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Heart failure remains the leading cause of human death worldwide. After a heart attack, the formation of scar tissue due to the massive death of cardiomyocytes leads to heart failure and sudden death in most cases. In addition, the regenerative ability of the adult heart is limited after injury, partly due to cell-cycle arrest in cardiomyocytes. In the current post-COVID-19 era, urgently authorized modified mRNA (modRNA) vaccines have been widely used to prevent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Therefore, modRNA-based protein replacement may act as an alternative strategy for improving heart disease. It is a safe, effective, transient, low-immunogenic, and integration-free strategy for in vivo protein expression, in addition to recombinant protein and stem-cell regenerative therapies. In this review, we provide a summary of various cardiac factors that have been utilized with the modRNA method to enhance cardiovascular regeneration, cardiomyocyte proliferation, fibrosis inhibition, and apoptosis inhibition. We further discuss other cardiac factors, modRNA delivery methods, and injection methods using the modRNA approach to explore their application potential in heart disease. Factors for promoting cardiomyocyte proliferation such as a cocktail of three genes comprising FoxM1, Id1, and Jnk3-shRNA (FIJs), gp130, and melatonin have potential to be applied in the modRNA approach. We also discuss the current challenges with respect to modRNA-based cardiac regenerative medicine that need to be overcome to apply this approach to heart disease. This review provides a short description for investigators interested in the development of alternative cardiac regenerative medicines using the modRNA platform.

Vascularized composite allotransplantation has great potential in face transplantation by supporting functional restoration following tissue grafting. However, the need for lifelong administration of immunosuppressive drugs still limits its wide use. Modified mRNA (modRNA) technology provides an efficient and safe method to directly produce protein in vivo. Nevertheless, the use of IL-10 modRNA-based protein replacement, which exhibits anti-inflammatory properties, has not been shown to prolong composite facial allograft survival. In this study, IL-10 modRNA was demonstrated to produce functional IL-10 protein in vitro, which inhibited pro-inflammatory cytokines and in vivo formation of an anti-inflammatory environments. We found that without any immunosuppression, C57BL/6J mice with fully major histocompatibility complex (MHC)-mismatched facial allografts and local injection of IL-10 modRNA had a significantly prolonged survival rate. Decreased lymphocyte infiltration and pro-inflammatory T helper 1 subsets and increased anti-inflammatory regulatory T cells (Tregs) were seen in IL-10 modRNA-treated mice. Moreover, IL-10 modRNA induced multilineage chimerism, especially the development of donor Treg chimerism, which protected allografts from destruction because of recipient alloimmunity. These results support the use of monotherapy based on immunomodulatory IL-10 cytokines encoded by modRNA, which inhibit acute rejection and prolong allograft survival through the induction of donor Treg chimerism.

Although modern object detection AI models have the potential to be widely used in various applications such as autonomous vehicles, these models are very computationally demanding. Using high-resolution image data further increases the computational burden. Hence, we propose an acceleration method called Group of Picture (GoP) mode for object detection in video sequences by removing the temporal redundancy, unlike the existing model compression schemes. A GoP structure is composed of only one key frame and several non-key frames. In GoP-mode, object detection is adopted for key frames only, while object tracking is employed to predict the position of each object in the following non-key frames based on the tracked trajectory and momentum of each object. By using the proposed method, the thrilling latency saving can result in multiple times of execution speed acceleration so that both high detection accuracy and high execution speed can be obtained. In theory, if we adopt a GoP structure of one key frame with N non-key frames, the execution speed of object detection is accelerated to (1+N) times by equipping the GoP-mode. The effect of the number of non-key frames on the accuracy variation of an object detector equipped with GoP-mode has been analyzed. According to the experimental results, the mean average precision (mAP) of adopting GoP mode with four non-key frames in one GoP structure is competitive to that using object detection for all frames. Meanwhile, the execution frame rate is increased from the original 8 frames per second (FPS) to 35.8 FPS on the mobile platform−Jetson Nano, i.e. a speedup of 348%.

Abstract Background This study tested whether two doses of human umbilical-derived mesenchymal stem cells (hUC-MSCs) were superior to one dose for protecting the brain against intracranial hemorrhage (ICH) induced by intracranial injection collagenase and the capacity of ironic-magnetic-nanoparticles (Ir-MNa) coated hUC-MSCs tracked by MRI. Methods and results Adult male SD rats (n = 40) were equally categorized into group 1 (sham-operated-control), group 2 (ICH), group 3 [ICH + Ir-MNa-coated hUC-MSCs/1.2 × 106 cells with an extracorporeal magnet over rat head (eCMag)/administered by left internal carotid artery (LICA) at post-3 h ICH], and group 4 (ICH + Ir-MNa-coated hUC-MSCs/1.2 × 106 cells with an eCMag/administered post-3 h ICH by LICA and 24 h by IV) and euthanized by day 28. The result showed that by day 28 after ICH induction the neurological function was severely impaired in group 2 than in group 1 that was significantly improved in group 3 and further significantly improved in group 4, whereas ICH volume exhibited an opposite pattern of neurological impairment among the groups (all p

This study tested whether combined hyperbaric oxygen (HBO) and allogenic adipose-derived mesenchymal stem cells (ADMSCs) would be superior to either one for improving the locomotor recovery in rat after acute traumatic spinal cord injury (TSCI) in rat. Adult-male Sprague–Dawley rats were equally categorized into group 1 (sham-operated control), group 2 (TSCI), group 3 (TSCI + HBO for 1.5 h/day for 14 consecutive days after TSCI), group 4 (TSCI + ADMSCs/1.2 × 10 6 cells by intravenous injection at 3 h and days 1/2 after TSCI), and group 5 (TSCI + HBO + ADMSCs), euthanized, and spinal cord tissue was harvested by day 49 after TSCI. The protein expressions of oxidative-stress (NOX-1/NOX-2), inflammatory-signaling (TLR-4/MyD88/IL-1β/TNF-α/substance-p), cell-stress signaling (PI3K/p-AKT/p-mTOR), and the voltage-gated sodium channel (Nav1.3/1.8/1.9) biomarkers were highest in group 2, lowest in group 1, and significantly lower in group 5 than in groups 3/4 (all P

Activated effector T cells (Teff) and/or compromised regulatory T cells (Treg) underlie many chronic inflammatory diseases. We discovered a novel pathway to regulate survival and expansion of Teff without compromising Treg survival and a potential therapeutic to treat these diseases. We found dimethylguanidino valeric acid (DMGV) as a rheostat for Teff survival: while cell-intrinsic DMGV generated by Alanine-Glyoxylate Aminotransferase 2 (AGXT2) is essential for survival and expansion by inducing mitochondrial ROS and regulation of glycolysis, an excessive (or exogenous) DMGV level inhibits activated Teff survival, thereby the AGXT2-DMGV-ROS axis functioning as a switch to turn on and off Teff expansion. DMGV-induced ROS is essential for glycolysis in Teff, and paradoxically DMGV induces ROS only when glycolysis is active. Mechanistically, DMGV rapidly activates mitochondrial calcium uniporter (MCU), causing a surge in mitochondrial Ca2+ without provoking calcium influx to the cytosol. The mitochondrial Ca2+ surge in turn triggers the mitochondrial Na+/Ca2+ exchanger (NCLX) and the subsequent mitochondrial Na+ import induces ROS by uncoupling the Coenzyme Q cycle in Complex III of the electron transport chain. In preclinical studies, DMGV administration significantly diminished the number of inflammatory T cells, effectively suppressing chronic inflammation in mouse models of colitis and rheumatoid arthritis. DMGV also suppressed expansion of cancer cells in vitro and in a mouse T cell leukemic model by the same mechanism. Our data provide a new pathway regulating T cell survival and a novel mode to treat autoimmune diseases and cancers.

In this paper, the tool-tip responses for ball end milling, due to the coupling effects of a flexible rotor-bearing system, are investigated numerically. The milling machine tool spindle is modelled as the flexible rotor-bearing system. The critical speeds, natural modes, and unbalance responses of the system are calculated by applying the generalized polynomial expansion method. This generalized polynomial expansion method expresses the displacement as a series formed by the product of generalized coordinates and axial coordinate polynomials. According to the dynamic cutting force obtained by some scholars in the past, combined with the characteristics of the flexible rotor, the dynamic response of the tool-tip for ball end milling is numerically analyzed. The responses, including time histories, orbits, and FFT diagrams, are plotted to analyze the dynamic behaviors of the tool-tip. The coupling effects of the flexible rotor-bearing system on the system for ball end milling are first studied using the generalized polynomial expansion method. Unlike previous studies, the natural frequency varies with spindle speed and which of the different modes are included in the tool-tip response depends mainly on the spindle speed. Thanks to the gyroscopic effect, the critical speeds and responses of tool-tips can be discussed with respect to various spindle speed and tool flutes. The natural modes are accurately determined, and will excite critical speeds for certain modes, including forward and backward modes, thereby significantly affecting tool-tip response. In addition, the cutting force component associated with the tool-tip response affects the rotor-bearing system parameters, complicating the issue. Milling at higher spindle speed (2160–19,950 rpm), an important new result is found that the tool-tip oscillates with the cutting-force frequency, accompanied by a longer period vibration of the first backward mode of the rotor-bearing system. It can also be seen from the frequency spectrum analysis that, as the spindle speed increases, the peak amplitude of the first backward mode becomes larger. Milling at lower spindle speed (960, 1320 rpm), the in-plane vibration trajectory of the tool-tip gradually expands outwards clockwise around the origin until a stable loop is reached. This is because only the first backward mode of the rotor-bearing system is excited. Considering the coupling effect of the rotor-bearing system to perform the vibration analysis of the milling machine system, the parameters of the system can be designed or the spindle speed can be selected to avoid severe vibration during machining.

Abstract We demonstrated the design of pre-additive manufacturing microalloying elements in tuning the microstructure of iron (Fe)-based alloys for their tunable mechanical properties. We tailored the microalloying stoichiometry of the feedstock to control the grain sizes of the metallic alloy systems. Two specific microalloying stoichiometries were reported, namely biodegradable iron powder with 99.5% purity (BDFe) and that with 98.5% (BDFe-Mo). Compared with the BDFe, the BDFe-Mo powder was found to have lower coefficient of thermal expansion (CTE) value and better oxidation resistance during consecutive heating and cooling cycles. The selective laser melting (SLM)-built BDFe-Mo exhibited high ultimate tensile strength (UTS) of 1200 MPa and fair elongation of 13.5%, while the SLM-built BDFe alloy revealed a much lower UTS of 495 MPa and a relatively better elongation of 17.5%, indicating the strength enhancement compared with the other biodegradable systems. Such an enhanced mechanical behavior in the BDFe-Mo was assigned to the dominant mechanism of ferrite grain refinement coupled with precipitate strengthening. Our findings suggest the tunability of outstanding strength-ductility combination by tailoring the pre-additive manufacturing microalloying elements with their proper concentrations.

Abstract Background Pyogenic spondylodiscitis (PSD) is challenging to the orthopedist with regards to diagnosis and treatment. The present study was designed to assess and suggest the most indicative diagnostic method and evaluate the effect of surgery comprising of debridement, instrumentation and fusion in treating PSD. Methods Seventy-six patients with PSD who underwent surgical intervention were retrospectively enrolled. Their medical documents, corrections of spinal alignment and improvements in neurological function were assessed. Surgical approaches were compared in lumbar surgeries regarding the improvements in lordotic angle and neurological function. Results Elevated c-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) were found in 77.6 and 71.1% patients respectively. Infectious lesions were found at lumbar (85.5%), cervical (10.5%) and thoracic (3.9%), ascertained with contrast-enhanced MRI. For lumbar patients, surgery was performed through the anterior (26.2%), posterior (49.2%) or combined approach (24.6%), and differences in improvement of lordosis and neurological function between each approach were insignificant. The pathogen was identified in 22.4% of the patients. Postoperative antibiotic therapy was managed against the result of susceptibility test, or empirically given to patients with negative cultures. All antibiotic therapy was initiated intravenously for 4–6 weeks and orally for 6 weeks. Conclusion Elevated CRP and/or ESR, with focal hyper-intensity on contrast-enhanced MRI are suggestive of possible PSD. Surgical intervention comprising of debridement, short-segment instrumentation and fusion that early applied to the PSD patients followed by postoperative antibiotic therapy have demonstrated preferable outcomes, but require further study. The translational potential of this article This article advocates early surgery to enable prompt diagnosis and treatment of PSD, and thus guarantee favorable outcomes for patients, as is shown in our study. In addition, different surgical approaches to the lesions were compared and discussed in this manuscript, but no differences in outcome between approaches were found. This suggests that thorough debridement should be prioritized over selection of surgical approach. In summary, this article has large translational potential to be applied clinically.

Vascularized composite allotransplantation is an emerging strategy for the reconstruction of unique defects such as amputated limbs that cannot be repaired with autologous tissues. In order to ensure the function of transplanted limbs, the functional recovery of the anastomosed peripheral nerves must be confirmed. The immunosuppressive drug, tacrolimus, has been reported to promote nerve recovery in animal models. However, its repeated dosing comes with risks of systemic malignancies and opportunistic infections. Therefore, drug delivery approaches for locally sustained release can be designed to overcome this issue and reduce systemic complications. We developed a mixed thermosensitive hydrogel (poloxamer (PLX)-poly(l-alanine-lysine with Pluronic F-127) for the time-dependent sustained release of tacrolimus in our previous study. In this study, we demonstrated that the hydrogel drug degraded in a sustained manner and locally released tacrolimus in mice over one month without affecting the systemic immunity. The hydrogel drug significantly improved the functional recovery of injured sciatic nerves as assessed using five-toe spread and video gait analysis. Neuroregeneration was validated in hydrogel–drug-treated mice using axonal analysis. The hydrogel drug did not cause adverse effects in the mouse model during long-term follow-up. The local injection of encapsulated-tacrolimus mixed thermosensitive hydrogel accelerated peripheral nerve recovery without systemic adverse effects.

Abstract Background Dynamic somatosensory evoked potentials (DSSEP) can be used to disclose abnormalities of ascending sensory pathways at dynamic positions and diagnose cervical spondylotic myelopathy (CSM). However, radiographic tests including magnetic resonance imaging (MRI) and dynamic X-ray are used much more widely in the management of CSM. Our study aims to clarify the correlations between several radiographic parameters and the DSSEP results, and further determine their reliability with clinical data. Methods We retrospectively enrolled 38 CSM patients with surgical intervention. DSSEP tests were performed before surgery. Amplitude ratios of DSSEP N13 and N20 waves at extension and flexion were calculated and recorded as N13_E, N20_E, N13_F, N20_F, respectively. Baseline severity was evaluated with the modified Japanese Orthopedic Association (mJOA) score and the Nurick grades. Prognosis was evaluated based on the 2-year recovery rate. Sagittal diameter and transverse areas of the cord and canal were measured and the the compressive ratios at the compressed site (Compression_Ratio), central (Central_Ratio), and 1/4-lateral points (1/4-Lateral_Compression_Ratio), and spinal cord/Canal Area Ratio were calculated. The intramedullary T2 hyperintensity patterns (Ax-CCM types) were also collected from MRI axial images. Dynamic X-rays were used to test for segmental instability of the cervical spine. The correlations between radiologic findings, DSSEP data, and clinical assessments were investigated. Results We found that DSSEP N13_E and N13_F correlated with the Compression_Ratio, Central_Ratio, 1/4-Lateral_Compression_Ratio (Pearson, p

This study tested the hypothesis that valsartan (Val) and melatonin (Mel)-assisted adipose-derived mesenchymal stem cells (ADMSCs) preserved the residual renal function in chronic kidney disease (CKD) rat through promoting cellular-prior-protein (PrPC) to upregulate PI3K/Akt/mTOR signaling and cell proliferation. In vitro study demonstrated that as compared with CKD-derived-ADMSCs, Val/Mel/overexpression of PrPC-treated CKD derived-ADMSCs significantly upregulated cell proliferation and protein expressions of PrPC and phosphorylated (p)-PI3K/p-Akt/p-mTOR, and downregulated oxidative stress (all p

Abstract Background This study tested the optimal time point for left intra-carotid arterial (LICA) administration of circulatory-derived autologous endothelial progenitor cells (EPCs) for improving the outcome in rat after acute ischemic stroke (IS). Methods and results Adult male SD rats (n = 70) were equally categorized into group 1 (sham-operated control), group 2 (IS), group 3 (IS+EPCs/1.2 × 106 cells/by LICA administration 3 h after IS), group 4 (IS+EPCs/LICA administration post-day-3 IS), group 5 (IS+EPCs/LICA administration post-day-7 IS), group 6 (IS+EPCs/LICA administration post-day-14 IS), and group 7 (IS+EPCs/LICA administration post-day-28 IS). The brain infarct volume (BIV) (at day 60/MRI) was lowest in group 1, highest in group 2, and significantly progressively increased from groups 3 to 7, whereas among the IS animals, the neurological function was significantly preserved in groups 3 to 6 than in groups 2 and 7 post-day-60 IS (all P

Vision-based respiratory measurement can remotely measure respiratory information without affecting the sleep quality of the user. However, several scenarios during sleeping, such as when blankets cover areas of the face or body, can be a challenge when estimate respiratory rate (RR) due to the uncertainty of the region of interest (ROI). In this study, we first investigate the metrics and physical meanings of ROI selection from the perspectives of array signal processing and the concept of linear combining. Then, we propose an ROI detection algorithm based on both temporal and spatial consistency (TSC), which aims to extract the representative characteristics of respiration with fewer computational resources. Furthermore, a sleeping database, containing more than 50 hours of data, was built to investigate the performance of benchmarked ROI methods during long-term sleeping. The experimental results demonstrate that TSC attains the highest signal-to-noise ratio (SNR) at 20.6 dB and a relatively low elapsed time of 100.2 frames per second (fps). For the RR estimation accuracy, TSC reduces the mean absolute error from 1.65 breaths per minute (bpm) to 0.97 bpm.

Background: We tested the hypothesis that extracorporeal shock wave (ECSW)-assisted 5-FU therapy effectively suppressed human tongue squamous carcinoma cell line SAS (i.e., SAS cells) proliferation and tumor growth. Methods and results: In vitro study showed that as compared with lower ECSW energy (≤0.12 mJ/mm2), higher ECSW energy (≥0.25–035 mJ/mm2) significantly suppressed the SAS cell proliferation and upregulated tumor cell apoptosis/DNA-damage/oxidative-stress, whereas combined higher ECSW energy (0.35 mJ/mm2) and 5-FU (20uM) further significantly altered the expressions of these parameters (all p

This study investigated the hypothesis that probiotics enhanced the therapeutic effect of adipose-derived mesenchymal stem cells (ADMSCs) on alleviating neuropathic pain (NP) due to chronic constriction injury (CCI) mainly through regulating the microbiota in rats. SD rats (n = 50) were categorized into group 1 (sham-control), group 2 (NP), group 3 (NP + probiotics (i.e., 1.5 billion C.F.U./day/rat, orally 3 h after NP procedure, followed by QOD 30 times)), group 4 (NP + ADMSCs (3.0 × 105 cells) 3 h after CCI procedure, followed by QOD six times (i.e., seven times in total, i.e., mimic a clinical setting of drug use) and group 5 (NP + probiotics + ADMSCs (3.0 × 105 cells)) and euthanized by day 60 after NP induction. By day 28 after NP induction, flow-cytometric analysis showed circulating levels of early (AN-V+/PI−) and late (AN-V+/PI+) apoptotic, and three inflammatory (CD11b-c+, Ly6G+ and MPO+) cells were lowest in group 1 and significantly progressively reduced in groups 2 to 5 (all p < 0.0001). By days 7, 14, 21, 28, and 60 after CCI, the thresholds of thermal paw withdrawal latency (PWL) and mechanical paw withdrawal threshold (PWT) were highest in group 1 and significantly progressively increased in groups 2 to 5 (all p < 0.0001). Numbers of pain-connived cells (Nav1.8+/peripherin+, p-ERK+/peripherin+, p-p38+/peripherin+ and p-p38+/NF200+) and protein expressions of inflammatory (p-NF-κB, IL-1ß, TNF-α and MMP-9), apoptotic (cleaved-caspase-3, cleaved-PARP), oxidative-stress (NOX-1, NOX-2), DNA-damaged (γ-H2AX) and MAPK-family (p-P38, p-JNK, p-ERK1/2) biomarkers as well as the protein levels of Nav.1.3, Nav.1.8, and Nav.1.9 in L4-L5 in dorsal root ganglia displayed an opposite pattern of mechanical PWT among the groups (all p < 0.0001). In conclusion, combined probiotic and ADMSC therapy was superior to merely one for alleviating CCI-induced NP mainly through suppressing inflammation and oxidative stress.

We previously developed chicken interleukin-1β (IL-1β) mutants as single-dose adjuvants that induce protective immunity when co-administered with an avian vaccine. However, livestock such as pigs may require a vaccine adjuvant delivery system that provides long-lasting protection to reduce the need for successive booster doses. Therefore, we developed chitosan-coated alginate microparticles as a carrier for bovine serum albumin (BSA) or porcine IL-1β (pIL-1β) and assessed their physical, chemical, and biological properties. Electrospraying of the BSA-loaded alginate microparticles (BSA/ALG MPs) resulted in an encapsulation efficiency of 50%, and those MPs were then coated with chitosan (BSA/ALG/CHI MPs). Optical and scanning electron microscopy, zeta potential analysis, and Fourier transform infrared spectroscopy were used to characterize these MPs. The BSA encapsulation parameters were applied to ALG/CHI MPs loaded with pIL-1β, which were not cytotoxic to porcine fibroblasts but had enhanced bio-activity over unencapsulated pIL-1β. The chitosan layer of the BSA/ALG/CHI MPs prevented burst release and facilitated sustained release of pIL-1β for at least 28 days. In conclusion, BSA/ALG/CHI MPs prepared as a carrier for pIL-1β may be used as an adjuvant for the formulation of pig vaccines.

Background: This study tested whether combined cyclosporin-A (CsA) and melatonin (Mel) was superior to either one on protecting the brain against ischemia (occluded left-middle-cerebral-artery for 90-min)-reperfusion (for 14 days) injury. Methods and results: Neuro-2a cells (N2a) were categorized into groups 1 (N2a), 2 (N2a-IR), 3 (N2a-IR-Mel), 4 (N2a-IR-CsA) and 5 (N2a-IR-CsA-Mel). in vitro results showed the protein expressions of cytosolic-cytochrome-C/mitochondrial-Bax/cleaved-capase-3/NOX-1/NOX-2 and flow-cytometric results of ROS (DCFDA/Mito-SOX) were highest in group 2, lowest in group 1, significantly lower in group 5 than in groups 3/4, but they showed no difference in groups 3/4 (all p < 0.001). Male-adult-SD rats (50) were equally categorized into groups 1 (sham-operated-control), 2 (IR), 3 (IR-CsA/20.0 mg/kg at 0.5/24/48 h intraperitoneally after IR), 4 (IR-Mel/50.0 mg/kg intraperitoneally at 30 min and 30 mg/kg at 6/24/48 h after IR) and 5 (IR-CsA-Mel). The brain-infarct-area (BIA) (at day-3 by TTC-stain) was lowest in group 1, highest in group 2, significantly lower in group 5 than groups 3/4, but it showed no difference between groups 3/4 whereas the brain-infarct-volume (at day 14 by MRI) was similar as BIA except for significantly lower in group 4 than in group 3 (all p < 0.0001). By day 14, microscopic finding showed the numbers of glial+/GFAP+/AQP + cells expressed an identical trend whereas the number of NeuN + cells exhibited an opposite pattern of BIA among the groups (all p < 0.0001). The protein expressions of oxidative-stress (NOX-1/NOX-2/p22phox/oxidized-protein), inflammatory (TNF-α/p-NF-κB/MMP-9), apoptotic (mitochondrial-Bax/caspase-3/PARP) and mitochondrial-damaged (Cyclophilin-D/DRP1/cytosolic-cytochrome-C) biomarkers displayed an identical pattern of BIA among the five groups (all p < 0.0001). Conclusion: Combined CsA-Mel was superior to either CsA or Mel on protecting the brain against IR injury.

This study tested whether sitagliptin and shock wave (SW)-assisted circulatory-derived autologous endothelial progenitor cell (EPC) therapy would effectively preserve residual renal function in chronic kidney disease (CKD) induced by 5/6 left-nephrectomy/remove right kidney plus daily feeding high-protein diet (HPD) in rat. Adult-male SD rats (n = 40) were categorized into group 1 (sham-operated control with HPD), group 2 (HPD-CKD), group 3 [HPD-CKD + EPC (1.2 × 106 cell)/intra-vessel administration by day 14 after CKD-induction], group 4 [HPD-CKD + SW (0.12 mJ/mm2/180 shorts) at days 14/21/28 after CKD-induction by ultrasound-guided application] and group 5 [HPD-CKD + SW + EPC + sitagliptin (Sita; 600 mg/kg/day since day 14 after CKD induction)]. All animals were euthanized by day 60. By day 60, renal blood flow (RBF) was highest in group 1 and progressively increased from groups 2 to 5, whereas the levels of creatinine/BUN/proteinuria exhibited an opposite pattern of RBF among the five groups (all p

This study tested the hypothesis that early administration of empagliflozin (Empa), an inhibitor of glucose recycling in renal tubules, could preserve heart function in cardiorenal syndrome (CRS) in rat. Chronic kidney disease (CKD) was caused by 5/6 subtotal nephrectomy and dilated cardiomyopathy (DCM) by doxorubicin (DOX) treatment. In vitro results showed that protein expressions of cleaved-caspase3 and autophagy activity at 24 h/48 h in NRK-52P cells were significantly upregulated by para-Creso treatment; these were significantly downregulated by Empa treatment. Flow cytometric analysis showed that annexin-V (i.e., early/late apoptosis) in NRK-52P cells expressed an identical pattern to cleaved-caspase3 between the two groups (all p

In this study, we attempt to establish an alternative method for estimating the groundwater levels and the specific yields of an unconfined aquifer for the evaluation of potential groundwater reservoirs. We first converted the inverted resistivity into the normalized water content. Then, we inverted the parameters of the Brooks-Corey model from the vertical profiles of the water content by assuming that the suction head was in proportion to the elevation regarding a predefined base level. Lastly, we estimated the groundwater level, the theoretical specific yield, and the specific yield capacity from the Brooks-Corey parameters at every survey site in the study area. The contour maps of the time-lapse groundwater levels show that the groundwater flows downstream, with a higher hydraulic gradient near the river channel than in the area away from the main channel. We conclude that the estimated maximum specific yield capacities are consistent with that derived from the pumping tests in the nearby observation well. Additionally, the specific yield capacities are only three quarters to two thirds of the theoretical specific yields derived from the difference between the residual and saturated water contents in the Brooks-Corey model. We conclude that the distribution pattern of the specific yields had been subjected to the distribution of natural river sediments in the Minzu Basin, since the modern channel was artificially modified. Although we had to make some simple assumptions for the estimations, the results show that the surface resistivity surveys provide reasonable estimations of the hydraulic parameters for a preliminary assessment in an area with few available wells.

Intracranial hemorrhage from stroke and head trauma elicits a cascade of inflammatory and immune reactions detrimental to neurological integrity and function at cellular and molecular levels. This study tested the hypothesis that human umbilical cord–derived mesenchymal stem cell (HUCDMSC) therapy effectively protected the brain integrity and neurological function in rat after acute traumatic brain injury (TBI). Adult male Sprague-Dawley rats ( n = 30) were equally divided into group 1 (sham-operated control), group 2 (TBI), and group 3 [TBI + HUCDMSC (1.2 × 10 6 cells/intravenous injection at 3 h after TBI)] and euthanized by day 28 after TBI procedure. The results of corner test and inclined plane test showed the neurological function was significantly progressively improved from days 3, 7, 14, and 28 in groups 1 and 3 than in group 2, and group 1 than in group 3 (all P < 0.001). By day 28, brain magnetic resonance imaging brain ischemic volume was significantly increased in group 2 than in group 3 ( P < 0.001). The protein expressions of apoptosis [mitochondrial-bax positive cells (Bax)/cleaved-caspase3/cleaved-poly(adenosine diphosphate (ADP)-ribose) polymerase], fibrosis (Smad3 positive cells (Smad3)/transforming growth factor-β), oxidative stress (NADPH Oxidase 1 (NOX-1)/NADPH Oxidase 2 (NOX-2)/oxidized-protein/cytochrome b-245 alpha chain (p22phox)), and brain-edema/deoxyribonucleic acid (DNA)–damaged biomarkers (Aquaporin-4/gamma H2A histone family member X ( (γ-H2AX)) displayed an identical pattern to neurological function among the three groups (all P < 0.0001), whereas the protein expressions of angiogenesis biomarkers (vascular endothelial growth factor/stromal cell–derived factor-1α/C-X-C chemokine receptor type 4 (CXCR4)) significantly increased from groups 1 to 3 (all P < 0.0001). The cellular expressions of inflammatory biomarkers (cluster of differentiation 14 (+) cells (CD14+)/glial fibrillary acidic protein positive cells (GFAP+)/ a member of a new family of EGF-TM7 molecules positive cells (F4/80+)) and DNA-damaged parameter (γ-H2AX) exhibited an identical pattern, whereas cellular expressions of neural integrity (hexaribonucleotide Binding Protein-3 positive cells (NeuN+)/nestin+/doublecortin+) exhibited an opposite pattern of neurological function among the three groups (all P < 0.0001). Xenogeneic HUCDMSC therapy was safe and it significantly preserved neurological function and brain architecture in rat after TBI.

Background: This study tested the hypothesis that intramuscular injections of erythropoietin (EPO) and endothelial progenitor cells (EPC) to critical limb ischemia (CLI; primary treatment site) could also improve heart function in rat after acute myocardial infarction (AMI; remote ischemic organ). Method: Adult-male SD rats (n = 40) were equally categorized into group 1 (sham-operated control), group 2 (CLI-AMI), group 3 [CLI-AMI + EPO (10 mg/kg)], group 4 [CLI-AMI + EPCs (1.2 × 106)] and group 5 (CLI-AMI + EPCs + EPO). Results: By day 21 (end of study period), 2-D echo and Laser doppler showed that left-ventricular injection fraction (LVEF) and the ratio of ischemic to normal blood flow were highest in group 1, lowest in group 2, significantly higher in group 5 than in groups 3 and 4, but not different in the latter two groups (all p

Three-phase wye–delta LLC topology is suitable for voltage step down and high output current, and has been used in the industry for some time, e.g., for server power and EV charger. However, no comprehensive circuit analysis has been performed for three-phase wye–delta LLC. This paper provides complete analysis methods for three-phase wye–delta LLC. The analysis methods include circuit operation, time domain analysis, frequency domain analysis, and state–plane analysis. Circuit operation helps determine the circuit composition and operation sequence. Time domain analysis helps understand the detail operation, equivalent circuit model, and circuit equation. Frequency domain analysis helps obtain the curve of the transfer function and assists in circuit design. State–plane analysis is used for optimal trajectory control (OTC). These analyses not only can calculate the voltage/current stress, but can also help design three-phase wye-delta connected LLC and provide the OTC control reference. In addition, this paper uses PSIM simulation to verify the correctness of analysis. At the end, a 5-kW three-phase wye–delta LLC prototype is realized. The specification of the prototype is a DC input voltage of 380 V and output voltage/current of 48 V/105 A. The peak efficiency is 96.57%.

Recently, three-phase series-resonant converters (SRCs) have been proposed for high power applications. Three-phase SRCs can achieve zero-voltage-switching (ZVS) of the primary power switches and regulate the output voltage by pulse-frequency modulation. The interleaving technique is also a conventional method for DC-DC converters to achieve a high power level, reducing the output voltage ripples due to operating out of phase at the same frequency between the two converters. However, an interleaved three-phase SRC cannot easily synchronize switching instants between the two modules due to the component tolerances of circuits. In the proposed control method, phase shift modulation (PSM) is used to solve the output current imbalance caused by component tolerances. The power switches of the converter can also maintain synchronizing switching instants between the two modules. Therefore, the lower output voltage ripple can be achieved. A detailed analysis and design of this new control method for interleaved three-phase SRCs are described. Finally, prototype converters with a 2.4 kW total output were built and successfully tested to verify the feasibility of the current sharing modulation.

This study tested whether circulatory endothelial progenitor cells (EPCs) derived from peripheral arterial occlusive disease (PAOD) patients after receiving combined autologous CD34+ cell and hyperbaric oxygen (HBO) therapy (defined as rejuvenated EPCs) would salvage nude mouse limbs against critical limb ischemia (CLI). Adult-male nude mice (n = 40) were equally categorized into group 1 (sham-operated control), group 2 (CLI), group 3 (CLI-EPCs (6 × 105) derived from PAOD patient’s circulatory blood prior to CD34+ cell and HBO treatment (EPCPr-T) by intramuscular injection at 3 h after CLI induction) and group 4 (CLI-EPCs (6 × 105) derived from PAOD patient’s circulatory blood after CD34+ cell and HBO treatment (EPCAf-T) by the identical injection method). By 2, 7 and 14 days after the CLI procedure, the ischemic to normal blood flow (INBF) ratio was highest in group 1, lowest in group 2 and significantly lower in group 4 than in group 3 (p < 0.0001). The protein levels of endothelial functional integrity (CD31/von Willebrand factor (vWF)/endothelial nitric-oxide synthase (eNOS)) expressed a similar pattern to that of INBF. In contrast, apoptotic/mitochondrial-damaged (mitochondrial-Bax/caspase-3/PARP/cytosolic-cytochrome-C) biomarkers and fibrosis (Smad3/TGF-ß) exhibited an opposite pattern, whereas the protein expressions of anti-fibrosis (Smad1/5 and BMP-2) and mitochondrial integrity (mitochondrial-cytochrome-C) showed an identical pattern of INBF (all p < 0.0001). The protein expressions of angiogenesis biomarkers (VEGF/SDF-1α/HIF-1α) were progressively increased from groups 1 to 3 (all p < 0.0010). The number of small vessels and endothelial cell surface markers (CD31+/vWF+) in the CLI area displayed an identical pattern of INBF (all p < 0.0001). CLI automatic amputation was higher in group 2 than in other groups (all p < 0.001). In conclusion, EPCs from HBO-C34+ cell therapy significantly restored the blood flow and salvaged the CLI in nude mice.

In this paper, a nanobiosensor with surface-enhanced Raman scattering (SERS) capability is introduced for highly sensitive miRNA detection in colorectal cancer. This sensor was designed and fabricated by employing a nanoshielding mechanism from nanopolystyrene beads to resist reactive ion etching and allow anisotropic electrochemical etching, producing high-aspect-ratio, surface-corrugated nanopillars (SiNPs) on a silicon wafer to create extensive hot spots along the nanopillars for improved SERS signals. SERS enhancements were correlated with nanorange roughness, indicating that hot spots along the pillars were the crucial factor to improve the SERS effect. We achieved the detection capability of a trace amount of R6G (10−8 M), and the SERS signal enhancement factor (EF) was close to 1.0 × 107 on surface-corrugated gold SiNPs. miRNA samples were also demonstrated on this sensor with good sensitivity and specificity. The target molecule miR-21-Cy5 was easily monitored through Raman spectrum variation with a PCR-comparable concentration at around 100 pM with clear nucleotide-specific Raman signals, which is also suitable for biomolecule sensing.

Abstract The insufficient availability and activity of interfacial water remain a major challenge for alkaline hydrogen evolution reaction (HER). Here, we propose an “on-site disruption and near-site compensation” strategy to reform the interfacial water hydrogen bonding network via deliberate cation penetration and catalyst support engineering. This concept is validated using tip-like bimetallic RuNi nanoalloys planted on super-hydrophilic and high-curvature carbon nanocages (RuNi/NC). Theoretical simulations suggest that tip-induced localized concentration of hydrated K+ facilitates optimization of interfacial water dynamics and intermediate adsorption. In situ synchrotron X-ray spectroscopy endorses an H* spillover-bridged Volmer‒Tafel mechanism synergistically relayed between Ru and Ni. Consequently, RuNi/NC exhibits low overpotential of 12 mV and high durability of 1600 h at 10 mA cm‒2 for alkaline HER, and demonstrates high performance in both water electrolysis and chlor-alkali electrolysis. This strategy offers a microscopic perspective on catalyst design for manipulation of the local interfacial water structure toward enhanced HER kinetics.

This study tested whether the soluble (s)ST2 is a superb biomarker predictive of moderate to severe cerebral−cardiac syndrome (CCS) (defined as coexisting National Institute of Health Stroke Scale (NIHSS) >8 and left-ventricular ejection fraction (LVEF) n = 66), group 2 (NIHSS = 9-15, n = 14) and group 3 (NIHSS ≥ 16, n = 19), respectively. Blood samples were collected immediately after hospitalization, followed by transthoracic echocardiographic examination. The results showed that the flow cytometric analysis for assessment of inflammatory biomarkers of TLR2+/CD14+cells, TLR4+/CD14+cells, Ly6g+/CD14+cells, and MPO+/CD14+cells, and ELISA assessment for circulatory level of sST2 were significantly higher in groups 2/3 than in group 1 (all p < 0.01). However, these parameters did not show significant differences between groups 2 and 3 (all p > 0.05). The LVEF was significantly lower in group 3 than in group 1 (p < 0.001), but it displayed no difference between groups 1/2 or between groups 2/3. These inflammatory biomarkers ((TLR2+/CD14+cells// TLR4+/CD14+cells// MPO+/CD14+cells) and sST2)) were significantly positively correlated to NIHSS and strongly negatively correlated to LVEF (all p < 0.05). Multivariate analysis demonstrated that both MPO/CD14+cells >20% (p = 0.027) and sST2 ≥ 17,600 (p = 0.004) were significantly and independently predictive of moderate-severe CCS after acute IS. Receiver operating characteristic curve analysis demonstrated that sST2 was the most powerful predictor of CCS with a sensitivity of 0.929 and a specificity of 0.731 (p < 0.001). In conclusion, sST2 is a useful biomarker for prediction of CCS severity in patients after acute IS.

This study tested the hypothesis that shock wave therapy (SW) enhances mitochondrial uptake into the lung epithelial and parenchymal cells to attenuate lung injury from acute respiratory distress syndrome (ARDS). ARDS was induced in rats through continuous inhalation of 100% oxygen for 48 h, while SW entailed application 0.15 mJ/mm2 for 200 impulses at 6 Hz per left/right lung field. In vitro and ex vivo studies showed that SW enhances mitochondrial uptake into lung epithelial and parenchyma cells (all p

Hair coloring products are one of the most important cosmetics for modern people; there are three major types of hair dyes, including the temporary, semi-permanent and permanent hair dyes. The selected hair dyes (such as ammonium persulfate, sodium persulfate, resorcinol and lawsone) are the important components for hair coloring products. Therefore, we analyzed the effects of these compounds on melanogenesis in B16-F10 melanoma cells. The results proved that hair dyes resorcinol and lawsone can reduce the production of melanin. The results also confirmed that resorcinol and lawsone inhibit mushroom and cellular tyrosinase activities in vitro. Resorcinol and lawsone can also downregulate the protein levels of tyrosinase and microphthalmia-associated transcription factor (MITF) in B16-F10 cells. Thus, we suggest that frequent use of hair dyes may have the risk of reducing natural melanin production in hair follicles. Moreover, resorcinol and lawsone may also be used as hypopigmenting agents to food, agricultural and cosmetic industry in the future.

Despite left ventricular (LV) dysfunction increases the risk of incidental acute ischemic stroke (AIS), the association between LV function and severity of neurological deficits after AIS remains unclear. Between November 2015 and October 1017, a total of 99 AIS patients were prospectively enrolled and categorized into two groups based on National Institute of Health Stroke Scale (NIHSS). The AIS patients with NIHSS n = 50) and those with NIHSS ≥6 were into Group 2 (n = 49). Echocardiography was performed within 5 days after AIS to assess chamber size, left ventricular ejection fraction (LVEF) and valvular regurgitation. Besides, two inflammatory biomarkers, neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR), were evaluated on admission. The results showed Group 2 had significantly higher value of NLR and PLR (all p-values < 0.01) but lower LVEF (p = 0.001) and frequency of mitral regurgitation (p = 0.021) than Group 1. The NIHSS and modified Rankin scale were significantly negatively correlated with LVEF, whereas both were significantly positively correlated with NLR and PLR (all p-values < 0.02). Multivariate analysis showed LVEF p-values < 0.01). In conclusion, the AIS patients with NIHSS ≥6 had lower LVEF but more clinically dominant mitral regurgitation and higher NLR and PLR compared to those with NIHSS

Background: This study tested the hypothesis that hyperbaric oxygen (HBO) therapy enhanced the circulating levels of endothelial progenitor cells (EPCs), soluble angiogenesis factors, and blood flow in ischemic areas in patients with peripheral arterial occlusive disease (PAOD). Methods: In total, 57 consecutive patients with PAOD undergoing the HBO therapy (3 atmospheres (atm) for 2 h each time) were prospectively enrolled into the present study. Venous blood sampling was performed to assess the circulating levels of EPCs and soluble angiogenesis factors prior to and during five sessions of HBO therapy. Additionally, skin perfusion pressure (SPP), an indicator of blood flow in ischemic areas, was measured by moorVMS-PRES. Results: The results demonstrated that the circulating levels of EPCs (cluster of differentiation (CD)34+/CD133+/CD45dim, CD31+/CD133+/CD45dim, CD34+) and soluble angiogenesis factors—vascular endothelial growth factor/stromal cell-derived factor 1/hepatocyte growth factor/fibroblast growth factor (VEGF/SDF-1α/HGF/FGF) were significantly increased post-HBO therapy as compared to pre-HBO therapy (all p < 0.01). Additionally, Matrigel assay showed that the angiogenesis was significantly increased in post-HBO therapy as compared to prior to therapy (p < 0.001). Furthermore, SPP was significantly increased in the ischemic area (i.e., plantar foot and mean SPP of the ischemic foot) in post-HBO therapy as compared to pre-HBO therapy (all p < 0.01). Importantly, the HBO therapy did appear to result in complications, and all the patients were uneventfully discharged without amputation. Conclusions: HBO therapy augmented circulating levels of EPCs and angiogenesis factors, and improved the blood flow in the ischemic area.

Myocardial ischemia-reperfusion (IR) injury contributes to adverse cardiac outcomes after myocardial ischemia, cardiac surgery, or circulatory arrest. In this study, we evaluated the ability of combined SS31-mitochondria (Mito) therapy to protect heart cells from myocardial IR injury. Adult male SD rats (n = 8/each group) were randomized: group 1 (sham-operated control), group 2 (IR, 30-min ischemia/72 h reperfusion), group 3 (IR-SS31 (2 mg intra-peritoneal injection at 30 min/24 h/48 h after IR)), group 4 (IR-mitochondria (2 mg/derived from donor liver/intra-venous administration/30 min after IR procedure)), and group 5 (IR-SS31-mitochondria). In H9C2 cells, SS31 suppressed menadione-induced oxidative-stress markers (NOX-1, NOX-2, oxidized protein) while it increased SIRT1/SIRT3 expression and ATP levels. In adult male rats 72 h after IR, left ventricular ejection fraction (LVEF) was highest in sham-operated control animals and lowest in the IR group. LVEF was also higher in IR rats treated with SS31-Mito than untreated IR rats or those treated with Mito or SS31 alone. Areas of fibrosis/collagen-deposition showed the opposite pattern. Likewise, levels of oxidative-stress markers (NOX-1, NOX-2, oxidized protein), inflammatory markers (MMP-9, CD11, IL-1β, TNF-α), apoptotic markers (mitochondrial-Bax, cleaved-caspase-3, PARP), fibrosis markers (p-Smad3, TGF-β), DNA-damage (γ-H2AX), sarcomere-length, and pressure/volume overload markers (BNP, β-MHC) all showed a pattern opposite that of LVEF. Conversely, anti-apoptotic (BMP-2, Smad1/5) and energy integrity (PGC-1α/mitochondrial cytochrome-C) markers exhibited a pattern identical to that of LVEF. This study demonstrates that the combined SS31-Mito therapy is superior to either therapy alone for protecting myocardium from IR injury and indicates that the responsible mechanisms involved increased SIRT1/SIRT3 expression, which suppresses inflammation and oxidative stress and protects mitochondrial integrity.

A series of ruthenium compounds containing a pyrrole-ketone bidentate ligand, 2-(2′-methoxybenzoyl)pyrrole (1), have been synthesized and characterized. Reacting 1 with [(η6-cymene)RuCl2]2 and RuHCl(CO)(PPh3)3 generated Ru(η6-cymene)[C4H3N-2-(CO-C6H4-2-OMe)]Cl (2) and {RuCl(CO)(PPh3)2[C4H3N-2-(COC6H4-2-OMe)]} (3), respectively, in moderate yields. Successively reacting 2 with sodium cyanate and sodium azide gave {Ru(η6-cymene)[C4H3N-2-(CO-C6H4-2-OMe)]X} (4, X=OCN; 5, X=N3) with the elimination of sodium chloride. Compounds 2–5 were all characterized by 1H and 13C-NMR spectra and their structures were also determined by X-ray single crystallography.

Chiayi County is located in the largest alluvial plain of Taiwan with extensive aquaculture and rice farming sustained by water extracted from groundwater wells. Chiayi is a typical aquaculture area affected by land subsidence, yet such lands worldwide combine to provide nearly 90% of global aquaculture products, greatly reducing oceanic overfishing problems. This study uses precision leveling, multi-layer compaction monitoring well (MLCW) and spaceborne SAR interferometry (InSAR) to examine the cause and effect of land subsidence in Chiayi associated with groundwater extractions and changes. Heights at benchmarks in a leveling network are measured annually and soil compactions at 24–26 layers up to 300-m depths at 7 MLCWs are collected at one-month intervals. Over 2007–2011, 15 ALOS/PALSAR images are processed by the method of TCPInSAR to produce subsidence rates. All sensors show that land subsidence occur in most parts of Chiayi, with rates reaching 4.5 cm/year around its coast, a result of groundwater pumping from shallow to deep aquifers. MLCWs detect mm-accuracy seasonal soil compactions coinciding with groundwater level fluctuations and causing dynamic compactions. Compactions near Taiwan High Speed Rail may reduce the strength of the rail’s supporting columns to degrade its safety. The SAR images yield subsidence rates consistent with those from leveling and compaction wells after corrections for systematic errors by the leveling result. Subsidence in Chiayi’s coastal area leads to relative sea level rises at rates up to 15 times larger than the global eustatic sea level rising rate, a risk typical for world’s aquaculture-rich regions. At the fish pond-covered Budai Township, InSAR identifies subsidence spots not detected by leveling, providing crucial geo-information for a sustainable land management for aquaculture industry.

We conducted magnetotelluric prospecting in the Taichung area to investigate subsurface resistivity structures of the Chelungpu fault and the resistivity of rock formations. The results indicate that the Chelungpu fault is a complex fault system consisting of two major fault zones, several fracture zones, and back thrust. The two major fault zones, the basal and the Chi-Chi fault zone are about 800 m apart on the ground and converge to a narrow band at a depth of 3000 m. The fault zones are not smooth, composed of ramps and platforms with an average eastward dipping angle of 35° - 37° within the depth of 3000 m. In the shallower region, the basal fault zone has developed along the boundary of the Toukoshan Formation (resistivity: 200 - 400 Ω-m) at the footwall and the Neogene formations on the hanging wall, where the Cholan Formation, the Chinshiu Shale, and the Kueichulai Formation have respective resistivity mainly in the ranges: 40 - 100, 8 - 60, and 50 - 150 Ω-m. While the Chi-Chi fault zone has developed along the weak layers of the Cholan Formation where resistivity is lower than the unsheared block.