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Abstract: Objective : To explore the association of serum transactive response DNA binding protein 43 (TDP-43) with 28-day poor neurologic outcome in patients with return of spontaneous circulation (ROSC) after cardiac arrest. Methods : We performed a study between January and December 2023. Eligible patients with ROSC following cardiac arrest were enrolled. Their baseline characteristics were collected, and serum levels of TDP-43, tumor necrosis factor-α, interleukin-6 and 10, C-reactive protein, and neuron-specific enolase (NSE) at 24 h after ROSC were measured. The neurologic function was assessed by the cerebral performance category scores on day 28 after ROSC. Results : A total of 92 patients were included, with 51 and 41 patients in the good and poor neurologic outcome groups, respectively. Serum TDP-43 was significantly higher in the poor than the good neurologic outcome group ( P < 0.05). Univariate and multivariate logistic regression analyses showed that TDP-43, Witnessed CA, IL-6, and NSE were associated with poor 28-day neurologic outcome (all P < 0.05). Restricted cubic spline analysis revealed that TDP-43 at the serum level of 11.64 pg/mL might be an ideal cutoff value for distinguishing between good and poor neurologic outcomes. Area under curve of serum TDP-43 (AUC = 0.78) was close to that of serum NSE (AUC = 0.82). A dynamic nomogram prediction model that combined TDP-43, Witnessed CA, IL-6, and NSE was constructed and validated. Conclusion : Elevated serum TDP-43 level was associated with and could be used together with Witnessed CA, IL-6, and NSE to predict poor 28-day neurologic outcome in patients after ROSC following cardiac arrest., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 by the Shock Society.)

In order to enhance the performance of Transformer models for long-term multivariate forecasting while minimizing computational demands, this paper introduces the Joint Time-Frequency Domain Transformer (JTFT). JTFT combines time and frequency domain representations to make predictions. The frequency domain representation efficiently extracts multi-scale dependencies while maintaining sparsity by utilizing a small number of learnable frequencies. Simultaneously, the time domain (TD) representation is derived from a fixed number of the most recent data points, strengthening the modeling of local relationships and mitigating the effects of non-stationarity. Importantly, the length of the representation remains independent of the input sequence length, enabling JTFT to achieve linear computational complexity. Furthermore, a low-rank attention layer is proposed to efficiently capture cross-dimensional dependencies, thus preventing performance degradation resulting from the entanglement of temporal and channel-wise modeling. Experimental results on eight real-world datasets demonstrate that JTFT outperforms state-of-the-art baselines in predictive performance., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

A precise quantification of energy gap for a molecular semiconductor is crucial. However, there has always been a lack of a suitable method which results in an inaccurate measurement. In this research, a three-terminal vertical structure (Al/AlO X /Au/ molecular semiconductor/Al), named hot electron transistor has been designed to be the most powerful method for energy gap determination. By analysing the I C-hot -V EB curves, the electron injected barrier and hole injected barrier can be extracted. In combination of the both, the energy gap of four objects, including PBDB-T-2Cl, C 60 , PTCDA, and Alq3, has been determined finally., (© 2024. The Author(s).)

Prolonged exposure to abiotic stresses causes oxidative stress, which affects plant development and survival. In this research, the overexpression of ZmARF1 improved tolerance to low Pi, drought and salinity stresses. The transgenic plants manifested tolerance to low Pi by their superior root phenotypic traits: root length, root tips, root surface area, and root volume, compared to wide-type (WT) plants. Moreover, the transgenic plants exhibited higher root and leaf Pi content and upregulated the high affinity Pi transporters PHT1;2 and phosphorus starvation inducing (PSI) genes PHO2 and PHR1 under low Pi conditions. Transgenic Arabidopsis displayed tolerance to drought and salt stress by maintaining higher chlorophyll content and chlorophyll fluorescence, lower water loss rates, and ion leakage, which contributed to the survival of overexpression lines compared to the WT. Transcriptome profiling identified a peroxidase gene, POX, whose transcript was upregulated by these abiotic stresses. Furthermore, we confirmed that ZmARF1 bound to the auxin response element (AuxRE) in the promoter of POX and enhanced its transcription to mediate tolerance to oxidative stress imposed by low Pi, drought and salt stress in the transgenic seedlings. These results demonstrate that ZmARF1 has significant potential for improving the tolerance of crops to multiple abiotic stresses., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Objective: Few studies have investigated the impact of basal metabolic rate (BMR) on the development of urolithiasis, and the causal relationship is yet to be established. In this study, a two-sample Mendelian randomization (MR) analysis was utilized to identify the causal relationship between BMR and risk of urolithiasis., Method: Genetic instruments for BMR were drawn from a public genome-wide association study (GWAS). Summary dates on BMR and urolithiasis were obtained from a GWAS meta-analysis with sample sizes of 454,874 and 212,453, respectively. The inverse-variance weighted (IVW) method was provided as the main approach to estimate the causal relationship. The weighted-median method and the MR-Egger method were used as supplements to the IVW method. In addition, we conducted sensitivity analyses, including heterogeneity tests, pleiotropy tests and leave-one-out analysis, to assess the robustness of the outcomes. Furthermore, the funnel plot asymmetry was visually inspected to evaluate possible bias., Results: The inverse-variance weighted data revealed that genetically predicted BMR significantly decreased the risk of urolithiasis [beta coefficient (beta): - 0.2366, odds ratio (OR): 0.7893, 95% confidence interval (CI) 0.6504-0.9579, p = 0.0166]., Conclusions: BMR has causal effects on urolithiasis in an MR study, and the risk of urolithiasis in patients with lower levels of BMR is higher., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Walking and running at different speeds are common in daily life. This study investigated 6 degrees of freedom (DOF) kinematics of normal knees of Chinese during walking and running. Forty healthy participants were investigated in 4 conditions: comfortable walking, normal walking, slow running and ordinary running. The range of motion (ROM) and peak values in 6 DOF kinematics were analysed . As the speed increased, a general increase in flexion, lateral and proximal translations occurred. Significant increases of ROM in flexion/extension, axial rotation and medial/lateral translations were observed. The ROM of adduction/abduction, anterior/posterior and proximal/distal translations were greatest during normal walking. The maximum and minimum flexion/extension, maximum internal rotation and tibial lateral translations increased with the increase of speed. The maximum and minimum tibial proximal translations in running were found being greater than walking. A phenomenon between walking and running was observed: both tibial proximal/distal and medial/lateral translations increased when changed from walking to running. Non-linear transition exists in 6 DOF kinematics during walking to running. Discoveries in this study may have potential clinical values to serve as references of normal walking and running in the management of knee injury and knee rehabilitation.

Objective: Maintaining the lower limb in a neutral posture following total knee arthroplasty (TKA) has long been a concept maintained by operators. This study aimed to investigate the relationship between changes in lower limb alignment and the dynamics of knee gait before and after TKA to understand the impact of alignment on gait better and offer a theoretical foundation for correcting lower limb alignment in TKA., Methods: Our study included a group of 20 participants. The cohort consisted of 1 male and 19 females, 11 left and 9 right knees, ages 58 to 81. Using the Opti&#95;Knee® Knee Motion Test System with infrared reflective markers and a high-speed camera, the step length and 6 degrees of freedom of the knee were recorded. Following that, we investigated the association between HKA angle and knee kinematic gait before and after surgery., Results: For preoperative HKA angles ranging from -28° to -3°, we observed increased step length, flexion-extension rotation, and varus-valgus rotation with an increase in HKA angle. Conversely, an increase in HKA angle from -3 ° to 15° corresponded with decreased step length, flexion-extension rotation, and varus-valgus rotation. An increase in HKA angle from 1° to 3° postoperatively increased step length, flexion-extension rotation, and varus-valgus rotation. In contrast, increasing the HKA angle from 3° to 5° resulted in less flexion-extension rotation. The flexion-extension rotation was at its maximum when the HKA angle was 3°. A 3° postoperative varus resulted in improved kinematic gait. Step length, varus-valgus rotation, and flexion-extension rotation increased with increasing HKA angle in the neutral alignment group. In contrast, the non-neutral alignment group exhibited decreased flexion-extension rotation as the HKA angle increased, while step length and varus-valgus rotation increased as the HKA angle increased. The varus-valgus rotation was statistically significant (P < .05) in the preoperative versus early postoperative period in the 6 degrees of freedom., Conclusions: A 3° varus alignment was found to have a superior postoperative knee kinematic gait, implying that a 3° varus alignment may be more suitable as a new gold standard for TKA than the traditional "0°" alignment. The neutral alignment group demonstrated a better knee kinematic gait than the non-neutral alignment group. During early postoperative walking, significant improvements in varus-valgus rotation were found in the 6 degrees of knee freedom.

Background: As an inevitable event after kidney transplantation, ischemia‒reperfusion injury (IRI) can lead to a decrease in kidney transplant success. The search for signature genes of renal ischemia‒reperfusion injury (RIRI) is helpful in improving the diagnosis and guiding clinical treatment., Methods: We first downloaded 3 datasets from the GEO database. Then, differentially expressed genes (DEGs) were identified and applied for functional enrichment analysis. After that, we performed three machine learning methods, including random forest (RF), Lasso regression analysis, and support vector machine recursive feature elimination (SVM-RFE), to further predict candidate genes. WGCNA was also executed to screen candidate genes from DEGs. Then, we took the intersection of candidate genes to obtain the signature genes of RIRI. Receiver operating characteristic (ROC) analysis was conducted to measure the predictive ability of the signature genes. Kaplan‒Meier analysis was used for association analysis between signature genes and graft survival. Verifying the expression of signature genes in the ischemia cell model., Results: A total of 117 DEGs were screened out. Subsequently, RF, Lasso regression analysis, SVM-RFE and WGCNA identified 17, 25, 18 and 74 candidate genes, respectively. Finally, 3 signature genes (DUSP1, FOS, JUN) were screened out through the intersection of candidate genes. ROC analysis suggested that the 3 signature genes could well diagnose and predict RIRI. Kaplan‒Meier analysis indicated that patients with low FOS or JUN expression had a longer OS than those with high FOS or JUN expression. Finally, we validated using the ischemia cell model that compared to the control group, the expression level of JUN increased under hypoxic conditions., Conclusions: Three signature genes (DUSP1, FOS, JUN) offer a good prediction for RIRI outcome and may serve as potential therapeutic targets for RIRI intervention, especially JUN. The prediction of graft survival by FOS and JUN may improve graft survival in patients with RIRI., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors. Published by Elsevier Ltd.)

Tuberculosis continues to pose a serious threat to global health. Mycobacterium tuberculosis, the causative agent of tuberculosis, is an intracellular pathogen that relies on various mechanisms to survive and persist within the host. Among their many virulence factors, mycobacteria encode Mce systems. Some of these systems are implicated in lipid uptake, but the molecular basis for Mce function(s) is poorly understood. To gain insights into the composition and architecture of Mce systems, we characterized the putative Mce1 complex involved in fatty acid transport. We show that the Mce1 system in Mycobacterium smegmatis comprises a canonical ATP-binding cassette transporter associated with distinct heterohexameric assemblies of substrate-binding proteins. Furthermore, we establish that the conserved membrane protein Mce1N negatively regulates Mce1 function via a unique mechanism involving blocking transporter assembly. Our work offers a molecular understanding of Mce complexes, sheds light on mycobacterial lipid metabolism and its regulation, and informs future anti-mycobacterial strategies., (© 2023. Springer Nature Limited.)

Bladder cancer (BLCA) is a common and difficult-to-manage disease worldwide. Most common type of BLCA is urothelial carcinoma (UC). Fibrillin 2 (FBN2) was first discovered while studying Marfan syndrome, and its encoded products are associated with elastin fibres. To date, the role of FBN2 in BLCA remains unclear. The authors first downloaded data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). The patients were divided into high FBN2 expression and low FBN2 expression groups, and the survival curve, clinical characteristics, tumour microenvironment (TME), and immune cell differences were analysed between the two groups. Then, the differentially expressed genes (DEGs) were filtered, and functional enrichment for DEGs was performed. Finally, chemotherapy drug susceptibility analysis based on the high and low FBN2 groups was conducted. The authors found upregulated expression of FBN2 in BLCA and proved that FBN2 could be an independent prognostic factor for BLCA. TME analysis showed that the expression of FBN2 affects several aspects of the TME. The upregulated expression of FBN2 was associated with a high stromal score, which may lead to immunosuppression and be detrimental to immunotherapy. In addition, the authors found that NK cells resting, macrophage M0 infiltration, and other phenomena of immune cell infiltration appeared in the high expression group of FBN2. The high expression of FBN2 was related to the high sensitivity of some chemotherapy drugs. The authors systematically investigated the effects and mechanisms of FBN2 on BLCA and provided a new understanding of the role of FBN2 as a risk factor and TME influencer in BLCA., (© 2023 The Authors. IET Systems Biology published by John Wiley & Sons Ltd on behalf of The Institution of Engineering and Technology.)

Background: Central catheter-related thrombosis (CRT) is the most common catheter-related complication in patients with end-stage renal disease (ESRD) but is often underappreciated and misdiagnosed by radiologist., Purpose: To find the computed tomography angiography (CTA) characteristics of central CRT, then raise the diagnosis of this disorder., Material and Methods: A total of 301 eligible patients with ESRD who experienced both chest multi-phase multidetector CTA (MDCTA) and digital subtraction angiography were enrolled in the final analysis. The location, shape, and related signs of the central CRT in MDCTA images were evaluated. Independent-samples T test, chi-square test, and binary logistic regression were analyzed using SPSS software., Results: In total, 166 patients were found to have CRT using MDCTA, and this was verified by DSA. Central CRT was usually irregular in the superior vena cava segment, and the angle of the contact area between central CRT and catheter was <180° (all P  < 0.05). Age, collateral circulation, and venous stenosis were shown to have significant differences when compared to patients without CRT (all P  < 0.05), but there were no significant differences about the sex or catheter insertion site. In addition, age and collateral circulation were the factors found to be significantly associated with thrombosis ( P  < 0.05). In particular, the thrombosis was 2.213 times more likely to be found in those patients with collateral circulation (odds ratio = 2.213, 95% confidence interval = 1.236-3.961)., Conclusion: Chest multi-phase MDCTA can effectively reduce the missed diagnosis and misdiagnosis of central CRT. It is worth paying more attention to the central CRT especially when the collateral circulation is observed.

Low temperatures are the main abiotic factor affecting wheat growth. Brassinolide is a novel plant hormone that can improve the cold resistance of plants; however, the molecular mechanism of brassinolide in winter wheat at low temperatures remains unclear. In this study, winter wheat Dongnong dongmai 1 was sprayed with 0.01, 0.1, or 1.0 mg·L -1 brassinolide (BR) at the three-leaf stage, and tillering nodes were sampled at different temperatures (5, -10 and -25 °C), and then physiological indexes were determined and the transcriptome was sequenced. The results showed that the optimum concentration of brassinolide for cold resistance is 0.1 mg·L -1 . A total of 15 302 (8198 upregulated and 7104 downregulated) differentially expressed genes (DEGs) were identified in the B1 vs D1 comparison (B1 represents 5 °C 0.1 mg·L -1 BR treatment, D1 represents 5 °C control); 3386 (1930 upregulated and 1456 downregulated) differentially expressed genes (DEGs) were identified in the B2 vs D2 comparison (B2 represents -10 °C 0.1 mg·L -1 BR treatment, D2 represents -10 °C control); and 2684 (2102 upregulated and 582 downregulated) differentially expressed genes (DEGs) were identified in the B3 vs D3 comparison (B3 represents -25 °C 0.1 mg·L -1 BR treatment, D3 represents -25 °C control). Further studies showed that these DEGs were mainly involved in carbon fixation in photosynthetic organs, photosynthesis and plant-pathogen interactions, all of which were related to stress and energy metabolism. This indicates that brassinolide can produce substances that improve cold resistance in wheat seedlings. This study provides a theoretical basis for further research on the improvement of cold resistance in winter wheat by brassinolide., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Annals of Botany Company.)

The internal structure of many aero-engines is designed with a dual-rotor system. Up to now, there have been few studies on the influence of aerodynamic excitation on the dual-rotor system. The phenomenon of synchronous impact may occur when the frequency of the aerodynamic excitation force of the fan blade is close to the characteristic frequency of the inter-shaft bearing. This paper investigates the dynamic characteristics of a dual-rotor system under the condition of synchronous impact. The system's motion equations are formulated considering the complex nonlinearities of the inter-shaft bearing, such as Hertz contact force of 10/9 exponential function, clearance, and periodic varying compliance. In addition, the inter-shaft bearing with a local defect is considered. The fan blade's aerodynamic excitation force is modeled by synthesizing multiple harmonic excitation forces, the amplitudes of which are obtained by the Fourier series expansion. Numerical simulations are employed to get the dynamic responses of the system. The results show that the dynamic characteristic of the dual-rotor system at the primary resonance caused by the high-pressure (H.P.) rotor is not changed by the aerodynamic excitation force, while the primary resonance caused by the low-pressure (L.P.) rotor increases significantly. However, three aerodynamic resonances of the amplitude-frequency response of the dual-rotor system are emerging in the low-frequency region (124, 146 and 186 rad/s). When the synchronous impact phenomenon occurs, the amplitude of the three resonance peaks will increase twice compared to the original status, leading to a doubled increase in the dynamic load of the inter-shaft bearing. The characteristics of the dual-rotor system affected by the parameters such as initial phase difference of local defect, rotor eccentricity of system, clearance of inter-shaft bearing, and the stiffness and damping of supports are discussed in detail. The results obtained provide a deep insight into the mechanism of synchronous impact., (© 2023. The Author(s).)

In this study, we aimed to identify transplantation tolerance (TOL)-related gene signature and use it to predict the different types of renal allograft rejection performances in kidney transplantation. Gene expression data were obtained from the Gene Expression Omnibus (GEO) database, differently expressed genes (DEGs) were performed, and the gene ontology (GO) function enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were also conducted. The machine learning methods were combined to analyze the feature TOL-related genes and verify their predictive performance. Afterward, the gene expression levels and predictive performances of TOL-related genes were conducted in the context of acute rejection (AR), chronic rejection (CR), and graft loss through heatmap plots and the receiver operating characteristic (ROC) curves, and their respective immune infiltration results were also performed. Furthermore, the TOL-related gene signature for graft survival was conducted to discover gene immune cell enrichment. A total of 25 TOL-related DEGs were founded, and the GO and KEGG results indicated that DEGs mainly enriched in B cell-related functions and pathways. 7 TOL-related gene signature was constructed and performed delightedly in TOL groups and different types of allograft rejection. The immune infiltration analysis suggested that gene signature was correlated with different types of immune cells. The Kaplan-Meier (KM) survival analysis demonstrated that BLNK and MZB1 were the prognostic TOL-related genes. Our study proposed a novel gene signature that may influence TOL in kidney transplantation, providing possible guidance for immunosuppressive therapy in kidney transplant patients.

The effective solution to avoid machinery damage caused by resonance has been perplexing the field of engineering as a core research direction since the resonance phenomenon was discovered by Euler in 1750. Numerous attempts have been performed to reduce the influence of resonance since the earlier of last century, by introducing a nonlinear structure or a closed-loop control system. However, the existed methodologies cannot eliminate resonance completely even extra problems were introduced inevitably, which means the technical choke-point of resonance-free remains unsolved. Here we propose a designable archetype model, which establishes a mapping between the mechanical properties and its structure. A general inverse method for structure construction is proposed based upon the required property for the system with quasi-zero stiffness of any designed finite order and the zero-stiffness properties. It is shown that an ellipse trajectory tracking of the designed model is the sufficient and necessary condition to satisfy the zero-stiffness property. Theoretical analysis shows that no resonant response happens in a zero-stiffness system to the full-band frequency excitation, or equivalently, the system can completely isolate the energy transfer between the load and environment, when the damping ratio approaches zero. Finally, an experimental rig for the prototype structure is built up according to the sufficient and necessary condition of the zero-stiffness system, for which the special dynamic behaviours are verified through experiments of frequency-sweep and random-vibration as well. Experimental results show that the prototype of the initial vibration isolation frequency of zero-stiffness system is much lower than 0.37 Hz, and the vibration attenuation of the proposed model is about 16.86 dB, 45.63 dB, and 112.37 dB at frequencies of 0.37 Hz, 1 Hz, and 10 Hz, respectively. The distinguished geometric structure of the zero-stiffness system leads to a new inspiration for the design of resonance-free in metamaterial unit and the inverse method can even adapt the design for a more targeted applications based on an arbitrary complex dynamic requirement., (© 2022. The Author(s).)

Background: In previous studies, haemorrhage occurred only with large infarct sizes, and studies found a moderate correlation between the extent of necrosis and haemorrhage, but the extent of infarction size in these studies was limited. This study aimed to find the correlations between intramyocardial haemorrhage (IMH), myocardial infarction (MI), and myocardial oedema (ME) from small to large sizes of MI in a 7.0-T MR scanner., Methods: Different sizes of myocardial infarction were induced by occluding different sections of the proximal left anterior descending coronary artery (1-3 mm under the left auricle). T2*-mapping, T2-mapping and late gadolinium enhancement (LGE) sequences were performed on a 7.0 T MR system at Days 2 and 7. T2*- and T2-maps were calculated using custom-made software. All areas were expressed as a percentage of the entire myocardial tissue of the left ventricle. The rats were divided into two groups based on the T2* results and pathological findings; MI with IMH was referred to as the + IMH group, while MI without IMH was referred to as the -IMH group., Results: The final experimental sample consisted of 25 rats in the + IMH group and 10 rats in the -IMH group. For the + IMH group on Day 2, there was a significant positive correlation between IMH size and MI size (r = 0.677, P < 0.01) and a positive correlation between IMH size and ME size (r = 0.552, P < 0.01). On Day 7, there was a significant positive correlation between IMH size and MI size (r = 0.711, P < 0.01), while no correlation was found between IMH size and ME size (r = 0.429, P = 0.097). The MI sizes of the + IMH group were larger than those of the -IMH group (P < 0.01)., Conclusions: Infarction size prior to reperfusion is a critical factor in determining IMH size in rats., (© 2022. The Author(s).)

In most sensory modalities, neuronal connectivity reflects behaviorally relevant stimulus features, such as spatial location, orientation, and sound frequency. By contrast, the prevailing view in the olfactory cortex, based on the reconstruction of dozens of neurons, is that connectivity is random. Here, we used high-throughput sequencing-based neuroanatomical techniques to analyze the projections of 5,309 mouse olfactory bulb and 30,433 piriform cortex output neurons at single-cell resolution. Surprisingly, statistical analysis of this much larger dataset revealed that the olfactory cortex connectivity is spatially structured. Single olfactory bulb neurons targeting a particular location along the anterior-posterior axis of piriform cortex also project to matched, functionally distinct, extra-piriform targets. Moreover, single neurons from the targeted piriform locus also project to the same matched extra-piriform targets, forming triadic circuit motifs. Thus, as in other sensory modalities, olfactory information is routed at early stages of processing to functionally diverse targets in a coordinated manner., Competing Interests: Declaration of interests A.M.Z. is a founder and equity owner of Cajal Neuroscience and a member of its scientific advisory board., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: To develop a compact MR-compatible ergometer for exercise stress and to initially evaluate the reproducibility of myocardial native T1 and myocardial blood flow (MBF) measurements during exercise stress performed on this ergometer., Methods: The compact ergometer consists of exercise, workload, and data processing components. The exercise stress can be achieved by pedaling on a pair of cylinders at a predefined frequency with adjustable resistances. Ten healthy subjects were recruited to perform cardiac MRI scans twice in a 3.0T MR scanner, at different days to assess reproducibility. Myocardial native T1 and MBF were acquired at rest and during a moderate exercise. The reproducibility of the two tests was determined by the intra-group correlation coefficient (ICC) and coefficient of variation (CoV)., Results: The mean exercise intensity in this pilot study was 45 Watts (W), with an exercise duration of 5 min. Stress induced a significant increase in systolic blood pressure (from 113 ± 11 mmHg to 141 ± 12, P < 0.05) and maximal increase in heart rate by 74 ± 19%. The rate pressure product increased two-fold (P < 0.001). Excellent reproducibility was demonstrated in native T1 during the exercise (CoV = 3.0%), whereas the reproducibility of MBF and myocardial perfusion reserve during the exercise was also good (CoV = 10.7% and 8.8%, respectively)., Conclusion: This pilot study demonstrated that it is possible to acquire reproducible measurements of myocardial native T1 and MBF during the exercise stress in healthy volunteers using our new compact ergometer., (© 2022 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Background: This study investigates the segmental myocardial strain of the early phase of intramyocardial hemorrhage (IMH) caused by reperfused myocardial infarction (MI) in rats by low-dose dobutamine (LDD) cardiovascular magnetic resonance (CMR) feature-tracking., Methods: Nine sham rats and nine rats with 60-min myocardial ischemia followed by 48-h reperfusion were investigated using CMR, including T2*-mapping sequence and fast imaging with steady-state precession (FISP)-cine sequence. Another FISP-cine sequence was acquired after 2 min of dobutamine injection; the MI, IMH, and Non-MI (NMI) areas were identified. The values of peak radial strains (PRS) and peak circumferential strains (PCS) of the MI, IMH and NMI segments were acquired. The efficiency of PRS and PCS (EPRS and EPCS, respectively) were calculated on the basis of the time of every single heartbeat., Results: The PRS, PCS, EPRS, and EPCS of the sham group increased after LDD injection. However, the PRS, PCS, EPRS, and EPCS of the IMH segment did not increase. Moreover, the PRS and PCS of the MI and NMI segments did not increase, but the EPRS and EPCS of these segments increased. The PRS, PCS, EPRS, and EPCS of the IMH segment were lower than those of the MI and NMI segments before and after LDD injection, but without a significant difference between MI segment and NMI segment before and after LDD injection., Conclusions: LDD could help assess dysfunctions in segments with IMH, especially using the efficiency of strain. IMH was a crucial factor that decreased segmental movement and reserved function., (© 2021. The Author(s).)

Background: Myocardial strain analysis can provide diagnostic and prognostic information for myocarditis. The aim of the present study was to assess early and acute myocarditis in a rat model using cardiac magnetic resonance tissue tracking (CMR-TT) for myocardial strain analysis. We compared the strain's findings with the histological and immunohistochemical results., Methods: Experimental autoimmune myocarditis (EAM) was induced by footpad injections of porcine cardiac myosin. The rats were examined by 7.0T preclinical CMR at day 14 (n=15) and day 21 (n=16) after EAM induction and the two control groups (each n=15) were also examined at day 14 and day 21, respectively. Using CMR-TT, we found a global peak systolic radial strain (Err SAX ) and a circumferential strain (Ecc SAX ) from the short-axis cine views and a radial strain (Err LAX ) and a longitudinal strain (Ell LAX ) from the long-axis cine views, which were calculated by dedicated TT software. Subsequently, histological and immunohistochemical evaluations were performed., Results: Ell LAX significantly decreased in early myocarditis compared with the control (-23.40%±1.48% vs . -22.02%±0.81%, P<0.05). Err SAX , Ecc SAX , Err LAX , and Ell LAX values significantly reduced in acute myocarditis compared with the controls (Err SAX : 34.27%±9.80% vs . 49.76%±4.97%, Ecc SAX : -18.98%±3.69% vs . -24.13±1.23, Err LAX : 33.21%±10.24% vs . 49.59%±5.69%, and Ell LAX : -17.75%±3.58% vs . -23.39%±1.48%; P<0.001, respectively). The receiver operating characteristic curve showed that myocardial strain analysis had a good diagnostic performance in early and acute myocarditis. The pathological evaluation revealed that inflammatory lesions began to appear in early myocarditis and peaked in acute myocarditis., Conclusions: The CMR-TT strain analysis allowed accurate and reliable evaluation of early and acute myocarditis in a rat model, and has the potential to serve as a diagnostic indicator for the assessment of myocardial dysfunction in myocarditis., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/qims-20-122). The authors have no conflicts of interest to declare., (2020 Quantitative Imaging in Medicine and Surgery. All rights reserved.)

Aims: To investigate the correlation of impairment in skeletal muscle and heart in spontaneous type 2 diabetes mellitus (T2DM) rhesus monkeys using magnetic resonance image (MRI)., Methods: Fifteen T2DM monkeys and fourteen healthy control (HC) monkeys were included. The microcirculation of skeletal muscle [skeletal muscle blood flow (SMBF), skeletal muscle oxygen extraction fraction (SMOEF)] and the function and strain of heart were evaluated by MRI. Three regions of interests were chosen on the soleus muscle (SOL), gastrocnemius muscle (GAS) and tibialis anterior muscle (TA) for image analysis., Results: Eight T2DM monkeys and eight HC monkeys were obtained the full data. The SMBF reserves and SMOEF reserves were found significantly decreased in T2DM during inflation in SOL, GAS and TA muscles (all p < 0.05), and the SMBF reserves decreased during hyperemia in GAS and TA muscles (all p < 0.05). In these monkeys, the global peak longitudinal strain (longitudinal PS), peak systolic longitudinal strain rate (longitudinal PSSR) and peak diastolic longitudinal strain rate (longitudinal PDSR) were seen significantly different in T2DM compared to HC monkeys (all p < 0.05). The longitudinal PSSR was found negatively correlated with SMBF reserves in SOL, GAS and TA during inflation in all monkeys., Conclusions: The impaired microcirculation of skeletal muscle and the myocardial deformation were found in T2DM monkeys with normal ejection fraction. And a negative correlation was existed in the longitudinal PSSR and the SMBF reserves.

Mycobacterium tuberculosis , the causative agent of tuberculosis, remains a major human pathogen, and current treatment options to combat this disease are under threat because of the emergence of multidrug-resistant and extensively drug-resistant tuberculosis. High-throughput whole-cell screening of an extensive compound library has recently identified a piperidinol-containing molecule, PIPD1, as a potent lead compound against M. tuberculosis Herein, we show that PIPD1 and related analogs exert in vitro bactericidal activity against the M. tuberculosis strain mc 2 6230 and also against a panel of multidrug-resistant and extensively drug-resistant clinical isolates of M. tuberculosis , suggesting that PIPD1's mode of action differs from those of most first- and second-line anti-tubercular drugs. Selection and DNA sequencing of PIPD1-resistant mycobacterial mutants revealed the presence of single-nucleotide polymorphisms in mmpL3 , encoding an inner membrane-associated mycolic acid flippase in M. tuberculosis Results from functional assays with spheroplasts derived from a M. smegmatis strain lacking the endogenous mmpL3 gene but harboring the M. tuberculosis mmpL3 homolog indicated that PIPD1 inhibits the MmpL3-driven translocation of trehalose monomycolate across the inner membrane without altering the proton motive force. Using a predictive structural model of MmpL3 from M. tuberculosis , docking studies revealed a PIPD1-binding cavity recently found to accommodate different inhibitors in M. smegmatis MmpL3. In conclusion, our findings have uncovered bactericidal activity of a new chemical scaffold. Its anti-tubercular activity is mediated by direct inhibition of the flippase activity of MmpL3 rather than by inhibition of the inner membrane proton motive force, significantly advancing our understanding of MmpL3-targeted inhibition in mycobacteria., (© 2019 Dupont et al.)

Fault diagnosis of rotating machinery is crucial to improve safety, enhance reliability and reduce maintenance cost. The manual feature extraction and selection of traditional fault diagnosis methods depend on signal processing skills and expert experience, which is labor-intensive and time-consuming. As a typical intelligent fault diagnosis method, the convolutional neural network automatically learns features from original data, but it is extremely difficult to design and train a deep network architecture. This paper proposes a fault diagnosis scheme combined of hierarchical symbolic analysis (HSA) and convolutional neural network (CNN), which achieves laborsaving and timesaving preliminary feature extraction and accomplishes automatically feature learning with simplified network architecture. Firstly, hierarchical symbolic analysis is employed to extract features from original signals. The extracted features are able to identify different health conditions under various operating conditions. Then, convolutional neural network instead of human labor is used to learn the complex non-linear relationship between features and health conditions automatically. The architecture of CNN diagnosis model is simple and convenient to implement. Finally, a centrifugal pump dataset and a motor bearing dataset are adopted to validate the effectiveness of the proposed method. The diagnosis results show that the proposed method exhibits superior performance compared with shallow methods and deep learning methods., (Copyright © 2019 ISA. Published by Elsevier Ltd. All rights reserved.)

Objective: To detect diffuse myocardial fibrosis in different severity levels of left ventricular diastolic dysfunction (DD) in spontaneous type 2 diabetes mellitus (T2DM) rhesus monkeys., Methods: Eighteen spontaneous T2DM and nine healthy monkeys were studied. Echocardiography was performed for diastolic function classification. Cardiac magnetic resonance (CMR) imaging was performed to obtain extracellular volume fraction (ECV) maps and T1ρ maps at two different spin-locking frequencies. ECV values, T1ρ values, and myocardial fibrosis index (mFI) values which are based on the dispersion of T1ρ, were calculated. Global peak diastolic longitudinal strain rates (GSrL) were also obtained., Results: Echocardiography results showed mild DD in nine T2DM monkeys and moderate DD in the other nine. The global ECV values were significantly different among healthy animals as compared with animals with mild DD or moderate DD, and the ECV values of animals with moderate DD were significantly higher as compared with those of mild DD. The mFI values increased progressively from healthy animals to those with mild DD and then to those with moderate DD. Diastolic function indicators (e.g., early diastolic mitral annulus velocity, GSrL) correlated well with ECV and mFI., Conclusions: Monkeys with T2DM exhibit increased ECV, T1ρ, and mFI values, which may be indicative of the expansion of extracellular volume and the deposition of excessive collagen. T1ρ mapping may have the potential to be used for diffuse myocardial fibrosis assessment., Key Points: • Monkeys with T2DM exhibit increased ECV, T1ρ, and mFI values, which may be indicative of the expansion of extracellular volume and the deposition of excessive collagen. • The relationship between diastolic dysfunction and diffuse myocardial fibrosis may be demonstrated by imaging markers. • Non-contrast T1ρ mapping may have the potential to be used for diffuse myocardial assessment.

Background: Spontaneous T2DM in rhesus monkeys manifests as isolated diastolic dysfunction in the early stage of diabetic cardiomyopathy, similar to humans. Myocardial deformation measurements have emerged as a superior way to measure left ventricular (LV) function in the early stage of cardiac dysfunction, making it possible to further evaluate early-stage LV dysfunction in spontaneous T2DM rhesus monkeys., Methods: Spontaneous T2DM rhesus monkeys with isolated diastolic dysfunction (T2DM-DD, n = 10) and corresponding nondiabetic healthy animals (ND, n = 9) were prospectively scanned for a CMR study. Circumferential and longitudinal peak systolic strain (Ecc, Ell), time to peak strain (tEcc, tEll) and peak diastolic strain rate (CSR, LSR) obtained from 2D/3D CMR-TT were compared with those obtained from CMR tagging separately. In addition, all CMR imaging protocols were performed twice in 9 ND animals to assess test-retest reproducibility., Results: Compared with the ND group, the T2DM-DD monkeys demonstrated significantly impaired LV Ecc (- 10.63 ± 3.23 vs - 14.18 ± 3.19, p < 0.05), CSR (65.50 ± 14.48 vs 65.50 ± 14.48, p < 0.01), Ell (- 9.11 ± 2.59 vs - 14.17 ± 1.68, p < 0.05), and LSR (59.43 ± 19.17 vs 108.46 ± 22.33, p < 0.01) with the tagging. Only Ecc (- 13.10 ± 2.47 vs - 19.03 ± 3.69, p < 0.01) and CSR (148.90 ± 31.27 vs 202.00 ± 51.88, p < 0.01) were significantly reduced with 2D CMR-TT, and only Ecc (- 13.77 ± 1.98 vs - 17.26 ± 3.78, p < 0.05) was significantly reduced with 3D CMR-TT. Moreover, 2D/3D CMR-TT-derived Ecc and CSR correlated with the corresponding tagging values collectively, with a statistically significant ICC value (p < 0.05). Test-retest repeatability analysis showed that most tagging-derived biomarkers had acceptable repeatability (p < 0.01). In addition, 2D CMR-TT-derived indicators were poorer than those derived from the tagging method but better than those obtained using the 3D method, with larger ICCs except for tEcc (p < 0.05)., Conclusions: LV systolic and diastolic deformations were impaired in spontaneous T2DM rhesus monkeys previously diagnosed with isolated diastolic dysfunction by echocardiography. The 2D CMR-TT-derived Ecc and CSR were effective in the evaluation of the myocardial systolic and diastolic functions of early-diabetic cardiomyopathy, with relatively higher test-retest reproducibility and acceptable correlation with the tagging method compared with the 3D CMR-TT method.

Multichannel electroencephalography (EEG) is widely used in typical brain-computer interface (BCI) systems. In general, a number of parameters are essential for a EEG classification algorithm due to redundant features involved in EEG signals. However, the generalization of the EEG method is often adversely affected by the model complexity, considerably coherent with its number of undetermined parameters, further leading to heavy overfitting. To decrease the complexity and improve the generalization of EEG method, we present a novel l 1 -norm-based approach to combine the decision value obtained from each EEG channel directly. By extracting the information from different channels on independent frequency bands (FB) with l1-norm regularization, the method proposed fits the training data with much less parameters compared to common spatial pattern (CSP) methods in order to reduce overfitting. Moreover, an effective and efficient solution to minimize the optimization object is proposed. The experimental results on dataset IVa of BCI competition III and dataset I of BCI competition IV show that, the proposed method contributes to high classification accuracy and increases generalization performance for the classification of MI EEG. As the training set ratio decreases from 80 to 20%, the average classification accuracy on the two datasets changes from 85.86 and 86.13% to 84.81 and 76.59%, respectively. The classification performance and generalization of the proposed method contribute to the practical application of MI based BCI systems.

Objective: A failed electrocardiography (ECG)-trigger often leads to a long acquisition time (TA) and deterioration in image quality. The purpose of this study was to evaluate and optimize the technique of self-gated (SG) cardiovascular magnetic resonance (CMR) for cardiac late gadolinium enhancement (LGE) imaging of rats with myocardial infarction/reperfusion., Materials and Methods: Cardiovascular magnetic resonance images of 10 rats were obtained using SG-LGE or ECG with respiration double-gating (ECG-RESP-gating) method at 7T to compare differences in image interference and TA between the two methods. A variety of flip angles (FA: 10°-80°) and the number of repetitions (NR: 40, 80, 150, and 300) were investigated to determine optimal scan parameters of SG-LGE technique based on image quality score and contrast-to-noise ratio (CNR)., Results: Self-gated late gadolinium enhancement allowed successful scan in 10 (100%) rats. However, only 4 (40%) rats were successfully scanned with the ECG-RESP-gating method. TAs with SG-LGE varied depending on NR used (TA: 41, 82, 154, and 307 seconds, corresponding to NR of 40, 80, 150, and 300, respectively). For the ECG-RESP-gating method, the average TA was 220 seconds. For SG-LGE images, CNR (42.5 ± 5.5, 43.5 ± 7.5, 54 ± 9, 59.5 ± 8.5, 56 ± 13, 54 ± 8, and 41 ± 9) and image quality score (1.85 ± 0.75, 2.20 ± 0.83, 2.85 ± 0.37, 3.85 ± 0.52, 2.8 ± 0.51, 2.45 ± 0.76, and 1.95 ± 0.60) were achieved with different FAs (10°, 15°, 20°, 25°, 30°, 35°, and 40°, respectively). Optimal FAs of 20°-30° and NR of 80 were recommended., Conclusion: Self-gated technique can improve image quality of LGE without irregular ECG or respiration gating. Therefore, SG-LGE can be used an alternative method of ECG-RESP-gating.

Objectives: The present study aimed to develop microparticles of phenolic hydroxyl derivative of carboxymethylcellulose (CMC-Ph) via Co-flow microfluidics technology and encapsulated gene-modified rat bone mesenchymal stem cells (BMSCs) for the detection of the growth factor release was controlled by Tet-on system. Meanwhile, we investigated the effect of the CMC-Ph microcapsules and Lentiviral transduction on osteogenesis of BMP2-BMSCs., Methods: The middle size of CMC-Ph microcapsules was prepared by optimized co-flow microfluidics through ejecting fluid CMC-Ph suspension (mixed with HRP) into co-flowing liquid paraffin which blends H 2 O 2 at priority. The Lentivirus-encoding hBMP-2 and Tet-On system were constructed and amplified by RT-PCR, then encapsulated in the microcapsules. The cellular viability of CMC-Ph microparticles was assessed by Live/dead staining and metabolic activity was estimated by colorimetric assay kit. In addition, BMP-2 secretion and kinetic studies were determined by ELISA, alkaline phosphatase (ALP) activity was evaluated using ALP assay kit, and ALP staining as well as mineral calcium deposition was detected by alizarin red S staining., Key Findings: The diameter of CMC-Ph microparticles was controlled between 100 and 150 μm by altering the flow speed of liquid paraffin and then encapsulated bone morphogenetic protein 2 (BMP-2) gene modified BMSCs transduced by a lentiviral vector. Moreover, the mitochondrial activity of the encapsulated cells was maintained at least 24 d and BMP-2 protein secretion into the supernatant sustained for 35 d without significant loss of efficiency under the induction of the doxycycline. Furthermore, mineral deposition staining and ALP activity detection showed that encapsulated lentiviral-BMP2 transduced BMSCs possess more osteogenic differentiation potential than normal cells., Conclusions: Co-flow microfluidics and phenolic hydroxyl derivative of carboxymethylcellulose (CMC-Ph) provide a promising strategy for cell-enclosed microcapsules in combination with BMP-2 gene and Tet-on system modified BMSCs and then controlled BMP-2 protein released effectively as well as promoted the osteogenic differentiation of BMSCs.

The aim of this study was to determine the myocardial area at risk (AAR), infarction-core size (IS) and the salvaged myocardial zone (SMZ), and to evaluate the imaging and histological characteristics of intramyocardial hemorrhage (IMH) after myocardial infarction using non-contrast T2 mapping on 7T magnetic resonance imaging (MRI). Twenty Sprague Dawley (SD) rats were randomly divided into the sham and model groups (n=10 in each). In the model group, myocardial infarction models were established by left anterior descending branch ligation. After 24 h, all animals were imaged on a 7.0 Tesla system with cine spiral imaging, T2 mapping with late gadolinium enhancement (LGE). The rats were then sacrificed for measurement of the IS and AAR using 2,3,5-triphenylterazolium chloride (TTC) and hematoxylin and eosin (H&E) staining. T2 mapping revealed that the AAR in the model group was significantly higher than that in the sham group. No remarkable T2 value was noted in the entire heart of the sham group. LGE and TTC staining demonstrated similar IS. T2 mapping and H&E staining revealed a similar AAR as well. T2 mapping characterized the IMH as a phenomenon resulting from the area of hypointensity in the hyperintensity involving the infarct-core zone and corresponding T2 value 928.6±1.52 msec with IMH vs. 35.8±2.61 msec without IMH; n=3 with 18 slices; P=0.032). In conclusion, non-contrast T2 mapping was a reliable approach to quantitatively evaluate the SMZ and IMH.

Microvascular lesions of the body are one of the most serious complications that can affect patients with type 2 diabetes mellitus. The blood-brain barrier (BBB) is a highly selective permeable barrier around the microvessels of the brain. This study investigated BBB disruption in diabetic rhesus monkeys using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Multi-slice DCE-MRI was used to quantify BBB permeability. Five diabetic monkeys and six control monkeys underwent magnetic resonance brain imaging in 3 Tesla MRI system. Regions of the frontal cortex, the temporal cortex, the basal ganglia, the thalamus, and the hippocampus in the two groups were selected as regions of interest to calculate the value of the transport coefficient K trans using the extended Tofts model. Permeability in the diabetic monkeys was significantly increased as compared with permeability in the normal control monkeys. Histopathologically, zonula occludens protein-1 decreased, immunoglobulin G leaked out of the blood, and nuclear factor E2-related factor translocated from the cytoplasm to the nuclei. It is likely that diabetes contributed to the increased BBB permeability., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The bending rigidity of small reverse aggregates involved in liquid-liquid extraction processes has been investigated by molecular dynamics simulations. Simulations of a common extractant (DMDOHEMA) with four hydrophobic chains in explicit solvent (n-heptane) and in vacuum have been performed to determine the effect of solvent penetration on film stiffness. Elastic film bending energy that is needed for mesoscopic modelling of transfer of species between complex fluids is harmonic in terms of curvature (Helfrich formalism) and the packing parameter only if the solvent is explicitly taken into account. In terms of the packing parameter of the real molecular film constituting the reverse water in oil aggregates and taking into account molecular volume, area and film thickness (that is in agreement with Tanford's model), the bending rigidity is calculated to be about 16 k B T per extractant molecule (about 40 kJ mol -1 ), which is smaller than the free energy of transfer from an isolated "monomer" molecule to a weak aggregate, but of the order of magnitude of the free energy of transfer used in liquid-liquid extraction processes.

Molecular complexes formed in the organic phase during solvent extraction may self-assemble as reverse micelles, and therefore induce a supramolecular organization of this phase. In most of the cases, water molecules play an essential role in the organization of this non polar medium. The aim of this work is to investigate the speciation of the aggregates formed in the organic phase during solvent extraction, and especially to assess their stability as a function of the number of water molecules included in their polar core. We have focused on malonamide extractants that have already been investigated experimentally. Different stoichiometries of reverse micelles in the organic phase have been studied by means of classical molecular dynamics simulations. Furthermore, umbrella-sampling molecular dynamics simulations have been used to calculate the equilibrium constant (K°) representing the association/dissociation pathways of water molecules in the aggregates and the corresponding reaction free energies (Δ r G°).

Mulberry anthocyanins possess many pharmacological effects including liver protection, anti-inflammation, and anticancer. The aim of this study was to evaluate whether mulberry anthocyanin extract (MAE) exerts beneficial effects against oxidative stress damage in HepG2 cells and Caenorhabditis elegans. In vitro, MAE prevented cytotoxicity, increased glucose consumption and uptake, and eliminated excessive intracellular free radicals in H 2 O 2 -induced cells. Moreover, MAE pretreatment maintained Nrf2, HO-1, and p38 MAPK stimulation and abolished upregulation of p-JNK, FOXO1, and PGC-1 α that were involved in oxidative stress and insulin signalling modulation. In vivo, extended lifespan was observed in C. elegans damaged by paraquat in the presence of MAE, while these beneficial effects were disappeared in pmk-1 and daf-16 mutants. PMK-1 and SKN-1 were activated after exposure to paraquat and MAE suppressed PMK-1 activation but enhanced SKN-1 stimulation. Our findings suggested that MAE recovered redox status in HepG2 cells and C. elegans that suffered from oxidative stress, which might be by targeting MAPKs and Nrf2.

BACKGROUND We explored the effect of parathyroid hormone (PTH)-induced bone marrow stem cells (BMSCs) complexed with fibrin glue (FG) in the repair of articular cartilage injury in rabbits. MATERIAL AND METHODS Forty-eight rabbits randomized into four groups were subjected to articular surgery (cartilage loss). The PTH and non-PTH intervention groups included transplantation with PTH/BMSC/FG xenogeneic and BMSC/FG xenogeneic complexes, respectively, into the injured area. The injured group contained no transplant while the control group comprised rabbits without any articular injury. Samples were monitored for cartilage repair up to three months post-surgery. Immunohistochemistry as well as real-time fluorescent quantitative PCR and Western blot were used to analyze the expression of type II collagen and aggrecan in the repaired tissue. RESULTS At 12 weeks post-surgery, the loss of articular cartilage in the PTH group was fully repaired by hyaline tissue. Typical cartilage lacunae and intact subchondral bone were found. The boundary separating the surrounding normal cartilage tissue disappeared. The gross and International Cartilage Repair Society (ICRS) histological ranking of the repaired tissue was significantly higher in the PTH intervention group than in the non-PTH intervention and injury groups (p<0.05) without any significant difference compared to the control group (p>0.05). Type II collagen and aggrecan stained positive and the average optical density, relative mRNA expression and protein-integrated optical density in the PTH group were higher than in non-PTH and injured groups (p<0.05) but not significantly different from the control group (p>0.05). CONCLUSIONS PTH/BMSC/FG xenogeneic complexes effectively repaired the loss of cartilage in rabbit knee injury.

This study aims to build the myocardial infarction model in SD rats transfected with pcDNA 3.1(+)/VEGF121 plasmid and study the effect of the transfection using 7T MRI. Twenty-four male SD rats were randomly divided into 2 groups, pcDNA 3.1(+)/VEGF121 plasmid transfection group (with improved coronary perfusion delivery) and myocardial infarction model group. Cardiac cine magnetic resonance imaging (Cine-MRI), T2-mapping and late gadolinium enhancement (LGE) cardiac imaging were performed at 24 h, 48 h, 72 h and 7 d after myocardial infarction, respectively. The signal intensity, area at risk (AAR), myocardium infarction core (MIC) and salvageable myocardial zone (SMZ) were compared. The hearts were harvested for anatomic characterization, which was related to pathological examination (TTC staining, HE staining, Masson staining and immunohistochemical staining). The Cine-MRI results showed that pcDNA 3.1(+)/VEGF121 plasmid transfection group had higher end-diastolic volume (EDV) with a reduction in MIC and SMZ, as compared with the myocardial infarction model group. MIC, SMZ and AAR of the plasmid transfection declined over time. At 7 d, the two groups did not differ significantly in AAR and T2 value. According to Western Blotting, VEGF was up-regulated, while CaSR and caspase-3 were downregulated in the plasmid transfection group, as compared with the model group. In conclusion, a good treatment effect was achieved by coronary perfusion of pcDNA 3.1(+)/VEGF121 plasmid. 7T CMR sequences provide a non-invasive quantification of the treatment efficacy. However, the assessment of myocardial injury using T2 value and AAR in the presence of edema is less accurate. The myocardial protection of the plasmid transfection group may be related to the inhibition of myocardial apoptosis, vascular endothelial cell (VEC) proliferation and collagen proliferation. The CaSR signaling pathway may contribute to reversing the apoptosis.

Purpose: To investigate T2 mapping at 7T magnetic resonance imaging (MRI) for the detection and quantification of reperfused intramyocardial hemorrhage (IMH) in a rat model., Materials and Methods: Myocardial infarction (MI) was induced in 25 female rats. Rats were scanned at a 7T MRI 48 hours after reperfusion, using T2 mapping and late gadolinium enhancement imaging. Gross sections of the left ventricular myocardium and corresponding hematoxylin and eosin staining were assessed for IMH. T2 mapping images were matched with the gross sections. The IMH volume, expressed as a percentage of the left ventricular myocardial volume, of each heart determined by T2 mapping was compared with that calculated by pathological gross examination., Results: Six rats died. In all, 97 gross sections of the left ventricular myocardium from the 19 rats were matched with T2 mapping images. IMH occurred pathologically in 68 gross sections, which was detected as hypointense cores by T2 mapping in 63 images (93% sensitivity). Three T2 mapping images with hypointense cores showed no hemorrhage on pathological sections (90% specificity). The positive and negative predictive values of hemorrhage on T2 mapping were 95% and 84%, respectively. In terms of the IMH volume, there was no significant difference between T2 mapping and pathological gross measurements (4.8 ± 2.4% vs. 5.3 ± 3.2%; P = 0.11)., Conclusion: T2 mapping at 7T MRI can reliably detect and quantify IMH in rats in vivo. This may be useful as a noninvasive quantitative approach to investigating the mechanisms and evolution of MI and reperfusion injury. J. Magn. Reson. Imaging 2016;44:194-203., (© 2016 Wiley Periodicals, Inc.)

Caenorhabditis eleganssenses gentle touch via a mechanotransduction channel formed from the DEG/ENaC proteins MEC-4 and MEC-10. An additional protein, the paraoxonase-like protein MEC-6, is essential for transduction, and previous work suggested that MEC-6 was part of the transduction complex. We found that MEC-6 and a similar protein, POML-1, reside primarily in the endoplasmic reticulum and do not colocalize with MEC-4 on the plasma membrane in vivo. As with MEC-6, POML-1 is needed for touch sensitivity, the neurodegeneration caused by themec-4(d)mutation, and the expression and distribution of MEC-4 in vivo. Both proteins are likely needed for the proper folding or assembly of MEC-4 channels in vivo as measured by FRET. MEC-6 detectably increases the rate of MEC-4 accumulation on theXenopusoocyte plasma membrane. These results suggest that MEC-6 and POML-1 interact with MEC-4 to facilitate expression and localization of MEC-4 on the cell surface. Thus MEC-6 and POML-1 act more like chaperones for MEC-4 than channel components., (© 2016 Chen et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).)

The Caenorhabditis elegans DEG/ENaC proteins MEC-4 and MEC-10 transduce gentle touch in the six touch receptor neurons . Gain-of-function mutations of mec-4 and mec-4(d) result in a hyperactive channel and neurodegeneration in vivo Loss of MEC-6, a putative DEG/ENaC-specific chaperone, and of the similar protein POML-1 suppresses the neurodegeneration caused by a mec-4(d) mutation. We find that mutation of two genes, mec-10 and a new gene mec-19 (previously named C49G9.1), prevents this action of POML-1, allowing the touch receptor neurons to die in poml-1 mec-4(d) animals. The proteins encoded by these genes normally inhibit mec-4(d) neurotoxicity through different mechanisms. MEC-10, a subunit of the mechanosensory transduction channel with MEC-4, inhibits MEC-4(d) activity without affecting MEC-4 expression. In contrast, MEC-19, a membrane protein specific to nematodes, inhibits MEC-4(d) activity and reduces MEC-4 surface expression., (Copyright © 2016 Chen et al.)

Purpose: To translate a recombinant peptide containing the amino-terminal fragment (ATF) of urokinase plasminogen activator receptor-targeted magnetic iron oxide (IO) nanoparticles (uPAR-targeted human ATF-IONPs) into clinical applications, we conducted a pilot study to evaluate the toxicity and pharmacokinetics of this nanoparticle in normal rhesus monkeys., Methods: We assessed the changes in the following: magnetic resonance imaging (MRI) signals from pretreatment stage to 14 days posttreatment, serum iron concentrations from 5 minutes posttreatment to 12 weeks posttreatment, routine blood examination and serum chemistry analysis results from pretreatment stage to 12 weeks after administration, and results of staining of the liver with Perls' Prussian Blue and hematoxylin-eosin at 24 hours and 3 months posttreatment in two rhesus monkeys following an intravenous administration of the targeted nanoparticles either with a polyethylene glycol (ATF-PEG-IONP) or without a PEG (ATF-IONP) coating., Results: The levels of alkaline phosphatase, alanine transaminase, and direct bilirubin in the two monkeys increased immediately after the administration of the IONPs but returned to normal within 20 days and stayed within the normal reference range 3 months after the injection. The creatinine levels of the two monkeys stayed within the normal range during the study. In addition, red blood cells, white blood cells, hemoglobin level, and platelets remained normal during the 3 months of the study., Conclusion: All of the results suggest that a transient injury in terms of normal organ functions, but no microscopic necrotic lesions, was observed at a systemic delivery dose of 5 mg/kg of iron equivalent concentration in the acute phase, and that no chronic toxicity was found 3 months after the injection. Therefore, we conclude that uPAR-targeted IONPs have the potential to be used as receptor-targeted MRI contrasts as well as theranostic agents for the detection and treatment of human cancers in future studies.

Caenorhabditis elegans senses gentle touch in the six touch receptor neurons (TRNs) using a mechanotransduction complex that contains the pore-forming degenerin/epithelial sodium channel (DEG/ENaC) proteins MEC-4 and MEC-10. Past work has suggested these proteins interact with the paraoxonase-like MEC-6 and the cholesterol-binding stomatin-like MEC-2 proteins. Using single molecule optical imaging in Xenopus oocytes, we found that MEC-4 forms homotrimers and MEC-4 and MEC-10 form 4:4:10 heterotrimers. MEC-6 and MEC-2 do not associate tightly with these trimers and do not influence trimer stoichiometry, indicating that they are not part of the core channel transduction complex. Consistent with the in vitro data, MEC-10, but not MEC-6, formed puncta in TRN neurites that colocalize with MEC-4 when MEC-4 is overexpressed in the TRNs.

Background: Diastolic heart failure is a common and deadly complication of diabetes mellitus, with the development of diabetic cardiomyopathy as one of the key determinants of the disease's complex pathology. The cause of the association is unknown and has no approved therapy strategies as of yet. However significant advances in this area may come from studies on suitable animal models., Methods: A total of 25 male rhesus monkeys (12-16 years, 9-13 kg) were enrolled. Fifteen of them were diagnosed as spontaneous type 2 diabetes mellitus (T2DM, FPG ≥ 104 mg/dl, HbA1c: 4.7-5.5 %, diabetes duration: 1-4 years). The other 10 monkeys were non-diabetic (ND, FPG < 90 mg/dl). Echocardiography and cardiac magnetic resonance were used for evaluating the cardiac structure and function. One T2DM monkey with impaired diastolic function and another ND monkey were both sacrificed to gain the necessary pathology and protein expression studies displayed here., Results: Six out of 15 T2DM rhesus monkeys were diagnosed with diastolic dysfunction (DD) by echocardiography. Additionally, no abnormalities were found in the group which we determined as the ND monkeys. The six DD monkeys all showed low e' velocity and decreased e'/a' ratio, among which three of them showing decreased E/A ratio and the other 3 having elevated E/A ratio, this appears to be similar to the impaired relaxation pattern and pseudonormal pattern found in human patients respectively. The EF and FS of monkeys with pseudonormal pattern decreased significantly compared with ND subjects. A CMR study showed that LVID at end systole of 5 DD monkeys is significantly longer than that of 3 ND monkeys. Of great interest, myocardium lesions and mitochondria impairments and increased expression of AGEs and caspase-3 were found in a sacrificed DD subject., Conclusion: The changes in the imaging and physiological markers of spontaneous T2DM rhesus monkeys are similar to those key markers found in human type 2 diabetes and diastolic dysfunction. This monkey model could help the medical community and us to understand the pathology of this debilitating disease and serve as a beginning to explore important measures to prevent and treat diabetic cardiomyopathy.

Both decalcified bone matrix (DBM) and fibrin gel possess good biocompatibility, so they are used as scaffolds to culture bone marrow mesenchymal stem cells (BMSCs). The feasibility and efficacy of using compound material being made of decalcified bone matrix and fibrin gel as a three-dimensional scaffold for bone growth were investigated. BMSCs were isolated from the femur of rabbit, then seeded in prepared scaffolds after incubation for 28 days in vitro. In vivo: 30 New Zealand White Rabbits received bone defect in left radius and divided three treatment groups randomly: (1) BMSCs/decalcified bone matrix/fibrin glue as experimental group; (2) decalcified bone matrix/fibrin glue without cells as control group; (3) nothing was implanted into the bone defects as blank group. The observation period of specimens was 12 weeks, and were analyzed bone formation in terms of serum proteomics (2D-PAGE and MALDI-TOF-TOF-MS), hematoxylin-eosin (HE) staining, ALP staining, and Osteopontin immunofluorescence detection. The experimental group present in three peculiar kinds of proteins, whose Geninfo identifier (GI) number were 136466, 126722803, and 126723746, respectively, correspond to TTR protein, ALB protein, RBP4 protein, and the histological inspections were superior to the other group. The content of osteopontin in experimental group was significantly higher than control group (p <  0.05). The overall results indicated that a combined material being made of BMSCs/decalcified bone matrix/fibrin glue can result in successful bone formation and decalcified bone matrix/fibrin glue admixtures can be used as a scaffold for bone tissue engineering., (Copyright © 2013 Wiley Periodicals, Inc.)

The present study was conducted in order to explore the mechanisms whereby parathyroid hormone (PTH) maintains in vitro proliferation of bone marrow mesenchymal stem cells (BMSCs). Bone marrow was isolated from Sprague Dawley (SD) rat femurs, cultured in vitro, and passaged using a cell adherent culture method. The BMSC proliferation was evaluated by the methyl thiazolyl tetrazolium (MTT) assay and the fluorescence intensity of calcium ions in BMSCs was analyzed by laser scanning confocal microscopy (LSCM). Our results show that BMSC proliferation in the experimental group treated with PTH was more significant than controls. The calcium ion fluorescence intensity in BMSCs was significantly higher for the experimental group as compared to the control group. For each group, there was significant difference in the fluorescence intensity of calcium ions in BMSCs between 7 d and 14 d. In conclusion, parathyroid hormone increased the fluorescence intensity of calcium ions in BMSCs, which might represent a key mechanism whereby BMSC proliferation is maintained.

The goal of this work was to check the ability of the PC-SAFT equation to represent the solubility of carbon dioxide (CO(2)) in ionic liquids. Parameters of pure imidazolium-based ionic liquids were estimated using experimental densities over a large range of temperatures and then correlated with respect to the molecular weight and structure of the solvents. It was found that such a correlation is able to predict the density with high accuracy. The solubility of carbon dioxide in such ionic liquids was then studied. The binary interaction parameter k(ij) needed for the representation of such binary systems was first fitted to experimental liquid-vapor equilibria data. In a second step, a correlation based on the group contribution concept was developed to determine this temperature-dependent parameter. The ability of the model to describe accurately carbon dioxide solubility in imidazolium-based ionic liquids is demonstrated.

Gentle touch sensation in Caenorhabditis elegans is mediated by the MEC-4/MEC-10 channel complex, which is expressed exclusively in six touch receptor neurons (TRNs). The complex contains two pore-forming subunits, MEC-4 and MEC-10, as well as the accessory subunits MEC-2, MEC-6, and UNC-24. MEC-4 is essential for channel function, but beyond its role as a pore-forming subunit, the functional contribution of MEC-10 to the channel complex and to touch sensation is unclear. We addressed this question using behavioral assays, in vivo electrophysiological recordings from TRNs, and heterologous expression of mutant MEC-10 isoforms. Animals with a deletion in mec-10 showed only a partial loss of touch sensitivity and a modest decrease in the size of the mechanoreceptor current (MRC). In contrast, five previously identified mec-10 alleles acted as recessive gain-of-function alleles that resulted in complete touch insensitivity. Each of these alleles produced a substantial decrease in MRC size and a shift in the reversal potential in vivo. The latter finding indicates that these mec-10 mutations alter the ionic selectivity of the transduction channel in vivo. All mec-10 mutant animals had properly localized channel complexes, indicating that the loss of MRCs was not attributable to a dramatic mislocalization of transduction channels. Finally, electrophysiological examination of heterologously expressed complexes suggests that mutant MEC-10 proteins may affect channel current via MEC-2.

The Slit-Robo (sr) GTPase-activating protein (GAPs) are important components in the intracellular pathway mediating Slit-Robo signaling in axon guidance and cell migration. We report the first crystal structure of the srGAP1 SH3 domain at 1.8-A resolution. The unusual side chain conformation of the conserved Phe-13 in the P1 pocket renders the ligand binding pocket shallow and narrow, which contributes toward the low binding affinity. Moreover, the opposing electrostatic charge and the hydrophobic properties of the P3 specificity pocket are consistent with the observed binding characteristics of the srGAP1 SH3 domain to its ligand. Surface plasmon resonance experiments indicate that the srGAP1 SH3 domain interacts with its natural ligand inaCtoN orientation. The srGAP1 SH3 domain can bind to both the CC2 and CC3 motifs in vitro. The N-terminal two acidic residues in the CC3 motif recognition site are necessary for srGAP1 SH3 domain binding. A longer CC3 peptide (CC3-FL) binds with greater affinity than its shorter counterpart, suggesting that the residues surrounding the proline-rich core are important for protein-peptide interactions. Our study reveals previously unknown properties of the srGAP-Robo interaction. Our data provide a structural basis for the srGAP-Robo interaction, consistent with the role of the Robo intracellular domain in interacting with other downstream signaling molecules and mediating versatile and dynamic responses to axon guidance and cell migration cues.