USP28 Serves as a Key Suppressor of Mitochondrial Morphofunctional Defects and Cardiac Dysfunction in the Diabetic Heart.

BACKGROUND: The majority of people with diabetes are susceptible to cardiac dysfunction and heart failure, and conventional drug therapy cannot correct diabetic cardiomyopathy progression. Herein, we assessed the potential role and therapeutic value of USP28 (ubiquitin-specific protease 28) on the metabolic vulnerability of diabetic cardiomyopathy. METHODS: The type 2 diabetes mouse model was established using db/db leptin receptor-deficient mice and high-fat diet/streptozotocin-induced mice. Cardiac-specific knockout of USP28 in the db/db background mice was generated by crossbreeding db/m and Myh6-Cre+/USP28fl/fl mice. Recombinant adeno-associated virus serotype 9 carrying USP28 under cardiac troponin T promoter was injected into db/db mice. High glucose plus palmitic acid-incubated neonatal rat ventricular myocytes and human induced pluripotent stem cell-derived cardiomyocytes were used to imitate diabetic cardiomyopathy in vitro. The molecular mechanism was explored through RNA sequencing, immunoprecipitation and mass spectrometry analysis, protein pull-down, chromatin immunoprecipitation sequencing, and chromatin immunoprecipitation assay. RESULTS: Microarray profiling of the UPS (ubiquitin-proteasome system) on the basis of db/db mouse hearts and diabetic patients' hearts demonstrated that the diabetic ventricle presented a significant reduction in USP28 expression. Diabetic Myh6-Cre+/USP28fl/fl mice exhibited more severe progressive cardiac dysfunction, lipid accumulation, and mitochondrial disarrangement, compared with their controls. On the other hand, USP28 overexpression improved systolic and diastolic dysfunction and ameliorated cardiac hypertrophy and fibrosis in the diabetic heart. Adeno-associated virus serotype 9-USP28 diabetic mice also exhibited less lipid storage, reduced reactive oxygen species formation, and mitochondrial impairment in heart tissues than adeno-associated virus serotype 9-null diabetic mice. As a result, USP28 overexpression attenuated cardiac remodeling and dysfunction, lipid accumulation, and mitochondrial impairment in high-fat diet/streptozotocin-induced type 2 diabetes mice. These results were also confirmed in neonatal rat ventricular myocytes and human induced pluripotent stem cell-derived cardiomyocytes. RNA sequencing, immunoprecipitation and mass spectrometry analysis, chromatin immunoprecipitation assays, chromatin immunoprecipitation sequencing, and protein pull-down assay mechanistically revealed that USP28 directly interacted with PPARα (peroxisome proliferator-activated receptor α), deubiquitinating and stabilizing PPARα (Lys152) to promote Mfn2 (mitofusin 2) transcription, thereby impeding mitochondrial morphofunctional defects. However, such cardioprotective benefits of USP28 were largely abrogated in db/db mice with PPARα deletion and conditional loss-of-function of Mfn2. CONCLUSIONS: Our findings provide a USP28-modulated mitochondria homeostasis mechanism that involves the PPARα-Mfn2 axis in diabetic hearts, suggesting that USP28 activation or adeno-associated virus therapy targeting USP28 represents a potential therapeutic strategy for diabetic cardiomyopathy.

A theoretical base for non-invasive prenatal paternity testing.

There is an increasing demand for prenatal paternity testing in the forensic applications, which identify biological fathers before the birth of children. Currently, one of the most effective and safe Non-Invasive Prenatal Paternity Testing (NIPPT) methods is high-throughput Next-Generation Sequencing (NGS)-based SNP genotyping of cell-free DNA in maternal peripheral blood. To the best of our knowledge, nearly all methods being used in such applications are based on traditional postnatal paternity tests and/or statistical models of conventional polymorphism sites. These methods have shown unsatisfactory performance due to the uncertainty of fetal genotype. In this study, we propose a cutting-edge methodology called the Prenatal paternity Test Analysis System (PTAS) for cell-free fetal DNA-based NIPPT using NGS-based SNP genotyping. With the implementation of our proposed PTAS methodology, 63 out of 64 early-pregnancy (i.e., less than seven weeks) samples can be precisely identified to determine paternity, except for one sample that does not meet quality control requirements. Although the fetal fraction of the non-identified sample is extremely low (0.51%), its paternity can still be detected by our proposed PTAS methodology through unique molecular identifier tagging. Paternity of the total 313 samples for mid-to-late pregnancy (i.e., more than seven weeks) can be accurately identified. Extensive experiments indicate that our methodology makes a significant breakthrough in the NIPPT theory and will bring substantial benefits to forensic applications.

Long-Term Activation of Glucagon-like peptide-1 receptor by Dulaglutide Prevents Diabetic Heart Failure and Metabolic Remodeling in Type 2 Diabetes.

Background Mechanistic insights of glucagon-like peptide-1 receptor agonists remain incompletely identified, despite the efficacy in heart failure observed in clinical trials. Here, we evaluated the effects of dulaglutide on heart complications and illuminated its underlying mechanism. Methods and Results We used mice with high-fat diet (HFD)/streptozotocin-induced type 2 diabetes to investigate the effects of dulaglutide upon diabetic cardiac dysfunction. After the onset of diabetes, control and diabetic mice were injected subcutaneously with either dulaglutide (type 2 diabetes-dulaglutide and control-dulaglutide groups) or vehicle (type 2 diabetes-vehicle and control-vehicle groups) for 8 weeks. Subsequently, heart characteristics, cardiometabolic profile and mitochondrial morphology and function were evaluated. Also, we analyzed the effects of dulaglutide on neonatal rat ventricular myocytes treated with high glucose plus palmitic acid. In addition, wild type and AMP-activated protein kinase α2 mutant mice were used to evaluate the underlying mechanism. In type 2 diabetes mouse model, dulaglutide ameliorated insulin resistance, improved glucose tolerance, reduced hyperlipidemia, and promoted fatty acid use in the myocardium. Dulaglutide treatment functionally attenuated cardiac remodeling and dysfunction and promoted metabolic reprogramming in diabetic mice. Furthermore, dulaglutide improved mitochondria fragmentation in myocytes, and simultaneously reinstated mitochondrial morphology and function in diabetic hearts. We also found that dulaglutide preserved AMP-activated protein kinase α2-dependent mitochondrial homeostasis, and the protective effects of dulaglutide on diabetic heart was almost abated by AMP-activated protein kinase α2 knockout. Conclusions Dulaglutide prevents diabetic heart failure and favorably affects myocardial metabolic remodeling by impeding mitochondria fragmentation, and we suggest a potential strategy to develop a long-term activation of glucagon-like peptide-1 receptor-based therapy to treat diabetes associated cardiovascular complications.

A Novel Crowdsourcing Model for Micro-Mobility Ride-Sharing Systems.

Substantial research is required to ensure that micro-mobility ride sharing provides a better fulfilment of user needs. This study proposes a novel crowdsourcing model for the ride-sharing system where light vehicles such as scooters and bikes are crowdsourced. The proposed model is expected to solve the problem of charging and maintaining a large number of light vehicles where these efforts will be the responsibility of the crowd of suppliers. The proposed model consists of three entities: suppliers, customers, and a management party responsible for receiving, renting, booking, and demand matching with offered resources. It can allow suppliers to define the location of their private e-scooters/e-bikes and the period of time they are available for rent. Using a dataset of over 9 million e-scooter trips in Austin, Texas, we ran an agent-based simulation six times using three maximum battery ranges (i.e., 35, 45, and 60 km) and different numbers of e-scooters (e.g., 50 and 100) at each origin. Computational results show that the proposed model is promising and might be advantageous to shift the charging and maintenance efforts to a crowd of suppliers.

A Wearable Flow-MIMU Device for Monitoring Human Dynamic Motion.

For personalized rehabilitation or sports training, it is necessary to monitor dynamic motions and track postures of human body and limbs. Traditional methods using micro inertial sensors usually suffer from drift problems in tracking dynamic motions. In this paper, a wearable flow-MIMU human motion capture device is proposed by incorporating micro flow sensor with micro inertial measurement unit (MIMU). Motion velocity is detected by a micro flow sensor and utilized to figure out the motion acceleration. The gravity accelerations are extracted by eliminating the motion accelerations from the accelerometer outputs. Finally, posture estimation is implemented by using a tailor-designed Kalman-based data fusion of the gyroscope outputs and the extracted gravity accelerations. The flow-MIMU device with wireless communication is designed like a watch to be wearable. Experimental results validate that the motion velocity, acceleration and posture of human limb are determined accurately and free of accumulative error in monitoring of dynamic motions using the proposed method. The wearable flow-MIMU device provides an advantageous monitoring approach for applications of personalized rehabilitation, sports training, intelligent prosthetics, etc.

A Wearable Human Motion Tracking Device Using Micro Flow Sensor Incorporating a Micro Accelerometer.

OBJECTIVE: This paper proposes a wearable human motion tracking device using micro flow sensor incorporating a micro accelerometer, which allows detecting postures of human limbs in dynamic motions. METHODS: A micro flow sensor is used to detect motion velocity, from which, motion acceleration can be estimated. Thereby, the limb postures are figured out by using the components of the gravity acceleration that are determined by subtracting the motion accelerations from the accelerometer outputs. The motion tracking device is packaged in a watch-type case, which allows it to be wearable. A Kalman filter is employed to implement sensor data fusion. RESULTS: The motion velocity, motion acceleration, and postures of human limbs can be effectively detected by the proposed motion tracking device and methodology. Experiments including human limb tracking are conducted to validate the effectiveness of the proposed device and methodology. CONCLUSION: The experimental results show that the measurements of human limb motion and posture are feasible and free of accumulative errors. SIGNIFICANCE: The flow-aid motion tracking device is wearable, environmental-restriction free, and practicable for long-term monitoring, and provides a promising approach for physical rehabilitation, intelligent prosthesis, personal athletic training, etc.

Experimental dataset for optimising the freight rail operations.

The freight rail systems have an essential role to play in transporting the commodities between the delivery and collection points at different locations such as farms, factories and mills. The fright transport system uses a daily schedule of train runs to meet the needs of both the harvesters and the mills (An Integrated Approach to Optimise Cane Rail Operations (M. Masoud, E. Kozan, G. Kent, Liu, Shi Qiang, 2016b) [1]). Producing an efficient daily schedule to optimise the rail operations requires integration of the main elements of harvesting, transporting and milling in the value chain of the Australian agriculture industry. The data utilised in this research involve four main tables: sidings, harvesters, sectional rail network and trains. The utilised data were collected from Australian sugar mills as a real application. Operations Research techniques such as metaheuristic and constraint programming are used to produce the optimised solutions in an analytical way.

System Error Compensation Methodology Based on a Neural Network for a Micromachined Inertial Measurement Unit.

Errors compensation of micromachined-inertial-measurement-units (MIMU) is essential in practical applications. This paper presents a new compensation method using a neural-network-based identification for MIMU, which capably solves the universal problems of cross-coupling, misalignment, eccentricity, and other deterministic errors existing in a three-dimensional integrated system. Using a neural network to model a complex multivariate and nonlinear coupling system, the errors could be readily compensated through a comprehensive calibration. In this paper, we also present a thermal-gas MIMU based on thermal expansion, which measures three-axis angular rates and three-axis accelerations using only three thermal-gas inertial sensors, each of which capably measures one-axis angular rate and one-axis acceleration simultaneously in one chip. The developed MIMU (100 × 100 × 100 mm³) possesses the advantages of simple structure, high shock resistance, and large measuring ranges (three-axes angular rates of ±4000°/s and three-axes accelerations of ± 10 g) compared with conventional MIMU, due to using gas medium instead of mechanical proof mass as the key moving and sensing elements. However, the gas MIMU suffers from cross-coupling effects, which corrupt the system accuracy. The proposed compensation method is, therefore, applied to compensate the system errors of the MIMU. Experiments validate the effectiveness of the compensation, and the measurement errors of three-axis angular rates and three-axis accelerations are reduced to less than 1% and 3% of uncompensated errors in the rotation range of ±600°/s and the acceleration range of ± 1 g, respectively.

Laparoscopy-assisted total gastrectomy with trans-orally inserted anvil (OrVil™): a single institution experience.

AIM: To investigate the feasibility of laparoscopy-assisted total gastrectomy (LATG) using trans-orally inserted anvil (OrVil™) in terms of operative characteristics and short term outcomes. RESULTS: Characteristics of 27 patients with gastric cancer who underwent LATG from October 2009 to October 2012 in the Foshan Affiliated Hospital of South Medical University were retrospectively reviewed. Among these patients, six were reconstructed by mini-laparotomy and 21 by OrVil™. The clinicopathological characteristics, total operation time, total blood loss, abdominal incision and complications of anastomosis including stenosis and leakage, were compared between the groups undergoing LATG with OrVil™ and the group undergoing mini-laparotomy. RESULTS: The operations were successfully performed on all the patients without intraoperative complications or conversion to open surgery. Two (10%) patients received palliative procedure under laparoscope who were prepared for LATG preoperatively. One case had hepatic metastatic carcinoma and 1 case had tumor recurrence near the anastomosis 8 mo after surgery. The mean follow-up duration was 10 mo (range, 2-24 mo). Operation time was significantly reduced by the use of OrVil™ (198.42 ± 30.28 min vs 240.83 ± 8.23 min). The postoperative course with regard to occurrence of stenosis and leakage was not different between the two groups. There were no significant differences in estimated blood loss. The upper abdominal incision was smaller in OrVil™ group than in mini-laparotomy group (4.31 ± 0.45 cm vs 6.43 ± 0.38 cm). CONCLUSION: LATG using OrVil™ is a technically feasible surgical procedure with sufficient lymph node dissection, less operation time and acceptable morbidity.

Synthesis and structure of nitrogen bridged calix[5]- and -[10]-pyridines and their complexation with fullerenes.

Azacalix[5]pyridine, a heteroatom bridged calixaromatic with an odd number of arene units, and azacalix[10]pyridine, a giant molecular belt, were selectively synthesized based on a 2 + 3 macrocyclic coupling strategy; both novel macrocyclic hosts formed strong 1 : 1 complexes with fullerenes C60 and C70 in a size-selective manner with association constants up to 1.3 x 10(5) +/- 0.03 x 10(5) M(-1).

[Childhood upper respiratory infection caused by Mycoplasma pneumoniae].

OBJECTIVE: This study was designed to investigate the prevalence, clinical characteristics and outcome of upper respiratory infection (URI) caused by Mycoplasma pneumoniae (MP) in children. METHODS: Pharyngeal cultures for MP antibody were performed in 960 children with acute URI. The samples were randomly collected from the outpatient room or emergency room (Observed group). Of the Observed group, there were 232 cases under 1 year of age, and the remainder, were between 1-12 years old. The samples from 100 healthy children aged from 6 months to 12 years were used as the Control group. The prevalence of MP infection between the two groups was compared. The clinical manifestations and the outcome between the patients with MP positive and negative were compared. RESULTS: MP antibody was positive in 31.7% (304/960) of the Observed group but only 9.0% (9/100) in the Control group (P < 0.05). The URI patients under 1 year of age had a lower positive rate of MP than those over 1 year old (P < 0.05). Coughs and tonsillitis were more common (P < 0.05), but catarrh, gastroenteritic symptoms, herpes, and tetter were rare (P < 0.01) in URI patients with MP positive compared with those with MP negative. Pneumonia developed in 14.8% of the patients with MP positive but only 7.0% in those with MP negative (P < 0.01). CONCLUSIONS: MP is one of the main pathogens of acute URI in children. Acute pharyngotonsillitis symptoms are predominately presented in children with MP infection. MP infection was commonly seen in children over 1 year old and they are prone to develop pneumonia.

[Isolation, expression analysis of a chilling induced cDNA from rice root with differential display: an evidence role for caffeine-sensitive calcium signal].

Chilling-sensitive rice varieties acquire chilling tolerance when their roots are exposed to water stress for short time. Caffeine-sensitive calcium signal was involved in this procedure. By using total RNA differential display, a chilling induced cDNA(ICT: induction of chilling treatment) was isolated from roots of chilling-sensitive rice variety. It was determined that it is a novel cDNA by homology searching. The transcript level of ict mRNA is up-regulated under chilling stress, it is decreased to low level when the samples were transferred to standard culture conditions. Pre-treated with mannitol for two hours is beneficial to inducing ICT level of expression. This chilling induction was inhibited by caffeine, suggesting that it may play a putative role in signal transduction of caffeine-sensitive calcium.