kd_Q8fjv-24MVbZpOS9ef3xuCCN-tSVH5eUoJKgNLM7E0-n0zMpW6xLq9gh9aUhkKEEA15rdDoCydncF99APBwVSaTPgEG_V_B1iT4wimdCTxV_4ZVbTlDewxyQtE4YgU4-Oza7KPi94RJ64Utel0yZfqg3Tlm-bVxFNOY-zXFP9JS7q8ZD7Xtz2Ly-b0kmuyAKRFSVJkkdwVUnyHAIJzSYJ6SfhFl0WMTCCasZ7zV2I2qfyrp5m-SELPVeREKgX_6yRmLu26qT8kGfcS-Yaeu3h9VXwMyh6PgyDIVSG1W-7D_Sko5YQtpDbs3uvezYkZcUUY4o9-zDPaoYelmMDs8u7I4TPvtCXaPp44YUJcQ9bHr-_RmKA5V8nji3daArhmWspDxyAEEo4kbsryBKb9Q&u_aref=NNH1nHSUCE6pNvCilV%2F1MD0aERs%3D), identifier (ChiCTR2000039327).

De novo transcriptome assembly and metabolomic analysis of three tissue types in Cinnamomum cassia.

Objective: The barks, leaves, and branches of Cinnamomum cassia have been historically used as a traditional Chinese medicine, spice, and food preservative, in which phenylpropanoids are responsible compounds. However phenylpropanoid biosynthesis pathways are not clear in C. cassia. We elucidated the pathways by descriptive analyses of differentially expressed genes related to phenylpropanoid biosynthesis as well as to identify various phenylpropanoid metabolites. Methods: Chemical analysis, metabolome sequencing, and transcriptome sequencing were performed to investigate the molecular mechanisms underlying the difference of active components content in the barks, branches and leaves of C. cassia. Results: Metabolomic analysis revealed that small amounts of flavonoids, coumarine, and cinnamaldehyde accumulated in both leaves and branches. Transcriptome analysis showed that genes associated with phenylpropanoid and flavonoid biosynthesis were downregulated in the leaves and branches relative to the barks. The observed differences in essential oil content among the three tissues may be attributable to the differential expression of genes involved in the phenylpropanoid and flavonoid metabolic pathways. Conclusion: This study identified the key genes in the phenylpropanoid pathway controling the flavonoid, coumarine, and cinnamaldehyde contents in the barks, branches and leaves by comparing the transcriptome and metabolome. These findings may be valuable in assessing phenylpropanoid and flavonoid metabolites and identifying specific candidate genes that are related to the synthesis of phenylpropanoids and flavonoids in C. cassia.

A prediction model for assessing hypoglycemia risk in critically ill patients with sepsis.

BACKGROUND: Few studies have reported the risk factors or developed a risk predictive model of hypoglycemia patients with sepsis. OBJECTIVE: To develop a predictive model to assess the hypoglycemia risk in critically ill patients with sepsis. METHODS: For this retrospective study, we collected the data from the Medical Information Mart for Intensive Care III and IV (MIMIC-III and MIMIC-IV). All eligible patients from the MIMIC-III were randomly divided into the training set for development of predictive model and testing set for internal validation of the predictive model at a ratio of 8:2. Patients from the MIMIC-IV database were used as the external validation set. The primary endpoint was the occurrence of hypoglycemia. Univariate and multivariate logistic model was used to screen predictors. Adopted receiver operating characteristics (ROC) and calibration curves to estimate the performance of the nomogram. RESULTS: The median follow-up time was 5.13 (2.61-9.79) days. Diabetes, dyslipidemia, mean arterial pressure, anion gap, hematocrit, albumin, sequential organ failure assessment, vasopressors, mechanical ventilation and insulin were identified as the predictors for hypoglycemia risk in critically ill patients with sepsis. We constructed a nomogram for predicting hypoglycemia risk in critically ill patients with sepsis based on these predictors. An online individualized predictive tool: https://ghongyang.shinyapps.io/DynNomapp/. The established nomogram had a good predictive ability by ROC and calibration curves in the training set, testing set and external validation cohort. CONCLUSION: A predictive model of hypoglycemia risk was constructed, with a good ability in predicting the risk of hypoglycemia in critically ill patients with sepsis.

High-Frequency Normalizing Flow for Image Rescaling.

It is desirable to develop efficient image rescaling methods to transmit digital images with different resolutions between devices and assure visual quality. In image downscaling, the inevitable loss of high-frequency information makes the reverse upscaling highly ill-posed. Recent approaches focus on joint learning of image downscaling and upscaling (e.g., rescaling). However, existing methods still fail to recover satisfactory high-frequency signals when upscaling. To solve it, we propose high-frequency flow (HfFlow), which learns the distribution of high-frequency signals during rescaling. HfFlow is an overall invertible framework with a conditional flow on the high-frequency space to compensate for the information lost during downscaling. To facilitate finding the optimal upscaling solution, we introduce a reference low-resolution (LR) manifold and propose a cross-entropy Gaussian loss (CGloss) to force the downscaled manifold closer to the reference LR manifold and simultaneously fulfill recovering missing details. HfFlow can be generalized to other scale transformation tasks such as image colorization with its excellent rescaling capacity. Qualitative and quantitative experimental evaluations demonstrate that HfFlow restores rich high-frequency details and outperforms state-of-the-art rescaling methods in PSNR, SSIM, and perceptual quality metrics.

Integrated metabolomic and transcriptomic analyses revealed metabolite variations and regulatory networks in Cinnamomum cassia Presl from four growth years.

To understand the mechanism of the dynamic accumulation of active ingredients in Cinnamomum cassia Presl, metabolomic and transcriptomic analyses of 5~8 years old C. cassia were performed. A total of 72 phenylpropanoids, 146 flavonoids, and 130 terpenoids showed marked changes. Most phenylpropanoids and flavonoids showed markedly higher abundances in 6-year-old C. cassia than in others, which was related to the higher expression of genes that synthesize and regulate phenylpropanoids and flavonoid. We identified transcription factors (TFs) and genes involved in phenylpropanoids and flavonoids synthesis and regulation through co-expression network analyses. Furthermore, most of the terpenoids in 5-year-old C. cassia showed markedly higher abundances than in others, which was due to the differentially expressed genes upstream of the terpenoids pathway. The results of our study provide new insights into the synthesis and accumulation of phenylpropanoid, flavonoids and terpenoids in C. cassia at four growth stages.

Hepatic AMPK signaling dynamic activation in response to REDOX balance are sentinel biomarkers of exercise and antioxidant intervention to improve blood glucose control.

Antioxidant intervention is considered to inhibit reactive oxygen species (ROS) and alleviate hyperglycemia. Paradoxically, moderate exercise can produce ROS to improve diabetes. The exact redox mechanism of these two different approaches remains largely unclear. Here, by comparing exercise and antioxidant intervention on type 2 diabetic rats, we found moderate exercise upregulated compensatory antioxidant capability and reached a higher level of redox balance in the liver. In contrast, antioxidant intervention achieved a low-level redox balance by inhibiting oxidative stress. Both of these two interventions could promote glucose catabolism and inhibit gluconeogenesis through activation of hepatic AMP-activated protein kinase (AMPK) signaling; therefore, ameliorating diabetes. During exercise, different levels of ROS generated by exercise have differential regulations on the activity and expression of hepatic AMPK. Moderate exercise-derived ROS promoted hepatic AMPK glutathionylation activation. However, excessive exercise increased oxidative damage and inhibited the activity and expression of AMPK. Overall, our results illustrate that both exercise and antioxidant intervention improve blood glucose control in diabetes by promoting redox balance, despite different levels of redox state(s). These results indicate that the AMPK signaling activation, combined with oxidative damage markers, could act as sentinel biomarkers, reflecting the threshold of redox balance that is linked to effective glucose control in diabetes. These findings provide theoretical evidence for the precise management of diabetes by antioxidants and exercise.

Molecules known as reactive oxygen species or ROS play vital roles in healthy cells. However, ROS can act as a double-edged sword: if their levels become too high, they can be harmful and interfere with many physiological processes. Indeed, diabetes, high blood pressure and many other chronic diseases are associated with imbalances in the levels of ROS in the body. To counter high ROS levels, cells have antioxidant mechanisms that reduce the excess ROS in the cell and keep the 'redox' (from reduction and oxidation) balance of the cell. Exercise and antioxidant nutritional supplements have attracted much attention as drug-free interventions for diabetes. Both strategies alter the levels of ROS in the body, with exercise increasing the levels of ROS, and antioxidant supplements reducing them. Individuals with diabetes and other metabolic health issues have different ROS levels depending on the severity of the disease, age, genetics and other factors, leading to different redox states in their cells. Thus, approaches that can accurately evaluate the redox balance status of individuals are necessary for clinicians to identify what types of exercise and antioxidant supplements are beneficial and which treatments are most appropriate for each patient. Wu, Zhao, Yan, Gao et al. examined the effects of exercise and antioxidant supplements on rats with diabetes, with the aim of identifying molecules ­ also known as biomarkers ­ that reflect the bodies' redox balance. They found that moderate exercise increased the levels of ROS in the liver, which, in turn, compensated by increasing the production of antioxidants to protect against the higher levels of ROS. This resulted in a healthy 'high-level' redox balance, in which both ROS and antioxidants levels were high in the rats. On the other hand, giving the rats antioxidant supplements decreased their levels of ROS, leading to a healthy low-level redox balance with low levels of ROS. These findings indicate that regular moderate exercise may be appropriate for people with pre-diabetes symptoms to restore a healthy redox balance. This is because the compensatory antioxidant mechanisms that kick in during exercise may be enough to counteract the excessive levels of ROS in these people. For patients with mild diabetes, exercise, antioxidant supplements, or a combination of both may be appropriate treatment, depending on their levels of ROS. Finally, patients with severe diabetes, who already have high levels of ROS, may benefit from antioxidant supplements to help reduce their excessive levels of ROS. In the future, the biomarkers identified by Wu, Zhao, Yan, Gao et al. may be used to monitor and assess the change in the redox balance status of various populations and guide personalized interventions to maintain health. Additionally, these findings provide a new strategy for precision prevention and treatment of diabetes and other metabolic diseases.

PEGylated Recombinant Human Growth Hormone Jintrolong® Exhibits Good Long-Term Safety in Cynomolgus Monkeys and Human Pediatric Growth Hormone Deficiency Patients.

Jintrolong® is a long-acting PEGylated recombinant human growth hormone (PEG-rhGH) developed for weekly injection in patients with pediatric growth hormone deficiency (PGHD). Although PEG modification of therapeutic proteins is generally considered safe, concerns persist about the potential for adverse vacuolation in tissues with long-term exposure to PEG-included therapies, particularly in children. We assessed the safety of Jintrolong® in cynomolgus monkeys with an examination of vacuolation in the brain choroid plexus (CP) and reported long-term clinical safety data obtained from children with PGHD. The toxicity of Jintrolong® was assessed following the 52-week administration with doses at 0.3, 1, or 3 mg/kg/week. The levels of vacuolation of CP in animals were dose-dependent and at least partially reversible after a 104- or 157-week recovery period. Vacuolation in the CP epithelium did not lead to obvious subcellular structural or cell functional abnormalities. Compared with the clinical dose of 0.2 mg/kg/week Jintrolong® in PGHD patients, exposure in monkeys under NOAEL 3 mg/kg/week exhibited safety margins greater than 120.5, the predicted minimum dose to induce vacuolation in monkeys is equivalent to 1.29 mg/kg/week in humans, which is 6.45-fold higher than the clinical dose. The safety data acquired in clinical trials for Jintrolong® were also analyzed, which included phase III (360 patients), phase IV (3,000 patients) of 26-week treatment, and a follow-up study with treatment lasting for 3 years. There was no statistically significant difference in the incidence of adverse reactions between the Jintrolong® group and the daily rhGH control group (no PEG), and no new adverse effects (AE) were observed in the Jintrolong® group at the clinical therapeutic dose of 0.2 mg/kg/week.

Critical roles of the activation of ethylene pathway genes mediated by DNA demethylation in Arabidopsis hyperhydricity.

Hyperhydricity (HH) often occurs in plant tissue culture, seriously influencing the commercial micropropagation and genetic improvement. DNA methylation has been studied for its function in plant development and stress responses. However, its potential role in HH is unknown. In this study, we report the first comparative DNA methylome analysis of normal and hyperhydric Arabidopsis thaliana (L.) Heynh. seedlings using whole-genome bisulfite sequencing (BS-seq). We found that the global methylation level decreased in hyperhydric seedlings, and most of the differentially methylated genes were CHH hypomethylated genes. Moreover, the bisulfite sequencing results showed that hyperhydric seedlings displayed CHH demethylation patterns in the promoter of the ACS1 and ETR1 genes, resulting in upregulated expression of both genes and increased ethylene accumulation. Furthermore, hyperhydric seedling displayed reduced stomatal aperture accompanied by decreased water loss and increased phosphorylation of aquaporins accompanied by increased water uptake. While silver nitrate (AgNO3 ) prevented HH by maintained the degree of methylation in the promoter regions of ACS1 and ETR1 and downregulated the transcription of both genes. AgNO3 also reduced the content of ethylene together with the phosphorylation of aquaporins and water uptake. Taken together, this study suggested that DNA demethylation is a key switch that activates ethylene pathway genes to enable ethylene synthesis and signal transduction, which may subsequently influence aquaporin phosphorylation and stomatal aperture, eventually causing HH; thus, DNA demethylation plays a crucial role in HH. These results provide insights into the epigenetic regulation mechanism of HH and confirm the role of ethylene and AgNO3 in hyperhydricity control.

Graph U-Nets.

We consider the problem of representation learning for graph data. Given images are special cases of graphs with nodes lie on 2D lattices, graph embedding tasks have a natural correspondence with image pixel-wise prediction tasks such as segmentation. While encoder-decoder architectures like U-Nets have been successfully applied to image pixel-wise prediction tasks, similar methods are lacking for graph data. This is because pooling and up-sampling operations are not natural on graph data. To address these challenges, we propose novel graph pooling and unpooling operations. The gPool layer adaptively selects some nodes to form a smaller graph based on their scalar projection values. We further propose the gUnpool layer as the inverse operation of the gPool layer. Based on our proposed methods, we develop an encoder-decoder model, known as the graph U-Nets. Experimental results on node classification and graph classification tasks demonstrate that our methods achieve consistently better performance than previous models. Along this direction, we extend our methods by integrating attention mechanisms. Based on attention operators, we proposed attention-based pooling and unpooling layers, which can better capture graph topology information. The empirical results on graph classification tasks demonstrate the promising capability of our methods.

Topology-Aware Graph Pooling Networks.

Pooling operations have shown to be effective on computer vision and natural language processing tasks. One challenge of performing pooling operations on graph data is the lack of locality that is not well-defined on graphs. Previous studies used global ranking methods to sample some of the important nodes, but most of them are not able to incorporate graph topology. In this work, we propose the topology-aware pooling (TAP) layer that explicitly considers graph topology. Our TAP layer is a two-stage voting process that selects more important nodes in a graph. It first performs local voting to generate scores for each node by attending each node to its neighboring nodes. The scores are generated locally such that topology information is explicitly considered. In addition, graph topology is incorporated in global voting to compute the importance score of each node globally in the entire graph. Altogether, the final ranking score for each node is computed by combining its local and global voting scores. To encourage better graph connectivity in the sampled graph, we propose to add a graph connectivity term to the computation of ranking scores. Results on graph classification tasks demonstrate that our methods achieve consistently better performance than previous methods.

[Systematic review and Meta-analysis of safety of Sanfu acupoint herbal patching in randomized controlled trial].

In order to systematically evaluate the safety of Sanfu acupoint herbal patching, CNKI, SinoMed, VIP, Wanfang, PubMed, Medline, EMbase, and Cochrane Library were searched in accordance with PICOS principles, with a time limit from database establishment to December 2019. Meta-analysis was used for a single-group rate analysis and a weighted combination of these two groups on rates of adverse reactions. A total of 9 articles meeting the inclusion criteria were included in the analysis, involving 2 119 patients. The single-group rate Meta-analysis showed that the adverse reactions incidence was 9% in the treatment group(OR=0.10,95%CI[0.06, 0.19], P<0.000 01), and 9% in the control group(OR=0.10, 95%CI[0.07, 0.13], P<0.000 01). In combined statistics of all samples OR=1.81, 95%CI[1.04, 3.15], P=0.04, the incidence of adverse reactions in the treatment group was slightly higher than that of the control group. In the subgroup analysis, the incidence of adverse reactions in terms of both single-group rate and weighed rate in the treatment group was higher than that in the control group in the asthma subgroup, rhinitis subgroup, ≥18 years old subgroup, and application time 2 h subgroup, with statistically significant differences(P<0.05). The results of the Meta-analysis and systematic review suggested that the incidence of adverse reactions in clinical use of the Sanfu acupoints herbal patching was relatively low. The main types of adverse reactions were skin ulcers, blisters and other skin symptoms. The symptoms were relatively mild, which could be relieved by drug withdrawal or symptomatic treatment. It shows that the safety of the Sanfu acupoint herbal patching was relatively high, and the occurrence of adverse reactions was related to the original disease and age, mainly in asthma and rhinitis or patients over 40 years old. Affected by clinical heterogeneity, the conclusions of the application time subgroup need to be further improved.

ChannelNets: Compact and Efficient Convolutional Neural Networks via Channel-Wise Convolutions.

Convolutional neural networks (CNNs) have shown great capability of solving various artificial intelligence tasks. However, the increasing model size has raised challenges in employing them in resource-limited applications. In this work, we propose to compress deep models by using channel-wise convolutions, which replace dense connections among feature maps with sparse ones in CNNs. Based on this novel operation, we build light-weight CNNs known as ChannelNets. ChannelNets use three instances of channel-wise convolutions; namely group channel-wise convolutions, depth-wise separable channel-wise convolutions, and the convolutional classification layer. Compared to prior CNNs designed for mobile devices, ChannelNets achieve a significant reduction in terms of the number of parameters and computational cost without loss in accuracy. Notably, our work represents an attempt to compress the fully-connected classification layer, which usually accounts for about 25 percent of total parameters in compact CNNs. Along this new direction, we investigate the behavior of our proposed convolutional classification layer and conduct detailed analysis. Based on our in-depth analysis, we further propose convolutional classification layers without weight-sharing. This new classification layer achieves a good trade-off between fully-connected classification layers and the convolutional classification layer. Experimental results on the ImageNet dataset demonstrate that ChannelNets achieve consistently better performance compared to prior methods.

[Advances in quality research of Cinnamomum cassia].

Cinnamomum cassis is one of the commonly used traditional Chinese medicines in China. Its genuine producing areas distribute in Guangdong and Guangxi provinces. As an important edible herb and export variety of China, the quality control and internationalization of quality standards of C. cassis is extremely significant. In the recent years, with the development of the cinnamon industry, relevant academic research and the upgrade of the international standards, it is necessary to summarize the quality-related progress of C. cassis. In the present review, the germplasm resources, specific quality marker(Q-marker) and quality standards of C. cassis were summarized on the basis of published research during the last 10 years.

Podocyte infolding glomerulopathy with undifferentiated connective tissue disease: a case report.

Podocyte infolding glomerulopathy (PIG) is a special type of glomerular disease that has been proposed in recent years and has attracted considerable attention. PIG is characterized by the formation of microspheres and microtubules in thickened glomerular basement membrane (GBM) on electron microscopy (EM), which is recognized as podocyte cytoplasmic infolding to the GBM. However, to date, only a few cases of PIG have been reported. Herein, we report a case of a 33-year-old female with PIG with undifferentiated connective tissue disease (UCTD) in China and review the literature.

Pixel Transposed Convolutional Networks.

Transposed convolutional layers have been widely used in a variety of deep models for up-sampling, including encoder-decoder networks for semantic segmentation and deep generative models for unsupervised learning. One of the key limitations of transposed convolutional operations is that they result in the so-called checkerboard problem. This is caused by the fact that no direct relationship exists among adjacent pixels on the output feature map. To address this problem, we propose the pixel transposed convolutional layer (PixelTCL) to establish direct relationships among adjacent pixels on the up-sampled feature map. Our method is based on a fresh interpretation of the regular transposed convolutional operation. The resulting PixelTCL can be used to replace any transposed convolutional layer in a plug-and-play manner without compromising the fully trainable capabilities of original models. The proposed PixelTCL may result in slight decrease in efficiency, but this can be overcome by an implementation trick. Experimental results on semantic segmentation demonstrate that PixelTCL can consider spatial features such as edges and shapes and yields more accurate segmentation outputs than transposed convolutional layers. When used in image generation tasks, our PixelTCL can largely overcome the checkerboard problem suffered by regular transposed convolutional operations.

Liver-targeted Nano-MitoPBN normalizes glucose metabolism by improving mitochondrial redox balance.

Recent advances in Nanomedicine provide promising disease treatment through improved drug delivery efficiency, but clinical applications have encountered difficulties, largely due to the majority of injected nanoparticle is sequestered in liver. In contrast, liver cells seem to be a perfect target for nanoparticles. Here we generated a new formula of liposome encapsulated Nano-MitoPBN as a liver mitochondrial-targeting free radical scavenger. We found that Nano-MitoPBN mainly accumulated in hepatocytes and scavenged hepatic mitochondrial superoxide/hydrogen peroxide generated from mono-electron leak of electron transport chain (ETC) complex I and III. Due to micro-compartmentalization, Nano-MitoPBN increased mitochondrial state 3 respiratory rate and respiratory control ratio (RCR), resulting in decreased NADH:NAD+ ratio, improved mitochondrial oxidative energy coupling and ATP synthesis, thus alleviating ROS-induced mitochondrial dysfunction. The functional mitochondria promoted the substrate oxidation by the liver, resulting in increased glycolysis and TCA cycle, which directly speeds glucose decomposition, thus decreasing the peripheral blood glucose level and improving the impaired glucose tolerance in diabetic animals. Our study suggests the potential of liver mitochondrial targeting antioxidative nanomedicines for diabetes mellitus.

High glucose-induced apoptosis and necroptosis in podocytes is regulated by UCHL1 via RIPK1/RIPK3 pathway.

Diabetic nephrology (DN) is attributed largely to the depletion of podocytes, which is closely associated to apoptosis. However, the complex mechanism of podocyte loss in DN pathogenesis remains unclear. Recently, necroptosis has emerged as an important cell death model in many pathological conditions, which is regulated through RIPK1/RIPK3 pathway. In addition, necroptosis was found to share several upstream signaling pathways with apoptosis. Therefore, it was speculated that both apoptosis and necroptosis may occur in podocytes during the process of podocyte injury in DN. Herein, necroptosis and apoptosis were shown to be involved in podocyte injury induced by high glucose (HG), both in vitro and in vivo, with a high level of positive signaling markers RIPK1 (298.4 ±â€¯17.35), cleaved caspase 3 (497.1 ±â€¯23.09), RIPK3 (108.4 ±â€¯14.92), and MLKL (470.4 ±â€¯15.73) than the control groups. Scaning electron microscopy examination revealed the morphological characteristics of necroptotic and apoptotic cells, which differed remarkably. z-VAD-fmk, a pan-inhibitor of apoptosis, could block apoptosis and enhance necroptosis. Furthermore, UCHL1 was found to play a major role in promoting podocyte necroptosis by regulating the ubiquitination state of the RIPK1/RIPK3 pathway. The half-life of RIPK1 and RIPK3 proteins reduced and the expression of RIPK1, RIPK3, and MLKL decreased significantly after the knockdown of UCHL1. It was shown that UCHL1 exerted a more regulatory response to necroptosis. These data suggested that necroptosis may have more effect on the loss of podocytes than apoptosis in DN with the regulation of UCHL1. Thus, inhibiting UCHL1 to downregulate the RIPK1/RIPK3 pathway may be a novel strategy to protect the podocytes in DN patients.

Pharmacokinetics and safety evaluation in healthy Chinese volunteers of alkaloids from leaf of Alstonia scholaris: A multiple doses phase I clinical trial.

BACKGROUND: Alstonia scholaris (Apocynaceae) was reported to be a rich source of indole alkaloids, which exhibited remarkably bioactivities. The leaf of A. scholaris has been used in 'dai' ethno-medicine for treatment of respiratory diseases, and the defined indole alkaloids from leaf of A. scholaris has been registered as investigational new botanical drug (No. 2011L01436) and was approved for phase I/II clinical trials by China Food and Drug Administration (CFDA). PURPOSE: The aim of the trial is to evaluate the safety and explore the relationship of dosing frequency and pharmacokinetics after oral administration of capsule of alkaloids from leaf of A. scholaris (CALAS) at different doses. METHODS: In this randomized, open-labelled, single-center clinical trial, the safety and pharmacokinetics of CALAS were assessed in eligible healthy Chinese volunteers after oral administration of different doses. Each volunteer (n = 10 per group) received single dose of CALAS from 20 mg, 40 mg, 80 mg to 120 mg orally. The pharmacokinetics of CALAS was investigated in healthy Chinese subjects' plasma by a fully-validated LC-MS/MS method. Safety was assessed biochemically and clinically throughout the study, and drug re-excitation research was conducted to verify the correlation between investigational product and minor adverse events. The trial was registered on August 26, 2015 (http://www.chictr.org.cn/showproj.aspx?proj=11736), number ChiCTR-IPR-15006976. RESULTS: 40 subjects completed the study, and as a result, vallesamine had the highest concentration in plasma of healthy volunteers, and the AUC exposure level in each compounds in turn is vallesamine > scholaricine > 19-epischolaricine > picrinine. For the safety evaluation of CALAS, two cases of minor adverse events were observed during the trial, but the drug re-excitation research indicated that these two adverse events were related to the individual's physiological variation. CONCLUSION: Pharmacokinetic characteristics of each ingredient showed different patterns. 19-epischolaricine, vallesamine and picrinine were match to the linear pharmacokinetic characteristics, but scholaricine conformed to the characteristics of nonlinear pharmacokinetics. The CALAS was safe in healthy subjects under the current dose regimen.

Rosuvastatin- and Heparin-Loaded Poly(l-lactide- co-caprolactone) Nanofiber Aneurysm Stent Promotes Endothelialization via Vascular Endothelial Growth Factor Type A Modulation.

This study explored a new rosuvastatin calcium- and heparin-loaded poly(l-lactide- co-caprolactone) (PLCL) scaffold for covered stents for treating aneurysms. The mechanism of rosuvastatin-induced endothelialization via vascular endothelial growth factor (VEGF)-A elevation was further explored. Rosu50, Rosu75, Rosu100, and phosphate-buffered saline (PBS) nanofibrous scaffolds were fabricated by coaxial electrospinning and observed by electron microscopy. Anticoagulation and pro-endothelialization properties were tested. Sixteen rabbits were selected for an in vivo assay and underwent microsurgery to establish a carotid aneurysm model. The animals were treated with covered stents and followed for 4 months using digital subtraction angiography (DSA), electron microscopy, and histology. Rosuvastatin-treated human umbilical vein endothelial cell (HUVEC) viability, function, and VEGF-A modulation were further studied to elucidate the pro-endothelialization mechanism of rosuvastatin. Our study demonstrates that rosuvastatin and heparin can be incorporated into PLCL nanofibers via electrospinning. Rosu100 nanofiber scaffolds exhibited significant anticoagulation properties. The viability of HUVECs transferred to Rosu100 nanofiber scaffolds was increased significantly. In vivo, DSA revealed that the Rosu100 group had better outcomes than the PBS group. In addition, the Rosu100 stents induced more integrated endothelialization. Further study demonstrated that rosuvastatin promoted HUVEC viability and function in vitro. The effects of rosuvastatin may be attributed to an elevation in VEGF-A. We demonstrated that rosuvastatin- and heparin-loaded PLCL-covered stents show favorable anticoagulation and pro-endothelialization properties in vitro and in vivo in a rabbit aneurysm model. VEGF-A elevation played a crucial role in rosuvastatin-promoted endothelialization. This work provides an additional option for treating cerebral aneurysms with covered stents.